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Cristina MUSSINI

Professore Ordinario
Dipartimento Chirurgico, Medico, Odontoiatrico e di Scienze Morfologiche con interesse Trapiantologico, Oncologico e di Medicina Rigenerativa

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Pubblicazioni

2024 - Advances and Challenges in Sepsis Management: Modern Tools and Future Directions [Articolo su rivista]
Santacroce, Elena; D’Angerio, Miriam; Ciobanu, Alin Liviu; Masini, Linda; Lo Tartaro, Domenico; Coloretti, Irene; Busani, Stefano; Rubio, Ignacio; Meschiari, Marianna; Franceschini, Erica; Mussini, Cristina; Girardis, Massimo; Gibellini, Lara; Cossarizza, Andrea; De Biasi, Sara
abstract

: Sepsis, a critical condition marked by systemic inflammation, profoundly impacts both innate and adaptive immunity, often resulting in lymphopenia. This immune alteration can spare regulatory T cells (Tregs) but significantly affects other lymphocyte subsets, leading to diminished effector functions, altered cytokine profiles, and metabolic changes. The complexity of sepsis stems not only from its pathophysiology but also from the heterogeneity of patient responses, posing significant challenges in developing universally effective therapies. This review emphasizes the importance of phenotyping in sepsis to enhance patient-specific diagnostic and therapeutic strategies. Phenotyping immune cells, which categorizes patients based on clinical and immunological characteristics, is pivotal for tailoring treatment approaches. Flow cytometry emerges as a crucial tool in this endeavor, offering rapid, low cost and detailed analysis of immune cell populations and their functional states. Indeed, this technology facilitates the understanding of immune dysfunctions in sepsis and contributes to the identification of novel biomarkers. Our review underscores the potential of integrating flow cytometry with omics data, machine learning and clinical observations to refine sepsis management, highlighting the shift towards personalized medicine in critical care. This approach could lead to more precise interventions, improving outcomes in this heterogeneously affected patient population.

2024 - Ageism: the -ism affecting the lives of older people living with HIV [Articolo su rivista]
Guaraldi, Giovanni; Milic, Jovana; Cascio, Mario; Mussini, Cristina; Martinez, Esteban; Levin, Jules; Calzavara, Daniele; Mbewe, Rebecca; Falutz, Julian; Orkin, Chloe; Cesari, Matteo; Lazarus, Jeffrey V
abstract

: WHO defines ageism as stereotypes, prejudice, and discrimination based on age. Ageism is a multidimensional concept that encompasses multiple components related to the individual, the social group, and the institution in different cultural and environmental settings. In people ageing with HIV these elements include self-stigma, discrimination in society, and experiences in care, many of which are unique to older people. In this Position Paper, we use experience of people with HIV and clinicians taking care of them to explore these issues in high-income countries. The intersectionality of multiple -isms, which affect the lives of older people living with HIV, and ageism enhance several HIV-related issues, including self-inflicted stigma, and loneliness. Research is needed to explore how ageism contributes to worse physical, mental, and social wellbeing outcomes for people with HIV. The model of care for older people living with HIV needs to go beyond virological success by adopting a geriatric mindset, which is attentive to the challenge of ageism and is proactive in promoting a comprehensive approach for the ageing population. All stakeholders and the community should work together to co-create institutional strategies and educational programmes and enable respectful intergenerational dialogue to foster a stigma-free future for older people living with HIV.

2024 - Comparing the efficacy and safety of a first-line regimen with emtricitabine/tenofovir alafenamide fumarate plus either bictegravir or dolutegravir: Results from clinical practice [Articolo su rivista]
Ciccullo, Arturo; Baldin, Gianmaria; Borghi, Vanni; Oreni, Letizia; Lagi, Filippo; Fusco, Paolo; Giacomelli, Andrea; Torti, Carlo; Sterrantino, Gaetana; Mussini, Cristina; Antinori, Spinello; Di Giambenedetto, Simona
abstract

Background: First-line integrase strand transfer inhibitor-based regimens have become commonly used in clinical practice over the last decade. This study aimed to analyse and compare the efficacy and safety of bictegravir (BIC) and dolutegravir (DTG) when prescribed in association with emtricitabine/tenofovir alafenamide (FTC/TAF) as part of a first-line regimen for the treatment of human immunodeficiency-1 (HIV-1) infection. Methods: Treatment-naïve people living with HIV (PLWHIV) starting a first-line regimen with either BIC/FTC/TAF (BIC group) or FTC/TAF+DTG (DTG group) were analysed. Snapshot analyses were performed after 24 and 48 weeks to evaluate virological efficacy. In addition, differences in the rate of treatment discontinuation (TD) between the two groups were evaluated using the Kaplan-Meier method and the log rank test. Results: Data from 327 PLWHIV were analysed: 140 in the DTG group and 187 in the BIC group. At 48 weeks, 90.0% of individuals in the DTG group and 86.7% of those in the BIC group achieved HIV-RNA <50 copies/mL. In total, 88 and 38 cases of TD were observed in the DTG group and BIC group, respectively. The estimated probability of maintaining the study regimen at week 48 was 59.5% in the DTG group and 84.2% in the BIC group. Analysing changes in immunological parameters after 48 weeks, median improvements of +169 cell/mm3 (P<0.001) and +233 cell/mm3 (P<0.001) were observed in the DTG group and the BIC group, respectively. Conclusions: Both BIC and DTG, in combination with FTC/TAF, show promising efficacy and safety as first-line strategies in clinical practice, with favourable immunological recovery even in the short term.

2024 - INTRAVENOUS FOSFOMYCIN IN COMBINATION REGIMENS AS A TREATMENT OPTION FOR DIFFICULT-TO-TREAT INFECTIONS DUE TO MULTIDRUG-RESISTANT GRAM-NEGATIVE ORGANISMS: A REAL-LIFE EXPERIENCE [Articolo su rivista]
Meschiari, Marianna; Faltoni, Matteo; Kaleci, Shaniko; Tassoni, Giovanni; Orlando, Gabriella; Franceschini, Erica; Burastero, Giulia; Bedini, Andrea; Serio, Lucia; Biagioni, Emanuela; Melegari, Gabriele; Venturelli, Claudia; Sarti, Mario; Bertellini, Elisabetta; Girardis, Massimo; Mussini, Cristina
abstract

Background: We aim to investigate the efficacy of intravenous (IV) Fosfomycin as combination therapy for treatment of difficult-to-treat (DTT) multidrug-resistant (MDR) gram negative bacteria (GNB) acute and subacute infections and risk factors associated with 90-day mortality. Methods: A retrospective, observational, monocentric study enrolled patients treated with IV Fosfomycin in combination regimens (>/= 72 h) for proven DTT-MDR-GNB based infection . Multivariate regression analysis identified independent risk factors for 90-day mortality. A propensity score for receiving Fosfomycin was performed to control for confounding factors. Results: 70 patients were included: 54.3% carbapenem-resistant isolates, 31.4% resistant to ceftazidime/avibactam and 28.6% to ceftolozane/tazobactam. The main pathogens were Pseudomonas aeruginosa (57.1%) and Klebsiella pneumoniae (22.9%). The most prevalent infections were nosocomial pneumonia (42.9%), followed by osteomyelitis (17.1%) and intra-abdominal infections (IAI). All-cause 30 and 90-day mortality were 15.7% and 31.4% (18.9% and 50%, considering only DTT-MDR-GNB acute infections). Relapse at 30 days occurred in 22.9% of cases (29% with emergence of fosfomycin resistance). Mortality at 90 days was independently associated with septic shock, and the evidence of ceftolozane/tazobactam resistance., Resistance to ceftolozane/tazobactam was confirmed significant after adjustment by propensity score analysis (HR 5.84, 95%CI 1.65-20.68, p=0.006). Conclusions: Fosfomycin seems a promising salvage, combination treatment in DTT- MDR-GNB infections. Resistance to ceftolozane/tazobactam seems to be independently associated with treatment failure. Randomized clinical trials focusing on pathogen and infection sites are urgently required to demonstrate the superiority of fosfomycin in combination with other agents for the resolution of difficult to treat GNB infections.

2024 - Impact of COVID-19 pandemic on retention in care of native and migrant people with HIV in the ICONA cohort [Articolo su rivista]
Gagliardini, Roberta; Giacomelli, Andrea; Bozzi, Giorgio; D'Arminio Monforte, Antonella; Tavelli, Alessandro; Mazzotta, Valentina; Bruzzesi, Elena; Cervo, Adriana; Saracino, Annalisa; Mussini, Cristina; Girardi, Enrico; Cozzi-Lepri, Alessandro; Antinori, Andrea
abstract

Background: COVID-19 pandemic challenged the UNAIDS 90-90-90 targets. How the COVID-19 pandemic affected HIV retention in care and whether it has disproportionally affected migrant people with HIV (PWH) remained to be investigated. Methods: PWH in ICONA Cohort in follow-up in each of the study periods were included: 01/09/2019-29/02/2020 (pandemic period) and 01/03/2018-31/08/2018 (historical period, as a control). Risk of temporary loss to follow-up (LTFU, defined as no data recorded for a person for one year) was analyzed by logistic regression, with migrant status as the main exposure variable. Difference in difference (DID) analysis was applied to evaluate the effect of COVID-19 pandemic in the different risk of LTFU between natives and migrants. Results: 8864 (17.1% migrants) and 8071 (16.8% migrants) PWH constituted the pandemic and the historical period population, respectively. Proportion of PWH defined as LTFU in the pandemic period was 10.5% in native and 19.6% in migrant PWH. After controlling for age, sex and geographical location of enrolling site, risk of temporary LTFU was higher for migrants than native PWH [adjusted odds ratio 1.85 (95%CI 1.54-2.22)] in pandemic period. In PWH contributing to both periods, LTFU was 9.0% (95% CI 8.3-9.8) in natives vs 17.0% (95% CI 14.7-19.4) in migrants during the pandemic. Instead, LTFU was 1.2% (95%CI 0.9, 1.5) in natives vs 2.2% (95% CI 1.3-3.1) in migrants during the historical period, with a resulting DID of 7.0% (95% CI 4.4-9.6). Conclusions: A greater proportion of LTFU in migrant PWH was observed in both periods, which remained unaltered over time. Interventions to reduce LTFU of migrants are necessary.

2024 - Persistent poor clinical outcomes of people living with HIV presenting with AIDS and late for HIV diagnosis – results from the Icona cohort in Italy, 2009-2022 [Articolo su rivista]
Mondi, Annalisa; Cozzi-Lepri, Alessandro; Tavelli, Alessandro; Cingolani, Antonella; Giacomelli, Andrea; Orofino, Giancarlo; De Girolamo, Gabriella; Pinnetti, Carmela; Gori, Andrea; Saracino, Annalisa; Bandera, Alessandra; Marchetti, Giulia; Girardi, Enrico; Mussini, Cristina; d'Arminio Monforte, Antonella; Antinori, Andrea
abstract

Background: Limited data are available on long-term outcomes in recent years for late HIV diagnosis (LD). Methods: All HIV-positive subjects enrolled in Icona Cohort in 2009-2022 starting ART within 4-months from diagnosis were included and divided into:1) pre-ART CD4 count≥350/mm3 without AIDS (non-LD), 2) pre-ART CD4 count<350/mm3 without AIDS (LD-Asymptomatic), 3) with AIDS events pre-ART (LD-AIDS). Estimated probability and independent risk for mortality (all-cause and cause-specific) and treatment failure (TF) were evaluated. Results: 6,813 participants: 2,448 non-LD, 3,198 LD-Asymptomatic, and 1,167 LD-AIDS, 161 (2.4%) died after ART initiation. At survival analysis, a higher probability of all-cause mortality has been identified for LD compared to non-LD (p<0.001), and within the former, for LD-AIDS over LD-Asymptomatic (p<0.001). After adjusting for confounders, LD showed a higher risk of all-cause mortality (vs non-LD aHR=5.51, p<0.001), and, in particular, being an AIDS presenter predicted a greater risk of all-cause (aHR=4.42, p<0.001), AIDS-related (aSHR=16.86, p<0.001) and not AIDS-related mortality (aSHR=1.74, p=0.022) compared to the rest of the late presenters. Among short-term survivors LD-AIDS, the long-term mortality was mediated by the lack of immune-recovery at 2-years. LD compared to non-LD, and particularly among the former, LD-AIDS over LD-Asymptomatic, showed also a greater risk of TF. Conclusions: In recent years, LD subjects, particularly AIDS-presenters, remained at a higher risk of poorer outcomes. Public health strategies for early HIV diagnosis are urgently needed to constrain the mortality gap.

2023 - A Fatal Case of Pseudomonas aeruginosa Community-Acquired Pneumonia in an Immunocompetent Patient: Clinical and Molecular Characterization and Literature Review [Articolo su rivista]
Barp, Nicole; Marcacci, Matteo; Biagioni, Emanuela; Serio, Lucia; Busani, Stefano; Ventura, Paolo; Franceschini, Erica; Orlando, Gabriella; Venturelli, Claudia; Menozzi, Ilaria; Tambassi, Martina; Scaltriti, Erika; Pongolini, Stefano; Sarti, Mario; Pietrangelo, Antonello; Girardis, Massimo; Mussini, Cristina; Meschiari, Marianna
abstract

Rare cases of Pseudomonas aeruginosa community-acquired pneumonia (PA-CAP) were reported in non-immunocompromised patients. We describe a case of Pseudomonas aeruginosa (PA) necrotizing cavitary CAP with a fatal outcome in a 53-year-old man previously infected with SARS-CoV-2, who was admitted for dyspnea, fever, cough, hemoptysis, acute respiratory failure and a right upper lobe opacification. Six hours after admission, despite effective antibiotic therapy, he experienced multi-organ failure and died. Autopsy confirmed necrotizing pneumonia with alveolar hemorrhage. Blood and bronchoalveolar lavage cultures were positive for PA serotype O:9 belonging to ST1184. The strain shares the same virulence factor profile with reference genome PA01. With the aim to better investigate the clinical and molecular characteristics of PA-CAP, we considered the literature of the last 13 years concerning this topic. The prevalence of hospitalized PA-CAP is about 4% and has a mortality rate of 33–66%. Smoking, alcohol abuse and contaminated fluid exposure were the recognized risk factors; most cases presented the same symptoms described above and needed intensive care. Co-infection of PA-influenza A is described, which is possibly caused by influenza-inducing respiratory epithelial cell dysfunction: the same pathophysiological mechanism could be assumed with SARS-CoV-2 infection. Considering the high rate of fatal outcomes, additional studies are needed to identify sources of infections and new risk factors, along with genetic and immunological features. Current CAP guidelines should be revised in light of these results.

2023 - A Machine Learning Approach to Predict Weight Change in ART-Experienced People Living with HIV [Articolo su rivista]
Motta, F.; Milic, J.; Gozzi, L.; Belli, M.; Sighinolfi, L.; Cuomo, G.; Carli, F.; Dolci, G.; Iadisernia, V.; Burastero, G.; Mussini, C.; Missier, P.; Mandreoli, F.; Guaraldi, G.
abstract

Introduction:The objective of the study was to develop machine learning (ML) models that predict the percentage weight change in each interval of time in antiretroviral therapy-experienced people living with HIV.Methods:This was an observational study that comprised consecutive people living with HIV attending Modena HIV Metabolic Clinic with at least 2 visits. Data were partitioned in an 80/20 training/test set to generate 10 progressively parsimonious predictive ML models. Weight gain was defined as any weight change >5%, at the next visit. SHapley Additive exPlanations values were used to quantify the positive or negative impact of any single variable included in each model on the predicted weight changes.Results:A total of 3,321 patients generated 18,322 observations. At the last observation, the median age was 50 years and 69% patients were male. Model 1 (the only 1 including body composition assessed with dual-energy x-ray absorptiometry) had an accuracy greater than 90%. This model could predict weight at the next visit with an error of <5%.Conclusions:ML models with the inclusion of body composition and metabolic and endocrinological variables had an excellent performance. The parsimonious models available in standard clinical evaluation are insufficient to obtain reliable prediction, but are good enough to predict who will not experience weight gain.

2023 - Association Between Pulmonary Aspergillosis And Cytomegalovirus Reactivation In Critically Ill Covid-19 Patients: A Prospective Observational Cohort Study. [Articolo su rivista]
Caciagli, Valeria; Coloretti, Irene; Talamonti, Marta; Farinelli, Carlotta; Gatto, Ilenia; Biagioni, Emanuela; Sarti, Mario; Franceschini, Erica; Meschiari, Marianna; Mussini, Cristina; Tonelli, Roberto; Clini, Enrico; Girardis, Massimo; Busani, Stefano
abstract

COVID-19-associated invasive pulmonary aspergillosis (CAPA) is common and is associated with poor outcomes in critically ill patients. This prospective observational study aimed to ex-plore the association between CAPA development and the incidence and prognosis of cytomegalo-virus (CMV) reactivation in critically ill COVID-19 patients. We included all consecutive criti-cally ill adult patients with confirmed COVID-19 infection who were admitted to three COVID-19 intensive care units (ICUs) in an Italian hospital from February 25, 2020, to May 8, 2022. A standardized procedure was employed for early detection of CAPA. Risk factors associ-ated with CAPA and CMV reactivation and the association between CMV recurrence and mor-tality were estimated using adjusted Cox proportional hazard regression models. CAPA oc-curred in 96 patients (16,6%) of the 579 patients analyzed. Among the CAPA population, 40 (41,7%) patients developed CMV blood reactivation with a median time of 18 days (IQR 7-27). The CAPA+CMV group did not exhibit a significantly higher 90-day mortality rate (62.5% vs. 48.2%) than the CAPA alone group (p=0.166). The CAPA+CMV group had a longer ICU stay, few-er ventilation-free days, and a higher rate of secondary bacterial infections than the control group of CAPA alone. In the CAPA population, prior immunosuppression was the only independent risk factor for CMV reactivation (HR 2.33, 95% C.I. 1.21-4.48, p=0.011). In critically ill COVID-19 pa-tients, CMV reactivation is common in those with a previous CAPA diagnosis. Basal immuno-suppression before COVID-19 appeared to be the primary independent variable affecting CMV reactivation in patients with CAPA. Furthermore, the association of CAPA+CMV versus CAPA alone appears to impact ICU length of stay and secondary bacterial infections but not mortality.

2023 - Blackwater Fever Treated with Steroids in Nonimmune Patient, Italy [Articolo su rivista]
Di Biase, Anna Rita; Buonfrate, Dora; Stefanelli, Francesca; Zavarise, Giorgio; Franceschini, Erica; Mussini, Cristina; Iughetti, Lorenzo; Gobbi, Federico
abstract

: Causes of blackwater fever, a complication of malaria treatment, are not completely clear, and immune mechanisms might be involved. Clinical management is not standardized. We describe an episode of blackwater fever in a nonimmune 12-year-old girl in Italy who was treated with steroids, resulting in a rapid clinical resolution.

2023 - Bone Mineral Density and Trabecular Bone Score Changes throughout Menopause in Women with HIV [Articolo su rivista]
Milic, Jovana; Renzetti, Stefano; Morini, Denise; Motta, Federico; Carli, Federica; Menozzi, Marianna; Cuomo, Gianluca; Mancini, Giuseppe; Simion, Mattia; Romani, Federico; Spadoni, Anna; Baldisserotto, Irene; Barp, Nicole; Diazzi, Chiara; Mussi, Chiara; Mussini, Cristina; Rochira, Vincenzo; Calza, Stefano; Guaraldi, Giovanni
abstract

Objective: The objectives of this study were to describe the trajectories of bone mineral density (BMD) and trabecular bone score (TBS) changes throughout pre-menopause (reproductive phase and menopausal transition) and post-menopause (early and late menopause) in women with HIV (WWH) undergoing different antiretroviral therapies (ARTs) and explore the risk factors associated with those changes. Methods: This was an observational longitudinal retrospective study in WWH with a minimum of two DEXA evaluations comprising BMD and TBS measurements, both in the pre-menopausal and post-menopausal periods. Menopause was determined according to the STRAW+10 criteria, comprising four periods: the reproductive period, menopausal transition, and early- and late-menopausal periods. Mixed-effects models were fitted to estimate the trajectories of the two outcomes (BMD and TBS) over time. Annualized lumbar BMD and TBS absolute and percentage changes were calculated in each STRAW+10 time window. A backward elimination procedure was applied to obtain the final model, including the predictors that affected the trajectories of BMD or TBS over time. Results: A total of 202 WWH, all Caucasian, were included. In detail, 1954 BMD and 195 TBS data were analyzed. The median number of DEXA evaluations per woman was 10 (IQR: 7, 12). The median observation periods per patient were 12.0 years (IQR = 8.9-14.4) for BMD and 6.0 years (IQR: 4.3, 7.9) for TBS. The prevalence of osteopenia (63% vs. 76%; p < 0.001) and osteoporosis (16% vs. 36%; p < 0.001) increased significantly between the pre-menopausal and post-menopausal periods. Both BMD (1.03 (±0.14) vs. 0.92 (±0.12) g/cm2; p < 0.001) and TBS (1.41 (IQR: 1.35, 1.45) vs. 1.32 (IQR: 1.28, 1.39); p < 0.001) decreased significantly between the two periods. The trend in BMD decreased across the four STRAW+10 periods, with a slight attenuation only in the late-menopausal period when compared with the other intervals. The TBS slope did not significantly change throughout menopause. The delta mean values of TBS in WWH were lower between the menopausal transition and reproductive period compared with the difference between menopause and menopausal transition. Conclusions: Both BMD and TBS significantly decreased over time. The slope of the change in BMD and TBS significantly decreased in the menopausal transition, suggesting that this period should be considered by clinicians as a key time during which to assess bone health and modifiable risk factors in WWH.

2023 - CASCADE protocol: exploring current viral and host characteristics, measuring clinical and patient-reported outcomes, and understanding the lived experiences and needs of individuals with recently acquired HIV infection through a multicentre mixed-methods observational study in Europe and Canada [Articolo su rivista]
Ruiz-Burga, Elisa; Tariq, Shema; Touloumi, Giota; Gill, John; Nicholls, Emily Jay; Sabin, Caroline; Mussini, Cristina; Meyer, Laurence; Volny Anne, Alain; Carlander, Christina; Grabar, Sophie; Jarrin, Inma; Van der Valk, Marc; Wittkop, Linda; Spire, Bruno; Pantazis, Nikos; Burns, Fiona M; Porter, Kholoud
abstract

Introduction: Despite the availability of pre-exposure prophylaxis (PrEP) and antiretroviral therapy (ART), 21 793 people were newly diagnosed with HIV in Europe in 2019. The Concerted action on seroconversion to AIDS and death in Europe study aims to understand current drivers of the HIV epidemic; factors associated with access to, and uptake of prevention methods and ART initiation; and the experiences, needs and outcomes of people with recently acquired HIV. Methods and analysis: This longitudinal observational study is recruiting participants aged ≥16 years with documented laboratory evidence of HIV seroconversion from clinics in Canada and six European countries. We will analyse data from medical records, self-administered questionnaires, semistructured interviews and participatory photography. We will assess temporal trends in transmitted drug resistance and viral subtype and examine outcomes following early ART initiation. We will investigate patient-reported outcomes, well-being, and experiences of, knowledge of, and attitudes to HIV preventions, including PrEP. We will analyse qualitative data thematically and triangulate quantitative and qualitative findings. As patient public involvement is central to this work, we have convened a community advisory board (CAB) comprising people living with HIV. Ethics and dissemination: All respective research ethics committees have approval for data to contribute to international collaborations. Written informed consent is required to take part. A dissemination strategy will be developed in collaboration with CAB and the scientific committee. It will include peer-reviewed publications, conference presentations and accessible summaries of findings on the study's website, social media and via community organisations.

2023 - COVID-19 omicron variant outbreak in a hematopoietic stem cell transplant unit [Articolo su rivista]
Gilioli, A.; Bresciani, P.; Franceschini, E.; Messerotti, A.; Pioli, V.; Colasante, C.; Bettelli, F.; Giusti, D.; Forghieri, F.; Morselli, M.; Colaci, E.; Potenza, L.; Gennari, W.; Pecorari, M.; Marasca, R.; Candoni, A.; Mussini, C.; Trenti, T.; Comoli, P.; Luppi, M.; Cuoghi, A.
abstract

Recommendations and guidelines for management of SARS-COV-2 infection in hematologic patients were developed in the very difficult context of dealing with novel viral variants from one pandemic wave to another, with different susceptibility to available drugs and vaccines. Moreover, the largest SARS-COV-2 case series in patients treated for hematologic malignancies, including stem cell transplant recipients, was published before the Omicron surge, and refers mainly to Alpha and Delta viral variants. These infections had very high mortality, in a period when antivirals and monoclonal antibodies were mostly unavailable. Here, we report for the first time a SARS-COV-2 Omicron variant outbreak inside a Bone Marrow Transplant (BMT) Unit, describing the characteristics, clinical course, and infection outcomes shortly before and shortly after myeloablative transplantation. We detail how infections were treated off-label and managed inside the BMT ward, to guarantee the best possible outcomes while avoiding risks for non-infected inpatients. The positive outcomes observed suggest that it may not be absolutely necessary to obtain SARS-CoV-2 PCR negativity before BMT in hematologic patients after treated infection, in cases with long-term PCR positivity and high-risk hematologic disease.

2023 - Case report of Usutu virus infection in an immunocompromised patient in Italy, 2022 [Articolo su rivista]
Gaibani, Paolo; Barp, Nicole; Massari, Marco; Negri, Emanuele Alberto; Rossini, Giada; Vocale, Caterina; Trenti, Chiara; Gallerani, Altea; Cantergiani, Samuele; Romani, Federico; Simion, Mattia; Mussini, Cristina; Lazzarotto, Tiziana
abstract

Usutu virus (USUV) is an arthropod-borne flavivirus emerged in Africa in 1950s and in Eruope in 1990s causing a massive number of birds' deaths. The role of USUV as human pathogen has been only recently hypothesized and cases of USUV infection in humans remain limited and often related to immunocompromised subjects. Herein, we report a case of USUV meningoencephalitis infection in an immunocompromised patient with no history of previous flavivirus infection. The infection due to USUV evolved rapidly since hospital admission thus resulting fatal in few days after symptoms onset and, although not proven, a suspected bacteria co-infection has been hypothesized. Based on these findings, we suggested that when USUV meningoencephalitis is suspected in countries endemic, careful attention should be applied to neurological syndromes during summer months especially among immunocompromised patients.

2023 - Comment on: Long-term outcome of dolutegravir-containing regimens according to sex: data from the ICONA study [Articolo su rivista]
Ciccullo, Arturo; Baldin, Gianmaria; Sterrantino, Gaetana; Madeddu, Giordano; D'Ettorre, Gabriella; Mussini, Cristina; Di Giambenedetto, Simona
abstract

2023 - Critical COVID-19 Patients Through First, Second And Third Wave: Retrospective Observational Study Comparing Outcomes In ICU. [Articolo su rivista]
Coloretti, Irene; Farinelli, Carlotta; Biagioni, Emanuela; Gatto, Ilenia; Munari, Elena; Dall'Ara, Lorenzo; Busani, Stefano; Meschiari, Marianna; Tonelli, Roberto; Mussini, Cristina; Guaraldi, Giovanni; Cossarizza, Andrea; Clini, Enrico; Girardis, Massimo
abstract

Introduction- The time-course of the COVID-19 pandemic was characterized by subsequent waves identified by peaks of Intensive Care Unit (ICU) admission rates. During these periods, progressive knowledge of the disease led to the development of specific therapeutic strategies. This retrospective study investigates whether this led to improvement in outcomes of COVID-19 patients admitted to ICU. Methods- Outcomes were evaluated in consecutive adult COVID19 patients admitted to our ICU, divided into three waves based on the admission period: the first wave from February 25th, 2020, to July 6th, 2020; the second wave from September 20th, 2020, to February 13th, 2021; the third wave from February 14th, 2021 to April 30th, 2021. Differences were assessed comparing outcomes and by using different multivariable Cox models adjusted for variables related to outcome. Further sensitivity analysis was performed in patients undergoing invasive mechanical ventilation. Results- Overall, 428 patients were included in the analysis: 102, 169 and 157 patients in the first, second and third wave. The ICU and in-hospital crude mortalities were lower by 7% and 10% in the third wave compared to the other 2 waves (p>0.05). A higher number of ICU and hospital free days at day 90 was found in the third wave when compared to the other 2 waves (p=0.001). Overall, 62.6% underwent invasive ventilation, with decreasing requirement during the waves (p=0.002). The adjusted Cox model showed no difference in the Hazard Ratio for mortality among the waves. In the propensity-matched analysis the hospital mortality rate was reduced by 11% in the third wave (p=0.044). Conclusions - With application of best practice as known by the time of the first three waves of the pandemic, our study failed to identify a significant improvement in mortality rate when comparing the different waves of the COVID-19 pandemic, notwithstanding, the sub-analyses showed a trend in mortality reduction in the third wave. Rather, our study identified a possible positive effect of dexamethasone on mortality rate reduction and the increased risk of death related to bacterial infections in the three waves.

2023 - Death After Liver Transplantation: Mining Interpretable Risk Factors for Survival Prediction [Relazione in Atti di Convegno]
Guidetti, V.; Dolci, G.; Franceschini, E.; Bacca, E.; Burastero, G. J.; Ferrari, D.; Serra, V.; Di Benedetto, F.; Mussini, C.; Mandreoli, F.
abstract

This study introduces a novel approach to mine risk factors for short-term death after liver transplantation (LT). The method outputs intelligible survival models by combining Cox's regression with a genetic programming technique known as multi-objective symbolic regression (MOSR). We consider 485 Electronic Health Records (EHRs) of patients who underwent LT, containing information on hospitalization and preoperative conditions, with a focus on infections and colonizations by multi-resistant Gram-negative bacteria. We evaluate MOSR outcomes against several performance metrics and demonstrate that they are well-calibrated, predictive, safe, and parsimonious. Finally, we select the most promising post-LT early survival risk score based on information criteria, performance, and out-of-distribution safety. Validating this technique at a multicenter level could improve service pipeline logistics through a trustworthy machine-learning method.

2023 - Detailed characterization of SARS-CoV-2-specific T and B cells after infection or heterologous vaccination [Articolo su rivista]
Lo Tartaro, Domenico; Paolini, Annamaria; Mattioli, Marco; Swatler, Julian; Neroni, Anita; Borella, Rebecca; Santacroce, Elena; Di Nella, Alessia; Gozzi, Licia; Busani, Stefano; Cuccorese, Michela; Trenti, Tommaso; Meschiari, Marianna; Guaraldi, Giovanni; Girardis, Massimo; Mussini, Cristina; Piwocka, Katarzyna; Gibellini, Lara; Cossarizza, Andrea; De Biasi, Sara
abstract

: The formation of a robust long-term antigen (Ag)-specific memory, both humoral and cell-mediated, is created following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or vaccination. Here, by using polychromatic flow cytometry and complex data analyses, we deeply investigated the magnitude, phenotype, and functionality of SARS-CoV-2-specific immune memory in two groups of healthy subjects after heterologous vaccination compared to a group of subjects who recovered from SARS-CoV-2 infection. We find that coronavirus disease 2019 (COVID-19) recovered patients show different long-term immunological profiles compared to those of donors who had been vaccinated with three doses. Vaccinated individuals display a skewed T helper (Th)1 Ag-specific T cell polarization and a higher percentage of Ag-specific and activated memory B cells expressing immunoglobulin (Ig)G compared to those of patients who recovered from severe COVID-19. Different polyfunctional properties characterize the two groups: recovered individuals show higher percentages of CD4+ T cells producing one or two cytokines simultaneously, while the vaccinated are distinguished by highly polyfunctional populations able to release four molecules, namely, CD107a, interferon (IFN)-γ, tumor necrosis factor (TNF), and interleukin (IL)-2. These data suggest that functional and phenotypic properties of SARS-CoV-2 adaptive immunity differ in recovered COVID-19 individuals and vaccinated ones.

2023 - Determinants of worse liver-related outcome according to HDV infection among HBsAg positive persons living with HIV: Data from the ICONA cohort [Articolo su rivista]
d'Arminio Monforte, Antonella; Tavelli, Alessandro; Salpini, Romina; Piermatteo, Lorenzo; D'Anna, Stefano; Carrara, Stefania; Malagnino, Vincenzo; Mazzotta, Valentina; Brancaccio, Giuseppina; Marchetti, Giulia Carla; Rosselli Del Turco, Elena; Rossotti, Roberto; Mussini, Cristina; Antinori, Andrea; Lo Caputo, Sergio; Ceccherini Silberstein, Francesca; Gaeta, Giovanni Battista; Svicher, Valentina; Puoti, Massimo
abstract

Objectives: We aimed to study hepatitis D virus (HDV) prevalence and risk of progression to severe liver-related events (SLRE) in HBsAg positive people living with HIV (PLWH) in Italy; role of HDV-RNA copy levels, HCV coinfection and nadir CD4 counts were also investigated.Methods: People living with HIV (PLWH) from Italian Foundation cohort Naive antiretrovirals (ICONA) with available HBsAg and HDV Ab were enrolled. HBsAg, HDV Ab, HDV-RNA and HDV genotypes were tested. Primary end-point: time from first HDV screening to Severe Liver Related Events (SLRE: decompensated cirrhosis, liver transplantation, HCC). Fine-grey regression models were used to evaluate the association of HDV Ab, HDV-RNA, HDV/HCV coinfection, CD4 nadir and outcome. Secondary end-points: time to SLRE or death; HDV Ab and HDV-RNA prevalence.Results: A total of 152/809 (18.8%) HBsAg positive PLWH showed HDV Ab reactivity; 63/93 (67.7%) were HDV-RNA positive. Being male, persons who inject drugs (PWID), HCV Ab positive, with FIB-4 > 3.25 were independent factors of HDV Ab positivity. In a median follow-up of 5 years, 37 PLWH (4.1% at 5-year) developed SLRE and 97 (12.0%) reached the SLRE or death end-point. HDV-RNA positive (independently from HDV-RNA copy level) PLWH had a 4.6-fold (95%CI 2.0-10.5) higher risk of SLRE than HDV negatives. PLWH positive for both HCV Ab and HDV Ab showed the highest independent risk of SLRE (ASHR: 11.9, 95%CI: 4.6-30.9 vs. HCV neg/HDV neg). Nadir CD4 < 200/mL was associated with SLRE (ASHR: 3.9, 95% 1.0-14.5).Conclusions: One-fifth of the HBsAg positive PLWH harbour HDV infection, and are at high risk of progression to advanced liver disease. HCV contributes to worse outcomes. This population needs urgently effective treatments.

2023 - Do all critically ill patients with COVID-19 disease benefit from adding tocilizumab to glucocorticoids? A retrospective cohort study. [Articolo su rivista]
Mussini, Cristina; Cozzi-Lepri, Alessandro; Meschiari, Marianna; Franceschini, Erica; Jole Burastero, Giulia; Faltoni, Matteo; Franceschi, Giacomo; Iadisernia, Vittorio; Volpi, Sara; Dessilani, Andrea; Gozzi, Licia; Conti, Jacopo; DEL MONTE, Martina; Milic, Jovana; Borghi, Vanni; Tonelli, Roberto; Brugioni, Lucio; Romagnoli, Elisa; Pietrangelo, Antonello; Corradini, Elena; Girardis, Massimo; Busani, Stefano; Cossarizza, Andrea; Clini, Enrico; Guaraldi, Giovanni
abstract

2023 - Duration of antibiotic treatment for Gram-negative bacteremia - Systematic review and individual participant data (IPD) meta-analysis [Articolo su rivista]
Turjeman, Adi; von Dach, Elodie; Molina, José; Franceschini, Erica; Koppel, Fidi; Yelin, Dana; Dishon-Benattar, Yael; Mussini, Cristina; Rodríguez-Baño, Jesús; Cisneros, José Miguel; Huttner, Angela; Paul, Mical; Leibovici, Leonard; Yahav, Dafna
abstract

Background: We aim to compare the effect of short versus long treatment duration in Gram-negative bacteremia on all-cause mortality in pre-specified sub-groups. Methods: Individual participant data meta-analysis of randomized controlled trials (RCTs) comparing short (≤7) versus longer (>7 days) antibiotic treatment for Gram-negative bacteremia. Participants were adults (≥18 years), with Gram-negative bacteremia during hospital stay. We searched PubMed, Cochrane Central Register of Controlled Trials, and Web of Science to identify trials conducted up to May 2022. Primary outcome was 90-day all-cause mortality. Secondary outcomes were 30-day mortality, relapse of bacteremia, length of hospital stay, readmission, local or distant infection complications, adverse events, and resistance emergence.Outcomes were assessed in pre-specified subgroups: women vs men; non-urinary vs urinary source; presence vs absence of hypotension on initial presentation; immunocompromised patients versus non-immunocompromised patients, and age (above/below 65). Fixed-effect meta-analysis model was used to estimate pooled odds ratio (OR) and 95% confidence interval (CI). All three trials had low risk of bias for allocation generation and concealment. Findings: Three RCTs (1186 patients) were included; 1121 with enterobacterales bacteremia. No significant difference in mortality was demonstrated between 7- and 14-days treatment (90-day mortality: OR 1.08, 95% CI 0.73-1.58; 30-day mortality: 1.08, 0.62-1.91). Relapse (1.00, 0.50-1.97); length of hospital stay (P = 0.78); readmission (0.96, 0.80-1.22); and infection complications (local: 1.62 0.76-3.47; distant: 2.00, 0.18-22.08), were without significant difference, and so were adverse events or resistance emergence.No significant difference in clinical outcomes between 7 and 14 days of antibiotics was demonstrated in the subgroups of gender, age, hemodynamic status, immune status, and source of infection. Interpretation: For patients hemodynamically stable and afebrile at 48 h prior to discontinuation, seven days of antibiotic therapy for enterobacterales bacteremia result in similar outcomes as 14 days, in terms of mortality, relapse, length of hospital stay, complications of infection, resistance emergence, and adverse events. These results apply for any adult age group, gender, source of infection, immune status, and hemodynamic status on presentation. Funding: There was no funding source for this study.

2023 - Early antiretroviral therapy not associated with higher cryptococcal meningitis mortality in people with HIV in high-income countries: an international collaborative cohort study [Articolo su rivista]
Ingle, Suzanne M; Miro, Jose M; May, Margaret T; Cain, Lauren E; Schwimmer, Christine; Zangerle, Robert; Sambatakou, Helen; Cazanave, Charles; Reiss, Peter; Brandes, Vanessa; Bucher, Heiner C; Sabin, Caroline; Vidal, Francesc; Obel, Niels; Mocroft, Amanda; Wittkop, Linda; D'arminio Monforte, Antonella; Torti, Carlo; Mussini, Cristina; Furrer, Hansjakob; Konopnicki, Deborah; Tiera, Ramon; Saag, Michael S; Crane, Heidi M; Moore, Richard D; Jacobson, Jeffrey M; Mathews, W Chris; Geng, Elvin; Eron, Joseph J; Althoff, Keri N; Kroch, Abigail; Lang, Raynell; Gill, M John; Sterne, Jonathan A C
abstract

Background: Randomized trials (RCTs) from low- and middle-income settings suggested early initiation of antiretroviral therapy (ART) leads to higher mortality among people with HIV (PWH) who present with cryptococcal meningitis (CM). There is limited information about impact of ART timing on mortality in similar people in high-income settings. Methods: Data on ART-naïve PWH diagnosed with CM from 1994-2012 from Europe/North America were pooled from the COHERE, NA-ACCORD and CNICS HIV cohort collaborations. Follow-up was considered from the date of CM diagnosis to earliest of the following: death, last follow-up or 6 months. We used marginal structural models to mimic an RCT comparing effects of early (within 14 days of CM) with late (14-56 days after CM) ART on all-cause mortality, adjusting for potential confounders. Results: Of 190 participants identified, 33 (17%) died within 6 months. At CM diagnosis, median age was 38 years (interquartile range 33-44); CD4 count was 19 cells/mm3 (10-56); and HIV viral load was 5.3 log10 copies/mL (4.9-5.6). Most participants (157, 83%) were males and 145 (76%) started ART. Mimicking an RCT, with 190 people in each group, there were 13 deaths among participants following early ART regimen and 20 deaths among those following late ART regimen. Crude and adjusted hazard ratios comparing late with early ART were 1.28 (95% CI: 0.64, 2.56) and 1.40 (0.66, 2.95). Conclusions: We found little evidence that early ART was associated with higher mortality among PWH presenting with CM in high income settings, although confidence intervals were wide.

2023 - Efficacy and tolerability of dolutegravir/lamivudine versus dolutegravir/rilpivirine in switching from a three-drug regimen based on nonnucleoside reverse transcriptase inhibitors: A retrospective cohort study [Articolo su rivista]
Lagi, Filippo; Giacomelli, Andrea; Borghi, Vanni; Ciccullo, Arturo; Taramasso, Lucia; Madeddu, Giordano; D'Ettorre, Gabriella; Giacometti, Andrea; Ducci, Filippo; De Vito, Andrea; Pincino, Rachele; Di Giambenedetto, Simona; Mussini, Cristina; Antinori, Spinello; Sterrantino, Gaetana
abstract

Real-life comparisons of dolutegravir/rilpivirine (DTG/RPV) and DTG/lamivudine (3TC) regimens in people living with human immunodeficiency virus (PLWHIV) who switched from a standard three-drug regimen based on nonnucleoside reverse transcriptase inhibitors (NNRTIs) are missing. This study aimed to compare DTG/3TC and DTG/RPV in virologically suppressed patients (HIV-RNA < 50 copies/mL) coming from any NNRTI-based regimen in terms of discontinuation due to virologic failure (VF) discontinuation rates due to all causes, and adverse events. As a secondary outcome, we evaluated the difference in creatinine, total cholesterol, CD4, and triglycerides from baseline to weeks 48 after the switch. Of the 415 PLWHs included in the study, 278 (66.9%) switched to DTG/3TC, and 137 (33.1%) switched to DTG/RPV. Overall, 48 PLWHs (11.6%) discontinued the treatment:38 with DTG/3TC and 10 with DTG/RPV with similar discontinuation rates: 5.01 x 100 py (95% confidence interval [CI] 3.64-6.94) and 4.66 x 100 py (95% CI 2.51-8.67), respectively. The most common reason for discontinuation was toxicity (26 patients, 22/278 [7.9%] in the DTG/3TC group and 4/137 [2.9%] in the DTG/RPV group), mainly neurologic toxicity (never above grade 2). We found no differences in discontinuation rates due to treatment adverse events. Two study participants experienced virological failure in the DTG/3TC arm. We observed no significant difference in CD4 cell counts, lipid parameters, or renal function between the two groups at 48 weeks. This study demonstrated that, in clinical practice, a two-drug regimen with DTG/3TC or DTG/RPV is characterized by a low discontinuation rate and VF in virologically suppressed PLWHs switched from an NNRTI-based three antiretroviral drugs regimen.

2023 - Efficacy of bezlotoxumab in preventing recurrence of Clostridioides difficile infection: an Italian multicenter cohort study [Articolo su rivista]
Meschiari, Marianna; Cozzi-Lepri, Alessandro; Cervo, Adriana; Granata, Guido; Rogati, Carlotta; Franceschini, Erica; Casolari, Stefania; Tatarelli, Paola; Giacobbe, Daniele Roberto; Bassetti, Matteo; Pinna, Simone Mornese; De Rosa, Francesco Giuseppe; Barchiesi, Francesco; Canovari, Benedetta; Lorusso, Carolina; Russo, Giuseppe; Cenderello, Giovanni; Cascio, Antonio; Petrosillo, Nicola; Mussini, Cristina
abstract

Objectives: Bezlotoxumab (BEZ) is a promising tool for preventing recurrence of Clostridioides difficile infection (rCDI). The aim of the study was to emulate, in a real-world setting, the MODIFY trials in a cohort of participants with multiple risk factors for rCDI treated with BEZ in addition to standard of care (SoC) vs. SoC alone. Methods: A multicenter cohort study was conducted including 442 patients with CDI from 2018 to 2022 collected from 18 Italian centers. The main outcome was the 30-days occurrence of rCDI. Secondary outcomes were: (i) all-cause mortality at 30 days (ii) composite outcome (30-day recurrence and/or all-cause death). Results: rCDI at day 30 occurred in 54 (12%): 11 in the BEZ+SoC group and 43 treated with SoC alone (8% vs. 14%, OR=0.58, 95%CI:0.31-1.09, p=0.09). The difference between BEZ+SoC vs. SoC was statistically significant after controlling for confounding factors (aOR=0.40, 95%CI:018-0.88, p=0.02) and even more using the composite outcome (aOR=0.35, 95%CI:0.17-0.73, p=0.005). Conclusion: Our study confirms the efficacy of BEZ+SoC for the prevention of rCDI and death in a real-world setting. BEZ should be routinely considered among participants at high risk of rCDI regardless of age, type of CDI therapy (vancomycin vs. fidaxomicin) and number of risk factors.

2023 - Epidemiology and Prevention of Early Infections by Multi-Drug-Resistant Organisms in Adults Undergoing Liver Transplant: A Narrative Review [Articolo su rivista]
Dolci, Giovanni; Burastero, Giulia Jole; Paglia, Francesca; Cervo, Adriana; Meschiari, Marianna; Guaraldi, Giovanni; Chester, Johanna; Mussini, Cristina; Franceschini, Erica
abstract

Invasive bacterial infections are a leading cause of morbidity and mortality after liver transplant (LT), especially during the first months after LT, and infections due to multi-drug-resistant organisms (MDRO) are increasing in this setting. Most of the infections in patients in intensive care unit arise from the endogenous microflora and, for this reason, pre-LT MDRO rectal colonization is a risk factor for developing MDRO infections in the post-LT. Moreover, the transplanted liver may carry an increased risk of MDRO infections due to organ transportation and preservation, to donor intensive care unit stay and previous antibiotic exposure. To date, little evidence is available about how MDRO pre-LT colonization in donors and recipients should address LT preventive and antibiotic prophylactic strategies, in order to reduce MDRO infections in the post-LT period. The present review provided an extensive overview of the recent literature on these topics, with the aim to offer a comprehensive insight about the epidemiology of MDRO colonization and infections in adult LT recipients, donor-derived MDRO infections, possible surveillance, and prophylactic strategies to reduce post-LT MDRO infections.

2023 - Evaluating immunological and inflammatory changes of treatment-experienced people living with HIV switching from first-line triple cART regimens to DTG/3TC vs. B/F/TAF: the DEBATE trial [Articolo su rivista]
Cossarizza, A.; Cozzi-Lepri, A.; Mattioli, M.; Paolini, A.; Neroni, A.; De Biasi, S.; Tartaro, D. L.; Borella, R.; Fidanza, L.; Gibellini, L.; Beghetto, B.; Roncaglia, E.; Nardini, G.; Milic, J.; Menozzi, M.; Cuomo, G.; Digaetano, M.; Orlando, G.; Borghi, V.; Guaraldi, G.; Mussini, C.
abstract

Background: The aim of this randomized clinical trial (RCT) was to compare immunological changes in virally suppressed people living with HIV (PLWH) switching from a three-drug regimen (3DR) to a two-drug regimen (2DR).Methods: An open-label, prospective RCT enrolling PLWH receiving a 3DR who switched to bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) or dolutegravir/lamivudine (DTG/3TC) was performed. Blood was taken at baseline and months 6 and 12. The primary outcome was the change in CD4+ or CD8+ T-cell counts and CD4/CD8 ratio over time points. The secondary outcomes were the changes in immunological and inflammatory parameters. Parametric mixed-linear models with random intercepts and slopes were fitted separately for each marker after controlling for potential confounders.Results: Between the two arms (33 PLWH each), there was no difference in CD4+ or CD8+ T cells, CD4/CD8 ratio, and IL-6 trajectories. PLWH switching to DTG/3TC had increased levels of both transitional memory and terminally differentiated CD4+ T cells (arm-time interaction p-value = 0.02) and to a lesser extent for the corresponding CD8+ T-cell subsets (p = 0.09). Significantly lower levels of non-classical monocytes were detected in the B/F/TAF arm at T6 (diff = -6.7 cells/mm(3); 95% CI; -16, +2.6; p-value for interaction between arm and time = 0.03). All differences were attenuated at T12.Conclusion: No evidence for a difference in absolute CD4+ and CD8+ T-cell counts, CD4/CD8 ratio, and IL-6 trajectories by study arm over 12 months was found. PLWH on DTG/3TC showed higher levels of terminally differentiated and exhausted CD4+ and CD8+ T lymphocytes and non-classical monocytes at T6. Further studies are warranted to better understand the clinical impact of our results.

2023 - External Validity of a Randomized Controlled Trial on Duration of Antibiotics for the Treatment of Gram-Negative Bacteremia [Articolo su rivista]
Turjeman, Adi; Koppel, Fidi; Franceschini, Erica; Yahav, Dafna; Dolci, Giovanni; Bacca, Erica; Babich, Tanya; Khazem, Ebtehal; Baum, Eyal; Nassar, Rima; Bitterman, Roni; Dishon-Benatta, Yael; Hassoun-Kheir, Nasreen; Santoro, Antonella; Eliakim-Raz, Noa; Poran, Itamar; Pertzov, Barak; Stern, Anat; Dickstein, Yaakov; Maroun, Elias; Raines, Marina; Meschiari, Marianna; Bishara, Jihad; Goldberg, Elad; Venturelli, Claudia; Sarti, Mario; Mussini, Cristina; Paul, Mical; Leibovici, Leonard
abstract

Introduction: Reports regarding the external validity of randomized controlled trials (RCTs) are scarce. We aimed to assess the population external validity of an investigator-initiated RCT on the duration of antibiotics for the treatment of Gram-negative bacteremia by comparing patients included in the RCT to patients that were not included in the trial. Methods: Hospitalized patients with Gram-negative bacteremia were recruited into an RCT and randomized to receive 7 or 14 days of covering antibiotic therapy in Israel and Italy from 2013 to 2017. In a concomitant observational study, RCT participants were compared with patients who fulfilled the inclusion criteria but were not included in the trial due to participation in other trials, discharge before approached by researchers, refusal to participate, or unwillingness of the treating physician to allow participants' recruitment. Results: Six hundred and four RCT patients were compared with 613 nonincluded patients. Almost 50% of nonincluded patients (288/613) were dependent on others for activities of daily living at baseline compared to 37.7% of RCT participants (228/604). Dementia was nearly 2-fold more frequent in nonincluded patients than those included (5.9% [36/613] versus 3.6% [22/604], p = 0.07). Patients who were not included in the RCT were more likely to acquire their infection in the hospital (53.3% [327/613] versus 29.1% [176/604], p < 0.001). The primary composite outcome of mortality, clinical failure, readmissions, or extended hospitalization at 90 days occurred in 353 of 613 nonincluded patients (57.6%) compared to 299 of 604 RCT participants (49.6%), p = 0.005. However, on multivariate analysis noninclusion in the RCT was not an independent risk factor for clinical failure and mortality. Conclusions: RCTs, even with broad eligibility criteria, do not represent the whole spectrum of patients and leave out a population with more severe illness for whom the evidence is lacking.

2023 - Heavy arv exposure and exhausted/limited arv options: predictors and clinical outcomes [Articolo su rivista]
Mocroft, Amanda; Pelchen-Matthews, Annegret; Hoy, Jennifer; Llibre, Josep M; Neesgaard, Bastian; Jaschinski, Nadine; Domingo, Pere; Rasmussen, Line Dahlerup; Günthard, Huldrych F; Surial, Bernard; Öllinger, Angela; Knappik, Michael; De Wit, Stephan; Wit, Ferdinand; Mussini, Cristina; Vehreschild, Joerg; Monforte, Antonella D'Arminio; Sonnerborg, Anders; Castagna, Antonella; Anne, Alain Volny; Vannappagari, Vani; Cohen, Cal; Greaves, Wayne; Wasmuth, Jan C; Spagnuolo, Vincenzo; Ryom, Lene
abstract

Objectives: People with HIV and extensive antiretroviral exposure may have limited/exhausted treatment options (LExTO) due to resistance, comorbidities, or antiretroviral-related toxicity. Predictors of LExTO were investigated in the RESPOND cohort. Methods: Participants on ART for at least 5 years were defined as having LExTO when switched to at least two anchor agents and one-third antiretroviral (any class), a two-drug regimen of two anchor agents (excluding rilpivirine with dolutegravir/cabotegravir), or at least three nucleoside reverse transcriptase inhibitors. Baseline was the latest of January 1, 2012, cohort enrolment or 5 years after starting antiretrovirals. Poisson regression modeled LExTO rates and clinical events (all-cause mortality, non-AIDS malignancy, cardiovascular disease [CVD], and chronic kidney disease [CKD]). Results: Of 23 827 participants, 2164 progressed to LExTO (9.1%) during 130 061 person-years follow-up (PYFU); incidence 1.66/100 PYFU (95% CI 1.59-1.73). Predictors of LExTO were HIV duration more than 15 years (vs. 7.5-15; adjusted incidence rate ratio [aIRR] 1.32; 95% CI 1.19-1.46), development of CKD (1.84; 1.59-2.13), CVD (1.64; 1.38-1.94), AIDS (1.18; 1.07-1.30), and current CD4+ cell count of 350 cells/μl or less (vs. 351-500 cells/μl, 1.51; 1.32-1.74). Those followed between 2018 and 2021 had lower rates of LExTO (vs. 2015-2017; 0.52; 0.47-0.59), as did those with baseline viral load of 200 cp/ml or less (0.46; 0.40-0.53) and individuals under 40. Development of LExTO was not significantly associated with clinical events after adjustment for age and current CD4, except CKD (1.74; 1.48-2.05). Conclusion: Despite an aging and increasingly comorbid population, we found declining LExTO rates by 2018-2021, reflecting recent developments in contemporary ART options and clinical management. Reassuringly, LExTO was not associated with a significantly increased incidence of serious clinical events apart from CKD.

2023 - Long-Term Suppressive Therapeutic-Drug-Monitoring-Guided Dalbavancin Therapy for Cardiovascular Prosthetic Infections [Articolo su rivista]
Gallerani, Altea; Gatti, Milo; Bedini, Andrea; Casolari, Stefania; Orlando, Gabriella; Puzzolante, Cinzia; Franceschini, Erica; Menozzi, Marianna; Santoro, Antonella; Barp, Nicole; Volpi, Sara; Soffritti, Alessandra; Pea, Federico; Mussini, Cristina; Meschiari, Marianna
abstract

Dalbavancin represents a promising treatment for cardiovascular prosthetic infections due to its prolonged half-life, bactericidal activity, large spectrum of activity, and excellent biofilm penetration. However, the use of dalbavancin in this setting is limited, and only a few cases have performed therapeutic drug monitoring (TDM) analysis to optimize dosage in suppressive treatments longer than 4 weeks. Our retrospective case series reports the use of dalbavancin in a small cohort of patients with cardiovascular prosthetic infections (cardiac implantable electronic device infections (CEDIs), prosthetic valve endocarditis (PVE), prosthetic vascular graft infections (PVGIs)) treated with dalbavancin as sequential therapy. From May 2019 to May 2023, 14 patients were included: eight cases of PVE (57.1%), seven cases of PVGI (50%), three cases of CEDI (21.4%), and four cases with overlap of infection sites (28.6%). The main pathogen was Staphylococcus aureus (35.7%). Prosthesis replacement was obtained in four patients (28.6%). The median time between symptom onset and the end of treatment was 15 weeks (IQR 7-53), with a median duration of dalbavancin therapy of 8 weeks (IQR 1 to 45 weeks) and 3.5 doses per patient. Among patients managed with TDM-guided strategy, dalbavancin infusion intervals ranged from 4 to 9 weeks. The median length of follow-up was 65 weeks (IQR 23 to 144 weeks). Clinical success was achieved in 10 cases (76.9%); all clinical failures occurred in patients with the implant retained. Among patients monitored by TDM, clinical success was 87.5% vs. 60% in patients treated without TDM. Because of pharmacokinetic individual variability, dalbavancin TDM-guided administration could improve clinical outcomes by individualizing dosing and selecting dosing intervals. This case series seems to suggest a promising role of long-term suppressive dalbavancin treatment for difficult-to-treat cardiovascular prosthesis infection, also with limited surgical indications.

2023 - Measures of Longitudinal Immune Dysfunction and Risk of AIDS and Non-AIDS Defining Malignancies in Antiretroviral Treated People With Human Immunodeficiency Virus (HIV) [Articolo su rivista]
Chammartin, Frédérique; Mocroft, Amanda; Egle, Alexander; Zangerle, Robert; Smith, Colette; Mussini, Cristina; Wit, Ferdinand; Vehreschild, Jörg Janne; d'Arminio Monforte, Antonella; Castagna, Antonella; Bailly, Laurent; Bogner, Johannes; de Wit, Stéphane; Matulionyte, Raimonda; Law, Matthew; Svedhem, Veronica; Tallada, Joan; Garges, Harmony P; Marongiu, Andrea; Borges, Álvaro H; Jaschinski, Nadine; Neesgaard, Bastian; Ryom, Lene; Bucher, Heiner C
abstract

Background: Human immunodeficiency virus (HIV) infection leads to chronic immune activation/inflammation that can persist in virally suppressed persons on fully active antiretroviral therapy (ART) and increase risk of malignancies. The prognostic role of low CD4:CD8 ratio and elevated CD8 cell counts on the risk of cancer remains unclear. Methods: We investigated the association of CD4:CD8 ratio on the hazard of non-AIDS defining malignancy (NADM), AIDS-defining malignancy (ADM) and most frequent group of cancers in ART-treated people with HIV (PWH) with a CD4 and CD8 cell counts and viral load measurements at baseline. We developed Cox proportional hazard models with adjustment for known confounders of cancer risk and time-dependent cumulative and lagged exposures of CD4:CD8 ratio to account for time-evolving risk factors and avoid reverse causality. Results: CD4:CD8 ratios below 0.5, compared to above 1.0, were independently associated with a 12-month time-lagged higher risk of ADM and infection-related malignancies (adjusted hazard ratio 2.61 [95% confidence interval {CI }1.10-6.19] and 2.03 [95% CI 1.24-3.33], respectively). CD4 cell counts below 350 cells/μL were associated with an increased risk of NADMs and ADMs, as did infection, smoking, and body mass index-related malignancies. Conclusions: In ART-treated PWH low CD4:CD8 ratios were associated with ADM and infection-related cancers independently from CD4 and CD8 cell counts and may alert clinicians for cancer screening and prevention of NADM.

2023 - New Antibiotics for Staphylococcus aureus Infection: An Update from the World Association of Infectious Diseases and Immunological Disorders (WAidid) and the Italian Society of Anti-Infective Therapy (SITA) [Articolo su rivista]
Esposito, Susanna; Blasi, Francesco; Curtis, Nigel; Kaplan, Sheldon; Lazzarotto, Tiziana; Meschiari, Marianna; Mussini, Cristina; Peghin, Maddalena; Rodrigo, Carlos; Vena, Antonio; Principi, Nicola; Bassetti, Matteo
abstract

: Staphylococcus aureus is an extremely virulent pathogen that is capable of quickly evolving and developing antibiotic resistance. To overcome this problem, new antibiotics have been developed. Some of these have been licenced for use in clinical practice, mainly for the treatment of adults with acute skin and soft tissue infections, in addition to both community-acquired pneumonia (CAP) and nosocomial pneumonia (hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia). In this paper, the main characteristics and clinical use of new licenced anti-staphylococcal drugs have been discussed. In vitro studies have demonstrated that some new anti-staphylococcal antibiotics have better antimicrobial activity and, at least in certain cases, more favourable pharmacokinetic properties and higher safety and tolerability than the presently available anti-staphylococcal drugs. This suggests that they may have a potential use in reducing the risk of failure of S. aureus therapy. However, an in-depth analysis of microbiological and clinical studies carried out with these new drugs seems to indicate that further studies need to be conducted before the problem of resistance of S. aureus to the antibiotics available today can be completely solved. Considering the overall available research, the drugs that are active against S. aureus appear to present a great therapeutic opportunity for overcoming resistance to traditional therapy. There are advantages in the pharmacokinetic characteristics of some of these drugs and they have the potential to reduce hospital stays and economic costs associated with their use.

2023 - Persistent SARS-CoV-2 infection with multiple clinical relapses in two patients with follicular lymphoma treated with bendamustine and obinutuzumab or rituximab [Articolo su rivista]
Franceschini, Erica; Pellegrino, Mariachiara; Todisco, Vera; Dolci, Giovanni; Bettelli, Francesca; Meschiari, Marianna; Bedini, Andrea; Fregni-Serpini, Giulia; Grottola, Antonella; Guaraldi, Giovanni; Pecorari, Monica; Sarti, Mario; Luppi, Mario; Perno, Carlo Federico; Mussini, Cristina
abstract

Purpose: People with hematologic malignancies have a significantly higher risk of developing severe and protracted forms of SARS-CoV-2 infection compared to immunocompetent patients, regardless of vaccination status. Results: We describe two cases of prolonged SARS-CoV-2 infection with multiple relapses of COVID-19 pneumonia in patients with follicular lymphoma treated with bendamustine and obinutuzumab or rituximab. The aim is to highlight the complexity of SARS-CoV-2 infection in this fragile group of patients and the necessity of evidence-based strategies to treat them properly. Conclusions: Patients with hematological malignancies treated with bendamustine and anti-CD20 antibodies had a significant risk of prolonged and relapsing course of COVID-19. Specific preventive and therapeutic strategies should be developed for this group of patients.

2023 - Plasma HIV-1 RNA and CD4+ T-cell counts are determinants of virological non-suppression outcomes with initial integrase inhibitor-based regimens: A prospective RESPOND cohort study [Articolo su rivista]
Álvarez, Hortensia; Mocroft, Amanda; Ryom, Lene; Neesgaard, Bastian; Edwards, Simon; Svedhem, Vero-Nica; Günthard, Huldrych F; Zangerle, Robert; Smith, Colette; Castagna, Antonella; D Arminio Monforte, Antonella; Wit, Ferdinand; Stecher, Melanie; Lehman, Clara; Mussini, Cristina; Fontas, Eric; González, Eva; Wasmuth, Jan-Christian; Sönnerborg, Anders; De Wit, Stéphane; Chkhartishvili, Nikoloz; Stephan, Christoph; Petoumenos, Kathy; Jaschinski, Nadine; Vannappagari, Vani; Gallant, Joel; Young, Lital; Volny Anne, Alain; Greenberg, Lauren; Martín-Iguacel, Raquel; Poveda, Eva; Llibre, Josep M
abstract

Background: There are conflicting data regarding baseline determinants of virological non-suppression outcomes in persons with HIV who initiate antiretroviral treatment (ART). We evaluated the impact of different baseline variables in the RESPOND cohort. Methods: We included treatment-naïve participants aged ≥18 who initiated 3-drug ART, in 2014-2020. We assessed the odds of virological suppression (VS) at weeks 48 and 96 using logistic regression. Viral blips, low-level viremia (LLV), residual viremia (RV) and virological failure (VF) rates were assessed using Cox regression. Results: Out of 4,310 eligible participants, 72% initiated integrase strand transfer inhibitor (INSTI)-based regimens. At 48 and 96 weeks, 91·0% and 93·3% achieved VS, respectively. At 48 weeks, Kaplan-Meier estimates of rates of viral blips were 9·6%, LLV 2·1%, RV 22·2% and VF 2·1%. Baseline HIV-1 RNA >100,000 copies/mL and CD4+ count ≤200 cells/µL were negatively associated with VS at weeks 48 (aOR 0·51; 95%CI:0·39-0·68 and 0·40; 95%CI:0·27-0·58, respectively) and 96, and with significantly higher rates of blips, LLV and RV. CD4+ counts ≤200 cells/µL were associated with higher risk of VF (aHR 3·12; 95%CI:2·02-4·83). Results were consistent in those starting INSTIs versus other regimens and those initiating dolutegravir versus other INSTIs. Conclusions: Initial high HIV-1 RNA and low CD4+ counts are associated with lower rates of VS at 48 and 96 weeks and higher rates of viral blips, LLV and RV. Low baseline CD4+ counts are associated with higher VF rates.These associations remain with INSTI- and specifically dolutegravir-based regimens. These findings suggest that the impact of these baseline determinants is independent of the ART regimen initiated.

2023 - Pneumocystis jirovecii pneumonia in patients with decompensated cirrhosis: a case series [Articolo su rivista]
Franceschini, Erica; Dolci, Giovanni; Santoro, Antonella; Meschiari, Marianna; Riccò, Alice; Menozzi, Marianna; Burastero, Giulia Jole; Cuffari, Biagio; De Maria, Nicola; Serio, Lucia; Biagioni, Emanuela; Catellani, Barbara; Sandro, Stefano Di; Colecchia, Antonio; Girardis, Massimo; Benedetto, Fabrizio Di; Mussini, Cristina
abstract

Objectives: Pneumocystis jirovecii pneumonia (PCP) incidence is increasing in people without HIV. Decompensated liver cirrhosis is not currently considered a risk factor for PCP. The aim of this paper is to describe a case series of patients with decompensated liver cirrhosis and PCP. Methods: All consecutive patients hospitalized with decompensated cirrhosis and microbiology-confirmed PCP at Policlinico Modena University Hospital from January 1, 2016 to December 31, 2021 were included in our series. Results: Eight patients were included. All patients had advanced-stage liver disease with a model for end-stage liver disease score above 15 (6/8 above 20). Four were on an active orthotopic liver transplant waiting list at the time of PCP diagnosis. Five patients did not have any traditional risk factor for PCP, whereas the other three were on glucocorticoid treatment for acute-on-chronic liver failure. All patients were treated with cotrimoxazole, except two who died before the diagnosis. Five patients died (62.5%), four of them within 30 days from PCP diagnosis. Of the remaining three, one patient underwent liver transplantation. Conclusion: Although further studies are needed, liver cirrhosis can be an independent risk factor for PCP in patients with decompensated cirrhosis that is mainly due to severe alcoholic hepatitis and who are on corticosteroids therapy, and primary prophylaxis for PCP should be considered.

2023 - Predictors of survival in elderly patients with coronavirus disease 2019 admitted to the hospital: derivation and validation of the FLAMINCOV score [Articolo su rivista]
Tiseo, Giusy; Margalit, Ili; Ripa, Marco; Borghi, Vanni; Green, Hefziba; Prendki, Virginie; Riccardi, Niccolò; Dishon, Yael; Perego, Giovanni Battista; Grembiale, Alessandro; Galli, Laura; Tinelli, Marco; Castagna, Antonella; Mussini, Cristina; Yahav, Dafna; Paul, Mical; Falcone, Marco
abstract

Objective: To identify predictors of 30-day survival in elderly patients with coronavirus disease 2019 (COVID-19). Methods: Retrospective cohort study including patients with COVID-19 aged ≥65 years hospitalized in six European sites (January 2020 to May 2021). Data on demographics, comorbidities, clinical characteristics, and outcomes were collected. A predictive score (FLAMINCOV) was developed using logistic regression. Regression coefficients were used to calculate the score. External validation was performed in a cohort including elderly patients from a major COVID-19 centre in Israel. Discrimination was evaluated using the area under the receiver operating characteristic curve (AUC) in the derivation and validation cohorts. Survival risk groups based on the score were derived and applied to the validation cohort. Results: Among 3010 patients included in the derivation cohort, 30-day survival was 74.5% (2242/3010). The intensive care unit admission rate was 7.6% (228/3010). The model predicting survival included independent functional status (OR, 4.87; 95% CI, 3.93-6.03), a oxygen saturation to fraction of inspired oxygen (SpO2/FiO2) ratio of >235 (OR, 3.75; 95% CI, 3.04-4.63), a C-reactive protein level of <14 mg/dL (OR, 2.41; 95% CI, 1.91-3.04), a creatinine level of <1.3 (OR, 2.02; 95% CI, 1.62-2.52) mg/dL, and absence of fever (OR, 1.34; 95% CI, 1.09-1.66). The score was validated in 1174 patients. The FLAMINCOV score ranges from 0 to 15 and showed good discrimination in the derivation (AUC, 0.79; 95% CI, 0.77-0.81; p < 0.001) and validation cohorts (AUC, 0.79; 95% CI, 0.76-0.81; p < 0.001). Thirty-day survival ranged from 39.4% (203/515) to 95.3% (634/665) across four risk groups according to score quartiles in the derivation cohort. Similar proportions were observed in the validation set. Discussion: The FLAMINCOV score identifying elderly with higher or lower chances of survival may allow better triage and management, including intensive care unit admission/exclusion.

2023 - Prognostic immune markers identifying patients with severe COVID-19 who respond to tocilizumab [Articolo su rivista]
DE BIASI, Sara; Mattioli, Marco; Meschiari, Marianna; LO TARTARO, Domenico; Paolini, Annamaria; Borella, Rebecca; Neroni, Anita; Fidanza, LUCIA MICHELA PIA; Busani, Stefano; Girardis, Massimo; Coppi, Francesca; Mattioli, Anna Vittoria; Guaraldi, Giovanni; Mussini, Cristina; Cossarizza, Andrea; Gibellini, Lara
abstract

Introduction: A growing number of evidences suggest that the combination of hyperinflammation, dysregulated T and B cell response and cytokine storm play a major role in the immunopathogenesis of severe COVID-19. IL-6 is one of the main pro-inflammatory cytokines and its levels are increased during SARS-CoV-2 infection. Several observational and randomized studies demonstrated that tocilizumab, an IL-6R blocker, improves survival in critically ill patients both in infectious disease and intensive care units. However, despite transforming the treatment options for COVID-19, IL-6R inhibition is still ineffective in a fraction of patients. Methods: In the present study, we investigated the impact of two doses of tocilizumab in patients with severe COVID-19 who responded or not to the treatment by analyzing a panel of cytokines, chemokines and other soluble factors, along with the composition of peripheral immune cells, paying a particular attention to T and B lymphocytes. Results: We observed that, in comparison with non-responders, those who responded to tocilizumab had different levels of several cytokines and different T and B cells proportions before starting therapy. Moreover, in these patients, tocilizumab was further able to modify the landscape of the aforementioned soluble molecules and cellular markers. Conclusions: We found that tocilizumab has pleiotropic effects and that clinical response to this drug remain heterogenous. Our data suggest that it is possible to identify patients who will respond to treatment and that the administration of tocilizumab is able to restore the immune balance through the re-establishment of different cell populations affected by SARS-COV-2 infection, highlighting the importance of temporal examination of the pathological features from the diagnosis.

2023 - Quality of life and intrinsic capacity in patients with post-acute COVID-19 syndrome is in relation to frailty and resilience phenotypes. [Articolo su rivista]
Guaraldi, Giovanni; Milic, Jovana; Barbieri, Sara; Marchio', Tommaso; Caselgrandi, Agnese; Motta, Federico; Beghe', Bianca; Verduri, Alessia; Belli, Michela; Gozzi, Licia; Iadisernia, Vittorio; Faltoni, Matteo; Burastero, Giulia; Dessilani, Andrea; DEL MONTE, Martina; Dolci, Giovanni; Bacca, Erica; Franceschi, Giacomo; Yaacoub, Dina; Volpi, Sara; Mazzochi, Alice; Clini, Enrico; Mussini, Cristina
abstract

Background- The objective of this study was to characterize frailty and resilience in people evaluated for Post-Acute COVID-19 Syndrome (PACS), in relation to quality of life (QoL) and Intrinsic Capacity (IC). Methods- This cross-sectional, observational, study included consecutive people previously hospitalized for severe COVID-19 pneumonia attending Modena (Italy) PACS Clinic from July 2020 to April 2021. Four frailty-resilience phenotypes were built: “fit/resilient”, “fit/non-resilient”, “frail/resilient” and “frail/non-resilient”. Frailty and resilience were defined according to frailty phenotype and Connor Davidson resilience scale (CD-RISC-25) respectively. Study outcomes were: QoL assessed by means of Symptoms Short form health survey (SF-36) and health-related quality of life (EQ-5D-5L) and IC by means of a dedicated questionnaire. Their predictors including frailty-resilience phenotypes were explored in logistic regressions. Results- 232 patients were evaluated, median age was 58.0 years. PACS was diagnosed in 173 (74.6%) patients. Scarce resilience was documented in 114 (49.1%) and frailty in 72 (31.0%) individuals. Predictors for SF-36 score <61.60 were the phenotypes “frail/non-resilient” (OR=4.69, CI:2.08-10.55), “fit/non-resilient” (OR=2.79, CI:1.00-7.73). Predictors for EQ-5D-5L <89.7% were the phenotypes “frail/non-resilient” (OR=5.93, CI: 2.64-13.33) and “frail/resilient” (OR=5.66, CI:1.93-16.54). Predictors of impaired IC (below the mean score value) were “frail/non-resilient” (OR=7.39, CI:3.20-17.07), and “fit/non-resilient” (OR=4.34, CI:2.16-8.71) phenotypes. Conclusions- Resilience is complementary to frailty in the identification of clinical phenotypes with different impact on wellness and QoL. Frailty and resilience should be evaluated in hospitalized COVID-19 patients to identify vulnerable individuals to prioritize urgent health interventions in people with PACS.

2023 - Real world efficacy of dolutegravir plus lamivudine in PLWH with undetectable viral load after previous failures [Articolo su rivista]
Gagliardini, Roberta; Lorenzini, Patrizia; Cozzi-Lepri, Alessandro; Tavelli, Alessandro; Borghi, Vanni; Galli, Laura; Tagliaferri, Gianmarco; Maggiolo, Franco; Mussini, Cristina; Castagna, Antonella; Monforte, Antonella d'Arminio; Antinori, Andrea
abstract

Background: Dolutegravir (DTG) +lamivudine (3TC) combination has shown to be as effective as triple therapy as maintenance therapy and has been extensively prescribed in clinical practice. We aimed to investigate the impact of previous virological failures (VF) on virological efficacy. Methods: The analysis included data of PLWH with HIV-RNA≤50 copies/mL enrolled in an Italian retrospective multi-cohort study, switching to DTG+3TC. Primary endpoint was viral rebound (VR, confirmed HIV-RNA ≥ 50 copies/mL or a single HIV-RNA ≥ 50 copies/mL followed by change of ART). Kaplan-Meier curves were used to estimate probabilities of VR according to history of previous VF (single HIV-RNA >=1000 or confirmed HIV-RNA >=50 copies/mL). A weighted Cox regression model was fitted to estimate the causal hazard ratio (HR) of history of failure on the risk of VR. Results: A total of 966 PLWH were included, 20.1% of them with history of previous VF. VR was detected in 23 PLWH. The 1-year probability was 1.2% (95% CI 0.2%-2.2%) in PLWH without previous VF and 3.3% (95% CI 0.4%-6.2%) in those with >= 1 VF (log-rank p=0.042). By multivariate analysis adjusted for CD4+ cells count at nadir, duration of virological suppression and mode of HIV transmission, PLWH with >= 1 previous VF had a higher risk of virological rebound than those without previous VF (adjusted HR 3.06 [95% CI 1.00-9.44], p=0.051). Conclusions: Despite the low absolute 1 year risk in both groups, real-world data confirmed that PLWH with a previous failure have an increased risk of viral rebound.

2023 - Real-life experience with remdesivir for treatment of COVID-19 among older adults: a multicentre retrospective study [Articolo su rivista]
Margalit, Ili; Tiseo, Giusy; Ripa, Marco; Borghi, Vanni; Green, Hefziba; Prendki, Virginie; Riccardi, Niccolò; Perego, Giovanni Battista; Grembiale, Alessandro; Galli, Laura; Tinelli, Marco; Castagna, Antonella; Mussini, Cristina; Falcone, Marco; Yahav, Dafna
abstract

Introduction The effect of remdesivir on COVID-19 mortality remains conflicting. Elderly individuals are at risk for poor COVID-19 outcomes. We aimed to assess the effect of remdesivir on COVID-19 mortality among elderly individuals, using real-world data. Methods Retrospective multinational cohort of individuals aged >= 65 years, hospitalized with COVID-19 in six medical centres between January 2020 and May 2021. Associations with in-hospital mortality were evaluated using a multivariable logistic regression model with propensity score adjustment for remdesivir therapy and while implementing generalized estimating equations to control for centre effect. Sensitivity analysis was performed by stratification according to the degree of respiratory support. Results Of 3010 individuals included, 2788 individuals required either oxygen supplementation or non-invasive/invasive mechanical ventilation, 489 (16%) were treated with remdesivir, and 836 (28%) died. Median age was 77 (IQR 70-84) years and 42% were women. Remdesivir was the only therapeutic intervention associated with decreased mortality [adjusted OR (aOR) 0.49, 95% CI 0.37-0.66, P < 0.001]. This protective effect was shown for individuals requiring oxygen support and non-invasive mechanical ventilation, while no association was found among individuals necessitating invasive mechanical ventilation. Risk factors for mortality included invasive ventilation (aOR 5.18, 95% CI 2.46-10.91, P < 0.001), higher serum creatinine (aOR 1.25, 95% CI 1.09-1.43, P = 0.001) and dyspnoea (aOR 1.40, 95% CI 1.07-1.84, P = 0.015) on presentation, and other non-modifiable factors, such as comorbidities. Conclusions Among elderly individuals hospitalized with COVID-19, remdesivir carries survival benefit for those with moderate to severe disease. Its role among individuals with critical illness should be further assessed.

2023 - Recent abacavir use and incident cardiovascular disease in contemporary-treated people with HIV [Articolo su rivista]
Jaschinski, Nadine; Greenberg, Lauren; Neesgaard, Bastian; Miró, Jose M; Grabmeier-Pfistershammer, Katharina; Wandeler, Gilles; Smith, Colette; De Wit, Stéphane; Wit, Ferdinand; Pelchen-Matthews, Annegret; Mussini, Cristina; Castagna, Antonella; Pradier, Christian; Monforte, Antonella; Vehreschild, Jörg; Sönnerborg, Anders; Anne, Alain Volny; Carr, Andrew; Bansi-Matharu, Loveleen; Lundgren, Jens; Garges, Harmony; Rogatto, Felipe; Zangerle, Robert; Günthard, Huldrych F; Rasmussen, Line D; Nescoi, Coca; Van Der Valk, Marc; Menozzi, Marianna; Muccini, Camilla; Mocroft, Amanda; Peters, Lars; Ryom, Lene
abstract

Assessing whether the previously reported association between abacavir (ABC) and cardiovascular disease (CVD) remained amongst contemporarily treated people living with HIV (PLWH).

2023 - Reduced probability of improving viro-immunological state in subjects with vertical transmission of HIV reaching adult age: A multicenter retrospective cohort study [Articolo su rivista]
Pennati, Francesca; Calza, Stefano; Di Biagio, Antonio; Mussini, Cristina; Rusconi, Stefano; Bonora, Stefano; Borghetti, Alberto; Quiros-Roldan, Eugenia; Sarteschi, Giovanni; Menozzi, Marianna; Ferrara, Micol; Celotti, Anna; Ciccullo, Arturo; Giacomet, Vania; Izzo, Ilaria; Dotta, Laura; Badolato, Raffaele; Castelli, Francesco; Focà, Emanuele
abstract

Introduction: Young adults with vertical transmission (VT) of human immunodeficiency virus (HIV) represent a fragile population. This study evaluates factors associated with viro-immunological outcome of these patients. Methods: We performed a multicenter study including HIV-infected subjects with VT ≥ 18 years old from six Italian clinics. Subjects were observed from birth to death, lost to follow-up, or last visit until December 31, 2019. Condition of "optimal viro-immunological status" (OS) was defined as the simultaneous presence of HIV ribonucleic acid (RNA) < 50 copies/mL, CD4+ > 500 cells/mm3 , and CD4+/CD8+ ratio ≥ 1. Results: A total of 126 subjects were enrolled. At 18 years of age, 52/126 (44.4%) had HIV-RNA > 50 copies/mL, 47/126 (38.2%) had CD4+ < 500/mm3 , and 78/126 (67.2%) had CD4+/CD8+ < 1; 28 subjects (23.7%) presented in the condition of OS. Having a CD4+/CD8+ ratio ≥ 1 at 18 years of age was related with an increased probability of shift from suboptimal viro-immunological status (SOS) to OS (HR: 7.7, 95% confidence interval [CI]: 4.23-14.04), and a reduced risk of shift from the OS to the SOS (HR: 0.49, 95% CI: 0.26-0.92). Acquired immunodeficiency syndrome (AIDS) diagnosis significantly reduced the probability of shift from a viro-immunological SOS to OS (HR: 0.09, 95% CI: 0.03-0.30). Subjects who had not achieved an OS at 18 years of age had an increased risk of discontinuation of combination antiretroviral therapy (cART, p = .019). Conclusions: Only a small proportion of subjects with VT of HIV reached the adult age with "OS". Transition to the adult care with a compromised viro-immunological condition represents a negative driver for future optimal infection control, with a higher risk of discontinuation of cART and a reduced probability to improve the immunological status later in the years.

2023 - Rezafungin versus caspofungin for treatment of candidaemia and invasive candidiasis (ReSTORE): a multicentre, double-blind, double-dummy, randomised phase 3 trial [Articolo su rivista]
Thompson, G. R.; Soriano, A.; Cornely, O. A.; Kullberg, B. J.; Kollef, M.; Vazquez, J.; Honore, P. M.; Bassetti, M.; Pullman, J.; Chayakulkeeree, M.; Poromanski, I.; Dignani, C.; Das, A. F.; Sandison, T.; Pappas, P. G.; Akova, M.; Alagha, R.; Alangaden, G.; Albrecht, S. J.; Alexander, B.; Al-Obaidi, M.; Ambasch, G.; Armestar Rodriguez, F.; Azap, A.; Baffoe-Bonnie, A.; Belkhir, L.; Ben-Ami, R.; Boutoille, D.; Cascio, A.; Chai, L. Y.; Chaiwarith, R.; Chen, S.; Chen, Y. -C.; Chen, Y. -H.; Choi, J. Y.; Choi, Y. H.; Chotiprasitsakul, D.; Chung, J. W.; Danion, F.; Denis, B.; Diaz Santos, E.; Dictar, M. O.; Diltoer, M.; Dupont, H.; Feng, S.; Ferre Colomer, M. A.; Ferrer, R.; Forel, J. -M. F. R.; Fortun-Abete, J.; Garcia-Diaz, J.; Girardis, M.; He, F.; Hites, M.; Ho, M. -W.; Honore, P.; Horcajada Gallego, J. P.; Huang, H.; Huang, P. -Y.; Huang, Y.; Hussein, O.; Intalapaporn, P.; Jaruratanasirikul, S.; Jauregui-Peredo, L.; Johnson, M.; Jung, D. S.; Jutivorakool, K.; Kern, W. V.; Kett, D. H.; Khawcharoenporn, T.; Kim, Y. K.; Koehler, P.; Kotanidou, A.; Lachiewicz, A.; Lin, Q.; Lopez Cortes, L. E.; Luo, H.; Luzzati, R.; Maor, Y.; Mccarty, T.; Merelli, M.; Merino Amador, P.; Midturi, J.; Migliorino, G. M.; Mira, J. -P.; Mootsikapun, P.; Morrissey, O.; Munoz Garcia de Paredes, P.; Mussini, C.; Mylonakis, E.; Nseir, S.; Nseir, W.; Odabasi, Z.; Papastamopoulos, V.; Paterson, D.; Patterson, T. F.; Peck, K. R.; Peng, Z.; Permpalung, N.; Plantefeve, G. J.; Poromanski, I. G.; Powell, D.; Psichogiou, M.; Puah, S. H.; Rahav, G.; Martinez, A. R.; Ramos Ramos, J. C.; Raz-Pasteur, A.; Restrepo Castro, C. A.; Riera, F.; Roblot, F.; Rodriguez Alvarez, R. J.; Rogers, B.; Roilides, E.; Sanchez Vallejo, G.; Sganga, G.; Sipsas, N.; Slavin, M.; Spec, A.; Strahilevitz, J.; Tancheva, D. M.; Tao, Z.; Teschner, D.; Van Wijngaerden, E.; Vergidis, P.; Viale, P.; Wang, F. -D.; Wang, S.; Weber, G.; Weng, J.; Xu, J.; Yao, L.; Yavuz, S.; Yilmaz, M.; Young, J. -A.; Zarate, A. H.; Zeng, J.; Zhang, Y.
abstract

Background: Rezafungin is a next-generation, once-a-week echinocandin in development for the treatment of candidaemia and invasive candidiasis and for the prevention of invasive fungal disease caused by Candida, Aspergillus, and Pneumocystis spp after blood and marrow transplantation. We aimed to compare the efficacy and safety of intravenous rezafungin versus intravenous caspofungin in patients with candidaemia and invasive candidiasis. Methods: ReSTORE was a multicentre, double-blind, double-dummy, randomised phase 3 trial done at 66 tertiary care centres in 15 countries. Adults (≥18 years) with systemic signs and mycological confirmation of candidaemia or invasive candidiasis were eligible for inclusion and randomly assigned (1:1) to receive intravenous rezafungin once a week (400 mg in week 1, followed by 200 mg weekly, for a total of two to four doses) or intravenous caspofungin (70 mg loading dose on day 1, followed by 50 mg daily) for no more than 4 weeks. The primary endpoints were global cure (consisting of clinical cure, radiological cure, and mycological eradication) at day 14 for the European Medical Agency (EMA) and 30-day all-cause mortality for the US Food and Drug Administration (FDA), both with a target non-inferiority margin of 20%, assessed in the modified intention-to-treat population (all patients who received one or more doses of study drug and had documented Candida infection based on a culture from blood or another normally sterile site obtained within 96 h before randomisation). Safety was evaluated by the incidence and type of adverse events and deaths in the safety population, defined as all patients who received any amount of study drug. The trial is registered with ClinicalTrials.gov, NCT03667690, and is complete. Findings: Between Oct 12, 2018, and Aug 29, 2021, 222 patients were screened for inclusion, and 199 patients (118 [59%] men; 81 [41%] women; mean age 61 years [SD 15·2]) were randomly assigned (100 [50%] patients to the rezafungin group and 99 [50%] patients to the caspofungin group). 55 (59%) of 93 patients in the rezafungin group and 57 (61%) of 94 patients in the caspofungin group had a global cure at day 14 (weighted treatment difference −1·1% [95% CI −14·9 to 12·7]; EMA primary endpoint). 22 (24%) of 93 patients in the rezafungin group and 20 (21%) of 94 patients in the caspofungin group died or had an unknown survival status at day 30 (treatment difference 2·4% [95% CI −9·7 to 14·4]; FDA primary endpoint). In the safety analysis, 89 (91%) of 98 patients in the rezafungin group and 83 (85%) of 98 patients in the caspofungin group had at least one treatment-emergent adverse event. The most common treatment-emergent adverse events that occurred in at least 5% of patients in either group were pyrexia, hypokalaemia, pneumonia, septic shock, and anaemia. 55 (56%) patients in the rezafungin group and 52 (53%) patients in the caspofungin group had serious adverse events. Interpretation: Our data show that rezafungin was non-inferior to caspofungin for the primary endpoints of day-14 global cure (EMA) and 30-day all-cause mortality (FDA). Efficacy in the initial days of treatment warrants evaluation. There were no concerning trends in treatment-emergent or serious adverse events. These phase 3 results show the efficacy and safety of rezafungin and support its ongoing development. Funding: Cidara Therapeutics and Mundipharma.

2023 - Role of selective digestive decontamination in the prevention of VAP in COVID-19 patients: a pre-post observational study. [Articolo su rivista]
Biagioni, Emanuela; Ferrari, Elena; Gatto, Ilenia; Serio, Lucia; Farinelli, Carlotta; Coloretti, Irene; Talamonti, Marta; Tosi, Martina; Meschiari, Marianna; Tonelli, Roberto; Venturelli, Claudia; Mussini, Cristina; Clini, Enrico; Sarti, Mario; Cossarizza, Andrea; Busani, Stefano; Girardis, Massimo.
abstract

The aim of our study was to evaluate whether the introduction of SDD in a structured protocol for VAP prevention was effective in reducing the occurrence of ventilator associated pneumonia (VAP) in COVID19 patients without changes in the microbiological pattern of antibiotic resistances. This observational pre-post study including adult patients requiring invasive mechanical ventilation (IMV) for severe respiratory failure related to SARS-CoV-2 admitted in three COVID19 intensive care units (ICUs) in an Italian hospital from February 22, 2020, to March 8, 2022. Selective digestive decontamination (SDD) was introduced from the end of April 2021 in the structured protocol for VAP prevention. The SDD consisted of a tobramycin sulphate, colistin sulphate and amphotericin B suspension applied in the patient oropharynx and the stomach via nasogastric tube. Three-hundred forty-eight patients were included in the study. In the 86 patients (32,9%) who received SDD the occurrence of VAP decreased by 7,7% (p = 0,192) compared to patients who did not receive SDD. Onset time of VAP, the occurrence of multidrug-resistant microorganisms AP, the length of invasive mechanical ventilation and hospital mortality were similar in patients who received and who did not receive SDD. The multivariate analysis adjusted for confounders showed that the use of SDD reduces the occurrence of VAP (HR 0,536, CI 0,338-0,851; p = 0,017) Our pre-post observational study indicates that the use of SDD in a structured protocol for VAP prevention seems to reduce the occurrence of VAP without changes in the incidence of multidrug-resistant bacteria in COVID19 patients.

2023 - Sarcopenic Obesity Phenotypes in Patients With HIV: Implications for Cardiovascular Prevention and Rehabilitation [Articolo su rivista]
Milic, Jovana; Calza, Stefano; Cantergiani, Samuele; Albertini, Maddalena; Gallerani, Altea; Menozzi, Marianna; Barp, Nicole; Todisco, Vera; Renzetti, Stefano; Motta, Federico; Mussini, Cristina; Sebastiani, Giada; Raggi, Paolo; Guaraldi, Giovanni
abstract

Background: To describe prevalence, incidence and risk factors for sarcopenic obesity (SO) phenotypes in people living with HIV (PWH) and their association with subclinical cardiovascular disease (CVD). Methods: Observational, longitudinal study of PWH. A minimum of one criterion was necessary to diagnose sarcopenia: (i) weak hand grip (HG), (ii) low appendicular skeletal muscle index (ASMI), (iii) short physical performance battery (SPPB <11). Obesity was defined as (i) body mass index (BMI) ≥30 kg/m2 or (ii) visceral adipose tissue (VAT) ≥160 cm2. These variables combined generated five SO phenotypes: (i) severe SO: low HG+ low ASMI + low SPPB + high BMI; (ii) SO1: weak HG + high VAT; (iii) SO2: weak HG + high BMI; (iv) SO3: low ASMI + high VAT; (v) SO4: low ASMI + high BMI. Subclinical CVD was defined as carotid intima media thickness (IMT) ≥1 mm, presence of carotid plaque, or CAC score >10. Results: Among 2379 PWH 72% men, median age was 52 years, median HIV vintage 21 years, and median BMI 24 kg/m2. Two PWH had severe SO. The prevalence of SO1-SO4 was 19.7%, 3.6%, 20.8% and 0.8% respectively. Incidence of SO1-SO4 was 6.90, 1.2, 5.6 and 0.29 x 100 persons-year, respectively. SO1 was associated with risk of IMT ≥ 1, and SO3 with risk of CAC score >10. Conclusions: There was a large variability in incidence and prevalence of SO phenotypes. The presence of SO may have important implications for cardiovascular prevention and cardiac rehabilitation of PWH who suffered an event.

2023 - Temporal trend of drug-resistance and APOBEC editing in PBMC genotypic resistance tests from HIV-1 infected virologically suppressed individuals [Articolo su rivista]
Armenia, D; Gagliardini, R; Alteri, C; Svicher, V; Cento, V; Borghi, V; Vergori, A; Cicalini, S; Forbici, F; Fabeni, L; Bertoli, A; Brugneti, M; Gennari, W; Malagnino, V; Andreoni, M; Mussini, C; Antinori, A; Perno, C F; Santoro, M M; Ceccherini-Silberstein, F
abstract

Background: We aimed at evaluating the temporal trend of drug-resistance and APOBEC editing from HIV-DNA genotypic resistance tests (GRT) in virologically suppressed individuals.Material and methods: Major resistance mutations (MRM), genotypic susceptibility score (GSS) for the current regimen and APOBEC-related mutations (APO-M) were evaluated. Potential changes in trends of MRM and APO-M over-time were assessed and predictors of MRM detection or sub-optimal GSS (GSS<2) at HIV-DNA-GRT were estimated through logistic regression analyses.Results: Among the 1126 individuals included, 396 (35.2%) harboured at least one MRM (23.4% to NRTI, 18.8% to NNRTI, 7.7% to PI and 1.4% to INSTI [N=724]); 132 (12.3%) individuals showed a GSS <2. APO-M and stop codons were found in 229 (20.3%) and 105 (9.3%) individuals, respectively. APO-DRMs were found in 16.8% of individuals and were more likely observed in those individuals with stop codons (40.0%) compared to those without (14.4%, P<0.001). From 2010 to 2021 no significant changes of resistance or APO-M were found. Positive predictors of MRM detection at HIV-DNA GRT were drug abuse, subtype B infection, and a prolonged and complex treatment history. Perinatal infection and having at least 2 stop codons were associated with a current suboptimal regimen.Conclusions: In virologically suppressed individuals, resistance in HIV-DNA and the extent of APOBEC editing were generally stable in the last decade. A careful evaluation of APOBEC editing might be helpful to improve the reliability of HIV-DNA GRT. Further investigations are required to understand how to apply the estimation of APOBEC editing in refining genotypic evaluation.

2023 - The WEST Study: A Retrospective and Multicentric Study on the Impact of Steroid Therapy in West Nile Encephalitis [Articolo su rivista]
Colaneri, Marta; Lissandrin, Raffaella; Calia, Matteo; Bassoli, Cecilia; Seminari, Elena; Pavesi, Alessandro; Rovida, Francesca; Baldanti, Fausto; Muzzi, Alba; Chichino, Guido; Regazzetti, Angelo; Grecchi, Cecilia; Pan, Angelo; Lupi, Matteo; Franceschini, Erica; Mussini, Cristina; Bruno, Raffaele
abstract

Background: The use of steroid therapy in potentially life-threatening neuroinvasive forms of West Nile infection (WNND) is controversial. The aim of this study is to assess the efficacy of steroid therapy in reducing intrahospital mortality, length of stay, and neurological sequelae at discharge. Methods: This was a multicenter, retrospective, observational study conducted in 5 hospitals in Northern Italy, headed by the Fondazione IRCSS Policlinico San Matteo (Pavia). We extracted all patient data with WNND diagnoses, comparing patients who received steroid treatment with patients who did not receive steroid treatment between January 2014 and January 2022. Comparisons between the 2 groups were performed using chi-square tests for categorical variables and Mann-Whitney tests for non-normal continuous data, and a generalized linear model for the binomial family was carried out. Results: Data from 65 WNND patients were extracted. Among these patients, 33 (50.7%) received steroid therapy at any point during their hospitalization. Receiving steroid therapy did not significantly reduce intrahospital mortality (odds ratio [OR], 1.70; 95% CI, 0.3-13.8; P = .89) or neurological sequelae at discharge (OR, 0.53; 95% CI, 0.16-1.76; P = .47). Conclusions: Steroid treatment is currently used on a single-case basis in severe WNND. More prospective data are needed to demonstrate a protective effect on mortality and neurological sequelae.

2023 - The association of procalcitonin and C- reactive protein with bacterial infections acquired during ICU stay in COVID-19 critically ill patients. [Articolo su rivista]
Campani, Simone; Talamonti, Marta; Dall’Ara, Lorenzo; Coloretti, Irene; Gatto, Ilenia; Biagioni, Emanuela; Tosi, Martina; Meschiari, Marianna; Tonelli, Roberto; Clini, Enrico; Cossarizza, Andrea; Guaraldi, Giovanni; Mussini, Cristina; Sarti, Mario; Trenti, Tommaso; Girardis, Massimo
abstract

In COVID-19 patients, procalcitonin (PCT) and C-reactive protein (CRP) performance in identify-ing bacterial infections remains unclear. Our study aimed to evaluate the association of PCT and CRP with secondary infections acquired during ICU stay in critically ill COVID-19. This observa-tional study included adult patients admitted to three COVID-19 intensive care units (ICU) from February 2020 to May 2022 with respiratory failure caused by SARS-CoV-2 infection and ICU stay≥ 11 days. The values of PCT and CRP collected on the day of infection diagnosis were com-pared to those collected on day 11 after ICU admission, the median time for infection occurrence, in patients without secondary infection. The receiver operating characteristic curve (ROC) and multivariate logistic model were used to assess PCT and CRP association with secondary infec-tions. Two hundred and seventy-nine patients were included, of whom 169 (60,6%) developed secondary infection after ICU admission. The PCT and CRP values observed on the day of the in-fection diagnosis were larger (p< 0,001) than those observed on day 11 after ICU admission in pa-tients without secondary infections. The ROC analysis calculated an AUC of 0,744 (95%CI 0,685-0,803) and 0,754 (95%CI 0,695-0,812) for PCT and CRP, respectively. Multivariate logistic models showed that PCT ≥ 0,16 ng/ml and CRP≥ 1,35 mg/dl were associated (p<0,001) with infections acquired during ICU stay. Our results indicated that PCT and CRP values were associated with developing secondary infections in COVID-19 patients with an ICU stay > 11 days with an ac-ceptable level of diagnostic accuracy using cut-off values lower than those commonly used in no-COVID-19 patients.

2023 - The best place for doravirine [Articolo su rivista]
Mussini, Cristina; Guaraldi, Giovanni
abstract

2023 - Trends in Cancer Incidence in Different Antiretroviral Treatment-Eras amongst People with HIV [Articolo su rivista]
Greenberg, Lauren; Ryom, Lene; Bakowska, Elzbieta; Wit, Ferdinand; Bucher, Heiner C; Braun, Dominique L; Phillips, Andrew; Sabin, Caroline; d'Arminio Monforte, Antonella; Zangerle, Robert; Smith, Colette; De Wit, Stéphane; Bonnet, Fabrice; Pradier, Christian; Mussini, Cristina; Muccini, Camilla; Vehreschild, Jörg J; Hoy, Jennifer; Svedhem, Veronica; Miró, Jose M; Wasmuth, Jan-Christian; Reiss, Peter; Llibre, Josep M; Chkhartishvili, Nikoloz; Stephan, Christoph; Hatleberg, Camilla I; Neesgaard, Bastian; Peters, Lars; Jaschinski, Nadine; Dedes, Nikos; Kuzovatova, Elena; Van Der Valk, Marc; Menozzi, Marianna; Lehmann, Clara; Petoumenos, Kathy; Garges, Harmony; Rooney, Jim; Young, Lital; Lundgren, Jens D; Bansi-Matharu, Loveleen; Mocroft, Amanda; On Behalf Of The Respond And D A D Study Groups, Null
abstract

Simple Summary Cancer is a leading cause of death, both in the general population and in people with HIV. We aimed to assess temporal trends of cancer from 2006 to 2021 in two international HIV cohort collaborations (D:A:D and RESPOND). We assessed overall cancer, AIDS-defining cancers (ADCs), non-ADCs (NADCs), infection-related cancers, body mass index (BMI)-related cancers, and smoking-related cancers. Amongst almost 65,000 individuals, we found that the age-standardised incidence of all cancers remained fairly constant over time; however, the incidence of ADCs and infection-related cancers both decreased, whilst the incidence of NADCs, smoking-related cancers, and BMI-related cancers increased. Trends were similar after adjusting for demographics, comorbidities, and HIV-related factors. Our results highlight the need for better prevention strategies to reduce the incidence of NADCs, smoking-related cancers, and BMI-related cancers. Despite cancer being a leading comorbidity amongst individuals with HIV, there are limited data assessing cancer trends across different antiretroviral therapy (ART)-eras. We calculated age-standardised cancer incidence rates (IRs) from 2006-2021 in two international cohort collaborations (D:A:D and RESPOND). Poisson regression was used to assess temporal trends, adjusted for potential confounders. Amongst 64,937 individuals (31% ART-naive at baseline) and 490,376 total person-years of follow-up (PYFU), there were 3763 incident cancers (IR 7.7/1000 PYFU [95% CI 7.4, 7.9]): 950 AIDS-defining cancers (ADCs), 2813 non-ADCs, 1677 infection-related cancers, 1372 smoking-related cancers, and 719 BMI-related cancers (groups were not mutually exclusive). Age-standardised IRs for overall cancer remained fairly constant over time (8.22/1000 PYFU [7.52, 8.97] in 2006-2007, 7.54 [6.59, 8.59] in 2020-2021). The incidence of ADCs (3.23 [2.79, 3.72], 0.99 [0.67, 1.42]) and infection-related cancers (4.83 [4.2, 5.41], 2.43 [1.90, 3.05]) decreased over time, whilst the incidence of non-ADCs (4.99 [4.44, 5.58], 6.55 [5.67, 7.53]), smoking-related cancers (2.38 [2.01, 2.79], 3.25 [2.63-3.96]), and BMI-related cancers (1.07 [0.83, 1.37], 1.88 [1.42, 2.44]) increased. Trends were similar after adjusting for demographics, comorbidities, HIV-related factors, and ART use. These results highlight the need for better prevention strategies to reduce the incidence of NADCs, smoking-, and BMI-related cancers.

2023 - Ultra-rare RTEL1 gene variants associate with acute severity of COVID-19 and evolution to pulmonary fibrosis as a specific long COVID disorder [Articolo su rivista]
Bergantini, L.; Baldassarri, M.; D'Alessandro, M.; Brunelli, G.; Fabbri, G.; Zguro, K.; Degl'Innocenti, A.; Mari, F.; Daga, S.; Meloni, I.; Bruttini, M.; Croci, S.; Lista, M.; Maffeo, D.; Pasquinelli, E.; Serio, V. B.; Antolini, E.; Basso, S. L.; Minetto, S.; Tita, R.; Mencarelli, M. A.; Rizzo, C. L.; Pinto, A. M.; Ariani, F.; Montagnani, F.; Tumbarello, M.; Rancan, I.; Fabbiani, M.; Cameli, P.; Bennett, D.; Anedda, F.; Marcantonio, S.; Scolletta, S.; Franchi, F.; Mazzei, M. A.; Guerrini, S.; Conticini, E.; Cantarini, L.; Frediani, B.; Tacconi, D.; Raffaelli, C. S.; Emiliozzi, A.; Feri, M.; Donati, A.; Scala, R.; Guidelli, L.; Spargi, G.; Corridi, M.; Nencioni, C.; Croci, L.; Caldarelli, G. P.; Romani, D.; Piacentini, P.; Bandini, M.; Desanctis, E.; Cappelli, S.; Canaccini, A.; Verzuri, A.; Anemoli, V.; Pisani, M.; Ognibene, A.; Lorubbio, M.; Pancrazzi, A.; Vaghi, M.; Monforte, A. D. A.; Miraglia, F. G.; Mondelli, M. U.; Mantovani, S.; Bruno, R.; Vecchia, M.; Maffezzoni, M.; Martinelli, E.; Girardis, M.; Busani, S.; Venturelli, S.; Cossarizza, A.; Antinori, A.; Vergori, A.; Rusconi, S.; Siano, M.; Gabrieli, A.; Riva, A.; Francisci, D.; Schiaroli, E.; Pallotto, C.; Parisi, S. G.; Basso, M.; Panese, S.; Baratti, S.; Scotton, P. G.; Andretta, F.; Giobbia, M.; Scaggiante, R.; Gatti, F.; Castelli, F.; Quiros-Roldan, E.; Antoni, M. D.; Zanella, I.; Monica, M.; Piscopo, C.; Capasso, M.; Russo, R.; Andolfo, I.; Iolascon, A.; Fiorentino, G.; Carella, M.; Castori, M.; Merla, G.; Squeo, G. M.; Aucella, F.; Raggi, P.; Perna, R.; Bassetti, M.; Di Biagio, A.; Sanguinetti, M.; Masucci, L.; Guarnaccia, A.; Valente, S.; Di Florio, A.; Mandala, M.; Giorli, A.; Salerni, L.; Zucchi, P.; Parravicini, P.; Menatti, E.; Trotta, T.; Giannattasio, F.; Coiro, G.; Lena, F.; Lacerenza, G.; Mussini, C.; Tavecchia, L.; Crotti, L.; Parati, G.; Mene, R.; Sanarico, M.; Gori, M.; Raimondi, F.; Stella, A.; Biscarini, F.; Bachetti, T.; La Rovere, M. T.; Bussotti, M.; Ludovisi, S.; Capitani, K.; Dei, S.; Ravaglia, S.; Giliberti, A.; Gori, G.; Artuso, R.; Andreucci, E.; Pagliazzi, A.; Fiorentini, E.; Perrella, A.; Bianchi, F.; Bergomi, P.; Catena, E.; Colombo, R.; Luchi, S.; Morelli, G.; Petrocelli, P.; Iacopini, S.; Modica, S.; Baroni, S.; Micheli, G.; Falcone, M.; Urso, D.; Tiseo, G.; Matucci, T.; Grassi, D.; Ferri, C.; Marinangeli, F.; Brancati, F.; Vincenti, A.; Borgo, V.; Lombardi, S.; Lenzi, M.; Di Pietro, M. A.; Vichi, F.; Romanin, B.; Attala, L.; Costa, C.; Gabbuti, A.; Bellucci, A.; Colaneri, M.; Casprini, P.; Pomara, C.; Esposito, M.; Leoncini, R.; Cirianni, M.; Galasso, L.; Bellini, M. A.; Gabbi, C.; Picchiotti, N.; Furini, S.; Fallerini, C.; Bargagli, E.; Renieri, A.
abstract

Background: Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a novel coronavirus that caused an ongoing pandemic of a pathology termed Coronavirus Disease 19 (COVID-19). Several studies reported that both COVID-19 and RTEL1 variants are associated with shorter telomere length, but a direct association between the two is not generally acknowledged. Here we demonstrate that up to 8.6% of severe COVID-19 patients bear RTEL1 ultra-rare variants, and show how this subgroup can be recognized. Methods: A cohort of 2246 SARS-CoV-2-positive subjects, collected within the GEN-COVID Multicenter study, was used in this work. Whole exome sequencing analysis was performed using the NovaSeq6000 System, and machine learning methods were used for candidate gene selection of severity. A nested study, comparing severely affected patients bearing or not variants in the selected gene, was used for the characterisation of specific clinical features connected to variants in both acute and post-acute phases. Results: Our GEN-COVID cohort revealed a total of 151 patients carrying at least one RTEL1 ultra-rare variant, which was selected as a specific acute severity feature. From a clinical point of view, these patients showed higher liver function indices, as well as increased CRP and inflammatory markers, such as IL-6. Moreover, compared to control subjects, they present autoimmune disorders more frequently. Finally, their decreased diffusion lung capacity for carbon monoxide after six months of COVID-19 suggests that RTEL1 variants can contribute to the development of SARS-CoV-2-elicited lung fibrosis. Conclusion: RTEL1 ultra-rare variants can be considered as a predictive marker of COVID-19 severity, as well as a marker of pathological evolution in pulmonary fibrosis in the post-COVID phase. This notion can be used for a rapid screening in hospitalized infected people, for vaccine prioritization, and appropriate follow-up assessment for subjects at risk. Trial Registration NCT04549831 (www.clinicaltrial.org)

2023 - Vancomycin resistant enterococcus risk factors for hospital colonization in hematological patients: a matched case-control study [Articolo su rivista]
Meschiari, Marianna; Kaleci, Shaniko; Monte, Martina Del; Dessilani, Andrea; Santoro, Antonella; Scialpi, Francesco; Franceschini, Erica; Orlando, Gabriella; Cervo, Adriana; Monica, Morselli; Forghieri, Fabio; Venturelli, Claudia; Ricchizzi, Enrico; Chester, Johanna; Sarti, Mario; Guaraldi, Giovanni; Luppi, Mario; Mussini, Cristina
abstract

BackgroundVancomycin-resistant enterococcus (VRE) was the fastest growing pathogen in Europe in 2022 (+ 21%) but its clinical relevance is still unclear. We aim to identify risk factors for acquired VRE rectal colonization in hematological patients and evaluate the clinical impact of VRE colonization on subsequent infection, and 30- and 90-day overall mortality rates, compared to a matched control group.MethodsA retrospective, single center, case-control matched study (ratio 1:1) was conducted in a hematological department from January 2017 to December 2020. Case patients with nosocomial isolation of VRE from rectal swab screening (>= 48 h) were matched to controls by age, sex, ethnicity, and hematologic disease. Univariate and multivariate logistic regression compared risk factors for colonization.ResultsA total of 83 cases were matched with 83 controls. Risk factors for VRE colonization were febrile neutropenia, bone marrow transplant, central venous catheter, bedsores, reduced mobility, altered bowel habits, cachexia, previous hospitalization and antibiotic treatments before and during hospitalization. VRE bacteraemia and Clostridioides difficile infection (CDI) occurred more frequently among cases without any impact on 30 and 90-days overall mortality. Vancomycin administration and altered bowel habits were the only independent risk factors for VRE colonization at multivariate analysis (OR: 3.53 and 3.1; respectively).ConclusionsAntimicrobial stewardship strategies to reduce inappropriate Gram-positive coverage in hematological patients is urgently required, as independent risk factors for VRE nosocomial colonization identified in this study include any use of vancomycin and altered bowel habits. VRE colonization and infection did not influence 30- and 90-day mortality. There was a strong correlation between CDI and VRE, which deserves further investigation to target new therapeutic approaches.

2022 - A Machine learning approach to predict Weight change in ART experienced PLWH [Esposizione]
Motta, Federico; Milić, Jovana; Barbieri, Sara; Gozzi, Licia; Aprile, Emanuele; Belli, Michela; Venuta, Maria; Cuomo, Gianluca; Carli, Federica; Dolci, Giovanni; Iadisernia, Vittorio; Burastero, Giulia; Mussini, Cristina; Mandreoli, Federica; Guaraldi, Giovanni
abstract

2022 - A first update on mapping the human genetic architecture of COVID-19 [Articolo su rivista]
Pathak, Ga; Polimanti, R; Karjalainen, J; Daly, M; Ganna, A; Daly, Mj; Stevens, C; Kanai, M; Liao, Rg; Trankiem, A; Balaconis, Mk; Nguyen, H; Solomonson, M; Veerapen, K; Ripatti, S; Nkambul, L; Bryant, S; Sankaran, Vg; Neale, Bm; Karczewski, Kj; Martin, Ar; Atkinson, Eg; Tsuo, K; Baya, N; Turley, P; Gupta, R; Walters, Rk; Palmer, Ds; Sarma, G; Cheng, N; Lu, W; Churchhouse, C; Goldstein, Ji; King, D; Zhou, W; Seed, C; Finucane, H; Satterstrom, Fk; Andrews, Sj; Sloofman, Lg; Sealfon, Sc; Hoggart, C; Underwood, Sj; Cordioli, M; Pirinen, M; Donner, K; Kivinen, K; Palotie, A; Kaunisto, M; Harerimana, N; Chwialkowska, K; Wolford, B; Roberts, G; Park, D; Ball, Ca; Coignet, M; Mccurdy, S; Knight, S; Partha, R; Rhead, B; Zhang, M; Berkowitz, N; Gaddis, M; Noto, K; Ruiz, L; Pavlovic, M; Hong, El; Rand, K; Girshick, A; Guturu, H; Baltzell, Ah; Niemi, Mek; Pigazzini, S; Rahmouni, S; Georges, M; Belhaj, Y; Guntz, J; Claassen, S; Beguin, Y; Gofflot, S; Nkambule, L; Nkambul, L; Cusick, C; Moutschen, M; Misset, B; Darcis, G; Guiot, J; Azarzar, S; Malaise, O; Huynen, P; Meuris, C; Thys, M; Jacques, J; Leonard, P; Frippiat, F; Giot, Jb; Sauvage, As; Von Frenckell, C; Lambermont, B; Nakanishi, T; Morrison, Dr; Richards, Jb; Butler-Laporte, G; Forgetta, V; Ghosh, B; Laurent, L; Henry, D; Abdullah, T; Adeleye, O; Mamlouk, N; Kimchi, N; Afrasiabi, Z; Rezk, N; Vulesevic, B; Bouab, M; Guzman, C; Petitjean, L; Tselios, C; Xue, Xq; Afilalo, J; Adra, D; Mooser, V; Li, R; Belisle, A; Lepage, P; Ragoussis, J; Auld, D; Lathrop, Gm; Afilalo, M; Oliveira, M; Brenner, B; Brassard, N; Durand, M; Chasse, M; Kaufmann, De; Schurr, E; Hayward, C; Richmond, A; Baillie, Jk; Glessner, Jt; Hakonarson, H; Chang, X; Shaw, Dm; Below, J; Polikowski, H; Lauren, Pe; Chen, Hh; Zhu, Wy; Davis, L; Kerchberger, Ve; Campbell, A; Porteous, Dj; Fawns-Ritchie, C; Morris, M; Mccormick, Jb; North, K; Glessner, Jr; Gignoux, Cr; Wicks, Sj; Crooks, K; Barnes, Kc; Daya, M; Shortt, J; Rafaels, N; Chavan, S; Timmers, Prhj; Wilson, Jf; Tenesa, A; Kerr, Sm; D'Mellow, K; Shahin, D; El-Sherbiny, Ym; El-Jawhari, Jj; von Hohenstaufen, Ka; Sobh, A; Eltoukhy, Mm; Mohamed, Aas; Elhadidy, Ta; Abd Elghafar, Ms; Elnagdy, Mh; Samir, A; Hegazy, Maf; Abdel-Aziz, M; Khafaga, Wt; El-Lawaty, Wm; Torky, Ms; Moahmed, Hs; El-shanshory, Mr; Yassen, Am; Okasha, K; Eid, Ma; Medina-Gomez, C; Uitterlinden, Ag; Ikram, Ma; Magi, R; Milani, L; Metspalu, A; Laisk, T; Lall, K; Lepamets, M; Esko, T; Reimann, E; Alavere, H; Metsalu, K; Puusepp, M; Naaber, P; Laane, E; Pesukova, J; Peterson, P; Kisand, K; Tabri, J; Allos, R; Hensen, K; Starkopf, J; Ringmets, I; Tamm, A; Kallaste, A; Batini, C; Tobin, Md; Venn, Ld; Lee, Ph; Shrine, N; Williams, At; Guyatt, Al; John, C; Packer, Rj; Ali, A; Wang, X; Wain, Lv; Bee, Ce; Adams, El; Free, Rc; Hollox, Ej; Ruotsalainen, S; Kristiansson, K; Koskelainen, S; Perola, M; Rivolta, C; Quinodoz, M; Kamdar, D; Bochud, Py; Boillat, N; Bibert, S; Nussle, Sg; Albrich, W; Suh, N; Neofytos, D; Erard, V; Voide, C; Friolet, R; Vollenweider, P; Pagani, Jl; Oddo, M; zu Bentrup, Fm; Conen, A; Clerc, O; Marchetti, O; Guillet, A; Guyat-Jacques, C; Foucras, S; Rime, M; Chassot, J; Jaquet, M; Viollet, Rm; Lannepoudenx, Y; Portopena, L; Bochud, Py; Desgranges, F; Filippidis, P; Guery, B; Haefliger, D; Kampouri, Ee; Manuel, O; Munting, A; Papadimitriou-Olivgeris, M; Regina, J; Rochat-Stettler, L; Suttels, V; Tadini, E; Tschopp, J; Van Singer, M; Viala, B; Boillat-Blanco, N; Brahier, T; Hugli, O; Meuwly, Jy; Pantet, O; Nussle, Sg; Bochud, M; D'Acremont, V; Younes, Se; Albrich, Wc; Suh, N; Cerny, A; O'Mahony, L; von Mering, C; Frischknecht, M; Kleger, Gr; Filipovic, M; Kahlert, Cr; Wozniak, H; Negro, Tr; Pugin, J; Bouras, K; Knapp, C; Egger, T; Perret, A; Montillier, P; di Bartolomeo, C; Barda, B; de Cid, R; Carreras, A; Galvan-Femenia, I; Blay, N; Farre, X; Sumoy, L; Cortes, B; Moreno, V; Kogevinas, M; Garcia-Aymerich, J; Castano-Vinyals, G; Dobano, C; Mercader, Jm; Mercader, J; Guindo-Martinez, M; Torrents
abstract

2022 - A proof-of-concept study on the genomic evolution of Sars-Cov-2 in molnupiravir-treated, paxlovid-treated and drug-naïve patients [Articolo su rivista]
Alteri, Claudia; Fox, Valeria; Scutari, Rossana; Burastero, Giulia Jole; Volpi, Sara; Faltoni, Matteo; Fini, Vanessa; Granaglia, Annarita; Esperti, Sara; Gallerani, Altea; Costabile, Valentino; Fontana, Beatrice; Franceschini, Erica; Meschiari, Marianna; Campana, Andrea; Bernardi, Stefania; Villani, Alberto; Bernaschi, Paola; Russo, Cristina; Guaraldi, Giovanni; Mussini, Cristina; Perno, Carlo Federico
abstract

Little is known about SARS-CoV-2 evolution under Molnupiravir and Paxlovid, the only antivirals approved for COVID-19 treatment. By investigating SARS-CoV-2 variability in 8 Molnupiravir-treated, 7 Paxlovid-treated and 5 drug-naive individuals at 4 time-points (Days 0-2-5-7), a higher genetic distance is found under Molnupiravir pressure compared to Paxlovid and no-drug pressure (nucleotide-substitutions/site mean & PLUSMN;Standard error: 18.7 x 10(-4) & PLUSMN; 2.1 x 10(-4) vs. 3.3 x 10(-4) & PLUSMN; 0.8 x 10(-4) vs. 3.1 x 10(-4) & PLUSMN; 0.8 x 10(-4), P = 0.0003), peaking between Day 2 and 5. Molnupiravir drives the emergence of more G-A and C-T transitions than other mutations (P = 0.031). SARS-CoV-2 selective evolution under Molnupiravir pressure does not differ from that under Paxlovid or no-drug pressure, except for orf8 (dN > dS, P = 0.001); few amino acid mutations are enriched at specific sites. No RNA-dependent RNA polymerase (RdRp) or main proteases (Mpro) mutations conferring resistance to Molnupiravir or Paxlovid are found. This proof-of-concept study defines the SARS-CoV-2 within-host evolution during antiviral treatment, confirming higher in vivo variability induced by Molnupiravir compared to Paxlovid and drug-naive, albeit not resulting in apparent mutation selection.

2022 - Acid base disorders in patients with COVID-19 [Articolo su rivista]
Alfano, Gaetano; Fontana, Francesco; Mori, Giacomo; Giaroni, Francesco; Ferrari, Annachiara; Giovanella, Silvia; Ligabue, Giulia; Ascione, Elisabetta; Cazzato, Silvia; Ballestri, Marco; Di Gaetano, Margherita; Meschiari, Marianna; Menozzi, Marianna; Milic, Jovana; Andrea, Bedini; Franceschini, Erica; Cuomo, Gianluca; Magistroni, Riccardo; Mussini, Cristina; Cappelli, Gianni; Guaraldi, Giovanni; De Biasi, Sara; Cossarizza, Andrea; Gibellini, Lara
abstract

Purpose Acid-base derangement has been poorly described in patients with coronavirus disease 2019 (COVID-19). Considering the high prevalence of pneumonia and kidneys injury in COVID-19, frequent acid-base alterations are expected in patients admitted with SARS-Cov-2 infection. The study aimed to assess the prevalence of acid-base disorders in symptomatic patients with a diagnosis of COVID-19. Methods The retrospective study enrolled COVID-19 patients hospitalized at the University Hospital of Modena from 4 March to 20 June 2020. Baseline arterial blood gas (ABG) analysis was collected in 211 patients. In subjects with multiple ABG analysis, we selected only the first measurement. A pH of less than 7.37 was categorized as acidemia and a pH of more than 7.43 was categorized as alkalemia. Results ABG analyses revealed a low arterial partial pressure of oxygen (PO2, 70.2 +/- 25.1 mmHg), oxygen saturation (SO2, 92%) and a mild reduction of PO2/FiO(2) ratio (231 +/- 129). Acid-base alterations were found in 79.7% of the patient. Metabolic alkalosis (33.6%) was the main alteration followed by respiratory alkalosis (30.3%), combined alkalosis (9.4%), respiratory acidosis (3.3%), metabolic acidosis (2.8%) and other compensated acid-base disturbances (3.6%). All six patients with metabolic acidosis died at the end of the follow-up. Conclusion Variations of pH occurred in the majority (79.7%) of patients admitted with COVID-19. The patients experienced all the type of acid-base disorders, notably metabolic and respiratory alkalosis were the most common alterations in this group of patients.

2022 - Acinetobacter baumannii Resistance to Sulbactam/Durlobactam: A Systematic Review [Articolo su rivista]
Principe, Luigi; Di Bella, Stefano; Conti, Jacopo; Perilli, Mariagrazia; Piccirilli, Alessandra; Mussini, Cristina; Decorti, Giuliana
abstract

Infections caused by carbapenem-resistant Acinetobacter baumannii (CRAB) have limited therapeutic options. Sulbactam-durlobactam is a combination of two beta lactamase inhibitors with activity against CRAB under phase 3 clinical investigation. We performed a systematic review on in vitro studies reporting A. baumannii resistances against sulbactam/durlobactam. We considered "resistant" species to be those with MIC >= 8 mg/L. Ten studies were included in the review (9754 tested isolates). Overall, 2.3% of A. baumannii were resistant to sulbactam/durlobactam, and this percentage rose to 3.4% among CRAB subgroups and to 3.7% among colistin-resistant strains. Resistance was 100% among metallo beta-lactamase-producing strains. Overall, in 12.5% of cases, sulbactam/durlobactam resistance was associated with the production of NDM-1, in 31.7% of cases with the substitutions in the PBP3 determinants, and in the remaining cases the resistance mechanism was unknown. In conclusion, A. baumannii resistance towards sulbactam/durlobactam is limited, except for MBL-producing strains.

2022 - An explainable model of host genetic interactions linked to COVID-19 severity [Articolo su rivista]
Onoja, A.; Picchiotti, N.; Fallerini, C.; Baldassarri, M.; Fava, F.; Mari, F.; Daga, S.; Benetti, E.; Bruttini, M.; Palmieri, M.; Croci, S.; Amitrano, S.; Meloni, I.; Frullanti, E.; Doddato, G.; Lista, M.; Beligni, G.; Valentino, F.; Zguro, K.; Tita, R.; Giliberti, A.; Mencarelli, M. A.; Rizzo, C. L.; Pinto, A. M.; Ariani, F.; Di Sarno, L.; Montagnani, F.; Tumbarello, M.; Rancan, I.; Fabbiani, M.; Rossetti, B.; Bergantini, L.; D'Alessandro, M.; Cameli, P.; Bennett, D.; Anedda, F.; Marcantonio, S.; Scolletta, S.; Franchi, F.; Mazzei, M. A.; Guerrini, S.; Conticini, E.; Cantarini, L.; Frediani, B.; Tacconi, D.; Raffaelli, C. S.; Feri, M.; Donati, A.; Scala, R.; Guidelli, L.; Spargi, G.; Corridi, M.; Nencioni, C.; Croci, L.; Caldarelli, G. P.; Romani, D.; Piacentini, P.; Bandini, M.; Desanctis, E.; Cappelli, S.; Canaccini, A.; Verzuri, A.; Anemoli, V.; Pisani, M.; Ognibene, A.; Pancrazzi, A.; Lorubbio, M.; Vaghi, M.; D'Arminio Monforte, A.; Miraglia, F. G.; Bruno, R.; Vecchia, M.; Girardis, M.; Venturelli, S.; Busani, S.; Cossarizza, A.; Antinori, A.; Vergori, A.; Emiliozzi, A.; Rusconi, S.; Siano, M.; Gabrieli, A.; Riva, A.; Francisci, D.; Schiaroli, E.; Paciosi, F.; Tommasi, A.; Zuccon, U.; Vietri, L.; Scotton, P. G.; Andretta, F.; Panese, S.; Baratti, S.; Scaggiante, R.; Gatti, F.; Parisi, S. G.; Castelli, F.; Quiros-Roldan, E.; Antoni, M. D.; Zanella, I.; Della Monica, M.; Piscopo, C.; Capasso, M.; Russo, R.; Andolfo, I.; Iolascon, A.; Fiorentino, G.; Carella, M.; Castori, M.; Aucella, F.; Raggi, P.; Perna, R.; Bassetti, M.; Di Biagio, A.; Sanguinetti, M.; Masucci, L.; Guarnaccia, A.; Valente, S.; De Vivo, O.; Bargagli, E.; Mandala, M.; Giorli, A.; Salerni, L.; Zucchi, P.; Parravicini, P.; Menatti, E.; Trotta, T.; Giannattasio, F.; Coiro, G.; Lena, F.; Lacerenza, G.; Coviello, D. A.; Mussini, C.; Martinelli, E.; Tavecchia, L.; Belli, M. A.; Crotti, L.; Parati, G.; Sanarico, M.; Biscarini, F.; Stella, A.; Rizzi, M.; Maggiolo, F.; Ripamonti, D.; Suardi, C.; Bachetti, T.; La Rovere, M. T.; Sarzi-Braga, S.; Bussotti, M.; Capitani, K.; Dei, S.; Ravaglia, S.; Artuso, R.; Andreucci, E.; Gori, G.; Pagliazzi, A.; Fiorentini, E.; Perrella, A.; Bianchi, F.; Bergomi, P.; Catena, E.; Colombo, R.; Luchi, S.; Morelli, G.; Petrocelli, P.; Iacopini, S.; Modica, S.; Baroni, S.; Segala, F. V.; Menichetti, F.; Falcone, M.; Tiseo, G.; Barbieri, C.; Matucci, T.; Grassi, D.; Ferri, C.; Marinangeli, F.; Brancati, F.; Vincenti, A.; Borgo, V.; Lombardi, S.; Lenzi, M.; Di Pietro, M. A.; Vichi, F.; Romanin, B.; Attala, L.; Costa, C.; Gabbuti, A.; Mene, R.; Colaneri, M.; Casprini, P.; Merla, G.; Squeo, G. M.; Maffezzoni, M.; Mantovani, S.; Mondelli, M. U.; Ludovisi, S.; Colombo, F.; Chiaromonte, F.; Renieri, A.; Furini, S.; Raimondi, F.
abstract

We employed a multifaceted computational strategy to identify the genetic factors contributing to increased risk of severe COVID-19 infection from a Whole Exome Sequencing (WES) dataset of a cohort of 2000 Italian patients. We coupled a stratified k-fold screening, to rank variants more associated with severity, with the training of multiple supervised classifiers, to predict severity based on screened features. Feature importance analysis from tree-based models allowed us to identify 16 variants with the highest support which, together with age and gender covariates, were found to be most predictive of COVID-19 severity. When tested on a follow-up cohort, our ensemble of models predicted severity with high accuracy (ACC = 81.88%; AUCROC = 96%; MCC = 61.55%). Our model recapitulated a vast literature of emerging molecular mechanisms and genetic factors linked to COVID-19 response and extends previous landmark Genome-Wide Association Studies (GWAS). It revealed a network of interplaying genetic signatures converging on established immune system and inflammatory processes linked to viral infection response. It also identified additional processes cross-talking with immune pathways, such as GPCR signaling, which might offer additional opportunities for therapeutic intervention and patient stratification. Publicly available PheWAS datasets revealed that several variants were significantly associated with phenotypic traits such as “Respiratory or thoracic disease”, supporting their link with COVID-19 severity outcome.

2022 - Analysing the efficacy and tolerability of dolutegravir plus either rilpivirine or lamivudine in a multicentre cohort of virologically suppressed PLWHIV [Articolo su rivista]
Ciccullo, A; Baldin, G; Borghi, V; Cossu, M V; Giacomelli, A; Lagi, F; Farinacci, D; Iannone, V; Passerotto, R A; Capetti, A; Sterrantino, G; Mussini, C; Antinori, S; Di Giambenedetto, S
abstract

Objectives: We aimed to investigate and compare the efficacy and safety of two dolutegravir-based two-drug regimens: dolutegravir + lamivudine versus dolutegravir + rilpivirine. Methods: We analysed a cohort of people living with HIV (PLWHIV) switching to dolutegravir + lamivudine or dolutegravir + rilpivirine. We excluded from the analysis PLWHIV with no available pre-switch genotypic test or with a known resistance mutation to one of the study drugs. We evaluated incidence of virological failure (VF) and treatment discontinuation (TD), as well as changes in immunological and metabolic parameters. Results: We enrolled 592 PLWHIV: 306 in the lamivudine group and 286 in the rilpivirine group. We observed nine VFs in the lamivudine group [1.4 VF per 100 patient-years of follow-up (PYFU)] and four VFs in the rilpivirine group (0.6 VF per 100 PYFU). Subsequent genotypic analysis showed no acquired resistance-associated mutations in those experiencing VF. Estimated probability of maintaining virological suppression at 144 and 240 weeks were 96.6% and 92.7%, respectively, in the lamivudine group and 98.7% and 98.7%, respectively, in the rilpivirine group (log-rank P = 0.172). The estimated probability of maintaining study regimen at Week 240 was 82.3% in the lamivudine group and 85.9% in the rilpivirine group (log-rank P = 0.018). We observed a significant improvement in CD4+ cell count at Week 240 in the lamivudine group (P = 0.012); in the rilpivirine group we registered a significant increase in CD4/CD8 ratio (P = 0.014). Conclusions: Both analysed strategies are effective and safe as switch strategies in clinical practice, with a low incidence of VF and a favourable immunological recovery, even in the long term.

2022 - Another piece in the COVID-19 treatment puzzle [Articolo su rivista]
Mussini, C.; Cozzi-Lepri, A.
abstract

2022 - Association between respiratory distress time and invasive mechanical ventilation in COVID-19 patients: a multicentre regional cohort study. [Articolo su rivista]
Busani, Stefano; Coloretti, Irene; Baciarello, Marco; Bellini, Valentina; Sarti, Marco; Biagioni, Emanuela; Tonelli, Roberto; Marchioni, Alessandro; Clini, Enrico; Guaraldi, Giovanni; Mussini, Cristina; Meschiari, Marianna; Tonetti, Tommaso; Pisani, Lara; Nava, Stefano; Bignami, Elena; Ranieri, Marco; Girardis, Massimo
abstract

Aim: to determine whether the duration of respiratory distress symptoms in severe COVID-19 pneumonia affects the need for invasive mechanical ventilation and clinical outcomes. Materials and methods: an observational multicentre cohort study of patients hospitalised in five COVID-19–designated ICUs of the University Hospitals of Emilia-Romagna Region. Patients included were adults with pneumonia due to SARS-CoV-2 with PaO₂/FiO₂ ratio <300 mmHg, respiratory distress symptoms, and need for mechanical ventilation (invasive or non-invasive). Exclusion criteria were an uncertain time of respiratory distress, end-of-life decision, and mechanical respiratory support before hospital admission. Measurements and main results: we analysed 171 patients stratified into tertiles according to respiratory distress duration (distress time, DT) before application of mechanical ventilation support. The rate of patients requiring invasive mechanical ventilation was significantly different (p<0.001) among the tertiles: 17/57 patients in the shortest duration, 29/57 in the intermediate duration, and 40/57 in the longest duration. The respiratory distress time significantly increased the risk of invasive ventilation in the univariate analysis (OR 5.5 [CI 2.48–12.35], p = 0.003). Multivariable regression analysis confirmed this association (OR 10.7 [CI 2.89–39.41], p <0.001). Clinical outcomes (mortality and hospital stay) did not show significant differences between DT tertiles. Discussion: albeit preliminary and retrospective, our data raised the hypothesis that the duration of respiratory distress symptoms may play a role in COVID-19 patients’ need for invasive mechanical ventilation. Furthermore, our observations suggested that specific strategies may be directed towards identifying and managing early symptoms of respiratory distress, regardless of the levels of hypoxemia and the severity of the dyspnoea itself.

2022 - Associations between integrase strand-transfer inhibitors and cardiovascular disease in people living with HIV: a multicentre prospective study from the RESPOND cohort consortium [Articolo su rivista]
Neesgaard, B.; Greenberg, L.; Miro, J. M.; Grabmeier-Pfistershammer, K.; Wandeler, G.; Smith, C.; De Wit, S.; Wit, F.; Pelchen-Matthews, A.; Mussini, C.; Castagna, A.; Pradier, C.; d'Arminio Monforte, A.; Vehreschild, J. J.; Sonnerborg, A.; Anne, A. V.; Carr, A.; Bansi-Matharu, L.; Lundgren, J. D.; Garges, H.; Rogatto, F.; Zangerle, R.; Gunthard, H. F.; Rasmussen, L. D.; Necsoi, C.; van der Valk, M.; Menozzi, M.; Muccini, C.; Peters, L.; Mocroft, A.; Ryom, L.
abstract

2022 - Bictegravir/emtricitabine/tenofovir alafenamide ensures high rates of virological suppression maintenance despite previous resistance in PLWH who optimize treatment in clinical practice [Articolo su rivista]
Armenia, D; Forbici, F; Bertoli, A; Berno, G; Malagnino, V; Gagliardini, R; Borghi, V; Gennari, W; Cicalini, S; Buonomini, A; Teti, E; Lanini, S; Latini, A; Sarmati, L; Mussini, C; Andreoni, M; Antinori, A; Perno, C F; Ceccherini-Silberstein, F; Santoro, M M
abstract

We evaluated virological response and resistance profile in virologically suppressed individuals switching to bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) in real-life.

2022 - Ceftazidime/Avibactam in Ventilator-Associated Pneumonia Due to Difficult-to-Treat Non-Fermenter Gram-Negative Bacteria in COVID-19 Patients: A Case Series and Review of the Literature [Articolo su rivista]
Burastero, Giulia Jole; Orlando, Gabriella; Santoro, Antonella; Menozzi, Marianna; Franceschini, Erica; Bedini, Andrea; Cervo, Adriana; Faltoni, Matteo; Bacca, Erica; Biagioni, Emanuela; Coloretti, Irene; Melegari, Gabriele; Maccieri, Jessica; Busani, Stefano; Bertellini, Elisabetta; Girardis, Massimo; Ferrarini, Giulia; Rofrano, Laura; Sarti, Mario; Mussini, Cristina; Meschiari, Marianna
abstract

Ventilator-associated pneumonia (VAP) in critically ill patients with COVID-19 represents a very huge global threat due to a higher incidence rate compared to non-COVID-19 patients and almost 50% of the 30-day mortality rate. Pseudomonas aeruginosa was the first pathogen involved but uncommon non-fermenter gram-negative organisms such as Burkholderia cepacea and Stenotrophomonas maltophilia have emerged as other potential etiological causes. Against carbapenem-resistant gram-negative microorganisms, Ceftazidime/avibactam (CZA) is considered a first-line option, even more so in case of a ceftolozane/tazobactam resistance or shortage. The aim of this report was to describe our experience with CZA in a case series of COVID-19 patients hospitalized in the ICU with VAP due to difficult-to-treat (DTT) P. aeruginosa, Burkholderia cepacea, and Stenotrophomonas maltophilia and to compare it with data published in the literature. A total of 23 patients were treated from February 2020 to March 2022: 19/23 (82%) VAPs were caused by Pseudomonas spp. (16/19 DTT), 2 by Burkholderia cepacea, and 6 by Stenotrophomonas maltophilia; 12/23 (52.1%) were polymicrobial. Septic shock was diagnosed in 65.2% of the patients and VAP occurred after a median of 29 days from ICU admission. CZA was prescribed as a combination regimen in 86% of the cases, with either fosfomycin or inhaled amikacin or cotrimoxazole. Microbiological eradication was achieved in 52.3% of the cases and the 30-day overall mortality rate was 14/23 (60.8%). Despite the high mortality of critically ill COVID-19 patients, CZA, especially in combination therapy, could represent a valid treatment option for VAP due to DTT non-fermenter gram-negative bacteria, including uncommon pathogens such as Burkholderia cepacea and Stenotrophomonas maltophilia.

2022 - Changes in Inflammatory and Atherogenesis Biomarkers With the 2-Drug Regimen Dolutegravir Plus Lamivudine in Antiretroviral Therapy-Experienced, Virologically Suppressed People With HIV-1: A Systematic Literature Review [Articolo su rivista]
Llibre, Josep M; Cahn, Pedro E; Lo, Janet; Barber, Tristan J; Mussini, Cristina; van Welzen, Berend J; Hernandez, Beatriz; Donovan, Cynthia; Kisare, Michelle; Sithamparanathan, Myooran; van Wyk, Jean
abstract

Background: The 2-drug regimen dolutegravir plus lamivudine has demonstrated long-term noninferior efficacy vs 3-/4-drug regimens (3/4DRs) in phase 3 trials. This systematic literature review summarizes clinical trial and real-world evidence evaluating impact of dolutegravir plus lamivudine on inflammatory and atherogenesis biomarkers in people with human immunodeficiency virus type 1 (PWH). Methods: Using Ovid MEDLINE, Embase, PubMed, and Cochrane library databases and conference proceedings, we searched for studies published from 1 January 2013 to 14 July 2021, reporting changes in inflammatory and atherogenesis biomarkers with dolutegravir plus lamivudine in antiretroviral therapy-experienced, virologically suppressed PWH aged ≥18 years. Results: Four records representing 2 randomized controlled trials (RCTs) and 6 records of real-world evidence met eligibility criteria. All real-world studies evaluated CD4+/CD8+ ratio, while only 1 assessed inflammatory biomarkers. Across both RCTs, no consistent pattern of change in biomarkers was observed between dolutegravir/lamivudine and 3/4DR comparators. There were significant changes in soluble CD14 favoring dolutegravir/lamivudine in TANGO at weeks 48 and 144 and SALSA at week 48, and in interleukin-6 favoring the control group in TANGO at weeks 48 and 144. In the real-world study evaluating inflammatory biomarkers, median soluble CD14 significantly decreased 48 weeks postswitch to dolutegravir plus lamivudine (P < .001), while other biomarkers remained stable. In all 6 real-world studies, increases in CD4+/CD8+ ratio were reported after switch to dolutegravir plus lamivudine (follow-up, 12-60 months). Conclusions: Results show that dolutegravir plus lamivudine has a comparable impact on inflammatory and atherogenesis biomarkers vs 3/4DRs, with no consistent pattern of change after switch in virologically suppressed PWH.

2022 - Characteristics of long COVID among older adults: a cross-sectional study [Articolo su rivista]
Daitch, Vered; Yelin, Dana; Awwad, Muhammad; Guaraldi, Giovanni; Milić, Jovana; Mussini, Cristina; Falcone, Marco; Tiseo, Giusy; Carrozzi, Laura; Pistelli, Francesco; Nehme, Mayssam; Guessous, Idris; Kaiser, Laurent; Vetter, Pauline; Bordas-Martínez, Jaume; Durà-Miralles, Xavier; Peleato-Catalan, Dolores; Gudiol, Carlota; Shapira-Lichter, Irit; Abecasis, Donna; Leibovici, Leonard; Yahav, Dafna; Margalit, Ili
abstract

To describe long-COVID symptoms among older adults, and to assess risk factors for two common long-COVID symptoms: fatigue and dyspnea.

2022 - Compassionate use of meropenem/vaborbactam for infections caused by KPC-producing Klebsiella pneumoniae: a multicentre study [Articolo su rivista]
Tumbarello, Mario; Raffaelli, Francesca; Cascio, Antonio; Falcone, Marco; Signorini, Liana; Mussini, Cristina; De Rosa, Francesco Giuseppe; Losito, Angela Raffaella; De Pascale, Gennaro; Pascale, Renato; Giacobbe, Daniele Roberto; Oliva, Alessandra; Farese, Alberto; Morelli, Paola; Tiseo, Giusy; Meschiari, Marianna; Del Giacomo, Paola; Montagnani, Francesca; Fabbiani, Massimiliano; Vargas, Joel; Spanu, Teresa; Bassetti, Matteo; Venditti, Mario; Viale, Pierluigi
abstract

Objectives To explore the real-life performance of meropenem/vaborbactam for treating serious KPC-producing Klebsiella pneumoniae infections, including those resistant to ceftazidime/avibactam. Methods A retrospective observational cohort study was conducted in 12 Italian hospitals. Enrolled patients had K. pneumoniae carbapenemase (KPC)-producing K. pneumoniae (KPC-Kp) infections (59.5% of which were ceftazidime/avibactam resistant). Patients who received >= 72 h of meropenem/vaborbactam therapy (with or without other antimicrobials) in a compassionate-use setting were included. Results The 37 infections (all hospital-acquired) were mainly bacteraemic (BSIs, n = 23) or lower respiratory tract infections (LRTIs, n = 10). Clinical cure was achieved in 28 (75.6%) cases and microbiologically confirmed in all 25 with follow-up cultures. Three (10.7%) of the 28 clinical cures (all BSIs, 2/3 microbiologically confirmed) were followed by in-hospital recurrences after meropenem/vaborbactam was discontinued (median interval: 18 days). All three recurrences were susceptible to meropenem/vaborbactam and successfully managed with meropenem/vaborbactam combined with colistin or fosfomycin. Nine patients (24.3%) (all with BSIs or LRTIs) died in hospital with persistent signs of infection. Most were aged over 60 years, with high comorbidity burdens and INCREMENT scores >= 8. Only one had received meropenem/vaborbactam monotherapy. Six began meropenem/vaborbactam therapy >48 h after infection onset. Outcomes were unrelated to the isolate's ceftazidime/avibactam susceptibility status. The single adverse event observed consisted of severe leukopenia with thrombocytopenia. Conclusions With the well-known limitations of real-life retrospective studies, our results support previous findings indicating that meropenem/vaborbactam therapy will be a safe, effective tool for managing serious KPC-Kp infections, including the increasing proportion displaying resistance to ceftazidime/avibactam.

2022 - Contribution of integrase inhibitor use, body mass index, physical activity and caloric intake to weight gain in people living with HIV [Articolo su rivista]
Guaraldi, Giovanni; Milic, Jovana; Bacchi, Elena; Carli, Federica; Menozzi, Marianna; Franconi, Iacopo; Raimondi, Alessandro; Ciusa, Giacomo; Masi, Valentina; Belli, Michela; Guaraldi, Stefano; Aprile, Emanuele; Mancini, Maria; Mussini, Cristina; Lake, Jordan E; Erlandson, Kristine M
abstract

: Background: Integrase inhibitor (INSTI) use has been associated with greater weight gain (WG) among people living with HIV (PLWH), but it is unclear how this effect compares in magnitude to traditional risk factors for WG. We assessed the population attributable fractions (PAFs) of modifiable lifestyle factors and INSTI regimens in PLWH who experienced a ≥5% WG over follow-up. Methods: In an observational cohort study from 2007 to 2019 at Modena HIV Metabolic Clinic, Italy, ART-experienced but INSTI-naive PLWH were grouped as INSTI-switchers vs non-INSTI. Groups were matched for sex, age, baseline BMI and follow-up duration. Significant WG was defined as an increase of ≥5% from 1st visit weight over follow-up. PAFs and 95% CIs were estimated to quantify the proportion of the outcome that could be avoided if the risk factors were not present. Results: 118 PLWH switched to INSTI and 163 remained on current ART. Of 281 PLWH (74.3% males), mean follow-up was 4.2 years, age 50.3 years, median time since HIV diagnosis 17.8 years, CD4 cell count 630 cells/µL at baseline. PAF for weight gain was the greatest for high BMI (45%, 95% CI: 27-59, p < 0.001), followed by high CD4/CD8 ratio (41%, 21-57, p < 0.001) and lower physical activity (32%, 95% CI 5-52, p = 0.03). PAF was not significant for daily caloric intake (-1%, -9-13, p = 0.45), smoking cessation during follow-up (5%, 0-12, p = 0.10), INSTI switch (11%, -19-36; p = 0.34). Conclusions: WG in PLWH on ART is mostly influenced by pre-existing weight and low physical activity, rather than switch to INSTI.

2022 - Correction: Endobronchial valve positioning for alveolar-pleural fistula following ICU management complicating COVID-19 pneumonia (BMC Pulmonary Medicine, (2021), 21, 1, (307), 10.1186/s12890-021-01653-w) [Articolo su rivista]
Donatelli, P.; Trentacosti, F.; Pellegrino, M. R.; Tonelli, R.; Bruzzi, G.; Andreani, A.; Cappiello, G. F.; Andrisani, D.; Gozzi, F.; Mussini, C.; Busani, S.; Cavaliere, G. V.; Girardis, M.; Bertellini, E.; Clini, E.; Marchioni, A.
abstract

2022 - Cytomegalovirus blood reactivation in COVID-19 critically ill patients: risk factors and impact on mortality. [Articolo su rivista]
Gatto, Ilenia; Biagioni, Emanuela; Coloretti, Irene; Farinelli, Carlotta; Avoni, Camilla; Caciagli, Valeria; Busani, Stefano; Sarti, Mario; Pecorari, Monica; Gennari, William; Guaraldi, Giovanni; Franceschini, Erica; Meschiari, Marianna; Mussini, Cristina; Tonelli, Roberto; Clini, Enrico; Cossarizza, Andrea; Girardis, Massimo; Gibellini, Lara
abstract

Purpose: Cytomegalovirus (CMV) reactivation in immunocompetent critically ill patients is common and relates to a worsening outcome. In this large observational study, we evaluated the incidence and the risk factors associated with CMV reactivation and its effects on mortality in a large cohort of COVID-19 patients admitted to the intensive care unit (ICU). Methods: Consecutive patients with confirmed SARS-CoV-2 infection and acute respiratory distress syndrome admitted to three ICUs from February 2020 to July 2021 were included. The patients were screened at ICU admission and once or twice per week for quantitative CMV-DNAemia in the blood. The risk factors associated with CMV blood reactivation and its association with mortality were estimated by adjusted Cox proportional hazards regression models. Results: CMV blood reactivation was observed in 88 patients (20,4%) of the 431 patients studied. SAPS II score (HR 1,031, 95% CI 1,010-1,053, p=0,006), platelet count (HR 0,0996, 95% CI 0,993-0,999, p=0,004), invasive mechanical ventilation (HR 2,611, 95% CI 1,223-5,571, p=0,013) and secondary bacterial infection (HR 5,041; 95% CI 2,852-8,911, p<0,0001) during ICU stay were related to CMV reactivation. Hospital mortality was higher in patients with (67,0%) than in patients without (24,5%) CMV reactivation but the adjusted analysis did not confirm this association (HR 1,141, 95% CI 0,757-1,721, p=0,528). Conclusion: The severity of illness and the occurrence of secondary bacterial infections were associated with an increased risk of CMV blood reactivation, which, however, does not seem to influence the outcome of COVID-19 ICU patients independently.

2022 - Decay pattern of anti–SARS–CoV–2 antibodies in PWH [Abstract in Atti di Convegno]
Milić, Jovana; Tili, Alessandro; Renzetti, Stefano; Motta, Federico; Meschiari, Marianna; Fogliani, Rossella; Ferrari, Filippo; Meccugni, Barbara; Mimmi, Stefano; Borsari, Silvana; Calza, Stefano; Cossarizza, Andrea; Mussini, Cristina; Guaraldi, Giovanni
abstract

2022 - Early awake proning in critical and severe COVID-19 patients undergoing noninvasive respiratory support: A retrospective multicenter cohort study [Articolo su rivista]
Tonelli, R; Pisani, L; Tabbì, L; Comellini, V; Prediletto, I; Fantini, R; Marchioni, A; Andrisani, D; Gozzi, F; Bruzzi, G; Manicardi, L; Busani, S; Mussini, C; Castaniere, I; Bassi, I; Carpano, M; Tagariello, F; Corsi, G; D' amico, R; Girardis, M; Nava, S; Clini, E.
abstract

Introduction- In non-intubated patients with COVID-19 pneumonia, awake prone position associated with non-invasive respiratory support (NRS) demonstrated only physiological benefits. Nonetheless, it might be arguable that at least a selected subset of these patients is going to obtain significant clinical gains. Methods- This retrospective cohort study was conducted in two teaching hospitals comparing effects of awake prone position in addition to usual care (PP) with standard care alone (SC)in severe and critical COVID-19 patients undergoing NRS. Primary outcome was endotracheal intubation (ETI) rate. In-hospital mortality, time to ETI, tracheostomy, length of RICU and hospital stay served as secondary outcomes. Risk factors associated with ETI were also investigated in PP group. Results- A cohort of 114 patients (38 and 76 in PP and SC group, respectively) was analyzed. Greater ETI risk reduction rate was observed in PP as compared with SC both at unadjusted estimates (HR=0.45 95%CI [0.2-0.9], p=0.02), and even after adjustment for confounders (HR=0.59 95%CI[0.3-0.94], p=0.03). Compared with SC, PP group also showed a favorable difference in terms of days free from respiratory support, length of RICU and hospital stay, but not in mortality or tracheostomy rate. Conclusion- Early awake proning in spontaneously breathing Covid-19 patients is associated with a risk reduction of intubation rate.Findings prompt further randomized controlled trials to answer the pending questions on the real efficacy of PP in this setting.

2022 - Effective Treatment of Patients Experiencing Primary, Acute HIV Infection Decreases Exhausted/Activated CD4+ T Cells and CD8+ T Memory Stem Cells [Articolo su rivista]
Lo Tartaro, D.; Camiro-Zuniga, A.; Nasi, M.; De Biasi, S.; Najera-Avila, M. A.; Jaramillo-Jante, M. D. R.; Gibellini, L.; Pinti, M.; Neroni, A.; Mussini, C.; Soto-Ramirez, L. E.; Calva, J. J.; Belaunzaran-Zamudio, F.; Crabtree-Ramirez, B.; Hernandez-Leon, C.; Mosqueda-Gomez, J. L.; Navarro-Alvarez, S.; Perez-Patrigeon, S.; Cossarizza, A.
abstract

Several studies have identified main changes in T- and B-lymphocyte subsets during chronic HIV infection, but few data exist on how these subsets behave during the initial phase of HIV infection. We enrolled 22 HIV-infected patients during the acute stage of infection before the initiation of antiretroviral therapy (ART). Patients had blood samples drawn previous to ART initiation (T0), and at 2 (T1) and 12 (T2) months after ART initiation. We quantified cellular HIV-DNA content in sorted naïve and effector memory CD4 T cells and identified the main subsets of T- and B-lymphocytes using an 18-parameter flow cytometry panel. We identified correlations between the patients’ clinical and immunological data using PCA. Effective HIV treatment reduces integrated HIV DNA in effector memory T cells after 12 months (T2) of ART. The main changes in CD4+ T cells occurred at T2, with a reduction of activated memory, cytolytic and activated/exhausted stem cell memory T (TSCM) cells. Changes were present among CD8+ T cells since T1, with a reduction of several activated subsets, including activated/exhausted TSCM. At T2 a reduction of plasmablasts and exhausted B cells was also observed. A negative correlation was found between the total CD4+ T-cell count and IgM-negative plasmablasts. In patients initiating ART immediately following acute/early HIV infection, the fine analysis of T- and B-cell subsets has allowed us to identify and follow main modifications due to effective treatment, and to identify significant changes in CD4+ and CD8+ T memory stem cells.

2022 - First Human Case of Tick-Borne Encephalitis in Non-Endemic Region in Italy: A Case Report [Articolo su rivista]
Barp, N.; Cappi, C.; Meschiari, M.; Battistel, M.; Libbra, M. V.; Ferri, M. A.; Ballestri, S.; Gallerani, A.; Ferrari, F.; Meacci, M.; Sarti, M.; Capitelli, M.; Mussini, C.; Franceschini, E.
abstract

2022 - First and second wave among hospitalized COVID-19 patients with severe pneumonia: a comparison of 28-day mortality over 1-year pandemic in a tertiary university hospital in Italy. [Articolo su rivista]
Meschiari, M; Cozzi-Lepri, A; Tonelli, R; Bacca, E; Menozzi, M; Franceschini, E; Cuomo, G; Bedini, A; Volpi, S; Milic, J; Brugioni, L; Romagnoli, E; Pietrangelo, A; Corradini, E; Coloretti, I; Biagioni, E; Busani, S; Girardis, M; Cossarizza, A; Clini, E; Guaraldi, G; Mussini, C.
abstract

Objectives: The first COVID-19-19 epidemic wave was over the period February-May 2020. Since October 1st, 2020 Italy, as many other European countries, faced a second wave. The aim of this analysis was to compare the 28-day mortality between the two waves among COVID-19 hospitalised patients. Design: Observational cohort study. Standard survival analysis was performed to compare all-cause mortality within 28 days after hospital admission in the two waves. Kaplan-Meier curves as well as Cox regression model analysis were used. The effect of wave on risk of death was shown by means of hazard ratios (HRs) with 95% confidence intervals (CI). A sensitivity analysis around the impact of the circulating variant as a potential unmeasured confounder was performed. Setting: University Hospital of Modena, Italy. Patients admitted to hospital for severe COVID-19 pneumonia during the first (February 22nd – May 31st, 2020) and second wave (October 1st- December 31st, 2020) were included. Results: During the two study periods, a total of 1,472 patients with severe COVID-19 pneumonia were admitted to our hospital, 449 during the first wave and 1,023 during the second. Median age was 70 years (IQR:56-80), 37% females, 49% with PaO /FiO < 250 mmHg, 82% with ≥1 comorbidity, median duration of symptoms was 6 days. 28-day mortality rate was 20.0% (95% CI:16.3-23.7) during the first wave vs. 14.2% (95% CI:12.0-16.3) in the second (log-rank test p-value= 0.03). After including key predictors of death in the multivariable Cox regression model, the data still strongly suggested a lower 28-day mortality rate in the 2nd wave (aHR=0.64, 95% CI: 0.45, 0.90, p- value=0.01). Conclusions: In our hospitalized COVID-19 patients with severe pneumonia, the 28-day mortality appeared to be reduced by 36% during the second as compared to the first wave. Further studies are needed to identify factors that may have contributed to this improved survival.

2022 - From NAFLD to MAFLD: implications of change in terminology in PWH [Abstract in Atti di Convegno]
Gozzi, Licia; Milić, Jovana; Renzetti, Stefano; Motta, Federico; Cervo, Adriana; Burastero, Giulia; Iadisernia, Vittorio; Lebouche, Bertrand; Al Hinai, Shaima; Deschenes, Marc; Menozzi, Marianna; Raggi, Paolo; Calza, Stefano; Mussini, Cristina; Sebastiani, Giada; Guaraldi, Giovanni
abstract

2022 - From NAFLD to MAFLD: implications of change in terminology in PWH [Abstract in Atti di Convegno]
Guaraldi, Giovanni; Milić, Jovana; Renzetti, Stefano; Motta, Federico; Gozzi, Licia; Cervo, Adriana; Burastero, Giulia; Iadisernia, Vittorio; Lebouché, Bertrand; Al Hinai, Shaima; Deschenes, Marc; Raggi, Paolo; Calza, Stefano; Mussini, Cristina; Sebastiani, Giada
abstract

2022 - HCV reinfection after HCV therapy among HIV/HCV-coinfected individuals in Europe [Articolo su rivista]
Amele, S.; Sandri, A. K.; Rodger, A.; Vandekerckhove, L.; Benfield, T.; Milinkovic, A.; Duvivier, C.; Stellbrink, H. -J.; Sambatakou, H.; Chkhartishvili, N.; Caldeira, L.; Laguno, M.; Domingo, P.; Wandeler, G.; Gisinger, M.; Kuzovatova, E.; Dragovic, G.; Knysz, B.; Matulionyte, R.; Rockstroh, J. K.; Lundgren, J. D.; Mocroft, A.; Peters, L.; Harxhi, A.; Losso, M.; Kundro, M.; Schmied, B.; Zangerle, R.; Karpov, I.; Vassilenko, A.; Mitsura, V. M.; Paduto, D.; Clumeck, N.; Wit, S. D.; Delforge, M.; Florence, E.; Vandekerckhove, L.; Hadziosmanovic, V.; Begovac, J.; Machala, L.; Jilich, D.; Sedlacek, D.; Kronborg, G.; Benfield, T.; Gerstoft, J.; Katzenstein, T.; Pedersen, C.; Johansen, I. S.; Ostergaard, L.; Wiese, L.; Moller, N. F.; Nielsen, L. N.; Zilmer, K.; Smidt, J.; Aho, I.; Viard, J. -P.; Girard, P. -M.; Pradier, C.; Fontas, E.; Duvivier, C.; Rockstroh, J.; Behrens, G.; Degen, O.; Stellbrink, H. J.; Stefan, C.; Bogner, J.; Fatkenheuer, G.; Chkhartishvili, N.; Sambatakou, H.; Adamis, G.; Paissios, N.; Szlavik, J.; Gottfredsson, M.; Devitt, E.; Tau, L.; Turner, D.; Burke, M.; Shahar, E.; Hassoun, G.; Elinav, H.; Haouzi, M.; Elbirt, D.; D'Arminio Monforte, A.; Esposito, R.; Mazeu, I.; Mussini, C.; Mazzotta, F.; Gabbuti, A.; Lazzarin, A.; Castagna, A.; Gianotti, N.; Galli, M.; Ridolfo, A.; Sacco, L.; Uzdaviniene, V.; Matulionyte, R.; Staub, T.; Hemmer, R.; Dragas, S.; Stevanovic, M.; Reiss, P.; Trajanovska, J.; Reikvam, D. H.; Maeland, A.; Bruun, J.; Knysz, B.; Gasiorowski, J.; Inglot, M.; Bakowska, E.; Flisiak, R.; Grzeszczuk, A.; Parczewski, M.; Maciejewska, K.; Aksak-Was, B.; Beniowski, M.; Mularska, E.; Jablonowska, E.; Kamerys, J.; Wojcik, K.; Mozer-Lisewska, I.; Rozplochowski, B.; Zagalo, A.; Mansinho, K.; Maltez, F.; Radoi, R.; Oprea, C.; Davila, C.; Yakovlev, A.; Trofimora, T.; Khromova, I.; Kuzovatova, E.; Blokhina, I. N.; Novogrod, N.; Borodulina, E.; Vdoushkina, E.; Ranin, J.; Tomazic, J.; Miro, J. M.; Miro, J. M.; Martinez, E.; Garcia, F.; Blanco, J. L.; Martinez-Rebollar, M.; Mallolas, J.; Callau, P.; Rojas, J.; Inciarta, A.; Moreno, S.; del Campo, S.; Clotet, B.; Jou, A.; Paredes, R.; Puig, J.; Llibre, J. M.; Santos, J. R.; Domingo, P.; Gutierrez, M.; Mateo, G.; Sambeat, M. A.; Laporte, J. M.; Falconer, K.; Thalme, A.; Sonnerborg, A.; Brannstrom, J.; Flamholc, L.; Scherrer, A.; Weber, R.; Cavassini, M.; Calmy, A.; Furrer, H.; Battegay, M.; Schmid, P.; Kuznetsova, A.; Mikhalik, J.; Sluzhynska, M.; Milinkovic, A.; Johnson, A. M.; Simons, E.; Edwards, S.; Phillips, A.; Johnson, M. A.; Mocroft, A.; Orkin, C.; Winston, A.; Clarke, A.; Leen, C.; Karpov, I.; Losso, M.; Lundgren, J.; Rockstroh, J.; Aho, I.; Rasmussen, L. D.; Svedhem, V.; Wandeler, G.; Pradier, C.; Chkhartishvili, N.; Matulionyte, R.; Oprea, C.; Kowalska, J. D.; Begovac, J.; Miro, J. M.; Guaraldi, G.; Paredes, R.; Wandeler, G.; Paredes, R.; Peters, L.; Kirk, O.; Peters, L.; Bojesen, A.; Raben, D.; Hansen, E. V.; Kristensen, D.; Larsen, J. F.; Fischer, A. H.; Mocroft, A.; Phillips, A.; Cozzi-Lepri, A.; Amele, S.; Pelchen-Matthews, A.; Roen, A.; Tusch, E.; Bannister, W.; Reekie, J.
abstract

Objectives: Although direct-acting antivirals (DAAs) can clear HCV in nearly all HIV/HCV-coinfected individuals, high rates of reinfection may hamper efforts to eliminate HCV in this population. We investigated reinfection after sustained virological response (SVR) in HIV/HCV-coinfected individuals in Europe. Methods: Factors associated with odds of reinfection by 2 years after SVR in EuroSIDA participants with one or more HCV-RNA test and 2 years follow-up were assessed using logistic regression. Results: Overall, 1022 individuals were included. The median age was 50 (interquartile range: 43–54 years), and most were male (78%), injection drug users (52%), and received interferon (IFN)-free DAAs (62%). By 24 months, 75 [7.3%, 95% confidence interval (CI): 5.7–8.9%] individuals were reinfected. Among individuals treated prior to 2014, 16.1% were reinfected compared with 4.2% and 8.3%, respectively, among those treated during or after 2014 with IFN-free and IFN-based therapy. After adjustment, individuals who had started treatment during or after 2014 with IFN-free or IFN-based therapy had significantly lower odds of reinfection (adjusted odds ratio = 0.21, 95% CI: 0.11–0.38; 0.43, 95% CI: 0.22–0.83) compared with those who had received therapy before 2014. There were no significant differences in odds of reinfection according to age, gender, European region, HIV transmission risk group or liver fibrosis. Conclusions: Among HIV/HCV-coinfected individuals in Europe, 7.3% were reinfected with HCV within 24 months of achieving SVR, with evidence suggesting that this is decreasing over time and with use of newer HCV regimens. Harm reduction to reduce reinfection and surveillance to detect early reinfection with an offer of treatment are essential to eliminate HCV.

2022 - HIV and syphilis: incidence rate of co-infection and syphilis re-infection in a cohort of newly diagnosed HIV patients [Articolo su rivista]
DI Tullio, Francesca; Mandel, Victor D; Cuomo, Gianluca; Coppini, Maurizio; Guaraldi, Giovanni; Mussini, Cristina; Pellacani, Giovanni; Borghi, Vanni
abstract

Syphilis represents a major public health concern disproportionately affecting HIV positive patients and in many cases both infections are newly diagnosed at the same time. To date, limited studies are available on syphilis incidence in patients with a new HIV diagnosis.

2022 - Incidence of hypertension in people with HIV who are treated with integrase inhibitors versus other antiretroviral regimens in the RESPOND cohort consortium [Articolo su rivista]
Byonanebye, D. M.; Polizzotto, M. N.; Neesgaard, B.; Sarcletti, M.; Matulionyte, R.; Braun, D. L.; Castagna, A.; de Wit, S.; Wit, F.; Fontas, E.; Vehreschild, J.; Vesterbacka, J.; Greenberg, L.; Hatleberg, C.; Garges, H.; Gallant, J.; Volny Anne, A.; Ollinger, A.; Mozer-Lisewska, I.; Surial, B.; Spagnuolo, V.; Necsoi, C.; van der Valk, M.; Mocroft, A.; Law, M.; Ryom, L.; Petoumenos, K.; Hillebregt, M.; Rose, N.; Hutchinson, J.; Zangerle, R.; Appoyer, H.; Delforge, M.; Stephan, C.; Bucht, M.; Chkhartishvili, N.; Chokoshvili, O.; Mussini, C.; Borghi, V.; Pradier, C.; Dollet, K.; Caissotti, C.; Casabona, J.; Miro, J. M.; Smith, C.; Lampe, F.; Johnson, M.; Burns, F.; Chaloner, C.; Lazzarin, A.; Poli, A.; Sonnerborg, A.; Falconer, K.; Svedhem, V.; Gunthard, H.; Ledergerber, B.; Bucher, H.; Scherrer, A.; Wasmuth, J. C.; Rockstroh, J.; Fatkenheuer, G.; Stecher, M.; Schulze, N.; Franke, B.; Ryom, L.; Rooney, J.; Mcnicholl, I.; Vannappagari, V.; Wandeler, G.; Lundgren, J.; Kowalska, J.; Raben, D.; Mocroft, A.; Peters, L.; Williams, E. D.; Necsoi, C.; D'Arminio Monforte, A.; Bruguera, A.; Dedes, N.; Mendao, L.; Larsen, J. F.; Jaschinski, N.; Jakobsen, M. L.; Bruun, T.; Bojesen, A.; Hansen, E. V.; Traytel, A. K.; Elsing, T. W.; Kristensen, D.; Weide, T.; Bansi-Matharu, L.; Pelchen-Matthews, A.
abstract

Objective: To compare the incidence of hypertension in people living with HIV receiving integrase strand transfer inhibitor (INSTI)-based antiretroviral therapy (ART) versus non-nucleoside reverse transcriptase inhibitors (NNRTIs) or boosted protease inhibitors (PIs) in the RESPOND consortium of HIV cohorts. Methods: Eligible people with HIV were aged ≥18 years who initiated a new three-drug ART regimen for the first time (baseline), did not have hypertension, and had at least two follow-up blood pressure (BP) measurements. Hypertension was defined as two consecutive systolic BP measurements ≥140 mmHg and/or diastolic BP ≥90 mmHg or initiation of antihypertensives. Multivariable Poisson regression was used to determine adjusted incidence rate ratios (aIRRs) of hypertension, overall and in those who were ART naïve or experienced at baseline. Results: Overall, 4606 people living with HIV were eligible (INSTIs 3164, NNRTIs 807, PIs 635). The median baseline systolic BP, diastolic BP, and age were 120 (interquartile range [IQR] 113–130) mmHg, 78 (70–82) mmHg, and 43 (34–50) years, respectively. Over 8380.4 person-years (median follow-up 1.5 [IQR 1.0–2.7] years), 1058 (23.0%) participants developed hypertension (incidence rate 126.2/1000 person-years, 95% confidence interval [CI] 118.9–134.1). Participants receiving INSTIs had a higher incidence of hypertension than those receiving NNRTIs (aIRR 1.76; 95% CI 1.47–2.11), whereas the incidence was no different in those receiving PIs (aIRR 1.07; 95% CI 0.89–1.29). The results were similar when the analysis was stratified by ART status at baseline. Conclusion: Although unmeasured confounding and channelling bias cannot be excluded, INSTIs were associated with a higher incidence of hypertension than were NNRTIs, but rates were similar to those of PIs overall, in ART-naïve and ART-experienced participants within RESPOND.

2022 - Integrase Strand Transfer Inhibitor Use and Cancer Incidence in a Large Cohort Setting [Articolo su rivista]
Greenberg, L.; Ryom, L.; Neesgaard, B.; Miro, J. M.; Dahlerup Rasmussen, L.; Zangerle, R.; Grabmeier-Pfistershammer, K.; Gunthard, H. F.; Kusejko, K.; Smith, C.; Mussini, C.; Menozzi, M.; Wit, F.; Van Der Valk, M.; D'Arminio Monforte, A.; De Wit, S.; Necsoi, C.; Pelchen-Matthews, A.; Lundgren, J.; Peters, L.; Castagna, A.; Muccini, C.; Vehreschild, J. J.; Pradier, C.; Bruguera Riera, A.; Sonnerborg, A.; Petoumenos, K.; Garges, H.; Rogatto, F.; Dedes, N.; Bansi-Matharu, L.; Mocroft, A.
abstract

Background: Limited data exist examining the association between incident cancer and cumulative integrase inhibitor (INSTI) exposure. Methods: Participants were followed from baseline (latest of local cohort enrollment or January 1, 2012) until the earliest of first cancer, final follow-up, or December 31, 2019. Negative binomial regression was used to assess associations between cancer incidence and time-updated cumulative INSTI exposure, lagged by 6 months. Results: Of 29 340 individuals, 74% were male, 24% were antiretroviral treatment (ART)-naive, and median baseline age was 44 years (interquartile range [IQR], 36-51). Overall, 13 950 (48%) individuals started an INSTI during follow-up. During 160 657 person-years of follow-up ([PYFU] median 6.2; IQR, 3.9-7.5), there were 1078 cancers (incidence rate [IR] 6.7/1000 PYFU; 95% confidence interval [CI], 6.3-7.1). The commonest cancers were non-Hodgkin lymphoma (n=113), lung cancer (112), Kaposi's sarcoma (106), and anal cancer (103). After adjusting for potential confounders, there was no association between cancer risk and INSTI exposure (≤6 months vs no exposure IR ratio: 1.15 [95% CI, 0.89-1.49], >6-12 months; 0.97 [95% CI, 0.71-1.32], >12-24 months; 0.84 [95% CI, 0.64-1.11], >24-36 months; 1.10 [95% CI, 0.82-1.47], >36 months; 0.90 [95% CI, 0.65-1.26] [P=.60]). In ART-naive participants, cancer incidence decreased with increasing INSTI exposure, mainly driven by a decreasing incidence of acquired immune deficiency syndrome cancers; however, there was no association between INSTI exposure and cancer for those ART-experienced (interaction P<.0001). Conclusions: Cancer incidence in each INSTI exposure group was similar, despite relatively wide CIs, providing reassuring early findings that increasing INSTI exposure is unlikely to be associated with an increased cancer risk, although longer follow-up is needed to confirm this finding.

2022 - Is It Possible to Eradicate Carbapenem-Resistant Acinetobacter baumannii (CRAB) from Endemic Hospitals? [Articolo su rivista]
Medioli, Filippo; Bacca, Erica; Faltoni, Matteo; Burastero, Giulia Jole; Volpi, Sara; Menozzi, Marianna; Orlando, Gabriella; Bedini, Andrea; Franceschini, Erica; Mussini, Cristina; Meschiari, Marianna
abstract

Despite the global efforts to antagonize carbapenem-resistant Acinetobacter baumannii (CRAB) spreading, it remains an emerging threat with a related mortality exceeding 40% among critically ill patients. The purpose of this review is to provide evidence concerning the best infection prevention and control (IPC) strategies to fight CRAB spreading in endemic hospitals.

2022 - Long-Term Impact of the COVID-19 Pandemic on In-Hospital Antibiotic Consumption and Antibiotic Resistance: A Time Series Analysis (2015-2021) [Articolo su rivista]
Meschiari, Marianna; Onorato, Lorenzo; Bacca, Erica; Orlando, Gabriella; Menozzi, Marianna; Franceschini, Erica; Bedini, Andrea; Cervo, Adriana; Santoro, Antonella; Sarti, Mario; Venturelli, Claudia; Biagioni, Emanuela; Coloretti, Irene; Busani, Stefano; Girardis, Massimo; Lòpez-Lozano, José-María; Mussini, Cristina
abstract

The coronavirus disease 2019 (COVID-19)-pandemic-related overload of health systems has compromised the application of antimicrobial stewardship (AS) models and infection prevention and control (IPC) programs. We aimed to evaluate the impact of COVID-19 on antimicrobial consumption (AC) and antimicrobial resistance (AMR) in the University Hospital of Modena. A time series analysis with an autoregressive integrated moving average model was conducted from January 2015 to October 2021 to evaluate the AC in the whole hospital and the intensive care unit (ICU), the incidence density (ID) of bloodstream infections (BSIs) due to the main multidrug-resistant organisms, and of C. difficile infections (CDIs). After an initial peak during the COVID-19 period, a decrease in the trend of AC was observed, both at the hospital (CT: -1.104, p = 0.025) and ICU levels (CT: -4.47, p = 0.047), with no significant difference in the single classes. Among the Gram-negative isolates, we observed a significant increase only in the level of BSIs due to carbapenem-susceptible Pseudomonas aeruginosa (CL: 1.477, 95% CI 0.130 to 2.824, p = 0.032). Considering Gram-positive bacteria, an increase in the level of BSIs due to methicillin-resistant Staphylococcus aureus and in the trend of CDIs were observed, though they did not reach statistical significance (CL: 0.72, 95% CI -0.039 to 1.48, p = 0.062; CT: 1.43, 95% CI -0.002 to 2.863, p = 0.051; respectively). Our findings demonstrated that the increases in AMR and AC that appeared in the first COVID-19 wave may be later controlled by restoring IPC and AS programs to pre-epidemic levels. A coordinated healthcare effort is necessary to address the longer-term impact of COVID-19 on AC to avoid irreversible consequences on AMR.

2022 - Machine learning algorithm to predict >5% Weight Gain in PWH switching to InSTI [Abstract in Atti di Convegno]
Guaraldi, Giovanni; Motta, Federico; Milić, Jovana; Barbieri, Sara; Gozzi, Licia; Aprile, Emanuele; Belli, Michela; Venuta, Maria; Cuomo, Gianluca; Carli, Federica; Dolci, Giovanni; Iadisernia, Vittorio; Burastero, Giulia; Mussini, Cristina; Mandreoli, Federica
abstract

2022 - Machine learning algorithm to predict >5% weight gain in PWH switching to INSTI [Poster]
Guaraldi, Giovanni; Motta, Federico; Milić, Jovana; Barbieri, Sara; Gozzi, Licia; Aprile, Emanuele; Belli, Michela; Venuta, Maria; Cuomo, Gianluca; Carli, Federica; Dolci, Giovanni; Iadisernia, Vittorio; Burastero, Giulia; Mussini, Cristina; Mandreoli, Federica
abstract

Background: Weight gain (WG) is a well-described phenomenon in PWH starting or switching ART. Machine learning (ML) methods is a tool of P4 medicine (Predictive, Preventive, Personalized & Participatory) and can generate models to identify patients at risk of WG. The objective was to develop an ML algorithm that predicts a 9-month WG≥5% in PLWH switching to InSTI with/without TAF. Methods: This was an observational study that comprised ART-experienced PWH attending Modena HIV metabolic clinic from 2004 to 2020. The patients' medical, HIV and ART data were partitioned in an 80/20 training/test set to generate predictive models. A ML model was used to leverage a hybrid approach where clinical expertise is applied along with data-driven analysis. The study outcome was the prediction at 9 months of weight change with a cut of 5%: at any patient visit (model 1) and in the subset of PWH switching to InSTI with/without TAF (model 2). 9-month prediction was chosen as being the minimum time occurring between any two given visits in the 95% of the cases. A robust implementation of linear regressor algorithms were able to predict weight gain/loss while tolerating missing data. Intelligible explanations were obtained through Shapley Additive exPlanations values (SHAP), which quantified the positive or negative impact of each variable included in each model on the predicted outcome. A measure of effectiveness (E-measure) was chosen as a performance metric, because unlike accuracy it can penalize errors, particularly underestimation ones. Results: A total of 2817 patients contributed to generate 10877 observations, which allowed construction of 2 predictive models based on 44-variables including anthropometric, HIV and laboratory biomarkers. At last observation median age was 51 years (IQR 11); 70% were male. Median CD4 nadir was 200 cells/μL (IQR 217), current CD4 was 659 cells/μL (IQR 372), 97% had undetectable VL and time since HIV diagnosis was 20 years (IQR 13). Median BMI was 23.4 (IQR 4.5) and 5.8% had obesity. The highest ranked variables used to train the models were weight at time of prediction and the ones depicted in the figure. Model 1 had accuracy of 84.4% and 83.9% E-measure; model 2 had accuracy of 84.4% and 86.4% E-measure. Conclusion: We developed a ML tool with a remarkable E-measure that may assist clinicians in decision-making and shift HIV care towards a P4 medicine. Immune-metabolic variables were more relevant than ART switching in the prediction of WG.

2022 - Machine learning algorithm to predict weight change in ART experienced PWH [Abstract in Atti di Convegno]
Motta, Federico; Milić, Jovana; Barbieri, Sara; Gozzi, Licia; Aprile, Emanuele; Belli, Michela; Venuta, Maria; Cuomo, Gianluca; Carli, Federica; Dolci, Giovanni; Iadisernia, Vittorio; Burastero, Giulia; Mussini, Cristina; Mandreoli, Federica; Guaraldi, Giovanni
abstract

2022 - Metabolic reprograming shapes neutrophil functions in severe COVID-19 [Articolo su rivista]
Borella, Rebecca; De Biasi, Sara; Paolini, Annamaria; Boraldi, Federica; Tartaro, Domenico Lo; Mattioli, Marco; Fidanza, Lucia; Neroni, Anita; Caro-Maldonado, Alfredo; Meschiari, Marianna; Franceschini, Erica; Quaglino, Daniela; Guaraldi, Giovanni; Bertoldi, Carlo; Sita, Marco; Busani, Stefano; Girardis, Massimo; Mussini, Cristina; Cossarizza, Andrea; Gibellini, Lara
abstract

: To better understand the mechanisms at the basis of neutrophil functions during SARS-CoV-2 we studied patients with severe COVID-19 pneumonia. They had high blood proportion of degranulated neutrophils and elevated plasma levels of myeloperoxidase (MPO), elastase and MPO-DNA complexes, which are typical markers of neutrophil extracellular traps (NET). Their neutrophils display dysfunctional mitochondria, defective oxidative burst, increased glycolysis, glycogen accumulation in the cytoplasm, and increase glycogenolysis. Hypoxia-inducible factor 1α (ΗΙF-1α) is stabilized in such cells, and it controls the level of glycogen phosphorylase L (PYGL), a key enzyme in glycogenolysis. Inhibiting PYGL abolishes the ability of neutrophils to produce NET. Patients displayed significant increases of plasma levels of molecules involved in the regulation of neutrophils' function, including CCL2, CXCL10, CCL20, IL-18, IL-3, IL-6, G-CSF, GM-CSF, IFN-γ. Our data suggest that metabolic remodelling is vital for the formation of NET and for boosting neutrophil inflammatory response, thus suggesting that modulating ΗΙF-1α or PYGL could represent a novel approach for innovative therapies. This article is protected by copyright. All rights reserved.

2022 - Metabolic-Associated Fatty Liver Disease Is Highly Prevalent in the Postacute COVID Syndrome. [Articolo su rivista]
Milic, J; Barbieri, S; Gozzi, L; Brigo, A; Beghe', B; Verduri, A; Bacca, E; Iadisernia, V; Cuomo, G; Dolci, G; Yaacoub, D; Aprile, E; Belli, M; Venuta, M; Meschiari, M; Sebastiani, G; Clini, E; Mussini, C; Lonardo, A; Guaraldi, G; Raggi, P.
abstract

Background: A proposal has recently been advanced to change the traditional definition of nonalcoholic fatty liver disease to metabolic-associated fatty liver disease (MAFLD), to reflect the cluster of metabolic abnormalities that may be more closely associated with cardiovascular risk. Long coronavirus disease 2019 (COVID-19) is a smoldering inflammatory condition, characterized by several symptom clusters. This study aims to determine the prevalence of MAFLD in patients with postacute COVID syndrome (PACS) and its association with other PACS-cluster phenotypes. Methods: We included 235 patients observed at a single university outpatient clinic. The diagnosis of PACS was based on ≥1 cluster of symptoms: respiratory, neurocognitive, musculoskeletal, psychological, sensory, and dermatological. The outcome was prevalence of MAFLD detected by transient elastography during the first postdischarge follow-up outpatient visit. The prevalence of MAFLD at the time of hospital admission was calculated retrospectively using the hepatic steatosis index. Results: Of 235 patients, 162 (69%) were men (median age 61). The prevalence of MAFLD was 55.3% at follow-up and 37.3% on admission (P < .001). Insulin resistance (odds ratio [OR] = 1.5; 95% confidence interval [CI], 1.14-1.96), body mass index (OR = 1.14; 95% CI, 1.04-1.24), and the metabolic syndrome (OR = 2.54; 95% CI, 1.13-5.68) were independent predictors of MAFLD. The number of PACS clusters was inversely associated with MAFLD (OR = 0.86; 95% CI, .76-0.97). Thirty-one patients (13.2%) had MAFLD with no other associated PACS clusters. All correlations between MAFLD and other PACS clusters were weak. Conclusions: Metabolic-associated fatty liver disease was highly prevalent after hospital discharge and may represent a specific PACS-cluster phenotype, with potential long-term metabolic and cardiovascular health implications.

2022 - Molecular and cellular immune features of aged patients with severe COVID-19 pneumonia [Articolo su rivista]
Lo Tartaro, D.; Neroni, A.; Paolini, A.; Borella, R.; Mattioli, M.; Fidanza, L.; Quong, A.; Petes, C.; Awong, G.; Douglas, S.; Lin, D.; Nieto, J.; Gozzi, L.; Franceschini, E.; Busani, S.; Nasi, M.; Mattioli, A. V.; Trenti, T.; Meschiari, M.; Guaraldi, G.; Girardis, M.; Mussini, C.; Gibellini, L.; Cossarizza, A.; De Biasi, S.
abstract

Aging is a major risk factor for developing severe COVID-19, but few detailed data are available concerning immunological changes after infection in aged individuals. Here we describe main immune characteristics in 31 patients with severe SARS-CoV-2 infection who were >70 years old, compared to 33 subjects <60 years of age. Differences in plasma levels of 62 cytokines, landscape of peripheral blood mononuclear cells, T cell repertoire, transcriptome of central memory CD4+ T cells, specific antibodies are reported along with features of lung macrophages. Elderly subjects have higher levels of pro-inflammatory cytokines, more circulating plasmablasts, reduced plasmatic level of anti-S and anti-RBD IgG3 antibodies, lower proportions of central memory CD4+ T cells, more immature monocytes and CD56+ pro-inflammatory monocytes, lower percentages of circulating follicular helper T cells (cTfh), antigen-specific cTfh cells with a less activated transcriptomic profile, lung resident activated macrophages that promote collagen deposition and fibrosis. Our study underlines the importance of inflammation in the response to SARS-CoV-2 and suggests that inflammaging, coupled with the inability to mount a proper anti-viral response, could exacerbate disease severity and the worst clinical outcome in old patients.

2022 - Monkeypox Virus Infection in Humans across 16 Countries - April-June 2022 [Articolo su rivista]
Thornhill, John P; Barkati, Sapha; Walmsley, Sharon; Rockstroh, Juergen; Antinori, Andrea; Harrison, Luke B; Palich, Romain; Nori, Achyuta; Reeves, Iain; Habibi, Maximillian S; Apea, Vanessa; Boesecke, Christoph; Vandekerckhove, Linos; Yakubovsky, Michal; Sendagorta, Elena; Blanco, Jose L; Florence, Eric; Moschese, Davide; Maltez, Fernando M; Goorhuis, Abraham; Pourcher, Valerie; Migaud, Pascal; Noe, Sebastian; Pintado, Claire; Maggi, Fabrizio; Hansen, Ann-Brit E; Hoffmann, Christian; Lezama, Jezer I; Mussini, Cristina; Cattelan, Annamaria; Makofane, Keletso; Tan, Darrell; Nozza, Silvia; Nemeth, Johannes; Klein, Marina B; Orkin, Chloe M
abstract

BackgroundBefore April 2022, monkeypox virus infection in humans was seldom reported outside African regions where it is endemic. Currently, cases are occurring worldwide. Transmission, risk factors, clinical presentation, and outcomes of infection are poorly defined. MethodsWe formed an international collaborative group of clinicians who contributed to an international case series to describe the presentation, clinical course, and outcomes of polymerase-chain-reaction-confirmed monkeypox virus infections. ResultsWe report 528 infections diagnosed between April 27 and June 24, 2022, at 43 sites in 16 countries. Overall, 98% of the persons with infection were gay or bisexual men, 75% were White, and 41% had human immunodeficiency virus infection; the median age was 38 years. Transmission was suspected to have occurred through sexual activity in 95% of the persons with infection. In this case series, 95% of the persons presented with a rash (with 64% having <10 lesions), 73% had anogenital lesions, and 41% had mucosal lesions (with 54 having a single genital lesion). Common systemic features preceding the rash included fever (62%), lethargy (41%), myalgia (31%), and headache (27%); lymphadenopathy was also common (reported in 56%). Concomitant sexually transmitted infections were reported in 109 of 377 persons (29%) who were tested. Among the 23 persons with a clear exposure history, the median incubation period was 7 days (range, 3 to 20). Monkeypox virus DNA was detected in 29 of the 32 persons in whom seminal fluid was analyzed. Antiviral treatment was given to 5% of the persons overall, and 70 (13%) were hospitalized; the reasons for hospitalization were pain management, mostly for severe anorectal pain (21 persons); soft-tissue superinfection (18); pharyngitis limiting oral intake (5); eye lesions (2); acute kidney injury (2); myocarditis (2); and infection-control purposes (13). No deaths were reported. ConclusionsIn this case series, monkeypox manifested with a variety of dermatologic and systemic clinical findings. The simultaneous identification of cases outside areas where monkeypox has traditionally been endemic highlights the need for rapid identification and diagnosis of cases to contain further community spread.Clinical Features of Monkeypox in HumansIn this report, 528 cases of monkeypox across 16 countries are described. Rash, mucosal lesions, fever, lethargy, and lymphadenopathy were common clinical findings. Few patients were hospitalized.

2022 - Monkeypox vaccination—an opportunity for HIV prevention [Articolo su rivista]
Mussini, Cristina; Guaraldi, Giovanni; Orkin, Chloe
abstract

2022 - Non-B subtypes account for a large proportion of clustered primary HIV-1 infections in Italy [Articolo su rivista]
Bozzi, Giorgio; Fabeni, Lavinia; Abbate, Isabella; Berno, Giulia; Muscatello, Antonio; Taramasso, Lucia; Fabbiani, Massimiliano; Nozza, Silvia; Tambussi, Giuseppe; Rusconi, Stefano; Giacomelli, Andrea; Focà, Emanuele; Pinnetti, Carmela; D'Ettorre, Gabriella; Mussini, Cristina; Borghi, Vanni; Celesia, Benedetto Maurizio; Madeddu, Giordano; Di Biagio, Antonio; Ripamonti, Diego; Squillace, Nicola; Antinori, Andrea; Gori, Andrea; Capobianchi, Maria Rosaria; Bandera, Alessandra
abstract

Objectives and design Using pol sequences obtained for routine resistance testing, we characterised the molecular patterns of HIV-1 transmission and factors associated with being part of a transmission cluster among individuals who in 2008-2014 presented with primary HIV-1 infection (PHI) at 11 urban centres across Italy. Methods Pol sequences were obtained by Sanger sequencing. Transmission clusters were identified by phylogenetic analysis (maximum likelihood method, confirmed by Bayesian analysis). Multivariable logistic regression explored factors associated with a participant being part of a transmission cluster. Results The PHI cohort comprised 186 participants (159/186, 85.5% males) with median age 44 years, median CD4 count 464 cells/mm(3) and median plasma HIV-1 RNA 5.6 log(10) copies/mL. Drug resistance associated mutations were found in 16/186 (8.6%). A diversity of non-B subtypes accounted for 60/186 (32.3%) of all infections. A total of 17 transmission clusters were identified, including 44/186 (23.7%) participants. Each cluster comprised 2-6 sequences. Non-B subtypes accounted for seven clusters and 22/44 (50%) of clustered sequences. In multivariable logistic regression analysis, factors associated with being part of a transmission cluster comprised harbouring a non-B subtype (adjusted OR (adjOR) 2.28; 95% CI 1.03 to 5.05; p=0.04) and showing a lower plasma HIV-1 RNA (adjOR 0.80, 95% CI 0.64 to 0.99; p=0.04). Conclusions There was a large contribution of diverse non-B subtypes to transmission clusters among people presenting with acute or recent HIV-1 infection in this cohort, illustrating the evolving dynamics of the HIV-1 epidemic in Italy, where subtype B previously dominated.

2022 - Non-alcoholic to metabolic associated fatty liver disease: Cardiovascular implications of a change in terminology in patients living with HIV [Abstract in Atti di Convegno]
Raggi, Paolo; Milić, Jovana; Renzetti, Stefano; Motta, Federico; Gozzi, Licia; Cervo, Adriana; Burastero, Giulia; Iadisernia, Vittorio; Franceschi, Giacomo; Faltoni, Matteo; Mussini, Cristina; Sebastiani, Giada; Calza, Stefano; Guaraldi, Giovanni
abstract

Background and Aims: It has recently been suggested that the definition of non-alcoholic fatty liver disease (NAFLD) be changed to Metabolic Associated FLD (MAFLD) to better reflect the complex metabolic aspects of this syndrome. We compared the ability of MAFLD and NAFLD to correctly identify high CV risk patients, sub-clinical atherosclerosis or a history of prior CV events (CVEs) in patients living with HIV (PWH). Methods: Single center, cross-sectional study of PWH on stable anti-retrovirals. NAFLD was diagnosed by transient liver elastography; published criteria were used to diagnose MAFLD (JHepatol.2020;73(1):202-209). Four mutually exclusive groups were considered: low (<7.5%) vs high (>7.5%) ASCVD risk, subclinical CVD (carotid IMT ≥1 mm and/or coronary calcium score >100), and prior CVEs. The association of NAFLD and MAFLD with the CVD risk groups was explored via a multinominal model adjusted for age, sex, liver fibrosis, HIV duration, nadir CD4 and current CD4 cell count. Results: We included 1249 PWH (mean age 55 years, 74% men, median HIV duration 24 years). Prevalence of overweight/obesity and diabetes was 40% and 18%. Prevalence of NAFLD and MAFLD and overlapping groups are shown in Fig 1A. Fig 1B shows distribution of NAFLD/MAFLD in the 4 patient categories (p-for-trend <0.001). Both MAFLD and NAFLD were significantly associated with an increased risk of CVD compared to the reference level (ASCVD<7.5%) (all p-values <0.004; Fig 2). Conclusions: NAFLD and MAFLD perform equally in detecting CVD or its risk. The proposed change in terminology may not help to identify PWH requiring enhanced surveillance and preventative interventions for cardiovascular disease.

2022 - Non–alcoholic to metabolic associated fatty liver disease: cardiovascular implications of a change in terminology in patients living with HIV [Abstract in Atti di Convegno]
Milić, Jovana; Renzetti, Stefano; Motta, Federico; Gozzi, Licia; Cervo, Adriana; Burastero, Giulia; Iadisernia, Vittorio; Franceschi, Giacomo; Faltoni, Matteo; Volpi, Sara; Mazzocchi, Alice; Mussini, Cristina; Sebastiani, Giada; Calza, Stefano; Raggi, Paolo; Guaraldi, Giovanni
abstract

2022 - Patients Recovering from Severe COVID-19 Develop a Polyfunctional Antigen-Specific CD4+ T Cell Response [Articolo su rivista]
Paolini, A.; Borella, R.; Neroni, A.; Lo Tartaro, D.; Mattioli, M.; Fidanza, L.; Di Nella, A.; Santacroce, E.; Gozzi, L.; Busani, S.; Trenti, T.; Meschiari, M.; Guaraldi, G.; Girardis, M.; Mussini, C.; Gibellini, L.; De Biasi, S.; Cossarizza, A.
abstract

Specific T cells are crucial to control SARS-CoV-2 infection, avoid reinfection and confer protection after vaccination. We have studied patients with severe or moderate COVID-19 pneumonia, compared to patients who recovered from a severe or moderate infection that had occurred about 4 months before the analyses. In all these subjects, we assessed the polyfunctionality of virus-specific CD4+ and CD8+ T cells by quantifying cytokine production after in vitro stimulation with different SARS-CoV-2 peptide pools covering different proteins (M, N and S). In particular, we quantified the percentage of CD4+ and CD8+ T cells simultaneously producing interferon-γ, tumor necrosis factor, interleukin (IL)-2, IL-17, granzyme B, and expressing CD107a. Recovered patients who experienced a severe disease display high proportions of antigen-specific CD4+ T cells producing Th1 and Th17 cytokines and are characterized by polyfunctional SARS-CoV-2-specific CD4+ T cells. A similar profile was found in patients experiencing a moderate form of COVID-19 pneumonia. No main differences in polyfunctionality were observed among the CD8+ T cell compartments, even if the proportion of responding cells was higher during the infection. The identification of those functional cell subsets that might influence protection can thus help in better understanding the complexity of immune response to SARS-CoV-2.

2022 - Plasma Cytokine Atlas Reveals the Importance of TH2 Polarization and Interferons in Predicting COVID-19 Severity and Survival [Articolo su rivista]
Gibellini, L.; De Biasi, S.; Meschiari, M.; Gozzi, L.; Paolini, A.; Borella, R.; Mattioli, M.; Lo Tartaro, D.; Fidanza, L.; Neroni, A.; Busani, S.; Girardis, M.; Guaraldi, G.; Mussini, C.; Cozzi-Lepri, A.; Cossarizza, A.
abstract

Although it is now widely accepted that host inflammatory response contributes to COVID-19 immunopathogenesis, the pathways and mechanisms driving disease severity and clinical outcome remain poorly understood. In the effort to identify key soluble mediators that characterize life-threatening COVID-19, we quantified 62 cytokines, chemokines and other factors involved in inflammation and immunity in plasma samples, collected at hospital admission, from 80 hospitalized patients with severe COVID-19 disease who were stratified on the basis of clinical outcome (mechanical ventilation or death by day 28). Our data confirm that age, as well as neutrophilia, lymphocytopenia, procalcitonin, D-dimer and lactate dehydrogenase are strongly associated with the risk of fatal COVID-19. In addition, we found that cytokines related to TH2 regulations (IL-4, IL-13, IL-33), cell metabolism (lep, lep-R) and interferons (IFNα, IFNβ, IFNγ) were also predictive of life-threatening COVID-19.

2022 - Preferences of PLWH and of clinicians for HIV treatment aimed at long-term success [Articolo su rivista]
Andreoni, Massimo; Antinori, Andrea; Castagna, Antonella; D'Arminio Monforte, Antonella; Di Perri, Giovanni; Mastroianni, Claudio; Mussini, Cristina; Rizzardini, Giuliano; Tavio, Marcello; Nozza, Silvia; Teti, Elisabetta; Corbelli, Giulio Maria; Pasqualetti, Patrizio
abstract

: This study aimed to develop a new approach to manage people living with HIV (PLWH), investigating preferences of clinicians and PLWH in order to improve linkage to care of PLWH. A survey was performed with the Discrete Choice Experiment (DCE) method to investigate the preferences of two categories, clinicians and PLWH, for attributes of HIV care pathways, therapy and quality of life. Our results suggest that the most important feature of a care pathway was the site of testing for both categories, followed by modality of counselling for clinicians and by pre-exposure prophylaxis for PLWH. Regarding therapy, choices were mostly oriented by modality of administration for both categories, and by CD4 cells increase for clinicians and side effects for PLWH. People living with HIV reported that, out of 13 candidates, the two most important factors related to good long-term quality of life would be reduction of viral transmissibility and good emotional life. A tailored approach could be the key to long-term treatment success, but this approach must necessarily be based on evaluation of the specific complexities of the patient.

2022 - Real-Life Impact of Drug Toxicity on Dolutegravir Tolerability: Clinical Practice Data from a Multicenter Italian Cohort [Articolo su rivista]
Ciccullo, A.; Baldin, G.; Borghi, V.; Lagi, F.; Latini, A.; D'Ettorre, G.; Oreni, L.; Fusco, P.; Capetti, A.; Fabbiani, M.; Giacomelli, A.; Grimaldi, A.; Madeddu, G.; Sterrantino, G.; Mussini, C.; Di Giambenedetto, S.
abstract

Dolutegravir (DTG) is currently one of the most used Integrase inhibitors (INI) in antiretroviral therapies (ARV) in both naïve and experienced people living with HIV (PLWHIV). We analyzed a multicenter cohort of PLWHIV, both naïve and experienced, starting an ARV including DTG. We enrolled 3775 PLWHIV: 2763 (73.2%) were males, with a median age of 50 years. During 9890.7 PYFU, we observed 930 discontinuations (9.4 per 100 PYFU). Estimated probabilities of maintaining DTG at three and five years were 75.1% and 67.2%, respectively. Treatment-naïve pts showed a lower probability of maintaining DTG at three and five years compared to treatment-experienced PLWHIV (log-rank p < 0.001). At a multivariate analysis, a longer time of virological suppression (aHR 0.994, p < 0.001) and having experienced a previous virological failure (aHR 0.788, p = 0.016) resulted protective against DTG discontinuation. Most discontinuations (84.0%) happened within the first 12 months of DTG initiation, in particular, 92.2% of discontinuations due to neuropsychiatric toxicity were observed in the first year. Our data confirm the overall good tolerability of DTG in clinical practice, with a low rate of discontinuations. CNS toxicity resulted the main reason for DTG discontinuation, with most related interruptions happening in the first year from DTG introduction.

2022 - Relationship between weight gain and insulin resistance in people living with HIV switching to INSTI-based regimens [Articolo su rivista]
Milic, Jovana; Renzetti, Stefano; Ferrari, Davide; Barbieri, Sara; Menozzi, Marianna; Carli, Federica; Dolci, Giovanni; Ciusa, Giacomo; Mussini, Cristina; Calza, Stefano; Guaraldi, Giovanni
abstract

Objective: The primary objective was to explore weight and BMI changes in people with HIV (PWH) undergoing integrase strand transfer inhibitors (INSTI)-based regimens (vs. non-INSTI) in a large cohort and in the subsets of individuals without diabetes and insulin resistance (IR) at the time of switch to INSTI. The secondary objective was to identify risk factors for IR and cut-off of weight or BMI increase associated with IR in PWH switching to INSTI. Design: A longitudinal matched-cohort study including PWH attending Modena HIV Metabolic Clinic, Italy. Methods: PWH were divided into two groups: non-INSTI and INSTI-switch. The effect of switching to INSTI on weight and BMI change was tested through a linear mixed model. A mediation analysis explored the mediation effect of weight and BMI change in the association between the switch to INSTI and IR. Results: We analyzed 2437 PWH (1025 INSTI-switch, 1412 non-INSTI), in 54 826 weight assessments. Trends for weight increase were significantly higher in early-INSTI-switch (vs. early-non-INSTI), but no difference was observed in the late period after the switch. In the subset of 634 PWH without IR, switching to INSTI (vs. non-INSTI) was associated with a lower risk of IR (hazard ratio = 0.70, 95% confidence interval: 0.51, 0.98). A weight increase by 1% reduced the total protective effect of INSTI by 21.1% over 1 year of follow-up, which identifies a 5% weight increase as a clinically meaningful weight gain definition. Conclusion: A cut-off of 5% weight gain from the time of INSTI-switch is associated with IR, which may be a clinically meaningful endpoint to could be used in clinical and research settings.

2022 - Resilience and Frailty in People Living With HIV During the COVID Era: Two Complementary Constructs Associated With Health-Related Quality of Life [Articolo su rivista]
Guaraldi, Giovanni; Milic, Jovana; Barbieri, Sara; Marchiò, Tommaso; Caselgrandi, Agnese; Volpi, Sara; Aprile, Emanuele; Belli, Michela; Venuta, Maria; Mussini, Cristina
abstract

Background: Resilience is defined as an individual's positive adaptation to stressors. The COVID-19 pandemic represents a generalized stressor which may affect differently people living with HIV (PLWH). The objective of this study was to characterize resilience in PLWH with particular regarding the identification of frailty-resilience phenotypes, which may differently affect health-related quality of life (HR-QoL). Methods: This was an observational study of PLWH attending Modena HIV Metabolic Clinic. Frailty was assessed in 2019, before the onset of the COVID-19 pandemic by using 37-Item frailty index ranging from 0 to 1. The frailty index score was categorized as fit (<0.25) or frail (>0.25). In January 2021, PLWH were offered to complete a set of electronic questionnaires including the CD-RISC-25 for resilience and EQ-5D5L and SF-36 for HR-QoL. Resilience was defined as CD-RISC-25 score >75.7 (ranging from 0 to 100). Results: Of 800 PLWH reached by mail, 575 (72%) completed the questionnaires. The median age and HIV duration were 54.5 and 24.3 years, respectively. Impaired resilience was associated with loneliness [odds ratio (OR = 2.39; 1.20 to 4.76, P < 0.001)]. Predictors for EQ-5D5L <89.7% were the phenotypes "frail/nonresilient" [OR = 5.21, 95% confidence interval (CI): 2.62 to 10.33] and "fit/nonresilient" (OR = 5.48, 95% CI: 2.8 to 10.74). Predictors for SF-36 <64.40 were the phenotypes "frail/nonresilient" (OR = 7.43, 95% CI: 2.57 to 21.22) and "fit/nonresilient" (OR = 6.27, 95% CI: 2.17 to 18.16). Both models were corrected for age, sex, HIV duration, and nadir CD4. Conclusions: Resilience characterizes the well-being of PLWH during the COVID-19 crisis. This construct is complementary to frailty in the identification of clinical phenotypes with different impacts on HR-QoL.

2022 - Risk factors for pulmonary air leak and clinical prognosis in patients with COVID-19 related acute respiratory failure: a retrospective matched control study. [Articolo su rivista]
Tonelli, Roberto; Bruzzi, Giulia; Manicardi, Linda; Tabbì, Luca; Fantini, Riccardo; Castaniere, Ivana; Andrisani, Dario; Gozzi, Filippo; Rosaria Pellegrino, Maria; Trentacosti, Fabiana; Dall'Ara, Lorenzo; Busani, Stefano; Franceschini, Erica; Baroncini, Serena; Manco, Gianrocco; Meschiari, Marianna; Mussini, Cristina; Girardis, Massimo; Beghe', Bianca; Marchioni, Alessandro; Clini, Enrico
abstract

Background- The role of excessive inspiratory effort in promoting alveolar and pleural rupture resulting in air leak (AL) in patients with SARS-CoV-2 induced acute respiratory failure (ARF) while on spontaneous breathing is undetermined. Methods- Among all patients with COVID-19 related ARF admitted to a respiratory intensive care unit (RICU) and receiving non-invasive respiratory support, those developing an AL were and matched 1:1 (by means of PaO2/FiO2 ratio, age, body mass index-BMI and subsequent organ failure assessment [SOFA]) with a comparable population who did not (NAL group). Esophageal pressure (ΔPes) and dynamic transpulmonary pressure (ΔPL) swings were compared between groups. Risk factors affecting AL onset were evaluated. The composite outcome of ventilator-free-days (VFD) at day 28 (including ETI, mortality, tracheostomy) was compared between groups. Results- AL and NAL groups (n=28) showed similar ΔPes, whereas AL had higher ΔPL (20 [16‐21] and 17 [11‐20], p=0.01 respectively). Higher ΔPL (OR=1.5 95%CI[1‐1.8], p=0.01), positive end‐expiratory pressure (OR=2.4 95%CI[1.2‐5.9], p=0.04) and pressure support (OR=1.8 95%CI[1.1-3.5], p=0.03), D-dimer on admission (OR=2.1 95%CI[1.3-9.8], p=0.03), and features suggestive of consolidation on computed tomography scan (OR=3.8 95%CI[1.1-15], p= 0.04) were all significantly associated with AL. A lower VFD score resulted in a higher risk (HR=3.7 95%CI [1.2-11.3], p=0.01) in the AL group compared with NAL. RICU stay and 90-day mortality were also higher in the AL group compared with NAL. Conclusions- In spontaneously breathing patients with COVID‐19 related ARF, higher levels of ΔPL, blood D‐dimer, NIV delivery pressures and a consolidative lung pattern were associated with AL onset.

2022 - Signals were broadly positive for months, but never definitive: the tocilizumab story [Articolo su rivista]
Cozzi-Lepri, Alessandro; Smith, Colette; Mussini, Cristina
abstract

Most COVID-19 treatment guidelines currently recommend tocilizumab in combination with dexamethasone in critically ill patients who are exhibiting rapid respiratory decompensation.

2022 - The contribution of late HIV diagnosis on the occurrence of HIV-associated tuberculosis: a 5-year estimate using real-world data [Articolo su rivista]
Girardi, Enrico; Caro-Vega, Yanink; Cozzi-Lepri, Alessandro; Musaazi, Joseph; Carriquiry, Gabriela; Castelnuovo, Barbara; Gori, Andrea; Manabe, Yukari C; Gotuzzo, José Eduardo; D'arminio Monforte, Antonella; Crabtree-Ramírez, Brenda; Mussini, Cristina
abstract

To describe the timing of tuberculosis (TB) presentation in relation to diagnosis of HIV infection and antiretroviral therapy (ART) initiation and to evaluate whether the established impact from late presentation to care and late initiation of ART on the risk of TB is retained beyond the observation period of clinical trials.

2022 - The interplay of post-acute COVID-19 syndrome and aging: a biological, clinical and public health approach [Articolo su rivista]
Guaraldi, Giovanni; Milic, Jovana; Cesari, Matteo; Leibovici, Leonard; Mandreoli, Federica; Missier, Paolo; Rozzini, Renzo; Cattelan, Anna Maria; Motta, Federico; Mussini, Cristina; Cossarizza, Andrea
abstract

The post-acute COVID-19 syndrome (PACS) is characterized by the persistence of fluctuating symptoms over three months from the onset of the possible or confirmed COVID-19 acute phase. Current data suggests that at least 10% of people with previously documented infection may develop PACS, and up to 50-80% of prevalence is reported among survivors after hospital discharge. This viewpoint will discuss various aspects of PACS, particularly in older adults, with a specific hypothesis to describe PACS as the expression of a modified aging trajectory induced by SARS CoV-2. This hypothesis will be argued from biological, clinical and public health view, addressing three main questions: (i) does SARS-CoV-2-induced alterations in aging trajectories play a role in PACS?; (ii) do people with PACS face immuno-metabolic derangements that lead to increased susceptibility to age-related diseases?; (iii) is it possible to restore the healthy aging trajectory followed by the individual before pre-COVID?. A particular focus will be given to the well-being of people with PACS that could be assessed by the intrinsic capacity model and support the definition of the healthy aging trajectory.

2022 - The pathway of NAFLD vs MAFLD toward significant fibrosis [Abstract in Atti di Convegno]
Milić, Jovana; Renzetti, Stefano; Motta, Federico; Gozzi, Licia; Besutti, Giulia; Burastero, Giulia; Iadisernia, Vittorio; Dessilani, Andrea; Del Monte, Martina; Faltoni, Matteo; Volpi, Sara; Lebouche, Bertrand; Al Hinai, Shaima; Deschenes, Marc; Calza, Stefano; Raggi, Paolo; Mancini, Giuseppe; Mussini, Cristina; Sebastiani, Giada; Guaraldi, Giovanni
abstract

2022 - The pathway of NAFLD vs MAFLD toward significant fibrosis [Abstract in Atti di Convegno]
Milić, Jovana; Renzetti, Stefano; Motta, Federico; Gozzi, Licia; Besutti, Giulia; Burastero, Giulia; Iadisernia, Vittorio; Lebouché, Bertrand; Al Hinai, Shaima; Deschenes, Marc; Calza, Stefano; Mussini, Cristina; Sebastiani, Giada; Guaraldi, Giovanni
abstract

2022 - What have we learned from the first to the second wave of COVID-19 pandemic? An international survey from the ESCMID Study Group for Infection in the Elderly (ESGIE) group [Articolo su rivista]
Tiseo, G.; Yahav, D.; Paul, M.; Tinelli, M.; Gavazzi, G.; Mussini, C.; Prendki, V.; Falcone, M.
abstract

The purpose of this survey is to explore changes in the management of COVID-19 during the first versus the second wave, with particular emphasis on therapies, antibiotic prescriptions, and elderly care. An internet-based questionnaire survey was distributed to European Society of Clinical Microbiology and Infectious Diseases (ESCMID) members. Therapeutic approach to patients with mild-to-moderate (PiO2/FiO2 200–350) and severe (PiO2/FiO2 < 200) COVID-19, antibiotic use, and reasons for excluding patients from the intensive care unit (ICU) were investigated. A total of 463 from 21 countries participated in the study. Most representatives were infectious disease specialists (68.3%). During the second wave of pandemic, physicians abandoned the use of hydroxychloroquine, lopinavir/ritonavir, and azithromycin in favor of dexamethasone, low-molecular weight heparin (LMWH), and remdesivir in mild-to-moderate COVID-19. In critically ill patients, we detected an increased use of high-dose steroids (51%) and a decrease in tocilizumab use. The use of antibiotics at hospital admission decreased but remained high in the second wave. Age was reported to be a main consideration for exclusion of patients from ICU care by 25% of responders; a third reported that elderly were not candidates for ICU admission in their center. The decision to exclude patients from ICU care was based on the individual decision of an intensivist in 59.6% of cases. The approach of physicians to COVID-19 changed over time following evidence accumulation and guidelines. Antibiotic use at hospital admission and decision to exclude patients from ICU care remain critical aspects that should be better investigated and harmonized among clinicians.

2022 - Whole-genome sequencing reveals host factors underlying critical COVID-19 [Articolo su rivista]
Kousathanas, A.; Pairo-Castineira, E.; Rawlik, K.; Stuckey, A.; Odhams, C. A.; Walker, S.; Russell, C. D.; Malinauskas, T.; Wu, Y.; Millar, J.; Shen, X.; Elliott, K. S.; Griffiths, F.; Oosthuyzen, W.; Morrice, K.; Keating, S.; Wang, B.; Rhodes, D.; Klaric, L.; Zechner, M.; Parkinson, N.; Siddiq, A.; Goddard, P.; Donovan, S.; Maslove, D.; Nichol, A.; Semple, M. G.; Zainy, T.; Maleady-Crowe, F.; Todd, L.; Salehi, S.; Knight, J.; Elgar, G.; Chan, G.; Arumugam, P.; Patch, C.; Rendon, A.; Bentley, D.; Kingsley, C.; Kosmicki, J. A.; Horowitz, J. E.; Baras, A.; Abecasis, G. R.; Ferreira, M. A. R.; Justice, A.; Mirshahi, T.; Oetjens, M.; Rader, D. J.; Ritchie, M. D.; Verma, A.; Fowler, T. A.; Shankar-Hari, M.; Summers, C.; Hinds, C.; Horby, P.; Mcauley, D.; Montgomery, H.; Openshaw, P. J. M.; Elliott, P.; Walsh, T.; Tenesa, A.; Fawkes, A.; Murphy, L.; Rowan, K.; Ponting, C. P.; Vitart, V.; Wilson, J. F.; Yang, J.; Bretherick, A. D.; Scott, R. H.; Hendry, S. C.; Moutsianas, L.; Law, A.; Caulfield, M. J.; Baillie, J. K.; Begg, C.; Ling, L.; Millar, J.; Pereira, A. C.; Aravindan, L.; Armstrong, R.; Biggs, H.; Boz, C.; Brown, A.; Clark, R.; Coutts, A.; Coyle, J.; Cullum, L.; Das, S.; Day, N.; Donnelly, L.; Duncan, E.; Finernan, P.; Fourman, M. H.; Furlong, A.; Furniss, J.; Gallagher, B.; Gilchrist, T.; Golightly, A.; Hafezi, K.; Hamilton, D.; Hendry, R.; Law, D.; Law, R.; Law, S.; Lidstone-Scott, R.; Macgillivray, L.; Maclean, A.; Mal, H.; Mccafferty, S.; Mcmaster, E.; Meikle, J.; Moore, S. C.; Murphy, S.; Hellen, M.; Zheng, C.; Chen, J.; Paterson, T.; Schon, K.; Stenhouse, A.; Das, M.; Swets, M.; Szoor-McElhinney, H.; Taneski, F.; Turtle, L.; Wackett, T.; Ward, M.; Weaver, J.; Wrobel, N.; Arbane, G.; Bociek, A.; Campos, S.; Grau, N.; Jones, T. O.; Lim, R.; Marotti, M.; Ostermann, M.; Whitton, C.; Alldis, Z.; Astin-Chamberlain, R.; Bibi, F.; Biddle, J.; Blow, S.; Bolton, M.; Borra, C.; Bowles, R.; Burton, M.; Choudhury, Y.; Collier, D.; Cox, A.; Easthope, A.; Ebano, P.; Fotiadis, S.; Gurasashvili, J.; Halls, R.; Hartridge, P.; Kallon, D.; Kassam, J.; Lancoma-Malcolm, I.; Matharu, M.; May, P.; Mitchelmore, O.; Newman, T.; Patel, M.; Pheby, J.; Pinzuti, I.; Prime, Z.; Prysyazhna, O.; Shiel, J.; Taylor, M.; Tierney, C.; Wood, S.; Zak, A.; Zongo, O.; Bonner, S.; Hugill, K.; Jones, J.; Liggett, S.; Headlam, E.; Bandla, N.; Gellamucho, M.; Davies, M.; Thompson, C.; Abdelrazik, M.; Bakthavatsalam, D.; Elhassan, M.; Ganesan, A.; Haldeos, A.; Moreno-Cuesta, J.; Purohit, D.; Vincent, R.; Xavier, K.; Kumar, R.; Frater, A.; Saleem, M.; Carter, D.; Jenkins, S.; Lamond, Z.; Wall, A.; Fernandez-Roman, J.; Hamilton, D. O.; Johnson, E.; Johnston, B.; Martinez, M. L.; Mulla, S.; Shaw, D.; Waite, A. A. C.; Waugh, V.; Welters, I. D.; Williams, K.; Cavazza, A.; Cockrell, M.; Corcoran, E.; Depante, M.; Finney, C.; Jerome, E.; Mcphail, M.; Nayak, M.; Noble, H.; O'Reilly, K.; Pappa, E.; Saha, R.; Saha, S.; Smith, J.; Knighton, A.; Antcliffe, D.; Banach, D.; Brett, S.; Coghlan, P.; Fernandez, Z.; Gordon, A.; Rojo, R.; Arias, S. S.; Templeton, M.; Meredith, M.; Morris, L.; Ryan, L.; Clark, A.; Sampson, J.; Peters, C.; Dent, M.; Langley, M.; Ashraf, S.; Wei, S.; Andrew, A.; Bashyal, A.; Davidson, N.; Hutton, P.; Mckechnie, S.; Wilson, J.; Baptista, D.; Crowe, R.; Fernandes, R.; Herdman-Grant, R.; Joseph, A.; O'Connor, D.; Allen, M.; Loveridge, A.; Mckenley, I.; Morino, E.; Naranjo, A.; Simms, R.; Sollesta, K.; Swain, A.; Venkatesh, H.; Khera, J.; Fox, J.; Andrew, G.; Barclay, L.; Callaghan, M.; Campbell, R.; Clark, S.; Hope, D.; Marshall, L.; Mcculloch, C.; Briton, K.; Singleton, J.; Birch, S.; Brimfield, L.; Daly, Z.; Pogson, D.; Rose, S.; Nown, A.; Battle, C.; Brinkworth, E.; Harford, R.; Murphy, C.; Newey, L.; Rees, T.; Williams, M.; Arnold, S.; Polgarova, P.; Stroud, K.; Meaney, E.; Jones, M.; Ng, A.; Agrawal, S.; Pathan, N.; White, D.; Daubney, E.; Elston, K.; Grauslyte, L.; Hussain, M.; Phull, M.; Pogreban, T.; Rosaroso, L.; Salciute, E.; Franke, G.; Wong, J.
abstract

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2–4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease.

2021 - A five-component infection control bundle to permanently eliminate a carbapenem-resistant Acinetobacter baumannii spreading in an intensive care unit [Articolo su rivista]
Meschiari, Marianna; Lòpez-Lozano, José-María; Di Pilato, Vincenzo; Gimenez-Esparza, Carola; Vecchi, Elena; Bacca, Erica; Orlando, Gabriella; Franceschini, Erica; Sarti, Mario; Pecorari, Monica; Grottola, Antonella; Venturelli, Claudia; Busani, Stefano; Serio, Lucia; Girardis, Massimo; Rossolini, Gian Maria; Gyssens, Inge C; Monnet, Dominique L; Mussini, Cristina
abstract

Carbapenem-resistant Acinetobacter baumannii (CRAB) infection outbreaks are difficult to control and sometimes require cohorting of CRAB-positive patients or temporary ward closure for environmental cleaning. We aimed at controlling the deadly 2018 CRAB outbreak in a 12 bed- intensive care unit (ICU) including 9 beds in a 220 m2 open space. We implemented a new multimodal approach without ward closure, cohorting or temporarily limiting admissions.

2021 - AKI in hospitalized patients with COVID-19: a single-center experience [Articolo su rivista]
Alfano, Gaetano; Giovanella, Silvia; Fontana, Francesco; Milic, Jovana; Ligabue, Giulia; Morisi, Niccolò; Giaroni, Francesco; Mori, Giacomo; Magistroni, Riccardo; Franceschini, Erica; Bedini, Andrea; Cuomo, Giacomo; Digaetano, Margherita; Meschiari, Marianna; Mussini, Cristina; Cappelli, Gianni; Guaraldi, Giovanni
abstract

2021 - Accuracy of the serological detection of IgG and IgM to SARS-Cov-2: a prospective, cross-sectional study [Articolo su rivista]
Pecoraro, V.; Cassetti, T.; Meacci, M.; Gargiulo, R.; Capobianchi, M. R.; Mussini, C.; Vecchi, E.; Pecorari, M.; Gagliotti, C.; Trenti, T.; Sarti, M.
abstract

In response to the rapidly evolving of SARS-CoV-2 infection, numerous serological tests have been developed but their sensitivity and specificity are unclear. We collected serum samples of patients and health-care professionals to assess the accuracy of chemiluminescent (CLIA) and two lateral flow immunochromatographic assays (LFIA) to determine IgG and IgM antibodies to SARS-CoV-2 virus. We calculated the φ correlation for qualitative results and test accuracy, adopting the following case definition: either real-time-PCR positivity or serological positivity with at least two different tests. We analyzed 259 samples, obtaining strong correlation between CLIA and both LFIA for IgG (φ=0.9), and moderate correlation for IgM (φ=0.6). For patients, the sensitivity was suboptimal for all methods (CLIA 81%, LFIA A 85%, LFIA B 78%), while it was poor in asymptomatic health-care workers (CLIA 50%, LFIA A 50%, LFIA B 33%). Overall, CLIA is more sensitive and specific for the determination of both IgG and IgM, whilst both LFIA methods reported good sensitivity and specificity for IgG, but scarce sensitivity for the IgM determination. The determination of SARS-CoV-2-specific IgG is useful to detect infection 6 days from symptom onset.

2021 - Adherence to Lipid-Lowering Medication in People Living with HIV: An Outpatient Clinic Drug Direct Distribution Experience [Articolo su rivista]
Cuomo, Gianluca; Raimondi, Alessandro; Rivasi, Marianna; Guaraldi, Giovanni; Borghi, Vanni; Mussini, Cristina
abstract

Adherence to lipid-lowering drugs could be challenging in our patients as it is in the general population, which is described as low as 25%. Our aim was to evaluate adherence to statins and to investigate clinical event impact on it.

2021 - Anti-Tat immunity defines CD4+ T-cell dynamics in people living with HIV on long-term cART [Articolo su rivista]
Tripiciano, A.; Picconi, O.; Moretti, S.; Sgadari, C.; Cafaro, A.; Francavilla, V.; Arancio, A.; Paniccia, G.; Campagna, M.; Pavone-Cossut, M. R.; Sighinolfi, L.; Latini, A.; Mercurio, V. S.; Pietro, M. D.; Castelli, F.; Saracino, A.; Mussini, C.; Perri, G. D.; Galli, M.; Nozza, S.; Ensoli, F.; Monini, P.; Ensoli, B.
abstract

Background: Low-level HIV viremia originating from virus reactivation in HIV reservoirs is often present in cART treated individuals and represents a persisting source of immune stimulation associated with sub-optimal recovery of CD4+ T cells. The HIV-1 Tat protein is released in the extracellular milieu and activates immune cells and latent HIV, leading to virus production and release. However, the relation of anti-Tat immunity with residual viremia, persistent immune activation and CD4+ T-cell dynamics has not yet been defined. Methods: Volunteers enrolled in a 3-year longitudinal observational study were stratified by residual viremia, Tat serostatus and frequency of anti-Tat cellular immune responses. The impact of anti-Tat immunity on low-level viremia, persistent immune activation and CD4+ T-cell recovery was investigated by test for partitions, longitudinal regression analysis for repeated measures and generalized estimating equations. Findings: Anti-Tat immunity is significantly associated with higher nadir CD4+ T-cell numbers, control of low-level viremia and long-lasting CD4+ T-cell recovery, but not with decreased immune activation. In adjusted analysis, the extent of CD4+ T-cell restoration reflects the interplay among Tat immunity, residual viremia and immunological determinants including CD8+ T cells and B cells. Anti-Env immunity was not related to CD4+ T-cell recovery. Interpretation: Therapeutic approaches aiming at reinforcing anti-Tat immunity should be investigated to improve immune reconstitution in people living with HIV on long-term cART. Trial registration: ISS OBS T-002 ClinicalTrials.gov identifier: NCT01024556 Funding: Italian Ministry of Health, special project on the Development of a vaccine against HIV based on the Tat protein and Ricerca Corrente 2019/2020.

2021 - Association of toll-like receptor 7 variants with life-threatening COVID-19 disease in males: Findings from a nested case-control study [Articolo su rivista]
Fallerini, C.; Daga, S.; Mantovani, S.; Benetti, E.; Picchiotti, N.; Francisci, D.; Paciosi, F.; Schiaroli, E.; Baldassarri, M.; Fava, F.; Palmieri, M.; Ludovisi, S.; Castelli, F.; Quiros-Roldan, E.; Vaghi, M.; Rusconi, S.; Siano, M.; Bandini, M.; Spiga, O.; Capitani, K.; Furini, S.; Mari, F.; Renieri, A.; Mondelli, M. U.; Frullanti, E.; Valentino, F.; Doddato, G.; Giliberti, A.; Tita, R.; Amitrano, S.; Bruttini, M.; Croci, S.; Meloni, I.; Mencarelli, M. A.; Rizzo, C. L.; Pinto, A. M.; Sarno, L. D.; Beligni, G.; Tommasi, A.; Iuso, N.; Montagnani, F.; Fabbiani, M.; Rossetti, B.; Zanelli, G.; Bargagli, E.; Bergantini, L.; D'Alessandro, M.; Cameli, P.; Bennett, D.; Anedda, F.; Marcantonio, S.; Scolletta, S.; Franchi, F.; Mazzei, M. A.; Guerrini, S.; Conticini, E.; Cantarini, L.; Frediani, B.; Tacconi, D.; Spertilli, C.; Feri, M.; Donati, A.; Scala, R.; Guidelli, L.; Spargi, G.; Corridi, M.; Nencioni, C.; Croci, L.; Caldarelli, G. P.; Spagnesi, M.; Romani, D.; Piacentini, P.; Desanctis, E.; Cappelli, S.; Canaccini, A.; Verzuri, A.; Anemoli, V.; Ognibene, A.; D'Arminio Monforte, A.; Miraglia, F. G.; Girardis, M.; Venturelli, S.; Busani, S.; Cossarizza, A.; Antinori, A.; Vergori, A.; Emiliozzi, A.; Gabrieli, A.; Riva, A.; Scotton, P. G.; Andretta, F.; Panese, S.; Scaggiante, R.; Gatti, F.; Parisi, S. G.; Baratti, S.; Antoni, M. D.; Monica, M. D.; Piscopo, C.; Capasso, M.; Russo, R.; Andolfo, I.; Iolascon, A.; Fiorentino, G.; Carella, M.; Castori, M.; Merla, G.; Squeo, G. M.; Aucella, F.; Raggi, P.; Marciano, C.; Perna, R.; Bassetti, M.; Biagio, A. D.; Sanguinetti, M.; Masucci, L.; Valente, S.; Mandala, M.; Giorli, A.; Salerni, L.; Zucchi, P.; Parravicini, P.; Menatti, E.; Trotta, T.; Giannattasio, F.; Coiro, G.; Lena, F.; Coviello, D. A.; Mussini, C.; Bosio, G.; Martinelli, E.; Mancarella, S.; Tavecchia, L.; Gori, M.; Crotti, L.; Parati, G.; Gabbi, C.; Zanella, I.; Rizzi, M.; Maggiolo, F.; Ripamonti, D.; Bachetti, T.; Rovere, M. T. L.; Sarzi-Braga, S.; Bussotti, M.; Chiariello, M.; Belli, M. A.; Dei, S.
abstract

Background: Recently, loss-of-function variants in TLR7 were identified in two families in which COVID-19 segregates like an X-linked recessive disorder environmentally conditioned by SARS-CoV-2. We investigated whether the two families represent the tip of the iceberg of a subset of COVID-19 male patients. Methods: This is a nested case-control study in which we compared male participants with extreme phenotype selected from the Italian GEN-COVID cohort of SARS-CoV-2-infected participants (<60 y, 79 severe cases versus 77 control cases). We applied the LASSO Logistic Regression analysis, considering only rare variants on young male subsets with extreme phenotype, picking up TLR7 as the most important susceptibility gene.

2021 - Author Correction: Endogenous control of inflammation characterizes pregnant women with asymptomatic or paucisymptomatic SARS-CoV-2 infection (Nature Communications, (2021), 12, 1, (4677), 10.1038/s41467-021-24940-w) [Articolo su rivista]
De Biasi, S.; Tartaro, D. L.; Gibellini, L.; Paolini, A.; Quong, A.; Petes, C.; Awong, G.; Douglas, S.; Lin, D.; Nieto, J.; Galassi, F. M.; Borella, R.; Fidanza, L.; Mattioli, M.; Leone, C.; Neri, I.; Meschiari, M.; Cicchetti, L.; Iannone, A.; Trenti, T.; Sarti, M.; Girardis, M.; Guaraldi, G.; Mussini, C.; Facchinetti, F.; Cossarizza, A.
abstract

The original version of this Article contained an error in Table 1. The correct version of the first row of the 2nd, 3rd, 5th and 7th columns states ‘CTR’, ‘PN’, ‘CTR vs PN’ and ‘PN vs PP’, instead of the original, incorrect ‘HD’, ‘NP’, ‘CTR vs NP’ and ‘CTR vs PP’. This has been corrected in both the PDF and HTML versions of the Article.

2021 - Better prognosis in females with severe COVID-19 pneumonia: possible role of inflammation as potential mediator. [Articolo su rivista]
Mussini, C; Cozzi-Lepri, A; Menozzi, M; Meschiari, M; Franceschini, E; Rogati, C; Cuomo, G; Bedini, A; Iadisernia, M; Volpi, S; Milic, J; Tonelli, R; Brugioni, L; Pietrangelo, A; Girardis, M; Cossarizza, A; Clini, E; Guaraldi, G.; De biasi, S; Gibellini, Lara
abstract

Objectives: Sex differences in COVID-19 severity and mortality have been described. Key aims of this analysis were to compare the risk of invasive mechanical ventilation (IMV) and mortality by sex and to explore whether variation in specific biomarkers could mediate this difference. Methods: This was a retrospective, observational cohort study among patients with severe COVID- 19 pneumonia. A survival analysis was conducted to compare time to the composite endpoint of IMV or death by sex. Interaction was formally tested to compare the risk difference by sex in subsets. Mediation analysis with a binary endpoint IMV or death (yes/no) by end of follow-up for a number of inflammation/coagulation biomarkers in the context of counterfactual prediction was also conducted. Results: Among 415 patients, 134 were females (32%) and 281 males (67%), median age 66 years (IQR 54-77). At admission, females showed a significantly less severe clinical and respiratory profiles with a higher PaO2/FiO2 (254 mmHg vs 191 mmHg; p=0.023). By 28 days from admission, 49.2% (95% CI: 39.6-58.9%) of males vs. 31.7% (17.9-45.4%) of females underwent IMV or death (log-rank pvalue<0.0001) and this amounted to a difference in HR of 0.40 (0.26-0.63, p=0.0001). The AUC in Creactive protein (CRP) over the study period appeared to explain 85% of this difference in risk by sex. Conclusions: Our analysis confirms a difference in the risk of COVID-19 clinical progression by sex and provides a hypothesis for potential mechanisms leading to this. CRP showed a predominant role to mediate the difference in risk by sex.

2021 - Breakthrough invasive fungal infection after liver transplantation in patients on targeted antifungal prophylaxis: a prospective multicentre study [Articolo su rivista]
Rinaldi, Matteo; Bartoletti, Michele; Ferrarese, Alberto; Franceschini, Erica; Campoli, Caterina; Coladonato, Simona; Pascale, Renato; Tedeschi, Sara; Gatti, Milo; Cricca, Monica; Ambretti, Simone; Siniscalchi, Antonio; Morelli, Maria Cristina; Cescon, Matteo; Cillo, Umberto; Di Benedetto, Fabrizio; Burra, Patrizia; Mussini, Cristina; Cristini, Francesco; Lewis, Russell; Viale, Pierluigi; Giannella, Maddalena
abstract

OBJECTIVE: To investigate the rate of and the risk factors for breakthrough-IFI (b-IFI) after orthotopic liver transplantation (OLT) according to the new definition proposed by Mycoses-Study-Group-Education-and-Research-Consortium (MSG-ERC) and the European-Confederation-of-Medical-Mycology (ECMM).METHODS: Multicenter prospective study of adult patients who underwent OLT at three Italian hospitals, from January 2015 to December 2018. Targeted antifungal prophylaxis (TAP) protocol was developed and shared among participating centers. Follow-up was 1-year after OLT. B-IFI was defined as infection occurring during exposure to antifungal prophylaxis. Risk factors for b-IFI were analysed among patients exposed to prophylaxis by univariable analysis.RESULTS: We enrolled 485 OLT patients. Overall compliance to TAP protocol was 64.3%, 220 patients received antifungal prophylaxis, 172 according to TAP protocol. Twenty-nine patients were diagnosed of IFI within 1 year after OLT. Of them, 11 presented with b-IFI within 17 (IQR 11-33) and 16 (IQR 4-30) days from OLT and from antifungal onset, respectively. Then out of 11 patients with b-IFI were classified as having high risk of IFI and were receiving anti-mould prophylaxis, nine with echinocandins and one with polyenes. Comparison of patients with and without b-IFI showed significant differences for prior Candida colonization, need of renal replacement therapy after OLT, re-operation, and CMV infection (whole blood CMV-DNA >100,000 copies/mL). Although non-significant, a higher rate of b-IFI in patients on echinocandins was observed (8.2% vs. 1.8%, p=0.06).CONCLUSIONS: We observed 5% of b-IFI among OLT patients exposed to antifungal prophylaxis. The impact of echinocandins on b-IFI risk in this setting should be further explored.

2021 - C9orf72 intermediate repeats confer genetic risk for severe covid-19 pneumonia independently of age [Articolo su rivista]
Zanella, I.; Zacchi, E.; Piva, S.; Filosto, M.; Beligni, G.; Alaverdian, D.; Amitrano, S.; Fava, F.; Baldassarri, M.; Frullanti, E.; Meloni, I.; Renieri, A.; Castelli, F.; Quiros-Roldan, E.; Mari, F.; Daga, S.; Benetti, E.; Furini, S.; Fallerini, C.; Valentino, F.; Doddato, G.; Giliberti, A.; Tita, R.; Bruttini, M.; Croci, S.; Pinto, A. M.; Mencarelli, M. A.; Rizzo, C. L.; Montagnani, F.; Tumbarello, M.; Rancan, I.; Sarno, L. D.; Palmieri, M.; Carriero, M. L.; Fabbiani, M.; Rossetti, B.; Bargagli, E.; Bergantini, L.; D'Alessandro, M.; Cameli, P.; Bennett, D.; Anedda, F.; Marcantonio, S.; Scolletta, S.; Franchi, F.; Mazzei, M. A.; Guerrini, S.; Conticini, E.; Cantarini, L.; Frediani, B.; Tacconi, D.; Raffaelli, C. S.; Feri, M.; Donati, A.; Scala, R.; Guidelli, L.; Spargi, G.; Corridi, M.; Nencioni, C.; Croci, L.; Caldarelli, G. P.; Spagnesi, M.; Piacentini, P.; Bandini, M.; Desanctis, E.; Cappelli, S.; Canac-Cini, A.; Verzuri, A.; Anemoli, V.; Ognibene, A.; Pancrazi, A.; Lorubbio, M.; Vaghi, M.; Monforte, A. D.; Miraglia, F. G.; Mondelli, M. U.; Bruno, R.; Marco, V.; Mantovani, S.; Ludovisi, S.; Girardis, M.; Venturelli, S.; Busani, S.; Cossarizza, A.; Antinori, A.; Vergori, A.; Emiliozzi, A.; Rusconi, S.; Siano, M.; Gabrieli, A.; Riva, A.; Francisci, D.; Schiaroli, E.; Tommasi, A.; Paciosi, F.; Scotton, P. G.; Andretta, F.; Panese, S.; Scaggiante, R.; Gatti, F.; Parisi, S. G.; Antoni, M. D.; Monica, M. D.; Piscopo, C.; Capasso, M.; Russo, R.; Andolfo, I.; Iolascon, A.; Fiorentino, G.; Carella, M.; Castori, M.; Merla, G.; Squeo, G. M.; Aucella, F.; Raggi, P.; Marciano, C.; Perna, R.; Bassetti, M.; Biagio, A. D.; Sanguinetti, M.; Masucci, L.; Valente, S.; Mandala, M.; Giorli, A.; Salerni, L.; Zucchi, P.; Parravicini, P.; Menatti, E.; Baratti, S.; Trotta, T.; Giannattasio, F.; Coiro, G.; Lena, F.; Coviello, D. A.; Mussini, C.; Bosio, G.; Martinelli, E.; Mancarella, S.; Tavecchia, L.; Belli, M. A.; Crotti, L.; Parati, G.; Picchiotti, N.; Gori, M.; Gabbi, C.; Sanarico, M.; Ceri, S.; Pinoli, P.; Raimondi, F.; Bis-Carini, F.; Stella, A.; Rizzi, M.; Maggiolo, F.; Ripamonti, D.; Suardi, C.; Bachetti, T.; Rovere, M. T. L.; Sarzi-Braga, S.; Bussotti, M.; Capitani, K.; Zguro, K.; Dei, S.; Ravaglia, S.; Artuso, R.; Perrella, A.; Bianchi, F.; Bergomi, P.; Catena, E.; Colombo, R.; Perticaroli, V.; Gennarelli, M.; Magri, C.; Basiotto, G.; Zizioli, D.; Giliani, S.; Monti, E.; Foca, E.; Carriero, C.; Latronico, N.; Padovani, A.; Brugnoni, D.
abstract

A cytokine storm, autoimmune features and dysfunctions of myeloid cells significantly contribute to severe coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Genetic background of the host seems to be partly responsible for severe phenotype and genes related to innate immune response seem critical host determinants. The C9orf72 gene has a role in vesicular trafficking, autophagy regulation and lyso-some functions, is highly expressed in myeloid cells and is involved in immune functions, regulating the lysosomal degradation of mediators of innate immunity. A large non-coding hexanucleotide repeat expansion (HRE) in this gene is the main genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), both characterized by neuroinflammation and high systemic levels of proinflammatory cytokines, while HREs of intermediate length, although rare, are more frequent in autoimmune disorders. C9orf72 full mutation results in haploinsufficiency and intermediate HREs seem to modulate gene expression as well and impair autophagy. Herein, we sought to explore whether intermediate HREs in C9orf72 may be a risk factor for severe COVID-19. Although we found intermediate HREs in only a small portion of 240 patients with severe COVID-19 pneumonia, the magnitude of risk for requiring non-invasive or mechanical ventilation conferred by harboring intermediate repeats >10 units in at least one C9orf72 allele was more than twice respect to having shorter expansions, when adjusted for age (odds ratio (OR) 2.36; 95% confidence interval (CI) 1.04–5.37, p = 0.040). The association between intermediate repeats >10 units and more severe clinical outcome (p = 0.025) was also validated in an independent cohort of 201 SARS-CoV-2 infected patients. These data suggest that C9orf72 HREs >10 units may influence the pathogenic process driving more severe COVID-19 phenotypes.

2021 - CD4/CD8 Ratio and the Risk of Kaposi Sarcoma or Non-Hodgkin Lymphoma in the Context of Efficiently Treated Human Immunodeficiency Virus (HIV) Infection: A Collaborative Analysis of 20 European Cohort Studies [Articolo su rivista]
Caby, Fabienne; Guiguet, Marguerite; Weiss, Laurence; Winston, Alan; Miro, Jose M; Konopnicki, Deborah; Le Moing, Vincent; Bonnet, Fabrice; Reiss, Peter; Mussini, Cristina; Poizot-Martin, Isabelle; Taylor, Ninon; Skoutelis, Athanasios; Meyer, Laurence; Goujard, Cécile; Bartmeyer, Barbara; Boesecke, Christoph; Antinori, Andrea; Quiros-Roldan, Eugenia; Wittkop, Linda; Frederiksen, Casper; Castagna, Antonella; Thurnheer, Maria Christine; Svedhem, Veronica; Jose, Sophie; Costagliola, Dominique; Mary-Krause, Murielle; Grabar, Sophie
abstract

A persistently low CD4/CD8 ratio has been reported to inversely correlate with the risk of non-AIDS defining cancer in people living with human immunodeficiency virus (HIV; PLWH) efficiently treated by combination antiretroviral therapy (cART). We evaluated the impact of the CD4/CD8 ratio on the risk of Kaposi sarcoma (KS) or non-Hodgkin lymphoma (NHL), still among the most frequent cancers in treated PLWH.

2021 - Ceftazidime-avibactam use for KPC-Kp infections: a retrospective observational multicenter study [Articolo su rivista]
Tumbarello, Mario; Raffaelli, Francesca; Giannella, Maddalena; Mantengoli, Elisabetta; Mularoni, Alessandra; Venditti, Mario; De Rosa, Francesco Giuseppe; Sarmati, Loredana; Bassetti, Matteo; Brindicci, Gaetano; Rossi, Marianna; Luzzati, Roberto; Grossi, Paolo Antonio; Corona, Alberto; Capone, Alessandro; Falcone, Marco; Mussini, Cristina; Trecarichi, Enrico Maria; Cascio, Antonio; Guffanti, Elena; Russo, Alessandro; De Pascale, Gennaro; Tascini, Carlo; Gentile, Ivan; Losito, Angela Raffaella; Bussini, Linda; Conti, Giampaolo; Ceccarelli, Giancarlo; Corcione, Silvia; Compagno, Mirko; Giacobbe, Daniele Roberto; Saracino, Annalisa; Fantoni, Massimo; Antinori, Spinello; Peghin, Maddalena; Bonfanti, Paolo; Oliva, Alessandra; De Gasperi, Andrea; Tiseo, Giusy; Rovelli, Cristina; Meschiari, Marianna; Shbaklo, Nour; Spanu, Teresa; Cauda, Roberto; Viale, Pierluigi
abstract

BACKGROUND: A growing body of observational evidence supports the value of ceftazidime-avibactam (CAZ-AVI) in managing infections caused by carbapenem-resistant Enterobacteriaceae (CRE).METHODS: We retrospectively analyzed observational data on the use and outcomes of CAZ-AVI therapy for infections caused by KPC-producing K. pneumoniae (KPC-Kp) strains. Multivariate regression analysis was used to identify variables independently associated with 30-day mortality. Results were adjusted for propensity score for receipt of CAZ-AVI combination regimens vs. CAZ-AVI monotherapy.RESULTS: The cohort comprised 577 adults with bloodstream infections (BSIs) (n=391) or non-bacteremic infections (nBSIs) involving mainly the urinary tract, lower respiratory tract, intra-abdominal structures. All received treatment with CAZ-AVI alone (n=165) or with one or more other active antimicrobials (n=412). The all-cause mortality rate 30 days after infection onset was 25% (146/577). There was no statistically significant difference in mortality between patients managed with CAZ-AVI alone and those treated with combination regimens (26.1% vs. 25.0%, P=0.79). In multivariate analysis, mortality was positively associated with the presence at infection onset of septic shock (P=0.002), neutropenia (P <0.001), or an INCREMENT score >8 (P=0.01); with LRTI (P=0.04); and with CAZ-AVI dose adjustment for renal function (P=0.01). Mortality was negatively associated with CAZ-AVI administration by prolonged infusion (P=0.006). All associations remained significant after propensity score adjustment.CONCLUSIONS: CAZ-AVI is an important option for treating serious KPC-Kp infections, even when used alone. Further study is needed to explore the drug's seemingly more limited efficacy in LRTIs and the potential survival benefits of prolonging CAZ-AVI infusions to 3 hours or more.

2021 - Ceftazidime/avibactam and ceftolozane/tazobactam for the treatment of extensively drug-resistant Pseudomonas aeruginosa post-neurosurgical infections: three cases and a review of the literature [Articolo su rivista]
Meschiari, M.; Franconi, I.; Bacca, E.; Bianco, V.; Orlando, G.; Cuomo, G.; Bedini, A.; Mussini, C.
abstract

Purpose: Post-neurosurgical infection caused by extensively drug resistant Pseudomonas aeruginosa (XDR-PA) are becoming a matter of great concern due to limited therapeutic options. Although not approved for these indications, the new BetaLactam-BetaLactamase Inhibitor combinations (BLBLIs) could represent a valid salvage treatment. We describe one nosocomial meningitis and two cervical osteomyelitis due to an XDR-PA who were treated with ceftazidime/avibactam (CZA) and ceftolozane/tazobactam (C/T) and review the literature. Methods: The first and the third patients developed an osteomyelitis following cervical stabilization surgery due to an XDR-PA. Although the first patient started treatment with a high dose of C/T, resistance to C/T occurred, so therapy was switched to CZA plus aztreonam. The third patient switched to aztreonam plus CZA due to development of acute kidney injury during therapy with colistin. The second patient had an XDR-PA meningitis following the insertion of an external ventricular catheter and he was treated with C/T plus meropenem and amikacin. Results: All three cases reported were successfully conservatively treated thanks to the use of the new BLBLIs with different combinations. Only few experiences demonstrated an equally favorable outcome: one patient treated with C/T plus fosfomycin for otogenic meningitis caused by an XDR-PA and another case of XDR-PA post-surgical meningitis with CZA in combination with colistin. Finally, the combination of CZA plus aztreonam has proven to be effective on XDR-PA only in limited mostly in vitro studies. Conclusion: These recently developed antibiotics, C/T and CZA are promising and complementary therapy options against post-neurosurgical hard-to-treat P. aeruginosa infections. Further prospective real-life studies are required to validate these findings in this special setting.

2021 - Changes in central adipose tissue after switching to integrase inhibitors [Articolo su rivista]
Debroy, Paula; Feng, Han; Miao, Hongyu; Milic, Jovana; Ligabue, Guido; Draisci, Stefano; Besutti, Giulia; Carli, Federica; Menozzi, Marianna; Mussini, Cristina; Guaraldi, Giovanni; Lake, Jordan E
abstract

Background: Treatment with integrase strand transfer inhibitors (INSTIs) has been associated with excess weight gain, however the long-term effect of INSTI-based regimens on adipose tissue (AT) compartments remains unknown. Objectives: To evaluate the effect of switching to an INSTI on visceral (VAT) and subcutaneous (SAT) AT in virologically-suppressed adults with HIV. Methods: We performed a retrospective observational cohort study of ART experienced adults referred to the metabolic Clinic of the University of Modena and Reggio Emilia who had ≥2 assessments of body composition by abdominal computed tomography. An interrupted time series model with mixed-effect model incorporated was used to calculate VAT and SAT change rate, adjusting for smoking status, use of alcohol, and physical activity. Results: A total of 698 patients were included: 156 who switched to an INSTI-based regimen and 542 who did not. After switch to INSTI, mean SAT area increased approximately 3-fold (before 0.27 vs after 0.73 cm2/month; p = 0.011), and VAT area 7-fold (0.18 vs 1.30 cm2/month; p < 0.001). Conclusions: Among PLWH on ART, both SAT and VAT gain accelerated after switching to an INSTI-based regimen. The associations between INSTIs and central adiposity require further investigation.

2021 - Clinical outcomes of two-drug regimens vs. three-drug regimens in antiretroviral treatment-experienced people living with HIV [Articolo su rivista]
Greenberg, Lauren; Ryom, Lene; Neesgaard, Bastian; Wandeler, Gilles; Staub, Therese; Gisinger, Martin; Skoll, Michael; Günthard, Huldrych F; Scherrer, Alexandra; Mussini, Cristina; Smith, Colette; Johnson, Margaret; De Wit, Stéphane; Necsoi, Coca; Pradier, Christian; Wit, Ferdinand; Lehmann, Clara; d'Arminio Monforte, Antonella; Miró, Jose M; Castagna, Antonella; Spagnuolo, Vincenzo; Sönnerborg, Anders; Law, Matthew; Hutchinson, Jolie; Chkhartishvili, Nikoloz; Bolokadze, Natalia; Wasmuth, Jan-Christian; Stephan, Christoph; Vannappagari, Vani; Rogatto, Felipe; Llibre, Josep M; Duvivier, Claudine; Hoy, Jennifer; Bloch, Mark; Bucher, Heiner C; Calmy, Alexandra; Volny Anne, Alain; Pelchen-Matthews, Annegret; Lundgren, Jens D; Peters, Lars; Bansi-Matharu, Loveleen; Mocroft, Amanda
abstract

Limited data exist comparing clinical outcomes of two-drug regimens (2DRs) and three-drug regimens (3DRs) in people living with HIV.

2021 - Combined resistance to ceftolozane-tazobactam and ceftazidime-avibactam in extensively drug-resistant (Xdr) and multidrug-resistant (mdr) pseudomonas aeruginosa: Resistance predictors and impact on clinical outcomes besides implications for antimicrobial stewardship programs [Articolo su rivista]
Meschiari, M.; Orlando, G.; Kaleci, S.; Bianco, V.; Sarti, M.; Venturelli, C.; Mussini, C.
abstract

A retrospective case-control study was conducted at Modena University Hospital from December 2017 to January 2019 to identify risk factors and predictors of MDR/XDR Pseudomonas aeruginosa (PA) isolation with resistance to ceftazidime/avibactam (CZA) and ceftolozane/tazobactam (C/T), and of mortality among patients infected/colonized. Among 111 PA isolates from clinical/surveillance samples, 60 (54.1%) were susceptible to both drugs (S-CZA-C/T), while 27 (24.3%) were resistant to both (R-CZA-C/T). Compared to patients colonized/infected with S-CZA-C/T, those with R-C/T+CZA PA had a statistically significantly higher Charlson comorbidity score, greater rate of previous PA colonization, longer time before PA isolation, more frequent presence of CVC, higher exposure to C/T and cephalosporins, longer hospital stay, and higher overall and attributable mortality. In the multivariable analysis, age, prior PA colonization, longer time from admission to PA isolation, diagnosis of urinary tract infection, and exposure to carbapenems were associated with the isolation of a R-C/T+CZA PA strain, while PA-related BSI, a comorbidity score > 7, and ICU stay were significantly associated with attributable mortality. C/T and CZA are important therapeutic resources for hard-to-treat PA-related infections, thus specific antimicrobial stewardship interventions should be prompted in order to avoid the development of this combined resistance, which would jeopardize the chance to treat these infections.

2021 - Contemporary antiretrovirals and body-mass index: a prospective study of the RESPOND cohort consortium [Articolo su rivista]
Bansi-Matharu, Loveleen; Phillips, Andrew; Oprea, Cristiana; Grabmeier-Pfistershammer, Katharina; Günthard, Huldrych F; De Wit, Stephane; Guaraldi, Giovanni; Vehreschild, Jorg J; Wit, Ferdinand; Law, Matthew; Wasmuth, Jan-Christian; Chkhartishvili, Nikoloz; d'Arminio Monforte, Antonella; Fontas, Eric; Vesterbacka, Jan; Miro, Jose M; Castagna, Antonella; Stephan, Christoph; Llibre, Josep M; Neesgaard, Bastian; Greenberg, Lauren; Smith, Colette; Kirk, Ole; Duvivier, Claudine; Dragovic, Gordana; Lundgren, Jens; Dedes, Nikos; Knudsen, Andreas; Gallant, Joel; Vannappagari, Vani; Peters, Lars; Elbirt, Daniel; Sarcletti, Mario; Braun, Dominique L; Necsoi, Coca; Mussini, Cristina; Muccini, Camilla; Bolokadze, Natalie; Hoy, Jennifer; Mocroft, Amanda; Ryom, Lene
abstract

2021 - Darunavir/Cobicistat Is Associated with Negative Outcomes in HIV-Negative Patients with Severe COVID-19 Pneumonia [Articolo su rivista]
Milic, Jovana; Novella, Alessio; Meschiari, Marianna; Menozzi, Marianna; Santoro, Antonella; Bedini, Andrea; Cuomo, Gianluca; Franceschini, Erica; Digaetano, Margherita; Carli, Federica; Ciusa, Giacomo; Volpi, Sara; Bacca, Erica; Franceschi, Giacomo; Yaacoub, Dina; Rogati, Carlotta; Tutone, Marco; Burastero, Giulia; Faltoni, Matteo; Iadisernia, Vittorio; Dolci, Giovanni; Cossarizza, Andrea; Mussini, Cristina; Pasina, Luca; Guaraldi, Giovanni
abstract

The aim of this study was to evaluate both positive outcomes, including reduction of respiratory support aid and duration of hospital stay, and negative ones, including mortality and a composite of invasive mechanical ventilation or death, in patients with coronavirus disease 2019 (COVID-19) pneumonia treated with or without oral darunavir/cobicistat (DRV/c, 800/150mg/day) used in different treatment durations. The secondary objective was to evaluate the percentage of patients treated with DRV/c who were exposed to potentially severe drug-drug interactions (DDIs) and died during hospitalization. This observational retrospective study was conducted in consecutive patients with COVID-19 pneumonia admitted to a tertiary care hospital in Modena, Italy. Kaplan-Meier survival curves and Cox proportional hazards regression were used to compare patients receiving standard of care with or without DRV/c. Adjustment for key confounders was applied. Two hundred seventy-three patients (115 on DRV/c) were included, 75.8% males, mean age was 64.6 (±13.2) years. Clinical improvement was similar between the groups, depicted by respiratory aid switch (p>.05). The same was observed for duration of hospital stay [13.2 (±8.9) for DRV/c vs. 13.4 (±7.2) days for no-DRV/c, p=.9]. Patients on DRV/c had higher rates of mortality (25.2% vs. 10.1%, p<.0001. The rate of composite outcome of mechanical ventilation and death was higher in the DRV/c group (37.4% vs. 25.3%, p=.03). Multiple serious DDI associated with DRV/c were observed in the 19 patients who died. DRV/c should not be recommended as a treatment option for COVID-19 pneumonia outside clinical trials.

2021 - Decrease in Incidence Rate of Hospitalizations Due to AIDS-Defining Conditions but Not to Non-AIDS Conditions in PLWHIV on cART in 2008-2018 in Italy [Articolo su rivista]
Nozza, Silvia; Timelli, Laura; Saracino, Annalisa; Gianotti, Nicola; Lazzaretti, Claudia; Tavelli, Alessandro; Puoti, Massimo; Lo Caputo, Sergio; Antinori, Andrea; Monforte, Antonella d'Arminio; Mussini, Cristina; Girardi, Enrico; On Behalf Of Icona Foundation Study Group, Null
abstract

We aimed to describe the change in the incidence and causes of hospitalization between 2008 and 2018 among persons living with HIV (PLWHIV) who started antiretroviral therapy (ART) from 2008 onwards in Italy.

2021 - Determinants of loss to care and risk of clinical progression in PLWH who are re-engaged in care after a temporary loss [Articolo su rivista]
Mussini, Cristina; Lorenzini, Patrizia; Cozzi-Lepri, Alessandro; Mammone, Alessia; Guaraldi, Giovanni; Marchetti, Giulia; Lichtner, Miriam; Lapadula, Giuseppe; Lo Caputo, Sergio; Antinori, Andrea; d'Arminio Monforte, Antonella; Girardi, Enrico
abstract

The risk of developing AIDS is elevated not only among those with a late HIV diagnosis but also among those lost to care (LTC). The aims were to address the risk of becoming LTC and of clinical progression in LTC patients who re-enter care. Patients were defined as LTC if they had no visit for ≥ 18 months. Of these, persons with subsequent visits were defined as re-engaged in care (RIC). Factors associated with becoming LTC and RIC were investigated. The risk of disease progression was estimated by comparing RIC with patients continuously followed. Over 11,285 individuals included, 3962 became LTC, and of these, 1062 were RIC. Older age, presentation with AIDS and with higher HIV-RNA were associated with a reduced risk of LTC. In contrast, lower education level, irregular job, being an immigrant and injecting-drug user were associated with an increased LTC probability. Moreover, RIC with HIV-RNA > 200 copies/mL at the re-entry had a higher risk of clinical progression, while those with HIV-RNA ≤ 200 copies/mL had a higher risk of only non-AIDS progression. Patients re-entering care after being LTC appeared to be at higher risk of clinical progression than those continuously in care. Active strategies for re-engagement in care should be promoted.

2021 - Development and validation of a prediction model for tocilizumab failure in hospitalized patients with SARS-CoV-2 infection [Articolo su rivista]
Mussini, C; Cozzi-Lepri, A; Menozzi, M; Meschiari, M; Franceschini, E; Milic, J; Brugioni, L; Pietrangelo, A; Girardis, M; Cossarizza, A; Tonelli, R; Clini, E; Massari, M; Bartoletti, M; Ferrari, A; Cattelan, Am; Zuccalà, P; Lichtner, M; Rossotti, R; Girardi, E; Nicastri, E; Puoti, M; Antinori, A; Viale, Pl; Guaraldi, G.
abstract

Background: The aim of this secondary analysis of the TESEO cohort is to identify, early in the course of treatment with tocilizumab, factors associated with the risk of progressing to mechanical ventilation and death and develop a risk score to estimate the risk of this outcome according to patients’ profile. Methods: Patients with COVID-19 severe pneumonia receiving standard of care + tocilizumab who were alive and free from mechanical ventilation at day6 after treatment initiation were included in this retrospective, multicenter cohort study. Multivariable logistic regression models were built to identify predictors of mechanical ventilation or death by day-28 from treatment initiation and β-coefficients were used to develop a risk score. Secondary outcome was mortality. Patients with the same inclusion criteria as the derivation cohort from 3 independent hospitals were used as validation cohort. Results: 266 patients treated with tocilizumab were included. By day 28 of hospital follow-up post treatment initiation, 40 (15%) underwent mechanical ventilation or died [26 (10%)]. At multivariable analysis, sex, day-4 PaO2/FiO2 ratio, platelets and CRP were independently associated with the risk of developing the study outcomes and were used to generate the proposed risk score. The accuracy of the score in AUC was 0.80 and 0.70 in internal validation and test for the composite endpoint and 0.92 and 0.69 for death, respectively. Conclusions: Our score could assist clinicians in identifying, early after tocilizumab, patients who are likely to progress to mechanical ventilation or death so that they could be selected for eventual rescue therapies.

2021 - Development of a Risk Prediction Model for Carbapenem-resistant Enterobacteriaceae Infection after Liver Transplantation: A Multinational Cohort Study [Articolo su rivista]
Giannella, M.; Freire, M.; Rinaldi, M.; Abdala, E.; Rubin, A.; Mularoni, A.; Gruttadauria, S.; Grossi, P.; Shbaklo, N.; Tandoi, F.; Ferrarese, A.; Burra, P.; Fernandes, R.; Aranha Camargo, L. F.; Asensio, A.; Alagna, L.; Bandera, A.; Simkins, J.; Abbo, L.; Halpern, M.; Santana Girao, E.; Valerio, M.; Munoz, P.; Fernandez Yunquera, A.; Statlender, L.; Yahav, D.; Franceschini, E.; Graziano, E.; Morelli, M. C.; Cescon, M.; Viale, P.; Lewis, R.; Bartoletti, M.; Pascale, R.; Campoli, C.; Coladonato, S.; Cristini, F.; Tumietto, F.; Siniscalchi, A.; Laici, C.; Ambretti, S.; Romagnoli, R.; De Rosa, F. G.; Muscatello, A.; Mangioni, D.; Gori, A.; Antonelli, B.; Dondossola, D.; Rossi, G.; Invernizzi, F.; Peghin, M.; Cillo, U.; Mussini, C.; Benedetto, F. D.; Terrabuio, D. R. B.; Bittante, C. D.; Toniolo, A. D. R.; Balbi, E.; Garcia, J. H. P.; Morras, I.; Ramos, A.; Cruz, A. F.; Salcedo, M.
abstract

Background: Patients colonized with carbapenem-resistant Enterobacteriaceae (CRE) are at higher risk of developing CRE infection after liver transplantation (LT), with associated high morbidity and mortality. Prediction model for CRE infection after LT among carriers could be useful to target preventive strategies. Methods: Multinational multicenter cohort study of consecutive adult patients underwent LT and colonized with CRE before or after LT, from January 2010 to December 2017. Risk factors for CRE infection were analyzed by univariate analysis and by Fine-Gray subdistribution hazard model, with death as competing event. A nomogram to predict 30- and 60-day CRE infection risk was created. Results: A total of 840 LT recipients found to be colonized with CRE before (n = 203) or after (n = 637) LT were enrolled. CRE infection was diagnosed in 250 (29.7%) patients within 19 (interquartile range [IQR], 9-42) days after LT. Pre- and post-LT colonization, multisite post-LT colonization, prolonged mechanical ventilation, acute renal injury, and surgical reintervention were retained in the prediction model. Median 30- and 60-day predicted risk was 15% (IQR, 11-24) and 21% (IQR, 15-33), respectively. Discrimination and prediction accuracy for CRE infection was acceptable on derivation (area under the curve [AUC], 74.6; Brier index, 16.3) and bootstrapped validation dataset (AUC, 73.9; Brier index, 16.6). Decision-curve analysis suggested net benefit of model-directed intervention over default strategies (treat all, treat none) when CRE infection probability exceeded 10%. The risk prediction model is freely available as mobile application at https://idbologna.shinyapps.io/CREPostOLTPredictionModel/. Conclusions: Our clinical prediction tool could enable better targeting interventions for CRE infection after transplant.

2021 - Development of post-COVID-19 cardiovascular events: An analysis of clinical features and risk factors from a single hospital retrospective study [Articolo su rivista]
Cuomo, G.; Puzzolante, C.; Iadisernia, V.; Santoro, A.; Menozzi, M.; Carli, F.; Digaetano, M.; Orlando, G.; Franceschini, E.; Bedini, A.; Meschiari, M.; Manzini, L.; Corradi, L.; Milic, J.; Borghi, V.; Brugioni, L.; Pietrangelo, A.; Clini, E.; Girardis, M.; Guaraldi, G.; Mussini, C.
abstract

Cardiovascular complications after a SARS-CoV-2 infection are a phenomenon of relevant scientific inter-est. The aim of this study was to analyze the onset of post-COVID-19 cardiovascular events in patients hospitalized in a tertiary care center. This is a retrospective study conducted on patients hospitalized over a period of three months. The patients were older than 18 years of age and had a diagnosis of COVID-19 infection confirmed from a nasopharyngeal swab sample. Anamnestic and clinical-laboratory data were collected. Cardiovascular events at 30 days were defined as follows: arrhythmias, myocardial infarction, myocarditis, and pulmonary embolism. Univariate analysis (Student’s t-test or Mann-Whitney U test, as appropriate) and multivariate analysis (multinomial logistic regression) were applied to the data. A total of 394 patients were included; they were mostly males and had a median age of 65.5 years. Previous cardiovascular disease was present in 14.7% of patients. Oxygen therapy was required for 77.9%, and 53% received anticoagulant therapy. The overall 30-day mortality was 20.3%. A cardiovascular event developed in 15.7% of the subjects. These were mainly pulmonary embolism (9.4%), followed by arrhythmias (3.3%), myocardial infarction (2.3%), and myocarditis (0.8%). Patients who developed cardiovascular events upon univariate analysis were significantly older, with major comorbidities, a more compromised respiratory situation, and a higher mortality rate. Multivariate analysis revealed independent factors that were significantly associated with the development of cardiovascular events: hypertension, endotracheal intubation, and age older than 75 years. In patients with COVID-19, the development of a cardiovascular event occurs quite frequently and is mainly seen in elderly subjects with comorbidities (especially hypertension) in the presence of a severe respiratory picture.

2021 - Diagnostic stewardship based on patient profiles: differential approaches in acute versus chronic infectious syndromes [Articolo su rivista]
Tiseo, Giusy; Arena, Fabio; Borrè, Silvio; Campanile, Floriana; Falcone, Marco; Mussini, Cristina; Pea, Federico; Sganga, Gabriele; Stefani, Stefania; Venditti, Mario
abstract

Introduction: New diagnostics may be useful in clinical practice, especially in contexts of high prevalence of multidrug-resistant organisms (MDRO). However, misuse of diagnostic tools may lead to increased costs and worse patient outcome. Conventional and new techniques should be appropriately positioned in diagnostic algorithms to guide an appropriate use of antimicrobial therapy.Areas covered: A panel of experts identified 4 main areas in which the implementation of diagnostic stewardship is needed. Among chronic infections, bone and prosthetic joint infections and subacute-chronic intravascular infections and endocarditis represent common challenges for clinicians. Among acute infections, bloodstream infections and community-acquired pneumonia may be associated with high mortality and require appropriate diagnostic approach.Expert opinion: Diagnostic stewardship aims to improve appropriate use of microbiological diagnostics to guide therapeutic decisions, through the promotion of appropriate, timely diagnostic testing. Here, diagnostic algorithms based on different patient profiles are proposed in chronic and acute clinical syndromes. In each clinical scenario, combining conventional and new diagnostic techniques is crucial to make a rapid and accurate diagnosis and to guide the selection of antimicrobial therapy. Barriers related to the implementation of new rapid diagnostic tools, such as high initial costs, may be overcome through their rational and structured use.

2021 - Disentangling the association of hydroxychloroquine treatment with mortality in covid-19 hospitalized patients through hierarchical clustering [Articolo su rivista]
Di Castelnuovo, A.; Gialluisi, A.; Antinori, A.; Berselli, N.; Blandi, L.; Bonaccio, M.; Bruno, R.; Cauda, R.; Costanzo, S.; Guaraldi, G.; Menicanti, L.; Mennuni, M.; My, I.; Parruti, G.; Patti, G.; Perlini, S.; Santilli, F.; Signorelli, C.; Stefanini, G.; Vergori, A.; Ageno, W.; Agodi, A.; Agostoni, P.; Aiello, L.; Moghazi, S. A.; Arboretti, R.; Aucella, F.; Barbieri, G.; Barchitta, M.; Bonfanti, P.; Cacciatore, F.; Caiano, L.; Cannata, F.; Carrozzi, L.; Cascio, A.; Castiglione, G.; Cicullo, A.; Cingolani, A.; Cipollone, F.; Colomba, C.; Colombo, C.; Crisetti, A.; Crosta, F.; Danzi, G. B.; D'Ardes, D.; de Gaetano Donati, K.; Di Gennaro, F.; Di Tano, G.; D'Offizi, G.; Fusco, F. M.; Gaudiosi, C.; Gentile, I.; Gianfagna, F.; Giuliano, G.; Graziani, E.; Guarnieri, G.; Langella, V.; Larizza, G.; Leone, A.; Maccagni, G.; Magni, F.; Maitan, S.; Mancarella, S.; Manuele, R.; Mapelli, M.; Maragna, R.; Marcucci, R.; Maresca, G.; Marongiu, S.; Marotta, C.; Marra, L.; Mastroianni, F.; Mengozzi, A.; Meschiari, M.; Milic, J.; Minutolo, F.; Mussinelli, R.; Mussini, C.; Musso, M.; Odone, A.; Olivieri, M.; Palimodde, A.; Pasi, E.; Pesavento, R.; Petri, F.; Pivato, C. A.; Poletti, V.; Ravaglia, C.; Righetti, G.; Rognoni, A.; Rossato, M.; Rossi, I.; Rossi, M.; Sabena, A.; Salinaro, F.; Sangiovanni, V.; Sanrocco, C.; Moriello, N. S.; Scorzolini, L.; Sgariglia, R.; Simeone, P. G.; Spinicci, M.; Tamburrini, E.; Torti, C.; Trecarichi, E. M.; Vettor, R.; Vianello, A.; Vinceti, M.; Virdis, A.; de Caterina, R.; Iacoviello, L.
abstract

The efficacy of hydroxychloroquine (HCQ) in treating SARS-CoV-2 infection is harshly debated, with observational and experimental studies reporting contrasting results. To clarify the role of HCQ in Covid-19 patients, we carried out a retrospective observational study of 4,396 unselected patients hospitalized for Covid-19 in Italy (February–May 2020). Patients’ characteristics were collected at entry, including age, sex, obesity, smoking status, blood parameters, history of diabetes, cancer, cardiovascular and chronic pulmonary diseases, and medications in use. These were used to identify subtypes of patients with similar characteristics through hierarchical clustering based on Gower distance. Using multivariable Cox regressions, these clusters were then tested for association with mortality and modification of effect by treatment with HCQ. We identified two clusters, one of 3,913 younger patients with lower circulating inflammation levels and better renal function, and one of 483 generally older and more comorbid subjects, more prevalently men and smokers. The latter group was at increased death risk adjusted by HCQ (HR [CI95%] = 3.80[3.08-4.67]), while HCQ showed an independent inverse association (0.51[0.43-0.61]), as well as a significant influence of cluster∗HCQ interaction (p < 0.001). This was driven by a differential association of HCQ with mortality between the high (0.89[0.65-1.22]) and the low risk cluster (0.46[0.39-0.54]). These effects survived adjustments for additional medications in use and were concordant with associations with disease severity and outcome. These findings suggest a particularly beneficial effect of HCQ within low risk Covid-19 patients and may contribute to clarifying the current controversy on HCQ efficacy in Covid-19 treatment.

2021 - Durability of rilpivirine-based versus integrase inhibitor-based regimens in a large cohort of naïve HIV-infected patients starting antiretroviral therapy [Articolo su rivista]
Gagliardini, Roberta; Gianotti, Nicola; Maggiolo, Franco; Cozzi-Lepri, Alessandro; Antinori, Andrea; Nozza, Silvia; Lapadula, Giuseppe; De Luca, Andrea; Mussini, Cristina; Gori, Andrea; Saracino, Annalisa; Andreoni, Massimo; Monforte, Antonella d'Arminio
abstract

Comparisons between rilpivirine (RPV) and integrase strand transfer inhibitors (INSTIs) in antiretroviral therapy (ART)-naïve HIV-infected individuals are currently lacking. This study aimed to compare, in an observational cohort setting, the durability of treatment with RPV-based and INSTI-based first-line regimens.

2021 - Early discontinuation of DTG/ABC/3TC and BIC/TAF/FTC single-tablet regimens: a real-life multicenter cohort study [Articolo su rivista]
Lagi, Filippo; Botta, Annarita; Ciccullo, Arturo; Picarelli, Chiara; Fabbiani, Massimiliano; di Giambenedetto, Simona; Borghi, Vanni; Mussini, Cristina; Bartoloni, Alessandro; Sterrantino, Gaetana
abstract

Background: Data regarding the efficacy and tolerability of DTG/ABC/3TC/and BIC/TAF/FTC in switching strategies are still scarce. The rates and reasons of early discontinuation within 24 weeks from the switch to dolutegravir (DTG) or bictegravir (BIC) single-tablet regimens (STRs) were compared.Methods: This is a multicenter cohort study. Persons living with HIV (PLWH) with HIV-1 RNA <50 copies/mL switching to BIC-STR or DTG-STR were included and followed-up 24 weeks. Major outcome was the analysis of (quantitative assessment of) discontinuation due to adverse events and self-suspension (EDAEs). Second, we assessed virologic failure (VF), and all-cause discontinuation (EDAC). Cox model for regression analysis was employed.Results: We included 786 PLWH: 524 with DTG, 262 with BIC. At week 24, we observed 70 EDAC: 5 for VF (1 with BIC and 4 with DTG; p = 0.6276), 10 simplifications, more frequently with BIC than DTG (n = 5, 1.9% and n = 5, 0.9%; p = 0.072) and 55 EDAEs, 7 (2.7%) with BIC, 48 (9.2%) with DTG (p = 0.0323). EDAEs due to neurological and gastrointestinal toxicity were similar (p = 0.2398 and p = 0.1160, respectively). There were no significant differences in the rates of VF and EDAC. EDAEs rate was significantly higher for DTG than for BIC. The adjusted HR for EDAEs in DTG group was 3.28 (95% CI: 1.34-8.00; p = 0.009). We identified an association between EDAE in the DTG group and having an age >60 and having switched from a regimen without ABC.Conclusions: PLWH who received DTG or BIC do not show differences in VF or EDAC rates. However, EDAEs is more frequent with DTG especially in the over-sixties and in those who come from regimens without abacavir.

2021 - Effects of cytokine blocking agents on hospital mortality in patients admitted to ICU with acute respiratory distress syndrome by SARS-CoV2 infection: retrospective cohort study. [Articolo su rivista]
Coloretti, I; Busani, S; Biagioni, E; Venturelli, S; Munari, E; Marco, S; Dall’Ara, L; Tosi, M; Clini, E; Tonelli, R; Fantini, R; Mussini, C; Meschiari, M; Guaraldi, G; Cossarizza, A; Alfano, G; Girardis, M; Gibellini, Lara
abstract

Background- The use of cytokine-blocking agents has been proposed to modulate the inflammatory response in patients with COVID19. Tocilizumab and Anakinra were included in the local protocol as an optional treatment in critically ill patients with acute respiratory distress syndrome (ARDS) by SARS-CoV2 infection. This cohort study evaluated the effects of therapy with cytokine blocking agents on in-hospital mortality in COVID19 patients requiring mechanical ventilation and admitted to intensive care unit. Methods- The association between therapy with Tocilizumab or Anakinra and in-hospital mortality was assessed in consecutive adult COVID19 patients admitted to our ICU with moderate to severe ARDS. The association was evaluated by comparing patients who receive to those who did not receive Tocilizumab or Anakinra and by using different multivariable Cox models adjusted for variables related to poor outcome, for the propensity to be treated with Tocilizumab or Anakinra and after patient matching. Results- Sixty-six patients who received immunotherapy (49 Tocilizumab, 17 Anakinra) and 28 patients who did not receive immunotherapy were included. The in-hospital crude mortality was 30,3% in treated patients and 50% in non-treated (OR 0,77, 95% CI 0,56-1,05, p=0,069). The adjusted Cox model showed an association between therapy with immunotherapy and in-hospital mortality (HR 0,40, 95% CI 0,19-0,83, p=0,015). This protective effect was further confirmed in the analysis adjusted for propensity score, in the propensity-matched cohort and in the cohort of patients with invasive mechanical ventilation within 2 hours after ICU admission. Conclusions- Although important limitations, our study showed that cytokine-blocking agents seem to be safe and to improve survival in COVID-19 patients admitted to ICU with ARDS and the need of mechanical ventilation.

2021 - Employing a systematic approach to biobanking and analyzing clinical and genetic data for advancing COVID-19 research [Articolo su rivista]
Daga, S.; Fallerini, C.; Baldassarri, M.; Fava, F.; Valentino, F.; Doddato, G.; Benetti, E.; Furini, S.; Giliberti, A.; Tita, R.; Amitrano, S.; Bruttini, M.; Meloni, I.; Pinto, A. M.; Raimondi, F.; Stella, A.; Biscarini, F.; Picchiotti, N.; Gori, M.; Pinoli, P.; Ceri, S.; Sanarico, M.; Crawley, F. P.; Birolo, G.; Montagnani, F.; Di Sarno, L.; Tommasi, A.; Palmieri, M.; Croci, S.; Emiliozzi, A.; Fabbiani, M.; Rossetti, B.; Zanelli, G.; Bergantini, L.; D'Alessandro, M.; Cameli, P.; Bennet, D.; Anedda, F.; Marcantonio, S.; Scolletta, S.; Franchi, F.; Mazzei, M. A.; Guerrini, S.; Conticini, E.; Cantarini, L.; Frediani, B.; Tacconi, D.; Spertilli, C.; Feri, M.; Donati, A.; Scala, R.; Guidelli, L.; Spargi, G.; Corridi, M.; Nencioni, C.; Croci, L.; Caldarelli, G. P.; Spagnesi, M.; Piacentini, P.; Bandini, M.; Desanctis, E.; Cappelli, S.; Canaccini, A.; Verzuri, A.; Anemoli, V.; Ognibene, A.; Vaghi, M.; D'Arminio Monforte, A.; Merlini, E.; Mondelli, M. U.; Mantovani, S.; Ludovisi, S.; Girardis, M.; Venturelli, S.; Sita, M.; Cossarizza, A.; Antinori, A.; Vergori, A.; Rusconi, S.; Siano, M.; Gabrieli, A.; Riva, A.; Francisci, D.; Schiaroli, E.; Scotton, P. G.; Andretta, F.; Panese, S.; Scaggiante, R.; Gatti, F.; Parisi, S. G.; Castelli, F.; Quiros-Roldan, M. E.; Magro, P.; Zanella, I.; Della Monica, M.; Piscopo, C.; Capasso, M.; Russo, R.; Andolfo, I.; Iolascon, A.; Fiorentino, G.; Carella, M.; Castori, M.; Merla, G.; Aucella, F.; Raggi, P.; Marciano, C.; Perna, R.; Bassetti, M.; Di Biagio, A.; Sanguinetti, M.; Masucci, L.; Gabbi, C.; Valente, S.; Meloni, I.; Mencarelli, M. A.; Rizzo, C. L.; Bargagli, E.; Mandala, M.; Giorli, A.; Salerni, L.; Zucchi, P.; Parravicini, P.; Menatti, E.; Baratti, S.; Trotta, T.; Giannattasio, F.; Coiro, G.; Lena, F.; Coviello, D. A.; Mussini, C.; Bosio, G.; Mancarella, S.; Tavecchia, L.; Renieri, A.; Mari, F.; Frullanti, E.
abstract

Within the GEN-COVID Multicenter Study, biospecimens from more than 1000 SARS-CoV-2 positive individuals have thus far been collected in the GEN-COVID Biobank (GCB). Sample types include whole blood, plasma, serum, leukocytes, and DNA. The GCB links samples to detailed clinical data available in the GEN-COVID Patient Registry (GCPR). It includes hospitalized patients (74.25%), broken down into intubated, treated by CPAP-biPAP, treated with O2 supplementation, and without respiratory support (9.5%, 18.4%, 31.55% and 14.8, respectively); and non-hospitalized subjects (25.75%), either pauci- or asymptomatic. More than 150 clinical patient-level data fields have been collected and binarized for further statistics according to the organs/systems primarily affected by COVID-19: heart, liver, pancreas, kidney, chemosensors, innate or adaptive immunity, and clotting system. Hierarchical clustering analysis identified five main clinical categories: (1) severe multisystemic failure with either thromboembolic or pancreatic variant; (2) cytokine storm type, either severe with liver involvement or moderate; (3) moderate heart type, either with or without liver damage; (4) moderate multisystemic involvement, either with or without liver damage; (5) mild, either with or without hyposmia. GCB and GCPR are further linked to the GCGDR, which includes data from whole-exome sequencing and high-density SNP genotyping. The data are available for sharing through the Network for Italian Genomes, found within the COVID-19 dedicated section. The study objective is to systematize this comprehensive data collection and begin identifying multi-organ involvement in COVID-19, defining genetic parameters for infection susceptibility within the population, and mapping genetically COVID-19 severity and clinical complexity among patients.

2021 - Endobronchial valve positioning for alveolar-pleural fistula following ICU management of severe COVID-19 pneumonia. [Articolo su rivista]
Donatelli, P; Trentacosti, F; Pellegrino, Mr; Tonelli, R; Bruzzi, G; Andreani, A; Cappiello, Gf; Andrisani, D; Gozzi, F; Mussini, C; Busani, S; Cavaliere, Gv; Girardis, M; Bertellini, E; Clini, E; Marchioni, A.
abstract

Background- Since December 2019 the outbreak of novel Coronavirus (Severe Acute Respiratory Sindrome-2, SARS-CoV2) has spread across the world. The main clinical consequences are respiratory failure even requiring mechanical ventilation, and pneumonia frequently sharing clinical and radiologic similarities to Acute Respiratory Distress Syndrome (ARDS). In this context the lung parenchyma is highly prone to ventilator-related injury, with pneumothorax and persistent air leak as the most serious adverse events. So far, endobronchial valve (EBV) positioning has proved efficacy in treating air leaks with high success rate. Case presentation- We report, for the first time, two cases of patients affected by SARS-CoV2-related pneumonia suffering from pneumothorax and persistent air leaks after invasive mechanical ventilation, and successfully treated through EBV positioning. Conclusions- Persistent air leaks may result from lung tissue damage due to a complex interaction between inflammation and ventilator-related injury (VILI), especially in the advanced stages of ARDS. EBV positioning seems to be a feasible and effective least-invasive therapeutic option for caring this subset of patients.

2021 - Endogenous control of inflammation characterizes pregnant women with asymptomatic or paucisymptomatic SARS-CoV-2 infection [Articolo su rivista]
De Biasi, S.; Tartaro, D. L.; Gibellini, L.; Paolini, A.; Quong, A.; Petes, C.; Awong, G.; Douglas, S.; Lin, D.; Nieto, J.; Galassi, F. M.; Borella, R.; Fidanza, L.; Mattioli, M.; Leone, C.; Neri, I.; Meschiari, M.; Cicchetti, L.; Iannone, A.; Trenti, T.; Sarti, M.; Girardis, M.; Guaraldi, G.; Mussini, C.; Facchinetti, F.; Cossarizza, A.
abstract

SARS-CoV-2 infection can affect all human beings, including pregnant women. Thus, understanding the immunological changes induced by the virus during pregnancy is nowadays of pivotal importance. Here, using peripheral blood from 14 pregnant women with asymptomatic or mild SARS-CoV-2 infection, we investigate cell proliferation and cytokine production, measure plasma levels of 62 cytokines, and perform a 38-parameter mass cytometry analysis. Our results show an increase in low density neutrophils but no lymphopenia or gross alterations of white blood cells, which display normal levels of differentiation, activation or exhaustion markers and show well preserved functionality. Meanwhile, the plasma levels of anti-inflammatory cytokines such as interleukin (IL)-1RA, IL-10 and IL-19 are increased, those of IL-17, PD-L1 and D-dimer are decreased, but IL-6 and other inflammatory molecules remain unchanged. Our profiling of antiviral immune responses may thus help develop therapeutic strategies to avoid virus-induced damages during pregnancy.

2021 - Five years with dolutegravir plus lamivudine as a switch strategy: much more than a positive finding [Articolo su rivista]
Ciccullo, A; Borghi, V; Giacomelli, A; Cossu, M V; Sterrantino, G; Latini, A; Giacometti, A; De Vito, A; Gennari, W; Madeddu, G; Capetti, A; D'Ettorre, G; Mussini, C; Rusconi, S; Di Giambenedetto, S; Baldin, G
abstract

Results from clinical trials and observational studies suggest that dolutegravir plus lamivudine could be an effective and well-tolerated option for simplification in HIV-1 positive patients. We aimed to assess long-time efficacy and safety in our multicenter cohort.

2021 - Genetic mechanisms of critical illness in COVID-19 [Articolo su rivista]
Pairo-Castineira, E.; Clohisey, S.; Klaric, L.; Bretherick, A. D.; Rawlik, K.; Pasko, D.; Walker, S.; Parkinson, N.; Fourman, M. H.; Russell, C. D.; Furniss, J.; Richmond, A.; Gountouna, E.; Wrobel, N.; Harrison, D.; Wang, B.; Wu, Y.; Meynert, A.; Griffiths, F.; Oosthuyzen, W.; Kousathanas, A.; Moutsianas, L.; Yang, Z.; Zhai, R.; Zheng, C.; Grimes, G.; Beale, R.; Millar, J.; Shih, B.; Keating, S.; Zechner, M.; Haley, C.; Porteous, D. J.; Hayward, C.; Yang, J.; Knight, J.; Summers, C.; Shankar-Hari, M.; Klenerman, P.; Turtle, L.; Ho, A.; Moore, S. C.; Hinds, C.; Horby, P.; Nichol, A.; Maslove, D.; Ling, L.; Mcauley, D.; Montgomery, H.; Walsh, T.; Pereira, A. C.; Renieri, A.; Millar, J.; Nichol, A.; Walsh, T.; Shankar-Hari, M.; Ponting, C.; Meikle, J.; Finernan, P.; Mcmaster, E.; Law, A.; Baillie, J. K.; Paterson, T.; Wackett, T.; Armstrong, R.; Clark, R.; Coutts, A.; Donnelly, L.; Gilchrist, T.; Hafezi, K.; Macgillivray, L.; Maclean, A.; Mccafferty, S.; Morrice, K.; Weaver, J.; Boz, C.; Golightly, A.; Ward, M.; Mal, H.; Szoor-McElhinney, H.; Brown, A.; Hendry, R.; Stenhouse, A.; Cullum, L.; Law, D.; Law, S.; Law, R.; Swets, M.; Day, N.; Taneski, F.; Duncan, E.; Parkinson, N.; Collier, D.; Wood, S.; Zak, A.; Borra, C.; Matharu, M.; May, P.; Alldis, Z.; Mitchelmore, O.; Bowles, R.; Easthope, A.; Bibi, F.; Lancoma-Malcolm, I.; Gurasashvili, J.; Pheby, J.; Shiel, J.; Bolton, M.; Patel, M.; Taylor, M.; Zongo, O.; Ebano, P.; Harding, P.; Astin-Chamberlain, R.; Choudhury, Y.; Cox, A.; Kallon, D.; Burton, M.; Hall, R.; Blowes, S.; Prime, Z.; Biddle, J.; Prysyazhna, O.; Newman, T.; Tierney, C.; Kassam, J.; Shankar-Hari, M.; Ostermann, M.; Campos, S.; Bociek, A.; Lim, R.; Grau, N.; Jones, T. O.; Whitton, C.; Marotti, M.; Arbane, G.; Bonner, S.; Hugill, K.; Reid, J.; Welters, I.; Waugh, V.; Williams, K.; Shaw, D.; Roman, J. F.; Martinez, M. L.; Johnson, E.; Waite, A.; Johnston, B.; Hamilton, D.; Mulla, S.; Mcphail, M.; Smith, J.; Baillie, J. K.; Barclay, L.; Hope, D.; Mcculloch, C.; Mcquillan, L.; Clark, S.; Singleton, J.; Priestley, K.; Rea, N.; Callaghan, M.; Campbell, R.; Andrew, G.; Marshall, L.; Mckechnie, S.; Hutton, P.; Bashyal, A.; Davidson, N.; Summers, C.; Polgarova, P.; Stroud, K.; Pathan, N.; Elston, K.; Agrawal, S.; Battle, C.; Newey, L.; Rees, T.; Harford, R.; Brinkworth, E.; Williams, M.; Murphy, C.; White, I.; Croft, M.; Bandla, N.; Gellamucho, M.; Tomlinson, J.; Turner, H.; Davies, M.; Quinn, A.; Hussain, I.; Thompson, C.; Parker, H.; Bradley, R.; Griffiths, R.; Scriven, J.; Nilsson, A.; Bates, M.; Dasgin, J.; Gill, J.; Puxty, A.; Cathcart, S.; Salutous, D.; Turner, L.; Duffy, K.; Puxty, K.; Joseph, A.; Herdman-Grant, R.; Simms, R.; Swain, A.; Naranjo, A.; Crowe, R.; Sollesta, K.; Loveridge, A.; Baptista, D.; Morino, E.; Davey, M.; Golden, D.; Jones, J.; Moreno Cuesta, J.; Haldeos, A.; Bakthavatsalam, D.; Vincent, R.; Elhassan, M.; Xavier, K.; Ganesan, A.; Purohit, D.; Abdelrazik, M.; Morgan, J.; Akeroyd, L.; Bano, S.; Lawton, T.; Warren, D.; Bromley, M.; Sellick, K.; Gurr, L.; Wilkinson, B.; Nagarajan, V.; Szedlak, P.; Cupitt, J.; Stoddard, E.; Benham, L.; Preston, S.; Laha, S.; Slawson, N.; Bradshaw, Z.; Brown, J.; Caswell, M.; Melling, S.; Bamford, P.; Faulkner, M.; Cawley, K.; Jeffrey, H.; London, E.; Sainsbury, H.; Nagra, I.; Nasir, F.; Dunmore, C.; Jones, R.; Abraheem, A.; Al-Moasseb, M.; Girach, R.; Padden, G.; Egan, J.; Brantwood, C.; Alexander, P.; Bradley-Potts, J.; Allen, S.; Felton, T.; Manna, S.; Farnell-Ward, S.; Leaver, S.; Queiroz, J.; Maccacari, E.; Dawson, D.; Delgado, C. C.; Saluzzio, R. P.; Ezeobu, O.; Ding, L.; Sicat, C.; Kanu, R.; Durrant, G.; Texeira, J.; Harrison, A.; Samakomva, T.; Scriven, J.; Willis, H.; Hopkins, B.; Thrasyvoulou, L.; Jackson, M.; Zaki, A.; Tibke, C.; Bennett, S.; Woodyatt, W.; Kent, A.; Goodwin, E.; Brandwood, C.; Clark, R.; Smith, L.; Rooney, K.; Thomson, N.; Rodden, N.; Hughes, E.; Mcglynn, D.; Clark, C.; Clark, P.; Abel, L.; Sundaram, R.; Gemmell, L.; Brett, M.; Hornsby, J.;
abstract

Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10−8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10−8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 × 10−12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10−8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte–macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice.

2021 - Genotypic HIV-1 tropism determination might help to identify people with exhausted treatment options and advanced disease [Articolo su rivista]
Bouba, Yagai; Armenia, Daniele; Forbici, Federica; Bertoli, Ada; Borghi, Vanni; Gagliardini, Roberta; Vergori, Alessandra; Cicalini, Stefania; Mazzotta, Valentina; Malagnino, Vincenzo; Lichtner, Miriam; Latini, Alessandra; Mussini, Cristina; Andreoni, Massimo; Antinori, Andrea; Perno, Carlo Federico; Ceccherini-Silberstein, Francesca; Santoro, Maria Mercedes
abstract

To evaluate HIV-1 tropism in 1382 combined antiretroviral therapy (cART)-experienced patients failing therapy to characterize those with exhausted therapeutic options.

2021 - Has COVID-19 changed the approach to HIV diagnosis?: A multicentric Italian experience [Articolo su rivista]
Mazzitelli, Maria; Ciccullo, Arturo; Baldin, Gianmaria; Cauda, Roberto; Rusconi, Stefano; Giacomelli, Andrea; Oreni, Letizia; Borghi, Vanni; Mussini, Cristina; Guaraldi, Giovanni; Sterrantino, Gaetana; Lagi, Filippo; Candelaresi, Bianca; Cirioni, Oscar; De Vito, Andrea; Rossetti, Barbara; Torti, Carlo; Di Giambenedetto, Simona
abstract

The occurrence of COVID-19 pandemic had a significant negative effect on health care systems over the last year. Health care providers were forced to focus mainly on COVID-19 patients, neglecting in many cases equally important diseases, both acute and chronic. Therefore, also screening and diagnostic strategies for HIV could have been significantly impaired.This retrospective, multicenter, observational study aimed at assessing the number and characteristics of new HIV/AIDS diagnoses during COVID-19 pandemic in Italy and compared characteristics of people living with HIV at diagnosis between pre- and post-COVID-19 era (2019 vs 2020).Our results showed a significant reduction of HIV diagnoses during pandemic. By contrast, people living with HIV during pandemic were older and were diagnosed in earlier stage of disease (considering CD4+ T cell count) compared to those who were diagnosed the year before. Moreover, there was a significant decrease of new HIV diagnoses among men who have sex with men, probably for the impact of social distancing and restriction applied by the Italian Government. Late presentation incidence, if numbers in 2020 were lower than those in 2019, is still an issue.Routinely performing HIV testing in patients with suspected SARS-CoV-2 infection is identifying and linking to care underdiagnosed people living with HIV earlier. Thus, combined tests (HIV and SARS-CoV-2) should be implemented in patients with SARS-CoV-2 symptoms overlapping HIV's ones. Lastly, our results lastly showed how urgent implementation of a national policy for HIV screening is necessary.

2021 - Heparin in COVID-19 Patients Is Associated with Reduced In-Hospital Mortality: The Multicenter Italian CORIST Study [Articolo su rivista]
Di Castelnuovo, A.; Costanzo, S.; Antinori, A.; Berselli, N.; Blandi, L.; Bonaccio, M.; Cauda, R.; Guaraldi, G.; Menicanti, L.; Mennuni, M.; Parruti, G.; Patti, G.; Santilli, F.; Signorelli, C.; Vergori, A.; Abete, P.; Ageno, W.; Agodi, A.; Agostoni, P.; Aiello, L.; Al Moghazi, S.; Arboretti, R.; Astuto, M.; Aucella, F.; Barbieri, G.; Bartoloni, A.; Bonfanti, P.; Cacciatore, F.; Caiano, L.; Carrozzi, L.; Cascio, A.; Ciccullo, A.; Cingolani, A.; Cipollone, F.; Colomba, C.; Colombo, C.; Crosta, F.; Danzi, G. B.; D'Ardes, D.; De Gaetano Donati, K.; Di Gennaro, F.; Di Tano, G.; D'Offizi, G.; Fantoni, M.; Fusco, F. M.; Gentile, I.; Gianfagna, F.; Grandone, E.; Graziani, E.; Grisafi, L.; Guarnieri, G.; Larizza, G.; Leone, A.; Maccagni, G.; Madaro, F.; Maitan, S.; Mancarella, S.; Mapelli, M.; Maragna, R.; Marcucci, R.; Maresca, G.; Marongiu, S.; Marotta, C.; Marra, L.; Mastroianni, F.; Mazzitelli, M.; Mengozzi, A.; Menichetti, F.; Meschiari, M.; Milic, J.; Minutolo, F.; Molena, B.; Montineri, A.; Mussini, C.; Musso, M.; Niola, D.; Odone, A.; Olivieri, M.; Palimodde, A.; Parisi, R.; Pasi, E.; Pesavento, R.; Petri, F.; Pinchera, B.; Poletti, V.; Ravaglia, C.; Rognoni, A.; Rossato, M.; Rossi, M.; Sangiovanni, V.; Sanrocco, C.; Scorzolini, L.; Sgariglia, R.; Simeone, P. G.; Taddei, E.; Torti, C.; Vettor, R.; Vianello, A.; Vinceti, M.; Virano, A.; Vocciante, L.; De Caterina, R.; Iacoviello, L.
abstract

Introduction A hypercoagulable condition was described in patients with coronavirus disease 2019 (COVID-19) and proposed as a possible pathogenic mechanism contributing to disease progression and lethality. Aim We evaluated if in-hospital administration of heparin improved survival in a large cohort of Italian COVID-19 patients. Methods In a retrospective observational study, 2,574 unselected patients hospitalized in 30 clinical centers in Italy from February 19, 2020 to June 5, 2020 with laboratory-confirmed severe acute respiratory syndrome coronavirus-2 infection were analyzed. The primary endpoint in a time-to event analysis was in-hospital death, comparing patients who received heparin (low-molecular-weight heparin [LMWH] or unfractionated heparin [UFH]) with patients who did not. We used multivariable Cox proportional-hazards regression models with inverse probability for treatment weighting by propensity scores. Results Out of 2,574 COVID-19 patients, 70.1% received heparin. LMWH was largely the most used formulation (99.5%). Death rates for patients receiving heparin or not were 7.4 and 14.0 per 1,000 person-days, respectively. After adjustment for propensity scores, we found a 40% lower risk of death in patients receiving heparin (hazard ratio = 0.60; 95% confidence interval: 0.49-0.74; E-value = 2.04). This association was particularly evident in patients with a higher severity of disease or strong coagulation activation. Conclusion In-hospital heparin treatment was associated with a lower mortality, particularly in severely ill COVID-19 patients and in those with strong coagulation activation. The results from randomized clinical trials are eagerly awaited to provide clear-cut recommendations.

2021 - Herpes Simplex re-activation in patients with SARS-CoV2 pneumonia: a prospective observational study. [Articolo su rivista]
Franceschini, E; Cozzi-Lepri, A; Santoro, A; Bacca, E; Lancellotti, G; Menozzi, M; Gennari, W; Meschiari, M; Bedini, A; Orlando, G; Puzzolante, C; Digaetano, M; Milic, J; Codeluppi, M; Pecorari, M; Carli, F; Cuomo, G; Alfano, G; Corradi, L; Tonelli, R; De Maria, N; Busani, S; Biagioni, E; Coloretti, I; Guaraldi, G; Sarti, M; Luppi, M; Clini, E; Girardis, M; Gyssens, I; Mussini, C.
abstract

Background: Herpes simplex 1 co-infections in patients with COVID-19 are considered relatively uncommon; some reports on re-activations in patients in intensive-care unit have been published. The aim of the study was to analyze herpetic re-activations and their clinical manifestations in hospitalized COVID-19 patients, performing HSV-1 PCR on plasma twice a week. Methods: We conducted a prospective, observational, single-center study involving 70 consecutive patients with severe/critical SARS-CoV-2 pneumonia tested for HSV-1 hospitalized at Azienda Ospedaliero-Universitaria of Modena. Results: Of these 70 patients, 21 (30.0%) showed detectable viremia and 13 (62%) had clinically relevant manifestations of HSV-1 infection corresponding to 15 events (4 pneumonia, 5 herpes labialis, 3 gingivostomatitis, one encephalitis and two hepatitis). HSV-1 positive patients were more frequently treated with steroids than HSV-1 negative patients (76.2% vs 49.0%, p 0.036) and more often underwent mechanical ventilation (IMV) (57.1% vs 22.4%, p 0.005). In the unadjusted logistic regression analysis, steroid treatment, IMV, and higher LDH were significantly associated with an increased risk of HSV1 re-activation (odds ratio 3.33, 4.61, and 16.9, respectively). The association with use of steroids was even stronger after controlling for previous use of both tocilizumab and IMV (OR=5.13, 95% CI:1.36-19.32, p=0.016). The effect size was larger when restricting to participants who were treated with high dose of steroids while there was no evidence to support an association with use of tocilizumab. Conclusions: Our study shows a high incidence of HSV-1 reactivation both virologically and clinically in patients with SARS-CoV-51 2 severe pneumonia, especially in those treated with steroids.

2021 - Human Immunodeficiency Virus (HIV) Care Models During the Coronavirus Disease 2019 (COVID-19) Era [Articolo su rivista]
Guaraldi, Giovanni; Milic, Jovana; Martinez, Esteban; Kamarulzaman, Adeeba; Mussini, Cristina; Waters, Laura; Pozniak, Anton; Mallon, Patrick; Rockstroh, Jürgen; Lazarus, Jeffrey V
abstract

The COVID-19 pandemic is an unprecedented global challenge that substantially risks reversing the progress in ending HIV. At the same time, it may offer the opportunity for a new era of HIV management. This viewpoint presents the impact of COVID-19 on HIV care, including the Joint United Nations Programme on HIV/AIDS (UNAIDS) "three 90s" targets. It outlines how to enhance a patient-centered care approach, now known as the "fourth 90," by integrating face-to-face patient-physician and telemedicine encounters. It suggests a framework for prevention and treatment of multimorbidity and frailty, to achieve a good health-related quality of life and preserve intrinsic capacity in all people living with HIV.

2021 - Hypokalemia in Patients with COVID-19 [Articolo su rivista]
Alfano, G.; Ferrari, A.; Fontana, F.; Perrone, R.; Mori, G.; Ascione, E.; Magistroni, R.; Venturi, G.; Pederzoli, S.; Margiotta, G.; Romeo, M.; Piccinini, F.; Franceschi, G.; Volpi, S.; Faltoni, M.; Ciusa, G.; Bacca, E.; Tutone, M.; Raimondi, A.; Menozzi, M.; Franceschini, E.; Cuomo, G.; Orlando, G.; Santoro, A.; Di Gaetano, M.; Puzzolante, C.; Carli, F.; Bedini, A.; Milic, J.; Meschiari, M.; Mussini, C.; Cappelli, G.; Guaraldi, G.; Borghi, V.; Burastero, G.; Corradi, L.; Di Gaetano, M.; Dolci, G.; Fantini, R.; Iadisernia, V.; Larne, D.; Pellegrino, F.; Rogati, C.; Santoro, A.; Tonelli, R.; Yaacoub, D.; Alfan, S.; Marco, B.; Pulizzi, R.; Leonelli, M.; Facchini, F.; Damiano, F.; Girardis, M.; Andreotti, A.; Biagioni, E.; Bondi, F.; Busani, S.; Chierego, G.; Scotti, M.; Cossarizza, L. S. A.; Bellinazzi, C.; Borella, R.; De Biasi, S.; De Gaetano, A.; Fidanza, L.; Gibellini, L.; Iannone, A.; Tartaro, D. L.; Mattioli, M.; Nasi, M.; Paolini, A.; Pinti, M.
abstract

Background: Patients with COVID-19 experience multiple clinical conditions that may cause electrolyte imbalances. Hypokalemia is a concerning electrolyte disorder closely associated with severe complications. This study aimed to estimate prevalence, risk factors and outcome of hypokalemia in a cohort of patients with confirmed COVID-19. Methods: A retrospective analysis was conducted on 290 non-ICU admitted patients with COVID-19 at the tertiary teaching hospital of Modena, Italy, from February 16 to April 14, 2020. Results: Hypokalemia was detected in 119 out of 290 patients (41%) during hospitalization. Mean serum potassium was 3.1 ± 0.1 meq/L. The majority of patients (90.7%) patients experienced only a mild decrease in serum potassium level (3–3.4 mEq/L). Hypokalemia was associated with hypocalcemia, which was detected in 50% of subjects. Urine potassium-to-creatinine ratio, measured in a small number of patients (n = 45; 36.1%), revealed an increase of urinary potassium excretion in most cases (95.5%). Risk factors for hypokalemia were female sex (odds ratio (OR) 2.44; 95% CI 1.36–4.37; P 0.003) and diuretic therapy (OR 1.94, 95% CI 1.08–3.48; P 0.027). Hypokalemia, adjusted for sex, age and SOFA score, was not associated with ICU transfer (OR 0.52; 95% CI 0.228–1.212; P = 0.131), in-hospital mortality (OR, 0.47; 95% CI 0.170–1.324; P = 0.154) and composite outcome of ICU transfer or in-hospital mortality (OR 0.48; 95% CI 0.222–1.047; P = 0.065) in our cohort of patients. Conclusions: Hypokalemia was a frequent disorder in subjects with COVID-19. Female sex and diuretic therapy were identified as risk factors for low serum potassium levels. Hypokalemia was unrelated to ICU transfer and death in this cohort of patients.

2021 - Identification and characterization of a SARS-CoV-2 specific CD8+ T cell response with immunodominant features [Articolo su rivista]
Gangaev, Anastasia; Ketelaars, Steven L C; Isaeva, Olga I; Patiwael, Sanne; Dopler, Anna; Hoefakker, Kelly; De Biasi, Sara; Gibellini, Lara; Mussini, Cristina; Guaraldi, Giovanni; Girardis, Massimo; Ormeno, Cami M P Talavera; Hekking, Paul J M; Lardy, Neubury M; Toebes, Mireille; Balderas, Robert; Schumacher, Ton N; Ovaa, Huib; Cossarizza, Andrea; Kvistborg, Pia
abstract

The COVID-19 pandemic caused by SARS-CoV-2 is a continuous challenge worldwide, and there is an urgent need to map the landscape of immunogenic and immunodominant epitopes recognized by CD8+ T cells. Here, we analyze samples from 31 patients with COVID-19 for CD8+ T cell recognition of 500 peptide-HLA class I complexes, restricted by 10 common HLA alleles. We identify 18 CD8+ T cell recognized SARS-CoV-2 epitopes, including an epitope with immunodominant features derived from ORF1ab and restricted by HLA-A*01:01. In-depth characterization of SARS-CoV-2-specific CD8+ T cell responses of patients with acute critical and severe disease reveals high expression of NKG2A, lack of cytokine production and a gene expression profile inhibiting T cell re-activation and migration while sustaining survival. SARS-CoV-2-specific CD8+ T cell responses are detectable up to 5 months after recovery from critical and severe disease, and these responses convert from dysfunctional effector to functional memory CD8+ T cells during convalescence.

2021 - Immunomodulation for the management of severe SARS-CoV2 infections. State of the art and review of the literature [Articolo su rivista]
Bacca, E.; Digaetano, M.; Meschiari, M.; Franceschini, E.; Menozzi, M.; Cuomo, G.; Mussini, C.
abstract

This Mini Review of the literature aimed to assess the role of tocilizumab for the treatment of severe coronavirus disease 2019 (COVID-19). Based on the available scientific evidence, it is not clear to date what is the best therapeutic strategy for the treatment of COVID-19. Since SARS-CoV-2 infection stimulates a vigorous proinflammatory response and may cause the so-called “cytokine storm”, immunomodulator drugs have been investigated as potential treatment for severe COVID-19 pneumonia. Among immunomodulators, tocilizumab, a recombinant humanized monoclonal antibody directed against IL-6 receptor, seems to be promising. An increasing number of clinical trials are exploring the role of tocilizumab in COVID-19, focusing on outcomes like mortality, risk of intensive care unit admission and the need for mechanical ventilation. At the moment, there is no conclusive evidence that tocilizumab would be proper outright in all patients with COVID-19 pneumonia, but some studies suggest that its use may be beneficial in selected categories of patients.

2021 - Incidence, risk factors and outcome of acute kidney injury (AKI) in patients with COVID-19 [Articolo su rivista]
Alfano, Gaetano; Ferrari, Annachiara; Fontana, Francesco; Mori, Giacomo; Magistroni, Riccardo; Meschiari, Marianna; Franceschini, Erica; Menozzi, Marianna; Cuomo, Gianluca; Orlando, Gabriella; Santoro, Antonella; Digaetano, Margherita; Puzzolante, Cinzia; Carli, Federica; Bedini, Andrea; Milic, Jovana; Coloretti, Irene; Raggi, Paolo; Mussini, Cristina; Girardis, Massimo; Cappelli, Gianni; Guaraldi, Giovanni
abstract

Background Acute kidney injury (AKI) is a severe complication of coronavirus disease-2019 (COVID-19). This study aims to evaluate incidence, risk factors and case-fatality rate of AKI in patients with COVID-19. Methods We reviewed the health medical records of 307 consecutive patients with COVID-19 hospitalized at the University Hospital of Modena, Italy. Results AKI was diagnosed in 69 out of 307 (22.4%) COVID-19 patients. Stages 1, 2, or 3 AKI accounted for 57.9%, 24.6% and 17.3%, respectively. AKI patients had a mean age of 74.7 +/- 9.9 years. These patients showed higher serum levels of the main markers of inflammation and higher rate of severe pneumonia than non-AKI patients. Kidney injury was associated with a higher rate of urinary abnormalities including proteinuria (0.44 +/- 0.85 vs 0.18 +/- 0.29 mg/mg; P = < 0.0001) and microscopic hematuria (P = 0.032) compared to non-AKI patients. Hemodialysis was performed in 7.2% of the subjects and 33.3% of the survivors did not recover kidney function after AKI. Risk factors for kidney injury were age, male sex, CKD and higher non-renal SOFA score. Patients with AKI had a mortality rate of 56.5%. Adjusted Cox regression analysis revealed that COVID-19-associated AKI was independently associated with in-hospital death (hazard ratio [HR] = 4.82; CI 95%, 1.36-17.08) compared to non-AKI patients. Conclusion AKI was a common and harmful consequence of COVID-19. It manifested with urinary abnormalities (proteinuria, microscopic hematuria) and conferred an increased risk for death. Given the well-known short-term sequelae of AKI, prevention of kidney injury is imperative in this vulnerable cohort of patients.

2021 - Inspiratory effort and lung mechanics in spontaneously breathing patients with acute respiratory failure due to COVID-19. A matched control study. [Articolo su rivista]
Tonelli, R; Busani, S; Tabbì, L; Fantini, R; Castaniere, I; Biagioni, E; Mussini, C; Girardis, M; Clini, E; Marchioni, A.
abstract

Several physical and biological mechanisms can drive progression between the different phases of lung injury due to SARS-CoV-2 infection, thus modifying the mechanical properties and behavior of COVID-19 over time. In this research letter we have presented the findings of a registered clinical trial aimed at describing and comparing the inspiratory effort (primary outcome) and the breathing pattern of spontaneously breathing patients with ARF in COVID-19 and historically matched non-COVID-19 patients, either candidate to NIV. Moreover, we reported the response to a 2 hours NIV trial in the two groups. Spontaneously breathing COVID-19 at their early onset of acute respiratory failure with indication for NIV showed different mechanical characteristics and breathing pattern when compared with non-COVID-19.

2021 - Lopinavir/Ritonavir and Darunavir/Cobicistat in Hospitalized COVID-19 Patients: Findings From the Multicenter Italian CORIST Study [Articolo su rivista]
Di Castelnuovo, Augusto; Costanzo, Simona; Antinori, Andrea; Berselli, Nausicaa; Blandi, Lorenzo; Bonaccio, Marialaura; Bruno, Raffaele; Cauda, Roberto; Gialluisi, Alessandro; Guaraldi, Giovanni; Menicanti, Lorenzo; Mennuni, Marco; My, Ilaria; Parruti, Agostino; Patti, Giuseppe; Perlini, Stefano; Santilli, Francesca; Signorelli, Carlo; Stefanini, Giulio G; Vergori, Alessandra; Ageno, Walter; Aiello, Luca; Agostoni, Piergiuseppe; Al Moghazi, Samir; Arboretti, Rosa; Aucella, Filippo; Barbieri, Greta; Barchitta, Martina; Bartoloni, Alessandro; Bologna, Carolina; Bonfanti, Paolo; Caiano, Lucia; Carrozzi, Laura; Cascio, Antonio; Castiglione, Giacomo; Chiarito, Mauro; Ciccullo, Arturo; Cingolani, Antonella; Cipollone, Francesco; Colomba, Claudia; Colombo, Crizia; Crosta, Francesco; Dalena, Giovanni; Dal Pra, Chiara; Danzi, Gian Battista; D'Ardes, Damiano; de Gaetano Donati, Katleen; Di Gennaro, Francesco; Di Tano, Giuseppe; D'Offizi, Gianpiero; Filippini, Tommaso; Maria Fusco, Francesco; Gaudiosi, Carlo; Gentile, Ivan; Gini, Giancarlo; Grandone, Elvira; Guarnieri, Gabriella; Lamanna, Gennaro L F; Larizza, Giovanni; Leone, Armando; Lio, Veronica; Losito, Angela Raffaella; Maccagni, Gloria; Maitan, Stefano; Mancarella, Sandro; Manuele, Rosa; Mapelli, Massimo; Maragna, Riccardo; Marra, Lorenzo; Maresca, Giulio; Marotta, Claudia; Mastroianni, Franco; Mazzitelli, Maria; Mengozzi, Alessandro; Menichetti, Francesco; Milic, Jovana; Minutolo, Filippo; Molena, Beatrice; Mussinelli, R; Mussini, Cristina; Musso, Maria; Odone, Anna; Olivieri, Marco; Pasi, Emanuela; Perroni, Annalisa; Petri, Francesco; Pinchera, Biagio; Pivato, Carlo A; Poletti, Venerino; Ravaglia, Claudia; Rossato, Marco; Rossi, Marianna; Sabena, Anna; Salinaro, Francesco; Sangiovanni, Vincenzo; Sanrocco, Carlo; Scorzolini, Laura; Sgariglia, Raffaella; Simeone, Paola Giustina; Spinicci, Michele; Trecarichi, Enrico Maria; Veronesi, Giovanni; Vettor, Roberto; Vianello, Andrea; Vinceti, Marco; Visconti, Elena; Vocciante, Laura; De Caterina, Raffaele; Iacoviello, Licia
abstract

Background: Protease inhibitors have been considered as possible therapeutic agents for COVID-19 patients. Objectives: To describe the association between lopinavir/ritonavir (LPV/r) or darunavir/cobicistat (DRV/c) use and in-hospital mortality in COVID-19 patients. Study Design: Multicenter observational study of COVID-19 patients admitted in 33 Italian hospitals. Medications, preexisting conditions, clinical measures, and outcomes were extracted from medical records. Patients were retrospectively divided in three groups, according to use of LPV/r, DRV/c or none of them. Primary outcome in a time-to event analysis was death. We used Cox proportional-hazards models with inverse probability of treatment weighting by multinomial propensity scores. Results: Out of 3,451 patients, 33.3% LPV/r and 13.9% received DRV/c. Patients receiving LPV/r or DRV/c were more likely younger, men, had higher C-reactive protein levels while less likely had hypertension, cardiovascular, pulmonary or kidney disease. After adjustment for propensity scores, LPV/r use was not associated with mortality (HR = 0.94, 95% CI 0.78 to 1.13), whereas treatment with DRV/c was associated with a higher death risk (HR = 1.89, 1.53 to 2.34, E-value = 2.43). This increased risk was more marked in women, in elderly, in patients with higher severity of COVID-19 and in patients receiving other COVID-19 drugs. Conclusions: In a large cohort of Italian patients hospitalized for COVID-19 in a real-life setting, the use of LPV/r treatment did not change death rate, while DRV/c was associated with increased mortality. Within the limits of an observational study, these data do not support the use of LPV/r or DRV/c in COVID-19 patients.

2021 - Mapping the human genetic architecture of COVID-19 [Articolo su rivista]
Niemi, M. E. K.; Karjalainen, J.; Liao, R. G.; Neale, B. M.; Daly, M.; Ganna, A.; Pathak, G. A.; Andrews, S. J.; Kanai, M.; Veerapen, K.; Fernandez-Cadenas, I.; Schulte, E. C.; Striano, P.; Marttila, M.; Minica, C.; Marouli, E.; Karim, M. A.; Wendt, F. R.; Savage, J.; Sloofman, L.; Butler-Laporte, G.; Kim, H. -N.; Kanoni, S.; Okada, Y.; Byun, J.; Han, Y.; Uddin, M. J.; Smith, G. D.; Willer, C. J.; Buxbaum, J. D.; Mehtonen, J.; Finucane, H.; Cordioli, M.; Martin, A. R.; Zhou, W.; Pasaniuc, B.; Julienne, H.; Aschard, H.; Shi, H.; Yengo, L.; Polimanti, R.; Ghoussaini, M.; Schwartzentruber, J.; Dunham, I.; Chwialkowska, K.; Francescatto, M.; Trankiem, A.; Balaconis, M. K.; Davis, L.; Lee, S.; Priest, J.; Renieri, A.; Sankaran, V. G.; van Heel, D.; Deelen, P.; Brent Richards, J.; Nakanishi, T.; Biesecker, L.; Eric Kerchberger, V.; Kenneth Baillie, J.; Mari, F.; Bernasconi, A.; Ceri, S.; Canakoglu, A.; Wolford, B.; Faucon, A.; Dutta, A. K.; Schurmann, C.; Harry, E.; Birney, E.; Nguyen, H.; Nasir, J.; Kaunisto, M.; Solomonson, M.; Dueker, N.; Vadgama, N.; Limou, S.; Rahmouni, S.; Mbarek, H.; Darwish, D.; Uddin, M. M.; Albertos, R.; Perez-Tur, J.; Li, R.; Folkersen, L.; Moltke, I.; Koelling, N.; Teumer, A.; Kousathanas, A.; Utrilla, A.; Verdugo, R. A.; Zarate, R.; Medina-Gomez, C.; Gomez-Cabrero, D.; Carnero-Montoro, E.; Cadilla, C. L.; Moreno-Estrada, A.; Garmendia, A.; Moya, L.; Sedaghati-Khayat, B.; Boua, P. R.; Fave, M. -J.; Francioli, L.; Lemacon, A.; Migeotte, I.; Patel, S.; Varnai, R.; Szentpeteri, J. L.; Sipeky, C.; Colombo, F.; von Hohenstaufen, K.; Lio, P.; Vallerga, C.; Wang, Q.; Tanigawa, Y.; Im, H.; Han, C.; Song, H.; Lim, J.; Lee, Y.; Kim, S.; Im, S.; Atanasovska, B.; Ahmad, H. F.; Boer, C.; Jansen, P.; Kaja, E.; Pasko, D.; Kennis-Szilagyi, I.; Kornilov, S. A.; Prijatelj, V.; Prokic, I.; Sivanadhan, I.; Perumal, S.; Esmaeeli, S.; Pearson, N. M.; Auton, A.; Shelton, J. F.; Shastri, A. J.; Filshtein-Sonmez, T.; Coker, D.; Symons, A.; Esparza-Gordillo, J.; Aslibekyan, S.; O'Connell, J.; Ye, C.; Weldon, C. H.; Perera, M.; O'Leary, K.; Tuck, M.; O'Brien, T.; Meltzer, D.; O'Donnell, P.; Nutescu, E.; Yang, G.; Alarcon, C.; Herrmann, S.; Mazurek, S.; Banagan, J.; Hamidi, Z.; Barbour, A.; Raffat, N.; Moreno, D.; Friedman, P.; Ferwerda, B.; van de Beek, D.; Brouwer, M. C.; Vlaar, A. P. J.; Joost Wiersinga, W.; Posthuma, D.; Tissink, E.; Koos Zwinderman, A. H.; Uffelmann, E.; van Agtmael, M.; Algera, A. G.; van Baarle, F.; Bax, D.; Beudel, M.; Bogaard, H. J.; Bomers, M.; Bonta, P. I.; Bos, L.; Botta, M.; de Brabander, J.; de Bree, G.; de Bruin, S.; Bugiani, M.; Bulle, E.; Chouchane, O.; Cloherty, A.; Dongelmans, D.; Elbers, P.; Fleuren, L.; Geerlings, S.; Geerts, B.; Geijtenbeek, T.; Girbes, A.; Goorhuis, B.; Grobusch, M. P.; Hafkamp, F.; Hagens, L.; Hamann, J.; Harris, V.; Hemke, R.; Hermans, S. M.; Heunks, L.; Hollmann, M.; Horn, J.; Hovius, J. W.; de Jong, M. D.; Koning, R.; van Mourik, N.; Nellen, J.; Nossent, E. J.; Paulus, F.; Peters, E.; van der Poll, T.; Preckel, B.; Prins, J. M.; Raasveld, J.; Reijnders, T.; Schinkel, M.; Schultz, M. J.; Schuurman, A.; Sigaloff, K.; Smit, M.; Stijnis, C. S.; Stilma, W.; Teunissen, C.; Thoral, P.; Tsonas, A.; van der Valk, M.; Veelo, D.; de Vries, H.; van Vugt, M.; Wouters, D.; Minnaar, R. P.; Kromhout, A.; van Uffelen, K. W. J.; Wolterman, R. A.; Roberts, G.; Park, D.; Ball, C. A.; Coignet, M.; Mccurdy, S.; Knight, S.; Partha, R.; Rhead, B.; Zhang, M.; Berkowitz, N.; Gaddis, M.; Noto, K.; Ruiz, L.; Pavlovic, M.; Hong, E. L.; Rand, K.; Girshick, A.; Guturu, H.; Baltzell, A. H.; Guntz, J.; Beguin, Y.; Pigazzini, S.; Nkambule, L.; Bouysran, Y.; Busson, A.; Peyrassol, X.; Wilkin, F.; Pichon, B.; Smits, G.; Vandernoot, I.; Goffard, J. -C.; Georges, M.; Moutschen, M.; Misset, B.; Darcis, G.; Guiot, J.; Jadot, L.; Azarzar, S.; Dellot, P.; Gofflot, S.; Claassen, S.; Bertrand, A.; Parzibut, G.; Clarinval, M.; Moermans, C.; Malaise, O.; El Kandoussi, K.; Thonon, R.; Huynen, P.; Mesdagh, A.; Melo, S.
abstract

The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-191,2, host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases3–7. They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease.

2021 - Measles-induced immune amnesia likely recorded in the 18th century [Articolo su rivista]
Galassi, F. M.; Varotto, E.; Mussini, C.; Cossarizza, A.
abstract

2021 - Methylprednisolone as rescue therapy after tocilizumab failure in patients with severe COVID-19 pneumonia [Articolo su rivista]
Guaraldi, Giovanni; Banchelli, Federico; Milic, Jovana; Dolci, Giovanni; Massari, Marco; Corsini, Romina; Meschiari, Marianna; Girardis, Massimo; Busani, Stefano; Cossarizza, Andrea; Salvarani, Carlo; Mussini, Cristina; D'Amico, Roberto
abstract

2021 - Monocyte Distribution Width (MDW) as novel inflammatory marker with prognostic significance in COVID-19 patients [Articolo su rivista]
Riva, G.; Castellano, S.; Nasillo, V.; Ottomano, A. M.; Bergonzini, G.; Paolini, A.; Lusenti, B.; Milic, J.; De Biasi, S.; Gibellini, L.; Cossarizza, A.; Busani, S.; Girardis, M.; Guaraldi, G.; Mussini, C.; Manfredini, R.; Luppi, M.; Tagliafico, E.; Trenti, T.
abstract

Monocyte Distribution Width (MDW), a new cytometric parameter correlating with cytomorphologic changes occurring upon massive monocyte activation, has recently emerged as promising early biomarker of sepsis. Similar to sepsis, monocyte/macrophage subsets are considered key mediators of the life-threatening hyper-inflammatory disorder characterizing severe COVID-19. In this study, we longitudinally analyzed MDW values in a cohort of 87 COVID-19 patients consecutively admitted to our hospital, showing significant correlations between MDW and common inflammatory markers, namely CRP (p < 0.001), fibrinogen (p < 0.001) and ferritin (p < 0.01). Moreover, high MDW values resulted to be prognostically associated with fatal outcome in COVID-19 patients (AUC = 0.76, 95% CI: 0.66–0.87, sensitivity 0.75, specificity 0.70, MDW threshold 26.4; RR = 4.91, 95% CI: 1.73–13.96; OR = 7.14, 95% CI: 2.06–24.71). This pilot study shows that MDW can be useful in the monitoring of COVID-19 patients, as this innovative hematologic biomarker is: (1) easy to obtain, (2) directly related to the activation state of a fundamental inflammatory cell subset (i.e. monocytes, pivotal in both cytokine storm and sepsis immunopathogenesis), (3) well correlated with clinical severity of COVID-19-associated inflammatory disorder, and, in turn, (4) endowed with relevant prognostic significance. Additional studies are needed to define further the clinical impact of MDW testing in the management of COVID-19 patients.

2021 - NLRP3 and IL-1β gene expression is elevated in monocytes from HIV treated patients with neurocognitive disorders [Articolo su rivista]
Mazaheri-Tehrani, Elham; Mohraz, Minoo; Nasi, Milena; Chester, Johanna; De Gaetano, Anna; Lo Tartaro, Domenico; Seyedalinaghi, Seyedahmad; Gholami, Mohammad; De Biasi, Sara; Gibellini, Lara; Mattioli, Anna Vittoria; Pinti, Marcello; Mussini, Cristina; Cossarizza, Andrea
abstract

Systemic immune activation and inflammation in chronic HIV infection are driving factors of non-AIDS related events, including neurocognitive impairment. The role of inflammasome in monocytes from patients with HIV infection has been extensively studied but its association with the extent of neurocognitive dysfunction has been poorly investigated.

2021 - No need for secondary Pneumocystis jirovecii pneumonia prophylaxis in adult people living with HIV from Europe on ART with suppressed viraemia and a CD4 cell count greater than 100 cells/µL [Articolo su rivista]
Atkinson, A.; Miro, J. M.; Mocroft, A.; Reiss, P.; Kirk, O.; Morlat, P.; Ghosn, J.; Stephan, C.; Mussini, C.; Antoniadou, A.; Doerholt, K.; Girardi, E.; De Wit, S.; Kraus, D.; Zwahlen, M.; Furrer, H.; De Wit, S.; Antoniadou, A.; Castagna, A.; Doerholt, K.; Fatkenheuer, G.; Raben, D.; Teira, R.; Zangerle, R.; Judd, A.; Zangerle, R.; Touloumi, G.; Warszawski, J.; Meyer, L.; Dabis, F.; Krause, M. M.; Leport, C.; Wittkop, L.; Wit, F.; Prins, M.; Bucher, H.; Gibb, D.; Fatkenheuer, G.; Del Amo, J.; Obel, N.; Thorne, C.; Perez-Hoyos, S.; Hamouda, O.; Bartmeyer, B.; Chkhartishvili, N.; Noguera-Julian, A.; Antinori, A.; d'Arminio Monforte, A.; Brockmeyer, N.; Prieto, L.; Conejo, P. R.; Soriano-Arandes, A.; Battegay, M.; Kouyos, R.; Casabona, J.; Castagna, A.; Goetghebuer, T.; Sonnerborg, A.; Torti, C.; Sabin, C.; Teira, R.; Garrido, M.; Haerry, D.; Costagliola, D.; d'Arminio-Monforte, A.; Castagna, A.; del Amo, J.; Raben, D.; Chene, G.; Judd, A.; Conejo, P. R.; Barger, D.; Schwimmer, C.; Termote, M.; Wittkop, L.; Frederiksen, C. M.; Raben, D.; Brandt, R. S.; Berenguer, J.; Bohlius, J.; Bouteloup, V.; Bucher, H.; Cozzi-Lepri, A.; Dabis, F.; d'Arminio Monforte, A.; Davies, M. -A.; del Amo, J.; Dorrucci, M.; Dunn, D.; Egger, M.; Guiguet, M.; Grabar, S.; Judd, A.; Lambotte, O.; Leroy, V.; Lodi, S.; Matheron, S.; Meyer, L.; Monge, S.; Nakagawa, F.; Paredes, R.; Phillips, A.; Puoti, M.; Rohner, E.; Schomaker, M.; Smit, C.; Sterne, J.; Thiebaut, R.; Thorne, C.; Wqetu, C.; van der Valk, M.; Wittkop, L.
abstract

Introduction: Since the beginning of the HIV epidemic in resource-rich countries, Pneumocystis jirovecii pneumonia (PjP) is one of the most frequent opportunistic AIDS-defining infections. The Collaboration of Observational HIV Epidemiological Research Europe (COHERE) has shown that primary Pneumocystis jirovecii Pneumonia (PjP) prophylaxis can be safely withdrawn in patients with CD4 counts of 100 to 200 cells/µL if plasma HIV-RNA is suppressed on combination antiretroviral therapy. Whether this holds true for secondary prophylaxis is not known, and this has proved difficult to determine due to the much lower population at risk. Methods: We estimated the incidence of secondary PjP by including patient data collected from 1998 to 2015 from the COHERE cohort collaboration according to time-updated CD4 counts, HIV-RNA and use of PjP prophylaxis in persons >16 years of age. We fitted a Poisson generalized additive model in which the smoothed effect of CD4 was modelled by a restricted cubic spline, and HIV-RNA was stratified as low (<400), medium (400 to 10,000) or high (>10,000copies/mL). Results: There were 373 recurrences of PjP during 74,295 person-years (py) in 10,476 patients. The PjP incidence in the different plasma HIV-RNA strata differed significantly and was lowest in the low stratum. For patients off prophylaxis with CD4 counts between 100 and 200 cells/µL and HIV-RNA below 400 copies/mL, the incidence of recurrent PjP was 3.9 (95% CI: 2.0 to 5.8) per 1000 py, not significantly different from patients on prophylaxis in the same stratum (1.9, 95% CI: 0.1 to 3.7). Conclusions: HIV viraemia importantly affects the risk of recurrent PjP. In virologically suppressed patients on ART with CD4 counts of 100 to 200/µL, the incidence of PjP off prophylaxis is below 10/1000 py. Secondary PjP prophylaxis may be safely withheld in such patients. While European guidelines recommend discontinuing secondary PjP prophylaxis only if CD4 counts rise above 200 cells/mL, the latest US Guidelines consider secondary prophylaxis discontinuation even in patients with a CD4 count above 100 cells/µL and suppressed viral load. Our results strengthen and support this US recommendation.

2021 - Nucleoside Reverse-Transcriptase Inhibitor Resistance Mutations Predict Virological Failure in Human Immunodeficiency Virus-Positive Patients during Lamivudine plus Dolutegravir Maintenance Therapy in Clinical Practice [Articolo su rivista]
Borghetti, A.; Giacomelli, A.; Borghi, V.; Ciccullo, A.; Dusina, A.; Fabbiani, M.; Rusconi, S.; Zazzi, M.; Mussini, C.; Di Giambenedetto, S.
abstract

The TANGO trial demonstrated the efficacy of lamivudine plus dolutegravir in virologically suppressed patients without previous virological failures (VFs). In this dataset from clinical practice investigating the impact of past nucleoside reverse-transcriptase inhibitor resistance on this strategy, the combination of M184V/I plus at least 1 thymidine analog-associated mutation significantly increased the risk of VF.

2021 - Patient-reported olfactory recovery after SARS-CoV-2 infection: A 6-month follow-up study [Articolo su rivista]
Lucidi, D.; Molinari, G.; Silvestri, M.; De Corso, E.; Guaraldi, G.; Mussini, C.; Presutti, L.; Fernandez, I. J.
abstract

2021 - Piperacillin-tazobactam versus meropenem for treatment of bloodstream infections caused by third-generation cephalosporin-resistant Enterobacteriaceae: A study protocol for a non-inferiority open-label randomised controlled trial (PeterPen) [Articolo su rivista]
Bitterman, R.; Koppel, F.; Mussini, C.; Geffen, Y.; Chowers, M.; Rahav, G.; Nesher, L.; Ben-Ami, R.; Turjeman, A.; Huberman Samuel, M.; Cheng, M. P.; Lee, T. C.; Leibovici, L.; Yahav, D.; Paul, M.
abstract

Introduction The optimal treatment for extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae bloodstream infections has yet to be defined. Retrospective studies have shown conflicting results, with most data suggesting the non-inferiority of beta-lactam-beta-lactamase inhibitor combinations compared with carbapenems. However, the recently published MERINO trial failed to demonstrate the non-inferiority of piperacillin-tazobactam to meropenem. The potential implications of the MERINO trial are profound, as widespread adoption of carbapenem treatment will have detrimental effects on antimicrobial stewardship in areas endemic for ESBL and carbapenem-resistant bacteria. Therefore, we believe that it is justified to re-examine the comparison in a second randomised controlled trial prior to changing clinical practice. Methods and analysis PeterPen is a multicentre, investigator-initiated, open-label, randomised controlled non-inferiority trial, comparing piperacillin-tazobactam with meropenem for third-generation cephalosporin-resistant Escherichia coli and Klebsiella bloodstream infections. The study is currently being conducted in six centres in Israel and one in Canada with other centres from Israel, Italy and Canada expected to join. The two primary outcomes are all-cause mortality at day 30 from enrolment and treatment failure at day seven (death, fever above 38°C in the last 48 hours, continuous symptoms, increasing Sequential Organ Failure Assessment Score or persistent blood cultures with the index pathogen). A sample size of 1084 patients was calculated for the mortality endpoint assuming a 12.5% mortality rate in the control group with a 5% non-inferiority margin and assuming 100% follow-up for this outcome. Ethics and dissemination The study is approved by local and national ethics committees as required. Results will be published, and trial data will be made available. Trial registration numbers ClinicalTrials.gov Registry (NCT03671967); Israeli Ministry of Health Trials Registry (MOH_2018-12-25_004857).

2021 - Prevalence and Outcomes for Heavily Treatment-Experienced Individuals Living With Human Immunodeficiency Virus in a European Cohort [Articolo su rivista]
Pelchen-Matthews, A.; Borges, A. H.; Reekie, J.; Rasmussen, L. D.; Wiese, L.; Weber, J.; Pradier, C.; Degen, O.; Paredes, R.; Tau, L.; Flamholc, L.; Gottfredsson, M.; Kowalska, J. D.; Jablonowska, E.; Mozer-Lisewska, I.; Radoi, R.; Vasylyev, M.; Kuznetsova, A.; Begovac, J.; Svedhem, V.; Clark, A.; Cozzi-Lepri, A.; Harxhi, A.; Losso, M.; Kundro, M.; Schmied, B.; Zangerle, R.; Karpov, I.; Vassilenko, A.; Mitsura, V. M.; Paduto, D.; Clumeck, N.; De Wit, S.; Delforge, M.; Florence, E.; Vandekerckhove, L.; Hadziosmanovic, V.; Machala, L.; Jilich, D.; Sedlacek, D.; Kronborg, G.; Benfield, T.; Gerstoft, J.; Katzenstein, T.; Pedersen, C.; Johansen, I. S.; Ostergaard, L.; Moller, N. F.; Nielsen, L. N.; Zilmer, K.; Smidt, J.; Aho, I.; Viard, J. -P.; Girard, P. -M.; Fontas, E.; Duvivier, C.; Rockstroh, J.; Behrens, G.; Stellbrink, H. J.; Stephan, C.; Goethe, J. W.; Bogner, J.; Fatkenheuer, G.; Chkhartishvili, N.; Sambatakou, H.; Adamis, G.; Paissios, N.; Szlavik, J.; Kelly, C.; Turner, D.; Burke, M.; Shahar, E.; Hassoun, G.; Elinav, H.; Haouzi, M.; Elbirt, D.; D'Arminio Monforte, A.; Esposito, R.; Mazeu, I.; Mussini, C.; Mazzotta, F.; Gabbuti, A.; Lazzarin, A.; Castagna, A.; Gianotti, N.; Galli, M.; Ridolfo, A.; Uzdaviniene, V.; Matulionyte, R.; Staub, T.; Hemmer, R.; Dragas, S.; Stevanovic, M.; Reiss, P.; Trajanovska, J.; Reikvam, D. H.; Maeland, A.; Bruun, J.; Knysz, B.; Gasiorowski, J.; Inglot, M.; Bakowska, E.; Flisiak, R.; Grzeszczuk, A.; Parczewski, M.; Maciejewska, K.; Aksak-Was, B.; Beniowski, M.; Mularska, E.; Kamerys, J.; Wojcik, K.; Rozplochowski, B.; Zagalo, A.; Mansinho, K.; Maltez, F.; Oprea, C.; Yakovlev, A.; Trofimora, T.; Khromova, I.; Kuzovatova, E.; Borodulina, E.; Vdoushkina, E.; Ranin, J.; Tomazic, J.; Miro, J. M.; Miro, J. M.; Laguno, M.; Martinez, E.; Garcia, F.; Blanco, J. L.; Martinez-Rebollar, M.; Mallolas, J.; Callau, P.; Rojas, J.; Inciarta, A.; Moreno, S.; del Campo, S.; Clotet, B.; Jou, A.; Puig, J.; Llibre, J. M.; Santos, J. R.; Domingo, P.; Gutierrez, M.; Mateo, G.; Sambeat, M. A.; Laporte, J. M.; Falconer, K.; Thalme, A.; Sonnerborg, A.; Treutiger, C. J.; Scherrer, A.; Weber, R.; Cavassini, M.; Calmy, A.; Furrer, H.; Battegay, M.; Schmid, P.; Mikhalik, J.; Sluzhynska, M.; Milinkovic, A.; Johnson, A. M.; Simons, E.; Edwards, S.; Phillips, A.; Johnson, M. A.; Mocroft, A.; Orkin, C.; Winston, A.; Leen, C.; Wandeler, G.; Lundgren, J.; Guaraldi, G.; Kirk, O.; Peters, L.; Bojesen, A.; Raben, D.; Hansen, E. V.; Kristensen, D.; Larsen, J. F.; Fischer, A. H.; Amele, S.; Roen, A.
abstract

Background: Although antiretroviral treatments have improved survival of persons living with HIV, their long-term use may limit available drug options. We estimated the prevalence of heavily treatmentexperienced (HTE) status and the potential clinical consequences of becoming HTE. Setting: EuroSIDA, a European multicenter prospective cohort study. Methods: A composite definition for HTE was developed, based on estimates of antiretroviral resistance and prior exposure to specific antiretroviral regimens. Risks of progressing to clinical outcomes were assessed by Poisson regression, comparing every HTE individual with 3 randomly selected controls who never became HTE. Results: Of 15,570 individuals under follow-up in 2010-2016, 1617 (10.4%, 95% CI: 9.9% to 10.9%) were classified as HTE. 1093 individuals became HTE during prospective follow-up (HTE incidence rate 1.76, CI: 1.66 to 1.87 per 100 person-years of follow-up). The number of HTE individuals was highest in West/Central Europe (636/4019 persons, 15.7%) and lowest in East Europe (26/2279 persons, 1.1%). Although most HTE individuals maintained controlled viral loads (<400 copies/mL), many had low CD4 counts (≤350 cells/μL). After controlling for age, immunological parameters and pre-existing comorbidities, HTE status was not associated with the risk of new AIDS (adjusted incidence rate ratio, aIRR 1.44, CI: 0.86 to 2.40, P = 0.16) or non-AIDS clinical events (aIRR 0.96, CI: 0.74 to 1.25, P = 0.77). Conclusions: HTE prevalence increased with time. After adjusting for key confounding factors, there was no evidence for an increased risk of new AIDS or non-AIDS clinical events in HTE. Additional therapeutic options and effective management of comorbidities remain important to reduce clinical complications in HTE individuals.

2021 - Prospective Study on Incidence, Risk Factors and Outcome of Recurrent Clostridioides difficile Infections [Articolo su rivista]
Granata, Guido; Petrosillo, Nicola; Adamoli, Lucia; Bartoletti, Michele; Bartoloni, Alessandro; Basile, Gregorio; Bassetti, Matteo; Bonfanti, Paolo; Borromeo, Raffaella; Ceccarelli, Giancarlo; De Luca, Anna; Di Bella, Stefano; Fossati, Sara; Franceschini, Erica; Gentile, Ivan; Giacobbe, Daniele; Giacometti, Enrica; Ingrassia, Fabrizio; Lagi, Filippo; Lobreglio, Giambattista; Lombardi, Andrea; Lupo, Laura; Luzzati, Roberto; Maraolo, Alberto; Mikulska, Malgorzata; Mondelli, Mario; Mularoni, Alessandra; Mussini, Cristina; Oliva, Alessandra; Pandolfo, Alessandro; Rogati, Carlotta; Trapani, Filippo; Venditti, Mario; Viale, Pierluigi; Caraffa, Emanuela; Cataldo, Maria
abstract

Background: Limited and wide-ranging data are available on the recurrent Clostridioides difficile infection (rCDI) incidence rate. Methods: We performed a cohort study with the aim to assess the incidence of and risk factors for rCDI. Adult patients with a first CDI, hospitalized in 15 Italian hospitals, were prospectively included and followed-up for 30 d after the end of antimicrobial treatment for their first CDI. A case-control study was performed to identify risk factors associated with 30-day onset rCDI. Results: Three hundred nine patients with a first CDI were included in the study; 32% of the CDI episodes (99/309) were severe/complicated; complete follow-up was available for 288 patients (19 died during the first CDI episode, and 2 were lost during follow-up). At the end of the study, the crude all-cause mortality rate was 10.7% (33 deaths/309 patients). Two hundred seventy-one patients completed the follow-up; rCDI occurred in 21% of patients (56/271) with an incidence rate of 72/10,000 patient-days. Logistic regression analysis identified exposure to cephalosporin as an independent risk factor associated with rCDI (RR: 1.7; 95% CI: 1.1-2.7, p = 0.03). Conclusion: Our study confirms the relevance of rCDI in terms of morbidity and mortality and provides a reliable estimation of its incidence.

2021 - Protective role of a tmprss2 variant on severe covid-19 outcome in young males and elderly women [Articolo su rivista]
Monticelli, M.; Mele, B. H.; Benetti, E.; Fallerini, C.; Baldassarri, M.; Furini, S.; Frullanti, E.; Mari, F.; Andreotti, G.; Cubellis, M. V.; Renieri, A.; Daga, S.; Fava, F.; Valentino, F.; Doddato, G.; Giliberti, A.; Tita, R.; Amitrano, S.; Bruttini, M.; Croci, S.; Meloni, I.; Pinto, A. M.; Mencarelli, M. A.; Rizzo, C. L.; Montagnani, F.; Sarno, L. D.; Tommasi, A.; Palmieri, M.; Carriero, M. L.; Alaverdian, D.; Beligni, G.; Iuso, N.; Inchingolo, G.; Fabbiani, M.; Rossetti, B.; Zanelli, G.; Bargagli, E.; Bergantini, L.; D'Alessandro, M.; Cameli, P.; Bennet, D.; Anedda, F.; Marcantonio, S.; Scolletta, S.; Franchi, F.; Mazzei, M. A.; Guerrini, S.; Conticini, E.; Cantarini, L.; Frediani, B.; Tacconi, D.; Spertilli, C.; Feri, M.; Donati, A.; Scala, R.; Guidelli, L.; Spargi, G.; Corridi, M.; Nencioni, C.; Croci, L.; Caldarelli, G. P.; Spagnesi, M.; Piacentini, P.; Bandini, M.; Desanctis, E.; Cappelli, S.; Canaccini, A.; Verzuri, A.; Anemoli, V.; Ognibene, A.; Pancrazi, A.; Lorusso, M.; Vaghi, M.; D'Arminio Monforte, A.; Merlini, E.; Miraglia, F. G.; Mondelli, M. U.; Bruno, R.; Marco, V.; Mantovani, S.; Ludovisi, S.; Girardi, M.; Venturelli, S.; Sita, M.; Cossarizza, A.; Antinori, A.; Vergori, A.; Emiliozzi, A.; Rusconi, S.; Siano, M.; Gabrieli, A.; Riva, A.; Francisci, D.; Schiarol, E.; Paciosi, F.; Scotton, P. G.; Andretta, F.; Panese, S.; Scaggiante, R.; Gatti, F.; Parisi, S. G.; Castelli, F.; Quiros-Roldan, E.; Antoni, M. D.; Zanella, I.; Monica, M. D.; Piscopo, C.; Capasso, M.; Russo, R.; Andolfo, I.; Iolascon, A.; Fiorentino, G.; Carella, M.; Castori, M.; Merla, G.; Squeo, G. M.; Aucella, F.; Raggi, P.; Marciano, C.; Perna, R.; Bassetti, M.; Biagio, A. D.; Sanguinetti, M.; Masucci, L.; Valente, S.; Mandala, M.; Giorli, A.; Salerni, L.; Zucchi, P.; Parravicini, P.; Menatti, E.; Baratti, S.; Trotta, T.; Giannattasio, F.; Coiro, G.; Lena, F.; Coviello, D. A.; Mussini, C.; Bosio, G.; Martinelli, E.; Mancarella, S.; Tavecchia, L.; Crotti, L.; Parati, G. -F.; Picchiotti, N.; Gori, M.; Gabbi, C.; Sanarico, M.; Ceri, S.; Pinoli, P.; Raimondi, F.; Bis-Carini, F.; Stella, A.; Rizzi, M.; Maggiolo, F.; Ripamonti, D.; Suardi, C.; Bachetti, T.; Rovere, M. T. L.; Sarzi-Braga, S.; Bussotti, M.; Bergomi, M.; Capitani, K.; Zguro, K.; Dei, S.
abstract

The protease encoded by the TMPRSS2 gene facilitates viral infections and has been implicated in the pathogenesis of SARS-CoV-2. We analyzed the TMPRSS2 sequence and correlated the protein variants with the clinical features of a cohort of 1177 patients affected by COVID-19 in Italy. Nine relatively common variants (allele frequency > 0.01) and six missense variants which may affect the protease activity according to PolyPhen-2 in HumVar-trained mode were identified. Among them, p.V197M (p.Val197Met) (rs12329760) emerges as a common variant that has a deleterious effect on the protease and a protective effect on the patients. Its role appears particularly relevant in two subgroups of patients—young males and elderly women—and among those affected by co-morbidities, where the variant frequency is higher among individuals who were mildly affected by the disease and did not need hospitalization or oxygen therapy than among those more severely affected, who required oxygen therapy, ventilation or intubation. This study provides useful information for the identification of patients at risk of developing a severe form of COVID-19, and encourages the usage of drugs affecting the expression of TMPRSS2 or inhibiting protein activity.

2021 - Rare variants in Toll-like receptor 7 results in functional impairment and downregulation of cytokine-mediated signaling in COVID-19 patients [Articolo su rivista]
Mantovani, S.; Daga, S.; Fallerini, C.; Baldassarri, M.; Benetti, E.; Picchiotti, N.; Fava, F.; Galli, A.; Zibellini, S.; Bruttini, M.; Palmieri, M.; Croci, S.; Amitrano, S.; Alaverdian, D.; Capitani, K.; Furini, S.; Mari, F.; Meloni, I.; Montagnani, F.; Tumbarello, M.; Rancan, I.; Fabbiani, M.; Rossetti, B.; Bergantini, L.; D'Alessandro, M.; Cameli, P.; Bennett, D.; Anedda, F.; Marcantonio, S.; Scolletta, S.; Franchi, F.; Mazzei, M. A.; Guerrini, S.; Conticini, E.; Cantarini, L.; Frediani, B.; Tacconi, D.; Raffaelli, C. S.; Feri, M.; Donati, A.; Scala, R.; Guidelli, L.; Spargi, G.; Corridi, M.; Nencioni, C.; Croci, L.; Caldarelli, G. P.; Romani, D.; Piacentini, P.; Bandini, M.; Desanctis, E.; Cappelli, S.; Canaccini, A.; Verzuri, A.; Anemoli, V.; Pisani, M.; Ognibene, A.; Pancrazzi, A.; Lorubbio, M.; Vaghi, M.; D'Arminio Monforte, A.; Miraglia, F. G.; Bruno, R.; Vecchia, M.; Girardis, M.; Venturelli, S.; Busani, S.; Cossarizza, A.; Antinori, A.; Vergori, A.; Emiliozzi, A.; Rusconi, S.; Siano, M.; Gabrieli, A.; Riva, A.; Francisci, D.; Schiaroli, E.; Paciosi, F.; Tommasi, A.; Scotton, P. G.; Andretta, F.; Panese, S.; Baratti, S.; Scaggiante, R.; Gatti, F.; Parisi, S. G.; Castelli, F.; Quiros-Roldan, E.; Antoni, M. D.; Zanella, I.; Della Monica, M.; Piscopo, C.; Capasso, M.; Russo, R.; Andolfo, I.; Iolascon, A.; Fiorentino, G.; Carella, M.; Castori, M.; Aucella, F.; Raggi, P.; Perna, R.; Bassetti, M.; Di Biagio, A.; Sanguinetti, M.; Masucci, L.; Guarnaccia, A.; Valente, S.; De Vivo, O.; Doddato, G.; Lista, M.; Beligni, G.; Valentino, F.; Zguro, K.; Tita, R.; Giliberti, A.; Mencarelli, M. A.; Rizzo, C. L.; Pinto, A. M.; Ariani, F.; Di Sarno, L.; Bargagli, E.; Mandala, M.; Giorli, A.; Salerni, L.; Zucchi, P.; Parravicini, P.; Menatti, E.; Trotta, T.; Giannattasio, F.; Coiro, G.; Lena, F.; Lacerenza, G.; Mussini, C.; Martinelli, E.; Tavecchia, L.; Belli, M. A.; Crotti, L.; Parati, G.; Sanarico, M.; Raimondi, F.; Biscarini, F.; Stella, A.; Bachetti, T.; La Rovere, M. T.; Ludovisi, S.; Bussotti, M.; Dei, S.; Ravaglia, S.; Artuso, R.; Andreucci, E.; Gori, G.; Pagliazzi, A.; Fiorentini, E.; Perrella, A.; Bianchi, F.; Bergomi, P.; Catena, E.; Colombo, R.; Luchi, S.; Morelli, G.; Petrocelli, P.; Iacopini, S.; Modica, S.; Baroni, S.; Segala, F. V.; Falcone, M.; Tiseo, G.; Barbieri, C.; Matucci, T.; Grassi, D.; Ferri, C.; Marinangeli, F.; Brancati, F.; Vincenti, A.; Borgo, V.; Lombardi, S.; Lenzi, M.; Di Pietro, M. A.; Vichi, F.; Romanin, B.; Attala, L.; Costa, C.; Gabbuti, A.; Mene, R.; Colaneri, M.; Casprini, P.; Merla, G.; Squeo, G. M.; Maffezzoni, M.; Frullanti, E.; Mondelli, M. U.; Renieri, A.
abstract

Toll-like receptors (TLR) are crucial components in the initiation of innate immune responses to a variety of pathogens, triggering the production of pro-inflammatory cytokines and type I and II interferons, which are responsible for innate antiviral responses. Among the different TLRs, TLR7 recognizes several single-stranded RNA viruses including SARS-CoV-2. We and others identified rare loss-of-function variants in X-chromosomal TLR7 in young men with severe COVID-19 and with no prior history of major chronic diseases, that were associated with impaired TLR7 signaling as well as type I and II IFN responses. Here, we performed RNA sequencing to investigate transcriptome variations following imiquimod stimulation of peripheral blood mononuclear cells isolated from patients carrying previously identified hypomorphic, hypofunctional, and loss-of-function TLR7 variants. Our investigation revealed a profound impairment of the TLR7 pathway in patients carrying loss-of-function variants. Of note, a failure in IFNγ upregulation following stimulation was also observed in cells harboring the hypofunctional and hypomorphic variants. We also identified new TLR7 variants in severely affected male patients for which a functional characterization of the TLR7 pathway was performed demonstrating a decrease in mRNA levels in the IFNα, IFNγ, RSAD2, ACOD1, IFIT2, and CXCL10 genes.

2021 - Re: 'methodological evaluation of bias in observational COVID-19 studies on drug effectiveness' by Wolkewitz et al [Articolo su rivista]
Cozzi-Lepri, Alessandro; Guaraldi, Giovanni; Meschiari, Marianna; Mussini, Cristina
abstract

2021 - Re: “No Significant Changes in Weight and Body Fat Mass in Suppressed HIV Infected Patients Switched to Dual Combination Lamivudine Plus Dolutegravir or Raltegravir” by Calza et al. [Articolo su rivista]
Ciccullo, Arturo; Baldin, Gianmaria; Borghi, Vanni; Lassandro, Anna Pia; Farinacci, Damiano; Guaraldi, Giovanni; Mussini, Cristina; Di Giambenedetto, Simona
abstract

N/A.

2021 - Real-life experience with compassionate use of cefiderocol for difficult-to-treat resistant Pseudomonas aeruginosa (DTR-P) infections [Articolo su rivista]
Meschiari, Marianna; Volpi, Sara; Faltoni, Matteo; Dolci, Giovanni; Orlando, Gabriella; Franceschini, Erica; Menozzi, Marianna; Sarti, Mario; Del Fabro, Giovanni; Fumarola, Benedetta; Guarneri, Francesco; Lanza, Paola; Lorenzotti, Silvia; Saccani, Barbara; Signorini, Liana; Van Hauwermeiren, Evelyn; Gatti, Milo; Pea, Federico; Castelli, Francesco; Mussini, Cristina
abstract

Objectives: To describe our real-life experience with cefiderocol in XDR and difficult-to-treat resistant Pseudomonas aeruginosa (DTR-P) infections without any other available treatment options. Methods: We included patients with a proven infection due to an XDR/DTR-P, who had failed on previous regimens, and were treated with cefiderocol, following them prospectively to day 90 or until hospital discharge or death. Results: Seventeen patients treated for >72 h with cefiderocol were included: 14 receiving combination regimens (82.4%) and 3 receiving monotherapy (17.6%). Fourteen patients were males (82%) with a median age of 64 years (IQR 58-73). Fifteen patients (88.2%) were admitted to the ICU and five had septic shock (29%). Seven cases (41.2%) were ventilator-associated pneumonia, of which 71% (5/7) occurred in COVID-19 patients. Four were complicated intrabdominal infections, one ecthyma gangrenosum, one nosocomial pneumonia and one empyema, one osteomyelitis, one primary bacteraemia, and one nosocomial external ventricular drainage meningitis. Clinical cure and microbiological cure rates were 70.6% and 76.5%, respectively. There were six deaths (35.3%) after a median of 8 days (IQR 3-10) from the end of treatment, but only two of them (11.7%) were associated with P. aeruginosa infection progression. Conclusions: Our experience collecting this large case series of DTR-P treated with cefiderocol may help clinicians consider this new option in this hard-to-manage setting. Our results are even more relevant in the current scenario of ceftolozane/tazobactam shortage. Importantly, this is the first study providing real-life data indicating adequate cefiderocol concentrations in CSF.

2021 - Risk factors for functional decline among survivors of Gram-negative bloodstream infection: A prospective cohort study [Articolo su rivista]
Turjeman, Adi; Koppel, Fidi; Franceschini, Erica; Yahav, Dafna; Dolci, Giovanni; Babich, Tanya; Bitterman, Roni; Neuberger, Ami; Ghanem-Zoubi, Nesrin; Santoro, Antonella; Eliakim-Raz, Noa; Pertzov, Barak; Stern, Anat; Dickstein, Yaakov; Maroun, Elias; Zayyad, Hiba; Meschiari, Marianna; Bishara, Jihad; Goldberg, Elad; Venturelli, Claudia; Mussini, Cristina; Paul, Mical; Leibovici, Leonard
abstract

To identify risk factors for functional decline after hospitalization for Gram-negative bacteremia.

2021 - Risk factors for nosocomial rectal colonization with carbapenem-resistant Acinetobacter baumannii in hospital: a matched case–control study [Articolo su rivista]
Meschiari, M.; Kaleci, S.; Orlando, G.; Selmi, S.; Santoro, A.; Bacca, E.; Menozzi, M.; Franceschini, E.; Puzzolante, C.; Bedini, A.; Sarti, M.; Venturelli, C.; Vecchi, E.; Mussini, C.
abstract

Background: During the last decade carbapenem-resistant Acinetobacter baumannii (CRAB) became hyper-endemic in hospitals due to difficult to control spreading. Our aim is to identify risk factors for nosocomial rectal CRAB colonization in an endemic hospital. Methods: A retrospective matched case–control study (ratio 1:2) with a prospective inclusion of cases and concurrent selection of controls was conducted from January 2017 to December 2018 in a tertiary-care hospital. Universal active surveillance for CRAB was implemented. Univariate and multivariate logistic regression was carried out using a stepwise selection method to compare prognostic factors between cases and controls. A sub-analysis was carried out according to the type of department. Results: Forty-five cases with nosocomial rectal CRAB colonization and 90 controls were included. One hundred and two (75%) patients were hospitalized in medical departments. At multivariable analysis significant risk factors associated with CRAB colonization were: use of permanent devices (OR 10.15, 95% CI 2.27–45.39; P = 0.002), mechanical ventilation (OR 40.01, 95% CI 4.05–395.1; P = 0.002), urinary catheters (OR 4.9, 95% CI 1.52–16.19; P = 0.008), McCabe score (OR 5.45, 95% CI 1.87–15.89; P = 0.002), length of stay (OR 1.03, 95% CI 1.01–1.05; P = 0.002), carbapenem use (OR 5.39, 95% CI 1.14–25.44; P = 0.033). The sub-analysis showed that patients admitted to different departments had different risk factors. In geriatric department a fatal disease and a longer hospital stay represented significant risk factors both in univariate and multivariate analysis, while in internal medicine department the use of permanent devices, current antibiotic therapy and antibiotic polytherapy represented significant risk factors for CRAB at the univariate analysis, also confirmed in multivariate analysis. Conclusions: Our data suggest that active surveillance for rectal CRAB colonization should be addressed to patients with an unfavourable prognosis, longer hospitalizations and carriers of multiple devices. To counter CRAB spreading in endemic settings, clinicians must limit the use of carbapenems, and reinforce interventions aimed at proper use of devices.

2021 - Risk for non-AIDS-defining and AIDS-defining cancer of early versus delayed initiation of antiretroviral therapy: A multinational prospective cohort study [Articolo su rivista]
Chammartin, F.; Lodi, S.; Logan, R.; Ryom, L.; Mocroft, A.; Kirk, O.; D'Arminio Monforte, A.; Reiss, P.; Phillips, A.; El-Sadr, W.; Hatleberg, C. I.; Pradier, C.; Bonnet, F.; Law, M.; De Wit, S.; Sabin, C.; Lundgren, J. D.; Bucher, H. C.; Calvo, G.; Dabis, F.; Morfeldt, L.; Weber, R.; Lind-Thomsen, A.; Salbol Brandt, R.; Hillebreght, M.; Zaheri, S.; Wit, F. W. N. M.; Scherrer, A.; Schoni-Affolter, F.; Rickenbach, M.; Tavelli, A.; Fanti, I.; Leleux, O.; Mourali, J.; Le Marec, F.; Boerg, E.; Thulin, E.; Sundstrom, A.; Bartsch, G.; Thompsen, G.; Necsoi, C.; Delforge, M.; Fontas, E.; Caissotti, C.; Dollet, K.; Mateu, S.; Torres, F.; Petoumenos, K.; Blance, A.; Huang, R.; Puhr, R.; Gronborg Laut, K.; Kristensen, D.; Kamara, D. A.; Smith, C. J.; Raben, D.; Matthews, C.; Bojesen, A.; Grevsen, A. L.; Powderly, B.; Shortman, N.; Moecklinghoff, C.; Reilly, G.; Smit, C.; Ross, M.; Fux, C. A.; Morlat, P.; Friis-Moller, N.; Kowalska, J.; Bohlius, J.; Bower, M.; Fatkenheuer, G.; Grulich, A.; Sjol, A.; Meidahl, P.; Iversen, J. S.; Hillebregt, M.; Prins, J. M.; Kuijpers, T. W.; Scherpbier, H. J.; Van Der Meer, J. T. M.; Godfried, M. H.; Van Der Poll, T.; Nellen, F. J. B.; Geerlings, S. E.; Van Vugt, M.; Pajkrt, D.; Bos, J. C.; Wiersinga, W. J.; Van Der Valk, M.; Goorhuis, A.; Hovius, J. W.; Van Eden, J.; Henderiks, A.; Van Hes, A. M. H.; Mutschelknauss, M.; Nobel, H. E.; Pijnappel, F. J. J.; Jurriaans, S.; Back, N. K. T.; Zaaijer, H. L.; Berkhout, B.; Cornelissen, M. T. E.; Schinkel, C. J.; Thomas, X. V.; Van Den Berge, M.; Stegeman, A.; Baas, S.; Hage De Looff, L.; Versteeg, D.; Pronk, M. J. H.; Ammerlaan, H. S. M.; de Munnik, E. S.; Jansz, A. R.; Tjhie, J.; Wegdam, M. C. A.; Deiman, B.; Scharnhorst, V.; Van Der Plas, A.; Weijsenfeld, A. M.; Van Der Ende, M. E.; de Vries-Sluijs, T. E. M. S.; van Gorp, E. C. M.; Schurink, C. A. M.; Nouwen, J. L.; Verbon, A.; Rijnders, B. J. A.; Bax, H. I.; Van Der Feltz, M.; Bassant, N.; Van Beek, J. E. A.; Vriesde, M.; Van Zonneveld, L. M.; De Oude-Lubbers, A.; Van Den Berg-Cameron, H. J.; Bruinsma-Broekman, F. B.; de Groot, J.; De Zeeuw-De Man, M.; Boucher, C. A. B.; Koopmans, M. P. G.; van Kampen, J. J. A.; Pas, S. D.; Driessen, G. J. A.; van Rossum, A. M. C.; Van Der Knaap, L. C.; Visser, E.; Branger, J.; Rijkeboer-Mes, A.; Duijf-Van De Ven, C. J. H. M.; Schippers, E. F.; van Nieuwkoop, C.; van IJperen, J. M.; Geilings, J.; van der Hut, G.; Franck, P. F. H.; Van Eeden, A.; Brokking, W.; Groot, M.; Elsenburg, L. J. M.; Damen, M.; Kwa, I. S.; Groeneveld, P. H. P.; Bouwhuis, J. W.; Van Den Berg, J. F.; Van Hulzen, A. G. W.; Van Der Bliek, G. L.; Bor, P. C. J.; Bloembergen, P.; Wolfhagen, M. J. H. M.; Ruijs, G. J. H. M.; Kroon, F. P.; De Boer, M. G. J.; Bauer, M. P.; Jolink, H.; Vollaard, A. M.; Dorama, W.; Van Holten, N.; Claas, E. C. J.; Wessels, E.; Den Hollander, J. G.; Pogany, K.; Roukens, A.; Kastelijns, M.; Smit, J. V.; Smit, E.; Struik-Kalkman, D.; Tearno, C.; Bezemer, M.; van Niekerk, T.; Pontesilli, O.; Lowe, S. H.; Oude Lashof, A. M. L.; Posthouwer, D.; Ackens, R. P.; Schippers, J.; Vergoossen, R.; Weijenberg-Maes, B.; van Loo, I. H. M.; Havenith, T. R. A.; Leyten, E. M. S.; Gelinck, L. B. S.; van Hartingsveld, A.; Meerkerk, C.; Wildenbeest, G. S.; Mutsaers, J. A. E. M.; Jansen, C. L.; Mulder, J. W.; Vrouenraets, S. M. E.; Lauw, F. N.; van Broekhuizen, M. C.; Paap, H.; Vlasblom, D. J.; Smits, P. H. M.; Weijer, S.; El Moussaoui, R.; Bosma, A. S.; van Vonderen, M. G. A.; van Houte, D. P. F.; Kampschreur, L. M.; Dijkstra, K.; Faber, S.; Weel, J.; Kootstra, G. J.; Delsing, C. E.; van der Burg-Van de Plas, M.; Heins, H.; Lucas, E.; Kortmann, W.; van Twillert, G.; Cohen Stuart, J. W. T.; Diederen, B. M. W.; van Truijen-Oud, F. A.; van der Reijden, W. A.; Jansen, R.; Brinkman, K.; van den Berk, G. E. L.; Blok, W. L.; Frissen, P. H. J.; Lettinga, K. D.; Schouten, W. E. M.; Veenstra, J.; Brouwer, J. C.; Geerders, F. G.; Hoeksema, K.; Kleene, J. M.; van der Meche, B. I.; Spelbrink, M.; Sulman, H.; Toonen, A.
abstract

Background: Immediate initiation of antiretroviral therapy (ART) regardless of CD4 cell count reduces risk for AIDS and non-AIDS-related events in asymptomatic, HIV-positive persons and is the standard of care. However, most HIV-positive persons initiate ART when their CD4 count decreases below 500 × 109 cells/L. Consequences of delayed ART on risk for non-AIDS-defining and AIDS-defining cancer, one of the most common reasons for death in HIV, are unclear. Objective: To estimate the long-term risk difference for cancer with the immediate ART strategy. Design: Multinational prospective cohort study. Setting: The D:A:D (Data collection on Adverse events of anti-HIV Drugs) study, which included HIV-positive persons from Europe, Australia, and the United States. Participants: 8318 HIV-positive persons with at least 1 measurement each of CD4 cell count and viral load while ART-naive (study period, 2006 to 2016). Measurements: The parametric g-formula was used, with adjustment for baseline and time-dependent confounders (CD4 cell count and viral load), to assess the 10-year risk for non-AIDS-defining and AIDS-defining cancer of immediate versus deferred (at CD4 counts < 350 and < 500 × 109 cells/L) ART initiation strategies. Results: During 64 021 person-years of follow-up, 231 cases of non-AIDS-defining cancer and 272 of AIDS-defining cancer occurred among HIV-positive persons with a median age of 36 years (interquartile range, 29 to 43 years). With immediate ART, the 10-year risk for non-AIDS-defining cancer was 2.97% (95% CI, 2.37% to 3.50%) and that for AIDS-defining cancer was 2.50% (CI, 2.37% to 3.38%). Compared with immediate ART initiation, the 10-year absolute risk differences when deferring ART to CD4 counts less than 500 × 109 cells/L and less than 350 × 109 cells/L were 0.12 percentage point (CI, -0.01 to 0.26 percentage point) and 0.29 percentage point (CI, -0.03 to 0.73 percentage point), respectively, for non-AIDS-defining cancer and 0.32 percentage point (CI, 0.21 to 0.44 percentage point) and 1.00 percentage point (CI, 0.67 to 1.44 percentage points), respectively, for AIDS-defining cancer. Limitation: Potential residual confounding due to observational study design. Conclusion: In this young cohort, effects of immediate ART on 10-year risk for cancer were small, and further supportive data are needed for non-AIDS-defining cancer. Primary Funding Source: Highly Active Antiretroviral Therapy Oversight Committee.

2021 - SARS-CoV-2 susceptibility and COVID-19 disease severity are associated with genetic variants affecting gene expression in a variety of tissues [Articolo su rivista]
D'Antonio, M.; Nguyen, J. P.; Arthur, T. D.; Matsui, H.; D'Antonio-Chronowska, A.; Frazer, K. A.; Neale, B. M.; Daly, M.; Ganna, A.; Stevens, C.; Pathak, G. A.; Andrews, S. J.; Kanai, M.; Cordioli, M.; Ganna, A.; Karjalainen, J.; Pathak, G. A.; Polimanti, R.; Andrews, S. J.; Cordioli, M.; Pirinen, M.; Kanai, M.; Harerimana, N.; Veerapen, K.; Wolford, B.; Nguyen, H.; Solomonson, M.; Stevens, C.; Liao, R. G.; Chwialkowska, K.; Trankiem, A.; Balaconis, M. K.; Hayward, C.; Richmond, A.; Campbell, A.; Morris, M.; Fawns-Ritchie, C.; Glessner, J. T.; Shaw, D. M.; Chang, X.; Polikowski, H.; Lauren, P. E.; Chen, H. -H.; Wanying, Z.; Hakonarson, H.; Porteous, D. J.; Below, J.; North, K.; Mccormick, J. B.; Timmers, P. R. H. J.; Wilson, J. F.; Tenesa, A.; D'Mellow, K.; Kerr, S. M.; Niemi, M. E. K.; Cordioli, M.; Nkambul, L.; von Hohenstaufen, K. A.; Sobh, A.; Eltoukhy, M. M.; Yassen, A. M.; Hegazy, M. A. F.; Okasha, K.; Eid, M. A.; Moahmed, H. S.; Shahin, D.; El-Sherbiny, Y. M.; Elhadidy, T. A.; Abd Elghafar, M. S.; El-Jawhari, J. J.; Mohamed, A. A. S.; Elnagdy, M. H.; Samir, A.; Abdel-Aziz, M.; Khafaga, W. T.; El-Lawaty, W. M.; Torky, M. S.; El-Shanshory, M. R.; Batini, C.; Lee, P. H.; Shrine, N.; Williams, A. T.; Tobin, M. D.; Guyatt, A. L.; John, C.; Packer, R. J.; Ali, A.; Free, R. C.; Wang, X.; Wain, L. V.; Hollox, E. J.; Venn, L. D.; Bee, C. E.; Adams, E. L.; Niemi, M. E. K.; Niavarani, A.; Cordioli, M.; Nkambul, L.; Sharififard, B.; Aliannejad, R.; Amirsavadkouhi, A.; Naderpour, Z.; Tadi, H. A.; Aleagha, A. E.; Ahmadi, S.; Moghaddam, S. B. M.; Adamsara, A.; Saeedi, M.; Abdollahi, H.; Hosseini, A.; Chariyavilaskul, P.; Chamnanphon, M.; Suttichet, T. B.; Shotelersuk, V.; Pongpanich, M.; Phokaew, C.; Chetruengchai, W.; Jantarabenjakul, W.; Putchareon, O.; Torvorapanit, P.; Puthanakit, T.; Suchartlikitwong, P.; Hirankarn, N.; Nilaratanakul, V.; Sodsai, P.; Brumpton, B. M.; Hveem, K.; Willer, C.; Wolford, B.; Zhou, W.; Rogne, T.; Solligard, E.; Asvold, B. O.; Abedalthagafi, M.; Alaamery, M.; Alqahtani, S.; Baraka, D.; Al Harthi, F.; Alsolm, E.; Safieh, L. A.; Alowayn, A. M.; Alqubaishi, F.; Al Mutairi, A.; Mangul, S.; Alshareef, A.; Sawaji, M.; Almutairi, M.; Aljawini, N.; Albesher, N.; Arabi, Y. M.; Mahmoud, E. S.; Khattab, A. K.; Halawani, R. T.; Alahmadey, Z. Z.; Albakri, J. K.; Felemban, W. A.; Suliman, B. A.; Hasanato, R.; Al-Awdah, L.; Alghamdi, J.; Alzahrani, D.; Aljohani, S.; Al-Afghani, H.; Alrashed, M.; Aldhawi, N.; Albardis, H.; Alkwai, S.; Alswailm, M.; Almalki, F.; Albeladi, M.; Almohammed, I.; Barhoush, E.; Albader, A.; Massadeh, S.; Almalik, A.; Alotaibi, S.; Alghamdi, B.; Jung, J.; Fawzy, M. S.; Lee, Y.; Magnus, P.; Trogstad, L. -I. S.; Helgeland, O.; Harris, J. R.; Mangino, M.; Spector, T. D.; Emma, D.; Smieszek, S. P.; Przychodzen, B. P.; Polymeropoulos, C.; Polymeropoulos, V.; Polymeropoulos, M. H.; Fernandez-Cadenas, I.; Perez-Tur, J.; Llucia-Carol, L.; Cullell, N.; Muino, E.; Carcel-Marquez, J.; Dediego, M. L.; Iglesias, L. L.; Planas, A. M.; Soriano, A.; Rico, V.; Aguero, D.; Bedini, J. L.; Lozano, F.; Domingo, C.; Robles, V.; Ruiz-Jaen, F.; Marquez, L.; Gomez, J.; Coto, E.; Albaiceta, G. M.; Garcia-Clemente, M.; Dalmau, D.; Arranz, M. J.; Dietl, B.; Serra-Llovich, A.; Soler, P.; Colobran, R.; Martin-Nalda, A.; Martinez, A. P.; Bernardo, D.; Rojo, S.; Fiz-Lopez, A.; Arribas, E.; de la Cal-Sabater, P.; Segura, T.; Gonzalez-Villa, E.; Serrano-Heras, G.; Marti-Fabregas, J.; Jimenez-Xarrie, E.; de Felipe Mimbrera, A.; Masjuan, J.; Garcia-Madrona, S.; Dominguez-Mayoral, A.; Villalonga, J. M.; Menendez-Valladares, P.; Chasman, D. I.; Buring, J. E.; Ridker, P. M.; Franco, G.; Sesso, H. D.; Manson, J. E.; Chang, X.; Glessner, J. R.; Hakonarson, H.; Hayward, C.; Richmond, A.; Porteous, D. J.; Campbell, A.; Fawns-Ritchie, C.; Medina-Gomez, C.; Uitterlinden, A. G.; Arfan Ikram, M.; Kristiansson, K.; Koskelainen, S.; Perola, M.; Donner, K.; Kivinen, K.; Palotie, A.; Ripatti, S.; Ruotsalainen, S.; Kaunisto, M.; Nakanishi, T.; B
abstract

Variability in SARS-CoV-2 susceptibility and COVID-19 disease severity between individuals is partly due to genetic factors. Here, we identify 4 genomic loci with suggestive associations for SARS-CoV-2 susceptibility and 19 for COVID-19 disease severity. Four of these 23 loci likely have an ethnicity-specific component. Genome-wide association study (GWAS) signals in 11 loci colocalize with expression quantitative trait loci (eQTLs) associated with the expression of 20 genes in 62 tissues/cell types (range: 1:43 tissues/gene), including lung, brain, heart, muscle, and skin as well as the digestive system and immune system. We perform genetic fine mapping to compute 99% credible SNP sets, which identify 10 GWAS loci that have eight or fewer SNPs in the credible set, including three loci with one single likely causal SNP. Our study suggests that the diverse symptoms and disease severity of COVID-19 observed between individuals is associated with variants across the genome, affecting gene expression levels in a wide variety of tissue types.

2021 - Sarilumab in patients admitted to hospital with severe or critical COVID-19: a randomised, double-blind, placebo-controlled, phase 3 trial [Articolo su rivista]
Lescure, F. -X.; Honda, H.; Fowler, R. A.; Lazar, J. S.; Shi, G.; Wung, P.; Patel, N.; Hagino, O.; Bazzalo, I. J.; Casas, M. M.; Nunez, S. A.; Pere, Y.; Ibarrola, C. M.; Solis Aramayo, M. A.; Cuesta, M. C.; Duarte, A. E.; Gutierrez Fernandez, P. M.; Iannantuono, M. A.; Miyazaki, E. A.; Silvio, J. P.; Scublinsky, D. G.; Bales, A.; Catarino, D.; Fiss, E.; Mohrbacher, S.; Sato, V.; Baylao, A.; Cavalcante, A.; Correa, F.; de Andrade, C. A.; Furtado, J.; Ribeiro Filho, N.; Telles, V.; Trevelin, L. T.; Vipich, R.; Boldo, R.; Borges, P.; Lobo, S.; Luckemeyer, G.; Machado, L.; Alves, M. B.; Iglessias, A. C.; Lago, M. M.; Santos, D. W.; Chapdelaine, H.; Falcone, E. L.; Jamal, R.; Luong, M. -L.; Durand, M.; Doucet, S.; Carrier, F. -M.; Coburn, B. A.; Del Sorbo, L.; Walmsley, S. L.; Belga, S.; Chen, L. Y.; Mah, A. D.; Steiner, T.; Wright, A. J.; Hajek, J.; Adhikari, N.; Fowler, R. A.; Daneman, N.; Khwaja, K. A.; Shahin, J.; Gonzalez, C.; Silva, R.; Lindh, M.; Maluenda, G.; Fernandez, P.; Oyonarte, M.; Lasso, M.; Boyer, A.; Bronnimann, D.; Bui, H. -N.; Cazanave, C.; Chaussade, H.; Desclaux, A.; Ducours, M.; Duvignaud, A.; Malvy, D.; Martin, L.; Neau, D.; Nguyen, D.; Pistone, T.; Soubrane-Wirth, G.; Leitao, J.; Allavena, C.; Biron, C.; Bouchez, S.; Gaborit, B.; Gregoire, A.; Le Turnier, P.; Lecompte, A. -S.; Lecomte, R.; Lefebvre, M.; Raffi, F.; Boutoille, D.; Morineau, P. H.; Guery, R.; Chatelus, E.; Dumoussaud, N.; Felten, R.; Luca, F.; Goichot, B.; Schneider, F.; Taquet, M. -C.; Groh, M.; Roumier, M.; Neuville, M.; Bachelard, A.; Isernia, V.; Lescure, F. -X.; Phung, B. -C.; Rachline, A.; Sautereau, A.; Vallois, D.; Bleher, Y.; Boucher, D.; Coudon, C.; Esnault, J.; Guimard, T.; Leautez-Nainville, S.; Merrien, D.; Morrier, M.; Motte-Vincent, P.; Gabeff, R.; Leclerc, H.; Cozic, C.; Decours, R.; Fevrier, R.; Colin, G.; Abgrall, S.; Vignes, D.; Sterpu, R.; Kuellmar, M.; Meersch-Dini, M.; Weiss, R.; Zarbock, A.; Antony, C.; Berger, M.; Brenner, T.; Taube, C.; Herbstreit, F.; Dolff, S.; Konik, M.; Schmidt, K.; Zettler, M.; Witzke, O.; Boell, B.; Garcia Borrega, J.; Koehler, P.; Zander, T.; Dusse, F.; Al-Sawaf, O.; Kohler, P.; Eichenauer, D.; Kochanek, M.; Shimabukuro-Vornhagen, A.; Mellinghoff, S.; Classen, A.; Heger, J. -M.; Meyer-Schwickerath, C.; Liedgens, P.; Heindel, K.; Belkin, A.; Biber, A.; Gilboa, M.; Levy, I.; Litachevsky, V.; Rahav, G.; Finesod Wiedner, A.; Zilberman-Daniels, T.; Oster, Y.; Strahilevitz, J.; Sviri, S.; Baldissera, E. M.; Campochiaro, C.; Cavalli, G.; Dagna, L.; De Luca, G.; Della Torre, E.; Tomelleri, A.; Bernasconi De Luca, D.; Capetti, A. F.; Coen, M.; Cossu, M. V.; Galli, M.; Giacomelli, A.; Gubertini, G. A.; Rusconi, S.; Burastero, G. J.; Digaetano, M.; Guaraldi, G.; Meschiari, M.; Mussini, C.; Puzzolante, C.; Volpi, S.; Aiello, M.; Ariani, A.; Chetta, A. A.; Frizzelli, A.; Ticinesi, A.; Tuttolomondo, D.; Aliberti, S.; Blasi, F. B.; Di Pasquale, M. F.; Misuraca, S.; Pilocane, T.; Simonetta, E.; Aghelmo, A. M.; Angelini, C.; Brunetta, E.; Canonica, G. W.; Ciccarelli, M.; Dal Farra, S.; De Santis, M.; Ferri, S.; Folci, M.; Guidelli, G. M.; Heffler, E. M.; Loiacono, F.; Malipiero, G.; Paoletti, G.; Pedale, R.; Puggioni, F. A.; Racca, F.; Zumbo, A.; Satou, M.; Lisun, T.; Protsenko, D.; Rubtsov, N.; Beloglazova, I.; Fomina, D.; Lysenko, M.; Serdotetskova, S.; Firstov, V.; Gordeev, I.; Kokorin, I.; Komissarova, K.; Lapochkina, N.; Luchinkina, E.; Malimon, V.; Mamedguseyinova, S.; Polubatonova, K.; Suvorova, N.; Arribas, J.; Borobia Perez, A. M.; de la Calle Prieto, F.; Figueira, J. C.; Motejano Sanchez, R.; Mora-Rillo, M.; Prados Sanchez, C.; Queiruga Parada, J.; Fernandez Arnalich, F.; Guerro Barrientos, M.; Bendala Estrada, A.; Caballero Marcos, A.; Garcia Leoni, M. E.; Garcia-Martinez, R.; Collado, A. M.; Munoz Garcia, P.; Torres do Rego, A.; Villalba Garcia, M. V.; Burrillo, A.; Valerio Minero, M.; Gijon Vidaurreta, P.; Infante Herrero, S.; Velilla, E.; Machado, M.; Olmedo, M.; Pinilla, B.; Almirante Gragera, B.;
abstract

Background: Elevated proinflammatory cytokines are associated with greater COVID-19 severity. We aimed to assess safety and efficacy of sarilumab, an interleukin-6 receptor inhibitor, in patients with severe (requiring supplemental oxygen by nasal cannula or face mask) or critical (requiring greater supplemental oxygen, mechanical ventilation, or extracorporeal support) COVID-19. Methods: We did a 60-day, randomised, double-blind, placebo-controlled, multinational phase 3 trial at 45 hospitals in Argentina, Brazil, Canada, Chile, France, Germany, Israel, Italy, Japan, Russia, and Spain. We included adults (≥18 years) admitted to hospital with laboratory-confirmed SARS-CoV-2 infection and pneumonia, who required oxygen supplementation or intensive care. Patients were randomly assigned (2:2:1 with permuted blocks of five) to receive intravenous sarilumab 400 mg, sarilumab 200 mg, or placebo. Patients, care providers, outcome assessors, and investigators remained masked to assigned intervention throughout the course of the study. The primary endpoint was time to clinical improvement of two or more points (seven point scale ranging from 1 [death] to 7 [discharged from hospital]) in the modified intention-to-treat population. The key secondary endpoint was proportion of patients alive at day 29. Safety outcomes included adverse events and laboratory assessments. This study is registered with ClinicalTrials.gov, NCT04327388; EudraCT, 2020-001162-12; and WHO, U1111-1249-6021. Findings: Between March 28 and July 3, 2020, of 431 patients who were screened, 420 patients were randomly assigned and 416 received placebo (n=84 [20%]), sarilumab 200 mg (n=159 [38%]), or sarilumab 400 mg (n=173 [42%]). At day 29, no significant differences were seen in median time to an improvement of two or more points between placebo (12·0 days [95% CI 9·0 to 15·0]) and sarilumab 200 mg (10·0 days [9·0 to 12·0]; hazard ratio [HR] 1·03 [95% CI 0·75 to 1·40]; log-rank p=0·96) or sarilumab 400 mg (10·0 days [9·0 to 13·0]; HR 1·14 [95% CI 0·84 to 1·54]; log-rank p=0·34), or in proportions of patients alive (77 [92%] of 84 patients in the placebo group; 143 [90%] of 159 patients in the sarilumab 200 mg group; difference −1·7 [−9·3 to 5·8]; p=0·63 vs placebo; and 159 [92%] of 173 patients in the sarilumab 400 mg group; difference 0·2 [−6·9 to 7·4]; p=0·85 vs placebo). At day 29, there were numerical, non-significant survival differences between sarilumab 400 mg (88%) and placebo (79%; difference +8·9% [95% CI −7·7 to 25·5]; p=0·25) for patients who had critical disease. No unexpected safety signals were seen. The rates of treatment-emergent adverse events were 65% (55 of 84) in the placebo group, 65% (103 of 159) in the sarilumab 200 mg group, and 70% (121 of 173) in the sarilumab 400 mg group, and of those leading to death 11% (nine of 84) were in the placebo group, 11% (17 of 159) were in the sarilumab 200 mg group, and 10% (18 of 173) were in the sarilumab 400 mg group. Interpretation: This trial did not show efficacy of sarilumab in patients admitted to hospital with COVID-19 and receiving supplemental oxygen. Adequately powered trials of targeted immunomodulatory therapies assessing survival as a primary endpoint are suggested in patients with critical COVID-19. Funding: Sanofi and Regeneron Pharmaceuticals.

2021 - Shorter androgen receptor polyQ alleles protect against life-threatening COVID-19 disease in European males [Articolo su rivista]
Baldassarri, M.; Picchiotti, N.; Fava, F.; Fallerini, C.; Benetti, E.; Daga, S.; Valentino, F.; Doddato, G.; Furini, S.; Giliberti, A.; Tita, R.; Amitrano, S.; Bruttini, M.; Croci, S.; Meloni, I.; Pinto, A. M.; Iuso, N.; Gabbi, C.; Sciarra, F.; Venneri, M. A.; Gori, M.; Sanarico, M.; Crawley, F. P.; Pagotto, U.; Fanelli, F.; Mezzullo, M.; Dominguez-Garrido, E.; Planas-Serra, L.; Schluter, A.; Colobran, R.; Soler-Palacin, P.; Lapunzina, P.; Tenorio, J.; Pujol, A.; Castagna, M. G.; Marcelli, M.; Isidori, A. M.; Renieri, A.; Frullanti, E.; Mari, F.; Montagnani, F.; Di Sarno, L.; Tommasi, A.; Palmieri, M.; Fabbiani, M.; Rossetti, B.; Zanelli, G.; Sestini, F.; Bergantini, L.; D'Alessandro, M.; Cameli, P.; Bennett, D.; Anedda, F.; Marcantonio, S.; Scolletta, S.; Franchi, F.; Mazzei, M. A.; Guerrini, S.; Conticini, E.; Cantarini, L.; Frediani, B.; Tacconi, D.; Spertilli, C.; Feri, M.; Donati, A.; Scala, R.; Guidelli, L.; Spargi, G.; Corridi, M.; Nencioni, C.; Croci, L.; Caldarelli, G. P.; Spagnesi, M.; Piacentini, P.; Bandini, M.; Desanctis, E.; Cappelli, S.; Canaccini, A.; Verzuri, A.; Anemoli, V.; Ognibene, A.; Vaghi, M.; Monforte, A. D.; Merlini, E.; Miraglia, F. G.; Mondelli, M. U.; Mantovani, S.; Ludovisi, S.; Girardis, M.; Venturelli, S.; Sita, M.; Cossarizza, A.; Antinori, A.; Vergori, A.; Emiliozzi, A.; Rusconi, S.; Siano, M.; Gabrieli, A.; Riva, A.; Francisci, D.; Schiaroli, E.; Paciosi, F.; Scotton, P. G.; Andretta, F.; Panese, S.; Baratti, S.; Scaggiante, R.; Gatti, F.; Parisi, S. G.; Castelli, F.; Quiros-Roldan, E.; Antoni, M. D.; Zanella, I.; Monica, M. D.; Piscopo, C.; Capasso, M.; Russo, R.; Andolfo, I.; Iolascon, A.; Fiorentino, G.; Carella, M.; Castori, M.; Merla, G.; Aucella, F.; Raggi, P.; Marciano, C.; Perna, R.; Bassetti, M.; Di Biagio, A.; Sanguinetti, M.; Masucci, L.; Valente, S.; Mencarelli, M. A.; Lo Rizzo, C.; Bargagli, E.; Mandala, M.; Giorli, A.; Salerni, L.; Zucchi, P.; Parravicini, P.; Menatti, E.; Trotta, T.; Giannattasio, F.; Coiro, G.; Lena, F.; Coviello, D. A.; Mussini, C.; Bosio, G.; Martinelli, E.; Mancarella, S.; Tavecchia, L.; Crotti, L.; Parati, G.; Aguilera-Albesa, S.; Albu, S.; Casasnovas, C.; Velez-Santamaria, V.; Horcajada, J. P.; Villar, J.; Rodriguez-Palmero, A.; Ruiz, M.; Seijo, L. M.; Troya, J.; Valencia-Ramos, J.; Gut, M.
abstract

Background: While SARS-CoV-2 similarly infects men and women, COVID-19 outcome is less favorable in men. Variability in COVID-19 severity may be explained by differences in the host genome. Methods: We compared poly-amino acids variability from WES data in severely affected COVID-19 patients versus SARS-CoV-2 PCR-positive oligo-asymptomatic subjects. Findings: Shorter polyQ alleles (≤22) in the androgen receptor (AR) conferred protection against severe outcome in COVID-19 in the first tested cohort (both males and females) of 638 Italian subjects. The association between long polyQ alleles (≥23) and severe clinical outcome (p = 0.024) was also validated in an independent cohort of Spanish men <60 years of age (p = 0.014). Testosterone was higher in subjects with AR long-polyQ, possibly indicating receptor resistance (p = 0.042 Mann-Whitney U test). Inappropriately low serum testosterone level among carriers of the long-polyQ alleles (p = 0.0004 Mann-Whitney U test) predicted the need for intensive care in COVID-19 infected men. In agreement with the known anti-inflammatory action of testosterone, patients with long-polyQ and age ≥60 years had increased levels of CRP (p = 0.018, not accounting for multiple testing). Interpretation: We identify the first genetic polymorphism that appears to predispose some men to develop more severe disease. Failure of the endocrine feedback to overcome AR signaling defects by increasing testosterone levels during the infection leads to the polyQ tract becoming dominant to serum testosterone levels for the clinical outcome. These results may contribute to designing reliable clinical and public health measures and provide a rationale to test testosterone as adjuvant therapy in men with COVID-19 expressing long AR polyQ repeats. Funding: MIUR project “Dipartimenti di Eccellenza 2018-2020” to Department of Medical Biotechnologies University of Siena, Italy (Italian D.L. n.18 March 17, 2020) and “Bando Ricerca COVID-19 Toscana” project to Azienda Ospedaliero-Universitaria Senese. Private donors for COVID-19 research and charity funds from Intesa San Paolo.

2021 - The Impact of COVID-19 on UNAIDS 90-90-90 Targets: Calls for New HIV Care Models [Articolo su rivista]
Guaraldi, G.; Borghi, V.; Milic, J.; Carli, F.; Cuomo, G.; Menozzi, M.; Santoro, A.; Orlando, G.; Puzzolante, C.; Meschiari, M.; Franceschini, E.; Bedini, A.; Ferrari, F.; Gennari, W.; Sarti, M.; Mussini, C.
abstract

We compared 90-90-90 targets in 2020, during the coronavirus disease 2019 (COVID-19) pandemic, with the targets across the period 2017-2019 in people with HIV. We observed a significant loss in the 90-90-90 objectives in 2020 when compared with 2017-2019 that might be attributable to the COVID-19 crisis.

2021 - The Importance of Understanding the Stages of COVID-19 in Treatment and Trials [Articolo su rivista]
Griffin, Daniel O; Brennan-Rieder, Denise; Ngo, Binh; Kory, Pierre; Confalonieri, Marco; Shapiro, Leland; Iglesias, Jose; Dube, Michael; Nanda, Neha; In, Gino K; Arkfeld, Daniel; Chaudhary, Preet; Campese, Vito M; Hanna, Diana L; Sawcer, David; Ehresmann, Glenn; Peng, David; Smorgorzewski, Miroslaw; Amstrong, April; Vinjevoll, Eivind H; Dasgupta, Rajkumar; Sattler, Fred R; Mussini, Cristina; Mitjà, Oriol; Soriano, Vicente; Peschanski, Nicolas; Hayem, Gilles; Piccirillo, Maria Carmela; Lobo-Ferreira, António; Rivero, Iraldo B; Hung, Ivan F H; Rendell, Marc; Ditmore, Stephen; Varon, Joseph; Marik, Paul
abstract

COVID-19, caused by SARS-CoV-2, continues to be a major health problem since its first description in Wuhan, China, in December 2019. Multiple drugs have been tried to date in the treatment of COVID-19. Critical to treatment of COVID-19 and advancing therapeutics is an appreciation of the multiple stages of this disease and the importance of timing for investigation and use of various agents. We considered articles related to COVID-19 indexed on PubMed published January 1, 2020-November 15, 2020, and considered papers on the medRxiv preprint server. We identified relevant stages of COVID-19 including three periods: pre-exposure, incubation, and detectable viral replication; and five phases: the viral symptom phase, the early inflammatory phase, the secondary infection phase, the multisystem inflammatory phase, and the tail phase. This common terminology should serve as a framework to guide when COVID-19 therapeutics being studied or currently in use is likely to provide benefit rather than harm.

2021 - The Time to Offer Treatments for COVID-19 [Articolo su rivista]
Ngo, Binh T; Marik, Paul; Kory, Pierre; Shapiro, Leland; Thomadsen, Raphael; Iglesias, Jose; Ditmore, Stephen; Rendell, Marc; Varon, Joseph; Dubé, Michael; Nanda, Neha; In, Gino; Arkfeld, Daniel; Chaudhary, Preet; Campese, Vito M; Hanna, Diana L; Sawcer, David E; Ehresmann, Glenn; Peng, David; Smogorewski, Miroslaw; Armstrong, April; Dasgupta, Rajkumar; Sattler, Fred; Brennan-Rieder, Denise; Mussini, Cristina; Mitja, Oriol; Soriano, Vicente; Peschanski, Nicolas; Hayem, Gilles; Confalonieri, Marco; Piccirillo, Maria Carmela; Lobo-Ferreira, Antonio; Bello Rivero, Iraldo; Turkia, Mika; Vingevoll, Eivind H; Griffin, Daniel; Hung, Ivan Fn
abstract

INTRODUCTION: COVID-19 has several overlapping phases. Treatment has focused on the late stage of the disease in hospital. Yet, the continuation of the pandemic is by propagation of the disease in outpatients. The current public health strategy relies solely on vaccines to prevent disease.Areas Covered: We searched the major national registries, pubmed.org, and the preprint servers for all ongoing, completed and published trial results with subject numbers of 100 or more on, and used a targeted search to find announcements of unpublished trial results. As of 2/15/2021, we found 111 publications reporting findings in human studies on 14 classes of agents, and on 9 vaccines. There were 62 randomized controlled studies, the rest retrospective observational analyses. Only 21 publications dealt with outpatient care, the rest all in hospitalized patients. Remdesivir and convalescent plasma have emergency use authorization for hospitalized patients in the U.S.A. There is also support for glucocorticoid treatment of the COVID-19 respiratory distress syndrome. Monoclonal antibodies are authorized for outpatients, but the supply is inadequate to treat all at time of diagnosis. Favipiravir, ivermectin, and interferons are approved in certain countries.Expert Opinion: Worldwide vaccination is now underway. Vaccines and antibodies are highly antigen specific and new variants are appearing. There is a need for treatment of outpatients who contract the disease, in addition to mass immunization. We call on public health authorities to authorize treatments with known low risk and potential benefit for use in parallel with mass immunization.

2021 - The association between hepatitis B virus infection and nonliver malignancies in persons living with HIV: results from the EuroSIDA study [Articolo su rivista]
Mocroft, A.; Miro, J. M.; Wandeler, G.; Llibre, J. M.; Boyd, A.; van Bremen, K.; Beniowski, M.; Mikhalik, J.; Cavassini, M.; Maltez, F.; Duvivier, C.; Uberti Foppa, C.; Knysz, B.; Bakowska, E.; Kuzovatova, E.; Domingo, P.; Zagalo, A.; Viard, J. -P.; Degen, O.; Milinkovic, A.; Benfield, T.; Peters, L.; Harxhi, A.; Losso, M.; Kundro, M.; Schmied, B.; Zangerle, R.; Karpov, I.; Vassilenko, A.; Mitsura, V. M.; Paduto, D.; Clumeck, N.; De Wit, S.; Delforge, M.; Florence, E.; Vandekerckhove, L.; Hadziosmanovic, V.; Begovac, J.; Machala, L.; Sedlacek, D.; Kronborg, G.; Gerstoft, J.; Katzenstein, T.; Pedersen, C.; Johansen, I. S.; Ostergaard, L.; Wiese, L.; Moller, N. F.; Nielsen, L. N.; Zilmer, K.; Smidt, J.; Aho, I.; Lacombe, K.; Pradier, C.; Fontas, E.; Rockstroh, J.; Behrens, G.; Hoffmann, C.; Stellbrink, H. J.; Stefan, C.; Bogner, J.; Fatkenheuer, G.; Chkhartishvili, N.; Sambatakou, H.; Adamis, G.; Paissios, N.; Szlavik, J.; Gottfredsson, M.; Devitt, E.; Tau, L.; Turner, D.; Burke, M.; Shahar, E.; Wattad, L. M.; Elinav, H.; Haouzi, M.; Elbirt, D.; D'Arminio Monforte, A.; Esposito, R.; Mazeu, I.; Mussini, C.; Mazzotta, F.; Gabbuti, A.; Lazzarin, A.; Castagna, A.; Gianotti, N.; Galli, M.; Ridolfo, A.; Uzdaviniene, V.; Matulionyte, R.; Staub, T.; Hemmer, R.; Dragas, S.; Stevanovic, M.; vd Valk, M.; Trajanovska, J.; Reikvam, D. H.; Maeland, A.; Bruun, J.; Szetela, B.; Inglot, M.; Flisiak, R.; Grzeszczuk, A.; Parczewski, M.; Maciejewska, K.; Aksak-Was, B.; Mularska, E.; Jablonowska, E.; Kamerys, J.; Wojcik, K.; Mozer-Lisewska, I.; Rozplochowski, B.; Mansinho, K.; Radoi, R.; Oprea, C.; Gusev, D.; Trofimova, T.; Khromova, I.; Borodulina, E.; Ranin, J.; Tomazic, J.; Miro, J. M.; Laguno, M.; Martinez, E.; Garcia, F.; Blanco, J. L.; Martinez-Rebollar, M.; Mallolas, J.; Callau, P.; Rojas, J.; Inciarta, A.; Moreno, S.; del Campo, S.; Clotet, B.; Jou, A.; Paredes, R.; Puig, J.; Santos, J. R.; Gutierrez, M.; Mateo, G.; Sambeat, M. A.; Laporte, J. M.; Svedhem, V.; Thalme, A.; Sonnerborg, A.; Brannstrom, J.; Flamholc, L.; Kusejko, K.; Braun, D.; Calmy, A.; Furrer, H.; Battegay, M.; Schmid, P.; Kuznetsova, A.; Sluzhynska, M.; Johnson, A. M.; Simons, E.; Edwards, S.; Phillips, A.; Johnson, M. A.; Orkin, C.; Winston, A.; Clarke, A.; Leen, C.; Karpov, I.; Losso, M.; Lundgren, J.; Rockstroh, J.; Aho, I.; Rasmussen, L. D.; Svedhem, V.; Pradier, C.; Chkhartishvili, N.; Matulionyte, R.; Oprea, C.; Kowalska, J. D.; Begovac, J.; Miro, J. M.; Guaraldi, G.; Paredes, R.; Paredes, R.; Larsen, J. F.; Bojesen, A.; Neesgaard, B.; Jaschinski, N.; Fursa, O.; Sather, M.; Raben, D.; Hansen, E. V.; Kristensen, D.; Fischer, A. H.; Jensen, S. K.; Elsing, T. W.; Phillips, A.; Reekie, J.; Cozzi-Lepri, A.; Amele, S.; Pelchen-Matthews, A.; Roen, A.; Tusch, E. S.; Bannister, W.
abstract

Objectives: The aim of this study was to assess the impact of hepatitis B virus (HBV) infection on non-liver malignancies in people living with HIV (PLWH). Methods: All persons aged ≥ 18 years with known hepatitis B virus (HBV) surface antigen (HBsAg) status after the latest of 1 January 2001 and enrolment in the EuroSIDA cohort (baseline) were included in the study; persons were categorized as HBV positive or negative using the latest HBsAg test and followed to their first diagnosis of nonliver malignancy or their last visit. Results: Of 17 485 PLWH included in the study, 1269 (7.2%) were HBV positive at baseline. During 151 766 person-years of follow-up (PYFU), there were 1298 nonliver malignancies, 1199 in those currently HBV negative [incidence rate (IR) 8.42/1000 PYFU; 95% confidence interval (CI) 7.94–8.90/1000 PYFU] and 99 in those HBV positive (IR 10.54/1000 PYFU; 95% CI 8.47–12.62/1000 PYFU). After adjustment for baseline confounders, there was a significantly increased incidence of nonliver malignancies in HBV-positive versus HBV-negative individuals [adjusted incidence rate ratio (aIRR) 1.23; 95% CI 1.00–1.51]. Compared to HBV-negative individuals, HBsAg-positive/HBV-DNA-positive individuals had significantly increased incidences of nonliver malignancies (aIRR 1.37; 95% CI 1.00–1.89) and NHL (aIRR 2.57; 95% CI 1.16–5.68). There was no significant association between HBV and lung or anal cancer. Conclusions: We found increased rates of nonliver malignancies in HBsAg-positive participants, the increases being most pronounced in those who were HBV DNA positive and for NHL. If confirmed, these results may have implications for increased cancer screening in HIV-positive subjects with chronic HBV infection.

2021 - The impact of DAA-mediated HCV eradication on CD4+ and CD8+ T lymphocyte trajectories in HIV/HCV coinfected patients: data from the ICONA Foundation Cohort [Articolo su rivista]
Bandera, A; Lorenzini, P; Taramasso, L; Cozzi-Lepri, A; Lapadula, G; Mussini, C; Saracino, A; Ceccherini-Silberstein, F; Puoti, M; Quiros-Roldan, E; Montagnani, F; Antinori, A; d'Arminio Monforte, A; Gori, A
abstract

HCV infection has been hypothesized as a contributor of poor CD4+ recovery in patients living with HIV (PLWHIV). Aim of this study was to evaluate CD4+ , CD8+ cells and CD4/CD8 ratio trends before and after HCV treatment with direct acting agents (DAA) in PLWHIV. HIV/HCV patients enrolled in ICONA and HepaICONA cohorts with HIV-RNA≤50 copies/mL who achieved a sustained viral response after DAA treatment were studied. A linear regression model was used to investigate CD4+ , CD8+ , and CD4/CD8 changes 12 months before and after DAA treatment. A total of 939 HIV/HCV patients were included, 225 (24.0%) female, median age: 53 years (IQR 50-56). At DAA initiation, CD4+ T cell count was <350 cells/mm3 in 164 patients (17.5%), and 246 patients (26.2%) had liver stiffness> 12.5 kPa. Trends of CD4+ and CD4/CD8 ratio were similar before and after DAA in all study populations (CD4+ change +17.6 cells/mm3 (95%CI -33.5;69.4, p= 0.494); CD4/CD8 change 0.013 (95%CI -0.061; 0.036, p= 0.611). However, patients treated with ribavirin (RBV)-free DAA showed a significant decrease in CD8+ cells (-204.3 cells/mm3 , 95%CI -375.0;-33.4, p=0.019), while patients treated with RBV experienced CD8+ cell increase (+141.2 cells/mm3 , 95%CI 40.3;242.1, p=0.006). In conclusion, HCV eradication following DAA treatment does not seem to have an impact on CD4+ T cell recovery in PLWHIV. However, a fast decline of CD8+ T cells has been observed in patients treated without RBV, suggesting a favorable effect of HCV clearance on the general state of immune activation.

2021 - The impact of tocilizumab on respiratory support states transition and clinical outcomes in COVID-19 patients. A Markov model multi-state study [Articolo su rivista]
Milic, J.; Banchelli, F.; Meschiari, M.; Franceschini, E.; Ciusa, G.; Gozzi, L.; Volpi, S.; Faltoni, M.; Franceschi, G.; Iadisernia, V.; Yaacoub, D.; Dolci, G.; Bacca, E.; Rogati, C.; Tutone, M.; Burastero, G.; Raimondi, A.; Menozzi, M.; Cuomo, G.; Corradi, L.; Orlando, G.; Santoro, A.; Digaetano, M.; Puzzolante, C.; Carli, F.; Bedini, A.; Busani, S.; Girardis, M.; Cossarizza, A.; Miglio, R.; Mussini, C.; Guaraldi, G.; D'Amico, R.
abstract

Background The benefit of tocilizumab on mortality and time to recovery in people with severe COVID pneumonia may depend on appropriate timing. The objective was to estimate the impact of tocilizumab administration on switching respiratory support states, mortality and time to recovery. Methods In an observational study, a continuous-time Markov multi-state model was used to describe the sequence of respiratory support states including: no respiratory support (NRS), oxygen therapy (OT), non-invasive ventilation (NIV) or invasive mechanical ventilation (IMV), OT in recovery, NRS in recovery. Results Two hundred seventy-one consecutive adult patients were included in the analyses contributing to 695 transitions across states. The prevalence of patients in each respiratory support state was estimated with stack probability plots, comparing people treated with and without tocilizumab since the beginning of the OT state. A positive effect of tocilizumab on the probability of moving from the invasive and non-invasive mechanical NIV/IMV state to the OT in recovery state (HR = 2.6, 95% CI = 1.2–5.2) was observed. Furthermore, a reduced risk of death was observed in patients in NIV/IMV (HR = 0.3, 95% CI = 0.1–0.7) or in OT (HR = 0.1, 95% CI = 0.0–0.8) treated with tocilizumab. Conclusion To conclude, we were able to show the positive impact of tocilizumab used in different disease stages depicted by respiratory support states. The use of the multi-state Markov model allowed to harmonize the heterogeneous mortality and recovery endpoints and summarize results with stack probability plots. This approach could inform randomized clinical trials regarding tocilizumab, support disease management and hospital decision making.

2021 - The role of antimicrobial stewardship in preventing KPC-producing Klebsiella pneumoniae [Articolo su rivista]
Carrara, Elena; Conti, Michela; Meschiari, Marianna; Mussini, Cristina
abstract

Antimicrobial stewardship programmes are widely considered to be a core component of the response to the antimicrobial resistance threat. However, a positive impact of these interventions in terms of microbiological outcomes remains difficult to demonstrate, especially when focusing on specific resistant phenotypes. The first part of this review aims to explore the complex relationship between antibiotic exposure and resistance development in KPC-producing Klebsiella pneumoniae. In the second part we aim to summarize published examples of antimicrobial stewardship interventions intended to impact on the epidemiology of KPC-producing K. pneumoniae. For this purpose, a literature search was performed and seven studies were included in the review. Both restrictive and non-restrictive interventions were associated with an overall reduction in antibiotic consumption, and a decrease in carbapenem resistance rates was observed in five studies. The overall quality of the evidence was low, mainly due to the poor reporting of microbiological outcomes, lack of a control group and suboptimal study design. Although the link between antibiotic use and resistance development is supported by strong evidence, demonstrating the impact of antimicrobial stewardship interventions on microbiological outcomes remains difficult. Studies with adequate design and appropriate outcome measures are needed to further promote antimicrobial stewardship and elucidate which interventions are more successful for controlling the spread of KPC-producing K. pneumoniae.

2021 - Twenty-four-hour serum creatinine variation is associated with poor outcome in the novel coronavirus disease 2019 (COVID-19) patients [Articolo su rivista]
Alfano, Gaetano; Ferrari, Annachiara; Fontana, Francesco; Mori, Giacomo; Ligabue, Giulia; Giovanella, Silvia; Magistroni, Riccardo; Meschiari, Marianna; Franceschini, Erica; Menozzi, Marianna; Cuomo, Gianluca; Orlando, Gabriella; Santoro, Antonella; Di Gaetano, Margherita; Puzzolante, Cinzia; Carli, Federica; Bedini, Andrea; Milic, Jovana; Mussini, Cristina; Cappelli, Gianni; Guaraldi, Giovanni
abstract

Background: The prognostic value of within-day sCr variation serum creatinine variation is unknown in the setting of the novel coronavirus disease 2019 (COVID-19). We evaluated the prognostic significance of 24-hour serum creatinine variation in COVID-19 patients.Methods: A monocentric retrospective analysis was conducted in COVID-19 patients not admitted to the intensive care unit. Three groups were subdivided based on 24 hours serum creatinine variation from admission. In the stable kidney function group, 24-hour serum creatinine variation ranged from +0.05 to -0.05 mg/dL; in the decreased kidney function group, 24-hour serum creatinine variation was &gt;0.05 mg/dL; in the improved kidney function group, 24-hour serum creatinine variation was &lt;-0.05 mg/dL.Results: The study population included 224 patients with a median age of 66.5 years and a predominance of males (72.3%). Within 24 hours of admission, renal function remained stable in 37.1% of the subjects, whereas it displayed improved and deteriorated patterns in 45.5% and 17.4%, respectively. Patients with decreased kidney function were older and had more severe COVID-19 symptoms than patients with stable or improved kidney function. About half of patients with decreased kidney function developed an episode of acute kidney injury (AKI) during hospitalization. Decreased kidney function was significantly associated with AKI during hospitalization (hazard ratio [HR], 4.6; 95% confidence interval [CI], 1.9-10.8; p &lt; 0.001) and was an independent risk factor for 30-day in-hospital mortality (HR, 5.5; 95% CI, 1.1-28; p = 0.037).Conclusion: COVID-19 patients with decreased kidney function within 24 hours of admission were at high risk of AKI and 30-day in-hospital mortality.

2021 - Viral resistance burden and APOBEC editing correlate with virological response in heavily treatment-experienced people living with multi-drug resistant HIV [Articolo su rivista]
Armenia, Daniele; Santoro, Maria Mercedes; Bellocchi, Maria Concetta; Carioti, Luca; Galli, Laura; Galli, Andrea; Scutari, Rossana; Salsi, Eleonora; Mussini, Cristina; Sterrantino, Gaetana; Calza, Leonardo; Rossetti, Barbara; Zazzi, Maurizio; Castagna, Antonella
abstract

Background: The impact of drug resistance mutational load and APOBEC editing in heavily treatment-experienced (HTE) people living with multidrug-resistant HIV has not been investigated. Material and methods: We explored the HIV-DNA and HIV-RNA mutational load of drug resistance and APOBEC-related mutations through next-generation sequencing (NGS, Illumina MiSeq) in 20 failing HTE persons enrolled in the PRESTIGIO registry. Results: Patients showed high levels of both HIV-DNA (4.5 [4.0-5.2] log10 copies/106 T-CD4+ cell) and HIV-RNA (4.5 [4.1-5.0] log10 copies/mL) with complex resistance patterns in both compartments. Among the 255 drug resistance mutations found, 66.3% were concordantly detected in both HIV-DNA and HIV-RNA; 71.3% of mutations were already present in historical Sanger genotypes. At intra-patient frequency &gt;5%, a considerable proportion of mutations detected through DNA-NGS were found in historical genotypes but not through RNA-NGS, and few patients had APOBEC-related mutations. Of 14 individuals who switched therapy, those five who failed treatment had DNA resistance with higher intra-patient frequency, higher DNA/RNA mutational load in a context of tendentially less pronounced APOBEC editing compared to those who responded. Conclusions: Using NGS in HIV-DNA and HIV-RNA together with APOBEC editing evaluation might help to identify HTE individuals with MDR who are more prone to experience virological failure.

2021 - Virological response and resistance profile in highly treatment-experienced HIV-1-infected patients switching to dolutegravir plus boosted darunavir in clinical practice [Articolo su rivista]
Armenia, D.; Bouba, Y.; Gagliardini, R.; Fabeni, L.; Borghi, V.; Berno, G.; Vergori, A.; Cicalini, S.; Mussini, C.; Antinori, A.; Ceccherini-Silberstein, F.; Perno, C. F.; Santoro, M. M.
abstract

Objectives: We evaluated the virological response and resistance profile in combined antiretroviral therapy (cART)-experienced HIV-1-infected patients starting a dual therapy with dolutegravir (DTG) and boosted darunavir (bDRV) for the first time. Methods: Survival analyses were used to evaluate virological success (VS) and virological rebound (VR) in viraemic and virologically suppressed patients, respectively. Major resistance mutations (MRMs) and genotypic susceptibility score (GSS) were evaluated at baseline and after switch. Results: Overall, 130 patients [62 (47.7%) viraemic; 68 (52.3%) virologically suppressed] were retrospectively analysed. At the moment of switch, 81.5% accumulated one or more MRM [protease inhibitor (PI), 35.7%; nucleoside(t)ide reverse transcriptase inhibitor (NRTI), 77.5%; non-NRTI, 69.0%; integrase inhibitor (INI), 10.1%), but 77.7% harboured strains fully susceptible to DTG&nbsp;+&nbsp;bDRV. In viraemic patients, the overall probability of VS by 12&nbsp;months of treatment was 91.7%. In virologically suppressed patients, the overall probability of VR was 10.5% by 24&nbsp;months after therapy start. Patients with previous time under virological suppression&nbsp;≤&nbsp;6&nbsp;months showed a higher VR probability compared with others (37.5% vs. 6.7%, P&nbsp;&lt;&nbsp;0.002). Among 13 non-responding patients for whom a genotypic resistance test result at failure was available, only two (15.4%) accumulated further resistance in integrase (Y143C/H/R; S147G and N155H) and protease (V32I, L33F, I54L). Conclusions: In highly treatment-experienced patients, the use of dual therapy based on DTG&nbsp;+&nbsp;bDRV appears to be a very good regimen for switch therapy, with a high rate of virological control in both viraemic and virologically suppressed patients. Among non-responding patients, the selection of further resistance is a rare event.

2021 - Voice assistance to develop a participatory research and action to improve health trajectories of people with PACS [Abstract in Atti di Convegno]
Caselgrandi, Agnese; Milić, Jovana; Motta, Federico; Belli, Michela; Venuta, Maria; Aprile, Emanuele; Gozzi, Licia; Burastero, Giulia; Iadisernia, Vittorio; Yaacoub, Dina; Orsini, M.; Pacchioni, M.; Mescoli, E.; Mussini, Cristina; Guaraldi, Giovanni
abstract

2021 - Week 96 subgroup analyses of the phase 3, randomized AMBER and EMERALD trials evaluating the efficacy and safety of the once daily darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) single-tablet regimen in antiretroviral treatment (ART)-naïve and -experienced, virologically-suppressed adults living with HIV-1 [Articolo su rivista]
Huhn, Gregory D; Wilkin, Aimee; Mussini, Cristina; Spinner, Christoph D; Jezorwski, John; El Ghazi, Mohsine; Van Landuyt, Erika; Lathouwers, Erkki; Brown, Kimberley; Baugh, Bryan
abstract

Darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) 800/150/200/10 mg was investigated in AMBER (treatment-naïve adults; NCT02431247) and EMERALD (treatment-experienced, virologically-suppressed adults; NCT02269917).

2021 - Withholding primary PcP prophylaxis in virologically suppressed HIV patients: An emulation of a pragmatic trial in COHERE [Articolo su rivista]
Atkinson, A; Zwahlen, M; Barger, D; d'Arminio Monforte, A; De Wit, S; Ghosn, J; Girardi, E; Svedhem-Johansson, V; Morlat, P; Mussini, C; Noguera-Julian, A; Stephan, C; Touloumi, G; Kirk, O; Mocroft, A; Reiss, P; Miro, J M; Carpenter, J R; Furrer, H
abstract

Using data from the COHERE collaboration, we investigated whether primary prophylaxis for Pneumocystis Pneumonia (PcP) might be withheld in all patients on antiretroviral therapy with suppressed plasma HIV RNA (≤ 400c/mL) irrespective of CD4 count.

2020 - 18Fluoride-based molecular imaging of coronary atherosclerosis in HIV infected patients [Articolo su rivista]
Guaraldi, G.; Milic, J.; Prandini, N.; Ligabue, G.; Esposito, F.; Ciusa, G.; Malagoli, A.; Scaglioni, R.; Besutti, G.; Beghetto, B.; Nardini, G.; Roncaglia, E.; Mussini, C.; Raggi, P.
abstract

Background and aims: Molecular imaging with 18Fluorodeoxyglucose (FDG) and 18F-sodium-fluoride (NaF) captures arterial inflammation and micro-calcification and can reveal potentially unstable atherosclerotic plaques. Methods: We performed FDG and NaF PET/CT imaging in two clinically similar cohorts of patients living with HIV (PLWH) with no symptomatic cardiovascular disease. The prevalence and intensity of coronary artery uptake of each tracer, measured as target-to-background ratio (TBR), were assessed in patients at low and high cardiovascular risk. Results: Ninety-three PLWH were submitted to PET/CT imaging with FDG (N = 43) and NaF (N = 50); 42% were at low and 58% at high cardiovascular risk. The intensity of uptake and multivessel coronary artery uptake were significantly higher with NaF than FDG both in low and high-risk patients. When each 18F-tracer was tested in low and high-risk patients, an equal proportion of subjects showed no vessel, single and multivessel NaF uptake; the same was true for no and single vessel uptake of FDG (no multivessel FDG uptake was noted). Waist circumference, CRP, D-dimer, HIV duration and treatment with nucleoside reverse transcriptase inhibitors were associated with high NaF uptake in univariable analyses; D-dimer remained significant in multivariable analyses (OR = 1.05; p=0.02). There were no significant associations with FDG uptake. Conclusions: The prevalence of coronary artery uptake was higher with NaF compared to FDG both in high and low risk patients, hence microcalcification imaging may be a more sensitive tool to detect coronary atherosclerosis than inflammation imaging. However, the uptake of each 18Fluoride tracer was similar between low and high-risk subjects, and this underscores the discordance between clinical and imaging based risk assessment. Future investigation should address the prognostic significance of NaF coronary artery uptake.

2020 - A patient-centred approach to deprescribing antiretroviral therapy in people living with HIV [Articolo su rivista]
Guaraldi, Giovanni; Milić, Jovana; Marcotullio, Simone; Mussini, Cristina
abstract

2020 - A retrospective whole-genome sequencing analysis of carbapenem and colistin-resistant klebsiella pneumoniae nosocomial strains isolated during an MDR surveillance program [Articolo su rivista]
Gentile, B.; Grottola, A.; Orlando, G.; Serpini, G. F.; Venturelli, C.; Meschiari, M.; Anselmo, A.; Fillo, S.; Fortunato, A.; Lista, F.; Pecorari, M.; Mussini, C.
abstract

Multidrug-resistant Klebsiella pneumoniae (MDR Kp), in particular carbapenem-resistant Kp (CR-Kp), has become endemic in Italy, where alarming data have been reported on the spread of colistin-resistant CR-Kp (CRCR-Kp). During the period 2013–2014, 27 CRCR-Kp nosocomial strains were isolated within the Modena University Hospital Policlinico (MUHP) multidrug resistance surveillance program. We retrospectively investigated these isolates by whole-genome sequencing (WGS) analysis of the resistome, virulome, plasmid content, and core single nucleotide polymorphisms (cSNPs) in order to gain insights into their molecular epidemiology. The in silico WGS analysis of the resistome revealed the presence of genes, such as blaKPC, related to the phenotypically detected resistances to carbapenems. Concerning colistin resistance, the plasmidic genes mcr 1–9 were not detected, while known and new genetic variations in mgrB, phoQ, and pmrB were found. The virulome profile revealed the presence of type-3 fimbriae, capsular polysaccharide, and iron acquisition system genes. The detected plasmid replicons were classified as IncFIB(pQil), IncFIB(K), ColRNAI, IncX3, and IncFII(K) types. The cSNPs genotyping was consistent with the multi locus sequence typing (MLST) and with the distribution of mutations related to colistin resistance genes. In a nosocomial drug resistance surveillance program, WGS proved to be a useful tool for elucidating the spread dynamics of CRCR-Kp nosocomial strains and could help to limit their diffusion.

2020 - ACE2 gene variants may underlie interindividual variability and susceptibility to COVID-19 in the Italian population [Articolo su rivista]
Benetti, E.; Tita, R.; Spiga, O.; Ciolfi, A.; Birolo, G.; Bruselles, A.; Doddato, G.; Giliberti, A.; Marconi, C.; Musacchia, F.; Pippucci, T.; Torella, A.; Trezza, A.; Valentino, F.; Baldassarri, M.; Brusco, A.; Asselta, R.; Bruttini, M.; Furini, S.; Seri, M.; Nigro, V.; Matullo, G.; Tartaglia, M.; Mari, F.; Elisa, F.; Chiara, F.; Sergio, D.; Susanna, C.; Sara, A.; Francesca, F.; Montagnani, F.; Di Sarno, L.; Tommasi, A.; Palmieri, M.; Emiliozzi, A.; Fabbiani, M.; Rossetti, B.; Zanelli, G.; Bergantini, L.; D'Alessandro, M.; Cameli, P.; Bennet, D.; Anedda, F.; Marcantonio, S.; Scolletta, S.; Franchi, F.; Mazzei, M. A.; Conticini, E.; Cantarini, L.; Frediani, B.; Tacconi, D.; Feri, M.; Scala, R.; Spargi, G.; Corridi, M.; Nencioni, C.; Caldarelli, G. P.; Spagnesi, M.; Piacentini, P.; Bandini, M.; Desanctis, E.; Canaccini, A.; Spertilli, C.; Donati, A.; Guidelli, L.; Croci, L.; Verzuri, A.; Anemoli, V.; Ognibene, A.; Vaghi, M.; D'Arminio Monforte, A.; Merlini, E.; Mondelli, M. U.; Mantovani, S.; Ludovisi, S.; Girardis, M.; Venturelli, S.; Sita, M.; Cossarizza, A.; Antinori, A.; Vergori, A.; Rusconi, S.; Siano, M.; Gabrieli, A.; Riva, A.; Francisci, D.; Schiaroli, E.; Scotton, P. G.; Andretta, F.; Panese, S.; Scaggiante, R.; Parisi, S. G.; Castelli, F.; Quiros-Roldan, M. E.; Magro, P.; Minardi, C.; Castelli, D.; Polesini, I.; Della Monica, M.; Piscopo, C.; Capasso, M.; Russo, R.; Andolfo, I.; Iolascon, A.; Carella, M.; Castori, M.; Merla, G.; Aucella, F.; Raggi, P.; Marciano, C.; Perna, R.; Bassetti, M.; Di Biagio, A.; Sanguinetti, M.; Masucci, L.; Gabbi, C.; Valente, S.; Guerrini, S.; Meloni, I.; Mencarelli, M. A.; Rizzo, C. L.; Bargagli, E.; Mandala, M.; Giorli, A.; Salerni, L.; Fiorentino, G.; Zucchi, P.; Parravicini, P.; Menatti, E.; Baratti, S.; Trotta, T.; Giannattasio, F.; Coiro, G.; Lena, F.; Coviello, D. A.; Mussini, C.; Renieri, A.; Pinto, A. M.
abstract

In December 2019, an initial cluster of interstitial bilateral pneumonia emerged in Wuhan, China. A human-to-human transmission was assumed and a previously unrecognized entity, termed coronavirus disease-19 (COVID-19) due to a novel coronavirus (SARS-CoV-2) was described. The infection has rapidly spread out all over the world and Italy has been the first European country experiencing the endemic wave with unexpected clinical severity in comparison with Asian countries. It has been shown that SARS-CoV-2 utilizes angiotensin converting enzyme 2 (ACE2) as host receptor and host proteases for cell surface binding and internalization. Thus, a predisposing genetic background can give reason for interindividual disease susceptibility and/or severity. Taking advantage of the Network of Italian Genomes (NIG), here we mined whole-exome sequencing data of 6930 Italian control individuals from five different centers looking for ACE2 variants. A number of variants with a potential impact on protein stability were identified. Among these, three more common missense changes, p.(Asn720Asp), p.(Lys26Arg), and p.(Gly211Arg) were predicted to interfere with protein structure and stabilization. Rare variants likely interfering with the internalization process, namely p.(Leu351Val) and p.(Pro389His), predicted to interfere with SARS-CoV-2 spike protein binding, were also observed. Comparison of ACE2 WES data between a cohort of 131 patients and 258 controls allowed identifying a statistically significant (P value &lt; 0.029) higher allelic variability in controls compared with patients. These findings suggest that a predisposing genetic background may contribute to the observed interindividual clinical variability associated with COVID-19, allowing an evidence-based risk assessment leading to personalized preventive measures and therapeutic options.

2020 - Acute myeloid leukemia in patients living with HIV infection: Several questions, fewer answers [Articolo su rivista]
Forghieri, F.; Nasillo, V.; Bettelli, F.; Pioli, V.; Giusti, D.; Gilioli, A.; Mussini, C.; Tagliafico, E.; Trenti, T.; Cossarizza, A.; Maffei, R.; Barozzi, P.; Potenza, L.; Marasca, R.; Narni, F.; Luppi, M.
abstract

Both human immunodeficiency virus (HIV) infection and acute myeloid leukemia (AML) may be considered relatively uncommon disorders in the general population, but the precise incidence of AML in people living with HIV infection (PLWH) is uncertain. However, life expectancy of newly infected HIV-positive patients receiving anti-retroviral therapy (ART) is gradually increasing, rivaling that of age-matched HIV-negative individuals, so that the occurrence of AML is also expected to progressively increase. Even if HIV is not reported to be directly mutagenic, several indirect leukemogenic mechanisms, mainly based on bone marrow microenvironment disruption, have been proposed. Despite a well-controlled HIV infection under ART should no longer be considered per se a contraindication to intensive chemotherapeutic approaches, including allogeneic hematopoietic stem cell transplantation, in selected fit patients with AML, survival outcomes are still generally unsatisfactory. We discussed several controversial issues about pathogenesis and clinical management of AML in PLWH, but few evidence-based answers may currently be provided, due to the limited number of cases reported in the literature, mainly as case reports or small retrospective case series. Prospective multicenter clinical trials are warranted to more precisely investigate epidemiology and cytogenetic/molecular features of AML in PLWH, but also to standardize and further improve its therapeutic management.

2020 - Acute myocarditis as the main clinical manifestation of SARS-CoV 2 infection: A case report [Articolo su rivista]
Cuomo, G.; Menozzi, M.; Carli, F.; Digaetano, M.; Raimondi, A.; Reggianini, L.; Ligabue, G.; Guaraldi, G.; Mussini, C.
abstract

We describe a case of acute myocarditis which was reported as the main COVID-19 clinical manifestation, with a favorable outcome. In addition to symptoms, laboratory tests (BNP and troponin), echocardiogram and cardiac MRI contributed to diagnosis. Regardless heart biopsy was not obtained, it is likely an immunological pathogenesis of this condition which pave the way to further therapeutic implications, since there are currently no standardized treatments.

2020 - Altered bioenergetics and mitochondrial dysfunction of monocytes in patients with COVID-19 pneumonia [Articolo su rivista]
Gibellini, L.; De Biasi, S.; Paolini, A.; Borella, R.; Boraldi, F.; Mattioli, M.; Lo Tartaro, D.; Fidanza, L.; Caro-Maldonado, A.; Meschiari, M.; Iadisernia, V.; Bacca, E.; Riva, G.; Cicchetti, L.; Quaglino, D.; Guaraldi, G.; Busani, S.; Girardis, M.; Mussini, C.; Cossarizza, A.
abstract

In patients infected by SARS-CoV-2 who experience an exaggerated inflammation leading to pneumonia, monocytes likely play a major role but have received poor attention. Thus, we analyzed peripheral blood monocytes from patients with COVID-19 pneumonia and found that these cells show signs of altered bioenergetics and mitochondrial dysfunction, had a reduced basal and maximal respiration, reduced spare respiratory capacity, and decreased proton leak. Basal extracellular acidification rate was also diminished, suggesting reduced capability to perform aerobic glycolysis. Although COVID-19 monocytes had a reduced ability to perform oxidative burst, they were still capable of producing TNF and IFN-γ in vitro. A significantly high amount of monocytes had depolarized mitochondria and abnormal mitochondrial ultrastructure. A redistribution of monocyte subsets, with a significant expansion of intermediate/pro-inflammatory cells, and high amounts of immature monocytes were found, along with a concomitant compression of classical monocytes, and an increased expression of inhibitory checkpoints like PD-1/PD-L1. High plasma levels of several inflammatory cytokines and chemokines, including GM-CSF, IL-18, CCL2, CXCL10, and osteopontin, finally confirm the importance of monocytes in COVID-19 immunopathogenesis.

2020 - Beyond Italian guidelines in the management of HIV-positive patient [Articolo su rivista]
Andreoni, Massimo; Antinori, Andrea; Castagna, Antonella; D'Arminio Monforte, Antonella; Di Perri, Giovanni; Galli, Massimo; Gori, Andrea; Mussini, Cristina; Perno, Carlo Federico
abstract

Although AIDS/HIV infection and related deaths have significantly decreased in Italy in recent years, new problems have made it more challenging to manage the disease. To overcome the new hurdles, the Italian National Plan of Interventions against HIV and AIDS was recently issued by the National Health Authorities, and the Italian Guidelines (GL) for diagnosis, therapy and management of HIV-1 infection were subsequently drafted by the Italian Society of Infectious and Tropical Diseases (SIMIT). Although the GLs provide clear recommendations, they are open to personal interpretation depending on the experience and/or background of individual healthcare professionals. To minimize the interpretative variability, eight residential meetings were organized in Italy in 2019 to promote a multidisciplinary approach and discuss specific HIV-associated conditions, such as cardiovascular or neuro-psychological comorbidities, advanced stage of infection, and high CD4 cell counts. To undertake this educational program, the GLs were simplified into key steps by creating ad hoc decisional algorithms, and an innovative multimedia technology was used during the meetings to collect and summarize individual opinions up to the final statements. For HIV patients with cardiovascular diseases, "CV risk factor identification" and "change of patients' lifestyle" were the most commonly shared approaches by all healthcare professionals, regardless of individual attitudes. Among HIV individuals with neurocognitive and psychological comorbidities, "more neurocognitive tests", "better customization of antiretroviral therapy (ART)", and "assessment of psychological symptoms" were the most frequently identified options to carry out. Advanced HIV infection and low CD4 cell count being a particularly serious condition burdened by high mortality, almost all specialists oriented their opinion toward a prompt and scrupulous clinical evaluation to be performed just before and immediately after the start of ART. Finally, the most pursued recommendations in patients with acute HIV infection and high CD4 cell count were the achievement of a "prompt diagnosis" and "start of well-shaped ART", as the most appropriate means to keep the viral load as low as possible. Undoubtedly, despite negligible discrepancies in individual interpretation among specialists, this nationwide educational program was able to capture local differences, but to guarantee at the same time a constant alignment of individual specialists towards the Italian clinical practice GLs. Different priorities in the daily management of the four HIV-1 subpopulations highlighted during the meetings reflect the presence of different regional health policies nationwide, in turn generating different healthcare offers. This program offered state-of-the-art management of four widely represented subpopulations of HIV-1 patients.

2020 - COVID-19-associated vasculitis and thrombotic complications: from pathological findings to multidisciplinary discussion [Articolo su rivista]
Vacchi, Caterina; Meschiari, Marianna; Milic, Jovana; Marietta, Marco; Tonelli, Roberto; Alfano, Gaetano; Volpi, Sara; Faltoni, Matteo; Franceschi, Giacomo; Ciusa, Giacomo; Bacca, Erica; Tutone, Marco; Raimondi, Alessandro; Menozzi, Marianna; Franceschini, Erica; Cuomo, Gianluca; Orlando, Gabriella; Santoro, Antonella; Di Gaetano, Margherita; Puzzolante, Cinzia; Carli, Federica; Bedini, Andrea; Cossarizza, Andrea; Castaniere, Ivana; Ligabue, Guido; De Ruvo, Nicola; Manco, Gianrocco; Rolando, Giovanni; Gelmini, Roberta; Maiorana, Antonino; Girardis, Massimo; Mascia, Maria Teresa; Mussini, Cristina; Salvarani, Carlo; Guaraldi, Giovanni
abstract

Neutrophilic arterial vasculitis in COVID-19 represents a novel finding and could be responsible for thrombotic complications.

2020 - COVID-19: Importance of the Awareness of the Clinical Syndrome by Urologists [Articolo su rivista]
Sighinolfi, M. C.; Rocco, B.; Mussini, C.
abstract

2020 - Ceftolozane/Tazobactam for Treatment of Severe ESBL-Producing Enterobacterales Infections: A Multicenter Nationwide Clinical Experience (CEFTABUSE II Study) [Articolo su rivista]
Bassetti, Matteo; Vena, Antonio; Giacobbe, Daniele Roberto; Falcone, Marco; Tiseo, Giusy; Giannella, Maddalena; Pascale, Renato; Meschiari, Marianna; Digaetano, Margherita; Oliva, Alessandra; Rovelli, Cristina; Carannante, Novella; Losito, Angela Raffaella; Carbonara, Sergio; Mariani, Michele Fabiano; Mastroianni, Antonio; Angarano, Gioacchino; Tumbarello, Mario; Tascini, Carlo; Grossi, Paolo; Mastroianni, Claudio Maria; Mussini, Cristina; Viale, Pierluigi; Menichetti, Francesco; Viscoli, Claudio; Russo, Alessandro
abstract

Few data are reported in the literature about the outcome of patients with severe extended-spectrum β-lactamase-producing Enterobacterales (ESBL-E) infections treated with ceftolozane/tazobactam (C/T), in empiric or definitive therapy.

2020 - Cervical cancer risk in women living with HIV across four continents: A multicohort study [Articolo su rivista]
Rohner, E.; Butikofer, L.; Schmidlin, K.; Sengayi, M.; Maskew, M.; Giddy, J.; Taghavi, K.; Moore, R. D.; Goedert, J. J.; Gill, M. J.; Silverberg, M. J.; D'Souza, G.; Patel, P.; Castilho, J. L.; Ross, J.; Sohn, A.; Bani-Sadr, F.; Taylor, N.; Paparizos, V.; Bonnet, F.; Verbon, A.; Vehreschild, J. J.; Post, F. A.; Sabin, C.; Mocroft, A.; Dronda, F.; Obel, N.; Grabar, S.; Spagnuolo, V.; Quiros-Roldan, E.; Mussini, C.; Miro, J. M.; Meyer, L.; Hasse, B.; Konopnicki, D.; Roca, B.; Barger, D.; Clifford, G. M.; Franceschi, S.; Egger, M.; Bohlius, J.
abstract

We compared invasive cervical cancer (ICC) incidence rates in Europe, South Africa, Latin and North America among women living with HIV who initiated antiretroviral therapy (ART) between 1996 and 2014. We analyzed cohort data from the International Epidemiology Databases to Evaluate AIDS (IeDEA) and the Collaboration of Observational HIV Epidemiological Research in Europe (COHERE) in EuroCoord. We used flexible parametric survival models to determine regional ICC rates and risk factors for incident ICC. We included 64,231 women from 45 countries. During 320,141 person-years (pys), 356 incident ICC cases were diagnosed (Europe 164, South Africa 156, North America 19 and Latin America 17). Raw ICC incidence rates per 100,000 pys were 447 in South Africa (95% confidence interval [CI]: 382-523), 136 in Latin America (95% CI: 85-219), 76 in North America (95% CI: 48-119) and 66 in Europe (95% CI: 57-77). Compared to European women ICC rates at 5 years after ART initiation were more than double in Latin America (adjusted hazard ratio [aHR]: 2.43, 95% CI: 1.27-4.68) and 11 times higher in South Africa (aHR: 10.66, 95% CI: 6.73-16.88), but similar in North America (aHR: 0.79, 95% CI: 0.37-1.71). Overall, ICC rates increased with age (&gt;50 years vs. 16-30 years, aHR: 1.57, 95% CI: 1.03-2.40) and lower CD4 cell counts at ART initiation (per 100 cell/μl decrease, aHR: 1.25, 95% CI: 1.15-1.36). Improving access to early ART initiation and effective cervical cancer screening in women living with HIV should be key parts of global efforts to reduce cancer-related health inequities.

2020 - Circulating Mitochondrial DNA and Lipopolysaccharide-Binding Protein but Not Bacterial DNA Are Increased in Acute Human Immunodeficiency Virus Infection. [Articolo su rivista]
Nasi, Milena; Pecorini, Simone; DE BIASI, Sara; Digaetano, Margherita; Chester, JOHANNA MARY; Aramini, Beatrice; Lo Tartaro, Domenico; Pinti, Marcello; De Gaetano, Anna; Gibellini, Lara; Mattioli, Anna Vittoria; Mussini, Cristina; Cossarizza, Andrea
abstract

Microbial translocation has been suggested as a major driver of chronic immune activation HIV infection. Thus, we compared the extent of microbial translocation in patients with acute HIV infection and patients followed after CD4-guided structured treatment interruption (STI) by measuring different circulating markers: (1) lipopolysaccharide (LPS)-binding protein (LBP), (2) bacterial DNA, (3) soluble CD14 (sCD14), and (4) mitochondrial DNA (mtDNA). Bacterial DNA and sCD14 levels were similar in all groups. Patients in acute phase showed higher levels of LBP and mtDNA. In STI, we found a positive correlation between the percentage of CD8+ T cells and bacterial DNA levels. Considering all patients, LBP was positively correlated with the percentage and the absolute count of CD8+ T cells, and with mtDNA stressing the importance of mitochondrial products in sustaining chronic immune activation.

2020 - Clinical Efficacy of Ceftolozane-tazobactam Versus Other Active Agents for the Treatment of Bacteremia and Nosocomial Pneumonia Due to Drug resistant P. aeruginosa [Articolo su rivista]
Vena, Antonio; Giacobbe, Daniele Roberto; Mussini, Cristina; Cattelan, Annamaria; Bassetti, Matteo
abstract

2020 - Clinical Experience with Ceftazidime-Avibactam for the Treatment of Infections due to Multidrug-Resistant Gram-Negative Bacteria Other than Carbapenem-Resistant Enterobacterales [Articolo su rivista]
Vena, Antonio; Giacobbe, Daniele Roberto; Castaldo, Nadia; Cattelan, Annamaria; Mussini, Cristina; Luzzati, Roberto; Rosa, Francesco Giuseppe De; Puente, Filippo Del; Mastroianni, Claudio Maria; Cascio, Antonio; Carbonara, Sergio; Capone, Alessandro; Boni, Silvia; Sepulcri, Chiara; Meschiari, Marianna; Raumer, Francesca; Oliva, Alessandra; Corcione, Silvia; Bassetti, Matteo
abstract

Experience in real clinical practice with ceftazidime-avibactam for the treatment of serious infections due to gram-negative bacteria (GNB) other than carbapenem-resistant Enterobacterales (CRE) is very limited.

2020 - Clinical Outcomes in Persons Coinfected With Human Immunodeficiency Virus and Hepatitis C Virus: Impact of Hepatitis C Virus Treatment [Articolo su rivista]
Mocroft, Amanda; Lundgren, Jens; Gerstoft, Jan; Rasmussen, Line D; Bhagani, Sanjay; Aho, Inka; Pradier, Christian; Bogner, Johannes R; Mussini, Cristina; Uberti Foppa, Caterina; Maltez, Fernando; Laguno, Montse; Wandeler, Gilles; Falconer, Karolin; Trofimova, Tatyana; Borodulina, Elena; Jevtovic, Djordje; Bakowska, Elzbieta; Kase, Kerstin; Kyselyova, Galina; Haubrich, Richard; Rockstroh, Jürgen K; Peters, Lars
abstract

A hepatitis C (HCV) cure is associated with changes in lipids and inflammatory biomarkers, but its impact on clinical endpoints among treated human immunodeficiency virus (HIV)/HCV coinfected persons is unclear.

2020 - Common cardiovascular risk factors and in-hospital mortality in 3,894 patients with COVID-19: survival analysis and machine learning-based findings from the multicentre Italian CORIST Study [Articolo su rivista]
Di Castelnuovo, A.; Bonaccio, M.; Costanzo, S.; Gialluisi, A.; Antinori, A.; Berselli, Nausicaa; Blandi, L.; Bruno, R.; Cauda, R.; Guaraldi, Giovanni; My, I.; Menicanti, L.; Parruti, G.; Patti, G.; Perlini, S.; Santilli, F.; Signorelli, C.; Stefanini, G. G.; Vergori, A.; Abdeddaim, A.; Ageno, W.; Agodi, A.; Agostoni, P.; Aiello, L.; Al Moghazi, S.; Aucella, F.; Barbieri, G.; Bartoloni, A.; Bologna, C.; Bonfanti, P.; Brancati, S.; Cacciatore, F.; Caiano, L.; Cannata, F.; Carrozzi, L.; Cascio, A.; Cingolani, A.; Cipollone, F.; Colomba, C.; Crisetti, A.; Crosta, F.; Danzi, G. B.; D'Ardes, D.; de Gaetano Donati, K.; Di Gennaro, F.; Di Palma, G.; Di Tano, G.; Fantoni, M.; Filippini, Tommaso; Fioretto, P.; Fusco, F. M.; Gentile, I.; Grisafi, L.; Guarnieri, G.; Landi, F.; Larizza, G.; Leone, A.; Maccagni, G.; Maccarella, S.; Mapelli, M.; Maragna, R.; Marcucci, R.; Maresca, G.; Marotta, C.; Marra, L.; Mastroianni, F.; Mengozzi, A.; Menichetti, F.; Milic, Jovana; Murri, R.; Montineri, A.; Mussinelli, R.; Mussini, Cristina.; Musso, M.; Odone, A.; Olivieri, M.; Pasi, E.; Petri, F.; Pinchera, B.; Pivato, C. A.; Pizzi, R.; Poletti, V.; Raffaelli, F.; Ravaglia, C.; Righetti, G.; Rognoni, A.; Rossato, M.; Rossi, M.; Sabena, A.; Salinaro, F.; Sangiovanni, V.; Sanrocco, C.; Scarafino, A.; Scorzolini, L.; Sgariglia, R.; Simeone, P. G.; Spinoni, E.; Torti, C.; Trecarichi, E. M.; Vezzani, F.; Veronesi, G.; Vettor, R.; Vianello, A.; Vinceti, Marco; De Caterina, R.; Iacoviello, L.
abstract

Background and aims: There is poor knowledge on characteristics, comorbidities and laboratory measures associated with risk for adverse outcomes and in-hospital mortality in European Countries. We aimed at identifying baseline characteristics predisposing COVID-19 patients to in-hospital death. Methods and results: Retrospective observational study on 3894 patients with SARS-CoV-2 infection hospitalized from February 19th to May 23rd, 2020 and recruited in 30 clinical centres distributed throughout Italy. Machine learning (random forest)-based and Cox survival analysis. 61.7% of participants were men (median age 67 years), followed up for a median of 13 days. In-hospital mortality exhibited a geographical gradient, Northern Italian regions featuring more than twofold higher death rates as compared to Central/Southern areas (15.6% vs 6.4%, respectively). Machine learning analysis revealed that the most important features in death classification were impaired renal function, elevated C reactive protein and advanced age. These findings were confirmed by multivariable Cox survival analysis (hazard ratio (HR): 8.2; 95% confidence interval (CI) 4.6–14.7 for age ≥85 vs 18–44 y); HR = 4.7; 2.9–7.7 for estimated glomerular filtration rate levels &lt;15 vs ≥ 90 mL/min/1.73 m2; HR = 2.3; 1.5–3.6 for C-reactive protein levels ≥10 vs ≤ 3 mg/L). No relation was found with obesity, tobacco use, cardiovascular disease and related-comorbidities. The associations between these variables and mortality were substantially homogenous across all sub-groups analyses. Conclusions: Impaired renal function, elevated C-reactive protein and advanced age were major predictors of in-hospital death in a large cohort of unselected patients with COVID-19, admitted to 30 different clinical centres all over Italy.

2020 - Comparison of two perioperative antibiotic schedules in patients undergoing surgical reconstruction with dermal matrix after excision of skin cancer [Articolo su rivista]
Fiorentini, Chiara; Bedini, Andrea; Mandel, Victor Desmond; Bacca, Erica; Menozzi, Marianna; Reggiani, Camilla; De Pace, Barbara; Meschiari, Marianna; Santoro, Antonella; Franceschini, Erica; Mussini, Cristina; Terrenato, Irene; Giacomelli, Luca; Magnoni, Cristina
abstract

Perioperative antibiotic treatment duration in skin reconstruction with dermal substitutes is not well established. This study compares the incidence of infective complications after two different durations of perioperative antibiotic treatment in patients undergoing surgical reconstruction with skin dermal substitutes (SDS) after excision of skin cancer. Infective complications at the site of SDS were compared in subjects undergoing surgical reconstruction who received either a &gt; 24-hour (extended protocol) or a ≤ 24-hour (short protocol) perioperative antibiotic treatment. Of 116 patients undergoing SDS surgical reconstruction, 62 (53.4%) received an extended schedule, and 54 (46.6%) received a short schedule. The two groups were similar for gender, age, comorbidities, American Society of Anesthesiologists score, and type of skin cancer. Overall incidence rate of infection was 20.7% (24/116). No differences in terms of risk of infection were observed between the two groups (OR: 1.04, 95% CI: 0.42-2.55; P = .937). Patients undergoing SDS reconstruction in the limb/foot had a higher risk of infection in comparison with those undergoing SDS reconstruction in the chest/head (OR: 2.69, 95% CI: 1.06-6.86; P = .038). The short protocol was demonstrated to be beneficial to patients undergoing surgical reconstruction with SDS. A ≤ 24-hour perioperative antibiotic schedule did not increase the infection rate, potentially allowing a reduction of antibiotic exposure.

2020 - Considerations for the optimal management of antibiotic therapy in elderly patients [Articolo su rivista]
Falcone, Marco; Paul, Mical; Tiseo, Giusy; Yahav, Dafna; Prendki, Virginie; Friberg, Lena E; Guerri, Roberto; Gavazzi, Gaetan; Mussini, Cristina; Tinelli, Marco
abstract

To maximise efficacy and minimise toxicity, special considerations are required for antibiotic prescription in elderly patients. This review aims to provide practical suggestions for the optimal management of antibiotic therapy in elderly patients.

2020 - Development and validation of a prediction model for severe respiratory failure in hospitalized patients with SARS-Cov-2 infection: a multicenter cohort study (PREDI-CO study) [Articolo su rivista]
Bartoletti, Michele; Giannella, Maddalena; Scudeller, Luigia; Tedeschi, Sara; Rinaldi, Matteo; Bussini, Linda; Fornaro, Giacomo; Pascale, Renato; Pancaldi, Livia; Pasquini, Zeno; Trapani, Filippo; Badia, Lorenzo; Campoli, Caterina; Tadolini, Marina; Attard, Luciano; Puoti, Massimo; Merli, Marco; Mussini, Cristina; Menozzi, Marianna; Meschiari, Marianna; Codeluppi, Mauro; Barchiesi, Francesco; Cristini, Francesco; Saracino, Annalisa; Licci, Alberto; Rapuano, Silvia; Tonetti, Tommaso; Gaibani, Paolo; Ranieri, Vito Marco; Viale, Pierluigi
abstract

We aimed to develop and validate a risk score to predict severe respiratory failure (SRF) among patients hospitalized with coronavirus disease-2019 (COVID-19).

2020 - Efficient T cell compartment in HIV+ patients receiving orthotopic liver transplant and immunosuppressive therapy [Articolo su rivista]
Franceschini, Erica; De Biasi, Sara; Digaetano, Margherita; Bianchini, Elena; Lo Tartaro, Domenico; Gibellini, Lara; Menozzi, Marianna; Zona, Stefano; Tarantino, Giuseppe; Nasi, Milena; Codeluppi, Mauro; Guaraldi, Giovanni; Magistri, Paolo; Di Benedetto, Fabrizio; Pinti, Marcello; Mussini, Cristina; Cossarizza, Andrea
abstract

In patients undergoing orthotopic liver transplant (OLT), immunosuppressive (IS) treatment is mandatory and infections are leading causes of morbidity/mortality. Thus, it is essential to understand the functionality of cell-mediated immunity after OLT. The aim of the study was to identify changes in T cell phenotype and polyfunctionality in HIV+ and HIV- patients treated with IS after OLT.

2020 - Enhanced Immunological Recovery With Early Start of Antiretroviral Therapy During Acute or Early HIV Infection-Results of Italian Network of ACuTe HIV InfectiON (INACTION) Retrospective Study [Articolo su rivista]
Muscatello, Antonio; Nozza, Silvia; Fabbiani, Massimiliano; De Benedetto, Ilaria; Ripa, Marco; Dell'Acqua, Raffaele; Antinori, Andrea; Pinnetti, Carmela; Calcagno, Andrea; Ferrara, Micol; Focà, Emanuele; Quiros-Roldan, Eugenia; Ripamonti, Diego; Campus, Marco; Maurizio Celesia, Benedetto; Torti, Carlo; Cosco, Lucio; Di Biagio, Antonio; Rusconi, Stefano; Marchetti, Giulia; Mussini, Cristina; Gulminetti, Roberto; Cingolani, Antonella; D'Ettorre, Gabriella; Madeddu, Giordano; Franco, Antonina; Orofino, Giancarlo; Squillace, Nicola; Gori, Andrea; Tambussi, Giuseppe; Bandera, Alessandra
abstract

Viral load peak and immune activation occur shortly after exposure during acute or early HIV infection (AEHI). We aimed to define the benefit of early start of antiretroviral treatment (ART) during AEHI in terms of immunological recovery, virological suppression, and treatment discontinuation.

2020 - Epidemiology and Outcomes of Bloodstream Infections in HIV-Patients during a 13-Year Period [Articolo su rivista]
Franceschini, E.; Santoro, Antonella; Menozzi, Marianna; Bacca, Erica; Venturelli, Claudia; Zona, Stefano; Bedini, Andrea; Digaetano, Margherita; Puzzolante, Cinzia; Meschiari, Marianna; Cuomo, Gianluca; Orlando, Gabriella; Sarti, Mario; Guaraldi, Giovanni; Cozzi-Lepri, Alessandro; Mussini, Cristina
abstract

2020 - Epidemiology and Risk Factors Associated with Mortality in Consecutive Patients with Bacterial Bloodstream Infection: Impact of MDR and XDR Bacteria [Articolo su rivista]
Santoro, A.; Franceschini, E.; Meschiari, M.; Menozzi, M.; Zona, S.; Venturelli, C.; Digaetano, M.; Rogati, C.; Guaraldi, G.; Paul, M.; Gyssens, I. C.; Mussini, C.
abstract

Background. Mortality related to bloodstream infections (BSIs) is high. The epidemiology of BSIs is changing due to the increase in multidrug resistance, and it is unclear whether the presence of multidrug-resistant (MDR) organisms, per se, is an independent risk factor for mortality. Our objectives were, first, to describe the epidemiology and outcome of BSIs and, second, to determine the risk factors associated with mortality among patients with BSI. Methods. This research used a single-center retrospective observational study design. Patients were identified through microbiological reports. Data on medical history, clinical condition, bacteria, antimicrobial therapy, and mortality were collected. The primary outcome was crude mortality at 30 days. The relationships between mortality and demographic, clinical, and microbiological variables were analyzed by multivariate analysis. Results. A total of 1049 inpatients were included. MDR bacteria were isolated in 27.83% of patients, where 2.14% corresponded to an extremely drug-resistant (XDR) isolate. The crude mortality rates at days 7, 30, and 90 were 12.11%, 25.17%, and 36.13%, respectively. Pitt score &gt;2, lung and abdomen as site of infection, and XDR Pseudomonas aeruginosa were independent risk factors for 7-, 30-, and 90-day mortality. Charlson score &gt;4, carbapenem-resistant Klebsiella pneumoniae, and XDR Acinetobacter baumannii were independent risk factors for 30- and 90-day mortality. Infection by XDR gram-negative bacteria, Charlson score &gt;4, and immunosuppression were independent risk factors for mortality in patients who were stable at the time of BSI. Conclusions. BSI is an event with an extreme impact on mortality. Patients with severe clinical condition are at higher risk of death. The presence of XDR gram-negative bacteria in blood is strongly and independently associated with patient death.

2020 - Epidemiology and clinical outcomes of latent tuberculosis infection in adults affected with acute leukemia or aplastic anemia: a retrospective single-center study [Articolo su rivista]
Bettelli, F.; Giusti, D.; Morselli, M.; Colaci, E.; Nasillo, V.; Pioli, V.; Gilioli, A.; Iotti, S.; Galassi, L.; Giubbolini, R.; Colasante, C.; Catellani, H.; Barozzi, P.; Lagreca, I.; Vallerini, D.; Maffei, R.; Franceschini, E.; Mussini, C.; Banchelli, F.; D'Amico, R.; Marasca, R.; Narni, F.; Potenza, L.; Comoli, P.; Luppi, M.; Forghieri, F.
abstract

2020 - Erratum: The Role of the Renin-Angiotensin System in Severe Acute Respiratory Syndrome-CoV-2 Infection (Journal of Physical Chemistry DOI: 10.1159/000507914) [Articolo su rivista]
Alfano, G.; Guaraldi, G.; Fontana, F.; Ferrari, A.; Magistroni, R.; Mussini, C.; Cappelli, G.
abstract

In the article by Alfano et al. entitled “The Role of the Renin-Angiotensin System in Severe Acute Respiratory Syndrome-CoV-2 Infection” [Blood Purif. DOI: 10.1159/000507914], the affiliations should be indicated as follows:.

2020 - Evaluation of HIV transmission clusters among natives and foreigners living in Italy [Articolo su rivista]
Fabeni, L.; Santoro, M. M.; Lorenzini, P.; Rusconi, S.; Gianotti, N.; Costantini, A.; Sarmati, L.; Antinori, A.; Ceccherini-Silberstein, F.; d'Arminio Monforte, A.; Saracino, A.; Girardi, E.; Castagna, A.; Castelli, F.; Cauda, R.; Di Perri, G.; Galli, M.; Iardino, R.; Ippolito, G.; Lazzarin, A.; Marchetti, G. C.; Rezza, G.; von Schloesser, F.; Viale, P.; Cozzi-Lepri, A.; Gori, A.; Lo Caputo, S.; Maggiolo, F.; Mussini, C.; Puoti, M.; Perno, C. F.; Bai, F.; Bandera, A.; Bonora, S.; Borderi, M.; Calcagno, A.; Capobianchi, M. R.; Cicalini, S.; Cingolani, A.; Cinque, P.; Di Biagio, A.; Gagliardini, R.; Guaraldi, G.; Lapadula, G.; Lichtner, M.; Lai, A.; Madeddu, G.; Merlini, E.; Nozza, S.; Piconi, S.; Pinnetti, C.; Quiros Roldan, E.; Rossotti, R.; Spagnuolo, V.; Svicher, V.; Taramasso, L.; Fanti, I.; Galli, L.; Rodano, A.; Macchia, M.; Tavelli, A.; Bove, A.; Camposeragna, A.; Errico, M.; Manfredini, M.; Perziano, A.; Calvino, V.; Carrara, S.; Di Caro, A.; Graziano, S.; Petroni, F.; Prota, G.; Truffa, S.; Giacometti, A.; Barocci, V.; Angarano, G.; Monno, L.; Milano, E.; Suardi, C.; Donati, V.; Verucchi, G.; Castelnuovo, F.; Minardi, C.; Menzaghi, B.; Abeli, C.; Chessa, L.; Pes, F.; Cacopardo, B.; Celesia, B.; Vecchiet, J.; Falasca, K.; Pan, A.; Lorenzotti, S.; Sighinolfi, L.; Segala, D.; Blanc, P.; Vichi, F.; Cassola, G.; Bassetti, M.; Alessandrini, A.; Bobbio, N.; Mazzarello, G.; Fondaco, L.; Bonfanti, P.; Molteni, C.; Chiodera, A.; Milini, P.; Nunnari, G.; Pellicano, G.; Rizzardini, G.; Cannizzo, E. S.; Moioli, M. C.; Piolini, R.; Bernacchia, D.; Poli, A.; Tincati, C.; Puzzolante, C.; Migliorino, C.; Sangiovanni, V.; Borgia, G.; Esposito, V.; Di Flumeri, G.; Gentile, I.; Rizzo, V.; Cattelan, A. M.; Marinello, S.; Cascio, A.; Trizzino, M.; Francisci, D.; Schiaroli, E.; Parruti, G.; Sozio, F.; Lazzaretti, C.; Corsini, R.; Cristaudo, A.; Vullo, V.; Acinapura, R.; Lamonica, S.; Capozzi, M.; Mondi, A.; Rivano Capparuccia, M.; Iaiani, G.; Latini, A.; Onnelli, G.; Plazzi, M. M.; de Girolamo, G.; Vergori, A.; Cecchetto, M.; Viviani, F.; de Vito, A.; Rossetti, B.; Montagnani, F.; Franco, A.; Fontana Del Vecchio, R.; Di Giuli, C.; Caramello, P.; Orofino, G. C.; Sciandra, M.; Londero, A.; Manfrin, V.; Battagin, G.; Starnini, G.; Ialungo, A.
abstract

We aimed at evaluating the characteristics of HIV-1 molecular transmission clusters (MTCs) among natives and migrants living in Italy, diagnosed between 1998 and 2018. Phylogenetic analyses were performed on HIV-1 polymerase (pol) sequences to characterise subtypes and identify MTCs, divided into small (SMTCs, 2-3 sequences), medium (MMTCs, 4-9 sequences) and large (LMTCs, ≥10 sequences). Among 3499 drug-naïve individuals enrolled in the Italian Cohort Naive Antiretroviral (ICONA) cohort (2804 natives; 695 migrants), 726 (20.8%; 644 natives, 82 migrants) were involved in 228 MTCs (6 LMTCs, 36 MMTCs, 186 SMTCs). Migrants contributed 14.4% to SMTCs, 7.6% to MMTCs and 7.1% to LMTCs, respectively. HIV-1 non-B subtypes were found in 51 MTCs; noteworthy was that non-B infections involved in MTCs were more commonly found in natives (n = 47) than in migrants (n = 4). Factors such as Italian origin, being men who have sex with men (MSM), younger age, more recent diagnosis and a higher CD4 count were significantly associated with MTCs. Our findings show that HIV-1 clustering transmission among newly diagnosed individuals living in Italy is prevalently driven by natives, mainly MSM, with a more recent diagnosis and frequently infected with HIV-1 non-B subtypes. These results can contribute to monitoring of the HIV epidemic and guiding the public health response to prevent new HIV infections.

2020 - Evaluation of virological response and resistance profile in HIV-1 infected patients starting a first-line integrase inhibitor-based regimen in clinical settings [Articolo su rivista]
Armenia, D.; Bouba, Y.; Gagliardini, R.; Gori, C.; Bertoli, A.; Borghi, V.; Gennari, W.; Micheli, V.; Callegaro, A. P.; Gazzola, L.; Bruzzone, B.; Giannetti, A.; Mazzotta, V.; Vergori, A.; Mastrorosa, I.; Colafigli, M.; Lichtner, M.; di Biagio, A.; Maggiolo, F.; Rizzardini, G.; d'Arminio Monforte, A.; Andreoni, M.; Mussini, C.; Antinori, A.; Ceccherini-Silberstein, F.; Perno, C. F.; Santoro, M. M.
abstract

Background: Virological response and resistance profile were evaluated in drug-naïve patients starting their first-line integrase inhibitors (INIs)-based regimen in a clinical setting. Study design: Virological success (VS) and virological rebound (VR) after therapy start were assessed by survival analyses. Drug-resistance was evaluated at baseline and at virological failure. Results: Among 798 patients analysed, 38.6 %, 27.1 % and 34.3 % received raltegravir, elvitegravir and dolutegravir, respectively. Baseline resistance to NRTIs, NNRTIs, PIs and INIs was: 3.9 %, 13.9 %, 1.6 % and 0.5 %, respectively. Overall, by 12 months of treatment, the probability of VS was 95 %, while the probability of VR by 36 months after VS was 13.1 %. No significant differences in the virological response were found according to the INI used. The higher pre-therapy viremia strata was (&lt;100,000 vs. 100,000-500,000 vs. &gt; 500,000 copies/mL), lower was the probability of VS (96.0 % vs. 95.2 % vs. 91.1 %, respectively, P &lt; 0.001), and higher the probability of VR (10.2 % vs. 15.8 % vs. 16.6 %, respectively, P = 0.010). CD4 cell count &lt;200 cell/mm3 was associated with the lowest probability of VS (91.5 %, P &lt; 0.001) and the highest probability of VR (20.7 %, P = 0.008) compared to higher CD4 levels. Multivariable Cox-regression confirmed the negative role of high pre-therapy viremia and low CD4 cell count on VS, but not on VR. Forty-three (5.3 %) patients experienced VF (raltegravir: 30; elvitegravir: 9; dolutegravir: 4). Patients failing dolutegravir did not harbor any resistance mutation either in integrase or reverse transcriptase. Conclusions: Our findings confirm that patients receiving an INI-based first-line regimen achieve and maintain very high rates of VS in clinical practice.

2020 - Expansion of plasmablasts and loss of memory B cells in peripheral blood from COVID-19 patients with pneumonia [Articolo su rivista]
De Biasi, S.; Lo Tartaro, D.; Meschiari, M.; Gibellini, L.; Bellinazzi, C.; Borella, R.; Fidanza, L.; Mattioli, M.; Paolini, A.; Gozzi, L.; Jaacoub, D.; Faltoni, M.; Volpi, S.; Milic, J.; Sita, M.; Sarti, M.; Pucillo, C.; Girardis, M.; Guaraldi, G.; Mussini, C.; Cossarizza, A.
abstract

Studies on the interactions between SARS-CoV-2 and humoral immunity are fundamental to elaborate effective therapies including vaccines. We used polychromatic flow cytometry, coupled with unsupervised data analysis and principal component analysis (PCA), to interrogate B cells in untreated patients with COVID-19 pneumonia. COVID-19 patients displayed normal plasma levels of the main immunoglobulin classes, of antibodies against common antigens or against antigens present in common vaccines. However, we found a decreased number of total and naïve B cells, along with decreased percentages and numbers of memory switched and unswitched B cells. On the contrary, IgM+ and IgM− plasmablasts were significantly increased. In vitro cell activation revealed that B lymphocytes showed a normal proliferation index and number of dividing cells per cycle. PCA indicated that B-cell number, naive and memory B cells but not plasmablasts clustered with patients who were discharged, while plasma IgM level, C-reactive protein, D-dimer, and SOFA score with those who died. In patients with pneumonia, the derangement of the B-cell compartment could be one of the causes of the immunological failure to control SARS-Cov2, have a relevant influence on several pathways, organs and systems, and must be considered to develop vaccine strategies.

2020 - HIV MDR is still a relevant issue despite its dramatic drop over the years [Articolo su rivista]
Armenia, D; Di Carlo, D; Flandre, P; Bouba, Y; Borghi, V; Forbici, F; Bertoli, A; Gori, C; Fabeni, L; Gennari, W; Pinnetti, C; Mondi, A; Cicalini, S; Gagliardini, R; Vergori, A; Bellagamba, R; Malagnino, V; Montella, F; Colafigli, M; Latini, A; Marocco, R; Licthner, M; Andreoni, M; Mussini, C; Ceccherini-Silberstein, F; Antinori, A; Perno, C F; Santoro, M M
abstract

To evaluate the prevalence and therapeutic relevance of drug resistance among isolates from ART-experienced HIV-1-infected patients over the past two decades in Italy.

2020 - Handling and processing of blood specimens from patients with Covid-19 for safe studies on cell phenotype and cytokine storm [Articolo su rivista]
Cossarizza, Andrea; Gibellini, Lara; DE BIASI, Sara; LO TARTARO, Domenico; Mattioli, Marco; Paolini, Annamaria; Fidanza, Lucia; Bellinazzi, Caterina; Borella, Rebecca; Castaniere, Ivana; Meschiari, Marianna; Sita, Marco; Manco, Gianrocco; Clini, Enrico; Gelmini, Roberta; Girardis, Massimo; Guaraldi, Giovanni; Mussini, Cristina
abstract

The pandemic caused by SARS-CoV-2 heavily involves all those working in a laboratory. Samples from known infected patients or donors who are considered healthy can arrive, and a colleague might be asymptomatic but able to transmit the virus. Working in a clinical laboratory is posing several safety challenges. Few years ago, ISAC published guidelines to safely analyze and sort human samples that were revised in these days. We describe the procedures that we have been following since the first patient appeared in Italy, which have only slightly modified our standard one, being all human samples associated with risks.

2020 - How to RESPOND to modern challenges for people living with HIV: A profile for a new cohort consortium [Articolo su rivista]
Wit, F.; Reiss, P.; Hillebregt, M.; Law, M.; Petoumenos, K.; Rose, N.; Hutchinson, J.; Zangerle, R.; Appoyer, H.; De Wit, S.; Delforge, M.; Wandeler, G.; Stephan, C.; Bucht, M.; Chkhartishvili, N.; Chokoshvili, O.; D'Arminio Monforte, A.; Rodano, A.; Tavelli, A.; Fanti, I.; Mussini, C.; Borghi, V.; Pradier, C.; Fontas, E.; Dollet, K.; Caissotti, C.; Casabona, J.; Miro, J. M.; Riera, A.; Reyes-Uruena, J.
abstract

Background: the International Cohort Consortium of Infectious Disease (RESPOND) is a collaboration dedicated to research on HIV and other infectious diseases. Methods: RESPOND is a flexible organization, with several independent substudies operating under one shared governance. HIV-related variables, including full antiretroviral therapy (ART) history, are collected annually for all participants and merged with substudy specific data into a shared data pool. Incident clinical events are reported using standardized forms. Prospective follow-up started 1/10/17 (enrolment) with retrospective data collected back to 01/01/12. Results: Overall, 17 cohorts from Europe and Australia provided data on 26,258 people living with HIV (PLWH). The majority (43.3%) of the population were white, with men-sex-with-men accounting for 43.3% of the risk for HIV acquisition. The median age was 48 years (IQR 40–56) and 5.2% and 25.5% were known to be co-infected with hepatitis B or C. While 5.3% were ART-naïve, the median duration on ART was 10.1 years (4.8–17.6), with 89.5% having a VL &lt;200 copies/mL and the median CD4 count being 621 cells/µL (438–830). Malignancies (n = 361) and cardiovascular disease (n = 168) were the predominant reported clinical events. Conclusion: RESPOND’s large, diverse study population and standardized clinical endpoints puts the consortium in a unique position to respond to the diverse modern challenges for PLWH.

2020 - Human immunodeficiency virus continuum of care in 11 european union countries at the end of 2016 overall and by key population: Have we made progress? [Articolo su rivista]
Vourli, G.; Noori, T.; Pharris, A.; Porter, K.; Axelsson, M.; Begovac, J.; Cazein, F.; Costagliola, D.; Cowan, S.; Croxford, S.; Monforte, A. D.; Delpech, V.; Diaz, A.; Girardi, E.; Gunsenheimer-Bartmeyer, B.; Hernando, V.; Leierer, G.; Lot, F.; Nunez, O.; Obel, N.; Op de Coul, E.; Paraskeva, D.; Patrinos, S.; Reiss, P.; Schmid, D.; Sonnerborg, A.; Suligoi, B.; Supervie, V.; van Sighem, A.; Zangerle, R.; Touloumi, G.; Egle, A.; Kanatschnig, M.; Ollinger, A.; Rieger, A.; Schmied, B.; Wallner, E.; Dewasurendra, D.; Gisinger, M.; Kitchen, M.; Plattner, A.; Rieser, E.; Sarcletti, M.; Greil, R.; Schachner, M.; Skocic, M.; Muller, M.; Aichwalder, R.; Chromy, D.; Grabmeier-Pfstershammer, K.; Skoll, M.; Touzeau, V.; Cichon, P.; Wolf-Nussmuller, S.; Laferl, H.; Zoufaly, A.; Genger-Hackl, C.; Kapper, A.; Schneeberger, T.; Trattner, E.; Schober, G.; Atzl, M.; Hartmann, B.; Puchhammer-Stockl, E.; Berg, J.; Appoyer, H.; Rappold, M.; Strickner, S.; Schindelwig, K.; Ledergerber, B.; Fatkenheuer, G.; Gerstof, J.; Kronborg, G.; Pedersen, C.; Larsen, C. S.; Pedersen, G.; Mohey, R.; Nielsen, L.; Weise, L.; Kvinesdal, B.; Jensen, J.; Abgrall, S.; Bernard, L.; Billaud, E.; Boue, F.; Boyer, L.; Cabie, A.; Caby, F.; Canestri, A.; Cotte, L.; de Truchis, P.; Duval, X.; Duvivier, C.; Enel, P.; Fischer, H.; Gasnault, J.; Gaud, C.; Grabar, S.; Khuong-Josses, M. A.; Launay, O.; Marchand, L.; Mary-Krause, M.; Matheron, S.; Melica-Gregoire, G.; Melliez, H.; Meynard, J. L.; Nacher, M.; Pavie, J.; Piroth, L.; Poizot-Martin, I.; Pradier, C.; Reynes, J.; Rouveix, E.; Simon, A.; Slama, L.; Tattevin, P.; Tissot-Dupont, H.; Biga, J.; Kurth, T.; Jacquemet, N.; Guiguet, M.; Leclercq, S.; Lievre, L.; Marshall, E.; Roul, H.; Selinger-Leneman, H.; Potard, V.; Benveniste, O.; Breton, G.; Lupin, C.; Bourzam, E.; Girard, P. M.; Fonquernie, L.; Valin, N.; Lefebvre, B.; Sebire, M.; Pialoux, G.; Lebrette, M. G.; Tibaut, P.; Adda, A.; Hamidi, M.; Cadranel, J.; Lavole, A.; Parrot, A.; Bouchaud, O.; Vignier, N.; Mechai, F.; Makhlouf, S.; Honore, P.; Bergmann, J. F.; Delcey, V.; Lopes, A.; Sellier, P.; Parrinello, M.; Oksenhendler, E.; Gerard, L.; Molina, J. M.; Rozenbaum, W.; Denis, B.; De Castro, N.; Lascoux, C.; Yazdanpanah, Y.; Lariven, S.; Joly, V.; Rioux, C.; Poupard, M.; Taverne, B.; Sutton, L.; Masse, V.; Genet, P.; Wifaq, B.; Gerbe, J.; Grefe, S.; Dupont, C.; Freire Maresca, A.; Reimann, E.; Bloch, M.; Meier, F.; Mortier, E.; Zeng, F.; Montoya, B.; Perronne, C.; Mathez, D.; Marigot-Outtandy, D.; Berthe, H.; Greder Belan, A.; Terby, A.; Godin Collet, C.; Marque Juillet, S.; Ruquet, M.; Roussin-Bretagne, S.; Colardelle, P.; Granier, F.; Laurichesse, J. J.; Perronne, V.; Akpan, T.; Marcou, M.; Daneluzzi, V.; Veyssier-Belot, C.; Masson, H.; Welker, Y.; Brazille, P.; Kahn, J. E.; Zucman, D.; Majerholc, C.; Fourn, E.; Bornarel, D.; Chambrin, V.; Kansau, I.; Raho-Moussa, M.; Lelievre, J. D.; Saidani, M.; Chesnel, C.; Dumont, C.; Vittecoq, D.; Derradji, O.; Bolliot, C.; Goujard, C.; Teicher, E.; Mole, M.; Bourdic, K.; Salmon, D.; Le Jeunne, C.; Guet, P.; Pietri, M. P.; Pannier Metzger, E.; Marcou, V.; Loulergue, P.; Dupin, N.; Morini, J. P.; Deleuze, J.; Gerhardt, P.; Chanal, J.; Weiss, L.; Lucas, M. L.; Jung, C.; Ptak, M.; Viard, J. P.; Ghosn, J.; Gazalet, P.; Cros, A.; Maignan, A.; Lortholary, O.; Rouzaud, C.; Touam, F.; Benhadj, K.; Consigny, P. H.; Bossi, P.; Gergely, A.; Cessot, G.; Durand, F.; Beck-Wirth, G.; Michel, C.; Benomar, M.; Rey, D.; Partisani, M.; Cheneau, C.; Batard, M. L.; Fischer, P.; Leclercq, P.; Blanc, M.; Morand, P.; Epaulard, O.; Signori-Schmuck, A.; Laurichesse, H.; Jacomet, C.; Vidal, M.; Coban, D.; Casanova, S.; Fresard, A.; Guglielminotti, C.; Botelho-Nevers, E.; Brunon-Gagneux, A.; Ronat, V.; Verdon, R.; Dargere, S.; Haustraete, E.; Feret, P.; Goubin, P.; Chavanet, P.; Fillion, A.; Croisier, D.; Gohier, S.; Arvieux, C.; Souala, F.; Chapplain, J. M.; Ratajczak, M.; Rohan, J.; Faller, J. P.; Ruyer, O.; Gendrin, V.; Toko, L.; Chirouze, C.; Hustache-Mat
abstract

Background. High uptake of antiretroviral treatment (ART) is essential to reduce human immunodeficiency virus (HIV) transmission and related mortality; however, gaps in care exist. We aimed to construct the continuum of HIV care (CoC) in 2016 in 11 European Union (EU) countries, overall and by key population and sex. To estimate progress toward the Joint United Nations Programme on HIV/AIDS (UNAIDS) 90-90-90 target, we compared 2016 to 2013 estimates for the same countries, representing 73% of the population in the region. Methods. A CoC with the following 4 stages was constructed: number of people living with HIV (PLHIV); proportion of PLHIV diagnosed; proportion of those diagnosed who ever initiated ART; and proportion of those ever treated who achieved viral suppression at their last visit. Results. We estimated that 87% of PLHIV were diagnosed; 92% of those diagnosed had ever initiated ART; and 91% of those ever on ART, or 73% of all PLHIV, were virally suppressed. Corresponding figures for men having sex with men were: 86%, 93%, 93%, 74%; for people who inject drugs: 94%, 88%, 85%, 70%; and for heterosexuals: 86%, 92%, 91%, 72%. The proportion suppressed of all PLHIV ranged from 59% to 86% across countries. Conclusions. The EU is close to the 90-90-90 target and achieved the UNAIDS target of 73% of all PLHIV virally suppressed, significant progress since 2013 when 60% of all PLHIV were virally suppressed. Strengthening of testing programs and treatment support, along with prevention interventions, are needed to achieve HIV epidemic control.

2020 - Liver steatosis and non-alcoholic fatty liver disease with fibrosis are predictors of frailty in people living with HIV [Articolo su rivista]
Milic, Jovana; Menozzi, Valentina; Schepis, Filippo; Malagoli, Andrea; Besutti, Giulia; Franconi, Iacopo; Raimondi, Alessandro; Carli, Federica; Mussini, Cristina; Sebastiani, Giada; Guaraldi, Giovanni
abstract

2020 - Long-term consequences of COVID-19: research needs [Articolo su rivista]
Yelin, D.; Wirtheim, E.; Vetter, P.; Kalil, A. C.; Bruchfeld, J.; Runold, M.; Guaraldi, G.; Mussini, C.; Gudiol, C.; Pujol, M.; Bandera, A.; Scudeller, L.; Paul, M.; Kaiser, L.; Leibovici, L.
abstract

2020 - Machine learning in predicting respiratory failure in patients with COVID-19 pneumonia - challenges, strengths, and opportunities in a global health emergency. [Articolo su rivista]
Ferrari, D; Milic, J; Tonelli, R; Ghinelli, F; Meschiari, M; Volpi, S; Faltoni, M; Franceschi, G; Iadisernia, V; Yaacoub, D; Ciusa, G; Bacca, E; Rogati, C; Tutone, M; Burastero, G; Raimondi, A; Menozzi, M; Franceschini, E; Cuomo, G; Corradi, L; Orlando, G; Santoro, A; Di Gaetano, M; Puzzolante, C; Carli, F; Borghi, V; Bedini, A; Fantini, R; Tabbì, L; Castaniere, I; Busani, S; Clini, E; Girardis, M; Sarti, M; Cossarizza, A; Mussini, C; Mandreoli, F; Missier, P; Guaraldi, G.
abstract

Aims- The aim of this study was to estimate a 48 hour prediction of moderate to severe respiratory failure, requiring mechanical ventilation, in hospitalized patients with COVID-19 pneumonia. Methods- This was an observational study that comprised consecutive patients with COVID-19 pneumonia admitted to hospital from 21 February to 6 April 2020. The patients’ medical history, demographic, epidemiologic and clinical data were collected in an electronic patient chart. The dataset was used to train predictive models using an established machine learning framework leveraging a hybrid approach where clinical expertise is applied alongside a data-driven analysis. The study outcome was the onset of moderate to severe respiratory failure defined as PaO 2 /FiO 2 ratio &lt;150 mmHg in at least one of two consecutive arterial blood gas analyses in the following 48 hours. Shapley Additive exPlanations values were used to quantify the positive or negative impact of each variable included in each model on the predicted outcome. Results- A total of 198 patients contributed to generate 1068 usable observations which allowed to build 3 predictive models based respectively on 31-variables signs and symptoms, 39-variables laboratory biomarkers and 91-variables as a composition of the two. A fourth “boosted mixed model” included 20 variables was selected from the model 3, achieved the best predictive performance (AUC=0.84) without worsening the FN rate. Its clinical performance was applied in a narrative case report as an example. Conclusion- This study developed a machine model with 84% prediction accuracy, which is able to assist clinicians in decision making process and contribute to develop new analytics to improve care at high technology readiness levels.

2020 - Marked T cell activation, senescence, exhaustion and skewing towards TH17 in patients with Covid-19 pneumonia. [Articolo su rivista]
De Biasi, S; Meschiari, M; Gibellini, L; Bellinazzi, C; Borella, R; Fidanza, L; Gozzi, L; Iannone, A; Lo Tartaro, D; Mattioli, M; Paolini, A; Menozzi, M; Milić, J; Franceschi, G; Fantini, R; Tonelli, R; Sita, M; Sarti, M; Trenti, T; Brugioni, L; Cicchetti, L; Facchinetti, F; Pietrangelo, A; Clini, E; Girardis, M; Guaraldi, G; Mussini, C; Cossarizza, A.
abstract

We provide an in-depth investigation of the T cell compartment and functionality, cytokine production and plasma levels in a total of 39 patients affected by Covid-19 pneumonia. At admission, patients were lymphopenic; for all, SARS-CoV-2 was detected in a nasopharyngeal swab specimen by real-time RT-PCR, and pneumonia was subsequently confirmed by X-rays. Detailed 18-parameter flow cytometry coupled with unsupervised data analysis revealed that patients showed similar percentages of CD4+ and CD8+ T cells, but a decreased absolute number in both populations. For CD4+ T lymphocytes, we found a significant decrease in the number of naïve, central and effector memory cells and an increased percentage of terminally differentiated cells, regulatory T cells, and of those that were activated or that were expressing PD1 and CD57 markers. Studies on chemokine receptors and lineage-specifying transcription factors revealed that, among CD4+ T cells, patients displayed a lower percentage of cells expressing CCR6 or CXCR3, and of those co-expressing CCR6 and CD161, but higher percentages of 62 CXCR4+ or CCR4+ cells. No differences were noted in the expression of T-bet or GATA-3. Analyses of patients' CD8+ T cells showed decreased numbers of naïve and central memory and increased amounts of activated cells, accompanied by increased percentages of activated cells and of lymphocytes expressing CD57, PD1, or both. CD8+ T cells expressed lower percentages of CCR6+, CXCR3+ or T-bet+ cells and of CXCR3+,T-bet+ or CCR6+,CD161+ lymphocytes. We also found higher percentages of cells expressing CCR4+, CXCR4 or GATA-3. Analyses of lymphocyte proliferation revealed that terminally differentiated CD4+ and CD8+ T cell from patients had a lower proliferative index than controls, whereas cellular bioenergetics, measured by the quantification of mitochondrial oxygen consumption and extracellular acidification rate, was similar in CD4+ T cells from both groups. We measured plasma level of 31 cytokines linked to inflammation, including T helper (TH)type-1 and TH2 cytokines, chemokines, galectins, pro- and anti-inflammatory mediators, finding that most were dramatically increased in Covid-19 patients, confirming the presence of a massive cytokine storm. Analysis of the production of different cytokines after stimulation by anti-CD3/CD28 monoclonal antibodies revealed that patients not only had a high capacity to produce tumour necrosis factor (TNF)-α, interferon (IFN)-γ and interleukin (IL)-2, but also showed a significant skewing of CD4+ T cells towards the TH17 phenotype. A therapeutic approach now exists based on the administration of drugs that block IL-6pathway, and seems to improve the disease. IL-17 is crucial in recruiting and activating neutrophils, cells that can migrate to the lung and are heavily involved in the pathogenesis of Covid-19. We show here that a skewing of activated T cells towards the TH17 functional phenotype exists in Covid-19 patients. We therefore suggest that blocking the IL-17 pathway by biological drugs that are already used to treat different pathologies could provide a novel, additional strategy to improve the health of patients infected by SARS-CoV-2.

2020 - Never Give Up: lesson learned from a severe COVID-19 patient. [Articolo su rivista]
Tonelli, Roberto; Iattoni, Andrea; Girardis, Massimo; De Pietri, Lesley; Clini, Enrico; Mussini, Cristina
abstract

We here report the clinical course of a 72-year old Caucasian male (M.A.) admitted for SARS-CoV2 pneumonia at our University Hospital in Modena. A multidisciplinary medical staff composed by different specialists (infectious diseases, pulmonology, intensive care) was in charge for caring and assuming shared clinical decisions.

2020 - Peritoneal dialysis in the time of coronavirus disease 2019 [Articolo su rivista]
Alfano, Gaetano; Fontana, Francesco; Ferrari, Annachiara; Guaraldi, Giovanni; Mussini, Cristina; Magistroni, Riccardo; Cappelli, Gianni; Bacca, Erica; Bedini, Andrea; Borghi, Vanni; Burastero, Giulia; Carli, Federica; Ciusa, Giacomo; Corradi, Luca; Cuomo, Gianluca; Digaetano, Margherita; Dolci, Giovanni; Faltoni, Matteo; Fantini, Riccardo; Franceschi, Giacomo; Franceschini, Ericad; Iadisernia, Vittorio; Larnõ, Damiano; Menozzi, Marianna; Meschiari, Marianna; Milic, Jovana; Orlando, Gabriella; Pellegrino, Francesco; Raimondi, Alessandro; Rogati, Carlotta; Santoro, Antonella; Tonelli, Roberto; Tutone, Marco; Volpi, Sara; Yaacoub, Dina; Aten, G.; Marco, Ballestri; Mori, Giacomo; Girardis, Massimo; Andreotti, Alberto; Biagioni, Emanuela; Bondi, Filippo; Busani, Stefano; Chierego, Giovanni; Scotti, Marzia; Serio, Lucia; Cossarizza, Andrea; Bellinazzi, Caterina; Borella, Rebecca; de Biasi, Sara; de Gaetano, Anna; Fidanza, Lucia; Gibellini, Lara; Iannone, Anna; Lo Tartaro, Domenico; Mattioli, Marco; Nasi, Milena; Paolini, Annamariag; Pinti, Marcello
abstract

In the current setting of global containment, peritoneal dialysis (PD) and home haemodialysis are the best modalities of renal replacement therapy (RRT) to reduce the rate of transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)&nbsp;infection. Considering the shorter and easier training programme of PD compared to home haemodialysis, PD appears a practical solution for patients with end-stage renal disease to reduce the risk of hospital-acquired infection. PD offers the advantage of minimizing the risk of viral transmission through interpersonal contact that commonly occurs during the haemodialysis session and while travelling from home to the haemodialysis facility using public transport services. To overcome barriers to health care access due to the containment measures for this emerging disease, telemedicine is a useful and reliable tool for delivering health care without exposing patients to the risk of contact. However, novel issues including handling of potentially infected dialysate, caregivers' infectious risk and adequacy of PD in critically ill patients with acute respiratory distress syndrome remain to be clarified. In conclusion, PD should be preferred to the other modalities of RRT during the coronavirus disease 2019 (COVID-19) outbreak because it can be a solution to cope with the increased number of infected patients worldwide.

2020 - Plea for multitargeted interventions for severe COVID-19 [Articolo su rivista]
Gaborit, B. J.; Bergmann, J. -F.; Mussini, C.; Arribas, J. R.; Behrens, G.; Walmsley, S.; Pozniak, A.; Raffi, F.
abstract

2020 - Predictors of incomplete viral response and virologic failure in patients with acute and early HIV infection. Results of Italian Network of ACuTe HIV InfectiON (INACTION) cohort [Articolo su rivista]
Taramasso, L; Fabbiani, M; Nozza, S; De Benedetto, I; Bruzzesi, E; Mastrangelo, A; Pinnetti, C; Calcagno, A; Ferrara, M; Bozzi, G; Focà, E; Quiros-Roldan, E; Ripamonti, D; Campus, M; Celesia, B M; Torti, C; Cosco, L; Di Biagio, A; Rusconi, S; Marchetti, G; Mussini, C; Gulminetti, R; Cingolani, A; d'Ettorre, G; Madeddu, G; Franco, A; Orofino, G; Squillace, N; Muscatello, A; Gori, A; Antinori, A; Tambussi, G; Bandera, A
abstract

The aim of this study was to evaluate the factors that can influence an incomplete viral response (IVR) after acute and early HIV infection (AEHI).

2020 - Prevalence of HIV-associated Neurocognitive Disorder (HAND) and its subgroups among HIV-positive persons on anti-retroviral therapy in Iran [Articolo su rivista]
Elham, M. -T.; Vahid, N.; Seyed Ahmad, S. A.; Omid, D.; Cossarizza, A; Mussini, C.; Sara, A. N.; Leila, S.; Mohammad, G.; Hanieh, G.; Minoo, M.
abstract

This study aimed to determine the prevalence and determinants of HIV-associated neurocognitive disorder (HAND) and its subgroups in HIV-positive patients in Tehran, Iran. Ninety-three HIV-positive individuals were assessed; the majority were male (60%) and the mean age of patients was 36.5 years (SD = 9), with 8 years as the median duration of HIV infection. The relationship between demographic and clinical variables was examined using logistic regression analysis. The overall prevalences of HAND and cognitive complaints were 50.5% and 73%, respectively. Lower nadir CD4 counts (≤ 200), lower educational levels (≤ 12 years), longer disease duration (≥ 5years), and higher depression rates were positively associated with the presence of HAND. This study shows that the prevalence of HANDs in Iran is high, but similar to the prevalence levels found in Western societies. Further studies are needed to longitudinally evaluate the presence of HAND, in particularly to recognize new biomarkers and specific neurocognitive domains in HIV.

2020 - Prevalence of doravirine-associated resistance mutations in HIV-1-infected antiretroviral-experienced patients from two large databases in France and Italy [Articolo su rivista]
Soulie, Cathia; Santoro, Maria Mercedes; Storto, Alexandre; Abdi, Basma; Charpentier, Charlotte; Armenia, Daniele; Jary, Aude; Forbici, Federica; Bertoli, Ada; Gennari, William; Andreoni, Massimo; Mussini, Cristina; Antinori, Andrea; Perno, Carlo Federico; Calvez, Vincent; Ceccherini-Silberstein, Francesca; Descamps, Diane; Marcelin, Anne-Genevieve
abstract

Doravirine, a novel NNRTI, selects for specific mutations in vitro, including mutations at reverse transcriptase (RT) positions 106, 108, 188, 227, 230 and 234. The aim of this study was to examine the prevalence of doravirine-associated resistance mutations in HIV-1-infected antiretroviral-experienced patients.

2020 - RAAS inhibitors are not associated with mortality in COVID-19 patients: findings from an observational multicenter study in Italy and a meta-analysis of 19 studies [Articolo su rivista]
Di Castelnuovo, Augusto; Costanzo, Simona; Antinori, Andrea; Berselli, Nausicaa; Blandi, Lorenzo; Bonaccio, Marialaura; Cauda, Roberto; Gialluisi, Alessandro; Guaraldi, Giovanni; Menicanti, Lorenzo; Mennuni, Marco; Mussinelli, Roberta; My, Ilaria; Parruti, Giustino; Patti, Giuseppe; Perlini, Stefano; Santilli, Francesca; Signorelli, Carlo; Stefanini, Giulio G; Vergori, Alessandra; Abete, Paolo; Ageno, Walter; Agostoni, Piergiuseppe; Aiello, Luca; Al Moghazi, Samir; Arboretti, Rosa; Aucella, Filippo; Barbieri, Greta; Barchitta, Martina; Bartoloni, Alessandro; Bonfanti, Paolo; Cacciatore, Francesco; Caiano, Lucia; Carrozzi, Laura; Cascio, Antonio; Castiglione, Giacomo; Cianfrone, Stefania; Ciccullo, Arturo; Cingolani, Antonella; Cipollone, Francesco; Colomba, Claudia; Colombo, Crizia; Cozzi, Ottavia; Crisetti, Annalisa; Crosta, Francesca; Danzi, Gian Battista; D'Ardes, Damiano; de Gaetano Donati, Katleen; Di Gennaro, Francesco; Di Tano, Giuseppe; D'Offizi, Gianpiero; Fusco, Francesco Maria; Gentile, Ivan; Graziani, Emauele; Guarnieri, Gabriella; Larizza, Giovanni; Leone, Armando; Lio, Veronica; Lucia, Mothanje Barbara; Maccagni, Gloria; Madaro, Ferruccio; Maitan, Stefano; Mancarella, Sandro; Manuele, Rosa; Mapelli, Massimo; Maragna, Riccardo; Marcucci, Rossella; Maresca, Giulio; Marongiu, Silvia; Marotta, Claudia; Marra, Lorenzo; Mastroianni, Franco; Mazzitelli, Maria; Mengozzi, Alessandro; Menichetti, Francesco; Meschiari, Marianna; Milic, Jovana; Minutolo, Filippo; Molena, Beatrice; Mussini, Cristina; Musso, Maria; Odone, Anna; Olivieri, Marco; Palimodde, Antonella; Pasi, Emanuela; Pesavento, Raffaele; Petri, Francesco; Pinchera, Biagio; Pivato, Carlo A; Poletti, Venerino; Ravaglia, Claudia; Rossato, Marco; Rossi, Marianna; Sabena, Anna; Salinaro, Francesco; Sangiovanni, Vincenzo; Sanrocco, Carlo; Scoppettuolo, Giancarlo; Scorzolini, Laura; Sgariglia, Raffaella; Simeone, Paola Giustina; Trecarichi, Enrico Maria; Vettor, Roberto; Vianello, Andrea; Vinceti, Marco; Virano, Alexandra; Vocciante, Laura; Iacoviello, Licia; Caterina, Null
abstract

OBJECTIVE: The hypothesis that been set forward that use of Renin Angiotensin Aldosterone System (RAAS) inhibitors is associated with COVID-19 severity. We set-up a multicenter Italian collaboration (CORIST Project, ClinicalTrials.gov ID: NCT04318418) to retrospectively investigate the relationship between RAAS inhibitors and COVID-19 in-hospital mortality. We also carried out an updated meta-analysis on the relevant studies.METHODS: We analyzed 4,069 unselected patients with laboratory-confirmed SARS-CoV-2 infection and hospitalized in 34 clinical centers in Italy from February 19, 2020 to May 23, 2020. The primary end-point in a time-to event analysis was in-hospital death, comparing patients who received angiotensin-converting-enzyme inhibitors (ACE-I) or angiotensin-receptor blockers (ARB) with patients who did not. Articles for the meta-analysis were retrieved until July 13th, 2020 by searching in web-based libraries, and data were combined using the general variance-based method.RESULTS: Out of 4,069 COVID-19 patients, 13.5% and 13.3% received ACE-I or ARB, respectively. Use of neither ACE-I nor ARB was associated with mortality (multivariable hazard ratio (HR) adjusted also for COVID-19 treatments: 0.96, 95% confidence interval 0.77-1.20 and HR=0.89, 0.67-1.19 for ACE-I and ARB, respectively). Findings were similar restricting the analysis to hypertensive (N=2,057) patients (HR=1.00, 0.78-1.26 and HR=0.88, 0.65-1.20) or when ACE-I or ARB were considered as a single group. Results from the meta-analysis (19 studies, 29,057 COVID-19 adult patients, 9,700 with hypertension) confirmed the absence of association.CONCLUSIONS: In this observational study and meta-analysis of the literature, ACE-I or ARB use was not associated with severity or in-hospital mortality in COVID-19 patients.

2020 - Randomised controlled trial comparing efficacy and safety of high versus low Low-Molecular Weight Heparin dosages in hospitalized patients with severe COVID-19 pneumonia and coagulopathy not requiring invasive mechanical ventilation (COVID-19 HD): A structured summary of a study protocol [Articolo su rivista]
Marietta, M; Vandelli, P; Mighali, P; Vicini, R; Coluccio, V; D'Amico, R; Aschieri, D; Brugioni, L; Clini, E; Codeluppi, M; Imberti, D; Magnacavallo, A; Meschiari, M; Mussini, C; Orlando, S; Pinelli, G; Pietrangelo, A; Sarti, L; Silva, M.
abstract

To assess whether high doses of Low Molecular Weight Heparin (LMWH) (i.e. Enoxaparin 70 IU/kg twice daily) compared to standard prophylactic dose (i.e., Enoxaparin 4000 IU once day), in hospitalized patients with COVID19 not requiring Invasive Mechanical Ventilation [IMV], are: a)more effective in preventing clinical worsening, defined as the occurrence of at least one of the following events, whichever comes first: 1.Death2.Acute Myocardial Infarction [AMI]3.Objectively confirmed, symptomatic arterial or venous thromboembolism [TE]4.Need of either: a.Continuous Positive Airway Pressure (Cpap) or Non-Invasive Ventilation (NIV) orb.IMV in patients who at randomisation were receiving standard oxygen therapy5.IMV in patients who at randomisation were receiving non-invasive mechanical ventilationb)Similar in terms of major bleeding risk TRIAL DESIGN: Multicentre, randomised controlled, superiority, open label, parallel group, two arms (1:1 ratio), in-hospital study.

2020 - Rituximab in people living with HIV affected by immune-mediated renal diseases: a case-series [Articolo su rivista]
Alfano, G.; Giaroni, F.; Fontana, F.; Neri, L.; Mosconi, G.; Mussini, C.; Guaraldi, G.; Cappelli, G.
abstract

Over the last two decades, rituximab (RTX) has played an important role in the treatment of some lymphoproliferative malignancies and immune-mediated diseases. RTX administration is generally safe and well-tolerated, but side effects including late-onset neutropenia, hypogammaglobulinemia, hepatitis B reactivation and rare cases of progressive multifocal leukoencephalopathy have been observed after its administration. Although there are no absolute contraindications regarding its use in people living with HIV (PLWH), the prescription of this drug has been principally limited in patients with oncohematological diseases. In this report, we described the outcome of four PLWH who underwent RTX therapy after the diagnosis of immune-mediated renal disease. The main RTX-associated adverse effects were leukopenia, late-onset neutropenia and decline of CD4+ and CD8+ T-cell counts. In addition, two of the four patients experienced pneumonia requiring hospitalization within six months from the last RTX infusion. We suggest that RTX should be used with caution in PLWH until further evidence emerges on its safety profile in this vulnerable population.

2020 - Role of Maraviroc in minimizing the risk of graft rejection in HIV-infected kidney transplant recipients [Articolo su rivista]
Alfano, Gaetano; Guaraldi, Giovanni; Fontana, Francesco; Franceschini, Erica; Dolci, Giovanni; Mussini, Cristina; Cappelli, Gianni
abstract

Background Kidney transplantation in HIV-infected patients is characterized by a concerning high rate of allograft rejections. The etiological mechanisms leading to this increased immunoreactivity are still unknown. Maraviroc is a new antiretroviral agent that has been associated with immunomodulatory proprieties; therefore, its use may be a promising strategy to minimize the rate of rejections in HIV-infected kidney transplant (KT) recipients.Methods We conducted a retrospective study in our cohort of HIV-KT recipients with the aim to explore the effects of maraviroc in reducing the risk of graft rejection.Results Twenty-two HIV-infected KT recipients predominantly of Caucasian origin (86%) and with a median age of 49 (IQR, 51.9-42.2) years were evaluated. Ten HIV-infected patients were treated with maraviroc and 12 with a maraviroc-free antiretroviral regimen. After a median follow-up of 3.01 years, half of the maraviroc-treated patients (n = 5) developed seven episodes of graft rejection, most of them were T cell-mediated rejections (85.7%). Five episodes were recorded in the maraviroc-free group. The difference in the rate of graft rejections was not statistically significant (P = .23).Conclusions The administration of maraviroc was ineffective in preventing graft rejections in our cohort of patients.

2020 - SARS-CoV-2, the Virus that Causes COVID-19: Cytometry and the New Challenge for Global Health [Articolo su rivista]
Cossarizza, A.; De Biasi, S.; Guaraldi, G.; Girardis, M.; Mussini, C.
abstract

2020 - Safety and efficacy of daclatasvir at doses other than 60 mg daily in HIV/HCV co-infected subjects: Data from the ICONA/HepaICONA foundation cohorts [Articolo su rivista]
Rossotti, R.; Tavelli, A.; Bonora, S.; Cingolani, A.; Lo Caputo, S.; Saracino, A.; Soria, A.; Marinaro, L.; Uberti-Foppa, C.; Mussini, C.; Puoti, M.; d'Arminio Monforte, A.
abstract

Background: Daclatasvir (DCV) is a HCV NS5A inhibitor whose plasma exposure may be influenced by co-administration with inducers or inhibitors of CYP3A4 such as many antiretrovirals. Aims: Describe the use of different DCV dosages; assess if dose prescription complies with Summaries of Product Characteristics (SmPC); evaluate safety and efficacy of 60 versus 30/90 mg and adequate (i.e. concordant with SmPC) versus incorrect prescriptions. Methods: Retrospective analysis of patients included in ICONA/HepaICONA starting a DCV-including treatment. Incidence rates of liver adverse events (LAE) were calculated; Poisson regression model was used to identify factors associated with LAE. Results: 311 patients were included: 250 (80.4%) received DCV at a dosage of 60 mg, 52 (16.7%) 30 mg and 9 (2.9%) 90 mg. An inadequate dosage was used in 18 individuals (5.8%). No difference in SVR was observed (93.8% with 60 mg and 94.2% with 30/90 mg, p = 0.910; 93.5% with adequate and 100% with incorrect dosage, p = 0.277). There were 36 LAE with no differences in the two-paired groups. Decompensated liver disease was a risk factor for LAE (aRR = 2.37; p = 0.034), while HIV RNA &lt; 50 copies/ml resulted protective (aRR = 0.22; p = 0.003). Conclusions: DCV use resulted in high SVR rate regardless of dosage and correctness of prescription.

2020 - Safety and efficacy of the Russian COVID-19 vaccine: more information needed [Articolo su rivista]
Bucci, E.; Andreev, K.; Bjorkman, A.; Calogero, R. A.; Carafoli, E.; Carninci, P.; Castagnoli, P.; Cossarizza, A.; Mussini, C.; Guerin, P.; Lipworth, B.; Sbardella, G.; Stocki, T.; Tuosto, L.; van Tulleken, C.; Viola, A.
abstract

2020 - Sex Differences in People Aging With HIV [Articolo su rivista]
Brañas, Fátima; Sánchez-Conde, Matilde; Carli, Federica; Menozzi, Marianna; Raimondi, Alessandro; Milic, Jovana; Franconi, Jacopo; Cuomo, Gianluca; Mussini, Cristina; Moreno, Santiago; Guaraldi, Giovanni
abstract

To evaluate differences between older women and men with HIV regarding HIV variables, comorbidity, physical function, and quality of life (QOL).

2020 - Shall we dance? Extending tango's results to clinical practice [Articolo su rivista]
Borghetti, Alberto; Ciccullo, Arturo; Baldin, Gianmaria; Rusconi, Stefano; Capetti, Amedeo; Sterrantino, Gaetana; Gennari, William; Mussini, Cristina; Borghi, Vanni; Di Giambenedetto, Simona
abstract

2020 - Successful treatment of BK virus associated-nephropathy in a human immunodeficiency virus-positive kidney transplant recipient [Articolo su rivista]
Alfano, Gaetano; Fontana, Francesco; Guaraldi, Giovanni; Cappelli, Gianni; Mussini, Cristina
abstract

BK virus (BKV) is an opportunistic pathogen in those with impaired immunity. Viral replication is generally asymptomatic but is able to induce cytopathic alterations in renal cells. If BKV infection is left untreated, it leads to BKV-associated nephropathy (BKVAN) and graft loss. There is scarce experience in the management of BKV infection in kidney transplant recipients living with HIV. We report the successful treatment of BKVAN in an HIV-positive kidney transplant recipient who experienced BKV replication in the immediate post-transplantation period. A change in therapy from calcineurin inhibitor to sirolimus, steroid withdrawal and a short course of an immunomodulatory agent (leflunomide) controlled BKV viremia in the absence of drug side-effects or impairment of graft function.

2020 - TOCIVID-19 - A multicenter study on the efficacy and tolerability of tocilizumab in the treatment of patients with COVID-19 pneumonia. Study protocol [Articolo su rivista]
Piccirillo, Maria Carmela; Ascierto, Paolo; Atripaldi, Luigi; Cascella, Marco; Costantini, Massimo; Dolci, Giovanni; Facciolongo, Nicola; Fraganza, Fiorentino; Marata, AnnaMaria; Massari, Marco; Montesarchio, Vincenzo; Mussini, Cristina; Negri, Emanuele Alberto; Parrella, Roberto; Popoli, Patrizia; Botti, Gerardo; Arenare, Laura; Chiodini, Paolo; Gallo, Ciro; Salvarani, Carlo; Perrone, Francesco
abstract

Pneumonia is the most frequent complication of COVID-19, due to an aberrant host immune response that is associated with an acute respiratory distress syndrome, and, in most critical patients, with a "cytokine storm". IL-6 might play a key role in the cytokine storm and might be a potential target to treat severe and critical COVID-19. Tocilizumab is a recombinant humanized monoclonal antibody, directed against IL-6 receptor.

2020 - The Lisbon patient: Exceptional longevity with HIV suggests healthy aging as an ultimate goal for HIV care [Articolo su rivista]
Pintassilgo, I.; Cesari, M.; Santos, H. N.; Milic, J.; Franconi, I.; Mussini, C.; Marques, N.; Guaraldi, G.
abstract

In the context of global aging, HIV infection has become a new chronic disease and requires innovative models of care. Treating isolated comorbidities represents a useless and potentially harmful practice at advanced age. Therefore, a patient-centered approach, in which the interventions are focused on the biology and function of the individual, with understanding of the importance of securing social and home environment that provides psychosocial support, better suits unmet health needs. We present a paradigmatic case of healthy aging: the first reported HIV-infected patient who achieved 100th of life - the Lisbon patient. The construct of healthy aging, recently introduced by the World Health Organization, is the best example of this comprehensive model and could represent the fourth target of UNAIDS agenda of the end of AIDS.

2020 - The Role of the Renin-Angiotensin System in Severe Acute Respiratory Syndrome-CoV-2 Infection [Articolo su rivista]
Alfano, Gaetano; Guaraldi, Giovanni; Fontana, Francesco; Ferrari, Annachiara; Magistroni, Riccardo; Mussini, Cristina; Cappelli, Gianni
abstract

2020 - Therapeutic strategies for severe COVID-19: a position paper from the Italian Society of Infectious and Tropical Diseases (SIMIT) [Articolo su rivista]
Mussini, Cristina; Falcone, Marco; Nozza, Silvia; Sagnelli, Caterina; Parrella, Roberto; Meschiari, Marianna; Petrosillo, Nicola; Mastroianni, Claudio; Cascio, Antonio; Iaria, Chiara; Galli, Massimo; Chirianni, Antonio; Sagnelli, Evangelista; Iacobello, Carmelo; Di Perri, Giovanni; Mazzotta, Francesco; Carosi, Giampiero; Tinelli, Marco; Grossi, Paolo; Armignacco, Orlando; Portelli, Vincenzo; Andreoni, Massimo; Tavio, Marcello
abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has become pandemic, reaching almost one million death worldwide. At present, standard treatment for COVID-19 is not well defined, since the evidences either from randomized or observational studies, somehow with conflicting results, lead to rapid changes in guidelines. Our aim is to narratively summarize the available literature on the management of COVID-19 in order to combine current evidence and interpretation of the data by experts who are treating patients in the frontline.

2020 - Tocilizumab for patients with COVID-19 pneumonia. The single-arm TOCIVID-19 prospective trial [Articolo su rivista]
Perrone, F.; Piccirillo, M. C.; Ascierto, P. A.; Salvarani, C.; Parrella, R.; Marata, A. M.; Popoli, P.; Ferraris, L.; Marrocco-Trischitta, M. M.; Ripamonti, D.; Binda, F.; Bonfanti, P.; Squillace, N.; Castelli, F.; Muiesan, M. L.; Lichtner, M.; Calzetti, C.; Salerno, N. D.; Atripaldi, L.; Cascella, M.; Costantini, M.; Dolci, G.; Facciolongo, N. C.; Fraganza, F.; Massari, M.; Montesarchio, V.; Mussini, C.; Negri, E. A.; Botti, G.; Cardone, C.; Gargiulo, P.; Gravina, A.; Schettino, C.; Arenare, L.; Chiodini, P.; Gallo, C.
abstract

Background: Tocilizumab blocks pro-inflammatory activity of interleukin-6 (IL-6), involved in pathogenesis of pneumonia the most frequent cause of death in COVID-19 patients. Methods: A multicenter, single-arm, hypothesis-driven trial was planned, according to a phase 2 design, to study the effect of tocilizumab on lethality rates at 14 and 30&nbsp;days (co-primary endpoints, a priori expected rates being 20 and 35%, respectively). A further prospective cohort of patients, consecutively enrolled after the first cohort was accomplished, was used as a secondary validation dataset. The two cohorts were evaluated jointly in an exploratory multivariable logistic regression model to assess prognostic variables on survival. Results: In the primary intention-to-treat (ITT) phase 2 population, 180/301 (59.8%) subjects received tocilizumab, and 67 deaths were observed overall. Lethality rates were equal to 18.4% (97.5% CI: 13.6–24.0, P = 0.52) and 22.4% (97.5% CI: 17.2–28.3, P &lt; 0.001) at 14 and 30&nbsp;days, respectively. Lethality rates were lower in the validation dataset, that included 920 patients. No signal of specific drug toxicity was reported. In the exploratory multivariable logistic regression analysis, older age and lower PaO2/FiO2 ratio negatively affected survival, while the concurrent use of steroids was associated with greater survival. A statistically significant interaction was found between tocilizumab and respiratory support, suggesting that tocilizumab might be more effective in patients not requiring mechanical respiratory support at baseline. Conclusions: Tocilizumab reduced lethality rate at 30&nbsp;days compared with null hypothesis, without significant toxicity. Possibly, this effect could be limited to patients not requiring mechanical respiratory support at baseline. Registration EudraCT (2020-001110-38); clinicaltrials.gov (NCT04317092).

2020 - Tocilizumab for severe COVID-19 pneumonia – Authors' reply [Articolo su rivista]
Guaraldi, Giovanni; Meschiari, Marianna; Milic, Jovana; Cozzi-Lepri, Alessandro; Mussini, Cristina
abstract

2020 - Tocilizumab in COVID-19: finding the optimal route and dose – Authors' reply [Articolo su rivista]
Guaraldi, G.; Milic, J.; Cozzi-Lepri, A.; Pea, F.; Mussini, C.
abstract

2020 - Tocilizumab in patients with severe COVID-19: a retrospective cohort study [Articolo su rivista]
Guaraldi, G; Meschiari, M; Cozzi-Lepri, A; Milic, J; Tonelli, R; Menozzi, M; Franceschini, E; Cuomo, G; Orlando, G; Borghi, V; Santoro, A; Di Gaetano, M; Puzzolante, C; Carli, F; Bedini, A; Corradi, L; Fantini, R; Castaniere, I; Tabbì, L; Girardis, M; Tedeschi, S; Giannella, M; Bartoletti, M; Pascale, R; Dolci, G; Brugioni, L; Pietrangelo, A; Cossarizza, A; Pea, F; Clini, E; Salvarani, C; Massari, M; Viale, Pl; Mussini, C.
abstract

Background- There is no approved therapy for COVID-19 pneumonia. The aim of this multicentre cohort study was to assess the role of tocilizumab in reducing the risk of invasive mechanical ventilation and/or death in patients with severe COVID-19 pneumonia who received standard of care (SoC) treatment. Methods- The TESEO Cohort Study is a retrospective, multicentre observational cohort study of patients with COVID-19 severe pneumonia treated with SoC with or without tocilizumab using intravenous (IV) or subcutaneous (SC) formulations, identifying respectively treated and comparator groups. Survival analysis was performed with participants’ follow-up accruing from the date of entry into clinics until initiation of invasive mechanical ventilation or death, used as a composite outcome. Treatment groups were compared using Kaplan-Meier curves and Cox regression analysis after adjusting for gender, age and baseline Sequential Organ Failure Assessment (SOFA) score. Findings- Of 544 patients included, 179 patients were treated with tocilizumab: 88 with the IV (16.1%) and 91 with SC formulation (16.7%). Mortality was significantly higher in the comparator group (20%) as opposed to tocilizumab IV (6.8%) and tocilizumab SC (7.7%) (p&lt;0.001). A reduced risk of invasive mechanical ventilation/death was shown for participants treated with tocilizumab from fitting a Cox regression analysis adjusted for gender, age and SOFA score (aHR=0.61, 95% CI:0.40-0.92; p=0.02). We found no evidence for a difference between IV and SC administration route of tocilizumab. With regards to the mortality endpoint alone, a reduced risk was observed comparing tocilizumab with the comparator group (aHR=0.38 95% CI:0.17-0.83, p=0.02) . Interpretation- Tocilizumab, regardless of IV or SC administration may be capable of reducing invasive mechanical ventilation or death in severe COVID-19 pneumonia. Our observations should be confirmed in randomised studies. Funding- This study was not funded.

2020 - Treating cancer with immunotherapy in HIV-positive patients: A challenging reality [Articolo su rivista]
Guaitoli, G.; Baldessari, C.; Maur, M.; Mussini, C.; Meschiari, M.; Barbieri, F.; Cascinu, S.; Bertolini, F.
abstract

Immunotherapy has widely changed the management of different malignancies. However, efficacy and safety of immune checkpoint inhibitors (ICIs) are not well established in people living with HIV (PLWH). Population of HIV-positive patients has deeply changed after the introduction of modern antiretroviral therapy (ART) and available data of immunotherapy in this subgroup are inadequate considering that cancer has become a leading cause of death and morbidity in this population. Moreover, there are many similarities between cancer and infectious antigen stimulation so that ICIs are even under evaluation as specific HIV treatment. Most of literature on this topic is based on small case series that suggest that immunotherapy for PLWH seems to be as effective as in HIV-negative population with a good safety profile. In this article we review literature on HIV and immunotherapy and we collect many case series available in different malignancies, with a brief focus on lung cancer.

2020 - Two fatal cases of acute liver failure due to HSV-1 infection in COVID-19 patients following immunomodulatory therapies. [Articolo su rivista]
Busani, S; Bedini, A; Biagioni, E; Serio, L; Tonelli, R; Meschiari, M; Franceschini, E; Guaraldi, G; Cossarizza, A; Clini, E; Maiorana, A; Gennari, W; De Maria, N; Luppi, M; Mussini, C; Girardis, M.; Gibellini, Lara
abstract

We reported two fatal cases of acute liver failure secondary to Herpes Simplex Virus 1 infection in COVID-19 patients, following tocilizumab and corticosteroid therapy. Screening for and prompt recognition of Herpes Simplex Virus 1 reactivation in these patients, undergoing immunomodulatory treatment, may have potentially relevant clinical consequences.

2020 - Uptake and Discontinuation of Integrase Inhibitors (INSTIs) in a Large Cohort Setting [Articolo su rivista]
Greenberg, L.; Ryom, L.; Wandeler, G.; Grabmeier-Pfistershammer, K.; Ollinger, A.; Neesgaard, B.; Stephan, C.; Calmy, A.; Rauch, A.; Castagna, A.; Spagnuolo, V.; Johnson, M.; Stingone, C.; Mussini, C.; De Wit, S.; Necsoi, C.; Campins, A. A.; Pradier, C.; Stecher, M.; Wasmuth, J. -C.; Monforte, A. D.; Law, M.; Puhr, R.; Chkhartishvilli, N.; Tsertsvadze, T.; Garges, H.; Thorpe, D.; Lundgren, J. D.; Peters, L.; Bansi-Matharu, L.; Mocroft, A.
abstract

BACKGROUND: Despite increased integrase strand transfer inhibitor (INSTI) use, limited large-scale, real-life data exists on INSTI uptake and discontinuation. SETTING: International multicohort collaboration. METHODS: RESPOND participants starting dolutegravir (DTG), elvitegravir (EVG), or raltegravir (RAL) after January 1, 2012 were included. Predictors of INSTI used were assessed using multinomial logistic regression. Kaplan-Meier and Cox proportional hazards models describe time to and factors associated with discontinuation. RESULTS: Overall, 9702 persons were included; 5051 (52.1%) starting DTG, 1933 (19.9%) EVG, and 2718 (28.0%) RAL. The likelihood of starting RAL or EVG vs DTG decreased over time and was higher in Eastern and Southern Europe compared with Western Europe. At 6 months after initiation, 8.9% (95% confidence interval: 8.3% to 9.5%) had discontinued the INSTI (6.4% DTG, 7.4% EVG, and 14.0% RAL). The main reason for discontinuation was toxicity (44.2% DTG, 42.5% EVG, 17.3% RAL). Nervous system toxicity accounted for a higher proportion of toxicity discontinuations on DTG (31.8% DTG, 23.4% EVG, 6.6% RAL). Overall, treatment simplification was highest on RAL (2.7% DTG, 1.6% EVG, and 19.8% RAL). Factors associated with a higher discontinuation risk included increasing year of INSTI initiation, female gender, hepatitis C coinfection, and previous non-AIDS-defining malignancies. Individuals in Southern and Eastern Europe were less likely to discontinue. Similar results were seen for discontinuations after 6 months. CONCLUSIONS: Uptake of DTG vs EVG or RAL increased over time. Discontinuation within 6 months was mainly due to toxicity; nervous system toxicity was highest on DTG. Discontinuation was highest on RAL, mainly because of treatment simplification.

2020 - Use of hydroxychloroquine in hospitalised COVID-19 patients is associated with reduced mortality: Findings from the observational multicentre Italian CORIST study [Articolo su rivista]
Castelnuovo, A. D.; Costanzo, S.; Antinori, A.; Berselli, N.; Blandi, L.; Bruno, R.; Cauda, R.; Guaraldi, G.; Menicanti, L.; My, I.; Parruti, G.; Patti, G.; Perlini, S.; Santilli, F.; Signorelli, C.; Spinoni, E.; Stefanini, G. G.; Vergori, A.; Ageno, W.; Agodi, A.; Aiello, L.; Agostoni, P.; Moghazi, S. A.; Astuto, M.; Aucella, F.; Barbieri, G.; Bartoloni, A.; Bonaccio, M.; Bonfanti, P.; Cacciatore, F.; Caiano, L.; Cannata, F.; Carrozzi, L.; Cascio, A.; Ciccullo, A.; Cingolani, A.; Cipollone, F.; Colomba, C.; Crosta, F.; Pra, C. D.; Danzi, G. B.; D'Ardes, D.; Donati, K. D. G.; Giacomo, P. D.; Gennaro, F. D.; Tano, G. D.; D'Offizi, G.; Filippini, T.; Fusco, F. M.; Gentile, I.; Gialluisi, A.; Gini, G.; Grandone, E.; Grisafi, L.; Guarnieri, G.; Lamonica, S.; Landi, F.; Leone, A.; Maccagni, G.; Maccarella, S.; Madaro, A.; Mapelli, M.; Maragna, R.; Marra, L.; Maresca, G.; Marotta, C.; Mastroianni, F.; Mazzitelli, M.; Mengozzi, A.; Menichetti, F.; Meschiari, M.; Minutolo, F.; Montineri, A.; Mussinelli, R.; Mussini, C.; Musso, M.; Odone, A.; Olivieri, M.; Pasi, E.; Petri, F.; Pinchera, B.; Pivato, C. A.; Poletti, V.; Ravaglia, C.; Rinaldi, M.; Rognoni, A.; Rossato, M.; Rossi, I.; Rossi, M.; Sabena, A.; Salinaro, F.; Sangiovanni, V.; Sanrocco, C.; Scorzolini, L.; Sgariglia, R.; Simeone, P. G.; Spinicci, M.; Trecarichi, E. M.; Venezia, A.; Veronesi, G.; Vettor, R.; Vianello, A.; Vinceti, M.; Vocciante, L.; De Caterina, R.; Iacoviello, L.
abstract

Background: Hydroxychloroquine (HCQ) was proposed as potential treatment for COVID-19. Objective: We set-up a multicenter Italian collaboration to investigate the relationship between HCQ therapy and COVID-19 in-hospital mortality. Methods: In a retrospective observational study, 3,451 unselected patients hospitalized in 33 clinical centers in Italy, from February 19, 2020 to May 23, 2020, with laboratory-confirmed SARS-CoV-2 infection, were analyzed. The primary end-point in a time-to event analysis was in-hospital death, comparing patients who received HCQ with patients who did not. We used multivariable Cox proportional-hazards regression models with inverse probability for treatment weighting by propensity scores, with the addition of subgroup analyses. Results: Out of 3,451 COVID-19 patients, 76.3% received HCQ. Death rates (per 1,000 person-days) for patients receiving or not HCQ were 8.9 and 15.7, respectively. After adjustment for propensity scores, we found 30% lower risk of death in patients receiving HCQ (HR=0.70; 95%CI: 0.59 to 0.84; E-value=1.67). Secondary analyses yielded similar results. The inverse association of HCQ with inpatient mortality was particularly evident in patients having elevated C-reactive protein at entry. Conclusions: HCQ use was associated with a 30% lower risk of death in COVID-19 hospitalized patients. Within the limits of an observational study and awaiting results from randomized controlled trials, these data do not discourage the use of HCQ in inpatients with COVID-19.

2020 - Virologic and immunologic outcomes of treatment with integrase inhibitors in a real-world setting: The RESPOND cohort consortium [Articolo su rivista]
Neesgaard, B.; Mocroft, A.; Zangerle, R.; Wit, F.; Lampe, F.; Gunthard, H. F.; Necsoi, C.; Law, M.; Mussini, C.; Castagna, A.; Monforte, A. D.; Pradier, C.; Chkhartisvilli, N.; Reyes-Uruena, J.; Vehreschild, J. J.; Wasmuth, J. -C.; Sonnerborg, A.; Stephan, C.; Greenberg, L.; Llibre, J. M.; Volny-Anne, A.; Peters, L.; Pelchen-Matthews, A.; Vannappagari, V.; Gallant, J.; Rieger, A.; Youle, M.; Braun, D.; de Wit, S.; Petoumenos, K.; Borghi, V.; Spagnuolo, V.; Tsertsvadze, T.; Lundgren, J.
abstract

Objectives To compare virologic and immunologic outcomes of integrase inhibitor (INSTI)-containing, contemporary boosted protease inhibitor (PI/b)-containing and non-nucleotide reverse transcriptase inhibitor (NNRTI)-containing regimens in a real-life setting. Methods Using logistic regression, virologic and immunologic outcomes of INSTI use were compared to outcomes of PI/b or NNRTI treatment 12 months after treatment start or switch, for participants in the RESPOND cohort consortium. A composite treatment outcome (cTO) was used, defining success as viral load (VL) &lt;200 copies/mL and failure as at least one of: VL ≥200 copies/mL, unknown VL in the time window, any changes of antiretroviral therapy (ART) regimen, AIDS, or death. In addition, on-treatment analysis including only individuals with known VL and no regimen changes was performed. Favorable immunologic response was defined as a 25% increase in CD4 count or as reaching ≥750 CD4 cells/μL. Results Between January 2012 and January 2019, 13,703 (33.0% ART-naïve) individuals were included, of whom 7,147 started/switched to a regimen with an INSTI, 3,102 to a PI/b and 3,454 to an NNRTI-containing regimen. The main reason for cTO failure in all treatment groups were changes in ART regimen. Compared to INSTIs, the adjusted odds ratio (aOR) of cTO success was significantly lower for PI/b (0.74 [95% confidence interval, CI 0.67–0.82], p &lt;0.001), but similar for NNRTIs (1.07 [CI 0.97–1.17], p = 0.11). On-treatment analysis and sensitivity analyses using a VL cut-off of 50 copies/mL were consistent. Compared to INSTIs, the aORs of a 25% increase in CD4 count were lower for NNRTIs (0.80 [CI 0.71–0.91], p&lt;0.001) and PI/b (0.87 [CI 0.76–0.99], p = 0.04). Conclusion In this large analysis of a real-world population, cTO and on-treatment success were similar between INSTIs and NNRTIs, but lower for PI/b, though residual confounding cannot be fully excluded. Obtaining favorable immunologic outcomes were more likely for INSTIs than the other drug classes.

2020 - Virological response and retention in care according to time of starting ART in Italy: Data from the Icona Foundation Study cohort [Articolo su rivista]
D'Arminio Monforte, A.; Tavelli, A.; Cozzi-Lepri, A.; Castagna, A.; Passerini, S.; Francisci, D.; Saracino, A.; Maggiolo, F.; Lapadula, G.; Girardi, E.; Perno, C. F.; Antinori, A.; Andreoni, M.; Castelli, F.; Cauda, R.; Di Perri, G.; Galli, M.; Iardino, R.; Ippolito, G.; Lazzarin, A.; Marchetti, G. C.; Rezza, G.; Von Schloesser, F.; Viale, P.; Ceccherini-Silberstein, F.; Lo Caputo, S.; Mussini, C.; Puoti, M.; Bai, F.; Balotta, C.; Bandera, A.; Bonora, S.; Borderi, M.; Calcagno, A.; Capetti, A.; Capobianchi, M. R.; Cicalini, S.; Cingolani, A.; Cinque, P.; De Luca, A.; Di Biagio, A.; Gianotti, N.; Gori, A.; Guaraldi, G.; Lichtner, M.; Madeddu, G.; Monno, L.; Nozza, S.; Pinnetti, C.; Quiros Roldan, E.; Rossotti, R.; Rusconi, S.; Santoro, M. M.; Sarmati, L.; Fanti, I.; Galli, L.; Lorenzini, P.; Rodano, A.; Macchia, M.; Carletti, F.; Carrara, S.; Di Caro, A.; Graziano, S.; Petroni, F.; Prota, G.; Truffa, S.; Giacometti, A.; Costantini, A.; Barocci, V.; Angarano, G.; Milano, E.; Suardi, C.; Donati, V.; Verucchi, G.; Castelnuovo, F.; Minardi, C.; Menzaghi, B.; Abeli, C.; Cacopardo, B.; Celesia, B.; Vecchiet, J.; Falasca, K.; Pan, A.; Lorenzotti, S.; Sighinolfi, L.; Segala, D.; Blanc, P.; Vichi, F.; Cassola, G.; Viscoli, C.; Alessandrini, A.; Bobbio, N.; Mazzarello, G.; Fondaco, L.; Bonfanti, P.; Molteni, C.; Chiodera, A.; Milini, P.; Nunnari, G.; Pellicano, G.; Rizzardini, G.; Cannizzo, E. S.; Moioli, M. C.; Piolini, R.; Bernacchia, D.; Salpietro, S.; Tincati, C.; Puzzolante, C.; Migliorino, C.; Sangiovanni, V.; Borgia, G.; Esposito, V.; Di Flumeri, G.; Gentile, I.; Rizzo, V.; Cattelan, A. M.; Marinello, S.; Cascio, A.; Trizzino, M.; Schiaroli, E.; Parruti, G.; Sozio, F.; Magnani, G.; Ursitti, M. A.; Cristaudo, A.; Vullo, V.; Acinapura, R.; Moschese, D.; Capozzi, M.; Mondi, A.; Rivano Capparuccia, M.; Iaiani, G.; Latini, A.; Gagliardini, R.; Plazzi, M. M.; De Girolamo, G.; Vergori, A.; Cecchetto, M.; Viviani, F.; De Vito, A.; Rossetti, B.; Montagnani, F.; Franco, A.; Fontana Del Vecchio, R.; Di Giuli, C.; Caramello, P.; Orofino, G. C.; Sciandra, M.; Bassetti, M.; Londero, A.; Manfrin, V.; Battagin, G.; Starnini, G.; Ialungo, A.
abstract

Objectives: To describe: (i) factors associated with rapid and delayed ART initiation; (ii) rates of 12 week virological response; and (iii) virologically controlled retention in care by 1 year from ART initiation according to timing of start in a real-life setting. Methods: All individuals in the Icona cohort diagnosed with HIV in 2016-17 who initiated ART were grouped according to the time between HIV diagnosis and ART initiation: Group 1, ≤7 days; Group 2, 8-14 days; Group 3, 15-30 days; Group 4, 31-120 days; and Group 5, &gt;120 days. Multivariable logistic regression models were used to identify factors associated with: (i) the probability of rapid (Group 1) and very delayed (Group 5) ART initiation; (ii) the 12 week virological response (by a modified snapshot algorithm); and (iii) the probability of retention in care at 1 year (on ART with HIV-RNA &lt;50 copies/mL). Results: A total of 1247 individuals were included [82 (6.6%) in Group 1, 115 (9.2%) in Group 2, 267 (21.4%) in Group 3, 641 (51.4%) in Group 4 and 142 (11.4%) in Group 5]. Main predictors of rapid ART start (Group 1) were low CD4 cell count and high HIV-RNA at first contact with the infectious diseases centre. There was no association between probability of virological response and timing of ART initiation. Overall, 90% of individuals remained on ART after 1 year, 91% with undetectable HIV-RNA. Participants of Italian nationality, those with higher CD4 cell count and lower HIV-RNA at ART initiation were more likely to be retained in care after 1 year. Conclusions: In our high-income observational setting, we did not observe differences in the 1 year rate of virological response and retention in care according to timing of ART initiation.

2019 - A prospective randomized trial on abacavir/ lamivudine plus darunavir/ritonavir or raltegravir in HIV-positive drug-naïve patients with CD4<200 cells/uL (the PRADAR study) [Articolo su rivista]
Mussini, C.; Roncaglia, E.; Borghi, V.; Rusconi, S.; Nozza, S.; Cattelan, A. M.; Segala, D.; Bonfanti, P.; Biagio, A. D.; Barchi, E.; Foca, E.; Antoni, A. D.; Bonora, S.; Francisci, D.; Limonta, S.; Antinori, A.; D'Ettorre, G.; Maggiolo, F.
abstract

Very few data are available on treatment in HIV Late presenter population that still represents a clinical challenge.

2019 - Age of HIV Acquisition Affects the Risk of Multi-Morbidity after 25 Years of Infection Exposure [Articolo su rivista]
Guaraldi, G; Malagoli, A; Milic, J; Pintassilgo, I; Rossi, E; Riva, N; Franconi, I; Santoro, A; Sorin, P; Streinu-Cercel, A; De Rosa, M; Mussini, C
abstract

Introduction: Understanding the intersection of HIV, aging and health is crucial due to the increasing number of people aging with HIV. Objective: The objective of the study was to assess the prevalence of, and risk factors for individual comorbidities and multi-morbidity in people living with HIV with similar duration of HIV infection, notwithstanding a 25-year difference at the time of HIV acquisition. Methods: In a cross-sectional multicentre retrospective study, we compared three match-control age groups. The "Young" were selected from Romania and included HIV-positive patients prenatally infected and assessed at the age of 25-30 years. The "Old" and the "Geriatric" were selected from Italy. These respectively included subjects infected with HIV at the age of 25 years and assessed at the age of 50-55 years, and those infected at the age of 50 years and assessed at the age of 75-80 years. Each group was sex and age matched in a 1: 5 ratio with controls selected from the CINECA ARNO database from Italy. We described non-infectious comorbidities (NICM), including cardiovascular disease, hypertension, dyslipidaemia, diabetes, chronic kidney disease, and multi-morbidity (MM >= 3 NICM). Results: MM prevalence in the "Young" group compared to controls was 6.2% vs 0%, while in the "Geriatric" was "68.2% vs 3.6%. Using "Young" as a reference, in multivariate analyses, predictors for MM were as follows: HIV serostatus (OR=47.75, IQR 14.78-154.25, p<0.01) and "Geriatric" vs "Young" (OR=30.32, IQR 5.89-155.98, p<0.01). Conclusion: These data suggest that age at acquisition of HIV should be considered as a risk factor for NICM and MM.

2019 - Aging with HIV [Articolo su rivista]
Guaraldi, G.; Milic, J.; Mussini, C.
abstract

Purpose of Review: This review points out unmet medical needs and open research questions of older adults living with HIV. Starting from the definition of aging in HIV, it explores the mosaic of this condition at epidemiological, pathophysiological, and clinical level. Antiretroviral management and diverse models of care are critically discussed. Recent Findings: Aging cohorts suggest HIV as a paradigm of chronic inflammation and immune activation with specific aging trajectory patterns in which antiretroviral therapy may play a role. In the absence of randomized clinical trials, observational cohorts show that therapy is driven by duration of HIV infection and burden of non-infectious comorbidities. Summary: This review suggests that geriatric approach should be used to recognize the complexity of aging goes beyond the viro-immunological success and management of progressive accumulation of non-communicable diseases. This requires recognition of frailty and geriatric syndromes to stratify patients’ diversity by using comprehensive geriatric assessment tools.

2019 - Altered Expression of PYCARD, Interleukin 1β, Interleukin 18, and NAIP in Successfully Treated HIV-Positive Patients With a Low Ratio of CD4+ to CD8+ T Cells [Articolo su rivista]
Nasi, Milena; Pecorini, Simone; De Biasi, Sara; Bianchini, Elena; Digaetano, Margherita; Neroni, Anita; Lo Tartaro, Domenico; Pullano, Rosalberta; Pinti, Marcello; Gibellini, Lara; Mussini, Cristina; Cossarizza, Andrea
abstract

The expression and activity of main inflammasome components in monocytes from successfully treated HIV+ patients are poorly studied. Thus, we enrolled 18 patients with low and 17 with normal CD4/CD8 ratio compared to 11 healthy donors. Our results show that patients with low ratio have a decreased CCR2 expression among classical and intermediate monocytes and an increased CCR5 expression among classical, compared to whose with normal ratio. They also showed higher NAIP and PYCARD mRNA levels after LPS-stimulation suggesting an altered ability to control immune activation that could affect their immune reconstitution.

2019 - Antiviral activity of sirolimus in an HIV-positive kidney transplant recipient [Articolo su rivista]
Alfano, G.; Fontana, F.; Mori, G.; Vicari, Emanuela; Dolci, G.; Franceschini, E.; Guaraldi, G.; Mussini, C.; Cappelli, G.
abstract

Sirolimus (SIR) is a potent immunosuppressive agent with multiple proprieties. We report beneficial antiviral effects of SIR in an HIV-positive kidney transplant recipient who experienced low-level HIV-1 replication. The immunosuppressive agent was well tolerated by the patient, and no side effects were reported during follow-up. Despite immunosuppressive monotherapy, SIR ensured stable graft function.

2019 - Bloodstream infections caused by carbapenem-resistant Acinetobacter baumannii: Clinical features, therapy and outcome from a multicenter study [Articolo su rivista]
Russo, A.; Bassetti, M.; Ceccarelli, G.; Carannante, N.; Losito, A. R.; Bartoletti, M.; Corcione, S.; Granata, G.; Santoro, A.; Giacobbe, D. R.; Peghin, M.; Vena, A.; Amadori, F.; Segala, F. V.; Giannella, M.; Di Caprio, G.; Menichetti, F.; Del Bono, V.; Mussini, C.; Petrosillo, N.; De Rosa, F. G.; Viale, P.; Tumbarello, M.; Tascini, C.; Viscoli, C.; Venditti, M.
abstract

Objectives: bloodstream infections (BSI) due to multidrug-resistant (MDR) Acinetobacter baumannii (AB) have been increasingly observed among hospitalized patients.Methods: prospective, observational study conducted among 12 large tertiary-care hospitals, across 7 Italian regions. From June 2017 to June 2018 all consecutive hospitalized patients with bacteremia due to MDR-AB were included and analyzed in the study.Results: During the study period 281 episodes of BSI due to MDR-AB were observed: 98 (34.8%) episodes were classified as primary bacteremias, and 183 (65.2%) as secondary bacteremias; 177 (62.9%) of them were associated with septic shock. Overall, 14-day mortality was observed in 172 (61.2%) patients, while 30-day mortality in 207 (73.6%) patients. On multivariate analysis, previous surgery, continuous renal replacement therapy, inadequate source control of infection, and pneumonia were independently associated with higher risk of septic shock. Instead, septic shock and Charlson Comorbidity Index &gt;3 were associated with 14-day mortality, while adequate source control of infection and combination therapy with survival. Finally, septic shock, previous surgery, and aminoglycoside-containing regimen were associated with 30-day mortality, while colistin-containing regimen with survival.Conclusions: BSI caused by MDR-AB represents a difficult challenge for physicians, considering the high rates of septic shock and mortality associated with this infection. (C) 2019 The British Infection Association. Published by Elsevier Ltd. All rights reserved.

2019 - Breast tuberculosis: A case report of primary type mammary tuberculosis [Articolo su rivista]
Tazzioli, G.; Macolino, A.; Combi, F.; Palma, E.; Papi, S.; Codeluppi, M.; Mussini, C.
abstract

Mammary tuberculosis is exceptional in developed countries. It can mimic an abscess or a granulomatous mastitis. In subjects coming from endemic areas, it is necessary to suspect a tuberculosis infection in case of recurrent mastitis refractory to antibiotics. Positivity of Quantiferon-TB Gold assay can help to confirm the clinical suspicion.

2019 - Ceftolozane/tazobactam for the treatment of serious P. aeruginosa infections: a multicenter nationwide clinical experience [Articolo su rivista]
Bassetti, Matteo; Castaldo, Nadia; Cattelan, Annamaria; Mussini, Cristina; Righi, Elda; Tascini, Carlo; Menichetti, Francesco; Mastroianni, Claudio Maria; Tumbarello, Mario; Grossi, Paolo; Artioli, Stefania; Carrannante, Novella; Cipriani, Ludovica; Coletto, Davide; Russo, Alessandro; Digaetano, Margherita; Losito, Raffaella; Peghin, Maddalena; Capone, Alessandro; Nicolè, Stefano; Vena, Antonio
abstract

To describe the largest clinical experience using ceftolozane-tazobactam (C/T) for treatment of different type of Pseudomonas aeruginosa infections. A retrospective study was performed at 22 hospitals in Italy from June 2016 to March 2018. All adult patients treated with at least 4 days of C/T were enrolled. A successful clinical outcome was defined as complete resolution of clinical signs and symptoms related to P. aeruginosa infection and lack of microbiological evidence of infection. C/T treatment was documented in 101 patients with diverse infections, including nosocomial pneumonia (31.7%), acute bacterial skin and skin structure infections (30.8%), complicated UTI (13.8%), complicated IAI (12.8%), bone infections (8.9%) and primary bacteraemia (7.9%). Almost half of P.aeruginosa strains were XDR (51%), with 78% of the isolates resistant to at least one carbapenem. C/T was used as first-line therapy in 39 patients (34.6%). When used as second or later line, the most common reasons for discontinuation of previous antibiotics were in vitro resistance of P.aeuruginosa strain and clinical failure of previous therapy. Concomitant antibiotics was reported in 35% of patients. C/T doses were 1.5 grams/8h in 70 patients (69.3%) and 3 grams/8h in 31 patients (30.7%); the median duration of C/T therapy was 14 days. The overall clinical success was 83.2%. Significant lower success rates were observed in patients with sepsis or those receiving continuous renal replacement therapy. Mild adverse events were reported in only three patients. C/T demonstrated a favourable safety and tolerability profile regardless of the type of infection. Clinicians should be aware of the risk of clinical failure with C/T therapy in septic patients receiving continuous renal replacement therapy

2019 - Characterisation of HIV-1 molecular transmission clusters among newly diagnosed individuals infected with non-B subtypes in Italy [Articolo su rivista]
Fabeni, Lavinia; Alteri, Claudia; Berno, Giulia; Scutari, Rossana; Orchi, Nicoletta; De Carli, Gabriella; Bertoli, Ada; Carioti, Luca; Gori, Caterina; Forbici, Federica; Salpini, Romina; Vergori, Alessandra; Gagliardini, Roberta; Cicalini, Stefania; Mondi, Annalisa; Pinnetti, Carmela; Mazzuti, Laura; Turriziani, Ombretta; Colafigli, Manuela; Borghi, Vanni; Montella, Francesco; Pennica, Alfredo; Lichtner, Miriam; Girardi, Enrico; Andreoni, Massimo; Mussini, Cristina; Antinori, Andrea; Ceccherini-Silberstein, Francesca; Perno, Carlo Federico; Santoro, Maria Mercedes
abstract

We evaluated the characteristics of HIV-1 molecular transmission clusters (MTCs) in 1890 newly diagnosed individuals infected with non-B subtypes between 2005 and 2017 in Italy.

2019 - Cohort profile: The Observational cohort for the study of DOlutegravir in Antiretroviral Combination REgimens (ODOACRE) [Articolo su rivista]
Ciccullo, Arturo; Baldin, Gianmaria; Capetti, Amedeo; Borghi, Vanni; Sterrantino, Gaetana; Latini, Alessandra; Madeddu, Giordano; Celani, Luigi; Vignale, Francesca; Rossetti, Barbara; Dusina, Alex; Cossu, Maria Vittoria; Restelli, Sibilla; Gennari, William; Lagi, Filippo; Giacomelli, Andrea; Colafigli, Manuela; Brescini, Lucia; Borghetti, Alberto; Mussini, Cristina; Rusconi, Stefano; Di Giambenedetto, Simona
abstract

The Observational cohort for the study of DOlutegravir in Antiretroviral Combination REgimens (ODOACRE) cohort was established in Italy in 2016 to evaluate the overall efficacy and tolerability of dolutegravir (DTG)-based antiretroviral (ARV) regimens in clinical practice.

2019 - Collaboration experience between Dermatology Unit and Infectious Disease Clinic in Modena: optimization strategies for HIV, hepatitis and syphilis screening tests [Relazione in Atti di Convegno]
DI TULLIO, Francesca; Mandel, Victor Desmond; Coppini, Maurizio; Mussini, Cristina; Borghi, Vanni; Pellacani, Giovanni
abstract

Introduction Screening tests for HIV, HBV, HCV and syphilis are very important to detect and treat these infections at an early stage and prevent their diffusion inside communities. Sexually Transmitted Diseases Ambulatory of Dermatology Unit (STDs-DU) and “Test &amp; Counselling” Ambulatory of Infectious Disease Clinic (T&amp;C-IDC) in Modena began collaboration in 2010 and adopted a common diagnostic serological profile since 2013. Objective The main aim of the study was to analyse the results of screening tests performed in the STDs-DU and T&amp;C-IDC, comparing the results obtained after the adoption of the shared protocol with the previous period. The secondary objective was to evaluate the efficacy of our collaboration in term of number of new diagnoses and linkage to care. Materials and Methods Consecutive patients referred to the STDs-DU and T&amp;C-IDC from January 2010 to December 2016, with at least one performed screening test for HIV, HBV, HCV and syphilis were enrolled. Referral of patients with a new infection was obtained by capture-recapture methods in hospital databases. Results During the seven-years observation we collected 13117 admittances for 9154 patients. We observed a significant increase in the number of screening tests (p&lt;0.001) and ratio between tests and admissions (p=0.002). 644 (7.0%) people with at least one infection were diagnosed. Among these, the most common was syphilis (41.9%), followed by HBV (25.7%), HCV (21.4%) and HIV (10.9%). Syphilis and HCV occurred predominantly in Italians (72.5% and 81.1%) and males (75.7% and 75.5%), while foreign-born (85.5%) mainly harboured HBV infection. HIV diagnosis was detected more frequently among males (67.1%) with a similar proportion between Italians and foreign-born. 543 out of 644 (84.3%) patients were linked to care. Conclusions The cooperation between STDs-DU and T&amp;C-IDC has proven to work well increasing the diagnosis over the time and obtaining good results in linkage to care.

2019 - Compression of frailty in adults living with HIV [Articolo su rivista]
Guaraldi, G.; Francesco, D. D.; Malagoli, A.; Zona, S.; Franconi, I.; Santoro, A.; Mussini, C.; Mussi, C.; Cesari, M.; Theou, O.; Rockwood, K.
abstract

Background: Contemporary HIV care may reduce frailty in older adults living with HIV (OALWH). Objective of the study was to estimate prevalence of frailty at the age of 50 and 75 years, and build a model to quantify the burden of frailty in the year 2030. Methods: This study included OALWH attending Modena HIV Metabolic Clinic between 2009 and 2015. Patients are referred from more than 120 HIV clinics well distributed across Italy, therefore being country representative. Our model forecasts the new entries on yearly basis up to 2030. Changes in frailty over a one-year period using a 37-variable frailty index (FI) and death rates were modelled using a validated mathematical algorithm with parameters adjusted to best represent the changes observed at the clinic. In this study, we assessed the number of frailest individuals (defined with a FI &gt; 0.4) at the age of 50 and at the age 75 by calendar year. Results: In the period 2015-2030 we model that frailest OALWH at age 50 will decrease from 26 to 7%, and at the age of 75 years will increase from 43 to 52%. This implies a shift of the frailty prevalence at an older age. Conclusion: We have presented projections of how the burden of frailty in older adults, living with HIV will change. We project fewer people aged 50+ with severe frailty, most of whom will be older than now. These results suggest a compression of age-related frailty.

2019 - Darunavir/cobicistat/emtricitabine/tenofovir alafenamide in treatment-naïve patients with HIV-1: subgroup analyses of the phase 3 AMBER study [Articolo su rivista]
Rashbaum, Bruce; Spinner, Christoph D; Mcdonald, Cheryl; Mussini, Cristina; Jezorwski, John; Luo, Donghan; Van Landuyt, Erika; Brown, Kimberley; Wong, Eric Y
abstract

Background: The once-daily, single-tablet regimen darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) 800/150/200/10 mg is approved for the treatment of HIV-1 infection. The 48-week efficacy and safety of D/C/F/TAF versus darunavir/cobicistat + emtricitabine/tenofovir disoproxil fumarate (control) in treatment-naïve adults were demonstrated in the phase 3 AMBER study. Objective: To describe AMBER outcomes across patient subgroups based on demographic and clinical characteristics at baseline. Methods: AMBER patients had viral load (VL) ≥1000 copies/mL, CD4+ cell count &gt;50 cells/µL, and genotypic susceptibility to darunavir, emtricitabine, and tenofovir. Primary endpoint was the proportion of patients with virologic response (VL &lt;50 copies/mL; FDA snapshot). Safety was assessed by adverse events, estimated glomerular filtration rate (cystatin C; eGFRcystC), and bone mineral density. Outcomes were assessed by age (≤/&gt;50 years), gender, race (black/non-black), baseline VL (≤/&gt;100,000 copies/mL), baseline CD4+ cell count (50 years and women, relative to their comparator groups, regardless of treatment arm (notably, sample sizes were small for patients &gt;50 years and women). Improvements in eGFRcystC and stable bone mineral density were observed with D/C/F/TAF overall, and results were generally consistent across subgroups. Conclusions: For treatment-naïve patients in AMBER, initiating therapy with the D/C/F/TAF single-tablet regimen was an effective and well-tolerated option, regardless of demographic or clinical characteristics.

2019 - Dolutegravir plus lamivudine versus dolutegravir plus tenofovir disoproxil fumarate and emtricitabine in antiretroviral-naive adults with HIV-1 infection (GEMINI-1 and GEMINI-2): week 48 results from two multicentre, double-blind, randomised, non-inferiority, phase 3 trials [Articolo su rivista]
Cahn, P.; Madero, J. S.; Arribas, J. R.; Antinori, A.; Ortiz, R.; Clarke, A. E.; Hung, C. -C.; Rockstroh, J. K.; Girard, P. -M.; Sievers, J.; Man, C.; Currie, A.; Underwood, M.; Tenorio, A. R.; Pappa, K.; Wynne, B.; Fettiplace, A.; Gartland, M.; Aboud, M.; Smith, K.; Cassetti, L.; David, D.; Figueras, L.; Losso, M.; Lopardo, G.; Lupo, S.; Porteiro, N.; Sanchez, M.; Bloch, M.; Cooper, D.; Finlayson, R.; Kelleher, A.; Koh, K.; Lewis, D.; Mcmahon, J.; Moore, R.; Roth, N.; Shields, M.; De Wit, S.; Florence, E.; Goffard, J. -C.; Demeester, R.; Lacor, P.; Vandercam, B.; Vandekerckhove, L.; Angel, J.; Baril, J. -G.; Conway, B.; De Pokomandy, A.; Szabo, J.; Walmsley, S.; Bouchaud, O.; Chidiac, C.; Delobel, P.; Goujard, C.; Katlama, C.; Molina, J. -M.; Pialoux, G.; Philibert, P.; Bogner, J.; Esser, S.; Krznaric, I.; Lehmann, C.; Spinner, C.; Stellbrink, H. -J.; Stephan, C.; Stoehr, A.; Barchi, E.; Caramello, P.; Castelli, F.; Cattelan, A. M.; D'Arminio Monforte, A.; Di Biagio, A.; Di Perri, G.; Gori, A.; Maggiolo, F.; Menzaghi, B.; Migliorino, G.; Mussini, C.; Penco, G.; Puoti, M.; Rizzardini, G.; Gulminetti, R.; Lazzarin, A.; Quirino, T.; Sighinolfi, L.; Viale, P.; Amaya Tapia, G.; Andrade Villanueva, J.; Granados Reyes, E. R.; Perez Rios, A.; Santoscoy Gomez, M.; Den Hollander, J.; Rijnders, B.; Hidalgo, J. A.; Hercilla Vasquez, L.; Illescas, L.; Olczak, A.; Mansinho, K.; Correia Pacheco, P. P.; Teofilo, E.; Saraiva da Cunha, J.; Sarmento e Castro, R.; Serrao, R.; Arbune, M.; Jianu, C.; Oprea, A.; Preotescu, L.; Prisacariu, L. -J.; Belonosova, E.; Borodkina, O.; Chernova, O.; Gankina, N.; Kizhlo, S.; Kulagin, V.; Kurina, N.; Nagimova, F.; Pokrovsky, V.; Ryamova, E.; Voronin, E.; Yakovlev, A.; Kaplan, R.; Lee, S. H.; Kim, S. -W.; Kim, S. -I.; Kim, W. J.; Antela Lopez, A.; Casado Osorio, J. L.; Castano Carracedo, M. A.; De Los Santos Gil, I.; Estrada Perez, V.; Falco Ferrer, V.; Force, L.; Galinda Puerto, M. J.; Garcia Deltoro, M.; Gatell, J. M.; Goenaga Sanchez, M. A.; Gonzalez Cordon, A.; Knobel, H.; Lopez Bernaldo de Quiros, J. C.; Losa Garcia, J. E.; Masia, M.; Montero-Alsonso, M.; Ocampo Hermida, A.; Pasquau Liano, J.; Portilla Sogorb, J.; Pulido Ortega, F.; Rivera Roman, A.; Santos Fernandez, J. R.; Torres Perea, R.; Troya Garcia, J.; Viciana Fernandez, P.; Calmy, A.; Hauser, C.; Fehr, J.; Cheng, S. -H.; Ko, W. -C.; Lin, H. -H.; Lu, P. -L.; Tseng, Y. -T.; Wang, N. -C.; Wong, W. -W.; Yang, C. -J.; Arduino, R.; Benson, P.; Berhe, M.; Bredeek, F.; Brinson, C.; Campbell, T.; Crofoot, G.; Cunningham, D.; Dejesus, E.; Dretler, R.; Eron, J.; Fife, K.; Fichtenbaum, C.; Flamm, J.; Goldstein, D.; Gupta, S.; Hagins, D.; Hoffman-Terry, M.; Jayaweera, D.; Kinder, C.; Klein, D.; Mcdonald, C.; Mills, A.; Nahass, R.; Osiyemi, O.; Overton, E.; Parks, D.; Prelutsky, D.; Ramgopal, M.; Schrader, S.; Sha, B.; Simon, G.; Sims, J.; Skiest, D.; Slim, J.; Tashima, K.; Thedinger, B.; Gazzard, B.; Fox, J.; Johnson, M.; Kegg, S.; Khoo, S.; Mazhude, C.; Orkin, C.; Schembri, G.; Ustianowski, A.
abstract

Background: Effective two-drug regimens could decrease long-term drug exposure and toxicity with HIV-1 antiretroviral therapy (ART). We therefore aimed to evaluate the efficacy and safety of a two-drug regimen compared with a three-drug regimen for the treatment of HIV-1 infection in ART-naive adults. Methods: We conducted two identically designed, multicentre, double-blind, randomised, non-inferiority, phase 3 trials: GEMINI-1 and GEMINI-2. Both studies were done at 192 centres in 21 countries. We included participants (≥18 years) with HIV-1 infection and a screening HIV-1 RNA of 500 000 copies per mL or less, and who were naive to ART. We randomly assigned participants (1:1) to receive a once-daily two-drug regimen of dolutegravir (50 mg) plus lamivudine (300 mg) or a once-daily three-drug regimen of dolutegravir (50 mg) plus tenofovir disoproxil fumarate (300 mg) and emtricitabine (200 mg). Both drug regimens were administered orally. We masked participants and investigators to treatment assignment: dolutegravir was administered as single-entity tablets (similar to its commercial formulation, except with a different film colour), and lamivudine tablets and tenofovir disoproxil fumarate and emtricitabine tablets were over-encapsulated to visually match each other. Primary endpoint was the proportion of participants with HIV-1 RNA of less than 50 copies per mL at week 48 in the intention-to-treat-exposed population, using the Snapshot algorithm and a non-inferiority margin of −10%. Safety analyses were done on the safety population. GEMINI-1 and GEMINI-2 are registered with ClinicalTrials.gov, numbers NCT02831673 and NCT02831764, respectively. Findings: Between July 18, 2016, and March 31, 2017, 1441 participants across both studies were randomly assigned to receive either the two-drug regimen (n=719) or three-drug regimen (n=722). At week 48 in the GEMINI-1 intention-to-treat-exposed population, 320 (90%) of 356 participants receiving the two-drug regimen and 332 (93%) of 358 receiving the three-drug regimen achieved plasma HIV-1 RNA of less than 50 copies per mL (adjusted treatment difference −2·6%, 95% CI −6·7 to 1·5); in GEMINI-2, 335 (93%) of 360 in the two-drug regimen and 337 (94%) of 359 in the three-drug regimen achieved HIV-1 RNA of less than 50 copies per mL (adjusted treatment difference −0·7%, 95% CI −4·3 to 2·9), showing non-inferiority at a −10% margin in both studies (pooled analysis: 655 [91%] of 716 in the two-drug regimen vs 669 [93%] of 717 in the three-drug regimen; adjusted treatment difference −1·7%, 95% CI −4·4 to 1·1). Numerically, more drug-related adverse events occurred with the three-drug regimen than with the two-drug regimen (169 [24%] of 717 vs 126 [18%] of 716); few participants discontinued because of adverse events (16 [2%] in the three-drug regimen and 15 [2%] in the two-drug regimen). Two deaths were reported in the two-drug regimen group of GEMINI-2, but neither was considered to be related to the study medication. Interpretation: The non-inferior efficacy and similar tolerability profile of dolutegravir plus lamivudine to a guideline-recommended three-drug regimen at 48 weeks in ART-naive adults supports its use as initial therapy for patients with HIV-1 infection. Funding: ViiV Healthcare.

2019 - Durability of different initial regimens in HIV-infected patients starting antiretroviral therapy with CD4+ counts <200 cells/mm3 and HIV-RNA >5 log10 copies/mL [Articolo su rivista]
Gianotti, N.; Lorenzini, P.; Cozzi-Lepri, A.; De Luca, A.; Madeddu, G.; Sighinolfi, L.; Pinnetti, C.; Santoro, C.; Meraviglia, P.; Mussini, C.; Antinori, A.; D'Arminio Monforte, A.; D'Arminio Monforte, A.; Andreoni, M.; Angarano, G.; Antinori, A.; Castelli, F.; Cauda, R.; Di Perri, G.; Galli, M.; Iardino, R.; Ippolito, G.; Lazzarin, A.; Perno, C. F.; Von Schloesser, F.; Viale, P.; D'Arminio Monforte, A.; Antinori, A.; Castagna, A.; Ceccherini-Silberstein, F.; Cozzi-Lepri, A.; Girardi, E.; Lo Caputo, S.; Mussini, C.; Puoti, M.; Andreoni, M.; Ammassari, A.; Antinori, A.; Balotta, C.; Bandera, A.; Bonfanti, P.; Bonora, S.; Borderi, M.; Calcagno, A.; Calza, L.; Capobianchi, M. R.; Castagna, A.; Ceccherini-Silberstein, F.; Cingolani, A.; Cinque, P.; Cozzi-Lepri, A.; D'Arminio Monforte, A.; De Luca, A.; Di Biagio, A.; Girardi, E.; Gianotti, N.; Gori, A.; Guaraldi, G.; Lapadula, G.; Lichtner, M.; Lo Caputo, S.; Madeddu, G.; Maggiolo, F.; Marchetti, G.; Marcotullio, S.; Monno, L.; Mussini, C.; Nozza, S.; Puoti, M.; Quiros Roldan, E.; Rossotti, R.; Rusconi, S.; Santoro, M. M.; Saracino, A.; Zaccarelli, M.; Cozzi-Lepri, A.; Fanti, I.; Galli, L.; Lorenzini, P.; Rodano, A.; Shanyinde, M.; Tavelli, A.; Carletti, F.; Carrara, S.; Di Caro, A.; Graziano, S.; Petrone, F.; Prota, G.; Quartu, S.; Truffa, S.; Giacometti, A.; Costantini, A.; Valeriani, C.; Angarano, G.; Monno, L.; Santoro, C.; Maggiolo, F.; Suardi, C.; Viale, P.; Donati, V.; Verucchi, G.; Castelli, F.; Quiros, E.; Minardi, C.; Quirino, T.; Abeli, C.; Manconi, P. E.; Piano, P.; Cacopardo, B.; Celesia, B.; Vecchiet, J.; Falasca, K.; Sighinolfi, L.; Segala, D.; Mazzotta, F.; Vichi, F.; Cassola, G.; Viscoli, C.; Alessandrini, A.; Bobbio, N.; Mazzarello, G.; Mastroianni, C.; Belvisi, V.; Bonfanti, P.; Caramma, I.; Chiodera, A.; Castelli, A. P.; Galli, M.; Lazzarin, A.; Rizzardini, G.; Puoti, M.; D'Arminio Monforte, A.; Ridolfo, A. L.; Piolini, R.; Castagna, A.; Salpietro, S.; Carenzi, L.; Moioli, M. C.; Tincati, C.; Marchetti, G.; Mussini, C.; Puzzolante, C.; Gori, A.; Lapadula, G.; Abrescia, N.; Chirianni, A.; Borgia, G.; Di Martino, F.; Maddaloni, L.; Gentile, I.; Orlando, R.; Baldelli, F.; Francisci, D.; Parruti, G.; Ursini, T.; Magnani, G.; Ursitti, M. A.; Cauda, R.; Andreoni, M.; Antinori, A.; Vullo, V.; Cristaudo, A.; Cingolani, A.; Baldin, G.; Cicalini, S.; Gallo, L.; Nicastri, E.; Acinapura, R.; Capozzi, M.; Libertone, R.; Savinelli, S.; Latini, A.; Cecchetto, M.; Viviani, F.; Mura, M. S.; Madeddu, G.; De Luca, A.; Rossetti, B.; Caramello, P.; Di Perri, G.; C Orofino, G.; Bonora, S.; Sciandra, M.; Bassetti, M.; Londero, A.; Pellizzer, G.; Manfrin, V.
abstract

Objectives: Our aim was to investigate the durability of different initial regimens in patients starting ART with CD4+ counts &lt;200 cells/mm(3) and HIV-RNA &gt;5 log(10) copies/mL.Methods: This was a retrospective study of HIV-infected patients prospectively followed in the ICONA cohort. Those who started ART with boosted protease inhibitors (bPIs), NNRTIs or integrase strand transfer inhibitors (InSTIs), with CD4+ &lt;200 cells/mm(3) and HIV-RNA &gt;5 log(10) copies/mL, were included. The primary endpoint was treatment failure (TF), a composite endpoint defined as virological failure (VF, first of two consecutive HIV-RNA &gt;50 copies/mL after 6 months of treatment), discontinuation of class of the anchor drug or death. Independent associations were investigated by Poisson regression analysis in a model including age, gender, mode of HIV transmission, CDC stage, HCV and HBV co-infection, pre-treatment HIV-RNA, CD4+ count and CD4+/CD8+ ratio, ongoing opportunistic disease, fibrosis FIB-4 index, estimated glomerular filtration rate, haemoglobin, platelets, neutrophils, calendar year of ART initiation, anchor drug class (treatment group) and nucleos(t)ide backbone.Results: A total of 1195 patients fulfilled the inclusion criteria: 696 started ART with a bPI, 315 with an InSTI and 184 with an NNRTI. During 2759 person-years of follow up, 642 patients experienced TF. Starting ART with bPIs [adjusted incidence rate ratio (aIRR) (95% CI) 1.62 (1.29-2.03) versus starting with NNRTIs; P &lt; 0.001] and starting ART with InSTIs [aIRR (95% CI) 0.68 (0.48-0.96) versus starting with NNRTIs; P = 0.03] were independently associated with TF.Conclusions: In patients starting ART with &lt;200 CD4+ cells/mm(3) and &gt;5 log10 HIV-RNA copies/mL, the durability of regimens based on InSTIs was longer than that of NNRTI- and bPI-based regimens.

2019 - Effectiveness of dolutegravir-based regimens as either first-line or switch antiretroviral therapy: data from the Icona cohort [Articolo su rivista]
Mondi, A.; Cozzi-Lepri, A.; Tavelli, A.; Rusconi, S.; Vichi, F.; Ceccherini-Silberstein, F.; Calcagno, A.; De Luca, A.; Maggiolo, F.; Marchetti, G.; Antinori, A.; d'Arminio Monforte, A.; Andreoni, M.; Castagna, A.; Castelli, F.; Cauda, R.; Di Perri, G.; Galli, M.; Iardino, R.; Ippolito, G.; Azzarin, A.; Rezza, G.; von Schloesser, F.; Viale, P.; Ceccherini-Silberstein, F.; Cozzi-Lepri, A.; Girardi, E.; Lo Caputo, S.; Mussini, C.; Puoti, M.; Perno, C. F.; Balotta, C.; Bandera, A.; Bonora, S.; Borderi, M.; Capetti, A.; Capobianchi, M. R.; Cicalini, S.; Cingolani, A.; Cinque, P.; Di Biagio, A.; Gianotti, N.; Gori, A.; Guaraldi, G.; Lapadula, G.; Lichtner, M.; Madeddu, G.; Maggiolo, F.; Monno, L.; Nozza, S.; Quiros Roldan, E.; Rossotti, R.; Rusconi, S.; Santoro, M. M.; Aracino, A.; Sarmati, L.; Fanti, I.; Galli, L.; Lorenzini, P.; Rodano', A.; Macchia, M.; Tavelli, A.; Carletti, F.; Carrara, S.; Di Caro, A.; Graziano, S.; Petrone, F.; Prota, G.; Quartu, S.; Truffa, S.; Giacometti, I. A.; Costantini, A.; Barocci, V.; Angarano, G.; Fabrizio, C.; Suardi, C.; I, V.; Verucchi, G.; Castelnuovo, F.; Minardi, C.; Menzaghi, B.; Abeli, C.; Cacopardo, B.; Celesia, B.; Vecchiet, J.; Falasca, K.; Pan, A.; Lorenzotti, S.; Sighinolfi, L.; Segala, D.; Blanc, P.; Cassola, G.; Viscoli, C.; Lessandrini, A.; Bobbio, N.; Mazzarello, G.; Pozzetto, I.; Bonfanti, P.; Molteni, C.; Chiodera, A.; Milini, P.; Nunnari, G.; Pellicano, G.; Rizzardini, G.; Bai, F.; Moioli, M. C.; Piolini, R.; Ridolfo, A. L.; Salpietro, S.; Tincati, C.; Puzzolante, C.; Migliorino, C.; Sangiovanni, V.; Borgia, G.; Esposito, V.; Di Martino, F.; Gentile, I.; Maddaloni, L.; Cattelan, A. M.; Marinello, S.; Cascio, A.; Colomba, C.; Baldelli, F.; Schiaroli, E.; Parruti, G.; Sozio, F.; Magnani, G.; Ursitti, M. A.; Cristaudo, A.; Vullo, V.; Acinapura, R.; Baldin, G.; Capozzi, M.; Rivano Capparucia, M.; Iaiani, G.; Atini, A.; Mastrorosa, I.; Plazzi, M. M.; Savinelli, S.; Vergori, A.; Cecchetto, M.; Viviani, F.; Bagella, P.; Rossetti, B.; Fontana Del Vecchio, R.; Francisci, D.; Di Giuli, C.; Caramello, P.; Orofino, G. C.; Sciandra, M.; Bassetti, M.; Ondero, A.; Pellizzer, G.; Manfrin, V.; Starnini, G.; Alungo, A.
abstract

Introduction: Concerns about dolutegravir (DTG) tolerability in the real-life setting have recently arisen. We aimed to estimate the risk of treatment discontinuation and virological failure of DTG-based regimens from a large cohort of HIV-infected individuals. Methods: We performed a multicentre, observational study including all antiretroviral therapy (ART)-naïve and virologically suppressed treatment-experienced (TE) patients from the Icona (Italian Cohort Naïve Antiretrovirals) cohort who started, for the first time, a DTG-based regimen from January 2015 to December 2017. We estimated the cumulative risk of DTG discontinuation regardless of the reason and for toxicity, and of virological failure using Kaplan–Meier curves. We used Cox regression model to investigate predictors of DTG discontinuation. Results: About 1679 individuals (932 ART-naïve, 747 TE) were included. The one- and two-year probabilities (95% CI) of DTG discontinuation were 6.7% (4.9 to 8.4) and 11.5% (8.7 to 14.3) for ART-naïve and 6.6% (4.6 to 8.6) and 7.6% (5.4 to 9.8) for TE subjects. In both ART-naïve and TE patients, discontinuations of DTG were mainly driven by toxicity with an estimated risk (95% CI) of 4.0% (2.6 to 5.4) and 2.5% (1.3 to 3.6) by one year and 5.6% (3.8 to 7.5) and 4.0% (2.4 to 5.6) by two years respectively. Neuropsychiatric events were the main reason for stopping DTG in both ART-naïve (2.1%) and TE (1.7%) patients. In ART-naïve, a concomitant AIDS diagnosis predicted the risk of discontinuing DTG for any reason (adjusted relative hazard (aRH)&nbsp;=&nbsp;3.38, p&nbsp;=&nbsp;0.001), whereas starting DTG in combination with abacavir (ABC) was associated with a higher risk of discontinuing because of toxicity (aRH&nbsp;=&nbsp;3.30, p&nbsp;=&nbsp;0.009). TE patients starting a DTG-based dual therapy compared to a triple therapy had a lower risk of discontinuation for any reason (adjusted hazard ratio (aHR)&nbsp;=&nbsp;2.50, p&nbsp;=&nbsp;0.037 for ABC-based triple-therapies, aHR&nbsp;=&nbsp;3.56, p&nbsp;=&nbsp;0.012 for tenofovir-based) and for toxicity (aHR&nbsp;=&nbsp;5.26, p&nbsp;=&nbsp;0.030 for ABC-based, aHR&nbsp;=&nbsp;6.60, p&nbsp;=&nbsp;0.024 for tenofovir-based). The one- and two-year probabilities (95% CI) of virological failure were 1.2% (0.3 to 2.0) and 4.6% (2.7 to 6.5) in the ART naïve group and 2.2% (1.0 to 3.3) and 2.9% (1.5 to 4.3) in the TE group. Conclusions: In this large cohort, DTG showed excellent efficacy and optimal tolerability both as first-line and switching ART. The low risk of treatment-limiting toxicities in ART-naïve as well as in treated individuals reassures on the use of DTG in everyday clinical practice.

2019 - Efficacy of Ceftazidime-Avibactam Salvage Therapy in Patients With Infections Caused by Klebsiella pneumoniae Carbapenemase-producing K. pneumoniae [Articolo su rivista]
Tumbarello, Mario; Trecarichi, Enrico Maria; Corona, Alberto; De Rosa, Francesco Giuseppe; Bassetti, Matteo; Mussini, Cristina; Menichetti, Francesco; Viscoli, Claudio; Campoli, Caterina; Venditti, Mario; De Gasperi, Andrea; Mularoni, Alessandra; Tascini, Carlo; Parruti, Giustino; Pallotto, Carlo; Sica, Simona; Concia, Ercole; Cultrera, Rosario; De Pascale, Gennaro; Capone, Alessandro; Antinori, Spinello; Corcione, Silvia; Righi, Elda; Losito, Angela Raffaella; Digaetano, Margherita; Amadori, Francesco; Giacobbe, Daniele Roberto; Ceccarelli, Giancarlo; Mazza, Ernestina; Raffaelli, Francesca; Spanu, Teresa; Cauda, Roberto; Viale, Pierluigi
abstract

Background: Ceftazidime-avibactam (CAZ-AVI) has been approved in Europe for the treatment of complicated intra-abdominal and urinary tract infections, as well as hospital-acquired pneumonia, and for gram-negative infections with limited treatment options. CAZ-AVI displays in vitro activity against Klebsiella pneumoniae carbapenemase (KPC) enzyme producers, but clinical trial data on its efficacy in this setting are lacking. Methods: We retrospectively reviewed 138 cases of infections caused by KPC-producing K. pneumoniae (KPC-Kp) in adults who received CAZ-AVI in compassionate-use programs in Italy. Case features and outcomes were analyzed, and survival was then specifically explored in the large subcohort whose infections were bacteremic. Results: The 138 patients started CAZ-AVI salvage therapy after a first-line treatment (median, 7 days) with other antimicrobials. CAZ-AVI was administered with at least 1 other active antibiotic in 109 (78.9%) cases. Thirty days after infection onset, 47 (34.1%) of the 138 patients had died. Thirty-day mortality among the 104 patients with bacteremic KPC-Kp infections was significantly lower than that of a matched cohort whose KPC-Kp bacteremia had been treated with drugs other than CAZ-AVI (36.5% vs 55.8%, P = .005). Multivariate analysis of the 208 cases of KPC-Kp bacteremia identified septic shock, neutropenia, Charlson comorbidity index ≥3, and recent mechanical ventilation as independent predictors of mortality, whereas receipt of CAZ-AVI was the sole independent predictor of survival. Conclusions: CAZ-AVI appears to be a promising drug for treatment of severe KPC-Kp infections, especially those involving bacteremia.

2019 - Establishing a hepatitis C continuum of care among HIV/hepatitis C virus-coinfected individuals in EuroSIDA [Articolo su rivista]
Amele, S.; Peters, L.; Sluzhynska, M.; Yakovlev, A.; Scherrer, A.; Domingo, P.; Gerstoft, J.; Viard, J. P.; Gisinger, M.; Flisiak, R.; Bhaghani, S.; Ristola, M.; Leen, C.; Jablonowska, E.; Wandeler, G.; Stellbrink, H.; Falconer, K.; D'Arminio Monforte, A.; Horban, A.; Rockstroh, J. K.; Lundgren, J. D.; Mocroft, A.; Losso, M.; Kundro, M.; Schmied, B.; Zangerle, R.; Karpov, I.; Vassilenko, A.; Mitsura, V. M.; Paduto, D.; Clumeck, N.; De Wit, S.; Delforge, M.; Florence, E.; Vandekerckhove, L.; Hadziosmanovic, V.; Begovac, J.; Machala, L.; Jilich, D.; Sedlacek, D.; Kronborg, G.; Benfield, T.; Katzenstein, T.; Pedersen, C.; Johansen, I. S.; Ostergaard, L.; Wiese, L.; Moller, N. F.; Nielsen, L. N.; Zilmer, K.; Smidt, J.; Aho, I.; Girard, P. -M.; Pradier, C.; Fontas, E.; Duvivier, C.; Behrens, G.; Degen, O.; Stefan, C.; Bogner, J.; Fatkenheuer, G.; Chkhartishvili, N.; Gargalianos, P.; Xylomenos, G.; Armenis, K.; Sambatakou, H.; Szlavik, J.; Gottfredsson, M.; Mulcahy, F.; Yust, I.; Turner, D.; Burke, M.; Shahar, E.; Hassoun, G.; Elinav, H.; Haouzi, M.; Elbirt, D.; Sthoeger, Z. M.; Esposito, R.; Mazeu, I.; Mussini, C.; Mazzotta, F.; Gabbuti, A.; Vullo, V.; Lichtner, M.; Zaccarelli, M.; Antinori, A.; Acinapura, R.; Plazzi, M.; Lazzarin, A.; Castagna, A.; Gianotti, N.; Galli, M.; Ridolfo, A.; Rozentale, B.; Uzdaviniene, V.; Matulionyte, R.; Staub, T.; Hemmer, R.; Reiss, P.; Reikvam, D. H.; Maeland, A.; Bruun, J.; Knysz, B.; Gasiorowski, J.; Inglot, M.; Bakowska, E.; Grzeszczuk, A.; Parczewski, M.; Maciejewska, K.; Aksak-Was, B.; Beniowski, M.; Mularska, E.; Smiatacz, T.; Gensing, M.; Kamerys, J.; Wojcik, K.; Mozer-Lisewska, I.; Caldeira, L.; Mansinho, K.; Maltez, F.; Radoi, R.; Oprea, C.; Panteleev, A.; Panteleev, O.; Trofimora, T.; Khromova, I.; Kuzovatova, E.; Borodulina, E.; Vdoushkina, E.; Jevtovic, D.; Tomazic, J.; Miro, J. M.; Laguno, M.; Martinez, E.; Garcia, F.; Blanco, J. L.; Martinez-Rebollar, M.; Mallolas, J.; Moreno, S.; Rodriguez, J. M.; Clotet, B.; Jou, A.; Paredes, R.; Tural, C.; Puig, J.; Bravo, I.; Gutierrez, M.; Mateo, G.; Sambeat, M. A.; Laporte, J. M.; Sonnerborg, A.; Treutiger, C. J.; Flamholc, L.; Weber, R.; Cavassini, M.; Calmy, A.; Furrer, H.; Battegay, M.; Schmid, P.; Kuznetsova, A.; Kyselyova, G.; Gazzard, B.; Johnson, A. M.; Simons, E.; Edwards, S.; Phillips, A.; Johnson, M. A.; Orkin, C.; Weber, J.; Scullard, G.; Clarke, A.; Rasmussen, L. D.; Svedhem, V.; Kowalska, J. D.; Guaraldi, G.; Kirk, O.; Bojesen, A.; Raben, D.; Kristensen, D.; Laut, K.; Larsen, J. F.; Podlekareva, D.; Nykjaer, B.; Cozzi-Lepri, A.; Pelchen-Matthews, A.
abstract

Objectives: The aim of the study was to establish a methodology for evaluating the hepatitis C continuum of care in HIV/hepatitis C virus (HCV)-coinfected individuals and to characterize the continuum in Europe on 1 January 2015, prior to widespread access to direct-acting antiviral (DAA) therapy. Methods: Stages included in the continuum were as follows: anti-HCV antibody positive, HCV RNA tested, currently HCV RNA positive, ever HCV RNA positive, ever received HCV treatment, completed HCV treatment, follow-up HCV RNA test, and cure. Sustained virological response (SVR) could only be assessed for those with a follow-up HCV RNA test and was defined as a negative HCV RNA result measured &gt; 12 or 24&nbsp;weeks after stopping treatment. Results: Numbers and percentages for the stages of the HCV continuum of care were as follows: anti-HCV positive (n&nbsp;=&nbsp;5173), HCV RNA tested (4207 of 5173; 81.3%), currently HCV RNA positive (3179 of 5173; 61.5%), ever HCV RNA positive (n&nbsp;=&nbsp;3876), initiated HCV treatment (1693 of 3876; 43.7%), completed HCV treatment (1598 of 3876; 41.2%), follow-up HCV RNA test to allow SVR assessment (1195 of 3876; 30.8%), and cure (629 of 3876; 16.2%). The proportion that achieved SVR was 52.6% (629 of 1195). There were significant differences between regions at each stage of the continuum (P&nbsp;&lt;&nbsp;0.0001). Conclusions: In the proposed HCV continuum of care for HIV/HCV-coinfected individuals, we found major gaps at all stages, with almost 20% of anti-HCV-positive individuals having no documented HCV RNA test and a low proportion achieving SVR, in the pre-DAA era.

2019 - Granulicatella adiacens and Abiotrophia defectiva Native Vertebral Osteomyelitis: Three Cases and Literature Review of Clinical Characteristics and Treatment Approach [Articolo su rivista]
Puzzolante, Cinzia; Cuomo, Gianluca; Meschiari, Marianna; Bedini, Andrea; Bonazza, Aurora; Venturelli, Claudia; Sarti, Mario; Mussini, Cristina
abstract

Granulicatella adiacens and Abiotrophia defectiva are an increasingly recognized cause of osteoarticular infections. We describe two cases of G. adiacens and one case of A. defectiva native vertebral osteomyelitis (NVO) and review all published cases. Nine cases of G. adiacens NVO and two cases of A. defectiva NVO were previously described. Patients were usually middle-aged men, and classical risk factors for NVO were present in half of the cases. Concomitant bacteremia was reported in 78.6% of cases, and concurrent infective endocarditis occurred in 36.4% of this sub-group of patients. Many different antibiotic schemes were recorded, with median treatment duration of 6weeks. In the most recent reports, glycopeptides represented the most frequent empirical therapy, possibly due to the increasing emergence of G. adiacens and A. defectiva penicillin-resistant strains. Stabilization surgery was rarely required (14.3% of cases), and clinical cure was generally achieved. In conclusion, Granulicatella spp. and Abiotrophia spp. NVO is rare but increasingly described. A total antibiotic course of six weeks seems to be appropriate for noncomplicated cases, and clinical outcome is generally favorable.

2019 - Impact of genotypic susceptibility score on cART outcomes during primary HIV infection [Articolo su rivista]
Giacomelli, A.; Fabbiani, M.; De Benedetto, I.; Nozza, S.; Foca, E.; Celesia, B. M.; Marchetti, G.; Mussini, C.; Antinori, A.; D'Ettorre, G.; Madeddu, G.; Bandera, A.; Muscatello, A.; Rusconi, S.
abstract

To assess the impact of genotypic susceptibility score (GSS) on combined antiretroviral therapy (cART) outcomes during primary HIV infection (PHI) we retrospectively enrolled patients with PHI diagnosed between 2008 and 2015 at 9/24 Italian Network ACuTe HIV InfectiON centers. One hundred-seventy-six patients were enrolled. Of these, 55 (32.9%) patients started with more than three drugs and 11 (7.2%) started with a GSS &lt; 3. Regimen's GSS (per 1 point increase) (adjusted odds ratio [aOR], 4.82; 95% confidence interval [CI], 1.62-14.28; P = .005) and baseline HIV-RNA (per 1 log10 increase) (aOR, 2.02; 95% CI, 1.09-3.73; P = .025) resulted associated with early cART initiation. In conclusion, regimen's GSS resulted to be associated to the time to cART initiation during PHI.

2019 - Is physician assessment of alcohol consumption useful in predicting risk of severe liver disease among people with HIV and HIV/HCV co-infection? [Articolo su rivista]
Shanyinde, M.; Girardi, E.; Puoti, M.; De Luca, A.; Sighinolfi, L.; Caterina, U. F.; Caramello, P.; Lampe, F. C.; D'Arminio Monforte, A.; Cozzi-Lepri, A.; Andreoni, M.; Angarano, G.; Antinori, A.; Castelli, F.; Cauda, R.; Di Perri, G.; Galli, M.; Iardino, R.; Ippolito, G.; Lazzarin, A.; Perno, C. F.; Von Schloesser, F.; Viale, P.; Castagna, A.; Ceccherini-Silberstein, F.; Caputo, S. L.; Mussini, C.; Ammassari, A.; Balotta, C.; Bandera, A.; Bonfanti, P.; Bonora, S.; Borderi, M.; Calcagno, A.; Calza, L.; Capobianchi, M. R.; Cingolani, A.; Cinque, P.; Di Biagio, A.; Gianotti, N.; Gori, A.; Guaraldi, G.; Lapadula, G.; Lichtner, M.; Madeddu, G.; Maggiolo, F.; Marchetti, G.; Marcotullio, S.; Monno, L.; Nozza, S.; Roldan, E. Q.; Rossotti, R.; Rusconi, S.; Santoro, M. M.; Saracino, A.; Zaccarelli, M.; Fanti, I.; Galli, L.; Lorenzini, P.; Rodano, A.; Tavelli, A.; Carletti, F.; Carrara, S.; Di Caro, A.; Graziano, S.; Petrone, F.; Prota, G.; Quartu, S.; Truffa, S.; Giacometti, A.; Costantini, A.; Valeriani, C.; Santoro, C.; Suardi, C.; Donati, V.; Verucchi, G.; Minardi, C.; Quirino, T.; Abeli, C.; Manconi, P. E.; Piano, P.; Cacopardo, B.; Celesia, B.; Vecchiet, J.; Falasca, K.; Segala, D.; Mazzotta, F.; Vichi, F.; Cassola, G.; Viscoli, C.; Alessandrini, A.; Bobbio, N.; Mazzarello, G.; Mastroianni, C.; Belvisi, V.; Caramma, I.; Chiodera, A.; Milini, P.; Rizzardini, G.; Ridolfo, A. L.; Piolini, R.; Salpietro, S.; Carenzi, L.; Moioli, M. C.; Tincati, C.; Puzzolante, C.; Abrescia, N.; Chirianni, A.; Borgia, G.; Orlando, R.; Di Martino, F.; Maddaloni, L.; Gentile, I.; Bonadies, G.; Cascio, A.; Colomba, C.; Baldelli, F.; Schiaroli, E.; Parruti, G.; Ursini, T.; Magnani, G.; Ursitti, M. A.; Vullo, V.; Cristaudo, A.; Baldin, G.; Cicalini, S.; Gallo, L.; Nicastri, E.; Acinapura, R.; Capozzi, M.; Libertone, R.; Savinelli, S.; Latini, A.; Iaiani, G.; Sulekova, L. F.; Cecchetto, M.; Viviani, F.; Mura, M. S.; Rossetti, B.; Francisci, D.; Di Giuli, C.; Orofino, G. C.; Sciandra, M.; Bassetti, M.; Londero, A.; Pellizzer, G.; Manfrin, V.
abstract

Background: Alcohol consumption is a known risk factor for liver disease in HIV-infected populations. Therefore, knowledge of alcohol consumption behaviour and risk of disease progression associated with hazardous drinking are important in the overall management of HIV disease. We aimed at assessing the usefulness of routine data collected on alcohol consumption in predicting risk of severe liver disease (SLD) among people living with HIV (PLWHIV) with or without hepatitis C infection seen for routine clinical care in Italy. Methods: We included PLWHIV from two observational cohorts in Italy (ICONA and HepaICONA). Alcohol consumption was assessed by physician interview and categorized according to the National Institute for Food and Nutrition Italian guidelines into four categories: abstainer; moderate; hazardous and unknown. SLD was defined as presence of FIB4 &gt; 3.25 or a clinical diagnosis of liver disease or liver-related death. Cox regression analysis was used to evaluate the association between level of alcohol consumption at baseline and risk of SLD. Results: Among 9542 included PLWHIV the distribution of alcohol consumption categories was: abstainers 3422 (36%), moderate drinkers 2279 (23%), hazardous drinkers 637 (7%) and unknown 3204 (34%). Compared to moderate drinkers, hazardous drinking was associated with higher risk of SLD (adjusted hazard ratio, aHR = 1.45; 95% CI: 1.03-2.03). After additionally controlling for mode of HIV transmission, HCV infection and smoking, the association was attenuated (aHR = 1.32; 95% CI: 0.94-1.85). There was no evidence that the association was stronger when restricting to the HIV/HCV co-infected population. Conclusions: Using a brief physician interview, we found evidence for an association between hazardous alcohol consumption and subsequent risk of SLD among PLWHIV, but this was not independent of HIV mode of transmission, HCV-infection and smoking. More efforts should be made to improve quality and validity of data on alcohol consumption in cohorts of HIV/HCV-infected individuals.

2019 - Italian expert panel consensus statements on two-drug antiretroviral regimens to treat naïve and virologically suppressed HIV-1 infected patients [Articolo su rivista]
Antinori, Andrea;  , ; Santoro, Maria Mercedes; Gagliardini, Roberta;  , ; Marchetti, Giulia;  , ; Mondi, Annalisa;  , ; Cento, Valeria;  , ; Perno, Carlo Federico;  , ; Andreoni, Massimo;  , ; Ceccherini-Silberstein, Francesca;  , ; Cossarizza, Andrea;  , ; Clerici, Mario;  , ; Monforte, Antonella D'Arminio;  , ; Luca, Andrea;  , ; Di Biagio, Antonio;  , ; Di Perri, Giovanni;  , ; Galli, Massimo;  , ; Girardi, E.  ;  , ; Gori, Andrea;  , ; Lazzarin, Adriano;  , ; Lichtner, Miriam;  , ; Lo Caputo, Sergio;  , ; Madeddu, Giordano;  , ; Maggiolo, Franco;  , ; Mussini, Cristina;  , ; Re, Maria Carla;  , ; Ripamonti, Diego;  , ; Rizzardini, Giuliano;  , ; Zazzi, Maurizio
abstract

New strategies for HIV treatment able to reduce drug-exposure, medium-long term toxicities and costs are a recognized clinical need. The availability of newer drugs with improved potency and tolerability, as well as high genetic barrier to resistance, makes antiretroviral-sparing strategies with two-drug regimens (2DRs) particularly attractive. Substantial evidence has been generated over the last few years supporting 2DR in virologically suppressed HIV infected patients for whom a therapy switch is planned. More recently, very promising data on 2DR in naïve patients have also been reported. The main purpose of this consensus is to provide an overview of guideline indications and recommendations, and the most recent data from clinical studies of 2DR in both naïve and virologically suppressed patients. As an expert consensus, suggestions and indications on the use and management of 2DR are also provided.

2019 - Local Epidemics Gone Viral: Evolution and Diffusion of the Italian HIV-1 Recombinant Form CRF60_BC [Articolo su rivista]
Lai, Alessia; Simonetti, Francesco Roberto; Brindicci, Gaetano; Bergna, Annalisa; Di Giambenedetto, Simona; Sterrantino, Gaetana; Mussini, Cristina; Menzo, Stefano; Bagnarelli, Patrizia; Zazzi, Maurizio; Angarano, Gioacchino; Galli, Massimo; Monno, Laura; Balotta, Claudia
abstract

The molecular epidemiology of HIV-1 in Italy is becoming increasingly complex, mainly due to the spread of non-B subtypes and the emergence of new recombinant forms. We previously characterized the outbreak of the first Italian circulating recombinant form (CRF6O_BC), occurring among young MSM living in Apulia between the years 2009 and 2011. Here we show a 5-year follow-up surveillance to trace the evolution of CRF6O_BC and to investigate its further spread in Italy. We collected additional sequences and clinical data from patients harboring CRF6O_BC, enrolled at the Infectious Diseases Clinic of the University of Bari. In addition to the 24 previously identified sequences, we retrieved 27 CRF6O_BC sequences from patients residing in Apulia, whose epidemiological and clinical features did not differ from those of the initial outbreak, i.e., the Italian origin, young age at HIV diagnosis (median: 24 years; range: 18-37), MSM risk factor (23/25, 92%) and recent infection (from 2008 to 2017). Sequence analysis revealed a growing overall nucleotide diversity, with few nucleotide changes that were fixed over time. Twenty-seven additional sequences were detected across Italy, spanning multiple distant regions. Using a BLAST search, we also identified a CRF6O_BC sequence isolated in United Kingdom in 2013. Three patients harbored a unique second generation recombinant form in which CRF6O_BC was one of the parental strains. Our data show that CRF6O_BC gained epidemic importance, spreading among young MSM in multiple Italian regions and increasing its population size in few years, as the number of sequences identified so far has triplicated since our first report. The observed further divergence of CRF6O_BC is likely due to evolutionary bottlenecks and host adaptation during transmission chains. Of note, we detected three second-generation recombinants, further supporting a widespread circulation of CRF6O_BC and the increasing complexity of the HIV-1 epidemic in Italy.

2019 - Long-term data on the efficacy and tolerability of lamivudine plus dolutegravir as a switch strategy in a multi-centre cohort of HIV-1-infected, virologically suppressed patients [Articolo su rivista]
Baldin, Gianmaria; Ciccullo, Arturo; Rusconi, Stefano; Capetti, Amedeo; Sterrantino, Gaetana; Colafigli, Manuela; d'Ettorre, Gabriella; Giacometti, Andrea; Cossu, Maria Vittoria; Borghetti, Alberto; Gennari, William; Mussini, Cristina; Borghi, Vanni; Di Giambenedetto, Simona
abstract

Results from clinical trials and observational studies suggest that lamivudine plus dolutegravir (3TC+DTG) could be an effective and tolerated option for simplification in human immunodeficiency virus (HIV)-1-positive patients.

2019 - Low compliance with hepatocellular carcinoma screening guidelines in hepatitis B/C virus co-infected HIV patients with cirrhosis [Articolo su rivista]
Willemse, S.; Smit, C.; Sogni, P.; Sarcletti, M.; Uberti-Foppa, C.; Wittkop, L.; Raben, D.; D'Arminio Monforte, A.; Dabis, F.; Van Der Valk, M.; Judd, A.; Zangerle, R.; Touloumi, G.; Warszawski, J.; Meyer, L.; Murielle, M.; Ghosn, J.; Leport, C.; Reiss, P.; Wit, F.; Prins, M.; Bucher, H.; Gibb, D.; Fatkenheuer, G.; Obel, N.; Thorne, C.; Mocroft, A.; Kirk, O.; Stephan, C.; Perez-Hoyos, S.; Hamouda, O.; Clinsurv, G.; Bartmeyer, B.; Chkhartishvili, N.; Noguera-Julian, A.; Antinori, A.; Brockmeyer, N.; Prieto, L.; Pablo, R.; Soriano-Arandes, A.; Battegay, M.; Kouyos, R.; Mussini, C.; Tookey, P.; Casabona, J.; Miro, J. M.; Castagna, A.; Konopnick, D.; Goetghebuer, T.; Sonnerborg, A.; Torti, C.; Sabin, C.; Teira, R.; Garrido, M.; Haerry, D.; Stephane, D.; Jose, M.; Costagliola, D.; Raffaele, S.; Julia, D.; Chene, G.; Barger, D.; Schwimmer, C.; Termote, M.; Campbell, M.; Frederiksen, C. M.; Friis-Moller, N.; Kjaer, J.; Bohlius, J.; Bouteloup, V.; Cozzi-Lepri, A.; Davies, M. -A.; Dorrucci, M.; Dunn, D.; Egger, M.; Furrer, H.; Guiguet, M.; Grabar, S.; Lambotte, O.; Leroy, V.; Lodi, S.; Matheron, S.; Jose, M.; Monge, S.; Nakagawa, F.; Paredes, R.; Phillips, A.; Puoti, M.; Rohner, E.; Schomaker, M.; Sterne, J.; Thiebaut, R.
abstract

2019 - Migration and health: A retrospective study about the prevalence of HBV, HIV, HCV, tuberculosis and syphilis infections amongst newly arrived migrants screened at the Infectious Diseases Unit of Modena, Italy [Articolo su rivista]
Cuomo, Gianluca; Franconi, Iacopo; Riva, Nicoletta; Bianchi, Alessandro; Digaetano, Margherita; Santoro, Antonella; Codeluppi, Mauro; Bedini, Andrea; Guaraldi, Giovanni; Mussini, Cristina
abstract

Introduction Aim of the study is to evaluate the prevalence of HBV, HIV, HCV, tuberculosis and syphilis infection among immigrants assigned to the immigrant centre of the province of Modena. Methods At the time of arrival all immigrant were tested for: HBsAg, HBsAb, HBcAb, Ag p24/HIVAb, HCVAb, RPR, TPPA, Mantoux test (&gt;10 mm diameter of induration was considered to be positive), Chest X-rays. In case of positive samples, second level tests were performed (HbeAg, HBeAb, HDVAb, and baseline management and treatment of the infection detected). Results A total of 304 immigrant people were enrolled in the study. HBsAg positivity was 12.2%, HCVAb 3.3%, HIVAb 1.6%, TPPA + RPR positivity in the 0.7%; 10.2% had a positive Mantoux test; 5.6% had Chest X-rays positive for signs of infection and 6 patients had an active tuberculosis. 83.8% HBsAg were HBeAb positive/HBeAg negative. HDVAb resulted positive in 1 patient (2.7%). Previous HBV infection was detected in 28.6% of cases, isolated HBcAb in 2.3%; 5.6% of patients resulted to be positive to HbsAb alone (probable vaccinated). Conclusion Our study confirms the high prevalence of HBsAg positivity and latent tuberculosis among immigrants, underlying the importance of screening for infections in this special population.

2019 - Molecular Imaging of Vascular Calcification with 18 F-Sodium-Fluoride in Patients Infected with Human Immunodeficiency Virus [Articolo su rivista]
Raggi, Paolo; Prandini, Napoleone; Ligabue, Guido; Braglia, Giovanni; Esposito, Francesco; Milic, Jovana; Malagoli, Andrea; Scaglioni, Riccardo; Besutti, Giulia; Beghetto, Barbara; Nardini, Giulia; Roncaglia, Enrica; Mussini, Cristina; Guaraldi, Giovanni
abstract

18F-Sodium Fluoride (NaF) accumulates in areas of active hydroxyapatite deposition and potentially unstable atherosclerotic plaques. We assessed the presence of atherosclerotic plaques in 50 adult patients with HIV (HIV+) who had undergone two cardiac computed tomography scans to measure coronary artery calcium (CAC) progression. CAC and its progression are predictive of an unfavorable prognosis. Tracer uptake was quantified in six arterial territories: aortic arch, innominate carotid artery, right and left internal carotid arteries, left coronary (anterior descending and circumflex) and right coronary artery. Thirty-one patients showed CAC progression and 19 did not. At least one territory with high NaF uptake was observed in 150 (50%) of 300 arterial territories. High NaF uptake was detected more often in non-calcified than calcified areas (68% vs. 32%), and in patients without than in those with prior CAC progression (68% vs. 32%). There was no correlation between clinical and demographic variables and NaF uptake. In clinically stable HIV+ patients, half of the arterial territories showed a high NaF uptake, often in the absence of macroscopic calcification. NaF uptake at one time point did not correlate with prior progression of CAC. Prospective studies will demonstrate the prognostic significance of high NaF uptake in HIV+ patients.

2019 - Mortality in Patients With Septic Shock by Multidrug Resistant Bacteria: Risk Factors and Impact of Sepsis Treatments [Articolo su rivista]
Busani, Stefano; Serafini, Giulia; Mantovani, Elena; Venturelli, Claudia; Giannella, Maddalena; Viale, Pierluigi; Mussini, Cristina; Cossarizza, Andrea; Girardis, Massimo
abstract

Background: Patients with septic shock by multidrug resistant (MDR) microorganism maybe considered a specific population of critical patients at very high risk of death in whom the effects of standard sepsis treatment has never been assessed. The objective of this retrospective analysis was to evaluate the risk factors for 30-day mortality and the impact of sepsis management in patients with septic shock caused by MDR bacteria. Methods: Patients with septic shock by MDR bacteria admitted to the mixed intensive care unit (ICU) of Modena University Hospital during a 6-year period were studied. The clinical and microbiological characteristics and sepsis treatments provided were analyzed and compared between survivors (S) and nonsurvivors (NS) at 30 days after septic shock appearance. Results: Ninety-four patients were studied. All therapeutic interventions applied to patients during their ICU stay did not show statistical significance between S and NS groups, except for administration of immunoglobulin M (IgM) preparation which were provided more frequently in S group (P &lt;.05). At the multivariate adjusted analysis, preexisting cancer (odds ratio [OR] = 2.965) and Acinetobacter baumannii infections (OR = 3.197) were independently correlated with an increased risk of 30-day mortality, whereas treatment with IgM preparation was protective (OR = 0.283). Conclusions: This retrospective study showed that in patients with septic shock caused by MDR bacteria, history of cancer and infection sustained by A baumannii increase the risk of mortality and that standard sepsis treatments do not seem to provide any protective effect. Adjunctive therapy with IgM preparation seems to be beneficial, but further appropriate studies are needed to confirm the results observed.

2019 - Optimization strategies for HIV, hepatitis and syphilis testing in Infectious Disease Clinic and Dermatology Unit of Modena: 7-year results of collaboration experience [Articolo su rivista]
Mandel, Victor Desmond; Di Tullio, Francesca; Rugge, Walter; Coppini, Maurizio; Mussini, Cristina; Pellacani, Giovanni; Borghi, Vanni
abstract

Background: Screening tests for human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV) and syphilis infections performed in at-risk population show a higher number of positive tests compared to those carried out in the general population. 'Test &amp; Counselling' Ambulatory of Infectious Disease Clinic (T&amp;C-IDC) and Sexually Transmitted Diseases Ambulatory of Dermatology Unit (STDs-DU) of Modena began collaboration in 2010 and adopted a common diagnostic serological profile since 2013. Objectives: The main objective was to analyse the number of screening tests performed in the T&amp;C-IDC and STDs-DU, comparing the results obtained after the adoption of the shared protocol with the previous period. The secondary aim was to evaluate the linkage to care of newly diagnosed patients. Methods: Consecutive patients referred to the T&amp;C-IDC and STDs-DU from January 2010 to December 2016, with at least one performed screening test for HIV, HBV, HCV and syphilis were enrolled. Referral of patients with a new infection was obtained by capture-recapture methods in hospital databases. Results: During the 7-year observation, we collected 13 117 admittances for 9154 patients. A significant increase in the number of screening tests (P &lt; 0.001) and ratio between tests and admissions (P = 0.002) was observed. A total of 644 (7.0%) people with at least one infection were diagnosed. Among these, the most common was syphilis (41.9%), followed by HBV (25.7%), HCV (21.4%) and HIV (10.9%). Syphilis occurred predominantly in Italians (72.5%) and males (75.7%), as like as HCV, while foreign-born (85.5%) mainly harboured HBV infection. HIV diagnosis was detected more frequently among males (67.1%) with a similar proportion between Italians and foreign-born. Five hundred and forty-three out of 644 (84.3%) patients were linked to care. Conclusion: The collaboration between T&amp;C-IDC and STDs-DU has proven to work well increasing the diagnosis over the time and obtaining good results in linkage to care.

2019 - Pneumocystosis as a Complication of H1N1 Influenza A Infection in an HIV-Positive Patient on Effective cART [Articolo su rivista]
Franconi, Iacopo; Monari, Caterina; Tutone, Marco; Ciusa, Giacomo; Corradi, Luca; Franceschini, Erica; Meschiari, Marianna; Puzzolante, Cinzia; Gennari, William; Pecorari, Monica; Guaraldi, Giovanni; Mussini, Cristina
abstract

H1N1 influenza A virus can affect the immune system, causing lymphopenia. This might be of great concern for HIV individuals undergoing effective antireroviral therapy (cART). We report the first confirmed case of H1N1-induced AIDS and Pneumocystis jiroveci pneumonia in an HIV-positive woman on effective cART since 2006.

2019 - Prevalence of acquired resistance mutations in a large cohort of perinatally infected HIV-1 patients [Articolo su rivista]
Ungaro, R.; Taramasso, L.; Bruzzone, B.; Vicenti, I.; Galli, L.; Borghi, V.; Francisci, D.; Pecorari, Monica; Zoncada, A.; Callegaro, A. P.; Paolini, E.; Monno, L.; Bonora, S.; Di Biagio, A.; Giacometti, A.; Butini, L.; del Gobbo, R.; Bagnarelli, P.; Tacconi, D.; Corbelli, G.; Zanussi, S.; Monno, L.; Punzi, G.; Maggiolo, F.; Calza, L.; Carla Re, M.; Pristera, R.; Turconi, P.; Mandas, A.; Tini, S.; Zoncada, A.; Paolini, E.; Amadio, G.; Sighinolfi, L.; Corsi, P.; Galli, L.; Di Pietro, M.; Colao, G.; Tosti, A.; Setti, M.; Bruzzone, B.; Cenderello, G.; Trezzi, M.; Orani, A.; Arcidiacono, I.; Degiuli, A.; De Gennaro, M.; Chiodera, A.; Scalzini, A.; Palvarini, L.; Todaro, G.; Rusconi, S.; Gismondo, M. R.; Micheli, V.; Biondi, M. L.; Capetti, A.; Meraviglia, P.; Boeri, E.; Mussini, C.; Pecorari, M.; Soria, A.; Vecchi, L.; Santirocchi, M.; Brustia, D.; Ravanini, P.; Dal Bello, F.; Romano, N.; Mancuso, S.; Calzetti, C.; Maserati, R.; Filice, G.; Baldanti, F.; Parruti, G.; Polilli, E.; Sacchini, D.; Martinelli, C.; Consolini, R.; Vatteroni, L.; Vivarelli, A.; Nerli, A.; Lenzi, L.; Magnani, G.; Ortolani, P.; Andreoni, M.; Fimiani, C.; Palmisano, L.; Di Giambenedetto, S.; Vullo, V.; Turriziani, O.; Montano, M.; Antinori, A.; Zaccarelli, M.; Dentone, C.; Gonnelli, A.; De Luca, A.; Palumbo, M.; Ghisetti, V.; Bonora, S.; Delle Foglie, P.; Rossi, C.; Mondino, V.; Malena, M.; Grossi, P.; Seminari, E.; Poletti, F.
abstract

2019 - Reply to De Greef et al. on "Should we treat bacteremic prostatitis for 7 days?" [Articolo su rivista]
Yahav, Dafna; Mussini, Cristina; Leibovici, Leonard; Paul, Mical
abstract

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2019 - Reply to MacFadden and Hanage and to Pallett et al [Articolo su rivista]
Paul, M.; Yahav, D.; Mussini, C.; Leibovici, L.
abstract

2019 - Rhodococcus equi Pneumonia in Kidney Transplant Recipient Affected by Acute Intermittent Porphyria: A Case Report [Articolo su rivista]
Alfano, G.; Ventura, P.; Fontana, F.; Marcacci, M.; Ligabue, G.; Scarlini, S.; Franceschini, E.; Codeluppi, M.; Guaraldi, G.; Mussini, C.; Cappelli, G.
abstract

Rhodococcus equi is a gram-positive coccobacillus responsible for severe infections in patients with weakened immune systems. R equi generally causes pnumonia that may evolve into fatal systemic infection if left untreated. Here, we present a case of a 67-year-old woman affected by acute intermittent porphyria (AIP) who developed R equi pneumonia 7 months after kidney transplant. Although clinical features at presentation were nonspecific, lung computed tomography showed right perihilar consolidation with a mass-like appearance causing bronchial obstruction. Appropriate antibiotic including intravenous meropenem and oral azithromycin that was then switched to oral levofloxacin and oral azithromycin along with reduction of immunosuppressive therapy resolved pneumonia without provoking an acute attack of porphyria. AIP limited the choice of antibiotics for the treatment of R equi infection because some potentially porphyrinogenic antibacterial agents were avoided. Based on this experience, azithromycin and meropenem can be safely administered for the treatment of R Equi infection in patients with AIP.

2019 - Risk factors for treatment failure and mortality among hospitalized patients with complicated urinary tract infection: A multicenter retrospective cohort study (RESCUING study group) [Articolo su rivista]
Eliakim-Raz, N.; Babitch, T.; Shaw, E.; Addy, I.; Wiegand, I.; Vank, C.; Torre-Vallejo, L.; Joan-Miquel, V.; Steve, M.; Grier, S.; Stoddart, M.; Nienke, C.; Leo, V. D. H.; Vuong, C.; MacGowan, A.; Carratala, J.; Leibovici, L.; Pujol, M.; Tancheva, D.; Vatcheva-Dobrevska, R.; Tsiodras, S.; Roilides, E.; Varkonyi, I.; Bodnar, J.; Farkas, A.; Zak-Doron, Y.; Carmeli, Y.; Mangoni, E. D.; Mussini, C.; Petrosillo, N.; Vata, A.; Hristea, A.; Origuen, J.; Rodriguez-Bano, J.; Yetkin, A.; Saltoglu, N.
abstract

Background. Complicated urinary tract infections (cUTIs) are responsible for a major share of all antibiotic consumption in hospitals. We aim to describe risk factors for treatment failure and mortality among patients with cUTIs. Methods. A multinational, multicentre retrospective cohort study, conducted in 20 countries in Europe and the Middle East. Data were collected from patients' files on hospitalised patients with a diagnosis of cUTI during 2013-2014. Primary outcome was treatment failure, secondary outcomes included 30 days all-cause mortality,among other outcomes. Multivariable analysis using a logistic model and the hospital as a random variable was performed to identify independent predictors for these outcomes. Results. A total of 981 patients with cUTI were included. Treatment failure was observed in 26.6% (261/981), all cause 30-day mortality rate was 8.7% (85/976), most of these in patients with catheter related UTI (CaUTI). Risk factors for treatment failure in multivariable analysis were ICU admission (OR 5.07, 95% CI 3.18-8.07), septic shock (OR 1.92, 95% CI 0.93-3.98), corticosteroid treatment (OR 1.92, 95% CI 1.12-3.54), bedridden (OR 2.11, 95%CI 1.4-3.18), older age (OR 1.02, 95% CI 1.0071.03-), metastatic cancer (OR 2.89, 95% CI 1.46-5.73) and CaUTI (OR 1.48, 95% CI 1.04-2.11). Management variables, such as inappropriate empirical antibiotic treatment or days to starting antibiotics were not associated with treatment failure or 30-day mortality. More patients with pyelonephritis were given appropriate empirical antibiotic therapy than other CaUTI [110/171; 64.3% vs. 116/270; 43%, p &lt;0.005], nevertheless, this afforded no advantage in treatment failure rates nor mortality in these patients. Conclusions. In patients with cUTI we found no benefit of early appropriate empirical treatment on survival rates or other outcomes. Physicians might consider supportive treatment and watchful waiting in stable patients until the causative pathogen is defined.

2019 - Risk of HIV transmission through condomless sex in serodifferent gay couples with the HIV-positive partner taking suppressive antiretroviral therapy (PARTNER): final results of a multicentre, prospective, observational study [Articolo su rivista]
Rodger, A. J.; Cambiano, V.; Phillips, A. N.; Bruun, T.; Raben, D.; Lundgren, J.; Vernazza, P.; Collins, S.; Degen, O.; Corbelli, G. M.; Estrada, V.; Geretti, A. M.; Beloukas, A.; Beloukas, A.; Coll, P.; Antinori, A.; Nwokolo, N.; Rieger, A.; Prins, J. M.; Blaxhult, A.; Weber, R.; Van Eeden, A.; Brockmeyer, N. H.; Clarke, A.; del Romero Guerrero, J.; Raffi, F.; Bogner, J. R.; Wandeler, G.; Gerstoft, J.; Gutierrez, F.; Brinkman, K.; Kitchen, M.; Ostergaard, L.; Leon, A.; Ristola, M.; Jessen, H.; Stellbrink, H. -J.; Coll, P.; Cobarsi, P.; Nieto, A.; Meulbroek, M.; Carrillo, A.; Saz, J.; Guerrero, J. D. R.; Garcia, M. V.; Gutierrez, F.; Masia, M.; Robledano, C.; Leon, A.; Leal, L.; Redondo, E. G.; Estrada, V. P.; Marquez, R.; Sandoval, R.; Viciana, P.; Espinosa, N.; Lopez-Cortes, L.; Podzamczer, D.; Tiraboschi, J.; Morenilla, S.; Antela, A.; Losada, E.; Nwokolo, N.; Sewell, J.; Clarke, A.; Kirk, S.; Knott, A.; Rodger, A. J.; Fernandez, T.; Gompels, M.; Jennings, L.; Ward, L.; Fox, J.; Lwanga, J.; Lee, M.; Gilson, R.; Leen, C.; Morris, S.; Clutterbuck, D.; Brady, M.; Asboe, D.; Fedele, S.; Fidler, S.; Brockmeyer, N.; Potthoff, A.; Skaletz-Rorowski, A.; Bogner, J.; Seybold, U.; Roider, J.; Jessen, H.; Jessen, A.; Ruzicic, S.; Stellbrink, H. -J.; Kummerle, T.; Lehmann, C.; Degen, O.; Bartel, S.; Hufner, A.; Rockstroh, J.; Mohrmann, K.; Boesecke, C.; Krznaric, I.; Ingiliz, P.; Weber, R.; Grube, C.; Braun, D.; Gunthard, H.; Wandeler, G.; Furrer, H.; Rauch, A.; Vernazza, P.; Schmid, P.; Rasi, M.; Borso, D.; Stratmann, M.; Caviezel, O.; Stoeckle, M.; Battegay, M.; Tarr, P.; Christinet, V.; Jouinot, F.; Isambert, C.; Bernasconi, E.; Bernasconi, B.; Gerstoft, J.; Jensen, L. P.; Bayer, A. A.; Ostergaard, L.; Yehdego, Y.; Bach, A.; Handberg, P.; Kronborg, G.; Pedersen, S. S.; Bulow, N.; Ramskover, B.; Ristola, M.; Debnam, O.; Sutinen, J.; Blaxhult, A.; Ask, R.; Hildingsson-Lundh, B.; Westling, K.; Frisen, E. -M.; Cortney, G.; O'Dea, S.; De Wit, S.; Necsoi, C.; Vandekerckhove, L.; Goffard, J. -C.; Henrard, S.; Prins, J.; Nobel, H. -H.; Weijsenfeld, A.; Van Eeden, A.; Elsenburg, L.; Brinkman, K.; Vos, D.; Hoijenga, I.; Gisolf, E.; Van Bentum, P.; Verhagen, D.; Raffi, F.; Billaud, E.; Ohayon, M.; Gosset, D.; Fior, A.; Pialoux, G.; Thibaut, P.; Chas, J.; Leclercq, V.; Pechenot, V.; Coquelin, V.; Pradier, C.; Breaud, S.; Touzeau-Romer, V.; Rieger, A.; Kitchen - Maria Geit, M.; Sarcletti, M.; Gisinger, M.; Oellinger, A.; Menichetti, S.; Bini, T.; Mussini, C.; Meschiari, M.; Di Biagio, A.; Taramasso, L.; Celesia, B. M.; Gussio, M.; Janeiro, N.
abstract

Background: The level of evidence for HIV transmission risk through condomless sex in serodifferent gay couples with the HIV-positive partner taking virally suppressive antiretroviral therapy (ART) is limited compared with the evidence available for transmission risk in heterosexual couples. The aim of the second phase of the PARTNER study (PARTNER2) was to provide precise estimates of transmission risk in gay serodifferent partnerships. Methods: The PARTNER study was a prospective observational study done at 75 sites in 14 European countries. The first phase of the study (PARTNER1; Sept 15, 2010, to May 31, 2014) recruited and followed up both heterosexual and gay serodifferent couples (HIV-positive partner taking suppressive ART) who reported condomless sex, whereas the PARTNER2 extension (to April 30, 2018) recruited and followed up gay couples only. At study visits, data collection included sexual behaviour questionnaires, HIV testing (HIV-negative partner), and HIV-1 viral load testing (HIV-positive partner). If a seroconversion occurred in the HIV-negative partner, anonymised phylogenetic analysis was done to compare HIV-1 pol and env sequences in both partners to identify linked transmissions. Couple-years of follow-up were eligible for inclusion if condomless sex was reported, use of pre-exposure prophylaxis or post-exposure prophylaxis was not reported by the HIV-negative partner, and the HIV-positive partner was virally suppressed (plasma HIV-1 RNA &lt;200 copies per mL) at the most recent visit (within the past year). Incidence rate of HIV transmission was calculated as the number of phylogenetically linked HIV infections that occurred during eligible couple-years of follow-up divided by eligible couple-years of follow-up. Two-sided 95% CIs for the incidence rate of transmission were calculated using exact Poisson methods. Findings: Between Sept 15, 2010, and July 31, 2017, 972 gay couples were enrolled, of which 782 provided 1593 eligible couple-years of follow-up with a median follow-up of 2·0 years (IQR 1·1–3·5). At baseline, median age for HIV-positive partners was 40 years (IQR 33–46) and couples reported condomless sex for a median of 1·0 years (IQR 0·4–2·9). During eligible couple-years of follow-up, couples reported condomless anal sex a total of 76 088 times. 288 (37%) of 777 HIV-negative men reported condomless sex with other partners. 15 new HIV infections occurred during eligible couple-years of follow-up, but none were phylogenetically linked within-couple transmissions, resulting in an HIV transmission rate of zero (upper 95% CI 0·23 per 100 couple-years of follow-up). Interpretation: Our results provide a similar level of evidence on viral suppression and HIV transmission risk for gay men to that previously generated for heterosexual couples and suggest that the risk of HIV transmission in gay couples through condomless sex when HIV viral load is suppressed is effectively zero. Our findings support the message of the U=U (undetectable equals untransmittable) campaign, and the benefits of early testing and treatment for HIV. Funding: National Institute for Health Research.

2019 - Seven versus fourteen Days of Antibiotic Therapy for uncomplicated Gram-negative Bacteremia: a Non-inferiority Randomized Controlled Trial [Articolo su rivista]
Yahav, Dafna; Franceschini, Erica; Koppel, Fidi; Turjeman, Adi; Babich, Tanya; Bitterman, Roni; Neuberger, Ami; Ghanem-Zoubi, Nesrin; Santoro, Antonella; Eliakim-Raz, Noa; Pertzov, Barak; Steinmetz, Tali; Stern, Anat; Dickstein, Yaakov; Maroun, Elias; Zayyad, Hiba; Bishara, Jihad; Alon, Danny; Edel, Yonatan; Goldberg, Elad; Venturelli, Claudia; Mussini, Cristina; Leibovici, Leonard; Paul, Mical
abstract

Gram-negative bacteremia is a major cause of morbidity and mortality in hospitalized patients. Data to guide the duration of antibiotic therapy are limited.

2019 - The Interplay Between Age and Frailty in People Living With HIV: Results From an 11-Year Follow-up Observational Study [Articolo su rivista]
Guaraldi, Giovanni; De Francesco, Davide; Milic, Jovana; Franconi, Iacopo; Mussini, Cristina; Falutz, Julian; Cesari, Matteo
abstract

Between 2006 and 2017, frailty prevalence decreased in HIV-positive individuals aged 50 years but presented a 3-fold increase among those 75 years of age. This dynamic relationship, defined as the frailty compression ratio, represents the net result of gero-inducing and gero-protective competing forces, described in the cohort.

2019 - The dynamic association between Frailty, CD4 and CD4/CD8 ratio in people aging with HIV [Articolo su rivista]
Guaraldi, Giovanni; Zona, Stefano; Silva, Ana Rita; Menozzi, Marianna; Dolci, Giovanni; Milic, Jovana; Carli, Federica; Mussini, Cristina
abstract

To investigate the association between current CD4+ T-cell count and CD4/CD8+ ratio with severity of frailty among people aging with HIV.

2019 - Thymus Imaging Detection and Size Is Inversely Associated With Metabolic Syndrome and Frailty in People With HIV [Articolo su rivista]
Guaraldi, Giovanni; Franconi, Iacopo; Milic, Jovana; Besutti, Giulia; Pintassilgo, Ines; Scaglioni, Riccardo; Ligabue, Guido; Riva, Nicoletta; Raimondi, Alessandro; Menozzi, Marianna; Carli, Federica; Zona, Stefano; Santoro, Antonella; Malagoli, Andrea; Borghi, Vanni; Torricelli, Pietro; Cossarizza, Andrea; Mussini, Cristina
abstract

People with HIV (PWH) may experience accentuating aging in relation to immuno-activation. Little is known regarding thymus (THY) involution in this process. We sought to investigate the relationship between THY imaging detection/size and clinically relevant aging outcomes such as metabolic syndrome (MetS), multimorbidity (MM), and frailty in PWH.

2019 - Very high pre-therapy viral load is a predictor of virological rebound in HIV-1-infected patients starting a modern first-line regimen [Articolo su rivista]
Armenia, Daniele; Di Carlo, Domenico; Cozzi-Lepri, Alessandro; Calcagno, Andrea; Borghi, Vanni; Gori, Caterina; Bertoli, Ada; Gennari, William; Bellagamba, Rita; Castagna, Antonella; Latini, Alessandra; Pinnetti, Carmela; Cicalini, Stefania; Saracino, Annalisa; Lapadula, Giuseppe; Rusconi, Stefano; Castelli, Francesco; Di Giambenedetto, Simona; Andreoni, Massimo; Di Perri, Giovanni; Antinori, Andrea; Mussini, Cristina; Ceccherini-Silberstein, Francesca; Monforte, Antonella D'Arminio; Perno, Carlo F; Santoro, Maria M
abstract

Pre-cART (combined antiretroviral therapy) plasma viral load &gt;500,000 copies/ml has been associated with a lower probability of achieving virological suppression, while few data about its role on maintenance of virological suppression are available. In this study we aimed to clarify whether high levels of pre-cART viraemia are associated with virological rebound (VR) after virological suppression.

2018 - Abacavir usage patterns and hypersensitivity reactions in the EuroSIDA cohort [Articolo su rivista]
Roen, A.; Laut, K.; Pelchen-Matthews, A.; Borodulina, E.; Caldeira, L.; Clarke, A.; Clotet, B.; d'Arminio Monforte, A.; Fatkenheuer, G.; Gatell Artigas, J. M.; Karpov, I.; Kuznetsova, A.; Kyselyova, G.; Mozer-Lisewska, I.; Mulcahy, F.; Ragone, L.; Scherrer, A.; Uzdaviniene, V.; Vandekerckhove, L.; Vannappagari, V.; Ostergaard, L.; Mocroft, A.; Losso, M.; Kundro, M.; Schmied, B.; Zangerle, R.; Vassilenko, A.; Mitsura, V. M.; Paduto, D.; Clumeck, N.; De Wit, S.; Delforge, M.; Florence, E.; Hadziosmanovic, V.; Begovac, J.; Machala, L.; Jilich, D.; Sedlacek, D.; Kronborg, G.; Benfield, T.; Gerstoft, J.; Katzenstein, T.; Moller, N. F.; Pedersen, C.; Wiese, L.; Nielsen, L. N.; Zilmer, K.; Smidt, J.; Ristola, M.; Aho, I.; Viard, J. -P.; Girard, P. -M.; Pradier, C.; Fontas, E.; Duvivier, C.; Rockstroh, J.; Behrens, G.; Degen, O.; Stellbrink, H. J.; Stefan, C.; Bogner, J.; Chkhartishvili, N.; Gargalianos, P.; Xylomenos, G.; Armenis, K.; Sambatakou, H.; Szlavik, J.; Gottfredsson, M.; Yust, I.; Turner, D.; Burke, M.; Shahar, E.; Hassoun, G.; Elinav, H.; Haouzi, M.; Elbirt, D.; Sthoeger, Z. M.; Esposito, R.; Mazeu, I.; Mussini, C.; Mazzotta, F.; Gabbuti, A.; Vullo, V.; Lichtner, M.; Zaccarelli, M.; Antinori, A.; Acinapura, R.; Plazzi, M.; Lazzarin, A.; Castagna, A.; Gianotti, N.; Galli, M.; Ridolfo, A.; Rozentale, B.; Matulionyte, R.; Staub, T.; Hemmer, R.; Reiss, P.; Reikvam, D. H.; Maeland, A.; Bruun, J.; Knysz, B.; Gasiorowski, J.; Inglot, M.; Horban, A.; Bakowska, E.; Flisiak, R.; Grzeszczuk, A.; Parczewski, M.; Maciejewska, K.; Aksak-Was, B.; Beniowski, M.; Mularska, E.; Smiatacz, T.; Gensing, M.; Jablonowska, E.; Malolepsza, E.; Wojcik, K.; Mansinho, K.; Maltez, F.; Radoi, R.; Oprea, C.; Panteleev, A.; Panteleev, O.; Yakovlev, A.; Trofimora, T.; Khromova, I.; Kuzovatova, E.; Vdoushkina, E.; Jevtovic, D.; Tomazic, J.; Gatell, J. M.; Miro, J. M.; Moreno, S.; Rodriguez, J. M.; Jou, A.; Paredes, R.; Tural, C.; Puig, J.; Bravo, I.; Domingo, P.; Gutierrez, M.; Mateo, G.; Sambeat, M. A.; Laporte, J. M.; Falconer, K.; Thalme, A.; Sonnerborg, A.; Blaxhult, A.; Flamholc, L.; Weber, R.; Cavassini, M.; Calmy, A.; Furrer, H.; Battegay, M.; Schmid, P.; Sluzhynska, M.; Gazzard, B.; Johnson, A. M.; Simons, E.; Edwards, S.; Phillips, A.; Johnson, M. A.; Orkin, C.; Weber, J.; Scullard, G.; Leen, C.; Gatell, J.; Lundgren, J.; Rasmussen, L. D.; Svedhem, V.; Wandeler, G.; Kowalska, J. D.; Miro, J.; Guaraldi, G.; Kirk, O.; Peters, L.; Bojesen, A.; Raben, D.; Kristensen, D.; Larsen, J. F.; Podlekareva, D.; Nykjaer, B.; Cozzi-Lepri, A.; Shepherd, L.; Amele, S.
abstract

Objectives: Five to eight per cent of HIV-positive individuals initiating abacavir (ABC) experience potentially fatal hypersensitivity reactions (HSRs). We sought to describe the proportion of individuals initiating ABC and to describe the incidence and factors associated with HSR among those prescribed ABC. Methods: We calculated the proportion of EuroSIDA individuals receiving ABC-based combination antiretroviral therapy (cART) among those receiving cART after 1 January 2009. Poisson regression was used to identify demographic, and current clinical and laboratory factors associated with ABC utilization and discontinuation. Results: Between 2009 and 2016, of 10 076 individuals receiving cART, 3472 (34%) had ever received ABC-based cART. Temporal trends of ABC utilization were also heterogeneous, with 28% using ABC in 2009, dropping to 26% in 2010 and increasing to 31% in 2016, and varied across regions and over time. Poisson models showed lower ABC utilization in older individuals, and in those with higher CD4 cell counts, higher cART lines, and prior AIDS. Higher ABC utilization was associated with higher HIV RNA and poor renal function, and was more common in Central-East and Eastern Europe and lowest during 2014. During 779 person-years of follow-up (PYFU) in 2139 individuals starting ABC after 1 January 2009, 113 discontinued ABC within 6 weeks of initiation for any reason [incidence rate (IR) 14.5 (95% confidence interval (CI) 12.1, 17.5) per 100 PYFU], 13 because of reported HSR [IR 0.3 (95% CI 0.1, 1.0) per 100 PYFU] and 35 because of reported HSR/any toxicity [IR 4.5 (95% CI 3.2, 6.3) per 100 PYFU]. There were no factors significantly associated with ABC discontinuation because of reported HSR/any toxicity. Conclusions: ABC remains commonly used across Europe and the incidence of discontinuation because of reported HSR was low in our study population.

2018 - Bacterial pneumonia in patients with liver cirrhosis, with or without HIV co-infection: a possible definition of antibiotic prophylaxis associated pneumonia (APAP) [Articolo su rivista]
Cuomo, Gianluca; Brancaccio, Giuseppina; Stornaiuolo, Gianfranca; Manno, Daniela; Gaeta, Giuseppe L.; Mussini, Cristina; Puoti, Massimo; Gaeta, Giovanni B.
abstract

Introducion: Bacterial infections frequently complicate liver cirrhosis. The aim of this study was to identify risk factors and clinical impact of bacterial pneumonia in patients with cirrhosis. Materials and methods: Bacterial infection prevalence study: consecutive patients with cirrhosis were enroled over a six-month period in 13 Italian centres. Pneumonia and other infections were diagnosed by standard methods. Pneumonia study: cirrhotic patients with pneumonia were enroled for an additional six-month period and HIV-positive patients were included. Results: Pneumonia was the fourth most frequent infection. In the two parts of the study, 79 cases of pneumonia were recorded and 441 patients with cirrhosis without infections served as controls. Seventy-eight patients had extra-pulmonary infections. There were no clinical differences between HIV-negative and -positive cases with pneumonia. Previous gastro-intestinal bleeding (p =.02) and long-term prophylactic antibiotic use (p &lt;.0001) were associated with pneumonia. Hospital stay was longer and renal failure more frequent than in patients without infections. Pneumonia was hospital acquired (HAP) in 6 cases, healthcare associated (HCAP) in 24 and community acquired (CAP) in 28. A new category of antibiotic prophylaxis associated pneumonia (APAP) was proposed for 21 cases. Cultures were positive in 21/79 patients (26.6%) with Gram-positive isolates in 57%. Unfavourable outcomes were recorded in 11.4% of the cases (3.6% of CAP, 33% of HAP, 12.5% of HCAP and 14.3% of APAP). Conclusions: Receiving antibiotic prophylaxis was associated with pneumonia and the study identified a new sub-group of patients, who require broad spectrum initial antibiotic therapy.

2018 - Clinical outcome of kidney transplantation in HIV-infected recipients: a retrospective study [Articolo su rivista]
Alfano, G; Mori, G; Fontana, F; Dolci, G; Baisi, A; Ligabue, G; Ferrari, A; Solazzo, A; Franceschini, E; Guaradi, G; Mussini, C; Cappelli, G.
abstract

Kidney transplantation is a safe and effective option for HIV-positive (HIV+) patients. We conducted a retrospective study on HIV+ kidney transplant recipients who underwent transplantation from March 2008 to September 2016.Inclusion criteria for transplantation were CD4þ T-cell count 200 per mm3 and undetectable HIV load. The current study reports the outcome of 19 HIV+ recipients, mostly of Caucasian origin (79%) with a median age of 50 years (interquartile range [IQR], 42–52), who were followed up for a median period of 2.4 years (IQR, 1.2–4.6) after transplantation. Compared with HIV-negative (HIV-) controls, HIV+ recipients had similar one- and three-year graft and patient survival, but significantly lower five-year patient survival (P¼0.03). The differences in graft outcome became less evident with the analysis of death-censored graft survival rates. Cumulative incidence of allograft rejection at one year was 32.9%. Rates of infections were not particularly elevated and HIV replication remained well controlled in all but one patient. A high prevalence of metabolic and endocrine complications (68%) was reported after transplantation. Further studies are needed to evaluate long-term outcomes of HIV+ recipients who underwent kidney transplantation.

2018 - Construct validation of a Frailty Index, an HIV Index and a Protective Index from a clinical HIV database [Articolo su rivista]
Franconi, Iacopo; Theou, Olga; Wallace, Lindsay; Malagoli, Andrea; Mussini, Cristina; Rockwood, Kenneth; Guaraldi, Giovanni
abstract

Standard care for HIV clinical practice has started focusing on age-related problems, but despite this recent change physicians involved in HIV care do not often screen HIV patients for frailty. Our aim was to construct three indexes from an HIV clinical database (i.e. Frailty Index, (FI), HIV Index, (HIVI), and Protective Index (PI)) and to assess levels of frailty, HIV severity and demographic and protective lifestyle factors among HIV patients. Methods and findings We included data from 1612 patients who attended an Italian HIV clinic between September 2016 and December2017 (mean±SD age: 53.1±8 years, 73.9% men).We used 92 routine variables collected by physicians and other health care professionals to construct three indexes: A 72-item FI (biometric, psychiatric, blood test, daily life activities, geriatric syndromes and nutrition data), a 10-item HIVI (immunological, viral and therapeutics) and a 10-item PI (income, education, social engagement, and lifestyle habits data)(the lower the FI and HIVI scores, and the higher the PI scores, the lower the risk for participants).The FI, HIVI and PI scores were 0.19±0.08, 0.48±0.17 and 0.62±0.13, respectively. Men had higher FI (0.19±0.08 vs 0.18±0.08; p = 0.010) and lower HIVI (0.47±0.18 vs 0.50±0.15; p = 0.038) scores than women. FI and HIVI scores both increased 1.9% per year of age (p &lt; 0.001), whereas the PI decreased 0.2% per year (p&lt;0.050). In addition, the FI score increased 1.6% and the PI score decreased 0.5% per year of HIV infection (p &lt; 0.001). Conclusion It is feasible to assess levels of frailty, HIV severity and protective lifestyle factors in HIV patients using data from a clinical database. Frailty levels are high among HIV patients and even higher among older patients and those with a long duration of HIV. Future studies need to examine the ability of the three indices to predict adverse health outcomes such as hospitalization and mortality.

2018 - Durability and tolerability of first-line regimens including two nucleoside reverse transcriptase inhibitors and raltegravir or ritonavir boosted-atazanavir or -darunavir: data from the ICONA Cohort* [Articolo su rivista]
d’Arminio Monforte, Antonella; Lorenzini, Patrizia; Cozzi-Lepri, Alessandro; Mussini, Cristina; Castagna, Antonella; Baldelli, Franco; Puoti, Massimo; Vichi, Francesca; Maddaloni, Adelaide; Lo Caputo, Sergio; Gianotti, Nicola; Antinori, Andrea
abstract

Background: We aimed to mimic the ACTG 5257 trial, comparing raltegravir (RAL), ritonavir-boosted atazavavir (ATV/r) and ritonavir-boosted darunavir (DRV/r) in the observational setting. Methods: All the ICONA patients starting a first cART with 2NRTI&nbsp;+&nbsp;ATV/r, DRV/r or RAL were included. Primary end-point was treatment failure, i.e. virological failure (confirmed HIV-RNA&nbsp;&gt;&nbsp;200copies/mL&nbsp;&gt;&nbsp;6&nbsp;months therapy) or discontinuation for any reason of the third drug. Secondary end-points: virological failure50 (50 copies/mL threshold), and discontinuation of the third drug due to intolerance/toxicity. Cox regression analyses were run to compare the risk of outcomes between the three regimens. Results: 2249 patients were included, 985 (44%) initiated ATV/r, 1023 (45%) DRV/r and 241 (11%) RAL; median follow-up of 3.6&nbsp;years (IQR: 2.3–5.2). After controlling for baseline confounding factors, patients given ATV/r showed a 26% higher risk of treatment failure (TF) vs. DRV/r (AHR 1.26, 95%CI 1.11–1.43); patients on RAL had a lower risk of TF vs. ATV/r (AHR 0.81, 95%CI 0.66–0.99). The probability of virological failure50 was significantly lower for people initiating RAL vs. DRV/r (AHR 0.46, 95%CI 0.24–0.87) or ATV/r (AHR 0.52, 95%CI 0.27–0.99). In addition, RAL was associated to a lower risk of discontinuation for toxicity vs. both DRV/r (AHR: 0.37, 95%CI: 0.19–0.72) and ATV/r (AHR: 0.18, 95%CI: 0.09–0.34). ATV/r was associated with a higher risk of discontinuing due to toxicity (AHR 2.09, 95%CI 1.63–2.67) vs. DRV/r. Conclusions: In our observational study, we confirmed higher risk of treatment failure and lower tolerability of ATV/r-based regimens as compared to those including DRV/r or RAL.

2018 - European AIDS Clinical Society Second Standard of Care Meeting, Brussels 16-17 November 2016: a summary [Articolo su rivista]
De Wit, S.; Battegay, M.; D'Arminio Monforte, A.; Lundgren, J. D.; Oprea, C.; Antinori, A.; Bhagani, S.; Fätkenheuer, G.; Friis-Moller, N.; Furrer, H.; Mussini, C.
abstract

The European AIDS Clinical Society (EACS) organized a second meeting on Standard of Care in Europe on November 16-17 th, 2016. The aims of the meeting were to discuss and propose actions on three topics, namely: Adherence to guidelines for treatment initiation, treatment monitoring and outcomes, Retention in care and HIV and tuberculosis co-infection. Several actions need to be implemented in order to further improve quality of care and treatment of HIV in Europe. A common ground for standard of care, based on the EACS Guidelines should be established throughout Europe. EACS plans to interact with policy makers and other stakeholders to insure this common minimal level of standard of care, in particular for initiating of ART, accessibility of drugs and monitoring of ART with viral load. Progress should be made to monitor retention in care, prevent lost to follow and insure return to care. Improving integration of services and accessibility to care play a major role. Integration is also key for optimizing care of HIV-tuberculosis co-infection, as well as diagnosis and prevention of tuberculosis in population at risk. The Standard of Care meeting organized every other year by EACS provides a unique opportunity to monitor progresses and pitfalls in HIV patient care throughout Europe. It is also a forum for advocacy towards policy makers and other stakeholders to constantly improve HIV patient global management, aiming to provide the same level of quality on the whole continent.

2018 - European Society of Cardiology-Proposed Diagnostic Echocardiographic Algorithm in Elective Patients with Clinical Suspicion of Infective Endocarditis: Diagnostic Yield and Prognostic Implications in Clinical Practice [Articolo su rivista]
Barbieri, A.; Mantovani, F.; Lugli, R.; Bursi, F.; Fabbri, M.; Bartolacelli, Y.; Manicardi, M.; Stefanelli, G.; Mussini, C.; Boriani, G.
abstract

Echocardiography plays a central role in diagnosing infective endocarditis (IE). Accordingly, the European Society of Cardiology (ESC) has proposed a diagnostic echocardiographic algorithm. However, new studies are still needed to evaluate the degree of implementation of these guidelines in clinical practice and their consequences on incidence and prognosis of IE.

2018 - Evidence-based renewal of the Italian guidelines for the use of antiretroviral agents and the diagnostic-clinical management of HIV-1 infected persons [Articolo su rivista]
Antinori, A; Di Biagio, A; Marcotullio, S; Sarmati, L; Andreoni, M; Angarano, G; Chirianni, A; d’Arminio Monforte, A; Di Perri, G; Galli, M; Gianotti, N; Girardi, E; Gori, A; Mussini, C; Perno, Cf; Lazzarin, A
abstract

The Italian Society for Infectious and Tropical Diseases (SIMIT) in collaboration with the Technical Health Committee (Sections L and M) of the Italian Ministry of Health have supported the renewal of the recommendations for the Italian guidelines for the use of antiretroviral agents and the diagnostic-clinical management of HIV-1 infected persons. This publication summarizes the latest updates to the 2017 version of the Italian Guidelines for the management of HIV-1 infected patients and the use of antiretroviral drugs. New recommendations were released framing the clinical questions the use of antiretrovirals according to the Patient Intervention Comparator Outcome (PICO) methodology and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. Diagnostic tools for immunological and virological monitoring, when to start, what to start, optimization and therapeutic failure were updated in order to include the recommendation obtained with these newly developed methods. For a complete review of clinical and therapeutic relevant topics we refer the reader to the extended version of the Guidelines.

2018 - Evolution of HIV-1 transmitted drug resistance in Italy in the 2007–2014 period: A weighted analysis [Articolo su rivista]
Franzetti, M.; De Luca, A.; Ceccherini-Silberstein, F.; Spagnuolo, V.; Nicastri, E.; Mussini, C.; Antinori, A.; Monno, L.; Vecchiet, J.; Fanti, I.; d'Arminio Monforte, A.; Balotta, C.
abstract

Background: Recent studies suggest that transmitted drug resistance (TDR) may be decreasing in latest years, likely because of the reduced frequency of acquired resistance. However, specific risk factors, geographical areas and special HIV-infected populations may be disproportionally affected by TDR. Objectives: Correlates of TDR and time trends were evaluated from 2007 to 2014. Study design: We evaluated the genotypic results of 2155 naïve patients enrolled in the I.Co.N.A cohort at 23 clinical Centers in Italy between 2007 and 2014. A weighted analysis was performed to account for the patients enrolled in the cohort in each clinical Centre at each biennium (total number of patients: 3737). Results: Overall prevalence of TDR was 10.7%. Independent predictors of TDR were sexual risk factor (OR 2.315, p = 0.020) and non-Italian geographical origin (OR 1.57, p = 0.038). The weighted prevalence of TDR was 10.5% with a stable proportion over calendar years. Generally, TDR prevalence was numerically higher, although not significantly, in clinical Centers of metropolitan areas with more than 3 millions of residents as compared to others (11.3% vs. 9.2%). The difference in TDR prevalence between these Centers decreased in more recent years. Conclusions: A stable frequency of TDR was observed during the most recent years in Italy, with opposite and converging trends in large metropolitan areas as compared to the rest of the country, suggesting a more homogeneous spread of TDR across the country in latest years. Concerns remain for sexual route of infection and non-Italian origin, reinforcing the need for specific prevention strategies prioritizing specific populations.

2018 - Evolution of transmitted HIV-1 drug resistance and viral subtypes circulation in Italy from 2006 to 2016 [Articolo su rivista]
Rossetti, B.; Di Giambenedetto, S.; Torti, C.; Postorino, M. C.; Punzi, G.; Saladini, F.; Gennari, W.; Borghi, V.; Monno, L.; Pignataro, A. R.; Polilli, E.; Colafigli, M.; Poggi, A.; Tini, S.; Zazzi, M.; De Luca, A.; Mellace, V.; Capetti, A.; Gismondo, M. R.; Biondi, M. L.; Mussini, C.; Pecorari, M.; Gianotti, N.; Sacchini, D.; Parruti, G.; Baldelli, F.; Zanussi, S.; Nerli, A.; Lenzi, L.; Calzetti, C.; Vivarelli, A.; Maserati, R.; Baldanti, F.; Poletti, F.; Mondino, V.; Malena, M.; Cascio, A.; Filice, G.; Magnani, G.; Zerbini, A.; Lombardi, F.; Di Gaimbenedetto, S.; Andreoni, M.; Montano, M.; Vullo, V.; Turriziani, O.; Gonnelli, A.; Boeri, E.; Bonora, S.; Ghisetti, V.; Francisci, D.; Grossi, P.; Bagnarelli, P.; Butini, L.; del Gobbo, R.; Giacometti, A.; Tacconi, D.; Callegaro, A.; Maggiolo, F.; Zoncada, A.; Paolini, E.; Sighinolfi, L.; Colao, G.; Corsi, P.; Blanc, P.; Galli, L.; Meraviglia, P.; Tosti, A.; Bruzzone, B.; Setti, M.; Penco, G.; Di Biagio, A.; Nencioni, C.; Pardelli, R.; Arcidiacono, I.; Degiuli, A.; De Gennaro, M.; Soria, A.; Foc, A.; Latella, S.; Cosco, L.; Malandrin, S.; Milini, P.; Cicconi, P.; Rusconi, S.; Micheli, V.
abstract

Objectives: The aim was to evaluate the evolution of transmitted HIV-1 drug resistance (TDR) prevalence in antiretroviral therapy (ART)-naïve patients from 2006 to 2016. Methods: HIV-1 sequences were retrieved from the Antiviral Response Cohort Analysis (ARCA) database and TDR was defined as detection of at least one mutation from the World Health Organization (WHO) surveillance list. Results: We included protease/reverse transcriptase sequences from 3573 patients; 455 had also integrase sequences. Overall, 68.1% of the patients were Italian, the median CD4 count was 348 cells/μL [interquartile range (IQR) 169–521 cells/μL], and the median viral load was 4.7 log 10 HIV-1 RNA copies/mL (IQR 4.1–5.3 log 10 copies/mL). TDR was detected in 10.3% of patients: 6% carried mutations to nucleos(t)ide reverse transcriptase inhibitors (NRTIs), 4.4% to nonnucleos(t)ide reverse transcriptase inhibitors (NNRTIs), 2.3% to protease inhibitors (PIs), 0.2% to integrase strand transfer inhibitors (INSTIs) and 2.1% to at least two drug classes. TDR declined from 14.5% in 2006 to 7.3% in 2016 (P&nbsp;=&nbsp;0.003): TDR to NRTIs from 9.9 to 2.9% (P&nbsp;=&nbsp;0.003) and TDR to NNRTIs from 5.1 to 3.7% (P&nbsp;=&nbsp;0.028); PI TDR remained stable. The proportion carrying subtype B virus declined from 76.5 to 50% (P&nbsp;&lt;&nbsp;0.001). The prevalence of TDR was higher in subtype B vs. non-B (12.6 vs. 4.9%, respectively; P&nbsp;&lt;&nbsp;0.001) and declined significantly in subtype B (from 17.1 to 8.8%; P&nbsp;=&nbsp;0.04) but not in non-B subtypes (from 6.1 to 5.8%; P&nbsp;=&nbsp;0.44). Adjusting for country of origin, predictors of TDR were subtype B [adjusted odds ratio (AOR) for subtype B vs. non-B 2.91; 95% confidence interval (CI) 1.93–4.39; P&nbsp;&lt;&nbsp;0.001], lower viral load (per log 10 higher: AOR 0.86; 95% CI 0.75–0.99; P&nbsp;=&nbsp;0.03), site in northern Italy (AOR for southern Italy/island vs. northern Italy, 0.61; 95% CI 0.40–0.91; P&nbsp;=&nbsp;0.01), and earlier calendar year (per 1&nbsp;year more recent: AOR 0.95; 95% CI 0.91–0.99; P&nbsp;=&nbsp;0.02). Conclusions: The prevalence of HIV-1 TDR has declined during the last 10&nbsp;years in Italy.

2018 - Exploring viral reservoir: The combining approach of cell sorting and droplet digital PCR [Articolo su rivista]
Gibellini, Lara; Pecorini, Simone; De Biasi, Sara; Pinti, Marcello; Bianchini, Elena; DE GAETANO, Anna; Digaetano, Margherita; Pullano, Rosalberta; Lo Tartaro, Domenico; Iannone, Anna; Mussini, Cristina; Cossarizza, Andrea; Nasi, Milena
abstract

Combined antiretroviral therapy (cART) blocks different steps of HIV replication and maintains plasma viral RNA at undetectable levels. The virus can remain in long-living cells and create a reservoir where HIV can restart replicating after cART discontinuation. A persistent viral production triggers and maintains a persistent immune activation, which is a well-known feature of chronic HIV infection, and contributes either to precocious aging, or to the increased incidence of morbidity and mortality of HIV positive patients. The new frontier of the treatment of HIV infection is nowadays eradication of the virus from all host cells and tissues. For this reason, it is crucial to have a clear and precise idea of where the virus hides, and which are the cells that keep it silent. Important efforts have been made to improve the detection of viral reservoirs, and new techniques are now giving the opportunity to characterize viral reservoirs. Among these techniques, a strategic approach based upon cell sorting and droplet digital PCR (ddPCR) is opening new horizons and opportunities of research. This review provides an overview of the methods that combine cell sorting and ddPCR for the quantification of HIV DNA in different cell types, and for the detection of its maintenance.

2018 - First-line antiretroviral therapy with efavirenz plus tenofovir disiproxil fumarate/emtricitabine or rilpivirine plus tenofovir disiproxil fumarate/emtricitabine: a durability comparison [Articolo su rivista]
Taramasso, L.; Di Biagio, A.; Maggiolo, F.; Tavelli, A.; Lo Caputo, S.; Bonora, S.; Zaccarelli, M.; Caramello, P.; Costantini, A.; Viscoli, C.; d'Arminio Monforte, A.; Cozzi-Lepri, A.; Andreoni, M.; Angarano, G.; Antinori, A.; Castelli, F.; Cauda, R.; Di Perri, G.; Galli, M.; Iardino, R.; Ippolito, G.; Lazzarin, A.; Perno, C. F.; von Schloesser, F.; Viale, P.; Castagna, A.; Ceccherini-Silberstein, F.; Girardi, E.; Mussini, C.; Puoti, M.; Ammassari, A.; Balotta, C.; Bandera, A.; Bonfanti, P.; Borderi, M.; Calcagno, A.; Calza, L.; Capobianchi, M. R.; Cingolani, A.; Cinque, P.; De Luca, A.; Gianotti, N.; Gori, A.; Guaraldi, G.; Lapadula, G.; Lichtner, M.; Madeddu, G.; Marchetti, G.; Marcotullio, S.; Monno, L.; Nozza, S.; Quiros Roldan, E.; Rossotti, R.; Rusconi, S.; Santoro, M. M.; Saracino, A.; Fanti, I.; Galli, L.; Lorenzini, P.; Rodano, A.; Shanyinde, M.; Carletti, F.; Carrara, S.; Di Caro, A.; Graziano, S.; Petrone, F.; Prota, G.; Quartu, S.; Truffa, S.; Giacometti, A.; Valeriani, C.; Santoro, C.; Suardi, C.; Donati, V.; Verucchi, G.; Minardi, C.; Quirino, T.; Abeli, C.; Manconi, P. E.; Piano, P.; Cacopardo, B.; Celesia, B.; Vecchiet, J.; Falasca, K.; Sighinolfi, L.; Segala, D.; Mazzotta, F.; Vichi, F.; Cassola, G.; Alessandrini, A.; Bobbio, N.; Mazzarello, G.; Mastroianni, C.; Belvisi, V.; Caramma, I.; Chiodera, A.; Castelli, A. P.; Rizzardini, G.; Ridolfo, A. L.; Piolini, R.; Salpietro, S.; Carenzi, L.; Moioli, M. C.; Tincati, C.; Puzzolante, C.; Abrescia, N.; Chirianni, A.; Borgia, G.; Di Martino, F.; Maddaloni, L.; Gentile, I.; Orlando, R.; Baldelli, F.; Francisci, D.; Parruti, G.; Ursini, T.; Magnani, G.; Ursitti, M. A.; Vullo, V.; Cristaudo, A.; Baldin, G.; Cicalini, S.; Gallo, L.; Nicastri, E.; Acinapura, R.; Capozzi, M.; Libertone, R.; Savinelli, S.; Latini, A.; Cecchetto, M.; Viviani, F.; Mura, M. S.; Rossetti, B.; Orofino, G. C.; Sciandra, M.; Bassetti, M.; Londero, A.; Pellizzer, G.; Manfrin, V.
abstract

Objectives: The aim of this study was to compare the durabilities of efavirenz (EFV) and rilpivirine (RPV) in combination with tenofovir/emtricitabine (TDF/FTC) in first-line regimens. Methods: A multicentre prospective and observational study was carried out. We included all patients participating in the Italian Cohort Naive Antiretrovirals (ICONA) Foundation Study who started first-line combination antiretroviral therapy (cART) with TDF/FTC in combination with RPV or EFV, with a baseline viral load &lt; 100 000 HIV-1 RNA copies/mL. Survival analyses using Kaplan–Meier (KM) curves and Cox regression with time-fixed covariates at baseline were employed. Results: Overall, 1490 ART-naïve patients were included in the study, of whom 704 were initiating their first cART with EFV and 786 with RPV. Patients treated with EFV, compared with those on RPV, were older [median 36 (interquartile range (IQR) 30–43) years vs. 33 (IQR 27–39) years, respectively; P &lt; 0.001], were more frequently at Centers for Disease Control and Prevention (CDC) stage C (3.1% vs. 1.4%, respectively; P = 0.024), and had a lower median baseline CD4 count [340 (IQR 257–421) cells/μL vs. 447 (IQR 347–580) cells/μL, respectively; P &lt; 0.001] and a higher median viral load [4.38 (IQR 3.92–4.74) log10 copies/mL vs. 4.23 (IQR 3.81–4.59) log10 copies/mL, respectively], (P = 0.004). A total of 343 patients discontinued at least one drug of those included in the first cART regimen, more often EFV (26%) than RPV (13%), by 2 years (P &lt; 0.0001). After adjustment, patients treated with EFV were more likely to discontinue at least one drug for any cause [relative hazard (RH) 4.09; 95% confidence interval (CI) 2.89–5.80], for toxicity (RH 2.23; 95% CI 1.05–4.73) for intolerance (RH 5.17; 95% CI 2.66–10.07) and for proactive switch (RH 10.96; 95% CI 3.17–37.87) than those starting RPV. Conclusions: In our nonrandomized comparison, RPV was better tolerated, less toxic and showed longer durability than EFV, without a significant difference in rates of discontinuation because of failures.

2018 - Gastric Mucormycosis in a Liver and Kidney Transplant Recipient: Case Report and Concise Review of Literature [Articolo su rivista]
Alfano, G.; Fontana, F.; Francesca, D.; Assirati, Giacomo; Magistri, P.; Tarantino, G.; Ballarin, R.; Rossi, G.; Franceschini, E.; Codeluppi, M.; Guaraldi, G.; Mussini, C.; Di Benedetto, F.; Cappelli, G.
abstract

Mucormycosis is an uncommonly encountered fungal infection in solid organ transplantation. The infection is severe and often results in a fatal outcome. The most common presentations are rhino-sino-orbital and pulmonary disease. We describe a rare case of gastric mucormycosis in a patient with a combined liver-kidney transplant affected by glycogen storage disease type Ia. A 42-year-old female patient presented with gastric pain and melena 26 days after transplantation. Evaluation with upper endoscopy showed two bleeding gastric ulcers. Histological examination of gastric specimens revealed fungal hyphae with evidence of Mucormycetes at subsequent molecular analysis. Immunosuppressive therapy was reduced and antifungal therapy consisting of liposomal amphotericin B and posaconazole was promptly introduced. Gastrointestinal side effects of posaconazole and acute T-cell rejection of renal graft complicated further management of the case. A prolonged course of daily injections of amphotericin B together with a slight increase of immunosuppression favored successful treatment of mucormycosis as well as of graft rejection. After 2-year follow-up examination, the woman was found to have maintained normal renal and liver function tests. We conclude that judicious personalization of antimicrobial and antirejection therapy should be considered to resolve every life-threatening case of mucormycosis in solid organ transplantation.

2018 - Genetic divergence of HIV-1 B subtype in Italy over the years 2003–2016 and impact on CTL escape prevalence [Articolo su rivista]
Alteri, Claudia; Fabeni, Lavinia; Scutari, Rossana; Berno, Giulia; Di Carlo, Domenico; Gori, Caterina; Bertoli, Ada; Vergori, Alessandra; Mastrorosa, Ilaria; Bellagamba, Rita; Mussini, Cristina; Colafigli, Manuela; Montella, Francesco; Pennica, Alfredo; Mastroianni, Claudio Maria; Girardi, Enrico; Andreoni, Massimo; Antinori, Andrea; Svicher, Valentina; Ceccherini-Silberstein, Francesca; Perno, Carlo Federico; Santoro, Maria Mercedes
abstract

HIV-1 is characterized by high genetic variability, with implications for spread, and immune-escape selection. Here, the genetic modification of HIV-1 B subtype over time was evaluated on 3,328 pol and 1,152 V3 sequences belonging to B subtype and collected from individuals diagnosed in Italy between 2003 and 2016. Sequences were analyzed for genetic-distance from consensus-B (Tajima-Nei), non-synonymous and synonymous rates (dN and dS), CTL escapes, and intra-host evolution over four time-spans (2003–2006, 2007–2009, 2010–2012, 2013–2016). Genetic-distance increased over time for both pol and V3 sequences (P < 0.0001 and 0.0003). Similar results were obtained for dN and dS. Entropy-value significantly increased at 16 pol and two V3 amino acid positions. Seven of them were CTL escape positions (protease: 71; reverse-transcriptase: 35, 162, 177, 202, 207, 211). Sequences with ≥3 CTL escapes increased from 36.1% in 2003–2006 to 54.0% in 2013–2016 (P < 0.0001), and showed better intra-host adaptation than those containing ≤2 CTL escapes (intra-host evolution: 3.0 × 10−3 [2.9 × 10−3–3.1 × 10−3] vs. 4.3 × 10−3 [4.0 × 10−3–5.0 × 10−3], P[LRT] < 0.0001[21.09]). These data provide evidence of still ongoing modifications, involving CTL escape mutations, in circulating HIV-1 B subtype in Italy. These modifications might affect the process of HIV-1 adaptation to the host, as suggested by the slow intra-host evolution characterizing viruses with a high number of CTL escapes.

2018 - Global Trends in CD4 Cell Count at the Start of Antiretroviral Therapy: Collaborative Study of Treatment Programs [Articolo su rivista]
Anderegg, N; Panayidou, K; Abo, Y; Alejos, B; Althoff, Kn; Anastos, K; Antinori, A; Balestre, E; Becquet, R; Castagna, A; Castelnuovo, B; Chêne, G; Coelho, L; Collins, Ij; Costagliola, D; Crabtree-Ramírez, B; Dabis, F; d'Arminio Monforte, A; Davies, Ma; De Wit, S; Delpech, V; De La Mata, Nl; Duda, S; Freeman, A; Gange, Sj; Grabmeier-Pfistershammer, K; Gunsenheimer-Bartmeyer, B; Jiamsakul, A; Kitahata, Mm; Law, M; Manzardo, C; Mcgowan, C; Meyer, L; Moore, R; Mussini, C; Nakigoz, G; Nash, D; Tek Ng, O; Obel, N; Pantazis, N; Poda, A; Raben, D; Reiss, P; Riggen, L; Sabin, C; d'Amour Sinayobye, J; Sönnerborg, A; Stoeckle, M; Thorne, C; Torti, C; Twizere, C; Wasmuth, Jc; Wittkop, L; Wools-Kaloustian, K; Yotebieng, M; Kirk, O; Egger, M.
abstract

Early initiation of combination antiretroviral therapy (cART), at higher CD4 cell counts, prevents disease progression and reduces sexual transmission of human immunodeficiency virus (HIV). We describe the temporal trends in CD4 cell counts at the start of cART in adults from low-income, lower-middle-income, upper-middle-income, and high-income countries (LICs, LMICs, UMICs, and HICs, respectively).

2018 - Global temporal changes in the proportion of children with advanced disease at the start of combination antiretroviral therapy in an era of changing criteria for treatment initiation [Articolo su rivista]
Panayidou, K.; Davies, M. -A.; Anderegg, N.; Egger, M.; Fatti, G.; Vinikoor, M.; Sawry, S.; Ehmer, J.; Eley, B.; Phiri, S.; Technau, K. -G. u. N.; Chimbetete, C.; Rabie, H.; Boulle, A.; Tanser, F.; Wood, R.; Wools-Kaloustian, K.; Vreeman, R.; Oyaro, P.; Ayaya, S.; Nakigozi, G.; Musick, B.; Yiannoutsos, C.; Amorissani-Folquet, M.; Takassi, E.; Sylla, M.; Renner, L.; Malateste, K.; Desmonde, S.; Leroy, V.; Kurniati, N.; Hansudewechakul, R.; Nguyen, L. V.; Ly, P. S.; Truong, K. H.; Kariminia, A.; Sohn, A. H.; Edmonds, A.; Yumo, H. A.; Dusingize, J. C.; Yotebieng, M.; Judd, A.; Rojo, P.; Smit, C.; Grabar, S.; Warszwarski, J.; Chene, G.; Raban, D.; Patel, K.; Seage, G. R.; Van Dyke, R. B.; Oleske, J.; Williams, P. L.; Abzug, M. J.; Succi, R.; Machado, D. M.; Pinto, J.; Rouzier, V.; Luque, M.; Mejia, F.; Ly, P. S.; Khol, V.; Tucker, J.; Kumarasamy, N.; Saghayam, S.; Chandrasekaran, E.; Wati, D. K.; Vedaswari, D.; Malino, I. Y.; Kurniati, N.; Muktiarti, D.; Fong, S. M.; Lim, M.; Daut, F.; Nik Yusoff, N. K.; Mohamad, P.; Mohamed, T. J.; Drawis, M. R.; Nallusamy, R.; Chan, K. C.; Sudjaritruk, T.; Sirisanthana, V.; Aurpibul, L.; Oberdorfer, P.; Hansudewechakul, R.; Denjanta, S.; Watanaporn, S.; Kongphonoi, A.; Lumbiganon, P.; Kosalaraksa, P.; Tharnprisan, P.; Udomphanit, T.; Jourdain, G.; Puthanakit, T.; Anugulruengkitt, S.; Phadungphon, C.; Chokephaibulkit, K.; Lapphra, K.; Phongsamart, W.; Sricharoenchai, S.; Truong, K. H.; Du, Q. T.; Nguyen, C. H.; Do, V. C.; Ha, T. M.; An, V. T.; Nguyen, L. V.; Khu, D. T. K.; Pham, A. N.; Nguyen, L. T.; Le, O. N.; Sohn, A. H.; Ross, J. L.; Sethaputra, C.; Law, M. G.; Kariminia, A.; Cahn, P.; Cesar, C.; Fink, V.; Sued, O.; Dell'Isola, E.; Perez, H.; Valiente, J.; Yamamoto, C.; Grinsztejn, B.; Veloso, V.; Luz, P.; de Boni, R.; Wagner, S. C.; Friedman, R.; Moreira, R.; Pinto, J.; Ferreira, F.; Maia, M.; de Menezes Succi, R. C.; Machado, D. M.; Barbosa Gouv E A, A. F. a. T.; Wolff, M.; Cortes, C.; Rodriguez, M. F.; Allendes, G.; Pape, J. W.; Rouzier, V.; Marcelin, A.; Perodin, C.; Luque, M. T.; Padgett, D.; Madero, J. S.; Ramirez, B. C.; Belaunzaran, P.; Vega, Y. C.; Gotuzzo, E.; Mejia, F.; Carriquiry, G.; Mcgowan, C. C.; Shepherd, B. E.; Sterling, T.; Jayathilake, K.; Person, A. K.; Rebeiro, P. F.; Giganti, M.; Castilho, J.; Duda, S. N.; Maruri, F.; Vansell, H.; P E Lagie, N.; Gateretse, P.; Munezero, J.; Nitereka, V.; Niyongabo, T.; Twizere, C.; Bukuru, H.; Nahimana, T.; Biziragusenyuka, J.; Manyundo, R. S.; Atsu, K.; Mbuh, T.; Ajeh, R.; Benwi, M.; Dzudie, A.; Mbuh, A.; Ngamani, M. L.; Nkome, V.; Amadou, D.; Ngassam, E.; Pefura Yone, E. W.; Ewanoge, A. N.; Fuhngwa, N.; Moki, C.; Akele, C.; Kitetele, F.; Lelo, P.; Tabala, M.; Okitolonda, E. W.; Wenzi, L.; Diafouka, M.; Ekat, M. H.; Nsonde, D. M.; Mafou, A.; Ntarambirwa, F.; Tuyishimire, Y.; Hakizimana, T.; Ayinkamiye, J.; Mukantwali, S.; Kayitesi, H.; Uwamahoro, O.; Habumuremyi, V.; Mukamana, J.; Dusingize, J. C.; Kubwimana, G.; Mugenzi, P.; Muhoza, B.; Munyaneza, A.; Ndahiro, E.; Nyiransabimana, D.; D'Amour Sinayobye, J.; Sugira, V.; Benekigeri, C.; Mbaraga, G.; Adedimeji, A.; Anastos, K.; Dilorenzo, M.; Murchison, L.; Ross, J.; Addison, D.; Baker, M.; Brazier, E.; Jones, H.; Kelvin, E.; Kulkarni, S.; Nash, D.; Tymejczyk, O.; Elul, B.; Cai, X.; Hoover, D.; Kim, H. -Y.; Li, C.; Shi, Q.; Lancaster, K.; Yotebieng, M.; Kuniholm, M.; Edmonds, A.; Parcesepe, A.; Duda, S.; Kimmel, A.; Mcnairy, M.; Diero, L.; Ayaya, S.; Plus, A. M. P. A. T. H.; Bukusi, E.; Ssali, J.; Nalugoda, F.; Somi, G. R.; Lyamuya, R. E.; Ngonyani, K.; Lugina, E.; Urassa, M.; Michael, D.; Zannou, M. D.; Poda, A.; Sarfo, F. S.; Messou, E.; Chenal, H.; Minga, K. A.; Bissagnene, E.; Tanon, A.; Seydi, M.; Patassi, A. A.; Koumakpai-Adeothy, S. A.; Renner, L. A.; N'Gbeche, S. M.; Bosse, C. A.; Kouakou, K.; Folquet, M. A.; Eboua, F. c. O. T.; Traore, F. D.; Sylla, M.; Takassi, E.; Dabis, F. c. O.; Arrive, E.; Balestre, E.; Becquet, R.; Bernard, C.; Arikawa, S. C.; Doring, A.; Jaquet, A.; Malates
abstract

Introduction: The CD4 cell count and percent at initiation of combination antiretroviral therapy (cART) are measures of advanced HIV disease and thus are important indicators of programme performance for children living with HIV. In particular, World Health Organization (WHO) 2017 guidelines on advanced HIV disease noted that &gt;80% of children aged &lt;5&nbsp;years started cART with WHO Stage 3 or 4 disease or severe immune suppression. We compared temporal trends in CD4 measures at cART start in children from low-, middle- and high-income countries, and examined the effect of WHO treatment initiation guidelines on reducing the proportion of children initiating cART with advanced disease. Methods: We included children aged &lt;16&nbsp;years from the International Epidemiology Databases to Evaluate acquired immunodeficiency syndrome (AIDS) (IeDEA) Collaboration (Caribbean, Central and South America, Asia-Pacific, and West, Central, East and Southern Africa), the Collaboration of Observational HIV Epidemiological Research in Europe (COHERE), the North American Pediatric HIV/AIDS Cohort Study (PHACS) and International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) 219C study. Severe immunodeficiency was defined using WHO guidelines. We used generalized weighted additive mixed effect models to analyse temporal trends in CD4 measurements and piecewise regression to examine the impact of 2006 and 2010 WHO cART initiation guidelines. Results: We included 52,153 children from fourteen low-, eight lower middle-, five upper middle- and five high-income countries. From 2004 to 2013, the estimated percentage of children starting cART with severe immunodeficiency declined from 70% to 42% (low-income), 67% to 64% (lower middle-income) and 61% to 43% (upper middle-income countries). In high-income countries, severe immunodeficiency at cART initiation declined from 45% (1996) to 14% (2012). There were annual decreases in the percentage of children with severe immunodeficiency at cART initiation after the WHO guidelines revisions in 2006 (low-, lower middle- and upper middle-income countries) and 2010 (all countries). Conclusions: By 2013, less than half of children initiating cART had severe immunodeficiency worldwide. WHO treatment initiation guidelines have contributed to reducing the proportion of children and adolescents starting cART with advanced disease. However, considerable global inequity remains, in 2013, &gt;40% of children in low- and middle-income countries started cART with severe immunodeficiency compared to &lt;20% in high-income countries.

2018 - Highlights of the 2017 European AIDS Clinical Society (EACS) Guidelines for the treatment of adult HIV-positive persons version 9.0 [Articolo su rivista]
Ryom, L.; Boesecke, C.; Bracchi, M.; Ambrosioni, J.; Pozniak, A.; Arribas, J.; Behrens, G.; Mallon, P. G. M.; Puoti, M.; Rauch, A.; Miro, J. M.; Kirk, O.; Marzolini, C.; Lundgren, J. D.; Battegay, M.; d'Arminio Monforte, A.; Clumeck, N.; Dedes, N.; Gatell, J. M.; Horban, A.; Katlama, C.; McCormack, S.; Molina, J. -M.; Mussini, C.; Raffi, F.; Reiss, P.; Stellbrink, H. -J.; Bower, M.; Cinque, P.; Collins, S.; Compston, J.; De Wit, S.; Fabbri, L. M.; Fux, C. A.; Guaraldi, G.; Martinez, E.; Papapoulos, S.; du Pasquier, R.; Poulter, N.; Williams, I.; Winston, A.; Berenguer, J.; Bhagani, S.; Bruno, R.; Konov, S.; Lacombe, K.; Mauss, S.; Mendao, L.; Peters, L.; Rockstroh, J. K.; Fatkenheuer, G.; Furrer, H.; Mocroft, A.; Morlat, P.; Volny-Anne, A.
abstract

Background: The European AIDS Clinical Society (EACS) Guidelines have since 2005 provided multidisciplinary recommendations for the care of HIV-positive persons in geographically diverse areas. Guideline highlights: Major revisions have been made in all sections of the 2017 Guidelines: antiretroviral treatment (ART), comorbidities, coinfections and opportunistic diseases. Newly added are also a summary of the main changes made, and direct video links to the EACS online course on HIV Management. Recommendations on the clinical situations in which tenofovir alafenamide may be considered over tenofovir disoproxil fumarate are provided, and recommendations on which antiretrovirals can be used safely during pregnancy have been revised. Renal and bone toxicity and hepatitis C virus (HCV) treatment have been added as potential reasons for ART switches in fully virologically suppressed individuals, and dolutegravir/rilpivirine has been included as a treatment option. In contrast, dolutegravir monotherapy is not recommended. New recommendations on non-alcoholic fatty liver disease, chronic lung disease, solid organ transplantation, and prescribing in elderly are included, and human papilloma virus (HPV) vaccination recommendations have been expanded. All drug–drug interaction tables have been updated and new tables are included. Treatment options for direct-acting antivirals (DAAs) have been updated and include the latest combinations of sofosbuvir/velpatasvir/voxilaprevir and glecaprevir/pibrentasvir. Recommendations on management of DAA failure and acute HCV infection have been expanded. For treatment of tuberculosis (TB), it is underlined that intermittent treatment is contraindicated, and for resistant TB new data suggest that using a three-drug combination may be as effective as a five-drug regimen, and may reduce treatment duration from 18-24 to 6-10&nbsp;months. Conclusions: Version 9.0 of the EACS Guidelines provides a holistic approach to HIV care and is translated into the six most commonly spoken languages.

2018 - Immunological and virological response to antiretroviral treatment in migrant and native men and women in Western Europe; is benefit equal for all? [Articolo su rivista]
Monge, S.; Mocroft, A.; Sabin, A.; Touloumi, G.; Sighem, A.; Abgrall, S.; Dray-Spira, R.; Spire, B.; Castagna, A.; Mussini, C.; Zangerle, R.; Hessamfar, M.; Anderson, J.; Hamouda, O.; Ehren, K.; Obel, N.; Kirk, O.; Antinori, A.; Girardi, E.; Saracino, A.; Calmy, A.; Wit, S.; Wittkop, L.; Bucher, C.; Montoliu, A.; Raben, D.; Prins, M.; Meyer, L.; Chene, G.; Burns, F.; Amo, J.; Judd, Ali; Zangerle, Robert; Touloumi, Giota; Warszawski, Josiane; Meyer, Laurence; Dabis, François; Krause, Murielle; Ghosn, Jade; Leport, Catherine; Wittkop, Linda; Reiss, Peter; Wit, Ferdinand; Prins, Maria; Bucher, Heiner; Gibb, Diana; Fätkenheuer, Gerd; Amo, Julia; Obel, Niels; Thorne, Claire; Mocroft, Amanda; Kirk, Ole; Stephan, Christoph; Pérez-Hoyos, Santiago; Bartmeyer, Barbara; Chkhartishvili, Nikoloz; Noguera-Julian, Antoni; Antinori, Andrea; Monforte, Antonella; Brockmeyer, Norbert; Prieto, Luis; Conejo, Pablo; Soriano-Arandes, Antoni; Battegay, Manuel; Kouyos, Roger; Mussini, Cristina; Tookey, Pat; Casabona, Jordi; Miró, Josem; Castagna, Antonella; Konopnick, Deborah; Goetghebuer, Tessa; Sönnerborg, Anders; Torti, Carlo; Sabin, Caroline; Teira, Ramon; Garrido, Myriam; Haerry, David; Wit, Stéphane; Miró, M.; Costagliola, Dominique; d'Arminio-Monforte, Antonella; Raben, Dorthe; Chêne, Geneviève; Barger, Diana; Schwimmer, Christine; Termote, Monique; Campbell, Maria; Frederiksen, Casper M; Friis-Møller, Nina; Kjaer, Jesper; Brandt, Rikke; Berenguer, Juan; Bohlius, Julia; Bouteloup, Vincent; Cozzi-Lepri, Alessandro; Davies, Mary-Anne; Dorrucci, Maria; Dunn, David; Egger, Matthias; Furrer, Hansjakob; Guiguet, Marguerite; Grabar, Sophie; Lambotte, Olivier; Leroy, Valériane; Lodi, Sara; Matheron, Sophie; Miró, Jose; Monge, Susana; Nakagawa, Fumiyo; Paredes, Roger; Phillips, Andrew; Puoti, Massimo; Rohner, Eliane; Schomaker, Michael; Smit, Colette; Sterne, Jonathan; Thiebaut, Rodolphe; Valk, Marc
abstract

Objectives: The aim of the study was to evaluate differences in immunovirological response to combination antiretroviral therapy (cART) in migrant and native men and women within a European collaboration of HIV cohorts Collaboration of Observational HIV Epidemiological Research in Europ (COHERE) in EuroCoord, 2004–2013. Methods: Migrants were defined as those with geographical origin (GO) different from the reporting country and were grouped as originating from Western Europe and Western Countries (WEWC), Eastern Europe (EE), North Africa and the Middle East (NAME), sub-Saharan Africa (SSA), Latin America (LA), Caribbean (CRB) and Asia/Oceania (ASIA/OCE). Native (NAT) individuals were defined as those originating from the reporting country. CD4 cell counts were modelled using piecewise linear mixed-effects models with two slopes, whereas models to estimate subdistribution hazard ratios (sHRs) were used for time to virological response (VR) (i.e. time from cART initiation to the first of two successive HIV RNA measurements &lt; 400 HIV-1 RNA copies/ml). Results: Of 32 817 individuals, 25 799 (78.6%) were men. The percentage of migrants was higher in women (48.9%) than in men (21.2%) and migrants from SSA accounted for the largest migrant group (29.9% in men and 63.3% in women). Migrant men and women from SSA started at lower CD4 cell counts than NAT individuals, which remained lower over time. VR was ≥ 85% at 12 months for all groups except CRB women (77.7%). Compared with NAT men and women, lower VR was experienced by NAME [sHR 0.91; 95% confidence interval (CI) 0.86–0.97] and SSA (sHR 0.88; 95% CI 0.82–0.95) men and CRB (sHR 0.77; 85% CI 0.67–0.89) women, respectively. Conclusions: Immunovirological response to cART in Western Europe varies by GO and sex of patients. ART benefits are not equal for all, underlining the point that efforts need to prioritize those most in need.

2018 - Immunophenotypic Profile and Clinical Outcome of Monoclonal B-cell Lymphocytosis in Kidney Transplantation [Articolo su rivista]
Alfano, G; Fontana, F; Colaci, E; Franceschini, E; Ligabue, G; Messerotti, A; Bettelli, Francesca; Grottola, A; Gennari, W; Potenza, L; Guaraldi, G; Mussini, C; Luppi, M; Cappelli, G
abstract

Monoclonal B-cell lymphocytosis (MBL) is a lymphoproliferative disorder characterized by clonal expansion of a B-cell population in peripheral blood of otherwise healthy subjects. MBL is divided into CLL (chronic lymphocytic leukemia)-like, atypical CLL-like and non-CLL MBL. The aim of this study was to evaluate immunophenotypic characteristics and clinical outcomes of MBL in kidney transplant (KT) recipients. We retrospectively evaluated 593 kidney transplant (KT) recipients in follow-up at our center. Among them, 157 patients underwent peripheral blood flow-cytometry for different clinical indications. A 6-color panel flow-cytometry was used to diagnose MBL. MBL was detected in 5 of 157 KT recipients. Immunophenotypic characterization of MBL showed four cases of non-CLL MBL and one case of CLL-like MBL. At presentation, median age was 65 years (range 61-73). After a median follow-up of 3.1 years (95%CI; 1.1-5) from diagnosis, patients did not progress either to CLL or lymphoma. The disorder did not increase the risk of malignancy, severe infections, graft loss and mortality among our KT recipients. Surprisingly, all cases were also affected by concomitant monoclonal gammopathy of undetermined significance, which did not progress to multiple myeloma during follow-up. In conclusion, our data suggest that MBL is an age-related disorder, with non-CLL MBL being the most common subtype among KT recipients. This article is protected by copyright. All rights reserved.

2018 - Impact of social determinants on antiretroviral therapy access and outcomes entering the era of universal treatment for people living with HIV in Italy [Articolo su rivista]
Saracino, A.; Zaccarelli, M.; Lorenzini, P.; Bandera, Alessandra; Marchetti, G.; Castelli, F.; Gori, A.; Girardi, E.; Mussini, C.; Bonfanti, P.; Ammassari, A.; D'Arminio Monforte, A.; Moroni, M.; Andreoni, M.; Angarano, G.; Antinori, A.; Cauda, R.; Di Perri, G.; Galli, M.; Iardino, R.; Ippolito, G.; Lazzarin, A.; Perno, C. F.; Von Schloesser, F.; Viale, P.; Castagna, A.; Ceccherini-Silberstein, F.; Cozzi-Lepri, A.; Lo Caputo, S.; Puoti, M.; Balotta, C.; Bonora, S.; Borderi, M.; Capobianchi, M. R.; Cingolani, A.; Cinque, P.; De Luca, A.; Di Biagio, A.; Gianotti, N.; Guaraldi, G.; Lapadula, G.; Lichtner, M.; Madeddu, G.; Maggiolo, F.; Marcotullio, S.; Monno, L.; Quiros Roldan, E.; Rusconi, S.; Cicconi, P.; Fanti, I.; Galli, L.; Shanyinda, M.; Tavelli, A.; Giacometti, A.; Costantini, A.; Mazzoccato, S.; Santoro, C.; Suardi, C.; Vanino, E.; Verucchi, G.; Minardi, C.; Quirino, T.; Abeli, C.; Manconi, P. E.; Piano, P.; Vecchiet, J.; Falasca, K.; Sighinolfi, L.; Segala, D.; Mazzotta, F.; Cassola, G.; Viscoli, C.; Alessandrini, A.; Piscopo, R.; Mazzarello, G.; Mastroianni, C.; Belvisi, V.; Caramma, I.; Chiodera, A.; Castelli, A. P.; Rizzardini, G.; Ridolfo, A. L.; Piolini, R.; Salpietro, S.; Carenzi, L.; Moioli, M. C.; Tincati, C.; Puzzolante, C.; Abrescia, N.; Chirianni, A.; Borgia, G.; Guida, M. G.; Gargiulo, M.; Gentile, I.; Orlando, R.; Baldelli, F.; Francisci, D.; Parruti, G.; Ursini, T.; Magnani, G.; Ursitti, M. A.; Vullo, V.; D'Avino, A.; Gallo, L.; Nicastri, E.; Acinapura, R.; Capozzi, M.; Libertone, R.; Tebano, G.; Viviani, F.; Sasset, L.; Mura, M. S.; Rossetti, B.; Caramello, P.; Orofino, G. C.; Sciandra, M.; Bassetti, M.; Londero, A.; Pellizzer, G.; Manfrin, V.
abstract

Background: Social determinants are known to be a driving force of health inequalities, even in high income countries. Aim of our study was to determine if these factors can limit antiretroviral therapy (ART) access, outcome and retention in care of people living with HIV (PLHIV) in Italy. Methods: All ART naïve HIV+ patients (pts) of Italian nationality enrolled in the ICONA Cohort from 2002 to 2016 were included. The association of socio-demographic characteristics (age, sex, risk factor for HIV infection, educational level, occupational status and residency area) with time to: ART initiation (from the first positive anti-HIV test), ART regimen discontinuation, and first HIV-RNA < 50 cp/mL, were evaluated by Cox regression analysis, Kaplan Meier method and log-rank test. Results: A total of 8023 HIV+ pts (82% males, median age at first pos anti-HIV test 36 years, IQR: 29-44) were included: 6214 (77.5%) started ART during the study period. Women, people who inject drugs (PWID) and residents in Southern Italy presented the lowest levels of education and the highest rate of unemployment compared to other groups. Females, pts aged > 50 yrs., unemployed vs employed, and people with lower educational levels presented the lowest CD4 count at ART initiation compared to other groups. The overall median time to ART initiation was 0.6 years (yrs) (IQR 0.1-3.7), with a significant decrease over time [2002-2006 = 3.3 yrs. (0.2-9.4); 2007-2011 = 1.0 yrs. (0.1-3.9); 2012-2016 = 0.2 yrs. (0.1-2.1), p < 0.001]. By multivariate analysis, females (p < 0.01) and PWID (p < 0.001), presented a longer time to ART initiation, while older people (p < 0.001), people with higher educational levels (p < 0.001), unemployed (p = 0.02) and students (p < 0.001) were more likely to initiate ART. Moreover, PWID, unemployed vs stable employed, and pts. with lower educational levels showed a lower 1-year probability of achieving HIV-RNA suppression, while females, older patients, men who have sex with men (MSM), unemployed had higher 1-year risk of first-line ART discontinuation. Conclusions: Despite median time to ART start decreased from 2002 to 2016, socio-demographic factors still contribute to disparities in ART initiation, outcome and durability.

2018 - Incidence of HCV infection amongst HIV positive men who had sex with men and prevalence data from patients followed at the Infectious Diseases Clinic of Modena, Italy [Articolo su rivista]
Cuomo, Gianluca; Digaetano, Margherita; Menozzi, Marianna; Tagliazucchi, Sara; Guaraldi, Giovanni; Borghi, Vanni; Mussini, Cristina
abstract

Background: Men who had sex with men (MSM) living with HIV are at higher risk of developing sexual transmitted diseases. This study reports two years incidence rate and prevalence of HCV in a cohort of HIV positive MSM. Methods: MSM HIV-positive outpatients negative to HCV-Ab at first observation entered a Kaplan–Meier model in order to assess the HCV infection incidence rate. Prevalence analysis was performed with MSM HIV-positive that were on follow-up at 2016. An MSM population HIV-negative served as control. Results: 421 patients entered the incidence analysis. The incidence rate of HCV infection among MSM-HIV people was 0.44 per 100 patients-years (19 events). 40 out of 442 (9%) patients were HCV-positive (prevalence analysis); they were mostly genotype 1a and 3 with APRI score &lt;0.7 (87.5%). Univariate analysis between MSM HIV-positive patients and MSM HIV-negative showed significant differences in the prevalence rate (9.0% vs 0.6%, P &lt; 0.001) and median age (39 vs 47, P &lt; 0.001). Conclusion: Incidence and prevalence rate of HCV amongst MSM HIV-positive patients is higher than in other settings. Annual HCV-Ab screening for MSM HIV-positive patients should be enforced and early treatment of HCV recommended.

2018 - Incidence of cancer and overall risk of mortality in individuals treated with raltegravir-based and non-raltegravir-based combination antiretroviral therapy regimens [Articolo su rivista]
Cozzi-Lepri, A.; Zangerle, R.; Machala, L.; Zilmer, K.; Ristola, M.; Pradier, C.; Kirk, O.; Sambatakou, H.; Fatkenheuer, G.; Yust, I.; Schmid, P.; Gottfredsson, M.; Khromova, I.; Jilich, D.; Flisiak, R.; Smidt, J.; Rozentale, B.; Radoi, R.; Losso, M. H.; Lundgren, J. D.; Mocroft, A.; Kundro, M.; Schmied, B.; Karpov, I.; Vassilenko, A.; Mitsura, V. M.; Paduto, D.; Clumeck, N.; De Wit, S.; Delforge, M.; Florence, E.; Vandekerckhove, L.; Hadziosmanovic, V.; Begovac, J.; Sedlacek, D.; Kronborg, G.; Benfield, T.; Gerstoft, J.; Katzenstein, T.; Moller, N. F.; Pedersen, C.; Ostergaard, L.; Wiese, L.; Nielsen, L. N.; Aho, I.; Viard, J. -P.; Girard, P. -M.; Fontas, E.; Duvivier, C.; Rockstroh, J.; Schmidt, R.; Degen, O.; Stellbrink, H. J.; Stefan, C.; Bogner, J.; Chkhartishvili, N.; Gargalianos, P.; Xylomenos, G.; Lourida, P.; Szlavik, J.; Mulcahy, F.; Turner, D.; Burke, M.; Shahar, E.; Hassoun, G.; Elinav, H.; Haouzi, M.; Elbirt, D.; Sthoeger, Z. M.; D'Arminio Monforte, A.; Esposito, R.; Mazeu, I.; Mussini, C.; Mazzotta, F.; Gabbuti, A.; Vullo, V.; Lichtner, M.; Zaccarelli, M.; Antinori, A.; Acinapura, R.; Plazzi, M.; Lazzarin, A.; Castagna, A.; Gianotti, N.; Galli, M.; Ridolfo, A.; Uzdaviniene, V.; Matulionyte, R.; Staub, T.; Hemmer, R.; Reiss, P.; Ormaasen, V.; Maeland, A.; Bruun, J.; Knysz, B.; Gasiorowski, J.; Inglot, M.; Horban, A.; Bakowska, E.; Grzeszczuk, A.; Parczewski, M.; Maciejewska, K.; Aksak-Was, B.; Beniowski, M.; Mularska, E.; Smiatacz, T.; Gensing, M.; Jablonowska, E.; Malolepsza, E.; Wojcik, K.; Mozer-Lisewska, I.; Caldeira, L.; Mansinho, K.; Maltez, F.; Oprea, C.; Panteleev, A.; Panteleev, O.; Yakovlev, A.; Trofimora, T.; Kuzovatova, E.; Borodulina, E.; Vdoushkina, E.; Jevtovic, D.; Tomazic, J.; Gatell, J. M.; Miro, J. M.; Moreno, S.; Rodriguez, J. M.; Clotet, B.; Jou, A.; Paredes, R.; Tural, C.; Puig, J.; Bravo, I.; Domingo, P.; Gutierrez, M.; Mateo, G.; Sambeat, M. A.; Laporte, J. M.; Falconer, K.; Thalme, A.; Sonnerborg, A.; Blaxhult, A.; Flamholc, L.; Scherrer, A.; Weber, R.; Cavassini, M.; Calmy, A.; Furrer, H.; Battegay, M.; Kuznetsova, A.; Kyselyova, G.; Sluzhynska, M.; Gazzard, B.; Johnson, A. M.; Simons, E.; Edwards, S.; Phillips, A.; Johnson, M. A.; Orkin, C.; Weber, J.; Scullard, G.; Clarke, A.; Leen, C.; Thiebaut, R.; Burger, D.; Peters, L.; Matthews, C.; Fischer, A. H.; Bojesen, A.; Raben, D.; Kristensen, D.; Gronborg Laut, K.; Larsen, J. F.; Podlekareva, D.; Shepherd, L.; Schultze, A.; Amele, S.
abstract

Objectives: There are currently few data on the long-term risk of cancer and death in individuals taking raltegravir (RAL). The aim of this analysis was to evaluate whether there is evidence for an association. Methods: The EuroSIDA cohort was divided into three groups: those starting RAL-based combination antiretroviral therapy (cART) on or after 21 December 2007 (RAL); a historical cohort (HIST) of individuals adding a new antiretroviral (ARV) drug (not RAL) to their cART between 1 January 2005 and 20 December 2007, and a concurrent cohort (CONC) of individuals adding a new ARV drug (not RAL) to their cART on or after 21 December 2007. Baseline characteristics were compared using logistic regression. The incidences of newly diagnosed malignancies and death were compared using Poisson regression. Results: The RAL cohort included 1470 individuals [with 4058 person-years of follow-up (PYFU)] compared with 3787 (4472 PYFU) and 4467 (10 691 PYFU) in the HIST and CONC cohorts, respectively. The prevalence of non-AIDS-related malignancies prior to baseline tended to be higher in the RAL cohort vs. the HIST cohort [adjusted odds ratio (aOR) 1.31; 95% confidence interval (CI) 0.95–1.80] and vs. the CONC cohort (aOR 1.89; 95% CI 1.37–2.61). In intention-to-treat (ITT) analysis (events: RAL, 50; HIST, 45; CONC, 127), the incidence of all new malignancies was 1.11 (95% CI 0.84–1.46) per 100 PYFU in the RAL cohort vs. 1.20 (95% CI 0.90–1.61) and 0.83 (95% CI 0.70–0.99) in the HIST and CONC cohorts, respectively. After adjustment, there was no evidence for a difference in the risk of malignancies [adjusted rate ratio (RR) 0.73; 95% CI 0.47–1.14 for RALvs. HIST; RR 0.95; 95% CI 0.65–1.39 for RALvs. CONC] or mortality (adjusted RR 0.87; 95% CI 0.53–1.43 for RALvs. HIST; RR 1.14; 95% CI 0.76–1.72 for RALvs. CONC). Conclusions: We found no evidence for an oncogenic risk or poorer survival associated with using RAL compared with control groups.

2018 - Indications for starting ART [Articolo su rivista]
Mussini, Cristina; Cossarizza, Andrea
abstract

Invited Editorial for explaining when. starting antiretroviral therapy.

2018 - Infective complications in patients undergoing surgical reconstruction with dermal matrix: the Modena experience [Poster]
Bedini, Andrea; Fiorentini, Chiara; Mandel, Victor Desmond; Menozzi, Marianna; Bacca, Erica; Ferrari, Federica; DE PACE, Barbara; Meschiari, Marianna; Santoro, Antonella; Orlando, Gabriella; Franceschini, Erica; Puzzolante, Cinzia; Mussini, Cristina; Magnoni, Cristina
abstract

Background: Bioengineered skin dermal substitutes (SDS) represent a novel therapeutic opportunity for restoring damaged tissue1,2,3. Antimicrobial prophylaxis duration in such procedures has not been well established yet. The aim of the study was to evaluate the changing of infective complications following shortening of perioperative prophylaxis in patients undergoing surgical reconstruction with SDS. Material &amp; Methods: Infective complications at the site of SDS were compared in 2 groups: subjects undergoing surgical reconstruction between September 2014 and January 2016 (PERIOD A) who received a &gt;24H-antibiotic-prophylaxis, and between May 2016 and June 2017 (PERIOD B) who received a ≤24H-antibiotic-prophylaxis. Differences in the incidence of infection and pathogen prevalence were explored. Results: Between September 2014 and June 2017, 116 patients underwent a surgical reconstruction with a SDS. The mean age was 73-years, 77 were male (66.4%), 78 (67.2%) were positive for hypertension, 20 (17.2%) for diabetes mellitus, 16 (13.8%) for chronic renal impairment, 22 (19%) were smokers, and 45 (38.8%) had an ASA score ≥3. In the 94.8% (n=110) the reason of surgical intervention was a skin cancer. Surgical SDS reconstruction involved the scalp in 44 cases (37.9%), the face in 28 (24.1%), the chest in 11 (9.5%), the limbs in 33 (28.5%). Among 116 patients, 62 (53.4%) received &gt;24H-antibiotic and 54 (46.6%) ≤24H-antibiotic-prophylaxis. The average duration of prophylaxis in the 2 groups of patients was 6.6 days and 0.5 day, respectively. Overall incidence rate of infection was 20.7% (24/116). The most frequently isolated pathogen was S. aureus (41.6%), followed by P. aeruginosa (29.1%), P. mirabilis (8.3%), and E. faecalis (4.1%). Patients undergoing SDS reconstruction in limbs had higher infection rate in comparison with chest/head (33.3% and 15.6%, respectively; p=0.034). No differences in the infection rate were observed between the patients who received &gt;24H or ≤24H-antibiotic-prophylaxis (22.5% and 18.5%, respectively; p=0.590). The two groups resulted similar for gender, age, comorbidities, ASA score, and type of skin cancer. Discussion: As far as we know, this is the first study that compared two perioperative antibiotic prophylaxis regimes in patients undergoing SDS reconstruction. Comparing the two patient groups (≤24-hour and &gt;24-hour prophylaxis), no differences in the rate of infection were found. The result is very important: it shows that prolongation of prophylaxis in this type of surgical patients does not reduce the rate of infection. Shortening of antibiotic prophylaxis allowed to reduce of 6 days-per-patient the antibiotic exposure. It was surprising that only the reconstruction of the limbs, in comparison with other sites, was associated with a higher risk of infection (33.3 and 15.7 respectively). Nor the most critical patients (with an ASA score ≥3), nor patients undergoing major surgical reconstructions (surgical area &gt;60 cm2) resulted associated with a higher risk. Conclusion: Antibiotic prophylaxis reduction to 24 hours or less demonstrated to be beneficial to patients undergoing surgical reconstruction with SDS. Shortening of antibiotic prophylaxis did not increase infection rate, and it allowed a reduction of 6 days-per-patient the antibiotic exposure. Randomized and controlled trials, with greater population, could give a more accurate response on the duration of antibiotic prophylaxis in patients undergoing surgical SDS reconstruction.

2018 - Long-term effectiveness of recommended boosted protease inhibitor-based antiretroviral therapy in Europe [Articolo su rivista]
Santos, J. R.; Cozzi-Lepri, A.; Phillips, A.; De Wit, S.; Pedersen, C.; Reiss, P.; Blaxhult, A.; Lazzarin, A.; Sluzhynska, M.; Orkin, C.; Duvivier, C.; Bogner, J.; Gargalianos-Kakolyris, P.; Schmid, P.; Hassoun, G.; Khromova, I.; Beniowski, M.; Hadziosmanovic, V.; Sedlacek, D.; Paredes, R.; Lundgren, J. D.; Losso, M.; Kundro, M.; Schmied, B.; Zangerle, R.; Karpov, I.; Vassilenko, A.; Mitsura, V. M.; Paduto, D.; Clumeck, N.; Delforge, M.; Florence, E.; Vandekerckhove, L.; Begovac, J.; Machala, L.; Jilich, D.; Kronborg, G.; Benfield, T.; Gerstoft, J.; Katzenstein, T.; Moller, N. F.; Ostergaard, L.; Wiese, L.; Nielsen, L. N.; Zilmer, K.; Smidt, J.; Ristola, M.; Aho, I.; Viard, J. -P.; Girard, P. -M.; Pradier, C.; Fontas, E.; Rockstroh, J.; Schmidt, R.; Degen, O.; Stellbrink, H. J.; Stefan, C.; Fatkenheuer, G.; Chkhartishvili, N.; Gargalianos, P.; Xylomenos, G.; Lourida, P.; Sambatakou, H.; Szlavik, J.; Gottfredsson, M.; Mulcahy, F.; Yust, I.; Turner, D.; Burke, M.; Shahar, E.; Elinav, H.; Haouzi, M.; Elbirt, D.; Sthoeger, Z. M.; D'Arminio Monforte, A.; Esposito, R.; Mazeu, I.; Mussini, C.; Mazzotta, F.; Gabbuti, A.; Vullo, V.; Lichtner, M.; Zaccarelli, M.; Antinori, A.; Acinapura, R.; Plazzi, M.; Castagna, A.; Gianotti, N.; Galli, M.; Ridolfo, A.; Rozentale, B.; Uzdaviniene, V.; Matulionyte, R.; Staub, T.; Hemmer, R.; Ormaasen, V.; Maeland, A.; Bruun, J.; Knysz, B.; Gasiorowski, J.; Inglot, M.; Horban, A.; Bakowska, E.; Flisiak, R.; Grzeszczuk, A.; Parczewski, M.; Pynka, M.; Maciejewska, K.; Mularska, E.; Smiatacz, T.; Gensing, M.; Jablonowska, E.; Malolepsza, E.; Wojcik, K.; Mozer-Lisewska, I.; Caldeira, L.; Mansinho, K.; Maltez, F.; Radoi, R.; Panteleev, A.; Panteleev, O.; Yakovlev, A.; Trofimora, T.; Kuzovatova, E.; Borodulina, E.; Vdoushkina, E.; Jevtovic, D.; Tomazic, J.; Gatell, J. M.; Miro, J. M.; Moreno, S.; Rodriguez, J. M.; Clotet, B.; Jou, A.; Tural, C.; Puig, J.; Bravo, I.; Domingo, P.; Gutierrez, M.; Mateo, G.; Sambeat, M. A.; Laporte, J. M.; Falconer, K.; Thalme, A.; Sonnerborg, A.; Flamholc, L.; Scherrer, A.; Weber, R.; Cavassini, M.; Calmy, A.; Furrer, H.; Battegay, M.; Kuznetsova, A.; Kyselyova, G.; Gazzard, B.; Johnson, A. M.; Simons, E.; Edwards, S.; Johnson, M. A.; Mocroft, A.; Weber, J.; Scullard, G.; Clarke, A.; Leen, C.; Gatell, J.; Ledergerber, B.; Kirk, O.; Peters, L.; Matthews, C.; Fischer, A. H.; Bojesen, A.; Raben, D.; Kristensen, D.; Gronborg Laut, K.; Larsen, J. F.; Podlekareva, D.; Shepherd, L.; Schultze, A.; Thiebaut, R.; Burger, D.
abstract

Objectives: The aim of the study was to evaluate the long-term response to antiretroviral treatment (ART) based on atazanavir/ritonavir (ATZ/r)-, darunavir/ritonavir (DRV/r)-, and lopinavir/ritonavir (LPV/r)-containing regimens. Methods: Data were analysed for 5678 EuroSIDA-enrolled patients starting a DRV/r-, ATZ/r- or LPV/r-containing regimen between 1 January 2000 and 30 June 2013. Separate analyses were performed for the following subgroups of patients: (1) ART-naïve subjects (8%) at ritonavir-boosted protease inhibitor (PI/r) initiation; (2) ART-experienced individuals (44%) initiating the new PI/r with a viral load (VL) ≤500 HIV-1 RNA copies/mL; and (3) ART-experienced patients (48%) initiating the new PI/r with a VL &gt;500 copies/mL. Virological failure (VF) was defined as two consecutive VL measurements &gt;200 copies/mL ≥24 weeks after PI/r initiation. Kaplan–Meier and multivariable Cox models were used to compare risks of failure by PI/r-based regimen. The main analysis was performed with intention-to-treat (ITT) ignoring treatment switches. Results: The time to VF favoured DRV/r over ATZ/r, and both were superior to LPV/r (log-rank test; P &lt; 0.02) in all analyses. Nevertheless, the risk of VF in ART-naïve patients was similar regardless of the PI/r initiated after controlling for potential confounders. The risk of VF in both treatment-experienced groups was lower for DRV/r than for ATZ/r, which, in turn, was lower than for LPV/r-based ART. Conclusions: Although confounding by indication and calendar year cannot be completely ruled out, in ART-experienced subjects the long-term effectiveness of DRV/r-containing regimens appears to be greater than that of ATZ/r and LPV/r.

2018 - Long-term efficacy of dolutegravir in treatment-experienced subjects failing therapy with HIV-1 integrase strand inhibitor-resistant virus [Articolo su rivista]
Castagna, A.; Ferrara, M.; Galli, L.; Comi, L.; Sterrantino, G.; Cenderello, G.; Zaccarelli, M.; Foca, E.; Roncadori, A.; Lazzarin, A.; Chichino, G.; Mantia, E.; Butini, L.; Costantini, A.; Giacometti, A.; Tavio, M.; Grassini, M.; Valle, M.; Vaccher, E.; Martellotta, F.; Schioppa, O.; Maggiolo, F.; Viale, P.; Borderi, M.; Calza, L.; Moratello, L.; Magistrelli, E.; Castelli, F.; Festa, E.; Quirino, T.; Campus, M.; Businco, F.; Celesia, B. M.; La Rosa, R.; Pan, A.; Fornabaio, C.; Mazzotta, F.; Di Pietro, M.; Bartoloni, A.; Ferrara, S.; Mastroianni, A.; Di Cesare, S.; Viscoli, C.; Di Biagio, A.; Cassola, G.; Penco, G.; Cericola, A.; Nencioni, C.; Carli, T.; Vigano, P.; Re, T.; Del Fiorentino, A.; Gattuso, G.; Palvarini, L.; Taurozzi, M.; Gianotti, N.; Galizzi, N.; Poli, A.; Rusconi, S.; Galli, S. E. S. M.; Rizzardini, G.; Mussini, C.; Menozzi, M.; Gori, A.; Muscatello, A.; Cappelletti, E.; Gargiulo, M.; Garavelli, P. L.; Bargiacchi, O.; Prestileo, T.; Di Lorenzo, F.; Bonanno, S.; Ferrari, C.; degli Antoni, A. M.; Cattelan, A. M.; Gulminetti, R.; Pagnucco, L.; Menichetti, F.; Iapoce, R.; Baldelli, F.; Schiaroli, E.; Italiani, F.; Aquilini, D.; Magnani, G.; Corsini, R.; Barchi, E.; Ferrari, E.; Antinori, A.; Cristaudo, A.; Latini, A.; Cauda, R.; Vullo, V.; Maffongelli, G.; Andreoni, M.; Sassett, L.; Viviani, F.; De Luca, A.; Rossetti, B.; Franco, A.; Resta, F.; Di Perri, G.; Bonora, S.; Bassetti, M.; Londero, A.; Malena, M.; Luzzati, R.
abstract

Objectives: This study evaluated the virological efficacy of dolutegravir 50mg twice daily in 190 HIV-1 failing antiretroviral-experienced patients with previous exposure to first-generation integrase strand transfer inhibitor (INSTI) over a 5 year follow-up using data fromclinical practice. Patients and methods: This analysis included HIV-1-infected patients who were ≥ 18 years of age, treatment experienced, had HIV-1 RNA .50 copies/mL, with INSTI-resistant virus, who started dolutegravir 50mg twice daily plus optimized background therapy (OBT), recorded in the national prospective database PRESTIGIO (www.proget toprestigio.it). Follow-up accrued fromthe start of dolutegravir 50mg twice daily!OBT until virological failure (VF) or dolutegravir discontinuation for any reason or the last treatment visit on dolutegravir 50mg twice daily treatment. VF was defined by the lack of achievement of HIV-1 RNA, 50 copies/mL by 6months and thereafter, or the occurrence of two consecutive HIV-1 RNA ≥50 copies/mL after achievement of undetectable viral load. Results: The estimated VF probabilities were 17% (95% CI=12%-24%), 28% (95% CI=21%-37%), 33% (95% CI=25%-43%), 39% (95% CI=29%-51%) and 52% (95% CI=39%-67%) at 12, 24, 36, 48 and 60months since baseline, respectively. A higher risk of VF was independently associated with baseline viral load .100000 copies/mL (adjusted HR=4.73, 95% CI=1.33-16.78, P=0.016) and with ≥ 1 INSTI mutations plus Q148H/K/R/N and the G140S/A/C as compared with other subjects (adjusted HR=4.18, 95% CI=1.32-13.23, P=0.015). Conclusions: Our data showed a favourable long-term efficacy of dolutegravir 50mg twice daily in association with OBT in treatment-experienced failing subjects, with INSTI-resistant virus, in the real world. A close monitoring of adherence is crucial for maintenance of virological response in this fragile subgroup of subjects.

2018 - Managing antiretroviral therapy in the elderly HIV patient [Articolo su rivista]
Guaraldi, Giovanni; Pintassilgo, Ines; Milic, Jovana; Mussini, Cristina
abstract

Owing to more effective and less toxic antiretroviral therapy (ART), people living with HIV (PLWH) live longer, a phenomenon expected to grow in the next decades. With advancing age, effectively treated PLWH experience not only a heightened risk for non-infective comorbidities and multimorbidity, but also for geriatric syndromes and frailty. In addition, older adults living with HIV (OALWH) have a higher prevalence of so-called iatrogenic triad described as polypharmacy (PP), potentially inappropriate medication use, and drug-drug interactions. Areas covered: This review will focus the management of ART in OALWH. We will discuss iatrogenic triad and best way to address PP. Special focus will be given to pharmacokinetic and pharmacodynamic aspects of ART in the elderly, evaluation of ART toxicities, and specific ART strategies commonly used in this population. Expert commentary: Research should be focused on recruiting more OALWH, frail individuals in particular, into the clinical trials and specific geriatric outcome need to be considered together with traditional viroimmunological outcomes.

2018 - Managing the long surviving HIV patient: a proposal for a multidimensional first-level diagnostic assessment [Articolo su rivista]
Borderi, Marco; Angarano, Gioacchino; Antinori, Andrea; Chirianni, Antonio; Cinque, Paola; D'Arminio Monforte, Antonella; Di Biagio, Antonio; Di Perri, Giovanni; Galli, Massimo; Gori, Andrea; Lazzarin, Adriano; Mussini, Cristina; Perno, Carlo Federico; Quirino, Tiziana; Rizzardini, Giuliano; Calza, Leonardo; Viale, Pierluigi; Acone, Benedetto; Andreoni, Massimo
abstract

We propose a multidimensional first-level diagnostic assessment easy to use in routine clinical practice to allow infectious disease specialists to have a general and complete overview of persons living with HIV. Following the Delphi method, articles published from January 1, 2011 on controlled trials, clinical reports and observational studies dealing specifically with HIV and its co-morbidities were selected for review by the authors. Participants in the poll were selected among clinicians and infectious diseases specialists, working in 38 different dedicated HIV centres in Italy. The participants were given access to a website dedicated to the project and received a standardized information package containing a synopsis of the study and a description of the Delphi process and the selected literature. A total of 131 Items were divided into 10 first-level survey areas: anamnesis, objective examination, infectious diseases, osteoporosis diagnosis, metabolic pathologies diagnosis, cardiovascular diagnosis, nephrologic diagnosis, hepatological diagnosis, central nervous system diagnosis, evaluation of quality of life (QoL). This simple and concise first level tool identifies a few areas of multi-organ diagnostic assessment beyond the infectivity area. The identification of these areas will allow us to find shared and validated evaluation procedures with the intent to increase the likelihood of early recognition of patients at risk of comorbidity development, in order to facilitate more effective prevention, thereby reducing the overall impact on the quality of life of patients affected by this chronic illness.

2018 - Optimization strategies for HIV, hepatitis and syphilis testing in Infectious Disease Clinic and Dermatology Unit of Modena: seven-years results of collaboration experience [Poster]
DI TULLIO, Francesca; Mandel, Victor Desmond; Coppini, Maurizio; Mussini, Cristina; Borghi, Vanni; Pellacani, Giovanni
abstract

Introduction: Human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV) and syphilis infections modify the epidemiology and presentation of each other. Screening tests are very important for detection of sexually transmitted infections (STIs), for treating them at an early stage and prevent the diffusion inside communities. “Test &amp; Counselling” Ambulatory of Infectious Disease Clinic (T&amp;C-IDC) and Sexually Transmitted Diseases Ambulatory of Dermatology Unit (STDs-DU) of the Azienda Ospedaliero-Universitaria Policlinico of Modena began collaboration in 2010 and adopted a common diagnostic profile since 2013. The main objective was to analyse the results of screening tests performed in the T&amp;C-IDC and STDs-DU during the study period in order to identify early HIV, HBV, HCV and syphilis infections. The secondary objective was to evaluate the efficacy of our collaboration in term of number of new STIs diagnoses and linkage to care. Material and Methods: Consecutive patients referred to the T&amp;C-IDC and STDs-DU from January 2010 to December 2016, with at least one performed screening test for HIV, HBV, HCV and syphilis were enrolled. Demographic and laboratory data were acquired from each patient. Linkage to care of positive patients was obtained through a join of different outpatient clinical databases. Results: During the seven-years observation we collected 13117 admittances for 9154 patients. Median age was 35.1 years ± 12.6 and foreign-born population represents 29% of the tested people. People who resulted positive for at least one screening test increased during the study period. A total of 668 infections were detected in 644 patients. Discussion: The agreement between T&amp;C-IDC and STDs-DU has proven to work well increasing the diagnosis over the time and obtaining a good results in linkage to care, which allows to patients with positive screening test to be sent to the pertinent Clinic for further investigations and therapeutic management.

2018 - Persistent disparities in antiretroviral treatment (ART) coverage and virological suppression across Europe, 2004 to 2015 [Articolo su rivista]
Laut, Kamilla; Shepherd, Leah; Radoi, Roxana; Karpov, Igor; Parczewski, Milosz; Mussini, Cristina; Maltez, Fernando; Losso, Marcelo; Chkhartishvili, Nikoloz; Elinav, Hila; Kovari, Helen; Blaxhult, Anders; Zangerle, Robert; Trofimova, Tatiana; Inglot, Malgorzata; Zilmer, Kai; Kuzovatova, Elena; Staub, Thérèse; Raben, Dorthe; Lundgren, Jens; Mocroft, Amanda; Kirk, Ole
abstract

Background: Direct comparisons between countries in core HIV care parameters are often hampered by differences in data collection. Aim: Within the EuroSIDA study, we compared levels of antiretroviral treatment (ART) coverage and virological suppression (HIV RNA < 500 copies/mL) across Europe and explored temporal trends. Methods: In three cross-sectional analyses in 2004—05, 2009—10 and 2014—15, we assessed country-specific percentages of ART coverage and virological suppression among those on ART. Temporal changes were analysed using logistic regression. Results: Overall, the percentage of people on ART increased from 2004—05 (67.8%) to 2014—15 (78.2%), as did the percentage among those on ART who were virologically suppressed (75.2% in 2004—05, 87.7% in 2014—15). However, the rate of improvement over time varied significantly between regions (p < 0.01). In 2014—15, six of 34 countries had both ART coverage and virological suppression of above 90% among those on ART. The pattern varied substantially across clinics within countries, with ART coverage ranging from 61.9% to 97.0% and virological suppression from 32.2% to 100%. Compared with Western Europe (as defined in this study), patients in other regions were less likely to be virologically suppressed in 2014—15, with the lowest odds of suppression (adjusted odds ratio = 0.16; 95% confidence interval (CI): 0.13—0.21) in Eastern Europe. Conclusions: Despite overall improvements over a decade, we found persistent disparities in country-specific estimates of ART coverage and virological suppression. Underlying reasons for this variation warrant further analysis to identify a best practice and benchmark HIV care across EuroSIDA.

2018 - Pre-ART HIV-1 DNA in CD4+ T cells correlates with baseline VIRO-immunological status and outcome in patients under first-line ART [Articolo su rivista]
Ceccherini-Silberstein, F.; Cozzi Lepri, A.; Alteri, C.; Merlini, E.; Surdo, M.; Marchetti, G.; Capobianchi, M. R.; De Luca, A.; Gianotti, N.; Viale, P.; Andreoni, M.; Antinori, A.; Perno, C. F.; D'Arminio Monforte, A.; Castagna, A.; Castelli, F.; Cauda, R.; Di Perri, G.; Galli, M.; Iardino, R.; Ippolito, G.; Lazzarin, A.; Marchetti, G. C.; Rezza, G.; Von Schloesser, F.; Cozzi-Lepri, A.; Girardi, E.; Lo Caputo, S.; Mussini, C.; Puoti, M.; Ammassari, A.; Balotta, C.; Bandera, A.; Bonfanti, P.; Bonora, S.; Borderi, M.; Calcagno, A.; Calza, L.; Cingolani, A.; Cinque, P.; Di Biagio, A.; Gori, A.; Guaraldi, G.; Lapadula, G.; Lichtner, M.; Madeddu, G.; Maggiolo, F.; Marcotullio, S.; Monno, L.; Nozza, S.; Quiros Roldan, E.; Rossotti, R.; Rusconi, S.; Santoro, M. M.; Saracino, A.; Zaccarelli, M.; Fanti, I.; Galli, L.; Lorenzini, P.; Rodano, A.; Shanyinde, M.; Tavelli, A.; Carletti, F.; Carrara, S.; Di Caro, A.; Graziano, S.; Petrone, F.; Prota, G.; Quartu, S.; Truffa, S.; Giacometti, A.; Costantini, A.; Barocci, V.; Angarano, G.; Santoro, C.; Suardi, C.; Donati, V.; Verucchi, G.; Minardi, C.; Quirino, T.; Abeli, C.; Manconi, P. E.; Piano, P.; Cacopardo, B.; Celesia, B.; Vecchiet, J.; Falasca, K.; Sighinolfi, L.; Segala, D.; Blanc, P.; Vichi, F.; Cassola, G.; Viscoli, C.; Alessandrini, A.; Bobbio, N.; Mazzarello, G.; Mastroianni, C.; Pozzetto, I.; Molteni, C.; Chiodera, A.; Milini, P.; Nunnari, G.; Pellicano, G.; Rizzardini, G.; Moioli, M. C.; Piolini, R.; Ridolfo, A. L.; Salpietro, S.; Tincati, C.; Puzzolante, C.; Chirianni, A.; Borgia, G.; Esposito, V.; Orlando, R.; Bonadies, G.; Di Martino, F.; Gentile, I.; Maddaloni, L.; Cattelan, A. M.; Marinello, S.; Cascio, A.; Colomba, C.; Baldelli, F.; Schiaroli, E.; Parruti, G.; Sozio, F.; Magnani, G.; Ursitti, M. A.; Acinapura, R.; Baldin, G.; Capozzi, M.; Cicalini, S.; Cristaudo, A.; Fontanelli Sulekova, L.; Iaiani, G.; Latini, A.; Mastrorosa, I.; Plazzi, M. M.; Savinelli, S.; Vergori, A.; Vullo, V.; Cecchetto, M.; Viviani, F.; Bagella, P.; Rossetti, B.; Franco, A.; Fontana Del Vecchio, R.; Francisci, D.; Di Giuli, C.; Caramello, P.; Orofino, G. C.; Sciandra, M.; Bassetti, M.; Londero, A.; Pellizzer, G.; Manfrin, V.; Starnini, G.; Ialungo, A.
abstract

Objectives We evaluated the association between pre-ART HIV DNA and HIV-infected participant characteristics at baseline as well as with their response to first-line ART. Methods Four hundred and thirty-three patients from the ICONA cohort, starting first-line ART after the year 2000, were analysed. Pre-ART HIV DNA was quantified with the modified COBAS TaqMan HIV-1 Test and normalized by CD4+ T cells. Linear correlation between pre-ART HIV DNA and other continuous markers (HIV RNA, CD4 count, markers of inflammation and coagulation) at baseline was evaluated by means of Pearson correlation coefficient and a linear regression model. Survival analyses and Cox regression models were used to study the association between pre-ART HIV DNA and time to VIRO-immunoclinical events. Results Pre-ART HIV DNA [median (IQR): 10 € 702 (3397-36 € 632) copies/10 6 CD4+ T cells] was correlated with pre-ART HIV RNA [R 2 = +0.44, (P &lt; 0.0001)], CD4+ T cells [R 2 = '0.58, (P &lt; 0.0001)] and CD4/CD8 ratio [R 2 = '0.48, (P &lt; 0.0001)], while weaker correlations were observed with CD8+ T cells (R 2 = '0.20, P = 0.01), IL-6 (R 2 = +0.16, P = 0.002) and soluble CD14 (R 2 = +0.09, P = 0.05). Patients with higher pre-ART HIV DNA showed lower rate and delayed VIROlogical response (defined as HIV RNA ≤50 copies/mL), compared with those having lower HIV DNA (67.2% for &gt;10 € 000, 81.1% for 1000-10 € 000 and 86.4% for 10-1000 copies/10 6 CD4+ T cells; P = 0.0004). Higher pre-ART HIV DNA was also correlated with increased risk of VIROlogical rebound (defined as HIV RNA &gt;50 copies/mL) by 24 months (17.2% for &gt;10 € 000, 7.4% for 1000-10 € 000 and 4.3% for 10-1000 copies/10 6 CD4+ T cells; P = 0.0048). Adjusted HRs of all VIROlogical rebound definitions confirmed these findings (P ≤ 0.02). Conclusions Pre-ART HIV DNA, along with HIV RNA and CD4+ T cell count, should be considered as a new staging marker to better identify people at lower (or higher) risk of viral rebound following achievement of VIROlogical suppression (≤50 copies/mL).

2018 - Promoting high standards of care for women living with HIV: position statement from the Women Against Viruses in Europe Working Group [Articolo su rivista]
Kowalska, J. D.; Aebi-Popp, K.; Loutfy, M.; Post, F. A.; Perez-Elias, M. J.; Johnson, M.; Mulcahy, F.; d'Arminio Monforte, A.; Branco, T.; Latysheva, K.; Seed, A.; Verluyten, J.; Geretti, A. M.; Dagnall, R.; Anderson, J.; De Jesus Albino Caixa, U.; Gatell, J. M.; Gjonbalaj, A.; Gokengin, A. D.; Haberl, A.; Lyons, F.; Mardarescu, M.; Oprea, C.; Papadopulous, A.; Stoycheva, M.; Voronin, E.; Youle, M.; Dixon-Williams, E.; Konopnicki, D.; Krasniqi, V.; Lacombe, K.; Mussini, C.; Boffito, M.; Battegay, M.; Friis-MOller, N.; Gilleece, Y.; Mackie, N.; Tariq, S.
abstract

Objectives: Gender-related factors can influence management decisions, treatment outcomes and the overall long-term wellbeing of people living with HIV (PLWH). The Women Against Viruses in Europe (WAVE) Working Group was established to promote the health and wellbeing of women living with HIV (WLWH). WAVE is part of the European AIDS Clinical Society (EACS) and organizes annual workshops to discuss different issues in the management of WLWH. Methods: In 2016, 34 WAVE members including community representatives, HIV clinicians and researchers met to discuss standards of care for WLWH and to review current guidelines. Participants focused on three different themes: (1) access to and engagement and retention in care; (2) monitoring of women on antiretroviral therapy and management of comorbidities; and (3) review of EACS treatment guidelines. Results: Five priority areas for optimizing the care of WLWH were identified: (1) psychosocial aspects of HIV diagnosis and care; (2) mental health and wellbeing; (3) pharmacokinetics, toxicity and tolerability of antiretroviral therapy; (4) coinfections and comorbidities; and (5) sexual and reproductive health. WAVE recommendations are provided for each of these areas, and gaps in knowledge and needs for changes in currently existing standards are discussed. Conclusions: This position statement provides an overview of the key recommendations to optimize the care of WLWH that emerged during the 2016 WAVE workshop.

2018 - Re: Lebentrau S, Gilfrich C, Vetterlein MW, Schumacher H, Spachmann PJ, Brookman-May SD, Fritsche HM, Schostak M, Wagenlehner F, Burger M, May M, MR2 study group (2017) Impact of the medical specialty on knowledge regarding multidrug-resistant organisms and strategies toward antimicrobial stewardship. Int Urol Nephrol 49:1311–1318 [Articolo su rivista]
Sighinolfi, Maria Chiara; Rocco, Bernardo Maria Cesare; Micali, Salvatore; Orlando, Gabriella; Venturelli, Claudia; Mussini, Cristina; Bianchi, Giampaolo
abstract

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2018 - Resistance detected in PBMCs predicts virological rebound in HIV-1 suppressed patients switching treatment [Articolo su rivista]
Armenia, Daniele; Zaccarelli, Mauro; Borghi, Vanni; Gennari, William; Di Carlo, Domenico; Giannetti, Alberto; Forbici, Federica; Bertoli, Ada; Gori, Caterina; Fabeni, Lavinia; Pinnetti, Carmela; Marocco, Raffaella; Latini, Alessandra; Ceccherini-Silberstein, Francesca; Mastroianni, Claudio Maria; Mussini, Cristina; Antinori, Andrea; Perno, Carlo Federico; Santoro, Maria Mercedes
abstract

Background: Genotypic resistance test (GRT) performed in peripheral blood mononuclear cells (PBMC) represents a chance to evaluate resistance in virologically suppressed HIV infected patients. Objectives: To evaluate the impact of baseline resistance detected through PBMC GRT on virological rebound after switching treatment. Study design: Baseline genotypic susceptibility scores (GSS) from PBMC GRT (DNA-GSS) and from previous cumulative plasma GRTs (when available, pRNA-GSS) were evaluated. Survival analysis was used to assess the probability and predictors of virological rebound (VR). Results: 227 virologically suppressed patients were analysed. Twenty-four months after switching therapy, the probability of VR was 15.3%. Patients showing an intermediate or full resistant DNA-GSS had a higher probability of experiencing VR compared to those carrying a fully susceptible DNA-GSS (27.2% vs. 13.7%, p = 0.001). By multivariable Cox regression, patients with an intermediate/full resistant DNA-GSS, with a nadir CD4 count &lt;100 cell/mm3 and with a shorter time of previous virological suppression showed a higher adjusted hazard of experiencing VR. In a sub-group of 114 patients with previous plasma GRTs available, patients with an intermediate or fully resistance showed by both GSSs (from plasma and PBMCs) had the highest probability of experiencing VR. Conclusions: Resistance detected in proviral DNA, together with a low nadir CD4 count and a short previous virological control, predicts VR after therapy switching in virologically suppressed patients. PBMC GRT can be a useful tool for tailoring treatment switch, especially if paired with information about previous cumulative resistance and previous viro-immunological history.

2018 - Switching to dual/monotherapy determines an increase in CD8+ in HIV-infected individuals: An observational cohort study [Articolo su rivista]
Mussini, C.; Lorenzini, P.; Cozzi-Lepri, A.; Marchetti, G.; Rusconi, S.; Gori, A.; Nozza, S.; Lichtner, M.; Antinori, A.; Cossarizza, Andrea; d'Arminio Monforte, A.; Castagna, A.; Castelli, F.; Cauda, R.; Di Perri, G.; Galli, M.; Iardino, R.; Ippolito, G.; Lazzarin, A.; Marchetti, G. C.; Perno, C. F.; Rezza, G.; von Schloesser, F.; Viale, P.; Ceccherini-Silberstein, F.; Girardi, E.; Lo Caputo, S.; Puoti, M.; Andreoni, M.; Ammassari, A.; Balotta, C.; Bandera, A.; Bonfanti, P.; Bonora, S.; Borderi, M.; Calcagno, A.; Calza, L.; Capobianchi, M. R.; Cingolani, A.; Cinque, P.; De Luca, A.; Di Biagio, A.; Gianotti, N.; Guaraldi, G.; Lapadula, G.; Madeddu, G.; Maggiolo, F.; Marcotullio, S.; Monno, L.; Quiros Roldan, E.; Rossotti, R.; Santoro, M. M.; Saracino, A.; Zaccarelli, M.; Fanti, I.; Galli, L.; Rodano, A.; Shanyinde, M.; Tavelli, A.; Carletti, F.; Carrara, S.; Di Caro, A.; Graziano, S.; Petrone, F.; Prota, G.; Quartu, S.; Truffa, S.; Giacometti, A.; Costantini, A.; Barocci, V.; Angarano, G.; Santoro, C.; Suardi, C.; Donati, V.; Verucchi, G.; Minardi, C.; Quirino, T.; Abeli, C.; Manconi, P. E.; Piano, P.; Cacopardo, B.; Celesia, B.; Vecchiet, J.; Falasca, K.; Sighinolfi, L.; Segala, D.; Blanc, P.; Vichi, F.; Cassola, G.; Viscoli, C.; Alessandrini, A.; Bobbio, N.; Mazzarello, G.; Mastroianni, C.; Pozzetto, I.; Caramma, I.; Chiodera, A.; Milini, P.; Rizzardini, G.; Moioli, M. C.; Piolini, R.; Ridolfo, A. L.; Salpietro, S.; Tincati, C.; Puzzolante, C.; Abrescia, N.; Chirianni, A.; Borgia, G.; Orlando, R.; Bonadies, G.; Di Martino, F.; Gentile, I.; Maddaloni, L.; Cattelan, A. M.; Marinello, S.; Cascio, A.; Colomba, C.; Baldelli, F.; Schiaroli, E.; Parruti, G.; Sozio, F.; Magnani, G.; Ursitti, M. A.; Cristaudo, A.; Vullo, V.; Acinapura, R.; Baldin, G.; Capozzi, M.; Cicalini, S.; Fontanelli Sulekova, L.; Iaiani, G.; Latini, A.; Mastrorosa, I.; Plazzi, M. M.; Savinelli, S.; Vergori, A.; Cecchetto, M.; Viviani, F.; Bagella, P.; Rossetti, B.; Franco, A.; Fontana Del Vecchio, R.; Francisci, D.; Di Giuli, C.; Caramello, P.; Orofino, G. C.; Sciandra, M.; Bassetti, M.; Londero, A.; Pellizzer, G.; Manfrin, V.; Starnini, G.; Ialungo, A.
abstract

Background: The CD4/CD8 ratio has been associated with the risk of AIDS and non-AIDS events. We describe trends in immunological parameters in people who underwent a switch to monotherapy or dual therapy, compared to a control group remaining on triple antiretroviral therapy (ART). Methods: We included patients in Icona who started a three-drug combination ART regimen from an ART-naïve status and achieved a viral load ≤ 50 copies/mL; they were subsequently switched to another triple or to a mono or double regimen. Standard linear regression at fixed points in time (12-24 months after the switch) and linear mixed model analysis with random intercepts and slopes were used to compare CD4 and CD8 counts and their ratio over time according to regimen types (triple vs. dual and vs. mono). Results: A total of 1241 patients were included; 1073 switched to triple regimens, 104 to dual (72 with 1 nucleoside reverse transcriptase inhibitor (NRTI), 32 NRTI-sparing), and 64 to monotherapy. At 12 months after the switch, for the multivariable linear regression the mean change in the log10 CD4/CD8 ratio for patients on dual therapy was -0.03 (95% confidence interval (CI) -0.05, -0.0002), and the mean change in CD8 count was +99 (95% CI +12.1, +186.3), taking those on triple therapy as reference. In contrast, there was no evidence for a difference in CD4 count change. When using all counts, there was evidence for a significant difference in the slope of the ratio and CD8 count between people who were switched to triple (points/year change ratio = +0.056, CD8 = -25.7) and those to dual regimen (ratio = -0.029, CD8 = +110.4). Conclusions: We found an increase in CD8 lymphocytes in people who were switched to dual regimens compared to those who were switched to triple. Patients on monotherapy did not show significant differences. The long-term implications of this difference should be ascertained.

2018 - The degree of HIV-1 amino acid variability is strictly related to different disease progression rates [Articolo su rivista]
Scutari, Rossana; Faieta, Monica; D’Arrigo, Roberta; Fabeni, Lavinia; Mussini, Cristina; Cossarizza, Andrea; Casoli, Claudio; Perno, Carlo Federico; Svicher, Valentina; Alteri, Claudia; Aquaro, Stefano
abstract

The aim of this study is to evaluate the amino acid variability of HIV-1 Gp41, C2–V3, and Nef in a group of patients characterized by different disease progression rates. HIV-1 sequences were collected from 19 Long term non progressor patients (LTNPs), 9 slow progressors (SPs), and 11 rapid progressors (RPs). Phylogenetic trees were estimated by MEGA 6. Differences in amino acid variability among sequences belonging to the 3 groups have been evaluated by amino acid divergence, Shannon entropy analysis, and the number of amino acid mutations (defined as amino acid variations compared with HxB2). The involvement of amino acid mutations on epitope rich regions was also investigated. The population was mainly composed of males (74.3%) and HIV-1 subtype B strains (B: 92.32%, CRF_12BF, A1, C: 2.56% each). Viral load (log10 copies/mL) and CD4+T cell count (cells/mm3) were 3.9 (3.5–4.2) and 618 (504–857) in LTNPs, 3.3 (2.8–4.7) and 463 (333–627) in SPs, and 4.6 (4.3–5.3) and 201 (110–254) in RPs. Gp41 and C2–V3 amino acid divergence was lower in LTNP and SP strains compared to RPs (median value: 0.085 and 0.091 vs. 0.114, p = 0.005 and 0.042) and a trend of lower variability was observed for Nef (p = 0.198). A lower entropy value was observed at 10, 3, and 7 positions of Gp41, C2–V3, and Nef belonging to LTNPs and at 7, 3, and 1 positions of Gp41, C2–V3, and Nef belonging to SPs compared with RPs (p &lt; 0.05). Focusing on epitope rich regions, again a higher degree of conservation was observed in Gp41 and C2–V3 sequences belonging to LTNPs and SPs compared to those belonging to RPs. This study shows that the extent of amino acid variability correlates with a different HIV-1 progression rate. This variability also involves CTL epitope rich regions, thus suggesting its involvement in the immune escape process modulation.

2018 - The extent of B-cell activation and dysfunction preceding lymphoma development in HIV-positive people [Articolo su rivista]
Shepherd, L.; Borges, Ã . H.; Harvey, R.; Bower, M.; Grulich, A.; Silverberg, M.; Weber, J.; Ristola, M.; Viard, J. -P.; Bogner, J. R.; Gargalianos-Kakolyris, P.; Mussini, C.; Mansinho, K.; Yust, I.; Paduta, D.; Jilich, D.; Smiatacz, T.; Radoi, R.; Tomazic, J.; Plomgaard, P.; Frikke-Schmidt, R.; Lundgren, J.; Mocroft, A.; Losso, M.; Kundro, M.; Schmied, B.; Karpov, I.; Vassilenko, A.; Mitsura, V. M.; Paduto, D.; Clumeck, N.; De Wit, S.; Delforge, M.; Florence, E.; Vandekerckhove, L.; Hadziosmanovic, V.; Begovac, J.; Machala, L.; Sedlacek, D.; Kronborg, G.; Benfield, T.; Gerstoft, J.; Katzenstein, T.; Møller, N. F.; Pedersen, C.; Ostergaard, L.; Wiese, L.; Nielsen, L. N.; Zilmer, K.; Jelena, S.; Nakkusosakond, S.; Kohtla-Järve, Null; Ristola, M.; Aho, I.; Girard, P. -M.; Pradier, C.; Fontas, E.; Duvivier, C.; Rockstroh, J.; Schmidt, R.; Degen, O.; Stellbrink, H. J.; Stefan, C.; Fätkenheuer, G.; Chkhartishvili, N.; Gargalianos, P.; Xylomenos, G.; Armenis, K.; Sambatakou, H.; Szlávik, J.; Gottfredsson, M.; Mulcahy, F.; Turner, D.; Burke, M.; Shahar, E.; Hassoun, G.; Elinav, H.; Haouzi, M.; Elbirt, D.; Sthoeger, Z. M.; D'Arminio Monforte, A.; Esposito, R.; Mazeu, I.; Mazzotta, F.; Gabbuti, A.; Vullo, V.; Lichtner, M.; Zaccarelli, M.; Antinori, A.; Acinapura, R.; Plazzi, M.; Lazzarin, A.; Castagna, A.; Gianotti, N.; Galli, M.; Ridolfo, A.; Sacco, Osp. L; Rozentale, B.; Uzdaviniene, V.; Matulionyte, R.; Staub, T.; Hemmer, R.; Reiss, P.; Ormaasen, V.; Maeland, A.; Bruun, J.; Knysz, B.; Gasiorowski, J.; Inglot, M.; Horban, A.; Bakowska, E.; Flisiak, R.; Grzeszczuk, A.; Parczewski, M.; Maciejewska, K.; Aksak-Was, B.; Beniowski, M.; Mularska, E.; Gensing, M.; Jablonowska, E.; Malolepsza, E.; Wojcik, K.; Mozer-Lisewska, I.; Caldeira, L.; Maltez, F.; Oprea, C.; Victor, B.; Panteleev, A.; Panteleev, O.; Yakovlev, A.; Trofimora, T.; Khromova, I.; Kuzovatova, E.; Borodulina, E.; Vdoushkina, E.; Jevtovic, D.; Gatell, J. M.; Miró, J. M.; Moreno, S.; Rodriguez, J. M.; Clotet, B.; Jou, A.; Paredes, R.; Tural, C.; Puig, J.; Bravo, I.; Domingo, P.; Gutierrez, M.; Mateo, G.; Sambeat, M. A.; Laporte, J. M.; Falconer, K.; Thalme, A.; Sonnerborg, A.; Blaxhult, A.; Flamholc, L.; Scherrer, A.; Weber, R.; Cavassini, M.; Calmy, A.; Furrer, H.; Battegay, M.; Schmid, P.; Kuznetsova, A.; Kyselyova, G.; Sluzhynska, M.; Gazzard, B.; Johnson, A. M.; Simons, E.; Edwards, S.; Phillips, A.; Johnson, M. A.; Mocroft, A.; Orkin, C.; Scullard, G.; Clarke, A.; Leen, C.; Gatell, J.; Gazzard, B.; Horban, A.; Karpov, I.; Losso, M.; d'Arminio Monforte, A.; Pedersen, C.; Reiss, P.; Rockstroh, J.; Rockstroh, J.; Kirk, O.; Kirk, O.; Peters, L.; Matthews, C.; Fischer, A. H.; Bojesen, A.; Raben, D.; Kristensen, D.; Grønborg Laut, K.; Larsen, J. F.; Podlekareva, D.; Cozzi-Lepri, A.; Schultze, A.; Amele, S.
abstract

Objectives: B-cell dysfunction and activation are thought to contribute to lymphoma development in HIV-positive people; however, the mechanisms are not well understood. We investigated levels of several markers of B-cell dysfunction [free light chain (FLC)-κ, FLC-λ, immunoglobulin G (IgG), IgA, IgM and IgD] prior to lymphoma diagnosis in HIV-positive people. Methods: A nested matched case–control study was carried out within the EuroSIDA cohort, including 73 HIV-positive people with lymphoma and 143 HIV-positive lymphoma-free controls. Markers of B-cell dysfunction were measured in prospectively stored serial plasma samples collected before the diagnosis of lymphoma (or selection date in controls). Marker levels ≤ 2 and &gt; 2 years prior to diagnosis were investigated. Results: Two-fold higher levels of FLC-κ [odds ratio (OR) 1.84; 95% confidence interval (CI) 1.19, 2.84], FLC-λ (OR 2.15; 95% CI 1.34, 3.46), IgG (OR 3.05; 95% CI 1.41, 6.59) and IgM (OR 1.46; 95% CI 1.01, 2.11) were associated with increased risk of lymphoma &gt; 2 years prior to diagnosis, but not ≤ 2 years prior. Despite significant associations &gt; 2 years prior to diagnosis, the predictive accuracy of each marker was poor, with FLC-λ emerging as the strongest candidate with a c-statistic of 0.67 (95% CI 0.58, 0.76). Conclusions: FLC-κ, FLC-λ and IgG levels were higher &gt; 2 years before lymphoma diagnosis, suggesting that B-cell dysfunction occurs many years prior to lymphoma development. However, the predictive value of each marker was low and they are unlikely candidates for risk assessment for targeted intervention.

2018 - Treatment rate for HCV in the direct acting antivirals era in HIV co-infected patients: data from an italian cohort [Articolo su rivista]
Cuomo, Gianluca; Puzzolante, Cinzia; Lazzaretti, Claudia; Guaraldi, Giovanni; Borghi, Vanni; Mussini, Cristina
abstract

New Direct Antiviral Agents (DAA) are now effective in HCV infection; persons living with HIV (PLWH) were undertreated. Aim of this study was to describe the management of HCV treatment in a HIV/HCV cohort during a 16 years period.

2018 - Viro-immunological response of drug-naive HIV-1-infected patients starting a first-line regimen with viraemia >500,000 copies/ml in clinical practice [Articolo su rivista]
Santoro, Maria Mercedes; Di Carlo, Domenico; Armenia, Daniele; Zaccarelli, Mauro; Pinnetti, Carmela; Colafigli, Manuela; Prati, Francesca; Boschi, Andrea; Antoni, Anna Maria Degli; Lagi, Filippo; Sighinolfi, Laura; Gervasoni, Cristina; Andreoni, Massimo; Antinori, Andrea; Mussini, Cristina; Perno, Carlo Federico; Borghi, Vanni; Sterrantino, Gaetana
abstract

Virological success (VS) and immunological reconstitution (IR) of antiretroviral-naïve HIV-1 infected patients with pre-therapy viral load (VL) &gt;500,000 copies/mL was assessed after 12 months of treatment according to initial drug-class regimens.

2017 - A frailty index predicts post-liver transplant morbidity and mortality in HIV-positive patients [Articolo su rivista]
Guaraldi, Giovanni; Dolci, Giovanni; Zona, Stefano; Tarantino, Giuseppe; Serra, Valentina; Ballarin, Roberto; Franceschini, Erica; Codeluppi, Mauro; Brothers, Thomas D.; Mussini, Cristina; DI BENEDETTO, Fabrizio
abstract

Background: We hypothesized that frailty acts as a measure of health outcomes in the context of LT. The aim of this study was to explore frailty index across LT, as a measure of morbidity and mortality. This was a retrospective observational study including all consecutive 47 HIV+patients who received LT in Modena, Italy from 2003 to June 2015. Methods: frailty index (FI) was constructed from 30 health variables. It was used both as a continuous score and as a categorical variable, defining 'most frail' a FI > 0.45. FI change across transplant (deltaFI, ΔFI) was calculated as the difference between year 1 FI (FI-Y1) and pre-transplant FI (FI-t0). The outcomes measures were mortality and "otpimal LT" (defined as being alive without multi-morbidity). Results: Median value of FI-t0 was 0.48 (IQR 0.42-0.52), FI-Y1 was 0.31 (IQR 0.26-0.41). At year five mortality rate was 45%, "optimal transplant" rate at year 1 was 38%. All the patients who died in the post-LT were most frail in the pre-LT. ΔFI was a predictor of mortality after correction for age and MELD (HR = 1.10, p = 0.006) and was inversely associated with optimal transplant after correction for age (HR = 1.04, p = 0.01). Conclusions: We validated FI as a valuable health measure in HIV transplant. In particular, we found a relevant correlation between FI strata at baseline and mortality and a statistically significant correlation between, ΔFI and survival rate.

2017 - Access and response to direct antiviral agents (DAA) in HIV-HCV co-infected patients in Italy: Data from the Icona cohort [Articolo su rivista]
Monforte, Antonella D'Arminio; Cozzi-Lepri, Alessandro; Ceccherini-Silberstein, Francesca; De Luca, Andrea; Caputo, Sergio Lo; Castagna, Antonella; Mussini, Cristina; Cingolani, Antonella; Tavelli, Alessandro; Shanyinde, Milensu; Gori, Andrea; Girardi, Enrico; Andreoni, Massimo; Antinori, Andrea; Puoti, Massimo
abstract

Background Real-life data on access and response to direct antiviral agents (DAA) in HIV-HCV coinfected individuals are lacking. Methods HCV viremic, HIV-positive patients from Icona and Hepaicona cohorts nave to DAA by January 2013 were included. Access and predictors of starting DAA were evaluated. Switches of antiretroviral drugs at starting DAA were described. We calculated sustained virological response (SVR12) in those reaching 12 weeks after end-of-treatment (EOT), and defined treatment failure (TF) as discontinuation of DAA before EOT or non-SVR12. Statistical analyses included Kaplan-Meier curves, univariable and multivariable analyses evaluating predictors of access to DAA and of treatment outcome (non-SVR and TF). Results 2,607 patients included. During a median follow-up of 38 (IQR:30-41) months, 920 (35.3%) patients started DAA. Eligibility for reimbursement was the strongest predictor to access to treatment: 761/1,090 (69.8%) eligible and 159/1,517 (10.5%) non-eligible to DAA reimbursement. Older age, HIV-RNA50 copies/mL were associated to faster DAA initiation, higher CD4 count and HCV-genotype 3 with delayed DAA initiation in those eligible to DAA reimbursement. Up to 28% of patients (36% of those on ritonavir-boosted protease inhibitors, PI/r) underwent antiretroviral (ART) modification at DAA initiation. 545/595 (91.6%) patients reaching EOT achieved SVR12. Overall, TF occurred in 61/606 patients (10.1%), with 11 discontinuing DAA before EOT. Suboptimal DAA was the only independent predictor of both non-SVR12 (AHR 2.52, 95%CI:1.24-5.12) and TF (AHR: 2.19; 95%CI:1.13-4.22). Conclusions Only 35.3% had access to HCV treatment. Despite excellent rates of SVR12 rates (91.6%), only 21% (545/2,607) of our HIV-HCV co-infected patients are cured.

2017 - Acute human herpes virus 7 (HHV-7) encephalitis in an immunocompetent adult patient: a case report and review of literature [Articolo su rivista]
Riva, Nicoletta; Franconi, Iacopo; Meschiari, Marianna; Franceschini, Erica; Puzzolante, Cinzia; Cuomo, Gianluca; Bianchi, Alessandro; Cavalleri, Francesca; Genovese, Maurilio; Mussini, Cristina
abstract

We report a case of an acute HHV-7 encephalitis involving the nucleus of the VI cranial nerve in an immunocompetent host. The patient was an adult male admitted to our Clinic with headache, diplopia, fever, nausea, vertigo, asthenia and general malaise. PCR for viral and bacterial genomes was run on both serum and cerebral spinal fluid (CSF) after performing lumbar puncture, resulting positive only for HHV-7 DNA on CSF. MRI showed hyperintensity in FLAIR signal in the dorsal pons, in the area of the VI cranial nerve nucleus. Empirical therapy with Acyclovir and Dexamethasone was started at the time of admission and was continued after the microbiology results. After three days of therapy diplopia, fever and other previous clinical manifestations improved and the patient recovered normal sight. Our case report contributes to a better understanding of the presentation, diagnosis and treatment of HHV-7 encephalitis in immunocompetent patients due to reactivation in adult age.

2017 - Ageing and inflammation in patients with HIV infection [Articolo su rivista]
Nasi, Milena; DE BIASI, Sara; Gibellini, Lara; Bianchini, Elena; Pecorini, S.; Bacca, V.; Guaraldi, Giovanni; Mussini, Cristina; Pinti, Marcello; Cossarizza, Andrea
abstract

Nowadays, HIV+ patients have an expected lifespan that is only slightly shorter than healthy individuals. For this reason, along with the fact that infection can be acquired at a relatively advanced age, the effects of ageing on HIV+ people have begun to be evident. Successful anti-viral treatment is, on one hand, responsible for the development of side effects related to drug toxicity; on the other hand, it is not able to inhibit the onset of several complications caused by persistent immune activation and chronic inflammation. Therefore, patients with a relatively advanced age, i.e. aged more than 50 years, can experience pathologies that affect much older citizens. HIV+ individuals with non-AIDS-related complications can thus come to the attention of clinicians because of the presence of neurocognitive disorders, cardiovascular diseases, metabolic syndrome, bone abnormalities and non-HIV-associated cancers. Chronic inflammation and immune activation, observed typically in elderly people and defined as 'inflammaging', can be present in HIV+ patients who experience a type of premature ageing, which affects the quality of life significantly. This relatively new condition is extremely complex, and important factors have been identified as well as the traditional behavioural risk factors, e.g. the toxicity of anti-retroviral treatments and the above-mentioned chronic inflammation leading to a functional decline and a vulnerability to injury or pathologies. Here, we discuss the role of inflammation and immune activation on the most important non-AIDS-related complications of chronic HIV infection, and the contribution of aging per se to this scenario.

2017 - Awareness, discussion and non-prescribed use of HIV pre-exposure prophylaxis among persons living with HIV/AIDS in Italy: a Nationwide, cross-sectional study among patients on antiretrovirals and their treating HIV physicians [Articolo su rivista]
Palummieri, Antonio; De Carli, Gabriella; Rosenthal, Éric; Cacoub, Patrice; Mussini, Cristina; Puro, Vincenzo
abstract

Before Pre-Exposure Prophylaxis (PrEP) was officially recommended and made available, a few surveys among gay and bisexual men, and persons living with HIV/AIDS (PLWHA), identified an informal use of antiretrovirals (ARVs) for PrEP among HIV-negative individuals. Before PrEP availability in Italy, we aimed to assess whether PLWHA in Italy shared their ARVs with HIV-negative individuals, whether they knew people who were on PrEP, and describe the level of awareness and discussion on this preventive measure among them and people in their close circle.

2017 - Brief Report: Drop in CD4+ Counts Below 200 Cells/μL After Reaching (or Starting From) Values Higher than 350 Cells/μL in HIV-Infected Patients With Virological Suppression [Articolo su rivista]
Gianotti, Nicola; Marchetti, Giulia; Antinori, Andrea; Saracino, Annalisa; Gori, Andrea; Rizzardini, Giuliano; Lichtner, Miriam; Bandera, Alessandra; Mussini, Cristina; Girardi, Enrico; dʼArminio Monforte, Antonella; Cozzi-Lepri, Alessandro
abstract

The aim of the study was to quantify the risk of a drop in CD4 counts below 200 cells/μL after reaching values &gt;350 cells/μL on antiretroviral therapy (ART) (or after starting ART with CD4 count &gt;350 cells/μL) in the absence of virological failure.

2017 - CD4 cell count response to first-line combination ART in HIV-2+ patients compared with HIV-1+ patients: A multinational, multicohort European study [Articolo su rivista]
Wittkop, Linda; Arsandaux, Julie; Trevino, Ana; van der Loeff, Maarten Schim; Anderson, Jane; van Sighem, Ard; Böni, Jürg; Brun-Vezinet, Françoise; Soriano, Vicente; Boufassa, Faroudy; Brockmeyer, Norbert; Calmy, Alexandra; Dabis, François; Jarrin, Inma; Dorrucci, Maria; Duque, Vitor; Fätkenheuer, Gerd; Zangerle, Robert; Ferrer, Elena; Porter, Kholoud; Judd, Ali; Sipsas, Nikolaos V.; Lambotte, Olivier; Shepherd, Leah; Leport, Catherine; Morrison, Charles; Mussini, Cristina; Obel, Niels; Ruelle, Jean; Schwarze-Zander, Carolyne; Sonnerborg, Anders; Teira, Ramon; Torti, Carlo; Valadas, Emilia; Colin, Celine; Friis-Møller, Nina; Costagliola, Dominique; Thiebaut, Rodolphe; Chene, Geneviève; Matheron, Sophie; Touloumi, Giota; Warszawski, Josiane; Meyer, Laurence; Krause, Murielle Mary; Ghosn, Jade; Reiss, Peter; Wit, Ferdinand; Prins, Maria; Bucher, Heiner; Gibb, Diana; Del Amo, Julia; Thorne, Claire; Mocroft, Amanda; Kirk, Ole; Stephan, Christoph; Pérez-Hoyos, Santiago; Hamouda, Osamah; Bartmeyer, Barbara; Chkhartishvili, Nikoloz; Noguera-Julian, Antoni; Antinori, Andrea; Monforte, Antonella d'Arminio; Prieto, Luis; Conejo, Pablo Rojo; Soriano-Arandes, Antoni; Battegay, Manuel; Kouyos, Roger; Tookey, Pat; Casabona, Jordi; Mirò, Jose M.; Castagna, Antonella; Konopnick, Deborah; Goetghebuer, Tessa; Sönnerborg, Anders; Sabin, Caroline; Garrido, Myriam; Haerry, David; Berenguer, Juan; Bohlius, Julia; Bouteloup, Vincent; Cozzi-Lepri, Alessandro; Monforte, Antonella d'Arminio; Davies, Mary-Anne; Amo, Julia del; Dunn, David; Egger, Matthias; Furrer, Hansjakob; Guiguet, Marguerite; Grabar, Sophie; Leroy, Valériane; Lodi, Sara; Monge, Susana; Nakagawa, Fumiyo; Paredes, Roger; Phillips, Andrew; Puoti, Massimo; Schomaker, Michael; Smit, Colette; Sterne, Jonathan; van der Valk, Marc; Wyss, Natasha
abstract

Background: CD4 cell recovery following first-line combination ART (cART) is poorer in HIV-2+ than in HIV-1+ patients. Only large comparisons may allow adjustments for demographic and pretreatment plasma viral load (pVL). Methods: ART-naive HIV+ adults from two European multicohort collaborations, COHERE (HIV-1 alone) and ACHIeV2e (HIV-2 alone), were included, if they started first-line cART (without NNRTIs or fusion inhibitors) between 1997 and 2011. Patients without at least one CD4 cell count before start of cART, without a pretreatment pVL and with missing a priori-defined covariables were excluded. Evolution of CD4 cell count was studied using adjusted linear mixed models. Results: We included 185 HIV-2+ and 30321 HIV-1+ patients with median age of 46 years (IQR 36-52) and 37 years (IQR 31-44), respectively. Median observed pretreatment CD4 cell counts/mm3 were 203 (95% CI 100-290) in HIV-2+ patients and 223 (95% CI 100-353) in HIV-1+ patients. Mean observed CD4 cell count changes from start of cART to 12months were +105 (95% CI 77-134) in HIV-2+ patients and +202 (95% CI 199-205) in HIV-1+ patients, an observed difference of 97 cells/mm3in 1 year. In adjusted analysis, the mean CD4 cell increase was overall 25 CD4 cells/mm3/year lower (95% CI 5-44; P=0.0127) in HIV-2+ patients compared with HIV-1+ patients. Conclusions: A poorer CD4 cell increase during first-line cART was observed in HIV-2+patients, even after adjusting for pretreatment pVL and other potential confounders. Our results underline the need to identify more potent therapeutic regimens or strategies against HIV-2.

2017 - Cardiovascular disease in women with HIV-1 infection [Articolo su rivista]
Volpe, Massimo; Uglietti, Alessia; Castagna, Antonella; Mussini, Cristina; Marchetti, Giulia; Bellagamba, Rita; Bini, Teresa; Mancusi, Daniela; Termini, Roberta
abstract

Cardiovascular disease is a leading cause of death in women, nevertheless it is often underestimated in female patients without overt risk factors. The chronic infection by Human Immunodeficiency Virus (HIV) is clearly associated, along with the use of certain antiretroviral drugs and traditional risk factors, with an increased risk of cardiovascular diseases. The aim of this manuscript is to review the epidemiology, risk factors, pathogenesis, diagnostic approach, primary and secondary prevention strategies of cardiovascular disease in HIV-negative and HIV-positive female subjects. The ultimate goal is to promote knowledge and development of specific and appropriate clinical interventions and guidelines in this group of high-risk patients, mostly in view of the expected growth of ageing females with HIV.

2017 - Changing in the post-surgery infective complications following the shortening of the antibiotic prophylaxis in the patients undergoing skin dermal substitutes reconstruction [Poster]
Bedini, Andrea; Fiorentini, Chiara; Mandel, Victor Desmond; Bacca, Erica; Ferrari, Federica; DE PACE, Barbara; Meschiari, Marianna; Santoro, Antonella; Orlando, Gabriella; Franceschini, Erica; Puzzolante, Cinzia; Mussini, Cristina; Magnoni, Cristina
abstract

Background: Bioengineered skin dermal substitutes (SDS) represent a novel therapeutic opportunity for restoring damaged tissue, both in massive deep burns, extensive full-thickness wounds, and reconstruction after cancer resection. Antimicrobial prophylaxis duration in such procedures has not been well established yet. The aim of the study was to evaluate the changing of infective complications following shortening of perioperative prophylaxis in patients undergoing surgical reconstruction with SDS. Material &amp; Methods: Infective complications at the site of SDS were compared in two groups of patients: subjects undergoing surgical reconstruction between September 2014 and January 2016 (PERIOD A) who received a &gt;24h-antibiotic prophylaxis, and subjects undergoing surgical reconstruction between May 2016 and June 2017 (PERIOD B) who received a ≤24h-antibiotic prophylaxis. Differences in the incidence of infection and pathogen prevalence were explored. Univariate linear regression analysis was performed to evaluate the risk factors for infection (sex, age, ASA code, perioperative antibiotic prophylaxis, site of SDS intervention, type of SDS, dimensions of surgical area, chronic renal impairment, and diabetes mellitus). Results: Between September 2014 and June 2017, 116 patients underwent a surgical reconstruction with a SDS. The 66.4% (n=77) of the study population was male, and the mean age was 73 years (22-92 years). Seventy-eight patients (67.2%) were positive for hypertension, 20 (17.2%) for diabetes mellitus, 16 (13.8%) for chronic renal impairment, 22 (19%) were former or current smokers, and 45 (38.8%) had an ASA code ≥3. In the 94.8% of the patients (n=110) the reason of surgical intervention was a skin cancer. Surgical SDS reconstruction involved the scalp in 44 cases (37.9%), the face in 28 (24.1%), the chest in 11 (9.5%), the arm or the hand in 9 (7.8%), the leg in 12 (10.3%) and the foot in 12 (10.3%). Among 116 patients undergoing SDS surgical reconstruction, 62 (53.4%) received a &gt;24h-prophylaxis and 54 (46.6%) received a ≤24h-prophylaxis. The average duration of prophylaxis in the 2 groups of patients was 6.6 days and 0.5 day, respectively. Overall incidence rate of infection was 20.7% (24/116). The most frequently isolated pathogen was S. aureus (41.6%), followed by P. aeruginosa (29.1%), P. mirabilis (8.3%), and E. faecalis (4.1%). Patients undergoing SDS reconstruction in limb/foot had higher infection rate in comparison with those undergoing SDS reconstruction in chest/head (33.3% and 15.6%, respectively; p=0.034). No differences in the infection rate were observed between the patients who received &gt;24h or ≤24h-antibiotic prophylaxis (22.5% and 18.5%, respectively; p=0.590). The two groups resulted similar for gender, age, comorbidities, ASA score, and type of skin cancer. No significant differences in pathogen prevalence were found (p=0.692). Conclusion: Antibiotic prophylaxis reduction to 24 hours or less demonstrated to be beneficial to patients undergoing surgical reconstruction with SDS. Shortening of antibiotic prophylaxis did not increase infection rate, and it allowed to reduce of 6 days-per-patient the antibiotic exposure.

2017 - Chronic hepatitis B and C virus infection and risk for non-hodgkin lymphoma in HIV-infected patients: A cohort study [Articolo su rivista]
Wang, Qing; De Luca, Andrea; Smith, Colette; Zangerle, Robert; Sambatakou, Helen; Bonnet, Fabrice; Smit, Colette; Schommers, Philipp; Thornton, Alicia; Berenguer, Juan; Peters, Lars; Spagnuolo, Vincenzo; Ammassari, Adriana; Antinori, Andrea; Roldan, Eugenia Quiros; Mussini, Cristina; Miro, Jose M.; Konopnicki, Deborah; Fehr, Jan; Campbell, Maria A.; Termote, Monique; Bucher, Heiner C.; De Wit, Stéphane; Costagliola, Dominique; D'Arminio-Monforte, Antonella; Castagna, Antonella; Del Amo, Julia; Mocroft, Amanda; Raben, Dorthe; Chêne, Geneviève; Touloumi, Giota; Warszawski, Josiane; Meyer, Laurence; Dabis, François; Krause, Murielle Mary; Ghosn, Jade; Leport, Catherine; Wittkop, Linda; Reiss, Peter; Wit, Ferdinand; Prins, Maria; Sabin, Caroline; Gibb, Diana; Fätkenheuer, Gerd; Obel, Niels; Thorne, Claire; Kirk, Ole; Stephan, Christoph; Pérez-Hoyos, Santiago; Hamouda, Osamah; Bartmeyer, Barbara; Chkhartishvili, Nikoloz; Noguera-Julian, Antoni; D'Arminio Monforte, Antonella; Brockmeyer, Norbert; Prieto, Luis; Conejo, Pablo Rojo; Soriano-Arandes, Antoni; Battegay, Manuel; Rauch, Andri; Tookey, Pat; Casabona, Jordi; Goetghebuer, Tessa; Sönnerborg, Anders; Torti, Carlo; Teira, Ramon; Garrido, Myriam; Haerry, David; Bohlius, Julia; Bouteloup, Vincent; Cozzi-Lepri, Alessandro; Davies, Mary-Anne; Dorrucci, Maria; Dunn, David; Egger, Matthias; Furrer, Hansjakob; Guiguet, Marguerite; Grabar, Sophie; Judd, Ali; Lambotte, Olivier; Leroy, Valériane; Lodi, Sara; Matheron, Sophie; Monge, Susana; Nakagawa, Fumiyo; Paredes, Roger; Phillips, Andrew; Puoti, Massimo; Schomaker, Michael; Sterne, Jonathan; Thiebaut, Rodolphe; Van Der Valk, Marc; Wyss, Natasha; Barger, Diana; Schwimmer, Christine; Friis-Møller, Nina; Kjaer, Jesper; Brandt, Rikke Salbøl
abstract

Background: Non-Hodgkin lymphoma (NHL) is the most common AIDS-defining condition in the era of antiretroviral therapy (ART). Whether chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infection promote NHL in HIV-infected patients is unclear. Objective: To investigate whether chronic HBV and HCV infection are associated with increased incidence of NHL in HIVinfected patients. Design: Cohort study. Setting: 18 of 33 cohorts from the Collaboration of Observational HIV Epidemiological Research Europe (COHERE). Patients: HIV-infected patients with information on HBV surface antigen measurements and detectable HCV RNA, or a positive HCV antibody test result if HCV RNA measurements were not available. Measurements: Time-dependent Cox models to assess risk for NHL in treatment-naive patients and those initiating ART, with inverse probability weighting to control for informative censoring. Results: A total of 52 479 treatment-naive patients (1339 [2.6%] with chronic HBV infection and 7506 [14.3%] with HCV infection) were included, of whom 40 219 (77%) later started ART. The median follow-up was 13 months for treatment-naive patients and 50 months for those receiving ART. A total of 252 treatmentnaive patients and 310 treated patients developed NHL, with incidence rates of 219 and 168 cases per 100 000 person-years, respectively. The hazard ratios for NHL with HBV and HCV infection were 1.33 (95% CI, 0.69 to 2.56) and 0.67 (CI, 0.40 to 1.12), respectively, in treatment-naive patients and 1.74 (CI, 1.08 to 2.82) and 1.73 (CI, 1.21 to 2.46), respectively, in treated patients. Limitation: Many treatment-naive patients later initiated ART, which limited the study of the associations of chronic HBV and HCV infection with NHL in this patient group. Conclusion: In HIV-infected patients receiving ART, chronic coinfection with HBV and HCV is associated with an increased risk for NHL.

2017 - Clinical Utility of Epstein-Barr Virus Viral Load Monitoring and Risk Factors for Posttransplant Lymphoproliferative Disorders After Kidney Transplantation [Articolo su rivista]
Franceschini, Erica; Plessi, Jessica; Zona, Stefano; Santoro, Antonella; Digaetano, Margherita; Fontana, Francesco; Alfano, Gaetano; Guaraldi, Giovanni; Comoli, Patrizia; Facchini, Francesca; Potenza, Leonardo; Gennari, William; Codeluppi, Mauro; Luppi, Mario; Cappelli, Gianni; Gyssens, Inge C.; Mussini, Cristina
abstract

Background. Posttransplant lymphoproliferative disease (PTLD) is an important cause of morbidity and mortality in solid organ transplants. Epstein Barr virus (EBV) plays a major role in PTLD development. Guidelines recommend EBV viral load (VL) monitoring in high-risk populations in the first year. Methods. Retrospective observational study in all adult patients who had at least 1 EBV-VL performed in the postkidney transplant (KT) period from January 2005 to December 2014 at the Policlinico Modena Hospital. We compared patients with negative EBV-DNA to patients with positive EBV-DNA and we described PTLD developed in the study period. Results.One hundred ninety (36.3%) KT patients of 523 were screened for EBV-DNA with 796 samples. One hundred twenty-eight (67.4%) of 190 tested patients presented at least 1 positive sample for EBV. Older age, the use of sirolimus, everolimus, and steroids were associated with EBV-DNA positivity in the univariate analysis. Nine (1.7%) of 523 patients had PTLD. Incidence rate of PTLD in the KT cohort was 0.19/100 person year follow-up (95% confidence interval, 0.09-0.37). One of 9 patients developed early PTLD and was a high-risk patient. Only this PTLD case was positive for EBV. No PTLD case had an EBV-VL superior to 4000 copies/mL. Conclusions. Our results suggest that the keystone of PTLD diagnosis is the clinical suspicion. Our study suggests that, in line with guidelines, EBV-VL assays may be avoided in low-risk patients in the absence of a strong clinical PTLD suspicion without increasing patients' risk of developing PTLD. This represents a safe and cost-saving clinical strategy for our center

2017 - Comparative evaluation of subtyping tools for surveillance of newly emerging HIV-1 strains [Articolo su rivista]
Fabeni, Lavinia; Berno, Giulia; Fokam, Joseph; Bertoli, Ada; Alteri, Claudia; Gori, Caterina; Forbici, Federica; Takou, Desiré; Vergori, Alessandra; Zaccarelli, Mauro; Maffongelli, Gaetano; Borghi, Vanni; Latini, Alessandra; Pennica, Alfredo; Mastroianni, Claudio Maria; Montella, Francesco; Mussini, Cristina; Andreoni, Massimo; Antinori, Andrea; Perno, Carlo Federico; Santoro, Maria Mercedes; Armenia, Daniele; Bellocchi, Maria Concetta; Biddittu, Andrea; Bruni, Massimiliano; Buonomini, Anna Rita; Carioti, Luca; Ceccherini-Silberstein, Francesca; Cerva, Carlotta; Cesta, Novella; Di Carlo, Domenico; Dori, Luca; Foroghi, Luca; Gentilotti, Elisa; Giannella, Sara; Guenci, Tania; Malagnino, Vincenzo; Ricciardi, Alessandra; Romani, Marzia; Salpini, Omina; Sarmati, Loredana; Scutari, Rossana; Serafini, Valentina; Sordillo, Pasquale; Stazi, Francesca; Stingone, Cristof; Svicher, Valentina; Teti, Elisabetta; Viscione, Magdalena; Abbate, Isabella; Acinapura, Rosa; Alba, Lucia; Ammassari, Adriana; Baldini, Franco; Bellagamba, Rita; Boumis, Evangelo; Capobianchi, Maria Rosaria; Carta, Stefania; Cicalini, Stefania; Continenza, Fabio; De Carli, Gabriella; D'Arrigo, Roberta; D'Offizi, Gianpiero; Fedele, Valentina; Galati, Vincenzo; Giannetti, Alberto; Girardi, Enrico; Grisetti, Susanna; Libertone, Raffaella; Liuzzi, Giuseppina; Lorenzini, Patrizia; Maddaluno, Rita; Mariano, Andrea; Navarra, Assunta; Nicastri, Emanuele; Nurra, Giuseppina; Orchi, Nicoletta; Palummieri, Antonio; Pinnetti, Carmela; Pittalis, Silvia; Pizzi, Daniele; Puro, Vincenzo; Sampaolesi, Alessandro; Sciarrone, Maria Rosaria; Scognamiglio, Paola; Sias, Catia; Visco-Comandini, Ubaldo; Colafigli, Manuela; Cristaudo, Antonio; Giuliani, Massimo; Pacifici, Anna; Di Sora, Fiorella; Iebba, Filippo; Lichtner, Miriam; Marocco, Raffaella; Bernardi, Stefania; Anzalone, Enza; Bonaventura, Maria Elena; Marchili, Mauro; Pitorri, Antonella; Di Francesco, Luigi Falconi; Di Giammartino, Dante; Caterini, Antonio; Armignacco, Orlando; Mariani, Rinalda; Paoloni, Maurizio; Parruti, Giustino; Pieri, Alessandro; Sozio, Federica; Cellini, Antonio; Grimaldi, Alessandro; Mariani, Maurizio; Picchi, Giovanna; Gennari, William; Nanfack, Aubin J.; Ndjolo, Alexis; Torimiro, Judith N.
abstract

HIV-1 non-B subtypes/circulating recombinant forms (CRFs) are increasing worldwide. Since subtype identification can be clinically relevant, we assessed the added value in HIV-1 subtyping using updated molecular phylogeny (Mphy) and the performance of routinely used automated tools. Updated Mphy (2015 updated reference sequences), used as a gold standard, was performed to subtype 13,116 HIV-1 protease/reverse transcriptase sequences and then compared with previous Mphy (reference sequences until 2014) and with COMET, REGA, SCUEAL, and Stanford subtyping tools. Updated Mphy classified subtype B as the most prevalent (73.4%), followed by CRF02-AG (7.9%), C (4.6%), F1 (3.4%), A1 (2.2%), G (1.6%), CRF12-BF (1.2%), and other subtypes (5.7%). A 2.3% proportion of sequences were reassigned as different subtypes or CRFs because of misclassification by previous Mphy. Overall, the tool most concordant with updated Mphy was Stanford-v8.1 (95.4%), followed by COMET (93.8%), REGA-v3 (92.5%), Stanford-old (91.1%), and SCUEAL (85.9%). All the tools had a high sensitivity (≥98.0%) and specificity (≥95.7%) for subtype B. Regarding non-B subtypes, Stanford-v8.1 was the best tool for C, D, and F subtypes and for CRFs 01, 02, 06, 11, and 36 (sensitivity, ≥92.6%; specificity, ≥99.1%). A1 and G subtypes were better classified by COMET (92.3%) and REGA-v3 (98.6%), respectively. Our findings confirm Mphy as the gold standard for accurate HIV-1 subtyping, although Stanford-v8.1, occasionally combined with COMET or REGA-v3, represents an effective subtyping approach in clinical settings. Periodic updating of HIV-1 reference sequences is fundamental to improving subtype characterization in the context of an effective epidemiological surveillance of non-B strains.

2017 - Comparison of Kaposi Sarcoma risk in human immunodeficiency virus-positive adults across 5 continents: A multiregional multicohort study [Articolo su rivista]
Rohner, E.; Butikofer, L.; Schmidlin, K.; Sengayi, M.; Maskew, M.; Giddy, J.; Garone, D.; Moore, R. D.; D'Souza, G.; Goedert, J. J.; Achenbach, C.; Gill, M. J.; Kitahata, M. M.; Patel, P.; Silverberg, M. J.; Castilho, J.; Mcgowan, C.; Chen, Y. -M. A.; Law, M.; Taylor, N.; Paparizos, V.; Bonnet, F.; Verbon, A.; Fatkenheuer, G.; Post, F. A.; Sabin, C.; Mocrof, A.; Le Moing, V.; Dronda, F.; Obel, N.; Grabar, S.; Spagnuolo, V.; Antinori, A.; Quiros-Roldan, E.; Mussini, C.; Miro, J. M.; Meyer, L.; Hasse, B.; Konopnicki, D.; Roca, B.; Barger, D.; Raben, D.; Cliford, G. M.; Franceschi, S.; Brockmeyer, N.; Chakraborty, R.; Egger, M.; Bohlius, J.
abstract

Background: We compared Kaposi sarcoma (KS) risk in adults who started antiretroviral therapy (ART) across the Asia-Pacific, South Africa, Europe, Latin, and North America. Methods: We included cohort data of human immunodeficiency virus (HIV)-positive adults who started ART after 1995 within the framework of 2 large collaborations of observational HIV cohorts. We present incidence rates and adjusted hazard ratios (aHRs). Results: We included 208 140 patients from 57 countries. Over a period of 1 066 572 person-years, 2046 KS cases were diagnosed. KS incidence rates per 100 000 person-years were 52 in the Asia-Pacific and ranged between 180 and 280 in the other regions. KS risk was 5 times higher in South African women (aHR, 4.56; 95% confidence intervals [CI], 2.73-7.62) than in their European counterparts, and 2 times higher in South African men (2.21; 1.34-3.63). In Europe, Latin, and North America KS risk was 6 times higher in men who have sex with men (aHR, 5.95; 95% CI, 5.09-6.96) than in women. Comparing patients with current CD4 cell counts ≥700 cells/μL with those whose counts were &lt;50 cells/μL, the KS risk was halved in South Africa (aHR, 0.53; 95% CI, .17-1.63) but reduced by ≥95% in other regions. Conclusions. Despite important ART-related declines in KS incidence, men and women in South Africa and men who have sex with men remain at increased KS risk, likely due to high human herpesvirus 8 coinfection rates. Early ART initiation and maintenance of high CD4 cell counts are essential to further reducing KS incidence worldwide, but additional measures might be needed, especially in Southern Africa.

2017 - Correlates of frailty phenotype and frailty index and their associations with clinical outcomes [Articolo su rivista]
Guaraldi, Giovanni; Malagoli, Andrea; Theou, O; Brothers, T. D; Wallace, Lmk; Torelli, Riccardo; Mussini, Cristina; Sartini, Silvana; Kirkland, S. A; Rockwood, K.
abstract

Frailty is a predictor of adverse health outcomes and can be measured across the life course, including among people living with HIV. The purpose of this study was to examine two commonly used measures of frailty - the frailty index (FI) and frailty phenotype - to assess common characteristics and to describe associations with multimorbidity, falls, and disability in people aging with HIV.

2017 - Dynamics and phylogenetic relationships of HIV-1 transmitted drug resistance according to subtype in Italy over the years 2000-14 [Articolo su rivista]
Fabeni, Lavinia; Alteri, C.; Di Carlo, D.; Orchi, N.; Carioti, L.; Bertoli, A.; Gori, C.; Forbici, F.; Continenza, F.; Maffongelli, G.; Pinnetti, C.; Vergori, A.; Mondi, A.; Ammassari, A.; Borghi, V.; Giuliani, M.; De Carli, Gabriella; Pittalis, S.; Grisetti, S.; Pennica, A.; Mastroianni, C. M.; Montella, F.; Cristaudo, A.; Mussini, C.; Girardi, E.; Andreoni, M.; Antinori, A.; Ceccherini-Silberstein, F.; Perno, C. F.; Santoro, M. M.; Girardi, E.; Capobianchi, M. R.; Perno, C. F.; Orchi, N.; Navarra, A.; Palummieri, A.; Abbate, I.; Ammassari, A.; D'Arrigo, R.; Forbici, F.; Fusco, F. M.; Gori, C.; Grisetti, S.; Mariano, A.; Nicastri, E.; Nurra, G.; Pinnetti, C.; Pittalis, S.; Puro, V.; Sampaolesi, A.; Sciarrone, M. R.; Scognamiglio, P.; Selleri, M.; Sias, C.; Zaccarelli, M.; Di Carlo, A.; Giuliani, M.; Vullo, V.; Falciano, M.; Pennica, A.; Errigo, F.; Gattari, P.; Spizzichino, L.; Schito, S.; Andreoni, M.; Sarmati, L.; Buonomini, A. R.; Cerva, C.; Mastroianni, C.; Lichtner, M.; Mercurio, V. S.; Anzalone, E.; Pitorri, A.; Caterini, A.; Aviani Barbacci, S.
abstract

Background Transmitted drug-resistance (TDR) remains a critical aspect for the management of HIV-1-infected individuals. Thus, studying the dynamics of TDR is crucial to optimize HIV care. Methods In total, 4323 HIV-1 protease/reverse-transcriptase sequences from drug-naive individuals diagnosed in north and central Italy between 2000 and 2014 were analysed. TDR was evaluated over time. Maximum-likelihood and Bayesian phylogenetic trees with bootstrap and Bayesian-probability supports defined transmission clusters. Results Most individuals were males (80.2%) and Italian (72.1%), with a median (IQR) age of 37 (30-45) years. MSM accounted for 42.2% of cases, followed by heterosexuals (36.4%). Non-B subtype infections accounted for 30.8% of the overall population and increased over time (&lt;2005-14: 19.5%-38.5%, P &lt; 0.0001), particularly among Italians (&lt;2005-14: 6.5%-28.8%, P &lt; 0.0001). TDR prevalence was 8.8% and increased over time in non-B subtypes (&lt;2005-14: 2%-7.1%, P = 0.018). Overall, 467 transmission clusters (involving 1207 individuals; 27.9%) were identified. The prevalence of individuals grouping in transmission clusters increased over time in both B (&lt;2005-14: 12.9%-33.5%, P = 0.001) and non-B subtypes (&lt;2005-14: 18.4%-41.9%, P = 0.006). TDR transmission clusters were 13.3% within the overall cluster observed and dramatically increased in recent years (&lt;2005-14: 14.3%-35.5%, P = 0.005). This recent increase was mainly due to non-B subtype-infected individuals, who were also more frequently involved in large transmission clusters than those infected with a B subtype [median number of individuals in transmission clusters: 7 (IQR 6-19) versus 4 (3-4), P = 0.047]. Conclusions The epidemiology of HIV transmission changed greatly over time; the increasing number of transmission clusters (sometimes with drug resistance) shows that detection and proper treatment of the multi-transmitters is a major target for controlling HIV spread.

2017 - Efficacy and tolerability of switching to a dual therapy with darunavir/ritonavir plus raltegravir in HIV-infected patients with HIV-1 RNA ≤50 cp/mL [Articolo su rivista]
Madeddu, G.; Rusconi, S.; Cozzi-Lepri, A.; Di Giambenedetto, S.; Bonora, S.; Carbone, A.; De Luca, A.; Gianotti, N.; Di Biagio, A.; Antinori, A.; d'Arminio Monforte, A.; Andreoni, M.; Angarano, G.; Castelli, F.; Cauda, R.; Di Perri, G.; Galli, M.; Iardino, R.; Ippolito, G.; Lazzarin, A.; Perno, C. F.; von Schloesser, F.; Viale, P.; Castagna, A.; Ceccherini-Silberstein, F.; Girardi, E.; Lo Caputo, S.; Mussini, C.; Puoti, M.; Ammassari, A.; Balotta, C.; Bandera, A.; Bonfanti, P.; Borderi, M.; Calcagno, A.; Calza, L.; Capobianchi, M. R.; Cingolani, A.; Cinque, P.; Lichtner, A.; Maggiolo, F.; Marchetti, G.; Marcotullio, S.; Monno, L.; Nozza, S.; Quiros Roldan, E.; Rossotti, R.; Santoro, M. M.; Saracino, A.; Zaccarelli, M.; Fanti, I.; Galli, L.; Lorenzini, P.; Rodano, A.; Shanyinde, M.; Tavelli, A.; Carletti, F.; Carrara, S.; Di Caro, A.; Graziano, S.; Petrone, F.; Prota, G.; Quartu, S.; Truffa, S.; Giacometti, A.; Costantini, A.; Valeriani, C.; Santoro, C.; Suardi, C.; Donati, V.; Verucchi, G.; Minardi, C.; Quirino, T.; Abeli, C.; Manconi, P. E.; Piano, P.; Cacopardo, B.; Celesia, B.; Vecchiet, J.; Falasca, K.; Sighinolfi, L.; Segala, D.; Mazzotta, F.; Vichi, F.; Cassola, G.; Viscoli, C.; Alessandrini, A.; Bobbio, N.; Mazzarello, G.; Mastroianni, C.; Belvisi, V.; Caramma, I.; Chiodera, A.; Castelli, A. P.; Rizzardini, G.; Ridolfo, A. L.; Piolini, R.; Salpietro, S.; Carenzi, L.; Moioli, M. C.; Puzzolante, C.; Gori, A.; Guaraldi, G.; Lapadula, G.; Abrescia, N.; Chirianni, A.; Borgia, G.; Di Martino, F.; Maddaloni, L.; Gentile, I.; Orlando, R.; Cascio, A.; Colomba, C.; Baldelli, F.; Francisci, D.; Parruti, G.; Ursini, T.; Magnani, G.; Ursitti, M. A.; Vullo, V.; Cristaudo, A.; Baldin, G.; Cicalini, S.; Gallo, L.; Nicastri, E.; Acinapura, R.; Capozzi, M.; Libertone, R.; Savinelli, S.; Latini, A.; Iaiani, G.; Cecchetto, M.; Viviani, F.; Mura, M. S.; Rossetti, B.; Caramello, P.; Orofino, G. C.; Sciandra, M.; Bassetti, M.; Londero, A.; Pellizzer, G.; Manfrin, V.
abstract

Background: Nucleos(t)ide reverse transcriptase inhibitors (NRTI) toxicity may represent a threat for long-term success of combined antiretroviral therapy. Some studies have suggested a possible improvement of NRTI-related toxicity after switching to NRTI-sparing regimens. Objectives: We aimed to explore the efficacy and tolerability of switching to darunavir/ritonavir (DRV/r) plus raltegravir (RAL) while having a viral load (VL) ≤50 copies/mL in the clinical setting. Study design: Treatment-experienced HIV 1-infected patients enrolled in the ICONA Foundation Study cohort were included if they switched their current regimen to DRV/r&nbsp;+&nbsp;RAL with a HIV-RNA ≤50&nbsp;copies/mL. Different definitions of virological failure (VF) and treatment failure (TF) were employed. Kaplan–Meier curves and Cox regression models were performed to estimate time to event probability. Results: We included 72 HIV-infected patients, 22 (31%) of these were female, 31 (43%) men who have sex with men (MSM) amd 15 (21%) had hepatitis co-infections. Median age was 44 (IQR: 35-50) years amd CD4 count was 389 (IQR 283-606) cells/mmc. Median follow-up time for TF was 24 (IQR 9–31)&nbsp;months. Twenty-five discontinuations occurred (60% simplifications); only 2 (8%) were toxicity-driven (lipid elevations). The probability of VF (confirmed VL &gt;50 copies/mL) was estimated at 7% [95% confidence interval (CI) 1–13%] by 12 and 9% (95% CI 2–16%) by 24&nbsp;months. When considering TF, we found a probability of stop/intensification/single VL&nbsp;&gt;&nbsp;200 copies/mL of 13% (95% CI 1–17%) and 22% (95% CI 11–33%) by 12 and 24&nbsp;months. Female gender (adjusted relative hazard, ARH&nbsp;=&nbsp;0.10; 95% CI 0.01–0.74; p&nbsp;=&nbsp;0.024) and older age (AHR&nbsp;=&nbsp;0.50 per 10&nbsp;years older; 95% CI 0.25–0.99; p&nbsp;=&nbsp;0.045) were associated with a lower risk of TF. A previous PI failure was strongly associated with TF (AHR&nbsp;=&nbsp;52.6, 95% CI 3.6–779; p&nbsp;=&nbsp;0.004). Conclusions: DRV/r&nbsp;+&nbsp;RAL is a valuable NRTI-sparing option, especially in female and older patients, with a relatively low risk of VF and good tolerability after 2&nbsp;years since start in an ART-experienced population. However, previous PI-failure should be a limiting factor for this strategy.

2017 - Evolving treatment implementation among HIV- infected pregnant women and their partners: Results from a national surveillance study in Italy, 2001-2015 [Articolo su rivista]
Floridia, M.; Frisina, V.; Ravizza, M.; Marconi, A. M.; Pinnetti, C.; Cetin, I.; Sansone, M.; Molinari, A.; Cervi, F.; Meloni, A.; Luzi, K.; Masuelli, G.; Tamburrini, E.; Ensoli, B.; Moroni, M.; Lazzarin, A.; Sagnelli, E.; Antinori, A.; Carosi, G.; Marcotullio, S.; Mazzotta, F.; Vella, S.; Ammassari, A.; Antonucci, G.; Andreoni, M.; Angarano, G.; Armignacco, O.; Babudieri, S.; Baldelli, F.; Bini, T.; Bonfanti, P.; Bonora, S.; Borderi, M.; Bruno, R.; Bucciardini, R.; Castagna, A.; Cattelan, A. M.; Cauda, R.; Cerioli, A.; Chirianni, A.; Cingolani, A.; Cinque, P.; d'Arminio Monforte, A.; De Carli, G.; De Luca, A.; Di Perri, G.; Di Pietro, M.; El Hamad, I.; Errico, M.; Ferrazzi, E.; Gabrielli, E.; Galli, M.; Giaquinto, C.; Girardi, E.; Gori, A.; Grossi, P.; Guaraldi, G.; Liuzzi, G.; Lo Caputo, S.; Maggiolo, F.; Malena, M.; Maserati, R.; Mastroianni, C.; Matteelli, A.; Morrone, A.; Murri, R.; Mussini, C.; Nasta, P.; Oldrini, M.; Oleari, F.; Orlando, G.; Palu, G.; Pempinello, R.; Perno, C. -F.; Prestileo, T.; Pompa, M. G.; Puoti, M.; Puro, V.; Rancilio, L.; Rasi, G.; Rizzardini, G.; Savasi, V. M.; Signorini, L.; Sighinolfi, L.; Stagnitta, M.; Starace, F.; Starnini, G.; Sterrantino, G.; Suter, F.; Tambussi, G.; Tavio, M.; Torti, C.; Tozzi, V.; Trotta, M. P.; Vaccher, E.; Vigano, A.; Visintini, R.; Vullo, V.; Zuccotti, G. V.; Dell'Isola, S.; Manfredini, V.; Parisi, S.; Pezzoli, M. C.; Zona, S.
abstract

Background The current global and national indications for antiretroviral treatment (ART, usually triple combination therapy) in adolescent and adults, including pregnant women, recommend early ART before immunologic decline, pre-exposure chemoprophylaxis (PrEP), and treatment of HIV-negative partners in serodiscordant couples. There is limited information on the implementation of these recommendations among pregnant women with HIV and their partners. Methods The present analysis was performed in 2016, using data from clinical records of pregnant women with HIV, followed between 2001 and 2015 at hospital or university clinics within a large, nationally representative Italian cohort study. The study period was divided in three intervals of five years each (2001-2005, 2006-2010, 2011-2015), and the analysis evaluated temporal trends in rates of HIV diagnosis in pregnancy, maternal antiretroviral treatment at conception, prevalence of HIV infection among partners of pregnant women with HIV, and proportion of seronegative and seropositive male partners receiving antiretroviral treatment. Results The analysis included 2755 pregnancies in women with HIV. During the three time intervals considered the rate of HIV diagnosis in pregnancy (overall 23.3%), and the distribution of HIV status among male partners (overall 48.7% HIV- negative, 28.6% HIV-positive and 22.8% unknown) remained substantially unchanged. Significant increases were observed in the proportion of women with HIV diagnosed before pregnancy who were on antiretroviral treatment at conception (from 62.0% in 2001-2005 to 81.3% in 2011-2015, P &lt; 0.001), and in the proportion of HIV-positive partners on antiretroviral treatment (from 73.3% in 2001-2005 to 95.8% in 2011-2015, P = 0.002). Antiretroviral treatment was administered in 99.1% of the pregnancies that did not end early because of miscarriage, termination, or intrauterine death, and in 75.3% of those not ending in a live birth. No implementation of antiretroviral treatment was introduced among male HIV-negative partners. Conclusions The results suggest good implementation of antiretroviral treatment among HIV-positive women and their HIV-positive partners, but no implementation, even in recent years, of Pre-Exposure Prophylaxis (PrEP) among uninfected male partners. Further studies should assess the determinants of this occurrence and clarify the attitudes and the potential barriers to PrEP use.

2017 - HIV-DNA content in different CD4+ T-cell subsets correlates with CD4+ cell : CD8+ cell ratio or length of efficient treatment [Articolo su rivista]
Gibellini, Lara; Pecorini, Simone; DE BIASI, Sara; Bianchini, Elena; Digaetano, Margherita; Pinti, Marcello; Carnevale, Gianluca; Borghi, Vanni; Guaraldi, Giovanni; Mussini, Cristina; Cossarizza, Andrea; Nasi, Milena
abstract

Objectives: HIV establishes a latent infection at different degrees within naïve (TN) or central (TCM) and effector memory (TEM) CD4+ T cell. Studying patients in whom HIV production was suppressed by combined antiretroviral therapy, our main aim was to find which factors are related or can influence intracellular viral reservoir in different CD4+ T-cell subsets. Methods: We enrolled 32 HIV+ patients successfully treated for more than 2 years, with a CD4+ T-cell count more than 500 cells/μl and plasma viremia undetectable from at least 1 year. Proviral HIV-DNA, the amount of cells expressing signal-joint T-cell receptor rearrangement excision circles and telomere length were quantified by droplet digital PCR in highly purified, sorted CD4+ T-cell subsets; plasma IL-7 and IL-15 were measured by ELISA. Results: HIV-DNA was significantly lower in TN cells compared with TCM or to TEM. Conversely, TN cells contained more signal-joint T-cell receptor rearrangement excision circles compared with TCM or to TEM; no appreciable changes were observed in telomere length. HIV-DNA content was significantly higher in TN and TCM cells, but not in TEM, from patients with shorter time of treatment, or in those with lower CD4+ : CD8+ ratio. Conclusion: Length of treatment or recovery of CD4+ : CD8+ ratio significantly influences viral reservoir in both TN and TCM. Measuring HIV-DNA in purified lymphocyte populations allows a better monitoring of HIV reservoir and could be useful for designing future eradication strategies.

2017 - HIV-Positive Individuals on Antiretroviral Therapy and with Viral Load Suppressed in 12 Infectious Diseases Clinics in Italy: Successes and Disparities in the HIV Continuum of Care [Articolo su rivista]
Raimondo, M.; Camoni, L.; Suligoi, B.; Pezzotti, P.; Paternoster, C.; Rizzardini, G.; Atzori, C.; Mussini, C.; Borghi, V.; Chimenti, M.; Baldelli, F.; Francisci, D.; Antinori, A.; Giannetti, A.; Borgia, G.; Filippo, G. D.; Parruti, G.; Di Stefano, P.; Fontana, T.; Losappio, R.; Mura, M. S.; Madeddu, G.; Farinella, E. M.; Occhino, C.; Portelli, V.
abstract

The HIV care continuum is a tool that describes the quality of HIV care for people living with HIV and assesses the extent to which the goal of viral suppression has been achieved. In 2014, we conducted a retrospective cross-sectional study to assess the characteristics associated with three steps of the HIV continuum of care in Italy [i.e., most recent diagnoses, people diagnosed and in care who are on therapy, and people with viral load (VL) suppressed among those on therapy]. Among the 10,262 individuals diagnosed and linked to care, 9,810 (95.6%) were on therapy and among these 8,383 (85.7%) had VL suppressed. The comparison between people diagnosed in 2013 to those diagnosed before 2013 shows that they were more likely to be male [adjusted odds ratios (AOR) = 1.46; 95% confidence interval (95% CI): 1.18-1.79], &lt;25 years of age (AOR = 7.59; 95% CI: 4.17-13.79), and born in Italy (AOR = 1.33; 95% CI: 1.09-1.62). Factors significantly associated with not being in therapy were as follows: age &lt;35 years (AOR = 4.03; 95% CI: 2.50-6.51), age 35-55 years (AOR = 1.85; 95% CI: 1.19-2.87), being migrants (AOR = 1.25; 95% CI: 1.13-1.39), being men who have sex with men (MSM) (AOR = 1.54; 95% CI: 1.22-1.95), have been diagnosed in 2010-2012 (AOR = 4.51; 95% CI: 3.03-6.73), or before 2010 (AOR = 3.18; 95% CI: 2.41-4.21), and not had previous clinical AIDS (AOR = 8.24; 95% CI: 3.33-20.23), whereas factors significantly associated with not having VL suppressed were as follows: age &lt;35 years (AOR = 1.56; 95% CI: 1.13-2.13) and age 35-55 years (AOR = 1.23; 95% CI: 1.10-1.38), being migrants (AOR = 1.38; 95% CI: 1.11-1.70), have been diagnosed in 2010-2012 (AOR = 1.34; 95% CI: 1.14-1.57), in 2013 (AOR = 4.35; 95% CI: 2.47-7.68), and not having had previous clinical AIDS (AOR = 0.74; 95% CI: 0.63-0.86). Despite this we observed significant disparities for young people, MSM, and migrants, overall in Italy the vast majority of people diagnosed with HIV and in care in 2013 received therapy and the percentage of people who are VL suppressed is near the Joint United Nations Programme on HIV/AIDS goal.

2017 - Higher rates of triple-class virological failure in perinatally HIV-infected teenagers compared with heterosexually infected young adults in Europe [Articolo su rivista]
Judd, A.; Lodwick, R.; Noguera-Julian, A.; Gibb, D. M.; Butler, K.; Costagliola, D.; Sabin, C.; van Sighem, A.; Ledergerber, B.; Torti, C.; Mocroft, A.; Podzamczer, D.; Dorrucci, M.; De Wit, S.; Obel, N.; Dabis, F.; Cozzi-Lepri, A.; Garcia, F.; Brockmeyer, N. H.; Warszawski, J.; Gonzalez-Tome, M. I.; Mussini, C.; Touloumi, G.; Zangerle, R.; Ghosn, J.; Castagna, A.; Fatkenheuer, G.; Stephan, C.; Meyer, L.; Campbell, M. A.; Chene, G.; Phillips, A.; Mary Krause, M.; Leport, C.; Wittkop, L.; Reiss, P.; Wit, F.; Prins, M.; Bucher, H.; Gibb, D.; Amo, J. D.; Thorne, C.; Kirk, O.; Perez-Hoyos, S.; Hamouda, O.; Bartmeyer, B.; Chkhartishvili, N.; Antinori, A.; Monforte, A. D.; Prieto, L.; Rojo, P.; Soriano-Arandes, A.; Battegay, M.; Kouyos, R.; Tookey, P.; Casabona, J.; Miro, J. M.; Konopnick, D.; Goetghebuer, T.; Sonnerborg, A.; Teira, R.; Garrido, M.; Haerry, D.; Raben, D.; Chene, G.; Barger, D.; Schwimmer, C.; Termote, M.; Frederiksen, C. M.; Friis-Moller, N.; Kjaer, J.; Salbol Brandt, R.; Berenguer, J.; Bohlius, J.; Bouteloup, V.; Davies, M. -A.; Dunn, D.; Egger, M.; Furrer, H.; Guiguet, M.; Grabar, S.; Lambotte, O.; Leroy, V.; Lodi, S.; Matheron, S.; Monge, S.; Nakagawa, F.; Paredes, R.; Puoti, M.; Schomaker, M.; Smit, C.; Sterne, J.; Thiebaut, R.; Thorne, C.; van der Valk, M.; Wyss, N.
abstract

Objectives: The aim of the study was to determine the time to, and risk factors for, triple-class virological failure (TCVF) across age groups for children and adolescents with perinatally acquired HIV infection and older adolescents and adults with heterosexually acquired HIV infection. Methods: We analysed individual patient data from cohorts in the Collaboration of Observational HIV Epidemiological Research Europe (COHERE). A total of 5972 participants starting antiretroviral therapy (ART) from 1998, aged &lt; 20 years at the start of ART for those with perinatal infection and 15–29 years for those with heterosexual infection, with ART containing at least two nucleoside reverse transcriptase inhibitors (NRTIs) and a nonnucleoside reverse transcriptase inhibitor (NNRTI) or a boosted protease inhibitor (bPI), were followed from ART initiation until the most recent viral load (VL) measurement. Virological failure of a drug was defined as VL &gt; 500 HIV-1 RNA copies/mL despite ≥ 4 months of use. TCVF was defined as cumulative failure of two NRTIs, an NNRTI and a bPI. Results: The median number of weeks between diagnosis and the start of ART was higher in participants with perinatal HIV infection compared with participants with heterosexually acquired HIV infection overall [17 (interquartile range (IQR) 4–111) vs. 8 (IQR 2–38) weeks, respectively], and highest in perinatally infected participants aged 10–14 years [49 (IQR 9–267) weeks]. The cumulative proportion with TCVF 5 years after starting ART was 9.6% [95% confidence interval (CI) 7.0−12.3%] in participants with perinatally acquired infection and 4.7% (95% CI 3.9−5.5%) in participants with heterosexually acquired infection, and highest in perinatally infected participants aged 10–14 years when starting ART (27.7%; 95% CI 13.2−42.1%). Across all participants, significant predictors of TCVF were those with perinatal HIV aged 10–14 years, African origin, pre-ART AIDS, NNRTI-based initial regimens, higher pre-ART viral load and lower pre-ART CD4. Conclusions: The results suggest a beneficial effect of starting ART before adolescence, and starting young people on boosted PIs, to maximize treatment response during this transitional stage of development.

2017 - Impact of CD4 and CD8 dynamics and viral rebounds on loss of virological control in HIV controllers [Articolo su rivista]
Chereau, Fanny; Madec, Yoann; Sabin, Caroline; Obel, Niels; Ruiz-Mateos, Ezequiel; Chrysos, Georgios; Fidler, Sarah; Lehmann, Clara; Zangerle, Robert; Wittkop, Linda; Reiss, Peter; Hamouda, Osamah; Perez, Vicente Estrada; Leal, Manuel; Mocroft, Amanda; De Olalla, Patricia Garcia; Ammassari, Adriana; Monforte, Antonella D'Arminio; Mussini, Cristina; Segura, Ferran; Castagna, Antonella; Cavassini, Matthias; Grabar, Sophie; Morlat, Philippe; De Wit, Stéphane; Lambotte, Olivier; Meyer, Laurence; Judd, Ali; Touloumi, Giota; Warszawski, Josiane; Dabis, François; Krause, Murielle Mary; Ghosn, Jade; Leport, Catherine; Wit, Ferdinand; Prins, Maria; Bucher, Heiner; Gibb, Diana; Fätkenheuer, Gerd; Del Amo, Julia; Thorne, Claire; Kirk, Ole; Stephan, Christoph; Pérez-Hoyos, Santiago; Bartmeyer, Barbara; Chkhartishvili, Nikoloz; Noguera-Julian, Antoni; Antinori, Andrea; Brockmeyer, Norbert; Prieto, Luis; Conejo, Pablo Rojo; Soriano-Arandes, Antoni; Battegay, Manuel; Kouyos, Roger; Tookey, Pat; Casabona, Jordi; Miró, Jose M.; Konopnick, Deborah; Goetghebuer, Tessa; Sönnerborg, Anders; Torti, Carlo; Teira, Ramon; Garrido, Myriam; Haerry, David; Miró, Jose Ma; Costagliola, Dominique; D'Arminio-Monforte, Antonella; Raben, Dorthe; Chêne, Geneviève; Barger, Diana; Schwimmer, Christine; Termote, Monique; Campbell, Maria; Frederiksen, Casper M.; Friis-Møller, Nina; Kjaer, Jesper; Brandt, Rikke Salbøl; Berenguer, Juan; Bohlius, Julia; Bouteloup, Vincent; Cozzi-Lepri, Alessandro; Davies, Mary-Anne; Dorrucci, Maria; Dunn, David; Egger, Matthias; Furrer, Hansjakob; Guiguet, Marguerite; Leroy, Valériane; Lodi, Sara; Matheron, Sophie; Monge, Susana; Nakagawa, Fumiyo; Paredes, Roger; Phillips, Andrew; Puoti, Massimo; Rohner, Eliane; Schomaker, Michael; Smit, Colette; Sterne, Jonathan; Thiebaut, Rodolphe; Van Der Valk, Marc
abstract

Objective: HIV controllers (HICs) spontaneously maintain HIV viral replication at low level without antiretroviral therapy (ART), a small number of whom will eventually lose this ability to control HIV viremia. The objective was to identify factors associated with loss of virological control. Methods: HICs were identified in COHERE on the basis of ≥5 consecutive viral loads (VL) ≤500 copies/mL over ≥1 year whilst ART-naive, with the last VL ≤500 copies/mL measured ≥5 years after HIV diagnosis. Loss of virological control was defined as 2 consecutive VL &gt;2000 copies/mL. Duration of HIV control was described using cumulative incidence method, considering loss of virological control, ART initiation and death during virological control as competing outcomes. Factors associated with loss of virological control were identified using Cox models. CD4 and CD8 dynamics were described using mixed-effect linear models. Results: We identified 1067 HICs; 86 lost virological control, 293 initiated ART, and 13 died during virological control. Six years after confirmation of HIC status, the probability of losing virological control, initiating ART and dying were 13%, 37%, and 2%. Current lower CD4/CD8 ratio and a history of transient viral rebounds were associated with an increased risk of losing virological control. CD4 declined and CD8 increased before loss of virological control, and before viral rebounds. Discussion: Expansion of CD8 and decline of CD4 during HIV control may result from repeated low-level viremia. Our findings suggest that in addition to superinfection, other mechanisms, such as low grade viral replication, can lead to loss of virological control in HICs.

2017 - Impact of Pre-Analytical Time on the Recovery of Pathogens from Blood Cultures: Results from a Large Retrospective Survey [Articolo su rivista]
Venturelli, Claudia; Righi, Elena; Borsari, Lucia; Aggazzotti, Gabriella; Busani, Stefano; Mussini, Cristina; Rumpianesi, Fabio; Rossolini, Gian Maria; Girardis, Massimo
abstract

Prompt identification of bloodstream pathogens is essential for optimal management of patients. Significant changes in analytical methods have improved the turnaround time for laboratory diagnosis. Less attention has been paid to the time elapsing from blood collection to incubation and to its potential effect on recovery of pathogens. We evaluated the performance of blood cultures collected under typical hospital conditions in relation to the length of their pre-analytical time. We carried out a large retrospective study including 50,955 blood cultures collected, over a 30-month period, from 7,035 adult septic patients. Cultures were accepted by the laboratory only during opening time (Mon-Fri: 8am±4pm; Sat: 8am±2pm). Samples collected outside laboratory hours were stored at room temperature at clinical wards. All cultures were processed by automated culture systems. Day and time of blood collection and of culture incubation were known for all samples. A maximum pre-analytical interval of 2 hours is recommended by guidelines. When the laboratory was open, 57% of cultures were processed within 2 h. When the laboratory was closed, 4.9% of cultures were processed within 2 h (P<0.001). Samples collected when the laboratory was closed showed pre-analytical times significantly longer than those collected when laboratory was open (median time: 13 h and 1 h, respectively, P<0.001). The prevalence of positive cultures was significantly lower for samples collected when the laboratory was closed compared to open (11% vs 13%, P<0.001). The probability of a positive result decreased of 16% when the laboratory was closed (OR:0.84; 95%CI:0.80±0.89, P<0.001). Further, each hour elapsed from blood collection to incubation resulted associated with a decrease of 0.3% (OR:0.997; 95%CI:0.994±0.999, P<0.001) in the probability of a positive result. Delayed insertions of cultures into automated systems was associated with lower detection rates, with potentially important consequences for patients. In each hospital setting the logistic factors able to shorten pre-analytical time should be carefully investigated and specifically targeted.

2017 - Impact of polypharmacy on antiretroviral prescription in people living with HIV. [Articolo su rivista]
Guaraldi, Giovanni; Menozzi, Marianna; Zona, Stefano; Calcagno, Andrea; Domingues Da Silva, Ana Rita; Santoro, Antonella; Malagoli, Andrea; Dolci, Giovanni; Mussi, Chiara; Mussini, Cristina; Cesari, Matteo; Khoo Saye, H.
abstract

OBJECTIVES: To evaluate the relationship between polypharmacy and ART, delivered as conventional multi-tablet three-drug regimens, single-tablet regimens or less-drug regimens (simplified mono or dual regimens). METHODS: We conducted a cross-sectional analysis of electronic data from the prospective Modena HIV Metabolic Clinic Cohort Study. We included the last clinical observation for each patient from January 2006 to December 2015. Polypharmacy was defined as the use of five or more medications (excluding ART). Multi-morbidity was classified as the presence of two or more non-infectious comorbidities. Factors associated with different ART regimens were analysed using multivariable multinomial logistic regression analyses with multi-tablet three-drug regimens as the reference. RESULTS: A total of 2944 patients (33.7% females) were included in the analysis. Multinomial logistic regression analysis identified polypharmacy to be negatively associated with single-tablet regimens [relative risk reduction (RRR) = 0.48, 95% CI = 0.28-0.81] independently from frailty (RRR = 0.68, 95% CI = 0.59-0.78), after correction for age, gender, HIV infection duration, current and nadir CD4 and calendar year. This association was not found comparing multi-tablet three-drug regimens and less-drug regimens. CONCLUSIONS: Single-tablet regimens are less likely to be prescribed in patients with polypharmacy. Single-tablet regimens are perceived to be less flexible in patients with multi-morbidity and at higher risk of drug-drug interaction.

2017 - Incidence and progression to cirrhosis of new hepatitis C virus infections in persons living with human immunodeficiency virus [Articolo su rivista]
Puoti, M.; Lorenzini, P.; Cozzi-Lepri, A.; Gori, A.; Mastroianni, C.; Rizzardini, G.; Mazzarello, G.; Antinori, A.; d'Arminio Monforte, A.; Girardi, E.; Andreoni, M.; Angarano, G.; Castelli, F.; Cauda, R.; Di Perri, G.; Galli, M.; Iardino, R.; Ippolito, G.; Lazzarin, A.; Perno, C. F.; von Schloesser, F.; Viale, P.; Castagna, A.; Ceccherini-Silberstein, F.; Lo Caputo, S.; Mussini, C.; Ammassari, A.; Balotta, C.; Bandera, A.; Bonfanti, P.; Bonora, S.; Borderi, M.; Calcagno, A.; Calza, L.; Capobianchi, M. R.; Cingolani, A.; Cinque, P.; De Luca, A.; Di Biagio, A.; Gianotti, N.; Guaraldi, G.; Lapadula, G.; Lichtner, M.; Madeddu, G.; Maggiolo, F.; Marchetti, G.; Marcotullio, S.; Monno, L.; Nozza, S.; Quiros Roldan, E.; Rossotti, R.; Rusconi, S.; Santoro, M. M.; Saracino, A.; Zaccarelli, M.; Fanti, I.; Galli, L.; Rodano, A.; Shanyinde, M.; Tavelli, A.; Carletti, F.; Carrara, S.; Di Caro, A.; Graziano, S.; Petrone, F.; Prota, G.; Quartu, S.; Truffa, S.; Giacometti, I. A.; Costantini, A.; Valeriani, C.; Santoro, C.; Suardi, C.; Donati, V.; Verucchi, G.; Minardi, C.; Quirino, T.; Abeli, C.; Manconi, P. E.; Piano, P.; Cacopardo, B.; Celesia, B.; Vecchiet, J.; Falasca, K.; Sighinolfi, L.; Segala, D.; Mazzotta, F.; Vichi, F.; Cassola, G.; Viscoli, C.; Alessandrini, A.; Bobbio, N.; Belvisi, V.; Caramma, I.; Chiodera, A.; Castelli, A. P.; Ridolfo, A. L.; Piolini, R.; Salpietro, S.; Carenzi, L.; Moioli, M. C.; Tincati, C.; Puzzolante, C.; Abrescia, N.; Chirianni, A.; Borgia, G.; Di Martino, F.; Maddaloni, L.; Gentile, I.; Orlando, R.; Baldelli, F.; Francisci, D.; Parruti, G.; Ursini, T.; Magnani, G.; Ursitti, M. A.; Vullo, V.; Cristaudo, A.; Cicalini, S.; Gallo, L.; Nicastri, E.; Acinapura, R.; Capozzi, M.; Libertone, R.; Savinelli, S.; Latini, A.; Iaiani, G.; Fontanelli Sulekova, L.; Cecchetto, M.; Viviani, F.; Mura, M. S.; Rossetti, B.; Caramello, P.; Orofino, G. C.; Sciandra, M.; Bassetti, M.; Londero, A.; Pellizzer, G.; Manfrin, V.; Baldin, G.
abstract

Objective To estimate the incidence of hepatitis C virus (HCV) seroconversion and the risk of severe fibrosis/cirrhosis in HCV seroconverters among persons with human immunodeficiency virus (HIV) infection. Methods We analysed data on 4059 persons with HIV enrolled in a cohort study in Italy. Results Incidence rate of seroconversion was 0.6/100 person-years overall, and drug users and men-who-have-sex-with-men were at highest risk. The cumulative risk of progression to severe fibrosis/cirrhosis was 30% by 10 years after seroconversion. Conclusions New HCV infections have a rapidly progressive course in this population. Persons with HIV and HCV superinfection should be prioritized for treatment with anti-HCV direct-acting antivirals.

2017 - Italian guidelines for the use of antiretroviral agents and the diagnostic-clinical management of HIV-1 infected persons. Update 2016. [Articolo su rivista]
Antinori, A; Di Biagio, A; Marcotullio, S; Andreoni, M; Chirianni, A; d'Arminio Monforte, A; Galli, M; Mazzotta, F; Mussini, C; Puoti, M; Lazzarin, A
abstract

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2017 - Lamivudine/dolutegravir dual therapy in HIV-infected, virologically suppressed patients [Articolo su rivista]
Maggiolo, Franco; Gulminetti, Roberto; Pagnucco, Layla; Digaetano, Margherita; Benatti, Simone; Valenti, Daniela; Callegaro, Annapaola; Ripamonti, Diego; Mussini, Cristina
abstract

Background: Little is known about the applicability of dual treatments based on integrase inhibitors. We explored the combination of lamivudine + dolutegravir as an option when switching from standard cART in virologically suppressed patients. Methods: In this prospective cohort we enrolled patients previously switched to 3TC + DTG who were 18 years or older, with no previous resistance mutations to the used drugs, having a HIV-RNA <50 copies/ml for 6 months or longer, negative for HBsAg and on a stable (>6 months) cART. Results: Ninety-four individuals were included. They were mostly men (77.7%) with a mean age of 53 years. They presented 159 co-morbidities including cardiovascular, bone, hepatic, kidney, and CNS diseases. Because of these pathologies, they took 207 non-ARV drugs (mean 2.2 per patient). Median duration of viral suppression was 77.5 months (IQR 61). All subjects were prospectively followed up to week 24 and all remained on dual therapy during the whole period. Neither virological failure, nor viral blip was detected. The median CD4 count rose from 658 cells/mcl (IQR 403) to 724 cells/mcl (IQR 401) (P = 0.006) without a significant (P = 0.44) change in the CD4/CD8 ratio. A significant (P < 0.0001) increment of median creatinine from 0.87 mg/dl (IQR 0.34) to 0.95 mg/dl (IQR 0.29) was observed in the first 2 months but thereafter leveled on these values (1.00 mg/dl; IQR 0.35) (P = 0.111 compared to 2 months). The lipid profile slightly improved. The daily cost of cART was significantly (P < 0.0001) reduced of 6.89 euros (SD 6.10). Discussion: Switching to a dual cART regimen based on lamivudine + dolutegravir maintains virological efficacy up to week 24, and is associated to slight improvements of the immunologic and metabolic status. The strategy allows to freely using concomitant medications for associated pathologies. The dual therapy is less expensive in economic terms. Conclusion: Although still limited evidence exists, a dolutegravir-based dual therapy in combination with lamivudine shows promising results to be confirmed in larger controlled trials.

2017 - Late presentation increases risk and costs of non-infectious comorbidities in people with HIV: An Italian cost impact study [Articolo su rivista]
Guaraldi, Giovanni; Zona, Stefano; Menozzi, Marianna; Brothers, Thomas D.; Carli, Federica; Stentarelli, Chiara; Dolci, Giovanni; Santoro, Antonella; Da Silva, Ana Rita Domingues; Rossi, Elisa; Falutz, Julian; Mussini, Cristina
abstract

Background: Late presentation (LP) at the time of HIV diagnosis is defined as presentation with AIDS whatever the CD4 cell count or with CD4 <350 cells/mm. The objective of our study was to assess the prevalence of non-infectious comorbidities (NICM) and multimorbidity among HIV-positive individuals with and without a history of LP (HIV + LP and HIV + EP, respectively), and compare them to matched HIV-negative control participants from a community-based cohort. The secondary objective was to provide estimates and determinants of direct cost of medical care in HIV patients. Methods: We performed a matched cohort study including HIV + LP and HIV + EP among people attending the Modena HIV Metabolic Clinic (MHMC) in 2014. HIV-positive participants were matched in a 1:3 ratio with HIV-negative participants from the CINECA ARNO database. Multimorbidity was defined as the concurrent presence of ≥2 NICM. Logistic regression models were constructed to evaluate associated predictors of NICM and multimorbidity. Results: We analyzed 452 HIV + LP and 73 HIV + EP participants in comparison to 1575 HIV-negative controls. The mean age was 46 ± 9 years, 27.5% were women. Prevalence of NICM and multimorbidity were fourfold higher in the HIV + LP compared to the general population (p < 0.001), while HIV + EP present an intermediate risk. LP was associated with increased total costs in all age strata, but appear particularly relevant in patients above 50 years of age, after adjusting for age, multimorbidity, and antiretroviral costs. Conclusions: LP with HIV infection is still very frequent in Italy, is associated with higher prevalence of NICM and multimorbidity, and contributes to higher total care costs. Encouraging early testing and access to care is still urgently needed.

2017 - Lower Frailty Is Associated with Successful Cognitive Aging Among Older Adults with HIV [Articolo su rivista]
Wallace, Lindsay M. K; Ferrara, Maria; Brothers, Thomas D; Garlassi, Sara; Kirkland, Susan A; Theou, Olga; Zona, Stefano; Mussini, Cristina; Moore, David; Rockwood, Kenneth; Guaraldi, Giovanni
abstract

Aging with HIV poses unique and complex challenges, including avoidance of neurocognitive disorder. Our objective here is to identify the prevalence and predictors of successful cognitive aging (SCA) in a sample of older adults with HIV. One hundred three HIV-infected individuals aged 50 and older were recruited from the Modena HIV Metabolic Clinic in Italy. Participants were treated with combination antiretroviral therapy for at least 1 year and had suppressed plasma HIV viral load. SCA was defined as the absence of neurocognitive impairment (as defined by deficits in tasks of episodic learning, information processing speed, executive function, and motor skills) depression, and functional impairment (instrumental activities of daily living). In cross-sectional analyses, odds of SCA were assessed in relation to HIV-related clinical data, HIV-Associated Non-AIDS (HANA) conditions, multimorbidity (≥2HANA conditions), and frailty. A frailty index was calculated as the number of deficits present out of 37 health variables. SCA was identified in 38.8% of participants. Despite no differences in average chronologic age between groups, SCA participants had significantly fewer HANA conditions, a lower frailty index, and were less likely to have hypertension. In addition, hypertension (odds ratio [OR] = 0.40, p = .04), multimorbidity (OR = 0.35, p = .05), and frailty (OR = 0.64, p = .04) were significantly associated with odds of SCA. Frailty is associated with the likelihood of SCA in people living with HIV. This defines an opportunity to apply knowledge from geriatric population research to people aging with HIV to better appreciate the complexity of their health status.

2017 - Multiclass HCV resistance to direct-acting antiviral failure in real-life patients advocates for tailored second-line therapies [Articolo su rivista]
Di Maio, Velia C.; Cento, Valeria; Lenci, Ilaria; Aragri, Marianna; Rossi, Piera; Barbaliscia, Silvia; Melis, Michela; Verucchi, Gabriella; Magni, Carlo F.; Teti, Elisabetta; Bertoli, Ada; Antonucci, Francescopaolo; Bellocchi, Maria C.; Micheli, Valeria; Masetti, Chiara; Landonio, Simona; Francioso, Simona; Santopaolo, Francesco; Pellicelli, Adriano M.; Calvaruso, Vincenza; Gianserra, Laura; Siciliano, Massimo; Romagnoli, Dante; Cozzolongo, Raffaele; Grieco, Antonio; Vecchiet, Jacopo; Morisco, Filomena; Merli, Manuela; Brancaccio, Giuseppina; Di Biagio, Antonio; Loggi, Elisabetta; Mastroianni, Claudio M.; Pace Palitti, Valeria; Tarquini, Pierluigi; Puoti, Massimo; Taliani, Gloria; Sarmati, Loredana; Picciotto, Antonino; Vullo, Vincenzo; Caporaso, Nicola; Paoloni, Maurizio; Pasquazzi, Caterina; Rizzardini, Giuliano; Parruti, Giustino; Craxì, Antonio; Babudieri, Sergio; Andreoni, Massimo; Angelico, Mario; Perno, Carlo F.; Ceccherini-Silberstein, Francesca; MARIANI COSTANTINI, Renato; Iapadre, N.; Grimaldi, A.; Cozzolongo, R.; Andreone, P.; Verucchi, G.; Menzaghi, B.; Quirino, T.; Pisani, Vincenzo; Torti, C.; Vecchiet, J.; Bruzzone, B.; De Maria, A.; Marenco, S.; Nicolini, L. A.; Viscoli, C.; Casinelli, K.; Delle Monache, M.; Lichtner, M.; Aghemo, A.; Boccaccio, V.; Bruno, S.; Cerrone, M.; Colombo, M.; D'Arminio Monforte, A.; Danieli, E.; Donato, Francesco; Gubertini, G.; Lleo, A.; Magni, C. F.; Mancon, A.; Monico, S.; Niero, F.; Russo, M. L.; Gnocchi, M.; Orro, A.; Milanesi, L.; Baldelli, E.; Bertolotti, M.; Borghi, V.; Mussini, C.; Brancaccio, Giulia; Gaeta, G. B.; Lembo, V.; Sangiovanni, V.; Di Marco, V.; Mazzola, A.; Petta, S.; D'Amico, maria ester; Cacciatore, P.; Consorte, A.; Pieri, A.; Polilli, E.; Sozio, F.; Antenucci, Francesca; Aragri, M.; Baiocchi, L.; Barbaliscia, S.; Biliotti, E.; Biolato, M.; Carioti, L.; Ceccherini-Silberstein, F.; Cerasari, G.; Cerva, C.; Ciotti, M.; D'Ambrosio, C.; D'Ettorre, G.; De Leonardis, F.; De Sanctis, A.; Di Maio, V. C.; Di Paolo, D.; Furlan, C.; Gallo, P.; Gasbarrini, A.; Giannelli, V.; Grieco, S.; Lambiase, L.; Lattanzi, B.; Lenci, I.; Lula, R.; Malagnino, V.; Manuelli, M.; Miglioresi, L.; Milana, M.; Moretti, A.; Nosotti, L.; Palazzo, D.; Pellicelli, A.; Romano, M.; Sarrecchia, C.; Sforza, Diego; Sorbo, M. C.; Spaziante, M.; Svicher, V.; Tisone, G.; Vespasiani-Gentilucci, U.; D'Adamo, G.; Mangia, A.; Maida, I.; Mura, M. S.; Falconi, L.; Di Giammartino, D.
abstract

Background &amp; Aims: Despite the excellent efficacy of direct-acting antivirals (DAA) reported in clinical trials, virological failures can occur, often associated with the development of resistance-associated substitutions (RASs). This study aimed to characterize the presence of clinically relevant RASs to all classes in real-life DAA failures. Methods: Of the 200 virological failures that were analyzed in 197 DAA-treated patients, 89 with pegylated-interferon+ribavirin (PegIFN+RBV) and 111 without (HCV-1a/1b/1g/2/3/4=58/83/1/6/24/25; 56.8% treatment experienced; 65.5% cirrhotic) were observed. Sanger sequencing of NS3/NS5A/NS5B was performed by home-made protocols, at failure (N=200) and whenever possible at baseline (N=70). Results: The majority of the virological failures were relapsers (57.0%), 22.5% breakthroughs, 20.5% non-responders. RAS prevalence varied according to IFN/RBV use, DAA class, failure type and HCV genotype/subtype. It was 73.0% in IFN group vs 49.5% in IFN free, with the highest prevalence of NS5A-RASs (96.1%), compared to NS3-RASs (75.9% with IFN, 70.5% without) and NS5B-RASs (66.6% with IFN, 20.4% without, in sofosbuvir failures). In the IFN-free group, RASs were higher in breakthrough/non-responders than in relapsers (90.5% vs 40.0%, P&lt;.001). Interestingly, 57.1% of DAA IFN-free non-responders had a misclassified genotype, and 3/4 sofosbuvir breakthroughs showed the major-RAS-S282T, while RAS-L159F was frequently found in sofosbuvir relapsers (18.2%). Notably, 9.0% of patients showed also extra target RASs, and 47.4% of patients treated with ≥2 DAA classes showed multiclass resistance, including 11/11 NS3+NS5A failures. Furthermore, 20.0% of patients had baseline-RASs, which were always confirmed at failure. Conclusions: In our failure setting, RAS prevalence was remarkably high in all genes, with a partial exception for NS5B, whose limited resistance is still higher than previously reported. This multiclass resistance advocates for HCV resistance testing at failure, in all three genes for the best second-line therapeutic tailoring.

2017 - Novelties in evaluation and monitoring of human immunodeficiency virus-1 infection: Is standard virological suppression enough for measuring antiretroviral treatment success? [Articolo su rivista]
Svicher, V.; Marchetti, G.; Ammassari, A.; Ceccherini-Silberstein, F.; Sarmati, L.; Andreoni, M.; Angarano, G.; Antinori, A.; Antonelli, G.; Bandera, A.; Bonfanti, P.; Bonora, S.; Borderi, M.; Calcagno, A.; Capobianchi, M. R.; Castagna, A.; Castelli, F.; Cauda, R.; Celesia, B. M.; Chirianni, A.; Cicalini, S.; Cingolani, A.; Cinque, P.; Clementi, M.; Cossarizza, A.; Monforte, A. D.; D'Ettorre, G.; De Luca, A.; Di Biagio, A.; Di Perri, G.; Galli, M.; Gianotti, N.; Girardi, E.; Guaraldi, G.; Lazzarin, A.; Lichtner, M.; Lo Caputo, S.; Madeddu, G.; Maggi, P.; Maggiolo, F.; Marchetti, G. C.; Mastroianni, C.; Mussini, C.; Nozza, S.; Nunnari, G.; Parisi, S.; Parruti, G.; Perno, C. F.; Piconi, S.; Carla, M.; Ripamonti, D.; Rusconi, S.; Santoro, M.; Sterrantino, G.; Svicher, V.; Vullo, V.; Zaccarelli, M.; Zazzi, M.
abstract

The high potency and tolerability of the currently available antiretroviral drugs has modified HIV-1 infection from a life-threatening disease to a chronic illness. Nevertheless, some issues still remain open to optimize the management of HIV-1 infected patients in term of maintenance of virological suppression over time, identifying patients that could benefit from simplification therapy, and reducing co-mordibities driven by chronic inflammation. The availability of robust and affordable virological and immunological markers can help in solving these issues by providing information on the burden of HIV-1 reservoir in all the anatomical compartments in which the virus replicates as well as on persistent inflammation, immune activation and senescence despite successful virological suppression. In this light, this review is aimed at providing new insights (arising from a two-day Italian expert meeting hold in Rome in March 2016) in evaluation and monitoring of HIV-1 infection from a virological, immunological and clinical perspective. Particular attention has been focused on role of novel parameters (such as total HIV-1 DNA, residual viremia, and immunological markers) in optimizing treatment strategies, enhancing medical adherence, and individualizing monitoring.

2017 - Optimization strategies for HIV, syphilis and hepatitis testings in infectious disease and dermatology clinics: preliminary results of Modena collaboration experience [Poster]
DI TULLIO, Francesca; Mandel, Victor Desmond; Coppini, Maurizio; Pellacani, Giovanni; Mussini, Cristina; Borghi, Vanni
abstract

Background: HIV and sexually transmitted diseases (STDs) screening tests are usually offered in many Italian health institutions. These tests are very important for detection of HIV and STDs, for treating them at an early stage and for prevention of diffusion inside communities. Generally, HIV test is the only screening exam performed in Infectious Disease Clinic (IDC). Increased collaboration between IDC and STDs Centre using the same approach to test sexually transmitted infections could implement the number of new diagnoses. In the Azienda Ospedaliero-Universitaria (AOU) of Modena, the IDC and STDs Centre of Dermatology Clinic began a strict collaboration and adopted a common diagnostic profile including HIV, syphilis, HBV and HCV screening tests since 2013. The aim of the study was to observe the results of a seven-years collaboration in term of number of new HIV and STDs diagnoses. Material &amp; Methods: Consecutive patients who underwent at least 1 screening test for HIV, syphilis, HBV and HCV from January 2010 to September 2016 in IDC or STDs Centre were included. Demographical data were electronically recorded in clinical databases. “Linkage to care” was obtained through a capture and recapture method using Modena HIV surveillance System and Modena HIV clinic databases. Results: During the study period 10675 admittances related to 8623 patients, who carried out at least 1 screening test, were registered in the centres. They were mainly male (68.2%). Median age was 33 years-old (IQR 26-43). Foreigners represented 26.5% of tested people. Since 2013 an increasing number of admittances was observed (1343 accesses in 2010 and 1901 in 2015). HBV, HCV and syphilis tests increased in IDC after 2013 as well as HIV tests in STDs Centre (Figure 1). A total of 700 people were positive for at least 1 screening test: 71 with HIV infection (2016 incidence rate 1.4%), 314 with syphilis (2016 incidence rate 1.3%), 182 with HCV infection (2016 incidence rate 1.64%) and 161 with HBV infection (2016 incidence rate 3.8%). The number of HIV and HBV positive tests increased in the last 2 years but the trend was statistically significant only for HIV (p&lt;0.001). 57% of HIV new infections were observed in Italian men, while 82% of new HBV infections were detected in young foreigners. During the study period the number of new syphilis infections showed a reduction (p&lt;0.001) while HCV positive tests were changeless (p=0.245). 87.6% of new infections were found be linked in care in AOU of Modena. Conclusion: The agreement between IDC and STDs Centre has proven to work well increasing the diagnosis over the time and obtaining a good results in “linkage to care”, which allows to patients with positive screening test to be sent to the pertinent Clinic for further investigations and therapeutical management.

2017 - Predictors of transitions in frailty severity and mortality among people aging with HIV [Articolo su rivista]
Brothers, Thomas D.; Kirkland, Susan; Theou, Olga; Zona, Stefano; Malagoli, Andrea; Wallace, Lindsay M. K.; Stentarelli, Chiara; Mussini, Cristina; Falutz, Julian; Guaraldi, Giovanni; Rockwood, Kenneth
abstract

Background: People aging with HIV show variable health trajectories. Our objective was to identify longitudinal predictors of frailty severity and mortality among a group aging with HIV. Methods: Exploratory analyses employing a multistate transition model, with data from the prospective Modena HIV Metabolic Clinic Cohort Study, based in Northern Italy, begun in 2004. Participants were followed over four years from their first available visit. We included all 963 participants (mean age 46.8±7.1; 29% female; 89% undetectable HIV viral load; median current CD4 count 549, IQR 405–720; nadir CD4 count 180, 81–280) with four-year data. Frailty was quantified using a 31-item frailty index. Outcomes were frailty index score or mortality at four-year follow-up. Candidate predictor variables were baseline frailty index score, demographic (age, sex), HIV-disease related (undetectable HIV viral load, current CD4+ T-cell count, nadir CD4 count, duration of HIV infection, and duration of antiretroviral therapy [ARV] exposure), and behavioral factors (smoking, injection drug use (IDU), and hepatitis C virus co-infection). Results: Four-year mortality was 3.0% (n = 29). In multivariable analyses, independent predictors of frailty index at follow-up were baseline frailty index (RR 1.06, 95% CI 1.05–1.07), female sex (RR 0.93, 95% CI 0.87–0.98), nadir CD4 cell count (RR 0.96, 95% CI 0.93–0.99), duration of HIV infection (RR 1.06, 95% CI 1.01–1.12), duration of ARV exposure (RR 1.08, 95% CI 1.02–1.14), and smoking pack-years (1.03, 1.01–1.05). Independent predictors of mortality were baseline frailty index (OR 1.19, 1.02–1.38), current CD4 count (0.34, 0.20–0.60), and IDU (2.89, 1.30–6.42). Conclusions: Demographic, HIV-disease related, and social and behavioral factors appear to confer risk for changes in frailty severity and mortality among people aging with HIV.

2017 - Reference curves for CD4 T-cell count response to combination antiretroviral therapy in HIV-1-infected treatment-naïve patients [Articolo su rivista]
Bouteloup, V.; Sabin, C.; Mocroft, A.; Gras, L.; Pantazis, N.; Le Moing, V.; d'Arminio Monforte, A.; Mary-Krause, M.; Roca, B.; Miro, J. M.; Battegay, M.; Brockmeyer, N.; Berenguer, J.; Morlat, P.; Obel, N.; De Wit, S.; Fatkenheuer, G.; Zangerle, R.; Ghosn, J.; Perez-Hoyos, S.; Campbell, M.; Prins, M.; Chene, G.; Meyer, L.; Dorrucci, M.; Torti, C.; Thiebaut, R.; Touloumi, G.; Warszawski, J.; Dabis, F.; Leport, C.; Wittkop, L.; Reiss, P.; Wit, F.; Bucher, H.; Gibb, D.; Amo, J. D.; Thorne, C.; Kirk, O.; Stephan, C.; Hamouda, O.; Bartmeyer, B.; Chkhartishvili, N.; Noguera-Julian, A.; Antinori, A.; Prieto, L.; Conejo, P. R.; Soriano-Arandes, A.; Rauch, A.; Mussini, C.; Tookey, P.; Casabona, J.; Castagna, A.; Deborah, Konopnick; Goetghebuer, T.; Sonnerborg, A.; Teira, R.; Garrido, M.; Haerry, D.; Costagliola, D.; Castagna, A.; del Amo, J.; Raben, D.; Judd, A.; Conejo, P. R.; Barger, D.; Colin, C.; Schwimmer, C.; Termote, M.; Friis-Moller, N.; Kjaer, J.; Raben, D.; Brandt, R. S.; Bohlius, J.; Bucher, H.; Cozzi-Lepri, A.; Dabis, F.; Davies, M. -A.; del Amo, J.; Dunn, D.; Egger, M.; Furrer, H.; Guiguet, M.; Grabar, S.; Judd, A.; Kirk, O.; Lambotte, O.; Leroy, V.; Lodi, S.; Matheron, S.; Monge, S.; Nakagawa, F.; Paredes, R.; Phillips, A.; Puoti, M.; Schomaker, M.; Smit, C.; Sterne, J.; Thiebaut, R.; Thorne, C.; van der Valk, M.; Wyss, N.; Bouteloup, V.; Sabin, C.; Mocroft, A.; Gras, L.; Pantazis, N.; Le Moing, V.; d'Arminio Monforte, A.; Mary-Krause, M.; Roca, B.; Miro, J. M.; Battegay, M.; Brockmeyer, N.; Berenguer, J.; Morlat, P.; Morlat, P.; Obel, N.; Fatkenheuer, G.; Zangerle, R.; Ghosn, J.; Ghosn, J.; Perez-Hoyos, S.; Campbell, M.; Prins, M.; Chene, G.; Meyer, L.; Dorrucci, M.; Thiebaut, R.
abstract

Objectives: The aim of this work was to provide a reference for the CD4 T-cell count response in the early months after the initiation of combination antiretroviral therapy (cART) in HIV-1-infected patients. Methods: All patients in the Collaboration of Observational HIV Epidemiological Research Europe (COHERE) cohort who were aged ≥ 18 years and started cART for the first time between 1 January 2005 and 1 January 2010 and who had at least one available measurement of CD4 count and a viral load ≤ 50 HIV-1 RNA copies/mL at 6 months (± 3 months) after cART initiation were included in the study. Unadjusted and adjusted references curves and predictions were obtained using quantile regressions. Results: A total of 28 992 patients were included in the study. The median CD4 T-cell count at treatment initiation was 249 [interquartile range (IQR) 150, 336] cells/μL. The median observed CD4 counts at 6, 9 and 12 months were 382 (IQR 256, 515), 402 (IQR 274, 543) and 420 (IQR 293, 565) cells/μL. The two main factors explaining the variation of CD4 count at 6 months were AIDS stage and CD4 count at cART initiation. A CD4 count increase of ≥ 100 cells/mL is generally required in order that patients stay ‘on track’ (i.e. with a CD4 count at the same percentile as when they started), with slightly higher gains required for those starting with CD4 counts in the higher percentiles. Individual predictions adjusted for factors influencing CD4 count were more precise. Conclusions: Reference curves aid the evaluation of the immune response early after antiretroviral therapy initiation that leads to viral control.

2017 - Refining criteria for selecting candidates for a safe lopinavir/ritonavir or darunavir/ritonavir monotherapy in HIV-infected virologically suppressed patients [Articolo su rivista]
Gianotti, Nicola; Cozzi-Lepri, Alessandro; Antinori, Andrea; Castagna, Antonella; De Luca, Andrea; Celesia, Benedetto Maurizio; Galli, Massimo; Mussini, Cristina; Pinnetti, Carmela; Spagnuolo, Vincenzo; D'Arminio Monforte, Antonella; Ceccherini-Silberstein, Francesca; Andreoni, Massimo
abstract

Objective: The primary objective of this study was to estimate the incidence of treatment failure (TF) to protease inhibitor monotherapies (PI/r-MT) with lopinavir/ritonavir (LPV/r) or darunavir/ritonavir (DRV/r). Design: A multicenter cohort of HIV-infected patients with viral load (VL) ≤50 copies/mL, who underwent a switch from any triple combination therapy to PI/r-MT with either LPV/r or DRV/r. Methods: VL was assessed in each center according to local procedures. Residual viremia was defined by any HIV-RNA value detectable below 50 copies/mL by a Real-Time PCR method. Standard survival analysis was used to estimate the rate of TF (defined by virological failure or interruption of monotherapy or reintroduction of combination therapy). A multivariable Cox regression analysis with automatic stepwise procedures was used to identify factors independently associated with TF among nadir and baseline CD4+ counts, residual viremia, time spent with <50 HIV-RNA copies/mL before switch, history of virological failure, HCV co-infection, being on a PI/r and hemoglobin concentrations at baseline. Results: Six hundred ninety patients fulfilled the inclusion criteria and were included in this analysis. Their median follow-up was 20 (10-37) months. By month 36, TF occurred in 176 (30.2%; 95% CI:25.9-34.5) patients. Only CD4+ nadir counts (adjusted hazard ratio [aHR] = 2.03 [95% CI: 1.35, 3.07] for counts ≤100 vs. >100 cells/μL) and residual viremia (aHR = 1.48 [95% CI: 1.01-2.17] vs. undetectable VL) were independently associated to TF. Conclusions: Residual viremia and nadir CD4+ counts <100 cells/μL should be regarded as the main factors to be taken into account before considering switching to a PI/r-MT.

2017 - Timing of combined antiretroviral treatment initiation in male and female migrants living with HIV in Western Europe [Articolo su rivista]
Monge, S.; Jarrin, I.; Pantazis, N.; Mocroft, A.; Sabin, C. A.; Touloumi, G.; van Sighem, A.; Abgrall, S.; Dray-Spira, R.; Spire, B.; Castagna, A.; Mussini, C.; Zangerle, R.; Hessamfar, M.; Anderson, J.; Hamouda, O.; Ehren, K.; Obel, N.; Kirk, O.; de Monteynard, L. A.; Antinori, A.; Girardi, E.; Saracino, A.; Calmy, A.; de Wit, S.; Wittkop, L.; Bucher, H. C.; Montoliu, A.; Raben, D.; Prins, M.; Meyer, L.; Chene, G.; Burns, F.; Del Amo, J.
abstract

Background: We evaluate differences in timing of cART (combined antiretroviral treatment) initiation by geographical origin in male and female HIV-positive patients in the Collaboration of Observational HIV Epidemiological Research Europe, a large European Collaboration of HIV Cohorts. Methods: We included individuals recruited in Western Europe between January 1997 and March 2013, with known geographical origin and at least 1 CD4þ cell count measurement while cART-naive. Timing of cART was assessed through modified time-to-event methods, in which a scale of CD4þ cell counts was used instead of time, with cART being the outcome. We estimated the median CD4þ cell count at cART initiation (estimated CD4þ levels at which the probability of having started cART is 50%) using Kaplan-Meier and adjusted hazard ratios of cART initiation using Cox regression. Results: Of 151 674 individuals, 110 592 (72.9%) were men. Median (95% confidence interval) CD4þ cell count falls far below 250 cells/ml in all groups and was lowest in sub-Saharan African [SSA: 161 (158-167)], Caribbean men [161 (150-174)] and in Asian women [Asian Continent and Oceania: 185 (165-197)]. Among men, the adjusted probability of cART initiation was lower in migrants compared with natives, but differences depended on initial CD4þ cell count. For example, in the group with more than 500 CD4þ at recruitment, they were 45% (36-53%), 30% (17-40%) and 25% (19-30%) lower for Caribbean, Eastern European and SSA men, respectively. In women, no meaningful differences were observed between natives and most migrant groups. However, SSA women had a 31% (24-38%) higher probability of cART initiation when recruited at a CD4þ more than 500 cells/ml and 9% (4-14%) lower when recruited at CD4þ less than 100 cells/ml. Conclusion: Most migrant men initiate cART at lower CD4þ cell count than natives, whereas this does not hold for migrant women.

2017 - Virological response and resistance profile in HIV-1-infected patients starting darunavir-containing regimens [Articolo su rivista]
Armenia, D.; Di Carlo, D.; Maffongelli, G.; Borghi, V.; Alteri, C.; Forbici, F.; Bertoli, A.; Gori, C.; Giuliani, M.; Nicastri, E.; Zaccarelli, M.; Pinnetti, C.; Cicalini, S.; D'Offizi, G.; Ceccherini-Silberstein, F.; Mussini, C.; Antinori, A.; Andreoni, M.; Perno, C. F.; Santoro, M. M.
abstract

Objectives: We evaluated the virological response in patients starting a regimen based on darunavir/ritonavir (DRV/r), which is currently the most widely used ritonavir-boosted protease inhibitor. Methods: Data from 206 drug-naïve and 327 PI-experienced patients starting DRV/r 600/100&nbsp;mg twice daily (DRV600) or 800/100&nbsp;mg once daily (DRV800) were examined. The probabilities of virological success (VS) and virological rebound (VR) were evaluated in survival analyses. Baseline DRV/r resistance and its evolution at failure were also examined. Results: DRV600 was preferentially administered in patients with complex requirements (older age, higher viraemia, lower CD4 cell count and DRV/PI resistance) compared with DRV800. By 12&nbsp;months, the probability of achieving VS was 93.2% and 84.3% in drug-naïve and PI-experienced patients, respectively. The higher the baseline viraemia, the longer was the time required to achieve VS, both in drug-naïve patients [&gt;500&nbsp;000 HIV-1 RNA copies/mL: median [interquartile range (IQR)] 6.1 (5.1–10.3) months; 100&nbsp;000–500&nbsp;000 copies/mL: median (IQR) 4.9 (3.8–6.1) months; &lt;100&nbsp;000 copies/mL: median (IQR) 3.9 (3.5–4.8) months; P&nbsp;&lt;&nbsp;0.001] and in PI-experienced patients [≥100&nbsp;000 copies/mL: median (IQR) 7.2 (5.7–11.6) months; &lt;100&nbsp;000 copies/mL: median (IQR) 2.8 (2.4–3.3) months; P&nbsp;&lt;&nbsp;0.001]. In PI-experienced patients, the probability of VR was higher for higher viraemia levels (22.3% for ≥100&nbsp;000 copies/ml vs. 9.7% for &lt;100&nbsp;000 copies/mL; P&nbsp;=&nbsp;0.007). Baseline resistance did not affect the virological response. At failure, a high percentage of patients maintained virus susceptible to all PIs (drug-naïve: 95%; PI-experienced: 80%). Despite being used more often in patients with more complex requirements, DRV600 performed as well as DRV800. Conclusions: In clinical practice, use of DRV/r (with its flexible dosage) results in high rates of virological response. These data support the use of PI/r in patients whose characteristics require potent drugs with a high genetic barrier.

2016 - A randomized, double-blind comparison of tenofovir alafenamide versus tenofovir disoproxil fumarate, each coformulated with elvitegravir, cobicistat, and emtricitabine for initial HIV-1 treatment: Week 96 results [Articolo su rivista]
Wohl, D.; Oka, S.; Clumeck, N.; Clarke, A.; Brinson, C.; Stephens, J.; Tashima, K.; Arribas, J. R.; Rashbaum, B.; Cheret, A.; Brunetta, J.; Mussini, C.; Tebas, P.; Sax, P. E.; Cheng, A.; Zhong, L.; Callebaut, C.; Das, M.; Fordyce, M.; Friborg, S.; Villamejor, K.; Huang, J.; Guo, S.; Liu, H.; Wang, H.; Miller, M.; Margot, N.
abstract

In 2 double-blinded Phase 3 trials, 1733 antiretroviralnaive participants were randomized to tenofovir alafenamide (TAF), a tenofovir prodrug versus tenofovir disoproxil fumarate (TDF), each coformulated with elvitegravir/cobicistat/emtricitabine (E/C/F). At 96 weeks, 86.6% in the TAF arm and 85.2% in the TDF arm had HIV-1 RNA&lt;50 c/mL [difference 1.5%; (95% CI: 21.8% to 4.8%)]. With TAF, there are smaller declines in bone mineral density and more favorable changes in proteinuria, albuminuria, and tubular proteinuria, and no cases of proximal tubulopathy compared with 2 for TDF. These longer-term data support E/C/F/TAF as a safe, welltolerated, and durable regimen for initial HIV-1 treatment.

2016 - Antimicrobial stewardship in a Gastroenterology Department: Impact on antimicrobial consumption, antimicrobial resistance and clinical outcome [Articolo su rivista]
Bedini, Andrea; De Maria, Nicola; Del Buono, Mariagrazia; Bianchini, Marcello; Mancini, Mauro; Binda, Cecilia; Brasacchio, Andrea; Orlando, Gabriella; Franceschini, Erica; Meschiari, Marianna; Sartini, Alessandro; Zona, Stefano; Paioli, Serena; Villa, Erica; Gyssens, Inge C.; Mussini, Cristina
abstract

Background A major cause of the increase in antimicrobial resistance is the inappropriate use of antimicrobials. Aims To evaluate the impact on antimicrobial consumption and clinical outcome of an antimicrobial stewardship program in an Italian Gastroenterology Department. Methods Between October 2014 and September 2015 (period B), a specialist in infectious diseases (ID) controlled all antimicrobial prescriptions and decided about the therapy in agreement with gastroenterologists. The defined daily doses of antimicrobials (DDDs), incidence of MDR-infections, mean length of stay and overall in-hospital mortality rate were compared with those of the same period in the previous 12-months (period A). Results During period B, the ID specialist performed 304 consultations: antimicrobials were continued in 44.4% of the cases, discontinued in 13.8%, not recommended in 12.1%, de-escalated 9.9%, escalated in 7.9%, and started in 4.0%. Comparing the 2 periods, we observed a decreased of antibiotics consumption (from 109.81 to 78.45 DDDs/100 patient-days, pÂ&nbsp;=Â&nbsp;0.0005), antifungals (from 41.28 to 24.75 DDDs/100pd, pÂ&nbsp;=Â&nbsp;0.0004), carbapenems (from 15.99 to 6.80 DDDsx100pd, pÂ&nbsp;=Â&nbsp;0.0032), quinolones (from 35.79 to 17.82 DDDsx100pd, pÂ&nbsp;=Â&nbsp;0.0079). No differences were observed in incidence of MDR-infections, length of hospital stay (LOS), and mortality rate. Conclusions ASP program had a positive impact on reducing the consumption of antimicrobials, without an increase in LOS and mortality.

2016 - Benefits and medium-term outcome of the Sorin Pericarbon Freedom stentless aortic prosthesis in cases of acute bacterial endocarditis [Articolo su rivista]
Stefanelli, G.; Pirro, F.; Meli, M.; Trevisan, D.; Telesca, M.; Campisano, B.; Mussini, C.; Barbieri, A.
abstract

OBJECTIVES The aim of this study is to evaluate the ease of use and the advantages of Sorin Pericarbon Freedom (SPF) stentless valve in cases of acute bacterial endocarditis and to check the intermediate-term results after the implant of SPF with respect to resistance to infection, valve deterioration and durability. METHODS Between June 2003 and February 2015, 26 patients with active aortic valve bacterial endocarditis underwent aortic valve replacement with SPF pericardial stentless aortic prosthesis. The mean age was 57 ± 18 years; 73% of the patients were in preoperative NYHA class III and VI. Mean Logistic EuroSCORE was 14.2 ± 12.7. Endocarditis occurred in 18 patients with native valves, and in 9 patients with prosthetic valves (4 mechanical aortic valve prostheses; 5 aortic bioprostheses). Aortic root abscesses were observed in 16 cases (61.5%). Surgery was emergent in 3 cases (11.5%). Redo surgery was performed in 9 cases (35%). Cumulative follow-up was 126.8 patient-years (mean 4.9 ± 3.3 years). RESULTS Operative hospital mortality was 0% for all patients. Residual mean prosthetic gradient at discharge was 9.4 ± 3.6 mmHg. Neither residual aortic incompetence nor residual abscess cavity was observed at discharge. Mean ejection fraction at discharge was 54 ± 8% (Min; Max: 35%; 65%). A total of 4 patients died at follow-up, all for non-cardiac causes. One patient was lost to follow-up. Two patients (8%) underwent non-valve-related reoperation with 0% mortality. Residual mean gradient at follow-up was 7.2 ± 2.1 mmHg. Three patients (17%) presented with mild/moderate aortic incompetence and 89% of patients were in NYHA Class I-II at follow-up. At 9 years, actuarial freedom from valve-related reoperation and from structural valve deterioration was 100%. CONCLUSIONS The SPF aortic prosthesis is a true pericardial stentless prosthesis suitable for the treatment of acute bacterial endocarditis. Intermediate-time results in terms of freedom from reoperation, structural valve deterioration and resistance to infections are satisfactory. Haemodynamic performances are excellent since a complete exclusion of aortic root abscesses is achieved without any reduction of the aortic annular diameter, usually due to marsupialization or patch closure of the infected cavities.

2016 - Cancer immunotherapy with anti-CTLA-4 monoclonal antibodies induces an inflammatory bowel disease [Articolo su rivista]
Marthey, L.; Mateus, C.; Mussini, C.; Nachury, M.; Nancey, S.; Grange, F.; Zallot, C.; Peyrin-Biroulet, L.; Rahier, J. F.; de Beauregard, M. B.; Mortier, L.; Coutzac, C.; Soularue, E.; Lanoy, E.; Kapel, N.; Planchard, D.; Chaput, N.; Robert, C.; Carbonnel, F.
abstract

Background: Therapeutic monoclonal anti-cytotoxic T-lymphocyte-associated antigen 4 (CTLA- 4) antibodies are associated with immune-mediated enterocolitis. The aim of this study was to provide a detailed description of this entity. Methods: We included patients with endoscopic signs of inflammation after anti-CTLA-4 infusions for cancer treatment. Other causes of enterocolitis were excluded. Clinical, biological and endoscopic data were recorded. A single pathologist reviewed endoscopic biopsies and colectomy specimens from 27 patients. Patients with and without enterocolitis after ipilimumab-treated melanoma were compared, to identify clinical factors associated with enterocolitis. Results: Thirty-nine patients with anti-CTLA-4 enterocolitis were included (ipilimumab n = 37; tremelimumab n = 2). The most frequent symptom was diarrhoea. Ten patients had extra-intestinal manifestations. Most colonoscopies showed ulcerations involving the rectum and sigmoid, 66% of patients had extensive colitis, 55% had patchy distribution and 20% had ileal inflammation. Endoscopic colonic biopsies showed acute colitis in most patients, while half of the patients had chronic duodenitis. Thirty-five patients received steroids that led to complete clinical remission in 13 patients (37%). Twelve patients required infliximab, of whom 10 (83%) responded. Six patients underwent colectomy (perforation n = 5; toxic megacolon n = 1); one of them died postoperatively. Four patients had a persistent enterocolitis at follow-up colonoscopy. Patients with enterocolitis were more frequently prescribed NSAIDs compared with patients without enterocolitis (31 vs 5%, p = 0.003). Conclusions: Ipilimumab and tremelimumab may induce a severe and extensive form of inflammatory bowel disease. Rapid escalation to infliximab should be advocated in patients who do not respond to steroids. Patients treated with anti-CTLA-4 should be advised to avoid NSAIDs.

2016 - Changing Incidence and Risk Factors for Kaposi Sarcoma by Time since Starting Antiretroviral Therapy: Collaborative Analysis of 21 European Cohort Studies [Articolo su rivista]
Wyss, N.; Zwahlen, M.; Clifford, G.; Campbell, M.; Chakraborty, R.; Bonnet, F.; Chene, G.; Bani-Sadr, F.; Verbon, A.; Zangerle, R.; Paparizos, V.; Prins, M.; Dronda, F.; Le Moing, V.; Antinori, A.; Quiros-Roldan, E.; Mussini, C.; Miro, J. M.; Meyer, L.; Vehreschild, J.; Obel, N.; Mocroft, A.; Brockmeyer, N.; Boue, F.; Sabin, C.; Spagnuolo, V.; Hasse, B.; De Wit, S.; Roca, B.; Egger, M.; Bohlius, J.
abstract

Background. Kaposi sarcoma (KS) remains a frequent cancer in human immunodeficiency virus (HIV)-positive patients starting combination antiretroviral therapy (cART). We examined incidence rates and risk factors for developing KS in different periods after starting cART in patients from European observational HIV cohorts. Methods. We included HIV-positive adults starting cART after 1 January 1996. We analyzed incidence rates and risk factors for developing KS up to 90 and 180 days and 1, 2, 5, and 8 years after cART start and fitted univariable and multivariable Cox regression models. Results. We included 109 461 patients from 21 prospective clinical cohorts in Europe with 916 incident KS cases. The incidence rate per 100 000 person-years was highest 6 months after starting cART, at 953 (95% confidence interval, 866-1048), declining to 82 (68-100) after 5-8 years. In multivariable analyses adjusted for exposure group, origin, age, type of first-line regimen, and calendar year, low current CD4 cell counts increased the risk of developing KS throughout all observation periods after cART initiation. Lack of viral control was not associated with the hazard of developing KS in the first year after cART initiation, but was over time since starting cART increasingly positively associated (P &lt;. 001 for interaction). Conclusion. In patients initiating cART, both incidence and risk factors for KS change with time since starting cART. Whereas soon after starting cART low CD4 cell count is the dominant risk factor, detectable HIV-1 RNA viral load becomes an increasingly important risk factor in patients who started cART several years earlier, independently of immunodeficiency.

2016 - Clinical and Microbiological Characteristics of Visceral Leishmaniasis Outbreak in a Northern Italian Nonendemic Area: A Retrospective Observational Study [Articolo su rivista]
Franceschini, E.; Puzzolante, C.; Menozzi, M.; Rossi, Luna; Bedini, A.; Orlando, G.; Gennari, W.; Meacci, M.; Rugna, G.; Carra, E.; Codeluppi, M.; Mussini, C.
abstract

Background. Visceral leishmaniasis (VL) caused by Leishmania infantum is endemic in the Mediterranean area. In the last decades a northward spread of the parasite has been observed in Italy. This paper describes a VL outbreak in Modena province (Emilia-Romagna, Northern Italy) between 2012 and 2015. Methods. Retrospective, observational study to evaluate epidemiological, microbiological characteristics, and clinical management of VL in patients referring to Policlinico Modena Hospital. Results. Sixteen cases of VL occurred in the study period. An immunosuppressive condition was present in 81.3%. Clinical presentation included anemia, fever, leukopenia, thrombocytopenia, and hepatosplenomegaly. Serology was positive in 73.3% of cases, peripheral blood PCR in 92.3%, and bone marrow blood PCR in 100%. Culture was positive in 3/6 cases (50%) and all the isolates were identified as L. infantum by ITS1/ITS2 sequencing. The median time between symptom onset and diagnosis was 22 days (range 6-131 days). All patients were treated with liposomal amphotericin b. 18.8% had a VL recurrence and were treated with miltefosine. Attributable mortality was 6.3%. Conclusions. VL due to L. infantum could determine periodical outbreaks, as the one described; thus it is important to include VL in the differential diagnosis of fever of unknown origin, even in low-endemic areas.

2016 - Curare la malattia da HIV: ritorno al paziente? [Articolo su rivista]
Girardi, Enrico; D’ARMINIO MONFORTE, Antonella; Camoni, Laura; Pezzotti, Patrizio; Guaraldi, Giovanni; Ammassari, Adriana; Antinori, Andrea; Bonora, Stefano; Mussini, Cristina; Cingolani, Antonella; Corbelli, GIULIO MARIA; Adami, Silvia; DEGLI ESPOSTI, Luca; Andretta, Margherita
abstract

Negli ultimi 20 anni la malattia da HIV è an-data progressivamente trasformandosi da una patologia invariabilmente letale a una condizione cronica trattabi-le, grazie alla disponibilità di terapie antiretrovirali sempre più efficaci. Un uso diffuso di queste terapie ha inoltre la potenzialità di contribuire al controllo della diffusione del contagio. È significativamente diminuita nelle persone con HIV l’incidenza di manifestazioni opportunistiche favorite dalla immunodepressione, mentre sono divenute molto più comuni patologie cronico-degenerative, come patolo-gie cardio- e cerebrovascolari, metaboliche, ossee, renali ed epatiche, legate allo stato di infiammazione cronica e all’invecchiamento della popolazione di queste persone. Nel 2030, si prevede che oltre l’80% delle persone con HIV più anziani avrà almeno una patologia cronico-degenerati-va, rispetto al 19% delle persone HIV-negative, e oltre un quarto di essi avrà tre o più patologie. Tra le persone con HIV va incrementandosi la prevalenza di una condizione di fragilità. La scelta delle strategie terapeutiche per la malat-tia da HIV quindi deve oggi essere basata non più soltanto sulla capacità dei farmaci di indurre una completa soppres-sione della replicazione virale nel breve/medio termine. Le scelte terapeutiche devono favorire l’aderenza e l’assenza di tossicità sul lungo termine, avere la capacità di ripristina-re l’omeostasi immunitaria e ridurre quindi l’infiammazione cronica e il rischio di patologie correlate, avere un impatto positivo nel tempo sulle condizioni complessive di vita del-la persona con HIV, misurato anche con indicatori quali i patient related oucomes.

2016 - Discontinuation of initial antiretroviral therapy in clinical practice: Moving toward individualized therapy [Articolo su rivista]
Di Biagio, A.; Cozzi-Lepri, A.; Prinapori, R.; Angarano, G.; Gori, A.; Quirino, T.; De Luca, A.; Costantini, A.; Mussini, C.; Rizzardini, G.; Castagna, A.; Antinori, A.; Monforte, A. D.; Moroni, M.; Andreoni, M.; D'Arminio Monforte, A.; Castelli, F.; Cauda, R.; Di Perri, G.; Galli, M.; Iardino, R.; Ippolito, G.; Lazzarin, A.; Perno, C. F.; Von Schloesser, F.; Viale, P.; Ceccherini-Silberstein, F.; Girardi, E.; Lo Caputo, S.; Puoti, M.; Ammassari, A.; Balotta, C.; Bandera, A.; Bonfanti, P.; Bonora, S.; Borderi, M.; Calcagno, A.; Calza, L.; Capobianchi, M. R.; Cingolani, A.; Cinque, P.; Caputo, N.; Gianotti, N.; Guaraldi, G.; Lapadula, G.; Lichtner, M.; Madeddu, G.; Maggiolo, F.; Marchetti, G.; Marcotullio, S.; Monno, L.; Quiros Roldan, E.; Rossotti, R.; Rusconi, S.; Santoro, M.; Saracino, A.; Zaccarelli, M.; Fanti, I.; Galli, L.; Lorenzini, P.; Rodano, A.; Shanyinde, M.; Tavelli, A.; Giacometti, A.; Mazzoccato, S.; Santoro, C.; Suardi, C.; Vanino, E.; Verucchi, G.; Minardi, C.; Abeli, C.; Manconi, P. E.; Piano, P.; Vecchiet, J.; Falasca, K.; Sighinolfi, L.; Segala, D.; Mazzotta, F.; Alessandrini, A.; Piscopo, R.; Mazzarello, G.; Mastroianni, C.; Belvisi, V.; Caramma, I.; Chiodera, A.; Castelli, A. P.; Ridolfo, A. L.; Piolini, R.; Salpietro, S.; Carenzi, L.; Moioli, M. C.; Tincati, C.; Puzzolante, C.; Abrescia, N.; Chirianni, A.; Borgia, G.; Guida, M. G.; Gargiulo, M.; Gentile, I.; Orlando, R.; Baldelli, F.; Francisci, D.; Parruti, G.; Ursini, T.; Magnani, G.; Ursitti, M. A.; Vullo, V.; D'Avino, A.; Gallo, L.; Nicastri, E.; Acinapura, R.; Capozzi, M.; Libertone, R.; Tebano, G.; Viviani, F.; Sasset, L.; Mura, M. S.; Caramello, P.; Orofino, G. C.; Rossetti, B.; Sciandra, M.; Bassetti, M.; Londero, A.; Pellizzer, G.; Manfrin, V.
abstract

Background: Study aim was to estimate the rate and identify predictors of discontinuation of first combination antiretroviral therapy (cART) in recent years. Methods: Patients who initiated first cART between January 2008 and October 2014 were included. Discontinuation was defined as stop of at least 1 drug of the regimen, regardless of the reason. All causes of discontinuation were evaluated and 3 main endpoints were considered: toxicity, intolerance, and simplification. Predictors of discontinuation were examined separately for all 3 endpoints. Kaplan-Meier analysis was used for the outcome discontinuation of ≥1 drug regardless of the reason. Cox regression analysis was used to identify factors associated with treatment discontinuation because of the 3 reasons considered. Results: A total of 4052 patients were included. Main reason for stopping at least 1 drug were simplification (29%), intolerance (21%), toxicity (19%), other causes (18%), failure (8%), planned discontinuation (4%), and nonadherence (2%). In a multivariable Cox model, predictors of discontinuation for simplification were heterosexual transmission (P = 0.007), being immigrant (P = 0.017), higher nadir lymphocyte T CD4+cell (P = 0.011), and higher lymphocyte T CD8+cell count (P = 0.025); for discontinuation due to intolerance: the use of statins (P = 0.029), higher blood glucose levels (P = 0.050). About toxicity: higher blood glucose levels (P = 0.010) and the use of zidovudine/lamivudine as backbone (P = 0.044). Conclusions: In the late cART era, the main reason for stopping the initial regimen is simplification. This scenario reflects the changes in recommendations aimed to enhance adherence and quality of life, and minimize drug toxicity.

2016 - Effectiveness, durability, and safety of darunavir/ritonavir in HIV-1-infected patients in routine clinical practice in Italy: A postauthorization noninterventional study [Articolo su rivista]
Antinori, A.; Meraviglia, P.; Monforte, A. D.; Castagna, A.; Mussini, C.; Bini, T.; Gianotti, N.; Rusconi, S.; Colella, E.; Airoldi, G.; Mancusi, D.; Termini, R.
abstract

Current antiretroviral (ARV) therapy for the treatment of human immunodeficiency virus (HIV-1)-infected patients provides long-term control of viral load (VL). Darunavir (DRV) is a nonpeptidomimetic protease inhibitor approved for use with a ritonavir booster (DRV/r). This study evaluated the effectiveness of DRV/r in combination with other ARV agents in routine clinical practice in Italy. In this descriptive observational study, data on utilization of DRV/r, under the conditions described in the marketing authorization, were collected from June 2009 to December 2012. Effectiveness (VL &lt;50 copies/mL), tolerability, and durability in four patient groups (two DRV/r-experienced, one ARV-experienced DRV/r-naïve, and one ARV-naïve) were analyzed. Secondary objectives included immunological response, safety, and persistence/discontinuation rates. In total, 875 of 883 enrolled patients were included in the analysis: of these, 662 (75.7%) completed the follow-up until the end of 2012 and 213 (24.3%) withdre from the study earlier. Initial DRV dose was 600 mg twice daily (67.1%) or 800 mg once daily (32.9%). Only 16 patients (1.8%) withdrew from the study due to virological failure. Virological response proportions were higher in patients virologically suppressed at study entry versus patients with baseline VL ≥50 copies/mL in each ARV-experienced group, while there was no consistent difference across study groups and baseline VL strata according to baseline CD4+ cell count. CD4+ cell count increased from study entry to last study visit in all the four groups. DRV/r was well tolerated, with few discontinuations due to study-emergent nonfatal adverse events (3.0% overall, including 2.1% drug-related) or deaths (3.0% overall, all non-drug-related); 35.3% of patients reported ≥1 adverse events. These observational data show that DRV/r was effective and well tolerated in the whole patient population described here. The DRV/r-containing regimen provided viral suppression in a high percentage of patients in all group, with low rates of discontinuation due to virological failure.

2016 - Essentials from the 2015 European AIDS Clinical Society (EACS) guidelines for the treatment of adult HIV-positive persons [Articolo su rivista]
Ryom, L.; Boesecke, C.; Gisler, V.; Manzardo, C.; Rockstroh, J. K.; Puoti, M.; Furrer, H.; Miro, J. M.; Gatell, J. M.; Pozniak, A.; Behrens, G.; Battegay, M.; Lundgren, J. D.; Monforte, A. D.; Arribas, J.; Clumeck, N.; Dedes, N.; Geretti, A. M.; Horban, A.; Katlama, C.; McCormack, S.; Molina, J. M.; Mussini, C.; Raffi, F.; Reiss, P.; Stellbrink, H. J.; Bower, M.; Cinque, P.; Collins, S.; Compston, J.; Deray, G.; De Wit, S.; Fux, C. A.; Guraldi, G.; Mallon, P.; Martinez, E.; Marzolini, C.; Papapoulos, S.; du Pasquier, R.; Poulter, N.; Williams, I.; Winston, A.; Bhagani, S.; Bruno, R.; Konov, S.; Lacombe, K.; Mauss, S.; Mendao, L.; Peters, L.; Rauch, A.; Tural, C.; Fatkenheuer, G.; Kirk, O.; Mocroft, A.; Morlat, P.; Volny-Anne, A.; Mulcahy, F.; Oprea, C.; Youle, M.
abstract

Background: The European AIDS Clinical Society (EACS) guidelines are intended for all clinicians involved in the care of HIV-positive persons, and are available in print, online, and as a free App for download for iPhone and Android. Guideline highlights: The 2015 version of the EACS guidelines contains major revisions in all sections; antiretroviral treatment (ART), comorbidities, coinfections and opportunistic diseases. Among the key revisions is the recommendation of ART for all HIV-positive persons, irrespectively of CD4 count, based on the Strategic Timing of AntiRetroviral Treatment (START) study results. The recommendations for the preferred and the alternative ART options have also been revised, and a new section on the use of pre-exposure prophylaxis (PrEP) has been added. A number of new antiretroviral drugs/drug combinations have been added to the updated tables on drug-drug interactions, adverse drug effects, dose adjustment for renal/liver insufficiency and for ART administration in persons with swallowing difficulties. The revisions of the coinfection section reflect the major advances in anti-hepatitis C virus (HCV) treatment with direct-acting antivirals with earlier start of treatment in individuals at increased risk of liver disease progression, and a phasing out of interferon-containing treatment regimens. The section on opportunistic diseases has been restructured according to individual pathogens/diseases and a new overview table has been added on CD4 count thresholds for different primary prophylaxes. Conclusions: The diagnosis and management of HIV infection and related coinfections, opportunistic diseases and comorbidities continue to require a multidisciplinary effort for which the 2015 version of the EACS guidelines provides an easily accessable and updated overview.

2016 - European AIDS Clinical Society Standard of Care meeting on HIV and related coinfections: The Rome Statements [Articolo su rivista]
Mussini, C.; Antinori, A.; Bhagani, S.; Branco, T.; Brostrom, M.; Dedes, N.; Bereczky, T.; Girardi, E.; Gokengin, D.; Horban, A.; Lacombe, K.; Lundgren, J. D.; Mendao, L.; Mocroft, A.; Oprea, C.; Porter, K.; Podlekareva, D.; Battegay, M.; d'Arminio Monforte, A.; Mulcahy, F.; Geretti, A. M.; Clumeck, N.; Reiss, P.; Arribas, J.; Gatell, J.; Katlama, C.; Pozniak, A.; Rockstroh, J.; Youle, M.; Friis-Moller, N.; Rusconi, S.; Behrens, G.; De Wit, S.; Furrer, H.; Wensing, A.; John Gill, M.; Letendre, S.
abstract

Objectives: The objective of the 1st European AIDS Clinical Society meeting on Standard of Care in Europe was to raise awareness of the European scenario and come to an agreement on actions that could be taken in the future. Methods: Data-driven presentations were given on specific topics followed by interactive panel discussions. Results: In Eastern European countries, the epidemic is largely driven by injecting drug use, in contrast with Western Europe where the infection mainly occurs through heterosexual contact. A high proportion of people living with HIV remain unaware of their infection. Substantial differences exist in Eastern Europe and Central Asia with respect to treatment coverage, regimen availability and continuity of drug supply. In 2012, tuberculosis case notification rates were 5–10 times higher in Eastern Europe compared with Western Europe, with an alarming proportion of newly diagnosed multi-drug-resistant cases. Hepatitis C is widespread in selected geographical areas and risk groups. Conclusions: The key conclusion from the meeting was that a high-priority group of actions could be identified, including: increasing HIV awareness and testing, improving training for health care providers, ensuring equitable patient access to treatments and diagnostics for HIV and comorbidities, and implementing best practices in infection control and treatment of HIV-infected patients coinfected with tuberculosis and hepatitis C virus, for whom direct acting antiviral treatment. should be considered.

2016 - Evaluation of serum (1 → 3)-β-D-glucan clinical performance: kinetic assessment, comparison with galactomannan and evaluation of confounding factors [Articolo su rivista]
Pini, Pietro; Bettua, C; Orsi, Carlotta Francesca; Venturelli, C; Forghieri, F; Bigliardi, S; Faglioni, L; Luppi, Fabrizio; Serio, L; Codeluppi, M; Luppi, Mario; Mussini, Cristina; Girardis, Massimo; Blasi, Elisabetta
abstract

Purpose We investigated the clinical performance of (1 → 3)-β-d-glucan (BG), as an early marker of invasive fungal infections (IFI), in different clinical settings. Methods BG serum levels were assessed by Fungitell (Associates of Cape Cod, Inc), in parallel with galactomannan (GM) when requested by clinicians. By a prospective monocentric study, 270 episodes at risk or with suspect of IFI were enrolled, namely 58 proven-probable invasive aspergillosis (IA), 27 proven invasive candidiasis (IC), 11 possible IC, 16 P.jirovecii pneumonia (PJP), 4 episodes of other IFI and 154 non-IFI controls. Results We found that (a) the BG overall sensitivity, specificity, positive predictive value and negative predictive value (NPV) were 87.9, 80.5, 76.7 and 89.9 %, respectively; (b) the highest sensitivity was found in the IC groups, followed by PJP, IA and other IFI groups; (c) an association was observed between BG kinetics and patients outcome; (d) in the IA episodes, the combination of BG or GM vs GM alone increased sensitivity from 60.0 to 83.3 % in the haematological patients; (e) false-positive BG results were related to Gram-negative infections or infusion of polyclonal IgM-enriched immunoglobulins, where high levels of BG were indeed detected. Conclusion Besides strengthening its overall good clinical performance, we provide evidence that serum BG correlates with clinical outcome and that, once used in combination with GM, BG allows to enhance IFI diagnosis rate. The high sensitivity and NPV, observed in the Intensive Care Unit setting, open to BG validation as a marker for assessment of antifungal treatment.

2016 - Genotypic resistance test in proviral DNA can identify resistance mutations never detected in historical genotypic test in patients with low level or undetectable HIV-RNA [Articolo su rivista]
Zaccarelli, M.; Santoro, M. M.; Armenia, D.; Borghi, V.; Gennari, W.; Gori, C.; Forbici, F.; Bertoli, A.; Fabeni, L.; Giannetti, A.; Cicalini, S.; Bellagamba, R.; Andreoni, M.; Mastroianni, C. M.; Mussini, C.; Ceccherini-Silberstein, F.; Perno, C. F.; Antinori, A.
abstract

Background Beyond the detection of resistant HIV strains found in plasma samples, archival HIV-DNA in peripheral blood mononuclear cells (PBMCs) might represent a reservoir of additional resistance. Objective To characterize the HIV-1 resistance in PBMCs from patients with suppressed or low-level viremia (50–1000 copies/mL) and evaluate its added value compared to the resistance detected in previous plasma genotypic resistance tests (GRTs). Study design HIV-1 infected patients selected for treatment change despite low/undetectable viremia were tested. Number and type of primary resistance mutations (PRMs) detected in PBMCs were compared to those detected in previous plasma GRTs. Logistic regression assessed factors associated with presence of at least one PRM in PBMCs. Result 468 patients with a PBMC GRT were analyzed; 149 of them had at least 2 plasma GRTs performed before PBMC genotyping. 42.3% of patients showed at least one PRM in PBMCs. The highest proportion of PRMs in PBMCs was observed for NRTI class (30.6%), followed by NNRTI (22.2%), PI (14.1%) and INI (4.9%). In 20.1% of patients, PRMs were detected only in PBMCs and not in any of the plasma GRT previously performed. By using multivariable analysis, a higher number of previous regimens, injecting drug-use route and a lower nadir CD4 were associated with significantly higher risk of detecting PRMs in PBMCs. Conclusion Our findings support the usage of PBMC GRT in addition to the current recommended plasma RNA test, especially when therapeutic and/or resistance information is not available.

2016 - Global epidemiology of drug resistance after failure of WHO recommended first-line regimens for adult HIV-1 infection: A multicentre retrospective cohort study [Articolo su rivista]
Gregson, J.; Tang, M.; Ndembi, N.; Hamers, R. L.; Marconi, V. C.; Brooks, K.; Theys, K.; Arruda, M.; Garcia, F.; Monge, S.; Kanki, P. J.; Kumarasamy, N.; Kerschberger, B.; Mor, O.; Charpentier, C.; Todesco, E.; Rokx, C.; Gras, L.; Halvas, E. K.; Sunpath, H.; Carlo, D. D.; Antinori, A.; Andreoni, M.; Latini, A.; Mussini, C.; Aghokeng, A.; Sonnerborg, A.; Neogi, U.; Fessel, W. J.; Agolory, S.; Yang, C.; Blanco, J. L.; Juma, J. M.; Smit, E.; Schmidt, D.; Watera, C.; Asio, J.; Kirungi, W.; Tostevin, A.; Clumeck, N.; Goedhals, D.; Bester, P. A.; Sabin, C.; Mukui, I.; Santoro, M. M.; Perno, C. F.; Hunt, G.; Morris, L.; Pillay, D.; Schulter, E.; Reyes-Teran, G.; Romero, K.; Avila-Rios, S.; Sirivichayakul, S.; Ruxrungtham, K.; Mekprasan, S.; Dunn, D.; Kaleebu, P.; Raizes, E.; Kantor, R.; Gupta, R. K.; Rhee, S. -Y.; Shafer, R. W.; de Wit, T. F. R.; Diero, L.; Camacho, R.; Gunthard, H. F.; Hoffmann, C. J.; Di Carlo, D.; El-Hay, T.; van Vuuren, C.; de Oliveira, T.; Murakami-Ogasawara, A.
abstract

Background: Antiretroviral therapy (ART) is crucial for controlling HIV-1 infection through wide-scale treatment as prevention and pre-exposure prophylaxis (PrEP). Potent tenofovir disoproxil fumarate-containing regimens are increasingly used to treat and prevent HIV, although few data exist for frequency and risk factors of acquired drug resistance in regions hardest hit by the HIV pandemic. We aimed to do a global assessment of drug resistance after virological failure with first-line tenofovir-containing ART. Methods: The TenoRes collaboration comprises adult HIV treatment cohorts and clinical trials of HIV drug resistance testing in Europe, Latin and North America, sub-Saharan Africa, and Asia. We extracted and harmonised data for patients undergoing genotypic resistance testing after virological failure with a first-line regimen containing tenofovir plus a cytosine analogue (lamivudine or emtricitabine) plus a non-nucleotide reverse-transcriptase inhibitor (NNRTI; efavirenz or nevirapine). We used an individual participant-level meta-analysis and multiple logistic regression to identify covariates associated with drug resistance. Our primary outcome was tenofovir resistance, defined as presence of K65R/N or K70E/G/Q mutations in the reverse transcriptase (RT) gene. Findings: We included 1926 patients from 36 countries with treatment failure between 1998 and 2015. Prevalence of tenofovir resistance was highest in sub-Saharan Africa (370/654 [57%]). Pre-ART CD4 cell count was the covariate most strongly associated with the development of tenofovir resistance (odds ratio [OR] 1·50, 95% CI 1·27-1·77 for CD4 cell count &lt;100 cells per μL). Use of lamivudine versus emtricitabine increased the risk of tenofovir resistance across regions (OR 1·48, 95% CI 1·20-1·82). Of 700 individuals with tenofovir resistance, 578 (83%) had cytosine analogue resistance (M184V/I mutation), 543 (78%) had major NNRTI resistance, and 457 (65%) had both. The mean plasma viral load at virological failure was similar in individuals with and without tenofovir resistance (145 700 copies per mL [SE 12 480] versus 133 900 copies per mL [SE 16 650; p=0·626]). Interpretation: We recorded drug resistance in a high proportion of patients after virological failure on a tenofovir-containing first-line regimen across low-income and middle-income regions. Effective surveillance for transmission of drug resistance is crucial. Funding: The Wellcome Trust.

2016 - Improved darunavir genotypic mutation score predicting treatment response for patients infected with HIRaben-1 subtype B and non-subtype B receiving a salvage regimen [Articolo su rivista]
De Luca, A.; Flandre, P.; Dunn, D.; Zazzi, M.; Wensing, A.; Santoro, M. M.; Gunthard, H. F.; Wittkop, L.; Kordossis, T.; Garcia, F.; Castagna, A.; Cozzi-Lepri, A.; Churchill, D.; De Wit, S.; Brockmeyer, N. H.; Imaz, A.; Mussini, C.; Obel, N.; Perno, C. F.; Roca, B.; Reiss, P.; Schulter, E.; Torti, C.; van Sighem, A.; Zangerle, R.; Descamps, D.; Mocroft, A.; Kirk, O.; Sabin, C.; Casadi, W.; Casabona, J.; Miro, J. M.; Touloumi, G.; Garrido, M.; Teira, R.; Wit, F.; Warszawski, J.; Meyer, L.; Dabis, F.; Krause, M. M.; Ghosn, J.; Leport, C.; Prins, M.; Bucher, H.; Gibb, D.; Fatkenheuer, G.; del Amo, J.; Thorne, C.; Stephan, C.; Perez-Hoyos, S.; Hamouda, O.; Bartmeyer, B.; Chkhartishvili, N.; Noguera-Julian, A.; Antinori, A.; d'Arminio Monforte, A.; Prieto, L.; Conejo, P. R.; Soriano-Arandes, A.; Battegay, M.; Kouyos, R.; Tookey, P.; Konopnick, D.; Goetghebuer, T.; Sonnerborg, A.; Haerry, D.; de Wit, S.; Costagliola, D.; Raben, D.; Chene, G.; Ceccherini-Silberstein, F.; Gunthard, H.; Judd, A.; Barger, D.; Schwimmer, C.; Termote, M.; Campbell, M.; Frederiksen, C. M.; Friis-Moller, N.; Kjaer, J.; Brandt, R. S.; Berenguer, J.; Bohlius, J.; Bouteloup, V.; Davies, M. -A.; Dorrucci, M.; Egger, M.; Furrer, H.; Guiguet, M.; Grabar, S.; Lambotte, O.; Leroy, V.; Lodi, S.; Matheron, S.; Monge, S.; Nakagawa, F.; Paredes, R.; Phillips, A.; Puoti, M.; Schomaker, M.; Smit, C.; Sterne, J.; Thiebaut, R.; van der Valk, M.; Wyss, N.; Aubert, V.; Battegay, M.; Bernasconi, E.; Boni, J.; Burton-Jeangros, C.; Calmy, A.; Cavassini, M.; Dollenmaier, G.; Egger, M.; Elzi, L.; Fehr, J.; Fellay, J.; Furrer, H.; Fux, C. A.; Gorgievski, M.; Gunthard, H.; Haerry, D.; Hasse, B.; Hirsch, H. H.; Hoffmann, M.; Hosli, I.; Kahlert, C.; Kaiser, L.; Keiser, O.; Klimkait, T.; Kouyos, R.; Kovari, H.; Ledergerber, B.; Martinetti, G.; Martinez de Tejada, B.; Metzner, K.; Muller, N.; Nadal, D.; Nicca, D.; Pantaleo, G.; Rauch, A.; Regenass, S.; Rickenbach, M.; Rudin, C.; Schoni-Affolter, F.; Schmid, P.; Schupbach, J.; Speck, R.; Tarr, P.; Telenti, A.; Trkola, A.; Vernazza, P.; Weber, R.; Yerly, S.
abstract

Objectives: The objective of this studywas to improve the prediction of the impact of HIV-1 protease mutations in different viral subtypes on virological response to darunavir. Methods: Darunavir-containing treatment change episodes (TCEs) in patients previously failing PIs were selected from large European databases. HIV-1 subtype B-infected patients were used as the derivation dataset and HIV- 1 non-B-infected patients were used as the validation dataset. The adjusted association of each mutation with week 8 HIV RNA change from baseline was analysed by linear regression. A prediction model was derived based on best subset least squares estimation with mutational weights corresponding to regression coefficients. Virological outcome prediction accuracy was compared with that from existing genotypic resistance interpretation systems (GISs) (ANRS 2013, Rega 9.1.0 and HIVdb 7.0). Results: TCEs were selected from 681 subtype B-infected and 199 non-B-infected adults. Accompanying drugs were NRTIs in 87%, NNRTIs in 27%and raltegravir ormaraviroc or enfuvirtide in 53%. The predictionmodel included weighted protease mutations, HIV RNA, CD4 and activity of accompanying drugs. The model's association with week 8 HIV RNA change in the subtype B (derivation) set was R2=0.47 [average squared error (ASE)=0.67, P&gt;10-6]; in the non-B (validation) set, ASE was 0.91. Accuracy investigated by means of area under the receiver operating characteristic curves with a binary response (above the threshold value of HIV RNA reduction) showed that our finalmodel outperformed models with existing interpretation systems in both training and validation sets. Conclusions: A model with a new darunavir-weighted mutation score outperformed existing GISs in both B and non-B subtypes in predicting virological response to darunavir.

2016 - Increased risk of virologic failure to the first antiretroviral regimen in HIV-infected migrants compared to natives: Data from the ICONA cohort [Articolo su rivista]
Saracino, A.; Lorenzini, P.; Lo Caputo, S.; Girardi, E.; Castelli, F.; Bonfanti, P.; Rusconi, S.; Caramello, P.; Abrescia, N.; Mussini, C.; Monno, L.; d'Arminio Monforte, A.; Moroni, M.; Andreoni, M.; Angarano, G.; Antinori, A.; Cauda, R.; Di Perri, G.; Galli, M.; Iardino, R.; Ippolito, G.; Lazzarin, A.; Perno, C. F.; von Schloesser, F.; Viale, P.; Castagna, A.; Cozzi-Lepri, A.; Puoti, M.; Ammassari, A.; Balotta, C.; Bonora, S.; Borderi, M.; Capobianchi, M. R.; Ceccherini-Silberstein, F.; Cingolani, A.; Cinque, P.; De Luca, A.; Di Biagio, A.; Gianotti, N.; Gori, A.; Guaraldi, G.; Lapadula, G.; Lichtner, M.; Madeddu, G.; Maggiolo, F.; Marchetti, G.; Marcotullio, S.; Quiros Roldan, E.; Cicconi, P.; Fanti, I.; Galli, L.; Shanyinda, M.; Tavelli, A.; Giacometti, A.; Costantini, A.; Mazzoccato, S.; Santoro, C.; Suardi, C.; Vanino, E.; Verucchi, G.; Minardi, C.; Quirino, T.; Abeli, C.; Manconi, P. E.; Piano, P.; Vecchiet, J.; Falasca, K.; Sighinolfi, L.; Segala, D.; Mazzotta, F.; Cassola, G.; Viscoli, C.; Alessandrini, A.; Piscopo, R.; Mazzarello, G.; Mastroianni, C.; Belvisi, V.; Caramma, I.; Chiodera, A.; Castelli, A. P.; Rizzardini, G.; Ridolfo, A. L.; Piolini, R.; Salpietro, S.; Carenzi, L.; Moioli, M. C.; Tincati, C.; Puzzolante, C.; Chirianni, A.; Borgia, G.; Guida, M. G.; Gargiulo, M.; Gentile, I.; Orlando, R.; Baldelli, F.; Francisci, D.; Parruti, G.; Ursini, T.; Magnani, G.; Ursitti, M. A.; Vullo, V.; d'Avino, A.; Gallo, L.; Nicastri, E.; Acinapura, R.; Capozzi, M.; Libertone, R.; Tebano, 1G.; Zaccarelli, M.; Viviani, F.; Sasset, L.; Mura, M. S.; Rossetti, B.; Orofino, G. C.; Sciandra, M.; Bassetti, M.; Londero, A.; Pellizzer, G.; Manfrin, V.
abstract

Migrant and Italian HIV-infected patients (n = 5773) enrolled in the ICONA cohort in 2004-2014 were compared for disparities in access to an initial antiretroviral regimen and/or risk of virologic failure (VF), and determinants of failure were evaluated. Variables associated with initiating antiretroviral therapy (ART) were analysed. Primary endpoint was time to failure after at least 6 months of ART and was defined as: VF, first of two consecutive virus loads (VL) &gt;200 copies/mL; treatment discontinuation (TD) for any reason; and treatment failure as confirmed VL &gt;200 copies/mL or TD. A Poisson multivariable analysis was performed to control for confounders. Migrants presented significantly lower CD4 counts and more frequent AIDS events at baseline. When adjusting for baseline confounders, migrants presented a lower likelihood to begin ART (odds ratio 0.80, 95% confidence interval (CI) 0.67-0.95, p 0.012). After initiating ART, the incidence VF rate was 6.4 per 100 person-years (95% CI 4.8-8.5) in migrants and 2.7 in natives (95% CI 2.2-3.3). Multivariable analysis confirmed that migrants had a higher risk of VF (incidence rate ratio 1.90, 95% CI 1.25-2.91, p 0.003) and treatment failure (incidence rate ratio 1.16, 95% CI 1.01-1.33, p 0.031), with no differences for TD. Among migrants, variables associated with VF were age, unemployment and use of a boosted protease inhibitor-based regimen versus nonnucleoside reverse transcriptase inhibitors. Despite the use of more potent and safer drugs in the last 10 years, and even in a universal health care setting, migrants living with HIV still present barriers to initiating ART and an increased risk of VF compared to natives.

2016 - Infection-related and -unrelated malignancies, HIV and the aging population [Articolo su rivista]
Shepherd, L.; Borges, A. H.; Ledergerber, B.; Domingo, P.; Castagna, A.; Rockstroh, J.; Knysz, B.; Tomazic, J.; Karpov, I.; Kirk, O.; Lundgren, J.; Mocroft, A.; Losso, M.; Kundro, M.; Vetter, N.; Zangerle, R.; Vassilenko, A.; Mitsura, V. M.; Suetnov, O.; Clumeck, N.; De Wit, S.; Delforge, M.; Florence, E.; Vandekerckhove, L.; Hadziosmanovic, V.; Kostov, K.; Begovac, J.; Machala, L.; Jilich, D.; Sedlacek, D.; Nielsen, J.; Kronborg, G.; Benfield, T.; Larsen, M.; Gerstoft, J.; Katzenstein, T.; Hansen, A. -B. E.; Skinhoj, P.; Pedersen, C.; Ostergaard, L.; Dragsted, U. B.; Nielsen, L. N.; Zilmer, K.; Smidt, J.; Ristola, M.; Katlama, C.; Viard, J. -P.; Girard, P. -M.; Vanhems, P.; Pradier, C.; Dabis, F.; Neau, D.; Duvivier, C.; Schmidt, R.; van Lunzen, J.; Degen, O.; Stellbrink, H. J.; Bickel, M.; Bogner, J.; Fatkenheuer, G.; Kosmidis, J.; Gargalianos, P.; Xylomenos, G.; Perdios, J.; Sambatakou, H.; Banhegyi, D.; Gottfredsson, M.; Mulcahy, F.; Yust, I.; Turner, D.; Burke, M.; Pollack, S.; Hassoun, G.; Elinav, H.; Haouzi, M.; D'Arminio Monforte, A.; Esposito, R.; Mazeu, I.; Mussini, C.; Arici, C.; Pristera, R.; Mazzotta, F.; Gabbuti, A.; Vullo, V.; Lichtner, M.; Chirianni, A.; Montesarchio, E.; Gargiulo, M.; D'Offizi, G.; Taibi, C.; Antinori, A.; Lazzarin, A.; Gianotti, N.; Galli, M.; Ridolfo, A.; Rozentale, B.; Zeltina, I.; Chaplinskas, S.; Staub, T.; Hemmer, R.; Reiss, P.; Ormaasen, V.; Maeland, A.; Bruun, J.; Gasiorowski, J.; Horban, A.; Bakowska, E.; Grzeszczuk, A.; Flisiak, R.; Boron-Kaczmarska, A.; Pynka, M.; Parczewski, M.; Beniowski, M.; Mularska, E.; Trocha, H.; Jablonowska, E.; Malolepsza, E.; Wojcik, K.; Doroana, M.; Caldeira, L.; Mansinho, K.; Maltez, F.; Duiculescu, D.; Rakhmanova, A.; Buzunova, S.; Khromova, I.; Kuzovatova, E.; Jevtovic, D.; Mokras, M.; Stanekova, D.; Gonzalez-Lahoz, J.; Soriano, V.; Labarga, P.; Moreno, S.; Rodriguez, J. M.; Clotet, B.; Jou, A.; Paredes, R.; Tural, C.; Puig, J.; Bravo, I.; Gatell, J. M.; Miro, J. M.; Gutierrez, M.; Mateo, G.; Sambeat, M. A.; Medrano, J.; Blaxhultblaxhult, A.; Flamholc, L.; Thalme, A.; Sonnerborg, A.; Weber, R.; Francioli, P.; Cavassini, M.; Hirschel, B.; Boffi, E.; Furrer, H.; Battegay, M.; Elzi, L.; Vernazza, P.; Kravchenko, E.; Chentsova, N.; Frolov, V.; Kutsyna, G.; Servitskiy, S.; Kuznetsova, A.; Kyselyova, G.; Gazzard, B.; Johnson, A. M.; Simons, E.; Phillips, A.; Johnson, M. A.; Orkin, C.; Weber, J.; Scullard, G.; Fisher, M.; Leen, C.; Gatell, J.; De Witt, S.; Cozzi-Lepri, A.; Grint, D.; Schultze, A.; Raben, D.; Podlekareva, D.; Kjaer, J.; Peters, L.; Nielsen, J. E.; Matthews, C.; Fischer, A. H.; Bojesen, A.; Grarup, J.; Thiebaut, R.; Burger, D.
abstract

Objectives: HIV-positive people have increased risk of infection-related malignancies (IRMs) and infection-unrelated malignancies (IURMs). The aim of the study was to determine the impact of aging on future IRM and IURM incidence. Methods: People enrolled in EuroSIDA and followed from the latest of the first visit or 1 January 2001 until the last visit or death were included in the study. Poisson regression was used to investigate the impact of aging on the incidence of IRMs and IURMs, adjusting for demographic, clinical and laboratory confounders. Linear exponential smoothing models forecasted future incidence. Results: A total of 15 648 people contributed 95 033 person-years of follow-up, of whom 610 developed 643 malignancies [IRMs: 388 (60%); IURMs: 255 (40%)]. After adjustment, a higher IRM incidence was associated with a lower CD4 count [adjusted incidence rate ratio (aIRR) CD4 count &lt; 200 cells/μL: 3.77; 95% confidence interval (CI) 2.59, 5.51; compared with ≥ 500 cells/μL], independent of age, while a CD4 count &lt; 200 cells/μL was associated with IURMs in people aged &lt; 50 years only (aIRR: 2.51; 95% CI 1.40–4.54). Smoking was associated with IURMs (aIRR: 1.75; 95% CI 1.23, 2.49) compared with never smokers in people aged ≥ 50 years only, and not with IRMs. The incidences of both IURMs and IRMs increased with older age. It was projected that the incidence of IRMs would decrease by 29% over a 5-year period from 3.1 (95% CI 1.5–5.9) per 1000 person-years in 2011, whereas the IURM incidence would increase by 44% from 4.1 (95% CI 2.2–7.2) per 1000 person-years over the same period. Conclusions: Demographic and HIV-related risk factors for IURMs (aging and smoking) and IRMs (immunodeficiency and ongoing viral replication) differ markedly and the contribution from IURMs relative to IRMs will continue to increase as a result of aging of the HIV-infected population, high smoking and lung cancer prevalence and a low prevalence of untreated HIV infection. These findings suggest the need for targeted preventive measures and evaluation of the cost−benefit of screening for IURMs in HIV-infected populations.

2016 - Italian guidelines for the use of antiretroviral agents and the diagnostic-clinical management of HIV-1 infected persons. Update 2015 [Articolo su rivista]
Antinori, A; Marcotullio, S; Andreoni, M; Chirianni, A; Monforte, Ad; Di Biagio, A; Galli, M; Mazzotta, F; Mussini, C; Puoti, M; Lazzarin, A
abstract

2016 - Kaposi sarcoma risk in HIV-infected children and adolescents on combination antiretroviral therapy from sub-Saharan Africa, Europe, and Asia [Articolo su rivista]
Rohner, E.; Schmidlin, K.; Zwahlen, M.; Chakraborty, R.; Clifford, G.; Obel, N.; Grabar, S.; Verbon, A.; Noguera-Julian, A.; Judd, A.; Collins, I. J.; Rojo, P.; Brockmeyer, N.; Campbell, M.; Chene, G.; Prozesky, H.; Eley, B.; Stefan, D.; Davidson, A.; Chimbetete, C.; Sawry, S.; Davies, M. -A.; Kariminia, A.; Vibol, U.; Sohn, A.; Egger, M.; Bohlius, J.; Tanser, F.; Vinikoor, M.; Macete, E.; Wood, R.; Stinson, K.; Garone, D.; Fatti, G.; Phiri, S.; Giddy, J.; Malisita, K.; Fritz, C.; Hobbins, M.; Kamenova, K.; Fox, M.; Technau, K.; Zangerle, R.; Touloumi, G.; Warszawski, J.; Meyer, L.; Dabis, F.; Krause, M. M.; Ghosn, J.; Leport, C.; Wittkop, L.; Reiss, P.; Wit, F.; Prins, M.; Bucher, H.; Sabin, C.; Gibb, D.; Fatkenheuer, G.; Del Amo, J.; Thorne, C.; Mocroft, A.; Kirk, O.; Stephan, C.; Perez-Hoyos, S.; Hamouda, O.; Bartmeyer, B.; Chkhartishvili, N.; Antinori, A.; Monforte, A. D.; Prieto, L.; Soriano-Arandes, A.; Battegay, M.; Kouyos, R.; Mussini, C.; Tookey, P.; Casabona, J.; Miro, J. M.; Castagna, A.; Konopnick, D.; Goetghebuer, T.; Sonnerborg, A.; Torti, C.; Teira, R.; Garrido, M.; Haerry, D.; De Wit, S.; Costagliola, D.; Raben, D.; Barger, D.; Schwimmer, C.; Termote, M.; Frederiksen, C.; Friis-Moller, N.; Berenguer, J.; Bouteloup, V.; Cozzi-Lepri, A.; Dorrucci, M.; Dunn, D.; Furrer, H.; Guiguet, M.; Lambotte, O.; Leroy, V.; Lodi, S.; Matheron, S.; Monge, S.; Nakagawa, F.; Paredes, R.; Peters, L.; Phillips, A.; Puoti, M.; Schomaker, M.; Smit, C.; Sterne, J.; Thiebaut, R.; Van Der Valk, M.; Ly, P. S.; Khol, V.; Sarun, S. M.; Ung, V. B.; Tucker, J.; Kumarasamy, N.; Saghayam, S.; Chandrasekaran, E.; Wati, D. K.; Atmikasari, L. P. P.; Malino, I. Y.; Kurniati, N.; Muktiarti, D.; Fong, S. M.; Lim, M.; Daut, F.; Nik Yusoff, N. K.; Mohamad, P.; Razali, K. A.; Mohamed, T. J.; Mohammed, N. A. D. R.; Nallusamy, R.; Chan, K. C.; Sudjaritruk, T.; Sirisanthana, V.; Aurpibul, L.; Oberdorfer, P.; Hansudewechakul, R.; Denjanta, S.; Srisuk, W.; Kongphonoi, A.; Lumbiganon, P.; Kosalaraksa, P.; Tharnprisan, P.; Udomphanit, T.; Jourdain, G.; Bunupuradah, T.; Puthanakit, T.; Prasitsuebsai, W.; Chanthaweethip, W.; Chokephaibulkit, K.; Lapphra, K.; Phongsamart, W.; Sricharoenchai, S.; Truong, K. H.; Du, Q. T.; Nguyen, C. H.; Do, V. C.; Ha, T. M.; An, V. T.; Nguyen, L. V.; Khu, D. T. K.; Pham, A. N.; Nguyen, L. T.; Le, O. N.; Sohn, A. H.; Sethaputra, C.; Cooper, D. A.; Law, M. G.
abstract

Background. The burden of Kaposi sarcoma (KS) in human immunodeficiency virus (HIV)-infected children and adolescents on combination antiretroviral therapy (cART) has not been compared globally. Methods. We analyzed cohort data from the International Epidemiologic Databases to Evaluate AIDS and the Collaboration of Observational HIV Epidemiological Research in Europe.We included HIV-infected children aged &lt;16 years at cART initiation from 1996 onward. We used Cox models to calculate hazard ratios (HRs), adjusted for region and origin, sex, cART start year, age, and HIV/AIDS stage at cART initiation. Results. We included 24 991 children from eastern Africa, southern Africa, Europe and Asia; 26 developed KS after starting cART. Incidence rates per 100 000 person-years (PYs) were 86 in eastern Africa (95% confidence interval [CI], 55-133), 11 in southern Africa (95% CI, 4-35), and 81 (95% CI, 26-252) in children of sub-Saharan African (SSA) origin in Europe. The KS incidence rates were 0/100 000 PYs in children of non-SSA origin in Europe (95% CI, 0-50) and in Asia (95% CI, 0-27). KS risk was lower in girls than in boys (adjusted HR [aHR], 0.3; 95% CI, .1-.9) and increased with age (10-15 vs 0-4 years; aHR, 3.4; 95% CI, 1.2-10.1) and advanced HIV/AIDS stage (CDC stage C vs A/B; aHR, 2.4; 95% CI, .8-7.3) at cART initiation. Conclusions. HIV-infected children from SSA but not those from other regions, have a high risk of developing KS after cART initiation. Early cART initiation in these children might reduce KS risk.

2016 - Long-term durability of tenofovir-based antiretroviral therapy In relation to the Co-administration of other drug classes in routine clinical practice [Articolo su rivista]
Costarelli, S.; Cozzi-Lepri, A.; Lapadula, G.; Bonora, S.; Madeddu, G.; Maggiolo, F.; Antinori, A.; Galli, M.; Di Perri, G.; Viale, P.; D'Arminio Monforte, A.; Gori, A.; Moroni, M.; Andreoni, M.; Angarano, G.; Castelli, F.; Cauda, R.; Iardino, R.; Ippolito, G.; Lazzarin, A.; Perno, C. F.; Von Schloesser, F.; Castagna, A.; Ceccherini-Silberstein, F.; Girardi, E.; Lo Caputo, S.; Mussini, C.; Puoti, M.; Ammassari, A.; Balotta, C.; Bonfanti, P.; Borderi, M.; Capobianchi, M. R.; Cingolani, A.; Cinque, P.; De Luca, A.; Di Biagio, A.; Gianotti, N.; Guaraldi, G.; Lichtner, M.; Marchetti, G.; Marcotullio, S.; Monno, L.; Quiros Roldan, E.; Rusconi, S.; Saracino, A.; Cicconi, P.; Fanti, I.; Galli, L.; Lorenzini, P.; Tavelli, A.; Giacometti, A.; Costantini, A.; Mazzoccato, S.; Santoro, C.; Suardi, C.; Vanino, E.; Verucchi, G.; Minardi, C.; Quirino, T.; Abeli, C.; Manconi, P. E.; Piano, P.; Vecchiet, J.; Falasca, K.; Sighinolfi, L.; Segala, D.; Mazzotta, F.; Cassola, G.; Viscoli, C.; Alessandrini, A.; Piscopo, R.; Mazzarello, G.; Mastroianni, C.; Belvisi, V.; Caramma, I.; Chiodera, A.; Castelli, A. P.; Rizzardini, G.; Ridolfo, A. L.; Piolini, R.; Salpietro, S.; Carenzi, L.; Moioli, M. C.; Tincati, C.; Puzzolante, C.; Abrescia, N.; Chirianni, A.; Guida, M. G.; Gargiulo, M.; Baldelli, F.; Francisci, D.; Parruti, G.; Ursini, T.; Magnani, G.; Ursitti, M. A.; Vullo, V.; D'Avino, A.; Gallo, L.; Nicastri, E.; Acinapura, R.; Capozzi, M.; Libertone, R.; Tebano, G.; Cattelan, A.; Sasset, L.; Mura, M. S.; Rossetti, B.; Caramello, P.; Orofino, G. C.; Sciandra, M.; Bassetti, M.; Londero, A.; Pellizzer, G.; Manfrin, V.
abstract

Background: In clinical trials, toxicity leading to tenofovir disoproxil fumarate (TDF) discontinuation is rare (3% by 2 years); however in clinical practice it seems to be higher, particularlywhen TDF is co-administered with ritonavir-boosted protease inhibitors (PI/r). Aims of this study were to assess the rate of TDF discontinuations in clinical practice and to identify factors associated with the risk of stopping TDF. Methods: All antiretroviral treatment (ART)-naive patients initiating a TDF-based regimen were selected from the ICONA Foundation Study cohort. The primary outcome was TDF discontinuation regardless of the reason; secondary outcome measures were TDF discontinuation due to toxicity and selective TDF discontinuation (that is, TDF discontinuation or substitution, maintaining unchanged the remaining antiretroviral treatment). Results: 3,618 ART-naïve patients were included: 54% started a PI/r-based and 46% a NNRTIbased based regimen. Two-hundred-seventy-seven patients discontinued TDF and reintroduced ART within 30 days without TDF. The probability of TDF discontinuation regardless of the reason was of 7.4% (95%CI:6.4-8.5) by 2 years and 14.1% (95%CI:12.2-16.1) by 5 years. The 5-year KM estimates in the PI/r vs. NNRTI group were 20.4% vs. 7.6%, respectively (log-rank p = 0.0001), for the outcome of stopping regardless of the reason, and 10.7% vs. 4.7% (p = 0.0001) for discontinuation due to toxicity. PI/r use and lower eGFR were associated with an increased risk of discontinuing TDF. Conclusion: In our cohort, the frequency of TDF discontinuations was higher than that observed in clinical trials. Co-administration of TDF with PI/r was associated with an increased rate of TDF discontinuations. Further studies are needed to clarify the mechanisms that might have led to this outcome.

2016 - Long-term effectiveness of unboosted atazanavir plus abacavir/lamivudine in subjects with virological suppression: A prospective cohort study [Articolo su rivista]
Llibre, J. M.; Cozzi-Lepri, A.; Pedersen, C.; Ristola, M.; Losso, M.; Mocroft, A.; Mitsura, V.; Falconer, K.; Maltez, F.; Beniowski, M.; Vullo, V.; Hassoun, G.; Kuzovatova, E.; Szlavik, J.; Kuznetsova, A.; Stellbrink, H. -J.; Duvivier, C.; Edwards, S.; Laut, K.; Paredes, R.; Losso, M.; Kundro, M.; Vetter, N.; Zangerle, R.; Karpov, I.; Vassilenko, A.; Mitsura, V. M.; Paduto, D.; Clumeck, N.; De Wit, S.; Delforge, M.; Florence, E.; Vandekerckhove, L.; Hadziosmanovic, V.; Kostov, K.; Begovac, J.; Machala, L.; Jilich, D.; Sedlacek, D.; Kronborg, G.; Benfield, T.; Gerstoft, J.; Katzenstein, T.; Moller, N. F.; Pedersen, C.; Ostergaard, L.; Dragsted, U. B.; Nielsen, L. N.; Zilmer, K.; Smidt, J.; Ristola, M.; Aho, I.; Viard, J. -P.; Girard, P. -M.; Cotte, L.; Pradier, C.; Fontas, E.; Dabis, F.; Neau, D.; Duvivier, C.; Rockstroh, J.; Schmidt, R.; Degen, O.; Stellbrink, H. J.; Stefan, C.; Bogner, J.; Fatkenheuer, G.; Chkhartishvili, N.; Kosmidis, J.; Gargalianos, P.; Xylomenos, G.; Lourida, P.; Sambatakou, H.; Szlavik, J.; Gottfredsson, M.; Mulcahy, F.; Yust, I.; Turner, D.; Burke, M.; Shahar, E.; Hassoun, G.; Elinav, H.; Haouzi, M.; Elbirt, D.; Sthoeger, Z. M.; D'Arminio Monforte, A.; Esposito, R.; Mazeu, I.; Mussini, C.; Mazzotta, F.; Gabbuti, A.; Vullo, V.; Lichtner, M.; Zaccarelli, M.; Antinori, A.; Acinapura, R.; Plazzi, M.; Lazzarin, A.; Castagna, A.; Gianotti, N.; Galli, M.; Ridolfo, A.; Rozentale, B.; Uzdaviniene, V.; Matulionyte, R.; Staub, T.; Hemmer, R.; Reiss, P.; Ormaasen, V.; Maeland, A.; Bruun, J.; Knysz, B.; Gasiorowski, J.; Inglot, M.; Horban, A.; Bakowska, E.; Flisiak, R.; Grzeszczuk, A.; Parczewski, M.; Pynka, M.; Maciejewska, K.; Beniowski, M.; Mularska, E.; Smiatacz, T.; Gensing, M.; Jablonowska, E.; Malolepsza, E.; Wojcik, K.; Mozer-Lisewska, I.; Doroana, M.; Caldeira, L.; Mansinho, K.; Maltez, F.; Radoi, R.; Oprea, C.; Rakhmanova, A.; Rakhmanova, A.; Trofimora, T.; Khromova, I.; Kuzovatova, E.; Jevtovic, D.; Shunnar, A.; Stanekova, D.; Tomazic, J.; Gatell, J. M.; Miro, J. M.; Moreno, S.; Rodriguez, J. M.; Clotet, B.; Jou, A.; Paredes, R.; Tural, C.; Puig, J.; Bravo, I.; Domingo, P.; Gutierrez, M.; Mateo, G.; Sambeat, M. A.; Laporte, J. M.; Falconer, K.; Thalme, A.; Sonnerborg, A.; Blaxhult, A.; Flamholc, L.; Ledergerber, B.; Weber, R.; Cavassini, M.; Calmy, A.; Furrer, H.; Battegay, M.; Schmid, P.; Kravchenko, E.; Frolov, V.; Kutsyna, G.; Baskakov, I.; Kuznetsova, A.; Kyselyova, G.; Sluzhynska, M.; Gazzard, B.; Johnson, A. M.; Simons, E.; Edwards, S.; Phillips, A.; Johnson, M. A.; Mocroft, A.; Orkin, C.; Weber, J.; Scullard, G.; Clarke, A.; Leen, C.; Lundgren, J.; Grarup, J.; Thiebaut, R.; Burger, D.; Peters, L.; Matthews, C.; Fischer, A. H.; Bojesen, A.; Raben, D.; Kristensen, D.; Larsen, J. F.; Podlekareva, D.; Shepherd, L.; Schultze, A.
abstract

Effectiveness data of an unboosted atazanavir (ATV) with abacavir/lamivudine (ABC/3TC) switch strategy in clinical routine are scant. We evaluated treatment outcomes of ATV + ABC/3TC in pretreated subjects in the EuroSIDA cohort when started with undetectable plasma HIV-1 viral load (pVL), performing a time to loss of virological response (TLOVR &lt;50copies/mL) and a snapshot analysis at 48, 96, and 144 weeks. Virological failure (VF) was defined as confirmed pVL &gt;50copies/mL. We included 285 subjects, 67% male, with median baseline CD4 530 cells, and 44 months with pVL ≤50copies/mL. The third drug in the previous regimen was ritonavir-boosted atazanavir (ATV/r) in 79 (28%), and another ritonavir-boosted protease inhibitor (PI/r) in 29 (10%). Ninety (32%) had previously failed with a PI. Proportions of people with virological success at 48/96/144 weeks were 90%/87%/88% (TLOVR) and 74%/67%/59% (snapshot analysis), respectively. The rates of VF were 8%/8%/6%. Rates of adverse events leading to study discontinuation were 0.4%/1%/2%. The multivariable adjusted analysis showed an association between VF and nadir CD4+ (hazard ratio [HR] 0.63 [95% confidence interval [CI]: 0.42-0.93] per 100 cells higher), time with pVL ≤50copies/mL (HR 0.87 [95% CI: 0.79-0.96] per 6 months longer), and previous failure with a PI (HR 2.78 [95% CI: 1.28-6.04]). Resistance selection at failure was uncommon. A switch to ATV + ABC/3TC in selected subjects with suppressed viremia was associated with low rates of VF and discontinuation due to adverse events, even in subjects not receiving ATV/r. The strategy might be considered in those with long-term suppression and no prior PI failure.

2016 - Mucorales-specific T cells in patients with hematologic malignancies [Articolo su rivista]
Potenza, Leonardo; Vallerini, Daniela; Barozzi, Patrizia; Riva, Giovanni; Gilioli, Andrea; Forghieri, Fabio; Candoni, Anna; Cesaro, Simone; Quadrelli, Chiara; Maertens, Johan; Rossi, Giulio; Morselli, Monica; Codeluppi, Mauro; Mussini, Cristina; Colaci, Elisabetta; Messerotti, Andrea; Paolini, Ambra; Maccaferri, Monica; Fantuzzi, Valeria; DEL GIOVANE, Cinzia; Stefani, Alessandro; Morandi, Uliano; Maffei, Rossana; Marasca, Roberto; Narni, Franco; Fanin, Renato; Comoli, Patrizia; Romani, Luigina; Beauvais, Anne; Viale, Pier Luigi; Latgè, Jean Paul; Lewis, Russell E.; Luppi, Mario
abstract

Background: Invasive mucormycosis (IM) is an emerging life-threatening fungal infection. It is difficult to obtain a definite diagnosis and to initiate timely intervention. Mucorales-specific T cells occur during the course of IM and are involved in the clearance of the infection. We have evaluated the feasibility of detecting Mucorales-specific T cells in hematological patients at risk for IM, and have correlated the detection of such cells with the clinical conditions of the patients. Methods and Findings: By using an enzyme linked immunospot assay, the presence of Mucorales-specific T cells in peripheral blood (PB) samples has been investigated at three time points during highdose chemotherapy for hematologic malignancies. Mucorales-specific T cells producing interferon-γ, interleukin-10 and interleukin-4 were analysed in order to detect a correlation between the immune response and the clinical picture. Twenty-one (10.3%) of 204 patients, accounting for 32 (5.3%) of 598 PB samples, tested positive for Mucorales-specific T cells. Two groups could be identified. Group 1, including 15 patients without signs or symptoms of invasive fungal diseases (IFD), showed a predominance of Mucorales-specific T cells producing interferon-gamma. Group 2 included 6 patients with a clinical picture consistent with invasive fungal disease (IFD):2 cases of proven IM and 4 cases of possible IFD. The proven patients had significantly higher number of Mucorales-specific T cells producing interleukin-10 and interleukin-4 and higher rates of positive samples by using derived diagnostic cut-offs when compared with the 15 patients without IFD. Conclusions: Mucorales-specific T cells can be detected and monitored in patients with hematologic malignancies at risk for IM. Mucorales-specific T cells polarized to the production of T helper type 2 cytokines are associated with proven IM and may be evaluated as a surrogate diagnostic marker for IM.

2016 - Multidrug-resistant tuberculosis outbreak in an Italian prison: Tolerance of pyrazinamide plus levofloxacin prophylaxis and serial interferon gamma release assays [Articolo su rivista]
Bedini, Andrea; Garlassi, Elisa; Stentarelli, Chiara; Petrella, S.; Meacci, M.; Meccugni, B.; Meschiari, Marianna; Franceschini, Elisa; Cerri, Stefania; Brasacchio, A.; Rumpianesi, F.; Richeldi, Luca; Mussini, Cristina
abstract

The optimal treatment for latent tuberculosis infection (LTBI) in subjects exposed to multidrug-resistant (MDR) tuberculosis (TB) remains unclear, and the change in response of the QuantiFERON-TB Gold In-Tube (QTB-IT) test during and after treatment is unknown. Between May 2010 and August 2010, 39 prisoners at the 'Casa Circondariale' of Modena, Italy, were exposed to a patient with active pulmonary MDR TB. All contacts were tested with the tuberculin skin test and QTB-IT. Upon exclusion of active TB, subjects positive to both tests were offered 6 months' treatment with pyrazinamide (PZA) and levofloxacin (LVX). QTB-IT testing was repeated at 3 and 6 months after initial testing in all subjects who were offered LTBI treatment. Seventeen (43.5%) of 39 subjects tested positive to both tuberculin skin test and QTB-IT test, and 12 (70.5%) agreed to receive therapy with PZA and LVX at standard doses. Only five (41.6%) of 12 subjects completed 6 months' treatment. Reasons for discontinuation were asymptomatic hepatitis, gastritis and diarrhoea. The QTB-IT values decreased in all subjects who completed the treatment, in two (33%) of six of those who received treatment for less than 3 months and in one (50%) of two patients who discontinued therapy after 3 months. The QTB-IT test results never turned negative. Despite the small number of subjects, the study confirmed that PZA plus LVX is a poorly tolerated option for MDR LTBI treatment. We observed a large degree of variation in the results of the QTB-IT test results among participants. The study confirmed that the interferon gamma release assay is not a reliable tool for monitoring the treatment of MDR LTBI in clinical practice.

2016 - Prediction of hard cardiovascular events in HIV patients [Articolo su rivista]
Raggi, Paolo; De Francesco, Davide; Manicardi, Marcella; Zona, Stefano; Bellasi, Antonio; Stentarelli, Chiara; Carli, Federica; Beghetto, Barbara; Mussini, Cristina; Malagoli, Andrea; Guaraldi, Giovanni
abstract

To assess the accuracy of risk prediction algorithms used in the general population and an HIV-specific algorithm to predict hard cardiovascular events.

2016 - Recommended immunization schedules for adults: Clinical practice guidelines by the Escmid Vaccine Study Group (EVASG), European Geriatric Medicine Society (EUGMS) and the World Association for Infectious Diseases and Immunological Disorders (WAidid) [Articolo su rivista]
Esposito, S.; Bonanni, P.; Maggi, S.; Tan, L.; Ansaldi, F.; Lopalco, P. L.; Dagan, R.; Michel, J. -P.; van Damme, P.; Gaillat, J.; Prymula, R.; Vesikari, T.; Mussini, C.; Frank, U.; Osterhaus, A.; Celentano, L. P.; Rossi, M.; Guercio, V.; Gavazzi, G.
abstract

ABSTRACT: Rapid population aging has become a major challenge in the industrialized world and progressive aging is a key reason for making improvement in vaccination a cornerstone of public health strategy. An increase in age-related disorders and conditions is likely to be seen in the near future, and these are risk factors for the occurrence of a number of vaccine-preventable diseases. An improvement in infectious diseases prevention specifically aimed at adults and the elderly can therefore also decrease the burden of these chronic conditions by reducing morbidity, disability, hospital admissions, health costs, mortality rates and, perhaps most importantly, by improving the quality of life. Among adults, it is necessary to identify groups at increased risk of vaccine-preventable diseases and highlight the epidemiological impact and benefits of vaccinations using an evidence-based approach. This document provides clinical practice guidance on immunization for adults in order to provide recommendations for decision makers and healthcare workers in Europe. Although immunization is considered one of the most impactful and cost-effective public health measures that can be undertaken, vaccination coverage rates among adults are largely lower than the stated goal of ≥ 95% among adults, and stronger efforts are needed to increase coverage in this population. Active surveillance of adult vaccine-preventable diseases, determining the effectiveness of the vaccines approved for marketing in the last 5&nbsp;y, the efficacy and safety of vaccines in immunocompromised patients, as well as in pregnant women, represent the priorities for future research.

2016 - Response to first-line ritonavir-boosted protease inhibitors (PI/r)-based regimens in HIV positive patients presenting to care with low CD4 counts: Data from the Icona Foundation Cohort [Articolo su rivista]
D'Arminio Monforte, A.; Cozzi-Lepri, A.; Maggiolo, F.; Rizzardini, G.; Manconi, P. E.; Gianotti, N.; Quirino, T.; Pinnetti, C.; Rusconi, S.; De Luca, A.; Antinori, A.; Andreoni, M.; Angarano, G.; Castelli, F.; Cauda, R.; Di Perri, G.; Galli, M.; Iardino, R.; Ippolito, G.; Lazzarin, A.; Perno, C. F.; Von Schloesser, F.; Viale, P.; Castagna, A.; Ceccherini-Silberstein, F.; Girardi, E.; Lo Caputo, S.; Mussini, C.; Puoti, M.; Ammassari, A.; Balotta, C.; Bandera, A.; Bonfanti, P.; Bonora, S.; Borderi, M.; Calcagno, A.; Calza, L.; Capobianchi, M. R.; Cingolani, A.; Cinque, P.; Di Biagio, A.; Gori, A.; Guaraldi, G.; Lapadula, G.; Lichtner, M.; Madeddu, G.; Marchetti, G.; Marcotullio, S.; Monno, L.; Nozza, S.; Quiros Roldan, E.; Rossotti, R.; Santoro, M. M.; Saracino, A.; Zaccarelli, M.; Fanti, I.; Galli, L.; Lorenzini, P.; Rodano, A.; Shanyinde, M.; Tavelli, A.; Carletti, F.; Carrara, S.; Di Caro, A.; Graziano, S.; Petrone, F.; Prota, G.; Quartu, S.; Truffa, S.; Giacometti, A.; Costantini, A.; Valeriani, C.; Santoro, C.; Suardi, C.; Donati, V.; Verucchi, G.; Minardi, C.; Abeli, C.; Piano, P.; Cacopardo, B.; Celesia, B.; Vecchiet, J.; Falasca, K.; Sighinolfi, L.; Segala, D.; Mazzotta, F.; Vichi, F.; Cassola, G.; Viscoli, C.; Alessandrini, A.; Bobbio, N.; Mazzarello, G.; Mastroianni, C.; Belvisi, V.; Caramma, I.; Chiodera, A.; Castelli, A. P.; Ridolfo, A. L.; Piolini, R.; Salpietro, S.; Carenzi, L.; Moioli, M. C.; Tincati, C.; Puzzolante, C.; Monza, G.; Abrescia, N.; Chirianni, A.; Borgia, G.; Di Martino, F.; Maddaloni, L.; Gentile, I.; Orlando, R.; Baldelli, F.; Francisci, D.; Parruti, G.; Ursini, T.; Magnani, G.; Ursitti, M. A.; Vullo, V.; Cristaudo, A.; Baldin, G.; Cicalini, S.; Gallo, L.; Nicastri, E.; Acinapura, R.; Capozzi, M.; Libertone, R.; Savinelli, S.; Latini, A.; Cecchetto, M.; Viviani, F.; Mura, M. S.; Rossetti, B.; Caramello, P.; Orofino, G. C.; Sciandra, M.; Bassetti, M.; Londero, A.; Pellizzer, G.; Manfrin, V.
abstract

Background There are no data comparing the response to PI/r-based regimens in people presenting for care with low CD4 counts or AIDS (LC). Aim To compare the response to LPV/r-, DRV/r- or ATV/r-based cART regimens in LC initiating cART from ART-naive. Methods We included people enrolled in Icona with either CD4 counts ≤350 cells/mm3 (low CD4-LC) or CD4 counts ≤200 cells/mm3 (very low CD4-VLC) and/or AIDS, starting their first PI/rbased regimen after 2008. Initial regimens were compared by intention-to-treat: i) time to viral failure (VF) (first of 2 consecutive VL&gt;200 copies/mL after ≥6 months); II) time to PI/r discontinuation/switching for any cause (TD) and for toxicity (TDT); III) treatment failure (TF) (VF or TD). Kaplan-Meier and Cox analyses were used. Results 1,362 LC patients were included (DRV/r 607; ATV/r 552; LPV/r 203); 813 VLC. In a median of 18 months (IQR:7-35), the 1-year probability of VF and TF were 2.8% (1.9-3.8) and 21.1% (18.7-23.4). In the adjusted analysis, patients initiating ATV/r had a 53% lower chance, and those initiating DRV/r a 61% lower chance of TD, as compared to LPV/r; the risk of TF was more likely in people starting LPV/r. Results were similar among VLC; in this subgroup LPV/r including regimens demonstrated a lower chance of VF. Conclusions We confirmed in LC a low chance of virological failure by 1 year, with small differences according to PI/r. However, larger differences were observed when comparing longer-term endpoints such as treatment failure. These results are important for people presenting late for care.

2016 - Th1 and Th17 pro-inflammatory profile characterizes iNKT cells in virologically suppressed HIV+ patients with low CD4/CD8 ratio [Articolo su rivista]
DE BIASI, Sara; Bianchini, Elena; Nasi, Milena; Digaetano, Margherita; Gibellini, Lara; Carnevale, Gianluca; Borghi, Vanni; Guaraldi, Giovanni; Pinti, Marcello; Mussini, Cristina; Cossarizza, Andrea
abstract

INTRODUCTION:: Scanty data exist on the phenotype and functionality of invariant natural killer T (iNKT) cells in HIV+ patients (pts). METHODS:: By flow cytometry, we studied iNKT cells from 54 HIV+ pts who started combined antiretroviral therapy (cART) and had undetectable viral load for &gt;1 year. Twenty-five maintained a CD4/CD8 ratio &lt;0.4, while 29 reached a ratio &gt;1.1; 32 age- and sex-matched subjects were healthy controls (CTR). RESULTS:: Pts with low ratio had lower percentage of CD4+ iNKT cells compared to pts with high ratio, and higher CD8+ iNKT cell percentage; double negative (DN) iNKT cells were lower in HIV+ pts compared to CTR. Pts with low ratio had higher percentage of CD4+ and DN iNKT cells expressing CD38 and HLA-DR compared to pts with high ratio. CD4+ iNKT cells expressing PD-1 were higher in pts with CD4/CD8 ratio &lt;0.4, while DN iNKT cells expressing PD-1 were lower compared to pts with ratio &gt;1.1. Pts with low ratio had higher CD4+ iNKT cells producing IL-17, CD8+ iNKT cells producing IFN-γ, TNF-α or IFN-γ plus TNF-α, and DN iNKT cells producing IL-17 or IL-17 plus IFN-γ compared to CTR. Activated CD4+ (or CD8+) T cells correlated with activated CD4+ (or CD8+) iNKT cells, as well as the percentages of CD4+ (or CD8+) T cells expressing PD-1 was correlated to that of CD4+ (or CD8+) iNKT cells expressing PD-1. CONCLUSIONS:: Low CD4/CD8 ratio despite effective cART is associated with altered iNKT cell subsets, enhanced activation and prominent Th1/Th17 pro-inflammatory profile.

2016 - The cardiovascular risk management for people living with HIV in Europe: How well are we doing? [Articolo su rivista]
Shahmanesh, M.; Schultze, A.; Burns, F.; Kirk, O.; Lundgren, J.; Mussini, C.; Pedersen, C.; De Wit, S.; Kutsyna, G.; Mocroft, A.
abstract

Objectives: HIV has become a chronic condition associated with comorbidities. We investigated cardiovascular risk and risk modification in a European HIV cohort. Methods: EuroSIDA patients (from 1 January 2000) for whom cardiovascular risk could be calculated (DAD risk equation) were included in the analysis. Moderate-to-high risk was defined as 5-year cardiovascular risk more than 5% and risk modification as two measurements meeting the EuropeanAIDSClinicalSocietyguidelines. Factorsassociated with risk development and modifications were investigated using Poisson regression. Results: Of 8762 individuals, 32.1% were hypertensive, 45.0% had high cholesterol, 47.4% were current smokers, and 27.1% were overweight. A total of 1504 (17.2%) had a 5-year cardiovascular risk of more than 5%. Of 7258 individuals with a 5-year risk less than 5%, 1905 (26.2%) developed cardiovascular risk more than 5% (6.53/100 personyears). These patients were more likely to be older, men, living in East Europe, with traditional cardiovascular risk factors. MSM with longer exposure to antiretroviral therapy, low CD4 nadir, higher current CD4 and prior AIDS events were more likely to develop cardiovascular risk. Those on antihypertensive treatment and living in central Europe were less likely to develop cardiovascular risk. Of those clinically indicated for risk modification, 1205 of 2077 (58.0%) successfully modified BP; 1283 of 3919 (32.8%) stopped smoking; 277 of 1394 (19.9%) modified cholesterol and 543 of 2163 (25.1%) reduced their BMI. There was variation in modification of individual risk factors, by sex, age, HIV-related factors and region of follow-up. Risk modification for BP and smoking improved over time (P &lt; 0.001). Conclusion: Cardiovascular risk was common. More than half modified their cardiovascular risk, and this improved over time.

2016 - Transmission of HIV drug resistance and the predicted effect on current first-line regimens in Europe [Articolo su rivista]
Hofstra, L. M.; Sauvageot, N.; Albert, J.; Alexiev, I.; Garcia, F.; Struck, D.; Van De Vijver, D. A. M. C.; Asjo, B.; Beshkov, D.; Coughlan, S.; Descamps, D.; Griskevicius, A.; Hamouda, O.; Horban, A.; Van Kasteren, M.; Kolupajeva, T.; Kostrikis, L. G.; Liitsola, K.; Linka, M.; Mor, O.; Nielsen, C.; Otelea, D.; Paraskevis, D.; Paredes, R.; Poljak, M.; Puchhammer-Stockl, E.; Sonnerborg, A.; Stanekova, D.; Stanojevic, M.; Van Laethem, K.; Zazzi, M.; Lepej, S. Z.; Boucher, C. A. B.; Schmit, J. -C.; Wensing, A. M. J.; Puchhammer-Stockl, E.; Sarcletti, M.; Schmied, B.; Geit, M.; Balluch, G.; Vandamme, A. -M.; Vercauteren, J.; Derdelinckx, I.; Sasse, A.; Bogaert, M.; Ceunen, H.; De Roo, A.; De Wit, S.; Echahidi, F.; Fransen, K.; Goffard, J. -C.; Goubau, P.; Goudeseune, E.; Yombi, J. -C.; Lacor, P.; Liesnard, C.; Moutschen, M.; Pierard, D.; Rens, R.; Schrooten, Y.; Vaira, D.; Vandekerckhove, L. P. R.; Van Den Heuvel, A.; Van Der Gucht, B.; Van Ranst, M.; Van Wijngaerden, E.; Vandercam, B.; Vekemans, M.; Verhofstede, C.; Clumeck, N.; Begovac, J.; Demetriades, I.; Kousiappa, I.; Demetriou, V.; Hezka, J.; Maly, M.; Machala, L.; Jorgensen, L. B.; Gerstoft, J.; Mathiesen, L.; Pedersen, C.; Nielsen, H.; Laursen, A.; Kvinesdal, B.; Ristola, M.; Suni, J.; Sutinen, J.; Assoumou, L.; Castor, G.; Grude, M.; Flandre, P.; Storto, A.; Kucherer, C.; Berg, T.; Braun, P.; Poggensee, G.; Daumer, M.; Eberle, J.; Heiken, H.; Kaiser, R.; Knechten, H.; Korn, K.; Muller, H.; Neifer, S.; Schmidt, B.; Walter, H.; Gunsenheimer-Bartmeyer, B.; Harrer, T.; Hatzakis, A.; Zavitsanou, A.; Vassilakis, A.; Lazanas, M.; Chini, M.; Lioni, A.; Sakka, V.; Kourkounti, S.; Paparizos, V.; Antoniadou, A.; Papadopoulos, A.; Poulakou, G.; Katsarolis, I.; Protopapas, K.; Chryssos, G.; Drimis, S.; Gargalianos, P.; Xylomenos, G.; Lourida, G.; Psichogiou, M.; Daikos, G. L.; Sipsas, N. V.; Kontos, A.; Gamaletsou, M. N.; Koratzanis, G.; Sambatakou, E.; Mariolis, H.; Skoutelis, A.; Papastamopoulos, V.; Georgiou, O.; Panagopoulos, P.; Maltezos, E.; De Gascun, C.; Byrne, C.; Duffy, M.; Bergin, C.; Reidy, D.; Farrell, G.; Lambert, J.; O'Connor, E.; Rochford, A.; Low, J.; Coakely, P.; O'Dea, S.; Hall, W.; Levi, I.; Chemtob, D.; Grossman, Z.; De Luca, A.; Balotta, C.; Riva, C.; Mussini, C.; Caramma, I.; Capetti, A.; Colombo, M. C.; Rossi, C.; Prati, F.; Tramuto, F.; Vitale, F.; Ciccozzi, M.; Angarano, G.; Rezza, G.; Vasins, O.; Lipnickiene, V.; Hemmer, R.; Arendt, V.; Michaux, C.; Staub, T.; Sequin-Devaux, C.; Van Kessel, A.; Van Bentum, P. H. M.; Brinkman, K.; Connell, B. J.; Van Der Ende, M. E.; Hoepelman, I. M.; Kuipers, M.; Langebeek, N.; Richter, C.; Santegoets, R. M. W. J.; Schrijnders-Gudde, L.; Schuurman, R.; Van De Ven, B. J. M.; Kran, A. -M. B.; Ormaasen, V.; Aavitsland, P.; Stanczak, J. J.; Stanczak, G. P.; Firlag-Burkacka, E.; Wiercinska-Drapalo, A.; Jablonowska, E.; Maolepsza, E.; Leszczyszyn-Pynka, M.; Szata, W.; Camacho, R.; Palma, C.; Borges, F.; Paixao, T.; Duque, V.; Araujo, F.; Paraschiv, S.; Tudor, A. M.; Cernat, R.; Chiriac, C.; Dumitrescu, F.; Prisecariu, L. J.; Jevtovic, Dj.; Salemovic, D.; Stanekova, D.; Habekova, M.; Chabadova, Z.; Drobkova, T.; Bukovinova, P.; Shunnar, A.; Truska, P.; Lunar, M.; Babic, D.; Tomazic, J.; Vidmar, L.; Vovko, T.; Karner, P.; Monge, S.; Moreno, S.; Del Amo, J.; Asensi, V.; Sirvent, J. L.; De Mendoza, C.; Delgado, R.; Gutierrez, F.; Berenguer, J.; Garcia-Bujalance, S.; Stella, N.; De Los Santos, I.; Blanco, J. R.; Dalmau, D.; Rivero, M.; Segura, F.; Elias, M. J. P.; Alvarez, M.; Chueca, N.; Rodriguez-Martin, C.; Vidal, C.; Palomares, J. C.; Viciana, I.; Viciana, P.; Cordoba, J.; Aguilera, A.; Domingo, P.; Galindo, M. J.; Miralles, C.; Del Pozo, M. A.; Ribera, E.; Iribarren, J. A.; Ruiz, L.; De La Torre, J.; Vidal, F.; Clotet, B.; Heidarian, A.; Aperia-Peipke, K.; Axelsson, M.; Mild, M.; Karlsson, A.; Thalme, A.; Naver, L.; Bratt, G.; Blaxhult, A.; Gisslen, M.; Svennerholm, B.; Bjorkman, P.; Sall, C.; Mellgren, A.; Lindholm, A.; Kuylenst
abstract

Background. Numerous studies have shown that baseline drug resistance patterns may influence the outcome of antiretroviral therapy. Therefore, guidelines recommend drug resistance testing to guide the choice of initial regimen. In addition to optimizing individual patient management, these baseline resistance data enable transmitted drug resistance (TDR) to be surveyed for public health purposes. The SPREAD program systematically collects data to gain insight into TDR occurring in Europe since 2001. Methods. Demographic, clinical, and virological data from 4140 antiretroviral-naive human immunodeficiency virus (HIV)-infected individuals from 26 countries who were newly diagnosed between 2008 and 2010 were analyzed. Evidence of TDR was defined using the WHO list for surveillance of drug resistance mutations. Prevalence of TDR was assessed over time by comparing the results to SPREAD data from 2002 to 2007. Baseline susceptibility to antiretroviral drugs was predicted using the Stanford HIVdb program version 7.0. Results. The overall prevalence of TDR did not change significantly over time and was 8.3% (95% confidence interval, 7.2%-9.5%) in 2008-2010. The most frequent indicators of TDR were nucleoside reverse transcriptase inhibitor (NRTI) mutations (4.5%), followed by nonnucleoside reverse transcriptase inhibitor (NNRTI) mutations (2.9%) and protease inhibitor mutations (2.0%). Baseline mutations were most predictive of reduced susceptibility to initial NNRTI-based regimens: 4.5% and 6.5% of patient isolates were predicted to have resistance to regimens containing efavirenz or rilpivirine, respectively, independent of current NRTI backbones. Conclusions. Although TDR was highest for NRTIs, the impact of baseline drug resistance patterns on susceptibility was largest for NNRTIs. The prevalence of TDR assessed by epidemiological surveys does not clearly indicate to what degree susceptibility to different drug classes is affected.

2016 - Triglyceride/HDL ratio and its impact on the risk of diabetes mellitus development during ART [Articolo su rivista]
Squillace, N.; Lorenzini, P.; Lapadula, G.; Bandera, A.; Cozzi-Lepri, A.; Rusconi, S.; Puoti, M.; Castagna, A.; Antinori, A.; Gori, A.; D'Arminio Monforte, A.; Moroni, M.; Andreoni, M.; Angarano, G.; Castelli, F.; Cauda, R.; Di Perri, G.; Galli, M.; Iardino, R.; Ippolito, G.; Lazzarin, A.; Perno, C. F.; Von Schloesser, F.; Viale, P.; Ceccherini-Silberstein, F.; Cozzi-Lepri, A.; Girardi, E.; Lo Caputo, S.; Mussini, C.; Andreoni, M.; Ammassari, A.; Balotta, C.; Bonfanti, P.; Bonora, S.; Borderi, M.; Capobianchi, M. R.; Ceccherini-Silberstein, F.; Cingolani, A.; Cinque, P.; Cozzi-Lepri, A.; De Luca, A.; Di Biagio, A.; Girardi, E.; Gianotti, N.; Gori, A.; Guaraldi, G.; Lichtner, M.; Madeddu, G.; Maggiolo, F.; Marchetti, G.; Marcotullio, S.; Monno, L.; Roldan, E. Q.; Saracino, A.; Cozzi-Lepri, A.; Cicconi, P.; Fanti, I.; Galli, L.; Lorenzini, P.; Rodano, A.; Shanyinda, M.; Tavell, i. A.; Giacometti, A.; Costantini, A.; Mazzoccato, S.; Angarano, G.; Monno, L.; Santoro, C.; Maggiolo, F.; Suardi, C.; Viale, P.; Vanino, E.; Verucchi, G.; Resi, F.; Minardi, C.; Quirino, T.; Abeli, C.; Manconi, P. E.; Piano, P.; Vecchiet, J.; Falasca, K.; Sighinolfi, L.; Segala, D.; Mazzotta, F.; Cassola, G.; Viscoli, C.; Alessandrini, A.; Piscopo, R.; Mazzarello, G.; Mastroianni, C.; Belvisi, V.; Caramma, I.; Chiodera, A.; Dtelli, S.; Galli, M.; Lazzarin, A.; Rizzardini, G.; Ridolfo, A. L.; Piolini, R.; Salpietro, S.; Carenzi, L.; Moioli, M. C.; Tincati, C.; Puzzolante, C.; Gori, A.; Abrescia, N.; Chirianni, A.; Borgia, G.; Guida, M. G.; Gargiulo, M.; Gentile, I.; Orlando, R.; Baldelli, F.; Francisci, D.; Parruti, G.; Ursini, T.; Magnani, G.; Ursitti, M. A.; Cauda, R.; Wendreoni, Q.; Qtinoria, A.; Vullo, V.; Cingolani, A.; D'Avino, A.; Gallo, L.; Nicastri, E.; Acinapura, R.; Capozzi, M.; Libertone, R.; Tebano, G.; Zaccarelli, M.; Viviani, F.; Sasset, L.; Mura, M. S.; Madeddu, G.; De Luca, A.; Rossetti, B.; Caramello, P.; Orofino, G. C.; Bonora, S.; Sciandra, M.; Bassetti, M.; Londero, A.; Pellizzer, G.; Manfrin, V.
abstract

Objectives: Our primary aim was to study diabetes mellitus (DM) arising during combination ART (cART) and to attempt to identify associations between these cases and triglycerides (TRG) and the TRG to HDL-cholesterol (TRG/HDL) ratio. Our secondary aim was to analyse the association between DM development and hepatic fibrosis. Methods: This was a retrospective cohort study. Patients from the Icona Foundation study initiating first-line cART between 1997 and 2013 were selected and observed until new-onset DM or most recent clinical follow-up. The predictive value of TRG and TRG/HDL ratio levels on DM was evaluated using multivariable Poisson regression models. Results: Three-thousand, five-hundred and forty-six patients (males, 73.7%; median age, 38 years; median BMI, 23.1 kg/m2; and hepatitis C virus antibody positive, 22.1%) were included. Of these, 80 developed DM over 13 911 person-years of follow-up (PYFU), corresponding to 5.7 cases per 1000 PYFU (95% CI = 4.6-7.1). At multivariable analysis, latest TRG/HDL ratio, when high, was associated with significant increases in DM risk [relative risk (RR) = 1.63; 95% CI = 1.32-2.01 per 10 points higher], while current TRG, in contrast, was associated with new-onset DM only at crude analysis. Advanced liver fibrosis (defined as fibrosis-4 index &gt;3.25) was also shown to be an independent risk factor for DM (RR = 2.91; 95% CI = 1.10-7.72). Conclusions: High TRG/HDL ratio predicted risk of new-onset DM, independently of other traditional risk factors. Furthermore, our findings suggest that advanced hepatic fibrosis, estimated using the fibrosis-4 score, could provide an additional predictor for DM.

2015 - A frailty index predicts survival and incident multimorbidity independent of markers of HIV disease severity [Articolo su rivista]
Guaraldi, Giovanni; Brothers, Thomas D.; Zona, Stefano; Stentarelli, Chiara; Carli, Federica; Malagoli, Andrea; Santoro, Antonella; Menozzi, Marianna; Mussi, Chiara; Mussini, Cristina; Kirkland, Susan; Falutz, Julian; Rockwood, Kenneth
abstract

Objectives: Aging with HIV is associated with multisystem vulnerability that might be well characterized by frailty. We sought to construct a frailty index based on health deficit accumulation in a large HIV clinical cohort and evaluate its validity including the ability to predict mortality and incident multimorbidity. Design and methods: This is an analysis of data from the prospective Modena HIV Metabolic Clinic cohort, 2004–2014. Routine health variables were screened for potential inclusion in a frailty index. Content, construct, and criterion validity of the frailty index were assessed. Multivariable regression models were built to investigate the ability of the frailty index to predict survival and incident multimorbidity (at least two chronic disease diagnoses) after adjusting for known HIV-related and behavioral factors. Results: Two thousand, seven hundred and twenty participants (mean age 46!8; 32% women) provided 9784 study visits; 37 non-HIV-related variables were included in a frailty index. The frailty index exhibited expected characteristics and met validation criteria. Predictors of survival were frailty index (0.1 increment, adjusted hazard ratio 1.63, 95% confidence interval 1.05–2.52), current CD4þ cell count (0.48, 0.32–0.72), and injection drug use (2.51, 1.16–5.44). Predictors of incident multimorbidity were frailty index (adjusted incident rate ratio 1.98, 1.65–2.36), age (1.07, 1.05–1.09), female sex (0.61, 0.40–0.91), and current CD4þ cell count (0.71, 0.59–0.85). Conclusion: Among people aging with HIV in northern Italy, a frailty index based on deficit accumulation predicted survival and incident multimorbidity independently of HIV-related and behavioral risk factors. The frailty index holds potential value in quantifying vulnerability among people aging with HIV.

2015 - Aging with HIV vs. HIV Seroconversion at Older Age: A Diverse Population with Distinct Comorbidity Profiles [Articolo su rivista]
Guaraldi, Giovanni; Zona, Stefano; Brothers, Thomas D; Carli, Federica; Stentarelli, Chiara; Dolci, Giovanni; Santoro, Antonella; Beghetto, Barbara; Menozzi, Marianna; Mussini, Cristina; Falutz, Julian
abstract

People aging with HIV might have different health conditions compared with people who seroconverted at older ages. The study objective was to assess the prevalence of, and risk factors for, individual co-morbidities and multimorbidity (MM) between HIV-positive patients with a longer duration of HIV infection, and patients who seroconverted at an older age. We compared estimates across both groups to a matched community-based cohort sampled from the general population.

2015 - An update on integrase inhibitors: new opportunities for a personalized therapy? The NEXTaim Project [Articolo su rivista]
Andreoni, Massimo; Marcotullio, Simone; Puro, Vincenzo; De Carli, Gabriella; Tambussi, Giuseppe; Nozza, Silvia; Gori, Andrea; Rusconi, Stefano; Santoro, Maria Mercedes; Clementi, Massimo; Perno, Carlo Federico; d’Arminio Monforte, Antonella; Maggiolo, Franco; Castagna, Antonella; De Luca, Andrea; Galli, Massimo; Giacomelli, Andrea; Borderi, Marco; Guaraldi, Giovanni; Calcagno, Andrea; Di Perri, Giovanni; Bonora, Stefano; Mussini, Cristina; Di Biagio, Antonio; Puoti, Massimo; Bruno, Raffaele; Zuccaro, Valentina; Antinori, Andrea; Cinque, Paola; Croce, Davide; Restelli, Umberto; Rizzardini, Giuliano; Lazzarin, Adriano
abstract

Thanks to the development of antiretroviral agents to control HIV replication, HIV infection has turned from a fatal disease into a treatable chronic infection. The present work collects the opinions of several experts on the efficacy and safety of recently approved second generation of integrase inhibitors and, in particular, on the role of this new class of drugs in antiretroviral therapy. The availability of new therapeutic options represents an opportunity to ameliorate the efficacy of cART in controlling HIV replication also within viral reservoirs. The personalization of the treatment driven mainly by the management of comorbidities, HIV-HCV co-infections and aging, will be easier with antiretroviral drugs without drug-drug interactions and with a better toxicity and tolerability profile. Future assessment of economic impact for the introduction of new innovative drugs in the field of antiretroviral therapy will likely need some degree of adjustment of the evaluation criteria of costs and benefit which are currently based almost exclusively on morbidity and mortality.

2015 - Analysis of inflammasomes and antiviral sensing components reveals decreased expression of NLRX1 in HIV-positive patients assuming efficient antiretroviral therapy [Articolo su rivista]
Nasi, Milena; DE BIASI, Sara; Bianchini, Elena; Digaetano, Margherita; Pinti, Marcello; Gibellini, Lara; Pecorini, Simone; Carnevale, Gianluca; Guaraldi, Giovanni; Borghi, Vanni; Mussini, Cristina; Cossarizza, Andrea
abstract

Objective: Few studies have investigated the importance of different components of the inflammasome system and of innate mitochondrial sensing (IMS) pathways in HIV infection and its treatment. We analysed the expression of several components of the inflammasome and of the IMS in HIV-positive patients taking successful combination antiretroviral therapy (cART). Methods: We enrolled 20 HIV-positive patients under cART, who achieved viral suppression since at least 10 months and 20 age and sex-matched healthy donors. By RT-PCR, using peripheral blood mononuclear cells (PBMCs), we quantified the mRNA expression of 16 genes involved in inflammasome activation and regulation (AIM2, NAIP, PYCARD, CASP1, CASP5, NLRP6, NLRP1, NLRP3, TXNIP, BCL2, NLRC4, PANX1, P2RX7, IL-18, IL-1β, SUGT1) and eight genes involved in IMS (MFN2, MFN1, cGAS, RIG-I, MAVS, NLRX1, RAB32, STING). Results: Compared with controls, HIV-positive patients showed significantly lower mRNA levels of the mitochondrial protein NLRX1, which plays a key role in regulating apoptotic cell death; main PBMC subpopulations behave in a similar manner. No differences were observed in the expression of inflammasome components, which however showed complex correlations. Conclusion: The decreased level of NLRX1 in HIV infection could suggest that the virus is able to downregulate mechanisms linked to triggering of cell death in several immune cell types. The fact that HIV-positive patients did not show altered expression of inflammasome components, nor of most genes involved in IMS, suggests that the infection and/or the chronic immune activation does not influence the transcriptional machinery of innate mechanisms able to trigger inflammation at different levels.

2015 - Automic Function Tests and Pulse wave velocity in HIV Disease: correlation to vascular ageing. [Abstract in Rivista]
Manicardi, Marcella; Guaraldi, P; Santoro, Antonella; Lattanzi, A; Malagoli, Andrea; Salvi, P; Grillo, A; Rossi, Rosario; Mussini, Cristina; Raggi, P; Cortelli, P; Guaraldi, Giovanni
abstract

Autonomic dysfunction is related to increased cardiovascular disease and mortality, being responsible of both subclinical coronary artery disease and cardiac arhythmias. In addition augmented sympathetic activity arises vascular constriction contributing to parietal arterial stiffness. Arterial stiffness can be assessed by measuring the velocity of the initial pulse wave propagation between two sites measured with PulsePen tonometer. We assessed whether subclinical autonomic dysfunction, as evaluated by a complete battery of autonomic function tests, correlates with pulse wave velocity change over 10 year follow up.

2015 - CD4/CD8 ratio normalisation and non-AIDS-related events in individuals with HIV who achieve viral load suppression with antiretroviral therapy: An observational cohort study [Articolo su rivista]
Mussini, Cristina; Lorenzini, Patrizia; Cozzi-Lepri, Alessandro; Lapadula, Giuseppe; Marchetti, Giulia; Nicastri, Emanuele; Cingolani, Antonella; Lichtner, Miriam; Antinori, Andrea; Gori, Andrea; Monforte, Antonella d'Arminio; Moroni, M.; Andreoni, M.; Angarano, G.; Antinori, A.; d'Arminio Monforte, A.; Castelli, F.; Cauda, R.; Di Perri, G.; Galli, M.; Iardino, R.; Ippolito, G.; Lazzarin, A.; Perno, C. F.; von Schloesser, F.; Viale, P.; d'Arminio Monforte, A.; Antinori, A.; Castagna, A.; Ceccherini-Silberstein, F.; Cozzi-Lepri, A.; Girardi, E.; Lo Caputo, S.; Mussini, C.; Puoti, M.; Ammassari, A.; Antinori, A.; d'Arminio Monforte, A.; Balotta, C.; Bonfanti, P.; Bonora, S.; Borderi, M.; Capobianchi, M. R.; Castagna, A.; Ceccherini-Silberstein, F.; Cingolani, A.; Cinque, P.; Cozzi-Lepri, A.; d'Arminio Monforte, A.; De Luca, A.; Di Biagio, A.; Girardi, E.; Gianotti, N.; Gori, A.; Guaraldi, G.; Lapadula, G.; Lichtner, M.; Lo Caputo, S.; Madeddu, Giordano; Maggiolo, F.; Marchetti, G.; Marcotullio, S.; Monno, L.; Mussini, C.; Puoti, M.; Quiros Roldan, E.; Rusconi, S.; Saracino, Gloria Anna Ada; Cozzi-Lepri, A.; Cicconi, P.; Fanti Galli, I.; Lorenzini, P.; Tavelli, A.; Giacometti, A.; Costantini, Alberto; Mazzoccato, S.; Angarano, G.; Monno, L.; Santoro, C.; Maggiolo, F.; Suardi, C.; Viale, P.; Vanino, E.; Verucchi, G.; Castelli, F.; Minardi, C.; Quirino, T.; Abeli, C.; E Manconi, P.; Piano, P.; Vecchiet, J.; Falasca, K.; Sighinolfi, L.; Segala, D.; Mazzotta, F.; Lo Caputo, S.; Cassola, G.; Viscoli, C.; Alessandrini, A.; Piscopo, R.; Mazzarello, G.; Mastroianni, C.; Belvisi, V.; Caramma, I.; Chiodera, A.; Castelli, A. P.; Galli, M.; Lazzarin, A.; Rizzardini, G.; Puoti, M.; d'Arminio Monforte, A.; Ridolfo, A. L.; Piolini, R.; Castagna, A.; Salpietro, S.; Carenzi, L.; Moioli, M. C.; Tincati, C.; Marchetti, G.; Mussini, C.; Puzzolante, C.; Gori, A.; Lapadula, G.; Abrescia, N.; Chirianni, A.; Guida, M. G.; Gargiulo, M.; Baldelli, F.; Francisci, D.; Parruti, G.; Ursini, T.; Magnani, G.; Ursitti, M. A.; Andreoni, M.; Antinori, A.; Vullo, V.; Cingolani, A.; D'Avino, A.; Gallo, Luigi; Nicastri, E.; Acinapura, R.; Capozzi, M.; Libertone, R.; Tebano, G.; Cattelan, A.; Sasset, L.; Mura, M. S.; De Luca, A.; Rossetti, B.; Caramello, P.; Di Perri, G.; Orofino, G. C.; Bonora, Sara; Sciandra, M.; Bassetti, M.; Londero, A.; Pellizzer, G.; Manfrin, V.
abstract

Background: In patients with HIV, immune reconstitution after antiretroviral therapy (ART) is often incomplete. We assessed the probability of patients reaching a CD4/CD8 ratio of 1 or more after the start of ART and its association with the onset of non-AIDS-defining events and death. Methods: We did an analysis of the ICONA cohort, which recruited treatment-naive patients with HIV in Italy. We included participants in the cohort who started ART, reached an undetectable viral load (≤80 copies per mL), and had a CD4/CD8 ratio of less than 0·8 at the time of an undetectable viral load. We defined ratio normalisation in patients as two consecutive values of 1 or more. We used Kaplan-Meier curves to estimate the cumulative probability of ratio normalisation. We then used Poisson regression models to identify factors independently associated with normalisation and with progression to non-AIDS-defining events or death. Findings: We included 3236 participants, enrolled between Jan 22, 1997, and Feb 25, 2013. At the start of ART, median CD4/CD8 ratio in our population was 0·39 (IQR 0·26-0·55). 458 (14%) patients reached a CD4/CD8 ratio of 1 or more; the estimated probability of normalisation was 4·4% (95% CI 3·7-5·2) by 1 year from baseline, 11·5% (10·2-13·0) by 2 years, and 29·4% (26·7-32·4) by 5 years. Factors associated with normalisation were high pre-ART CD4 cell counts, a high CD4/CD8 ratio at baseline, and negative cytomegalovirus serological findings. The incidence rate of non-AIDS-defining events for patients with a CD4/CD8 ratio of less than 0·30 (4·2 per 100 patient-years, 95% CI 3·4-5·3) was double that for those with a ratio of 0·30-0·45 (2·3, 2·1-2·5) or more than 0·45 (2·2, 1·7-2·9). A ratio of less than 0·30 was independently associated with an increased risk of non-AIDS-defining events or death compared with one of more than 0·45. Interpretation: Few patients had normalised CD4/CD8 ratios, even though they had viral suppression. Low ratios were associated with increased risk of serious events and deaths. The CD4/CD8 ratio could be used by clinicians to identity patients at risk of non-AIDS-related events. Funding: AbbVie, Bristol-Myers Squibb, Gilead, Janssen, Merck Sharp &amp; Dohme, ViiV Italy.

2015 - Changes with menopause in the distribution of frailty index (FI) in HIV infected women. [Abstract in Rivista]
Zona, Stefano; Brothers, T; Malagoli, Andrea; Menozzi, Marianna; Carli, Federica; Stentarelli, Chiara; Wallace, L; Theou, O; Kirkland, S; Mussini, Cristina; Rockwood, K; Guaraldi, Giovanni
abstract

Menopause is a physiological aging transition associated with rapid metabolic and physical changes. The aim of this study was to describe changes with menopause in the longitudinal distributions of a frailty index in HIV infected women.

2015 - Changing utilization of Stavudine (d4T) in HIV-positive people in 2006-2013 in the EuroSIDA study [Articolo su rivista]
Podlekareva, D.; Grint, D.; Karpov, I.; Vassilenko, A.; Rakmanova, A.; Mansinho, K.; Chentsova, N.; Kravchenko, E.; Zeltina, I.; Losso, M.; Parczewski, M.; Lundgren, J.; Mocroft, A.; Kirk, O.; Losso, M.; Kundro, M.; Vetter, N.; Zangerle, R.; Mitsura, V. M.; Suetnov, O.; Clumeck, N.; De Wit, S.; Delforge, M.; Florence, E.; Vandekerckhove, L.; Hadziosmanovic, V.; Kostov, K.; Begovac, J.; Machala, L.; Jilich, D.; Sedlacek, D.; Nielsen, J.; Kronborg, G.; Benfield, T.; Larsen, M.; Gerstoft, J.; Katzenstein, T.; Hansen, A. -B. E.; Skinhoj, P.; Pedersen, C.; Ostergaard, L.; Dragsted, U. B.; Nielsen, L. N.; Zilmer, K.; Jelena, Smidt; Ristola, M.; Katlama, C.; Viard, J. -P.; Girard, P. -M.; Vanhems, P.; Pradier, C.; Dabis, F.; Neau, D.; Duvivier, C.; Rockstroh, J.; Schmidt, ; van Lunzen, J.; Degen, O.; Stellbrink, H. J.; Bickel, M.; Goethe, J. W.; Bogner, J.; Fatkenheuer, G.; Kosmidis, J.; Gargalianos, P.; Xylomenos, G.; Perdios, J.; Sambatakou, H.; Banhegyi, D.; Gottfredsson, M.; Mulcahy, F.; Yust, I.; Turner, D.; Burke, M.; Pollack, S.; Hassoun, G.; Elinav, H.; Haouzi, M.; D'Arminio Monforte, A.; Esposito, R.; Mazeu, I.; Mussini, C.; Arici, C.; Pristera, R.; Mazzotta, F.; Gabbuti, A.; Vullo, V.; Lichtner, M.; Chirianni, A.; Montesarchio, E.; Gargiulo, M.; D'Offizi, G.; Taibi, C.; Antinori, A.; Lazzarin, A.; Castagna, A.; Gianotti, N.; Galli, M.; Ridolfo, A.; Rozentale, B.; Zeltina, I.; Chaplinskas, S.; Staub, T.; Hemmer, R.; Reiss, P.; Ormaasen, V.; Maeland, A.; Bruun, J.; Knysz, B.; Gasiorowski, J.; Horban, A.; Bakowska, E.; Grzeszczuk, A.; Flisiak, R.; A., Boron-Kaczmarska; Pynka, M.; Parczewski, M.; Beniowski, M.; Mularska, E.; Trocha, H.; Jablonowska, E.; Malolepsza, E.; Wojcik, K.; Doroana, M.; Doroana, M.; Caldeira, L.; Maltez, F.; Duiculescu, D.; Rakhmanova, A.; Buzunova, S.; Khromova, I.; Kuzovatova, E.; Jevtovic, D.; Mokras, M.; Stanekova, D.; Tomazic, J.; Gonzalez-Lahoz, J.; Soriano, V.; Labarga, P.; Moreno, S.; Rodriguez, J. M.; Clotet, B.; Jou, A.; Paredes, R.; Tural, C.; Puig, J.; Bravo, I.; Gatell, J. M.; Miro, J. M.; Domingo, P.; Gutierrez, M.; Mateo, G.; Sambeat, M. A.; Medrano, J.; Blaxhult, A.; Flamholc, L.; Thalme, A.; Sonnerborg, A.; Ledergerber, B.; Weber, R.; Francioli, P.; Cavassini, M.; Hirschel, B.; Boffi, E.; Furrer, H.; Battegay, M.; Elzi, L.; Vernazza, P.; Frolov, V.; Kutsyna, G.; Servitskiy, S.; Kuznetsova, A.; Kyselyova, G.; Gazzard, B.; Johnson, A. M.; Simons, E.; Phillips, A.; Johnson, M. A.; Mocroft, A.; Orkin, C.; Weber, J.; Scullard, G.; Fisher, M.; Leen, C.
abstract

Objectives: The long-term side effects of stavudine (d4T) led to recommendations in 2009 to phase out use of this drug. We aimed to describe temporal patterns of d4T use across Europe. Methods: Patients taking combination antiretroviral therapy (cART) in EuroSIDA with follow-up after 1 January 2006 were included in the study. cART was defined as d4T-containing [d4T plus at least two other antiretrovirals (ARVs) from any class] or non-d4T-containing (at least three ARVs from any class, excluding d4T). Poisson regression was used to describe temporal changes in the prevalence of d4T use and factors associated with initiating d4T. Results: A total of 5850 patients receiving cART on 1 January 2006 were included in the current analysis, rising to 7768 patients on January 1 2013. During this time, the prevalence of d4T use fell from 11.2% to 0.7%, with an overall decline of 19% per 6 months [95% confidence interval (CI) 19-20%]. d4T use declined fastest in Northern Europe [26% (95% CI 23-29%) per 6 months], and slowest in Eastern Europe [17% (95% CI 16-19%) per 6 months]. In multivariable Poisson regression models, new d4T initiations decreased by 14% per 6 months [adjusted incidence rate ratio (aIRR) 0.86; 95% CI 0.80-0.91]. Factors associated with initiating d4T were residence in Eastern Europe (aIRR 4.31; 95% CI 2.17-9.98) versus other European regions and HIV RNA&gt;400 copies/mL (aIRR 3.11; 95% CI 1.60-6.02) versus HIV RNA&lt;400 copies/mL. Conclusions: d4T use has declined sharply since 2006 to low levels in most regions; however, a low but persistent level of d4T use remains in Eastern Europe, where new d4T initiations post 2006 are also more common. The reasons for the regional differences may be multifactorial, but it is important to ensure that all clinicians treating HIV-positive patients are aware of the potential harmful effects associated with d4T.

2015 - Cytomegalovirus coinfection is associated with an increased risk of severe non-AIDS-defining events in a large cohort of HIV-infected patients [Articolo su rivista]
Moroni, M.; Angarano, G.; Antinori, A.; Armignacco, O.; Castelli, F.; Cauda, R.; Di Perri, G.; Galli, M.; Iardino, R.; Ippolito, G.; Lazzarin, A.; Perno, C. F.; Von Schloesser, F.; Viale, P.; Castagna, A.; Ceccherini-Silberstein, F.; Cozzi-Lepri, A.; Girardi, E.; Caputo, S. L.; Mussini, C.; Puoti, M.; Andreoni, M.; Ammassari, A.; Balotta, C.; Bonfanti, P.; Bonora, S.; Borderi, M.; Capobianchi, M. R.; Cingolani, A.; Cinque, P.; De Luca, A.; Di Biagio, A.; Gianotti, N.; Gori, A.; Guaraldi, G.; Lapadula, G.; Lichtner, M.; Madeddu, G.; Maggiolo, F.; Marchetti, G.; Marcotullio, S.; Monno, L.; Roldan, E. Q.; Rusconi, S.; Fanti, I.; Formenti, T.; Galli, L.; Lorenzini, P.; Giacometti, A.; Costantini, A.; Carrisa, C.; Suardi, C.; Vanino, E.; Verucchi, G.; Minardi, C.; Quirino, T.; Abeli, C.; Manconi, P. E.; Piano, P.; Vecchiet, J.; Falasca, K.; Sighinolfi, L.; Segala, D.; Mazzotta, F.; Cassola, G.; Viscoli, G.; Alessandrini, A.; Piscopo, R.; Mazzarello, G.; Mastroianni, C.; Belvisi, V.; Caramma, I.; Castelli, A. P.; Rizzardini, G.; Monforte, A. D.; Ridolfo, A. L.; Piolini, R.; Salpietro, S.; Carenzi, L.; Moioli, M.; Cicconi, P.; Puzzolante, C.; Abrescia, N.; Chirianni, A.; Guida, M. G.; Gargiulo, M.; Baldelli, F.; Francisci, D.; Parruti, G.; Ursini, T.; Magnani, G.; Ursitti, M. A.; Vullo, V.; D'Avino, A.; Gallo, L.; Nicastri, E.; Acinapura, R.; Capozzi, M.; Libertone, R.; Tebano, G.; Cattelan, A.; Mura, M. S.; Caramello, P.; Orofino, G. C.; Sciandra, M.; Pellizzer, G.; Manfrin, V.; Vita, S.; Saracino, A.
abstract

Background. Chronic cytomegalovirus (CMV) infection has been associated with immunosenescence and immunoactivation in the general population. In human immunodeficiency virus type 1 (HIV-1)-infected people, CMV coinfection, in addition to residual HIV replication and microbial translocation, has been proposed as a key factor in sustaining immune activation, even in individuals with a controlled HIV load. Methods. Patients from the ICONA Study with at least 1 CMV immunoglobulin G (IgG) test available without active CMV disease were included in the analysis. AIDS-defining event or AIDS-related death and severe non- AIDS-defining event or non-AIDS-related death were taken as clinical progression end points. Independent predictors of CMV were identified by multivariable logistic regression. Probabilities of reaching the end points were estimated by survival analyses. Results. A total of 6111 subjects were included, of whom 5119 (83.3%) were CMV IgG positive at baseline. Patients with CMV IgG positivity at baseline were more likely to develop a severe non-AIDS-defining event/ non-AIDS-related death (adjusted hazard ratio [HR], 1.53 [95% confidence interval {CI}, 1.08-2.16]. In particular, CMV seropositivity was an independent risk factor for cardiovascular and cerebrovascular diseases (adjusted HR, 2.27 [95% CI, .97-5.32]). Conclusions. In our study population, CMV/HIV coinfection was associated with the risk of severe non- AIDS-defining events/non-AIDS-related death, especially with cardiovascular and cerebrovascular events, independently of other prognostic factors. This finding supports a potential independent role of CMV coinfection in vascular/degenerative organ disorders in HIV-infected subjects.

2015 - Decrease of renal function in HCV and HIV/HCV-infected patients with telaprevir-based therapy [Articolo su rivista]
Prinapori, R.; Ricci, E.; Menzaghi, B.; Borghi, V.; Maggi, P.; Martinelli, C.; Magni, C.; Parruti, G.; Bonfanti, P.; Mussini, C.; Di Biagio, A.
abstract

2015 - Development and Validation of a Risk Score for Chronic Kidney Disease in HIV Infection Using Prospective Cohort Data from the D:A:D Study [Articolo su rivista]
Mocroft, A.; Lundgren, J. D.; Ross, M.; Law, M.; Reiss, P.; Kirk, O.; Smith, C.; Wentworth, D.; Neuhaus, J.; Fux, C. A.; Moranne, O.; Morlat, P.; Johnson, M. A.; Ryom, L.; Powderly, B.; Shortman, N.; Moecklinghoff, C.; Reilly, G.; Franquet, X.; Sabin, C. A.; Phillips, A.; Weber, R.; Pradier, C.; d'Arminio Monforte, A.; Dabis, F.; El-Sadr, W. M.; De Wit, S.; Kamara, D.; Tverland, J.; Mansfeld, M.; Nielsen, J.; Raben, D.; Salbol Brandt, R.; Rickenbach, M.; Fanti, I.; Krum, E.; Hillebregt, M.; Geffard, S.; Sundstrom, A.; Delforge, M.; Fontas, E.; Torres, F.; Mcmanus, H.; Wright, S.; Kjaer, J.; Sjol, A.; Meidahl, P.; Helweg-Larsen, J.; Schmidt Iversen, J.; Kesselring, A. M.; Friis-Moller, N.; Kowalska, J.; Sabin, C.; Bruyand, M.; Kamara, D. A.; Bower, M.; Fatkenheuer, G.; Donald, A.; Grulich, A.; Prins, J. M.; Kuijpers, T. W.; Scherpbier, H. J.; van der Meer, J. T. M.; Wit, F. W. M. N.; Godfried, M. H.; van der Poll, T.; Nellen, F. J. B.; Geerlings, S. E.; van Vugt, M.; Pajkrt, D.; Bos, J. C.; Wiersinga, W. J.; van der Valk, M.; Goorhuis, A.; Hovius, J. W.; van Eden, J.; Henderiks, A.; van Hes, A. M. H.; Mutschelknauss, M.; Nobel, H. E.; Pijnappel, F. J. J.; Westerman, A. M.; Jurriaans, S.; Back, N. K. T.; Zaaijer, H. L.; Berkhout, B.; Cornelissen, M. T. E.; Schinkel, C. J.; Thomas, X. V.; van den Berge, M.; Stegeman, A.; Baas, S.; Hage de Looff, L.; Versteeg, D.; Pronk, M. J. H.; Ammerlaan, H. S. M.; Korsten-Vorstermans, E. M. H. M.; de Munnik, E. S.; Jansz, A. R.; Tjhie, J.; Wegdam, M. C. A.; Deiman, B.; Scharnhorst, V.; van der Plas, A.; Weijsenfeld, A. M.; van der Ende, M. E.; de Vries-Sluijs, T. E. M. S.; C. M. van Gorp, E.; Schurink, C. A. M.; Nouwen, J. L.; Verbon, A.; Rijnders, B. J. A.; Bax, H. I.; Hassing, R. J.; van der Feltz, M.; Bassant, N.; van Beek, J. E. A.; Vriesde, M.; van Zonneveld, L. M.; de Oude-Lubbers, A.; van den Berg-Cameron, H. J.; Bruinsma-Broekman, F. B.; de Groot, J.; de Zeeuw- de Man, M.; Broekhoven-Kruijne, M. J.; Schutten, M.; Osterhaus, A. D. M. E.; Boucher, C. A. B.; Driessen, G. J. A.; van Rossum, A. M. C.; van der Knaap, L. C.; Visser, E.; Branger, J.; H. M. Duijf-van de Ven C., J.; Schippers, E. F.; van Nieuwkoop, C.; Brimicombe, R. W.; van IJperen, J. M.; van der Hut, G.; Franck, P. F. H.; van Eeden, A.; Brokking, W.; Groot, M.; Damen, M.; Kwa, I. S.; Groeneveld, P. H. P.; Bouwhuis, J. W.; van den Berg, J. F.; van Hulzen, A. G. W.; van der Bliek, G. L.; Bor, P. C. J.; Bloembergen, P.; Wolfhagen, M. J. H. M.; Ruijs, G. J. H. M.; van Lelyveld, S. F. L.; Soetekouw, R.; Hulshoff, N.; van der Prijt, L. M. M.; Schoemaker, M.; Bermon, N.; van der Reijden, W. A.; Jansen, R.; Herpers, B. L.; Veenendaal, D.; Kroon, F. P.; Arend, S. M.; de Boer, M. G. J.; Bauer, M. P.; Jolink, H.; Vollaard, A. M.; Dorama, W.; Moons, C.; Claas, E. C. J.; Kroes, A. C. M.; den Hollander, J. G.; Pogany, K.; Kastelijns, M.; Smit, J. V.; Smit, E.; Bezemer, M.; van Niekerk, T.; Pontesilli, O.; Lowe, S. H.; Oude Lashof, A.; Posthouwer, D.; Ackens, R. P.; Schippers, J.; Vergoossen, R.; Weijenberg Maes, B.; Savelkoul, P. H. M.; Loo, I. H.; Weijer, S.; El Moussaoui, R.; Heitmuller, M.; Kortmann, W.; van Twillert, G.; Cohen Stuart, J. W. T.; Diederen, B. M. W.; Pronk, D.; van Truijen-Oud, F. A.; Leyten, E. M. S.; Gelinck, L. B. S.; van Hartingsveld, A.; Meerkerk, C.; Wildenbeest, G. S.; Mutsaers, J. A. E. M.; Jansen, C. L.; van Vonderen, M. G. A.; van Houte, D. P. F.; Dijkstra, K.; Faber, S.; Weel, J.; Kootstra, G. J.; Delsing, C. E.; van der Burg-van de Plas, M.; Heins, H.; Lucas, E.; Brinkman, K.; Frissen, P. H. J.; Blok, W. L.; Schouten, W. E. M.; Bosma, A. S.; Brouwer, C. J.; Geerders, G. F.; Hoeksema, K.; Kleene, M. J.; van der Meche, I. B.; Toonen, A. J. M.; Wijnands, S.; van Ogtrop, M. L.; Koopmans, P. P.; Keuter, M.; van der Ven, A. J. A. M.; ter Hofstede, H. J. M.; Dofferhoff, A. S. M.; van Crevel, R.; Albers, M.; Bosch, M. E. W.; Grintjes-Huisman, K. J. T.; Zomer, B. J.; Stelma, F. F.; Burger, D.; Richter, C.; van der Berg
abstract

Chronic kidney disease (CKD) is a major health issue for HIV-positive individuals, associated with increased morbidity and mortality. Development and implementation of a risk score model for CKD would allow comparison of the risks and benefits of adding potentially nephrotoxic antiretrovirals to a treatment regimen and would identify those at greatest risk of CKD. The aims of this study were to develop a simple, externally validated, and widely applicable long-term risk score model for CKD in HIV-positive individuals that can guide decision making in clinical practice. A total of 17,954 HIV-positive individuals from the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) study with ≥3 estimated glomerular filtration rate (eGFR) values after 1 January 2004 were included. Baseline was defined as the first eGFR &gt; 60 ml/min/1.73 m2 after 1 January 2004; individuals with exposure to tenofovir, atazanavir, atazanavir/ritonavir, lopinavir/ritonavir, other boosted protease inhibitors before baseline were excluded. CKD was defined as confirmed (&gt;3 mo apart) eGFR ≤ 60 ml/min/1.73 m2. Poisson regression was used to develop a risk score, externally validated on two independent cohorts. In the D:A:D study, 641 individuals developed CKD during 103,185 person-years of follow-up (PYFU; incidence 6.2/1,000 PYFU, 95% CI 5.7–6.7; median follow-up 6.1 y, range 0.3–9.1 y). Older age, intravenous drug use, hepatitis C coinfection, lower baseline eGFR, female gender, lower CD4 count nadir, hypertension, diabetes, and cardiovascular disease (CVD) predicted CKD. The adjusted incidence rate ratios of these nine categorical variables were scaled and summed to create the risk score. The median risk score at baseline was −2 (interquartile range –4 to 2). There was a 1:393 chance of developing CKD in the next 5 y in the low risk group (risk score &lt; 0, 33 events), rising to 1:47 and 1:6 in the medium (risk score 0–4, 103 events) and high risk groups (risk score ≥ 5, 505 events), respectively. Number needed to harm (NNTH) at 5 y when starting unboosted atazanavir or lopinavir/ritonavir among those with a low risk score was 1,702 (95% CI 1,166–3,367); NNTH was 202 (95% CI 159–278) and 21 (95% CI 19–23), respectively, for those with a medium and high risk score. NNTH was 739 (95% CI 506–1462), 88 (95% CI 69–121), and 9 (95% CI 8–10) for those with a low, medium, and high risk score, respectively, starting tenofovir, atazanavir/ritonavir, or another boosted protease inhibitor. The Royal Free Hospital Clinic Cohort included 2,548 individuals, of whom 94 individuals developed CKD (3.7%) during 18,376 PYFU (median follow-up 7.4 y, range 0.3–12.7 y). Of 2,013 individuals included from the SMART/ESPRIT control arms, 32 individuals developed CKD (1.6%) during 8,452 PYFU (median follow-up 4.1 y, range 0.6–8.1 y). External validation showed that the risk score predicted well in these cohorts. Limitations of this study included limited data on race and no information on proteinuria. Both traditional and HIV-related risk factors were predictive of CKD. These factors were used to develop a risk score for CKD in HIV infection, externally validated, that has direct clinical relevance for patients and clinicians to weigh the benefits of certain antiretrovirals against the risk of CKD and to identify those at greatest risk of CKD.

2015 - Dissociation of aortic pulse wave velocity from risk factors for cardiovascular disease other than hypertension and age: a prospective study on frailty in HIV-infected patients. [Abstract in Rivista]
Guaraldi, Giovanni; Malagoli, Andrea; Manicardi, Marcella; Grillo, A; Santoro, Antonella; Lattanzi, A; Rossi, Rosario; Mussini, Cristina; Raggi, P; Salvi, P.
abstract

Pulse Wave Velocity (PWV) is a measure of arterial stiffness (arteriosclerosis) and vascular ageing. Both in cross-sectional and prospective studies it was a predictor of cardiovascular disease (CVD)events independent of traditional risk factors for artherosclerosis. CVD is an increasing cause of morbidity and mortality among HIV-infected patients: traditional and non-traditional risk factors are involved. We hypothesized that factors influencing PWV may measure biological ageing in these patients. Therefore we aimed to identify predictors of PWV change over time in HIV-infected patients on stable antiretroviral therapy.

2015 - Does rapid HIV disease progression prior to combination antiretroviral therapy hinder optimal CD4 + T-cell recovery once HIV-1 suppression is achieved? [Articolo su rivista]
Jarrin, I.; Pantazis, N.; Dalmau, J.; Phillips, A. N.; Olson, A.; Mussini, C.; Boufassa, F.; Costagliola, D.; Porter, K.; Blanco, J.; Del Amo, J.; Martinez-Picado, J.; Chene, G.; Sabin, C.; Walker, S.; Fisher, M.; Kelleher, T.; Cooper, D.; Finlayson, R.; Bloch, M.; Ramacciotti, T.; Gelgor, L.; Smith, D.; Zangerle, R.; Gill, J.; Lutsar, I.; Dabis, F.; Thiebaut, R.; Guiguet, M.; Vanhems, P.; Chaix, M. -L.; Ghosn, J.; Meyer, L.; Hamouda, O.; Kucherer, C.; Bartmeyer, B.; Antoniadou, A.; Chrysos, G.; Daikos, G. L.; Touloumi, G.; Katsarou, O.; Rezza, G.; Dorrucci, M.; Monforte, A. D.; De Luca, A.; Prins, M.; Geskus, R.; Van Der Helm, J.; Schuitemaker, H.; Sannes, M.; Brubakk, O.; Kran, A. -M. B.; Rosinska, M.; Muga, R.; Tor, J.; De Olalla, P. G.; Cayla, J.; Moreno, S.; Monge, S.; Del Romero, J.; Perez-Hoyos, S.; Sonnerborg, A.; Bucher, H. C.; Gunthard, H.; Rickenbach, M.; Malyuta, R.; Murphy, G.; Johnson, A.; Babiker, A.; Pillay, D.; Morrison, C.; Salata, R.; Mugerwa, R.; Chipato, T.; Amornkul, P. N.; Gilmour, J.; Kamali, A.; Karita, E.; Burns, F.; Giaquinto, C.; Grarup, J.; Kirk, O.; Bailey, H.; Anne, A. V.; Panteleev, A.; Thorne, C.; Aboulker, J. -P.; Albert, J.; Asandi, S.; De Wit, S.; Reiss, P.; Gatell, J.; Karpov, I.; Ledergerber, B.; Lundgren, J.; Moller, C.; Rakhmanova, A.; Rockstroh, J.; Sandhu, M.; Dedes, N.; Fenton, K.; Pizzuti, D.; Vitoria, M.; Faggion, S.; Fradette, L.; Frost, R.; Cartier, A.; Raben, D.; Schwimmer, C.; Scott, M.
abstract

Objective: This article compares trends in CD4 + T-cell recovery and proportions achieving optimal restoration (≥500cells/μl) after viral suppression following combination antiretroviral therapy (cART) initiation between rapid and nonrapid progressors. Methods: We included HIV-1 seroconverters achieving viral suppression within 6 months of cART. Rapid progressors were individuals experiencing at least one CD4 + less than 200cells/μl within 12 months of seroconverters before cART. We used piecewise linear mixed models and logistic regression for optimal restoration. Results: Of 4024 individuals, 294 (7.3%) were classified as rapid progressors. At the same CD4 + T-cell count at cART start (baseline), rapid progressors experienced faster CD4 + T-cell increases than nonrapid progressors in first month [difference (95% confidence interval) in mean increase/month (square root scale): 1.82 (1.61; 2.04)], which reversed to slightly slower increases in months 1-18 [-0.05 (-0.06; -0.03)] and no significant differences in 18-60 months [-0.003 (-0.01; 0.01)]. Percentage achieving optimal restoration was significantly lower for rapid progressors than nonrapid progressors at months 12 (29.2 vs. 62.5%) and 36 (47.1 vs. 72.4%) but not at month 60 (70.4 vs. 71.8%). These differences disappeared after adjusting for baseline CD4 + T-cell count: odds ratio (95% confidence interval) 0.86 (0.61; 1.20), 0.90 (0.38; 2.17) and 1.56 (0.55; 4.46) at months 12, 36 and 60, respectively. Conclusion: Among people on suppressive antiretroviral therapy, rapid progressors experience faster initial increases of CD4 + T-cell counts than nonrapid progressors, but are less likely to achieve optimal restoration during the first 36 months after cART, mainly because of lower CD4 + T-cell counts at cART initiation.

2015 - Effect of abacavir on sustained virologic response to HCV treatment in HIV/HCV co-infected patients, Cohere in Eurocoord [Articolo su rivista]
Smit, C.; Arends, J.; Peters, L.; Montforte, A. A.; Dabis, F.; Zangerle, R.; Daikos, G.; Mussini, C.; Mallolas, J.; de Wit, S.; Zinkernagel, A.; Cosin, J.; Chene, G.; Raben, D.; Rockstroh, J.
abstract

Background: Contradicting results on the effect of abacavir (ABC) on hepatitis C virus (HCV) treatment responses in HIV/HCV co-infected patients have been reported. We evaluated the influence of ABC on the response to pegylated interferon (pegIFN) and ribavirin (RBV)-containing HCV treatment in HIV/HCV co-infected patients in a large European cohort collaboration, including data from different European countries. Methods: HIV/HCV co-infected patients were included if they were aged ≥16 years, received pegIFN alfa-2a or 2b and RBV combination treatment and were enrolled in the COHERE cohort collaboration. Logistic regression was used to evaluate the impact of abacavir on achieving a sustained virologic response (SVR) to HCV treatment. Results: In total 1309 HIV/HCV co-infected patients who had received HCV therapy were included, of whom 490 (37 %) had achieved an SVR. No statistically significant difference was seen for patients using ABC-containing regimens compared to patients using an emtricitabine + tenofovir (FTC + TDF)-containing backbone, which was the most frequently used backbone. In the multivariate analyses, patients using a protease inhibitor (PI)-boosted regimen were less likely to achieve an SVR compared to patients using a non-nucleoside reverse-transcriptase inhibitor (NNRTI)-based regimen (OR: 0.61, 95 % CI: 0.41-0.91). The backbone combinations zidovudine&amp;lamivudine (AZT + 3TC) and stavudine&amp;lamivudine (d4t + 3TC) were associated with lower SRV rates (0.45 (0.24-0.82) and 0.46 (0.22-0.96), respectively). Conclusion: The results of this large European cohort study validate that SVR rates are generally not affected by ABC. Use of d4T or AZT as part of the HIV treatment regimen was associated with a lower likelihood of achieving an SVR.

2015 - Epidemiology and clinical outcome of lower respiratory tract infections by respiratory syncytial virus or parainfluenza virus type 3 in adults receiving treatment for either acute leukemia or severe aplastic anemia: a retrospective single center study [Articolo su rivista]
Bigliardi, Sara; Morselli, Monica; Potenza, Leonardo; Riva, Giovanni; Coluccio, Valeria; Maccaferri, Monica; Paolini, Ambra; Colaci, Elisabetta; Fantuzzi, Valeria; Soci, Francesco; Nasillo, Vincenzo; Messerotti, Andrea; Arletti, Laura; Pioli, Valeria; Lugli, Elisabetta; Gilioli, Andrea; Quadrelli, Chiara; Vallerini, Daniela; Barozzi, Patrizia; Lagreca, Ivana; Marasca, Roberto; Narni, Franco; Franceschini, Erica; Codeluppi, Mauro; Mussini, Cristina; Luppi, Mario; Forghieri, Fabio
abstract

Epidemiology and clinical outcome of lower respiratory tract infections by respiratory syncytial virus or parainfluenza virus type 3 in adults receiving treatment for either acute leukemia or severe aplastic anemia: a retrospective single center study

2015 - Estimating minimum adult HIV prevalence: A cross-sectional study to assess the characteristics of people living with HIV in Italy [Articolo su rivista]
Camoni, L.; Raimondo, M.; Dorrucci, M.; Regine, V.; Salfa, M. C.; Suligoi, B.; Di Giammartino, D.; Parruti, G.; Di Stefano, P.; Paoloni, M.; D'Alessandro, M.; Grimaldi, A.; Sciotti, M. P.; Pizzigallo, E.; Vecchiett, J.; De Stefano, C.; La Gala, A.; De Stefano, G.; Linzalone, A.; Cesario, F.; Cosco, L.; Caroleo, B.; Foti, G.; Serrao, N.; Lucchino, D.; Chirianni, A.; Abrescia, N.; Pempinello, R.; Izzo, C. M.; Borgia, G.; Filippini, P.; Sagnelli, E.; Iodice, A.; Megna, A. S.; D'Alessio, G.; Acone, N.; Mazzeo, M.; Sacchini, D.; Ferrari, C.; Degli Antoni, A.; Magnani, G.; Mussini, C.; Borghi, V.; Viale, P.; Colangeli, V.; Sighinolfi, L.; Libanore, M.; Govoni, A.; Cancellieri, C.; Bassi, P.; Arlotti, M.; Luzzati, R.; Bassetti, M.; Tirelli, U.; Vaccher, E.; Moise, G.; Palamara, G.; Bernardi, S.; Falciano, M.; Vullo, V.; D'Ettore, G.; Renda, V.; Guariglia, C.; Taliani, G.; Mezzaroma, I.; Paoletti, F.; Ajassa, C.; Gastaldi, R.; Andreoni, M.; Sarmati, L.; Montella, F.; Antinori, A.; Giannetti, A.; Pietrosillo, N.; Girardi, E.; Pennica, A.; Cauda, R.; Colafigli, M.; Di Gianbenedetto, S.; Caterini, A.; Monarca, R.; Barbacci, S. A.; Ramponi, G. N.; Marchili, M.; Anzalone, E.; Lichtner, M.; Ferrea, G.; Cassola, G.; Viscoli, C.; Mazzarello, G.; Setti, M.; Artioli, S.; Riccio, G.; Finocchio, G. C.; Anselmo, M.; Rizzi, M.; Scalzini, A.; Castelli, F.; Quirino, T.; Santoro, D.; Pan, A.; Zoncada, A.; Bonfanti, P.; Vigano, P.; Villa, M.; Tinelli, M.; Perboni, G.; Palvarini, L.; Costa, P.; Puoti, M.; Galli, M.; Rizzardini, G.; Monforte, A. D.; Lazzarin, A.; Castagna, A.; Gori, A.; Minoli, L.; Filice, G.; Grossi, P.; Giacometti, A.; Tavio, M.; Montroni, M.; Butini, L.; Osimani, P.; Petrelli, E.; Chiodera, A.; Vittucci, P.; Sabbatini, P.; Pasqualini, C.; Valle, M.; Zoppi, M.; Mantia, E.; Schettino, G.; Deseraca, M.; Vitullo, D.; Bargiacchi, O.; Orofino, G.; Bramato, C.; Busso, M.; Salassa, B.; Farenga, M.; Bonora, S.; Leo, G.; Poletti, F.; Gobber, M.; Cristina, G.; Gabiano, C.; Mian, P.; Moling, O.; Paternoster, C.; Dorigoni, N.; Fontana, T.; Angarano, G.; Ladisa, N.; La Rovere, D.; Fico, C.; Bulla, F.; Santantonio, T.; Grisorio, B.; Chiriaco, P.; Congedo, P.; Tundo, P.; Resta, F.; Cristiano, L.; Mura, M. S.; Madeddu, G.; Mesina, P.; Piga, S.; Campus, M.; Manconi, P. E.; Ortu, F.; Salvo, A.; Baretti, C.; La Sala, R.; Bellissima, P.; Bonfante, S.; Galvagna, S.; Celesia, B. M.; La Rosa, R.; Maiuzzo, S.; Guarnieri, L.; Bruno, S.; Picerno, I.; Tripodi, N.; Farinella, E. M.; Occhino, C.; Titone, L.; Colomba, C.; Prestileo, T.; Saitta, M.; Dones, P.; Boncoraglio, R.; Davi, A.; Franco, A.; Portelli, V.; Savalli, F.; Geraci, C.; Chimenti, M.; Luchi, S.; Catalani, C.; Trezzi, M.; Aquilini, D.; Sani, S.; Nencioni, C.; Carli, T.; Mazzotta, F.; Lo Caputo, S.; Zuccati, G.; Iapoce, R.; Consolini, R.; Bartolozzi, D.; Bartoloni, A.; Bartalesi, F.; De Luca, A.; De Martino, M.; Tacconi, D.; Tini, S.; Baldelli, F.; Francisci, D.; Frongillo, R. F.; Traverso, A.; Francavilla, E.; Ferretto, R.; Marranconi, F.; Manfrin, V.; Cortese, P.; Rossi, C.; Cattelan, F.; Petrucci, A.; Brugnaro, P.; Sgarabotto, D.; Scaggiante, R.; Cattelan, A.; Bosco, O.; Concia, E.; Rovere, P.
abstract

In 2012, we conducted a retrospective cross-sectional study to assess the number of people living with HIV linked to care and, among these, the number of people on antiretroviral therapy. The health authority in each of the 20 Italian Regions provided the list of Public Infectious Diseases Clinics providing antiretroviral therapy and monitoring people with HIV infection. We asked every Public Infectious Diseases Clinic to report the number of HIV-positive people diagnosed and linked to care and the number of those on antiretroviral therapy during 2012. In 2012, 94,146 people diagnosed with HIV and linked to care were reported. The majority were males (70.1%), Italians (84.4%), and aged between 25 and 49 years (63.4%); the probable route of transmission was heterosexual contact in 37.5% of cases, injecting drug use in 28.1%, and male-to-male contact in 27.9%. Among people in care, 20.1% had less than 350 CD4 cells/μl, 87.6% received antiretroviral therapy, and among these, 62.4% had a CD4 cell count higher than 350 cells/μl. The overall estimated prevalence of individuals diagnosed and linked to care in 2012 in Italy was 0.16 per 100 residents (all ages). Adding the estimated proportion of undiagnosed people, the estimated HIV prevalence would range between 0.19 and 0.26 per 100 residents. In Italy, the majority of people diagnosed and linked to care receive antiretroviral therapy. A higher prevalence of individuals diagnosed and linked to care was observed in Northern Italy and among males. More information for developing the HIV care continuum is necessary to improve the entire engagement in care, focusing on test-and-treat strategies to substantially reduce the proportion of people still undiagnosed or with a detectable viral load.

2015 - European survey on principles of prudent antibiotic prescribing teaching in undergraduate students [Articolo su rivista]
Pulcini, C.; Wencker, F.; Frimodt-Moller, N.; Kern, W. V.; Nathwani, D.; Rodriguez-Bano, J.; Simonsen, G. S.; Vlahovic-Palcevski, V.; Gyssens, I. C.; Jacobs, F.; Peetermans, W.; Francetic, I.; Hoiby, N.; Kilian, M.; Ader, F.; Cazorla, C.; Etienne, M.; Fatkenheuer, G.; Pletz, M. W.; Salzberger, B.; Cacopardo, B.; Mikulska, M.; Mussini, C.; Orlando, G.; Stefani, S.; Lowe, S. H.; Nouwen, J. L.; Afset, J. E.; Bergh, K.; Muller, F.; Carevic, B.; Horvat, O.; Jankovic, S.; Beovic, B.; Gorisek, J. R.; Canton, R.; Farinas, M. C.; Gudiol, F.; Pano Pardo, J. R.; Harbarth, S.; Zanetti, G.; Barlow, G.; Brown, N.; Healy, B.
abstract

We surveyed European medical schools regarding teaching of prudent antibiotic prescribing in the undergraduate curriculum. We performed a cross-sectional survey in 13 European countries (Belgium, Croatia, Denmark, France, Germany, Italy, Netherlands, Norway, Serbia, Slovenia, Spain, Switzerland, United Kingdom) in 2013. Proportional sampling was used, resulting in the selection of two to four medical schools per country. A standardized questionnaire based on literature review and validated by a panel of experts was sent to lecturers in infectious diseases, medical microbiology and clinical pharmacology. In-depth interviews were conducted with four lecturers. Thirty-five of 37 medical schools were included in the study. Prudent antibiotic use principles were taught in all but one medical school, but only four of 13 countries had a national programme. Interactive teaching formats were used less frequently than passive formats. The teaching was mandatory for 53% of the courses and started before clinical training in 71%. We observed wide variations in exposure of students to important principles of prudent antibiotic use among countries and within the same country. Some major principles were poorly covered (e.g. reassessment and duration of antibiotic therapy, communication skills). Whereas 77% of the respondents fully agreed that the teaching of these principles should be prioritized, lack of time, mainly due to rigid curriculum policies, was the main reported barrier to implementation. Given the study design, these are probably optimistic results. Teaching of prudent antibiotic prescribing principles should be improved. National and European programmes for development of specific learning outcomes or competencies are urgently needed.

2015 - Evaluation of the prognostic value of impaired renal function on clinical progression in a large cohort of HIV-infected people seen for care in Italy [Articolo su rivista]
Bandera, A.; Gori, A.; Sabbatini, F.; Madeddu, G.; Bonora, S.; Libertone, R.; Mastroianni, C.; Bonfanti, P.; Monforte, A. D.; Cozzi-Lepri, A.; Giacometti, A.; Costantini, A.; Mazzoccato, S.; Angarano, G.; Monno, L.; Santoro, C.; Maggiolo, F.; Suardi, C.; Viale, P.; Borderi, M.; Vanino, E.; Verucchi, G.; Castelli, F.; Roldan, E. Q.; Minardi, C.; Quirino, T.; Abeli, C.; Manconi, P. E.; Piano, P.; Vecchiet, J.; Falasca, K.; Sighinolfi, L.; Segala, D.; Mazzotta, F.; Lo Caputo, S.; Cassola, G.; Viscoli, C.; Di Biagio, A.; Alessandrini, A.; Piscopo, R.; Mazzarello, G.; Belvisi, V.; Caramma, I.; Chiodera, A.; Castelli, P.; Moroni, M.; Puoti, M.; Galli, M.; Lazzarin, A.; Rizzardini, G.; Ridolfo, A. L.; Piolini, R.; Rusconi, S.; Balotta, C.; Castagna, A.; Marchetti, G.; Tincati, C.; Cicconi, P.; Moioli, M. C.; Cinque, P.; Gianotti, N.; Salpietro, S.; Galli, L.; Carenzi, L.; Iardino, R.; Tavelli, A.; Mussini, C.; Guaraldi, G.; Marcotullio, S.; Puzzolante, C.; Lapadula, G.; Abrescia, N.; Chirianni, A.; Borgia, G.; Maddaloni, A.; Gargiulo, M.; Gentile, I.; Orlando, R.; Baldelli, F.; Francisci, D.; Parruti, G.; Ursini, T.; Magnani, G.; Ursitti, Ma.; Cauda, R.; Antinori, A.; Andreoni, M.; Vullo, V.; Ceccherini-Silberstein, F.; Cingolani, A.; Girardi, E.; D'Avino, A.; Fanti, I.; Gallo, L.; Ippolito, G.; Perno, C. F.; Lichtner, M.; Capobianchi, M. R.; Nicastri, E.; Acinapura, R.; Ammassari, A.; Capozzi, M.; Tebano, G.; Lorenzini, P.; Von Schloesser, F.; Zaccarelli, M.; Viviani, F.; Sasset, L.; Mura, M. S.; De Luca, A.; Rossetti, B.; Caramello, P.; Di Perri, G.; Orofino, G.; Sciandra, M.; Bassetti, M.; Londero, A.; Pellizzer, G.; Manfrin, V.
abstract

Whilst renal dysfunction, especially mild impairment (60 die;ve (Icona) Foundation Study collected between January 2000 and February 2014 with at least two creatinine values available. eGFR (CKD-epi) and renal dysfunction defined using a priori cut-offs of 60 (severely impaired) and 90 ml/min/1.73m2 (mildly impaired). Characteristics of patients were described after stratification in these groups and compared using chi-square test (categorical variables) or Kruskal Wallis test comparing median values. Follow-up accrued from baseline up to the date of the CCVD or AIDS related events or death or last available visit. Kaplan Meier curves were used to estimate the cumulative probability of occurrence of the events over time. Adjusted analysis was performed using a proportional hazards Cox regression model. We included 7,385 patients, observed for a median follow-up of 43 months (interquartile range [IQR]: 21-93 months). Over this time, 130 cerebro-cardiovascular events (including 11 deaths due to CCVD) and 311 AIDS-related events (including 45 deaths) were observed. The rate of CCVD events among patients with eGFR &gt;90, 60-89, &lt;60 ml/min, was 2.91 (95% CI 2.30-3.67), 4.63 (95% CI 3.51-6.11) and 11.9 (95% CI 6.19-22.85) per 1,000 PYFU respectively, with an unadjusted hazard ratio (HR) of 4.14 (95%CI 2.07-8.29) for patients with eGFR &lt;60 ml/min and 1.58 (95%CI 1.10-2.27) for eGFR 60-89 compared to those with eGFR ≥90. Of note, these estimates are adjusted for traditional cardiovascular risk factors (e.g. smoking, diabetes, hypertension, dyslipidemia). Incidence of AIDS-related events was 9.51 (95%CI 8.35-10.83), 6.04 (95%CI 4.74-7.71) and 25.0 (95% CI 15.96-39.22) per 1,000 PYFU, among patients with eGFR &gt;90, 60-89, &lt;60 ml/min, respectively, with an unadjusted HR of 2.49 (95%CI 1.56-3.97) for patients with eGFR &lt;60 ml/min and 0.68 (95%CI 0.52-0.90) for eGFR 60-89. The risk of AIDS events was significantly lower in mild renal dysfunction group even after adjustment for HIV-related characteristics. Our data confirm that impaired renal function is an important risk marker for CCVD events in the HIV-population; importantly, even those with mild renal impairment (90&lt;60)&gt;

2015 - Genotypic tropism testing in HIV-1 proviral DNA can provide useful information at low-level viremia [Articolo su rivista]
Fabeni, L.; Berno, G.; Svicher, V.; Ceccherini-Silberstein, F.; Gori, C.; Bertoli, A.; Mussini, C.; Lichtner, M.; Zaccarelli, M.; Ammassari, A.; Pinnetti, C.; Cicalini, S.; Mastroianni, C. M.; Andreoni, M.; Antinori, A.; Perno, C. F.; Santoro, M. M.
abstract

The possibility of performing genotypic tropism testing (GTT) with proviral DNA (pvDNA) even during suppressed viremia would facilitate the use of CCR5 inhibitors as part of switching, simplification, or intensification strategies. Thus, we aimed to evaluate the tropism concordance between plasma RNA and pvDNA samples and to assess which factors could affect possible discrepancies between the two compartments. GTT was performed using both plasma RNA and pvDNA from 55 sample pairs from drug-experienced patients. Potential differences between the two compartments were evaluated by analyzing coreceptor usage and genetic variability. Paired samples were also stratified in three levels of viremia (&lt;50, 51 to 500, and&gt;500 copies/ml). Overall, Geno2Pheno comparisons of false-positive rates in the two compartments showed good correlation (r=0.72). A high level of concordance in tropism predictions for the two compartments was found (46/55 sample pairs [83.6%]). Among the 9 sample pairs with discordant tropisms, a larger proportion of pvDNA samples harboring CXCR4/dual-mixed-tropic viruses was found, in comparison with plasma RNA samples (88.9% versus 11.1%; P=0.0034). Discordant samples were characterized by greater genetic variability than were concordant samples. With stratification of the paired samples according to viremia levels, the prevalence of discordant samples decreased with increasing viremia (&lt;50 copies/ml, 21.4%; 51 to 500 copies/ml, 15.4%; &gt;500 copies/ml, 6.7%; P=0.2). Our findings confirm that prediction of viral tropism using pvDNA is feasible even in low-level viremia and provides useful information for therapy optimization for patients with low or suppressed viremia.

2015 - HEFFICON: HIV effectiveness Italian conference [Articolo su rivista]
Antinori, A.; Andreoni, M.; Perno, C. F.; Lazzarin, A.; Ammassari, A.; Bonfanti, P.; Bonora, S.; Borderi, M.; Capobianchi, M. R.; Castagna, A.; Clementi, M.; Cinque, P.; D'Arminio Monforte, A.; Di Perri, G.; Galli, M.; Gori, A.; Maggi, P.; Mastroianni, C.; Mussini, C.; Nicastri, E.; Puoti, M.; Rusconi, S.; Santoro, M.; Tambussi, G.
abstract

Since the first acquired immunodeficiency syndrome cases were reported in 1981, more than 1.5 million people have been diagnosed with Human Immunodeficiency Virus-1 in Europe, including more than 136,000 new HIV cases in 2013. Recent epidemiological data estimate an incidence of 5-10 newly diagnosed HIV infections per 100,000 population per year in Europe and an average prevalence of infection of 5.7 cases per 100,000 population. In the absence of an effective curative strategy for HIV, optimization of prevention policies and clinical management of HIV positive patients is fundamental to reduce the impact of the HIV pandemic on public health. Clinical trials represent an essential tool for translating research findings into routine clinical practice. Careful evaluation and planning of clinical trials are therefore mandatory in order to provide relevant information to clinicians. The HEFFICON Project was conceived to investigate and pinpoint methodological issues and critical points that need to be addressed in future clinical studies to increase the translation of experimental results to the real life environment.

2015 - HIV patients undergoing second generation antipsychotics show high cardiovascular disease burden [Abstract in Rivista]
Ferrara, M; Malagoli, Andrea; Garlassi, Sara; Stentarelli, Chiara; Zona, Stefano; Carli, Federica; Menozzi, Marianna; Santoro, Antonella; Raggi, P; Starace, F; Mussini, Cristina; Guaraldi, Giovanni
abstract

Cardiovascular disease is highly prevalent in HIV-positive patients and can be explored with coronary artery calcium score as a biomarker of preclinical coronary disease. Antiretroviral drugs and concomitant treatment including second generation anti-psychotics may contribute to metabolic derangement with potential impact on traditional cardiovascular risk factors associated with the metabolic syndrome phenotype. The objective of the study was to assess the impact of second generation anti-psychotics on subclinical cardiovascular disease in HIV positive patients.

2015 - HIV-1 Tat immunization restores immune homeostasis and attacks the HAART-resistant blood HIV DNA: Results of a randomized phase II exploratory clinical trial [Articolo su rivista]
Ensoli, F.; Cafaro, A.; Casabianca, A.; Tripiciano, A.; Bellino, S.; Longo, O.; Francavilla, V.; Picconi, O.; Sgadari, C.; Moretti, S.; Cossut, M. R. P.; Arancio, A.; Orlandi, C.; Sernicola, L.; Maggiorella, M. T.; Paniccia, G.; Mussini, C.; Lazzarin, A.; Sighinolfi, L.; Palamara, G.; Gori, A.; Angarano, G.; Di Pietro, M.; Galli, M.; Mercurio, V. S.; Castelli, F.; Di Perri, G.; Monini, P.; Magnani, M.; Garaci, E.; Ensoli, B.
abstract

Background: The phase II multicenter, randomized, open label, therapeutic trial (ISS T-002, Clinicaltrials.gov NCT00751595) was aimed at evaluating the immunogenicity and the safety of the biologically active HIV-1 Tat protein administered at 7.5 or 30 μg, given 3 or 5 times monthly, and at exploring immunological and virological disease biomarkers. The study duration was 48 weeks, however, vaccinees were followed until the last enrolled subject reached the 48 weeks. Results: The vaccine was safe and well tolerated and induced anti-Tat Abs in most patients (79%), with the highest frequency and durability in the Tat 30 μg groups (89%) particularly when given 3 times (92%). Vaccination promoted a durable and significant restoration of T, B, natural killer (NK) cells, and CD4+ and CD8+ central memory subsets. Moreover, a significant reduction of blood proviral DNA was seen after week 72, particularly under PI-based regimens and with Tat 30 μg given 3 times (30 μg, 3x), reaching a predicted 70% decay after 3 years from vaccination with a half-life of 88 weeks. This decay was significantly associated with anti-Tat IgM and IgG Abs and neutralization of Tat-mediated entry of oligomeric Env in dendritic cells, which predicted HIV-1 DNA decay. Finally, the 30 μg, 3x group was the only one showing significant increases of NK cells and CD38+HLA-DR+/CD8+ T cells, a phenotype associated with increased killing activity in elite controllers. Conclusions: Anti-Tat immune responses are needed to restore immune homeostasis and effective anti-viral responses capable of attacking the virus reservoir. Thus, Tat immunization represents a promising pathogenesis-driven intervention to intensify HAART efficacy.

2015 - Health transitions in HIV-seropositive individulas undergoing NRTI-based and NRTI-sparing treatment strategies. [Abstract in Rivista]
Zona, Stefano; Malagoli, Andrea; Stentarelli, Chiara; Mussini, Cristina; Guaraldi, Giovanni
abstract

NRTI-sparing strategies are often prescribed to reduce the impact of drug toxicities on age related co-morbidities, particularly relevant in frail individuals. The objective of this study was to assess the impact of NRTI-sparing strategies on health transitions in HIV-infected patients with well-controlled HIV infection using a multi-item frailty index.

2015 - How do frailty mediate pathway leading to disability [Abstract in Rivista]
Malagoli, Andrea; Garlassi, Sara; Stentarelli, Chiara; Carli, Federica; Menozzi, Marianna; Santoro, Antonella; Beghetto, Barbara; Nardini, Giulia; Mussini, Cristina; Guaraldi, Giovanni
abstract

HIV infection increases the risk of multimorbidity (MM) and disability but factors influencing the association between the two are still poorly understood. We hypothesized that frailty mediate pathway leading to disability.

2015 - Impact of body weight on virological and immunological responses to efavirenz-containing regimens in HIV-infected, treatment-naive adults [Articolo su rivista]
Marzolini, C.; Sabin, C.; Raffi, F.; Siccardi, M.; Mussini, C.; Launay, O.; Burger, D.; Roca, B.; Fehr, J.; Bonora, S.; Mocroft, A.; Obel, N.; Dauchy, F. -A.; Zangerle, R.; Gogos, C.; Gianotti, N.; Ammassari, A.; Torti, C.; Ghosn, J.; Chene, G.; Grarup, J.; Battegay, M.
abstract

Objective: The prevalence of overweight and obesity is increasing among HIV-infected patients. Whether standard antiretroviral drug dosage is adequate in heavy individuals remains unresolved.We assessed the virological and immunological responses to initial efavirenz (EFV)-containing regimens in heavy compared to normal-weight HIV-infected patients. Design: Observational European cohort collaboration study. Methods: Eligible patients were antiretroviral-naïve with documented weight prior to EFV start and follow-up viral loads after treatment initiation. Cox regression analyses evaluated the association between weight and time to first undetectable viral load (&lt;50 copies/ml) after treatment initiation, and time to viral load rebound (two consecutive viral load &gt;50 copies/ml) after initial suppression over 5 years of follow-up. Recovery of CD4+ cell count was evaluated 6 and 12 months after EFV initiation. Analyses were stratified by weight (kg) group (I - &lt;55; II - &gt;55, &lt;80 (reference); III - &gt;80, &lt;85; IV - &gt;85, &lt;90; V - &gt;90, &lt;95; VI - &gt;95). Results: The study included 19 968 patients, of whom 9.1, 68.3, 9.1, 5.8, 3.5, and 4.3% were in weight groups I-VI, respectively. Overall, 81.1% patients attained virological suppression, of whom 34.1% subsequently experienced viral load rebound. After multiple adjustments, no statistical difference was observed in time to undetectable viral load and virological rebound for heavier individuals compared to their normal-weight counterparts. Although heaviest individuals had significantly higher CD4+ cell count at baseline, CD4+ cell recovery at 6 and 12 months after EFV initiation was comparable to normal-weight individuals. Conclusion: Virological and immunological responses to initial EFV-containing regimens were not impaired in heavy individuals, suggesting that the standard 600mg EFV dosage is appropriate across a wide weight range.

2015 - Italian guidelines for the use of antiretroviral agents and the diagnostic-clinical management of HIV-1 infected persons. Update December 2014 [Articolo su rivista]
Antinori, A.; Marcotullio, S.; Andreoni, M.; Ammassari, A.; Monforte, A. D.; Galli, M.; Girardi, E.; Mazzotta, F.; Mussini, C.; Puoti, M.; Lazzarin, A.; Adriana, A.; Gioacchino, A.; Orlando, A.; Sergio, B.; Teresa, B.; Paolo, B.; Stefano, B.; Marco, B.; Michele, B.; Raffaele, B.; Rosaria, C. M.; Roberto, C.; Emilia-Romagna, R.; Andrea, C.; Antonella, C.; Francesco, C.; Maria, C. A.; Roberto, C.; Alessandra, C.; Antonio, C.; Antonella, C.; Paola, C.; Maria, C. G.; Antonella, D. M.; Gabriella, D.; Gabriella, D. C.; Andrea, D. L.; Antonio, D. B.; Giovanni, D. P.; Massimo, D. P.; Issa, E. H.; Margherita, E.; Carola, F. A.; Raffaele, O. S.; Carlo, M. G.; Gerardo, O. S.; Battista, G. G.; Cristina, G.; Massimo, G.; Vania, G.; Nicola, G.; Enrico, G.; Andrea, G.; Paolo, G.; Giovanni, G.; Jelena, I.; Miriam, L.; Giuseppina, L.; Sergio, L. C.; Paolo, M.; Franco, M.; Marina, M.; Giulia, M.; Renato, M.; Claudio, M.; Alberto, M.; Francesco, M.; Cristina, M.; Emanuele, N.; Silvia, N.; Massimo, O.; Grazia, P. M.; Carlo-Federico, P.; Tullio, P.; Massimo, P.; Vincenzo, P.; Laura, R.; Marina, R.; Ospedaliera, A.; Giuliano, R.; Stefano, R.; Maria, S.; Laura, S.; Maria, S.; Giulio, S.; Enrica, T.; Giuseppe, T.; Marcello, T.; Carlo, T.; Emanuela, V.; Claudio, V.; Raffaele, V.; Vincenzo, V.; Mauro, Z.; Vincenzo, Z. G.
abstract

2015 - Late presentation for HIV care across Europe: update from the Collaboration of Observational HIV Epidemiological Research Europe (COHERE) study, 2010 to 2013 [Articolo su rivista]
Mocroft, Amanda; Lundgren, Jens; Antinori, Andrea; Monforte, Antonella d'Arminio; Brännström, Johanna; Bonnet, Fabrice; Brockmeyer, Norbert; Casabona, Jordi; Castagna, Antonella; Costagliola, Dominique; De Wit, Stéphane; Fätkenheuer, Gerd; Furrer, Hansjakob; Jadand, Corinne; Johnson, Anne; Lazanas, Mario; Leport, Catherine; Moreno, Santiago; Mussini, Cristina; Obel, Niels; Post, Frank; Reiss, Peter; Sabin, Caroline; Skaletz-Rorowski, Adriane; Suarez-Loano, Ignacio; Torti, Carlo; Warszawski, Josiane; Wittkop, Linda; Zangerle, Robert; Chene, Genevieve; Raben, Dorthe; Kirk, Ole
abstract

Late presentation (LP) for HIV care across Europe remains a significant issue. We provide a cross-European update from 34 countries on the prevalence and risk factors of LP for 2010-2013. People aged &gt;= 16 presenting for HIV care (earliest of HIV-diagnosis, first clinic visit or cohort enrolment) after 1 January 2010 with available CD4 count within six months of presentation were included. LP was defined as presentation with a CD4 count &lt; 350/mm(3) or an AIDS defining event (at any CD4), in the six months following HIV diagnosis. Logistic regression investigated changes in LP over time. A total of 30,454 people were included. The median CD4 count at presentation was 368/mm(3) (interquartile range (IQR) 193-555/mm(3)), with no change over time (p = 0.70). In 2010, 4,775/10,766 (47.5%) were LP whereas in 2013, 1,642/3,375 (48.7%) were LP (p = 0.63). LP was most common in central Europe (4,791/9,625, 49.8%), followed by northern (5,704/11,692; 48.8%), southern (3,550/7,760; 45.8%) and eastern Europe (541/1,377; 38.3%; p &lt; 0.0001). There was a significant increase in LP in male and female people who inject drugs (PWID) (adjusted odds ratio (aOR)/year later 1.16; 95% confidence interval (CI): 1.02-1.32), and a significant decline in LP in northern Europe (aOR/year later 0.89; 95% CI: 0.85-0.94). Further improvements in effective HIV testing strategies, with a focus on vulnerable groups, are required across the European continent.

2015 - Liver-related death among HIV/hepatitis C virus-co-infected individuals: Implications for the era of directly acting antivirals [Articolo su rivista]
Grint, D.; Peters, L.; Rockstroh, J. K.; Rakmanova, A.; Trofimova, T.; Lacombe, K.; Karpov, I.; Galli, M.; Domingo, P.; Kirk, O.; Lundgren, J. D.; Mocrofta, A.; Losso, M.; Kundro, M.; Vetter, N.; Zangerle, R.; Karpov, I.; Vassilenko, A.; Mitsura, V. M.; Paduto, D.; Clumeck, N.; De Wit, S.; Delforge, M.; Florence, E.; Vandekerckhove, L.; Hadziosmanovic, V.; Kostov, K.; Begovac, J.; Machala, L.; Jilich, D.; Sedlacek, D.; Nielsen, J.; Kronborg, G.; Benfield, T.; Larsen, M.; Gerstoft, J.; Katzenstein, T.; Hansen, A. -B. E.; Skinhoj, P.; Pedersen, C.; Moller, N. F.; Ostergaard, L.; Dragsted, U. B.; Nielsen, L. N.; Zilmer, K.; Smidt, J.; Ristola, M.; Katlama, C.; Viard, J. -P.; Girard, P. -M.; Vanhems, P.; Pradier, C.; Dabis, F.; Neau, D.; Duvivier, C.; Rockstroh, J.; Schmidt, R.; Van Lunzen, J.; Degen, O.; Stellbrink, H. J.; Stefan, C.; Bogner, J.; Fatkenheuer, G.; Chkhartishvili, N.; Kosmidis, J.; Gargalianos, P.; Xylomenos, G.; Perdios, J.; Sambatakou, H.; Banhegyi, D.; Gottfredsson, M.; Mulcahy, F.; Yust, I.; Turner, D.; Burke, M.; Shahar, E.; Hassoun, G.; Elinav, H.; Haouzi, M.; Sthoeger, Z. M.; Monforte, A. D.; Esposito, R.; Mazeu, I.; Mussini, C.; Pristera, R.; Mazzotta, F.; Gabbuti, A.; Vullo, V.; Lichtner, M.; Zaccarelli, M.; Antinori, A.; Acinapura, R.; D'Offizi, G.; Lazzarin, A.; Castagna, A.; Gianotti, N.; Galli, M.; Ridolfo, A.; Rozentale, B.; Uzdaviniene, V.; Staub, T.; Hemmer, R.; Reiss, P.; Ormaasen, V.; Maeland, A.; Bruun, J.; Knysz, B.; Gasiorowski, J.; Inglot, M.; Horban, A.; Bakowska, E.; Grzeszczuk, A.; Flisiak, R.; Parczewski, M.; Pynka, M.; Maciejewska, K.; Beniowski, M.; Mularska, E.; Smiatacz, T.; Jablonowska, E.; Malolepsza, E.; Wojcik, K.; Mozer-Lisewska, I.; Doroana, M.; Caldeira, L.; Mansinho, K.; Maltez, F.; Radoi, R.; Oprea, C.; Babes, V.; Rakhmanova, A.; Rakhmanova, A.; Trofimora, T.; Khromova, I.; Kuzovatova, E.; Jevtovic, D.; Shunnar, A.; Stanekova, D.; Tomazic, J.; Moreno, S.; Rodriguez, J. M.; Clotet, B.; Jou, A.; Paredes, R.; Tural, C.; Puig, J.; Bravo, I.; Gatell, J. M.; Miro, J. M.; Domingo, P.; Gutierrez, M.; Mateo, G.; Sambeat, M. A.; Laporte, J. M.; Blaxhult, A.; Flamholc, L.; Thalme, A.; Sonnerborg, A.; Ledergerber, B.; Weber, R.; Cavassini, M.; Calmy, A.; Furrer, H.; Battegay, M.; Elzi, L.; Schmid, P.; Kravchenko, E.; Chentsova, N.; Frolov, V.; Kutsyna, G.; Baskakov, I.; Servitskiy, S.; Kuznetsova, A.; Kyselyova, G.; Gazzard, B.; Johnson, A. M.; Simons, E.; Edwards, S.; Phillips, A.; Johnson, M. A.; Mocroft, A.; Orkin, C.; Weber, J.; Scullard, G.; Fisher, M.; Leen, C.
abstract

Background: Potent, less toxic, directly acting antivirals (DAAs) for treatment of hepatitis C virus (HCV) infection promise to improve HCV cure rates among HIV/ HCV-co-infected individuals. However, the costs of treatment will necessitate prioritization of those at greatest risk of liver-related death (LRD) for therapy. This study aims to provide guidance on who should be prioritized for DAA treatment. Methods: Three thousand, nine hundred and forty-one HCV antibody-positive PSHREG and FIB-4 are names not acronyms (EuroSIDA) patients with follow-up after 1 January 2000 were included, with causes of death classified using Coding causes of Death in HIV (CoDe) methodology. Crude death rates, competing-risks Cox proportional- hazards models and cumulative incidence functions were used to describe factors associated with LRD. Results: LRD accounted for 145 of 670 (21.6%) deaths in the study population. LRD rates peaked in those aged 35'45 years, and occurred almost exclusively in those with at least F2 fibrosis at baseline. In adjustedCoxmodels, risk factors for LRDincluded F4 or F2/F3 fibrosis [sub-distribution hazard ratio (sHR) 6.3, 95%confidence interval (CI)4.1'9.6; andsHR2.5, 95%CI 1.5'4.2 vs. F0/F1, respectively), CD4 cell count (sHR 0.83, 95%CI 0.73'0.95 per doubling) and hepatitis B surface antigen-positive (sHR 2.2, 95% CI 1.3'3.5 vs. hepatitis B surface antigen-negative). The 5-year probability of LRD was low in those with F0/F1 fibrosis (sHR2.2%, 95%CI 1.7''2.9), but substantial in those withF2/F3 and F4 fibrosis (sHR 10.3%, 95% CI 7.6'13.5; and sHR 14.0%, 95% CI 10.3'18.3, respectively). Conclusion: Treatment with DAAs should be prioritized for those with at least F2 fibrosis. Early initiation of cART with the aim of avoiding low CD4 cell counts should be considered essential to decrease the risk of LRD and the need for HCV treatment.

2015 - Mortality in migrants living with HIV in western Europe (1997-2013): A collaborative cohort study [Articolo su rivista]
Monge, S.; Jarrin, I.; Mocroft, A.; Sabin, C. A.; Touloumi, G.; van Sighem, A.; Abgrall, S.; Dray-Spira, R.; Spire, B.; Castagna, A.; Mussini, C.; Zangerle, R.; Hessamfar, M.; Anderson, J.; Hamouda, O.; Ehren, K.; Obel, N.; Kirk, O.; de Monteynard, L. A.; Antinori, A.; Girardi, E.; Saracino, A. L.; Calmy, A.; De Wit, S.; Wittkop, L.; Bucher, H. C.; Montoliu, A.; Raben, D.; Prins, M.; Meyer, L.; Chene, G.; Burns, F.; Warszawski, J.; Dabis, F.; Krause, M. M.; Ghosn, J.; Leport, C.; Reiss, P.; Wit, F.; Bucher, H.; Gibb, D.; Fatkenheuer, G.; Del Amo, J.; Thorne, C.; Stephan, C.; Perez-Hoyos, S.; Bartmeyer, B.; Chkhartishvili, N.; Noguera-Julian, A.; d'Arminio Monforte, A.; Brockmeyer, N.; Prieto, L.; Conejo, P. R.; Soriano-Arandes, A.; Battegay, M.; Kouyos, R.; Tookey, P.; Casabona, J.; Miro, J. M.; Konopnick, D.; Goetghebuer, T.; Sonnerborg, A.; Torti, C.; Sabin, C.; Teira, R.; Garrido, M.; Haerry, D.; Costagliola, D.; Chene, G.; Barger, D.; Schwimmer, C.; Termote, M.; Campbell, M.; Frederiksen, C. M.; Friis-Moller, N.; Kjaer, J.; Brandt, R. S.; Berenguer, J.; Bohlius, J.; Bouteloup, V.; Cozzi-Lepri, A.; Davies, M. -A.; del Amo, J.; Dorrucci, M.; Dunn, D.; Egger, M.; Furrer, H.; Guiguet, M.; Grabar, S.; Judd, A.; Lambotte, O.; Leroy, V.; Lodi, S.; Matheron, S.; Nakagawa, F.; Paredes, R.; Phillips, A.; Puoti, M.; Schomaker, M.; Smit, C.; Sterne, J.; Thiebaut, R.; van der Valk, M.; Wyss, N.
abstract

Background: Many migrants face adverse socioeconomic conditions and barriers to health services that can impair timely HIV diagnosis and access to life-saving treatments. We aimed to assess the differences in overall mortality by geographical origin in HIV-positive men and women using data from COHERE, a large European collaboration of HIV cohorts from 1997 to 2013. Methods: In this observational cohort study, we included HIV-positive, antiretroviral-naive people accessing care in western Europe from COHERE. Individuals were eligible if enrolled in a cohort that collected information on geographical origin or ethnic origin from Jan 1, 1997, to March 19, 2013, aged 18-75 years, they had available information about sex, they were not infected perinatally or after the receipt of clotting factor concentrates, and were naive to combination antiretroviral therapy at cohort entry. Migrants' origins were grouped into seven regions: western Europe and similar countries (Australia, Canada, New Zealand, and the USA); eastern Europe; North Africa and the Middle East; sub-Saharan Africa; Latin America; the Caribbean; and Asia and the rest of Oceania (excluding Australia and New Zealand). Crude and adjusted mortality rate ratios were calculated by use of Poisson regression stratified by sex, comparing each group with the native population. Multiple imputation with chained equations was used to account for missing values. Findings: Between Oct 25, 1979, and March 19, 2013, we recruited 279 659 individuals to the COHERE collaboration in EuroCoord. Of these 123 344 men and 45 877 women met the inclusion criteria. Our data suggested effect modification by transmission route (pinteraction=0·12 for men; pinteraction=0·002 for women). No significant difference in mortality was identified by geographical origin in men who have sex with men. In heterosexual populations, most migrant men had mortality lower than or equal to that of native men, whereas no group of migrant women had mortality lower than that in native women. High mortality was identified in heterosexual men from Latin America (rate ratio [RR] 1·46, 95% CI 1·00-2·12, p=0·049) and heterosexual women from the Caribbean (1·48, 1·29-1·70, p&lt;0·0001). Compared with that in the native population, mortality in injecting drug users was similar or low for all migrant groups. Interpretation: Characteristics of and risks faced by migrant populations with HIV differ for men and women and for populations infected heterosexually, by sex between men, or by injecting drug use. Further research is needed to understand how inequalities are generated and maintained for the groups with higher mortality identified in this study. Funding: EuroCoord.

2015 - Prognostic Value of the Fibrosis-4 Index in Human Immunodeficiency Virus Type-1 Infected Patients Initiating Antiretroviral Therapy with or without Hepatitis C Virus [Articolo su rivista]
Mussini, Cristina; Lorenzini, Patrizia; Puoti, Massimo; Lichtner, Miriam; Lapadula, Giuseppe; Di Giambenedetto, Simona; Antinori, Andrea; Madeddu, Giordano; Cozzi-Lepri, Alessandro; D'Arminio Monforte, Antonella; De Luca, Andrea; Moroni, M.; Andreoni, M.; Angarano, G.; Antinori, A.; D'Arminio Monforte, A.; Castelli, F.; Cauda, R.; Di Perri, G.; Galli, M.; Iardino, R.; Ippolito, G.; Lazzarin, A.; Perno, C. F.; Von Schloesser, F.; Viale, P.; D'Arminio Monforte, A.; Antinori, A.; Castagna, A.; Ceccherini-Silberstein, F.; Cozzi-Lepri, A.; Girardi, E.; Lo Caputo, S.; Mussini, C.; Puoti, M.; Andreoni, M.; Ammassari, A.; Antinori, A.; Balotta, C.; Bandera, A.; Bonfanti, P.; Bonora, S.; Borderi, M.; Calcagno, A.; Calza, L.; Capobianchi, M. R.; Castagna, A.; Ceccherini-Silberstein, F.; Cingolani, A.; Cinque, P.; Cozzi-Lepri, A.; D'Arminio Monforte, A.; De Luca, A.; Di Biagio, A.; Girardi, E.; Gianotti, N.; Gori, A.; Guaraldi, G.; Lapadula, G.; Lichtner, M.; Lo Caputo, S.; Madeddu, G.; Maggiolo, F.; Marchetti, G.; Marcotullio, S.; Monno, L.; Mussini, C.; Nozza, S.; Puoti, M.; Quiros Roldan, E.; Rossotti, R.; Rusconi, S.; Santoro, M. M.; Saracino, A.; Zaccarelli, M.; Cozzi-Lepri, A.; Fanti, I.; Galli, L.; Lorenzini, P.; Rodano, A.; Shanyinde, M.; Tavelli, A.
abstract

Objective: To evaluate the Fibrosis (FIB)-4 index as a predictor of major liver-related events (LRE) and liver-related death (LRD) in human immunodeficiency virus (HIV) type-1 patients initiating combination antiretroviral therapy (cART). Design: Retrospective analysis of a prospective cohort study. Setting: Italian HIV care centers participating to the ICONA Foundation cohort. Participants: Treatment-naive patients enrolled in ICONA were selected who: initiated cART, had hepatitis C virus (HCV) serology results, were HBsAg negative, had an available FIB-4 index at cART start and during follow up. Methods: Cox regression models were used to determine the association of FIB4 with the risk of major LRE (gastrointestinal bleeding, ascites, hepatic encephalopathy, hepato-renal syndrome or hepatocellular carcinoma) or LRD. Results: Three-thousand four-hundred seventy-five patients were enrolled: 73.3% were males, 27.2% HCV seropositive. At baseline (time of cART initiation) their median age was 39 years, had a median CD4+ T cell count of 260 cells/uL, and median HIV RNA 4.9 log copies/ mL, 65.9% had a FIB-4 &lt; 1.45, 26.4% 1.45-3.25 and 7.7% &gt; 3.25. Over a follow up of 18,662 person-years, 41 events were observed: 25 major LRE and 16 LRD (incidence rate, IR, 2.2 per 1,000 PYFU [95% confidence interval, CI 1.6-3.0]). IR was higher in HCV seropositives as compared to negatives (5.9 vs 0.5 per 1,000 PYFU). Higher baseline FIB-4 category as compared to &lt; 1.45 (FIB-4 1.45-3.25: HR 3.55, 95% CI 1.09-11.58; FIB-4 &gt; 3.25: HR 4.25, 1.21-14.92) and time-updated FIB-4 (FIB-4 1.45-3.25: HR 3.40, 1.02-11.40; FIB- 4&gt; 3.25: HR 21.24, 6.75-66.84) were independently predictive of major LRE/LRD, after adjusting for HIV- and HCV-related variables, alcohol consumption and type of cART. Conclusions: The FIB-4 index at cART initiation, and its modification over time are risk factors for major LRE or LRD, independently of infection with HCV and could be used to monitor patients on cART.

2015 - Reliable and Accurate CD4+ T Cell Count and Percent by the Portable Flow Cytometer CyFlow MiniPOC and “CD4 Easy Count Kit-Dry”, as Revealed by the Comparison with the Gold Standard Dual Platform Technology [Articolo su rivista]
Nasi, Milena; De Biasi, Sara; Bianchini, Elena; Gibellini, Lara; Pinti, Marcello; Scacchetti, Tiziana; Trenti, Tommaso; Borghi, Vanni; Mussini, Cristina; Cossarizza, Andrea
abstract

An accurate and affordable CD4+ T cells count is an essential tool in the fight against HIV/AIDS. Flow cytometry (FCM) is the "gold standard" for counting such cells, but this technique is expensive and requires sophisticated equipment, temperature-sensitive monoclonal antibodies (mAbs) and trained personnel. The lack of access to technical support and quality assurance programs thus limits the use of FCM in resource-constrained countries. We have tested the accuracy, the precision and the carry-over contamination of Partec CyFlow MiniPOC, a portable and economically affordable flow cytometer designed for CD4+ count and percentage, used along with the "CD4% Count Kit-Dry".

2015 - Renal hyperfiltration and outcome in HIV-infected subjects. [Abstract in Rivista]
Bellasi, A; Ascione, E; Malagoli, Andrea; Zona, Stefano; Rubbiani, E; Carli, Federica; Stentarelli, Chiara; Mussini, Cristina; Cappelli, Gianni; Guaraldi, Giovanni
abstract

Evidence from the general population suggests that renal hyperfiltration portends poor prognosis in the general population. No data in HIV-infected subjects is available. Hence, we investigated prevalence, associations with traditional and HIV-related risk factors as well as the prognostic significance of renal hyperfiltration in a large cohort of HIV-infected subjects.

2015 - Should we screen for NAFLD/NASH in HIV patients? [Abstract in Rivista]
Guaraldi, Giovanni; Malagoli, Andrea; Stentarelli, Chiara; Manicardi, Marcella; Zona, Stefano; Carli, Federica; Menozzi, Marianna; Santoro, Antonella; Franceschini, Erica; Mussini, Cristina
abstract

NAFLD is expected to be the most prevalent liver disease in the post-HCV era. The clinical impact of NAFLD and the benefit of screening with biochemical based algorithms is a metter of concern.

2015 - State of the art of dual therapy in 2015 [Articolo su rivista]
Nozza, S.; Svicher, V.; Saracino, A.; D'Ettorre, G.; De Luca, A.; Maggiolo, F.; Bonora, S.; Di Biagio, A.; Rusconi, S.; Mussini, C.
abstract

Dual therapy refers to combinations of two antiretroviral drugs applied in different clinical settings; they are considered and studied due to possibly reduced drug toxicities. In antiretroviral-naive patients, dual combinations have lower virologic efficacy than standard therapy; the sole efficacious regimen is lamivudine plus lopinavir/ ritonavir. Due to a higher possibility of virologic failure, these regimens are generally not allowed in this clinical setting. In antiretroviral-experienced patients, dual regimens are examined in studies with a small sample size, centered on clinical practice, and should be ritonavir-boosted protease inhibitor-based. These combinations have a good virological efficacy; combinations with the integrase inhibitor raltegravir have small sample size and demonstrated efficacy only with etravirine. Virological aspects involving dual therapy should always consider genetic barriers, particularly in simplification strategies, and ritonavir-boosted protease inhibitors are mandatory. As far as immunological aspects are concerned, nucleoside reverse transcriptase inhibitorsparing regimens have some encouraging data, probably due to the bone marrow toxicity of this class. Combinations with maraviroc were effective in reducing inflammation, but data about immunological recovery are conflicting. The choice of regimen should focus on specific class toxicity since dual regimens are studied in particular for improving safety and tolerability. This review will analyze different dual regimens in the clinical setting, with a peculiar focus on ameliorating toxicities and improving quality of life.

2014 - Aging with HIV infection: a journey to the center of inflammAIDS, immunosenescence and neuroHIV [Articolo su rivista]
Nasi, Milena; Pinti, Marcello; DE BIASI, Sara; Gibellini, Lara; Ferraro, Diana; Mussini, Cristina; Cossarizza, Andrea
abstract

In the last years, a significant improvement in life expectancy of HIV+ patients has been observed in Western countries. The parallel increase in the mean age of these patients causes a parallel increase in the frequency of non-AIDS related complications (i.e., neurocognitive, cardiovascular, liver and kidney diseases, metabolic syndrome, osteoporosis, non-HIV associated cancers, among others), even when antiviral treatment is successful. Immune activation and persistent inflammation characterizes both HIV infection and physiological aging, and both conditions share common detrimental pathways that lead to early immunosenescence. Furthermore, HIV-associated neurocognitive disorders represent important consequences of the infection. The persistent systemic immune activation, the continuous migration of activated monocytes to the central nervous system and progressive patients' aging contribute to develop neuronal injuries, that are in turn linked to HIV-associated neurocognitive disorders, which can persist despite successful antiretroviral treatment.

2014 - Burden of subclinical heart and lung disease detected on thoracic CT scans of HIV patients on HAART [Abstract in Rivista]
Zona, Stefano; Santoro, Antonella; Besutti, Giulia; Ligabue, Guido; Mussini, Cristina; Raggi, Paolo; Leipsic, Jonathon; Sin, Don D; Guaraldi, Giovanni
abstract

The aim was to determine the prevalence of lung and heart abnormalities on thoracic CT scans in HIV-infected patients who were treated with antiretroviral therapy (ART).

2014 - Combination therapy for carbapenem-resistant Gram-negative bacteria [Articolo su rivista]
Paul, Mical; Carmeli, Yehuda; Durante-Mangoni, Emanuele; Mouton, Johan W.; Tacconelli, Evelina; Theuretzbacher, Ursula; Mussini, Cristina; Leibovici, Leonard
abstract

Carbapenem-resistant Gram-negative bacteria (CR-GNB) represent an increasing hazard in healthcare settings. A central question concerning the treatment of invasive infections caused by CR-GNB involves the use of combination therapy. Potential advantages of combination therapy include improved efficacy due to synergy, while the disadvantages include adverse events and increased antibiotic use with a potential drive towards resistance. Several observational studies have examined whether combination therapy offers an advantage over colistin/ polymyxin monotherapy. We highlight the inherent limitations of these studies related to their observational design and sample size to show why they do not at present provide an answer to the question of combination versus monotherapy. This distinction is important to guide clinical practice until solid evidence has been obtained and to enable the recruitment of patients into randomized controlled trials. A few randomized controlled trials examining specific combinations have recently been completed or are ongoing. Currently, however, there is no evidence-based support for most combination therapies against CR-GNB, including colistin/carbapenem combination therapy. ©The Author 2014. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved.

2014 - Evolution of HIV-1 tropism at quasispecies level after 5 years of combination antiretroviral therapy in patients always suppressed or experiencing episodes of virological failure [Articolo su rivista]
Rozera, G.; Abbate, I.; Giombini, E.; Castagna, A.; de Luca, A.; Ceccherini-Silberstein, F.; Lepri, A. C.; Cassola, G.; Torti, C.; d'Arminio Monforte, A.; Ippolito, G.; Capobianchi, M. R.; Moroni, M.; Andreoni, M.; Angarano, G.; Antinori, A.; Castelli, F.; Cauda, R.; Di Perri, G.; Galli, M.; Iardino, R.; Lazzarin, A.; Perno, C. F.; von Schloesser, F.; Viale, P.; Cozzi-Lepri, A.; Girardi, E.; Lo Caputo, S.; Mussini, C.; Puoti, M.; Ammassari, A.; Balotta, C.; Bonfanti, P.; Bonora, S.; Borderi, M.; Cingolani, A.; Cinque, P.; di Biagio, A.; Gianotti, N.; Gori, A.; Guaraldi, G.; Lapadula, G.; Lichtner, M.; Madeddu, G.; Maggiolo, F.; Marchetti, G.; Marcotullio, S.; Monno, L.; Quiros Roldan, E.; Rusconi, S.; Cicconi, P.; Fanti, I.; Formenti, T.; Galli, L.; Lorenzini, P.; Carletti, F.; Carrara, S.; Castrogiovanni, A.; di Caro, A.; Petrone, F.; Prota, G.; Quartu, S.; Giacometti, A.; Costantini, A.; Mazzoccato, S.; Santoro, C.; Suardi, C.; Vanino, E.; Verucchi, G.; Minardi, C.; Quirino, T.; Abeli, C.; Manconi, P. E.; Piano, P.; Vecchiet, J.; Falasca, K.; Sighinolfi, L.; Segala, D.; Mazzotta, F.; Viscoli, C.; Alessandrini, A.; Piscopo, R.; Mazzarello, G.; Mastroianni, C.; Belvisi, V.; Caramma, I.; Chiodera, A.; Castelli, A. P.; Rizzardini, G.; Ridolfo, A. L.; Piolini, R.; Salpietro, S.; Carenzi, L.; Moioli, M. C.; Tincati, C.; Puzzolante, C.; Abrescia, N.; Chirianni, A.; Guida, M. G.; Gargiulo, M.; Baldelli, F.; Francisci, D.; Parruti, G.; Ursini, T.; Magnani, G.; Ursitti, M. A.; Vullo, V.; d'Avino, A.; Gallo, L.; Nicastri, E.; Acinapura, R.; Capozzi, M.; Libertone, R.; Tebano, G.; Cattelan, A.; Sasset, L.; Mura, M. S.; Rossetti, B.; Caramello, P.; Orofino, G. C.; Sciandra, M.; Bassetti, M.; Londero, A.; Pellizzer, G.; Manfrin, V.
abstract

Objectives: Tropism evolution of HIV-1 quasispecies was analysed by ultra-deep pyrosequencing (UDPS) in patients on first-line combination antiretroviral therapy (cART) always suppressed or experiencing virological failure episodes. Methods: Among ICONA patients, two groups of 20 patients on cART for ≥5 years, matched for baseline viraemia and therapy duration, were analysed [Group I, patients always suppressed; and Group II, patients experiencing episode(s) of virological failure]. Viral tropism was assessed by V3 UDPS on plasma RNA before therapy (T0) and on peripheral blood mononuclear cell proviral DNA before-after therapy (T0-T1), using geno2pheno false positive rate (FPR) (threshold for X4: 5.75). For each sample, quasispecies tropism was assigned according to X4 variant frequency: R5, &lt; 0.3% X4; minority X4, 0.3%-19.9% X4; and X4, ≥20% X4. An R5-X4 switch was defined as a change from R5/minority X4 in plasma/proviral genomes at T0 to X4 in provirus at T1. Results: At baseline, mean FPR and %X4 of viral RNA were positively correlated with those of proviral DNA. After therapy, proviral DNA load significantly decreased in Group I; mean FPR of proviral quasispecies significantly decreased and %X4 increased in Group II. An R5-X4 switch was observed in five patients (two in Group I and three in Group II), all harbouring minority X4 variants at T0. Conclusions: UDPS analysis reveals that the tropism switch is not an 'on-off' phenomenon, but may result from a profound re-shaping of viral quasispecies, even under suppressive cART. However, episodes of virological failure seem to prevent reduction of proviral DNA and to accelerate viral evolution, as suggested by decreased FPR and increased %X4 at T1 in Group II patients.

2014 - Intact parathyroid hormone levels are associated with increased carotid intima media thickness in HIV infected patients [Articolo su rivista]
Antonio, Bellasi; Paolo, Raggi; Rossi, Rosario; Rochira, Vincenzo; Stentarelli, Chiara; Zona, Stefano; Antonella, Lattanzi; Carli, Federica; Mussini, Cristina; Guaraldi, Giovanni
abstract

Aim. Preliminary evidence suggests that intact parathyroid hormone (iPTH) and bone mineral abnormalities may contribute to the development of vascular disease and are associated with reduced survival in the general population. Whether iPTH is associated with subclinical atherosclerosis in HIV-infected individuals has not been elucidated. Methods. Cross-sectional study of 470 consecutive HIV-infected patients in whom we measured carotid intima-media thickness (cIMT), and collected demographical, clinical and laboratory data. High-cIMT was defined as a mean IMT above the 75th percentile for the study cohort. Parametric, non-parametric tests and logistic regression analyses were used to compare patients' characteristics between low- and high-cIMT and to test the association between high-cIMT and log-transformed iPTH. Results. Of the 470 patients, 130 had high-cIMT. High-cIMT subjects were older and more likely to be male and have a history of cardiovascular disease. Glucose, lipid and iPTH levels were lower among low-cIMT subjects (p < 0.05). Unadjusted and multivariable adjusted analyses demonstrated an independent association between high-cIMT and iPTH (fully adjusted OR: 1.74; 95%CI: 1.08–2.79; p = 0.021). Bootstrap and sensitivity analyses confirmed these findings. Conclusions. Elevated iPTH was associated with subclinical atherosclerosis in HIV-infected subjects. Of note this association was statistically significant even for iPTH values within the range of normality. The existence of a causal relationship between iPTH and atherosclerosis needs to be fully explored in future investigations.

2014 - Life Expectancy in the Immune Recovery Era [Articolo su rivista]
Guaraldi, Giovanni; Cossarizza, Andrea; C., Franceschi; A., Roverato; E., Vaccher; G., Tambussi; E., Garlassi; Menozzi, Marianna; Mussini, Cristina; A., DʼArminio Monforte
abstract

INTRODUCTION: National cohort and intercohort studies have been set to describe the differences of life expectancy (LE) of HIV-infected individuals. OBJECTIVE: The aim of this study was to assess the impact of immune recovery (IR) on LE of patients with HIV undergoing combination antiretroviral therapy. METHODS: In this retrospective observational study, outcome measure was LE of patients with HIV compared with LE of northern Italian population. Group categorizations were as follows: patients with no immune recovery (nIR), patients with IR, patients who are immune maintained, and pre-highly active antiretroviral therapy (HAART) and post-HAART. Abridged life tables were constructed from age-specific mortality rates (per 1000 person years) to estimate LE from the age of 20-55 years. RESULTS: A total of 9671 patients, 71% men, were included. After 2005, we assisted to a rapid increase in the overall rate of patients attaining IR in the community coupled with a progressive decrease of AIDS death, but not of non-AIDS deaths. In a 40-year-old patient, LE was 38.10 years [standard error (SE) = 2.60], 30.08 years (SE = 0.98), and 22.9 (SE = 0.69) in the IR, post-HAART group and nIR, respectively, compared with 41.38 years of the general Italian population. An approximately 5-year gap in LE was observed in IR patients. DISCUSSION: We describe IR at a "community" level, related to calendar year and apparent 10 years after HAART introduction. HAART community IR is significantly influencing LE and is associated with the changing clinical picture of HIV disease. An increasing gradient of LE exists between nIR, post-HAART, and IR groups, with the latter, above the age of 40 years only, reaching LE of general population.

2014 - Longitudinal analysis of HIV-1 coreceptor tropism by single and triplicate HIV-1 RNA and DNA sequencing in patients undergoing successful first-line antiretroviral therapy [Articolo su rivista]
G., Meini; B., Rossetti; C., Bianco; F., Ceccherini Silberstein; S., Di Giambenedetto; L., Sighinolfi; L., Monno; A., Castagna; G., Rozera; A., D'Arminio Monforte; M., Zazzi; A., De Luca; M., Moroni; G., Angarano; A., Antinori; O., Armignacco; A., d'Arminio Monforte; F., Castelli; R., Cauda; G., Di Perri; M., Galli; R., Iardino; G., Ippolito; A., Lazzarin; C. F., Perno; F., von Schloesser; P., Viale; A., Castagna; F., Ceccherini Silberstein; A., Cozzi Lepri; E., Girardi; S., Lo Caputo; Mussini, Cristina; M., Puoti; M., Andreoni; A., Ammassari; C., Balotta; P., Bonfanti; S., Bonora; M., Borderi; M. R., Capobianchi; A., Cingolani; P., Cinque; A., De Luca; A., Di Biagio; N., Gianotti; A., Gori; Guaraldi, Giovanni; G., Lapadula; M., Lichtner; G., Madeddu; F., Maggiolo; G., Marchetti; S., Marcotullio; L., Monno; E., Quiros Roldan; S., Rusconi; P., Cicconi; I., Fanti; T., Formenti; L., Galli; P., Lorenzini; A., Giacometti; A., Costantini; C., Santoro; C., Suardi; E., Vanino; G., Verucchi; C., Minardi; T., Quirino; C., Abeli; P. E., Manconi; P., Piano; J., Vecchiet; K., Falasca; L., Sighinolfi; D., Segala; F., Mazzotta; G., Cassola; G., Viscoli; A., Alessandrini; R., Piscopo; G., Mazzarello; C., Mastroianni; V., Belvisi; I., Caramma; A. P., Castelli; G., Rizzardini; A. L., Ridolfo; R., Piolini; S., Salpietro; L., Carenzi; M. C., Moioli; C., Puzzolante; N., Abrescia; A., Chirianni; M. G., Guida; M., Gargiulo; F., Baldelli; D., Francisci; G., Parruti; T., Ursini; G., Magnani; M. A., Ursitti; V., Vullo; A., D'Avino; L., Gallo; E., Nicastri; R., Acinapura; M., Capozzi; R., Libertone; G., Tebano; A., Cattelan; M. S., Mura; P., Caramello; G. C., Orofino; M., Sciandra; G., Pellizzer; V., Manfrin
abstract

OBJECTIVES: Maraviroc has been shown to be effective in patients harbouring CCR5-tropic HIV-1. While this CCR5 antagonist has initially been used in salvage therapy, its excellent safety profile makes it ideal for antiretroviral treatment simplification strategies in patients with suppressed plasma viraemia. The aim of this study was to compare HIV-1 tropism as detected in baseline plasma RNA and peripheral blood mononuclear cell (PBMC) DNA prior to first-line therapy and to analyse tropism evolution while on successful treatment. METHODS: HIV-1 tropism was determined using triplicate genotypic testing combined with geno2pheno[coreceptor] analysis at a 10% false positive rate in 42 patients. Paired pre-treatment plasma RNA and PBMC DNA and two subsequent PBMC DNA samples (the first obtained after reaching undetectable plasma HIV-1 RNA and the second after at least 2 years of suppression of plasma viraemia) were evaluated. RESULTS: Coreceptor tropism was completely concordant in paired pre-treatment RNA and DNA, with 26.2% of HIV-1 sequences predicted to be non-CCR5-tropic. During follow-up, coreceptor tropism switches were detected in 4 (9.5%) patients without any preferential direction. Although false positive rate discrepancies within triplicates were common, the rate of discordance of coreceptor tropism assignment among triplicate results in this mostly CCR5-tropic dataset was only 2.1%, questioning the added value of triplicate testing compared with single testing. CONCLUSIONS: HIV-1 coreceptor tropism changes during virologically successful first-line treatment are infrequent. HIV-1 DNA analysis may thus support the choice of a CCR5 antagonist in treatment switch strategies; however, maraviroc treatment outcome data are required to confirm this option.

2014 - Metabolic alterations in HIV-infected pregnant women: moving to metabolic tailoring of antiretroviral drugs. [Articolo su rivista]
Guaraldi, Giovanni; Stentarelli, Chiara; A. D., Da Silva; K., Luzi; Neri, Isabella; M., Cellini; E., Petrella; E., Garlassi; Menozzi, Marianna; Facchinetti, Fabio; Mussini, Cristina
abstract

The most striking effect of increased survival and improved quality of life in HIV-infected women undergoing antiretroviral therapy is the feasibility of motherhood-desire satisfaction. However, such advantages are often associated with drug-related metabolic toxicities, particularly relevant in the pregnancy context. Recent guidelines provide recommendations and trends for the use of antiretroviral therapy in pregnant women, but current literature falls short of providing specific insights on the need for metabolic monitoring and treatment in HIV-infected pregnant women. In this review we provide specific insight into the state-of-the-art of: detection, evaluation, and management of metabolic alterations in this special population. Pregnancy is in fact a metabolic transition process, potentially associated with specific diseases in the mother, in the newborn, and in the adulthood of the child. We will not simply discuss antiretroviral therapy metabolic toxicities, but rather their interaction with the physiological metabolic changes occurring during pregnancy. Close monitoring is needed to diagnose metabolic alterations that can lead to adverse outcomes in the mother, in the newborn, and potentially in adulthood. Lifestyle interventions and an appropriate metabolic tailoring of antiretroviral therapy drugs need to be considered in the prevention and treatment of metabolic alteration during pregnancy.

2014 - Persistent inflammation in HIV infection: Established concepts, new perspectives. [Articolo su rivista]
Nasi, Milena; Pinti, Marcello; Mussini, Cristina; Cossarizza, Andrea
abstract

Immune activation is now considered a main driving force for the progressive immune failure in HIV infection. During the early phases of infection, a rapid depletion of gastrointestinal CD4+ T cells occurs that is followed by a deterioration of the gut epithelium and by the subsequent translocation of microbial products into the blood. Activation of innate immunity results in massive production of proinflammatory cytokines, which can trigger activation induced cell death phenomena among T lymphocytes. Moreover, persistent antigenic stimulation and inflammatory status causes immune exhaustion. The chronic immune activation also damages lymphoid tissue architecture, so contributing to the impairment of immune reconstitution. Recently, new mechanisms were identified, so opening new perspective on the innate immune sensing in HIV-1 infection. Cell death is followed by the release of molecules containing "damage-associated molecular patterns", that trigger a potent innate immune response through the engagement of Toll-like receptors. Then, also different types of HIV-related nucleic acids can act as potent stimulators of innate immunity. All these events contribute to the loss of T cell homeostatic regulation and to the failure of adaptive immunity.

2014 - Recommendations for the use of hepatitis C virus protease inhibitors for the treatment of chronic hepatitis C in HIV-infected persons. A position paper of the Italian Association for the Study of Infectious and Tropical Disease [Articolo su rivista]
Armignacco, Orlando; Andreoni, Massimo; Sagnelli, Evangelista; Puoti, Massimo; Bruno, Raffaele; Gaeta, Giovanni Battista; Perno, Carlo F; Santantonio, Teresa A; Bonfanti, Paolo; Bonora, Stefano; Borderi, Marco; Castagna, Antonella; d'Arminio Monforte, Antonella; De Luca, Andrea; Grossi, Paolo; Guaraldi, Giovanni; Maggiolo, Franco; Mussini, Cristina; Sagnelli, Caterina; Tavio, Marcello; Torti, Carlo; Uberti Foppa, Caterina; Andreoni, Massimo; Angarano, Gioacchino; Antinori, Andrea; Armignacco, Orlando; Carosi, Giampiero; Chirianni, Antonio; Di Perri, Giovanni; Galli, Massimo; Lazzarin, Adriano; Rizzardini, Giuliano; Sagnelli, Evangelista; Taliani, Gloria
abstract

The efficacy data obtained with boceprevir and telaprevir for persons with hepatitis C virus (HCV) genotype 1 infection raise the question of whether HCV protease inhibitors should be used in human immunodeficiency virus (HIV)/HCV co-infected persons. The Italian Association for the Study of Infectious and Tropical Diseases has made these recommendations to provide the rationale and practical indications for the use of triple anti-HCV therapy in persons living with HIV (PLWHIV). A Writing Committee of experts indicated by the President of the Association and a Consulting Committee con- tributed to the document. The final draft was submitted to the evaluation of external experts and the text modified according to their suggestions and comments. Treatment of HCV co-infection should be considered for all HCV RNA positive PLWHIV. Response-guided therapy with pegylated interferon and ribavirin is the standard treatment of PLWHIV with infection by HCV genotype 2, 3, 4, 5 and 6. Boceprevir and telaprevir should be used to treat HCV genotype 1 infection in HIV/HCV co-infected patients for 48 weeks on an individual basis, with close monitoring of their efficacy and tolerability with concur- rent antiretroviral therapy, taking into account potential drug-drug interactions. The decision to treat a patient or to wait for better treatment options, or to discontinue treatment should be made on an individual basis taking into account pre-treatment variables and the on-treatment HCV RNA kinetics.

2014 - Simplification to atazanavir/ritonavir monotherapy for HIV-1 treated individuals on virological suppression: 48-week efficacy and safety results [Articolo su rivista]
Castagna, A.; Spagnuolo, V.; Galli, L.; Vinci, C.; Nozza, S.; Carini, E.; Monforte, A. D.; Montella, F.; Antinori, A.; Di Biagio, A.; Rusconi, S.; Lazzarin, A.; Viscoli, C.; Parisini, A.; Prinapori, R.; Mazzotta, F.; Lo Caputo, S.; Di Pietro, M.; D'Arminio-Monforte, A.; Tincati, C.; Bini, T.; Merlini, E.; Puoti, M.; Moioli, M.; Montella, M.; Di Sora, F.; Ammassari, A.; Ottou, S.; Cauda, R.; Di Giambenedetto, S.; Galli, M.; Franzetti, M.; Rizzardini, G.; Capetti, A.; Cossarini, F.; Gianotti, N.; Mussini, C.; Guaraldi, G.
abstract

Objectives: The objective of this study was to assess the 48-week virological efficacy of atazanavir/ritonavir (ATV/r) monotherapy vs. ATV/r along with two nucleoside reverse transcriptase (NRTIs) in HIV-1 treated individuals with HIV-RNA less than 50 copies/ml. Methods: A multicentre, randomized, open-label, noninferiority trial. HIV-1 treated individuals on ATV/r 300/100mg along with two NRTIs were randomized to receive ATV/r monotherapy or to maintain their antiretroviral regimen. The primary endpoint was the confirmed viral rebound (CVR: Two consecutive HIV-RNA &gt;50 copies/ml) or treatment discontinuation for any reason. Individuals who experienced CVR on ATV/r monotherapy reintroduced NRTIs and discontinued the study if HIV-RNA was more than 50 copies/ml after 12 weeks since reintensification. Results: One hundred and three patients enrolled. By week 48, 11 patients in ATV/r arm and two in ATV/r along with twoNRTIs experienced CVR; four (8%) patients in ATV/r and eight (15%) in ATV/r along with twoNRTIs discontinued. At the 48-week primary efficacy analysis (re-intensification=failure), treatment success was73%inATV/r armand85%in ATV/r along with two NRTIs [difference 12.1%, 95% confidence interval (95% CI)27.8 to 2.1]. According to the analysis considering re-intensification is equal to success, treatment success was 92%in ATV/r armand 85%in the ATV/r along with twoNRTIs arm (difference 7.5%, 95%CI4.7 to 19.8). At CVR, no mutation was observed in ATV/r arm and reintensification with NRTIs was effective in all individuals. Overall, Grade 3-4 (P=0.003) and grade 3-4 drug-related (P=0.027) adverse events were less frequent in ATV/r arm. A significant increase in total and low-density lipoprotein (LDL)-cholesterol was observed as well as a significant improvement in high-density lipoprotein (HDL)- cholesterol, fasting glucose, liver fibrosis and alkaline phosphatase was observed in ATV/r monotherapy in comparison with ATV/r along with two NRTIs. Conclusion: ATV/r monotherapy treatment simplification showed lower virological efficacy in comparison with maintaining triple therapy; NRTIs reintroduction was effective in all the individuals.

2014 - Successful treatment of HIV-1 infection increases the expression of a novel, short transcript for IL-18 receptor α chain [Articolo su rivista]
Nasi, Milena; Alboni, Silvia; Pinti, Marcello; Tascedda, Fabio; Benatti, Cristina; Benatti, Stefania; Gibellini, Lara; DE BIASI, Sara; Borghi, Vanni; Brunello, Nicoletta; Mussini, Cristina; Cossarizza, Andrea
abstract

The importance of interleukin (IL)-18 in mediating immune activation during HIV infection has recently emerged. IL-18 activity is regulated by its receptor (IL-18R), formed by an α and a β chain, the IL-18-binding protein, and the newly identified shorter isoforms of both IL-18R chains. We evaluated gene expression of the IL-18/IL-18R system in peripheral blood mononuclear cells from HIV+ patients. Compared with healthy donors, IL-18 expression decreased in patients with primary infection. The IL-18Rα short transcript expression was strongly upregulated by successful highly active antiretroviral therapy. HIV progression and its treatment can influence the expression of different components of the complex IL-18/IL-18R system.

2014 - The natural history of HIV-associated lipodystrophy in the changing scenario of HIV infection [Articolo su rivista]
Guaraldi, Giovanni; Stentarelli, Chiara; Zona, Stefano; A., Santoro; Beghetto, Barbara; Carli, Federica; Orlando, Gabriella; Franceschetto, Antonella; A., Casolo; Mussini, Cristina
abstract

Objectives: In long-term HIV-infected patients, peripheral lipoatrophy (LA) and central lipohypertrophy (LH) appear to be related to the same insults (virus and antiretroviral drugs), but are likely to be associated with different fat depot physiologies. The objective of this study was to describe the natural history of lipodystrophy assessed using dual energy X-ray absorptiometry (DEXA) and computed tomography (CT) in a large HIV out-patients metabolic clinic. Methods: An observational retrospective study was carried out including HIV-infected patients recruited at the Metabolic Clinic of Modena, Modena, Italy, who were assessed for lipodystrophy and had at least two anthropometric evaluations using DEXA for leg fat per cent mass and abdominal CT for visceral adipose tissue (VAT). Factors associated with leg fat per cent and VAT changes were analysed using multivariable generalized estimating equation (GEE) regression models. Results: A total of 6789 DEXAs and 7566 CT scans were evaluated in the observation period. A total of 1840 patients were included; the mean age was 45.2±7.2 (standard deviation) years, 621 (34%) were women, and the median HIV infection duration was 176 (interquartile range 121-232) years. According to the GEE multivariable regression analysis, leg fat per cent evaluated with DEXA appeared to increase over calendar years (ß=0.92; P<0.001); moreover, a progressive increase in VAT was observed in the cohort (ß=5.69; P<0.001). No association with antiretroviral drugs was found. Conclusions: In our study, neither LA nor LH appeared to be associated with antiretroviral drug exposure. We observed a progressive increase in LH in HIV-infected patients over calendar years. This anthropometric change, together with loss of appendicular lean mass, could describe a physiological aging process in HIV-infected patients.

2013 - Absence of liver steatosis in HIV-HCV co-infected patients receiving regimens containing tenofovir or abacavir [Articolo su rivista]
Borghi, V; Bisi, Luca; Manzini, L; Cossarizza, Andrea; Mussini, Cristina
abstract

In human immunodeficiency virus-hepatitis C virus (HIV-HCV) co-infected patients, steatosis has been independently associated with a number of antiretroviral drugs, including stavudine, especially in patients with non-3 HCV genotypes. We retrospectively investigated the presence of steatosis among HIV-HCV co-infected and HCV mono-infected patients, and the role of tenofovir disoproxil fumarate (TDF) or abacavir (ABC) in determining hepatic steatosis. METHODS: Liver steatosis was retrospectively evaluated in all consecutive biopsies performed in the period 2000-2008 in HCV mono-infected and HIV-HCV co-infected patients. A steatosis rate of >5 % was considered to be significant, and a multivariate logistic analysis was performed to evaluate factors associated with steatosis. RESULTS: In total, 393 HCV-infected patients underwent liver biopsy during the study period, of whom 205 (52.2 %) were co-infected with HIV. A steatosis rate of >5 % was diagnosed in 33.0 % of HCV mono-infected and in 47.8 % of HIV-HCV co-infected patients (P = 0.003). The rate of steatosis was higher in patients resuming antiretroviral therapy (54.7 %) than in naïve patients (33.3 %; P = 0.006). When the overall population was considered, steatosis was associated to HCV genotype 3 [odds ratio (OR) 4.53, 95 % confidence interval (CI) 2.71-7.58; P < 0.001]. In terms of the use of nucleos(t)ide drugs in HIV co-infected patients, multivariate analysis showed that only in patients with HCV genotypes other than genotype 3 was steatosis related to the use of stavudine (OR 5.38, 95 % CI 1.18-24.53; P = 0.03). The use of TDF (OR 1.07, 95 % CI 0.39-2.88; P = 0.898) or ABC (OR 0.592, 95 % CI 0.09-4.07; P = 0.594) was not associated with steatosis. CONCLUSION: In HCV mono-infected and HIV-HCV co-infected patients, steatosis appears to be a virus-mediated effect of HCV genotype 3. In HIV patients infected with HCV genotypes other than genotype 3, the risk of developing steatosis was higher in those patients resuming antiretroviral regimens containing old drugs rather than the new antiretrovirals.

2013 - Associatioin of epicardial adipose tissue with incident coronary heart disease and death in HIV infected patients. [Abstract in Rivista]
Guaraldi, Giovanni; Scaglioni, Riccardo; Zona, Stefano; Orlando, Gabriella; Carli, Federica; Ligabue, Guido; Besutti, Giulia; Menozzi, Marianna; Santoro, Antonella; Beghetto, Barbara; Mussini, Cristina; P., Raggi
abstract

Epicardial adipose tissue has been reported to be highly inflamed and to be associated with incident coronary artery disease and all cause mortality in the general population. Its association with adverse events in HIV is unknown.

2013 - Characteristics and outcome predictors of patients involved in an outbreak of Burkholderia cepacia complex [Articolo su rivista]
Righi, Elena; Girardis, Massimo; P., Marchegiano; C., Venturelli; S., Tagliazucchi; M., Pecorari; Borsari, Lucia; Carluccio, Eugenia; M., Codeluppi; Mussini, Cristina; Aggazzotti, Gabriella
abstract

A Burkholderia cepacia complex outbreak occurred among ventilated non-cystic fibrosis patients in an intensive care unit (ICU) in Italy: 33 colonized and 13 infected patients were included in a retrospective study aimed at investigating factors related to clinical infection and mortality. Demographic/clinical conditions and mortality did not vary significantly between colonized and infected patients, both groups showing high mortality rates compared with the overall ICU population and similar to that observed in patients with other infections. In multivariate regression analysis, disease severity (defined by the Simplified Acute Physiology Score II) and age were the only independent predictors of early mortality (odds ratio: 1.12; 95% confidence interval: 1.02-1.26; and 1.07; 1.01-1.15, respectively).

2013 - Characteristics of HIV-infected patients not retained in care of two cohorts of northern Italy. [Abstract in Rivista]
Franceschini, Erica; Zona, Stefano; V., Borghi; T., Bini; P., Cicconi; Guaraldi, Giovanni; A., D’Arminio Monforte; Mussini, Cristina
abstract

The aim of the study was to assess the proportion of patients not-retained in care after HIV diagnosis in two cohorts of Northern Italy.

2013 - Cytometry, immunology, and HIV infection: Three decades of strong interactions. [Articolo su rivista]
Cossarizza, Andrea; DE BIASI, Sara; Gibellini, Lara; Bianchini, E; Bartolomeo, Regina; Nasi, Milena; Mussini, Cristina; Pinti, Marcello
abstract

Flow cytometry (FCM) has been extensively used to investigate immunological changes that occur from infection with the human immunodeficiency virus (HIV). This review describes some of the most relevant cellular and molecular changes in the immune system that can be detected by FCM during HIV infection. Finally, it will be discussed how this technology has facilitated the understanding not only of the biology of the virus but also of the mechanisms that the immune system activates to fight HIV and is allowing to monitor the efficacy of antiretroviral therapy.

2013 - Emphysema is an independent predictor of coronary artery calcium score in a large cohort of HIV infected patients [Abstract in Atti di Convegno]
Guaraldi, Giovanni; Besutti, Giulia; Scaglioni, Riccardo; Santoro, Antonella; Zona, Stefano; Ligabue, Guido; Orlando, Gabriella; Carli, Federica; Mussini, Cristina; J. Leipsic D. D., Sin; S. F. P., Man
abstract

The objective of this study was to evaluate the association between emphysema and CAC in a large cohort of HIV infected patients undergoing ART

2013 - Emphysema is an independent predictor of coronary artery calcium score in a large cohort of HIV-infected patients. [Abstract in Rivista]
Guaraldi, Giovanni; Besutti, Giulia; Scaglioni, Riccardo; Santoro, Antonella; Zona, Stefano; Ligabue, Guido; Mussini, Cristina; Orlando, Gabriella; Carli, Federica; J., Lipsic; D. D., Sin; S. F. P., Man
abstract

The complex relationship between chronic obstructive pulmonary disease and cardiovascular disease has not been investigated in patients chronically infected with HIV. The objective of this study was to evaluate the association between emphysema and coronary artery calcium score as surrogate for coronary artery diasease in a large cohort of HIV-infected patients on antiretroviral treatment.

2013 - Inverse correlation between vascular calcification and bone mineral density in human immunodeficiency virus-infected patients [Articolo su rivista]
Antonio, Bellasi; Zona, Stefano; Orlando, Gabriella; Carli, Federica; Ligabue, Guido; Rochira, Vincenzo; Antonello, Santoro; Mussini, Cristina; Guaraldi, Giovanni; Paolo, Raggi
abstract

HIV-infected individuals suffer from acceler- ated aging, which manifests as premature cardiovascular and bone disease. However, little is known of the association of these two disorders in the HIV population. Our objective was to investigate the association between a marker of ath- erosclerosis (coronary artery calcium [CAC]) and low bone mineral density (BMD) in a cross-sectional cohort of HIV- infected patients. The study was conducted at the University of Modena and Reggio Emilia, Italy. A total of 636 con- secutive middle-aged, HIV-infected subjects were recruited between January 2006 and December 2010. All patients underwent CAC and BMD assessment. Patients were cate- gorized according to a CAC score\100 or[100 units based on previous literature that identified this cut-point as a marker of increased risk. Low femoral and lumbar spine BMD was defined as \25th percentile value for the study cohort. Logistic regression and bootstrap analysis were used to assess the independent association between CAC and BMD. The main outcome measure was a CAC score[100. Patients with CAC [ 100 were older and more likely to be men, diabetic, and overweight. Patients with CAC \ 100 had better renal function and a lower cardiovascular risk profile. After adjusting for age, sex, traditional and HIV- specific risk factors, vitamin D level, and PTH level, there was a significant association between CAC [ 100 and low BMD for the femur (OR = 2.33, 95 % CI 1.09–4.99; p = 0.02) but not for the spine. Bootstrap analyses con- firmed these findings. In summary, CAC was independently associated with low femoral BMD in HIV-infected patients. Future studies should test whether therapies that attenuate cardiovascular risk in HIV favorably impact bone health.

2013 - Life expectancy in the immune-recovery era: the evolving scenario of HIV epidemic in Northern Italy [Abstract in Rivista]
Guaraldi, Giovanni; Cossarizza, Andrea; C., Franceschi; A., Roverato; E., Vaccher; G., Tambussi; Garlassi, Elisa; Menozzi, Marianna; Mussini, Cristina; A., D’Arminio Monforte
abstract

National cohort and inter-cohort studies have been set to describe differences of Life Expectancy (LE) of HIV-infected individuals. the aim of this study was to assess the impact of immune-recovery on LE of HIV-patients undergoing cART.

2013 - Non-AIDS defining cancers in the D:A:D Study - time trends and predictors of survival: A cohort study [Articolo su rivista]
Worm, S. W.; Bower, M.; Reiss, P.; Bonnet, F.; Law, M.; Fatkenheuer, G.; d'Arminio Monforte, A.; Abrams, D. I.; Grulich, A.; Fontas, E.; Kirk, O.; Furrer, H.; Wit, S. D.; Phillips, A.; Lundgren, J. D.; Sabin, C. A.; Butcher, D.; Delforge, M.; Fanti, I.; Franquet, X.; Geffard, S.; Gras, L.; Helweg-Larsen, J.; Hillebregt, M.; Kamara, D.; Kjaer, J.; Krum, E.; Mcmanus, H.; Meidahl, P.; Mocroft, A.; Nielsen, J.; Powderl, W.; Rickenbach, M.; Rode, R.; Ryom, L.; Salbol Brandt, R.; Schmidt Iversen, J.; Shortman, N.; Sjol, A.; Smith, C.; Torres, F.; Tverland, J.; Wright, S.; Zaheri, S.; de Wolf, F.; Smidt, J.; Ristola, M.; Katlama, C.; Viard, J-P.; Girard, P. -M.; Livrozet, J. M.; Vanhems, P.; Pradier, C.; Dabis, F.; Neau, D.; Rockstroh, J.; Schmidt, R.; Degen, O.; van Lunzen, J.; Stellbrink, H. J.; Staszewski, S.; Bogner, J.; Gargalianos, P.; Kosmidis, J.; Perdios, J.; Xylomenos, G.; Filandras, A.; Karabatsaki, E.; Panos, G.; Sambatakou, H.; Banhegyi, D.; Mulcahy, F.; Burke, M.; Turner, D.; Yust, I.; Hassoun, G.; Pollack, S.; Maayan, S.; Vella, S.; Esposito, R.; Mazeu, I.; Mussini, C.; Arici, C.; Pristera, R.; Gabbuti, A.; Mazzotta, F.; Lichtner, M.; Vullo, V.; Boer, K.; Geerlings, S. E.; Godfried, M. H.; Kuijpers, T. W.; Lange, J. M. A.; Nellen, F. J. B.; Pajkrt, D.; Prins, J. M.; Scherpbier, H. J.; Vrouenraets, S. M. E.; Wit, F. W. M. N.; van Vugt, M.; van der Meer, J. T. M.; van der Poll, T.; van der Valk, M.; Chirianni, A.; Gargiulo, M.; Montesarchio, E.; Antonucci, G.; Narciso, P.; Testa, A.; Vlassi, C.; Zaccarelli, M.; Castagna, A.; Gianotti, N.; Lazzarin, A.; Galli, M.; Ridolfo, A.; Rozentale, B.; Zeltina, I.; Chaplinskas, S.; Hemmer, R.; Staub, T.; Bruun, J.; Maeland, A.; Ormaasen, V.; Lowe, S.; Oude Lashof, A.; Schreij, G.; Gasiorowski, J.; Knysz, B.; Bakowska, E.; Horban, A.; Flisiak, R.; Grzeszczuk, A.; Boron-Kaczmarska, A.; Parczewski, M.; Pynka, M.; Beniowski, M.; Mularska, E.; Trocha, H.; Jablonowska, E.; Malolepsza, E.; Wojcik, K.; Antunes, F.; Caldeira, L.; Doroana, M.; Mansinho, K.; Maltez, F.; Bravenboer, B.; Pronk, M. J. H.; Duiculescu, D.; Rakhmanova, A.; Zakharova, N.; Buzunova, S.; Jevtovic, D.; Mokras, M.; Stanekova, D.; Tomazic, J.; Gonzalez-Lahoz, J.; Labarga, P.; Medrano, J.; Soriano, V.; Moreno, S.; Rodriguez, J. M.; Bravo, I.; Clotet, B.; Jou, A.; Paredes, R.; Puig, J.; Tural, C.; Gelinck, L. B. S.; Nouwen, J. L.; Rijnders, B. J. A.; Schurink, C. A. M.; Slobbe, L.; Verbon, A.; de Vries-Sluijs, T. E. M. S.; van der Ende, M. E.; van der Feltz, M.; Gatell, J. M.; Miro, J. M.; Domingo, P.; Gutierrez, M.; Mateo, G.; Sambeat, M. A.; Karlsson, A.; Flamholc, L.; Ledergerber, B.; Weber, J.; Cavassini, M.; Francioli, P.; Boffi, E.; Hirschel, B.; Battegay, M.; Elzi, L.; Chentsova, N.; Kravchenko, E.; Driessen, G. J. A.; Hartwig, N. G.; Frolov, V.; Kutsyna, G.; Servitskiy, S.; Krasnov, M.; Barton, S.; Johnson, A. M.; Mercey, D.; Johnson, M. A.; Murphy, M.; Scullard, G.; Fisher, M.; Leen, C.; Branger, J.; Akerlund, B.; Morfeldt, L.; Sundstro, m. A.; Thulin, G.; Koppel, K.; Hokangard, C.; Angarano, G.; Antinori, A.; Armignacco, O.; Castelli, F.; Cauda, R.; Di Perri, G.; Iardino, R.; Ippolito, G.; Moroni, M.; Perno, C. F.; Viale, P. L.; Von Schlosser, F.; Ammassari, A.; Andreoni, M.; Balotta, C.; Bonfanti, P.; Bonora, S.; Borderi, M.; Capobianchi, M. R.; Ceccherini-Silberstein, F.; Cinque, P.; Cozzi-Lepri, A.; De Luca, A.; Gervasoni, C.; Girardi, E.; Gori, A.; Guaraldi, G.; Lo Caputo, S.; Madeddu, G.; Maggiolo, F.; Marchetti, G.; Marcotullio, S.; Monno, L.; Murri, R.; Puoti, M.; Torti, C.; Cicconi, P.; Formenti, T.; Galli, L.; Lorenzini, P.; Costantini, A.; Giacometti, A.; Riva, A.; Carrisa, C.; Lazzari, G.; Verucchi, G.; Kauffmann, R. H.; Minardi, C.; Abeli, C.; Quirino, T.; Manconi, P. E.; Piano, P.; Falasca, K.; Vecchiet, J.; Segala, D.; Sighinolfi, L.; Alessandrini, A.; Cassola, G.; Mazzarello, G.; Piscopo, R.; Viscoli, G.; Belvisi, V.; Mastroianni, C.; Caramma, I.; Castelli, P.; Chiodera, A.; Alleman, M. A.; Bouwhuis
abstract

Background: Non-AIDS defining cancers (NADC) are an important cause of morbidity and mortality in HIV-positive individuals. Using data from a large international cohort of HIV-positive individuals, we described the incidence of NADC from 2004-2010, and described subsequent mortality and predictors of these.Methods: Individuals were followed from 1st January 2004/enrolment in study, until the earliest of a new NADC, 1st February 2010, death or six months after the patient's last visit. Incidence rates were estimated for each year of follow-up, overall and stratified by gender, age and mode of HIV acquisition. Cumulative risk of mortality following NADC diagnosis was summarised using Kaplan-Meier methods, with follow-up for these analyses from the date of NADC diagnosis until the patient's death, 1st February 2010 or 6&nbsp;months after the patient's last visit. Factors associated with mortality following NADC diagnosis were identified using multivariable Cox proportional hazards regression.Results: Over 176,775 person-years (PY), 880 (2.1%) patients developed a new NADC (incidence: 4.98/1000PY [95% confidence interval 4.65, 5.31]). Over a third of these patients (327, 37.2%) had died by 1st February 2010. Time trends for lung cancer, anal cancer and Hodgkin's lymphoma were broadly consistent. Kaplan-Meier cumulative mortality estimates at 1, 3 and 5&nbsp;years after NADC diagnosis were 28.2% [95% CI 25.1-31.2], 42.0% [38.2-45.8] and 47.3% [42.4-52.2], respectively. Significant predictors of poorer survival after diagnosis of NADC were lung cancer (compared to other cancer types), male gender, non-white ethnicity, and smoking status. Later year of diagnosis and higher CD4 count at NADC diagnosis were associated with improved survival. The incidence of NADC remained stable over the period 2004-2010 in this large observational cohort.Conclusions: The prognosis after diagnosis of NADC, in particular lung cancer and disseminated cancer, is poor but has improved somewhat over time. Modifiable risk factors, such as smoking and low CD4 counts, were associated with mortality following a diagnosis of NADC. © 2013 Worm et al.; licensee BioMed Central Ltd.

2013 - Novel genetic association of TNF-α-238 and PDCD1-7209 polymorphisms with long-term non-progressive HIV-1 infection. [Articolo su rivista]
Nasi, Milena; Riva, A; Borghi, V; D'Amico, Roberto; DEL GIOVANE, Cinzia; Casoli, C; Galli, M; Vicenzi, E; Gibellini, Lara; DE BIASI, Sara; Clerici, M; Mussini, Cristina; Cossarizza, Andrea; Pinti, Marcello
abstract

About 2-5% of HIV-1-infected subjects, defined as long-term non-progressors (LTNPs), remain immunologically stable for a long time without treatment. The factors governing this condition are known only in part, and include genetic factors. Thus, we studied 20 polymorphisms of 15 genes encoding proinflammatory and immunoregulatory cytokines, chemokines and their receptors, genes involved in apoptosis, and the gene HCP5. METHODS: We analyzed 47 Caucasian LTNPs infected for &gt;9 years, compared with 131 HIV-1-infected Caucasian patients defined as 'usual progressors'. The genotypes were determined by methods based upon PCR, and the statistical analysis was performed by univariate logistic regression. RESULTS: The well-known CCR5Δ32 del32 allele, the cell death-related TNF-α-238 A and PDCD1-7209 T alleles, and HCP5 rs2395029 G, a non-coding protein associated with the HLA-B*5701, were found positively associated with the LTNP condition. No association was observed for other single nucleotide polymorphisms (SDF-1-801, IL-10-592, MCP-1-2518, CX3CR1 V249I, CCR2V64I, RANTES-403, IL-2-330, IL-1β-511, IL-4-590, FASL IVS3nt-169, FAS-670, FAS-1377, FASL IVS2nt-124, PDCD1-7146, MMP-7-181, and MMP7-153). CONCLUSIONS: The novel genetic associations between allelic variants of genes TNF-α-238 and PDCD1-7209 with the LTNP condition underline the importance of host genetic factors in the progression of HIV-1 infection and in immunological preservation.

2013 - Prevalence and predictors of preclinical coronary heart disease in post-menopause period [Abstract in Rivista]
Guaraldi, Giovanni; Zona, Stefano; Besutti, Giulia; Scaglioni, Riccardo; Stentarelli, Chiara; Menozzi, Marianna; Garlassi, Elisa; Ligabue, Guido; Mussini, Cristina; P., Raggi
abstract

There are very few longitudinal studies of change in coronary artery calcium (CAC) across the menopause period, when it is expected there would be a significant increase in coronary heart disease. CAC>0 identifies preclinical coronary artery disease. We aimed to evaluate risk factors for detectable CAC among HIV-infected women across the menopause period.

2013 - TB meningitis in HIV-positive patients in Europe and Argentina: Clinical dutcome and factors associated with mortality [Articolo su rivista]
Efsen, A. M. W.; Panteleev, A. M.; Grint, D.; Podlekareva, D. N.; Vassilenko, A.; Rakhmanova, A.; Zeltina, I.; Losso, M. H.; Miller, R. F.; Girardi, E.; Cayla, J.; Post, F. A.; Miro, J. M.; Bruyand, M.; Furrer, H.; Obel, N.; Lundgren, J. D.; Mocroft, A.; Kirk, O.; Toibaro, J. J.; Warley, E.; Tamayo, N.; Cristina Ortiz, M.; Scapelatto, P.; Bottaro, E.; Murano, F.; Miachans, M.; Contarelli, J.; Massera, L.; Corral, J.; Hualde, M.; Miglioranza, C.; Corti, M.; Metta, H.; Casiro, A.; Cuini, R.; Laplume, H.; David, D.; Marson, C.; Lupo, S.; Trape, L.; Garcia Messina, O.; Gear, O.; Bruguera, J. M.; Karpov, I.; Skrahina, E.; Skrahin, A.; Zhavoronok, S.; Mitsura, V.; Ruzanov, D.; Bondarenko, V.; Suetnov, O.; Paduto, D.; Gerstoft, J.; Kronborg, G.; Pedersen, C.; Larsen, C. S.; Pedersen, G.; Laursen, A. L.; Nielsen, L.; Jensen, J.; Dabis, F.; Chene, G.; Lawson-Ayayi, S.; Thiebaut, R.; Wittkop, L.; Morlat, P.; Bonnet, F.; Bernard, N.; Hessamfar, M.; Lacoste, D.; Vandenhende, M. A.; Dupon, M.; Dauchy, F. A.; Dutronc, H.; Longy-Boursier, M.; Mercie, P.; Duffau, P.; Roger Schmeltz, J.; Malvy, D.; Pistone, T.; Receveur, M. C.; Neau, D.; Cazanave, C.; Ochoa, A.; Vareil, M. O.; Pellegrin, J. L.; Viallard, J. F.; Greib, C.; Lazaro, E.; Fleury, H.; Lafon, M. E.; Reigadas, S.; Trimoulet, P.; Breilh, D.; Molimard, M.; Bouchet, S.; Titier, K.; Moreau, J. F.; Pellegrin, I.; Haramburu, F.; Arcachon, G.; Dupont, A.; Gerard, Y.; Caunegre, L.; Andre, K.; Bonnal, F.; Farbos, S.; Gemain, M. C.; Ceccaldi, J.; Tchamgoue, S.; De Witte, S.; Courtault, K.; Monlun, E.; Gaborieau, V.; Lataste, P.; Meraud, J. P.; Chossat, I.; Carvalho, A. C.; Basche, R.; Hamad, I. E.; Ricci, B. A.; Maggiolo, F.; Ravasio, V.; Mussini, C.; Prati, F.; Castelletti, S.; Ammassari, A.; Antinori, A.; Bellagamba, R.; Busi Rizzi, E.; Cicalini, S.; Corpolongo, A.; Capaldo, A.; Di Caro, A.; Goletti, D.; Grisetti, S.; Gualano, G.; Lauria, F. N.; Parracino, L.; Palmieri, F.; Petrosillo, N.; Pinetti, C.; Sampaolesi, A.; Moroni, M.; Angarano, G.; Armignacco, O.; d'Arminio Monforte, A.; Castelli, F.; Cauda, R.; Di Perri, G.; Galli, M.; Iardino, R.; Ippolito, G.; Lazzarin, A.; Perno, C. F.; von Schloesser, F.; Viale, P.; Castagna, A.; Ceccherini-Silberstein, F.; Cozzi-Lepri, A.; Lo Caputo, S.; Puoti, M.; Andreoni, M.; Balotta, C.; Bonfanti, P.; Bonora, S.; Borderi, M.; Capobianchi, M. R.; Cingolani, A.; Cinque, P.; De Luca, A.; Di Biagio, A.; Gianotti, N.; Gori, A.; Guaraldi, G.; Lapadula, G.; Lichtner, M.; Madeddu, G.; Marchetti, G.; Marcotullio, S.; Monno, L.; Quiros Roldan, E.; Rusconi, S.; Cicconi, P.; Fanti, I.; Formenti, T.; Galli, L.; Lorenzini, P.; Giacometti, A.; Costantini, A.; Carrisa, C.; Suardi, C.; Vanino, E.; Verucchi, G.; Minardi, C.; Quirino, T.; Abeli, C.; Manconi, P. E.; Piano, P.; Vecchiet, J.; Falasca, K.; Sighinolfi, L.; Segala, D.; Mazzotta, F.; Cassola, G.; Viscoli, G.; Alessandrini, A.; Piscopo, R.; Mazzarello, G.; Mastroianni, C.; Belvisi, V.; Caramma, I.; Castelli, A. P.; Rizzardini, G.; Ridolfo, A. L.; Piolini, R.; Salpietro, S.; Carenzi, L.; Moioli, M. C.; Puzzolante, C.; Abrescia, N.; Chirianni, A.; Guida, M. G.; Gargiulo, M.; Baldelli, F.; Francisci, D.; Parruti, G.; Ursini, T.; Magnani, G.; Ursitti, M. A.; Vullo, V.; D'Avino, A.; Gallo, L.; Nicastri, E.; Acinapura, R.; Capozzi, M.; Libertone, R.; Tebano, G.; Cattelan, A.; Mura, M. S.; Caramello, P.; Orofino, G. C.; Sciandra, M.; Pellizzer, G.; Manfrin, V.; Riekstina, V.; Aldins, P.; Duiculescu, D.; Malashenkov, E.; Kozlov, A.; Buzunova, S.; Garcia-Goez, J. F.; Moreno Camacho, A.; Martinez, J. A.; Gonzalez, J.; Garcia-Alcaide, F.; de Lazzari, E.; Gatell, J. M.; Sanchez, P.; Lopezcolomes, J. L.; Martinez-Lacasa, X.; Falco, V.; Imaz, A.; Ocana, I.; Vidal, R.; Sambeat, M. A.; Moreno-Martinez, A.; Orcau, A.; Weber, R.; Battegay, M.; Hirschel, B.; Cavassini, M.; Bernasconi, E.; Schmid, P.; Rickenbach, M.; Campbell, L.; Arenas-Pinto, A.; Chentsova, N.; Kjaer, J.
abstract

Objectives. The study aimed at describing characteristics and outcome of tuberculous meningitis (TBM) in HIV-positive patients and comparing these parameters with those of extrapulmonary TB (TBEP) and pulmonary TB (TBP). Methods. Kaplan-Meier estimation and Poisson regression models were used to assess the mortality following TB diagnosis and to evaluate potential prognostic factors for the 3 groups of TB patients separately. Results. A total of 100 patients with TBM, 601 with TBEP, and 371 TBP were included. Patients with TBM had lower CD4 cell counts and only 17.0% received antiretroviral therapy (ART) at TB diagnosis. The cumulative probability of death at 12 months following TB was 51.2% for TBM (95% CI 41.4-61.6%), 12.3% for TBP (8.9-15.7%), and 19.4% for TBEP (16.1-22.6) (P &lt; 0.0001; log-rank test). For TBM, factors associated with a poorer prognosis were not being on ART (adjusted incidence rate ratio (aIRR) 4.00 (1.72-9.09), a prior AIDS diagnosis (aIRR = 4.82 (2.61-8.92)), and receiving care in Eastern Europe (aIRR = 5.41 (2.58-11.34))). Conclusions. TBM among HIV-positive patients was associated with a high mortality rate, especially for patients from Eastern Europe and patients with advanced HIV-infection, which urgently calls for public health interventions to improve both TB and HIV aspects of patient management. © 2013 Anne Marie W. Efsen et al.

2013 - The incidence of AIDS-defining illnesses at a current CD4 count ≥ 200 cells/μL in the post-combination antiretroviral therapy era [Articolo su rivista]
Mocroft, A; Furrer, H. J; Miro, J. M; Reiss, P; Mussini, Cristina; Kirk, O; Abgrall, S; Ayayi, S; Bartmeyer, B; Braun, D; Castagna, A; d'Arminio Monforte, A; Gazzard, B; Gutierrez, F; Hurtado, I; Jansen, K; Meyer, L; Muñoz, P; Obel, N; Soler Palacin, P; Papadopoulos, A; Raffi, F; Ramos, J. T; Rockstroh, J. K; Salmon, D; Torti, C; Warszawski, J; de Wit, S; Zangerle, R; Fabre Colin, C; Kjaer, J; Chene, G; Grarup, J; Lundgren, J. D.
abstract

Background. Few studies consider the incidence of individual AIDS-defining illnesses (ADIs) at higher CD4 counts, relevant on a population level for monitoring and resource allocation. Methods. Individuals from the Collaboration of Observational HIV Epidemiological Research Europe (COHERE) aged >= 14 years with >= 1 CD4 count of >= 200 mu L between 1998 and 2010 were included. Incidence rates (per 1000 person-years of follow-up [PYFU]) were calculated for each ADI within different CD4 strata; Poisson regression, using generalized estimating equations and robust standard errors, was used to model rates of ADIs with current CD4 >= 500/mu L. Results. A total of 12 135 ADIs occurred at a CD4 count of >= 200 cells/mu L among 207 539 persons with 1 154 803 PYFU. Incidence rates declined from 20.5 per 1000 PYFU (95% confidence interval [CI], 20.0-21.1 per 1000 PYFU) with current CD4 200-349 cells/mu L to 4.1 per 1000 PYFU (95% CI, 3.6-4.6 per 1000 PYFU) with current CD4 >= 1000 cells/mu L. Persons with a current CD4 of 500-749 cells/mu L had a significantly higher rate of ADIs (adjusted incidence rate ratio [aIRR], 1.20; 95% CI, 1.10-1.32), whereas those with a current CD4 of >= 1000 cells/mu L had a similar rate (aIRR, 0.92; 95% CI, .79-1.07), compared to a current CD4 of 750-999 cells/mu L. Results were consistent in persons with high or low viral load. Findings were stronger for malignant ADIs (aIRR, 1.52; 95% CI, 1.25-1.86) than for nonmalignant ADIs (aIRR, 1.12; 95% CI, 1.01-1.25), comparing persons with a current CD4 of 500-749 cells/mu L to 750-999 cells/mu L. Discussion. The incidence of ADIs was higher in individuals with a current CD4 count of 500-749 cells/mu L compared to those with a CD4 count of 750-999 cells/mu L, but did not decrease further at higher CD4 counts. Results were similar in patients virologically suppressed on combination antiretroviral therapy, suggesting that immune reconstitution is not complete until the CD4 increases to >750 cells/mu L.

2012 - All-cause mortality in treated HIV-infected adults with CD4 ≥500/mm3 compared with the general population: evidence from a large European observational cohort collaboration. [Articolo su rivista]
Lewden, C; Bouteloup, V; De Wit, S; Sabin, C; Mocroft, A; Wasmuth, Jc; van Sighem, A; Kirk, O; Obel, N; Panos, G; Ghosn, J; Dabis, F; Mary Krause, M; Leport, C; Perez Hoyos, S; Sobrino Vegas, P; Stephan, C; Castagna, A; Antinori, A; d'Arminio Monforte, A; Torti, C; Mussini, Cristina; Isern, V; Calmy, A; Teira, R; Egger, M; Grarup, J; Chêne, G; Collaboration of Observational HIV Epidemiological Research Europe in, Eurocoord
abstract

BACKGROUND: Using data from a large European collaborative study, we aimed to identify the circumstances in which treated HIV-infected individuals will experience similar mortality rates to those of the general population. METHODS: Adults were eligible if they initiated combination anti-retroviral treatment (cART) between 1998 and 2008 and had one prior CD4 measurement within 6 months. Standardized mortality ratios (SMRs) and excess mortality rates compared with the general population were estimated using Poisson regression. Periods of follow-up were classified according to the current CD4 count. RESULTS: Of the 80 642 individuals, 70% were men, 16% were injecting drug users (IDUs), the median age was 37 years, median CD4 count 225/mm(3) at cART initiation and median follow-up was 3.5 years. The overall mortality rate was 1.2/100 person-years (PY) (men: 1.3, women: 0.9), 4.2 times as high as that in the general population (SMR for men: 3.8, for women: 7.4). Among 35 316 individuals with a CD4 count ≥500/mm(3), the mortality rate was 0.37/100 PY (SMR 1.5); mortality rates were similar to those of the general population in non-IDU men [SMR 0.9, 95% confidence interval (95% CI) 0.7-1.3] and, after 3 years, in women (SMR 1.1, 95% CI 0.7-1.7). Mortality rates in IDUs remained elevated, though a trend to decrease with longer durations with high CD4 count was seen. A prior AIDS diagnosis was associated with higher mortality. CONCLUSIONS: Mortality patterns in most non-IDU HIV-infected individuals with high CD4 counts on cART are similar to those in the general population. The persistent role of a prior AIDS diagnosis underlines the importance of early diagnosis of HIV infection.

2012 - Aseptic Osteonecrosis: A Newly Diagnosed Complication in HIV-Infected Patients Undergoing Liver Transplantation. [Articolo su rivista]
Cocchi, Stefania; Franceschini, Erica; Meschiari, Marianna; Codeluppi, M; Rompianesi, Gianluca; DI BENEDETTO, Fabrizio; Gerunda, Giorgio Enrico; Mussini, Cristina; Guaraldi, Giovanni
abstract

Aseptic osteonecrosis: a newly diagnosed complication in HIV-infected patients undergoing liver transplantation

2012 - Body Composition changes in ageing HIV infected patients: the complex interplay between low muscle mass, lipodystrophy and osteopenia. [Abstract in Rivista]
Guaraldi, Giovanni; Zona, Stefano; Garlassi, Elisa; Orlando, Gabriella; Carli, Federica; Stentarelli, Chiara; AR Domingues da, Silva; Menozzi, Marianna; A., Santoro; Mussini, Cristina
abstract

Body composition is a key determinant of ageing phenotype. HIV patients on ART are frequently affected by lipodystrophy and osteopenia/osteoporosis (O/O), and in the aging process they experience a decline in fat free mass index (FFMi) similar to uninfected individuals. In an ageing HIV-infected cohort we aimed to describe the interaction between anthropometric changes of FFMi, leg fat % (surrogate of lipoatrophy), VAT/TAT (surrogate of lipohypertrophy) and lumbar BMD (surrogate for (O/O).

2012 - Calendar time trends in the incidence and prevalence of triple-class virologic failure in antiretroviral drug-experienced people with HIV in Europe. [Articolo su rivista]
Nakagawa, F; Lodwick, R; Costagliola, D; van Sighem, A; Torti, C; Podzamczer, D; Mocroft, A; Ledergerber, B; Dorrucci, M; Cozzi Lepri, A; Jansen, K; Masquelier, B; García, F; De Wit, S; Stephan, C; Obel, N; Fätkenhaeuer, G; Castagna, A; Sambatakou, H; Mussini, Cristina; Ghosn, J; Zangerle, R; Duval, X; Meyer, L; Perez Hoyos, S; Fabre Colin, C; Kjaer, J; Chene, G; Grarup, J; Phillips, A.
abstract

BACKGROUND: Despite the increasing success of antiretroviral therapy (ART), virologic failure of the 3 original classes [triple-class virologic failure, (TCVF)] still develops in a small minority of patients who started therapy in the triple combination ART era. Trends in the incidence and prevalence of TCVF over calendar time have not been fully characterised in recent years. METHODS: Calendar time trends in the incidence and prevalence of TCVF from 2000 to 2009 were assessed in patients who started ART from January 1, 1998, and were followed within the Collaboration of Observational HIV Epidemiological Research Europe (COHERE). RESULTS: Of 91,764 patients followed for a median (interquartile range) of 4.1 (2.0-7.1) years, 2722 (3.0%) developed TCVF. The incidence of TCVF increased from 3.9 per 1000 person-years of follow-up [95% confidence interval (CI): 3.7 to 4.1] in 2000 to 8.8 per 1000 person-years of follow-up (95% CI: 8.5 to 9.0) in 2005, but then declined to 5.8 per 1000 person-years of follow-up (95% CI: 5.6 to 6.1) by 2009. The prevalence of TCVF was 0.3% (95% CI: 0.27% to 0.42%) at December 31, 2000, and then increased to 2.4% (95% CI: 2.24% to 2.50%) by the end of 2005. However, since 2005, TCVF prevalence seems to have stabilized and has remained below 3%. CONCLUSIONS: The prevalence of TCVF in people who started ART after 1998 has stabilized since around 2005, which most likely results from the decline in incidence of TCVF from this date. The introduction of improved regimens and better overall HIV care is likely to have contributed to these trends. Despite this progress, calendar trends should continue to be monitored in the long term.

2012 - Combined use of waist and thigh circumference to identify high-risk,, abdominally obese HIV+ patients. [Abstract in Rivista]
O’Neil, T; Ross, R; Zona, Stefano; Orlando, Gabriella; Carli, Federica; Garlassi, Elisa; Stentarelli, Chiara; Mussini, Cristina; Guaraldi, Giovanni
abstract

We examined vhether the combination of waist (WC) and thigh (ThC) circumference improves the prediction of visceral adipose tissue (VAT) over WC and ThC independently in HIV-infected men and women after correction for age. We also examined the independent associations between VAT, and the combination of WC and ThC with metabolic risk facters, metabolic syndrome, type 2 diabetes mellitus and prior cardiovascular events in HIV-infected individuals.

2012 - Engagement and retention in care of patients diagnosed with HIV infection and enrolled in the Modena HIV surveillance cohort. [Abstract in Rivista]
Lazzaretti, C; Borghi, V; Franceschini, Erica; Guaraldi, Giovanni; Mussini, Cristina
abstract

Engagement and retention in care is one of the main aspects not only for the prognosis of the single patient, but also for the treatment as prevention strategy. Aim of our study was to evaluatethe engagement in care after diagnosis and the percentage of viral load suppression in an Italian Public Health System.

2012 - Menopause in HIV-infected women: somewhat different? [Abstract in Atti di Convegno]
Guaraldi, Giovanni; Garlassi, Elisa; Stentarelli, Chiara; Menozzi, Marianna; Zona, Stefano; Santoro, A; Borderi, M; Madeddu, G; Vescini, F; Mussini, Cristina
abstract

Menopause is a physiological aging, process. This complex biological process, involving both physical and psychological health, appears to be an appropriate setting where to study aging in people living with HIV. Some studies have found that HIV was independently associated with earlier onset of menopause. Little is known on menopausal symptoms in HIV infected women. The objective was to describe prevalence of clinical diagnosed comorbidities, polypathology, and patient related outcomes domains in HIV infected patients on menopause.

2012 - Mitochondrial DNA haplogroups and incidence of lipodystrophy in HIV-infected patients on long-term antiretroviral therapy. [Articolo su rivista]
De Luca, A; Nasi, Milena; Di Giambenedetto, S; Cozzi Lepri, A; Pinti, Marcello; Marzocchetti, A; Mussini, Cristina; Fabbiani, M; Bracciale, L; Cauda, R; Cossarizza, Andrea
abstract

We investigated the rates of lipodystrophy events, according to mitochondrial DNA haplogroup, in 187 patients starting combination antiretroviral therapy and following it. Incidence rates of lipoatrophy and fat accumulation were 8.2 and 4.8 per 100 person-years of follow-up, respectively. In multivariable models, patients with haplogroup K were at higher risk of any lipodystrophy [adjusted relative risk (aRR) 4.02, P = 0.0009], lipoatrophy (competing-risk aRR 2.42, P = 0.09; cause-specific aRR 2.99, P = 0.031), and fat accumulation (competing-risk aRR, 2.63, P = 0.11; cause-specific aRR 5.27, P = 0.019) than those with haplogroup H. Mitochondrial haplogroups may explain part of the genetic predisposition to lipodystrophy during combination antiretroviral therapy.

2012 - Mitochondrial DNA: a proinflammatory 'enemy from within' during HIV infection? [Articolo su rivista]
Pinti, Marcello; Mussini, Cristina; Cossarizza, Andrea
abstract

Mitochondria are crucial in cell life, as they are the main intracellular source of energy, and have a main role in cell death as they contain molecules able to trigger apoptosis. However, mitochondria can also release molecules called ‘damage-associated molecular patterns’ (DAMPs) that trigger a potent innate immune response and cause inflammation through the engagement of the Toll-like receptors (TLR). During human immunodeficiency virus (HIV) infection, a proinflammatory status is present that is not completely explained by the activity of the virus per se, or by the effective immune response against the virus. However, the presence of significant amounts of DAMPs of mitochondrial origin, such as extracellular plasmatic mtDNA, in the peripheral blood of subjects with HIV infection suggests that part of the inflammation typical of such infection could be because of the activity of these molecules, and thus opens new therapeutic perspectives.

2012 - Performance of genotypic tropism testing on proviral DNA in clinical practice: results from the DIVA study group. [Articolo su rivista]
Svicher, V; Alteri, C; Montano, M; D'Arrigo, R; Andreoni, M; Angarano, G; Antinori, A; Antonelli, G; Allice, T; Bagnarelli, P; Baldanti, F; Bertoli, A; Borderi, M; Boeri, E; Bon, I; Bruzzone, B; Callegaro, Ap; Capobianchi, Mr; Carosi, G; Cauda, R; Ceccherini Silberstein, F; Clementi, M; Chirianni, A; Colafigli, M; D'Arminio Monforte, A; De Luca, A; Di Biagio, A; Di Nicuolo, G; Di Perri, G; Di Pietro, M; Di Santo, F; Fabeni, L; Fadda, G; Galli, M; Gennari, W; Ghisetti, V; Giacometti, A; Gori, C; Gori, A; Gulminetti, R; Leoncini, F; Maffongelli, G; Maggiolo, F; Manca, G; Gargiulo, F; Martinelli, C; Maserati, R; Mazzotta, F; Meini, G; Micheli, V; Monno, L; Mussini, Cristina; Narciso, P; Nozza, S; Paolucci, S; Pal, G; Parisi, S; Parruti, G; Pignataro, Ar; Pollicita, M; Quirino, T; Re, Mc; Rizzardini, G; Santangelo, R; Scaggiante, R; Sterrantino, G; Turriziani, O; Vatteroni, Ml; Vecchi, L; Viscoli, C; Vullo, V; Zazzi, M; Lazzarini, A; Perno, Cf; Diva, Group
abstract

OBJECTIVE: The DIVA study is aimed at setting up a standardized genotypic tropism-testing on proviral-DNA for the routine clinical diagnostic-laboratory. METHODS: Twelve local centres and 5 reference centres (previously cross-validated) were identified. For inter-center validation-procedure, 60 peripheral-blood mononuclear cells (PBMCs) aliquots from 45 HAART-treated patients were randomly chosen for population V3 sequencing on proviral-DNA at local HIV centre and at reference-laboratory. Viral tropism was predicted by Geno2Pheno algorithm (False Positive Rate [FPR] = 20%) as proposed by the European-Guidelines. Quantification of total HIV-1 DNA was based on a method described by Viard (2004). RESULTS: Quantification of HIV-1 DNA was available for 35/45 (77.8%) samples, and gave a median value of 598 (IQR:252- 1,203) copies/10 PBMCs. A total of 56/60 (93.3%) samples were successfully amplified by both the reference and the local virological centers. The overall concordance of tropism prediction between local and reference centers was 54/56 (96.4%). Results of tropism prediction by local centers were: 33/54 (61.1%) R5 and 21/54 (38.9%) X4/DM. CONCLUSION: There was high concordance in the genotypic tropism prediction based on proviral DNA among different virological centers throughout Italy. Our results are in line with other European studies, and support the use of genotypic tropism testing on proviral DNA in patients with suppressed plasma HIV-1 RNA candidate to CCR5-antagonist treatment.

2012 - Renal Complications in HIV Disease: Between Present and Future [Articolo su rivista]
Maggi, P; Bartolozzi, D; Bonfanti, P; Calza, L; Cherubini, C; Di Biagio, A; Marcotullio, S; Montella, F; Montinaro, V; Mussini, Cristina; Narciso, P; Rusconi, S; Vescini, F.
abstract

The recent introduction of new antiretroviral drugs, characterized by high efficiency and improved safety profiles, has not reduced the incidence of long-term adverse effects, in some cases manifested as selective organ damage. The presence of organ damage in patients receiving antiretroviral treatment is not only the expression of treatment toxicity, but also a complex interaction between individual risk factors, HIV-correlated effects, and antiretroviral drug toxicity. Kidney damage belongs to these adverse events. Renal function abnormalities are present in a large percentage of patients with HIV infection. Moreover, HIV-associated renal disease seems to be associated with progression to AIDS and death. In this review we address the various aspects of the epidemiology of renal damage, the interaction and the convergent effect of HIV and antiretroviral drugs in the onset of kidney injury, the interplay between kidney function and other organ systems, early clinical management, the monitoring of renal function, and a proposal of clinical approach to kidney disease in daily practice. Finally, we discuss future perspectives of renal damage in HIV patients and evaluate the patient's perspective.

2012 - Stable changes in CD4+ T lymphocyte miRNA expression after exposure to HIV-1. [Articolo su rivista]
F., Bignami; E., Pilotti; Bertoncelli, Linda; P., Ronzi; M., Gulli; N., Marmiroli; Magnani, Giacomo; Pinti, Marcello; L., Lopalco; Mussini, Cristina; R., Ruotolo; M., Galli; Cossarizza, Andrea; C., Casoli
abstract

MicroRNAs (miRNAs) inhibit HIV-1 expression by either modulating host innate immunity or by directly interfering with viral mRNAs. We evaluated the expression of 377 miRNAs in CD4(+) T cells from HIV-1 élite long-term nonprogressors (éLTNPs), naive patients, and multiply exposed uninfected (MEU) patients, and we observed that the éLTNP patients clustered with naive patients, whereas all MEU subjects grouped together. The discriminatory power of miRNAs showed that 21 miRNAs significantly differentiated éLTNP from MEU patients and 23 miRNAs distinguished naive from MEU patients, whereas only 1 miRNA (miR-155) discriminated éLTNP from naive patients. We proposed that miRNA expression may discriminate between HIV-1-infected and -exposed but negative patients. Analysis of miRNAs expression after exposure of healthy CD4(+) T cells to gp120 in vitro confirmed our hypothesis that a miRNA profile could be the result not only of a productive infection but also of the exposure to HIV-1 products that leave a signature in immune cells. The comparison of normalized Dicer and Drosha expression in ex vivo and in vitro condition revealed that these enzymes did not affect the change of miRNA profiles, supporting the existence of a Dicer-independent biogenesis pathway.

2012 - T cell activation but not polyfunctionality after primary HIV infection predicts control of viral load and length of the time without therapy. [Articolo su rivista]
Cossarizza, Andrea; Bertoncelli, Linda; Nemes, Elisa; Lugli, Enrico; Pinti, Marcello; Nasi, Milena; DE BIASI, Sara; Gibellini, Lara; Montagna, Jp; Vecchia, M; Manzini, Lisa; Meschiari, Marianna; Borghi, Valentina; Guaraldi, Giovanni; Mussini, Cristina
abstract

Immune changes occurring after primary HIV infection (PHI) have a pivotal relevance. Our objective was to characterize the polyfunctionality of immune response triggered by PHI, and to characterize immune activation and regulatory T cells, correlating such features to disease progression. PATIENTS AND METHODS: We followed 11 patients experiencing PHI for 4 years. By polychromatic flow cytometry, we studied every month, for the first 6 months, T lymphocyte polyfunctionality after cell stimulation with peptides derived from HIV-1 gag and nef. Tregs were identified by flow cytometry, and T cell activation studied by CD38 and HLA-DR expression. RESULTS: An increase of anti-gag and anti-nef CD8+ specific T cells was observed 3 months after PHI; however, truly polyfunctional T cells, also able to produce IL-2, were never found. No gross changes in Tregs were present. T lymphocyte activation was maximal 1 and 2 months after PHI, and significantly decreased in the following period. The level of activation two months after PHI was strictly correlated to the plasma viral load 1 year after infection, and significantly influenced the length of period without therapy. Indeed, 80% of patients with less than the median value of activated CD8+ (15.5%) or CD4+ (0.9%) T cells remained free of therapy for &gt;46 months, while all patients over the median value had to start treatment within 26 months. CONCLUSIONS: T cell activation after PHI, more than T cell polyfunctionality or Tregs, is a predictive marker for the control of viral load and for the time required to start treatment.

2012 - Tenofovir accelerates bone mass loss of the lumbar spine in the first year of menopause in HIV infected women. [Abstract in Atti di Convegno]
Zona, Stefano; F., Vescini; A., Silva; C., Berardi; Orlando, Gabriella; Carli, Federica; Menozzi, Marianna; A., Santoro; Mussini, Cristina; Guaraldi, Giovanni
abstract

Menopause is a paradigm of physiological aging involving an impairement in bone metabolism. We hypothesized that in menopausal HIV infected women, Tenofovir exposure may contribute to a progressive Bone Mass Loss (BML). The aim of the study was to identify predictors of bone mineral density in HIV infected women entering menopause and to evaluate the bone mass loss after menopause.

2012 - Tenofovir accelerates bone mass loss of the lumbar spine in the first years of menopause in HIV infected women [Abstract in Rivista]
Garlassi, Elisa; Zona, Stefano; Vescini, F; Domingues da Silva, A; Berardi, C; Orlando, Gabriella; Carli, Federica; Menozzi, Marianna; Santoro, A; Mussini, Cristina; Guaraldi, Giovanni
abstract

HIV-infected postmenopausal women have higer rates of bone loss than HIV negative women. We aimed to identify predictors of body mass density (BMD) in HIV infected women entering menopause and to evaluate the pre- and post- menopausal BMD change, with regard to tenofovir use.

2012 - Tenofovir accelerates bone mass loss of the lumbar spine in the first years of menopause in HIV infected women. [Abstract in Atti di Convegno]
Guaraldi, Giovanni; Garlassi, Elisa; Stentarelli, Chiara; Zona, Stefano; Vescini, F; Mussi, Chiara; Orlando, Gabriella; Carli, Federica; Menozzi, Marianna; Santoro, A; Mussini, Cristina
abstract

Previous studies haveshown that HIV-infected postmenopausal women have higer rates of bone loss than HIV negative women. No studies so far have analyzed the slope of bone loss across the menopausal transition period. We hypothesized that in HIV infected women BMD decreases in the postmenopausal period and Tenofovir exposure may contribute to this impairment. The aim of the study was to identify predictors of BMD in HIV infected women entering menopause and to evaluate the pre- and post- menopausal BMD change.

2012 - The protease inhibitor atazanavir triggers autophagy and mitophagy in human preadipocytes [Articolo su rivista]
Gibellini, Lara; DE BIASI, Sara; Pinti, Marcello; Nasi, Milena; Riccio, Massimo; Carnevale, Gianluca; Cavallini, Gian Maria; F. J., Sala De Oyanguren; J. E., O’Connor; Mussini, Cristina; DE POL, Anto; Cossarizza, Andrea
abstract

Background: The association betweenHAARTand lipodystrophy iswell established, but lipodystrophy pathogenesis is still poorly understood. Drugs, and in particular protease inhibitors, accumulate in adipose tissue affecting adipocyte physiology and gene expression by several mechanisms. Recent studies have identified autophagy as another process affected by these classes of drugs, but no studies have been performed in adipose cells. Methods: SW872 preadipocytic human cell line was used to evaluate changes induced by amprenavir (APV), ritonavir (RTV), or atazanavir (ATV), all used at 10–200mmol/l. A subline was stably transfected with murine stem cell virus (pMSCV)-enhanced green fluorescent protein (EGFP)-LC3 plasmid (to obtain a fluorescent LC3 protein) and treated with ATV at different doses. The distribution of LC3 and the colocalization of mitochondria, lysosome, and autophagosome were assessed by confocal microscopy. Transmission electron microscopy of ATV-treated cells was also performed. The cellular content of lysosomes was assessed using Lysotracker Green; apoptosis was evaluated by annexin V/propidium iodide staining, and mitochondrial superoxide anion (mtO2-) was analyzed by mitoSOX red. Lysosomes, apoptosis, and mtO2 - were studied by flow cytometry and multispectral imaging flow cytometry. Results: In SW872 cells, RTV caused massive apoptosis, more than autophagy, whereas APV was almost ineffective. ATV induced both apoptosis (high doses) and autophagy (low doses). ATV-treated cells displayed LC3-specific punctae, suggesting the formation of autophagosomes that enclosed mitochondria, as revealed by electron microscopy. At low doses, ATV promoted mitochondrial superoxide generation, whereas at high doses, it induced mitochondrial membrane depolarization. Conclusion: Autophagy/mitophagy can be considered a mechanism triggered by ATV in SW872 preadipocytes.

2012 - Trends in virological and clinical outcomes in individuals with HIV-1 infection and virological failure of drugs from three antiretroviral drug classes: a cohort study. [Articolo su rivista]
Costagliola, D; Ledergerber, B; Torti, C; van Sighem, A; Podzamczer, D; Mocroft, A; Dorrucci, M; Masquelier, B; de Luca, A; Jansen, K; De Wit, S; Obel, N; Fätkenheuer, G; Touloumi, G; Mussini, Cristina; Castagna, A; Stephan, C; Garcia, F; Zangerle, R; Duval, X; Pérez Hoyos, S; Meyer, L; Ghosn, J; Fabre Colin, C; Kjaer, J; Chene, G; Fabre Colin, C; Kjaer, J; Grarup, J; Lodwick, R; Phillips, A.
abstract

BACKGROUND: Limited treatment options have been available for people with HIV who have had virological failure of the three original classes of HIV antiretroviral drugs-so-called triple-class virological failure (TCVF). However, introduction of new drugs and drug classes might have improved outcomes. We aimed to assess trends in virological and clinical outcomes for individuals with TCVF in 2000-09. METHODS: In our cohort study, we analysed data for adults starting antiretroviral therapy from 1998 in cohorts participating in the PLATO II project, which is part of COHERE, a collaboration of European cohorts. TCVF was defined as virological failure to at least two nucleoside reverse transcriptase inhibitors, one non-nucleoside reverse-transcriptase inhibitor, and one ritonavir-boosted protease inhibitor, with virological failure of a drug defined as one viral-load measurement of greater than 500 copies per mL after at least 4 months of continuous use. We used multivariable generalised estimating equation logistic models and Poisson regression models to study trends in virological suppression and incidence of AIDS or death after TCVF. We adjusted for sex, transmission group, age, AIDS status, CD4 cell count, plasma viral loads at TCVF, achievement of virological response (&lt;50 copies per mL), and number of drug failures before TCVF. FINDINGS: 28 of 33 cohorts in COHERE contributed data to the PLATO II project, of which four had no participants eligible for inclusion in this study. 2476 (3%) of 91 764 participants from the remaining 24 cohorts had TCVF and at least one viral load measurement in 2000-09. The proportion of patients with virological response after TCVF increased from 19·5% in 2000 to 57·9% in 2009 (adjusted p&lt;0·0001). Incidence of AIDS decreased from 7·7 per 100 person-years in 2000-02 to 2·3 in 2008 and 1·2 in 2009 (adjusted p&lt;0·0001). Mortality decreased from 4·0 per 100 person-years between 2000 and 2002 to 1·9 in 2007 and 1·4 in 2008 (unadjusted p=0·023), but the trend was not significant after adjustment (p=0·22). INTERPRETATION: A substantial improvement in viral load suppression and accompanying decrease in the rates of AIDS in people after extensive failure to drugs from the three original antiretroviral classes during 2000-09 was probably mainly driven by availability of newer drugs with better tolerability and ease of use and small cross-resistance profiles, suggesting the public health benefit of the introduction of new drugs.

2011 - CD4+ T-cell differentiation, regulatory T cells and gag-specific T lymphocytes are unaffected by CD4-guided treatment interruption and therapy resumption. [Articolo su rivista]
Nemes, Elisa; Lugli, Enrico; Bertoncelli, Linda; Nasi, Milena; Pinti, Marcello; Manzini, S; Prati, Francesca; Manzini, Lisa; DEL GIOVANE, Cinzia; D'Amico, Roberto; Cossarizza, Andrea; Mussini, Cristina
abstract

OBJECTIVES:Despite limiting exposure to antiretroviral drugs, structured treatment interruptions can influence multiple aspects of T-cell immunity, particularly those regarding CD4(+) T lymphocytes. We evaluated the impact of CD4-guided treatment interruption (CD4-GTI) and treatment resumption on regulatory T cells (Tregs), T-lymphocyte activation, differentiation and polyfunctional gag-specific response.METHODS:Patients were analyzed just prior to treatment interruption, at 2 and 6 months after treatment interruption, just prior to treatment resumption and at 2 and 6 months after treatment resumption. Thawed peripheral blood mononuclear cells were stained immediately for phenotype analysis or stimulated with HIV-gag peptides and analyzed by polychromatic flow cytometry.RESULTS:Treatment interruption resulted in a CD4(+) cell count decrease and plasma viral load (pVL) increase, but did not preclude a good immune reconstitution and a complete suppression of pVL after treatment resumption. Treatment interruption did not influence CD4(+) T-cell differentiation and Treg subsets. During treatment interruption, gag-specific CD4(+) T cells were not lost, although the frequency of HIV-specific CD8(+) cells increased. Most gag-specific CD4(+) T cells were potentially cytotoxic (CD107a(+)) and were not influenced by pVL or by HAART. Most helper (CD154(+)) gag-specific CD4(+) T lymphocytes did not produce interferon-γ or interleukin-2.CONCLUSION:CD4-GTI did not cause depletion of memory cells, Tregs or HIV-specific CD4(+) cells and, on the contrary, could induce HIV-specific responses. If guided by CD4(+) T-cell count, treatment interruption does not provoke irreversible immune damages.

2011 - Decline of CD4⁺ T-cell count before start of therapy and immunological response to treatment in antiretroviral-naive individuals. [Articolo su rivista]
Mussini, Cristina; Cossarizza, Andrea; Sabin, C; Babiker, A; De Luca, A; Bucher, Hc; Fisher, M; Rezza, G; Porter, K; Dorrucci, M.
abstract

OBJECTIVE:Treatment guidelines recommend initiation of therapy for individuals experiencing rapid CD4 cell decline. It is not known, however, whether the rate of CD4 cell decline before combination antiretroviral therapy (cART) is related to immunological response following cART.METHODS:We estimated precART and postcART CD4 cell slopes by mixed models and categorized patients into two groups according to whether estimated precART slopes were above or below the 75th percentile. We compared immunological responses of the two groups through both mixed models and survival techniques. Models were stratified by CD4 cell at baseline, adjusted for HIV RNA, age, sex, HIV transmission group, year of seroconversion, initiation during primary infection, hepatitis C virus and hepatitis B virus serostatus, and cART class.RESULTS:Of 2038 eligible patients, 1531 and 507 experienced median (interquartile range) precART CD4 cell slope of −105 (−471 to −61) and −42 (−62 to −80) cells/μl, respectively, over 2 years. After adjusting for potential confounders, individuals with shallower decline experienced a slower rate of CD4 cell recovery following cART initiation of +9.5 [95% confidence interval (CI) +6.6 to +12.2] compared to +13.9 (+13.0 to +14.8) cells/μl per month among those with steeper precART decline (P &lt; 0.001). After stratifying by the baseline CD4 cell count, the adjusted relative hazard of an increase from baseline of more than 50 cells/μl was 0.70 (95% CI 0.62−0.79) for those with a shallower vs. steeper precART decline.CONCLUSION:Findings highlight the existence of a subgroup of individuals with shallower precART CD4 cell decline who experience poorer CD4 cell increases after cART; new studies in this group may provide information to optimize responses to therapy.

2011 - Decreased mitochondrial DNA content in subcutaneous fat from HIV-infected women taking antiretroviral therapy as measured at delivery. [Articolo su rivista]
Nasi, Milena; Pinti, Marcello; Chiesa, E; Fiore, S; Manzini, S; DEL GIOVANE, Cinzia; D'Amico, Roberto; Palai, N; Campatelli, C; Sabbatini, F; Roccio, M; Tibaldi, C; Masuelli, G; Mussini, Cristina; Ferrazzi, E; d'Arminio Monforte, A; Cossarizza, Andrea
abstract

BACKGROUND: Increasing numbers of pregnant HIV-positive women are receiving combination antiretroviral regimens for preventing mother-to-child virus transmission or for treating the infection itself. Several studies have demonstrated that nucleoside reverse transcriptase inhibitors (NRTIs) induce mitochondrial toxicity by several mechanisms, including depletion of mitochondrial DNA (mtDNA). By the quantification of mtDNA levels, we studied mitochondrial toxicity in HIV-positive women at delivery and the possible correlations with antiretroviral regimens, viroimmunological and metabolic parameters.METHODS: We analysed 68 HIV-positive women enrolled in the Italian Prospective Cohort Study on Efficacy and Toxicity of Antiretroviral in Pregnancy (TARGET Study); all were taking ≥1 NRTI. We quantified mtDNA copies per cell in subcutaneous fat samples collected during delivery. At the 3rd, 6th and 9th month of pregnancy, we collected data concerning CD4(+) T-cell count, plasma HIV RNA, total and high-density lipoprotein (HDL) cholesterol, fasting plasma glucose and triglycerides. As a control, we analysed mtDNA levels in abdominal subcutaneous fat samples from 23 HIV-seronegative women at delivery.RESULTS: mtDNA content was significantly lower in HIV-infected women when compared with HIV-negative controls. mtDNA content varied independently from viroimmunological, lipid and glucose parameters at the different months, with the exceptions of triglycerides at the 9th month and of HDL at the 6th month of pregnancy.CONCLUSIONS: In subcutaneous tissue from women taking NRTI-based antiretroviral regimens, we observed a significant decrease of mtDNA content, compared with uninfected women not on antiviral treatment. Moreover, a significant correlation was noted between mtDNA content and HDL cholesterol and triglycerides.

2011 - HIV-1 Infection and the Aging of the Immune System: Facts, Similarities and Perspectives [Articolo su rivista]
DE BIASI, Sara; Pinti, Marcello; Nasi, Milena; Gibellini, Lara; Bertoncelli, Linda; Manzini, Serena; Mussini, Cristina; Cossarizza, Andrea
abstract

During infection with the human immunodeficiency type-1 virus (HIV), the immune system has to cope with the exposure to an unexpected number of different and new antigens that are generated by continuous mutations of the virus. This phenomenon causes a profound derangement of the immune response, which is similar to that defined immunosenescence, a complex remodeling, whereby clonotypical immunity deteriorates, and ancestral and innate immunity is largely preserved. Either in HIV+ patients or in elderly individuals, the lifelong chronic antigenic stress, along with the involution of the thymus, causes the accumulation of memory/effector T cells and the exhaustion of naïve T cells. Furthermore, in both these conditions a chronic inflammatory status exists in the aging process, which has been defined as "inflammaging" and is characterized by an enhanced production of proinflammatory cytokines. In this review, we will underline the similarities that exist between immunological changes present during the physiological aging process and HIV infection. © 2011.

2011 - INCREASED LEVELS OF PLASMATIC MITOCHONDRIAL DNA DURING HIV INFECTION REVEAL A NEW ROLE FOR MITOCHONDRIAL DAMAGE-ASSOCIATED MOLECULAR PATTERNS [Abstract in Rivista]
Cossarizza, Andrea; Pinti, Marcello; Nasi, Milena; Gibellini, Lara; DE BIASI, Sara; Montagna, J. P.; Bertoncelli, Linda; Bisi, Luca; Manzini, Lisa; Benatti, Stefania; Borghi, V.; Mussini, Cristina
abstract

Recently, it has been shown that mtDNA or degraded mitochondrial peptides can act as “damage-associated molecular patterns" (DAMPs), that are conceptually and functionally similar to PAMPs. Mitochondrial DAMPs, defined MTDs, can be involved in the pathogenesis of the systemic inflammatory response syndrome (SIRS), a condition that often affects patients who survive a trauma, characterized by the presence of shock and compromised function of several organs. During SIRS, mtDNA released from damaged or dead cells can bind TLR-9, whose activation causes a potent inflammatory reaction, with the production of proinflammatory cytokines. Since HIV infection is characterized by a proinflammatory status, and by a hyperproduction of proinflammatory cytokines, we asked whether soluble mtDNA circulating in the plasma could play a role in determining such condition.Thus, we have studied plasma levels of mtDNA in HIV+ patients showing a different course of the infection, and have correlated such levels to the activation of the immune system and to the plasma viremia. We analyzed individuals during acute, primary HIV infection (AHI), patients with an advanced infection (including those with full blown acquired immunodeficiency syndrome, AIDS) but still naive for antiretroviral therapy (ART), and those defined “long term non progressors” (LTNPs), who had been infected since at least 8 years, always out of treatment, but with a normal number of CD4+ T cells, a low grade of apoptosis and a good immunological control of the virus.In all HIV+ patients but LTNP plasma levels of mtDNA were significantly higher than in healthy controls. Furthermore, in naive patients, 6 months of efficient ART (able to increase CD4+ T cell count, decrease viral load and reduce T cell activation) did not modify mtDNA plasma levels. These levels were not correlated to CD4+ T cell count, nor to markers of immune activation, but had a significant correlation with plasma viral load, revealing a possible role for mtDNA not only as a molecule able to trigger inflammation, but also as a novel biomarker of virus-induced damage.The identification of the role of MTDs could relevant not only to identify possible new biomarkers of disease progression, but also in designing new therapeutic strategies that regard soluble mtDNA, as novel treatments could target either soluble MTDs, or the receptors they use. Thus, in HIV infection, as in other diseases characterized by excessive inflammation, interfering with MTDs could likely become a novel strategy to reduce the harmful immune activation.

2011 - Increased plasma levels of extracellular mitochondrial DNA during HIV infection: a new role for mitochondrial damage-associated molecular patterns during inflammation. [Articolo su rivista]
Cossarizza, Andrea; Pinti, Marcello; Nasi, Milena; Gibellini, Lara; Manzini, S; Roat, Erika; DE BIASI, Sara; Bertoncelli, Linda; Montagna, Jp; Bisi, Luca; Manzini, Lisa; Trenti, T; Borghi, V; Mussini, Cristina
abstract

HIV infection is characterized by a chronic inflammatory state. Recently, it has been shown that mitochondrial DNA (mtDNA) released from damaged or dead cells can bind Toll like receptor-9 (TLR9), an intracellular receptor that responds to bacterial or viral DNA molecules. The activation of TLR9 present within monocytes or neutrophils results in a potent inflammatory reaction, with the production of proinflammatory cytokines. We measured plasma levels of mtDNA in different groups of HIV(+) patients, i.e., those experiencing an acute HIV infection (AHI), long term non progressors (LTNP), late presenters (LP) taking antiretroviral therapy for the first time, and healthy controls. We found that in AHI and LP mtDNA plasma levels were significantly higher than in healthy individuals or in LTNP. Plasma mtDNA levels were not correlated to peripheral blood CD4(+) T cell count, nor to markers of immune activation, but had a significant correlation with plasma viral load, revealing a possible role for mtDNA in inflammation, or as a biomarker of virus-induced damage.

2011 - Late presenters in new HIV diagnoses from an Italian cohort of HIV-infected patients: prevalence and clinical outcome. [Articolo su rivista]
d'Arminio Monforte, A; Cozzi Lepri, A; Girardi, E; Castagna, A; Mussini, Cristina; Di Giambenedetto, S; Galli, M; Cassola, G; Vullo, V; Quiros Roldan, E; Lo Caputo, S; Antinori, A.
abstract

BACKGROUND: To study the prevalence, predictors and outcome of late HIV diagnosis in the Icona cohort, according to the new European consensus definition of late diagnosis.METHODS: In this observational cohort study we investigated patients diagnosed with HIV over 3 months preceding enrolment who were defined as diagnosed late if they presented with AIDS or a CD4(+) T-cell count ≤ 350/mm³ (European consensus definition). We estimated the prevalence of late diagnosis, identified factors associated with being diagnosed late and looked at the prognostic value of the European consensus definition of late presentation to predict subsequent clinical progression (new AIDS events or death).RESULTS: In total, 1,438/2,276 patients (63%) were defined as diagnosed late using the new European Consensus definition. Of these, 387 (16%) were AIDS-presenters. Predictors of being diagnosed late were older age, non-Italian origin, high HIV RNA and unemployment (versus retirement). A total of 293 patients showed clinical progression (3 events/100 person-years of follow-up, 95% CI: 2.7-3.4). Presenting late was strongly associated with a >5-fold increased risk of disease progression.CONCLUSIONS: In our observational setting with free access to care, more than 60% of new HIV diagnoses occurred below the recommended threshold for initiating antiretroviral treatment. Presenting late for care was associated with a high risk of clinical progression.

2011 - Long-term CD4+ T-cell count evolution after switching from regimens including HIV nucleoside reverse transcriptase inhibitors (NRTI) plus protease inhibitors to regimens containing NRTI plus non-NRTI or only NRTI. [Articolo su rivista]
Torti, C; d'Arminio Monforte, A; Pozniak, Al; Lapadula, G; Cologni, G; Antinori, A; De Luca, A; Mussini, Cristina; Castagna, A; Cicconi, P; Minoli, L; Costantini, A; Carosi, G; Liang, H; Cesana, Bm
abstract

BACKGROUND: Data regarding CD4+ recovery after switching from protease inhibitor (PI)-based regimens to regimens not containing PI are scarce. METHODS: Subjects with virological success on first-PI-regimens who switched to NNRTI therapy (NNRTI group) or to nucleoside reverse transcriptase (NRTI)-only (NRTI group) were studied. The effect of the switch on the ongoing CD4+ trend was assessed by two-phase linear regression (TPLR), allowing us to evaluate whether a change in the CD4+ trend (hinge) occurred and the time of its occurrence. Furthermore, we described the evolution of the frequencies in CD4-count classes across four relevant time-points (baseline, before and immediately after the switch, and last visit). Finally, we explored whether the CD4+ counts evolved differently in patients who switched to NNRTI or NRTI-only regimens by considering: the overall CD4+ trends, the time to CD4+≥ 500/mm3 after the switch, and the area-under-the-curve (AUC) of the CD4+ after the switch. RESULTS: Eight hundred and ninety-six patients, followed for a median of 2,121 days, were included. At TPLR, hinges occurred in 581/844 (68.9%), but in only 40/581 (6.9%) within a time interval (180 days) compatible with a possible relationship to the switch; furthermore, in 19/40 cases, CD4+ counts appeared to decrease after the hinges. In comparison with the NNRTI group, the NRTI group showed CD4+ count greater at baseline (P = 0.0234) and before the switch (P ≤ 0.0001), superior CD4+ T-cell increases after HAART was started, lower probability of not achieving CD4+ ≥ 500/mm3 (P = 0.0024), and, finally, no significant differences in the CD4+ T-cell AUC after the switch after adjusting for possible confounders (propensity score and pre-switch AUC). Persistence at CD4+ &lt; 200/mm3 was observed in 34/435 (7.5%) patients, and a decrease below this level was found in only 10/259 (3.9%) with baseline CD4+ ≥ 350/mm3. CONCLUSIONS: Switching from first-line PI to NNRTI- or NRTI-based regimens did not seem to impair CD4+ trend over long-term follow-up. Although the greater CD4+ increases in patients who switched to the NRTI-only regimen was due to higher CD4+ counts before the switch, several statistical analyses consistently showed that switching to this regimen did not damage the ongoing immune-reconstitution. Lastly, the observation that CD4+ T-cell counts remained low or decreased in the long term despite virological success merits further investigation.

2011 - NK-cell phenotype at interruption underlies widely divergent duration of CD4+-guided antiretroviral treatment interruption. [Articolo su rivista]
Bozzano, F; Nasi, Milena; Bertoncelli, Linda; Nemes, Elisa; Prati, F; Marras, F; Mussini, Cristina; Moretta, L; Cossarizza, Andrea; De Maria, A.
abstract

Long-term side effects may represent a relevant burden of antiretroviral treatment (ART) in HIV-infected patients with good CD4 immune reconstitution over extended time spans. CD4-guided treatment interruption (TI) has been evaluated to address this point and may result in a wide spectrum of time off ART in different patient cohorts. We studied whether differences in innate immune responses, in particular NK cells, are associated to patterns of longer (LoTI) or a shorter (ShTI) TI. Clinical cohort parameters were analyzed on a group of patients widely diverging for TI duration (<9 versus >18 months) on samples before TI, including NK-cell analysis and function by natural cytotoxicity receptor (NCR)-triggered γ-IFN production. Although persistently reduced NCR expression (NKp30) and function were observed in both LoTI and ShTI patients on ART compared with healthy donors, relevant differences were observed at baseline TI in those patients who subsequently developed LoTI course. Lower expression of NKG2D and NKp46 on NK cells. This also translates in reduced γ-IFN production in redirected functional assays. Thus, differences in innate immune balance exist during ART, may be associated to differential control of HIV infection and their understanding could explain clinical differences in individual patients that are not reflected by CD4(+) cell counts alone.

2011 - Survival outcomes and effect of early vs. deferred cART among HIV-infected patients diagnosed at the time of an AIDS-defining event: a cohort analysis. [Articolo su rivista]
Miro, Jm; Manzardo, C; Mussini, Cristina; Johnson, M; d'Arminio Monforte, A; Antinori, A; Gill, Mj; Sighinolfi, L; Uberti Foppa, C; Borghi, V; Sabin, C.
abstract

Objectives: We analyzed clinical progression among persons diagnosed with HIV at the time of an AIDS-defining event, and assessed the impact on outcome of timing of combined antiretroviral treatment (cART).Methods: Retrospective, European and Canadian multicohort study. Patients were diagnosed with HIV from 1997–2004 and had clinical AIDS from 30 days before to 14 days after diagnosis. Clinical progression (new AIDS event, death) was described using Kaplan-Meier analysis stratifying by type of AIDS event. Factors associated with progression were identified with multivariable Cox regression. Progression rates were compared between those starting early (&lt;30 days after AIDS event) or deferred (30–270 days after AIDS event) cART.Results: The median (interquartile range) CD4 count and viral load (VL) at diagnosis of the 584 patients were 42 (16, 119) cells/µL and 5.2 (4.5, 5.7) log10 copies/mL. Clinical progression was observed in 165 (28.3%) patients. Older age, a higher VL at diagnosis, and a diagnosis of non-Hodgkin lymphoma (NHL) (vs. other AIDS events) were independently associated with disease progression. Of 366 patients with an opportunistic infection, 178 (48.6%) received early cART. There was no significant difference in clinical progression between those initiating cART early and those deferring treatment (adjusted hazard ratio 1.32 [95% confidence interval 0.87, 2.00], p=0.20).Conclusions: Older patients and patients with high VL or NHL at diagnosis had a worse outcome. Our data suggest that earlier initiation of cART may be beneficial among HIV-infected patients diagnosed with clinical AIDS in our setting.

2010 - Cytotoxic granule release dominates gag-specific CD4+ T-cell response in different phases of HIV infection. [Articolo su rivista]
Nemes, Elisa; Bertoncelli, Linda; Lugli, Enrico; Pinti, Marcello; Nasi, Milena; Manzini, Lisa; Manzini, Simona; Prati, Francesca; Borghi, V; Cossarizza, Andrea; Mussini, Cristina
abstract

BACKGROUND: The activity of virus-specific T lymphocytes, among which those capable of a polyfunctional response against the viral protein gag, is crucial to control HIV infection. OBJECTIVE: The objective of this study is to investigate the polyfunctionality of gag-specific T cells in different phases of HIV infection, analyzing markers related to T-helper cell 1 (Th1) and degranulation/cytotoxicity, and the production of Th1 cytokines in peripheral blood lymphocytes from patients experiencing an acute primary infection, long-term nonprogressors, patients naive for antiretroviral drugs, and patients taking HAART. MATERIALS AND METHODS: Cells were stimulated with a pool of gag-derived peptides or with a superantigen (staphylococcal enterotoxin B). Using eight-color polychromatic flow cytometry, we analyzed the expression of interleukin-2, interferon-gamma, CD154, and CD107a by CD4 and CD8 T cells. RESULTS: The main finding was that in all HIV-positive patients, about half gag-specific CD4 T cells were CD107a, that is, able to degranulate. CD4CD154 cells unable to produce Th1 cytokines were the second most represented population. Truly polyfunctional CD4 T cells were very rare and present only in a few long-term nonprogressors. Superantigen stimulation showed that CD4 T lymphocytes from all patients displayed a typical Th response, including interleukin-2 and interferon-gamma production, lacking CD107a expression. CONCLUSION: In all the aforementioned phases of HIV infection, the large majority of gag-specific CD4 T lymphocytes cannot be identified by the sole expression of interleukin-2 and interferon-gamma, which is early impaired. Degranulation and helper functions other than Th1 cytokine production are the predominant features of HIV-specific CD4 lymphocytes.

2010 - Death rates in HIV-positive antiretroviral-naive patients with CD4 count greater than 350 cells per μl in Europe and North America: A pooled cohort observational study [Articolo su rivista]
Lodwick, Rk; Sabin, Ca; Porter, K; Ledergerber, B; van Sighem, A; Cozzi Lepri, A; Khaykin, P; Mocroft, A; Jacobson, L; De Wit, S; Obel, N; Castagna, A; Wasmuth, Jc; Gill, J; Klein, Mb; Gange, S; Riera, M; Mussini, Cristina; Gutiérrez, F; Touloumi, G; Carrieri, P; Guest, Jl; Brockmeyer, Nh; Phillips, A. N.
abstract

BACKGROUND: Whether people living with HIV who have not received antiretroviral therapy (ART) and have high CD4 cell counts have higher mortality than the general population is unknown. We aimed to examine this by analysis of pooled data from industrialised countries.METHODS: We merged data on demographics, CD4 cell counts, viral-load measurements, hepatitis C co-infection status, smoking status, date of death, and whether death was AIDS-related or not from 23 European and North American cohorts. We calculated standardised mortality ratios (SMRs) standardised by age, sex, and year, stratifying by risk group. Data were included for patients aged 20-59 years who had at least one CD4 count greater than 350 cells per microL while ART naive. All pre-ART CD4 counts greater than 350 cells per microL from January, 1990, to December, 2004, were included. We investigated mortality for four risk groups--men who have sex with men, heterosexual people, injecting drug users, and those at other or unknown risk. The association between CD4 cell count and death rate was investigated by use of Poisson regression methods.FINDINGS: Data were analysed for 40,830 patients contributing 80,682 person-years of follow-up. Of 419 deaths, 401 were used in the SMR analysis: 100 men who have sex with men (SMR 1.30, 95% CI 1.06-1.58); 68 heterosexual people (2.94, 2.28-3.73); 203 injecting drug users (9.37, 8.13-10.75); and 30 in the other or unknown risk category (4.57, 3.09-6.53). Compared with CD4 counts of 350-499 cells per microL, death rate was lower in patients with counts of 500-699 cells per microL (adjusted rate ratio 0.77, 95% CI 0.61-0.95) and counts of 700 cells per microL (0.66, 0.52-0.85).INTERPRETATION: In HIV-infected ART-naive patients with high CD4 cell counts, death rates were raised compared with the general population. In men who have sex with men this was modest, suggesting that a substantial proportion of the increased risk in other groups is due to confounding by other factors. Even though the increased risk is small, new studies of potential benefits of ART in this group are merited.

2010 - Effects of selective decontamination of the digestive tract on Acinetobacter baumanii related ventilation acquired pneumonia: preliminary data [Abstract in Rivista]
Ferrari, E; Serio, L; Venturelli, C; Codeluppi, M; Righi, Elena; Mussini, Cristina; Marchegiano, P; Bosi, I; Girardis, Massimo
abstract

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2010 - Incidence of malignancies in HIV-infected patients and prognostic role of current CD4 cell count: evidence from a large Italian cohort study. [Articolo su rivista]
Prosperi, Mc; Cozzi Lepri, A; Castagna, A; Mussini, Cristina; Murri, R; Giacometti, A; Torti, C; Costantini, A; Narciso, P; Ghinelli, F; Antinori, A; d'Arminio Monforte, A.
abstract

The incidence of and predictors of acquired immunodeficiency syndrome-defining malignancies (ADMs) and non-ADM (NADMs) were evaluated in a large Italian cohort. The incidence of ADM and NADM was 5.0 cases per 1000 person-years of follow-up (95% confidence interval, 4.3-5.8 cases per 1000 person-years of follow-up) and 2.4 cases per 1000 person-years of follow-up (95% confidence interval, 1.9-3.1 cases per 1000 person-years of follow-up), respectively. Lower current CD4 cell count was an independent predictor of developing malignancies, with the association being stronger for ADM than for NADM.

2010 - Is it safe to discontinue primary Pneumocystis jiroveci pneumonia prophylaxis in patients with virologically suppressed HIV infection and a CD4 cell count <200 cells/microL? [Articolo su rivista]
Mocroft, A; Reiss, P; Kirk, O; Mussini, Cristina; Girardi, E; Morlat, P; Stephan, C; De Wit, S; Doerholt, K; Ghosn, J; Bucher, Hc; Lundgren, Jd; Chene, G; Miro, Jm; Furrer, H.
abstract

Background. Current guidelines suggest that primary prophylaxis for Pneumocystis jiroveci pneumonia (PcP) can be safely stopped in human immunodeficiency virus (HIV)-infected patients who are receiving combined antiretroviral therapy (cART) and who have a CD4 cell count >200 cells/µL. There are few data regarding the incidence of PcP or safety of stopping prophylaxis in virologically suppressed patients with CD4 cell counts of 101–200 cells/µL.Methods. The Opportunistic Infections Project Team of the Collaboration of Observational HIV Epidemiological Research in Europe (COHERE) included data from 23,412 patients from 12 European cohorts who started taking cART after 1997. Poisson regression was used to model incidence rate ratios (IRRs) of primary PcP.Results. There were 253 PcP cases during 107,016 person-years of follow-up (PYFU). Prophylaxis significantly reduced the incidence of PcP among patients with current CD4 cell counts ⩽100 cells/µL (adjusted IRR, 0.41; 95% confidence interval [CI], 0.27–0.60) but not significantly among those with current CD4 cell counts of 101– 200 cells/µL (adjusted IRR, 0.63; 95% CI, 0.34–1.17). The incidence of PcP among patients who had a current CD4 cell count of 100–200 cells/µL, who had a viral load <400 copies/mL, and who were receiving prophylaxis was 2.1 cases per 1000 PYFU (95% CI, 0.8–4.3 cases per 1000 PYFU; 7 events occurred during 3363 PYFU), whereas 1.2 cases per 1000 PYFU (95% CI, 0.2–4.5 cases per 1000 PYFU; 2 events occurred during 1614 PYFU) occurred among persons who were not receiving prophylaxis (adjusted IRR, 1.65; 95% CI, 0.33–8.15). Among patients who discontinued PcP prophylaxis after starting cART, the incidence of primary PcP was 0 cases per 1000 PYFU (95% CI, 0.0–2.7 cases per 1000 PYFU; 0 events occurred during 1363 PYFU) for patients who had a current CD4 cell count of 101–200 cells/mL and who were receiving cART.Conclusions. The incidence of primary PcP among patients who had virologically suppressed HIV infection, were receiving cART, and who had CD4 cell counts >100 cells/µL was low irrespective of prophylaxis use. Discontinuation of prophylaxis may be safe in patients with CD4 counts of 101–200 cells/μL and suppressed viral load.

2010 - Is there any potential for first-line etravirine use? Analysis from a large data set of antiretroviral therapy-naive HIV-infected patients undergoing resistance test. [Articolo su rivista]
Zaccarelli, M; Antinori, A; Cozzi Lepri, A; Mussini, Cristina; Palamara, G; Santoro, Mm; Spagnuolo, V; Monforte, A; Perno, Cf; Ceccherini Silberstein, F.
abstract

Analysis from a large data set of antiretroviral therapy-naive HIV-infected patients undergoing resistance test.

2010 - Mitochondrial changes during D-drug-containing once-daily therapy in HIV-positive treatment-naive patients. [Articolo su rivista]
Maggiolo, F.; Roat, Erika; Pinti, Marcello; Nasi, Milena; Gibellini, Lara; DE BIASI, Sara; Airoldi, M.; Ravasio, V.; Mussini, Cristina; Suter, F.; Cossarizza, Andrea
abstract

BACKGROUND: Antiviral drugs of the category of nucleoside reverse transcriptase inhibitors (NRTIs), largely used for the treatment of HIV infection, can have toxic effects on mitochondria. We performed a cross-sectional study on mitochondrial toxicity in a randomized group of patients belonging to a larger randomized study on different NRTI-based once-daily regimens by quantifying mitochondrial DNA (mtDNA), three different mitochondrial RNAs (mtRNAs) and functional parameters in highly purified peripheral CD4+ and CD8+ T-cells.METHODS: A total of 49 previously treatment-naive patients treated for a mean of 15 months with efavirenz plus didanosine plus lamivudine (group 1), or tenofovir disoproxil fumarate plus lamivudine (group 2), or didanosine plus abacavir (group 3) were considered. The groups were matched for sex, age, CDC classification, risk factor for HIV, nadir CD4+ T-cell count and baseline viral load. mtDNA and mtRNA were quantified by using real-time PCR assays.RESULTS: No patient showed any clinical symptom; however, the amount of mtDNA in CD4+ and CD8+ T-cells was significantly lower in groups 1 and 3; similarly, the expression of different mtRNAs in both CD4+ and CD8+ T-cells showed significant differences that were dependent upon the drug used. No differences were found in mitochondrial membrane potential and mitochondrial mass in peripheral lymphocytes. The amount of total HIV DNA in CD4+ T-cells did not differ among the groups, who displayed a similar immune reconstitution and control of the virus.CONCLUSIONS: An efficient didanosine-containing once-daily therapy can have more mitochondrial toxicity than regimens devoid of this drug.

2010 - One-pill once-a-day HAART: a simplification strategy that improves adherence and quality of life of HIV-infected subjects. [Articolo su rivista]
Airoldi, M; Zaccarelli, M; Bisi, L; Bini, T; Antinori, A; Mussini, Cristina; Bai, F; Orofino, G; Sighinolfi, L; Gori, A; Suter, F; Maggiolo, F.
abstract

OBJECTIVE: The aim of the ADONE (ADherence to ONE pill) study was to verify the effect of a reduced number of pills on adherence and quality of life (QoL) in HIV-infected patients on highly active antiretroviral therapy (HAART). DESIGN: Prospective, multicenter, study. METHODS: Patients chronically treated with emtricitabine (FTC) + tenofovir (TDF) + efavirenz (EFV) or lamivudine (3TC) +TDF +EFV and with a HIV-RNA &lt; 50 copies/mL were switched to the single-pill fixed-dose regimen (FDR) of FTC +TDF +EFV. Data were collected with SF-36 using visual analog scales. Results of the final (6 months) primary as-treated analysis are reported. RESULTS: 212 patients (77.4% males) of mean age 45.8 years were enrolled; 202 completed the study. One month post switch to FDR the adherence rate increased significantly to 96.1% from a baseline value of 93.8% (P &lt; 0.01). The increase was steadily maintained throughout the study (96.2% at 6 months). QoL improved over time from 68.8% to 72.7% (P = 0.042) as well, and was significantly associated with the perception of health status, presence of adverse events (AEs) and number of reported AEs (P &lt; 0.0001). QoL significantly influenced adherence (P &lt; 0.0001). During FDR use the mean CD4 count increased from 556 to 605 cells/muL (P &lt; 0.0001). At the end of follow-up 98% of patients maintained HIV-RNA level &lt; 50 copies/mL and 100% &lt;400 copies/mL. Four patients stopped therapy because they were lost to follow-up and 6 because of AEs (insomnia/nervousness 4, allergy 1, difficulties swallowing pills 1). CONCLUSION: By substituting a one-pill once-a-day HAART, we observed an improvement of both adherence and QoL while maintaining high virologic and immunologic efficacy. HAART simplicity is an added value that favors adherence and may improve long-term success.

2010 - Performance of genotypic tropism testing in clinical practice using the enhanced sensitivity version of Trofile as reference assay: results from the OSCAR Study Group. [Articolo su rivista]
Svicher, V; D'Arrigo, R; Alteri, C; Andreoni, M; Angarano, G; Antinori, A; Antonelli, G; Bagnarelli, P; Baldanti, F; Bertoli, A; Borderi, M; Boeri, E; Bonn, I; Bruzzone, B; Callegaro, Ap; Cammarota, R; Canducci, F; Ceccherini Silberstein, F; Clementi, M; Monforte, Ad; De Luca, A; Di Biagio, A; Di Gianbenedetto, S; Di Perri, G; Di Pietro, M; Fabeni, L; Fadda, G; Galli, M; Gennari, W; Ghisetti, V; Giacometti, A; Gori, A; Leoncini, F; Maggiolo, F; Maserati, R; Mazzotta, F; Micheli, V; Meini, G; Monno, L; Mussini, Cristina; Nozza, S; Paolucci, S; Parisi, S; Pecorari, M; Pizzi, D; Quirino, T; Re, Mc; Rizzardini, G; Santangelo, R; Soria, A; Stazi, F; Sterrantino, G; Turriziani, O; Viscoli, C; Vullo, V; Lazzarin, A; Perno, Cf; OSCAR Study, Group
abstract

OBJECTIVE: The DIVA study is aimed at setting up a standardized genotypic tropism-testing on proviral-DNA for the routine clinical diagnostic-laboratory. METHODS: Twelve local centres and 5 reference centres (previously cross-validated) were identified. For inter-center validation-procedure, 60 peripheral-blood mononuclear cells (PBMCs) aliquots from 45 HAART-treated patients were randomly chosen for population V3 sequencing on proviral-DNA at local HIV centre and at reference-laboratory. Viral tropism was predicted by Geno2Pheno algorithm (False Positive Rate [FPR] = 20%) as proposed by the European-Guidelines. Quantification of total HIV-1 DNA was based on a method described by Viard (2004). RESULTS: Quantification of HIV-1 DNA was available for 35/45 (77.8%) samples, and gave a median value of 598 (IQR:252- 1,203) copies/10 PBMCs. A total of 56/60 (93.3%) samples were successfully amplified by both the reference and the local virological centers. The overall concordance of tropism prediction between local and reference centers was 54/56 (96.4%). Results of tropism prediction by local centers were: 33/54 (61.1%) R5 and 21/54 (38.9%) X4/DM. CONCLUSION: There was high concordance in the genotypic tropism prediction based on proviral DNA among different virological centers throughout Italy. Our results are in line with other European studies, and support the use of genotypic tropism testing on proviral DNA in patients with suppressed plasma HIV-1 RNA candidate to CCR5-antagonist treatment.

2010 - Predicting the magnitude of short-term CD4+ T-cell recovery in HIV-infected patients during first-line highly active antiretroviral therapy. [Articolo su rivista]
Castagna, A; Galli, L; Torti, C; D'Arminio Monforte, A; Mussini, Cristina; Antinori, A; Cozzi Lepri, A; Ladisa, N; De Luca, A; Seminari, E; Gianotti, N; Lazzarin, A.
abstract

BACKGROUND: The extent of short-term CD4(+) T-cell recovery in patients tolerating first-line highly active antiretroviral therapy (HAART) and attaining undetectable HIV RNA levels is inadequately defined.METHODS:We retrospectively analysed patients in four Italian cohorts who started HAART between January 1996 and September 2006. All patients had known HCV coinfection status, did not modify the regimen for 6 months and had <50 HIV RNA copies/ml at the end of the sixth month.RESULTS:The analysis involved 1,488 patients (1,096 males, 73.7%) with a median age of 43 years (interquartile range [IQR] 39-49); 435 (29.2%) were positive for HCV, 71 (4.8%) were positive for hepatitis B surface antigen (HBsAg) and 76 (5.1%) had experienced a previous AIDS-defining event. At baseline, patient CD4(+) T-cell counts were 226 cells/microl (IQR 99-332), CD4(+) T-cell percentages were 14.7% (IQR 8.7-21.2) and HIV RNA levels were 4.91 log(10) copies/ml (IQR 4.38-5.34). Overall, 24-week CD4(+) T-cell recovery was 144 cells/microl (IQR 70-240). At multivariable analysis, T-cell recovery was positively related to the use of a boosted protease inhibitor (P<0.0001) or thymidine analogues (P<0.0001), baseline HIV RNA levels (P<0.0001), the baseline percentage of CD4(+) T-cells (P<0.0001) and the absence of HCV coinfection (P=0.006). Age, gender, baseline CD4(+)/CD8(+) T-cell ratio and a history of AIDS-defining events had no independent effect on CD4(+) T-cell recovery.CONCLUSIONS:Among HIV-infected patients tolerating first-line HAART and with undetectable HIV RNA after 6 months, CD4(+) T-cell recovery is significantly greater in those without HCV coinfection, with a high baseline viral load, a high baseline percentage of CD4(+) T-cells and in those treated with a boosted protease inhibitor.

2010 - Predictive Value of Intracellular HIV-1 DNA Levels During CD4-Guided Treatment Interruption in HIV(+) Patients [Articolo su rivista]
Nasi, Milena; Pinti, Marcello; Manzini, S; Gibellini, Lara; Manzini, Lisa; Bisi, Luca; DE BIASI, Sara; DEL GIOVANE, Cinzia; D'Amico, Roberto; Borghi, V; Mussini, Cristina; Cossarizza, Andrea
abstract

The amount of HIV-1 DNA within peripheral blood mononuclear cells is an important marker of viral activity. We studied intracellular HIV-1 DNA content in purified CD4(+) T cells from 28 chronically HIV-1-infected adults with sustained CD4(+) T cell counts (>500 cells/microl) and undetectable plasma viral load (<50 copies/ml), who underwent CD4-guided treatment interruption (TI). Patients were followed up for 18 months during TI, and for 6 months after treatment resumption (TR). Six naïve HIV(+) patients starting therapy were also enrolled and followed up for 6 months. All patients were studied every 2 months; HIV-1 DNA copy number was quantified with real-time PCR. Considering all patients remaining off-treatment, in the first 18 months of TI, intracellular HIV-1 DNA levels (expressed as Log(10) copies/million cells) remained stable (mean, 3.82 and 3.77 at time 0 and after 18 months, respectively). Similarly, HIV-1 DNA values, either in patients who restarted treatment after TI (time 0, 4.90) or in naïve patients who started treatment for the first time (time 0, 4.37), did not change significantly in the first 6 months of therapy (4.42 and 3.67, respectively). Evaluating HIV-1 DNA variations during the first 2 months of TI, we found that patients with a stable level had a lower risk to reach a CD4(+) T cell count <350 cells/microl, and thus to restart therapy, whereas this risk was significantly higher in those with a marked increase of HIV-1 DNA. In conclusion, intracellular HIV-1 DNA is a predictive marker for the length of CD4-guided TI.

2010 - Pretreatment CD4 cell slope and progression to AIDS or death in HIV-infected patients initiating antiretroviral therapy--the CASCADE collaboration: a collaboration of 23 cohort studies. [Articolo su rivista]
Wolbers, M; Babiker, A; Sabin, C; Young, J; Dorrucci, M; Chêne, G; Mussini, Cristina; Porter, K; Bucher, Hc
abstract

BackgroundCD4 cell count is a strong predictor of the subsequent risk of AIDS or death in HIV-infected patients initiating combination antiretroviral therapy (cART). It is not known whether the rate of CD4 cell decline prior to therapy is related to prognosis and should, therefore, influence the decision on when to initiate cART.Methods and FindingsWe carried out survival analyses of patients from the 23 cohorts of the CASCADE (Concerted Action on SeroConversion to AIDS and Death in Europe) collaboration with a known date of HIV seroconversion and with at least two CD4 measurements prior to initiating cART. For each patient, a pre-cART CD4 slope was estimated using a linear mixed effects model. Our primary outcome was time from initiating cART to a first new AIDS event or death. We included 2,820 treatment-naïve patients initiating cART with a median (interquartile range) pre-cART CD4 cell decline of 61 (46–81) cells/µl per year; 255 patients subsequently experienced a new AIDS event or death and 125 patients died. In an analysis adjusted for established risk factors, the hazard ratio for AIDS or death was 1.01 (95% confidence interval 0.97–1.04) for each 10 cells/µl per year reduction in pre-cART CD4 cell decline. There was also no association between pre-cART CD4 cell slope and survival. Alternative estimates of CD4 cell slope gave similar results. In 1,731 AIDS-free patients with &gt;350 CD4 cells/µl from the pre-cART era, the rate of CD4 cell decline was also not significantly associated with progression to AIDS or death (hazard ratio 0.99, 95% confidence interval 0.94–1.03, for each 10 cells/µl per year reduction in CD4 cell decline).ConclusionsThe CD4 cell slope does not improve the prediction of clinical outcome in patients with a CD4 cell count above 350 cells/µl. Knowledge of the current CD4 cell count is sufficient when deciding whether to initiate cART in asymptomatic patients.

2010 - T cell homeostasis in centenarians: from the thymus to the periphery. [Articolo su rivista]
Pinti, Marcello; Nasi, Milena; Lugli, Enrico; Gibellini, Lara; Bertoncelli, Linda; Roat, Erika; DE BIASI, Sara; Mussini, Cristina; Cossarizza, Andrea
abstract

The immune system undergoes a process of profound remodelling during aging, referred to as immunosenescence, and characterized by complex modifications of several components. In this review, we discuss recent developments and observations regarding the generation of T cells in the thymus during aging and longevity, and the regulation and maintenance of peripheral blood lymphocytes. The generation of new T cells is indeed crucial to maintain a functional immune system, and is a fundamental step to avoid unsuccessful aging, thus reaching longevity in good health. Mechanisms will be described that are related to the production and maintenance of those lymphocytes defined "recent thymic emigrants", and to the detection of the so called "T cell receptor rearrangement excision circles (TREC)", along with the presence in the periphery of naïve and memory T cells, that can be influenced and regulated by several different mechanisms. Several strategies aimed at improving thymic functionality are currently receiving a growing interest, and some of them are based on molecules that are produced by, and/or act on immune cells. Data on the possible use of these molecules, including cytokines like interleukin (IL)-7, IL-15 and keratinocyte growth factor, to restore thymic function are reviewed and discussed.

2010 - Therapeutic immunization with HIV-1 Tat reduces immune activation and loss of regulatory T-cells and improves immune function in subjects on HAART. [Articolo su rivista]
Ensoli, B; Bellino, S; Tripiciano, A; Longo, O; Francavilla, V; Marcotullio, S; Cafaro, A; Picconi, O; Paniccia, G; Scoglio, A; Arancio, A; Ariola, C; Ruiz Alvarez, Mj; Campagna, M; Scaramuzzi, D; Iori, C; Esposito, R; Mussini, Cristina; Ghinelli, F; Sighinolfi, L; Palamara, G; Latini, A; Angarano, G; Ladisa, N; Soscia, F; Mercurio, Vs; Lazzarin, A; Tambussi, G; Visintini, R; Mazzotta, F; Di Pietro, M; Galli, M; Rusconi, S; Carosi, G; Torti, C; Di Perri, G; Bonora, S; Ensoli, F; Garaci, E.
abstract

Although HAART suppresses HIV replication, it is often unable to restore immune homeostasis. Consequently, non-AIDS-defining diseases are increasingly seen in treated individuals. This is attributed to persistent virus expression in reservoirs and to cell activation. Of note, in CD4(+) T cells and monocyte-macrophages of virologically-suppressed individuals, there is continued expression of multi-spliced transcripts encoding HIV regulatory proteins. Among them, Tat is essential for virus gene expression and replication, either in primary infection or for virus reactivation during HAART, when Tat is expressed, released extracellularly and exerts, on both the virus and the immune system, effects that contribute to disease maintenance. Here we report results of an ad hoc exploratory interim analysis (up to 48 weeks) on 87 virologically-suppressed HAART-treated individuals enrolled in a phase II randomized open-label multicentric clinical trial of therapeutic immunization with Tat (ISS T-002). Eighty-eight virologically-suppressed HAART-treated individuals, enrolled in a parallel prospective observational study at the same sites (ISS OBS T-002), served for intergroup comparison. Immunization with Tat was safe, induced durable immune responses, and modified the pattern of CD4(+) and CD8(+) cellular activation (CD38 and HLA-DR) together with reduction of biochemical activation markers and persistent increases of regulatory T cells. This was accompanied by a progressive increment of CD4(+) T cells and B cells with reduction of CD8(+) T cells and NK cells, which were independent from the type of antiretroviral regimen. Increase in central and effector memory and reduction in terminally-differentiated effector memory CD4(+) and CD8(+) T cells were accompanied by increases of CD4(+) and CD8(+) T cell responses against Env and recall antigens. Of note, more immune-compromised individuals experienced greater therapeutic effects. In contrast, these changes were opposite, absent or partial in the OBS population. These findings support the use of Tat immunization to intensify HAART efficacy and to restore immune homeostasis. TRIAL REGISTRATION: ClinicalTrials.gov NCT00751595.

2010 - Transmitted HIV Type 1 drug resistance and Non-B subtypes prevalence among seroconverters and newly diagnosed patients from 1992 to 2005 in Italy. [Articolo su rivista]
Riva, C; Lai, A; Caramma, I; Corvasce, S; Violin, M; Dehò, L; Prati, F; Rossi, C; Colombo, Mc; Capetti, A; Franzetti, M; Rossini, V; Tambussi, G; Ciccozzi, M; Suligoi, B; Mussini, Cristina; Rezza, G; Balotta, C.
abstract

The patterns of transmitted drug-resistant (TDR) HIV-1 variants, non-B subtype spread, and epidemiological trends were evaluated either in seroconverters or in newly diagnosed individuals in Italy over a 13-year period. We analyzed 119 seroconverters, enrolled from 1992 to 2003 for the CASCADE study, and 271 newly diagnosed individuals of the SPREAD study (2002-2005), of whom 42 had a known seroconversion date. Overall, TDR was 15.1% in the CASCADE and 12.2% in the SPREAD study. In the 1992-2003 period, men having sex with men (MSMs) and heterosexuals (HEs) were 48.7% and 36.8%, respectively; TDR was found to be higher in MSMs compared to HEs (78.9% vs. 21%, p = 0.006). The same groups were 39.1% and 53.3% in the SPREAD study; however, no association was detected between modality of infection and TDR. Overall, 9.2% and 22.1% of individuals harbored a non-B clade virus in the CASCADE and SPREAD study, respectively. As evidence of onward transmission, 40% (24/60) of non-B variants were carried by European individuals in the latter study; among these patients the F1 subtype was highly prevalent (p = 0.00001). One of every eight patients who received a diagnosis of HIV-1 in recent years harbored a resistant variant, reinforcing the arguments for baseline resistance testing to customize first-line therapy in newly infected individuals. The spread of non-B clades may act as a dilution factor of TDR concealing the proportion of TDR in seroconverters and MSMs.

2010 - Triple-class virologic failure in HIV-infected patients undergoing antiretroviral therapy for up to 10 years. [Articolo su rivista]
Lodwick, R; Costagliola, D; Reiss, P; Torti, C; Teira, R; Dorrucci, M; Ledergerber, B; Mocroft, A; Podzamczer, D; Cozzi Lepri, A; Obel, N; Masquelier, B; Staszewski, S; García, F; De Wit, S; Castagna, A; Antinori, A; Judd, A; Ghosn, J; Touloumi, G; Mussini, Cristina; Duval, X; Ramos, J; Meyer, L; Warsawski, J; Thorne, C; Masip, J; Pérez Hoyos, S; Pillay, D; van Sighem, A; Lo Caputo, S; Günthard, H; Paredes, R; De Luca, A; Paraskevis, D; Fabre Colin, C; Kjaer, J; Chêne, G; Lundgren, Jd; Phillips, A. N.
abstract

BACKGROUND: Life expectancy of people with human immunodeficiency virus (HIV) is now estimated to approach that of the general population in some successfully treated subgroups. However, to attain these life expectancies, viral suppression must be maintained for decades.METHODS: We studied the rate of triple-class virologic failure (TCVF) in patients within the Collaboration of Observational HIV Epidemiological Research Europe (COHERE) who started antiretroviral therapy (ART) that included a nonnucleoside reverse-transcriptase inhibitor (NNRTI) or a ritonavir-boosted protease inhibitor (PI/r) from 1998 onwards. We also focused on TCVF in patients who started a PI/r-containing regimen after a first-line NNRTI-containing regimen failed.RESULTS: Of 45 937 patients followed up for a median (interquartile range) of 3.0 (1.5-5.0) years, 980 developed TCVF (2.1%). By 5 and 9 years after starting ART, an estimated 3.4% (95% confidence interval [CI], 3.1%-3.6%) and 8.6% (95% CI, 7.5%-9.8%) of patients, respectively, had developed TCVF. The incidence of TCVF rose during the first 3 to 4 years on ART but plateaued thereafter. There was no significant difference in the risk of TCVF according to whether the initial regimen was NNRTI or PI/r based (P = .11). By 5 years after starting a PI/r regimen as second-line therapy, 46% of patients had developed TCVF.CONCLUSIONS: The rate of virologic failure of the 3 original drug classes is low, but not negligible, and does not appear to diminish over time from starting ART. If this trend continues, many patients are likely to need newer drugs to maintain viral suppression. The rate of TCVF from the start of a PI/r regimen after NNRTI failure provides a comparator for studies of response to second-line regimens in resource-limited settings.

2010 - Upregulation of nuclear-encoded mitochondrial LON protease in HAART-treated HIV-positive patients with lipodystrophy: implications for the pathogenesis of the disease [Articolo su rivista]
Pinti, Marcello; Gibellini, Lara; Guaraldi, Giovanni; Orlando, Gabriella; Gant, Tw; Morselli, Eugenia; Nasi, Milena; Salomoni, Paolo; Mussini, Cristina; Cossarizza, Andrea
abstract

BACKGROUND: HAART can provoke metabolic changes and body fat redistribution, resulting in lipodystrophy, a side effect significantly involving mitochondrial function. Mitochondrial DNA (mtDNA) depletion caused by nucleosidic reverse transcription inhibitors is supposed to be a crucial mechanism in the pathogenesis of mitochondrial damages. METHODS: In adipose tissue from 22 HIV-positive patients with lipodystrophy and 20 healthy controls, we analyzed gene expression by microarray analysis and real-time PCR. The most upregulated gene was further studied in the human adipocytic cell line SW872 by real-time PCR, western blot, transient transfection assays and flow cytometry. RESULTS: We identified 18 genes differently expressed between lipodystrophy patients and controls, and focused our attention on the nuclear-encoded mitochondrial protease LON, essential in mtDNA maintenance. In SW872 cells, treatment with stavudine (d4T) doubled LON levels, in parallel with mtDNA depletion. As d4T increased reactive oxygen species (ROS) intracellular content, we measured LON in presence of deoxyribose, which causes oxidative stress but not mtDNA depletion, and observed LON upregulation. Ethidium bromide, which markedly depletes mtDNA, did not alter LON levels. The antioxidant glutathione inhibited the increase of intracellular ROS and the increase in LON caused by d4T or deoxyribose. CONCLUSION: LON upregulation was due to d4T-induced ROS production, rather than due to mtDNA depletion, and represents a response to an oxidative stress. Other mechanisms than mtDNA depletion thus exist that explain nucleosidic reverse transcription inhibitors toxicity. This observation provides a rationale for possible therapeutic interventions aimed at reducing intracellular ROS content in patients assuming HAART.

2009 - Common genetic variation and the control of HIV-1 in humans. [Articolo su rivista]
Fellay, J; Ge, D; Shianna, Kv; Colombo, S; Ledergerber, B; Cirulli, Et; Urban, Tj; Zhang, K; Gumbs, Ce; Smith, Jp; Castagna, A; Cozzi Lepri, A; De Luca, A; Easterbrook, P; Günthard, Hf; Mallal, S; Mussini, Cristina; Dalmau, J; Martinez Picado, J; Miro, Jm; Obel, N; Wolinsky, Sm; Martinson, Jj; Detels, R; Margolick, Jb; Jacobson, Lp; Descombes, P; Antonarakis, Se; Beckmann, Js; O'Brien, Sj; Letvin, Nl; Mcmichael, Aj; Haynes, Bf; Carrington, M; Feng, S; Telenti, A; Goldstein, Db; NIAID Center for HIV/AIDS Vaccine, Immunology
abstract

To extend the understanding of host genetic determinants of HIV-1 control, we performed a genome-wide association study in a cohort of 2,554 infected Caucasian subjects. The study was powered to detect common genetic variants explaining down to 1.3% of the variability in viral load at set point. We provide overwhelming confirmation of three associations previously reported in a genome-wide study and show further independent effects of both common and rare variants in the Major Histocompatibility Complex region (MHC). We also examined the polymorphisms reported in previous candidate gene studies and fail to support a role for any variant outside of the MHC or the chemokine receptor cluster on chromosome 3. In addition, we evaluated functional variants, copy-number polymorphisms, epistatic interactions, and biological pathways. This study thus represents a comprehensive assessment of common human genetic variation in HIV-1 control in Caucasians.

2009 - HIV-infected long-term nonprogressors display a unique correlative pattern between the interleukin-7/interleukin-7 receptor circuit and T-cell homeostasis [Articolo su rivista]
Marchetti, G; Riva, A; Cesari, M; Bellistrì, Gm; Gianelli, E; Casabianca, A; Orlandi, C; Magnani, M; Meroni, L; d'Arminio Monforte, A; Mussini, Cristina; Cossarizza, Andrea; Galli, M; Gori, A.
abstract

BACKGROUND:We hypothesized that there may be a correlation between the interleukin-7 (IL-7)/IL-7 receptor (IL-7R) regulatory system and parameters of T-cell homeostasis in HIV-infected long-term nonprogressors (LTNPs) as compared with patients with disease progression.METHODS:The possibility of a correlation between T-cell homeostatic parameters and IL-7/IL-7R was investigated in 22 LTNPs (CD4 count > or =500 cells/microL for >10 years) vs. HIV-positive patients at different disease stages [12 early: CD4 count > or =400 cells/microL ; 15 late (AIDS-presenters): CD4 count < or =150 cells/microL ].RESULTS:Compared with early-stage HIV-positive patients, LTNPs displayed a higher circulating IL-7 concentration (P=0.05), which was positively associated with higher IL-7Ralpha expression and a higher T-cell receptor excision circle (TREC) content specifically within CD4 cells (P<0.05). Compared with late-stage disease patients, early-stage disease patients displayed a lower IL-7 concentration (P<0.01) and higher percentages of IL-7Ralpha+ CD4 and CD8 cells (P=0.05). IL-7 was positively correlated with the percentage of TREC+ CD4 cells (P<0.01), which translated into a higher percentage of naïve CD4 cells in early-stage disease patients than in late-stage disease patients; however, the CD4 cells in early-stage disease patients were less enriched in recent thymic emigrants (RTEs) compared with LTNPs (P<0.05). In late-stage AIDS-developing patients, substantially increased IL-7 was correlated with a decreased percentage of IL-7Ralpha+ CD4 cells (P=0.01), which resulted in these patients having a significantly lower percentage of naïve T cells (P<0.01) and a significantly lower content of TREC (P<0.01) than the other patients.CONCLUSIONS:The maintenance of high CD4 cell counts in LTNPs was associated with a specific IL-7/IL-7R pattern characterized by increased IL-7 and highest IL-7Ralpha-expressing CD4 cells relative to other patients. Compared with patients with late-stage disease, LTNPs displayed a phenotypically naïve, less activated CD4 cell pool highly enriched in RTEs, suggesting the existence of a compensatory IL-7-mediated pathway specifically sustaining peripheral CD4 counts.

2009 - Italian consensus statement on management of HIV-infected individuals with advanced disease naïve to antiretroviral therapy. [Articolo su rivista]
Antinori, A; Ammassari, A; Torti, C; Marconi, P; Andreoni, M; Angarano, G; Bonora, S; Castagna, A; Cauda, R; Clerici, M; Monforte, A; De Luca, A; Di Perri, G; Galli, M; Girardi, E; Gori, A; Lazzarin, A; Lo Caputo, S; Mazzotta, F; Montella, F; Mussini, Cristina; Perno, Cf; Puoti, M; Rizzardini, G; Rusconi, S; Vullo, V; Carosi, G.
abstract

BACKGROUND: Individuals with advanced HIV infection naïve to antiretroviral therapy represent a special population of patients frequently encountered in clinical practice. They are at high risk of disease progression and death, and their viroimmunologic response following the initiation of highly active antiretroviral therapy may be more incomplete or slower than that of other patients. Infection management in such patients can also be complicated by underlying conditions, comorbidities, and the need for concomitant medications. AIM: To provide practical guidelines to those clinicians providing care to HIV-infected patients in terms of diagnostic assessment, monitoring, and treatment. CONCLUSIONS: The principals of antiretroviral treatment in asymptomatic naïve patients with advanced HIV infection are the same as those applicable to the general population with asymptomatic HIV infection. Naïve patients with advanced HIV infection and a history of AIDS-defining illnesses urgently need antiretroviral treatment, with the choice of antiretroviral regimen and timetable based on such factors as concomitant treatment and prophylaxis, drug interactions, and potential concomitant drug toxicity. Finally, an adequate counseling program - both before and after HIV-testing - that includes aspects other than treatment adherence monitoring is a crucial step in disease management.

2009 - Magnitude and Determinants of CD4 Recovery After HAART Resumption After 1 Cycle of Treatment Interruption [Articolo su rivista]
Mussini, Cristina; Touloumi, G; Bakoyannis, G; Sabin, C; Castagna, A; Sighinolfi, L; Erikson, Le; Bratt, G; Borghi, V; Lazzarin, A; Cossarizza, Andrea; Esposito, R.
abstract

OBJECTIVE:The extent of immune reconstitution following HAART resumption after 1 cycle of treatment interruption (TI) is not well known.METHODS:Multicenter retrospective analysis of patients who discontinued HAART with a CD4 &gt; 500 cells/microL. Cox proportional hazards models were used to identify prognostic factors for immunologic response after treatment resumption. CD4 trends were investigated using linear mixed models.RESULTS:One hundred and eighty-three individuals were included. Median CD4 at TI and at treatment restart were 748 and 459 cells/microL, respectively. Median time from TI to treatment restart was 5.52 months. Ninety percent of the patients reached an undetectable viral load. One hundred and twenty-five subjects experienced immunologic response; 66 patients reached their pre-TI CD4 levels. At 3, 6, 12, and 24 months after treatment restart, the median CD4 increase was 149, 153, 161, and 178 cells/microL, respectively. Subjects with less steep CD4 declines during TI tended to have a lower initial CD4 increase, as did those reinitiating HAART with viral loads &lt; 5000 copies/mL, whereas subjects who had experienced a virologic response to their initial HAART regimen had slower CD4 increases.CONCLUSIONS:Patients willing to discontinue treatment should be advised that immune reconstitution to pre-TI values is possible in fewer than 50% of patients at 2 years after treatment restart.

2009 - Performance of tests for latent tuberculosis in different groups of immunocompromised patients. [Articolo su rivista]
Richeldi, Luca; Losi, M; D'Amico, Roberto; Luppi, M; Ferrari, A; Mussini, Cristina; Codeluppi, M; Cocchi, S; Prati, F; Paci, V; Meacci, M; Meccugni, B; Rumpianesi, F; Roversi, P; Cerri, Stefania; Luppi, F; Ferrara, G; Latorre, I; Gerunda, Giorgio Enrico; Torelli, G; Esposito, R; Fabbri, Leonardo
abstract

BACKGROUND: Immunocompromised persons infected with Mycobacterium tuberculosis (MTB) have increased risk of tuberculosis (TB) reactivation, but their managementis hampered by the occurrence of false-negative results of the tuberculin skin test (TST). The T-cell interferon (IFN)-gamma release blood assays T-SPOT.TB(TS.TB) [Oxford Immunotec; Abingdon, UK] and QuantiFERON-TB Gold In-Tube (QFT-IT) [Cellestis Ltd; Carnegie, VIC, Australia] might improve diagnostic accuracy forlatent TB infection (LTBI) in high-risk persons, although their performance in different groups of immunocompromised patients is largely unknown.METHODS AND RESULTS: Over a 1-year period, we prospectively enrolled patients in three different immunosuppressed groups, as follows: 120 liver transplantation candidates (LTCs); 116 chronically HIV-infected persons; and 95 patients with hematologic malignancies (HMs). TST, TS.TB, and QFT-IT were simultaneouslyperformed, their results were compared, and intertest agreement was evaluated.Overall, TST provided fewer positive results (10.9%) than TS.TB (18.4%; p <0.001) and QFT-IT (15.1%; p = 0.033). Significantly fewer HIV-infected individuals had at least one positive test (9.5%) compared with LTCs (35.8%; p < 0.001) and patients with HMs (29.5%; p < 0.001). Diagnostic agreement between tests was moderate (kappa = 0.40 to 0.65) and decreased in the HIV-infected group when the results of the TS.TB were compared with either TST (kappa = 0.16) orQFT-IT (kappa = 0.19). Indeterminate blood test results due to low positive control values were significantly more frequent with QFT-IT (7.2%) than with TS.TB (0.6%; p < 0.001).CONCLUSIONS: Blood tests identified significantly more patients as being infected with MTB than TST, although diagnostic agreement varied across groups. Based onthese results, we recommend tailoring application of the new blood IFN-gamma assays for LTBI in different high-risk groups and advise caution in their current use in immunosuppressed patients.

2009 - Risk of developing specific AIDS-defining illnesses in patients coinfected with HIV and hepatitis C virus with or without liver cirrhosis. [Articolo su rivista]
d'Arminio Monforte, A; Cozzi Lepri, A; Castagna, A; Antinori, A; De Luca, A; Mussini, Cristina; Caputo, Sl; Arlotti, M; Magnani, G; Pellizzer, G; Maggiolo, F; Puoti, M.
abstract

BACKGROUND:There are few data concerning the risk of specific opportunistic diseases in patients with and without hepatitis C virus (HCV) infection. We evaluated the correlation between the occurrence of different AIDS-defining illnesses (ADIs) and chronic HCV infection or HCV-related liver cirrhosis in a large Italian cohort of human immunodeficiency virus (HIV)-infected subjects.METHODS:Subjects were stratified into 2 groups: patients without HCV coinfection and with persistently normal aminotransferase levels and patients with HCV coinfection. The patients with HCV coinfection were stratified according to the diagnosis of liver cirrhosis. The incidences of new ADIs were calculated as the number of events per 1000 person-years of follow-up. The rates in the 2 groups were compared using a Poisson regression model adjusted for potential confounders.RESULTS:We observed a total of 496 ADIs among 5397 patients with 25,105 person-years of follow-up (50% tested positive for HCV). HCV coinfection was associated with increased risk of developing an ADI (adjusted relative rate [ARR], 2.61; 95% confidence interval [CI], 1.88-3.61), specifically bacterial infection (ARR, 3.15; 95% CI, 1.76-5.67), HIV-related disease (ARR, 2.68; 95% CI, 1.03-6.97), and mycotic disease (ARR, 3.87; 95% CI, 2.28-6.59) but not non-Hodgkin lymphoma (ARR, 0.88; 95% CI, 0.22-3.48). The rate of mycotic infection, bacterial infection, toxoplasmosis, and HIV-related ADI among patients with cirrhosis were significantly higher than that among HIV-monoinfected patients, and the risk was greater than that estimated for HCV antibody-positive patients without cirrhosis.CONCLUSIONS:HIV-related bacterial and mycotic infections are strongly associated with positive HCV serostatus and HCV-related cirrhosis. Clinicians should take into account these data when making decisions on initiation of antiretroviral therapy for HCV-coinfected individuals.

2009 - Two different patterns of mutations are involved in the genotypic resistance score for atazanavir boosted versus unboosted by ritonavir in multiple failing patients. [Articolo su rivista]
Santoro, Mm; Bertoli, A; Lorenzini, P; Ceccherini Silberstein, F; Gianotti, N; Mussini, Cristina; Torti, C; Di Perri, G; Barbarini, G; Bini, T; Melzi, S; Caramello, P; Maserati, R; Narciso, P; Micheli, V; Antinori, A; Perno, Cf; CARe Study, Group
abstract

OBJECTIVES: The protease inhibitor atazanavir (ATV) can be used either boosted by ritonavir (ATV300/r) or unboosted (ATV400). To date, however, genotypic resistance scores (GRSs) have been developed only for boosted-ATV. We have determined GRS associated with virologic response (VR) for both ATV300/r and ATV400 in highly pre-treated HIV-1 infected patients. PATIENTS AND METHODS: We analyzed the results of genotypic tests available 0-3 months before the initiation of an ATV-containing regimen in 159 patients with HIV-RNA >or= 500 copies/ml (ATV300/r group: 74; ATV400 group: 85) who were enrolled in the CARe study through an Early Access Program. The impact of baseline protease mutations on VR (>or= 1 log(10)copies/ml HIV-RNA decrease at 12-24 weeks) was analyzed using Fisher's exact test. Mutated protease amino acid positions (MPP) with p < 0.20 were retained for further analysis. The GRSs were determined by a step-by-step analysis using the chi(2) test for trend. RESULTS: The GRSs for ATV300/r and ATV400 revealed differing sets of mutations. For ATV300/r, 12 MPPs (10C/I/V + 32I + 34Q + 46I/L + 53L + 54A/M/V + 82A/F/I/T + 84V + 90M - 15E/G/L/V - 69K/M/N/Q/R/T/Y - 72M/ T/V; p = 1.38 x 10(-9)) were the most strongly associated with VR (VR: 100%, 78.3%, 83.3%, 75% and 0% of patients with a score of -2/-1, 0, 1, 2, and >or= 3, respectively); the last three MPPs (I15/H69/I72) were associated with a better VR. For ATV400, nine MPPs (16E + 20I/M/R/T/V + 32I + 33F/I/V + 53L/Y + 64L/M/ V + 71I/T/V + 85V + 93L/M; p = 9.42 x 10(-8)) were most strongly associated with VR (VR: 83.3%, 66.7%, 5.9%, 0% of patients with 0, 1/2, 3, and >or= 4 MPP, respectively). Differences between GRSs for ATV300/r and ATV400 may be due to different ATV drug levels (boosted vs unboosted), favoring different pathways of escape from antiviral pressure. CONCLUSIONS: Both GRSs were independent predictors of response in a multivariable logistic regression model. Nevertheless, cross-validation of these GRSs on different patient databases is required before their implementation in clinical practice.

2008 - Changes in the incidence and predictors of human immunodeficiency virus-associated dementia in the era of highly active antiretroviral therapy. [Articolo su rivista]
Bhaskaran, K; Mussini, Cristina; Antinori, A; Walker, As; Dorrucci, M; Sabin, C; Phillips, A; Porter, K; Cascade, Collaboration
abstract

Objective: Though effective anti–human immunodeficiency virus (HIV) therapies are now available, they have variable pene- tration into the brain. We therefore aimed to assess changes over calendar time in the risk for HIV-associated dementia (HIV- D), and factors associated with HIV-D risk.Methods: Using Concerted Action on Seroconversion to AIDS and Death in Europe (CASCADE) data, we analyzed factors associated with time from HIV seroconversion to HIV-D using Cox models with time-updated covariates. The effect of duration of infection was explored using flexible parametric survival models.Results: 222 of 15,380 seroconverters developed HIV-D. The incidence per 1,000 person-years was 6.49 pre-1997 (before highly active antiretroviral therapy was available), declining to 0.66 by 2003 to 2006. Compared with most recent CD4 count 350 cells/mm3, the adjusted relative risk (95% confidence interval) of HIV-D was 3.47 (1.91–6.28), 10.19 (5.72–18.15), and 39.03 (22.96–66.36) at 200 to 349, 100 to 199, and 0 to 99 cells/mm3, respectively. In 2003 to 2006, older age at serocon- version (relative risk 3.24 per 10-year increase [95% confidence interval, 2.00–5.24]) and previous acquired immune defi- ciency syndrome diagnosis (relative risk 4.92 [95% confidence interval, 1.43–16.92]) were associated with HIV-D risk, independently of current CD4 count. HIV-D risk appeared to increase during chronic infection, by 48% at 10 years after seroconversion compared with the lowest risk at 1.8 years.Interpretation: HIV-D incidence has reduced markedly since 1997. However, patients with low (200 cells/mm3) or even intermediate (200–349 cells/mm3) CD4 counts, previous acquired immune deficiency syndrome diagnosis, longer HIV infection duration, and older age at seroconversion are at increased risk and should be closely monitored for neurocognitive disorders.

2008 - Effects of the change from Stavudine to tenofovir in human immunodeficiency virus-infected children treated with highly active antiretroviral therapy: studies on mitochondrial toxicity and thymic function. [Articolo su rivista]
Rosso, Sabina; Nasi, Milena; Di Biagio, A.; Repetto, E.; Dentone, C.; Pinti, Marcello; Nemes, Elisa; Ferraresi, Roberta; Mussini, Cristina; Esposito, Roberto; Viscoli, C.; Cossarizza, Andrea
abstract

BACKGROUND:Changing from drugs that have significant mitochondrial toxicity to less toxic compounds may be of benefit in human immunodeficiency virus (HIV)-positive patients who receive highly active antiretroviral therapy. Few data on mitochondrial toxicity of antiviral drugs are available in HIV-positive children. METHODS: Eighteen HIV-positive children (median age, 10.9 years) receiving a stavudine-containing regimen were randomized to maintain stavudine (arm A) or change to tenofovir (arm B), while preserving the remaining drugs. Glucose, lipidic, and viro-immunologic factors were assessed at months 0, 1, 3, 6, 12, and 18. Thymic output and mtDNA content were measured in peripheral blood mononuclear cells at 0 and 6 months, mtDNA in isolated CD4+ and CD8+ T cells after 18 months. RESULTS: From baseline to month 6, arms A and B showed similar thymic output and mtDNA. After 18 months, a significant decrease in plasma HDL was observed in arm B, along with a small increase in blood glucose; mtDNA showed no difference. In the 2 arms other factors did not show significant differences from the baseline and from the previous values at 18 months. CONCLUSIONS: Changing from stavudine to tenofovir was well-tolerated, and viro-immunologic success was maintained.

2008 - Genetic polymorphisms differently influencing the emergence of atrophy and fat accumulation in HIV-related lipodystrophy [Articolo su rivista]
Zanone Poma, B.; Riva, A.; Nasi, Milena; Cicconi, P.; Broggini, V.; Cozzi Lepri, A.; Mologni, D.; Mazzotta, F.; D’Arminio Monforte, A.; Mussini, Cristina; Cossarizza, Andrea; Galli, M.
abstract

Objective and design: The present study aims at evaluating the influence of geneticpolymorphisms on antiretroviral therapy (ART)-associated lipodystrophy. We includedin the study 255 ICoNA. patients and we assessed the distribution of Fas 670 AGpolymorphism, ApoC3 455 CT and 482 CT polymorphisms, C161T silent substitutionin the PPAR g gene, the Adrenergic b3 Receptor (ARb3) codon 64 TC variant, andtwo polymorphisms in the Adrenergic b2 Receptor (ARb2) codon 16 AG and codon 27CG. Crude rates of lipoatrophy and fat accumulation and adjusted relative rates werecalculated using Poisson regression.Results: In a multivariate model after adjusting for gender, HIV exposure, age, currentviral load, hepatitis C virus (HCV) serology, nucleoside reverse-transcriptase inhibitor(NRTI) pair/‘third drugs’ currently used, months of pre-highly active antiretroviraltherapy (HAART) exposures to NRTI, the following genotypes resulted protectiveagainst lipoatrophy: ApoC3 455 CC genotype [adjusted relative risks (ARR) 0.2,95% confidence interval (CI) 0.046–0.91 vs CT/TT, P¼0.037], ARb3 codon 64 TTgenotype (ARR 0.39, 95% CI 0.14–1.06 vs TC/CC, P¼0.066), and Fas 670 GGgenotype (ARR 0.51, 95% CI 0.26–1.01 vs AG/AA, P¼0.053). With regard to fataccumulation, in the multivariate model, the ARb2 codon 27 CC genotype resultedprotective (ARR 0.21, 95% CI 0.08–0.51 vs CG/GG, P¼0.0006), whereas the ARb2codon 16 AA genotype resulted associated with higher risk (ARR 3.72, 95% CI 1.58–8.76 vs AG/GG, P¼0.0026).Conclusion: Our study suggests that genetic polymorphisms of genes involved inapoptosis and adipocyte metabolism are significantly related to ART associated lipodystrophy.Particularly, we evidenced a role for ApoC3 455 in lipoatrophy and for thetwo variants of ARb2 in fat accumulation.

2008 - HIV coinfection and antiretroviral therapy enhances liver steatosis in patients with hepatitis C, but only in those infected by HCV genotype other than 3. [Articolo su rivista]
Borghi, V; Puoti, M; Mussini, Cristina; Bellelli, S; Angeletti, C; Sabbatini, Francesca; Prati, Francesca; Cossarizza, Andrea; Esposito, Roberto
abstract

Liver steatosis is a common finding in hepatitis C virus (HCV) infection and is associated with an increased progression of the disease. However, HCV genotype 3 steatosis presents a peculiar and virus-induced pathogenesis. We analysed the effect of HIV coinfection and antiretroviral therapy on hepatic steatosis and the effect of the steatosis on fibrosis in patients with or without HCV genotype 3 infection. METHODS: All consecutive HIV-infected and uninfected patients who had undergone a liver biopsy for evaluation of HCV infection at the Infectious Diseases Clinic (Modena, Italy) were included in this study. Primary outcomes were the presence or absence of steatosis or the presence of moderate or advanced fibrosis. RESULTS: A total of 284 patients were enrolled: 187 infected by HCV and 97 coinfected with HIV and HCV. In HCV genotype 3 patients, only HCV-related variables, such as plasma HCV RNA levels (odds ratio [OR] per log10 1.68, P < 0.001) and estimated duration of HCV infection (OR per year 1.17, P = 0.004) were associated with steatosis. In patients infected with other HCV genotypes, steatosis was associated with older age (OR per 5 years 1.47, P < 0.001), with exposure to d-drugs in HIV-HCV-coinfected patients (OR 2.60, P = 0.04) and specifically exposure to stavudine (OR 2.76 HIV-HCV-coinfected versus not HIV-infected patients, P = 0.04). Steatosis was independently associated with bridging fibrosis only in patients infected by HCV genotype other than 3 (OR 4.03, P = 0.01). CONCLUSIONS: Hepatic steatosis, in both HCV-monoinfected and in HIV-HCV-coinfected patients, is strongly correlated with HCV genotype 3, probably through interactions between HCV virus and liver cells. HIV-related increase of steatosis in patients with HCV is probably related to antiretroviral drugs, especially stavudine, in patients infected by HCV genotype other than 3.

2008 - Late presenters in an HIV surveillance system in Italy during the period 1992-2006. [Articolo su rivista]
Borghi, V.; Girardi, E.; Bellelli, S.; Angeletti, C.; Mussini, Cristina; Porter, K.; Esposito, Roberto
abstract

Objectives: The objectives of this study are to describe trends over time from 1992 to 2006 in the number of newly diagnosed HIV-infected individuals in Modena (Italy) and to describe their clinical and immunological characteristics. We also identify risk factors associated with presenting at late stages of HIV disease.Methods: All new HIV diagnoses with at least 1 CD4+ cell count and known stage of HIV disease were included. Using multivariate logistic regression models, we examined factors associated with being a late presenter, defined as individuals presenting with CD4+ cell count <200 cells per microliter or AIDS within 3 months of their HIV-positive test. A quantile regression model was used to examine changes in CD4+ cell count at presentation and trends over time.Results: Of 844 newly diagnosed individuals included in analyses, 332 (39%) were late presenters, and this proportion remained constant over time (P = 0.106). Older age, male sex, and foreign born were the only determinants of being a late presenter. Persons newly diagnosed in 2002-2006 were less likely to present with an advanced clinical status.Discussion: A substantial proportion of new HIV diagnoses are still at advanced stages of disease. In particular, foreign-born and heterosexual males still represent the largest part of AIDS presenters. Efforts are needed to encourage HIV testing and reduce the proportion who first seek HIV care at such a late stage.

2008 - Mitochondrial DNA Haplogroups and Highly Active Antiretroviral Therapy–Related Lipodystrophy [Articolo su rivista]
Nasi, Milena; Guaraldi, Giovanni; Gabriella, Orlando; Caterina, Durante; Pinti, Marcello; Elisa, Nemes; Nardini, Giulia; Giuseppe, Passarino; Cocchi, Marina; Esposito, Roberto; Mussini, Cristina; Cossarizza, Andrea
abstract

Background. The combination of different point mutations in mitochondrial DNA (mtDNA), which are defined as haplogroups, may cause modification in organelle function and may be involved in several pathologies. We analyzed the distribution of mtDNA polymorphisms in human immunodeficiency virus (HIV)–infected patients with lipodystrophy, a relevant adverse event caused by highly active antiretroviral therapy, and their correlation with metabolic and viroimmunologic parameters. Methods. The frequency of the 9 most common European haplogroups was investigated in 346 white, HIV- infected patients with lipodystrophy. Haplogroups were identified on the basis of classic methods. Statistical analysis was performed with use of 1-way analysis of variance, the x2 test, and principal-components analysis. Results. The distribution of mtDNA haplogroups among patients with lipodystrophy was similar to that among the general European population. We found no differences between patients with different haplogroups with regard to viroimmunologic results (plasma HIV load, CD4+ T cell count, and nadir CD4+ T cell count), glucose data (glucose, insulin, C-peptide, and glycosylated hemoglobin concentrations and insulin resistance), lipid data (levels of triglycerides, total cholesterol, high- and low-density lipoproteins, and apolipoprotein A1 and B), acid-base balance parameters (lactate level and anion gap), or anthropometric measures (weight, body mass index, and waist- to-hip ratio). No differences were observed in trunk fat levels, leg-fat ratio (which was determined by dual-energy X-ray absorptiometry), or exposure to different drug classes. Principal-components analysis confirmed that the spatial distribution of patients belonging to a given haplogroup was not influenced by different clinical parameters. Conclusions. Our study indicates that, in HIV-infected patients with lipodystrophy, mtDNA haplogroups are not related to major metabolic changes or to particular viroimmunologic features.

2008 - Patients presenting with AIDS in the HAART era: a collaborative cohort analysis. [Articolo su rivista]
Mussini, Cristina; Manzardo, C; Johnson, M; Monforte, A; Uberti Foppa, C; Antinori, A; Gill, Mj; Sighinolfi, L; Borghi, V; Lazzarin, A; Miró, Jm; Sabin, C; Late Presenter, Investigators
abstract

OBJECTIVE: Many patients infected with HIV still present with an AIDS diagnosis. The aim of this study was to evaluate the virological, immunological and clinical outcomes of HAART in these patients. DESIGN: The present study was a multi-cohort study. All patients with an AIDS diagnosis between 30 days before and 14 days after HIV diagnosis, recruited between 1997 and 2004 from eight hospital cohorts, were evaluated. RESULTS: A total of 760 patients were included [268 (35.3%) had pneumocystis and 168 (22.1%) tuberculosis]. Six hundred and twenty-four patients (82.1%) started HAART a median of 31 days after HIV diagnosis. One hundred and fifty-three patients started a nonnucleoside transcriptase inhibitor-based regimen (20.1%), 409 a protease inhibitor-based regimen (53.8%) and 62 other regimens (8.2%). In adjusted analyses, HAART was started sooner in more recent years, in patients with lower CD4 cell count and in those with Kaposi's sarcoma, whereas it was started later in those with tuberculosis. Five hundred and five patients (89%) attained a viral load of less than 500 copies/ml. The factors associated with a better virological response were later calendar year, lower initial viral load and cytomegalovirus disease. Virological rebound was more common in those receiving nucleoside reverse transcriptase inhibitor-based regimens, in those with tuberculosis and in earlier calendar years. One hundred and twenty-five (16%) patients died; 61 had received HAART (48.6%). Mortality was more likely in those who were older, those with a higher viral load at diagnosis, those with nonsexual HIV risks and those with lower CD4 cell count and haemoglobin levels over follow-up. CONCLUSION: Virological suppression was achieved in most AIDS patients, though mortality remains high in these individuals.

2007 - Bloodstream infections complicating orthotopic liver transplant: comparison between the recipients from cadaver and living donors [Abstract in Rivista]
A., Bedini; C., Venturelli; M., Codeluppi; S., Cocchi; F., Prati; DI BENEDETTO, Fabrizio; Masetti, Michele; Mussini, Cristina; Guaraldi, Giovanni; V., Borghi; F., Rumpianesi; Gerunda, Giorgio Enrico; R., Esposito
abstract

We evaluated the incidence, the prevalence of the microorganisms isolated and the impact on the survival of the bloodstream infections in two groups of patients: recipients of orthotopic liver transplant from cadaveric donor and from living donor.

2007 - Congenital pyelectasis in children born from mothers on tenofovir containing therapy during pregnancy: report of two cases. [Articolo su rivista]
Sabbatini, F.; Prati, F.; Borghi, V.; Bedini, A.; Esposito, Roberto; Mussini, Cristina
abstract

Given the success of highly active antiretroviral therapy in slowing HIV disease progression, an increasing proportion of HIV-infected women are choosing to become pregnant. Antiretroviral treatment decisions in these women must consider not only the immunological and virological efficacy of different drugs, but also their possible effects on the unborn baby. At present, data concerning the teratogenicity of more recent drugs are lacking. Tenofovir disoproxil fumarate, a nucleotide reverse transcriptase inhibitor, is widely used in patients pre-exposed to other nucleoside analogues because of its efficacy and tolerability. The routine use of prenatal ultrasonography has improved early identification of birth defects. Fetal urinary tract bnormalities are among the most commonly diagnosed prenatal malformations, with a reported prevalence as high as 1 per 100 pregnancies. Pyelectasis is defined as a renal pelvic dilatation, and is one of the most commonly founded urologic anomalies. The aim of this present communication is to describe a possible association between in utero tenofovir exposure and this renal congenital malformation.

2007 - Differential course of HIV-1 infection and apolipoprotein E polymorphism [Articolo su rivista]
Corder, E. H.; Galeazzi, L.; Franceschi, C.; Cossarizza, A.; Paganelli, R.; Pinti, M.; Mussini, C.; Borghi, V.; Pinter, E.; De Cristofaro, R.; Galeazzi, R.; Perini, M.; Aiuti, F.; Giunta, S.
abstract

We studied the course of infection with human immunodeficiency virus type 1 (HIV-1) in relation to apolipoprotein E (APOE) polymorphism found for 209 Italians treated at Infectious Disease Clinics in Rome and Modena. Clinically, patients were classified into four groups according to the yearly rate of decline in CD4+ cell count (LTNP: long-term non-progression; SLOW, 'NORMAL' or RAPID). Patients at both extremes of the clinical spectrum, i.e. those who rapidly progressed to AIDS and those with stable high CD4 cell counts, had few APOE ε4 and ε2 alleles (P = 0.04). Detailed clinical information was then used to construct four model-based clinical profiles using grade-of-membership analysis (GoM), predictive of APOE genotypic frequencies: 1. The clinical profile associated with good long-term prognosis lacked ε2 (P=0.01); 2. Disease progression to AIDS was associated with ε4 and ε2, most evident for zidovudine-lamivudine regimens without a protease inhibitor (P = 0.03); and, 3. AIDS patients had low ε4 and ε2 frequencies, consistent with a high mortality rate among ε4+ and ε2+ AIDS patients. These findings suggest allele-specific immunomodulatory effects involving inherited APOE isoform important enough to alter the clinical course of HIV infection and, possibly, drug efficacy. They imply a connection between lipid metabolism and immunity potentially relevant to common disorders. © 2007 Versita Warsaw and Springer-Verlag.

2007 - Gram-positive bloodstream infections in liver transplant recipients: incidence, risk factors, and impact on survival. [Articolo su rivista]
A., Bedini; M., Codeluppi; S., Cocchi; Guaraldi, Giovanni; DI BENEDETTO, Fabrizio; C., Venturelli; Masetti, Michele; F., Prati; Mussini, Cristina; V., Borghi; Girardis, Massimo; Gerunda, Giorgio Enrico; F., Rumpianesi; Esposito, Roberto
abstract

The objective of the study was to assess the incidence, risk factors, and survival of gram-positive bloodstream infections (GP-BSIs) among liver transplant recipients during the first year after transplantation. Between October 2000 and September 2006, 42 episodes of GP-BSIs occurred in 205 patients with an overall incidence of 0.20 episodes/patient. Coagulase-negative staphylococci were detected in 45.2% of cases, Enterococcus species in 42.9% (E faecalis, eight; E faecium, seven; E avium, two; E gallinarum, one) and Staphylococcus aureus in 11.9%. Retransplantation was the only independent risk factor for GP-BSI (odds ratio [OR], 0.253; 95% confidence interval (CI), 0.089 to 0.715; P = .009). Thirty-day mortality rate was 28.5% and S aureus infections were related to a poorer outcome. It is noteworthy that all the isolates of S aureus were methicillin-resistant. Ampicillin was inactive against all the strains of E faecium and 50% of E avium isolates, but active against all E faecalis and E gallinarum strains. All the isolates were glycopeptide-susceptible. No significant differences in mortality rate were observed in relation to sex, etiologies of end-stage liver disease, cytomegalovirus infection/reinfection, type of donor, rejection, or retransplantation. GP-BSI, the only independent risk factor for death (OR, 0.262; 95% CI, 0.106 to 0.643; P = .003), reduced the survival rate by 26% in the first year posttransplant. In conclusion, GP-BSIs impact significantly on morbidity and mortality posttransplant, particularly among retransplantations. Control measures are required to reduce the incidence of GP-BSIs in liver transplant recipients. These findings must be considered when empirical antimicrobial therapy is indicated while awaiting blood-culture results.

2007 - Identification and characterization of an aspartyl protease from Cryptococcus neoformans [Articolo su rivista]
Pinti, Marcello; Orsi, Carlotta Francesca; Gibellini, Lara; Esposito, Roberto; Cossarizza, Andrea; Blasi, Elisabetta; Peppoloni, Samuele; Mussini, Cristina
abstract

Abstract Cryptococcosis, caused by Cryptococcus neoformans, is an invasive infection often occurring in AIDS patients. Potent therapy against HIV, which includes protease inhibitors (PIs), has beneficial effects also on opportunistic infections by pathogens such as C. neoformans and C. albicans. PIs inhibit growth of C. albicans by affecting the activity of its aspartyl proteases. We identified, cloned and sequenced a cDNA from C. neoformans encoding for a putative aspartyl protease (CnAP1), and the corresponding genomic region. The gene cnap1 codifies for a protein of 505 aa, with a canonical aspartyl protease structure. We purified the recombinant protein and analyzed its activity in the presence of PIs (Indinavir, Lopinavir, Ritonavir), but did not evidence any inhibition of protease activity. The transcriptional level of cnap1 in C. neoformans is constant in different media. The absence of any inhibition activity by PIs suggests that other targets for PIs might exist in C. neoformans.

2007 - Observational study on HIV-infected subjects failing HAART receiving tenofovir plus didanosine as NRTI backbone. [Articolo su rivista]
Bongiovanni, M; Gianotti, N; Chiesa, E; Nasta, P; Cicconi, P; Capetti, A; di Biagio, A; Matti, A; Tirelli, V; Marconi, P; de Luca, A; Mussini, Cristina; Gatti, F; Zaccarelli, M; Abeli, C; Torti, C; Antinori, A; Castagna, A; d'Arminio Monforte, A.
abstract

We evaluated the efficacy of tenofovir (TDF) - and didanosine (ddI)-containing backbones in HIV-infected experienced subjects. We included in the study 245 subjects who started a TDF/ddI-containing HAART with HIV-RNA > 3 log(10) cp/ml and an available genotypic resistance test at baseline. At baseline, median CD4 counts and HIV-RNA were 278 cell/mmc and 4.32 log(10) cp/ml, respectively. Seventy-four subjects (30.2%) discontinued TDF and/or ddI, 23 of them for drug-related toxicities or intolerance. One-hundred and twenty-six (51.4%) subjects achieved virologic success (HIV-RNA < 50 copies/ml in two consecutive determinations) in a median time of 6.1 months; higher HIV-RNA levels (HR: 0.66, 95% CI: 0.54- 0.79, p < 0.001 for each additional log(10) copies/ml), and the total number of mutations either for PI and NNRTI at baseline (HR: 0.87, 95% CI: 0.81-0.92, p < 0.001 for each additional mutation) were both predictors of virologic success. M184V was marginally associated with virologic success (HR: 1.34, 95% CI: 0.94-1.90, p = 0.10 vs no M184V), whilst the number of TAMs was not associated. One-hundred-thirty-three (54.3%) subjects achieved immunologic success (increase of > or = 100 cells/mm(3) from baseline) in a median time of 7.5 months; immunologic success was associated with HIV-RNA levels at baseline (HR: 0.91, 95% CI: 0.79-0.98, p = 0.04 for each additional log(10) copies/ml), the total number of mutations either for PI or NNRTI (HR: 0.91, 95% CI: 0.85-0.98, p = 0.01 for each additional mutation) and CD4 count at baseline (HR: 1.11, 95% CI: 1.00-1.23, p = 0.05 for each additional 100 cells/mm(3)). Results obtained by the on-treatment analyses were comparable. In our study, HAART containing TDF/ddI seem associated with a virologic and immunologic response, when such regimens are chosen according to a genotypic resistance test.

2007 - Virological response to salvage therapy in HIV-infected persons carrying the reverse transcriptase K65R mutation. [Articolo su rivista]
Antinori, A; Trotta, Mp; Lorenzini, P; Torti, C; Gianotti, N; Maggiolo, F; Ceccherini Silberstein, F; Nasto, P; Castagna, A; De Luca, A; Mussini, Cristina; Andreoni, M; Perno, Cf; GNOMO Study, Group
abstract

BACKGROUND: The effect of the HIV reverse transcriptase K65R mutation on virological response to salvage therapy has not been clearly defined. METHODS: From six Italian clinical centres, all consecutive patients starting salvage antiretroviral therapy after virological failure in the presence of the K65R mutation identified by a genotypic resistance test were selected. RESULTS: Among 145 subjects included over a 197 person-year follow-up, the estimated probability of virological response (VR, defined as reaching HIV RNA < 50 copies/ml after salvage therapy) at 24 and 48 weeks was 36% and 60%, respectively. The strongest independent predictor of VR was the inclusion of a thymidine analogue (TA) in the salvage regimen. The presence of M184V and the introduction of lopinavir/ritonavir as new drug were both marginally associated with better outcome. After 24 weeks of salvage therapy, the median reduction in HIV-1 RNA was -1.36 log10 copies/ml (interquartile range [IQR] 0.10-2.46): at multivariable regression analysis, salvage regimens containing a TA (beta = +0.80; P = 0.02) and lamivudine (beta = +1.21; P = 0.02) as new drug had a positive effect on the reduction of HIV-1 RNA. CONCLUSIONS: Development of the K65R mutation does not preclude a high rate of virological response to rescue therapy. Inclusion of a TA in the salvage regimen and the presence of a M184V mutation could have a favourable effect on virological outcome.

2006 - Access to gynecological services and Papanicolau tests in HIV-infected Italian women: a questionnaire survey. [Articolo su rivista]
Murri, R; Franceschi, S; Ravizza, M; Fiore, S; Bini, T; Mussini, Cristina; Fasolo, M; Liuzzi, G; Ippolito, G; D'Arminio Monforte, A.
abstract

The objective of the study was to evaluate the access to Papanicolau (Pap) tests of HIV-infected women in Italy. A cross-sectional survey on a cohort of HIV-infected women seen at 27 HIV clinics was performed. At each clinic a female physician involved in the care of HIV-infected women was asked questions on clinic and patients' characteristics and on access to Pap tests. The outcome of the study was to find the percentage of women who had not had a Pap test before coming to the HIV clinic and the percentage having had a Pap test in 2001. In the survey, 7,600 HIV-infected women were represented. Women who came to the clinic without having ever had a Pap test were 62+/-22%, while women who had had a Pap test in 2001 were 43+/-36%. Women who reported never having had a Pap test before coming to the HIV clinic were more often from the south than the north of Italy (17.9+/-49% from the north, 18+/-53% from the center and 9.3+/-83.9% from the south; p<0.001). This a difference disappeared when comparing the women who had had a Pap test in 2001 (28+/-39.6% from the north, 31.6+/-44.2% from the center and 25.6+/-45.7% from the south; p=0.88). Despite the published guidelines in Italy, only 38% of women had ever had a Pap test before coming to the HIV clinic and only 43% had had a Pap test in 2001. Strategies aimed to improve these proportions should be rapidly implemented at all levels of care organization.

2006 - Baseline HIV RNA and the when to start question: time to stop asking this question? [Articolo su rivista]
Mussini, Cristina
abstract

Editorial comment on when to start antiretroviral therapy

2006 - Bloodstream infections (BSIs) in Liver Transplant Recipients: Analisys at an Italian Tertiary-Care Hospital [Abstract in Atti di Convegno]
Bedini, A.; Cocchi, S.; DI BENEDETTO, Fabrizio; Codeluppi, M.; Guaraldi, Giovanni; Venturelli, C.; Mussini, Cristina; Prati, F.; Masetti, M.; Rumpianesi, F.; Gerunda, Giorgio Enrico; Esposito, Roberto
abstract

After liver transplantation, bacteriemia has been documented in 24% to 35%.We evaluated the incidence of BSIs and the impact on the survival in 205 consecutive liver-transplant recipients at the University Hospital of Modena-Italy

2006 - Epidemiology of candidaemia and antifungal susceptibility patterns in an Italian tertiary-care hospital [Articolo su rivista]
A., Bedini; C., Venturelli; Mussini, Cristina; Guaraldi, Giovanni; M., Codeluppi; V., Borghi; F., Rumpianesi; F., Barchiesi; Esposito, Roberto
abstract

The epidemiological and antifungal susceptibility data for 94 episodes of candidaemia in an Italian tertiary-care hospital between January 2000 and August 2003 were evaluated by prospective laboratory-based surveillance. The incidence of fungaemia was 0.90 episodes/10 000 patient-days, and the most common species isolated were Candida albicans (40.4%), Candida parapsilosis (22.3%), Candida tropicalis (16.0%) and Candida glabrata (12.8%). Among 24 patients who received antifungal prophylaxis, non-albicans Candida spp. were more prevalent than C. albicans (p 0.012). The 30-day mortality rate was high (38.2%), particularly for haematological (71.4%) and solid-organ transplant patients (50.0%), and in individuals with C. tropicalis and C. glabrata bloodstream infections (60.0% and 50.0%, respectively). In-vitro susceptibility tests demonstrated that 95% of the isolates were susceptible to amphotericin B (MIC < 2 mg/L), 98.1% to posaconazole (MIC < 1 mg/L), 95.8% to flucytosine (MIC < 32 mg/L) and fluconazole (MIC < 64 mg/L), and 94.7% to itraconazole (MIC < 1 mg/L). Posaconazole was active (MIC 0.5 mg/L) against all three isolates of Candida krusei, which had reduced susceptibility to both fluconazole and itraconazole. Overall, non-albicans Candida spp. accounted for 60% of the episodes of candidaemia, which could be related to the use of antifungal prophylaxis. Resistance is still uncommon in Candida spp. recovered from blood cultures. The in-vitro activity of posaconazole is encouraging, and this agent could play an important role in the management of invasive candidiasis, including episodes caused by inherently less susceptible species such as C. krusei.

2006 - Immunophenotype of HIV plus patients during CD4 cell-monitored treatment interruption: role of the IL-7/IL-7 receptor system [Articolo su rivista]
Nemes, E.; Lugli, E.; Nasi, M.; Ferraresi, R.; Pinti, M.; Bugarini, R.; Borghi, V.; Prati, F.; Esposito, R.; Cossarizza, A.; Mussini, C.
abstract

Objective: To investigate immunological changes during CD4-guided therapy interruption in HIV+ patients who suspended HAART. Patients: Seventeen patients aged &gt; 18 years, who had received HAART for at least 12 months, and had a pre-interruption CD4+ cell count &gt; 500 cells/mu d, interrupted treatment. Median nadir CD4+ cell count was 288 cells/mu l. HIV plasma viral load at discontinuation was &lt; 50 or &gt; 50 copies/ml. Criteria for restarting treatment were: a CD4+ T-lymphocyte count &lt; 350 cells/ d on two separate occasions, a clinical manifestation of AIDS, and the patient's desire to resume HAART. Eleven patients were still off therapy after 12 months (group A); according to the first criterion, six patients restarted therapy within 12 months (group B). Methods: Haernatological, viro-immunological, cytofluorimetic and molecular assays were performed at baseline and every 2 months following standard methods. Statistical analysis was performed under Stata 7.0. Results: In the first 2 months of treatment interruption, a significant increase in viral load and CD8+ lymphocyte activation occurred. Then such parameters decreased and remained stable. In all patients, a decrease in CD4+ lymphocytes took place as well, that affected in a similar manner naive, central memory, effector memory and terminally differentiated cells. Group B always presented lower amounts of CD4+ effector memory lymphocytes. The expression of CD`127 was always higher in group A. Conclusions: The loss of CD4+ lymphocytes upon viral rebound is equal among naive and memory subsets. Patients with higher expression of CD127, who are likely to exert a better capacity to utilize endogenous interleukin-7 by T cells, could remain off therapy for longer periods. (c) 2006 Lippincott Williams &amp; Wilkins

2006 - Impact of lamivudine on the risk of liver-related death in 2,041 HBsAg- and HIV-positive individuals: results from an inter-cohort analysis. [Articolo su rivista]
Puoti, M; Cozzi Lepri, A; Paraninfo, G; Arici, C; Moller, Nf; Lundgren, Jd; Ledergerber, B; Rickenbach, M; Suarez Lozano, I; Garrido, M; Dabis, F; Winnock, M; Milazzo, L; Gervais, A; Raffi, F; Gill, J; Rockstroh, J; Ourishi, N; Mussini, Cristina; Castagna, A; De Luca, A; Monforte, A; HBV HIV International Intercohort Study, Group
abstract

BACKGROUND: The impact of lamivudine (3TC) as part of combination antiretroviral therapy (cART) on the risk of liver-related death (LRD) in HIV/hepatitis B virus (HBV)-coinfected patients has not been extensively studied. METHODS: We performed an analysis involving HIV/HBV-coinfected patients in 13 cohorts who initiated cART. The end-point was LRD--that is, death with concomitant decompensated liver disease (DLD) or hepatocellular carcinoma--as the main cause. Incidence rates of LRD after initiation of cART were expressed as number of events per 100 person-years of follow-up (PYFU). A Poisson regression model adjusted for cohort, gender, mode of HIV transmission, CD4+ T-cell count at cART initiation, liver disease pre-cART, duration of 3TC before cART, and hepatitis C virus was used to assess the association between use of 3TC and risk of LRD. Results: We analysed 2,041 patients. Follow-up after starting cART was 7,648 PYFU (5,569 spent on 3TC-containing regimens) with a median per person of 48 months (range: 2-91). Of the total, 217 subjects died; 57 deaths were liver-related resulting in a rate of 7.5 per 1,000 PYFU [95% confidence intervals (CI): 5.6-9.7]. The relative risk of LRD per extra year of 3TC use was 0.73 (95% CI: 0.59-0.90, P = 0.004). CONCLUSION: The use of 3TC was associated with a reduced risk of LRD over 4 years of follow-up. This study supports the current view that the use of 3TC as part of cART should be considered in patients who are tested positive for HBsAg.

2006 - Sthapylococcus aureus Bacteremia: Incidence, survival and antimicrobial susceptibility patterns of the isoltes [Abstract in Atti di Convegno]
Bedini, A.; Borghi, R.; Guaraldi, Giovanni; Venturelli, C.; Mussini, Cristina; Baldini, T.; Codeluppi, M.; Prati, F.; Cocchi, S.; Rumpianesi, F.; Esposito, Roberto
abstract

S. aureus bacteriemia is a common cause of nosocomial infection and contributes significantly to morbidity and mortality in critically ill patients. During the past two decades, the frequency of methicillin-resistant S. aureus infections has dramatically increased, particularly in patients admitted in emergency wards.

2006 - Use in routine clinical practice of two commercial blood tests for diagnosis of infection with Mycobacterium tuberculosis: a prospective study [Articolo su rivista]
G., Ferrara; Losi, Monica; D'Amico, Roberto; P., Roversi; R., Piro; M., Meacci; B., Meccugni; Im, Dori; A., Andreani; Bergamini, Barbara Maria; Mussini, Cristina; F., Rumpianesi; Fabbri, Leonardo; Richeldi, Luca
abstract

BACKGROUND: Two commercial blood assays for the diagnosis of latent tuberculosis infection--T-SPOT.TB and QuantiFERON-TB Gold--have been separately compared with the tuberculin skin test. Our aim was to compare the efficacy of all three tests in the same population sample. METHODS: We did a prospective study in 393 consecutively enrolled patients who were tested simultaneously with T-SPOT.TB and QuantiFERON-TB Gold because of suspected latent or active tuberculosis. 318 patients also had results available for a tuberculin skin test. FINDINGS: Overall agreement with the skin test was similar (T-SPOT.TB kappa=0.508, QuantiFERON-TB Gold kappa=0.460), but fewer BCG-vaccinated individuals were identified as positive by the two blood assays than by the tuberculin skin test (p=0.003 for T-SPOT.TB and p&lt;0.0001 for QuantiFERON-TB Gold). Indeterminate results were significantly more frequent with QuantiFERON-TB Gold (11%, 43 of 383) than with T-SPOT.TB (3%, 12 of 383; p&lt;0.0001) and were associated with immunosuppressive treatments for both tests. Age younger than 5 years was significantly associated with indeterminate results with QuantiFERON-TB Gold (p=0.003), but not with T-SPOT.TB. Overall, T-SPOT.TB produced significantly more positive results (38%, n=144, vs 26%, n=100, with QuantiFERON-TB Gold; p&lt;0.0001), and close contacts of patients with active tuberculosis were more likely to be positive with T-SPOT.TB than with QuantiFERON-TB Gold (p=0.0010). INTERPRETATION: T-SPOT.TB and QuantiFERON-TB Gold have higher specificity than the tuberculin skin test. Rates of indeterminate and positive results, however, differ between the blood tests, suggesting that they might provide different results in routine clinical practice.

2005 - Altered mithocondrial RNA production in adipocytes from HIV-infected individuals with lipodystrophy [Abstract in Rivista]
Galluzzi, L.; Pinti, Marcello; Guaraldi, Giovanni; Mussini, Cristina; Troiano, L.; Roat, E.; Giovenzana, C.; Nemes, E.; Nasi, M.; Orlando, G.; Salomoni, P.; Cossarizza, Andrea
abstract

Damage to mitochondria (mt) is a major side effect of highly active antiretroviral therapy (HAART) tha includes a nucleoside reverse transcriptase inhibitor (NRTI).Such damage is associated with the onset of lipodystrophy in HAART-treated HIV+ patients. To further investigate mt changes during this syndrome, we analysed the expression of mtRNA in adipocytes from lipodystrophic HIV+ patients taking NRTI-containing HAART and compared it with similar cells from healthy individuals.

2005 - Altered mitochondrial RNA production in adipocytes from HIV-infected individuals with lipodystrophy [Articolo su rivista]
Galluzzi, Lorenzo; Pinti, Marcello; Guaraldi, Giovanni; Mussini, Cristina; Troiano, Leonarda; Roat, Erika; Giovenzana, Chiara; Nemes, Elisa; Nasi, Milena; Orlando, Gabriella; Salomoni, P; Cossarizza, Andrea
abstract

Background: Damage to mitochondria (mt) is a major side effect of highly active antiretroviral therapy (HAART) that includes a nucleoside reverse transcriptase inhibitor (NRTI). Such damage is associated with the onset of lipodystrophy in HAART-treated HIV+ patients. To further investigate mt changes during this syndrome, we analysed the expression of mtRNA in adipocytes from lipodystrophic HIV+ patients taking NIRTI-containing HAART and compared it with similar cells from healthy individuals. Materials and methods: Total RNA was extracted from adipocytes collected from different anatomical locations of 11 HIV+ lipodystrophic patients and seven healthy control individuals. RNA was reverse transcribed and Taqman-based real-time PCR was used to quantify three different mt transcripts (ND1, CYTB and ND6 gene products). mtRNA content was normalized versus the housekeeping transcript L13. Results: ND1, CYTB and ND6 expression was significantly reduced in HIV+ lipodystrophic patients. HIV+ men and women did not differ in a statistically significant way regarding the levels of ND1 and ND6, whereas the opposite occurred for CYTB. Conclusions: Lipodystrophy following treatment with NRTI-containing HAART is associated with a decrease in adipose tissue mtRNAs.

2005 - CD4 cell-monitored treatment interruption in patients with a CD4 cell count > 500 x 10(6) cells/I [Articolo su rivista]
Mussini, Cristina; Bedini, Andrea; V., Borghi; Guaraldi, Giovanni; Esposito, Roberto; E., Barchi; R., Emilia; A., Cozzi Lepri; A. N., Phillips; P., Ortolani; Cossarizza, Andrea; G., Bratt; L. E., Eriksson; L., Sighinolfi; A. D., Monforte; A., De Luca; S., Di Giambenedetto; A., Antinori
abstract

Background: Little is known about CD4 cell count changes in patients with high CD4 cell counts who interrupt antiretroviral therapy, especially in those with a nadir of 250350 x 10(6) cells/I. Methods: Data derived from 139 patients from seven prospective cohorts who had > 12 months highly active antiretroviral therapy (HAART), CD4 cell count nadir of > 250 x 10(6) cells/I and at pre-interruption of > 500 x 106 cells/I. Endpoint was time to CD4 cell count < 350 x 10(6) cells/I or reinitiation of treatment. Results: At interruption, the median CD4 cell count was 800 x 106 cells/I, median viral load was 1.7 log(10) copies/ml. At the time of analysis, 63 (45.3%) had resumed therapy or experienced < 350 x 10(6) cells/I CD4 cells over a median interruption of 75 weeks. Of these, 33 (52.4%) experienced a decline to < 350 x 10(6) cells/I and 30 (47.6%) restarted therapy before their CD4 cell count had fallen below this level. In 43 patients with CD4 cell nadir of 251-350 x 10(6) cells/I, median time to therapy resumption or CD4 cell count < 350 x 10(6) cells/I was 61 weeks. Higher CD4 cell count nadir, longer duration of viral load suppression on therapy, and higher viral load level at interruption were independently associated with longer time to restart therapy. The risk of clinical events was 5 per 1000 person-years of follow-up. Conclusions: Patients who started therapy with CD4 cell count of 250-350 x 10(6) cells/I and who later interrupted therapy appear able to remain off therapy with a CD4 cell count > 350 x 10(6) cells/I for a substantial period of time.

2005 - Changes in mitochondrial RNA production in cells treated with nucleoside analogues. [Articolo su rivista]
Galluzzi, Lorenzo; Pinti, Marcello; Troiano, Leonarda; Prada, Nicole; Nasi, Milena; Ferraresi, Roberta; Salomoni, P; Mussini, Cristina; Cossarizza, Andrea
abstract

BACKGROUND: To investigate mitochondrial (mt) toxicity of antiretroviral drugs further, we developed a novel real-time PCR-based assay for the quantification of mtRNA. We analysed the effects of stavudine (d4T), didanosine (ddl) and zidovudine (AZT) on the production of mtRNAs in different human cell lines and compared the production with the amount of mtDNA present in the same cells. MATERIALS AND METHODS: HUT78, CEM and U937 cells were exposed to different nucleoside reverse transcriptase inhibitors (NRTIs) for 7 days. Thereafter, nucleic acids were isolated and Taqman-based real-time PCR was used to quantify mtDNA and three different mtRNAs (ND1, CYTB and ND6 gene products). RESULTS: Different amounts of mtRNAs exist in different cell lines. When mtRNA was measured in cells exposed to an NRTI, a marked decrease was observed in cells treated with d4T, but not with ddl or AZT. Changes in mtRNA production did not always correspond to modifications in mtDNA content: 1 microM d4T significantly changed mtRNA but not mtDNA content. CONCLUSIONS: d4T, but not ddl or AZT, significantly alters mtRNA quantity and quality. The method we have developed can reveal changes that are not observed by measuring mtDNA content only, and can be used for ex vivo studies on drug toxicity.

2005 - Effect of treatment interruption monitored by CD4 cell count on mitochondrial DNA content in HIV-infected patients: a prospective study [Articolo su rivista]
Mussini, Cristina; Pinti, Marcello; R., Bugarini; V., Borghi; Nasi, Milena; Nemes, Elisa; Troiano, Leonarda; Guaraldi, Giovanni; Bedini, Andrea; C., Sabin; Esposito, Roberto; Cossarizza, Andrea
abstract

Background: HIV infection per se and HAART can alter mitochondrial functionality, leading to a decrease in mitochondrial DNA content. Objective: To evaluate whether treatment interruption monitored by CD4 cell count can restore mitochondrial DNA content in peripheral blood lymphocytes. Methods: Mitochondrial DNA content was measured in platelet-free CD4 and CD8 T cells by real-time polymerase chain reaction; flow cytometry was used to identify and quantify activated CD4 and CD8 T lymphocytes. Results: The 30 patients had been treated for a mean of 107 months (range, 27-197). Median CD4 cell count at discontinuation was 702 cells/mu l (range, 547-798). Median observational time from HAART discontinuation was 11.3 months (range, 4-26). Discontinuation of treatment provoked significant increases in mitochondrial DNA in CD8 T cells, which started only 6 months after therapy cliscontinuation [5.12 copies/ cell per month from 0 to 6 months (P = 0.3 7) and 2 6.96 copies/cel I per month from 6 to 12 months (P < 0.0001)]. Conclusions: This study is the first showing that mitochondrial DNA content can increase in peripheral blood lymphocytes during treatment interruption, but only after at least 6 months of interruption. Consequently, interruptions of shorter periods, whether by clinician or patient decision, are unlikely to allow restoration of mitochondrial DNA and so decrease HAART-related toxicity.

2005 - Genetic polymorphisms of Fas (CD95) and Fas ligand (CD178) influence the rise in CD4+ T cell count after antiretroviral therapy in drug-naive HIV-positive patients. [Articolo su rivista]
Nasi, Milena; Pinti, Marcello; Bugarini, R; Troiano, Leonarda; Lugli, E; Bellodi, C; Mussini, Cristina; Borghi, V; Trenti, T; Balli, Fiorella; Esposito, Roberto; Cossarizza, Andrea
abstract

Fas and Fas ligand (FasL) are the main genes that control cell death in the immune system. Indeed, they are crucial for the regulation of T lymphocyte homeostasis because they can influence cell proliferation. A strong debate exists on the importance of Fas/FasL system during HIV infection, which is characterized by the loss of CD4+ T cells directly, or indirectly, caused by the virus. To investigate whether the genetic background of the host plays a role in the immunoreconstitution, we studied the influence of different Fas and FasL polymorphisms on CD4+ T lymphocyte count and plasma viral load following initiation of highly active antiretroviral therapy (HAART) in drug-naive HIV+ patients. We studied 131 individuals, who were compared to 136 healthy donors. Statistical analysis was performed by using X-2 test, Fischer's Exact Test, and analysis for repeated measurements. The group of HIV+ patients had an unexpected lower frequency of FasLnt169 polymorphism (delT allele) than healthy controls (p=0.039). We then observed no significant differences in the immune reconstitution, in terms of CD4+ T cell increase, when the influence of single alleles of the gene Fas or FasL was considered. However, the combination of some polymorphisms of Fas or FasL significantly influenced CD4+ T cell production and viral load decrease, showing that these genes can play a role in the immunoreconstitution triggered by antiretroviral therapy.

2005 - Interruption of highly active antiretroviral therapy in HIV clinical practice: results from the Italian Cohort of Antiretroviral-Naive Patients. [Articolo su rivista]
d'arminio Monforte, A; Cozzi Lepri, A; Phillips, A; De Luca, A; Murri, R; Mussini, Cristina; Grossi, P; Galli, A; Zauli, T; Montroni, M; Tundo, P; Moroni, M; Italian Cohort of Antiretroviral Naive Patients Study, Group
abstract

OBJECTIVES: To investigate the frequency of a first therapy interruption (TI) > or = 12 weeks, to identify the factors associated with TI and with therapy resumption, and to compare the risk of developing clinical events during TI and during continuous therapy. METHODS: Observational study of 3142 patients who started a first highly active antiretroviral therapy (HAART) regimen. End points were time to (1) first TI of > or = 12 weeks, (2) subsequent therapy resumption, and (3) development of new AIDS-related events or death. RESULTS: Over a median follow-up period of 41 months (interquartile range: 18-60 months), 721 patients (22.9%) interrupted HAART for > or = 12 weeks, with a probability of 28.6% (95% confidence interval [CI]: 26.7-30.6) by 4 years from the date of therapy initiation. Patient decision (47.4%) and toxicity (24.0%) were the main reasons for TI. Women, injection drug users, and patients with a higher current CD4 cell count were more likely to interrupt. The median time to therapy resumption was 12 months (95% CI: 11-14). The higher the current CD4 count, the slower was the rate of resuming therapy; conversely, patients who stopped because of failure and those with a pre-HAART viral load >100,000 copies/mL resumed therapy sooner. Two hundred eighty-one patients experienced clinical progression at a rate of 2.6 per 100 person-years (pys) (95% CI: 2.3-3.0) while patients were on therapy and 3.5 per 100 pys (95% CI: 2.4-4.8) during TI. The adjusted relative hazard of clinical progression associated with TI was 2.75 (95% CI: 1.14-6.65; P = 0.03). CONCLUSIONS: TI occurring in clinical practice is associated with an increased risk of clinical progression; hence, it should be discouraged outside strictly experimental settings.

2005 - MMP-7 promoter polymorphisms do not influence CD4+ recovery and changes in plasma viral load during antiretroviral therapy for HIV-1 infection. [Articolo su rivista]
E., Lugli; Pinti, Marcello; Nasi, Milena; Troiano, Leonarda; Prada, Nicole; Mussini, Cristina; V., Borghi; Esposito, Roberto; Cossarizza, Andrea
abstract

Matrix metalloproteinase-7 (MMP-7) generates soluble Fas Ligand (FasL), which is involved in the apoptotic loss of CD4(+) T cells during HIV infection. We evaluated whether two polymorphisms in MMP-7 promoter could influence CD4(+) recover in response to antiretroviral therapy, and found that these polymorphisms are ineffective.

2004 - Discontinuation of maintenance therapy for cryptococcal meningitis in patients with AIDS treated with highly active antiretroviral therapy: An international observational study [Articolo su rivista]
Mussini, Cristina; P., Pezzotti; J., MIRO' MEDA; JC LOPEZ BERNALDO DE, Quiros; E., Martinez; P., Cinque; V., Borghi; Bedini, Andrea; P., Domingo; P., Cahn; P., Bossi; A., DE LUCA; A., D'ARMINIO MONFORTE; M., Nelson; N., Nwokolo; S., Helou; R., Neuroni; G., Jacchetti; S., Antinori; A., Lazzarin; Cossarizza, Andrea; Esposito, Roberto; A., Antinori; Ja, Aberg
abstract

We conducted a retrospective, multicenter study evaluating the safety of discontinuing maintenance therapy for cryptococcal meningitis after immune reconstitution. Inclusion criteria were a previous definitive diagnosis of cryptococcal meningitis, a CD4 cell count of &gt;100 cells/muL while receiving highly active antiretroviral therapy (HAART), and the subsequent discontinuation of maintenance therapy for cryptococcal meningitis. The primary end point was relapse of cryptococcal disease. As of July 2002, 100 patients were enrolled. When maintenance therapy was discontinued, the median CD4 cell count was 259 cells/muL and the median plasma virus load was &lt;2.30 log(10) copies/mL, and serum cryptococcal antigen was undetectable in 56 patients. During a median follow-up period of 28.4 months (range, 6.7-64.5; 262 person-years), 4 events were observed (incidence, 1.53 events per 100 person-years; 95% confidence interval, 0.42-3.92). Three of these patients had a CD4 cell count of &gt;100 cells/mL and a positive serum cryptococcal antigen test result during the recurrent episode. In conclusion, discontinuation of maintenance therapy for cryptococcal meningitis is safe if the CD4 cell count increases to &gt;100 cells/mL while receiving HAART. Recurrent cryptococcal infection should be suspected in patients whose serum cryptococcal antigen test results revert back to positive after discontinuation of maintenance therapy.

2004 - Epidemiology and Antifungal Susceptibility of Candida spp Isolates Causing Bloodstream Infections [Abstract in Atti di Convegno]
Bedini, A.; Venturelli, C.; Mussini, Cristina; Guaraldi, Giovanni; Codeluppi, M.; Borghi, V.; Rumpianesi, F.; Esposito, Roberto
abstract

During the past decade invasive fungal infections and antifungal resistance have dramatically increased in hospitalized patients.

2004 - Highly active antiretroviral therapy restores CD4(+) V beta T-cell repertoire in patients with primary acute HIV infection but not in treatment-naive HIV+ patients with severe chronic infection [Articolo su rivista]
Cossarizza, Andrea; F., Poccia; C., Agrati; G., D'Offizi; R., Bugarini; Pinti, Marcello; V., Borghi; Mussini, Cristina; Esposito, Roberto; G., Ippolito; P., Narciso
abstract

In drug-naive HIV+ patients, we analyzed the effects of highly active antiretroviral therapy (HAART) on the reconstitution of the T-cell receptor (TCR) repertoire. We followed 2 groups of patients for 1 year: 18 individuals who experienced acute HlV infection and 24 patients who had HIV infection for many years but never took HAART. They were compared with 10 healthy controls who were longitudinally analyzed for the same period. We performed cytofluorometric analysis of the Vbeta TCR repertoire and detected the clonality of different Vbeta families by the spectratyping method. A new statistical approach based on the use of mixed models was then employed to analyze the data. Before the beginning of therapy, the repertoire of patients with acute or chronic infection was significantly different from that of healthy controls. After therapy, patients with acute HIV infection showed an improvement of the repertoire among either CD4(+) or CD8(+) T lymphocytes. Conversely, patients with chronic infection were capable of changing their repertoire among CD8(+) but not CD4(+) T lymphocytes. Our results indicate that HAART can restore the T-cell repertoire in individuals whose immune system is not severely compromised by the infection.

2004 - Mitochondrial membrane potential and nucleosidic inhibitors of HIV reverse transcriptase: a cytometric approach. [Articolo su rivista]
Ferraresi, R; Troiano, L; Rossi, D; Gualdi, E; Lugli, E; Mussini, Cristina; Cossarizza, Andrea
abstract

Mitochondrial toxicity is a relevant side effect of anti-HIV antiretroviral therapy. Adequate experimental models and advanced technologies are crucial to investigate properly mitochondrial toxicity. Functional flow cytometry allows a rapid and sensitive evaluation of several parameters on single cells, and is an excellent tool to investigate the impact of antiviral drug on mitochondrial activity. We used such approach to analyze in vitro mitochondrial toxicity induced by stavudine and zidovudine on cell lines of different origin (hemopoietic: A301, U937, CEM, K562; hepatic: HepG2), and found that the cell lines had a different sensitivity to the action of the drugs.

2004 - Predictors of trend in CD4-positive T-cell count and mortality among HIV-1-infected individuals with virological failure to all three antiretroviral-drug classes. [Articolo su rivista]
Ledergerber, B; Lundgren, Jd; Walker, As; Sabin, C; Justice, A; Reiss, P; Mussini, Cristina; Wit, F; d'Arminio Monforte, A; Weber, R; Fusco, G; Staszewski, S; Law, M; Hogg, R; Lampe, F; Gill, Mj; Castelli, F; Phillips, An; Plato, Collaboration
abstract

Background Treatment strategies for patients in whom HIV replication is not suppressed after exposure to several drug classes remain unclear. We aimed to assess the inter-relations between viral load, CD4-cell count, and clinical outcome in patients who had experienced three-class virological failure.Methods We undertook collaborative joint analysis of 13 HIV cohorts from Europe, North America, and Australia, involving patients who had had three-class virological failure (viral load >1000 copies per mL for >4 months). Regression analyses were used to quantify the associations between CD4-cell-count slope, HIV-1 RNA concentration, treatment information, and demographic characteristics. Predictors of death were analysed by Cox’s proportional-hazards models.Findings 2488 patients were included. 2118 (85%) had started antiretroviral therapy with single or dual therapy. During 5015 person-years of follow-up, 276 patients died (mortality rate 5·5 per 100 person-years; 3-year mortality risk 15·3% (95% CI 13·5–17·3). Risk of death was strongly influenced by the latest CD4-cell count with a relative hazard of 15·8 (95% CI 9·28–27·0) for counts below 50 cells per μL versus above 200 cells per L. The latest viral load did not independently predict death. For any given viral load, patients on treatment had more favourable CD4- cell-count slopes than those off treatment. For patients on treatment and with stable viral load, CD4-cell counts tended to be increasing at times when the current viral load was below 10 000 copies per mL or 1·5 log10 copies per mL below off-treatment values.Interpretation In patients for whom viral-load suppression to below the level of detection is not possible, achievement and maintenance of a CD4-cell count above 200 per L becomes the primary aim. Treatment regimens that maintain the viral load below 10 000 copies per mL or at least provide 1·5 log10 copies per mL suppression below the off-treatment value do not seem to be associated with appreciable CD4-cell-count decline.

2004 - Prevalence, associated factors, and prognostic determinants of AIDS-related toxoplasmic encephalitis in the era of advanced highly active antiretroviral therapy [Articolo su rivista]
A., Antinori; D., Larussa; A., Cingolani; P., Lorenzini; S., Bossolasco; M. G., Finazzi; M., Bongiovanni; Guaraldi, Giovanni; S., Grisetti; B., Vigo; B., Gigli; A., Mariano; E. R., Dalle Nogare; M., De Marco; F., Moretti; P., Corsi; N., Abrescia; P., Rellecati; A., Castagna; Mussini, Cristina; A., Ammassari; P., Cinque; A., D' Arminio Monforte; Cingolani, A; Italian Registry Investigative, Neuroaids
abstract

Background. Characteristics, associated factors, and survival probability of toxoplasmic encephalitis (TE) in the era of advanced highly active antiretroviral therapy ( HAART) have not been fully clarified. Methods. Data for 205 individuals with acquired immunodeficiency syndrome ( AIDS)-related TE were derived from the Italian Registry Investigative NeuroAIDS database, and the cases were studied longitudinally to evaluate prevalence, clinical characteristics, and survival. Moreover, the relationship between the occurrence of TE and exposure to antiretroviral therapy and to TE prophylaxis was evaluated. Results. With an overall prevalence of 26%, TE represented the most frequent neurological disorder in the cohort. Female sex, severe immunodeficiency, and absence of primary TE prophylaxis significantly increased the risk of TE, and previous exposure to antiretroviral therapy reduced the probability of disease occurrence. Thirty-six percent of patients who had received antiretroviral therapy developed TE, although in most of these cases, the patient experienced failure of antiretroviral therapy. Of note, 66% of patients who had experienced antiretroviral therapy did not receive prophylaxis for TE at TE diagnosis. The 1-year probability of that infection with human immunodeficiency virus (HIV) would progress or that death would occur after TE was 40% and 23%, respectively. Cognitive symptoms, low CD4(+) cell count, not receiving HAART after TE, and initiating HAART 12 months after TE diagnosis were all significantly associated with an increased probability of progression of HIV infection. Not receiving HAART after diagnosis negatively affected survival. Conclusions. TE remains a highly prevalent disorder of the central nervous system, even in the late HAART era, particularly among severely immunosuppressed patients and in absence of prophylaxis. Considering that persons with TE have a high probability of early death, prophylaxis should be maintained in immunosuppressed patients who experience failure of antiretroviral therapy, and HAART should be initiated as soon as possible after TE diagnosis.

2004 - The human immunodeficiency virus (HIV) protease inhibitor indinavir directly affects the opportunistic fungal pathogen Cryptococcus neoformans [Articolo su rivista]
Blasi, Elisabetta; Colombari, Bruna; Orsi, Carlotta Francesca; Pinti, Marcello; Troiano, L.; Cossarizza, Andrea; Esposito, Roberto; Peppoloni, Samuele; Mussini, Cristina; Neglia, Rachele Giovanna
abstract

Highly active antiretroviral therapy (HAART), that includes human immunodeficiency virus (HIV) protease inhibitors (PIs), has been remarkably efficacious including against some opportunistic infections. In this report we investigated the effect(s) of the PI indinavir on protease activity by Cryptococcus neoformans, an opportunistic fungal pathogen responsible for recurrent meningoencephalitis in AIDS patients. Indinavir was also tested for potential effects on other parameters, such as fungal viability, growth ability and susceptibility to immune effector cells. It was found that indinavir impaired cryptococcal protease activity in a time- and dose-dependent fashion. The phenomenon was similarly detectable in ATCC/laboratory strains and clinical isolates. C neoformans growth rate was also significantly reduced upon exposure to indinavir, while fungal viability was not affected and mitochondrial toxicity not detected. Furthermore, as assessed by an in vitro infection model, indinavir significantly and consistently augmented C neoformans susceptibility to microglial cell-mediated phagocytosis and killing. Overall, by providing the first evidence that indinavir directly affects C neoformans, these data add new in vitro insights on the wide-spectrum efficacy of PIs, further arguing for the clinical relevance of HAART against opportunistic infections in AIDS. (C) 2004 Federation of European Microbiological Societies. Published by Elsevier B.V. All rights reserved.

2003 - Access to antiretroviral treatment, incidence of sustained therapy interruptions, and risk of clinical events according to sex: evidence from the I.Co.N.A. Study. [Articolo su rivista]
Murri, R; Lepri, Ac; Phillips, An; Girardi, E; Nasti, G; Ferrara, S; Mura, Ms; Mussini, Cristina; Petrelli, E; Arlotti, M; De Stefano, C; Vigano, P; Novati, R; Cargnel, A; Monforte, Ad; Study Group, I. C. o. N. A.
abstract

Objectives of the study were to assess the differences between sexes in the likelihood of starting antiretroviral therapy (ART), in rates of sustained discontinuation from highly active antiretroviral therapy (HAART), and in clinical progression. In a multicenter cohort study (I.Co.N.A. Study), 2323 men and 1335 women previously naive to antiretrovirals were enrolled. As of September 2002, 807 women and 1480 men started ART. The median time to starting ART was 28 weeks for women and 17 weeks for men (P = 0.0003 by log-rank test). This difference was no longer significant after adjusting for either HIV RNA (P = 0.21) or CD4 count (P = 0.28) at enrollment. Women tend to start HAART less frequently than mono/dual ART after adjusting for potential confounders (odds ratio = 0.78, 95% confidence interval [CI]: 0.60-1.01; P = 0.06). Women who started HAART were 1.4 times more likely than men (95% CI: 1.00-1.99; P = 0.05) to interrupt at least 1 drug because of toxicity. Twenty-one percent of women and 19% of men interrupted HAART altogether for more than 3 months (P = 0.3). Clinical progression was observed in 53 women (22.6%) and 137 men (23.4%; P = 0.56). Risk of developing a clinical event was found to be no different between women and men (relative hazard = 0.84, 95% CI: 0.56-1.26; P = 0.40).

2003 - CD4-Guided treatment interruptions: a new possibile therapeutic strategy [Abstract in Atti di Convegno]
Mussini, Cristina; Cozzi Lepri, A.; Borghi, V.; D’Arminio Monforte, A.; De Luca, A.; Sighinolfi, L.; Ortolani, P.; Barchi, E.; Guaraldi, Giovanni; Bedini, A.; Bratt, G.; Erikson, L.; Antinori, A.; Cossarizza, Andrea; Esposito, Roberto
abstract

Aim of this study is to evaluate the safety of CD4 guided treatment interruptions.

2003 - Different sensitivity to apoptosis in cells of monocytic or lymphocytic origin chronically infected with human immunodeficiency virus type-1 [Articolo su rivista]
Pinti, Marcello; Biswas, P; Troiano, L; Nasi, Milena; Ferraresi, Roberta; Mussini, Cristina; Vecchiet, J; Esposito, Roberto; Paganelli, R; Cossarizza, Andrea
abstract

Apoptotic death of CD4+ T lymphocytes is a major cause of the immunodeficiency caused by human immunodeficiency virus (HIV), but it is still unclear how this process precisely occurs. To characterize a potentially useful cellular model, we have analyzed the tendency of chronically HIV-infected CD4+ human cell lines of different origin to undergo apoptosis. We studied ACH-2 and U1 lines, derived from the CD4+ T-cell A301 and the promonocytic U937 cell lines, respectively, and induced apoptosis via several stimuli that trigger different pathways. Their capacity to regulate plasma membrane CD95 expression and to produce soluble CD95 was also analyzed. Using staurosporine, TNF-alpha plus cycloheximide, and gamma-radiations, we observed that ACH-2 were more sensitive to programmed cell death than A301, while U1 were less sensitive than U937. Both infected cell types had a lower sensitivity to CD95-induced apoptosis; the analysis of changes in mitochondrial membrane potential corroborated these observations. Plasma membrane CD95 was similarly regulated in all cell types, which, however, presented a different capacity to produce soluble CD95 molecules. Our in vitro results may offer a new perspective for developing further studies on the pathogenesis of HIV infection. A chronically infected cell line of lymphocytic origin is more susceptible to apoptosis than its parental cell type, while infected monocytic cells are less sensitive than their uninfected counterpart. Thus, it is possible to hypothesize that one of the reasons by which circulating monocytes survive and represent a viral reservoir is the capacity of HIV to decrease the sensitivity to apoptosis of this cell type. However, further studies on ex-vivo collected fresh cells, as well as on other cell lines, are urgently needed to confirm such hypothesis.

2003 - Discontinuation of secondary prophylaxis for Pneumocystis carinii pneumonia in human immunodeficiency virus-infected patients: A randomized trial by the CIOP Study Group [Articolo su rivista]
Mussini, Cristina; Pezzotti, P; Antinori, A; Borghi, V; Monforte, A; Govoni, A; De Luca, A; Ammassari, A; Mongiardo, N; Cerri, Mc; Bedini, Andrea; Beltrami, C; Ursitti, Ma; Bini, T; Cossarizza, Andrea; Esposito, R.
abstract

This subgroup analysis assessing secondary prophylaxis for Pneumocystis carinii pneumonia (PCP) describes a multicenter, open-labeled, randomized, controlled trial evaluating the discontinuation of PCP prophylaxis. The main inclusion criterion was a history of PCP and an increase in the CD4 cell count to >200 cells/microL associated with receipt of highly active antiretroviral therapy for >or=3 months. The primary end point was the development of definitive or presumptive PCP. A total of 146 patients were enrolled (77 in the treatment discontinuation arm). After >2 years, 1 definitive and 1 presumptive case of PCP were observed, both of which occurred in patients who discontinued therapy. In most patients, secondary prophylaxis for PCP can be safely discontinued after potent antiretroviral therapy is initiated, but the threshold of >200 CD4 cells/microL may not be considered absolutely safe. Patients who present with symptoms after discontinuation of secondary prophylaxis should be evaluated for PCP despite high CD4 count and complete virus suppression.

2003 - Epidemiologia della candidemia nosocomiale: 5 anni di esperienza in un ospedale universitario italiano [Abstract in Rivista]
Bedini, A.; Mussini, Cristina; Guaraldi, Giovanni; Esposito, Roberto
abstract

Lo scopo del presente studio era di valutare, in un Ospedale Universitario Italiano, l'incidenza della candidemia nosocomiale, gli agenti patogeni responsabili, il trattamento e i fattori di rischio per la letalità.

2003 - Increased mitochondrial DNA content in peripheral blood lymphocytes from HIV-infected patients with lipodystrophy. [Articolo su rivista]
Cossarizza, Andrea; Riva, A; Pinti, Marcello; Ammannato, S; Fedeli, P; Mussini, Cristina; Esposito, R; Galli, M.
abstract

We have evaluated mitochondrial (mt) DNA content in CD4 and CD8 peripheral blood lymphocytes (PBLs) from HIV-infected patients taking highly active antiretroviral therapy (HAART) who display different types of adipose tissue alterations. A cross-sectional study was performed in a total of 23 patients with lipodystrophy (LD): nine patients with fat accumulation, six patients with fat loss, eight patients with combined form, who were compared to 11 individuals infected by HIV without LD (HIV-positive) and 10 seronegative controls (CTRL). PBLs were obtained by standard methods, that is, gradient density centrifugation on Ficoll, and CD4 or CD8 cells were positively isolated by magnetic sorting to eliminate the contamination of platelets. mtDNA content was then measured by an original assay based upon real-time PCR. mtDNA content was significantly increased in CD4 T cells from patients with LD, while no differences were present between CD4 and CD8 cells from HIV-positive and CTRL individuals. Nor were any differences found when comparing LD or HIV-positive patients treated with stavudine or zidovudine, or taking D-drugs or non D-drugs. Patients with fat accumulation had significantly higher mtDNA content compared to HIV-positive and CTRL, this phenomenon regarding both CD4 and CD8 PBLs. Considering all HIV-positive patients (including LD), mtDNA content showed a significant, positive correlation with cholesterolaemia but not with triglyceridaemia and glycaemia. Relatively high mtDNA content in LD patients, as well as the correlation between mtDNA content and cholesterol in all HIV-positive subjects, suggest the involvement of mitochondria in such a pathology. However, further studies are needed to confirm these initial observations and ascertain whether the quantification of mtDNA in PBL is a useful and reliable marker to investigate and monitor HAART-related changes in fat distribution.

2003 - MDR1 C3435T genetic polymorphism does not influence the response to antiretroviral therapy in drug-naive HIV-positive patients [Articolo su rivista]
Nasi, Milena; V., Borghi; Pinti, Marcello; C., Bellodi; E., Lugli; S., Maffei; L., Troiano; Richeldi, Luca; Mussini, Cristina; Esposito, Roberto; Cossarizza, Andrea
abstract

P-glycoprotein, a membrane-localized protein transporter, codified by the MDR1 gene, influences the response to pharmacological treatments, including antiretroviral drugs. MDR1 polymorphism C3435T is correlated with the functionality of the protein. We investigated the influence of this polymorphism in the reconstitution of the peripheral C134 T cell pool in 149 drug-naive HIV-positive patients starting highly active antiretroviral therapy. The MDR1 C3435T polymorphism did not influence response to therapy, suggesting no disadvantages for individuals with a different genotype.

2003 - Simplification of protease inhibitor-containing regimens with efavirenz, nevirapine or abacavir: safety and efficacy outcomes. [Articolo su rivista]
Chiesa, E; Bini, T; Adorni, F; Capetti, A; Rizzardini, G; Faggion, I; Mussini, Cristina; Sollima, S; Melzi, S; Bongiovanni, M; Tordato, F; Cicconi, P; Castelnuovo, B; Rusconi, S; d'Arminio Monforte, A.
abstract

OBJECTIVE: To describe the immunological and virological outcome, and the factors associated to discontinuation in patients switching to a regimen containing efavirenz (EFV), nevirapine (NVP) or abacavir (ABC) after long-term viral suppression under protease inhibitor-including HAART. DESIGN: Observational study at three outpatient clinics for HIV care in Italy. METHODS: Patients with HIV RNA <80 copies/ml and CD4 >200 cells/ml for at least 6 months on a protease inhibitor-containing treatment who switched to NVP, EFV or ABC were included in the study. End-points were immunological failure, virological failure and discontinuation due to toxicity. Survival analyses were performed to find out any independent variables predictive of reaching the end-points. RESULTS: 177 patients were enrolled; 85 started EFV, 54 NVP and 38 ABC as part of the simplification regimen. 16/159 patients experienced immunological failure: the variables associated to CD4 count decrease were HIV RNA set point value (HR 2.32 for each log10 copies more, P=0.040) and intolerance/toxicity as reason for simplification (HR 3.96, P=0.05). 13/151 subjects showed virological failure; an AIDS diagnosis (HR 6.04, P=0.021) and the use of NVP (HR 7.98, P=0.027) were associated to a worse virological outcome, while patients naive before HAART showed a lower risk of failure (HR 0.008, P=0.007). 16/177 patients discontinued simplification regimen due to toxicity; longer HAART duration before switch was associated to risk reduction (HR 0.92, P=0.004). CONCLUSIONS: Simplification is safe and effective, but it should be offered to patients with shorter treatment duration, and in good clinical and immunovirological conditions.

2003 - The effect of highly active antiretroviral therapy-induced immune reconstitution on development and outcome of progressive multifocal leukoencephalopathy: study of 43 cases with review of the literature. [Articolo su rivista]
Cinque, P; Bossolasco, S; Brambilla, Am; Boschini, A; Mussini, Cristina; Pierotti, C; Campi, A; Casari, S; Bertelli, D; Mena, M; Lazzarin, A.
abstract

The authors investigated the effect of highly active antiretroviral therapy (HAART) on the onset and outcome of progressive multifocal leukoencephalopathy (PML) in a group of 43 patients with histological or clinicovirological diagnosis of PML. In eight of these cases (19%), PML symptoms presented 21 to 55 days after the start of HAART, concomitantly with a CD4 cell-count increase and plasma human immunodeficiency virus type 1 (HIV-1) RNA load (VL) decrease. Four of these patients died of PML. Apart from baseline VL, we did not identify any other variable that could distinguish these forms of immune reconstitution PML from those occurring in patients either untreated or failing to respond to therapy. To compare the viroimmunological response to HAART with PML outcome, we evaluated a subgroup of 23 patients untreated at the time of PML onset. No different pattern of response to HAART was observed between patients who died or survived to PML. However, start of HAART was delayed of > or =3 months after onset of PML in half of the latter patients. In conclusion, HAART-associated immune reconstitution seems to play a role on development of a substantial number of PML cases. Although the authors could not demonstrate a directly deleterious effect of HAART on PML progression, prompt initiation of HAART after diagnosis of PML and subsequent successful response were often associated with bad PML outcome.

2002 - An observational study on patients treated or not for acute HIV infection. [Articolo su rivista]
Mussini, Cristina; Cozzi Lepri, A; Bedini, A; Borghi, V; Mongiardo, N; Cossarizza, Andrea; Esposito, R.
abstract

BACKGROUND: A vast majority of HIV-infected subjects who experience HIV acute seroconversion actually receive treatment. Open questions are how can we identify patients who will be slow progressors or long-term non progressors, and, as a consequence, do not require treatment. METHODS: An observational retrospective study on patients who experienced acute HIV seroconversion from August 1995 to June 2001, who are still alive and followed as outpatients at the Clinic of Infectious Diseases of Modena, Italy. RESULTS: Twelve patients were studied. Five patients (45.4%) were treated during acute seroconversion, while 7 were not treated. Two of these seven subjects received antiretroviral treatment 12 and 26 weeks after acute seroconversion. All the untreated patients were in good viro-immunological condition 6 months after seroconversion, and 2 of them also after 3 and 7 years. Patients who were treated showed a significant daily increase in CD4/CD8 T cell ratio with longer time spent on therapy (0.04% increase per day longer on antiretroviral therapy, p=0.02). CONCLUSIONS: This study suggests that treatment during primary HIV infection should not be considered in all patients. Randomized clinical trials enrolling patients with an asymptomatic primary HIV infection, with a high CD4 count and low HIV plasma viremia are needed to evaluate the indications for treatment in this subgroup of patients. On the other hand, this study confirms the good viro-immunological response obtained after treating patients during primary HIV infection.

2002 - Candidemia nosocomiale: quattro anni di esperienza in un'ospedale universitario italiano [Abstract in Atti di Convegno]
Bedini, A.; Venturelli, C.; Mussini, Cristina; Guaraldi, Giovanni; Della Loggia, P.; Codeluppi, M.; Beghetto, Barbara; Nardini, Giulia; Rumpianesi, F.; Esposito, Roberto
abstract

Lo scopo del presente studio era di valutare, in un Ospedale Universitario Italiano, l'incidenza della candidemia nosocomiale, gli agenti patogeni responsabili, il trattamento e i fattori di rischio per la letalità

2002 - Features of 'CD4-exploders', HIV-positive patients with an optimal immune reconstitution after potent antiretroviral therapy [Articolo su rivista]
Mussini, Cristina; Pinti, Marcello; Borghi, V; Nasi, Milena; Amorico, G; Monterastelli, E; Moretti, L; Troiano, Leonarda; Esposito, Roberto; Cossarizza, Andrea
abstract

Objective: To identify crucial immunological characteristics of a group of patients, defined ´CD4-exploders´, who were able to fully reconstitute their immune system after receiving highly active antiretroviral therapy (HAART). Patients: Among a population of 540 HIV-positive patients treated with HAART, six individuals were identified who experienced a nadir of less than 85 X 10(6) CD4+ cells/l, had major opportunistic infections (four out of six), started HAART in 1996 or 1997, and showed a rapid and relevant CD4+ lymphocyte increase (mainly due to virgin cells), in some cases regardless of virological control. Methods: Enzyme-linked immunosorbent assay for the determination of interleukin (IL)-7 plasma levels; flow cytometry to analyse surface antigens and CD127 (IL-7 receptor alpha-chain) expression; quantitative-competitive (QC) PCR for detecting cells containing T-cell receptor rearrangement excision circles (TREC) chest-computed tomography (CT) to analyse thymus volume and content. Results: In ´CD4-exploders´, high levels of TREC+ lymphocytes were found among CD4+ T cells, which also contained a high percentage of naive cells. However, CT revealed a dramatic depletion of intrathymic lymphoid tissue. Plasma levels of IL-7 were significantly high. Most CD4+ and CD8+ T lymphocytes expressed CD127, whose level was similar to that of healthy donors. CD127 expression on CD8+ lymphocytes was markedly higher than in HIV-positive individuals treated with the same therapy or in patients with AIDS. Conclusion: In ´CD4-exploders´, HAART-incluced reconstitution of the T-cell compartment is independent from thymus volume, and is favoured by the upregulation of the IL-7/IL-7 receptor system.

2002 - Implementation of an Italian multicentric care network for early HIV infection diagnosis: 1999-2001 report. [Articolo su rivista]
Capiluppi, B; Saracco, A; Gianotti, N; Mussini, Cristina; Butini, L; Tomasoni, L; De Gennaro, M; Rizzolo, L; Monolo, G; Cargnel, A; Moioli, C; Arici, C; Portelli, V; Rizzardini, G; Lazzarin, A; Tambussi, G.
abstract

BACKGROUND: Diagnosis of a new HIV infection during the primary phase (PHI) is sometimes misleading in a primary care setting. Since 1999 the Italian network for the study of acute HIV infection (ISAI) has been operative. At the time of PHI diagnosis the case is reported to the coordinating centre and enrolled in the National Register which records all epidemiological, demographic and clinical information. PATIENTS AND METHODS: From 1999 to September 2001, 51 symptomatic or asymptomatic patients with diagnosis of primary HIV infection were signalled to the coordinating centre. At screening, assessments were: interview to collect demographic and epidemiological data, clinical history (regarding PHI signs and symptoms) and, if available, relevant index case information; physical examination; routine hematology and chemistry; lymphocyte count; plasma HIV-RNA. In a subset of patients PBMC HIV-DNA, HIV-RNA, resistance genotyping and HIV subtype characterization were assessed. RESULTS: 74.5% of patients were males and all but four were Italian. Hetero and homosexual contacts were the prevalent route of HIV transmission. Forty-five patients (89%) were symptomatic and the most frequent signs and symptoms were: fever, lymphadenopathy, malaise and pharyngodinia. Baseline reverse-transcriptase (RT) and protease (PR) genotyping analysis was available for 29 patients. Only one of 29 patients harbored a virus with a resistance-associated mutation in the RT region (215Y); NNRTI mutations were identified in 3 of 29 patients. In the remaining 20 (69%) patients no mutations were found in the RT region. Sequence data from PR region were successfully obtained in 21 patients. Only one of these had a high-level resistance mutation (46L); in an additional 10 cases 1 or more secondary mutations were identified. The remaining 10 patients harbored a PR region wild type virus. One patient presenting two secondary mutations in the PR region, even if highly adherent and tolerant to drug regimen, showed a slow viral load decrease. CONCLUSIONS: Our cohort confirms the uptrend of new infections through unsafe sexual contacts involving both homosexual and heterosexual couples. Genotype sequencing for antiretroviral resistant viral variants describes a low prevalence of RT resistance-associated mutations, as well as primary mutations in the PR region. On the contrary, a higher prevalence of PR gene polymorphisms and mutations is not known with any certainty to confer resistance to NRTI and NNRTI. The identification of antiretroviral drug resistant HIV strains is strategic for clinical and therapeutical intervention, even though from a public health point of view cost-efficacy must be considered.

2002 - Kinetics of CD4 cells after discontinuation of antiretroviral therapy in patients with virological failure and a CD4 cell count grater than 500 cells [Articolo su rivista]
Mussini, Cristina; Bugarini, R.; Perno, C. F.; Antinori, A.; Borghi, V.; Bertoli, A.; D`arrigo, R.; Bedini, A.; Cossarizza, Andrea; Esposito, Roberto
abstract

After a median of 37 months on antiretroviral therapy, 16 patients were asked to discontinue treatment instead of changing it. After a median observation time of 10.5 months, most patients experienced a rapid and progressive decrease in their CD4 cell count, even without a high viral load rebound. This decline was unrelated to the CD4 cell count and HIV-RNA values at interruption, but was more profound in patients in whom the M184V mutation had disappeared after lamivudine discontinuation.

2002 - Kinetics of CD4 cells after discontinuation of antiretroviral therapy in patients with virological failure and a CD4 cell count greater than 500 cells/μl [Articolo su rivista]
Mussini, Cristina; Bugarini, R; Perno, Cf; Antinori, A; Borghi, V; Bertoli, A; D'Arrigo, R; Bedini, A; Mongiardo, N; Cossarizza, Andrea; Esposito, R.
abstract

After a median of 37 months on antiretroviral therapy, 16 patients were asked to discontinue treatment instead of changing it. After a median observation time of 10.5 months, most patients experienced a rapid and progressive decrease in their CD4 cell count, even without a high viral load rebound. This decline was unrelated to the CD4 cell count and HIV-RNA values at interruption, but was more profound in patients in whom the M184V mutation had disappeared after lamivudine discontinuation.

2002 - Mitochondria and HIV infection: the first decade. [Articolo su rivista]
Cossarizza, Andrea; Troiano, Leonarda; Mussini, Cristina
abstract

In the last few years, the interactions between mitochondria and infection with the human immunodeficiency virus (HIV) have received careful attention. Starting from the first studies regarding the presence of mitochondrial damage in cardiac tissue from patients who died of AIDS, researchers have investigated different aspects of the interactions between the virus and mitochondria, from acute primary infection to the final stages of the disease. Only recently a significant impulse to this type of research has come from the observation that the so called "highly active antiretroviral therapy" (HAART), a combination of potent antiretroviral drugs such as viral protease inhibitors or nucleoside-analogue reverse-transcriptase inhibitors, is capable of damaging these organelles and cause a clinical syndrome called lipodystrophy. There is still an open debate concerning the exact responsibility of HAART as well as on metabolic pathways and mechanisms that are involved in the onset of lipodystrophy. The hypothesis that drug-induced damage to mitochondrial (mt) DNA is able to alter mitochondria functionality to a similar extent as that occurring in genetic disease affecting mtDNA suggests that mitochondria plays a crucial role in the pathogenesis of this syndrome. In this paper, data concerning the interactions between mitochondria and HIV infection will be reviewed.

2002 - Mitochondrial functionality and mitochondrial DNA content in lymphocytes of vertically infected human immunodeficiency virus-positive children with highly active antiretroviral therapy-related lipodystrophy. [Articolo su rivista]
Cossarizza, Andrea; Pinti, Marcello; Moretti, L; Bricalli, D; Bianchi, R; Troiano, Leonarda; Fernandez, Mg; Balli, Fiorella; Brambilla, P; Mussini, Cristina; Viganò, A.
abstract

Mitochondria functionality and apoptosis were studied in peripheral blood lymphocytes (PBL) of human immunodeficiency virus type 1-infected children, with or without lipodystrophy (LD), who were receiving highly active antiretroviral therapy (HAART) and in PBL of healthy control subjects (HCs). By flow cytometry, mitochondrial (mt) membrane potential, mt mass, intra-mt cardiolipin distribution, and early and late apoptosis in fresh PBL or in PBL cultured with different stimuli were assessed. mtDNA content was evaluated in fresh PBL by an original double-competitive quantitative polymerase chain reaction method, which enabled direct quantification of the number of mtDNA copies present in human lymphocytes. PBL from LD-positive and LD-negative children and from HCs were similar in mt functionality and in their tendency to undergo apoptosis. mtDNA content was also similar in PBL of LD-positive children and HCs, suggesting that normal mt functionality and normal tendency to undergo apoptosis are present in PBL of children with HAART-associated LD.

2002 - Mitochondrial functionality and mitochondrial DNA content in lymphocytes of vertically-infected HIV+ children with HAART-related lipodystrophy [Articolo su rivista]
Cossarizza, Andrea; Pinti, Marcello; Moretti, L.; Bricalli, D.; Bianchi, R.; Troiano, L.; Garcia Fernandez, M.; Balli, Fiorella; Brambilla, P.; Mussini, Cristina; Viganò, A.
abstract

Mitochondria functionality and apoptosis were studied in peripheral blood lymphocytes (PBL) of human immunodeficiency virus type 1-infected children, with or without lipodystrophy (LD), who were receiving highly active antiretroviral therapy (HAART) and in PBL of healthy control subjects (HCs). By flow cytometry, mitochondrial (mt) membrane potential, mt mass, intra-mt cardiolipin distribution, and early and late apoptosis in fresh PBL or in PBL cultured with different stimuli were assessed. mtDNA content was evaluated in fresh PBL by an original double-competitive quantitative polymerase chain reaction method, which enabled direct quantification of the number of mtDNA copies present in human lymphocytes. PBL from LD-positive and LD-negative children and from HCs were similar in mt functionality and in their tendency to undergo apoptosis. mtDNA content was also similar in PBL of LD-positive children and HCs, suggesting that normal mt functionality and normal tendency to undergo apoptosis are present in PBL of children with HAART-associated LD.

2002 - Physician estimates of adherence and the patient-physician relationship as a setting to improve adherence to antiretroviral therapy [Articolo su rivista]
Murri, R; Antinori, A; Ammassari, A; Nappa, S; Orofino, G; Abrescia, N; Mussini, Cristina; D'Arminio Monforte, A; Wu, Aw; AdICoNA Study, Group
abstract

Physicians estimate their patients' adherence to medications, and base decisions about treatment on these estimates. In HIV, misjudgment of patient adherence can have adverse consequences, including withholding of therapy, unnecessary changes in therapy, or unnecessary laboratory testing. A review of the literature demonstrates that physicians are often inaccurate in estimating patient adherence with antiretroviral therapy. These findings have implications for practice. Standardized methods for adherence assessment are currently available that can be used to enhance physicians' ability to understand adherence behavior and barriers. The patient-physician relationship presents a unique setting for improving adherence. The authors propose interventions to improve adherence within the context of the patient-physician relationship at the physician level, interpersonal level, and organizational level. Improved communication, including discussion about patient lifestyle and preferences, can facilitate a frank exchange of information, negotiation, and a spirit of cooperation. Active patient participation in the decision-making process is crucial.

2002 - Test di sensibilità antimicotica in vitro su isolati di Candida spp. da emocolture di pazienti ospedalizzati [Abstract in Atti di Convegno]
Venturelli, C.; Bedini, A.; Guaraldi, Giovanni; Casolari, Chiara; Codeluppi, M.; La Regina, A.; Piccinini, Lino; Mussini, Cristina; Esposito, Roberto; Rumpianesi, F.
abstract

L'obiettivo del presente studio era quello di istituire un programma di sorveglianza prospettica per gli isolati di Candida spp. dalle emocolture di pazienti ricoverati presso il Policlinico di Modena e di valutare la sensibilità in vitro dei ceppi isolati nei confronti di quattro agenti antimicotici

2002 - Un raro caso di prostatite da Candida albicans, Candida krusei ed Enterococcus fecium [Abstract in Atti di Convegno]
Bedini, A.; Venturelli, C.; Mussini, Cristina; Guaraldi, Giovanni; Pellegrino, F.; Codeluppi, M.; Beghetto, Barbara; Nardini, Giulia; Rumpianesi, F.; Esposito, Roberto
abstract

Le infezioni micotiche dell'apparato urogenitale sono un evento relativamente frequente nei pazienti ospedalizzati e non. I principali fattori di rischio sono rappresentati da condizioni che alterano la flora microbica della mucosa urogenitale, stati di immunosoppressione locale e generale, e, sopprattutto, nei soggetti ospedalizzati, l'utilizzo del cateterismo vescicale. Le infezioni micotiche più frequenti sono la vaginite, l'uretrite, la cistite, la balanite.

2001 - Low frequency of severe hepatotoxicity and association with HCV coinfection in HIV-positive patients treated with HAART [Articolo su rivista]
Monforte Ade, A; Bugarini, R; Pezzotti, P; De Luca, A; Antinori, A; Mussini, Cristina; Vigevani, Gm; Tirelli, U; Bruno, R; Gritti, F; Piazza, M; Chigiotti, S; Chirianni, A; De Stefano, C; Pizzigallo, E; Perrella, O; Moroni, M; ICONA Study, Group
abstract

BACKGROUND: Highly active antiretroviral therapy (HAART) is strongly effective in reducing morbidity and mortality in HIV-1-positive individuals. Its main drawback is the potential toxicity. Data on the frequency and determinants of severe hepatotoxicity in a clinical setting are still sparse. METHODS: This is a prospective study of HIV-1-positive individuals with known HBsAg and HCV-Ab serology. The study end point was progression to alanine aminotransferase (ALT) levels > or =200 IU/L after HAART initiation. Cumulative probability of progression to this end point was estimated by the Kaplan-Meier method. Crude and adjusted hazard ratios (HR) were estimated by proportional hazards regression model. RESULTS: One thousand two hundred fifty-five patients were included. HBsAg was found in 91 (7.2%), HCV-Ab in 578 (46.5%) patients; almost all injection drug users (451 of 482; 93.6%) were HCV-Ab positive. Sixty-one individuals progressed to the end point with a probability of 7.9% (95% confidence interval [CI], 5.6-10.0) of progression at 24 months from starting. Independent factors predicting progression to the end point were baseline ALT levels (HR, 5.29; 95% CI, 3.24-8.65; every 10 IU/L higher), HCV-Ab positivity (HR, 4.01; 95% CI, 1.48-10.85) or both HBsAg and HCV Ab positivity (HR, 3.85, 95% CI, 1.01-14.61), and previous non-HAART therapy (HR, 1.84, 95% CI, 1.04-3.42). Patients receiving stavudine-containing regimens had a lower risk than those receiving zidovudine-containing regimens (HR, 0.30, 95% CI, 0.12-0.71). CONCLUSIONS: There was a low risk of ALT > or =200 IU/L in our cohort. Hepatitis C coinfection and elevated ALT levels at HAART initiation are important predictors of progression to ALT > or =200 IU/L; stavudine-containing regimens were associated with a lower risk compared with zidovudine-containing regimens.

2001 - Markers of cell death-activation in lymphocytes of vertically HIV-infected children naive to highly active antiretroviral therapy: the role of age. [Articolo su rivista]
Viganò, A; Pinti, Marcello; Nasi, Milena; Moretti, L; Balli, Fiorella; Mussini, Cristina; Bricalli, D; Sala, N; Bugarini, R; Vella, S; Principi, N; Cossarizza, Andrea
abstract

BACKGROUND: Apoptosis plays a major role in depleting CD4(+) lymphocytes during infection with HIV-1. Few data exist on its role during HIV infection of children. Sensitivity of peripheral blood lymphocytes (PBLs) to apoptotic stimuli and the importance of the patient's age remain unclear. OBJECTIVES: We sought to analyze the following: (1) markers of cell death-activation (CD95, CD45 isoforms, and CD28) in PBLs from vertically HIV-infected children of different ages before highly active antiretroviral therapy; (2) changes in other PBL populations; (3) PBL sensitivity to cell death and mitochondrial damages; and (4) role of age during progression of infection. METHODS: Cell culture techniques and flow cytometry were used to analyze surface antigens, PBL susceptibility to apoptosis, or PBL susceptibility to change of mitochondrial membrane potential. RESULTS: Donor age had a strong negative correlation with numbers of CD4(+) and CD8(+) T cells. Virgin T lymphocyte (CD45RA(+), CD95(-)) levels and those of CD95(+) cells showed no correlation with the children's clinical status but did show a correlation with patient age. CD28(-) T lymphocytes were markedly augmented in HIV-infected children but were unrelated to stage of infection or age. A relevant decrease in B lymphocytes and an increase in natural killer cells were also found. Finally, PBLs from HIV-positive children had a marked tendency to undergo apoptosis and mitochondrial damage. CONCLUSION: Changes in PBL phenotype, increased expression of CD95, and high sensitivity to apoptosis suggest that a precocious aging of the immune system occurs in HIV-infected children.

2001 - Mitochondria in the pathogenesis of lipodystrophy induced by anti-HIV antiretroviral drugs: actors or bystanders? [Articolo su rivista]
Cossarizza, Andrea; Mussini, Cristina; Viganò, A.
abstract

Effective therapies are now available that can stop the progression of HIV infection and significantly delay the onset of AIDS. The "highly active antiretroviral therapy" (HAART) is a combination of potent antiretroviral drugs such as viral protease inhibitors or nucleoside-analogue reverse-transcriptase inhibitors, that has a variety of serious side effects, including lipodystrophy, a pathology characterized by accumulation of visceral fat, breast adiposity, cervical fat-pads, hyperlipidemia, insulin resistance as well as fat wasting in face and limbs. There is still an open debate that concerns the precise responsibility of HAART as well as metabolic pathways and mechanisms that are involved in the onset of lipodystrophy. The similarities with multiple symmetric lipomatosis (MSL), in which mitochondria impairment plays a crucial role, lead to the hypothesis that drug-induced damages to mitochondrial DNA are able to alter mitochondria functionality to an extent that is similar to what occurs in MSL. In addition, several evidences indicate that HAART is also linked to a deregulated production of tumour necrosis factor-alpha, which uses mitochondria as intracellular targets. In this paper, we review data concerning the role of mitochondria in the pathogenesis of lipodystrophy, and advance a unifying hypothesis involving either direct or indirect effects of the drugs employed during HAART.

2000 - Deregulation of the CD95/CD95L system in lymphocytes from patients with primary acute HIV infection [Articolo su rivista]
Cossarizza, Andrea; Stent, G; Mussini, Cristina; Paganelli, R; Borghi, V; Nuzzo, C; Pinti, Marcello; Pedrazzi, J; Benatti, F; Esposito, Roberto; Røsok, B; Nagata, S; Vella, S; Franceschi, C; DE RIENZO, Bruno
abstract

OBJECTIVE: To analyze the role of CD95/CD95 ligand (CD95L) expression and functionality in peripheral blood lymphocytes (PBL) during primary, acute HIV syndrome (AHS) and in the subsequent period. PATIENTS: Twelve patients were studied during the acute phase of the viral infection and most were followed for some months. METHODS: Cell culture and cytotoxicity assays based upon 51Cr release and flow cytometry were used to evaluate cell killing via CD95 molecule, flow cytometry to assess surface antigens, enzyme-linked immunosorbent assay (ELISA) for the determination of soluble CD95 and CD95L plasma levels, quantitative competitive (QC) reverse transcription polymerase chain reaction (RT-PCR) with an original RNA competitor for the analysis of CD95L mRNA expression and QC RT-PCR for determining plasma viral load. RESULTS: The analysis of PBL during this phase revealed that almost all cells, including CD8 T cells with a virgin phenotype, B lymphocytes and natural killer cells displayed CD95 molecules on the plasma membrane. Activation of CD95 on the surface of isolated lymphocytes by anti-CD95 monoclonal antibodies or binding to CD95L induced rapid apoptosis. However, CD95L mRNA was not expressed in PBL from these patients and was poorly inducible. Soluble CD95 was found in the plasma of all patients, but only in a few at high levels, even some months after seroconversion. In contrast, soluble CD95L was detected in only one patient, this occurring after the symptomatic period. For 10 of the 12 patients, expression of CD95 on the cell membrane or in the plasma did not correlate with the plasma viral load, which varied widely from patient to patient. Further, plasma levels of soluble CD95 were not altered by decreased lymphocyte activation or by efficient antiretroviral therapy. CONCLUSIONS: In patients experiencing an acute, primary HIV infection, a prolonged deregulation of the CD95/CD95L system may exist, which is probably not entirely related to virus production but may contribute to the pathogenesis of the disease. The hypothesis can be put forward that a complex balance exists between proapoptotic events (increase in CD95 expression), probably triggered by the host as a method to limit viral production, and antiapoptotic events (decrease in CD95L expression) probably triggered by the virus as a way to increase its production and survival.

2000 - Discontinuation of primary prophylaxis for Pneumocystis carinii pneumonia and toxoplasmic encephalitis in human immunodeficiency virus type I-infected patients: The changes in opportunistic prophylaxis study [Articolo su rivista]
Mussini, Cristina; P., Pezzotti; A., Govoni; V., Borghi; A., Antinori; A. D., Monforte; A., De Luca; N., Mongiardo; M. C., Cerri; F., Chiodo; E., Concia; L., Bonazzi; M., Moroni; L., Ortona; Esposito, Roberto; Cossarizza, Andrea; B., De Rienzo
abstract

A multicenter open, randomized, controlled trial was conducted to determine whether primary proyhylaxis for Pneumocystis carinii pneumonia and toxoplasmic encephalitis can be discontinued in patients infected with human immunodeficiency virus type 1 (HIV-1) whose CD4(+) T cell counts have increased to &gt;200 cells/mm(3) (and who have remained at this level for at least 3 months) as a result of highly active antiretroviral therapy (HAART), Patients were randomized to either the discontinuation arm (i.e., those who discontinued prophylaxis; 355) or to the continuation arm (n = 353); the 2 arms of the study were similar in terms of demographic, clinical, and immunovirologic characteristics. During the median follow-ups of 6.4 months (discontinuation arm) and 6.1 months (continuation arm) and with a total of 419 patient-years, no patient developed P. carinii pneumonia or toxoplasmic encephalitis. The results of this study strongly indicate that primary prophylaxis for P. carinii pneumonia and toxoplasmic encephalitis can be safely discontinued in patients whose CD4(+) T cell counts increase to &gt;200 cells/mm(3) during HAART.

2000 - Quantitation of CD95 and CD95L mRNA expression in chronic and acute HIV-1 infection by competitive RT-PCR [Articolo su rivista]
Pinti, Marcello; Nasi, Milena; Moretti, L; Mussini, Cristina; Petrusca, D; Esposito, Roberto; Cossarizza, Andrea
abstract

Human immunodeficiency virus-type 1 (HIV-1) infection is characterized by increased immune cell apoptosis. Apoptosis can be triggered by signals that arise from within the cell, or by signals that are elicited by binding of extracellular death ligands to their death receptors, most of which belong to the tumor necrosis factor (TNF)-receptor family, such as CD95 (Fas/Apo-1). In immune cells the oligomerization of CD95, induced by its ligand CD95L, and the recruitment of different intracytoplasmic molecules that in turn activate FLICE/caspase 8 are crucial. To study the role of CD95/CD95L interactions during HIV-1 infection, we developed an original method based upon quantitative-competitive (QC) RT-PCR that allowed us to quantify the amounts of mRNA coding for the total (tCD95) and membrane (mCD95) forms of CD95. We first studied the expression of different forms of CD95 mRNA in a classical model of chronic HIV infection using two infected cell lines of different origin-lymphocytic (ACH-2) or monocytic (U1). We have shown that infected cells of monocytic origin preferentially produce the protective (soluble) form of CD95, and no detectable CD95L mRNA, while lymphoid cells produce more mRNA for the membrane form of CD95 (which triggers apoptosis) along with low but detectable amounts of CD95L mRNA. One can hypothesize that a complex balance exists between pro-apoptotic events, perhaps triggered by the host to limit viral production, and anti-apoptotic events likely triggered by the virus to increase its production and survival. In cells of monocytic origin, which act as a reservoir for the virus, the anti-apoptotic molecules are favored; in cells of lymphocytic origin, molecules with an apoptotic meaning are prevalent.

1999 - Apoptotic features of peripheral blood granulocytes and monocytes during primary, acute HIV infection. [Articolo su rivista]
Cossarizza, Andrea; Mussini, Cristina; Borghi, V; Mongiardo, N; Nuzzo, C; Pedrazzi, J; Benatti, F; Moretti, L; Pinti, Marcello; Paganelli, R; Franceschi, Claudio; DE RIENZO, Bruno
abstract

Apoptosis plays a major role during HIV infection, including the primary, acute HIV syndrome (AHS), during which such phenomenon is massive. We asked whether apoptosis involved not only peripheral blood lymphocytes, but also monocytes (PBM) and granulocytes (PBG). Thus, we studied cells from different patients during the acute phase of the viral syndrome. The CD95 molecule was expressed at high density on the PBM and PBG surface during AHS. Culturing PBG for a few hours resulted in a significant membrane expression of phosphatidylserine, consistent with apoptosis. However, cells maintained for hours plasma membrane integrity and showed no relevant changes in mitochondrial membrane potential. The overexpression of CD95 was not associated with high plasmatic levels of sCD95 and, together with apoptosis and its related markers decreased after a few weeks of highly active antiretroviral therapy. During AHS, a deregulation of the CD95 system occurs in monocytes and granulocytes, is related to a high propensity of PBG to undergo apoptosis, and may contribute to the pathogenesis of the disease. Antiretroviral treatment resulted not only in a decrease of virus production, but also in a reduced PBG tendency to undergo spontaneous apoptosis. Even if the mechanism(s) responsible for this phenomenon remains to be elucidated, our data suggest a possible (indirect?) action of antiretroviral therapies on PBG and PBM which could explain, at least partially, the rescue of natural immunity and the reduced use of granulocyte-colony stimulating factor during such treatments.

1999 - Differential down-regulation of CD95 or CD95L in chronically HIV-infected cells of monocytic or lymphocytic origin: cellular studies and molecular analysis by quantitative competitive RT-PCR. [Articolo su rivista]
Pinti, Marcello; Pedrazzi, J; Benatti, F; Sorrentino, V; Nuzzo, C; Cavazzuti, V; Biswas, P; Petrusca, Dn; Mussini, Cristina; DE RIENZO, Bruno; Cossarizza, Andrea
abstract

We analysed the expression of CD95/CD95L in two widely used models for studying the cellular effects of chronic infection with human immunodeficiency virus type 1 (HIV-1), i.e. ACH-2 cells, derived from the lymphocytic cell line A301, and U1, derived from monocytic U937 cells. A301 and ACH-2 mounted the same amount of plasma membrane CD95, while U1 had a consistent decrease in CD95 expression. Using different antibodies, we failed to detect the plasma membrane form of its ligand, CD95L, but we could see the intracellular presence of that molecule in A301 cells and, to a lesser extent, in ACH-2 cells, but not in U937 or U1 cells. To confirm the cytofluorimetric data and quantify the expression of CD95L at the RNA level, we developed a quantitative competitive RT-PCR assay. The HUT78 cell line had about 50,000 copies mRNA/1000 cells, three times more after induction with a phorbol ester and ionomycin. ACH-2 expressed about 400- (basal) or 10- (induced) fold less CD95L mRNA than the parental cell line A301; U937 and U1 were below the limit of detection. In cells of lymphoid origin (ACH-2) chronic HIV infection inhibits the expression of CD95L, the phenomenon occurring at the transcriptional level. In cells of monocytic origin (U1) the infection decreases the plasma membrane expression of CD95. This suggests that HIV could trigger different anti-apoptotic strategies which likely depend upon the cell line which is infected. In monocytic cells which act as a viral reservoir, the expression of the molecule whose binding triggers apoptosis decreases, while in lymphoid cells, capable of exerting cytotoxicity, the expression of a molecule which induces apoptosis is reduced.

1997 - Mitochondria alterations and dramatic tendency to undergo apoptosis in peripheral blood lymphocytes during acute HIV syndrome. [Articolo su rivista]
Cossarizza, Andrea; Mussini, Cristina; Mongiardo, N; Borghi, V; Sabbatini, A; DE RIENZO, Bruno; Franceschi, Claudio
abstract

OBJECTIVE: To study alterations of mitochondrial membrane potential (delta psi) and the propensity to undergo apoptosis in peripheral blood lymphocytes (PBL) from subjects with acute HIV syndrome; and to evaluate possible modulations of these phenomena by antioxidants that can be used in therapy, such as N-acetyl-cysteine (NAC), nicotinamide (NAM), or L-acetyl-carnitine (LAC). METHODS: Mitochondrial function and the tendency of PBL to undergo spontaneous apoptosis were studied on freshly collected PBL from patients with symptomatic, acute HIV-1 primary infection, which were cultured for different durations in the presence of absence of NAC. NAM or LAC. By a cytofluorimetric method allowing analysis of delta psi in intact cells, we studied the function of these organelles under the different conditions. PBL apoptosis was evaluated by the classic cytofluorimetric method of propidium iodide staining, capable of revealing the typical DNA hypodiploid peak. RESULTS: Significant delta psi alterations and tendency to undergo apoptosis were present in PBL from the subjects we studied. Indeed, when cultured even for a few hours in the absence of any stimulus, a consistent number of cells died. However, the presence of even different levels of NAC, NAM or LAC was able to rescue most of them from apoptosis. Both a fall in delta psi and apoptosis were evident in PBL collected in the earliest phases of the syndrome (before seroconversion), and changed significantly after a few days. A significant correlation was found between spontaneous apoptosis and tumour necrosis factor (TNF)-alpha or p24 plasma levels, as well as between apoptosis and the percentages of circulating CD4+ or CD8+ T cells. CONCLUSIONS: PBL from patients with acute HIV syndrome are characterized by both significant mitochondrial alterations and a dramatic tendency to undergo apoptosis. The use of NAC, NAM or LAC seems to rescue cells through a protective effect on mitochondria, a well-known target for the action of TNF-alpha and for reactive oxygen species, the production of which is strongly induced by this cytokine. Thus, our data could provide the rationale for the use of such agents in addition to antiviral drugs in primary infection.

1997 - Relevance of clinical and laboratory findings in the diagnosis of cytomegalovirus encephalitis in patients with AIDS. [Articolo su rivista]
Mussini, Cristina; Mongiardo, N; Manicardi, G; Trenti, F; Alessandrì, A; Paolillo, F; Catania, A; Portolani, Marinella; Pecorari, M; Borghi, V; Ficarra, G; Cossarizza, Andrea; DE RIENZO, Bruno
abstract

A retrospective evaluation was conducted in patients with AIDS and an autopsy diagnosis of cytomegalovirus (CMV) encephalitis to determine the relevance of clinical and laboratory findings in establishing a diagnosis. On autopsy of 100 patients, CMV encephalitis was diagnosed in 13 patients; eight had periventricular CMV encephalitis, four micronodular CMV encephalitis, and one both conditions. Seven patients had had a CMV infection previously (6 cases of retinitis, 1 case of colitis), and at the onset of encephalitis all of them were receiving a maintenance dose of ganciclovir. Examination of the CSF showed specific changes in patients with periventricular encephalitis. CT revealed no characteristic findings, while MRI showed an increased signal intensity on T2 weighted images. CMV DNA amplification by nested PCR was performed in nine patients with CMV encephalitis; PCR was positive in eight patients whose CSF was collected during CMV encephalitis, and negative in one patient whose CSF was collected six months before death. In conclusion, some clinical findings suggest a presumptive diagnosis, especially of periventricular encephalitis, and nested PCR appears to be a reliable and rapid technique for making an antemortem diagnosis.

1995 - Lack of selective V beta deletion in CD4+ or CD8+ T lymphocytes and functional integrity of T-cell repertoire during acute HIV syndrome [Articolo su rivista]
Cossarizza, Andrea; C., Ortolani; Mussini, Cristina; Guaraldi, Giovanni; N., Mongiardo; V., Borghi; D., Barbieri; E., Bellesia; Mg, Franceschini; B., Derienzo; C., Franceschi
abstract

Objective: To study the V beta T-cell repertoire in peripheral blood lymphocytes (PBL) during acute HIV syndrome by using several anti-V beta monoclonal antibodies (MAb) and to analyse its functionality by stimulating PBL with superantigens (SAg) such as Staphylococcus aureus enterotoxins. Methods: Cytofluorimetric analysis of V beta T-cell-receptor expression was performed on PBL from eight patients with symptomatic, acute HIV-1 primary infection, showing a dramatic decrease of CD4+ PBL accompanied by a marked increase in activated/memory CD8+ T cells, and on 12 age- and sex-matched healthy controls. PBL were then isolated, stimulated with different SAg, anti-CD3 MAb or phytohaemagglutinin and cultured for 3 days. PBL capability to progress through cell cycle was studied by the classic cytofluorimetric method of bromodeoxyuridine incorporation and DNA staining with propidium iodide. Results: Despite the presence of a few expansions of some V beta families among CD8+ T lymphocytes, no gross alterations in T-cell repertoire were present in patients with acute HIV syndrome. Its functionality was maintained overall, as PBL responsiveness to SAg was well preserved. Interestingly, all CD8+ T cells, although bearing different V beta T-cell receptors, expressed marked signs of activation, i.e., CD45R0, CD38 and major histocompatibility complex class II molecules, and also high amounts of CD11a and CD18. Conclusions: Our data suggest, at least in the early phases and in the acute form of the infection, that HIV is not likely to act as a SAg. However, further studies are needed to analyse other sites, such as lymph nodes, where HIV could exert other, significant effects, and to study the expression of other V beta families than those investigated here.

1995 - Massive activation of immune cells with an intact T cell repertoire in acute human immunodeficiency virus syndrome [Articolo su rivista]
Cossarizza, Andrea; C., Ortolani; Mussini, Cristina; V., Borghi; Guaraldi, Giovanni; N., Mongiardo; E., Bellesia; Mg, Franceschini; B., Derienzo; C., Franceschi
abstract

In 8 patients with symptomatic, acute primary infection with human immunodeficiency virus (HIV), a dramatic and persistent decrease in CD4(+) lymphocytes was seen, accompanied by a marked increase in activated/memory CD8(+) T cells (CD38(+), CD45R0(+), HLA-DR(+), with high amounts of cell adhesion molecules), which represented most circulating lymphocytes, but no gross alterations in vp T cell repertoire. Extremely high plasma levels of proinflammatory cytokines were observed. Three patients were followed for 2-3 years: The number of CD4(+) cells, extremely low at first, increased significantly in a few months but decreased rapidly after a short stable period. Cytotoxic T lymphocytes bearing markers of immunologic activation/memory could play an important role in the earliest phases of the disease. It remains to be established how such a dramatic onset could determine the rapid progression of the infection that seems characteristic of patients with acute HIV syndrome.

1995 - Non-typhoid Salmonella subdural empyema in a patient with AIDS [Articolo su rivista]
Mussini, Cristina; F., Trenti; Manicardi, Giuliano; N., Mongiardo; M., Codeluppi; L., Dandrea; Guaraldi, Giovanni; F., Squadrini; B., Derienzo
abstract

In AIDS patients, non-typhoid salmonella metastatic abscesses in lung and brain due to bacteremia have ben described previously, Here we present a case in which a group B Salmonella, serotype Copenhagen, caused right parietal subdural empyema, The etiologic diagnosis was based on culture of pus obtained from the lesion. The patient was treated for bacterial meningitis and made a good recovery. He is at present reasonably well and is taking ciprofloxacin as prophylaxis against salmonella relapse.

1991 - [Prognostic value of serum immunoglobulins in patients with hepatic cirrhosis]. [Articolo su rivista]
Cristani, A; Cioni, G; Mussini, Cristina; Tincani, E; Ventura, Ezio
abstract

Immunoglobulin (Ig) serum levels have been assayed in 729 patients with liver cirrhosis of different etiologies, in order to evaluate their prognostic value. Serum levels of three classes of Ig resulted mainly elevated in the three etiological groups (post-hepatitic, post-alcoholic, cryptogenetic) and they were significantly related to the severity of the liver disease, evaluated according to the Child-Turcotte score. The computerized analysis of the survival curves of patients with IgG, IgM, IgA values normal or elevated demonstrated an adverse prognostic rate in those with elevated Ig values. The difference among the survival curves, compared by the Lee-Desu method, was statistically significant (p less than 0.001). Our data suggest that the Ig levels can be considered as a prognostic index in liver cirrhosis patients.

1990 - Fructosamine and glycated hemoglobin as indices of glycemic control in patients with liver cirrhosis. [Articolo su rivista]
Trenti, T; Cristani, A; Cioni, G; Pentore, R; Mussini, Cristina; Ventura, Ezio
abstract

Glucose intolerance often occurs in liver cirrhosis; therefore a long-term control of plasma glucose levels appears to be important. For this purpose glycated hemoglobin A (HbA1c) determination is proposed as a suitable method, while no data are available on fructosamine test. In 98 cirrhotic patients serum fructosamine and HbA1c levels were compared with those of normal controls and among cirrhotic patients grouped in non glucose-intolerant and with non insulin-dependent (NIDDM) or insulin-dependent diabetes mellitus (IDDM). The mean HbA1c values of cirrhotic patients with normal glycemic control were significantly lower than normal, and only a few IDDM and NIDDM cirrhotic patients showed high values of HbA1c, indicating that HbA1c is often underestimated in these patients. On the contrary, serum fructosamine levels were on the average higher than normal in nondiabetic patients, but they were significantly higher in IDDM and NIDDM patients than in nondiabetics, and the 72% of NIDDM and 85% of IDDM patients had fructosamine levels higher than the upper normal value. In conclusion, in diabetic patients with liver cirrhosis fructosamine seems to be a more suitable test than HbA1c for monitoring blood glucose levels.

1990 - Incidence and clinical significance of elevated fibrin(ogen) degradation product and/or D-dimer levels in liver cirrhosis patients. [Articolo su rivista]
Cioni, G; Cristani, A; Mussini, Cristina; Grandi, S; Pentore, R; Tizzanini, W; Zagni, G; Ventura, E.; Zeneroli, Maria Luisa
abstract

Fibrin(ogen) degradation product (FDP) and D-dimer levels were evaluated in 168 liver cirrhosis (LC) patients without evidence of bleeding. Eighty-two (48%) had FDP higher than 10 micrograms/ml; only 43 of them had a concomitant increase of D-dimer. These alterations were more frequent in older and decompensated patients and correlated to the Child-Turcotte score. In the patients with elevated FDP and/or D-dimer levels the mean values of platelets, prothrombin activity and fibrinogen were not significantly different from those of the other patients and remained fairly stable over the period of the study. Finally, an increase of FDP is frequent in LC and this may suggest a diagnosis of disseminated intravascular coagulation (DIC), but a concomitant increase of D-dimer is rarely detectable, thus excluding this diagnosis. Moreover, even in the cases with increased levels of D-dimer the presence of clinical or laboratory evidence of a consumption coagulopathy, expression of a manifest DIC, seems to be unusual.

1990 - [A proposed method for the laboratory diagnosis of disseminated intravascular coagulation in liver cirrhosis]. [Articolo su rivista]
Cristani, A; Cioni, G; Mussini, Cristina; Pentore, R; Zagni, G; Ventura, Ezio
abstract

Laboratory diagnosis of disseminated intravascular coagulation (DIC) in liver cirrhosis (LC) could be complicated by the presence of the usual decrement of the hemocoagulative parameters and of an increase of the fibrinogen/fibrin degradation products (FDP). The D-dimer test, more sensible than the one for FDP and specific for the cross-linked fibrin degradation products is now available. A significant difference between the two tests, assayed simultaneously has been demonstrated in 217 LC patients, without any recent or present hemorrhagic signs. The D-dimer was increased in only 60 of the 108 patients with high values of FDP; therefore this test has a screening value higher than FDP. If only the D-dimer is elevated, the FDP assay is indicated: if FDP are normal a thrombosis may be present and, finally, if the FDP are also increased with a concomitant decrement of fibrinogenemia, the laboratory diagnosis of DIC is reasonably certain.

1990 - [Doppler flowmetry in the study of portal hypertension in patients with liver cirrhosis. Qualitative and quantitative analyses]. [Articolo su rivista]
D'Alimonte, P; Cioni, G; Cristani, A; Leoni, A; Cerofolini, E; Ferrari, A; Pentore, R; Mussini, Cristina; Ventura, Ezio; Romagnoli, R.
abstract

The recent development of the duplex-Doppler technique, which combined real-time US with pulsed Doppler flowmetry, has allowed the flowmetric hemodynamic study of large abdominal vessels. As yet, however, both accuracy and possible applications of this method in the study of portal hypertension have not been fully investigated. This study was aimed at assessing whether or not the combined use of Doppler flowmetry and bidimensional US is able to detect portal hypertension in patients with liver cirrhosis (LC), and could therefore represent a valid alternative to endoscopic, angiographic, and direct pressure measurement techniques. Twenty-six patients with LC and 25 control patients were studied with a strictly standardized method; portal hypertension was detected in the patients with LC by EGDS and laparoscopy. The results demonstrated pulsed duplex-Doppler US to be able to detect portal hypertension in 92.4% of LC patients, with 2 false negatives only (7.6%). The difference in the flowmetric data of normal and LC patients was highly significant (p less than 0.001 Student's t test). In conclusion, duplex-Doppler US can be considered as a valid technique to detect portal hypertension in LC patients, and can thus be used as an alternative to more invasive techniques of general use in clinics.

1989 - [Role of combined etiology (alcohol and B virus) in the development of hepatocarcinoma in subjects with liver cirrhosis]. [Articolo su rivista]
Cristani, A; Pentore, R; Cioni, G; Mussini, Cristina; Grandi, S; Ventura, Ezio
abstract

107 (8.2%) of 1297 patients with liver cirrhosis admitted to our Clinic between 1980 and 1987 had hepatocellular carcinoma (HCC). This disorder was more frequent in patients with liver cirrhosis of dual etiology, alcoholic and post-hepatitic (9.9%), than in those with liver cirrhosis of unknown (7.82%), alcoholic (9.35%) or post-hepatitic (5.16%) etiology. The mean age of the patients with HCC of dual etiology (51.2 years) was significantly lower than that of the other three groups (61.0, 62.0 and 64.5 years, respectively; p less than 0.001). The conclusion is that in patients with liver cirrhosis of dual etiology the onset of HCC is frequent and precocious. This fact must be considered in epidemiological studies, in the prognosis and in the clinical management of the patient since early diagnosis is of importance in deciding therapy.

1988 - Effect of amrinone on myocardial mitochondria function. [Articolo su rivista]
Bobyleva Guarriero, V; Mussini, Cristina; Muscatello, U; Cappello, C; Mattioli, G.
abstract

The effect of amrinone on cardiac mitochondria of guinea pig was studied. It was found that amrinone does not change the respiratory function of cardiac mitochondria in the presence of alpha-ketoglutarate, whereas it inhibits glutamate oxidation. It was also found that amrinone strongly inhibits the activity of glutamic dehydrogenase of both crude extract from sonicated heart mitochondria and of purified preparation from bovine liver. This inhibition may explain the effect of amrinone on the oxidation of glutamate in mitochondria. These results are discussed in view of https://www.unimore.u-gov.it/unimore/#the contradictory effects of amrinone on cardiac and other tissues.