Pietro ANDREONE - personale UniMoRe

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Pietro ANDREONE

Professore Associato
Dipartimento di Scienze Mediche e Chirurgiche Materno-Infantili e dell'Adulto

Pubblicazioni

2023 - Adherence to Mediterranean diet in liver transplant recipients: a cross-sectional multicenter study [Articolo su rivista]
Gitto, Stefano; Golfieri, Lucia; Sofi, Francesco; Tamè, Maria R; Vitale, Giovanni; DE Maria, Nicola; Marzi, Luca; Mega, Andrea; Valente, Giovanna; Borghi, Alberto; Forte, Paolo; Cescon, Matteo; DI Benedetto, Fabrizio; Andreone, Pietro; Petranelli, Marco; Dinu, Monica; Carrai, Paola; Arcangeli, Giulio; Grandi, Silvana; Lau, Chloe; Morelli, Maria Cristina; DE Simone, Paolo; Chiesi, Francesca; Marra, Fabio
abstract

Background: Seeing the importance of healthy diet after liver transplant (LT), our study aimed to evaluate the adherence to Mediterranean diet (MD) in a large population of LT recipients. Methods: The present multicenter study was developed in clinically stable, liver transplanted patients, from June to September 2021. Patients completed a survey about adherence to MD, Quality of Life (QoL), sport, and employment. To analyze the correlations, we computed Pearson's coefficients; while to compare subgroups, independent samples t-tests and ANOVAs. We used a multivariable logistic regression analysis to find the predictors of impaired adherence to MD. Results: The questionnaire was administered to 511 patients. They were males in 71% of cases with a mean age of 63.1 years (SD±10.8). LT recipients coming from central Italy displayed higher adherence to the MD (M=11.10±1.91) than patients from northern (M=9.94±2.28, P<0.001) or southern Italy (M=10.04±2.16, P<0.001). Patients from central Italy showed a significantly higher consumption of fruit, vegetables, legumes, cereals, olive oil, fish and a significantly lower intake of dairy products than patients resident in the other Italian areas. At multivariate analysis, recipients from central Italy were 3.8 times more likely to report adherence to the MD. Patients with a high physical health score were more adherent to MD, as well as patients transplanted at an earlier time. Conclusions: We demonstrated that place of stay, time from transplant and physical dimension of QoL significantly influences the adherence to MD. Continuous information campaigns about a correct diet and lifestyle would be necessary.

2023 - Seladelpar efficacy and safety at 3 months in patients with primary biliary cholangitis: ENHANCE, a phase 3, randomized, placebo-controlled study [Articolo su rivista]
Hirschfield, Gideon M; Shiffman, Mitchell L; Gulamhusein, Aliya; Kowdley, Kris V; Vierling, John M; Levy, Cynthia; Kremer, Andreas E; Zigmond, Ehud; Andreone, Pietro; Gordon, Stuart C; Bowlus, Christopher L; Lawitz, Eric J; Aspinall, Richard J; Pratt, Daniel S; Raikhelson, Karina; Gonzalez-Huezo, Maria S; Heneghan, Michael A; Jeong, Sook-Hyang; Ladrón de Guevara, Alma L; Mayo, Marlyn J; Dalekos, George N; Drenth, Joost P H; Janczewska, Ewa; Leggett, Barbara A; Nevens, Frederik; Vargas, Victor; Zuckerman, Eli; Corpechot, Christophe; Fassio, Eduardo; Hinrichsen, Holger; Invernizzi, Pietro; Trivedi, Palak J; Forman, Lisa; Jones, David E J; Ryder, Stephen D; Swain, Mark G; Steinberg, Alexandra; Boudes, Pol F; Choi, Yun-Jung; Mcwherter, Charles A; Carubbi, F
abstract

Background and Aims: ENHANCEwas a phase 3 study that evaluated efficacy and safety of seladelpar, a selective peroxisome proliferator-activated receptor-delta (PPAR) agonist, versus placebo in patients with primary biliary cholangitis with inadequate response or intolerance to ursodeoxycholic acid (UDCA).Approach and Results: Patients were randomized 1:1:1 to oral seladelpar 5 mg (n= 89), 10 mg (n= 89), placebo (n= 87) daily (with UDCA, as appropriate). Primary end point was a composite biochemical response [alkaline phosphatase (ALP) < 1.67xupper limit of normal (ULN), >= 15% ALP decrease from baseline, and total bilirubin <= ULN] at month 12. Key secondary end points were ALP normalization at month 12 and change in pruritus numerical rating scale (NRS) at month 6 in patients with baseline score >= 4. Aminotransferases were assessed. ENHANCE was terminated early following an erroneous safety signal in a concurrent, NASH trial. While blinded, primary and secondary efficacy end points were amended to month 3. Significantly more patients receiving seladelpar met the primary end point (seladelpar 5 mg: 57.1%, 10mg: 78.2%) versus placebo (12.5%) (p < 0.0001). ALP normalization occurred in 5.4% (p= 0.08) and 27.3% (p < 0.0001) of patients receiving 5 and 10 mg seladelpar, respectively, versus 0% receiving placebo. Seladelpar 10 mg significantly reduced mean pruritus NRS versus placebo [10 mg: -3.14 (p= 0.02); placebo: -1.55]. Alanine aminotransferase decreased significantly with seladelpar versus placebo [5 mg: 23.4% (p= 0.0008); 10 mg: 16.7% (p= 0.03); placebo: 4%]. There were no serious treatment-related adverse events.Conclusions: Patients with primary biliary cholangitis (PBC) with inadequate response or intolerance to UDCA who were treated with seladelpar 10 mg had significant improvements in liver biochemistry and pruritus. Seladelpar appeared safe and well tolerated.

2023 - Treatment Options for Hepatitis A and E: A Non-Systematic Review [Articolo su rivista]
Gabrielli, F.; Alberti, F.; Russo, C.; Cursaro, C.; Seferi, H.; Margotti, M.; Andreone, P.
abstract

Hepatitis A and hepatitis E are relatively common causes of liver disease. Both viruses are mainly transmitted through the faecal–oral route and, consequently, most outbreaks occur in countries with poor sanitation. An important role of the immune response as the driver of liver injury is also shared by the two pathogens. For both the hepatitis A (HAV) and hepatitis E (HEV) viruses, the clinical manifestations of infection mainly consist of an acute disease with mild liver injury, which results in clinical and laboratory alterations that are self-limiting in most cases. However, severe acute disease or chronic, long-lasting manifestations may occur in vulnerable patients, such as pregnant women, immunocompromised individuals or those with pre-existing liver disease. Specifically, HAV infection rarely results in fulminant hepatitis, prolonged cholestasis, relapsing hepatitis and possibly autoimmune hepatitis triggered by the viral infection. Less common manifestations of HEV include extrahepatic disease, acute liver failure and chronic HEV infection with persistent viraemia. In this paper, we conduct a non-systematic review of the available literature to provide a comprehensive understanding of the state of the art. Treatment mainly consists of supportive measures, while the available evidence for aetiological treatment and additional agents in severe disease is limited in quantity and quality. However, several therapeutic approaches have been attempted: for HAV infection, corticosteroid therapy has shown outcome improvement, and molecules, such as AZD 1480, zinc chloride and heme oxygenase-1, have demonstrated a reduction in viral replication in vitro. As for HEV infection, therapeutic options mainly rely on the use of ribavirin, and some studies utilising pegylated interferon-alpha have shown conflicting results. While a vaccine for HAV is already available and has led to a significant reduction in the prevalence of the disease, several vaccines for HEV are currently being developed, with some already available in China, showing promising results.

2022 - A prospective study of direct-acting antiviral effectiveness and relapse risk in HCV cryoglobulinemic vasculitis by the Italian PITER cohort [Articolo su rivista]
Kondili, L. A.; Monti, M.; Quaranta, M. G.; Gragnani, L.; Panetta, V.; Brancaccio, G.; Mazzaro, C.; Persico, M.; Masarone, M.; Gentile, I.; Andreone, P.; Madonia, S.; Biliotti, E.; Filomia, R.; Puoti, M.; Fracanzani, A. L.; Laccabue, D.; Ieluzzi, D.; Coppola, C.; Rumi, M. G.; Benedetti, A.; Verucchi, G.; Coco, B.; Chemello, L.; Iannone, A.; Ciancio, A.; Russo, F. P.; Barbaro, F.; Morisco, F.; Chessa, L.; Massari, M.; Blanc, P.; Zignego, A. L.
abstract

Background and Aims: Mixed cryoglobulinemia is the most common HCV extrahepatic manifestation. We aimed to prospectively evaluate the cryoglobulinemic vasculitis (CV) clinical profile after a sustained virologic response (SVR) over a medium-term to long-term period. Approach and Results: Direct-acting antiviral–treated cryoglobulinemic patients, consecutively enrolled in the multicentric Italian Platform for the Study of Viral Hepatitis Therapy cohort, were prospectively evaluated. Cumulative incidence Kaplan-Meier curves were reported for response, clinical deterioration, relapse and relapse-free survival rates. Cox regression analysis evaluated factors associated with different outcomes. A clinical response was reported in at least one follow-up point for 373 of 423 (88%) patients with CV who achieved SVR. Clinical response increased over time with a 76% improvement rate at month 12 after the end of treatment. A full complete response (FCR) was reached by 164 (38.8%) patients in at least one follow-up point. CV clinical response fluctuated, with some deterioration of the initial response in 49.6% of patients (median time of deterioration, 19 months). In patients who achieved FCR and had an available follow-up (137 patients) a relapse was observed in 13% and it was transient in 66.7% of patients. The rate of patients without any deterioration was 58% and 41% at 12 and 24 months, respectively. After achieving SVR, a clinical nonresponse was associated with older age and renal involvement; a clinical deterioration/relapse was associated with high pretreatment rheumatoid factor values, and FCR was inversely associated with age, neuropathy, and high cryocrit levels. Conclusion: In patients with CV, HCV eradication may not correspond to a persistent clinical improvement, and clinical response may fluctuate. This implies an attentive approach to post-SVR evaluation through prognostic factors and tailored treatment.

2022 - Atopic dermatitis associated with autoimmune, cardiovascular and mental health comorbidities: a systematic review and meta-analysis [Articolo su rivista]
Chester, J.; Kaleci, S.; Liberati, S.; Alicandro, T.; Rivi, M.; Bonzano, L.; Guanti, M.; Andreone, P.; Pellacani, G.
abstract

Background: Previous studies have reported conflicting estimates of associations between atopic dermatitis (AD) and autoimmune, cardiovascular and mental health comorbidities. Objectives: Our objective was to determine and report these global associations based on a systematic literature review. Materials & Methods: A systematic search of studies published in PubMed/MEDLINE and Cochrane Library (January 1990–April 2020) including patients with physician-diagnosed AD and concurrent populations, were identified. The metanalysis (random-effect model) included 37 studies. Studies originated from Europe, UK, Asia, The USA and Canada, including 237,226,993 patients and subjects with 20 autoimmune, eight cardiovascular and eight mental illnesses. Results: Pooled analyses revealed significantly higher overall odds of autoimmune diseases (OR: 1.74; 95% CI: 1.55–1.94, p < 0.001; I2:98.39%) and mental illnesses (OR: 1.62; 95% CI: 1.53–1.72; p < 0.001; I2: 98.86%) and a smaller increased risk for cardiovascular diseases (OR: 1.08; 95% CI: 0.01–1.16, p < 0.001; I2: 99.45%). Conclusion: Our systematic review highlights that AD patients are at significantly increased risk for many autoimmune diseases and mental illnesses and at a relatively lower risk for cardiovascular diseases. Updated global estimates should encourage physician/patient empowerment to seek further medical and wellness interventions for optimal patient care

2022 - Corrigendum to ‘An international genome-wide meta-analysis of primary biliary cholangitis: Novel risk loci and candidate drugs’ [J Hepatol 2021;75(3):572–581] (Journal of Hepatology (2021) 75(3) (572–581), (S0168827821003342), (10.1016/j.jhep.2021.04.055)) [Articolo su rivista]
Cordell, H. J.; Fryett, J. J.; Ueno, K.; Darlay, R.; Aiba, Y.; Hitomi, Y.; Kawashima, M.; Nishida, N.; Khor, S. -S.; Gervais, O.; Kawai, Y.; Nagasaki, M.; Tokunaga, K.; Tang, R.; Shi, Y.; Li, Z.; Juran, B. D.; Atkinson, E. J.; Gerussi, A.; Carbone, M.; Asselta, R.; Cheung, A.; de Andrade, M.; Baras, A.; Horowitz, J.; Ferreira, M. A. R.; Sun, D.; Jones, D. E.; Flack, S.; Spicer, A.; Mulcahy, V. L.; Byun, J.; Han, Y.; Sandford, R. N.; Lazaridis, K. N.; Amos, C. I.; Hirschfield, G. M.; Seldin, M. F.; Invernizzi, P.; Siminovitch, K. A.; Ma, X.; Nakamura, M.; Mells, G. F.; Mason, A.; Vincent, C.; Xie, G.; Zhang, J.; Affronti, A.; Almasio, P. L.; Alvaro, D.; Andreone, P.; Andriulli, A.; Azzaroli, F.; Battezzati, P. M.; Benedetti, A.; Bragazzi, M. C.; Brunetto, M.; Bruno, S.; Calvaruso, V.; Cardinale, V.; Casella, G.; Cazzagon, N.; Ciaccio, A.; Coco, B.; Colli, A.; Colloredo, G.; Colombo, M.; Colombo, S.; Cristoferi, L.; Cursaro, C.; Croce, L. S.; Crosignani, A.; D'Amato, D.; Donato, F.; Elia, G.; Fabris, L.; Fagiuoli, S.; Ferrari, C.; Floreani, A.; Galli, A.; Giannini, E.; Grattagliano, I.; Lampertico, P.; Lleo, A.; Malinverno, F.; Mancuso, C.; Marra, F.; Marzioni, M.; Massironi, S.; Mattalia, A.; Miele, L.; Milani, C.; Morini, L.; Morisco, F.; Muratori, L.; Muratori, P.; Niro, G. A.; O'Donnell, S.; Picciotto, A.; Portincasa, P.; Rigamonti, C.; Ronca, V.; Rosina, F.; Spinzi, G.; Strazzabosco, M.; Tarocchi, M.; Tiribelli, C.; Toniutto, P.; Valenti, L.; Vinci, M.; Zuin, M.; Nakamura, H.; Abiru, S.; Nagaoka, S.; Komori, A.; Yatsuhashi, H.; Ishibashi, H.; Ito, M.; Migita, K.; Ohira, H.; Katsushima, S.; Naganuma, A.; Sugi, K.; Komatsu, T.; Mannami, T.; Matsushita, K.; Yoshizawa, K.; Makita, F.; Nikami, T.; Nishimura, H.; Kouno, H.; Kouno, H.; Ota, H.; Komura, T.; Nakamura, Y.; Shimada, M.; Hirashima, N.; Komeda, T.; Ario, K.; Nakamuta, M.; Yamashita, T.; Furuta, K.; Kikuchi, M.; Naeshiro, N.; Takahashi, H.; Mano, Y.; Tsunematsu, S.; Yabuuchi, I.; Shimada, Y.; Yamauchi, K.; Sugimoto, R.; Sakai, H.; Mita, E.; Koda, M.; Tsuruta, S.; Kamitsukasa, H.; Sato, T.; Masaki, N.; Kobata, T.; Fukushima, N.; Ohara, Y.; Muro, T.; Takesaki, E.; Takaki, H.; Yamamoto, T.; Kato, M.; Nagaoki, Y.; Hayashi, S.; Ishida, J.; Watanabe, Y.; Kobayashi, M.; Koga, M.; Saoshiro, T.; Yagura, M.; Hirata, K.; Tanaka, A.; Takikawa, H.; Zeniya, M.; Abe, M.; Onji, M.; Kaneko, S.; Honda, M.; Arai, K.; Arinaga-Hino, T.; Hashimoto, E.; Taniai, M.; Umemura, T.; Joshita, S.; Nakao, K.; Ichikawa, T.; Shibata, H.; Yamagiwa, S.; Seike, M.; Honda, K.; Sakisaka, S.; Takeyama, Y.; Harada, M.; Senju, M.; Yokosuka, O.; Kanda, T.; Ueno, Y.; Kikuchi, K.; Ebinuma, H.; Himoto, T.; Yasunami, M.; Murata, K.; Mizokami, M.; Kawata, K.; Shimoda, S.; Miyake, Y.; Takaki, A.; Yamamoto, K.; Hirano, K.; Ichida, T.; Ido, A.; Tsubouchi, H.; Chayama, K.; Harada, K.; Nakanuma, Y.; Maehara, Y.; Taketomi, A.; Shirabe, K.; Soejima, Y.; Mori, A.; Yagi, S.; Uemoto, S.; H, E.; Tanaka, T.; Yamashiki, N.; Tamura, S.; Sugawara, Y.; Kokudo, N.; Chalasani, N.; Luketic, V.; Odin, J.; Chopra, K.; Abecasis, G.; Cantor, M.; Coppola, G.; Economides, A.; Lotta, L. A.; Overton, J. D.; Reid, J. G.; Shuldiner, A.; Beechert, C.; Forsythe, C.; Fuller, E. D.; Gu, Z.; Lattari, M.; Lopez, A.; Schleicher, T. D.; Padilla, M. S.; Toledo, K.; Widom, L.; Wolf, S. E.; Pradhan, M.; Manoochehri, K.; Ulloa, R. H.; Bai, X.; Balasubramanian, S.; Barnard, L.; Blumenfeld, A.; Eom, G.; Habegger, L.; Hawes, A.; Khalid, S.; Maxwell, E. K.; Salerno, W.; Staples, J. C.; Jones, M. B.; Mitnaul, L. J.; Sturgess, R.; Healey, C.; Yeoman, A.; Gunasekera, A. V. J.; Kooner, P.; Kapur, K.; Sathyanarayana, V.; Kallis, Y.; Subhani, J.; Harvey, R.; Mccorry, R.; Rooney, P.; Ramanaden, D.; Evans, R.; Mathialahan, T.; Gasem, J.; Shorrock, C.; Bhalme, M.; Southern, P.; Tibble, J. A.; Gorard, D. A.; Jones, S.; Mells, G.; Mulcahy, V.; Srivastava, B.; Foxton, M. R.; Collins, C. E.; Elphick, D.; Karmo, M.; Porras-Perez, F.; Mendall, M.; Yapp, T.; Patel, M.; Ede, R.
abstract

It has come to our attention that the name of one of the authors in our manuscript was incorrectly spelled ‘Jinyoung Byan’; the correct spelling is ‘Jinyoung Byun’ as in the author list above. In addition, the excel files of the supplementary tables were not included during the online publication of our article. These have now been made available online. We apologize for any inconvenience caused.

2022 - Global multi-stakeholder endorsement of the MAFLD definition [Articolo su rivista]
Mendez-Sanchez, N.; Bugianesi, E.; Gish, R. G.; Lammert, F.; Tilg, H.; Nguyen, M. H.; Sarin, S. K.; Fabrellas, N.; Zelber-Sagi, S.; Fan, J. -G.; Shiha, G.; Targher, G.; Zheng, M. -H.; Chan, W. -K.; Vinker, S.; Kawaguchi, T.; Castera, L.; Yilmaz, Y.; Korenjak, M.; Spearman, C. W.; Ungan, M.; Palmer, M.; El-Shabrawi, M.; Gruss, H. -J.; Dufour, J. -F.; Dhawan, A.; Wedemeyer, H.; George, J.; Valenti, L.; Fouad, Y.; Romero-Gomez, M.; Eslam, M.; Abate, M. L.; Abbas, B.; Abbassy, A. A.; Abd El Ghany, W.; Abd Elkhalek, A.; Abd ElMajeed, E.; Abdalgaber, M.; Abdallah, M.; Abdallah, M.; Abdallah, N.; Abdelaleem, S.; Abdelghani, Y.; Abdelghany, W.; Abdelhalim, S. M.; Abdelhamid, W.; Abdelhamid, N.; Abdelkader, N. A.; Abdelkreem, E.; Abdelmohsen, A. M.; Abdelrahman, A. A.; Abd-elsalam, S. M.; Abdeltawab, D.; Abduh, A.; Abdulhakam, N.; Abdulla, M.; Abedpoor, N.; Abenavoli, L.; Aberg, F.; Ablack, O.; Abo elftouh, M.; Abo-Amer, Y. E. -E.; Aboubkr, A.; Aboud, A.; Abouelnaga, A. M.; Aboufarrag, G. A.; Aboutaleb, A.; Abundis, L.; Adali, G.; Adames, E.; Adams, L.; Adda, D.; Adel, N.; Adel, N.; Adel Sayed, M.; Afaa, T. J.; Afredj, N.; Aghayeva, G.; Aghemo, A.; Aguilar-Salinas, C. A.; Ahlenstiel, G.; Ahmady, W.; Ahmed, W.; MOHAMED IBRAHIM HELAL, Ahmed; Ahmed, S. N.; Ahmed, H. M.; Ahmed, R.; Aigner, E.; Akarsu, M.; Akroush, M.; Akyuz, U.; Al Mahtab, M.; Al Qadiri, T.; Al Rawahi, Y.; AL rubaee, R.; Al Saffar, M.; Alam, S.; Al-Ani, Z.; Albillos, A.; Alboraie, M.; Al-Busafi, S.; Al-Emam, M.; Alharthi, J.; Ali, K.; Ali, B. A.; Ali, M.; Ali, R. A. R.; Alisi, A.; AL-Khafaji, A. R.; Alkhatry, M.; Aller, R.; Almansoury, Y.; Al-Naamani, K.; Alnakeeb, A.; Alonso, A.; Alqahtani, S. A.; Alrabadi, L.; Alswat, K.; Altaher, M.; Altamimi, T.; Altamirano, J.; Alvares-da-Silva, M. R.; Aly, E. A. M.; Alzahaby, A.; Alzamzamy, A.; Amano, K.; Amer, M. A.; Amin, M. A.; Amin, S. A.; Amir, A. A.; Ampuero, J.; Anas, N.; Andreone, P.; Andriamandimby, S. F.; Anees, M.; Angela, P.; Antonios, M.; Arafat, W.; Araya, J. M.; Armendariz-Borunda, J.; Armstrong, M. J.; Ashktorab, H.; Aspichueta, P.; Assal, F.; Atef, M.; Attia, D.; Atwa, H.; Awad, R.; Awad, M. A. E.; Awny, S.; Awolowo, O.; Awuku, Y. A.; Ayada, I.; Aye, T. T.; Ayman, S.; Ayman, H.; Ayoub, H.; Azmy, H. M.; Babaran, R. P.; Badreldin, O.; Badry, A.; Bahcecioglu, I. H.; Bahour, A.; Bai, J.; Balaban, Y.; Balasubramanyam, M.; Bamakhrama, K.; Banales, J. M.; Bangaru, B.; Bao, J.; Barahona, J. S.; Barakat, S.; Barbalho, S. M.; Barbra, B.; Barranco, B.; Barrera, F.; Baumann, U.; Bazeed, S.; Bech, E.; Benayad, A.; Benesic, A.; Bernstein, D.; Bessone, F.; Birney, S.; Bisseye, C.; Blake, M.; Bobat, B.; Bonfrate, L.; Bordin, D. S.; Bosques-Padilla, F.; Boursier, J.; Boushab, B. M.; Bowen, D.; Bravo, P. M.; Brennan, P. N.; Bright, B.; Broekaert, I.; Buque, X.; Burgos-Santamaria, D.; Burman, J.; Busetto, L.; Byrne, C. D.; Cabral-Prodigalidad, P. A. I.; Cabrera-Alvarez, G.; Cai, W.; Cainelli, F.; Caliskan, A. R.; Canbay, A.; Cano-Contreras, A.; Cao, H. -X.; Cao, Z.; Carrion, A.; Carubbi, F.; Casanovas, T.; Castellanos Fernandez, M. I.; Chai, J.; Chan, S. P.; Charatcharoenwitthaya, P.; Chavez-Tapia, N.; Chayama, K.; Chen, J.; Chen, L.; Chen, Z. -W.; Chen, H.; Chen, S. -D.; Chen, Q.; Chen, Y.; Chen, G.; Chen, E. -Q.; Chen, F.; Chen, P. -J.; Cheng, R.; Cheng, W.; Chieh, J. T. W.; Chokr, I.; Cholongitas, E.; Choudhury, A.; Chowdhury, A.; Chukwudike, E. S.; Ciardullo, S.; Clayton, M.; Clement, K.; Cloa, M. M.; Coccia, C.; Collazos, C.; Colombo, M.; Cosar, A. M.; Cotrim, H. P.; Couillerot, J.; Coulibaly, A.; Crespo, G.; Crespo, J.; Cruells, M.; Cua, I. H. Y.; Dabbous, H. K.; Dalekos, G. N.; D'Alia, P.; Dan, L.; Dao, V. H.; Darwish, M.; Datz, C.; Davalos-Moscol, M. B.; Dawoud, H.; de Careaga, B. O.; de Knegt, R.; de Ledinghen, V.; de Silva, J.; Debzi, N.; Decraecker, M.; Del Pozo, E.; Delgado, T. C.; Delgado-Blanco, M.; Dembinski, L.; Depina, A.; Derbala, M.; Desalegn, H.; Desbois-Mouthon, C.; Desoky, M.; Dev, A.; Di Ciaula, A.; Diago, M.; Di
abstract

2022 - Predictors of solid extra-hepatic non-skin cancer in liver transplant recipients and analysis of survival: a long-term follow-up study [Articolo su rivista]
Gitto, Stefano; Magistri, Paolo; Marzi, Luca; Mannelli, Nicolò; De Maria, Nicola; Mega, Andrea; Vitale, Giovanni; Valente, Giovanna; Vizzutti, Francesco; Villa, Erica; Marra, Fabio; Andreone, Pietro; Di Benedetto, Fabrizio; Falcini, Margherita; Catellani, Barbara; Guerrini, Gian Piero; Serra, Valentina; Di Sandro, Stefano; Ballarin, Roberto; Piai, Guido; Schepis, Filippo; Margotti, Marzia; Cursaro, Carmela; De Simone, Paolo; Petruccelli, Stefania; Carrai, Paola; Forte, Paolo; Campani, Claudia; Zoller, Heinz
abstract

Introduction and objectives: De novo malignancies represent an important cause of death for liver transplant recipients. Our aim was to analyze predictors of extra-hepatic non-skin cancer (ESNSC) and the impact of ESNSC on the long-term outcome. Patients: We examined data from patients transplanted between 2000 and 2005 and followed-up in five Italian transplant clinics with a retrospective observational cohort study. Cox Regression was performed to identify predictors of ESNSC. A 1:2 cohort sub-study was developed to analyze the impact of ESNSC on 10-year survival. Results: We analyzed data from 367 subjects (median follow-up: 15 years). Patients with ESNSC (n=47) more often developed post-LT diabetes mellitus (DM) (57,4% versus 35,9%, p=0,004). At multivariate analysis, post-LT DM independently predicted ESNSC (HR 1.929, CI 1.029-3.616, p=0.040). Recipients with ESNSC showed a lower 10-year survival than matched controls (46,8% versus 68,1%, p=0,023). Conclusions: Post-LT DM seems to be a relevant risk factor for post-LT ESNSC. ESNSC could have a noteworthy impact on the long-term survival of LT recipients.

2022 - Quality of life in liver transplant recipients during the Corona virus disease 19 pandemic: A multicentre study [Articolo su rivista]
Gitto, S.; Golfieri, L.; Mannelli, N.; Tame, M. R.; Lopez, I.; Ceccato, R.; Montanari, S.; Falcini, M.; Vitale, G.; De Maria, N.; Presti, D. L.; Marzi, L.; Mega, A.; Valente, G.; Borghi, A.; Foschi, F. G.; Grandi, S.; Forte, P.; Cescon, M.; Di Benedetto, F.; Andreone, P.; Arcangeli, G.; De Simone, P.; Bonacchi, A.; Sofi, F.; Morelli, M. C.; Petranelli, M.; Lau, C.; Marra, F.; Chiesi, F.; Vizzutti, F.; Vero, V.; Di Donato, R.; Berardi, S.; Pianta, P.; D'Anzi, S.; Schepis, F.; Gualandi, N.; Miceli, F.; Villa, E.; Piai, G.; Valente, M.; Campani, C.; Lynch, E.; Magistri, P.; Cursaro, C.; Chiarelli, A.; Carrai, P.; Petruccelli, S.; Dinu, M.; Pagliai, G.
abstract

Background: Liver transplant recipients require specific clinical and psychosocial attention given their frailty. Main aim of the study was to assess the quality of life after liver transplant during the current pandemic. Methods: This multicentre study was conducted in clinically stable, liver transplanted patients. Enrollment opened in June and finished in September 2021. Patients completed a survey including lifestyle data, quality of life (Short Form health survey), sport, employment, diet. To examine the correlations, we calculated Pearson coefficients while to compare subgroups, independent samples t-tests and ANOVAs. To detect the predictors of impaired quality of life, we used multivariable logistic regression analysis. Results: We analysed data from 511 patients observing significant associations between quality of life’s physical score and both age and adherence to Mediterranean diet (p <.01). A significant negative correlation was observed between mental score and the sedentary activity (p <.05). Female patients scored significantly lower than males in physical and mental score. At multivariate analysis, females were 1.65 times more likely to report impaired physical score than males. Occupation and physical activity presented significant positive relation with quality of life. Adherence to Mediterranean diet was another relevant predictor. Regarding mental score, female patients were 1.78 times more likely to show impaired mental score in comparison with males. Sedentary activity and adherence to Mediterranean diet were further noteworthy predictors. Conclusions: Females and subjects with sedentary lifestyle or work inactive seem to show the worst quality of life and both physical activity and Mediterranean diet might be helpful to improve it.

2022 - Role of circulating microRNAs to predict hepatocellular carcinoma recurrence in patients treated with radiofrequency ablation or surgery [Articolo su rivista]
Canale, M.; Foschi, F. G.; Andreone, P.; Ercolani, G.; Marisi, G.; Conti, F.; Vukotic, R.; Guarneri, V.; Burgio, V.; Ratti, F.; Aldrighetti, L.; De Cobelli, F.; Cascinu, S.; Ulivi, P.; Casadei-Gardini, A.
abstract

Background: Loco-regional treatments have improved the survival of patients with early hepatocellular carcinoma (HCC), but tumor relapse is a frequent event and survival rates remain low. Moreover, conflicting evidences address early HCC patients to surgery or radiofrequency ablation (RFA), with the clinical need to find predictive non-invasive biomarkers able to guide treatment choice and define patients survival. Methods: Two independent case series of treatment-naïve HCC patients treated with local RFA, and a cohort of 30 HCC patients treated with liver surgery were enrolled. On the basis of literature evidence, we customized a panel of 21 miRNAs correlated with relapse and prognosis after local curative treatment of HCC. Results: Expression levels of let-7c predict tumor relapse after RFA; we also investigated the same panel in a small cohort of HCC patients undergoing surgery, finding no statistically significance in predicting tumor relapse or survival. Moreover, interaction test indicated that let-7c expression levels are predictive for identifying a subset of patients that should be addressed to surgery. Conclusion: Results from this study could predict prognosis of early HCC patients, helping to address early HCC patients to surgery or RFA treatment.

2022 - Severe acute respiratory syndrome coronavirus-2-associated cholangiopathies [Articolo su rivista]
Bartoli, A.; Cursaro, C.; Andreone, P.
abstract

Purpose of reviewSARS-CoV2 is a β-coronavirus, isolated for the first time in Wuhan in December 2019. Bilateral interstitial pneumonia is the hallmark of this disease. Liver is the second viral target for frequency and AST and ALT elevation is a common finding. From February 2020, two different cholangiopathies have been reported in COVID-19 patients. The aim of this article is to review the cases so far described in order to share information and awareness about these new clinical entities.Recent findingsSARS-CoV2 seems to trigger autoimmunity and two cases of primary biliary cholangitis (PBC) have been developed after viral infection while more than 30 patients have showed a rapidly progressing cholangiopathy with features of secondary sclerosing cholangitis (SSC). For what concerns SSC pathogenesis, a theory combining multiple hits is the most recognized.SummaryTwo different cholangiopathies have been reported in patients after severe-COVID-19. Attention should be paid to the development of cholestasis in ICU setting but above all after discharge and liver function tests should be, therefore, periodically performed. No treatment strategies are available and liver transplantation remains the last option in individuals with liver failure because of SSC. Other efforts are necessary to better understand the pathogenesis and to expand therapeutic options.

2022 - Spleen Stiffness Measurements Predict the Risk of Hepatic Decompensation after Direct-Acting Antivirals in HCV Cirrhotic Patients [Articolo su rivista]
Dajti, E.; Ravaioli, F.; Colecchia, A.; Marasco, G.; Bacchi Reggiani, M. L.; Colli, A.; Alemanni, L. V.; Tame, M.; Andreone, P.; Brillanti, S.; Azzaroli, F.; Mazzella, G.; Festi, D.
abstract

Purpose -Little evidence is available regarding the risk of hepatic decompensation (HD) after direct-acting antivirals (DAAs) in patients with advanced chronic liver disease. Our aim was to assess the risk of decompensation and the prognostic role of noninvasive tests, such as liver (LSM) and spleen (SSM) stiffness measurements, in the prediction of decompensation after sustained virologic response (SVR) by DAAs. Materials and Methods -A cohort study involving 146 cirrhotic patients treated with DAAs in our tertiary center with LSM and SSM available both before and six months after treatment (SVR24). A historical cohort of 92 consecutive cirrhotic patients with active HCV was used as a control group.-A propensity score inverse probability weighting method was used to account for differences between the groups. Time-dependent models for the prediction of decompensation were applied to account for changes in noninvasive tests after therapy. Results -The decompensation incidence in the DAA cohort was 7.07 (4.56-10.96) per 100 person-years (PYs), which was significantly lower than in the active HCV cohort. The DAA therapy was an independent protective factor for HD development (SHR: 0.071, 95-%-CI: 0.015-0.332). SSM ≥-54 kPa was independently associated with decompensation despite SVR achievement (SHR: 4.169, 95-%-CI: 1.050-16.559), alongside with a history of decompensation (SHR: 7.956, 95-%-CI: 2.556-24.762). SSM reduction <-10-% also predicted the risk of decompensation after SVR24. Conclusion -The risk of decompensation was markedly reduced after DAA therapy, but it was not eliminated. Paired SSM values stratified the risk of decompensation after SVR better than other noninvasive tests.

2022 - Virological Treatment Monitoring for Chronic Hepatitis B [Articolo su rivista]
Loggi, E.; Gitto, S.; Gabrielli, F.; Franchi, E.; Seferi, H.; Cursaro, C.; Andreone, P.
abstract

More than 250 million people worldwide are currently infected with hepatitis B, despite the effectiveness of vaccination and other preventive measures. In terms of treatment, new therapeutic approaches are rapidly developing, promising to achieve the elimination of infected cells and the complete cure of infection. The on-treatment monitoring of these innovative antiviral treatments will require the implementation of new virological tools. Therefore, new biomarkers are being evaluated besides the traditional virological and serological assays in order to obtain information on different steps of the viral replication cycle and to monitor response to therapy more accurately. The purpose of this work is to describe both standard and innovative tools for chronic hepatitis B treatment monitoring, and to analyse their potential and feasibility.

2021 - A review on extrahepatic manifestations of chronic hepatitis c virus infection and the impact of direct-acting antiviral therapy [Articolo su rivista]
Mazzaro, C.; Quartuccio, L.; Adinolfi, L. E.; Roccatello, D.; Pozzato, G.; Nevola, R.; Tonizzo, M.; Gitto, S.; Andreone, P.; Gattei, V.
abstract

Extrahepatic manifestations are a feature of chronic hepatitis C virus (HCV) infection. In the course of chronic HCV infection, about 70% of patients have one or more extrahepatic manifestations. The latter are often the first and only clinical sign of infection. Experimental and clinical data support a causal association for many extrahepatic manifestations and HCV infection, which include mixed cryoglobulinemia, non-Hodgkin lymphomas (NHL), cardiovascular disease, insulin resistance, type 2 diabetes, neurological and psychiatric disease and other rheumatic diseases. All these extrahepatic conditions influence the morbidity, quality of life and mortality of HCV-infected patients. Currently, interferon-free therapeutic regimens with direct-acting antiviral agents (DAA) offer the possibility of treatment to almost the entire infected population, irrespective of stage of cirrhosis and associated serious comorbidities, always maintaining a high efficacy and tolerability. Several studies have shown a close association between HCV clearance by DAAs and an improvement or reduction in the risk of extrahepatic manifestations. Patients with HCV after a sustained virologic response (SVR) by DAA treatment have a lower risk than non-responders of developing cryoglobulinemic vasculitis and B-cell non-Hodgkin’s lymphomas. Furthermore, the SVR by DAA also reduces the risk of acute coronary syndrome, cardiovascular disease, insulin resistance and type 2 diabetes, and it improves atherosclerosis. HCV clearance by DAA also improves the quality of life and survival of patients with chronic HCV infection with associated extrahepatic diseases. Thus, DAAs should be initiated as early as possible in HCV patients with extrahepatic manifestations.

2021 - An international genome-wide meta-analysis of primary biliary cholangitis: Novel risk loci and candidate drugs [Articolo su rivista]
Cordell, H. J.; Fryett, J. J.; Ueno, K.; Darlay, R.; Aiba, Y.; Hitomi, Y.; Kawashima, M.; Nishida, N.; Khor, S. -S.; Gervais, O.; Kawai, Y.; Nagasaki, M.; Tokunaga, K.; Tang, R.; Shi, Y.; Li, Z.; Juran, B. D.; Atkinson, E. J.; Gerussi, A.; Carbone, M.; Asselta, R.; Cheung, A.; de Andrade, M.; Baras, A.; Horowitz, J.; Ferreira, M. A. R.; Sun, D.; Jones, D. E.; Flack, S.; Spicer, A.; Mulcahy, V. L.; Byan, J.; Han, Y.; Sandford, R. N.; Lazaridis, K. N.; Amos, C. I.; Hirschfield, G. M.; Seldin, M. F.; Invernizzi, P.; Siminovitch, K. A.; Ma, X.; Nakamura, M.; Mells, G. F.; Mason, A.; Vincent, C.; Xie, G.; Zhang, J.; Affronti, A.; Almasio, P. L.; Alvaro, D.; Andreone, P.; Andriulli, A.; Azzaroli, F.; Battezzati, P. M.; Benedetti, A.; Bragazzi, M.; Brunetto, M.; Bruno, S.; Calvaruso, V.; Cardinale, V.; Casella, G.; Cazzagon, N.; Ciaccio, A.; Coco, B.; Colli, A.; Colloredo, G.; Colombo, M.; Colombo, S.; Cristoferi, L.; Cursaro, C.; Croce, L. S.; Crosignani, A.; D'Amato, D.; Donato, F.; Elia, G.; Fabris, L.; Fagiuoli, S.; Ferrari, C.; Floreani, A.; Galli, A.; Giannini, E.; Grattagliano, I.; Lampertico, P.; Lleo, A.; Malinverno, F.; Mancuso, C.; Marra, F.; Marzioni, M.; Massironi, S.; Mattalia, A.; Miele, L.; Milani, C.; Morini, L.; Morisco, F.; Muratori, L.; Muratori, P.; Niro, G. A.; O'Donnell, S.; Picciotto, A.; Portincasa, P.; Rigamonti, C.; Ronca, V.; Rosina, F.; Spinzi, G.; Strazzabosco, M.; Tarocchi, M.; Tiribelli, C.; Toniutto, P.; Valenti, L.; Vinci, M.; Zuin, M.; Nakamura, H.; Abiru, S.; Nagaoka, S.; Komori, A.; Yatsuhashi, H.; Ishibashi, H.; Ito, M.; Migita, K.; Ohira, H.; Katsushima, S.; Naganuma, A.; Sugi, K.; Komatsu, T.; Mannami, T.; Matsushita, K.; Yoshizawa, K.; Makita, F.; Nikami, T.; Nishimura, H.; Kouno, H.; Kouno, H.; Ota, H.; Komura, T.; Nakamura, Y.; Shimada, M.; Hirashima, N.; Komeda, T.; Ario, K.; Nakamuta, M.; Yamashita, T.; Furuta, K.; Kikuchi, M.; Naeshiro, N.; Takahashi, H.; Mano, Y.; Tsunematsu, S.; Yabuuchi, I.; Shimada, Y.; Yamauchi, K.; Sugimoto, R.; Sakai, H.; Mita, E.; Koda, M.; Tsuruta, S.; Kamitsukasa, H.; Sato, T.; Masaki, N.; Kobata, T.; Fukushima, N.; Ohara, Y.; Muro, T.; Takesaki, E.; Takaki, H.; Yamamoto, T.; Kato, M.; Nagaoki, Y.; Hayashi, S.; Ishida, J.; Watanabe, Y.; Kobayashi, M.; Koga, M.; Saoshiro, T.; Yagura, M.; Hirata, K.; Tanaka, A.; Takikawa, H.; Zeniya, M.; Abe, M.; Onji, M.; Kaneko, S.; Honda, M.; Arai, K.; Arinaga-Hino, T.; Hashimoto, E.; Taniai, M.; Umemura, T.; Joshita, S.; Nakao, K.; Ichikawa, T.; Shibata, H.; Yamagiwa, S.; Seike, M.; Honda, K.; Sakisaka, S.; Takeyama, Y.; Harada, M.; Senju, M.; Yokosuka, O.; Kanda, T.; Ueno, Y.; Kikuchi, K.; Ebinuma, H.; Himoto, T.; Yasunami, M.; Murata, K.; Mizokami, M.; Kawata, K.; Shimoda, S.; Miyake, Y.; Takaki, A.; Yamamoto, K.; Hirano, K.; Ichida, T.; Ido, A.; Tsubouchi, H.; Chayama, K.; Harada, K.; Nakanuma, Y.; Maehara, Y.; Taketomi, A.; Shirabe, K.; Soejima, Y.; Mori, A.; Yagi, S.; Uemoto, S.; H, E.; Tanaka, T.; Yamashiki, N.; Tamura, S.; Sugawara, Y.; Kokudo, N.; Chalasani, N.; Luketic, V.; Odin, J.; Chopra, K.; Abecasis, G.; Cantor, M.; Coppola, G.; Economides, A.; Lotta, L. A.; Overton, J. D.; Reid, J. G.; Shuldiner, A.; Beechert, C.; Forsythe, C.; Fuller, E. D.; Gu, Z.; Lattari, M.; Lopez, A.; Schleicher, T. D.; Padilla, M. S.; Toledo, K.; Widom, L.; Wolf, S. E.; Pradhan, M.; Manoochehri, K.; Ulloa, R. H.; Bai, X.; Balasubramanian, S.; Barnard, L.; Blumenfeld, A.; Eom, G.; Habegger, L.; Hawes, A.; Khalid, S.; Maxwell, E. K.; Salerno, W.; Staples, J. C.; Jones, M. B.; Mitnaul, L. J.; Sturgess, R.; Healey, C.; Yeoman, A.; Gunasekera, A. V.; Kooner, P.; Kapur, K.; Sathyanarayana, V.; Kallis, Y.; Subhani, J.; Harvey, R.; Mccorry, R.; Rooney, P.; Ramanaden, D.; Evans, R.; Mathialahan, T.; Gasem, J.; Shorrock, C.; Bhalme, M.; Southern, P.; Tibble, J. A.; Gorard, D. A.; Jones, S.; Mells, G.; Mulcahy, V.; Srivastava, B.; Foxton, M. R.; Collins, C. E.; Elphick, D.; Karmo, M.; Porras-Perez, F.; Mendall, M.; Yapp, T.; Patel, M.; Ede, R.; Saye
abstract

Backgrounds & Aims: Primary biliary cholangitis (PBC) is a chronic liver disease in which autoimmune destruction of the small intrahepatic bile ducts eventually leads to cirrhosis. Many patients have inadequate response to licensed medications, motivating the search for novel therapies. Previous genome-wide association studies (GWAS) and meta-analyses (GWMA) of PBC have identified numerous risk loci for this condition, providing insight into its aetiology. We undertook the largest GWMA of PBC to date, aiming to identify additional risk loci and prioritise candidate genes for in silico drug efficacy screening. Methods: We combined new and existing genotype data for 10,516 cases and 20,772 controls from 5 European and 2 East Asian cohorts. Results: We identified 56 genome-wide significant loci (20 novel) including 46 in European, 13 in Asian, and 41 in combined cohorts; and a 57th genome-wide significant locus (also novel) in conditional analysis of the European cohorts. Candidate genes at newly identified loci include FCRL3, INAVA, PRDM1, IRF7, CCR6, CD226, and IL12RB1, which each play key roles in immunity. Pathway analysis reiterated the likely importance of pattern recognition receptor and TNF signalling, JAK-STAT signalling, and differentiation of T helper (TH)1 and TH17 cells in the pathogenesis of this disease. Drug efficacy screening identified several medications predicted to be therapeutic in PBC, some of which are well-established in the treatment of other autoimmune disorders. Conclusions: This study has identified additional risk loci for PBC, provided a hierarchy of agents that could be trialled in this condition, and emphasised the value of genetic and genomic approaches to drug discovery in complex disorders. Lay summary: Primary biliary cholangitis (PBC) is a chronic liver disease that eventually leads to cirrhosis. In this study, we analysed genetic information from 10,516 people with PBC and 20,772 healthy individuals recruited in Canada, China, Italy, Japan, the UK, or the USA. We identified several genetic regions associated with PBC. Each of these regions contains several genes. For each region, we used diverse sources of evidence to help us choose the gene most likely to be involved in causing PBC. We used these ‘candidate genes’ to help us identify medications that are currently used for treatment of other conditions, which might also be useful for treatment of PBC.

2021 - Association of nonalcoholic fatty liver disease (Nafld) with peripheral diabetic polyneuropathy: A systematic review and meta-analysis [Articolo su rivista]
Greco, C.; Nascimbeni, F.; Carubbi, F.; Andreone, P.; Simoni, M.; Santi, D.
abstract

Aims. The relationship between nonalcoholic fatty liver disease (NAFLD) and diabetic polyneuropathy (DPN) has been demonstrated in many studies, although results were conflicting. This meta-analysis aims to summarize available data and to estimate the DPN risk among NAFLD patients. Materials and methods. We performed a comprehensive literature review until 4 June 2021. Clinical trials analyzing the association between NAFLD and DPN were included. Results. Thirteen studies (9614 participants) were included. DPN prevalence was significantly higher in patients with NALFD, compared to patients without NAFLD (OR (95%CI) 2.48 (1.42–4.34), p = 0.001; I2 96%). This finding was confirmed in type 2 diabetes (OR (95%CI) 2.51 (1.33–4.74), p = 0.005; I2 97%), but not in type 1 diabetes (OR (95%CI) 2.44 (0.85–6.99), p = 0.100; I2 77%). Also, body mass index and diabetes duration were higher in NAFLD subjects compared to those without NAFLD (p < 0.001), considering both type 2 and type 1 diabetes. Conclusion. Despite a high heterogeneity among studies, a significantly increased DPN prevalence among type 2 diabetes subjects with NAFLD was observed. This result was not found in type 1 diabetes, probably due to the longer duration of disease. Physicians should pay more attention to the early detection of DPN, especially in patients with NAFLD.

2021 - COVID-19 treatment options: a difficult journey between failed attempts and experimental drugs [Articolo su rivista]
Bartoli, A.; Gabrielli, F.; Alicandro, T.; Nascimbeni, F.; Andreone, P.
abstract

Since its outbreak in China in December 2019 a novel Coronavirus, named SARS-CoV-2, has spread worldwide causing many cases of severe pneumonia, referred to as COVID-19 disease, leading the World Health Organization to declare a pandemic emergency in March 2020. Up to now, no specific therapy against COVID-19 disease exists. This paper aims to review COVID-19 treatment options currently under investigation. We divided the studied drugs into three categories (antiviral, immunomodulatory and other drugs). For each molecule, we discussed the putative mechanisms by which the drug may act against SARS-CoV-2 or may affect COVID-19 pathogenesis and the main clinical studies performed so far. The published clinical studies suffer from methodological limitations due to the emergency setting in which they have been conducted. Nevertheless, it seems that the timing of administration of the diverse categories of drugs is crucial in determining clinical efficacy. Antiviral drugs, in particular Remdesivir, should be administered soon after symptoms onset, in the viraemic phase of the disease; whereas, immunomodulatory agents, such as tocilizumab, anakinra and steroids, may have better results if administered in pneumonia/hyperinflammatory phases. Low-molecular-weight heparin may also have a role when facing COVID-19-related coagulopathy. Up to now, treatment choices have been inferred from the experience with other coronaviruses or viral infection outbreaks. Hopefully, in the near future, new treatment strategies will be available thanks to increased knowledge on SARS-CoV2 virus and COVID-19 pathogenesis. In the meanwhile, further well-designed clinical trials are urgently needed to establish a standard of care in COVID-19 disease.

2021 - Central pontine myelinolysis secondary to glycemic variability in type 1 diabetes: a case report and a systematic review of the literature [Articolo su rivista]
Agostino, S. D.; Costanzo, A. A. C.; Andreone, P.; Maurantonio, M.
abstract

Central pontine myelinolysis (CPM) is a rare manifestation of osmotic demyelination syndrome (ODS) which involves the pons and causes significant morbidity and mortality. CPM usually occurs in the setting of rapid correction of severe chronic hyponatremia. A rare case of CPM due to hyperglycemia in a 27-year-old man with type 1 diabetes is reported. During the patient’s hospitalization, his plasma glucose level showed a wide variability ranging from 38 mg/dL to 530 mg/dL; while plasma sodium level was constantly normal. At computed tomography (CT) scans, areas of hypodensity with a hyperdense ring were identified in the anterior part of the pons. At magnetic resonance imaging (MRI) scan, pontine abnormalities compatible with CPM were observed. According to laboratory tests, we concluded that CPM resulted from rapid and wide shifts in osmolar gradient owing to variability in plasma glucose levels. While universally recognized in several clinical settings, CPM is rarely observed in diabetic patients. Our report supports the notion that hyperosmolarity per se plays a key role in the pathogenesis of CPM, which may occur independently of sodium abnormalities.

2021 - Clinical features and comorbidity pattern of HCV infected migrants compared to native patients in care in Italy: A real-life evaluation of the PITER cohort [Articolo su rivista]
Quaranta, M. G.; Ferrigno, L.; Tata, X.; D'Angelo, F.; Massari, M.; Coppola, C.; Biliotti, E.; Giorgini, A.; Laccabue, D.; Ciancio, A.; Blanc, P. L.; Margotti, M.; Ieluzzi, D.; Brunetto, M. R.; Barbaro, F.; Russo, F. P.; Beretta, I.; Morsica, G.; Verucchi, G.; Saracino, A.; Galli, M.; Kondili, L. A.; Mazzaro, C.; Bertola, M.; Benedetti, A.; Schiada, L.; Cucco, M.; Giacometti, A.; Brescini, L.; Castelletti, S.; Fiorentini, A.; Angarano, G.; Milella, M.; Leo, A. D.; Rendina, M.; Salvatore D'ABRAMO, F.; Lillo, C.; Iannone, A.; Piazzolla, M.; Badia, L.; Piscaglia, F.; Benevento, F.; Serio, I.; Castelli, F.; Zaltron, S.; Spinetti, A.; Odolini, S.; Bruno, R.; Mondelli, M.; Chessa, L.; Loi, M.; Torti, C.; Costa, C.; Mazzitelli, M.; Pisani, V.; Scaglione, V.; Trecarichi, E. M.; Zignego, A. L.; Monti, M.; Madia, F.; Attala, L.; Pierotti, P.; Salomoni, E.; Mariabelli, E.; Santantonio, T. A.; Bruno, S. R.; Cela, E. M.; Bassetti, M.; Mazzarello, G.; Alessandrini, A. I.; Biagio, A. D.; Nicolini, L. A.; Raimondo, G.; Filomia, R.; Aghemo, A.; Meli, R.; Lazzarin, A.; Salpietro, S.; Fracanzani, A. L.; Fatta, E.; Lombardi, R.; Lampertico, P.; Borghi, M.; D'Ambrosio, R.; Degasperi, E.; Puoti, M.; Baiguera, C.; D'Amico, F.; Vinci, M.; Rumi, M. G.; Zuin, M.; Zermiani, P.; Andreone, P.; Caraceni, P.; Guarneri, V.; Villa, E.; Bernabucci, V.; Bristot, L.; Paradiso, M. L.; Migliorino, G.; Gambaro, A.; Lapadula, G.; Spolti, A.; Soria, A.; Invernizzi, P.; Ciaccio, A.; Luca, M.; Malinverno, F.; Ratti, L.; Amoruso, D. C.; Pisano, F.; Scarano, F.; Staiano, L.; Morisco, F.; Cossiga, V.; Gentile, I.; Buonomo, A. R.; Foggia, M.; Zappulo, E.; Federico, A.; Dallio, M.; Coppola, N.; Sagnelli, C.; Martini, S.; Monari, C.; Nardone, G.; Sgamato, C.; Chemello, L.; Cavalletto, L.; Sterrantino, D.; Zanetto, A.; Zanaga, P.; Brancaccio, G.; Craxi, A.; Petta, S.; Calvaruso, V.; Crapanzano, L.; Madonia, S.; Cannizzaro, M.; Bruno, E. M.; Licata, A.; Amodeo, S.; Capitano, A. R.; Ferrari, C.; Negri, E.; Orlandini, A.; Pesci, M.; Gulminetti, R.; Pagnucco, L.; Parruti, G.; Stefano, P. D.; Coco, B.; Corsini, R.; Garlassi, E.; Andreoni, M.; Teti, E.; Cerva, C.; Baiocchi, L.; Grassi, G.; Gasbarrini, A.; Pompili, M.; Siena, M. D.; Taliani, G.; Spaziante, M.; Persico, M.; Masarone, M.; Aglitti, A.; Calvanese, G.; Anselmo, M.; Leo, P. D.; Marturano, M.; Saracco, G. M.
abstract

Background: Direct-acting antivirals are highly effective for the treatment of hepatitis C virus (HCV) infection, regardless race/ethnicity. We aimed to evaluate demographic, virological and clinical data of HCV-infected migrants vs. natives consecutively enrolled in the PITER cohort. Methods: Migrants were defined by country of birth and nationality that was different from Italy. Mann-Whitney U test, Chi-squared test and multiple logistic regression were used. Results: Of 10,669 enrolled patients, 301 (2.8%) were migrants: median age 47 vs. 62 years, (p < 0.001), females 56.5% vs. 45.3%, (p < 0.001), HBsAg positivity 3.8% vs. 1.4%, (p < 0.05). Genotype 1b was prevalent in both groups, whereas genotype 4 was more prevalent in migrants (p < 0.05). Liver disease severity and sustained virologic response (SVR) were similar. A higher prevalence of comorbidities was reported for natives compared to migrants (p < 0.05). Liver disease progression cofactors (HBsAg, HIV coinfection, alcohol abuse, potential metabolic syndrome) were present in 39.1% and 47.1% (p > 0.05) of migrants and natives who eradicated HCV, respectively. Conclusion: Compared to natives, HCV-infected migrants in care have different demographics, HCV genotypes, viral coinfections and comorbidities and similar disease severity, SVR and cofactors for disease progression after HCV eradication. A periodic clinical assessment after HCV eradication in Italians and migrants with cofactors for disease progression is warranted.

2021 - Cognitive, neurological and psychiatric disorders occurring in Hepatitis C Virus infection [Articolo su rivista]
Tassi, A.; Gitto, S.; Piras, C.; Cursaro, C.; Alicandro, T.; Margotti, M.; Rivi, M.; Andreone, P.
abstract

Chronic Hepatitis C is associated with many extrahepatic manifestations. Central nervous system is frequently involved, but the pathophysiological mechanisms are not fully understood. Local and systemic inflammation, ischemia, immune-mediated phenomena have been described in this context. Clinical manifestations include cognitive alterations, stroke, depression and demyelinating phenomena. It is unclear if cognitive deficits can be improved or resolved with viral eradication and to understand this, could have important therapeutical implications.

2021 - Effectiveness and safety of glecaprevir/pibrentasvir in chronic hepatitis C patients: Results of the Italian cohort of a post-marketing observational study [Articolo su rivista]
Aghemo, A.; Alberti, A.; Andreone, P.; Angelico, M.; Brunetto, M. R.; Chessa, L.; Ciancio, A.; Craxi, A.; Gaeta, G. B.; Galli, M.; Gasbarrini, A.; Giorgini, A.; Grilli, E.; Lampertico, P.; Lichtner, M.; Milella, M.; Morisco, F.; Persico, M.; Pirisi, M.; Puoti, M.; Raimondo, G.; Romano, A.; Russello, M.; Sangiovanni, V.; Schiavini, M.; Serviddio, G.; Villa, E.; Vinci, M.; De Michina, A.; Gallinaro, V.; Gualberti, G.; Roscini, A. S.; Zignego, A. L.
abstract

Background and Aims: The MARS post-marketing, observational study evaluates glecaprevir/pibrentasvir in a large population of Italian patients who are infected with HCV. Patients and Methods: Achievement of SVR12 was the primary endpoint in the overall population and by subpopulations of interest (treatment-naïve and treatment-experienced patients, subjects infected with different HCV genotype/sub-genotype, cirrhotic and non-cirrhotic patients, patients with different severity of fibrosis, patients with an APRI score ≥1, subjects with comorbidities, HIV-coinfected patients, elderly patients and people who use drugs). Safety and quality of life (assessed by SF-36 and Work Productivity and Activity Impairment) were also evaluated. Results: The SVR12 rate was 99.4% (319/321; 95% CI: 97.8–99.8%) in the core population with sufficient follow-up (n = 321), 99.7% (318/319) in 8-week treated patients, and high (>96%) across subgroups. Only three patients (0.9%) had treatment-related adverse events that led to treatment discontinuation. In total, 30.1% of patients showed an improvement of ≥2.5 points in the Physical Component Summary of the SF-36 from baseline to the end of treatment, and this figure raised to 37.5% with the achievement of SVR12. Corresponding values for MCS were 42.2% and 42.8%, respectively. Conclusion: Glecaprevir/pibrentasvir is safe and effective across subpopulations who are underserved in clinical trials.

2021 - External validation of surrogate indices of fatty liver in the general population: The Bagnacavallo study [Articolo su rivista]
Foschi, F. G.; Conti, F.; Domenicali, M.; Giacomoni, P.; Borghi, A.; Bevilacqua, V.; Napoli, L.; Berardinelli, D.; Altini, M.; Cucchetti, A.; Ercolani, G.; Casadei-Gardini, A.; Bellentani, S.; Gastaldelli, A.; Tiribelli, C.; Bedogni, G.; Andreone, P.; Dall'Aglio, A. C.; Bernardi, M.; Bucchi, L.; Dazzani, F.; Falcini, F.; Lanzi, A.; Ravaioli, A.; Rimini, M.; Rovesti, G.; Saini, G.; Stefanini, G. F.
abstract

We externally validated the fatty liver index (FLI), the lipid accumulation product (LAP), the hepatic steatosis index (HSI), and the Zhejiang University index (ZJU) for the diagnosis of fatty liver (FL) and non-alcoholic fatty liver disease (NAFLD) in the general population. The validation was performed on 2159 citizens of the town of Bagnacavallo (Ravenna, Italy). Calibration was evaluated by calculating the calibration slope and intercept and by inspecting calibration plots; discrimination was evaluated using the c-statistic. The average calibration slope was 1 and the average intercept was 0 for all combinations of outcomes and indices. For the diagnosis of FL, the c-statistic was 0.85 for FLI, 0.83 for ZJU, 0.82 for HSI, and 0.80 for LAP; for the diagnosis of NAFLD, the c-statistic was 0.77 for FLI, 0.76 for ZJU, 0.75 for HSI, and 0.74 for LAP. All indices were strongly correlated with each other. In conclusion, FLI, LAP, HSI, and ZJU perform similarly well to diagnose FL and NAFLD in the Bagnacavallo population, even if FLI has a small advantage as discrimination is concerned.

2021 - Hepatitis C Virus Core Antigen (HCVAg): An affordable assay to monitor the efficacy of treatment in DAAs era [Articolo su rivista]
Rossetti, B.; Loggi, E.; Raffaelli, C. S.; Mercinelli, S.; Gandolfo, C.; Savellini, G. G.; Galli, S.; Vitale, G.; Di Donato, R.; Vukotic, R.; Grandini, E.; Margotti, M.; Guarneri, V.; Furlini, G.; Re, M. C.; de Luca, A.; Andreone, P.; Galli, C.; Cusi, M. G.
abstract

Hepatitis C virus (HCV) Core Antigen (HCVAg) and HCV-RNA were tested in 962 plasma/serum samples from 180 patients during Direct Antiviral Agents (DAAs) treatment and at follow-up. One hundred and eighty individuals were included: 71% carried advanced fibrosis and 43% were treatment-experienced. A Sustained Virological Response (SVR) was achieved in 166/180 (92%) individuals: 96/102 (94.1%) naïve and 70/78 (89.7%) treatment-experienced (p=0.20). The baseline median levels of HCV-RNA and HCVAg were not significantly different between individuals achieving SVR (5.92 x 105 IU/mL, IQR 5.4-6.4, and 3,417 fmol/L, 2,900-3,795) and those without SVR (6.06 x 105 IU/mL, 5.63-6.57, and 3,391 fmol/L, 2,828-4,077). The HCV-RNA vs. HCVAg assays results showed a fair correlation with an overall moderate qualitative agreement (kappa=0.52). Among treatment-failed individuals, at failure 100% of the assays results were positive for both techniques, with HCV-RNA median value 3.09 x 105 IU/mL (2.10-29.09) and HCVAg median value 1570.28 fmol/L (360.15-9317.67). Undetectable HCV-RNA at EOT showed sensitivity 54%, specificity 100%, negative predictive value (NPV) 93% and positive predictive value (PPV) 100%. Undetectable HCVAg at EOT showed sensitivity 74%, specificity 100%, NPV 97% and PPV 100%. The operative and economic advantages of the HCVAg support the alternative use of HCVAg to monitor DAAs treatment outcome.

2021 - Hepatitis C virus-associated indolent B-cell lymphomas: A review on the role of the new direct antiviral agents therapy [Articolo su rivista]
Mazzaro, C.; Dal Maso, L.; Visentini, M.; Ermacora, A.; Andreone, P.; Gattei, V.; Pozzato, G.
abstract

Several studies have suggested that hepatitis C virus (HCV) may be the causative agent of some B-cell non-Hodgkin lymphomas (B-NHL). Several authors have demonstrated that pegylated interferon (Peg-IFN) plus ribavirin (RBV) can revert indolent low-grade B-NHL by inducing HCV eradication. Presently, the combination therapy (IFN plus RBV) has been abandoned since the direct antiviral agents (DAAs) have shown very high efficacy in achieving sustained virologic response (SVR) (range: 95%–100%). This review analyzed DAAs efficacy in HCV-associated indolent low-grade NHL, providing a detailed literature review. Overall, 122 B-cell NHL patients were treated with DAAs: complete/partial hematological response, particularly in those with marginal zone lymphoma, was obtained in most cases. Hematological response, obtained either with DAAs or IFN-based therapy, was similar. Nonetheless, DAAs therapy showed better tolerability and higher SVR. A fraction of the patients, despite SVR, underwent hematologic relapse or progression. In these cases, a recovery treatment with immunotherapy, or chemoimmunotherapy, had to be planned. In conclusion, data obtained from published studies mostly agree that HCV eradication with DAAs should be considered as the first-line treatment in HCV-related NHL. In fact, the chronic viral stimulation of the immune system might be the primary pathogenic mechanism in disease development and progression.

2021 - Hepatitis C: Clinical management and debated issues [Articolo su rivista]
Gitto, S.; Cursaro, C.; Bartoli, A.; Margotti, M.; Andreone, P.
abstract

Hepatitis C virus represents an important global health issue with 71 million of infected people in the word. Direct-acting antivirals are quite new molecules that hit specific Hepatitis C virus proteins useful for viral replication and assembly. Notably, Direct-acting antivirals bring to high sustained virological response rates showing also a great safety profile. This treatment revolution had an impact on transplantation world, in fact the number of liver transplants due to Hepatitis C virus-related cirrhosis and hepatocellular carcinoma is quickly decreasing. Even if this therapy has achieved excellent results in terms of morbility and mortality rates' reduction, there are some debated issues to consider. In the present review the main clinical challenges in every-day management of Hepatitis C virus patients treated with Direct-acting antivirals and the debated effects of viral clearance (metabolic, cardiovascular, immunologic and neoplastic) are discussed. The detection of barriers that can preclude the delivery of Hepatitis C virus care, is the most complex challenge for the scientific community. To obtain the Hepatitis C virus global eradication by 2030, as the World Health Organization has set, will be complex and laborious and will need a further multilevel effort.

2021 - Hepatitis b virus-related cryoglobulinemic vasculitis: Review of the literature and long-term follow-up analysis of 18 patients treated with nucleos(t)ide analogues from the italian study group of cryoglobulinemia (gisc) [Articolo su rivista]
Mazzaro, C.; Dal Maso, L.; Gragnani, L.; Visentini, M.; Saccardo, F.; Filippini, D.; Andreone, P.; Zignego, A. L.; Gattei, V.; Monti, G.; Galli, M.; Quartuccio, L.
abstract

Hepatitis B virus (HBV) chronic infection causes progressive liver damage, although about 20% of patients develop extrahepatic manifestations such as cryoglobulinemic vasculitis (CV). Clinical manifestations range from mild to moderate (purpura, asthenia, arthralgia) to severe (leg ulcers, peripheral neuropathy, glomerulonephritis, non-Hodgkin lymphoma). A comprehensive review of therapeutic options for HBV-related CV is lacking. Nucleos(t)ide analogues (NA) suppress HBV replication in 90–100% of cases and induce clinical response in most patients with mild-to-moderate CV. Plasma exchange can be performed in patients with severe CV and should be considered in severe or life-threatening cases combined with high doses of corticosteroids and antiviral treatment. A cautious use of rituximab can be considered only in association with NA treatment in refractory cases. A review of the literature and an analysis of data collected by six centers of the Italian Group for the Study of Cryoglobulinemia on 18 HBV-CV nucleotide/nucleoside analogues (NAs)-treated patients were carried out.

2021 - Primary biliary cholangitis associated with SARS-CoV-2 infection [Articolo su rivista]
Bartoli, A.; Gitto, S.; Sighinolfi, P.; Cursaro, C.; Andreone, P.
abstract

2021 - Resistance analysis and treatment outcomes in hepatitis C virus genotype 3-infected patients within the Italian network VIRONET-C [Articolo su rivista]
Di Maio, V. C.; Barbaliscia, S.; Teti, E.; Fiorentino, G.; Milana, M.; Paolucci, S.; Pollicino, T.; Morsica, G.; Starace, M.; Bruzzone, B.; Gennari, W.; Micheli, V.; Yu La Rosa, K.; Foroghi, L.; Calvaruso, V.; Lenci, I.; Polilli, E.; Babudieri, S.; Aghemo, A.; Raimondo, G.; Sarmati, L.; Coppola, N.; Pasquazzi, C.; Baldanti, F.; Parruti, G.; Perno, C. F.; Angelico, M.; Craxi, A.; Andreoni, M.; Ceccherini-Silberstein, F.; Andreone, P.; Aragri, M.; Bertoli, A.; Boeri, E.; Brancaccio, G.; Brunetto, M.; Callegaro, A. P.; Cenderello, G.; Cento, V.; Ciaccio, A.; Ciancio, A.; Cuomo, N.; De Santis, A.; Di Biagio, A.; Di Marco, V.; Di Perri, G.; Di Stefano, M. A.; Gaeta, G. B.; Ghisetti, V.; Gulminetti, R.; Lampertico, P.; Landonio, S.; Lichtner, M.; Lleo, A.; Maida, I.; Marenco, S.; Masetti, C.; Mastroianni, C.; Minichini, C.; Milano, E.; Monno, L.; Novati, S.; Pace Palitti, V.; Paternoster, C.; Pellicelli, A.; Pieri, A.; Puoti, M.; Rizzardini, G.; Ruggiero, T.; Rossetti, B.; Sangiovanni, V.; Santantonio, T.; Taliani, G.; Toniutto, P.; Vullo, V.; Zazzi, M.
abstract

Aim: This study aimed to investigate the role of resistance-associated substitutions (RASs) to direct-acting-antivirals (DAAs) in HCV genotype 3 (GT3). Methods: Within the Italian VIRONET-C network, a total of 539 GT3-infected patients (417 DAA-naïve and 135 DAA-failures, of them, 13 at both baseline and failure) were analysed. Sanger sequencing of NS3/NS5A/NS5B was performed following home-made protocols. Results: The majority of patients were male (79.4%), 91.4% were injection drug users, 49.3% were cirrhotic and 13.9% were HIV co-infected. Phylogenetic analysis classified sequences as GT3a-b-g-h (98%-0.4%-0.2%-1.2%) respectively. Overall, 135 patients failed a DAA regimen: sofosbuvir (SOF)/daclatasvir (DCV) or velpatasvir (VEL)±ribavirin (RBV) (N = 91/15) and glecaprevir (G)/pibrentasvir (P) (N = 9). Moreover, 14.8% of patients were treated with suboptimal regimens for GT3: 3D ± RBV (Paritaprevir/r + Ombitasvir+Dasabuvir, N = 15), SOF + Simeprevir (SIM) (N = 1) or SOF/Ledipasvir (LDV) ± RBV (N = 4). RAS prevalence was 15.8% in DAA-naïve patients. At failure, 81.5% patients showed at least one RAS: 11/25 (44.0%) in NS3, 109/135 (80.7%) in NS5A, 7/111 (6.3%) in NS5B SOF-failures. In NS5A-failures, Y93H RAS was the most prevalent (68.5% vs 5.1% DAA-naïve, P <.001) followed by A30K (12.7% vs 2.8% in DAA-naïve, P <.001). Analysing baseline samples, a higher prevalence of NS5A-RASs was observed before treatment in DAA-failures (5/13, 38.5%) vs DAA-naïves (61/393, 15.5%, P =.04). Regarding 228 DAA-naïve patients with an available outcome, 93.9% achieved a SVR. Interestingly, patients with baseline Y93H and/or A30K had SVR rate of 72.2% vs 95.7% for patients without NS5A-RASs (P =.002). Conclusions: In this real-life GT3 cohort, the majority of failures harboured resistant variants carrying NS5A-RASs, the most frequent being Y93H. The presence of natural NS5A-RASs before treatment was associated with failure. Further analyses are needed to confirm this observation, particularly for the new current regimens.

2021 - Risk factors in acute diabetic foot syndrome: analysis of 75 consecutive patients referred to a tertiary center in Modena, Italy [Articolo su rivista]
Maurantonio, M.; Gabrielli, F.; Castellano, C.; Carla, A.; Andreone, P.; Roncucci, L.
abstract

Aim: Diabetic foot syndrome (DFS) is a complication of diabetes in which the presence of infections, ulceration and/or destruction of deep tissue associated with neuropathy, peripheral atherosclerosis and comorbidity affect the prognosis, the need for limb amputation and quality of life. Purpose of the present study is to report the features of patients with acute DFS admitted to our Diabetic Foot Unit tertiary Center in 2019. Methods: In all patients admitted, the approach was performed through a multidisciplinary team (Diabetic Foot Care Team) and described in a specific diagnostic-therapeutic-assistance program. Criteria of inclusion were presence of sepsis and/or suspected osteomyelitis and/or critical limb ischemia. Clinical features and interventions performed were registered. Primary endpoints were mortality and amputation (major, minor). Secondary endpoints were length of hospitalization, type of revascularization and duration of antibiotic therapy. Results: Among 75 consecutive patients (mean age 70.9 years) enrolled, prevalence of acute DFS was higher among men (M/F 3:1). Poor glycemic control [mean hemoglobin A1c (HbA1c) 67.9 ± 22.3 mmol/mol], long duration of diabetes (mean 19 ± 16.3 years), high low-density lipoprotein-cholesterol (mean 89.5 ± 45.1 mg/ dL) and obesity (mean Body Mass Index 30.2 ± 7.6 kg/m2) were common. Diabetes-related complications as peripheral arterial disease (PAD) (76%), ischemic heart disease (48%), retinopathy (40.5%), hepatic steatosis (50%), heart failure (17.8%) were present. During hospitalization, 21 subjects (28.4%) underwent lower limb amputations (overall rate of major amputation 4%), and 41.3% underwent percutaneous angioplasty. Long period of hospitalization (18.4 ± 7.9 days) and prolonged antibiotic therapy (23.9 ± 15.9 days) were observed. Major amputation was associated with C-reactive protein > 6.5 mg/dL (P = 0.03), osteomyelitis (P = 0.001), prior insulin therapy (P = 0.015). Conclusions: Male sex, co-morbidity, PAD, systemic inflammation and poor glycemic control are major features of acute hospitalized DFS. An approach through a multidisciplinary team is recommended in order to treat vascular and extra-vascular complications aimed at reducing mortality and at improving quality of life.

2021 - The time has come to look for metabolic dysfunction-associated fatty liver disease in adult patients with type 1 Gaucher disease [Articolo su rivista]
Nascimbeni, F.; Lugari, S.; Andreone, P.; Carubbi, F.
abstract

MAFLD is highly prevalent in Gaucher type 1 adult patients as well as in the general population and may worsen liver disease progression. Hepatic complications should be followed up. A healthy lifestyle and therapies of cardiometabolic risk factors should be recommended in Gaucher disease patients.

2021 - Treatments for hbv: A glimpse into the future [Articolo su rivista]
Bartoli, A.; Gabrielli, F.; Tassi, A.; Cursaro, C.; Pinelli, A.; Andreone, P.
abstract

The hepatitis B virus is responsible for most of the chronic liver disease and liver cancer worldwide. As actual therapeutic strategies have had little success in eradicating the virus from hepatocytes, and as lifelong treatment is often required, new drugs targeting the various phases of the hepatitis B virus (HBV) lifecycle are currently under investigation. In this review, we provide an overview of potential future treatments for HBV.

2021 - X Chromosome Contribution to the Genetic Architecture of Primary Biliary Cholangitis [Articolo su rivista]
Asselta, R.; Paraboschi, E. M.; Gerussi, A.; Cordell, H. J.; Mells, G. F.; Sandford, R. N.; Jones, D. E.; Nakamura, M.; Ueno, K.; Hitomi, Y.; Kawashima, M.; Nishida, N.; Tokunaga, K.; Nagasaki, M.; Tanaka, A.; Tang, R.; Li, Z.; Shi, Y.; Liu, X.; Xiong, M.; Hirschfield, G.; Siminovitch, K. A.; Walker, E.; Xie, G.; Mason, A.; Myers, R.; Peltekian, K.; Ghent, C.; Atkinson, E.; Juran, B.; Lazaridis, K.; Lu, Y.; Gu, X.; Jing, K.; Amos, C.; Affronti, A.; Brunetto, M.; Coco, B.; Spinzi, G.; Elia, G.; Ferrari, C.; Lleo, A.; Muratori, L.; Muratori, P.; Portincasa, P.; Colli, A.; Bruno, S.; Colloredo, G.; Azzaroli, F.; Andreone, P.; Bragazzi, M.; Alvaro, D.; Cardinale, V.; Cazzagon, N.; Rigamonti, C.; Floreani, A.; Rosina, F.; Ciaccio, A.; Cristoferi, L.; D'Amato, D.; Malinverno, F.; Mancuso, C.; Massironi, S.; Milani, C.; O'Donnell, S. E.; Ronca, V.; Barisani, D.; Lampertico, P.; Donato, F.; Fagiuoli, S.; Almasio, P. L.; Giannini, E.; Cursaro, C.; Colombo, M.; Valenti, L.; Miele, L.; Andriulli, A.; Niro, G. A.; Grattagliano, I.; Morini, L.; Casella, G.; Vinci, M.; Battezzati, P. M.; Crosignani, A.; Zuin, M.; Mattalia, A.; Calvaruso, V.; Colombo, S.; Benedetti, A.; Marzioni, M.; Galli, A.; Marra, F.; Tarocchi, M.; Picciotto, A.; Morisco, F.; Fabris, L.; Croce, L. S.; Tiribelli, C.; Toniutto, P.; Strazzabosco, M.; Ch'Ng, C. L.; Rahman, M.; Yapp, T.; Sturgess, R.; Healey, C.; Czajkowski, M.; Gunasekera, A.; Gyawali, P.; Premchand, P.; Kapur, K.; Marley, R.; Foster, G.; Watson, A.; Dias, A.; Subhani, J.; Harvey, R.; Mccorry, R.; Ramanaden, D.; Gasem, J.; Evans, R.; Mathialahan, T.; Shorrock, C.; Lipscomb, G.; Southern, P.; Tibble, J.; Gorard, D.; Palegwala, A.; Jones, S.; Dawwas, M.; Alexander, G.; Dolwani, S.; Prince, M.; Foxton, M.; Elphick, D.; Mitchison, H.; Gooding, I.; Karmo, M.; Saksena, S.; Mendall, M.; Patel, M.; Ede, R.; Austin, A.; Sayer, J.; Hankey, L.; Hovell, C.; Fisher, N.; Carter, M.; Koss, K.; Piotrowicz, A.; Grimley, C.; Neal, D.; Lim, G.; Levi, S.; Ala, A.; Broad, A.; Saeed, A.; Wood, G.; Brown, J.; Wilkinson, M.; Gordon, H.; Ramage, J.; Ridpath, J.; Ngatchu, T.; Grover, B.; Shaukat, S.; Shidrawi, R.; Abouda, G.; Ali, F.; Rees, I.; Salam, I.; Narain, M.; Brown, A.; Taylor-Robinson, S.; Williams, S.; Grellier, L.; Banim, P.; Das, D.; Chilton, A.; Heneghan, M.; Curtis, H.; Gess, M.; Drake, I.; Aldersley, M.; Davies, M.; Jones, R.; Mcnair, A.; Srirajaskanthan, R.; Pitcher, M.; Sen, S.; Bird, G.; Barnardo, A.; Kitchen, P.; Yoong, K.; Chirag, O.; Sivaramakrishnan, N.; Macfaul, G.; Jones, D.; Shah, A.; Evans, C.; Saha, S.; Pollock, K.; Bramley, P.; Mukhopadhya, A.; Fraser, A.; Mills, P.; Shallcross, C.; Campbell, S.; Bathgate, A.; Shepherd, A.; Dillon, J.; Rushbrook, S.; Przemioslo, R.; Macdonald, C.; Metcalf, J.; Shmueli, U.; Davis, A.; Naqvi, A.; Lee, T.; Ryder, S. D.; Collier, J.; Klass, H.; Ninkovic, M.; Cramp, M.; Sharer, N.; Aspinall, R.; Goggin, P.; Ghosh, D.; Douds, A.; Hoeroldt, B.; Booth, J.; Williams, E.; Hussaini, H.; Stableforth, W.; Ayres, R.; Thorburn, D.; Marshall, E.; Burroughs, A.; Mann, S.; Lombard, M.; Richardson, P.; Patanwala, I.; Maltby, J.; Brookes, M.; Mathew, R.; Vyas, S.; Singhal, S.; Gleeson, D.; Misra, S.; Butterworth, J.; George, K.; Harding, T.; Douglass, A.; Panter, S.; Shearman, J.; Bray, G.; Butcher, G.; Forton, D.; Mclindon, J.; Cowan, M.; Whatley, G.; Mandal, A.; Gupta, H.; Sanghi, P.; Jain, S.; Pereira, S.; Prasad, G.; Watts, G.; Wright, M.; Neuberger, J.; Gordon, F.; Unitt, E.; Grant, A.; Delahooke, T.; Higham, A.; Brind, A.; Cox, M.; Ramakrishnan, S.; King, A.; Collins, C.; Whalley, S.; Li, A.; Fraser, J.; Bell, A.; Wong, V. S.; Singhal, A.; Gee, I.; Ang, Y.; Ransford, R.; Gotto, J.; Millson, C.; Bowles, J.; Thomas, C.; Harrison, M.; Galaska, R.; Kendall, J.; Whiteman, J.; Lawlor, C.; Gray, C.; Elliott, K.; Mulvaney-Jones, C.; Hobson, L.; Van Duyvenvoorde, G.; Loftus, A.; Seward, K.; Penn, R.; Maiden, J.; Damant, R.; Hails, J.; Cloudsdale, R.; Silvestre, V.; Glenn, S.; Dungca, E.; Wheatle
abstract

Background & Aims: Genome-wide association studies in primary biliary cholangitis (PBC) have failed to find X chromosome (chrX) variants associated with the disease. Here, we specifically explore the chrX contribution to PBC, a sexually dimorphic complex autoimmune disease. Methods: We performed a chrX-wide association study, including genotype data from 5 genome-wide association studies (from Italy, United Kingdom, Canada, China, and Japan; 5244 case patients and 11,875 control individuals). Results: Single-marker association analyses found approximately 100 loci displaying P < 5 × 10–4, with the most significant being a signal within the OTUD5 gene (rs3027490; P = 4.80 × 10–6; odds ratio [OR], 1.39; 95% confidence interval [CI], 1.028–1.88; Japanese cohort). Although the transethnic meta-analysis evidenced only a suggestive signal (rs2239452, mapping within the PIM2 gene; OR, 1.17; 95% CI, 1.09–1.26; P = 9.93 × 10–8), the population-specific meta-analysis showed a genome-wide significant locus in East Asian individuals pointing to the same region (rs7059064, mapping within the GRIPAP1 gene; P = 6.2 × 10–9; OR, 1.33; 95% CI, 1.21–1.46). Indeed, rs7059064 tags a unique linkage disequilibrium block including 7 genes: TIMM17B, PQBP1, PIM2, SLC35A2, OTUD5, KCND1, and GRIPAP1, as well as a superenhancer (GH0XJ048933 within OTUD5) targeting all these genes. GH0XJ048933 is also predicted to target FOXP3, the main T-regulatory cell lineage specification factor. Consistently, OTUD5 and FOXP3 RNA levels were up-regulated in PBC case patients (1.75- and 1.64-fold, respectively). Conclusions: This work represents the first comprehensive study, to our knowledge, of the chrX contribution to the genetics of an autoimmune liver disease and shows a novel PBC-related genome-wide significant locus.

2020 - A novel spleen-dedicated stiffness measurement by FibroScan® improves the screening of high-risk oesophageal varices [Articolo su rivista]
Stefanescu, H.; Marasco, G.; Cales, P.; Fraquelli, M.; Rosselli, M.; Ganne-Carrie, N.; de Ledinghen, V.; Ravaioli, F.; Colecchia, A.; Rusu, C.; Andreone, P.; Mazzella, G.; Festi, D.
abstract

Background & Aims Several non-invasive tests (NITs) have been developed to diagnose oesophageal varices (EV), including the recent Baveno VI criteria to rule out high-risk varices (HRV). Spleen stiffness measurement (SSM) with the standard FibroScan (R) (SSM@50Hz) has been evaluated. However, the EV grading could be underestimated because of a ceiling threshold (75 kPa) of the SSM@50Hz. The aims were to evaluate SSM by a novel spleen-dedicated FibroScan (R) (SSM@100Hz) for EV diagnosis compared with SSM@50Hz, other validated NITs and Baveno VI criteria. Methods This prospective multicentre study consecutively enrolled patients with chronic liver disease; blood data, endoscopy, liver stiffness measurement (LSM), SSM@50Hz and SSM@100Hz were collected. Results Two hundred and sixty patients met inclusion criteria. SSM@100Hz success rate was significantly higher than that of SSM@50Hz (92.5% vs 76.0%, P < .001). SSM@100Hz accuracy for the presence of EV (AUC = 0.728) and HRV (AUC = 0.756) was higher than in other NITs. SSM@100Hz AUC for large EV (0.782) was higher than SSM@50Hz (0.720, P = .027). AUC for HRV with SSM@100Hz (0.780) was higher than with LSM (0.615, P < .001). The spared endoscopy rate of Baveno VI criteria (8.1%) was significantly increased by the combination to SSM@50Hz (26.5%) or SSM@100Hz (38.9%, P < .001 vs others). The missed HRV rate was, respectively, 0% and 4.7% for combinations. Conclusions SSM@100Hz is a new performant non-invasive marker for EV and HRV providing a higher accuracy than SSM@50Hz and other NITs. The combination of Baveno VI criteria and SSM@100Hz significantly increased the spared endoscopy rate compared to Baveno VI criteria alone or combined with SSM@50Hz. Clinical trial number: NCT02180113.

2020 - A randomized, placebo-controlled, phase II study of obeticholic acid for primary sclerosing cholangitis [Articolo su rivista]
Kowdley, K. V.; Vuppalanchi, R.; Levy, C.; Floreani, A.; Andreone, P.; Larusso, N. F.; Shrestha, R.; Trotter, J.; Goldberg, D.; Rushbrook, S.; Hirschfield, G. M.; Schiano, T.; Jin, Y.; Pencek, R.; Macconell, L.; Shapiro, D.; Bowlus, C. L.
abstract

Background & Aims: Primary sclerosing cholangitis (PSC) is a rare, cholestatic liver disease with no currently approved therapies. Obeticholic acid (OCA) is a potent farnesoid X receptor (FXR) agonist approved for the treatment of primary biliary cholangitis. We investigated the efficacy and safety of OCA in patients with PSC. Methods: AESOP was a phase II, randomized, double-blind, placebo-controlled, dose-finding study. Eligible patients were 18 to 75 years of age with a diagnosis of PSC and serum alkaline phosphatase (ALP) ≥2× the upper limit of normal (ULN) and total bilirubin <2.5× ULN. Patients were randomized 1:1:1 to receive placebo, OCA 1.5–3.0 mg, or OCA 5–10 mg once daily for a 24-week, double-blind phase followed by a 2-year, long-term safety extension (LTSE). Primary endpoints were change in ALP from baseline to week 24, and safety. Results: The intent-to-treat population comprised 76 patients randomized to placebo (n = 25), OCA 1.5–3.0 mg (n = 25), and OCA 5–10 mg (n = 26). At week 24, serum ALP was significantly reduced with OCA 5–10 mg vs. placebo (least-square [LS] mean difference = −83.4 [SE = 40.3] U/L; 95% CI −164.28 to −2.57; p = 0.043). Serum ALP was not significantly reduced with OCA 1.5–3.0 mg vs. placebo at week 24 (LS mean [SE] difference = −78.29 [41.81] U/L; 95% CI −162.08 to 5.50; p = 0.067). Total bilirubin remained comparable to baseline in all groups. The most common treatment-emergent adverse event was dose-related pruritus (placebo 46%; OCA 1.5–3.0 mg 60%; OCA 5–10 mg 67%). Reductions in ALP were maintained during the LTSE, and no new safety signals emerged. Conclusions: Treatment with OCA 5–10 mg reduced serum ALP in patients with PSC. Mild to moderate dose-related pruritus was the most common adverse event. Registration: ClinicalTrials.gov: NCT02177136; EudraCT: 2014-002205-38. Lay summary: Primary sclerosing cholangitis (PSC) is a long-term disease that damages the bile ducts in the liver over time. In the AESOP clinical study in patients with PSC, obeticholic acid reduced serum alkaline phosphatase (a potential marker of disease severity) during an initial 24-week treatment period. The result was sustained during the 2-year, long-term extension of the study. The most common side effect of obeticholic acid in the study was itchy skin, which is consistent with earlier clinical studies.

2020 - Could inflammatory indices and metabolic syndrome predict the risk of cancer development? Analysis from the bagnacavallo population study [Articolo su rivista]
Rimini, M.; Casadei-Gardini, A.; Ravaioli, A.; Rovesti, G.; Conti, F.; Borghi, A.; Dall'Aglio, A. C.; Bedogni, G.; Domenicali, M.; Giacomoni, P.; Tiribelli, C.; Bucchi, L.; Falcini, F.; Foschi, F. G.; Gastaldelli, A.; Ercolani, G.; Cucchetti, A.; Dazzani, F.; Bevilacqua, V.; Napoli, L.; Mirici, F.; Bellentani, S.; Lanzi, A.; Saini, G.; Bernardi, M.; Andreone, P.; Stefanini, G. F.
abstract

Background: Despite the robust data available on inflammatory indices (neutrophil lymphocyte ratio (NLR), platelet lymphocyte ratio (PLR), and systemic immune-inflammation index (SII)) and clinical outcome in oncological patients, their utility as a predictor of cancer incidence in the general population has not been reported in literature. Methods: The Bagnacavallo study was performed between October 2005 and March 2009. All citizens of Bagnacavallo (Ravenna, Emilia-Romagna, Italy) aged 30-60 years as of January 2005 were eligible and were invited by written letter to participate to the study. All participants underwent a detailed clinical history and physical examination following the model of the Dionysos Study. All blood values included in the analysis were obtained the day of physical examination. Cancer incidence data were obtained from the population-based Romagna Cancer Registry, which operates according to standard methods. The aim of this analysis was to examine the association between metabolic syndrome and baseline SII, NLR, and PLR levels, and the diagnosis of an invasive cancer in the Bagnacavallo study cohort. Results: At univariate analysis, metabolic syndrome was not associated with an increase of cancer incidence (HR 1.30; p = 0.155). High glucose (HR 1.49; p = 0.0.16),NLRHR 1.54, p = 0.002), PLR (HR 1.58, p = 0.001), and SII (HR 1.47, p = 0.006) were associated with an increase of cancer incidence. After adjusting for clinical covariates (smoking, physical activity, education, age, and gender) SII, PLR, and NLR remained independent prognostic factors for the prediction of cancer incidence. Conclusions: Inflammatory indices are promising, easy to perform, and inexpensive tools for identifying patients with higher risk of cancer in cancer-free population.

2020 - Hepatitis C virus- related cryoglobulinemic vasculitis: A review of the role of the new direct antiviral agents (DAAs) therapy [Articolo su rivista]
Mazzaro, C.; Dal Maso, L.; Mauro, E.; Visentini, M.; Tonizzo, M.; Gattei, V.; Andreone, P.; Pozzato, G.
abstract

Hepatitis C virus (HCV) infection affects about 70 million people worldwide. HCV is responsible for both hepatitis and extra-hepatic manifestations. Chronic infection has been shown to develop in about 70% of cases and can progress to cirrhosis or hepatocellular carcinoma. Ten percent of HCV patients may develop extra-hepatic manifestations, including mixed cryoglobulinemia (MC) and non-Hodgkin lymphomas. Many studies have demonstrated that, after antiviral therapy, MC can disappear along with HCV eradication. After the introduction of the new direct antiviral agents (DAAs), the combination of pegylated interferon and ribavirin has been abandoned. Several studies on new DAAs have reported remarkable 90% to 100% eradication rates, regardless of HCV genotype. Treatment with DAAs has comparable efficacy on viral eradication in patients with MC, but definite clinical improvements of vasculitis can be observed only in half the patients. On the contrary, the regression of renal disease and lympho-proliferative disorders, induced by HCV, appears to have a lower remission rate after viral eradication with DAAs and most cases need immunosuppressive treatments. In HCV related CV, the main clinical goal must be early eradication of HCV, to avoid organ complication and manifestation of lympho-proliferative diseases. This review focuses on the role of DAAs in treatment of HCV-related cryoglobulinemic vasculitis.

2020 - Hepatocellular carcinoma and liver transplant: beyond the Milan criteria and the risk of "short-blanket" syndrome [Articolo su rivista]
Gitto, Stefano; Di Sandro, Stefano; Magistri, Paolo; Andreone, Pietro; Di Benedetto, Fabrizio
abstract

2020 - Liver steatosis is highly prevalent and is associated with metabolic risk factors and liver fibrosis in adult patients with type 1 Gaucher disease [Articolo su rivista]
Nascimbeni, F.; Lugari, S.; Cassinerio, E.; Motta, I.; Cavicchioli, A.; Dalla Salda, A.; Bursi, S.; Donatiello, S.; Spina, V.; Cappellini, M. D.; Andreone, P.; Carubbi, F.
abstract

Background and Aims: Gaucher disease (GD) is associated with peculiar metabolic abnormalities (ie hypermetabolic state, peripheral insulin resistance, dyslipidaemia), partially reverted by enzyme replacement therapy (ERT) at the expense of weight gain. Such metabolic alterations together with an unhealthy lifestyle acquired by an ageing GD population may favour the development of liver steatosis. We aimed at evaluating the prevalence of significant liver steatosis and at identifying the factors associated with liver steatosis in a cohort of patients with type 1 GD. Methods: Twenty adult type 1 GD patients from an Italian academic referral centre were prospectively submitted to vibration-controlled transient elastography (Fibroscan®) with controlled attenuation parameter (CAP); significant steatosis was defined as CAP values ≥250 dB/min. Results: Median CAP values were 234 [165-358] dB/min and 8 patients (40%) had significant steatosis. Significant steatosis was associated with indices of adiposity (weight, BMI and waist circumference), high blood pressure, insulin resistance and metabolic syndrome. GD-related variables and dose and duration of ERT were not associated with significant steatosis. In the subgroup of 16 patients on stable ERT for at least 24 months, CAP resulted significantly and positively associated with liver stiffness (rho 0.559, P =.024). Conclusions: Significant steatosis is highly prevalent in adult type 1 GD patients and is strongly associated with a worse metabolic profile, featuring metabolic dysfunction-associated fatty liver disease (MAFLD). MAFLD may determine liver fibrosis progression in GD patients on stable ERT and may be a risk factor for long-term liver-related complications.

2020 - Pre-transplant diabetes predicts atherosclerotic vascular events and cardiovascular mortality in liver transplant recipients: a long-term follow-up study [Articolo su rivista]
Gitto, S.; De Maria, N.; Marzi, L.; Magistri, P.; Falcini, M.; Vitale, G.; Olivieri, T.; Guerrini, G. P.; Serra, V.; Forte, P.; Carrai, P.; De Simone, P.; Mega, A.; Zoller, H.; Piai, G.; Schepis, F.; Marocchi, M.; Villa, E.; Marra, F.; Andreone, P.; Di Benedetto, F.; Vizzutti, F.; Laffi, G.; Borelli, E.; Ballarin, R.; Tarantino, G.; Di Sandro, S.; Puntili, R.; Petruccelli, S.; Valente, G.; Turco, L.
abstract

Background Early after surgery, liver transplant (LT) recipients often develop weight gain. Metabolic disorders and cardiovascular disease represent main drivers of morbidity and mortality. Our aim was to identify predictors of atherosclerotic vascular events (AVE) and to assess the impact of AVE on the long-term outcome. Methods We retrospectively analyzed data from patients transplanted between 2000 and 2005 and followed-up in five Italian transplant clinics. Cox Regression analysis was performed to identify predictors of AVE, global mortality, and cardiovascular mortality. Survival analysis was performed using the Kaplan-Meier method. Results We analyzed data from 367 subjects during a median follow-up of 14 years. Thirty-seven post-LT AVE were registered. Patients with AVE more frequently showed pre-LT diabetes mellitus (DM) (48.6 vs 13.9%, p=0.000). In the post-LT period, patients with AVE satisfied criteria of metabolic syndrome in 83.8% vs. 36.7% of subjects without AVE (p=0.000). At multivariate analysis, pre-LT DM independently predicted AVE (HR 2.250, CI 4.848-10.440, p=0.038). Moreover, both pre-LT DM and AVE strongly predicted cardiovascular mortality (HR 5.418, CI 1.060-29.183, p=0.049, and HR 86.097, CI 9.510-779.480, p=0.000, respectively). Conclusions Pre-LT DM is the main risk factor for post-LT AVE. Pre-LT DM and post-LT AVE are strong, long-term predictors of cardiovascular mortality. Patients with pre-LT DM should obtain a personalized follow-up for prevention or early diagnosis of AVE.

2020 - Recent news in the treatment of hepatitis B virus-related cryogobulinemic vasculitis [Articolo su rivista]
Mazzaro, C.; Dal Maso, L.; Visentini, M.; Ermacora, A.; Tonizzo, M.; Gattei, V.; Andreone, P.
abstract

Hepatitis B virus (HBv) is a hepatotropic virus that causes hepatitis, cirrhosis and hepatocellular carcinoma. Twenty percent of HBv patients may develop extra-hepatic manifestations, such as polyarthritis nodosa, glomerulonephritis, dermatitis, poly-arthralgia and arthritis, and aplastic anemia. The association of HBv and cryoglobulinemic vasculitis (cv) has been highlighted by several epidemiological investigations. cv can develop in 0.5-4% of HBv infected patients. it has been demonstrated that suppression of HBv replication by nucleot(s)ide analogues (nas) effectively induces clinical response in most patients with mild to moderate cv, but low responses are seen in severe cv. Based on this evidence, NAs therapy represents the first line therapeutic option in subjects with mild or moderate HBV related CV. Peg-interferon-alfa can be an alternative treatment for HBv related cv, but the few studies published so far have shown no encouraging results. in patients with severe vasculitis and/or skin ulcers, peripheral neuropathy and glomerulonephritis treatment with rituximab (RTX) and NAs should be considered as a first line treatment. The long-term administration of low-medium glucocorticoid doses has been widely used in few studies to control clinical symptoms, but it should be used as a second option, when rTX is ineffective or not tolerated and in association with nas. This review focuses on novel treatments for HBv related cv.

2020 - Soluble CD163 and mannose receptor as markers of liver disease severity and prognosis in patients with primary biliary cholangitis [Articolo su rivista]
Bossen, L.; Rebora, P.; Bernuzzi, F.; Jepsen, P.; Gerussi, A.; Andreone, P.; Galli, A.; Terziroli, B.; Alvaro, D.; Labbadia, G.; Aloise, C.; Baiocchi, L.; Giannini, E.; Abenavoli, L.; Toniutto, P.; Marra, F.; Marzioni, M.; Niro, G.; Floreani, A.; Moller, H. J.; Valsecchi, M. G.; Carbone, M.; Gronbaek, H.; Invernizzi, P.
abstract

Introduction: In primary biliary cholangitis (PBC), macrophages are involved in liver inflammation and fibrosis. The macrophage activation markers, soluble (s)CD163 and mannose receptor (sMR) are associated with liver disease severity and prognosis in other chronic liver diseases. We aimed to investigate sCD163 and sMR in patients with PBC. Methods: We investigated PBC patients from the Italian PBC Study Group cohort and measured macrophage activation markers in serum at study enrolment. Patients were followed from enrolment until they experienced an event or were censored at their last visit. Events were defined as follows: (a) death from a liver-related cause; or (b) liver transplantation (LT) for PBC. We used Cox regression to investigate the association between sCD163 and sMR and long-term prognosis. Results: In total, 202 PBC patients were included. Median age was 62 years (interquartile range (IQR), 53-71) at enrolment and 93% were women. Median sCD163 was 3.43 mg/L (IQR 2.48-5.35) and median sMR was 0.35 mg/L (IQR 0.28-0.45). There was an increase in sCD163 and sMR with increasing alkaline phosphatase. Two hundred and one patients were followed for a median of 8.6 years, and sCD163 and sMR predicted long-term risk of liver-related death or LT in univariate analyses, while sCD163 was also associated with outcome after confounder adjusting (adjusted HR = 1.14, 95% CI 1.00-1.30). Finally, we showed an increase in the prediction accuracy of poor outcome by adding sCD163 to the UK-PBC risk score. Conclusion: The macrophage activation markers sCD163 and sMR represent a non-invasive measure of PBC disease severity that provides useful long-term prognostic information.

2020 - Targeted pharmacotherapy for cardiovascular risk reduction in patients with diabetes undergoing liver transplantation: Author's reply [Articolo su rivista]
Gitto, S.; Andreone, P.
abstract

2020 - The Effect of Liraglutide on β-Blockade for Preventing Variceal Bleeding: A Case Series [Articolo su rivista]
Vukotic, R.; Raimondi, F.; Brodosi, L.; Vitale, G.; Petroni, M. L.; Marchesini, G.; Andreone, P.
abstract

2020 - Treatment with tenofovir disoproxil fumarate or entecavir in chronic hepatitis B virus-infected patients with renal impairment: results from a 7-year, multicentre retrospective cohort study [Articolo su rivista]
Lampertico, P.; Berg, T.; Buti, M.; Pathil, A.; Petersen, J.; Ryder, S. D.; Zoulim, F.; Botros, I.; Flaherty, J. F.; Jump, B.; Op den Brouw, M. L.; van Troostenburg, A.; Ramroth, H.; Bourliere, M.; De Ledinghen, V.; Riachi, G.; Zoulim, F.; Loustaud-Ratti, V.; Tran, A.; Larrey, D.; Dumortier, J.; Leroy, V.; Metivier, S.; Sellier, P.; Mauss, S.; Peterson, J.; Berg, T.; Schiefke, I.; Niederau, C.; Teuber, G.; Goeser, T.; Jung, M. C.; Grambihler, A.; Pathil-Warth, A.; Sprinzl, K.; Von der Ohe, M.; Antoni, C.; Weigand, K.; Andreone, P.; Lampertico, P.; Di Marco, V.; Madonia, S.; Puoti, M.; Santantonio, T.; Vigano, M.; Ciancio, A.; D'Offizi, G.; Pirisi, M.; Buti, M.; Suarez Garcia, E.; Pascasio Acevedo, J. M.; Andrade, R.; Gea, F.; Serra Desfilis, M. A.; Molina Perez, E.; Manzano Alonso, M.; Carrion, J. A.; Aoufi Rabih, S.; Planas, M. M.; Ryder, S.; Agarwal, K.; Ustianowski, A.; Aspinall, R.; Kennedy, P.; Geretti, A. M.; Mccorry, R.; Foxton, M.; Healy, B.
abstract

Background: Limited data exist regarding tenofovir disoproxil fumarate (TDF) safety and effectiveness in chronic hepatitis B virus–infected (CHB) patients with renal impairment (RI). Aims: To compare real-world data on renal safety and effectiveness of TDF vs entecavir (ETV) in CHB patients with moderate-to-severe RI. Methods: Retrospective, non-interventional, cohort study analysing medical records for TDF/ETV-treated CHB patients (54 European centres). Included patients experienced moderate-to-severe RI (creatinine clearance 20-60 mL/min [Cockcroft-Gault]) either before TDF/ETV initiation (‘before’ subgroup [baseline = treatment initiation]) or after TDF/ETV initiation (‘after’ subgroup [baseline = first RI occurrence]). The primary objective was TDF safety, particularly renal-related adverse events of special interest (AESI). TDF and ETV safety and effectiveness were compared and multivariate analyses were performed using inverse probability treatment weighting. Results: ‘Before’ subgroup included 107 TDF- and 91 ETV-treated patients; ‘after’ subgroup included 212 TDF- and 77 ETV-treated patients. Mean baseline creatinine clearance was higher for TDF- vs ETV-treated patients (both subgroups). Median follow-up was 3.1 years (both treatments). AESI were more frequent with TDF vs ETV (‘before’: 18.7% vs 8.8%; ‘after’: 9.9% vs 3.9%); however, differences were not significant by multivariate analysis. Only TDF-treated patients experienced renal tubular dysfunction (6.5% ‘before’; 1.9% ‘after’) as well as renal adverse events leading to treatment discontinuation (8.4% ‘before’; 7.1% ‘after’). Effectiveness was similar between treatments. Conclusions: Overall safety was similar for TDF vs ETV (both subgroups). Given that renal tubular dysfunction occurred with TDF and not with ETV, renal safety concerns may be greater with TDF in CHB patients with RI.

2020 - Utility of neutrophil-to-lymphocyte ratio to identify long-term survivors among HCC patients treated with sorafenib [Articolo su rivista]
Casadei-Gardini, A.; Dadduzio, V.; Rovesti, G.; Cabibbo, G.; Vukotic, R.; Rizzato, M. D.; Orsi, G.; Rossi, M.; Guarneri, V.; Lonardi, S.; D'Agostino, D.; Celsa, C.; Andreone, P.; Zagonel, V.; Scartozzi, M.; Cascinu, S.; Cucchetti, A.
abstract

Sorafenib is the first multikinase inhibitor demonstrating a survival benefit for patients suffering from advanced hepatocellular carcinoma (HCC). However, 1 issue remains open: what is the factor able to predict which patients will be long survivors?In the present study, we harnessed the potential of conditional survival, aiming at estimating the probability that a patient receiving sorafenib survives for more than 3 years.The present multicentric study was conducted on a cohort of 438 HCC patients. The primary end point was conditional overall survival. Kaplan-Meier survival analysis was used to calculate conditional overall survival probabilities at 3 years.The 3-year conditional survival of patients without disease progression highlights that NLR and ECOG are the factors that most accurately predict the probability of long survival. The 3-year conditional survival of patients with disease progression showed a medium effect size for HCV status, alpha-fetoprotein and NLR at all time-points. Macro-vascular portal vein invasion, extra hepatic disease, and BCLC we have a large effect size at 6 months and a medium effect size at 12 and 24 months.Our findings support the use of baseline NLR for the identification of patients with a higher probability of long-survival. NLR should be used as a stratification factor in the forthcoming clinical trials on the drugs for the advanced HCC now in pipeline.

2019 - Add-on peginterferon alfa-2a to nucleos(t)ide analogue therapy for Caucasian patients with hepatitis B ‘e’ antigen-negative chronic hepatitis B genotype D [Articolo su rivista]
Lampertico, Pietro; Brunetto, Maurizia R.; Craxì, Antonio; Gaeta, Giovanni B.; Rizzetto, Mario; Rozzi, Antonella; Colombo, Massimo; Antonio, D.; Andreone, P.; Antonio, D.; Brancaccio, G.; Bronte, F.; Bruzzone, L.; Caccamo, G.; Caccianotti, B.; Calvaruso, V.; Chessa, L.; Ciarallo, M.; Coco, B.; Colombatto, P.; Cursaro, C.; D'Aluisio, D.; Demelia, L.; Di Marco, V.; Dissegna, D.; Invernizzi, F.; Lenisa, I.; Lembo, T.; Levrero, M.; Marchese, V.; Mangia, G.; Picciotto, A.; Pierconti, S.; Antonio, D.; Raimondo, G.; Rastelli, C.; Rizzo, V.; Santantonio, T.; Scuteri, A.; Sorbello, O.; Squadrito, G.; Subic, M.; Toniutto, P.; Vukotic, R.
abstract

Nucleos(t)ide analogues (NAs) and peginterferon have complementary effects in chronic hepatitis B, but it is unclear whether combination therapy improves responses in genotype D-infected patients. We conducted an open-label study of peginterferon alfa-2a 180 μg/wk added to ongoing NA therapy in hepatitis B e antigen (HBeAg)-negative, genotype D-infected patients with hepatitis B virus DNA <20 IU/mL. The primary endpoint was proportion of patients with ≥50% decline in serum HBsAg by the end of the 48-week add-on phase. Seventy patients received treatment, 11 were withdrawn at week 24 for no decrease in HBsAg, and 14 withdrew for other reasons. Response rate (per-protocol population) was 67.4% (29/43) at week 48 (95% confidence interval [CI]: 51, 81) and 50.9% (28/55) at week 96 (95% CI: 38, 66). Median serum HBsAg decreased throughout peginterferon alfa-2a treatment and was significantly lower than baseline at weeks 48, 72 and 96 (P < 0.001). Decreases in HBsAg of ≥0.5-log10 and ≥1-log10 were documented in 19 (44.2%) and 6 (14.0%) patients at week 48 and 6 (10.9%) and 17 (30.9%) patients at week 96. The proportion of patients with HBsAg <1000, <500, <100 and <10 IU/mL at ≥1 timepoint during treatment was 78.6% (n = 44), 57.1% (n = 32), 21.4% (n = 12) and 7.1% (n = 4). Interferon gamma-induced protein 10 increased from baseline up to week 48, with week 12 levels significantly associated with response at week 48. Addition of peginterferon alfa-2a to ongoing NA therapy significantly decreased HBsAg levels in HBeAg-negative patients with genotype D infection (ClinicalTrials.gov NCT01706575).

2019 - Assessment of Liver Fibrosis With Elastography Point Quantification vs Other Noninvasive Methods [Articolo su rivista]
Conti, Fabio; Serra, Carla; Vukotic, Ranka; Felicani, Cristina; Mazzotta, Elena; Gitto, Stefano; Vitale, Giovanni; D'Errico, Antonietta; Andreone, Pietro
abstract

Background & Aims: Elastography point quantification (ElastPQ) is a non-invasive method for assessing liver fibrosis based on liver stiffness. We evaluated the accuracy of ElastPQ for the staging of liver fibrosis in patients with chronic liver disease (CLD) compared with aspartate transaminase to platelet ratio index, fibrosis-4 index, and transient elastography (TE), using liver biopsy as reference standard. Methods: We performed a retrospective study of 406 patients with CLD of any etiology who underwent liver biopsy analysis from September 2012 through June 2017 at a clinic in Bologna, Italy. We obtained liver stiffness measurements, made by ElastPQ and TE, for 361 patients. Liver fibrosis stage was assessed by the METAVIR scoring system. Areas under the receiver operating characteristic curve (AUROC) were used to assess the diagnostic performance of ElastPQ. Results: ElastPQ values correlated with histologic detection of fibrosis (r = 0.718; P <.001). The AUROC values were 0.856 for detection of significant fibrosis (F≥2), 0.951 for advanced fibrosis (F≥3), and 0.965 for cirrhosis. The best cut-off values identified for classifying patients with F≥2, F≥3, or cirrhosis were 6.0 kPa, 6.2 kPa, and 9.5 kPa, respectively: these were lower than those for TE. Comparison of ElastPQ with TE data resulted in superimposable diagnostic accuracy of both methods for each stage of liver fibrosis. Both elastography techniques performed better than aspartate transaminase to platelet ratio index or fibrosis-4 index scores (P <.05 for all AUROC comparisons). Conclusions: ElastPQ has good to excellent performance for the non-invasive staging of liver fibrosis in patients with CLD. ElastPQ identified patients with fibrosis or cirrhosis with levels of accuracy that were not inferior to those of TE, and outperformed serum fibrosis indexes in identifying each stage of liver fibrosis.

2019 - Assessment of Radiofrequency Ablation Efficacy for Hepatocellular Carcinoma by Histology and Pre-transplant Radiology [Articolo su rivista]
Serra, Carla; Cucchetti, Alessandro; Felicani, Cristina; Mosconi, Cristina; De Cinque, Antonio; Golfieri, Rita; Andreone, Pietro; Ercolani, Giorgio; Maroni, Lorenzo; Ravaioli, Matteo; D'Errico, Antonia; Pinna, Antonio Daniele; Cescon, Matteo
abstract

Radiofrequency ablation (RFA) represents a potentially curative option for hepatocellular carcinoma (HCC) in the early stages. This study aims at evaluating the histologic response after RFA of small HCCs arising in cirrhosis. Data from 78 patients with de-novo HCCs, treated with RFA and subsequently transplanted were reviewed. The last radiological assessment before liver transplantation (LT) was used for comparison between Modified Response Evaluation Criteria in Solid Tumors (mRECIST) and histological findings. A total of 125 de-novo HCCs (median diameter: 20mm) were treated with RFA only in 92 sessions. Ninety-eight nodules did not show local recurrence during follow-up (78.4%), the remaining were retreated, except one because of subsequent LT. On explanted livers, complete pathological response (CPR) was observed in 61.6%, being 76.9% when <2cm, 55.0% when 2-3cm and 30.8% when >3cm. Tumors near to hepatic vessels had CPR in 50% of cases versus 69.3% for tumors distant from vessels (p=0.039). Of the 125 HCCs, 114 had available radiological assessment within a median of 3 months before LT. mRECIST complete was observed in 77.2% of nodules before LT. The k-Cohen was 0.48 (moderate agreement). The overall accuracy was of 78.1%. A total of 18 complications were recorded, only one graded as major. CONCLUSIONS: RFA can provide high CPR for HCC, especially in smaller tumors distant from hepatic veins or portal branches. The agreement between mRECIST and histology is only moderate. Further refinements in radiological assessment are essential to accurately assess the true effectiveness of RFA. This article is protected by copyright. All rights reserved.

2019 - Clinical Impact and Safety of Anticoagulants for Portal Vein Thrombosis in Cirrhosis [Articolo su rivista]
Pettinari, I.; Vukotic, R.; Stefanescu, H.; Pecorelli, A.; Morelli, M.; Grigoras, C.; Sparchez, Z.; Andreone, P.; Piscaglia, F.; Badia, L.; Cappelli, A.; Cescon, M.; Conti, F.; Cucchetti, A.; Galaverni, Cristina; Golfieri, R.; Granito, A.; Mosconi, C.; Renzulli, M.; Tame, M.; Verucchi, G.; Vitale, G.; Bolondi, L.
abstract

Objectives: Portal vein thrombosis (PVT) is a frequent complication of cirrhosis. Benefit, safety, and duration of anticoagulant treatment in this setting are controversial issues. The aim of this study was to analyze the course of PVT in a large cohort of cirrhotic patients undergoing or not anticoagulation therapy. Methods: The data of 182 patients who presented between January 2008 and March 2016 with cirrhosis and PVT with at least 3 months of follow-up after the first PVT detection were analyzed. Eighty-one patients received anticoagulants and 101 were untreated per physician discretion. Results: The extension of the thrombosis decreased by >50% in 46 (56.8%, with complete recanalization in 31/46) patients under anticoagulation and in 26 (25.7%) untreated patients. Of the 46 patients who underwent recanalization, 17 (36%) suffered recurrent thrombosis after stopping anticoagulation therapy. Kaplan–Meier analysis showed a higher survival rate in the treated group (p = 0.010). At multivariate analysis, anticoagulation was an independent factor associated with longer survival (HR:0.30, CI:0.10–0.91, p = 0.014). The Child–Turcotte–Pugh classes B/C negatively influenced survival (hazard ratio, (HR):3.09, confidence interval (CI):1.14–8.36, p = 0.027 for Child–Turcotte–Pugh B and HR:9.27, CI:2.67–32.23, p < 0.001 for Child–Turcotte–Pugh C). Bleeding complications occurred in 22 (21.8%) untreated and 16 (19.7%) treated patients, but in only four cases was it judged to be related to the anticoagulant treatment. No death was reported as a consequence of the bleeding events. Conclusions: Anticoagulant treatment is a safe and effective treatment leading to partial or complete recanalization of the portal venous system in 56.8% of cases, improving the survival of patients with cirrhosis and PVT. Discontinuation of the therapy is associated with a high rate of PVT recurrence.

2019 - Combined GS-4774 and Tenofovir Therapy Can Improve HBV-Specific T-Cell Responses in Patients With Chronic Hepatitis [Articolo su rivista]
Boni, C.; Janssen, H. L. A.; Rossi, M.; Yoon, S. K.; Vecchi, A.; Barili, V.; Yoshida, E. M.; Trinh, H.; Rodell, T. C.; Laccabue, D.; Alfieri, A.; Brillo, F.; Fisicaro, P.; Acerbi, G.; Pedrazzi, G.; Andreone, P.; Cursaro, C.; Margotti, M.; Santoro, R.; Piazzolla, V.; Brunetto, M. R.; Coco, B.; Cavallone, D.; Zhao, Y.; Joshi, A.; Woo, J.; Lau, A. H.; Gaggar, A.; Subramanian, G. M.; Massetto, B.; Fung, S.; Ahn, S. H.; Ma, X.; Mangia, A.; Ferrari, C.
abstract

Background & Aims: One strategy to treat chronic hepatitis B virus (HBV) infection could be to increase the functions of virus-specific T cells. We performed a multicenter phase 2 study to evaluate the safety and efficacy of GS-4774, a yeast-based therapeutic vaccine engineered to express HBV antigens, given with tenofovir disoproxil fumarate (TDF) to untreated patients with chronic HBV infection. Methods: We performed an open-label study at 34 sites in Canada, Italy, New Zealand, Romania, South Korea, and United States from July 2014 to August 2016. Adults who were positive for HB surface antigen (HBsAg) > 6 months and levels of HBV DNA ≥2000 IU/mL who had not received antiviral treatment for HBV within 3 months of screening were randomly assigned (1:2:2:2) to groups given oral TDF 300 mg daily alone (n = 27; controls) or with 2, 10, or 40 yeast units GS-4774 (n = 168), administered subcutaneously every 4 weeks until week 20 for a total of 6 doses. Blood samples were collected and analyzed and patients received regular physical examinations. Efficacy was measured by decrease in HBsAg from baseline to week 24. Specific responses to HBV (production of interferon gamma [IFNG], tumor necrosis factor [TNF], interleukin 2 [IL2], and degranulation) were measured in T cells derived from 12 HBeAg-negative patients with genotype D infections, after overnight or 10 days of stimulation of peripheral blood mononuclear cells with peptides from the entire HBV proteome. T-regulatory cells were analyzed for frequency and phenotype. Data from studies of immune cells were compared with data on reductions in HBsAg, HBV DNA, and alanine aminotransferase in blood samples from patients. Results: GS-4774 was safe and well tolerated but did not produce significant decreases in levels of HBsAg. Production of IFNG, TNF, and IL2 increased significantly at weeks 24 and 48, compared with baseline, in HBV-specific CD8+ T cells from patients given GS-4774 but not from controls. GS-4774 had greater effects on CD8+ than CD4+ T cells, which were not affected at all or very weakly by TDF with or without GS-4774. GS-4774 did not affect responses of T cells to other viruses tested. HBV core peptides induced the greatest production of IFNG by T cells following overnight stimulation, whereas HBV envelope antigens did not induce a response. Following 10 days of stimulation, production of IFNG and TNF increased with time of exposure to GS-4774; the greatest levels of responses were to HBV envelope antigens followed by core and polymerase peptides. We observed a correlation in patients given GS-4774 between increased T-cell functions and reductions in numbers of T-regulatory cells. Conclusions: In a phase 2 study of patients with chronic HBV infection given TDF with or without GS-4774, we found that vaccination can increase production of IFNG, TNF, and IL2 by CD8+ T cells exposed to antigenic peptides, with little effect on CD4+ T cells. Although GS-4774 did not reduce levels of HBsAg in patients, its strong immune stimulatory effect on CD8+ T cells might be used in combination with other antiviral agents to boost the antivirus immune response. Clinicaltrials.gov no: NCT02174276.

2019 - Current and forthcoming perspectives in linkage to care of hepatitis C virus infection: Assessment of an Italian focus group [Articolo su rivista]
Andreone, P.; Di Marco, V.; Gaeta, G. B.; Fagiuoli, S.; Vukotic, R.; Craxi, A.
abstract

Hepatitis C virus (HCV) remains a significant public health problem and is one of the major causes of chronic liver disease worldwide. In recent years many new tools to facilitate widespread HCV screening and new therapeutic options with excellent efficacy and tolerability profiles and cost lowering policies have become available. To fully utilise these new tools, the link between local and specialist centres for the management of HCV infection must be reinforced. In order to GAIN further insight into these aspects, with a particular focus on the Italian scenario, a group of experts met to discuss relevant aspects and open issues on chronic HCV. As a summary of that meeting, the following aspects are here overviewed: (i) global situation of HCV; (ii) screening, diagnosis and indications for the treatment of HCV; (iii) the Italian situation of HCV referrals; (iv) ‘hard to reach’ patients; (v) treatment of HCV with extrahepatic manifestations; (vi) treatment of patients with advanced cirrhosis. It is the intention of the expert panel to further promote widespread screening and eradication policies that should be accompanied by greater interaction, by attempting to involve all healthcare providers in an organised process to facilitate linkage to care of patients with HCV infections.

2019 - Economic Consequences of Investing in Anti-HCV Antiviral Treatment from the Italian NHS Perspective: A Real-World-Based Analysis of PITER Data [Articolo su rivista]
Marcellusi, A.; Viti, R.; Kondili, L. A.; Rosato, S.; Vella, S.; Mennini, F. S.; Kondili, L. A.; Vella, S.; Quaranta, M. G.; Rosato, S.; Tosti, M. E.; Weimer, L. E.; Ferrigno, L.; D'Angelo, F.; Falzano, L.; Benedetti, A.; Schiada, L.; Cucco, M.; Giacometti, A.; Brescini, L.; Castelletti, S.; Drenaggi, D.; Mazzaro, C.; Angarano, G.; Milella, M.; Dileo, A.; Rendina, M.; Contaldo, A.; Iannone, A.; La Fortezza, F.; Rizzi, M.; Cologni, G.; Bolondi, L.; Benevento, F.; Serio, I.; Andreone, P.; Caraceni, P.; Guarneri, V.; Margotti, M.; Simonetti, G.; Mazzella, G.; Verucchi, G.; Donati, V.; Mian, P.; Rimenti, G.; Rossini, A.; Contessi, G. B.; Castelli, F.; Zaltron, S.; Spinetti, A.; Odolini, S.; Leandro, G.; Cozzolongo, R.; Zappimbulso, M.; Russello, M.; Benigno, R.; Coco, C.; Torti, C.; Costa, C.; Greco, G.; Mazzitelli, M.; Pisani, V.; Cosco, L.; Quintieri, F.; Desiena, M.; Giancotti, F.; Vecchiet, J.; Falasca, K.; Mastroianni, A.; Apuzzo, G.; Chidichimo, L.; Foschi, F. G.; Dall'Aglio, A. C.; Libanore, M.; Segala, D.; Sighinolfi, L.; Bartolozzi, D.; Salomoni, E.; Blanc, P.; Baragli, F.; Delpin, B.; Mariabelli, E.; Mazzotta, F.; Poggi, A.; Zignego, A. L.; Monti, M.; Madia, F.; Xheka, A.; Cela, E. M.; Santantonio, T. A.; Bruno, S. R.; Viscoli, C.; Alessandrini, A. I.; Curti, C.; Dibiagio, A.; Nicolini, L. A.; Balletto, E.; Mastroianni, C.; Blerta, K.; Prati, D.; Raffaele, L.; Andreoletti, M.; Perboni, G.; Costa, P.; Manzini, L.; Raimondo, G.; Filomia, R.; Lazzarin, A.; Morsica, G.; Salpietro, S.; Puoti, M.; Baiguera, C.; Vassalli, S.; Rumi, M. G.; Labanca, S.; Zuin, M.; Giorgini, A.; Orellana, D.; D'Arminiomonforte, A.; Debona, A.; Solaro, S.; Fargion, S.; Valenti, L.; Periti, G.; Pelusi, S.; Galli, M.; Calvi, E.; Milazzo, L.; Peri, A.; Lampertico, P.; Borghi, M.; D'Ambrosio, R.; Degasperi, E.; Vinci, M.; Villa, E.; Bernabucci, V.; Bristot, L.; Pereira, F.; Chessa, L.; Pasetto, M. C.; Loi, M.; Gori, A.; Beretta, I.; Pastore, V.; Soria, A.; Strazzabosco, M.; Ciaccio, A.; Gemma, M.; Borgia, G.; Foggia, A.; Zappulo, E.; Gentile, I.; Buonomo, A. R.; Abrescia, N.; Maddaloni, A.; Caporaso, N.; Morisco, F.; Camera, S.; Donnarumma, L.; Coppola, C.; Amoruso, D. C.; Staiano, L.; Saturnino, M. R.; Coppola, N.; Martini, S.; Monari, C.; Federico, A.; Dallio, M.; Loguercio, C.; Gaeta, G. B.; Brancaccio, G.; Nardone, G.; Sgamato, C.; D'Adamo, G.; Alberti, A.; Gonzo, M.; Piovesan, S.; Chemello, L.; Buggio, A.; Cavalletto, L.; Barbaro, F.; Castelli, E.; Floreani, A.; Cazzagon, N.; Franceschet, I.; Russo, F. P.; Zanetto, A.; Franceschet, E.; Madonia, S.; Cannizzaro, M.; Montalto, G.; Licata, A.; Capitano, A. R.; Craxi, A.; Petta, S.; Calvaruso, V.; Rini, F.; Ferrari, C.; Negri, E.; Orlandini, A.; Pesci, M.; Bruno, R.; Lombardi, A.; Zuccaro, V.; Gulminetti, R.; Asti, A.; Villaraggia, M.; Mondelli, M.; Ludovisi, S.; Baldelli, F.; Di Candilo, F.; Parruti, G.; Di Stefano, P.; Sozio, F.; Gizzi, M. C.; Brunetto, M. R.; Colombatto, P.; Coco, B.; Surace, L.; Foti, G.; Pellicano, S.; Fornaciari, G.; Schianchi, S.; Vignoli, P.; Massari, M.; Corsini, R.; Garlassi, E.; Ballardini, G.; Andreoni, M.; Cerva, C.; Angelico, M.; Gasbarrini, A.; Siciliano, M.; De Siena, M.; Nosotti, L.; Taliani, G.; Biliotti, E.; Santori, M.; Spaziante, M.; Tamburini, F.; Vullo, V.; D'Ettorre, G.; Cavallari, E. N.; Gebremeskel, T. S.; Pavone, P.; Cauda, R.; Cingolani, A.; Lamonica, S.; D'Offizi, G.; Lionetti, R.; Visco Comandini, U.; Grieco, A.; D'Aversa, F.; Picardi, A.; De Vincentis, A.; Galati, G.; Gallo, P.; Dell'Unto, C.; Aghemo, A.; Gatti Comini, A.; Persico, M.; Masarone, M.; Anselmo, M.; De Leo, P.; Marturano, M.; Brunelli, E.; Ridolfi, F.; Schimizzi, A. M.; Ayoubi Khajekini, M.; Framarin, L.; Di Perri, G.; Cariti, G.; Boglione, L.; Cardellino, C.; Marinaro, L.; Saracco, G. M.; Ciancio, A.; Toniutto, P.; Alterini, G.; Capra, F.; Ieluzzi, D.
abstract

Objective: We estimated the cost consequence of Italian National Health System (NHS) investment in direct-acting antiviral (DAA) therapy according to hepatitis C virus (HCV) treatment access policies in Italy. Methods: A multistate, 20-year time horizon Markov model of HCV liver disease progression was developed. Fibrosis stage, age and genotype distributions were derived from the Italian Platform for the Study of Viral Hepatitis Therapies (PITER) cohort. The treatment efficacy, disease progression probabilities and direct costs in each health state were obtained from the literature. The break-even point in time (BPT) was defined as the period of time required for the cumulative costs saved to recover the Italian NHS investment in DAA treatment. Three different PITER enrolment periods, which covered the full DAA access evolution in Italy, were considered. Results: The disease stages of 2657 patients who consecutively underwent DAA therapy from January 2015 to December 2017 at 30 PITER clinical centres were standardized for 1000 patients. The investment in DAAs was considered to equal €25 million, €15 million, and €9 million in 2015, 2016, and 2017, respectively. For patients treated in 2015, the BPT was not achieved, because of the disease severity of the treated patients and high DAA prices. For 2016 and 2017, the estimated BPTs were 6.6 and 6.2 years, respectively. The total cost savings after 20 years were €50.13 and €55.50 million for 1000 patients treated in 2016 and 2017, respectively. Conclusions: This study may be a useful tool for public decision makers to understand how HCV clinical and epidemiological profiles influence the economic burden of HCV.

2019 - Effectiveness and safety of switching to entecavir hepatitis B patients developing kidney dysfunction during tenofovir [Articolo su rivista]
Vigano, M.; Loglio, A.; Labanca, S.; Zaltron, S.; Castelli, F.; Andreone, P.; Messina, V.; Ganga, R.; Coppola, N.; Marrone, A.; Russello, M.; Marzano, A.; Tucci, A.; Taliani, G.; Fasano, M.; Fagiuoli, S.; Villa, E.; Bronte, F.; Santantonio, T.; Brancaccio, G.; Occhipinti, V.; Facchetti, F.; Grossi, G.; Rumi, M.; Lampertico, P.
abstract

Background and Aims: Tenofovir disoproxil fumarate (TDF) is recommended for chronic hepatitis B (CHB) treatment, but it may induce kidney dysfunction whose management is not yet known. This Italian, multicentre, retrospective study aimed to assess the efficacy and safety of switching to entecavir (ETV) patients who developed TDF-associated glomerular and/or tubular dysfunction. Methods: A total of 103 TDF-treated patients were included as follows: age 64 years, 83% male, 49% cirrhotics, 98% with undetectable HBV DNA, 47% with previous lamivudine resistance (LMV-R) and 71% previously treated with adefovir. Twenty-nine (28%) were switched to ETV because estimated glomerular filtration rate (eGFR MDRD ) was <60 mL/min, 37 (36%) because blood phosphate (P) levels were <2.5 mg/dL and 37 (36%) for both reasons. Kidney, liver and virological parameters were recorded every 4 months thereafter. Results: During 46 (4-115) months of ETV treatment, all patients’ renal parameters significantly improved as follows: creatinine from 1.30 to 1.10 mg/dL (P < 0.0001), eGFR MDRD from 54 to 65 mL/min (P = 0.002), P from 2.2 to 2.6 mg/dL (P < 0.0001) and maximal tubule phosphate reabsorption (TmPO4/eGFR) from 0.47 to 0.62 mmol/L (P < 0.0001). Thirteen patients (52%) improved their eGFR MDRD class, P levels were normalised in 13 (35%), and eight (22%) showed improvements in both parameters. Viral suppression was maintained in all but five patients (5%), all of whom had been LMV-R. The 5-year cumulative probability of ETV-R was 0% in LMV-naïve patients, and 11% in LMV-R patients (P = 0.018). Conclusions: Entecavir is an effective and safe rescue strategy for CHB patients who develop renal dysfunction during long-term TDF treatment.

2019 - Familial intrahepatic cholestasis: New and wide perspectives [Articolo su rivista]
Vitale, G.; Gitto, S.; Vukotic, R.; Raimondi, F.; Andreone, P.
abstract

Background: Progressive familial intrahepatic cholestasis (PFIC) includes autosomal recessive cholestatic rare diseases of childhood. Aims: To update the panel of single genes mutations involved in familial cholestasis. Methods: PubMed search for “familial intrahepatic cholestasis” alone as well as in combination with other key words was performed considering primarily original studies and meta-analyses. Results: PFIC1 involves ATP8B1 gene encoding for aminophospholipid flippase FIC1. PFIC2 includes ABCB11 gene, encoding for protein functioning as bile salt export pump. PFIC3 is due to mutations of ABCB4 gene responsible for the synthesis of class III multidrug resistance P-glycoprotein flippase. PFIC4 and PFIC5 involve tight junction protein-2 gene and NR1H4 gene encoding for farnesoid X receptor. Benign Intrahepatic Cholestasis, Intrahepatic Cholestasis of Pregnancy and Low-phospholipid-associated cholelithiasis involve the same genes and are characterized by intermittent attacks of cholestasis, no progression to cirrhosis, reversible pregnancy-specific cholestasis and cholelithiasis in young people. Blood and liver tissue levels of bile-excreted drugs can be influenced by the presence of mutations in PFIC genes, causing drug-induced cholestasis. Mutations in PFIC genes might increase the risk of liver cancer. Conclusion: There is a high proportion of unexplained cholestasis potentially caused by specific genetic pathophysiologic pathways. The use of next generation sequencing and whole-exome sequencing could improve the diagnostic process in this setting.

2019 - HEPATIC DECOMPENSATION RISK IS REDUCED, BUT NOT ELIMINATED AFTER DIRECT-ACTING ANTIVIRALS: THE ROLE OF SPLEEN STIFFNESS MEASUREMENT [Relazione in Atti di Convegno]
Marasco, G; Dajti, E; Ravaioli, F; Colecchia, A; Reggiani, Mlb; Colli, A; Alemanni, Lv; Tame, Mr; Andreone, P; Brillanti, S; Azzaroli, F; Mazzella, G; Festi, D
abstract

2019 - Hepatitis B virus-related cryogobulinemic vasculitis. The role of antiviral nucleot(s)ide analogues: a review [Articolo su rivista]
Mazzaro, C.; Dal Maso, L.; Visentini, M.; Gitto, S.; Andreone, P.; Toffolutti, F.; Gattei, V.
abstract

Cryoglobulinemic vasculitis (CV) can develop in 1.2–4% of hepatitis B virus (HBV)-infected patients. HBV infection affects about 350 million people worldwide. It can progress from acute or fulminant hepatitis to chronic hepatitis, cirrhosis or hepatocellular carcinoma. Twenty per cent of HBV patients may develop extra-hepatic manifestations, such as polyarteritis nodosa, glomerulonephritis, dermatitis, polyarthralgias and arthritis, lung disease, aplastic anaemia. Our review focuses on the role of antiviral agent nucleot(s)ide analogues (NAs) in treatment of HBV-related CV. The studies in literature have demonstrated that NAs therapy in HBV-related CV yields high virological and satisfying clinical responses in most patients with mild-and-moderate CV, but a low response in severe CV. Overall, NAs represent a promising therapeutic option for HBV-related CV. Obtaining early suppression of HBV viral load should be the main virological and clinical goal in order to prevent organ complications and lymphoproliferative disorders.

2019 - Immune inflammation indicators and ALBI score to predict liver cancer in HCV-patients treated with direct-acting antivirals [Articolo su rivista]
Casadei Gardini, Andrea; Foschi, Francesco Giuseppe; Conti, Fabio; Petracci, Elisabetta; Vukotic, Ranka; Marisi, Giorgia; Buonfiglioli, Federica; Vitale, Giovanni; Ravaioli, Federico; Gitto, Stefano; Verucchi, Gabriella; Lenzi, Marco; Bolondi, Luigi; Mazzella, Giuseppe; Brillanti, Stefano; Andreone, Pietro
abstract

Background: Unexpectedly high occurrence or recurrence rate of hepatocellular carcinoma (HCC) has been observed in patients with chronic hepatitis C receiving direct-acting antivirals (DAAs) therapy. Aims: We evaluated the predictive value of albumin-bilirubin (ALBI) score and immune-inflammation indicators to identify the risk of occurrence or recurrence of HCC in patients treated with DAAs in a real life setting. Methods: In this retrospective cohort study, we analysed data from 514 patients with cirrhosis who were prospectively enrolled for treatment with DAAs. We assessed baseline neutrophil to lymphocyte ratio (NLR), systemic immune-inflammation index (SII), platelet to lymphocyte ratio (PLR), aspartate aminotransferase-lymphocyte ratio (ALRI) index and ALBI score. Results: In patients with no history of HCC (N = 416), increased AST, bilirubin, ALRI, and ALBI score, and decreased albumin and platelets were significantly associated with an increased risk of HCC development, at univariate analysis. At multivariate analysis, increase in ALBI grade (p = 0.038, HR: 2.35, 95% CI: 1.05–5.25) and decrease in platelets (p = 0.048, HR: 0.92, 95% CI: 0.85–1.0) were independently associated with HCC development. In patients with previous HCC (N = 98), adjusting for the time from HCC treatment, increased ALRI (p = 0.008, HR: 1.05, 95% CI: 1.01–1.09) was significantly associated with a risk of recurrence. Conclusion: ALBI score, platelet count and ALRI are promising, easy to perform and inexpensive tools for identifying patients with higher risk of HCC after treatment with DAAs.

2019 - Impact of Baseline Characteristics on the Overall Survival of HCC Patients Treated with Sorafenib: Ten Years of Experience [Articolo su rivista]
Rovesti, Giulia; Orsi, Giulia; Kalliopi, Andrikou; Vivaldi, Caterina; Marisi, Giorgia; Faloppi, Luca; Foschi, Francesco Giuseppe; Silvestris, Nicola; Pecora, Irene; Aprile, Giuseppe; Molinaro, Eleonora; Riggi, Laura; Ulivi, Paola; Canale, Matteo; Cucchetti, Alessandro; Tamburini, Emiliano; Ercolani, Giorgio; Fornaro, Lorenzo; Andreone, Pietro; Zavattari, Patrizia; Scartozzi, Mario; Cascinu, Stefano; Casadei-Gardini, Andrea
abstract

Sorafenib has been established as the standard of care for patients with advanced hepatocellular carcinoma (HCC) since 2007 on the basis of two landmark trials (SHARP and Asia-Pacific). Ten years have passed since then and, despite much research in the field, still no validated real-life prognostic markers are available for HCC patients treated with this drug. Therefore, going through 10 years of research into sorafenib of several Italian Cancer Centers, we conducted a field-practice study aimed at identifying baseline clinical factors that could be significantly associated with overall survival (OS).

2019 - Impact of psychosocial status on liver transplant process [Articolo su rivista]
Golfieri, L.; Gitto, S.; Vukotic, R.; Andreone, P.; Marra, F.; Morelli, M. C.; Cescon, M.; Grandi, S.
abstract

Liver transplant candidates and recipients are at high risk of psychological distress. Social, psychological and psychiatric patterns seem to influence morbidity and mortality of patients before and after transplant. An accurate organ allocation is mandatory to guarantee an optimal graft and recipient survival. In this context, the pre-transplant social, psychological and psychiatric selection of potential candidates is essential for excluding major psychiatric illness and for estimating the patient compliance. Depression is one of the most studied psychological conditions in the field of organ transplantation. Notably, an ineffectively treated depression in the pre-transplant period has been associated to a worst long-term recipient survival. After transplant, personalized psychological intervention might favor recovery process, improvement of quality of life and immunosuppressant adherence. Active coping strategy represents one of the most encouraging ways to positively influence the clinical course of transplanted patients. In conclusion, multidisciplinary team should act in three directions: prevention of mood distress, early diagnosis and effective treatment. Active coping, social support and multidisciplinary approach might improve the clinical outcome of transplanted patients.

2019 - Long-term efficacy and safety of obeticholic acid for patients with primary biliary cholangitis: 3-year results of an international open-label extension study [Articolo su rivista]
Trauner, M.; Nevens, F.; Shiffman, M. L.; Drenth, J. P. H.; Bowlus, C. L.; Vargas, V.; Andreone, P.; Hirschfield, G. M.; Pencek, R.; Malecha, E. S.; Macconell, L.; Shapiro, D.
abstract

Background: The aim of this study was to evaluate the long-term efficacy and safety of obeticholic acid for patients with primary biliary cholangitis using 3-year interim data from the 5-year open-label extension of the pivotal phase 3 POISE trial. Methods: In the double-blind phase of POISE, 217 patients with primary biliary cholangitis with inadequate response to or intolerance to ursodeoxycholic acid were randomised to receive placebo, obeticholic acid 5 to 10 mg, or obeticholic acid 10 mg once daily for 12 months. During the open-label extension phase, patients received variable, adjusted doses of obeticholic acid. Markers of cholestasis and liver injury, alkaline phosphatase (ALP), and total and direct bilirubin were evaluated, and safety was assessed for up to 48 months of treatment with obeticholic acid. All analyses in the open-label extension were done in the safety population, defined as any patient randomised in the double-blind phase who received at least one dose of obeticholic acid during the open-label extension. This trial is registered at ClinicalTrials.gov (NCT01473524) and with EudraCT (2011-004728-36). Findings: 193 patients were treated during the open-label extension. In this 3-year interim analysis, ALP concentrations were significantly reduced compared with baseline at 12 months (mean change −105·2 U/L [SD 87·6]), 24 months (−101·0 U/L [98·5]), 36 months (−108·6 U/L [95·7]), and 48 months (−95·6 U/L [121·1]; p<0·0001 for all yearly time points). Total bilirubin concentrations were stabilised, with significant reductions versus baseline at 12 months (mean change −0·9 μmol/L [SD 4·1]; p=0·0042) and 48 months (−0·8 μmol/L [3·8]; p=0·016). Stabilisation was also noted for direct bilirubin, with a significant change from baseline at 12 months (mean change −0·5 μmol/L [SD 3·0]; p=0·021). However, changes in total and direct bilirubin were not significant at other time points. Obeticholic acid was generally well tolerated, with pruritus (149 [77%] patients) and fatigue (63 [33%]) being the most common adverse events. No serious adverse events were considered related to obeticholic acid. Interpretation: Interim analyses suggest long-term efficacy and safety of obeticholic acid in patients with primary biliary cholangitis who are intolerant to or inadequately responsive to ursodeoxycholic acid. Funding: Intercept Pharmaceuticals.

2019 - Nonalcoholic steatohepatitis before and after liver transplant: keeping up with the times [Articolo su rivista]
Gitto, S.; Marra, F.; De Maria, N.; Bihl, F.; Villa, E.; Andreone, P.; Burra, P.
abstract

Introduction: In the last years, nonalcoholic steatohepatitis (NASH) has become a leading indication for liver transplant (LT). After transplant, both recurrent and de novo nonalcoholic fatty liver disease (NAFLD) can be commonly diagnosed. However, dedicated surveillance programs for patients with pre- or post-transplant NAFLD are not available. Areas covered: Patients waiting for LT for NASH show specific peculiarities and would deserve targeted stratification of mortality risk. Obesity, hyperlipidemia, and diabetes mellitus can be often found after transplant. These conditions, together with immunosuppressive regimen, make LT recipients a high-risk population for both recurrent and de novo NAFLD. Development of fatty liver disease after LT has a relevant impact on both morbidity and mortality. Expert commentary: A targeted stratification of neoplastic and cardiovascular risk for patients with NASH waiting for LT would be mandatory. In both pre- and post-transplant period, NAFLD should be considered not only a liver disease but also a cardiovascular risk factor. Patients within Transplant Program, especially those with known metabolic risk factors, should be followed with personalized diagnostic and life-style interventions before and after LT.

2019 - Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial [Articolo su rivista]
Younossi, Z. M.; Ratziu, V.; Loomba, R.; Rinella, M.; Anstee, Q. M.; Goodman, Z.; Bedossa, P.; Geier, A.; Beckebaum, S.; Newsome, P. N.; Sheridan, D.; Sheikh, M. Y.; Trotter, J.; Knapple, W.; Lawitz, E.; Abdelmalek, M. F.; Kowdley, K. V.; Montano-Loza, A. J.; Boursier, J.; Mathurin, P.; Bugianesi, E.; Mazzella, G.; Olveira, A.; Cortez-Pinto, H.; Graupera, I.; Orr, D.; Gluud, L. L.; Dufour, J. -F.; Shapiro, D.; Campagna, J.; Zaru, L.; MacConell, L.; Shringarpure, R.; Harrison, S.; Sanyal, A. J.; Abdelmalek, M.; Abrams, G.; Aguilar, H.; Ahmed, A.; Aigner, E.; Aithal, G.; Ala, A.; Alazawi, W.; Albillos, A.; Allison, M.; Al-Shamma, S.; Andrade, R.; Andreone, P.; Angelico, M.; Ankoma-Sey, V.; Anstee, Q.; Anty, R.; Araya, V.; Arenas Ruiz, J. I.; Arkkila, P.; Arora, M.; Asselah, T.; Au, J.; Ayonrinde, O.; Bailey, R. J.; Balakrishnan, M.; Bambha, K.; Bansal, M.; Barritt, S.; Bate, J.; Beato, J.; Behari, J.; Bellot, P.; Ben Ari, Z.; Bennett, M.; Berenguer, M.; Beretta-Piccoli, B. T.; Berg, T.; Bonacini, M.; Bonet, L.; Borg, B.; Bourliere, M.; Bowman, W.; Bradley, D.; Brankovic, M.; Braun, M.; Bronowicki, J. -P.; Bruno, S.; Cai, C.; Calleja Panero, J. L.; Carey, E.; Carmiel, M.; Carrion, J. A.; Cave, M.; Chagas, C.; Chami, T.; Chang, A.; Coates, A.; Cobbold, J.; Corey, K.; Corless, L.; Crespo, J.; Cruz Pereira, O.; de Ledinghen, V.; deLemos, A.; Diago, M.; Dufour, J. -F.; Dugalic, P.; Dunn, W.; Elkhashab, M.; Epstein, M.; Escudero-Garcia, M. D.; Etzion, O.; Evans, L.; Falcone, R.; Fernandez, C.; Ferreira, J.; Fink, S.; Finnegan, K.; Firpi-Morell, R.; Floreani, A.; Fontanges, T.; Ford, R.; Forrest, E.; Fowell, A.; Fracanzani, A. L.; Francque, S.; Freilich, B.; Frias, J.; Fuchs, M.; Fuentes, J.; Galambos, M.; Gallegos, J.; Geerts, A.; George, J.; Ghali, M.; Ghalib, R.; Gholam, P.; Gines, P.; Gitlin, N.; Goeser, T.; Goff, J.; Gordon, S.; Gordon, F.; Goria, O.; Greer, S.; Grigorian, A.; Gronbaek, H.; Guillaume, M.; Gunaratnam, N.; Halegoua-De Marzio, D.; Hameed, B.; Hametner, S.; Hamilton, J.; Hartleb, M.; Hassanein, T.; Haussinger, D.; Hellstern, P.; Herring, R.; Heurich, E.; Hezode, C.; Hinrichsen, H.; Holland Fischer, P.; Horsmans, Y.; Huang, J.; Jakiche, A.; Jeffers, L.; Jones, B.; Jorge, R.; Jorquera, F.; Kahraman, A.; Kaita, K.; Karyotakis, N.; Kayali, Z.; Kechagias, S.; Kepczyk, T.; Khalili, M.; Khallafi, H.; Kluwe, J.; Kohli, A.; Korenblat, K.; Kowdley, K.; Krag, A.; Krause, R.; Kremer, A.; Krok, K.; Krstic, M.; Kugelmas, M.; Kumar, S.; Labarriere, D.; Lai, M.; Lampertico, P.; Lee, A.; Leroy, V.; Lidofsky, S.; Lim, T. H.; Lim, J.; Lipkis, D.; Little, E.; Lonardo, A.; Long, M.; Lurie, Y.; Macedo, G.; Makara, M.; Maliakkal, B.; Manns, M.; Manousou, P.; Mantry, P.; Marchesini, G.; Marinho, C.; Marotta, P.; Marschall, H. -U.; Mayo, M.; McCullen, M.; McLaughlin, W.; Merriman, R.; Modi, A.; Molina, E.; Montano-Loza, A.; Monteverde, C.; Moreea, S.; Moreno, C.; Morisco, F.; Mubarak, A.; Muellhaupt, B.; Mukherjee, S.; Muller, T.; Nagorni, A.; Naik, J.; Neff, G.; Nevah, M.; Newsome, P.; Nguyen-Khac, E.; Noureddin, M.; Oben, J.; Orlent, H.; Orr, J.; Ortiz-Lasanta, G.; Ozenne, V.; Pandya, P.; Paredes, A.; Park, J.; Patel, J.; Patel, K.; Uta, M.; Patton, H.; Peck-Radosavljevic, M.; Petta, S.; Pianko, S.; Piekarska, A.; Pimstone, N.; Pockros, P.; Pol, S.; Porayko, M.; Poulos, J.; Pound, D.; Pouzar, J.; Presa Ramos, J.; Pyrsopoulos, N.; Rafiq, N.; Muller, K.; Ramji, A.; Ravinuthala, R.; Reddy, C.; Reddy K G, G.; Reddy K R, K. R.; Regenstein, F.; Reindollar, R.; Riera, A.; Rivera Acosta, J.; Robaeys, G.; Roberts, S.; Rodriguez-Perez, F.; Romero-Gomez, M.; Rubin, R.; Rumi, M.; Rushbrook, S.; Rust, C.; Ryan, M.; Safadi, R.; Said, A.; Salminen, K.; Samuel, D.; Santoro, J.; Sanyal, A.; Sarkar, S.; Schaeffer, C.; Schattenberg, J.; Schiefke, I.; Schiff, E.; Schmidt, W.; Schneider, J.; Schouten, J.; Schultz, M.; Sebastiani, G.; Semela, D.; Sepe, T.; Sheikh, A.; Sheikh, M.; Sherman, K.; Shibolet, O.; Shiffman, M.; Siddique, A.; Sieberhagen, C.; Sigal, S.;
abstract

Background: Non-alcoholic steatohepatitis (NASH) is a common type of chronic liver disease that can lead to cirrhosis. Obeticholic acid, a farnesoid X receptor agonist, has been shown to improve the histological features of NASH. Here we report results from a planned interim analysis of an ongoing, phase 3 study of obeticholic acid for NASH. Methods: In this multicentre, randomised, double-blind, placebo-controlled study, adult patients with definite NASH, non-alcoholic fatty liver disease (NAFLD) activity score of at least 4, and fibrosis stages F2–F3, or F1 with at least one accompanying comorbidity, were randomly assigned using an interactive web response system in a 1:1:1 ratio to receive oral placebo, obeticholic acid 10 mg, or obeticholic acid 25 mg daily. Patients were excluded if cirrhosis, other chronic liver disease, elevated alcohol consumption, or confounding conditions were present. The primary endpoints for the month-18 interim analysis were fibrosis improvement (≥1 stage) with no worsening of NASH, or NASH resolution with no worsening of fibrosis, with the study considered successful if either primary endpoint was met. Primary analyses were done by intention to treat, in patients with fibrosis stage F2–F3 who received at least one dose of treatment and reached, or would have reached, the month 18 visit by the prespecified interim analysis cutoff date. The study also evaluated other histological and biochemical markers of NASH and fibrosis, and safety. This study is ongoing, and registered with ClinicalTrials.gov, NCT02548351, and EudraCT, 20150-025601-6. Findings: Between Dec 9, 2015, and Oct 26, 2018, 1968 patients with stage F1–F3 fibrosis were enrolled and received at least one dose of study treatment; 931 patients with stage F2–F3 fibrosis were included in the primary analysis (311 in the placebo group, 312 in the obeticholic acid 10 mg group, and 308 in the obeticholic acid 25 mg group). The fibrosis improvement endpoint was achieved by 37 (12%) patients in the placebo group, 55 (18%) in the obeticholic acid 10 mg group (p=0·045), and 71 (23%) in the obeticholic acid 25 mg group (p=0·0002). The NASH resolution endpoint was not met (25 [8%] patients in the placebo group, 35 [11%] in the obeticholic acid 10 mg group [p=0·18], and 36 [12%] in the obeticholic acid 25 mg group [p=0·13]). In the safety population (1968 patients with fibrosis stages F1–F3), the most common adverse event was pruritus (123 [19%] in the placebo group, 183 [28%] in the obeticholic acid 10 mg group, and 336 [51%] in the obeticholic acid 25 mg group); incidence was generally mild to moderate in severity. The overall safety profile was similar to that in previous studies, and incidence of serious adverse events was similar across treatment groups (75 [11%] patients in the placebo group, 72 [11%] in the obeticholic acid 10 mg group, and 93 [14%] in the obeticholic acid 25 mg group). Interpretation: Obeticholic acid 25 mg significantly improved fibrosis and key components of NASH disease activity among patients with NASH. The results from this planned interim analysis show clinically significant histological improvement that is reasonably likely to predict clinical benefit. This study is ongoing to assess clinical outcomes. Funding: Intercept Pharmaceuticals.

2019 - Predictors of hepatocellular carcinoma in HCV cirrhotic patients treated with direct acting antivirals [Articolo su rivista]
Lleo, Ana; Aglitti, Andrea; Aghemo, Alessio; Maisonneuve, Patrick; Bruno, Savino; Persico, Marcello; Villa, Erica; Andreone, Pietro
abstract

BACKGROUND: Despite the dramatic improvement in viral eradication rates that has been reached with direct antiviral agents (DAAs), the real benefit of viral eradication after DAAs on hepatocellular carcinoma (HCC) development is still controversial. AIM: To prospectively assess the risk of HCC occurrence and early recurrence in a large cohort of DAA-treated HCV-cirrhotic patients and to identify potential predictors of HCC development. METHODS: We analyzed data prospectively collected from 1927 consecutive HCV-infected cirrhotic patients treated with DAA from January to December 2015 in 10 tertiary liver centers in Italy and followed-up for one year after therapy. 161 patients had a previous HCC. RESULTS: 38/161 subjects developed tumor recurrence during the follow-up (recurrence rate = 24.8 per 100-year), patients with SVR had a significantly lower rate of recurrence. Lack of SVR and alpha-fetoprotein (AFP) were independent predictors of HCC recurrence. 50/1766 patients without a previous HCC history developed HCC during follow-up (incidence rate = 2.4 per 100-year). Lack of SVR was the strongest predictor of HCC development. Furthermore, patients with SVR and no stigmata of portal hypertension have a lower incidence rate of HCC (1.0 per 100-year). CONCLUSIONS: SVR is associated with a significant decrease of recurrent or de novo HCC. Baseline AFP and signs of portal hypertension can help to stratify the risk of HCC.

2019 - Range of Normal Liver Stiffness and Factors Associated With Increased Stiffness Measurements in Apparently Healthy Individuals [Articolo su rivista]
Bazerbachi, Fateh; Haffar, Samir; Wang, Zhen; Cabezas, Joaquín; Arias-Loste, Maria Teresa; Crespo, Javier; Darwish-Murad, Sarwa; Ikram, M. Arfan; Olynyk, John K.; Gan, Eng; Petta, Salvatore; Berzuini, Alessandra; Prati, Daniele; de Lédinghen, Victor; Wong, Vincent W.; Del Poggio, Paolo; Chávez-Tapia, Norberto C.; Chen, Yong-Peng; Cheng, Pin-Nan; Yuen, Man-Fung; Das, Kausik; Chowdhury, Abhijit; Caballeria, Llorenç; Fabrellas, Núria; Ginès, Pere; Kumar, Manoj; Sarin, Shiv Kumar; Conti, Fabio; Andreone, Pietro; Sirli, Roxana; Cortez-Pinto, Helena; Carvalhana, Sofia; Sugihara, Takaaki; Kim, Seung Up; Parikh, Pathik; Chayama, Kazuaki; Corpechot, Christophe; Kim, Kang Mo; Papatheodoridis, George; Alsebaey, Ayman; Kamath, Patrick S.; Murad, M. Hassan; Watt, Kymberly D.
abstract

Background & Aims: Transient elastography (TE) is a noninvasive technique used to measure liver stiffness to estimate the severity of fibrosis. The range of liver stiffness measurements (LSMs) in healthy individuals is unclear. We performed a systematic review to determine the range of LSMs, examined by TE, in healthy individuals and individuals who are susceptible to fibrosis. Methods: We collected data from 16,082 individuals, in 26 cohorts, identified from systematic searches of Embase, Ovid MEDLINE, Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews for studies of liver stiffness measurements. Studies analyzed included apparently healthy adults (normal levels of liver enzymes, low-risk alcohol use patterns, and negative for markers of viral hepatitis). The presence of diabetes, hypertension, dyslipidemia, or steatosis, based on ultrasound examination, was known for most participants. We performed a meta-analysis of data from individual participants. The cohort was divided into 4 groups; participants with a body mass index <30 kg/m2 were examined with the medium probe and those with a body mass index ≥30 kg/m2 were examined with the extra-large probe. Linear regression models were conducted after adjusting for potential confounding factors of LSMs. We performed several sensitivity analyses. Results: We established LSM ranges for healthy individuals measured with both probes—these did not change significantly in sensitivity analyses of individuals with platelets ≥150,000/mm3 and levels of alanine aminotransferase ≤33 IU/L in men or ≤25 IU/L in women. In multivariate analysis, factors that modified LSMs with statistical significance included diabetes, dyslipidemia, waist circumference, level of aspartate aminotransferase, and systolic blood pressure at examination time. Significant increases in LSMs were associated with the metabolic syndrome in individuals examined by either probe. Diabetes in obese individuals increased the risk of LSMs in the range associated with advanced fibrosis. Conclusions: In a systematic review and meta-analysis of data from individual participants, we established a comprehensive set of LSM ranges, measured by TE in large cohorts of healthy individuals and persons susceptible to hepatic fibrosis. Regression analyses identified factors associated with increased LSMs obtained by TE with the medium and extra-large probes.

2019 - Real life experiences in HCV management in 2018 [Articolo su rivista]
Vigano, M.; Andreoni, M.; Perno, C. F.; Craxi, A.; Aghemo, A.; Alberti, A.; Andreone, P.; Babudieri, S.; Bonora, S.; Brunetto, M. R.; Bruno, R.; Bruno, S.; Calvaruso, V.; Caporaso, N.; Cartabellotta, F.; Ceccherini-Silberstein, F.; Cento, V.; Ciancio, A.; Colombatto, P.; Coppola, N.; Di Marco, V.; Di Perri, G.; Fagiuoli, S.; Gaeta, G. B.; Gasbarrini, A.; Lampertico, P.; Pellicelli, A.; Prestileo, T.; Puoti, M.; Raimondo, G.; Rizzardini, G.; Taliani, G.; Zignego, A. L.
abstract

Introduction: Hepatitis C virus (HCV) infection is a major cause of chronic liver disease, with approximately 71 million chronically infected individuals worldwide. Treatment of chronic hepatitis C has considerably improved in the last few years thanks to the introduction of direct-acting antivirals able to achieve sustained virological response in more than 95% of patients. Successful anti-HCV treatment can halt liver disease progression and solve the HCV-related extra-hepatic manifestations, eventually reducing liver-related and overall mortality. Areas covered: With the aim to respond to unmet needs in patient’s identification, universal access to antiviral therapy and treatment optimization in specific setting of HCV-infected patients, a group of Italian experts met in Stresa in May 2018. The summary of the considerations arising from this meeting and the final statements are reported in this paper. Expert commentary: All the advances on HCV cure may have a real clinical impact not only in individual patients but also at the social health level if they are applied to all infected patients, independently from the stage of liver disease. Further improvements are needed in order to attain HCV elimination, such as the development of an enhanced screening program working in parallel to the present treatment options.

2019 - Serum hepatitis B core-related antigen is an effective tool to categorize patients with HBeAg-negative chronic hepatitis B [Articolo su rivista]
Loggi, Elisabetta; Vukotic, Ranka; Conti, Fabio; Grandini, Elena; Gitto, Stefano; Cursaro, Carmela; Galli, Silvia; Furlini, Giuliano; Re, Maria Carla; Andreone, Pietro
abstract

The discrimination between active chronic hepatitis B (CHB) and the clinically quiescent infection (CIB) is not always easy, as a significant portion of patients falls in a “grey” zone. Hepatitis B core-related antigen (HBcrAg) is a now quantifiable serological marker with potential applications in diagnosis and therapy monitoring. The aim of the present study was to evaluate the HBcrAg serum levels in HBeAg-negative HBV infection, and its ability in identifying the clinical profile, in comparison with HBsAg serum levels. HBcrAg was retrospectively assessed on serum samples from a population of treatment-naive HBeAg-negative patients by ChemiLuminescent Enzyme Immunoassay (CLEIA). HBsAg and HBV-DNA data were collected. Serological data were associated to clinical profile, defined in the subsequent follow-up of at least 1 year. In the overall population of 160 HBeAg-negative patients, HBcrAg results weakly correlated with qHBsAg levels (Spearman r = 0.471, P < 0.0001) and correlated closely with HBV-DNA (Spearman r = 0.746, P < 0.0001). HBcrAg levels were significantly higher in 85 CHB patients relative to 75 CIB carriers. A value of 2.5 logU/mL produced the optimal cut-off to identify CIB patients, with diagnostic accuracy comparable to HBsAg levels. In long-term clinical evaluation, a single measurement of HBcrAg at the established cut-off was optimally consistent with clinical outcome. Conversely, the HBsAg cut-off performed well in the true quiescent phase and less in more difficult-to-categorize patients. In conclusion, single-point use of HBcrAg serum levels provides an accurate identification of CIB and represents a useful tool for patient classification.

2019 - Sustained virologic response to direct-acting antiviral therapy in patients with chronic hepatitis C and hepatocellular carcinoma: A systematic review and meta-analysis [Articolo su rivista]
Ji, F.; Yeo, Y. H.; Wei, M. T.; Ogawa, E.; Enomoto, M.; Lee, D. H.; Iio, E.; Lubel, J.; Wang, W.; Wei, B.; Ide, T.; Preda, C. M.; Conti, F.; Minami, T.; Bielen, R.; Sezaki, H.; Barone, M.; Kolly, P.; Chu, P. -S.; Virlogeux, V.; Eurich, D.; Henry, L.; Bass, M. B.; Kanai, T.; Dang, S.; Li, Z.; Dufour, J. -F.; Zoulim, F.; Andreone, P.; Cheung, R. C.; Tanaka, Y.; Furusyo, N.; Toyoda, H.; Tamori, A.; Nguyen, M. H.
abstract

Background & Aims: The effect of hepatocellular carcinoma (HCC) on the response to interferon-free direct-acting antiviral (DAA) therapy in patients with chronic hepatitis C (CHC) infection remains unclear. Using a systematic review and meta-analysis approach, we aimed to investigate the effect of DAA therapy on sustained virologic response (SVR) among patients with CHC and either active, inactive or no HCC. Methods: PubMed, Embase, Web of Science, and the Cochrane Central Register of Controlled Trials were searched from 1/1/2013 to 9/24/2018. The pooled SVR rates were computed using DerSimonian-Laird random-effects models. Results: We included 49 studies from 15 countries, comprised of 3,341 patients with HCC and 35,701 without HCC. Overall, the pooled SVR was lower in patients with HCC than in those without HCC (89.6%, 95% CI 86.8–92.1%, I2 = 79.1% vs. 93.3%, 95% CI 91.9–94.7%, I2 = 95.0%, p = 0.0012), translating to a 4.8% (95% CI 0.2–7.4%) SVR reduction by meta-regression analysis. The largest SVR reduction (18.8%) occurred in patients with active/residual HCC vs. inactive/ablated HCC (SVR 73.1% vs. 92.6%, p = 0.002). Meanwhile, patients with HCC who received a prior liver transplant had higher SVR rates than those who did not (p <0.001). Regarding specific DAA regimens, patients with HCC treated with ledipasvir/sofosbuvir had lower SVR rates than patients without HCC (92.6%, n = 884 vs. 97.8%, n = 13,141, p = 0.026), but heterogeneity was high (I2 = 84.7%, p <0.001). The SVR rate was similar in patients with/without HCC who were treated with ombitasvir/paritaprevir/ritonavir ± dasabuvir (n = 101) (97.2% vs. 94.8%, p = 0.79), or daclatasvir/asunaprevir (91.7% vs. 89.8%, p = 0.66). Conclusion: Overall, SVR rates were lower in patients with HCC, especially with active HCC, compared to those without HCC, though heterogeneity was high. Continued efforts are needed to aggressively screen, diagnose, and treat HCC to ensure higher CHC cure rates. Lay summary: There are now medications (direct-acting antivirals or “DAAs”) that can “cure” hepatitis C virus, but patients with hepatitis C and liver cancer may be less likely to achieve cure than those without liver cancer. However, patients with liver cancer are also more likely to have advanced liver disease and risk factors that can decrease cure rates, so better controlled studies are needed to confirm these findings.

2019 - The present profile of chronic hepatitis B virus infection highlights future challenges: An analysis of the Multicenter Italian MASTER-B cohort [Articolo su rivista]
Brancaccio, Giuseppina; Nardi, Alessandra; Madonia, Salvatore; Fasano, Massimo; Verucchi, Gabriella; Massari, Marco; Maimone, Sergio; Contini, Carlo; Levantesi, Fabio; Alfieri, Arianna; Gavrila, Caius; Andreone, Pietro; Milella, Michele; Gaeta, Giovanni B.
abstract

Background: Chronic hepatitis B virus (HBV) infection remains a primary cause of morbidity and mortality worldwide. Aim: The study is aimed at updating the clinical and epidemiological profile of chronic HBV infection in Italy. Methods: A cross-sectional multicenter prospective study enrolled consecutive HBsAg positive patients seen in 73 Italian centers in the period 2012–2015. Individual patient data were collected using an electronic platform and analyzed using standard statistical methods. Results: Among 2877 HBsAg positive individuals (median age 49.8 years, 68% males), 27% were non-Italian natives (NINs); 20% had chronic infection, 58.5% chronic hepatitis and 21.5% cirrhosis. Among NINs, age was younger, male gender was less prevalent and liver disease less advanced than in Italians (all p < 0.0001). HBeAg positive cases were 23.6% among NINs vs 8.2% in Italians (p < 0.0001); HDV coinfections 11.1% vs 7.3% (p = 0.006) and HCV coinfections 2.3% vs 4.2% (p = 0.017), respectively. Anti-HDV or anti-HCV antibodies were detected more frequently in patients with cirrhosis. Fifty percent of NINs with cirrhosis were aged below 45 years. Conclusion: The study offers an insight into the evolving burden of chronic hepatitis B virus infection in the near future and highlights new territories for public health interventions.

2019 - Transjugular intrahepatic portosystemic shunt does not affect the efficacy and safety of direct-acting antivirals in patients with advanced cirrhosis: a real-life, case-control study [Articolo su rivista]
Gitto, Stefano; Vizzutti, Francesco; Schepis, Filippo; Turco, Laura; Aspite, Silvia; Vitale, Giovanni; Arena, Umberto; Villa, Erica; Laffi, Giacomo; Debernardi-Venon, Wilma; Fanelli, Fabrizio; Andreone, Pietro; Marra, Fabio
abstract

Background: Transjugular Intrahepatic Portosystemic Shunt (TIPS) is a well-established treatment for complications of portal hypertension. Aims: To analyze the impact of TIPS on virologic response and safety profile in patients treated with direct-acting antivirals (DAA). Methods: We analyzed data from HCV-positive cirrhotic patients treated with DAAs. Twenty-one patients with previous TIPS placement were compared with 42 matched subjects without TIPS. Logistic regression was used to identify predictors of hepatic function worsening and adverse events. Results: No differences were found between the two groups in particular regarding sustained virologic response (92.5 and 97.6% in TIPS vs no-TIPS, p=0.559). Model for End-stage Liver Disease (MELD) of both TIPS and no-TIPS groups declined from baseline to week 24 of follow-up (from 12.5±3.5 to 10.8±3.4 and from 11.1±3.5 to 10.3±3.4, p=0.044 and 0.025). There were no differences in adverse event rates. At univariate analysis, age was associated with MELD increase from baseline to week 24 (OR 1.111, 95% CI 1.019-1.211, p=0.017), and patients with higher baseline MELD developed serious adverse events more frequently (OR 0.815, 95% CI 0.658-1.010, p=0.062). Patients with or without TIPS did not show differences in transplant-free survival. Conclusion: TIPS placement does not affect virologic response and clinical outcome of patients receiving DAAs.

2018 - A New Two-Dimensional Shear Wave Elastography for Noninvasive Assessment of Liver Fibrosis in Healthy Subjects and in Patients with Chronic Liver Disease - Eine neue zweidimensionale Shear-Wave-Elastografie zur nicht-invasiven Beurteilung der Leberfibrose bei Gesunden und bei Patienten mit chronischer Lebererkrankung [Articolo su rivista]
Serra, Carla; Grasso, Valentina; Conti, Fabio; Felicani, Cristina; Mazzotta, Elena; Lenzi, Marco; Verucchi, Gabriella; D'Errico, Antonietta; Andreone, Pietro
abstract

Purpose To assess the performance of two-dimensional shear wave elastography (2D-SWE) on the GE LOGIQ E9 ultrasound system in a cohort of healthy subjects and to investigate its accuracy in the staging of liver fibrosis in patients with chronic liver disease (CLD) using liver biopsy as a reference standard. Materials and Methods From October 2014 to June 2016, 54 healthy subjects and 174 patients with CLD were consecutively enrolled. Liver fibrosis stage was assessed by the METAVIR scoring system. 18 (10.3%) and 17 (9.8%) patients had advanced fibrosis and cirrhosis, respectively. The correlation of liver stiffness measurement (LSM) and continuous variable was assessed using the Spearman rank correlation. The accuracy of 2D-SWE was evaluated with areas under the receiver operating characteristics curves (AUROC). Results Reliable LSMs were obtained in all subjects. The interobserver agreement ICC was excellent: 0.847. In healthy subjects, gender, but not anthropometric and biochemical data, were correlated with LSM. In patients with CLD, LSM had a strong positive correlation with fibrosis stage (rho=0.628; p>0.001). The AUROC was 0.724 for mild fibrosis (F≥1), 0.857 for moderate fibrosis (F≥2), 0.946 for severe fibrosis (F≥3), and 0.935 for cirrhosis (F4). Likewise, good accuracy was observed in the HCV subgroup.The optimal cut-off value in differentiating healthy subjects from CLD patients with any fibrosis was 5.47 kPa with an AUROC of 0.875. Conclusion 2D-SWE is a reliable and reproducible method to assess LSM with good diagnostic accuracy to assess liver fibrosis in patients with CLD.

2018 - Cryptogenic cholestasis in young and adults: ATP8B1, ABCB11, ABCB4, and TJP2 gene variants analysis by high-throughput sequencing [Articolo su rivista]
Vitale, Giovanni; Gitto, Stefano; Raimondi, Francesco; Mattiaccio, Alessandro; Mantovani, Vilma; Vukotic, Ranka; D’Errico, Antonietta; Seri, Marco; Russell, Robert B.; Andreone, Pietro
abstract

Background: Mutations in ATP-transporters ATPB81, ABCB11, and ABCB4 are responsible for progressive familial intrahepatic cholestasis (PFIC) 1, 2 and 3, and recently the gene for tight junction protein-2 (TJP2) has been linked to PFIC4. Aim: As these four genes have been poorly studied in young people and adults, we investigated them in this context here. Methods: In patients with cryptogenic cholestasis, we analyzed the presence of mutations by high-throughput sequencing. Bioinformatics analyses were performed for mechanistic and functional predictions of their consequences on biomolecular interaction interfaces. Results: Of 108 patients, 48 whose cause of cholestasis was not established were submitted to molecular analysis. Pathogenic/likely pathogenic mutations were found in ten (21%) probands for 13 mutations: two in ATP8B1, six in ABCB11, two in ABCB4, three in TJP2. We also identified seven variants of uncertain significance: two in ATP8B1, one in ABCB11, two in ABCB4 and two in TJP2. Finally, we identified 11 benign/likely benign variants. Patients with pathogenic/likely pathogenic mutations had higher levels of liver stiffness (measured by FibroScanÂ®) and bile acids, as well as higher rates of cholestatic histological features, compared to the patients without at least likely pathogenic mutations. The multivariate analysis showed that itching was the only independent factor associated with disease-causing mutations (OR 5.801, 95% CI 1.244â27.060, p = 0.025). Conclusions: Mutations in the genes responsible for PFIC may be involved in both young and adults with cryptogenic cholestasis in a considerable number of cases, including in heterozygous status. Diagnosis should always be suspected, particularly in the presence of itching.

2018 - De-novo nonalcoholic steatohepatitis is associated with long-term increased mortality in liver transplant recipients [Articolo su rivista]
Gitto, Stefano; de Maria, Nicola; di Benedetto, Fabrizio; Tarantino, Giuseppe; Serra, Valentina; Maroni, Lorenzo; Cescon, Matteo; Pinna, Antonio D; Schepis, Filippo; Andreone, Pietro; Villa, Erica
abstract

Patients who have undergone transplantation often develop metabolic syndrome (MetS) and de-novo nonalcoholic fatty liver disease (NAFLD). Our aim was to evaluate the impact of metabolic disease on cardiovascular and neoplastic risk and survival.

2018 - Fatty liver index is associated to pulse wave velocity in healthy subjects: Data from the Brisighella Heart Study [Articolo su rivista]
Cicero, Arrigo F G; Gitto, Stefano; Fogacci, Federica; Rosticci, Martina; Giovannini, Marina; D'Addato, Sergio; Andreone, Pietro; Borghi, Claudio
abstract

BACKGROUND: Non-Alcoholic Fatty Liver Disease (NAFLD) is associated to increased risk of cardiovascular disease. Our aim was to evaluate association of indexes of fatty liver with arterial stiffness (AS). METHODS: We analyzed data of adult volunteers visited during the last Brisighella survey. We evaluated the Pulse Wave Velocity (PWV) and the following non-invasive indexes of liver steatosis: Fatty Liver Index (FLI), Lipid Accumulation Product (LAP), Hepatic Steatosis Index (HSI). We compared patients according to the risk of Non-Alcoholic Steatohepatitis (NASH): low-risk (BMI < 28 and no diabetes), intermediate-risk (BMI ≥ 28 or diabetes), high-risk (BMI ≥ 28 and diabetes). Multiple Linear Regression analysis was assessed for predictors of AS. RESULTS: We studied 1731 volunteers. In subjects with low metabolic risk, HSI (RR = 0.138, 95%CI 0.105-0.170, p < 0.001), FLI (RR = 0.024, 95%CI 0.016-0.032, p < 0.001), LAP (RR = 0.014, 95%CI 0.008-0.020, p < 0.001) and Serum Uric Acid (RR = 0.150, 95%CI 0.024-0.275, p = 0.019) were significant predictors of AS. HSI and FLI emerged as predictors of PWV in intermediate risk group (RR = 0.116, 95%CI 0.071-0.160, p < 0.001; RR = 0.010, 95%CI 0.001-0.020, p = 0.041). In volunteers with high risk, FLI and Uric Acid were related to PWV (RR = 0.049, 95%CI 0.011-0.087, p = 0.013; RR = 0.632, 95% CI 0.222-1.041, p = 0.003). CONCLUSION: Fatty liver indirect indexes were associated to AS in subjects with different metabolic risk profiles.

2018 - Forecasting Hepatitis C liver disease burden on real-life data. Does the hidden iceberg matter to reach the elimination goals? [Articolo su rivista]
Kondili, Loreta A.; Robbins, Sarah; Blach, Sarah; Gamkrelidze, Ivane; Zignego, Anna L.; Brunetto, Maurizia R.; Raimondo, Giovanni; Taliani, Gloria; Iannone, Andrea; Russo, Francesco P.; Santantonio, Teresa A.; Zuin, Massimo; Chessa, Luchino; Blanc, Pierluigi; Puoti, Massimo; Vinci, Maria; Erne, Elke M.; Strazzabosco, Mario; Massari, Marco; Lampertico, Pietro; Rumi, Maria G.; Federico, Alessandro; Orlandini, Alessandra; Ciancio, Alessia; Borgia, Guglielmo; Andreone, Pietro; Caporaso, Nicola; Persico, Marcello; Ieluzzi, Donatella; Madonia, Salvatore; Gori, Andrea; Gasbarrini, Antonio; Coppola, Carmine; Brancaccio, Giuseppina; Andriulli, Angelo; Quaranta, Maria G.; Montilla, Simona; Razavi, Homie; Melazzini, Mario; Vella, Stefano; Craxì, Antonio
abstract

Background & Aims: Advances in direct-acting antiviral treatment of HCV have reinvigorated public health initiatives aimed at identifying affected individuals. We evaluated the possible impact of only diagnosed and linked-to-care individuals on overall HCV burden estimates and identified a possible strategy to achieve the WHO targets by 2030. Methods: Using a modelling approach grounded in Italian real-life data of diagnosed and treated patients, different linkage-to-care scenarios were built to evaluate potential strategies in achieving the HCV elimination goals. Results: Under the 40% linked-to-care scenario, viraemic burden would decline (60%); however, eligible patients to treat will be depleted by 2025. Increased case finding through a targeted screening strategy in 1948-1978 birth cohorts could supplement the pool of diagnosed patients by finding 75% of F0-F3 cases. Under the 60% linked-to-care scenario, viraemic infections would decline by 70% by 2030 but the patients eligible for treatment will run out by 2028. If treatment is to be maintained, a screening strategy focusing on 1958-1978 birth cohorts could capture 55% of F0-F3 individuals. Under the 80% linked-to-care scenario, screening limited in 1968-1978 birth cohorts could sustain treatment at levels required to achieve the HCV elimination goals. Conclusion: In Italy, which is an HCV endemic country, the eligible pool of patients to treat will run out between 2025 and 2028. To maintain the treatment rate and achieve the HCV elimination goals, increased case finding in targeted, high prevalence groups is required.

2018 - Frequent NS5A and multiclass resistance in almost all HCV genotypes at DAA failures: What are the chances for second-line regimens? [Articolo su rivista]
Di Maio, V. C.; Cento, V.; Aragri, M.; Paolucci, S.; Pollicino, T.; Coppola, N.; Bruzzone, B.; Ghisetti, V.; Zazzi, M.; Brunetto, M.; Bertoli, A.; Barbaliscia, S.; Galli, S.; Gennari, W.; Baldanti, F.; Raimondo, G.; Perno, C. F.; Ceccherini-Silberstein, F.; Andreone, P.; Andreoni, M.; Angelico, M.; Babudieri, S.; Barbarini, G.; Boccaccio, V.; Boglione, L.; Bolis, M.; Bonora, S.; Borghi, V.; Brancaccio, G.; Bruno, S.; Cacciatore, P.; Calvaruso, V.; Caporaso, N.; Ciaccio, A.; Ciancio, A.; Colombatto, P.; Cozzolongo, R.; Craxi, A.; D'Ambrosio, C.; D'Ettorre, G.; De Luca, A.; Di Biagio, A.; Di Perri, G.; Francioso, S.; Gaeta, G. B.; Giorgini, A.; Grieco, A.; Gubertini, G.; Gulminetti, R.; Lambiase, L.; Lenci, I.; Lichtner, M.; Maida, I.; Marenco, S.; Marinaro, L.; Maserati, R.; Masetti, C.; Melis, M.; Meregalli, E.; Micheli, V.; Morisco, F.; Niero, F.; Nicolini, L. A.; Palitti, V. P.; Paoloni, M.; Parruti, G.; Pasquazzi, C.; Pellicelli, A.; Polilli, E.; Ponti, M. L.; Puoti, M.; Rendina, M.; Rizzardini, G.; Rossetti, B.; Ruggiero, T.; Sangiovanni, V.; Starace, M.; Sticchi, L.; Tarquini, P.; Toniutto, P.; Vullo, V.
abstract

2018 - Gold standard assays for the monitoring of patients with chronic hepatitis C [Articolo su rivista]
Loggi, E.; Vukotic, R.; Conti, F.; Gitto, S.; Andreone, P.
abstract

Chronic HCV infection continues to be an important concern of public health, with still a high mortality from HCV-related disease. The landscape of chronic HCV infection has been dramatically changed by the introduction of the new antiviral agents, able to cure the infection in the large majority of patients. The laboratory management of HCV infection relies on serological and molecular tests, which have undergone significant technological advancements, able to ameliorate the performance both in diagnosis of infection and in the treatment monitoring. This article describes the main laboratory tools in the chronic HCV infection, with particular emphasis on the recent changes coming along with the new therapeutic approaches.

2018 - Hepatocellular carcinoma risk assessment by the measurement of liver stiffness variations in HCV cirrhotics treated with direct acting antivirals [Articolo su rivista]
Ravaioli, Federico; Conti, Fabio; Brillanti, Stefano; Andreone, Pietro; Mazzella, Giuseppe; Buonfiglioli, Federica; Serio, Ilaria; Verucchi, Gabriella; Bacchi Reggiani, Maria Letizia; Colli, Agostino; Marasco, Giovanni; Colecchia, Antonio; Festi, Davide
abstract

Background: Direct-acting antivirals (DAA) are an effective treatment for hepatitis C virus infection. However, sustained virologic response (SVR) after DAA treatment does not seem to reduce the risk of hepatocellular carcinoma (HCC) development in these patients. Liver stiffness measurement (LSM) may predict the risk of developing HCC in liver cirrhosis patients. Aims: The aim of our study was to evaluate the role of LSM variation as predictor of HCC development in patients treated with DAA. Methods: In 139 HCV-related cirrhotic patients, LSM and laboratory tests were carried out at baseline (BL) and at the end of DAA treatment (EOT). Patients were followed for at least 6 months after the EOT. LSM reduction was expressed as Delta LS (∆LS). Cox regression analysis was used to identify prognostic factors for HCC development after DAA. Results: Median LSM values were significantly reduced from BL to EOT (from 18.6 to 13.8 kPa; p < 0.001). The median ∆LS was −26.7% (IQR: −38.4% −13.6%). During a median follow-up of 15 months after DAA treatment, 20 (14.4%) patients developed HCC. Significant LSM reduction was observed both in patients who developed HCC and in those who did not, but this was significantly lower in the patients who developed HCC (−18.0% vs −28.9% p = 0.005). At multivariate analysis, ∆LS lower than −30%, Child-Turcotte-Pugh-B and history of HCC were independently associated with HCC development. Conclusion: Our results indicate that ∆LS is a useful non-invasive marker for predicting HCC development after DAA treatment.

2018 - High efficacy of direct-acting anti-viral agents in hepatitis C virus-infected cirrhotic patients with successfully treated hepatocellular carcinoma [Articolo su rivista]
Persico, M.; Aglitti, A.; Aghemo, A.; Rendina, M.; Lleo, A.; Ciancio, A.; Di Marco, V.; Lampertico, P.; Brunetto, M. R.; Zuin, M.; Andreone, P.; Villa, E.; Troshina, G.; Calvaruso, V.; Degasperi, E.; Coco, B.; Giorgini, A.; Conti, F.; Di Leo, A.; Marzi, L.; Boccaccio, V.; Bollani, S.; Maisonneuve, P.; Bruno, S.
abstract

Background: The efficacy of direct-acting anti-viral (DAA) therapy in patients with a history of hepatocellular carcinoma (HCC) is unknown. Aim: We prospectively evaluated whether previously treated HCC affects DAA efficacy in a large real-life cohort of cirrhotic patients. Methods: From January to December 2015 all consecutive HCV mono-infected patients with cirrhosis and/or history of HCC attending 10 Italian tertiary liver centres were enrolled. Baseline characteristics and response to therapy were recorded. 1927 patients were enrolled (mean age: 62.1 ± 10.9 years; 1.205 males). Genotype 1 was the most frequent (67.9%) followed by genotypes 3 (12.4%), 2 (11.2%) and 4 (8.6%). 88.4% and 10.9% of cases were classified Child A and B, respectively, and 14 (<1%) cases were classified Child C. Ascites and hepatic encephalopathy occurred in 10.7% and 3.2% of patients, respectively. Varices were detected in 39.3% of patients. Suboptimal and optimal treatment was prescribed: 15.9% of patients received sofosbuvir/simeprevir, 33.4% sofosbuvir/ledipasvir, 20.2% a Viekirax + Exviera regimen, 15.7% sofosbuvir/ribavirin, 9.9% sofosbuvir/daclatasvir and 3.4% Viekirax; 1.3% of patients received an interferon-based regimen. Results: The sustained virologic response (SVR) rate at intention-to-treat analysis was 95.1%. It differed significantly across Child classes, that is, 96.3%, 86.1% and 71.4% Child A, B and C, respectively (P < 0.0001) and across genotypes (P = 0.002). The SVR rate did not differ between patients with (95.0%) and those without previous HCC (95.1%). At multivariable analysis, SVR was significantly associated with HCV genotype, Child class. Conclusion: This large real-life study proves that the efficacy of DAA in cirrhotic patients is not impaired by successfully treated HCC.

2018 - Imaging features of microvascular invasion in hepatocellular carcinoma developed after direct-acting antiviral therapy in HCV-related cirrhosis [Articolo su rivista]
Renzulli, Matteo; Buonfiglioli, Federica; Conti, Fabio; Brocchi, Stefano; Serio, Ilaria; Foschi, Francesco Giuseppe; Caraceni, Paolo; Mazzella, Giuseppe; Verucchi, Gabriella; Golfieri, Rita; Andreone, Pietro; Brillanti, Stefano
abstract

Objectives: To evaluate imaging features of microvascular invasion (MVI) in hepatocellular carcinoma (HCC) developed after direct-acting antiviral (DAA) therapy in HCV-related cirrhosis. Methods: Retrospective cohort study on 344 consecutive patients with HCV-related cirrhosis treated with DAA and followed for 48â74 weeks. Using established imaging criteria for MVI, HCC features were analysed and compared with those in nodules not occurring after DAA. Results: After DAA, HCC developed in 29 patients (single nodule, 18 and multinodular, 11). Median interval between therapy end and HCC diagnosis was 82 days (0â318). Forty-one HCC nodules were detected (14 de novo, 27 recurrent): maximum diameter was 10â20 mm in 27, 20â50 mm in 13, and > 50 mm in 1. Imaging features of MVI were present in 29/41 nodules (70.7%, CI: 54â84), even in 17/29 nodules with 10â20 mm diameter (58.6%, CI: 39â76). MVI was present in only 17/51 HCC nodules that occurred before DAA treatment (33.3%, CI: 22â47) (p= 0.0007). MVI did not correlate with history of previous HCC. Conclusions: HCC occurs rapidly after DAA therapy, and aggressive features of MVI characterise most neoplastic nodules. Close imaging evaluations are needed after DAA in cirrhotic patients. Key Points: â¢ In HCV cirrhosis, hepatocellular carcinoma develops soon after direct-acting antiviral therapy. â¢ HCC presents imaging features of microvascular invasion, predictive of more aggressive progression. â¢ Cirrhotic patients need aggressive and close monitoring after direct-acting antiviral therapy.

2018 - Imbalance of Neutrophils and Lymphocyte Counts Can Be Predictive of Hepatocellular Carcinoma Occurrence in Hepatitis C-related Cirrhosis Treated With Direct-acting Antivirals [Articolo su rivista]
Casadei Gardini, Andrea; Conti, Fabio; Foschi, Francesco Giuseppe; Brillanti, Stefano; Andreone, Pietro; Mazzella, Giuseppe; Ravaioli, Federico; Buonfiglioli, Federica; Bolondi, Luigi; Crespi, Cristina; Lenzi, Marco; Muratori, Paolo; Verucchi, Gabriella; Badia, Lorenzo; Bernardi, Mauro; Caraceni, Paolo; Morelli, Maria Cristina; Berardi, Sonia
abstract

N/A

2018 - Managing HCV treatment failure and the potential of resistance testing in informing second-line therapy options [Articolo su rivista]
Loggi, Elisabetta; Vukotic, Ranka; Andreone, Pietro
abstract

Introduction: Direct acting antivirals have completely changed the landscape of the treatment of chronic hepatitis C. The management of the few patients who relapse to direct acting antivirals requires a careful analysis of the chances to achieve therapeutic success with a second antiviral course. In this context, the usefulness of viral resistances testing, able to detect resistance-associated substitutions in the viral sequence, is at present a matter of debate. Areas covered: The role of resistance associated substitutions is examined through the evaluation of the data from clinical trials that have assessed the impact of viral resistances on the treatment outcome. Special attention has been paid on the data from re-treatment studies. Expert commentary: The treatment failure in chronic hepatitis C is still a possible event. Therefore, additional real-world clinical data on relapse rates and on the relapse management are welcome to definitely address the clinical guidelines. At present, the testing of viral resistances is an exquisite tool for the choice of the re-treatment schedule. In the near future, widespread use of the most recently registered direct acting antivirals with high barrier to resistance will probably weaken the need of resistance testing as a support in clinical decisions.

2018 - Point quantification elastography in the evaluation of liver elasticity in healthy volunteers: a reliability study based on operator expertise [Articolo su rivista]
Felicani, Cristina; De Molo, Chiara; Stefanescu, Horia; Conti, Fabio; Mazzotta, Elena; Gabusi, Veronica; Nardi, Elena; Morselli-Labate, Antonio Maria; Andreone, Pietro; Serra, Carla
abstract

Purpose: The assessment of liver fibrosis is essential in the management of patients with chronic liver diseases. Liver biopsy is considered the gold standard procedure for this purpose, though the recent development of new elastosonographic techniques to measure liver stiffness (LS) noninvasively is promising. Point quantification elastography (PQE) showed good results but less is known about the level of skill needed to obtain reliable results. The aim of the study was to evaluate the reproducibility of PQE in assessing LS in healthy subjects comparing three operators with different expertise. Methods: Between December 2012 and April 2013, 50 consecutive healthy volunteers (18 males, 32 females), median age 30 years (range 25–66) and BMI 22.4 (range 16.7–33.6) were submitted to PQE (iU22 Philips, Bothell, WA, USA) by three operators: two US and elastography providers (one expert and one with intermediate skill) and a skilled transient elastography (Fibroscan) operator with no expertise in US. Intra- and inter-observer agreements were assessed by intraclass correlation coefficient (ICC). Results: PQE measurement was obtained in all subjects by all evaluators. No significant differences of mean liver stiffness were found among operators (P = 0.980). Intra-observer agreement was excellent 0.918 (0.941 for expert, 0.917 for intermediate and 0.888 for novice). The ICC of the inter-observer agreement among the three ratters was excellent (0.882) and was higher in normal than overweight patients (0.923 vs. 0.603; P = 0.011). Conclusion: PQE is a reliable and reproducible non-invasive method for the assessment of LE, and can be performed also by a non-experienced operator.

2018 - Premature ovarian senescence and a high miscarriage rate impair fertility in women with HCV [Articolo su rivista]
Karampatou, Aimilia; Han, Xue; Kondili, Loreta A; Taliani, Gloria; Ciancio, Alessia; Morisco, Filomena; Critelli, Rosina Maria; Baraldi, Enrica; Bernabucci, Veronica; Troshina, Giulia; Guarino, Maria; Tagliavini, Simonetta; D'Ambrosio, Federica; Bristot, Laura; Turco, Laura; Rosato, Stefano; Vella, Stefano; Trenti, Tommaso; Neri, Isabella; LA MARCA, Antonio; Manthena, Shivaji; Goldstein, Andrea S; Bruno, Savino; Bao, Yanjun; Gonzalez, Yuri Sanchez; Villa, Erica; Andreone, Pietro
abstract

Premenopausal women who are HCV positive (HCV+) have failing ovarian function, which is likely to impact their fertility. Thus, we investigated the reproductive history, risk of infertility, and pregnancy outcomes in women of childbearing age who were HCV+.

2018 - Pretreatment prediction of response to ursodeoxycholic acid in primary biliary cholangitis: development and validation of the UDCA Response Score [Articolo su rivista]
Carbone, Marco; Nardi, Alessandra; Flack, Steve; Carpino, Guido; Varvaropoulou, Nikoletta; Gavrila, Caius; Spicer, Ann; Badrock, Jonathan; Bernuzzi, Francesca; Cardinale, Vincenzo; Ainsworth, Holly F; Heneghan, Michael A; Thorburn, Douglas; Bathgate, Andrew; Jones, Rebecca; Neuberger, James M; Battezzati, Pier Maria; Zuin, Massimo; Taylor-Robinson, Simon; Donato, Maria F; Kirby, John; Mitchell-Thain, Robert; Floreani, Annarosa; Sampaziotis, Fotios; Muratori, Luigi; Alvaro, Domenico; Marzioni, Marco; Miele, Luca; Marra, Fabio; Giannini, Edoardo; Gaudio, Eugenio; Ronca, Vincenzo; Bonato, Giulia; Cristoferi, Laura; Malinverno, Federica; Gerussi, Alessio; Stocken, Deborah D; Cordell, Heather J; Hirschfield, Gideon M; Alexander, Graeme J; Sandford, Richard N; Jones, David E; Invernizzi, Pietro; Mells, George F; Thomas, Caradog; Rahman, Meshbah; Yapp, Tom; Lye Ch'ng, Chin; Harrison, Melanie; Sturgess, Richard; Galaska, Roman; Healey, Chris; Whiteman, Jessica; Czaijkowski, Marek; Gray, Catherine; Gunasekera, Anton; Gyawli, Pranab; Premchand, Purushothaman; Mann, Steven; Elliott, Keith; Kapur, Kapil; Watson, Alan; Foster, Graham; Trembling, Paul; Subhani, Javaid; Harvey, Rory; Mccorry, Roger; Adgey, Carolyn; Hobson, Lucie; Mulvaney-Jones, Caroline; Evans, Richard; Mathialahan, Thiriloganathan; Ramanaden, David; Gasem, Jaber; Van Duyvenvoorde, Greta; Shorrock, Christopher; Seward, Katie; Southern, Paul; Tibble, Jeremy; Penn, Ruth; Gorard, David; Maiden, Jane; Damant, Rose; Palegwala, Altaf; Jones, Susan; Alexander, Graeme; Mells, George; Sandford, Richard; Whiteman, Jessica; Dolwani, Sunil; Prince, Martin; Silvestre, Valeria; Foxton, Matthew; Dungca, Eleanor; Mitchison, Harriet; Wheatley, Natalie; Gooding, Ian; Doyle, Helen; Karmo, Mazn; Kent, Melanie; Saksena, Sushma; Braim, Delyth; Patel, Minesh; Lord, Susan; Ede, Roland; Paton, Alison; Austin, Andrew; Lancaster, Nicola; Sayer, Joanna; Gibbins, Andrew; Hogben, Karen; Hovell, Chris; Fisher, Neil; Carter, Martyn; Koss, Konrad; Musselwhite, Janine; Muscariu, Florin; Piotreowicz, Andrzej; Mckay, Alexandra; Grimley, Charles; Neal, David; Ting Tan, Lai; Lim, Guan; Brighton, Jacqueline; Foale, Carole; Ala, Aftab; Saeed, Athar; Flahive, Kerry; Wood, Gordon; Townshend, Paula; Ford, Chris; Brown, Jonathan; Kordula, Jean; Bowles, Jane; Wilkinson, Mark; Palmer, Caroline; Ramage, John; Gordon, Harriet; Featherstone, James; Ridpath, Jo; Ngatchu, Theodore; Levi, Sass; Shaukat, Syed; Sadeghian, Joy; Shidrawi, Ray; Williams, Bronwen; Abouda, George; Jones, Sarah; Duggan, Claire; Hynes, Abigail; Narain, Mark; Rees, Ian; Salam, Imroz; Crossey, Mary; Taylor-Robinson, Simon; Brown, Ashley; Macnicol, Carolyn; Williams, Simon; Wilhelmsen, Elva; Banim, Paul; Raymode, Parizade; Chilton, Andrew; Das, Debasish; Lee, Hye-Jeong; Curtis, Howard; Heneghan, Michael; Gess, Markus; Durant, Emma; Drake, I. M.; Bishop, Rebecca; Davies, Mervyn; Jones, Rebecca; Aldersley, Mark; Ncube, Noma; Mcnair, Alistair; Srirajaskanthan, Raj; Sen, Sambit; Casey, Rebecca; Bird, George; Mendall, Mike; Cowley, Caroline; Barnardo, Adrian; Kitchen, Paul; Yoong, Kevin; Amore, Kelly; Sirdefield, Dawn; Orpe, Jacky; Mathew, Ray; Macfaul, George; Wrigth, Aruna; Shah, Amir; Evans, Chris; Keggans, Janie; Bird, Bridget; Baxter, Gwen; Saha, Subrata; Pollock, Katharine; Hughes, Maggie; Bramley, Peter; Grieve, Emma; Young, Karin; Fraser, Andrew; Mukhopadhya, Ashis; Ocker, Kate; Mills, Peter; Hines, Francis; Shallcross, Chris; Wilkins, Joy; Grellier, Leonie; Campbell, Stewart; Martin, Kirsty; Bathgate, Andrew; Innes, Caron; Shepherd, Alan; Rushbrook, Simon; Valliani, Talal; Przemioslo, Robert; Fairlamb, Helen; Macdonald, Chris; Eastick, Anne; Metcalf, Jane; Tanqueray, Elizabeth; Shmueli, Udi; Holbrook, Becky; Davis, Andrew; Browning, Julie; Naqvi, Asifabbas; Walker, Kirsten; Lee, Tom; Verheyden, Juliette; Slininger, Susan; Ryder, Stephen D; Chapman, Roger; Collier, Jane; O'Donnell, Denise; Stafford, Lizzie; Williamson, Kate; Kent, Linda; Klass, Howar
abstract

Background: Treatment guidelines recommend a stepwise approach to primary biliary cholangitis: all patients begin treatment with ursodeoxycholic acid (UDCA) monotherapy and those with an inadequate biochemical response after 12 months are subsequently considered for second-line therapies. However, as a result, patients at the highest risk can wait the longest for effective treatment. We determined whether UDCA response can be accurately predicted using pretreatment clinical parameters. Methods: We did logistic regression analysis of pretreatment variables in a discovery cohort of patients in the UK with primary biliary cholangitis to derive the best-fitting model of UDCA response, defined as alkaline phosphatase less than 1·67 times the upper limit of normal (ULN), measured after 12 months of treatment with UDCA. We validated the model in an external cohort of patients with primary biliary cholangitis and treated with UDCA in Italy. Additionally, we assessed correlations between model predictions and key histological features, such as biliary injury and fibrosis, on liver biopsy samples. Findings: 2703 participants diagnosed with primary biliary cholangitis between Jan 1, 1998, and May 31, 2015, were included in the UK-PBC cohort for derivation of the model. The following pretreatment parameters were associated with lower probability of UDCA response: higher alkaline phosphatase concentration (p<0·0001), higher total bilirubin concentration (p=0·0003), lower aminotransferase concentration (p=0·0012), younger age (p<0·0001), longer interval from diagnosis to the start of UDCA treatment (treatment time lag, p<0·0001), and worsening of alkaline phosphatase concentration from diagnosis (p<0·0001). Based on these variables, we derived a predictive score of UDCA response. In the external validation cohort, 460 patients diagnosed with primary biliary cholangitis were treated with UDCA, with follow-up data until May 31, 2016. In this validation cohort, the area under the receiver operating characteristic curve for the score was 0·83 (95% CI 0·79–0·87). In 20 liver biopsy samples from patients with primary biliary cholangitis, the UDCA response score was associated with ductular reaction (r=–0·556, p=0·0130) and intermediate hepatocytes (probability of response was 0·90 if intermediate hepatocytes were absent vs 0·51 if present). Interpretation: We have derived and externally validated a model based on pretreatment variables that accurately predicts UDCA response. Association with histological features provides face validity. This model provides a basis to explore alternative approaches to treatment stratification in patients with primary biliary cholangitis. Funding: UK Medical Research Council and University of Milan-Bicocca.

2018 - Prevalence of Single and Multiple Natural NS3, NS5A and NS5B Resistance-Associated Substitutions in Hepatitis C Virus Genotypes 1-4 in Italy [Articolo su rivista]
Bertoli, Ada; Sorbo, Maria Chiara; Aragri, Marianna; Lenci, Ilaria; Teti, Elisabetta; Polilli, Ennio; Di Maio, Velia Chiara; Gianserra, Laura; Biliotti, Elisa; Masetti, Chiara; Magni, Carlo F.; Babudieri, Sergio; Nicolini, Laura A.; Milana, Martina; Cacciatore, Pierluigi; Sarmati, Loredana; Pellicelli, Adriano; Paolucci, Stefania; Craxì, Antonio; Morisco, Filomena; Palitti, Valeria Pace; Siciliano, Massimo; Coppola, Nicola; Iapadre, Nerio; Puoti, Massimo; Rizzardini, Giuliano; Taliani, Gloria; Pasquazzi, Caterina; Andreoni, Massimo; Parruti, Giustino; Angelico, Mario; Perno, Carlo Federico; Cento, Valeria; Ceccherini-Silberstein, Francesca; Andreone, Pietro; Baldanti, Fausto; Barbarini, Giorgio; Boccaccio, Vincenzo; Boglione, Lucio; Bolis, Matteo; Bonora, Stefano; Borghi, Vanni; Brancaccio, Giuseppina; Bruno, Savino; Bruzzone, Bianca; Calvaruso, Vincenza; Caporaso, Nicola; Ciaccio, Antonio; Ciancio, Alessia; Colombatto, Piero; Cozzolongo, Raffaele; D'Ambrosio, Cecilia; D'Ettorre, Gabriella; De Leonardis, Francesco; De Luca, Andrea; Di Biagio, Antonio; Di Perri, Giovanni; Francioso, Simona; Gaeta, Giovanni Battista; Gasbarrini, Antonio; Ghisetti, Valeria; Giorgini, Alessia; Grieco, Antonio; Gubertini, Guido; Gulminetti, Roberto; Lambiase, Lara; Landonio, Simona; Lichtner, Miriam; Maida, Ivana; Marenco, Simona; Marinaro, Letizia; Maserati, Renato; Melis, Michela; Menzaghi, Barbara; Meregalli, Elisa; Micheli, Valeria; Niero, Fosca; Paoloni, Maurizio; Pieri, Alessandro; Rendina, Maria; Romagnoli, Dante; Rossetti, Barbara; Ruggiero, Tina; Sangiovanni, Vincenzo; Starace, Mario; Sticchi, Laura; Tarquini, Pierluigi; Toniutto, Pierluigi; Vullo, Vincenzo; Zazzi, Maurizio
abstract

Natural resistance-associated substitutions (RASs) are reported with highly variable prevalence across different HCV genotypes (GTs). Frequency of natural RASs in a large Italian real-life cohort of patients infected with the 4 main HCV-GTs was investigated. NS3, NS5A and NS5B sequences were analysed in 1445 HCV-infected DAA-naïve patients. Sanger-sequencing was performed by home-made protocols on 464 GT1a, 585 GT1b, 92 GT2c, 199 GT3a, 16 GT4a and 99 GT4d samples. Overall, 20.7% (301/1455) of patients showed natural RASs, and the prevalence of multiclass-resistance was 7.3% (29/372 patients analysed). NS3-RASs were particularly common in GT1a and GT1b (45.2-10.8%, respectively), mainly due to 80K presence in GT1a (17%). Almost all GTs showed high prevalence of NS5A-RASs (range: 10.2-45.4%), and especially of 93H (5.1%). NS5A-RASs with fold-change >100x were detected in 6.8% GT1a (30H/R-31M-93C/H), 10.3% GT1b (31V-93H), 28.4% GT2c (28C-31M-93H), 8.5% GT3a (30K-93H), 45.5% GT4a (28M-30R-93H) and 3.8% GT4d (28V-30S-93H). Sofosbuvir RAS 282T was never detected, while the 159F and 316N RASs were found in GT1b (13.4-19.1%, respectively). Natural RASs are common in Italian patients infected with HCV-GTs 1-4. High prevalence of clinically-relevant RASs (such as Y93H) supports the appropriateness of HCV resistance-test to properly guide DAA-based therapy.

2018 - Prevalence of and risk factors for fatty liver in the general population of Northern Italy: The Bagnacavallo Study [Articolo su rivista]
Foschi, F. G.; Bedogni, G.; Domenicali, M.; Giacomoni, P.; Dall'Aglio, A. C.; Dazzani, F.; Lanzi, A.; Conti, F.; Savini, S.; Saini, G.; Bernardi, M.; Andreone, P.; Gastaldelli, A.; Casadei Gardini, A.; Tiribelli, C.; Bellentani, S.; Stefanini, G. F.
abstract

Background: The estimation of the burden of disease attributable to fatty liver requires studies performed in the general population. Methods: The Bagnacavallo Study was performed between October 2005 and March 2009. All the citizens of Bagnacavallo (Ravenna, Italy) aged 30 to 60 years as of January 2005 were eligible. Altered liver enzymes were defined as alanine transaminase > 40 U/l and/or aspartate transaminase > 37 U/l. Results: Four thousand and thirty-three (58%) out of 6920 eligible citizens agreed to participate and 3933 (98%) had complete data. 393 (10%) of the latter had altered liver enzymes and 3540 had not. After exclusion of subjects with HBV or HCV infection, liver ultrasonography was available for 93% of subjects with altered liber enzymes and 52% of those with normal liver enzymes. The prevalence of fatty liver, non-alcoholic fatty liver disease (NAFLD) and alcoholic fatty liver disease (AFLD) was 0.74 (95%CI 0.70 to 0.79) vs. 0.35 (0.33 to 0.37), 0.46 (0.41 to 0.51) vs. 0.22 (0.21 to 0.24) and 0.28 (0.24 to 0.33) vs. 0.13 (0.11 to 0.14) in citizens with than in those without altered liver enzymes. Ethanol intake was not associated and all the components of the metabolic syndrome (MS) were associated with fatty liver. All potential risk factors were associated with a lower odds of normal liver vs. NAFLD while they were unable to discriminate AFLD from NAFLD. Conclusions: Fatty liver as a whole was highly prevalent in Bagnacavallo in 2005/9 and was more common among citizens with altered liver enzymes.

2018 - Prevalent use of combined prophylaxis of hepatitis B after liver transplantation in Italy: results of a national survey in a large cohort [Articolo su rivista]
Marzano, Alfredo; Andreone, Pietro; Boccagni, Patrizia; Burra, Patrizia; Caneschi, Francesco; Conoscitore, Pasquale F; Coppola, Carmine; DE Carlis, Luciano; Fagiuoli, Stefano; Forte, Paolo; Gaeta, Giovanni B; Iemmolo, Rosa M; Lotti Suffredini, Anna; Mazzola, Michele; Merli, Manuela; Parrilli, Gianpaolo; Piai, Guido; Piras, Maria R; Salizzoni, Mauro; Tamè, Mariarosa; Tisone, Giuseppe; Toniutto, Pierluigi; Vennarecci, Giovanni; Volpes, Riccardo; Zamboni, Fausto; Caccamo, Lucio
abstract

Prophylaxis of hepatitis B after liver transplantation with antiviral(s) and immunoglobulins efficiently protect the majority of recipients; however recent experiences suggest a decline of HBsAg-positive candidates and the use of hepatitis B Immunoglobulin-free schedules.

2018 - Quality of life of hepatitis B virus surface antigen-positive patients with suppressed viral replication: comparison between inactive carriers and nucleot(s)ide analog-treated patients [Articolo su rivista]
Simonetti, Giulia; Gitto, Stefano; Golfieri, Lucia; Gamal, Nesrine; Loggi, Elisabetta; Taruschio, Gianfranco; Cursaro, Carmela; Nunzella, Serena; Grandi, Silvana; Andreone, Pietro
abstract

Hepatitis B virus infection is a relevant health problem with more than 400 million infected people worldwide. Our aim was to analyze quality of life of hepatitis B virus surface antigen-positive patients in inactive status or treated with antivirals.

2018 - Safety and efficacy of ombitasvir/paritaprevir/ritonavir/dasabuvir plus ribavirin in patients over 65 years with HCV genotype 1 cirrhosis [Articolo su rivista]
Ascione, Antonio; De Luca, Massimo; Melazzini, Mario; Montilla, Simona; Trotta, Maria Paola; Petta, Salvatore; Puoti, Massimo; Sangiovanni, Vincenzo; Messina, Vincenzo; Bruno, Savino; Izzi, Antonio; Villa, Erica; Aghemo, Alessio; Zignego, Anna Linda; Orlandini, Alessandra; Fontanella, Luca; Gasbarrini, Antonio; Marzioni, Marco; Giannini, Edoardo G.; Craxì, Antonio; Abbati, Giuseppe; Alberti, Alfredo; Andreone, Pietro; Andreoni, Massimo; Angeli, Paolo; Angelico, Mario; Angarano, Gioacchino; Angrisani, Debora; Antinori, Andrea; Antonini, Cinzia; Avancini, Ivo; Barone, Michele; Bruno, Raffaele; Benedetti, Antonio; Bernabucci, Veronica; Blanc, Pier; Boarini, Chiara; Boffa, Nicola; Boglione, Lucio; Borghi, Vanni; Borgia, Guglielmo; Brancaccio, Giuseppina; Brunetto, Maurizia; Cacciola, Irene; Calabrese, Paolo; Calvaruso, Vincenza; Campagnolo, Davide; Canovari, Benedetta; Caporaso, Nicola; Capra, Franco; Carolo, Giada; Cassola, Giovanni; Castelli, Francesco; Cauda, Roberto; Silberstein, Francesca Ceccherini; Cecere, Roberto; Chessa, Luchino; Chiodera, Alessandro; Chirianni, Antonio; Ciancio, Alessia; Cima, Serena; Coco, Barbara; Colombo, Massimo; Coppola, Nicola; Corti, Giampaolo; Cosco, Lucio; Corradori, Silvia; Cozzolongo, Raffaele; Cristaudo, Antonio; Danieli, Elena; Monforte, Antonella D’Arminio; Monache, Marco delle; Del Poggio, Paolo; de Luca, Andrea; Dentone, Chiara; Di Biagio, Antonio; Di Leo, Alfredo; Di Perri, Giovanni; Di Stefano, Marco; D’Offizi, Giampiero; Donato, Francesca; Durante, Emanuele; Erne, Elke; Fagiuoli, Stefano; Falasca, Katia; Federico, Alessandro; Felder, Martina; Ferrari, Carlo; Gaeta, Giovanni Battista; Ganga, Roberto; Gatti, Pietro; Giacomet, Vania; Giacometti, Andrea; Gianstefani, Alice; Giordani, Maria; Giorgini, Alessia; Grieco, Antonio; Guerra, Michele; Gulminetti, Roberto; Ieluzzi, Donatella; Imparato, Michele; Iodice, Valentina; La Monica, Silvia; Lazzarin, Adriano; Lenzi, Marco; Levrero, Massimo; Lichtner, Myriam; Lionetti, Raffaella; Guercio, Carmela Lo; Madonna, Salvatore; Magnani, Silvia; Maida, Ivana; Marignani, Massimo; Marrone, Aldo; Marsetti, Fabio; Martini, Silvia; Masarone, Mario; Maserati, Renato; Mastroianni, Claudio Maria; Memoli, Massimo; Menzaghi, Barbara; Merli, Manuela; Miele, Luca; Milella, Michele; Mondelli, Mario; Montalbano, Marzia; Monti, Monica; Morelli, Olivia; Morisco, Filomena; Nardone, Gaetano; Novara, Sergio; Onnelli, Giovanna; Onofrio, Mirella; Paganin, Simona; Pani, Luca; Parisi, Maria Rita; Parruti, Giustino; Pasquazzi, Caterina; Pasulo, Luisa; Perno, Carlo Federico; Persico, Marcello; Piai, Guido; Picciotto, Antonino; Pigozzi, Grazielle Marie; Piovesan, Sara; Piras, Maria Chiara; Pirisi, Massimo; Piscaglia, Anna Maria; Ponti, Laura; Potenza, Domenico; Pravadelli, Cecilia; Quartini, Mariano; Quirino, Tiziana; Raimondo, Giovanni; Rapaccini, Gian Ludovico; Rendina, Maria; Rizzardini, Giuliano; Rizzetto, Mario; Rizzo, Salvatore; Romagnoli, Dante; Romano, Antonietta; Rossi, Cristina; Rumi, Maria Grazia; Russello, Maurizio; Russo, Francesca Paolo; Russo, Maria Luisa; Sansonno, Domenico Ettore; Santantonio, Teresa Antonia; Saracco, Giorgio; Schimizzi, Anna Maria; Serviddio, Gaetano; Simeone, Filomena; Solinas, Attilio; Soria, Alessandro; Tabone, Marco; Taliani, Gloria; Tarantino, Giuseppe; Tarquini, Pierluigi; Tavio, Marcello; Termite, Antonio; Teti, Elisabetta; Toniutto, Pierluigi; Torti, Carlo; Tundi, Paolo; Vecchiet, Giacomo; Verucchi, Gabriella; Gentilucci, Umberto Vespasiani; Vinci, Maria; Vullo, Vincenzo; Zolfino, Teresa; Zuin, Massimo
abstract

Purpose: To analyse safety and efficacy of treatment based on ombitasvir/paritaprevir/ritonavir/dasabuvir plus ribavirin in the sub-group of GT1 patients older than 65 years. Methods: We collected data extracted from the ABACUS compassionate-use nationwide Italian programme, in patients with cirrhosis due to hepatitis C virus (HCV) Genotype-1 (GT1) or 4 and at high risk of decompensation. GT1-HCV-infected patients received once-daily ombitasvir/paritaprevir, with the pharmacokinetic enhancer ritonavir (25/150/100 mg) and twice-daily dasabuvir (250 mg) plus Ribavirin (RBV) (OBV/PTV/r + DSV + RBV) for 12 (GT1b) or 24 (GT1a) weeks. Endpoints were to evaluate safety and efficacy, the latter defined as HCV RNA negative 12 weeks after the end of treatment (SVR12). Results: Patients who suffered any adverse event (AE) were 74/240 (30.8%); 13/240 (5.4%) discontinued the treatment. A multivariate analysis found albumin < 3.5 g/dL (OR 2.04: 95% CI 1.0–4.2, p < 0.05) and hypertension (OR 4.6: 95% CI 2.3–9.2, p < 0.001) as variables independently associated with AE occurrence. The SVR12 was 95% (228/240). Multivariate analysis identified baseline bilirubin < 2 mg/dL (OR 4.9: 95% CI 1.17–20.71, p = 0.029) as the only variable independently associated with SVR12. Conclusion: Our findings suggest that OBV/PTV/r + DSV + RBV is safe and effective in real-life use in patients with compensated cirrhosis, HCV-GT1 infection, and age over 65.

2018 - Safety and efficacy of vesatolimod (GS-9620) in patients with chronic hepatitis B who are not currently on antiviral treatment [Articolo su rivista]
Agarwal, K.; Ahn, S. H.; Elkhashab, M.; Lau, A. H.; Gaggar, A.; Bulusu, A.; Tian, X.; Cathcart, A. L.; Woo, J.; Subramanian, G. M.; Andreone, P.; Kim, H. J.; Chuang, W. L.; Nguyen, M. H.
abstract

Vesatolimod is an oral agonist of toll-like receptor 7 designed to minimize systemic exposure and side effects. We assessed the safety and efficacy of vesatolimod in viremic chronic hepatitis B (CHB) patients not currently on oral antiviral treatment (OAV) in a phase 2, multicentre, double-blind, randomized, placebo-controlled study. A total of 192 patients stratified by HBeAg status and alanine aminotransferase level were randomized 2:2:2:1 to receive oral vesatolimod (1-, 2- or 4-mg) or placebo once weekly for 12 weeks; tenofovir disoproxil fumarate (300-mg daily) was administered daily for 48 weeks. Efficacy was assessed by quantitative serum HBsAg decline at Week 24 from baseline. In addition to safety assessments, changes in whole-blood interferon-stimulated gene (ISG) transcripts and serum cytokines were explored. Most patients were male (64.1%) and HBeAg-negative (60.9%) at baseline. Among vesatolimod-treated patients, most (60.4%-69.1%) experienced ≥1 treatment-emergent adverse event; the majority were mild or moderate in severity. No clinically meaningful differences in HBsAg changes from baseline were observed between treatment groups. No patients experienced HBsAg loss, while 3 patients experienced HBeAg loss and hepatitis B e-antibody seroconversion at week 48. HBV DNA suppression rates were similar across all treatment arms at Week 24. ISG15 induction was dose-dependent and did not correlate with HBsAg changes. A small proportion of patients exhibited dose-dependent interferon-α induction that correlated with grade of influenza-like adverse events. Overall, vesatolimod is safe and well tolerated in CHB patients. Although consistent dose-dependent pharmacodynamic induction of ISGs was demonstrated, it did not result in clinically significant HBsAg decline.

2018 - Study of the Serum Metabolomic Profile in Nonalcoholic Fatty Liver Disease: Research and Clinical Perspectives [Articolo su rivista]
Gitto, Stefano; Schepis, Filippo; Andreone, Pietro; Villa, Erica
abstract

In recent years, metabolomics has attracted great scientific attention. The metabolomics methodology might permit a view into transitional phases between healthy liver and nonalcoholic steatohepatitis. Metabolomics can help to analyze the metabolic alterations that play a main role in the progression of nonalcoholic steatohepatitis. Lipid, glucose, amino acid, and bile acid metabolism should be widely studied to understand the complex pathogenesis of nonalcoholic steatohepatitis. The discovery of new biomarkers would be important for diagnosis and staging of liver disease as well as for the assessment of efficacy of new drugs. Here, we review the metabolomics data regarding nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. We analyzed the main studies regarding the application of metabolomics methodology in the complex context of nonalcoholic steatohepatitis, trying to create a bridge from the basic to the clinical aspects.

2018 - The use of obeticholic acid for the management of non-viral liver disease: current clinical practice and future perspectives [Articolo su rivista]
Gitto, Stefano; Guarneri, Valeria; Sartini, Alessandro; Andreone, Pietro
abstract

Introduction: Farnesoid X nuclear receptor is involved in the regulation of lipid and glucose metabolism, though mainly in the homeostasis of bile acids. Indeed, the agonists of farnesoid X nuclear receptor represent promising drugs. Areas covered: Obeticholic acid, a novel semisynthetic analogue of the naturally occurring bile acid, has led to encouraging preliminary results in both cholestatic and metabolic liver disease. In patients with primary biliary cholangitis, obeticholic acid determines a significant biochemical improvement although the effects on liver fibrosis are lacking. Obeticholic acid has been suggested for the treatment of nonalcoholic liver disease with good laboratory results. In cirrhotic animal models, the drug seems to reduce both portal hypertension and gut bacterial translocation. Expert commentary: The use of obeticholic acid for the treatment of primary biliary cholangitis shows satisfying results. However, some open questions remain unresolved. Herein, we provide an overview of the current knowledge about the use of obeticholic acid in the field of nonviral chronic liver diseases. We tried to give a global point of view using a translational approach.

2018 - Worsening of Serum Lipid Profile after Direct Acting Antiviral Treatment [Articolo su rivista]
Gitto, Stefano; Cicero, Arrigo F G; Loggi, Elisabetta; Giovannini, Marina; Conti, Fabio; Grandini, Elena; Guarneri, Valeria; Scuteri, Alessandra; Vitale, Giovanni; Cursaro, Carmela; Borghi, Claudio; Andreone, Pietro
abstract

Host lipid metabolism influences viral replication and lifecycle of hepatitis C virus. Our aim was to evaluate changes in glucose and lipid metabolism of patients with chronic hepatitis C after therapy with direct acting antivirals (DAA).

2017 - Accuracy of elastography point quantification and steatosis influence on assessing liver fibrosis in patients with chronic hepatitis C [Articolo su rivista]
Conti, Fabio; Serra, Carla; Vukotic, Ranka; Fiorini, Erica; Felicani, Cristina; Mazzotta, Elena; D'Errico, Antonietta; Verucchi, Gabriella; Lenzi, Marco; Andreone, Pietro
abstract

Background & Aims: Elastography point quantification is a novel non-invasive method for the assessment of liver fibrosis by measuring liver stiffness. The aim of this study was to evaluate the accuracy of elastography point quantification for the diagnosis of liver fibrosis and to assess impact of steatosis on liver stiffness measurement, in a cohort of patients with chronic hepatitis C. Methods: In this single-centre cross-sectional study, 211 consecutive patients with chronic hepatitis C, scheduled for liver biopsy, were examined with the elastography point quantification technology. On the same day, all patients underwent clinical examination, laboratory tests and abdominal ultrasound. Results: The best cut-offs of liver stiffness measurement were 6.16 kPa for the diagnosis of significant fibrosis (≥S3) and 6.79 kPa for advanced fibrosis (≥S4). Areas under the receiver operating characteristic curve were 0.831 (CI: 0.773–0.880) for significant fibrosis, and 0.954 (CI: 0.916–0.978) for advanced fibrosis. Among patients within the same fibrosis stages (S0–S2 and S3–S6; S0–S3 and S4–S6), mean liver stiffness measurement values were similar in patients with steatosis (≥10% at liver biopsy or detected by ultrasound) compared to those without. Discordance between elastography point quantification and histology were affected by the presence of BMI>30 kg/m2 (P=.047, CI: 0.136–0.988 and P=.020, CI: 0.083–0.812 respectively). Conclusions: In patients with chronic hepatitis C, elastography point quantification is an accurate non-invasive method for the diagnosis of significant and advanced fibrosis. The presence of obesity is a risk factor for misclassification of significant and advanced liver fibrosis.

2017 - Corrigendum: Insights into cancer severity from biomolecular interaction mechanisms [Articolo su rivista]
Raimondi, F.; Singh, G.; Betts, M. J.; Apic, G.; Vukotic, R.; Andreone, P.; Stein, L.; Russell, R. B.
abstract

2017 - DAAs treatment in HCV recurrence after liver transplantation: Clinical usefulness of non-invasive methods [Abstract in Rivista]
Ravaioli, Federico; Tame', Mariarosa; Marasco, Giovanni; Vizioli, Luca; Morelli, M. C.; Pinna, ANTONIO DANIELE; Conti, Fabio; Andreone, Pietro; Colecchia, Antonio; Festi, Davide
abstract

2017 - DAAs treatment in hepatitis C virus recurrence after Liver Transplantation: clinical usefulness of non-invasive methods [Abstract in Rivista]
Ravaioli, Federico; Tame', Mariarosa; Marasco, Giovanni; Vizioli, Luca; Morelli, M. C.; Pinna, ANTONIO DANIELE; Conti, Fabio; Andreone, Pietro; Colecchia, Antonio; Festi, Davide
abstract

2017 - Efficacy, safety, and pharmacokinetics of simeprevir, daclatasvir, and ribavirin in patients with recurrent hepatitis C virus genotype 1b infection after orthotopic liver transplantation: The Phase II SATURN study [Articolo su rivista]
Forns, Xavier; Berenguer, Marina; Herzer, Kerstin; Sterneck, Martina; Donato, Maria Francesca; Andreone, Pietro; Fagiuoli, Stefano; Cieciura, Tomasz; Durlik, Magdalena; Calleja, Jose Luis; Mariño, Zoe; Shukla, Umesh; Verbinnen, Thierry; Lenz, Oliver; Ouwerkerk-Mahadevan, Sivi; Peeters, Monika; Janssen, Katrien; Kalmeijer, Ronald; Jessner, Wolfgang
abstract

Background: Recurrent hepatitis C virus (HCV) infection following liver transplantation is associated with accelerated progression to graft failure and reduced patient survival. Methods: The Phase II, open-label SATURN study (NCT01938625) investigated the combination of simeprevir (SMV), daclatasvir (DCV), and ribavirin (RBV) administered for 24Â weeks in 35 patients with recurrent HCV genotype (GT) 1b infection after orthotopic liver transplantation (OLT). Results: High rates of both on-treatment and sustained virologic response 12Â weeks after end of treatment (SVR12) were achieved in patients who were either treatment-naÃ¯ve or had failed post-OLT treatment with peginterferon and RBV. Overall, 91% of patients (32/35) achieved SVR12. The combination was generally well tolerated, with an adverse event profile consistent with that observed in previous clinical trials of SMV or DCV separately. Co-administration of SMV with cyclosporine resulted in significantly increased SMV plasma exposures, which was not the case with the co-administration of SMV with tacrolimus. Therefore, the concomitant use of SMV with cyclosporine is not recommended. Conclusion: The interferon-free combination of SMV, DCV, and RBV administered for 24Â weeks was shown to be effective and well tolerated in the treatment of post-OLT HCV GT1b-infected patients.

2017 - HCV clearance after direct-acting antivirals in patients with cirrhosis by stages of liver impairment: The ITAL-C network study [Articolo su rivista]
Ippolito, Antonio Massimo; Milella, Michele; Messina, Vincenzo; Conti, Fabio; Cozzolongo, Raffaele; Morisco, Filomena; Brancaccio, Giuseppina; Barone, Michele; Santantonio, Teresa; Masetti, Chiara; Tundo, Paolo; Smedile, Antonina; Carretta, Vito; Gatti, Pietro; Termite, Antonio Patrizio; Valvano, Maria Rosa; Bruno, Giuseppe; Fabrizio, Claudia; Andreone, Pietro; Zappimbulso, Marianna; Gaeta, Giovanni Battista; Napoli, Nicola; Fontanella, Luca; Lauletta, Gianfranco; Cuccorese, Giuseppe; Metrangolo, Antonio; Francavilla, Ruggiero; Ciracì, Emanuela; Rizzo, Salvatore; Andriulli, Angelo
abstract

Background Sustained virological response (SVR12) rates at 12 weeks after treatment for HCV-infected patients with decompensated cirrhosis are used when referring to those with moderate functional impairment, while few data are available for those with more severe impairment. The use of the cirrhosis staging system proposed by D'Amico might provide new insights on timing for antiviral therapy. Methods We investigated efficacy (SVR12), safety, and post-treatment variations in clinical and laboratory parameters in 2612 patients with advanced fibrosis (n = 575) or cirrhosis (n = 2037). Cirrhosis was in the compensated phase (without/with varices) or had previously been in the decompensated stage. Different direct-acting antiviral (DAA) regimens were administered in accordance with scientific guidelines. Results The SVR12 rate was 97.6% in patients with advanced fibrosis. For patients with cirrhosis, the rate was 96.5% in stage 1, 95.1% in stage 2, 100% in stage 3, 95.7% in stage 4, and 93.6% in stage 5. These rates were independent of gender, age, HCV genotype, and treatment schedule. Positive changes in biochemical parameters and CPT classes following therapy were evident in compensated and previously decompensated patients. Conclusion Our findings support the use of DAAs in patients with advanced cirrhosis (stages 3â5) who are at greatest risk and have the most to gain from therapy.

2017 - Hepatitis B virus reactivation among hepatitis C patients treated with direct-acting antiviral therapies in routine clinical practice [Articolo su rivista]
Loggi, Elisabetta; Gitto, Stefano; Galli, Silvia; Minichiello, Mario; Conti, Fabio; Grandini, Elena; Scuteri, Alessandra; Vitale, Giovanni; Di Donato, Roberto; Cursaro, Carmela; Furlini, Giuliano; Andreone, Pietro
abstract

Background Hepatitis B (HBV) reactivation in chronic hepatitis C (CHC) patients treated with IFN-free direct acting antiviral (DAA) therapies has recently emerged as a potential risk. Given the potential burden of this issue, further data are needed to establish its actual clinical impact. Objectives The aim of the present study was to analyze the occurrence of HBV reactivation in a cohort of CHC patient treated with DAAs in routine clinical practice. Study design Consecutive CHC patients with different genotypes, treated with DAA between January 2015 and January 2016 were included in the study. Subjects had been tested for HBsAg and anti-HBc antibodies before antiviral therapy. HBV-DNA levels were examined in anti-HBc positive patients at baseline and 24 weeks after the end of treatment. Post-treatment HBsAg determination was performed in case of HBV-DNA positivity. Serum anti-HBs kinetics was analysed in anti-HBs and anti-HBc positive subjects. Results A cohort of 137 consecutive HCV patients treated with IFN-free regimens in routine clinical practice was evaluated. From this cohort, plasma samples of 44 subjects with positive serology for HBV (anti-HBc positive) were tested for HBV-DNA levels at baseline and 24 weeks after the end of treatment. Two of them were HBsAg-positive, while the others had signs of a past HBV exposure (HBsAg-negativeÂ Â±Â HBsAb-positive). No reactivation was found in HBcAb-positive and HBsAg-negative subjects. In the two HBsAg-positive, one experienced an increase in HBV-DNA levels of â¥2 log10IU/mL during treatment. However, the reactivation was without clinical impact and, most important, was followed by HBsAg loss. Conclusions Based on our experience, a past HBV infection seems not to be a condition predisposing to HBV reactivation. On the contrary, in HBsAg-positive subjects not in suppressive treatment with nucleos(t)ide analogs, regular monitoring of HBV-DNA during and after DAA treatment should be considered.

2017 - Hepatitis C virus eradication in the elderly: The challenge worth a long-life elixir? [Articolo su rivista]
Vukotic, Ranka; Conti, Fabio; Andreone, Pietro
abstract

No abstract available

2017 - Impact of hepatitis C virus infection on health-related quality of life before and after liver transplantation: a multidisciplinary point of view [Articolo su rivista]
Golfieri, Lucia; Gitto, Stefano; Morelli, Maria Cristina; Pinna, Antonio Daniele; Grandi, Silvana; Andreone, Pietro
abstract

Hepatitis C negatively changes patient quality of life even in the absence of advanced liver disease. The specific patterns of quality of life of hepatitis C positive patients waiting for transplant or after surgery are not widely studied. Areas covered: A significant percentage of infected patients show cognitive impairment, fatigue, and/or a 'brain fog', that cannot be explained by the liver disease. Depression can be diagnosed in one third of hepatitis C positive patients. Conflicting data are available regarding the possible role of Model for End-Stage Liver Disease score as predictor of impaired quality of life. In the first period after liver transplant, quality of life tends to increase at the pre-transplant period but in the medium and long-term period, it declines. The recurrence of hepatitis C infection represents a strong predictor of morbidity and mortality and can significantly affect the global quality of life of patients. Expert commentary: Hepatologists, surgeons and psychologists should collaborate to support infected patients in all phases of transplant including the long-term period after surgery. Education and information should be implemented especially regarding the positive role of new direct antivirals.

2017 - Incidence of DAA failure and the clinical impact of retreatment in real-life patients treated in the advanced stage of liver disease: Interim evaluations from the PITER network [Articolo su rivista]
Kondili, Loreta A.; Gaeta, Giovanni Battista; Brunetto, Maurizia Rossana; Di Leo, Alfredo; Iannone, Andrea; Santantonio, Teresa Antonia; Giammario, Adele; Raimondo, Giovanni; Filomia, Roberto; Coppola, Carmine; Amoruso, Daniela Caterina; Blanc, Pierluigi; Del Pin, Barbara; Chemello, Liliana; Cavalletto, Luisa; Morisco, Filomena; Donnarumma, Laura; Rumi, Maria Grazia; Gasbarrini, Antonio; Siciliano, Massimo; Massari, Marco; Corsini, Romina; Coco, Barbara; Madonia, Salvatore; Cannizzaro, Marco; Zignego, Anna Linda; Monti, Monica; Russo, Francesco Paolo; Zanetto, Alberto; Persico, Marcello; Masarone, Mario; Villa, Erica; Bernabucci, Veronica; Taliani, Gloria; Biliotti, Elisa; Chessa, Luchino; Pasetto, Maria Cristina; Andreone, Pietro; Margotti, Marzia; Brancaccio, Giuseppina; Ieluzzi, Donatella; Borgia, Guglielmo; Zappulo, Emanuela; Calvaruso, Vincenza; Petta, Salvatore; Falzano, Loredana; Quaranta, Maria Giovanna; Weimer, Liliana Elena; Rosato, Stefano; Vella, Stefano; Giannini, Edoardo Giovanni
abstract

Background: Few data are available on the virological and clinical outcomes of advanced liver disease patients retreated after first-line DAA failure. Aim: To evaluate DAA failure incidence and the retreatment clinical impact in patients treated in the advanced liver disease stage. Methods: Data on HCV genotype, liver disease severity, and first and second line DAA regimens were prospectively collected in consecutive patients who reached the 12-week post-treatment and retreatment evaluations from January 2015 to December 2016 in 23 of the PITER network centers. Results: Among 3,830 patients with advanced fibrosis (F3) or cirrhosis, 139 (3.6%) failed to achieve SVR. Genotype 3, bilirubin levels >1.5mg/dl, platelet count <120,000/mm3 and the sofosbuvir+ribavirin regimen were independent predictors of failure by logistic regression analysis. The failure rate was 7.6% for patients treated with regimens that are no longer recommended or considered suboptimal (sofosbuvir+ribavirin or simeprevir+sofosbuvirÂ±ribavirin), whereas 1.4% for regimens containing sofosbuvir combined with daclatasvir or ledipasvir or other DAAs. Of the patients who failed to achieve SVR, 72 (51.8%) were retreated with a second DAA regimen, specifically 38 (52.7%) with sofosbuvir+daclatasvir, 27 (37.5%) with sofosbuvir+ledipasvir, and 7 (9.7%) with other DAAs Â±ribavirin. Among these, 69 (96%) patients achieved SVR12 and 3 (4%) failed. During a median time of 6 months (range: 5â14 months) between failure and the second DAA therapy, the Child-Pugh class worsened in 12 (16.7%) patients: from A to B in 10 patients (19.6%) and from B to C in 2 patients (10.5%), whereas it did not change in the remaining 60 patients. Following the retreatment SVR12 (median time of 6 months; range: 3â12 months), the Child-Pugh class improved in 17 (23.6%) patients: from B to A in 14 (19.4%) patients, from C to A in 1 patient (1.4%) and from C to B in 2 (2.9%) patients; it remained unchanged in 53 patients (73.6%) and worsened in 2 (2.8%) patients. Of patients who were retreated, 3 (4%) had undergone OLT before retreatment (all reached SVR12 following retreatment) and 2 (2.8%) underwent OLT after having achieved retreatment SVR12. Two (70%) of the 3 patients who failed to achieve SVR12 after retreatment, and 2 (2.8%) of the 69 patients who achieved retreatment SVR12 died from liver failure (Child-Pugh class deteriorated from B to C) or HCC complications. Conclusions: Failure rate following the first DAA regimen in patients with advanced disease is similar to or lower than that reported in clinical trials, although the majority of patients were treated with suboptimal regimens. Interim findings showed that worsening of liver function after failure, in terms of Child Pugh class deterioration, was improved by successful retreatment in about one third of retreated patients within a short follow-up period; however, in some advanced liver disease patients, clinical outcomes (Child Pugh class, HCC development, liver failure and death) were independent of viral eradication.

2017 - Liver stiffness and serum fibrosis biomarker variations after DAAs treatment: Predictive role in HCC development in cirrhotic patients [Abstract in Rivista]
Ravaioli, F.; Mazzella, G.; Andreone, P.; Conti, F.; Brillanti, S.; Buonfiglioli, F.; Serio, I.; Verucchi, G.; Bacchi Reggiani, M. L.; Marasco, G.; Colecchia, A.; Festi, D.
abstract

2017 - Long-term outcomes of direct acting antivirals in post-transplant advanced hepatitis C virus recurrence and fibrosing cholestatic hepatitis [Articolo su rivista]
Vukotic, R; Conti, F; Fagiuoli, S; Morelli, M C; Pasulo, L; Colpani, M; Foschi, F G; Berardi, S; Pianta, P; Mangano, M; Donato, M F; Malinverno, F; Monico, S; Tamè, M; Mazzella, G; Belli, L S; Viganò, R; Carrai, P; Burra, P; Russo, F P; Lenci, I; Toniutto, P; Merli, M; Loiacono, L; Iemmolo, R; Degli Antoni, A M; Romano, A; Picciotto, A; Rendina, M; Andreone, P
abstract

Long-term functional outcomes of sofosbuvir-based antiviral treatment were evaluated in a cohort study involving 16 Italian centres within the international compassionate use programme for post-transplant hepatitis C virus (HCV) recurrence. Seventy-three patients with cirrhosis (n=52) or fibrosing cholestatic hepatitis (FCH, n=21) received 24-week sofosbuvir with ribavirin±pegylated interferon or interferon-free sofosbuvir-based regimen with daclatasvir/simeprevir+ribavirin. The patients were observed for a median time of 103 (82-112) weeks. Twelve of 73 (16.4%) died (10 non-FCH, 2 FCH) and two underwent re-LT. Sustained virological response was achieved in 46 of 66 (69.7%): 31 of 47 (66%) non-FCH and 15 of 19 (79%) FCH patients. All relapsers were successfully retreated. Comparing the data of baseline with last follow-up, MELD and Child-Turcotte-Pugh scores improved both in non-FCH (15.3±6.5 vs 10.5±3.8, P<.0001 and 8.4±2.1 vs 5.7±1.3, P<.0001, respectively) and FCH (17.3±5.9 vs 10.1±2.8, P=.001 and 8.2±1.6 vs 5.5±1, P=.001, respectively). Short-treatment mortality was higher in patients with baseline MELD≥25 than in those with MELD<25 (42.9% vs 4.8%, P=.011). Long-term mortality was 53.3% among patients with baseline MELD≥20 and 7.5% among those with MELD<20 (P<.0001). Among deceased patients 75% were Child-Turcotte-Pugh class C at baseline, while among survivors 83.9% were class A or B (P<.0001). Direct acting antivirals-based treatments for severe post-transplant hepatitis C recurrence, comprising fibrosing cholestatic hepatitis, significantly improve liver function, even without viral clearance and permit an excellent long-term survival. The setting of severe HCV recurrence may require the identification of "too-sick-to-treat patients" to avoid futile treatments.

2017 - Modeling cost-effectiveness and health gains of a âuniversalâ versus âprioritizedâ hepatitis C virus treatment policy in a real-life cohort [Articolo su rivista]
Kondili, Loreta A.; Romano, Federica; Rolli, Francesca Romana; Ruggeri, Matteo; Rosato, Stefano; Brunetto, Maurizia Rossana; Zignego, Anna Linda; Ciancio, Alessia; Di Leo, Alfredo; Raimondo, Giovanni; Ferrari, Carlo; Taliani, Gloria; Borgia, Guglielmo; Santantonio, Teresa Antonia; Blanc, Pierluigi; Gaeta, Giovanni Battista; Gasbarrini, Antonio; Chessa, Luchino; Erne, Elke Maria; Villa, Erica; Ieluzzi, Donatella; Russo, Francesco Paolo; Andreone, Pietro; Vinci, Maria; Coppola, Carmine; Chemello, Liliana; Madonia, Salvatore; Verucchi, Gabriella; Persico, Marcello; Zuin, Massimo; Puoti, Massimo; Alberti, Alfredo; Nardone, Gerardo; Massari, Marco; Montalto, Giuseppe; Foti, Giuseppe; Rumi, Maria Grazia; Quaranta, Maria Giovanna; Cicchetti, Americo; Craxì, Antonio; Vella, Stefano
abstract

We evaluated the cost-effectiveness of two alternative direct-acting antiviral (DAA) treatment policies in a real-life cohort of hepatitis C virusâinfected patients: policy 1, âuniversal,â treat all patients, regardless of fibrosis stage; policy 2, treat only âprioritizedâ patients, delay treatment of the remaining patients until reaching stage F3. A liver disease progression Markov model, which used a lifetime horizon and health care system perspective, was applied to the PITER cohort (representative of Italian hepatitis C virusâinfected patients in care). Specifically, 8,125 patients naive to DAA treatment, without clinical, sociodemographic, or insurance restrictions, were used to evaluate the policiesâ cost-effectiveness. The patientsâ age and fibrosis stage, assumed DAA treatment cost of â¬15,000/patient, and the Italian liver disease costs were used to evaluate quality-adjusted life-years (QALY) and incremental cost-effectiveness ratios (ICER) of policy 1 versus policy 2. To generalize the results, a European scenario analysis was performed, resampling the study population, using the mean European country-specific health states costs and mean treatment cost of â¬30,000. For the Italian base-case analysis, the cost-effective ICER obtained using policy 1 was â¬8,775/QALY. ICERs remained cost-effective in 94%-97% of the 10,000 probabilistic simulations. For the European treatment scenario the ICER obtained using policy 1 was â¬19,541.75/QALY. ICER was sensitive to variations in DAA costs, in the utility value of patients in fibrosis stages F0-F3 postâsustained virological response, and in the transition probabilities from F0 to F3. The ICERs decrease with decreasing DAA prices, becoming cost-saving for the base price (â¬15,000) discounts of at least 75% applied in patients with F0-F2 fibrosis. Conclusion: Extending hepatitis C virus treatment to patients in any fibrosis stage improves health outcomes and is cost-effective; cost-effectiveness significantly increases when lowering treatment prices in early fibrosis stages. (Hepatology 2017;66:1814â1825).

2017 - Molecular and functional characterization of CD133+ stem/progenitor cells infused in patients with end-stage liver disease reveals their interplay with stromal liver cells [Articolo su rivista]
Catani, Lucia; Sollazzo, Daria; Bianchi, Elisa; Ciciarello, Marilena; Antoniani, Chiara; Foscoli, Licia; Caraceni, Paolo; Giannone, Ferdinando Antonino; Baldassarre, Maurizio; Giordano, Rosaria; Montemurro, Tiziana; Montelatici, Elisa; D'Errico, Antonia; Andreone, Pietro; Giudice, Valeria; Curti, Antonio; Manfredini, Rossella; Lemoli, Roberto Massimo
abstract

Background aims Growing evidence supports the therapeutic potential of bone marrow (BM)-derived stem/progenitor cells for end-stage liver disease (ESLD). We recently demonstrated that CD133+ stem/progenitor cell (SPC) reinfusion in patients with ESLD is feasible and safe and improve, albeit transiently, liver function. However, the mechanism(s) through which BM-derived SPCs may improve liver function are not fully elucidated. Methods Here, we characterized the circulating SPCs compartment of patients with ESLD undergoing CD133+ cell therapy. Next, we set up an in vitro model mimicking SPCs/liver microenvironment interaction by culturing granulocyte colony-stimulating factor (G-CSF)-mobilized CD133+and LX-2 hepatic stellate cells. Results We found that patients with ESLD show normal basal levels of circulating hematopoietic and endothelial progenitors with impaired clonogenic ability. After G-CSF treatment, patients with ESLD were capable to mobilize significant numbers of functional multipotent SPCs, and interestingly, this was associated with increased levels of selected cytokines potentially facilitating SPC function. Co-culture experiments showed, at the molecular and functional levels, the bi-directional cross-talk between CD133+ SPCs and human hepatic stellate cells LX-2. Human hepatic stellate cells LX-2 showed reduced activation and fibrotic potential. In turn, hepatic stellate cells enhanced the proliferation and survival of CD133+ SPCs as well as their endothelial and hematopoietic function while promoting an anti-inflammatory profile. Discussion We demonstrated that the interaction between CD133+ SPCs from patients with ESLD and hepatic stellate cells induces significant functional changes in both cellular types that may be instrumental for the improvement of liver function in cirrhotic patients undergoing cell therapy.

2017 - Monitoring the treatment of hepatitis C with directly acting antivirals by serological and molecular methods [Articolo su rivista]
Loggi, Elisabetta; Galli, Silvia; Vitale, Giovanni; Donato, Roberto Di; Vukotic, Ranka; Grandini, Elena; Margotti, Marzia; Guarneri, Valeria; Furlini, Giuliano; Galli, Claudio; Re, Maria Carla; Andreone, Pietro
abstract

Aim: To evaluate the potential value of using a serological assay to quantitate the hepatitis C virus core antigen (HCV-Ag) when monitoring patients with chronic hepatitis C being treated with direct-acting antivirals (DAAs). Methods: Ninety-six patients treated with DAAs, either alone (91) or in combination with PEG interferon (5), were tested for HCV-RNA and for HCV-Ag at baseline and at weeks 2, 4, 8 and 12 during treatment and 12 weeks after completion. The concordance and correlation between the viral parameters as well as the respective kinetics during and after treatment were evaluated. Results: A sustained viral response (SVR) was achieved in 82 patients (91%), whereas 11 relapsed (R) and 1 showed a virological breakthrough while receiving treatment. HCV-RNA and HCV-Ag showed good concordance (kappa = 0.62) and correlation. No significant differences between SVR and R was observed in either assay at 2 and 4 weeks after the start of treatment. At 8 weeks, HCV-Ag showed higher accuracy than HCV-RNA (AUC: 0.74 vs. 0.55) and there was a significantly greater decrease from baseline in SVR than in R (4.01 vs. 3.36 log10; p<0.05). Conclusions: Monitoring during treatment with DAAs by using either HCV-RNA or HCV-Ag has only a limited predictive value for SVR. Since those assays are equivalent for identifying a virological relapse, HCV-Ag may be preferred from an economical and organizational perspective.

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 & 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<.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 â¥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 - NS5A inhibitors for the treatment of hepatitis C infection [Articolo su rivista]
Gitto, Stefano; Gamal, Nesrine; Andreone, Pietro
abstract

Today, we are witnessing a new era for the treatment of hepatitis C with excellent rates of virologic response and very good safety profiles. Among the many classes of direct-acting antivirals, the inhibitors of nonstructural protein 5A are particularly interesting. NS5A is a phosphorylated protein with a relevant role in viral replication. HCV-NS5A inhibitors show high potency, very good safety profile and high barrier to resistance. The amazing in vitro effectiveness of this class is associated with great efficacy in clinical trials in combination protocols with antivirals of other classes, with sustained virological response (SVR) obtained in more than 90% of patients. Herein, we sought to review the current knowledge regarding the NS5A protease complex inhibitors with special emphasis on clinical efficacy and development of viral resistance.

2017 - Nivolumab-induced cholangitic liver disease: A novel form of serious liver injury [Articolo su rivista]
Gelsomino, Francesco; Vitale, Giovanni; D'Errico, Antonietta; Bertuzzi, Clara; Andreone, Pietro; Ardizzoni, Andrea
abstract

[No abstract available

2017 - Ombitasvir, paritaprevir, and ritonavir, with or without dasabuvir, plus ribavirin for patients with hepatitis C virus genotype 1 or 4 infection with cirrhosis (ABACUS): a prospective observational study [Articolo su rivista]
Petta, Salvatore; Marzioni, Marco; Russo, Pierluigi; Aghemo, Alessio; Alberti, Alfredo; Ascione, Antonio; Antinori, Andrea; Bruno, Raffaele; Bruno, Savino; Chirianni, Antonio; Gaeta, Giovanni Battista; Giannini, Edoardo G; Merli, Manuela; Messina, Vincenzo; Montilla, Simona; Perno, Carlo Federico; Puoti, Massimo; Raimondo, Giovanni; Rendina, Maria; Silberstein, Francesca Ceccherini; Villa, Erica; Zignego, Anna Linda; Pani, Luca; Craxì, Antonio; Tabone, Marco; Andreoni, Massimo; Teti, Elisabetta; Angelico, Mario; Persico, Marcello; Masarone, Mario; Chiodera, Aledssandro; Solinas, Attilio; delle Monache, Marco; Cecere, Roberto; Maria Schimizzi, Anna; Piovesan, Sara; Campagnolo, Davide; Chiara Piras, Maria; Zolfino, Teresa; Paolo Russo, Francesca; Morelli, Olivia; Sangiovanni, Vincenzo; Onofrio, Mirella; Iodice, Valentina; Izzi, Antonio; Pirisi, Massimo; Danieli, Elena; Vinci, Maria; Rizzardini, Giuliano; Fagiuoli, Stefano; Pasulo, Luisa; D'Arminio Monforte, Antonella; Zuin, Massimo; Giorgini, Alessia; Simeone, Filomena; Piali, Guido; Lo Guercio, Carmela; Federico, Alessandro; Brancaccio, Giuseppina; Marrone, Aldo; Abbati, Giuseppe; Boarini, Chiara; Borghi, Vanni; Bernabucci, Veronica; Corti, Giampaolo; Monti, Monica; Rizzetto, Mario; Martini, Silvia; Andreone, Pietro; Gianstefani, Alice; Lenzi, Marco; Verucchi, Gabriella; Toniutto, Pierluigi; Borgia, Guglielmo; Caporaso, Nicola; Morisco, Filomena; Nardone, Gaetano; Angrisani, Debora; Giacometti, Andrea; Benedetti, Antonio; Tarantino, Giuseppe; Marsetti, Fabio; Tavio, Marcello; Novara, Sergio; Antonia Santantonio, Teresa; Serviddio, Gaetano; Brunetto, Maurizia; Coco, Barbara; Angarano, Gioacchino; Milella, Michele; Barone, Michele; Di Leo, Alfredo; Ettore Sansonno, Domenico; Cacciola, Irene; Boffa, Nicola; Saracco, Giorgio; Di Biagio, Antonio; Picciotto, Antonino; de Luca, Andrea; Calvaruso, Vincenza; Corradori, Silvia; Ferrari, Carlo; Orlandini, Alessandra; Maida, Ivana; Torti, Carlo; Chessa, Luchino; Felder, Martina; Vespasiani Gentilucci, Umberto; Angeli, Paolo; Romano, Antonietta; Ludovico Rapaccini, Gian; Miele, Luca; Cima, Serena; Luisa Russo, Maria; Cozzolongo, Raffaele; Onnelli, Giovanna; D'Offizi, Giampiero; Lionetti, Raffaella; Montalbano, Marzia; Guerra, Michele; Di Perri, Giovanni; Boglione, Lucio; Capra, Franco; Carolo, Giada; Ieluzzi, Donatella; Antonini, Cinzia; Termite, Antonio; Madonia, Salvatore; Tarquini, Pierluigi; Parruti, Giustino; Vecchiet, Giacomo; Falasca, Katia; Menzaghi, Barbara; Quirino, Tiziana; Dentone, Chiara; Maria Piscaglia, Anna; Rossi, Cristina; Giordani, Maria; Fontanella, Luca; Cassola, Giovanni; Russello, Maurizio; Cristaudo, Antonio; Giacomet, Vania; Colombo, Massimo; Donato, Francesca; Durante, Emanuele; Cosco, Lucio; Marignani, Massimo; Quartini, Mariano; Memoli, Massimo; Ganga, Roberto; Ponti, Laura; Soria, Alessandro; Grazia Rumi, Maria; Gulminetti, Roberto; Maserati, Renato; Mondelli, Mario; Lazzarin, Adriano; Rita Parisi, Maria; Canovari, Benedetta; Avancini, Ivo; Pravadelli, Cecilia; Blanc, Pier; Pasquazzi, Caterina; Maria Mastroianni, Claudio; Lichtner, Myriam; Distefano, Marco; Magnani, Silvia; Paganin, Simona; Erne, Elke; Gatti, Pietro; Tundi, Paolo; Calabrese, Paolo; Gasbarrini, Antonio; Grieco, Antonio; Coppola, Nicola; Del Poggio, Paolo; Levrero, Massimo; Talliani, Gloria; Vullo, Vincenzo; Cauda, Roberto; La Monica, Silvia; Potenza, Domenico; Rizzo, Salvatore; Castelli, Francesco; Marie Pigozzi, Grazielle; Ciancio, Alessia; Romagnoli, Dante; Barchetti, Federica; Ivanovic, Jelena; Longo, Olimpia; Petraglia, Sandra; Paola Trotta, Maria
abstract

Background We ran a compassionate use nationwide programme (ABACUS) to provide access to ombitasvir, paritaprevir, and ritonavir, with dasabuvir, plus ribavirin for hepatitis C virus (HCV) genotype 1 infection and ombitasvir, paritaprevir, and ritonavir, plus ribavirin for HCV genotype 4 infection in patients with cirrhosis at high risk of decompensation while approval of these regimens was pending in Italy. Methods In this prospective observational study, we collected data from a compassionate use nationwide programme from March 17, 2014, to May 28, 2015. Patients with HCV genotype 1 infection and cirrhosis at high risk of decompensation were given coformulated ombitasvir (25 mg), paritaprevir (150 mg), and ritonavir (100 mg) once daily and dasabuvir (250 mg) twice daily for 12 weeks (patients with HCV genotype 1b infection) or 24 weeks (patients with HCV genotype 1a infection). Patients with HCV genotype 4 infection were given coformulated ombitasvir (25 mg), paritaprevir (150 mg), and ritonavir (100 mg) once per day for 24 weeks. All patients were given weight-based ribavirin. The primary efficacy endpoint was sustained virological response at week 12 after the end of treatment (SVR12), analysed by intention-to-treat. Univariate and multivariate logistic regression analyses were used to identify baseline characteristics associated with SVR12. Adverse events were recorded throughout the study. Findings 728 (96%) of 762 patients with cirrhosis who were given ombitasvir, paritaprevir, and ritonavir, with or without dasabuvir, plus ribavirin therapy for 12 or 24 weeks achieved SVR12. Logistic regression analyses identified that bilirubin concentrations of less than 2 mg/dL were associated with SVR12 (odds ratio [OR] 4·76 [95% CI 1·83–12·3]; p=0·001). 166 (23%) of 734 patients included in safety analyses had an adverse event. 25 (3%) patients discontinued treatment because of adverse events. Asthenia was the most commonly reported adverse event, occurring in 36 (5%) patients. Interpretation Our findings suggest that the safety and effectiveness of ombitasvir, paritaprevir, and ritonavir, with or without dasabuvir, plus ribavirin in patients with HCV genotype 1 or 4 infection and cirrhosis at high risk of decompensation in a real-life setting are similar to those reported in clinical trials. The concordance with clinical trials provides reassurance that the reported efficacy of this treatment in clinical trials will translate to its use in routine clinical practice. Funding Dipartimento Biomedico di Medicina Interna e Specialistica dell'Universita di Palermo.

2017 - Safety and efficacy of direct-acting antivirals for the treatment of chronic hepatitis C in a real-world population aged 65 years and older [Articolo su rivista]
Conti, Fabio; Brillanti, Stefano; Buonfiglioli, Federica; Vukotic, Ranka; Morelli, M. C.; Lalanne, Claudine; Massari, M.; Foschi, F. G.; Bernabucci, V.; Serio, Ilaria; Prati, G. M.; Negri, E.; Badia, L.; Caraceni, Paolo; Muratori, Paolo; Vitale, Giovanni; Porro, Alberto; Morotti, M.; Mazzella, Giuseppe; Andreone, Pietro
abstract

The availability of direct-acting antiviral agents (DAA) regimens has expanded the pool of patients eligible for treatment. However, data on the virologic response and tolerability of DAAs in elderly patients are lacking. We evaluated the efficacy and safety of DAAs in patients with advanced fibrosis/cirrhosis in real-life practice with the focus on those aged ≥65 years. Between January and December 2015, all consecutive patients with HCV-related advanced fibrosis/cirrhosis treated with DAA at eleven tertiary referral centres in Emilia Romagna (Italy) were enrolled. Regimen choice was based on viral genotype and stage of disease, according to guidelines. The primary end point was sustained virologic response 12 weeks after the end of treatment (SVR12). Overall, 282 of 556 (50.7%) patients evaluated were elderly, most of them with cirrhosis. Antiviral therapy was stopped prematurely in four (1.4%) patients. Two patients, both with cirrhosis, died during treatment due to worsening of liver/renal function. SVR12 was achieved by 94.7% and was comparable to that obtained in patients aged <65 (P=.074). Similar data were also reported in subgroup of patients aged ≥75 years. All patients with advanced fibrosis achieved virologic response. SVR12 was 80.8% in Child-Pugh-Turcotte (CTP)-B cirrhosis and 95.4% in CTP-A (P=.013). According to genotype, the SVR12 was achieved in 172 of 181 (95%) with genotype 1b cirrhosis and in 44 of 48 (91.7%) with genotype 2 cirrhosis. In conclusions, in a real-world setting, DAAs are safe and effective in elderly patients with HCV-related advanced fibrosis/cirrhosis, but SVR12 is lower with worsening CTP class.

2017 - Secondary prophylaxis of hepatocellular carcinoma: the comparison of direct-acting antivirals with pegylated interferon and untreated cohort [Articolo su rivista]
Vukotic, R.; Di Donato, R.; Conti, F.; Scuteri, A.; Serra, C.; Andreone, P
abstract

During the past two decades, several studies showed reduced rates of hepatocellular carcinoma recurrence in patients with HCV-related cirrhosis after interferon-based antiviral therapies respect to untreated controls, even without reaching viral clearance. The recent development of new all-oral regimens with direct-acting antivirals has radically improved the therapeutic management of hepatitis C. Nevertheless, paradoxical, or at least unexpected, high rates of both occurrence and recurrence of hepatocellular carcinoma after a treatment with direct-acting antivirals, have been reported in the recent literature. These findings generated a strong rebound in the hepatology community and are at present still controversial. We sought to compare the hepatocellular carcinoma recurrence-free survival of a historical cohort treated with pegylated interferon/ribavirin and an untreated cohort with a cohort treated with direct-acting antivirals.

2017 - THU-492 - Liver stiffness and serum fibrosis biomarker variations after DAAs treatment: predictive role in hepatocellular carcinoma development in in cirrhotic patients [Abstract in Rivista]
Ravaioli, Federico; Mazzella, Giuseppe; Andreone, Pietro; Conti, Fabio; Brillanti, Stefano; Buonfiglioli, Federica; Serio, Ilaria; Verucchi, Gabriella; BACCHI REGGIANI, MARIA LETIZIA; Marasco, Giovanni; Colecchia, Antonio; Festi, Davide
abstract

2017 - Treatment of Hepatitis C virus infection in Italy: A consensus report from an expert panel [Articolo su rivista]
Viganò, Mauro; Perno, Carlo Federico; Craxì, Antonio; Aghemo, Alessio; Alberti, Alfredo; Andreone, Pietro; Andreoni, Massimo; Bonora, Stefano; Brunetto, Maurizia Rossana; Bruno, Raffaele; Bruno, Savino; Calvaruso, Vincenza; Caporaso, Nicola; Ceccherini-Silberstein, Francesca; Cento, Valeria; Ciancio, Alessia; Colombatto, Piero; Degasperi, Elisabetta; DI MARCO, Vito; Di Perri, Giovanni; D'Offizi, Gianpiero; Fagiuoli, Stefano; Ferrari, Carlo; Gaeta, Giovanni Battista; Pellicelli, Adriano; Petta, Salvatore; Piovesan, Sara; Puoti, Massimo; Raimondo, Giovanni; Russo, Francesco Paolo; Taliani, Gloria; Trama, Ugo; Villa, Erica; Zignego, Anna Linda
abstract

Hepatitis C virus (HCV) infection remains one of the main causes of chronic liver disease worldwide. The advent of direct-acting antivirals (DAAs) has significantly improved the course of patients with chronic HCV infection (CHC), due to the ability of these drugs to achieve high rates of sustained virological response (SVR). These exceedingly high rates of SVR and the excellent safety data have been confirmed in real life practice. Evolving guidelines have been issued by national and international scientific societies in accordance with the progression of clinical knowledge and the availability of new DAAs. These recommendations, however, may not be applied universally because of delays in drugs reimbursability in different countries and because some National Health Systems identify only patients with advanced disease as a treatment priority. Italy in this regard is a prototype about DAAs treatment of CHC patients. With the aim to assess the Italian treatment experience with DAAs and to respond to unmet needs in treatment optimization of antiviral therapy in specific settings of CHC patients, a group of Italian experts met in Stresa in February 2017. The summary of the considerations arising from this two-day meeting and some statements regarding a few open issues are reported in this position paper.

2017 - Vitamin E for the treatment of E-antigen-positive chronic hepatitis B in paediatric patients: results of a randomized phase 2 controlled study [Articolo su rivista]
Fiorino, S; Loggi, Elisabetta; Verucchi, Gabriella; Comparcola, D; Vukotic, Ranka; Pavoni, Michele; Grandini, Elena; Cursaro, C; Maselli, Serena; BACCHI REGGIANI, MARIA LETIZIA; Puggioli, C; Badia, L; Galli, S; Viale, Pierluigi; Bernardi, Mauro; Andreone, Pietro
abstract

Background & Aims: The treatment of chronic hepatitis B infection (CHB) in children is still an area of great uncertainty. Vitamin E is an immunostimulating/antioxidant compound proven to be safe and effective for the treatment of adult CHB. The aim of this phase 2 controlled study was to evaluate the safety and efficacy of vitamin E for the treatment of paediatric HBeAg-positive CHB. Methods: Forty-six children were randomized in a 1:1 ratio to receive vitamin E at a dose of 15 mg/ kg/day (in galenic preparation) or no treatment for 12 months and were monitored for the subsequent 12 months. Clinical, biochemical, haematological and serovirological evaluations were carried out every 3 months. Results: No significant side effects were associated with the vitamin E treatment. At the end of the study, anti-HBe seroconversion was obtained in 7 of 23 (30.4%) of vitamin E-treated versus 1 of 23 (4.3%) of the control patients (P = 0.05), while a virological response (≥2 log decrease in HBV-DNA from baseline) was observed in 9 of 23 (39.1%) vs. 2 of 23 (8.7%) respectively (P = 0.035). Conclusions: Vitamin E administration for the treatment of paediatric CHB at the tested dosage has no significant side effects and may induce anti-HBe seroconversion. Vitamin E could represent a tool for the treatment of paediatric CHB.

2017 - Vitamin E for the treatment of children with hepatitis B e antigen-positive chronic hepatitis: A systematic review and meta-analysis [Articolo su rivista]
Fiorino, Sirio; BACCHI REGGIANI, MARIA LETIZIA; Leandri, Paolo; Loggi, Elisabetta; Andreone, Pietro
abstract

AIM to assess vitamin E efficacy, defined as its ability to induce hepatitis B e antigen (HBeAg) seroconversion, in children with HBeAg-positive persistent hepatitis. METHODS In July 2016, we extracted articles published in MEDLINE and the Cochrane Library using the following search terms: "chronic hepatitis B", "children", "childhood", "therapy", "treatment", "vitamin E", "tocopherols", "tocotrienols". Only randomized controlled trials (RCTs) published in English language were collected. RESULTS Three RCTs met inclusion criteria and were considered in the present meta-analysis. Overall, 23/122 children in the treatment group underwent HBeAg seroconversion vs 3/74 in the control group (OR = 3.96, 95%CI: 1.18-13.25, p = 0.025). CONCLUSION Although our meta-analysis has several limits, including the very small number of available studies and enrolled children with HBeAg positivity-related hepatitis, it suggests that vitamin E use may enhance the probability to induce HBeAg seroconversion in these patients. Further well designed and adequately sized trials are required to confirm or deny these very preliminary results.

2017 - What to start with in first line treatment of chronic hepatitis B patients: an Italian multicentre observational cohort, HBV-RER study group [Articolo su rivista]
Cuomo, Gianluca; Borghi, Vanni; Giuberti, Tiziana; Andreone, Pietro; Massari, Marco; Villa, Erica; Pietrangelo, Antonello; Verucchi, Gabriella; Levantesi, Fabio; Ferrari, Carlo
abstract

Treatment options for chronic hepatitis B (CHB) are pegylated interferon (Peg-IFN) in minimal-mild liver fibrosis and nucleot(s)ide analogues (NUC) in more advanced disease. Since little is known about their use in daily clinical practice, we conducted a multicentre prospective study to investigate treatment regimens applied to naïve CHB patients in real life. HBV-RER is an observational multicentre Italian network that collect clinic and virologic data of patients with CHB. Among the 2527 CHB patients seen during the study period (2009 - 2012), 502 patients started a first line antiviral treatment. Liver biopsy was performed in 30.9% of the patients, with high levels of fibrosis being detected in 19.4% of them. In 216 patients (43%) Peg-IFN was used as first-line therapy while the remaining patients started NUC therapy (entecavir and tenofovir in 75%, lamivudine in 15%, telbivudine and adefovir 10%). By multivariate logistic regression, an age under 40 (OR 0.92, 95%IC 0.90-0.94; p <0.001) and the execution of liver biopsy (OR 3.83; 95%IQR 1.76-8.36; p <0.001) were the only determinants of choice between Peg-IFN vs NUC. Peg-IFN was expected to be used in first-line treatment for CHB in 70% of the patients based on Italian recommendations, but a much lower proportion of patients were actually treated with Peg-IFN with a limited use of the biopsy. Thus, in daily clinical practice physicians prefer to use NUCs, presumably because of their optimal tolerability and anti-viral efficacy, even if they frequently require life-long treatment as opposed to the short duration of Peg-IFN.

2016 - A Case of Acute Liver Failure during Ritonavir-Boosted Paritaprevir, Ombitasvir and Dasabuvir Therapy in a Patient with HCV Genotype 1b Cirrhosis [Articolo su rivista]
Masetti, Marco; Magalotti, Donatella; Martino, Elena; Andreone, Pietro; Scuteri, Alessandra; Zoli, Marco
abstract

Ritonavir-boosted Paritaprevir, Ombitasvir and Dasabuvir plus Ribavirin is one of the current recommended therapies for HCV genotype 1b monoinfected patients in compensated (Child-Pugh A) cirrhosis. Whether it is known that the worsening of liver function is a rare but possible complication of Ritonavir-boosted Paritaprevir, Ombitasvir and Dasabuvir therapy, to our knowledge no description of treatment-related acute liver failure is available in the literature.

2016 - A Placebo-controlled trial of obeticholic acid in primary biliary cholangitis [Articolo su rivista]
Nevens, F.; Andreone, Pietro; Mazzella, Giuseppe; Strasser, S. I.; Bowlus, C.; Invernizzi, P.; Drenth, J. P. H.; Pockros, P. J.; Regula, J.; Beuers, U.; Trauner, M.; Jones, D. E.; Floreani, A.; Hohenester, S.; Luketic, V.; Shiffman, M.; Van Erpecum, K. J.; Vargas, V.; Vincent, C.; Hirschfield, G. M.; Shah, H.; Hansen, B.; Lindor, K. D.; Marschall, H. U.; Kowdley, K. V.; Hooshmand Rad, R.; Marmon, T.; Sheeron, S.; Pencek, R.; Macconell, L.; Pruzanski, M.; Shapiro, D.
abstract

BACKGROUND Primary biliary cholangitis (formerly called primary biliary cirrhosis) can progress to cirrhosis and death despite ursodiol therapy. Alkaline phosphatase and bilirubin levels correlate with the risk of liver transplantation or death. Obeticholic acid, a farnesoid X receptor agonist, has shown potential benefit in patients with this disease. METHODS In this 12-month, double-blind, placebo-controlled, phase 3 trial, we randomly assigned 217 patients who had an inadequate response to ursodiol or who found the side effects of ursodiol unacceptable to receive obeticholic acid at a dose of 10 mg (the 10-mg group), obeticholic acid at a dose of 5 mg with adjustment to 10 mg if applicable (the 5-10-mg group), or placebo. The primary end point was an alkaline phosphatase level of less than 1.67 times the upper limit of the normal range, with a reduction of at least 15% from baseline, and a normal total bilirubin level. RESULTS Of 216 patients who underwent randomization and received at least one dose of obeticholic acid or placebo, 93% received ursodiol as background therapy. The primary end point occurred in more patients in the 5-10-mg group (46%) and the 10-mg group (47%) than in the placebo group (10%; P<0.001 for both comparisons). Patients in the 5-10-mg group and those in the 10-mg group had greater decreases than those in the placebo group in the alkaline phosphatase level (least-squares mean, -113 and -130 U per liter, respectively, vs. -14 U per liter; P<0.001 for both comparisons) and total bilirubin level (-0.02 and -0.05 mg per deciliter [-0.3 and -0.9 μmol per liter], respectively, vs. 0.12 mg per deciliter [2.0 μmol per liter]; P<0.001 for both comparisons). Changes in noninvasive measures of liver fibrosis did not differ significantly between either treatment group and the placebo group at 12 months. Pruritus was more common with obeticholic acid than with placebo (56% of patients in the 5-10-mg group and 68% of those in the 10-mg group vs. 38% in the placebo group). The rate of serious adverse events was 16% in the 5-10-mg group, 11% in the 10-mg group, and 4% in the placebo group. CONCLUSIONS Obeticholic acid administered with ursodiol or as monotherapy for 12 months in patients with primary biliary cholangitis resulted in decreases from baseline in alkaline phosphatase and total bilirubin levels that differed significantly from the changes observed with placebo. There were more serious adverse events with obeticholic acid.

2016 - Bile salt export pump deficiency disease: Two novel, late onset, ABCB11 mutations identified by next generation sequencing [Articolo su rivista]
Vitale, Giovanni; Pirillo, Martina; Mantovani, Vilma; Marasco, Elena; Aquilano, Adelia; Gamal, Nesrine; Francalanci, Paola; Conti, Fabio; Andreone, Pietro
abstract

Progressive familial intrahepatic cholestasis (PFIC) is a heterogeneous group of autosomal recessive cholestatic diseases of childhood and represents the main indication for liver transplantation at this age; PFIC2 involves ABCB11 gene, that encodes the ATPdependent canalicular bile salt export pump (BSEP). Benign intrahepatic cholestasis (BRIC) identifies a group of diseases involving the same genes and characterized by intermittent attacks of cholestasis with no progression to liver cirrhosis. Diagnosis with standard sequencing techniques is expensive and available only at a few tertiary centers. We report the application of next generation sequencing (NGS) in the diagnosis of the familial intrahepatic cholestasis with a parallel sequencing of three causative genes. We identified the molecular defects in ABCB11 gene in two different probands who developed a severe cholestatic disease of unknown origin. In the first patient a compound heterozygosity for the novel frameshift mutation p.Ser1100GlnfsX38 and the missense variant p.Glu135Lys was detected. In the second patient, triggered by contraceptive therapy, we identified homozygosity for a novel missense variant p.Ala523Gly. In conclusion, these mutations seem to have a late onset and a less aggressive clinical impact, acting as an intermediate form between BRIC and PFIC.

2016 - Bipolar and related disorders induced by sodium 4-phenylbutyrate in a male adolescent with bile salt export pump deficiency disease [Articolo su rivista]
Vitale, Giovanni; Simonetti, Giulia; Pirillo, Martina; Taruschio, Gianfranco; Andreone, Pietro
abstract

Bile Salt Export Pump (BSEP) Deficiency disease, including Progressive Familial Intrahepatic Cholestasis type 2 (PFIC2), is a rare disease, usually leading within the first ten years to portal hypertension, liver failure, hepatocellular carcinoma. Often liver transplantation is needed. Sodium 4-phenylbutyrate (4-PB) seems to be a potential therapeutic compound for PFIC2. Psychiatric side effects in the adolescent population are little known and little studied since the drug used to treat children and infants. So we described a case of Caucasian boy, suffering from a late onset PFIC2, listed for a liver transplant when he was sixteen and treated with 4-FB (200 mg per kilogram of body weight per day). The drug was discontinued for the onset of bipolar and related disorders. This case illustrates possible psychiatric side effects of the drug.

2016 - DEVELOPMENT OF HEPATOCELLULAR CARCINOMA IN HCV CIRRHOTIC PATIENTS TREATED WITH DIRECT ACTING ANTIVIRALS [Abstract in Rivista]
Buonfiglioli, Federica; Conti, Fabio; Andreone, Pietro; Crespi, C; Foschi, Fg; Lenzi, Marco; Mazzella, Giuseppe; Verucchi, Gabriella; Brillanti, Stefano
abstract

Current all-oral interferon-free regimens offer sustained virological response (SVR) rates above 90% as well as 12-week treatment durations for the majority of patients with chronic hepatitis C virus (HCV), including treatment-naïve and -experienced patients with or without cirrhosis. There are multiple direct-acting antiviral (DAA) combinations that can be selected to optimize efficacy and safety outcomes. Each of them can be tailored according to different parameters including the use of ribarivin (RBV). For sofosbuvir (SOF)-based combinations, RBV is useful in the following situations: HCV genotype 1, treatment-experienced, cirrhotic patients, or patients with decompensated cirrhosis, and HCV genotype 3, cirrhotic patients. In these situations the addition of RBV allows to shorten the treatment to 12 weeks in the majority of cases and therefore decreases the cost of the treatment. The need of RBV remains to be determined in cirrhotic patients with a SOF plus simeprevir regimen. RBV-containing regimens are recommended in all HCV genotype 1a patients who receive the 3-DAA combination: paritaprevir/r, ombitasvir, dasabuvir. Globally, the addition of RBV to the different combinations of DAA increases slightly the risk of anaemia. However severe anaemia was rare and easily manageable with RBV dose reduction without any impact on SVR. In practice, because RBV is cheap and well tolerated when combined with interferon-free regimen, it remains a useful tool to fine tune anti-HCV treatment regimens and optimize their results.

2016 - De novo autoimmune hepatitis in liver transplant: State-of-the-art review [Articolo su rivista]
Vukotic, Ranka; Vitale, Giovanni; D'Errico, Antonietta; Muratori, Luigi; Andreone, Pietro
abstract

In the two past decades, a number of communications, case-control studies, and retrospective reports have appeared in the literature with concerns about the development of a complex set of clinical, laboratory and histological characteristics of a liver graft dysfunction that is compatible with autoimmune hepatitis. The de novo prefix was added to distinguish this entity from a pre-transplant primary autoimmune hepatitis, but the globally accepted criteria for the diagnosis of autoimmune hepatitis have been adopted in the diagnostic algorithm. Indeed, de novo autoimmune hepatitis is characterized by the typical liver necroinflammation that is rich in plasma cells, the presence of interface hepatitis and the consequent laboratory findings of elevations in liver enzymes, increases in serum gamma globulin and the appearance of nonorgan specific auto-antibodies. Still, the overall features of de novo autoimmune hepatitis appear not to be attributable to a univocal patho-physiological pathway because they can develop in the patients who have undergone liver transplantation due to different etiologies. Specifically, in subjects with hepatitis C virus recurrence, an interferon-containing antiviral treatment has been indicated as a potential inception of immune system derangement. Herein, we attempt to review the currently available knowledge about de novo liver autoimmunity and its clinical management.

2016 - Direct acting antivirals for the treatment of elderly patients with HCV advanced disease in the real life practice [Abstract in Rivista]
Conti, F.; Scuteri, Alessandra; Vitale, G.; Lazzarini, G.; Porro, A.; Muratori, P.; Serio, Ilaria; Buonfiglioli, Federica; Badia, L.; Lanzi, A.; Mastroroberto, Marianna; Appolloni, L.; Morotti, Marta; Morelli, M. C.; Foschi, F. G.; Verucchi, Gabriella; Brillanti, Stefano; Crespi, C.; Lenzi, M.; Mazzella, Giuseppe; Andreone, P.
abstract

Introduction: The availability of interferon-sparing therapy with direct acting antivirals (DAAs) has expanded the pool of patients eligible for treatment. Despite this, data on the efficacy and safety of these treatments in elderly are lacking. Aim: To evaluate the efficacy and safety of the treatment with DAA-based regimens in HCV patients aged ≥65 years with advanced fibrosis/cirrhosis in a real life clinical setting. Methods: Retrospective data of elderly patients treated with DAAs from January to November 2015 in 7 tertiary referral center of Emilia-Romagna Region (Italy) were collected. Patients received: sofosbuvir (SOF) [n = 35], SOF + simeprevir (SMV) [n = 78], SOF + daclatasvir (DCV) [n = 21], SOF + ledipasvir [n = 17], SMV + DCV [n = 4], ombitasvir/paritaprevir/ritonavir only [n = 3] or with dasasbuvir [n = 42]. Ribavirin was added at the physician's discretion according weight. The primary efficacy endpoint was sustained virological response 12 weeks after the last dose of study drug (SVR12). Results: Overall, 200 consecutive elderly patients were treated. The median age was 74 years (range: 65-85) and 90 (45%) aged ≥75 years; 49% were male, 50.5% were treatment experienced and 85% had cirrhosis. The majority (76%) had genotype (GT) 1b. To date, 155 patients completed treatment. Two cirrhotics died during the therapy and were excluded from final analysis because the cause of death was unrelated to the treatment. Overall, 94 have reached week 12 of post-treatment and the SVR12 was 91.5% (86/94). According to GT, the SVR12 was achieved in 69/73 (94.5%) with GT1, in 16/18 (88.9%) with GT2 and in 1/3 (33.4%) with GT4 infection. Relapse occurred more commonly in cirrhotic patients. No serious adverse events have been reported until now. Complete safety data for the cohort and updated SVR data will be presented. Conclusions: This preliminary data indicate that DAA-based regimen have a similar efficacy compared to registrative studies and without significant side effects in HCV elderly patients in a real-world setting.

2016 - Early occurrence and recurrence of hepatocellular carcinoma in HCV-related cirrhosis treated with direct-acting antivirals [Articolo su rivista]
Conti, Fabio; Buonfiglioli, Federica; Scuteri, Alessandra; Crespi, Cristina; Bolondi, Luigi; Caraceni, Paolo; Foschi, Francesco Giuseppe; Lenzi, Marco; Mazzella, Giuseppe; Verucchi, Gabriella; Andreone, Pietro; Brillanti, Stefano
abstract

Background & Aims Hepatocellular carcinoma (HCC) represents a serious complication of HCV-related cirrhosis. New direct-acting antivirals (DAA) cure HCV infection in over 90% of patients. The aim of this study was to evaluate the early occurrence and recurrence of HCC in cirrhotic patients treated with DAA. Methods We analysed 344 consecutive cirrhotic patients, without HCC, who were treated with DAA, and followed for 24 weeks. Fifty-nine patients had previous HCC. Results DAA therapy induced sustained virological response in 91% of patients. During 24-week follow-up, HCC was detected in 26 patients (7.6%, 95% CI: 4.99–10.84): 17 of 59 patients (28.81%, 95% CI: 17.76–42.07) with previous HCC and 9 of 285 patients (3.16%, 95% CI: 1.45–5.90) without previous HCC. Child-Pugh Class B, more severe liver fibrosis, lower platelet count, and previous HCC were significantly associated with HCC development, at univariate analysis. At multivariate analysis, Child-Pugh class (p = 0.03, OR: 4.18, 95% CI: 1.17–14.8) and history of HCC (p <0.0001, OR: 12.0, 95% CI: 4.02–35.74) resulted independently associated with HCC development. Among the 59 patients with previous HCC, younger age and more severe liver fibrosis were significantly associated with HCC recurrence, both at univariate and at multivariate analysis. Conclusions In patients with HCV-related cirrhosis, DAA-induced resolution of HCV infection does not seem to reduce occurrence of HCC, and patients previously treated for HCC have still a high risk of tumour recurrence, in the short term. For these reasons, all cirrhotic patients should be closely monitored and followed during and after antiviral therapy. Lay summary New direct-acting antivirals are able to eradicate HCV infection in over 90% of patients with advanced liver disease. Unfortunately, the occurrence of liver cancer is not reduced in effectively treated cirrhotic patients. In addition, patients previously treated for HCC have still a high risk of tumour recurrence in the short term, despite DAA treatment.

2016 - Efficacy and Safety of Daclatasvir in Hepatitis C: An Overview [Articolo su rivista]
Gamal, Nesrine; Gitto, Stefano; Andreone, Pietro
abstract

Hepatitis C virus (HCV) infection is a growing public health concern, with 184 million people infected worldwide. During the past decade, interferon has been the backbone of HCV treatment, even though it remains far from ideal. The latest development of the new direct antivirals has drastically changed the treatment approach for chronic hepatitis C (CHC). Inhibitors of the HCV NS5A region have garnered remarkable interest among treating physicians, due to their high potency and favourable safety profile. In particular, treatment with daclatasvir (DCV) has yielded high rates of vriologic response in patients infected with genotype (Gt) 1 and Gt 3, when used in combination with other antivirals of a different class, such as sofosbuvir. Although few data are available for DCV treatment of the other Gts, the results in patients with Gt 2 and Gt 4 infection appear promising, as do those for unique patient populations. NS5A-resistant viral variants can pre-exist or emerge after treatment failure for the HCV NS5A inhibitors. Nonetheless, DCV-resistant viral variants continue to be sensitive to interferon and other classes of antivirals such as NS3/4A and NS5B inhibitors. Herein, we aimed to provide an overview of the current knowledge about DCV in the treatment of CHC.

2016 - From current status to optimization of HCV treatment: Recommendations from an expert panel [Articolo su rivista]
Craxì, Antonio; Perno, Carlo Federico; Viganò, Mauro; Ceccherini-Silberstein, Francesca; Petta, Salvatore; Aghemo, Alessio; Alberti, Alfredo; Andreone, Pietro; Andreoni, Massimo; Bonora, Stefano; Brunetto, Maurizia Rossana; Bruno, Savino; Caporaso, Nicola; Chirianni, Antonio; Ciancio, Alessia; Degasperi, Elisabetta; Di Perri, Giovanni; Fagiuoli, Stefano; Ferrari, Carlo; Gaeta, Giovanni Battista; Pellicelli, Adriano; Puoti, Massimo; Raimondo, Giovanni; Taliani, Gloria; Villa, Erica; Zignego, Anna Linda
abstract

Chronic hepatitis C virus (HCV) infection is a major public health problem at a global level, causing an enormous burden of hepatic and extra-hepatic morbidity and mortality. Treatment of chronic HCV (CHC) has been revolutionized in the last few years by the introduction of highly effective and well tolerated direct acting antiviral agents (DAAs) able to achieve >90% rates of sustained virological response (SVR) in many groups of patients, including those previously excluded from interferon-based regimens. For such reason interferon-free regimens are now the treatments of choice for all patients. Successful anti-HCV treatment can stop liver disease progression and can solve the HCV-related extra hepatic manifestations, eventually reducing both liver-related and overall mortality. Together with the rapidly accumulating data about the evolution of treatment landscape, different guidelines from national and international Liver Scientific Societies have been published until today. However, these recommendations may not be applied worldwide as, due to high treatment costs, most of them identify as priority groups only patients with advanced liver disease. Moreover some types of patients pose clinical management problems for which even the guidelines do not always provide useful answers. With the aim of treatment optimization by filling some of the gaps of the current guidelines and addressing the remaining unmet needs in practice, a group of Italian experts, experienced on treatment of HCV infection, met in Stresa in February 2016. The summary of all the considerations arising from this two-day meeting and the final statements are reported in this position paper.

2016 - Grazoprevir/elbasvir fixed-dose combination for hepatitis C [Articolo su rivista]
Abdelall, NESRINE GAMAL MOHAMED; Andreone, Pietro
abstract

Hepatitis C virus (HCV) infection is an increasing public health concern with an estimated 184 million people infected worldwide and approximately 350,000 deaths yearly from HCV-related complications. There is a compelling medical need for new anti-HCV therapeutic agents that are potent, tolerable, safe, completely oral and with shorter treatment duration. To this end, a plethora of direct-acting antivirals have been developed and regulatory authorities have approved nine new molecules for the treatment of chronic hepatitis C (CHC). In January 2016, the U.S. Food and Drug Administration approved the fixed-dose combination medication incorporating the NS3/NS4A inhibitor grazoprevir (formerly MK-5172) and the NS5A inhibitor elbasvir (formerly MK-8742), with or without ribavirin, for the treatment of CHC genotypes 1 and 4 infection in adult patients. This all-oral combination has proven potent and safe even in patients with advanced kidney disease. Herein, we review the pharmacokinetics, clinical efficacy and safety profile pertaining to grazoprevir/elbasvir fixed-dose combination for CHC.

2016 - HBsAg kinetics in chronic hepatitis D during interferon therapy: On-treatment prediction of response [Articolo su rivista]
Niro, G. A; Smedile, A.; Fontana, R.; Olivero, A.; Ciancio, A.; Valvano, M. R.; Pittaluga, F.; Coppola, N.; Wedemeyer, H.; Zachou, K.; Marrone, A.; Fasano, M.; Lotti, G.; Andreone, Pietro; Iacobellis, A.; Andriulli, A.; Rizzetto, M.
abstract

Summary: Background: Therapy of chronic hepatitis D with Interferon is successful when testing for HDV-RNA turns negative. This end-point is disputed. Aim: To assess the role of serum hepatitis B surface antigen (HBsAg) in the clearance of HDV-RNA in pegylated interferon (Peg-IFN)-treated chronic hepatitis D (CHD). Methods: Sixty-two patients with CHD, treated with Peg-IFN, were considered. The patients belonged to three groups: 14 patients cleared the HBsAg and HDV-RNA (responders, R), 12 cleared the HDV-RNA remaining positive for HBsAg (partial responders, PR) and 36 cleared neither the HBsAg nor the HDV-RNA (nonresponders, NR). Results: In responders, at baseline the median value (mv) of HBsAg and HDV-RNA was 1187 and 188 663 IU/mL. By month 6 of therapy, HBsAg declined to less than 1000 IU/mL and HDV-RNA was undetectable in 12 patients. In NR, the pre-therapy median value of HBsAg and HDV viremia was 6577 and 676 319 IU/mL. There was no significant reduction of antigen at month 6; after a decline, HDV-RNA rebounded to baseline levels. In PR, the median value of baseline HBsAg was 7031 IU/mL; it declined at month 6 in the majority. HDV-RNA progressively declined from an initial median value of 171 405 IU/mL. HBsAg <1000 IU/mL at month 6 discriminated responders and PR from NR (P < 0.001). By ROC curve, the threshold of 0.105 log reduction of HBsAg associated with 1.610 log reduction of HDV-RNA from baseline to month 6 predicted the clearance of this marker. Conclusions: A reduction of serum HBsAg is mandatory for the definitive clearance of the HDV-RNA. Quantitative HBsAg may predict the long-term response to Peg-IFN therapy and provide a guide to prolong or stop treatment.

2016 - Hcverso1 and 2: Faldaprevir with deleobuvir (BI 207127) and ribavirin for treatment-naïve patients with chronic hepatitis C virus genotype-1b infection [Articolo su rivista]
Sarrazin, Christoph; Castelli, Francesco; Andreone, Pietro; Buti, Maria; Colombo, Massimo; Pol, Stanislas; Calinas, Filipe; Puoti, Massimo; Olveira, Antonio; Shiffman, Mitchell; Stern, Jerry O.; Kukolj, George; Roehrle, Michael; Aslanyan, Stella; Deng, Qiqi; Vinisko, Richard; Mensa, Federico J.; Nelson, David R.
abstract

The interferon-free combination of once-daily faldaprevir 120 mg, twice-daily deleobuvir 600 mg, and weight-based ribavirin was evaluated in two Phase III studies (HCVerso1, HCVerso2) in hepatitis C virus genotype-1b-infected, treatment-naïve patients, including those ineligible for peginterferon (HCVerso2). Patients without cirrhosis were randomized to 16 weeks (Arm 1; n=208 HCVerso1, n=213 HCVerso2) or 24 weeks (Arm 2; n=211 in both studies) of faldaprevir + deleobuvir + ribavirin. Patients with compensated cirrhosis received open-label faldaprevir + deleobuvir + ribavirin for 24 weeks (Arm 3; n=51, n=72). Primary endpoints were comparisons of adjusted sustained virologic response (SVR) rates with historical rates: 71% (HCVerso1) and 68% (HCVerso2). Adjusted SVR12 rates were significantly greater than historical controls for Arms 1 and 2 in HCVerso2 (76%, 95% confidence interval [CI] 71–81, P=0.002; 81%, 95% CI 76–86, P<0.0001) and Arm 2 in HCVerso1 (81%, 95% CI 77–86, P<0.0001), but not for Arm 1 of HCVerso1 (72%, 95% CI 66–77, P=0.3989). Unadjusted SVR12 rates in Arms 1, 2, and 3 were 71.6%, 82.5%, and 72.5%, respectively, in HCVerso1 and 75.6%, 82.0%, and 73.6%, respectively, in HCVerso2. Virologic breakthrough and relapse occurred in 24-week arms in 8%–9% and 1% of patients, respectively, and in 16-week arms in 7%–8% and 9%–11% of patients, respectively. The most common adverse events were nausea (46%–61%) and vomiting (29%–35%). Adverse events resulted in discontinuation of all medications in 6%–8% of patients. In treatmentnaïve patients with hepatitis C virus genotype-1b infection, with or without cirrhosis, faldaprevir + deleobuvir + ribavirin treatment for 24 weeks resulted in adjusted SVR12 rates significantly higher than historical controls. Both studies were registered in ClinicalTrials. gov (NCT01732796, NCT01728324).

2016 - Imaging Features of Microvascular Invasion in Hepatocellular Carcinoma Developed in HCV-Related Cirrhosis after Direct-Acting Antiviral Therapy [Abstract in Rivista]
Renzulli, Matteo; Buonfiglioli, Federica; Brocchi, Stefano; Conti, Fabio; Serio, Ilaria; Caraceni, Paolo; Foschi Francesco, G; Mazzella, Giuseppe; Verucchi, Gabriella; Andreone, Pietro; Golfieri, Rita; Brillanti, Stefano.
abstract

2016 - Insights into cancer severity from biomolecular interaction mechanisms [Articolo su rivista]
Raimondi, Francesco; Singh, Gurdeep; Betts, Matthew J.; Apic, Gordana; Vukotic, Ranka; Andreone, Pietro; Stein, Lincoln; Russell, Robert B.
abstract

To attain a deeper understanding of diseases like cancer, it is critical to couple genetics with biomolecular mechanisms. High-throughput sequencing has identified thousands of somatic mutations across dozens of cancers, and there is a pressing need to identify the few that are pathologically relevant. Here we use protein structure and interaction data to interrogate nonsynonymous somatic cancer mutations, identifying a set of 213 molecular interfaces (protein-protein, -small molecule or -nucleic acid) most often perturbed in cancer, highlighting several potentially novel cancer genes. Over half of these interfaces involve protein-small-molecule interactions highlighting their overall importance in cancer. We found distinct differences in the predominance of perturbed interfaces between cancers and histological subtypes and presence or absence of certain interfaces appears to correlate with cancer severity.

2016 - Liver Stiffness improvement in subjects with advanced chronic hepatitis C treated with direct antiviral agents [Abstract in Rivista]
Gamal, N.; Conti, F.; Mastroroberto, Marianna; Scuteri, A.; Cursaro, C.; Guarneri, Valeria; DI DONATO, Roberto; Vitale, G.; Andreone, Pietro
abstract

2016 - Liver grafts from hepatitis B surface antigen-positive donors: A review of the literature [Articolo su rivista]
Loggi, Elisabetta; Conti, Fabio; Cucchetti, Alessandro; Ercolani, Giorgio; Pinna, ANTONIO DANIELE; Andreone, Pietro
abstract

The scarcity of available organs and the gap between supply and demand continue to be the main limitations of liver transplantation. To relieve the organ shortage, current transplant strategies have implemented extended criteria, which include the use of liver from patients with signs of past or present hepatitis B virus (HBV) infection. While the use of liver grafts from donors with evidence of past HBV infection is quite limited, some data have been collected regarding the feasibility of transplanting a liver graft from a hepatitis B surface antigen (HBsAg) positive donor. The aim of the present work was to review the literature regarding liver transplants from HBsAg-positive donors. A total of 17 studies were identified by a search in Medline. To date, HBsAg positive grafts have preferentially been allocated to HBsAg positive recipients. The large majority of these patients continue to be HBsAg positive despite the use of immunoglobulin, and infection prevention can only be guaranteed by using antiviral prophylaxis. Although serological persistence is evident, no significant HBV-related disease has been observed, except in patients coinfected with delta virus. Consistently less data are available for HBsAg negative recipients, although they are mostly promising. HBsAg-positive grafts could be an additional organ source for liver transplantation, provided that the risk of reinfection/reactivation is properly prevented.

2016 - Missed treatment in an Italian HBV infected patients cohort: HBV RER [Articolo su rivista]
Cuomo, Gianluca; Borghi, Vanni; Andreone, Pietro; Massari, Marco; Villa, Erica; Pietrangelo, Antonello; Verucchi, Gabriella; Ferrari, Carlo
abstract

Very little is known about the access to treatment for Chronic Hepatitis B in the real clinical practice and the characteristics of the patients who do not receive antiviral therapy.

2016 - Multidisciplinary View of Alcohol Use Disorder: From a Psychiatric Illness to a Major Liver Disease [Articolo su rivista]
Gitto, Stefano; Golfieri, Lucia; Caputo, Fabio; Grandi, Silvana; Andreone, Pietro
abstract

Alcohol use disorder is a significant health problem being a cause of increased morbidity and mortality worldwide. Alcohol-related illness has a relevant economic impact on the society and a negative influence on the life of patients and their family members. Psychosocial support might be useful in the management of people affected by alcohol use disorder since psychiatric and pharmaceutical approaches show some limits. In fact, many drugs are accessible for the treatment of alcohol disorder, but only Baclofen is functional as an anti-craving drug in patients with advanced liver disease. The alcohol-related liver damage represents the most frequent cause of advanced liver disease in Europe, and it is the main cause of death among adults with high alcohol consumption. The multidisciplinary action of clinical-psychologists, psychiatrics and hepatologists, is essential in the management of patients with alcohol liver disease especially in the case of liver transplantation. In general, the multidisciplinary approach is necessary in prevention, in framing patients and in the treatment. More resources should be used in prevention and research with the main aim of decreasing the harmful alcohol consumption.

2016 - Non-alcoholic steatohepatitis and liver transplantation [Articolo su rivista]
Gitto, Stefano; Vukotic, Ranka; Vitale, Giovanni; Pirillo, Martina; Villa, Erica; Andreone, Pietro
abstract

Non-alcoholic steatohepatitis is a growing liver-related health problem. In Europe, non-alcoholic fatty liver disease is the most usual reason of chronic liver illness while steatohepatitis, its progressive form, affects 1% of Europeans and North Americans. In the United States steatohepatitis-related cirrhosis is one of the main indications for liver transplant. A targeted stratification for patients waiting for transplant and affected by this disease is mandatory especially because of their increased cardiovascular and cancer risk. The adequate treatment of NAFLD is crucial for the reduction of the disease related morbidity and mortality. In post-transplant setting, the recurrent or de novo steatosis might seriously affect the allograft short- and long-term outcome. Many conditions can represent the basis of the post-transplant steatohepatitis: obesity, hyperlipidaemia, diabetes mellitus, arterial hypertension, immunosuppressant treatment, alcoholic habit and liver graft steatosis. Today, the only consolidated therapy is represented by a deep life-style intervention since the use of drug-based alternative strategies is still limited and a very few data are available for the post-transplant period. Targeted and personalized behaviour and pharmacological interventions have to be developed for both the pre- and post-transplant phase.

2016 - Safety and efficacy of once daily ledipasvir/sofosbuvir fixed-dose combination in patients with chronic hepatitis C [Articolo su rivista]
Abdelall, NESRINE GAMAL MOHAMED; Andreone, Pietro
abstract

Introduction: During the past couple of years, the regulatory authorities have approved seven new direct-acting antivirals (DAAs) for the treatment of chronic hepatitis C (CHC). In 2014, the US FDA approved the fixed dose combination of ledipasvir (LDV) plus sofosbuvir (SOF) for the treatment of genotype (GT) 1 HCV and the European Commission Granted its marketing authorization to treat patients with GT1 and 4. This regimen showed outstanding rates of virologic response along with a favorable safety profile with a very low rate of both virologic failure and treatment discontinuation.Areas covered: In this review, we sought to review the pharmacokinetics, clinical efficacy and safety profile pertaining to LDV/SOF combination in treatment of CHC with special emphasis on phase III clinical trials.Expert opinion: In all phase III trials, the 12-week course of this new interferon (IFN)-sparing regimen has delivered high virologic cure rates among patient with GT1 and 4 both treatment-naïve and - experienced Data about its effectiveness in patients under 18 years of age, end-stage renal disease and patients with significant other organ involvement are eagerly awaited.

2016 - Tenofovir-induced Fanconi syndrome in a patient with chronic hepatitis B monoinfection [Articolo su rivista]
Conti, Fabio; Vitale, Giovanni; Cursaro, C; Bernardi, Mauro; Andreone, Pietro
abstract

Tenofovir disoproxil fumarate (TDF) is a nucleotide reverse transcriptase inhibitor indicated for treatment of patients with chronic hepatitis B virus (CHB) and human immunodeficiency virus (HIV) infections. Despite the good safety profile of the drug, Fanconi syndrome is a possible adverse reaction of TDF treatment, especially in HIV-infected patients. Only a few cases have been reported in patients with CHB-monoinfections. This report presents a case of a 58-year-old man with mild HBeAg-negative CHB who was exposed to TDF and developed drug-induced Fanconi syndrome. Renal dysfunction reverted after TDF discontinuation and a switch to entecavir, and viral replication remained suppressed. A literature review yielded six additional cases of TDF-induced Fanconi syndrome, all with risk factors for renal dysfunction despite the patients having normal glomerular filtration rates. We discuss the overall risk for Fanconi syndrome in CHB-monoinfected patients exposed to TDF and the importance of careful monitoring of glomerular and tubular functions even when pre-existing kidney disease is not present.

2016 - Transient elastography in healthy subjects and factors influencing liver stiffness in non-alcoholi fatty liver disease: an Italian community-based population study [Articolo su rivista]
Conti, F; Vukotic, R; Foschi, Fg; Domenicali, M; Giacomoni, G; Savini, S; Lanzi, A; Dall’Aglio, Ac; Saini, G; Matroroberto, M; Bernardi, M; Stefanini, Gf; Andreone, P
abstract

BACKGROUND: Few studies have been performed to explore parameters that influence liver stiffness measurement (LSM) using transient elastography in general population. AIM: To explore factors influencing LSM in healthy and in subjects with non-alcoholic fatty liver disease (NAFLD). METHODS: LSM was performed in a well-characterized cohort of subjects aged between 30 and 63 years. After exclusion of any causes of liver disease, the healthy cohort was defined and was compared with participants with NAFLD. The 95th percentile value of LSM in healthy was used as a cutoff suggesting relevant fibrosis. RESULTS: Among 780 subjects evaluated, 331 were defined as healthy. The median value was 4.4kPa (3.7-5.2) and the 95th percentile was 6.8kPa. LSM was not influenced by gender, age, anthropometrics and biochemical parameters. Only insulin resistance was independently associated with increasing of LSM. In the cohort of 157 subjects with NAFLD, LSM was higher than in healthy (5.6±1.9 vs 4.6±1.3kPa; p<0.001). On multivariate analysis, the degree of steatosis was independently associated with increasing of LSM in NAFLD cohort (β=0.271; 95% CI=0.026-0.095; p<0.001). Participants with diabetes and/or severe steatosis had the highest probabilities of relevant fibrosis. CONCLUSIONS: LSM varies between 3.7 and 5.2kPa in healthy Caucasians and is influenced only by insulin resistance. In NAFLD, severe steatosis and diabetes are factors influencing LSM.

2016 - Treatment with direct acting antiviral agents-based regimen in HCV patients with advanced liver disease: Analysis of an Italian multicenter observational study [Abstract in Rivista]
Conti, F.; Scuteri, Alessandra; DI DONATO, Roberto; Lazzarini, G.; Porro, A.; Muratori, P.; Serio, Ilaria; Buonfiglioli, Federica; Badia, L.; Lanzi, A.; Mastroroberto, Marianna; Appolloni, L.; Morotti, Marta; Morelli, M. C.; Foschi, F. G.; Verucchi, Gabriella; Brillanti, Stefano; Crespi, C.; Lenzi, M.; Mazzella, Giuseppe; Andreone, P.
abstract

Introduction: Non-interferon-based therapy with direct acting antiviral agents (DAA) have become an integral component of treatment for HCV infection but little is known about their real-world effectiveness. Aim: To evaluate the efficacy and safety of the treatment with DAA-based regimen in HCV patients with advanced fibrosis/cirrhosis in a real life clinical setting. Methods: Retrospective data of patients treated with DAA from January to November 2015 in 7 tertiary referral centers in the Emilia-Romagna Region (Italy) were collected. Patients on the waiting list for orthotopic liver transplantation and with HIV co-infection were excluded. Patients received: sofosbuvir (SOF) [n = 74], SOF + simeprevir (SMV) [n = 149], SOF + daclatasvir (DCV) [n = 69], SOF + ledipasvir [n = 43], SMV + DCV [n = 4], ombitasvir/paritaprevir/ritonavir only [n = 11] or with dasasbuvir [n = 84]. Ribavirin was added at the physician's discretion according to weight. The primary efficacy endpoint was sustained virological response 12 weeks after the last dose of study drug (SVR12). Results: Overall, 435 consecutive patients were treated. The median age was 63 years (range: 29–85); 60% were male, 55.2% were treatment experienced and 81.1% had cirrhosis. The majority (56.6%) had genotype (GT) 1b, 12.4% GT1a, 11.3% GT2, 12.6% GT3 and 7.1% GT4. To date, 347 patients completed treatment and 179 the week 12 of post-treatment follow-up. Three cirrhotics died during treatment and were excluded from analysis. Overall, the SVR12 was 88.8% (159/179). According to GT, the SVR12 was achieved in 17/19 (89.5%) GT1a, in 100/111 (90.1%) GT1b, in 24/26 (92.3%) GT2, in 9/11 (81.8%) GT3 and in 9/12 (75%) GT4. Patients with cirrhosis had a lower response rate than those with advanced fibrosis (86.7% vs 97.2%; p = 0.082). Complete safety data for the entire cohort, updated SVR12 will be presented. Conclusions: The DAA-based regimen was efficacious with low relapse rates in HCV patients in a real-world setting. Patients with cirrhosis seems to respond less well to the different regimens used.

2015 - A new approach to the use of α-fetoprotein as surveillance test for hepatocellular carcinoma in patients with cirrhosis [Articolo su rivista]
Biselli, M; Conti, F; Gramenzi, A; Frigerio, M; Cucchetti, A; Fatti, A; D'Angelo, M; Dall'Agata, M; Giannini, Eg; Farinati, F; Ciccarese, F; Andreone, P; Bernardi, M; Trevisani, F.
abstract

Background: Surveillance for hepatocellular carcinoma (HCC) is recommended in patients with cirrhosis. As a-fetoprotein (AFP) is considered a poor surveillance test, we tested the performance of its changes over time. Methods: Eighty patients were diagnosed with HCC (cases) during semiannual surveillance with ultrasonography and AFP measurement were recruited and matched for age, gender, etiology and Child-Pugh class with 160 contemporary cancer-free controls undergoing the same surveillance training group (TG). As a validation group (VG) we considered 36 subsequent patients diagnosed with HCC, matched 1:3 with contemporary cancer-free controls. a-Fetoprotein values at the time of HCC diagnosis (T0) and its changes over the 12 (D12) and 6 months (D6) before cancer detection were considered. Results: In both TG and VG, > 80% of HCCs were found at an early stage. In TG, AFP significantly increased over time only in cases. T0 AFP and a positive D6 were independently associated with HCC diagnosis (odds ratio: 1.031 and 2.402, respectively). The area under the curve of T0 AFP was 0.76 and its best cutoff (BC) was 10ngml (sensitivity 66.3%, specificity 80.6%). The combination of AFP > 10ngml or a positive D6 composite a-fetoprotein index (CAI) increased the sensitivity to 80% with a negative predictive value (NPV) of 86.2%. Negative predictive value rose to 99%, considering a cancer prevalence of 3%. In the VG, the AFP-BC was again 10ngml (sensitivity 66.7%, specificity 88.9%), and CAI sensitivity was 80.6% with a NPV value of 90.5%. Conclusions: CAI achieves adequate sensitivity and NPV as a surveillance test for the early detection of HCC in cirrhosi

2015 - A new prognostic model to predict dropout from the waiting list in cirrhotic candidates for liver transplantation with MELD score <18. [Articolo su rivista]
Biselli, M; Dall'Agata, M; Gramenzi, A; Gitto, S; Liberati, C; Brodosi, L; Ravaioli, M; Gambato, M; Montalti, R; Pinna, Antonio Daniele; Burra, P; Gerunda, Giorgio Enrico; Cillo, U; Andreone, P; Bernardi, Mauro
abstract

BACKGROUND & AIMS: The model for end-stage liver disease (MELD) is used for organ allocation in liver transplantation (LT), but its prognostic performance is less accurate in patients with low score. We assess the outcome of patients with MELD < 18 awaiting LT, finding prognostic variables to identify a high dropout risk. METHODS: Training set consisted of 277 patients and validation cohort of 292 patients. Competing risk regression analysis, taking into account LT, was used for univariate/multivariate analysis. RESULTS: Ascites, sodium, bilirubin, albumin and glomerular filtration rate were independently associated with a 12-month dropout risk in the training set. Combining these five prognostic parameters, we calculated a new score named liver-renal-risk (LIRER). In the validation set, the 12-month LIRER concordance index showed a discrimination power [0.798, 95% confidence interval (95% CI) 0.793-0.803] better than MELD (0.582, 95% CI 0.575-0.588), Child-Turcotte-Pugh (0.687, 95% CI 0.681-0.693), MELD-sodium (0.721, 95% CI 0.715-0.727) and MELD-ascites-sodium (0.729, 95% CI 0.724-0.735), with a remarkable calibration (Hosmer-Lemeshow test: P = 0.91; R(2) = 0.911). Considering all study patients, the risk of wait list dropout increased with the rise in LIRER. The survival benefit analysis comparing the wait list dropout risk with the mortality of the 216 transplanted patients with same LIRER showed an important benefit for LT in patients with LIRER > 15.9. CONCLUSIONS: In patients with low MELD (<18), combination of ascites, sodium, albumin, bilirubin and renal function in a new score (LIRER) discriminates patients at high risk of medium-term adverse outcome from those in whom LT may be safely deferred.

2015 - ABT-450: A novel agent for the treatment of CHC genotype 1: Focus on treatment-experienced patients [Articolo su rivista]
Abdelall, Nesrine Gamal Mohamad; Vitale, Giovanni; Andreone, Pietro
abstract

Chronic hepatitis C (CHC) constitutes a major health concern. Hepatitis C virus eradication by antiviral treatment can markedly reduce the risk of developing cirrhosis, hepatocellular carcinoma and liver-related death. A plethora of new direct antiviral agents have been developed and are being explored in clinical trials. One of the newest members of this family is the NS3/4A protease inhibitor ABT-450. The multi-targeted approach combining ritonavir-enhanced ABT-450 with ombitasvir and dasabuvir has been evaluated for the treatment of CHC Gt1 in treatment-naïve and treatment-experienced adults. In this article, we sought to discuss the current knowledge on ABT-450-containing regimens, with special emphasis on treatment-experienced CHC Gt1 patients. This new combination was found to be potent, safe and well tolerated. Future Phase III trials with larger sample size in patients with decompensated cirrhosis, non-Gt1, end-stage renal disease and liver transplant recipients are eagerly awaited.

2015 - Chronic hepatitis B: Are we close to a cure? [Articolo su rivista]
E, Loggi; Vitale, Giovanni; Conti, Fabio; Bernardi, Mauro; Andreone, Pietro
abstract

Approximately 300 million people worldwide are persistently infected with the hepatitis B virus and are at risk of developing hepatocellular carcinoma and liver cirrhosis, which can progress to end-stage liver disease. Despite the effectiveness of the current vaccination policy, the prevalence of the disease remains high, and the burden for health services is considerable. The currently available antiviral strategies are either poorly effective or only effective for non-curative suppression of viral replication. Recent efforts have been focused on improving the cure rate for chronic hepatitis B and developing strategies to eliminate infected cells. Several approaches are under evaluation, and these include targeting the virus at different stages of its life cycle and boosting the antiviral immune response. This article reviews these latest approaches and comments on their feasibility and potential translation into clinical applications.

2015 - DAUPHINE: a randomized phase II study of danoprevir/ritonavir plus peginterferon alpha-2a/ribavirin in HCV genotypes 1 or 4 [Articolo su rivista]
Everson, G; Cooper, C; Hézode, C; Shiffman, Ml; Yoshida, E; Beltran-Jaramillo, T; Andreone, P; Bruno, S; Ferenci, P; Zeuzem, S; Brunda, M; Le Pogam, S; Nájera, I; Zhou, J; Navarro, Mt; Voulgari, A; Shulman, Ns; Yetzer, Es
abstract

Danoprevir is a hepatitis C virus (HCV) protease inhibitor with activity against genotypes (G)1/G4, which is maintained at lower doses by ritonavir-boosting. We report results of a large, randomized, active-controlled phase IIb study of ritonavir-boosted danoprevir (danoprevir/r) plus peginterferon alpha-2a/ribavirin (P/R) in treatment-naive patients with HCV G1/4 infection. METHODS: Treatment-naive patients with HCV G1/4 infection were randomized to twice-daily danoprevir/r 200/100 mg (A, n = 92); 100/100 mg (B, n = 93); or 50/100 mg (C, n = 94) plus P/R for 24 weeks; twice-daily danoprevir/r 100/100 mg (D, n = 94) plus P/R for 12 or 24 weeks; or P/R alone (E, n = 44) for 48 weeks. Patients in the response-guided therapy arm (D) with an extended rapid virological response (eRVR2: HCV RNA <15 IU/ml during Weeks 2-10) stopped all therapy at Week 12; non-eRVR2 patients continued all treatment to Week 24. The primary efficacy endpoint was sustained the virological response (SVR24: HCV RNA <15 IU/ml after 24 weeks of untreated follow-up). RESULTS: SVR24 rates in Arms A, B, C, D and E were 89.1%, 78.5%, 66.0%, 69.1% and 36.4%, respectively, in the overall population; 83.6%, 69.6%, 60.3%, 59.2% and 38.5% in G1a-infected patients, 96.6%, 93.1%, 73.1%, 78.4% and 28.6% in G1b-infected patients and 100%, 87.5%, 100%, 100% and 66.7% in G4-infected patients. Danoprevir/r plus P/R was generally well tolerated compared with P/R alone. There was a higher incidence of serious adverse events in danoprevir-treatment arms, but most were associated with P/R. CONCLUSIONS: The combination of danoprevir/r plus P/R is efficacious in treatment-naïve patients with HCV genotype 1 or 4 infection.

2015 - DIAGNOSTIC ACCURACY OF LIVER AND SPLEEN STIFFNESS MEASUREMENT FOR PORTAL HYPERTENSION USING BIDIMENSIONAL SHEAR WEAVE ELASTOGRAPHY [Abstract in Rivista]
Stefanescu, HORIA OCTAVIAN; Procopet, B.; Allegretti, Giulia; Berzigotti, A.; Gamal, N.; Conti, Fabio; Festi, Davide; Andreone, Pietro; Bolondi, Luigi; Bosch, J.; Piscaglia, Fabio
abstract

2015 - Deregulation of microRNA expression in peripheral blood mononuclear cells from patients with HCV-related malignancies [Articolo su rivista]
Piluso, Alessia; Gragnani, Laura; Fognani, Elisa; Grandini, Elena; Monti, Monica; Stasi, Cristina; Loggi, Elisabetta; Margotti, Marzia; Conti, Fabio; Andreone, Pietro; Zignego Anna, Linda
abstract

Background and aim: Hepatocellular carcinoma is one of the major causes of death due to cancer worldwide, and its association with hepatitis C virus infection has been definitively established. Hepatitis C virus is also involved in the pathogenesis of non-Hodgkin’s lymphoma. This is the only virus infecting humans that is able to induce two different malignancies. We analyzed the expression levels of a panel of microRNA in peripheral blood mononuclear cells of patients with hepatitis C virus-related malignancies in order to find a disease-associated deregulation and identify specific biomarkers. Methods: We tested peripheral blood mononuclear cells isolated from patients with hepatocellular carcinoma, non-Hodgkin’s lymphoma, hepatitis C virus without malignancies and healthy subjects for a panel of microRNA selected on the basis of previous studies. MicroRNA expression was evaluated by real-time PCR. Results: Our results showed an upregulation of miRNA-21 and downregulation of miRNA-26b in hepatocellular carcinoma and non-Hodgkin’s lymphoma patients compared to controls (p < 0.001). Deregulation of miRNA-16 and miRNA-155 was limited to lymphoma patients. Conclusions: This study shows that some microRNAs are differently expressed in peripheral blood mononuclear cells from hepatitis C virus patients who develop hepatocellular carcinoma or lymphoma, while others share a common behavior. Thus, analysis of the expression of microRNAs could be a noninvasive marker of hepatitis C virus-related carcinogenesis. This analysis could be a suitable tool for identifying the existence of a malignancy and also discriminating between these two hepatitis C virus-related cancers.

2015 - Hepatitis C virus recurrence after liver transplantation: a 10-year evaluation [Articolo su rivista]
Gitto, S; Belli, Ls; Vukotic, R; Lorenzini, S; Airoldi, A; Cicero, Af; Vangeli, M; Brodosi, L; Martello Panno, A; Di Donato, R; Cescon, M; Grazi, Gl; De Carlis, L; Pinna, Ad; Bernardi, M; Andreone, P.
abstract

AIM: To evaluate the predictors of 10-year survival of patients with hepatitis C recurrence. METHODS: Data from 358 patients transplanted between 1989 and 2010 in two Italian transplant centers and with evidence of hepatitis C recurrence were analyzed. A χ 2, Fisher’s exact test and Kruskal Wallis’ test were used for categorical and continuous variables, respectively. Survival analysis was performed at 10 years after transplant using the Kaplan-Meier method, and a log-rank test was used to compare groups. A p level less than 0.05 was considered significant for all tests. Multivariate analysis of the predictive role of different variables on 10-year survival was performed by a stepwise Cox logistic regression. RESULTS: The ten-year survival of the entire population was 61.2%. Five groups of patients were identified according to the virological response or lack of a response to antiviral treatment and, among those who were not treated, according to the clinical status (mild hepatitis C recurrence, “too sick to be treated” and patients with comorbidities contraindicating the treatment). While the 10-year survival of treated and untreated patients was not different (59.1% vs 64.7%, p = 0.192), patients with a sustained virological response had a higher 10-year survival rate than both the “non-responders” (84.7% vs 39.8%, p < 0.0001) and too sick to be treated (84.7% vs 0%, p < 0.0001). Sustained virological responders had a survival rate comparable to patients untreated with mild recurrence (84.7% vs 89.3%). A sustained virological response and young donor age were independent predictors of 10-year survival. CONCLUSION: Sustained virological response significantly increased long-term survival. Awaiting the interferon-free regimen global availability, antiviral treatment might be questionable in selected subjects with mild hepatitis C recurrence.

2015 - IMPULSIONAL, POINT AND BIDIMENSIONAL SHEAR WAVE ELASTOMETRY FOR PORTAL HYPERTENSION: SAME STIFFNESS THRESHOLDS? [Abstract in Rivista]
Stefanescu, HORIA OCTAVIAN; Allegretti, Giulia; Serra, Carla; Marasco, Giovanni; Gamal, N.; Conti, Fabio; Colecchia, Antonio; Festi, Davide; Andreone, Pietro; Bolondi, Luigi; Piscaglia, Fabio
abstract

2015 - Indications for liver transplantation [Capitolo/Saggio]
Cucchetti, A.; Vukotic, R.; Andreone, P.; Piscaglia, F.; Pecorelli, A.; Bolondi, L.; Morelli, M. C.; Ercolani, G.; Cescon, M.; Ravaioli, M.; Del Gaudio, M.
abstract

2015 - International genome-wide meta-analysis identifies new primary biliary cirrhosis risk loci and targetable pathogenic pathways [Articolo su rivista]
Cordell, Heather J; Han, Younghun; Mells, George F.; Li, Yafang; Hirschfield, Gideon M.; Greene, Casey S.; Xie, Gang; Juran, Brian D.; Zhu, Dakai; Qian, David C.; Floyd, James A. B.; Morley, Katherine I.; Prati, Daniele; Lleo, Ana; Cusi, Daniele; Gershwin, M. Eric; Anderson, Carl A.; Lazaridis, Konstantinos N.; Invernizzi, Pietro; Seldin, Michael F.; Sandford, Richard N.; Amos, Christopher I.; Siminovitch, Katherine A.; Schlicht, Erik M.; Lammert, Craig; Atkinson, Elizabeth J.; Chan, Landon L.; De Andrade, Mariza; Balschun, Tobias; Mason, Andrew L.; Myers, Robert P.; Zhang, Jinyi; Milkiewicz, Piotr; Qu, Jia; Odin, Joseph A.; Luketic, Velimir A.; Bacon, Bruce R.; Bodenheimer, Henry C.; Liakina, Valentina; Vincent, Catherine; Levy, Cynthia; Gregersen, Peter K.; Almasio, Piero L.; Alvaro, Domenico; Andreone, Pietro; Andriulli, Angelo; Barlassina, Cristina; Battezzati, Pier Maria; Benedetti, Antonio; Bernuzzi, Francesca; Bianchi, Ilaria; Bragazzi, Maria Consiglia; Brunetto, Maurizia; Bruno, Savino; Casella, Giovanni; Coco, Barbara; Colli, Agostino; Colombo, Massimo; Colombo, Silvia; Cursaro, Carmela; Crocè, Lory Saveria; Crosignani, Andrea; Donato, Maria Francesca; Elia, Gianfranco; Fabris, Luca; Ferrari, Carlo; Floreani, Annarosa; Foglieni, Barbara; Fontana, Rosanna; Galli, Andrea; Lazzari, Roberta; Macaluso, Fabio; Malinverno, Federica; Marra, Fabio; Marzioni, Marco; Mattalia, Alberto; Montanari, Renzo; Morini, Lorenzo; Morisco, Filomena; Mousa Hani, S.; Muratori, Luigi; Muratori, Paolo; Niro, Grazia A.; Palmieri, Vincenzo O.; Picciotto, Antonio; Podda, Mauro; Portincasa, Piero; Ronca, Vincenzo; Rosina, Floriano; Rossi, Sonia; Sogno, Ilaria; Spinzi, Giancarlo; Spreafico, Marta; Strazzabosco, Mario; Tarallo, Sonia; Tarocchi, Mirko; Tiribelli, Claudio; Toniutto, Pierluigi; Vinci, Maria; Zuin, Massimo; Ch'Ng, Chin Lye; Rahman, Mesbah; Yapp, Tom; Sturgess, Richard; Healey, Christopher; Czajkowski, Marek; Gunasekera, Anton; Gyawali, Pranab; Premchand, Purushothaman; Kapur, Kapil; Marley, Richard; Foster, Graham; Watson, Alan; Dias, Aruna; Subhani, Javaid; Harvey, Rory; Mccorry, Roger; Ramanaden, David; Gasem, Jaber; Evans, Richard; Mathialahan, Thiriloganathan; Shorrock, Christopher; Lipscomb, George; Southern, Paul; Tibble, Jeremy; Gorard, David; Palegwala, Altaf; Jones, Susan; Carbone, Marco; Dawwas, Mohamed; Alexander, Graeme; Dolwani, Sunil; Prince, Martin; Foxton, Matthew; Elphick, David; Mitchison, Harriet; Gooding, Ian; Karmo, Mazn; Saksena, Sushma; Mendall, Mike; Patel, Minesh; Ede, Roland; Austin, Andrew; Sayer, Joanna; Hankey, Lorraine; Hovell, Christopher; Fisher, Neil; Carter, Martyn; Koss, Konrad; Piotrowicz, Andrzej; Grimley, Charles; Neal, David; Lim, Guan; Levi, Sass; Ala, Aftab; Broad, Andrea; Saeed, Athar; Wood, Gordon; Brown, Jonathan; Wilkinson, Mark; Gordon, Harriet; Ramage, John; Ridpath, Jo; Ngatchu, Theodore; Grover, Bob; Shaukat, Syed; Shidrawi, Ray; Abouda, George; Ali, Faiz; Rees, Ian; Salam, Imroz; Narain, Mark; Brown, Ashley; Taylor Robinson, Simon; Williams, Simon; Grellier, Leonie; Banim, Paul; Das, Debasish; Chilton, Andrew; Heneghan, Michael; Curtis, Howard; Gess, Markus; Drake, Ian; Aldersley, Mark; Davies, Mervyn; Jones, Rebecca; Mcnair, Alastair; Srirajaskanthan, Raj; Pitcher, Maxton; Sen, Sambit; Bird, George; Barnardo, Adrian; Kitchen, Paul; Yoong, Kevin; Chirag, Oza; Sivaramakrishnan, Nurani; Macfaul, George; Jones, David; Shah, Amir; Evans, Chris; Saha, Subrata; Pollock, Katharine; Bramley, Peter; Mukhopadhya, Ashis; Fraser, Andrew; Mills, Peter; Shallcross, Christopher; Campbell, Stewart; Bathgate, Andrew; Shepherd, Alan; Dillon, John; Rushbrook, Simon; Przemioslo, Robert; Macdonald, Christopher; Metcalf, Jane; Shmueli, Udi; Davis, Andrew; Naqvi, Asifabbas; Lee, Tom; Stephen, Dyder; Collier, Jane; Klass, Howard; Ninkovic, Mary; Cramp, Matthew; Sharer, Nicholas; Aspinall, Richard; Goggin, Patrick; Ghosh, Deb; Douds, Andrew; Hoeroldt, Barbara; Bo
abstract

Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery data sets from genome-wide association studies of European subjects (n=2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n=3,716 cases and 4,261 controls). We discover and validate six previously unknown risk loci for PBC (Pcombined <5 × 10-8) and used pathway analysis to identify JAK-STAT/IL12/IL27 signalling and cytokine-cytokine pathways, for which relevant therapies exist.

2015 - Liver Stiffness measurments using Fibroscan after three months of IFN-based antiviral therapy is unlikely to predict viral response in cirrhotic patients [Abstract in Rivista]
Abdelall, NESRINE GAMAL MOHAMED; Brodosi, Lucia; Scuteri, Alessandra; Simonetti, G; Cursaro, C; Mastroroberto, Marianna; Andreone, Pietro
abstract

Background and Aims: Chronic HCV infection (CHC) is the leading cause of mortality from liver cirrhosis and hepatocellular carcinoma. Antiviral therapy can prevent disease progression. Transient Elastografy (TE; Fibroscan) is an accurate surrogate marker to liver fibrosis, by measuring liver stiffness (LS). LS decrease has been associated with sustained virologic response (SVR). In this study we aimed to assess the changes of LS measurments in CHC patients during and one year after Interferon (IFN)-based antiviral therapy (IFN/ribavirin) or (telaprevir+IFN/ribavirin). Methods: This is an ongoing study, in which consecutive 69 CHC patients (53.6% females, mean age 57.9±11.4) who underwent antiviral therapy for at least 20 weeks were enrolled. LS was measured using Fibroscan at baseline, after three months, at the end of treatment and one year after treatment discontinuation. Fibrosis was graded using METAVIR score. Results: Twenty patients were treated with triple therapy and 49 with IFN/ribavirin. Fifty patients had SVR and 19 were non-responders. LS changed significantly in all patients and independently from the initial fibrosis stage, genotype, type of treatment, basal ALT and BMI. Twelve months after treatment discontinuation, we found that in SVR patients: F0–F1, F2 and F3 patients (39.1%, 7.2% and 17.4%; respectively) showed no significant LS decrease (P = 0.186, 0.068 and 0.075; respectively). Conversely, in F4 patients (36.2%) LS was significantly decreased (P = 0.015) after one year of treatment completion. In all patients with no SVR, no significant decrease in LS was observed. Interestingly, all Patients with F4 fibrosis (even non-responders) showed an initial significant decrease in LS (P = 0.024) at 3 months after the start of treatment. However, this decrease was not predictive of SVR; area under the ROC curve 0.369 (CI %: 0.145–0.592) P = 0.265. Conclusions: Performance of LS measurements for fibrosis assessment confirmed results from previous studies. Our preliminary data suggest that LS changes significantly in CHC patients treated with IFN-based antiviral therapy (standard and triple therapy with telaprevir) and it decreases significantly in responders with high initial LS measurements independently from the type treatment. Initial significant decrease in LS measurements in such patients is unlikely to predict an SVR.

2015 - Low-density lipoprotein and other predictors of response with telaprevir-based therapy in treatment-experienced HCV genotype 1 patients: REALIZE study [Articolo su rivista]
Berg, Thomas; Andreone, Pietro; Pol, Stanislas; Roberts, Stuart; Younossi, Zobair; Diago, Moises; Lawitz, Eric J.; Focaccia, Roberto; Foster, Graham R.; Horban, Andrzej; Lonjon-Domanec, Isabelle; Demasi, Ralph; Picchio, Gaston; Luo, Donghan; De Meyer, Sandra; Zeuzem, Stefan
abstract

BACKGROUND & AIMS: Predictors of response to treatment with peginterferon plus ribavirin are well established. In these post-hoc analyses of the REALIZE study, we sought to identify predictors of response for telaprevir-based triple therapy. METHODS: Patients from the REALIZE study with baseline data for all predictors evaluated (including baseline disease characteristics and demographics, prior treatment response and baseline laboratory assessments) were included in the post-hoc analyses (n = 465). Univariate and multivariate analyses were used to evaluate factors predicting treatment outcomes. RESULTS: Sustained viral response (SVR) rates were 86% in prior relapsers, 63% in prior partial responders and 32% in prior null-responders. In the final multivariate analysis, baseline factors predicting SVR were prior response to treatment [Odds ratio (OR) = 2.80; 95% confidence interval (CI), 2.13-3.69], low-density lipoprotein (LDL) (≥2.6 mmol/L) (OR = 2.11; 95% CI, 1.52-2.93), HCV genotype (OR = 0.58; 95% CI, 0.36-0.93), and maximum alanine amino transferase and aspartate amino transferase (OR = 0.62; 95% CI, 0.40-0.97). CONCLUSIONS: Prior response to peginterferon plus ribavirin treatment and LDL levels are the main independent predictive markers of response with telaprevir-based triple therapy.

2015 - Paritaprevir in patients with chronic hepatitis C genotype 1 [Articolo su rivista]
Gamal, N.; Vitale, G.; Andreone, P.
abstract

Chronic hepatitis C is found worldwide. According to the WHO, it affects approximately 184 million patients around the globe. For the past decade, the standard-of-care treatment of chronic hepatitis C consisted of IFN-based regimens. However, IFN has its own limitations and is not always well tolerated in all patients. In addition, it yields unsatisfactory rates of virologic response especially in difficult-to-treat genotype 1 patients. Recent scientific advances led to the development of new IFN-free antiviral agents that are more effective, better tolerated and with shorter treatment duration. An all-oral regimen (paritaprevir/ritonavir and ombitasvir, copackaged with dasabuvir) has recently received the US FDA approval and the European Commission marketing authorizations for treatment of patients with chronic hepatitis C genotype 1 infection, including those with cirrhosis. In this article, we sought to review the pharmacokinetics, clinical efficacy and side-effect profile pertaining to paritaprevir-containing regimens with special emphasis on Phase III clinical trials.

2015 - Prospective, observational real-life study on eligibility for and outcomes of antiviral treatment with peginterferon α plus ribavirin in chronic hepatitis C [Articolo su rivista]
Vukotic, Ranka; Abdelall, Nesrine Gamal Mohamad; Andreone, Pietro
abstract

Background: We aimed to investigate eligibility, reasons for treatment discontinuation and characteristics of chronic hepatitis C patients with treatment failure to peginterferon/ribavirin in clinical practice. Methods: 1128 chronic hepatitis C patients, from 45 Italian Hepatology centres, were enrolled in this phase-4, prospective, observational study from January 2009 to February 2010. Results: 687/1118 patients (61.4%) were eligible for antiviral treatment, of which 598 (87.0%) agreed with the physician's decision. Outcome information was available in 500/598 patients, among whom 348 (69.6%) completed treatment. Treatment was discontinued in 152 patients due to: lack of response (28.9%), personal reasons (29.6%), adverse events (38.2%), and decompensation (1.3%). Sustained virological response was obtained in 263/500 (52.6%), 71 (14.2%) relapsed and 61 (12.2%) were non-responders. Treatment outcome was not available in 105 (21%): lost while receiving treatment (33.3%), lost during follow-up (25.7%), withdrawn for adverse events (19.1%) or for administrative reasons (21.9%). Conclusion: In clinical practice, only 61% of chronic hepatitis C patients are considered eligible for peginterferon/ribavirin. Of these, 13% refuse treatment. Approximately 30% do not complete the scheduled treatment and, despite this, the sustained virological response rate is similar to that of randomized-controlled trials. In the era of new antiviral combinations, these findings have important implications for assessing eligibility and estimating drop-out rates.

2015 - Reinfusion of highly purified CD133+ bone marrow-derived stem/progenitor cells in patients with end-stage liver disease: a phase I clinical trial [Articolo su rivista]
Andreone, Pietro; Catani, Lucia; Margini, C; Brodosi, Lucia; Lorenzini, S; Sollazzo, Daria; Nicolini, Benedetta; Giordano, R; Montemurro, T; Rizzi, S; Dan, Elisa; Giudice, V; Viganò, M; Casadei, A; Foschi, F; Malvi, Deborah; Bernardi, Mauro; Conti, Fabio; Lemoli, R. M.
abstract

Background: Bone marrow stem/progenitor cells seem to be effective in liver regeneration after tissueinjury. Aim: To evaluate the feasibility and safety of the mobilization and reinfusion of CD133+stem/progenitorcells in patients with end-stage liver disease.Methods: Autologous CD133+stem/progenitor cells, mobilized with granulocyte-colony stimulating fac-tor, were collected by leukapheresis and reinfused at increasing doses through the hepatic artery startingfrom 5 × 104/kg up to 1 × 106/kg.Results: 16 subjects with Model for End-stage Liver Disease (MELD) score between 17 and 25 wereenrolled, 14 mobilized an adequate number of CD133+stem/progenitor cells and 12 were reinfused.No severe adverse events related to the procedure were reported. MELD score significantly worsenedduring mobilization in Child Turcotte Pugh-C patients. A significant improvement of liver function wasobserved 2 months after reinfusion (MELD 19.5 vs 16; P = 0.045). Overall, 5 patients underwent livertransplantation within 12 months from reinfusion and 2 died because of progressive liver failure.Conclusions: CD133+stem/progenitor cells reinfusion in patients with end-stage liver disease is feasi-ble and safe. A worsening of liver function was observed during mobilization in Child Turcotte Pugh-Cpatients. The temporary improvement of MELD score after reinfusion suggests that stem cells therapymay be a “bridge to transplant” approach for these patients.

2015 - Simeprevir versus telaprevir with peginterferon and ribavirin in previous null or partial responders with chronic hepatitis C virus genotype 1 infection (ATTAIN): A randomised, double-blind, non-inferiority phase 3 trial [Articolo su rivista]
Reddy, K Rajender; Zeuzem, Stefan; Zoulim, Fabien; Weiland, Ola; Horban, Andrzej; Stanciu, Carol; Villamil Federico, Guillermo; Andreone, Pietro; George, Jacob; Dammers, Elisabeth; Fu, Min; Kurland, Darryl; Lenz, Oliver; Ouwerkerk-Mahadevan, Sivi; Verbinnen, Thierry; Scott, Jane; Jessner, Wolfgang
abstract

Background: We did a phase 3 study in previous non-responders with chronic hepatitis C virus (HCV) genotype 1 infection and compensated liver disease that related to the standard of care for these patients at the time this study was initiated. We investigated whether simeprevir is non-inferior in terms of efficacy to telaprevir, each in combination with peginterferon alfa-2a and ribavirin. Methods: We did this randomised, double-blind, phase 3 trial at 169 investigational sites in 24 countries. We enrolled adults (≥18 years) with chronic HCV genotype 1 infection, compensated liver disease, and plasma HCV RNA higher than 10 000 IU/mL who were null or partial responders during at least one previous course of peginterferon alfa-2a and ribavirin treatment. We randomly assigned (1:1) patients (stratified by HCV genotype 1 subtype [1a plus other/1b] and previous treatment response [partial or null]) to receive simeprevir (150 mg once a day) plus telaprevir placebo (three times a day 7-9 h apart) or telaprevir (750 mg three times a day) plus simeprevir placebo (once a day) in combination with peginterferon alfa-2a and ribavirin for 12 weeks followed by 36 weeks of peginterferon alfa-2a and ribavirin alone. The primary efficacy endpoint was sustained virological response 12 weeks after end of treatment (SVR12) in the intention-to-treat and the per-protocol population. We compared groups with the Cochran-Mantel-Haenszel test. We established a non-inferiority margin of 12%. Adverse events were reported descriptively. This trial is registered with ClinicalTrials.gov, number NCT01485991. Findings: Patient screening began on Jan 19, 2012, and the last visit was on April 7, 2014. We included 763 patients (472 previous null responders [62%]). Simeprevir and peginterferon alfa-2a and ribavirin was non-inferior to telaprevir and peginterferon alfa-2a and ribavirin for SVR12 (54% [203/379] vs 55% [210/384]; difference -1·1%, 95% CI -7·8 to 5·5; p=0·0007). SVR12 was achieved in 70% (101/145) versus 68% (100/146) of previous partial responders and 44% (102/234) versus 46% (110/238) of previous null responders with simeprevir and peginterferon alfa-2a and ribavirin and telaprevir and peginterferon alfa-2a and ribavirin treatment, respectively. We recorded differences between treatment groups in simeprevir or telaprevir-related adverse events (69% [261/379] in the simeprevir group vs 86% [330/384] in the telaprevir group), serious adverse events (2% [8/379] vs 9% [33/384]), and adverse events leading to simeprevir or telaprevir discontinuation (2% [7/379] vs 8% [32/384]). Interpretation: Simeprevir once a day with peginterferon alfa-2a and ribavirin was well tolerated in HCV genotype 1-infected previous non-responders and was non-inferior to telaprevir, thus providing an alternative treatment in areas of the world where all-oral HCV regimens are not available or accessible. Funding: Janssen.

2015 - Treatment of nonalcoholic steatohepatitis in adults: present and future [Articolo su rivista]
Gitto, S; Vitale, G; Villa, Erica; Andreone, P.
abstract

Nonalcoholic steatohepatitis has become one of the most common liver-related health problems. This condition has been linked to an unhealthy diet and weight gain, but it can also be observed in nonobese people. The standard of care is represented by the lifestyle intervention. However, because this approach has several limitations, such as a lack of compliance, the use of many drugs has been proposed. The first-line pharmacological choices are vitamin E and pioglitazone, both showing a positive effect on transaminases, fat accumulation, and inflammation. Nevertheless, vitamin E has no proven effect on fibrosis and on long-term morbidity and mortality and pioglitazone has a negative impact on weight. Other drugs have been studied such as metformin, ursodeoxycholic acid, statins, pentoxiphylline, and orlistat with only partially positive results. Among the emerging treatments, telmisartan is particularly interesting as it seems to have an impact on insulin resistance, liver steatosis, inflammation, and fibrosis. However, the pathogenesis of steatohepatitis is highly complex and is determined by different parallel hits; indeed, the association of different drugs that act on various levels has been suggested. In conclusion, lifestyle intervention should be optimised and the associations of different drugs should be tested in large studies with long-term outcomes.

2015 - Undetectable HCV-RNA at treatment-week 8 results in high-sustained virological response in HCV G1 treatment-experienced patients with advanced liver disease: The International Italian/Spanish Boceprevir/Peginterferon/Ribavirin Name Patients Program [Articolo su rivista]
Bruno, S; Bollani, S.; Zignego, A. L.; Pascasio, J. M.; Magni, C.; Ciancio, A.; Caremani, M.; Mangia, A.; Marenco, S.; Piovesan, S.; Chemello, L.; Babudieri, S.; Moretti, A.; Gea, F.; Colletta, C.; Perez Alvarez, R.; Forns, X.; Larrubia, J. R.; Arenas, J.; Crespo, J.; Calvaruso, V.; Ceccherini Silberstein, F.; Maisonneuve, P.; Craxì, A.; Calleja, J. L.; Di Marco, V.; Monti, M.; Rizzardini, G.; Landonio, S.; Rizzetto, M.; Lapini, L. E.; Piazzolla, V.; Picciotto, A.; Alberti, A.; Cavaletto, L.; Koch, M.; Massari, M.; Muratori, Luigi; Cipriano, V.; Montineri, A.; Iacobello, C.; Fangazio, S.; Pirisi, M.; Colombo, A.; Bellati, G.; Mazzotta, F.; Pierotti, P.; Traverso, A.; Serviddio, G.; Russello, M.; Santantonio, T.; Drenaggi, D.; Marchionne, E.; Zuin, M.; Delliponti, M.; Farina, F.; Andreone, Pietro; Scuteri, A.; Galli, M.; Giannini, E. G.; Nerli, A.; Carbonai, S.; Coppola, N.; Montalbano, M.; Portelli, V.; Di Biagio, A.; Nicolini, L. A.; Mastroianni, C.; Madonia, S.; Licata, A.; Montalto, G.; Giannitrapani, L.; Mondelli, M.; Pellicelli, A.; Toniutto, P.; Borgia, G.; Gentile, I.; De Luca, M.; Di Costanzo, G. G.; Corti, G.; Sousa, M.; Delgado, M. B.; De La Revilla, J.; Navarro, J. M.; Barcena, R.; Romero Gomez, M.; Fernandez Rodriguez, C. M.; Narvaez, I.; Erdozain, J. C.; Molina, E.; Fernandez, I.; Cuenca, B.; Planas, R.; Garcia Samaniego, J.; Ladero, J. M.; Gonzalez, J. M.; Serra, M. A.; Castellote, I.; Sola, R.; Anton, T.; Ryan, I.; Gonzalez, F.; Martinez, E.; Portu, J.
abstract

In many countries, first-generation protease inhibitors (PIs)/peginterferon/ribavirin (P/R) still represent the only treatment option for HCV-infected patients. Subjects with advanced disease and previous failure to P/R urgently need therapy, but they are under-represented in clinical trials. All treatment-experienced F3/4 Metavir patients who received boceprevir (BOC)+P/R in the Italian-Spanish Name Patient Program have been included in this study. Multivariate logistic regression analysis (MLR) was used to identify baseline and on-treatment predictors of SVR and adverse events (AEs). Four hundred and sixteen patients, mean age 57.7 (range 25-78 years), 70% males, 69.5% (289/416) F4, 14% (41/289) Child-Pugh class A6, 24% (70/289) with varices and 42% (173/416) prior null responders to P/R, were analysed. Overall, SVR rate (all 381 patients who received one dose of BOC) was 49%, (58% in F3, 45% in F4, 61% in relapsers, 51% in partial, 38% in null responders, and 72% in subjects with undetectable HCV-RNA at treatment-week (TW)8. Among patients with TW8 HCV-RNA ≥ 1000 IU/L, SVR was 8% (negative predictive value = 92%). Death occurred in 3 (0.8%) patients, while decompensation and infections were observed in 2.9% and 11%, respectively. At MLR, SVR predictors were TW4 HCV-RNA ≥ 1log10-decline from baseline, undetectable TW8 HCV-RNA, prior relapse, albumin levels ≥3.5 g/dL and platelet counts ≥100 000/lL. Metavir F4, Child-Pugh A6, albumin, platelets, age and female gender were associated with serious and haematological AEs. Among treatment-experienced patients with advanced liver disease eligible for IFN-based therapy, TW8 HCV-RNA characterised the subset with either high or poor likelihood of achieving SVR. Using TW8 HCV-RNA as a futility rule, BOC/P/R appears to have a favourable benefit-risk profile.

2015 - Working together to tackle HCV infection: Ombitasvir/paritaprevir/ritonavir and dasabuvir combination [Articolo su rivista]
Gamal, N; Andreone, P.
abstract

An estimated 184 million people worldwide have hepatitis C virus (HCV) infection. Chronic infection can ultimately result in liver cirrhosis and hepatic failure. Eradication of the virus by antiviral treatment can hinder the development of the aforementioned complications. Historically, the combination therapy of PEGylated interferon/ribavirin was considered the standard-of-care therapy for HCV. Such therapy did not demonstrate satisfactory cure rates and had significant side effects that precluded its widespread use among HCV patients. In view of this situation, scientific advances have led to the development of new interferon-free regimens that are better tolerated, more effective and with shorter duration of therapy. One of the newest members of this family is the all-oral regimen (ombitasvir/paritaprevir/ritonavir co-packaged with dasabuvir) that has recently received FDA approval for the treatment of adult patients with genotype 1 HCV infection, including those with compensated cirrhosis. This new combination was found to be safe and well tolerated with high rates of sustained virologic response of up to 100%. An overview of the current knowledge about this regimen is reviewed herein.

2014 - ABT-450, Ritonavir, Ombitasvir, and Dasabuvir Achieves 97% and 100% Sustained Virologic Response With or Without Ribavirin in Treatment-Experienced Patients With HCV Genotype 1b Infection [Articolo su rivista]
Andreone, Pietro; Colombo, Massimo G.; Enejosa, Jeffrey V.; Koksal, Iftihar; Ferenci, Peter; Maieron, Andreas; Müllhaupt, Beat; Horsmans, Yves; Weiland, Ola; Reesink, Henk W.; Rodrigues, Lino; Hu, Yiran B.; Podsadecki, Thomas; Bernstein, Barry
abstract

BACKGROUND & AIMS: The interferon-free regimen of ABT-450 (a protease inhibitor), ritonavir, ombitasvir (an NS5A inhibitor), dasabuvir (a non-nucleoside polymerase inhibitor), and ribavirin has shown efficacy in patients with hepatitis C virus (HCV) genotype 1b infection-the most prevalent subgenotype worldwide. We evaluated whether ribavirin is necessary for ABT-450, ritonavir, ombitasvir, and dasabuvir to produce high rates of sustained virologic response (SVR) in these patients. METHODS: We performed a multicenter, open-label, phase 3 trial of 179 patients with HCV genotype 1b infection, without cirrhosis, previously treated with peginterferon and ribavirin. Patients were assigned randomly (1:1) to groups given ABT-450, ritonavir, ombitasvir, and dasabuvir, with ribavirin (group 1) or without (group 2) for 12 weeks. The primary end point was SVR 12 weeks after treatment (SVR12). We assessed the noninferiority of this regimen to the rate of response reported (64%) for a similar population treated with telaprevir, peginterferon, and ribavirin. RESULTS: Groups 1 and 2 each had high rates of SVR12, which were noninferior to the reported rate of response to the combination of telaprevir, peginterferon, and ribavirin (group 1: 96.6%; 95% confidence interval, 92.8%-100%; and group 2: 100%; 95% confidence interval, 95.9%-100%). The rate of response in group 2 was noninferior to that of group 1. No virologic failure occurred during the study. Two patients (1.1%) discontinued the study owing to adverse events, both in group 1. The most common adverse events in groups 1 and 2 were fatigue (31.9% vs 15.8%) and headache (24.2% vs 23.2%), respectively. Decreases in hemoglobin level to less than the lower limit of normal were more frequent in group 1 (42.0% vs 5.5% in group 2; P < .001), although only 2 patients had hemoglobin levels less than 10 g/dL. CONCLUSIONS: The interferon-free regimen of ABT-450, ritonavir, ombitasvir, and dasabuvir, with or without ribavirin, produces a high rate of SVR12 in treatment-experienced patients with HCV genotype 1b infection. Both regimens are well tolerated, as shown by the low rate of discontinuations and generally mild adverse events. ClinicalTrials.gov number: NCT01674725.

2014 - Adaptive response in Hepatitis B virus infection [Articolo su rivista]
Loggi, E.; Gamal, N.; Bihl, F.; Bernardi, M.; Andreone, P.
abstract

Hepatitis B virus (HBV) is a major cause of acute and chronic liver inflammation worldwide. The immune response against the virus represents a key factor in determining infection outcome, in terms of both viral clearance and the perpetuation of liver damage. Significant advances have recently been achieved regarding the functions of antiviral CD8+ T cells, leading to a better understanding of their abnormalities during chronic infection as well as the pathways to be manipulated to reverse the immune impairment of chronic infection. In this review, we aimed to analyse the patterns of adaptive immunity that develop during acute infection and the profiles in chronic infection. In addition to CD8+ T cells, which are the best-described subset to date, we reviewed and commented on the direct and indirect roles of CD4+ T cells and B cells.

2014 - Alopecia universalis after discontinuation of pegylated interferon and ribavirin combination therapy for hepatitis C: a case report [Articolo su rivista]
Gamal, N; Brodosi, L; Misciali, C; Patrizi, A; Vukatana, G; Malavolta, N; Bernardi, M; Andreone, P.
abstract

For the last decade, the combination therapy of pegylated interferon (Peg-IFN) plus ribavirin (RBV) has been considered as the standard of care treatment for chronic hepatitis C virus (HCV) infection. However, it has been associated with an increased incidence of many adverse cutaneous reactions and emergence of autoantibodies or even autoimmune diseases. We report a case of irreversible alopecia universalis (AU) with complete hair loss extended to the whole body, which started after discontinuation of Peg-IFN/RBV combination therapy for chronic HCV infection. In conclusion, this case represents an uncommon presentation of a common disease. Physicians must be aware of the potential adverse reactions of an antiviral therapy containing IFN, which might occur even after the discontinuation, and fully inform the patient at the beginning of his treatment course. We hope that interferon-free regimens will utterly supplant interferon-based therapy for most or all HCV patients avoiding the emergence of autoimmune manifestations.

2014 - Bone marrow derived stem cells for the treatment of end-stage liver disease [Articolo su rivista]
Margini, C; Vukotic, R; Brodosi, L; Bernardi, M; Andreone, P.
abstract

End-stage disease due to liver cirrhosis is an important cause of death worldwide. Cirrhosis results from progressive, extensive fibrosis and impaired hepatocyte regeneration. The only curative treatment is liver transplantation, but due to the several limitations of this procedure, the interest in alternative therapeutic strategies is increasing. In particular, the potential of bone marrow stem cell (BMSC) therapy in cirrhosis has been explored in different trials. In this article, we evaluate the results of 18 prospective clinical trials, and we provide a descriptive overview of recent advances in the research on hepatic regenerative medicine. The main message from the currently available data in the literature is that BMSC therapy is extremely promising in the context of liver cirrhosis. However, its application should be further explored in randomized, controlled trials with large cohorts and long follow-ups.

2014 - Calcineurin inhibitors levels reduction during treatment with Sofosbuvir in liver transplanted patients [Articolo su rivista]
Vukotic, Ranka; Morelli, M; Pinna, Antonio Daniele; Margotti, Marzia; Foschi, Fg; Loggi, Elisabetta; Bernardi, Mauro; Andreone, Pietro
abstract

In liver transplant, during anti-viral therapy for hepatitis C virus (HCV) recurrence, the immunosuppressant levels should be monitored to prevent both toxicity and rejection. Sofosbuvir (SOF) has been used within compassionate programs for HCV recurrence and, according to pharmacokinetic analyses, is not supposed to have significant pharmacological interactions with tacrolimus (Tac) or ciclosporin.1 This was reported in the review article by Koff recently published.2 We treated eight transplant recipients with SOF/ribavirin (RBV) for a severe HCV recurrence, and observed unexpected Tac/ciclosporin reduction during SOF.

2014 - Development of different psychiatric manifestations during antiviral therapy for chronic hepatitis C. [Articolo su rivista]
Simonetti, G; Vitale, G; Taruschio, G; Vukotic, R; Gamal, N; Pirillo, L; Boncompagni, G; Bernardi, M; Andreon, E.
abstract

Pegylated interferon and Ribavirin are the treatment backbone for chronic hepatitis C and may favour the development of psychiatric symptoms. These adverse events may reduce treatment adherence and are a risk factor for its failure. The recent experts’ recommendations of European Association for the Study of the Liver, suggest monitoring psychiatric manifestations on a regular basis during the antiviral treatment but the frequency of psychiatric controls sometimes might be insufficient. We present a particular case of a young woman without psychiatric history, who developed different mood and behavioural disturbances during antiviral therapy, that required an intensive psychiatric monitoring and supportive psychotherapy.

2014 - Ledipasvir and sofosbuvir for untreated HCV genotype 1 infection [Articolo su rivista]
Afdhal, Nezam; Zeuzem, Stefan; Kwo, Paul; Chojkier, Mario; Gitlin, Norman; Puoti, Massimo; Romero-Gomez, Manuel; Zarski, Jean-Pierre; Agarwal, Kosh; Buggisch, Peter; Foster Graham, R.; Bräu, Norbert; Buti, Maria; Jacobson Ira, M.; Subramanian G., Mani; Ding, Xiao; Mo, Hongmei; Yang Jenny, C.; Pang Phillip, S.; Symonds William, T.; Mchutchison John, G.; Muir Andrew, J.; Mangia, Alessandra; Marcellin, Patrick; ION-1 Investigators, [. . .; Andreone, Pietro; ], . .
abstract

BACKGROUND: In phase 2 studies, treatment with the all-oral combination of the nucleotide polymerase inhibitor sofosbuvir and the NS5A inhibitor ledipasvir resulted in high rates of sustained virologic response among previously untreated patients with hepatitis C virus (HCV) genotype 1 infection. METHODS: We conducted a phase 3, open-label study involving previously untreated patients with chronic HCV genotype 1 infection. Patients were randomly assigned in a 1:1:1:1 ratio to receive ledipasvir and sofosbuvir in a fixed-dose combination tablet once daily for 12 weeks, ledipasvir-sofosbuvir plus ribavirin for 12 weeks, ledipasvir-sofosbuvir for 24 weeks, or ledipasvir-sofosbuvir plus ribavirin for 24 weeks. The primary end point was a sustained virologic response at 12 weeks after the end of therapy. RESULTS: Of the 865 patients who underwent randomization and were treated, 16% had cirrhosis, 12% were black, and 67% had HCV genotype 1a infection. The rates of sustained virologic response were 99% (95% confidence interval [CI], 96 to 100) in the group that received 12 weeks of ledipasvir-sofosbuvir; 97% (95% CI, 94 to 99) in the group that received 12 weeks of ledipasvir-sofosbuvir plus ribavirin; 98% (95% CI, 95 to 99) in the group that received 24 weeks of ledipasvir-sofosbuvir; and 99% (95% CI, 97 to 100) in the group that received 24 weeks of ledipasvir-sofosbuvir plus ribavirin. No patient in either 12-week group discontinued ledipasvir- sofosbuvir owing to an adverse event. The most common adverse events were fatigue, headache, insomnia, and nausea. CONCLUSIONS: Once-daily ledipasvir-sofosbuvir with or without ribavirin for 12 or 24 weeks was highly effective in previously untreated patients with HCV genotype 1 infection. (Funded by Gilead Sciences; ION-1 ClinicalTrials.gov number NCT01701401.) Copyright © 2014 Massachusetts Medical Society.

2014 - Pegylated interferon α plus ribavirin for the treatment of chronic hepatitis C: A multicentre independent study supported by the Italian Drug Agency [Articolo su rivista]
Rosina, F.; Tosti, M. E.; Borghesio, E.; Masocco, M.; Mele, A.; Coppola, C.; Milella, M.; Borgia, G.; Andreone, P.; Koch, M.; Zignego, A. L.; Romano, M.; Carrara, M.; Almasio, P. L.; Azzola, E.; Nardone, G.; Benedetti, A.; Carosi, G.; Mazzotta, F.; Sagnelli, E.; Rizzetto, M.; Mascolo, M. C.; Cursaro, C.; Scuteri, A.; Crespi, C.; Gianstefani, A.; Ranieri, J.; Monti, M.; Corti, G.; Blanc, P. L.; Baragli, F.; Bellentani, S.; Gasbarrini, A.; Pompili, M.; Mecenate, F.; Picardi, A.; Vespasiani, U.; Nosotti, ; Gasbarrini, A.; Pompili, M.; Mecenate, F.; A., Picardi; Nosotti, ; Ricci, G. L.; Paffetti, A.; Mastropietro, C.; Moretti, A.; Spagnolo, A. L.; Puoti, C.; Bellis, L.; Regazzetti, A.; Maffezzini, E.; Pietrangelo, A.; Abbati, G.; Borghi, A.; Sardini, C.; Raimondo, G.; Scribano, L.; Martines, D.; Svegliati Baroni, G.; Faraci, G.; Schi-anchi, S.; Fornaciari, G.; Massari, M.; Fabris, P.; Bertin, T.; Salvagnini, M.; Madonia, S.; Cali, A.; Civitavecchia, G.; Pirisi, M.; Smirne, C.; Andreoletti, M.; Morisco, F.; Caporaso, N.; Gentile, I.; Brancaccio, G.; Gaeta, G. B.; Liberti, A.; Iannece, M. D.; Rocco, A.; Federico, A.; Loguercio, C.; Riegler, G.; Esposito, P.; Fargion, S.; Fatta, E.; Masutti, F.; Bonaventura, M. E.; Autolitano, A.; Russello, M.; Bellia, A.; Toniutto, P.; Bitetto, D.; Pasulo, L.; Luca, M. G.; Grattagliano, I.; Palasciano, G.; Romagno, D.; Giannelli, G.; Napoli, N.; Plattella, M. S.; Cassano, P.; Gobbo, G.; Monti, V.; Raspanti, A.; Cuccorese, ; Colombo, A. E.; Mandelli, G.; Spinzi, G. C.; Floridia, ; Messina, V.; Bonfante, S.; Bellissima, P.; Toti, M.; Vecchiet, J.; Falasca, K.; Portelli, V.; Stefano, G. D.; Pietromatera, G.; Vigano, P.; Re, T.; Andreoni, M.; G., Raineri; Grossi, P. A.; Caputo, S.; Cassola, G.; Feasi, M.; Biagio, A. D.; Nicolini, L.; Giannini, E. G.; Corbo, M.; Foti, G.; Kunkar, A.; Caterini, L.; Migliorini, D.; Chiodera, A.; Calleri, G.; Spezia, C.; Framarin, L.; M., Berrutti; Ciancio, A.; Baiguera, C.; Puoti, M.; Vento, S.; Contini, C.; Boccia, S.; Casiraghi, M. A.; Simone, L.; Tacconi, D.; Caremani, M.; Almi, P.; Chimenti, M.; Cosco, ; Messeri, D.; Esperti, F. C.; Lomonaco, L.; Pazzi, P.; Fornari, F.; Comparato, G.; Casetti, T.; Foschi, F. G.; Samori, A.; Ferretti, E.; Marin, R.; Campo, N.; Testa, R.; Rizzo, S.
abstract

Background: Data on the efficacy of Peg-interferon/ribavirin therapy for chronic hepatitis C are mostly derived from treatment of selected patients enrolled in clinical trials. This study aimed to assess the effectiveness of Peg-interferon/ribavirin therapy in "real world" chronic hepatitis C patients in Italy. Methods: Independent observational multicentre study including consecutive patients receiving Peg-interferon/ribavirin in the 18 months before (retrospective phase) and after (prospective phase) the start of the study. Results: 4176 patients were eligible. The final study population consisted of 2051 patients in the retrospective and 2073 in the prospective phase.Sustained virological response was achieved by 1036 patients (50.5%) during the retrospective phase: 325 were genotypes 1/4 (34.1%) and 684 were genotypes 2/3 (67.2%) and by 800 patients (38.6%) during the prospective phase: 300 were genotypes 1/4 (28.4%) and 473 were genotypes 2/3 (51.5%).During multivariate analysis genotypes 2/3 were significantly associated with higher sustained virological response rates; cirrhosis and γ-glutamil-transpeptidase >2 times the normal limit were associated with poorer response. Conclusions: The response to Peg-interferon/ribavirin therapy in "real world" clinical practice is distinctly lower than in registration trials. The difference in response rates was more pronounced among easy-to-treat than among difficult-to-treat hepatitis C virus genotypes. © 2014 Editrice Gastroenterologica Italiana S.r.l.

2014 - Simeprevir With Peginterferon and Ribavirin Leads to High Rates of SVR in Patients With HCV Genotype 1 Who Relapsed After Previous Therapy: A Phase 3 Trial [Articolo su rivista]
Forns, Xavier; Lawitz, Eric; Zeuzem, Stefan; Gane, Ed; Pierre Bronowicki, Jean; Andreone, Pietro; Horban, Andrzej; Brown, Ashley; Peeters, Monika; Lenz, Oliver; Ouwerkerk–mahadevan, Sivi; Scott, Jane; De La Rosa, Guy; Kalmeijer, Ronald; Sinha, Rekha; Beumont–mauviel, Maria
abstract

BACKGROUND & AIMS: Simeprevir is an oral, once-daily inhibitor of hepatitis c virus (HCV) protease NS3/4A. We investigated the safety and efficacy of simeprevir with peg-interferon α-2a and ribavirin (PR) in a randomized, double-blind, placebo-controlled, phase 3 trial of patients with HCV genotype 1 infection who relapsed after previous interferon-based therapy. METHODS: Patients were assigned randomly (2:1) to groups given simeprevir (150 mg, once daily) and PR (n = 260) or placebo and PR (n = 133) for 12 weeks. Patients then were given PR alone for 12 or 36 weeks (simeprevir group, based on response-guided therapy criteria) or 36 weeks (placebo group). RESULTS: Simeprevir and PR was significantly superior to placebo and PR; rates of sustained virologic response 12 weeks after planned end of treatment (SVR12) were 79.2% vs 36.1%, respectively (43.8% difference; 95% confidence interval, 34.6-53.0; P < .001). Among patients given simeprevir, 92.7% met the response-guided therapy criteria and were eligible to complete PR at week 24; of these, 83.0% achieved SVR12. HCV RNA was undetectable at week 4 in 77.2% of patients given simeprevir and 3.1% given placebo. On-treatment failure and relapse rates were lower among patients given simeprevir and PR than those given placebo and PR (3.1% vs 27.1%, and 18.5% vs 48.4%, respectively). Patients given simeprevir did not have adverse events beyond those that occurred in patients given PR alone. Most adverse events were grades 1/2; the prevalence of anemia and rash was similar in both groups. Patients in both groups reported similar severity of fatigue and functional impairments during the study, but duration was reduced among patients given simeprevir. CONCLUSIONS: In a phase 3 trial of patients who had relapsed after interferon-based therapy, the addition of simeprevir to PR was generally well tolerated, with an SVR12 rate of 79.2%. Most patients (92.7%) receiving simeprevir were able to shorten therapy to 24 weeks. ClinicalTrials.gov number: NCT01281839.

2014 - The increase of Ribavirin dose improves sustained virological response in HCV-Genotype 1 patients with a partial response to PEG-Interferon and Ribavirin. [Articolo su rivista]
Conti, F; Vukotic, R; Lorenzini, S; Riili, A; Cursaro, C; Scuteri, A; Loggi, E; Galli, S; Furlini, G; Bernardi, M; Andreone, P.
abstract

BACKGROUND AND AIM: In patients with chronic hepatitis C receiving Peg interferon/ribavirin (PEG-IFN/RBV) who do not achieve ≥ 2 log-reduction in HCV-RNA at week 12 (null responders, NR) and in those with ≥ 2 log-decrease but detectable at week 24 (partial responders, PR) the probability to achieve the sustained virological response (SVR) is almost null. The aim of this study was to investigate the efficacy of individualized schedule of progressively increased RBV doses in the setting of PEG-IFN/RBV treatment. MATERIAL AND METHODS: PR or NR to PEG-IFN/RBV instead of discontinuing treatment were enrolled to receive increasing doses of RBV until a target theoretical concentration ([tRBV]) of ≥ 15 μmol/L (by pharmacokinetic formula based on glomerular filtration rate). HCV-RNA was assessed every 4 weeks and, if detectable, RBV dose was gradually increased until negativization. Twelve weeks later, patients with detectable HCV-RNA discontinued therapy while those with undetectable HCV-RNA continued for further 48 weeks. RESULTS: Twenty genotype-1 patients (8 NR and 12 PR) were enrolled. After 12 weeks 9 (45%) were still HCV-RNA positive and were discontinued, while remaining 11 had undetectable HCV-RNA. One stopped treatment for side effects. Ten completed treatment. Five (all PR) achieved SVR. Side effects incidence was similar to that observed during PEG-IFN/RBV. CONCLUSIONS: In conclusion, RBV high doses, according to individualized schedule, increase SVR in PR on a similar extent to that of triple therapy but without increase of side effects. Such treatment should be considered in PR with no access or intolerant to protease inhibitors (PI).

2014 - Treating hepatitis C in the elderly: the future is near? [Articolo su rivista]
Conti, Fabio; Vitale, Giovanni; Andreone, Pietro
abstract

INTRODUCTION: The population of patients with hepatitis C is aging. In some countries, the prevalence of hepatitis C virus (HCV) is actually greater in older patients than in younger individuals. It is also anticipated that hepatitis C will increasingly become a disease of older persons. However, patients older than 70 years are typically excluded from clinical trials. The decision to treat older patients is complex and cannot be made at the sole discretion of the physician. AREAS COVERED: There is an urgent need to analyze treatment outcomes in the elderly to examine response rates in order to aid in therapeutic decision making. EXPERT OPINION: In geriatric HCV-infected patients, dual therapy with pegylated IFN plus ribavirin is associated with a lower sustained virologic response and a higher discontinuation rate. Even the first-generation protease inhibitors are associated with high rates of side effects, in particular in elderly patients with a high prevalence of comorbidities. The recent development of interferon-sparing regimens could change the treatment paradigm in this setting, and a much larger number of patients could have access to the antiviral therapy programs.

2014 - Update on Alcohol and Viral Hepatitis [Articolo su rivista]
Gitto, Stefano; Vitale, Giovanni; Villa, Erica; Andreone, Pietro
abstract

Alcohol consumption is often associated with viral hepatitis. Although alcohol is known to worsen viral liver disease, the interactions between alcohol and viral hepatitis are not fully understood. Molecular alterations in the liver due to alcohol and viral hepatitis include effects on viral replication, increased oxidative stress, cytotoxicity, and a weakened immune response. Clinically, alcohol enhances disease progression and favors induction of primitive liver neoplasm. The use of new antivirals for hepatitis C and well-established drugs for hepatitis B will determine how viral hepatitis can be controlled in a large percentage of these patients. However, alcohol-related liver disease continues to represent a barrier for access to antivirals, and it remains an unresolved health issue.

2013 - Authors’ reply: Comment to “Liver transplantation for patients with alcoholic liver disease: An open question” [Articolo su rivista]
Gramenzi, A; Biselli, M; Andreone, P
abstract

2013 - Decline in pulmonary function during chronic hepatitis C virus therapy with modified interferon alfa and ribavirin [Articolo su rivista]
Foster, G. R.; Zeuzem, S.; Pianko, S.; Sarin, S. K.; Piratvisuth, T.; Shah, S.; Andreone, P.; Sood, A.; Chuang, W. -L.; Lee, C. -M.; George, J.; Gould, M.; Flisiak, R.; Jacobson, I. M.; Komolmit, P.; Thongsawat, S.; Tanwandee, T.; Rasenack, J.; Sola, R.; Messina, I.; Yin, Y.; Cammarata, S.; Feutren, G.; Brown, K. K.
abstract

Rare interstitial lung disease cases have been reported with albinterferon alfa-2b (albIFN) and pegylated interferon alfa-2a (Peg-IFNα-2a) in chronic hepatitis C virus (HCV) patients. Systematic pulmonary function evaluation was conducted in a study of albIFN q4wk vs Peg-IFNα-2a qwk in patients with chronic HCV genotypes 2/3. Three hundred and ninety-one patients were randomly assigned 4:4:4:3 to one of four, open-label, 24-week treatment groups including oral ribavirin 800 mg/d: albIFN 900/1200/1500 μg q4wk or Peg-IFNα-2a 180 μg qwk. Standardized spirometry and diffusing capacity of the lung for carbon monoxide (DLCO) were recorded at baseline, weeks 12 and 24, and 6 months posttreatment, and chest X-rays (CXRs) at baseline and week 24. Baseline spirometry and DLCO were abnormal in 35 (13%) and 98 (26%) patients, respectively. Baseline interstitial CXR findings were rare (4 [1%]). During the study, clinically relevant DLCO declines (≥15%) were observed in 173 patients (48%), and were more frequent with Peg-IFNα-2a and albIFN 1500 μg; 24 weeks posttreatment, 57 patients (18%) still had significantly decreased DLCO, with a pattern for greater rates with albIFN vs Peg-IFNα-2a. One patient developed new interstitial CXR abnormalities, but there were no clinically relevant interstitial lung disease cases. The risk of persistent posttreatment DLCO decrease was not related to smoking, alcohol, HCV genotype, sustained virologic response, or baseline viral load or spirometry. Clinically relevant DLCO declines occurred frequently in chronic HCV patients receiving IFNα/ribavirin therapy and commonly persisted for ≥6 months posttherapy. The underlying mechanism and clinical implications for long-term pulmonary function impairment warrant further research.

2013 - Differential boosting of innate and adaptive antiviral responses during pegylated-interferon-alpha therapy of chronic hepatitis B [Articolo su rivista]
Micco, L; Peppa, D; Loggi, E; Schurich, A; Jefferson, L; Cursaro, C; Panno, Am; Bernardi, M; Brander, C; Bihl, F; Andreone, P; Maini, Mk.
abstract

Background & Aims: A better understanding of the immunomodulatory effects of PegIFNa therapy could allow more rational optimisation of future therapeutic approaches in chronic HBV infection. In this study, we evaluated dynamic changes in the innate and adaptive arms of the immune system induced by PegIFNa. Methods: PBMC were obtained from a cohort of patients with eAg-negative CHB before, during and after PegIFNa treatment. The number, phenotype and function of global and virus-specific T cells and NK cells were analyzed by flow cytometry and serum cytokines by ELISA or CBA. Results: The absolute number of CD8 T cells was strikingly reduced on PegIFNa therapy (p <0.001), with a predominant loss of end-stage effectors, including CMV-specific CD8 T cells. There was no significant recovery of the exhausted HBV-specific CD8 T cell response. By contrast, PegIFNa was able to potently and cumulatively drive the proliferation and expansion in absolute numbers of CD56bright NK cell numbers (p <0.001), with induction of the pro-proliferative cytokine IL-15. Expanded CD56bright NK cells showed enhanced expression of activation markers and the activating receptor NKp46, accompanied by augmentation of TRAIL and IFN-c expression (p <0.001). Peak virological response (temporal within individual patients and crosssectional within the cohort) correlated with the degree of expansion of functional CD56bright NK cells. Conclusions: IFN-a mediates divergent effects on the innate and adaptive arms of the immune system in vivo. The efficacy of Peg- IFNa may be limited by its depleting effect on CD8 T cells; conversely, it can cumulatively drive proliferation, activation and antiviral potential of CD56bright NK cells.

2013 - Homeostasis model assessment of insulin resistance does not seem to predict response to telaprevir in chronic hepatitis C in the REALIZE trial [Articolo su rivista]
Younossi, Zobair; Negro, Francesco; Serfaty, Lawrence; Pol, Stanislas; Diago, Moises; Zeuzem, Stefan; Andreone, Pietro; Lawitz, Eric J.; Roberts, Stuart; Focaccia, Roberto; Foster, Graham R.; Horban, Andrzej; Lonjon-Domanec, Isabelle; Coate, Bruce; DeMasi, Ralph; Picchio, Gaston; Witek, James
abstract

Baseline homeostasis model assessment-estimated insulin resistance (HOMA-IR), a marker for insulin resistance, has been associated with poor virologic response to peginterferon alpha/ribavirin (PR) in chronic hepatitis C. We evaluated the association between baseline HOMA-IR and pretreatment factors on sustained virologic response (SVR) to telaprevir (TVR) in genotype 1 patients with hepatitis C and prior peginterferon/ribavirin (PR) treatment failure. Patients were randomized to 12 weeks of TVR (750 mg q8h) plus peginterferon (180 μg/week) and ribavirin (1,000-1,200 mg/day) (with or without a 4-week lead-in) followed by PR, or PR alone (PR48), for 48 weeks. Univariate and multiple logistic regression analyses explored the prognostic significance of baseline HOMA-IR alone and adjusted for other pretreatment factors and SVR. The TVR arms were pooled for the purposes of this analysis. In all, 662 patients were randomized; 578 had baseline HOMA-IR and other prognostic data and were included in this analysis. Median baseline HOMA-IR was 2.6 (interquartile range [IQR] 1.7-4.3); 207 (36%), 206 (36%), and 165 (29%) patients had baseline HOMA-IR <2, 2 to <4, and ≥ 4, respectively. Male gender, higher body mass index, triglycerides, gamma-glutamyl transpeptidase, maximum alanine aminotransferase/aspartate aminotransferase, and fibrosis stage were associated with higher baseline HOMA-IR. Baseline HOMA-IR was associated with SVR in univariate analysis, but not after adjustment for other baseline prognostic factors (TVR: OR = 0.95, 95% confidence interval [CI]: 0.71,1.29; PR48: 0.60; 95% CI: 0.25,1.43). CONCLUSION: In patients with prior PR treatment failure, baseline HOMA-IR correlated with SVR in univariate but not multivariate analyses, suggesting other factors have a more direct causal relationship with virologic response to TVR-based therapy than HOMA-IR.

2013 - Limited impact of IL28B genotype on response rates in telaprevir-treated patients with prior treatment failure [Articolo su rivista]
Pol, S; Aerssens, J; Zeuzem, S; Andreone, P; Lawitz, Ej; Roberts, S; Younossi, Z; Foster, Gr; Focaccia, R; Horban, A; Pockros, Pj; Van Heeswijk, Rp; De Meyer, S; Luo, D; Botfield, M; Beumont, M; Picchio, G.
abstract

BACKGROUND & AIMS: Nucleotide polymorphisms upstream of the interleukin 28B (IL28B) gene are strongly associated with hepatitis C virus (HCV) clearance in treatment-naïve patients treated with peginterferon/ribavirin (PegIFN/RBV). This subanalysis of the REALIZE study evaluated the impact of IL28B polymorphisms on sustained virologic response (SVR) in telaprevir-treated, HCV genotype 1-infected patients with prior PegIFN/RBV treatment failure. METHODS: Treatment-experienced patients were randomized to 12 weeks of telaprevir (750 mg every 8h) with/without a 4-week PegIFN/RBV lead-in, or placebo, each with PegIFN-α-2a (180 μg/week) and ribavirin (1000-1200 mg/day) for 48 weeks overall. Data from telaprevir arms were pooled. RESULTS: Eighty percent (527/662) of patients consented to genetic testing and were included. Similar proportions of patients had IL28B CC, CT and TT genotypes across treatment arms; baseline characteristics were generally well balanced. SVR rates were higher in the pooled telaprevir versus placebo group for all IL28B genotypes; CC: 79% versus 29%, respectively; CT: 60% versus 16%, respectively; TT: 61% versus 13%, respectively. Within each prior response category (relapse, partial or null response), SVR and viral breakthrough rates with telaprevir-based treatment were comparable across IL28B genotypes. IL28B genotype did not significantly affect SVR (2-step multivariate analyses; p >0.16 in pairwise comparison among CC, TT, and CT). Variations in rapid virologic response and relapse rates were noted in certain patient subgroups. CONCLUSIONS: Our findings suggest that IL28B genotype has a limited impact on SVR rates with telaprevir-based therapy in treatment-experienced patients. IL28B genotyping may have limited utility in the baseline evaluation of similar patients considered for telaprevir-based therapy.

2013 - Metronomic capecitabine in advanced hepatocellular carcinoma patients:a phase II study [Articolo su rivista]
Brandi, G.; de Rosa, F.; Agostini, V.; Di Girolamo, S.; Andreone, P.; Bolondi, L.; Serra, C.; Sama, C.; Golfieri, R.; Gramenzi, A.; Cucchetti, A.; Pinna, A. D.; Trevisani, F.; Biasco, G.; and the Italian Liver Cancer, (ITA. LI. CA) group.
abstract

Anti-angiogenic treatment with targeted agents is effective in advanced hepatocellular carcinoma (HCC). This trial evaluated the safety and efficacy of metronomic capecitabine in patients with HCC. METHODS: This single-institution phase II trial included 59 previously untreated patients with advanced HCC and 31 patients resistant to or intolerant of sorafenib. The treatment schedule was capecitabine 500 mg twice daily until progression of disease, unacceptable toxicity level, or withdrawal of informed consent. Progression-free survival (PFS) was chosen as the primary endpoint. RESULTS: A total of 59 previously untreated and 31 previously treated patients with HCC were enrolled. The first cohort achieved a median PFS of 6.03 months and an overall survival (OS) of 14.47 months. Two patients achieved a complete response, 1 patient achieved partial response, and in 30 patients, stable disease was the best outcome. The second cohort achieved a median PFS of 3.27 months and a median OS of 9.77 months. No complete or partial responses were observed, but 10 patients had stable disease. An unscheduled comparison of the first cohort of patients with 3,027 untreated patients with HCC from the Italian Liver Cancer (ITA.LI.CA) database was performed. One-to-one matching according to demographic/etiologic/oncologic features was possible for 50 patients. The median OS for these 50 capecitabine-treated patients was 15.6 months, compared with a median OS of 8.0 months for the matched untreated patients (p = .043). CONCLUSION: Metronomic capecitabine is well tolerated by patients with advanced HCC and appears to have activity both in treatment-naive patients and in those previously treated with sorafenib.

2013 - Pathway-based analysis of primary biliary cirrhosis genome-wide association studies [Articolo su rivista]
Kar, Sp; Seldin, Mf; Chen, W; Lu, E; Hirschfield, Gm; Invernizzi, P; Heathcote, J; Cusi, D; the Italian PBC Genetics Study Group, [. . .; Andreone, P; Muratori, L; Muratori, P; ], . .; Gershwin, Me; Siminovitch, Ka; Amos, Ci
abstract

Genome-wide association studies (GWAS) have successfully identified several loci associated with primary biliary cirrhosis (PBC) risk. Pathway analysis complements conventional GWAS analysis. We applied the recently developed linear combination test for pathways to datasets drawn from independent PBC GWAS in Italian and Canadian subjects. Of the Kyoto Encyclopedia of Genes and Genomes and BioCarta pathways tested, 25 pathways in the Italian dataset (449 cases, 940 controls) and 26 pathways in the Canadian dataset (530 cases, 398 controls) were associated with PBC susceptibility (P<0.05). After correcting for multiple comparisons, only the eight most significant pathways in the Italian dataset had FDR <0.25 with tumor necrosis factor/stress-related signaling emerging as the top pathway (P=7.38 x 10(-)(4), FDR=0.18). Two pathways, phosphatidylinositol signaling and hedgehog signaling, were replicated in both datasets (P<0.05), and subjected to two additional complementary pathway tests. Both pathway signals remained significant in the Italian dataset on modified gene set enrichment analysis (P<0.05). In both GWAS, variants nominally associated with PBC were significantly overrepresented in the phosphatidylinositol pathway (Fisher exact P<0.05). These results point to established and novel pathway-level associations with inherited predisposition to PBC that, on further independent replication and functional validation, may provide fresh insights into PBC etiology.

2013 - Patterns of HCV-RNA and HCV core antigen in the early monitoring of standard treatment for chronic hepatitis C [Articolo su rivista]
Loggi, E; Cursaro, C; Scuteri, A; Grandini, E; Panno, Am; Galli, S; Furlini, G; Bernardi, M; Galli, C; Andreone, P.
abstract

Background: An early drop of HCV-RNA levels is useful in assessing response to antiviral treatment in chronic hepatitis C; the first recommended time point is 4 weeks after the start of therapy. Objectives: We evaluated retrospectively HCV-RNA and HCVAg levels at different time points to assess the clinical value of an early monitoring. Study design: Thirty-five patients with chronic hepatitis C infected by genotype 1b and consecutively enrolled in an open-label study on PegIFN plus Ribavirin and/or ketoprofene were tested for HCV-RNA (real-time PCR) and HCVAg (ARCHITECT) at baseline and after 1 and 2 days and 1, 2, 4 and 12 weeks after the start of treatment. Treatment response was assessed according to the EASL consensus criteria. Results: In the 17 sustained responders (SR) the median log decrease of HCV-RNA and HCVAg at the different time points was 0.40 and 0.37; 1.36 and 0.84; 1.47 and 0.97; 2.34 and 1.86; 2.51 and 2.32; 3.28 and 2.61, respectively. The best time point to predict SR was 2 weeks after the start of therapy, with a sensitivity, specificity and overall accuracy of 76.9%, 86.7% and 82.1% for HCV-RNA and 81.8%, 75.0% and 76.8% for HCVAg, respectively. Discussion: An early monitoring is at least equally effective than standard monitoring in predicting response to hepatitis C therapy. The similarity of HCV-RNA and HCVAg kinetics suggests that HCVAg may be useful in the early phases as a trigger to evaluate HCV-RNA levels at earlier time points for a personalized approach to therapy monitoring.

2013 - Predicting Early and Sustained Virological Responses in Prior Nonresponders to Pegylated Interferon alpha-2b Plus Ribavirin Retreated With Peginterferon alpha-2a Plus Ribavirin and the Benefit-Risk Ratio of Retreatment [Articolo su rivista]
Marcellin, Patrick; Craxi, Antonio; Brandao-Mello, Carlos E.; Di Bisceglie, Adrian M.; Andreone, Pietro; Freilich, Bradley; Rajender Reddy, K.; Olveira Martín, Antonio; Teuber, Gerlinde; Messinger, Diethelm; Hooper, Greg; Wat, Cynthia; Tatsch, Fernando; Jensen, Donald M.
abstract

GOALS: To evaluate the predictive value of complete early virological response (cEVR) on sustained virological response (SVR) following retreatment with peginterferon alpha-2a (40 kDa) plus ribavirin in previous nonresponders to peginterferon alpha-2b (12 kDa). BACKGROUND: In the randomized multinational retreatment with Pegasys in patients not responding to PegIntron therapy study, a 72-week regimen of peginterferon alpha-2a (40 kDa) plus ribavirin improved SVR rates over a standard 48-week regimen in previous nonresponders to peginterferon alpha-2b (12 kDa). cEVR, defined as hepatitis C virus RNA <50 IU/mL at treatment week 12, was an important predictor of SVR. STUDY: We conducted an exploratory analysis of the retreatment with Pegasys in patients not responding to PegIntron therapy study data to better define the predictive value of cEVR for SVR in this patient population. RESULTS: In total, 157 of the 942 patients achieved a cEVR (16.7%). SVR rates were higher with 72 versus 48 weeks of retreatment in patients with a cEVR (57% vs. 35%), whereas SVR rates were <5% in patients without cEVR in both groups. The relative adverse event (AE) burden was lower with 72 weeks of treatment (8.1 vs. 10.1 AEs/y of treatment) as was the estimated number of AEs per SVR achieved (55 vs. 100). Cumulative treatment duration required to achieve 1 SVR was lower with 72 weeks of treatment (6.7 vs. 10.0 y/SVR) and lower still assuming that treatment was stopped at week 12 for non-cEVR patients (3.6 vs. 7.1 y/SVR). CONCLUSIONS: cEVR is a reliable predictor of SVR in patients retreated with peginterferon alpha-2a (40 kDa) plus ribavirin. Seventy-two-week retreatment has a more favorable benefit-risk ratio than 48 weeks, especially when cEVR is used to identify patients most likely to be cured.

2013 - Randomised study comparing 48 and 96 weeks peginterferon α-2a therapy in genotype D HBeAg-negative chronic hepatitis B [Articolo su rivista]
Lampertico, P.; Vigano, M.; Di Costanzo, G. G.; Sagnelli, E.; Fasano, M.; Di Marco, V.; Boninsegna, S.; Farci, P.; Fargion, S.; Giuberti, T.; Iannacone, C.; Regep, L.; Massetto, B.; Facchetti, F.; Colombo, M.; Andreone, P.; Riili, A.; Scuteri, A.; Cursaro, C.; Andriulli, A.; Niro, G. A.; Angarano, G.; Santantonio, T. A.; Palattella, M. S.; Brunetto, M.; Colombatto, P.; Coco, B.; Ciccorossi, P.; Oliveri, F.; Sacco, R.; Bruno, S.; Bollani, S.; Chiesa, A.; Carosi, G.; Baiguera, C.; Rossi, S.; Zaltron, S.; Puoti, M.; Colombo, M.; Cozzolongo, R.; Giannuzzi, V.; Craxi, A.; Calvaruso, V.; Venezia, G.; Lanza, A. G.; Di Perri, G.; Cariti, G.; Mollaretti, O.; De Blasi, T.; Kulmiye, C.; Rostagno, R.; Lai, M. E.; Serra, G.; Chessa, L.; Balestrieri, C.; Cauli, C.; Bertelli, C.; Fatta, E.; Fattovich, G.; Pasino, M.; Zanni, S.; Olivari, N.; Zagni, I.; Ferrari, C.; Schivazappa, S.; Laccabue, D.; Penna, A.; Gaeta, G.; Stanzione, M.; Stornaiuolo, G.; Martines, D.; Raimondo, G.; Caccamo, G.; Squadrito, G.; Isgro, G.; Rizzetto, M.; Lagget, M.; Carenzi, S.; Ruggiero, G.; Marrone, A.; Messina, V.; Di Caprio, D. U.; Selva, V.; Toniutto, P.
abstract

Objective: Treatment with peginterferon α-2a (PegIFN) for 48 weeks is the standard of care for selected HBeAg-negative patients chronically infected with hepatitis B virus (HBV), but with limited treatment efficacy. A study was undertaken to investigate whether treatment extension to 96 weeks improves the outcome in this patient population. Methods: 128 HBeAg-negative patients (120 genotype D) were randomised to weekly 180 mg PegIFN for 48 weeks (group A, n=51), 180 μg PegIFN for 48 weeks followed by 135 mg weekly for an additional 48 weeks (group B, n=52) or 180 μg PegIFN plus lamivudine (100 mg/day) for 48 weeks then 135 μg PegIFN for 48 weeks (group C, n=25). Endpoints were alanine aminotransferase normalisation plus HBV DNA <3400 IU/ml (primary), HBV DNA <2000 IU/ml and HBsAg clearance at 48 weeks after treatment. Results: Forty-eight weeks after treatment, six patients in group A and 13 in group B achieved alanine aminotransferase normalisation plus HBV DNA <3400 IU/ml (11.8% vs 25.0%, p=0.08), 6 vs 15 patients had HBV DNA <2000 IU/ml (11.8% vs 28.8%, p=0.03), 0 vs 3 achieved HBsAg clearance (0% vs 5.8%, p=0.24) and 0 vs 5 had HBsAg <10 IU/ml (0% vs 9.6%, p=0.06). While extended PegIFN treatment was the strongest independent predictor of response, the combination with lamivudine did not improve responses. Discontinuation rates were similar among the groups (19.6%, 23.1%, 32.0%, p=0.81) and were mostly due to PegIFN-related adverse events. Conclusions: In HBeAg-negative genotype D patients with chronic hepatitis B, PegIFN treatment for 96 weeks was well tolerated and the post-treatment virological response improved significantly compared with 48 weeks of treatment. Trial registration number http://ClinicalTrials.gov registration number: NCT01095835.

2013 - Sustained virologic response rates with telaprevir by response after 4weeks of lead-in therapy in patients with prior treatment failure [Articolo su rivista]
Foster, Graham R.; Zeuzem, Stefan; Andreone, Pietro; Pol, Stanislas; Lawitz, Eric J.; Diago, Moises; Roberts, Stuart; Pockros, Paul J.; Younossi, Zobair; Lonjon-Domanec, Isabelle; De Meyer, Sandra; Luo, Don; George, Shelley; Beumont, Maria; Picchio, Gaston
abstract

BACKGROUND & AIMS: For hepatitis C virus (HCV)-infected patients who have not responded to previous PegIFN/ribavirin treatment, it is unclear whether subsequent direct-acting antiviral therapy outcomes are better predicted by prior treatment response or by on-treatment response to a PegIFN/ribavirin lead-in. METHODS: In REALIZE, treatment-experienced patients randomized to the lead-in telaprevir arm received 4 weeks of PegIFN-α-2a (180 μg/week) and ribavirin (1000-1200 mg/day), then 12 weeks of telaprevir (750 mg every 8h) plus PegIFN-α-2a/ribavirin, followed by 32 weeks of PegIFN-α-2a/ribavirin. This subanalysis only included patients in the lead-in telaprevir arm with available week 4 on-treatment response data (n=240). RESULTS: After 4weeks of PegIFN/ribavirin, 90% of relapsers, 60% of partial responders, and 41% of null responders in the lead-in telaprevir arm had ⩾1 log(10) HCV RNA reduction. Sustained virologic response (SVR) rates for telaprevir-treated patients with ≥1 versus <1 log(10) HCV RNA reduction after the PegIFN/ribavirin lead-in were 94% versus 62% in relapsers, 59% versus 56% in partial responders and 54% versus 15% in null responders. CONCLUSIONS: In prior relapsers and partial responders there is no apparent benefit of assessing response after a PegIFN/ribavirin lead-in with the aim of guiding telaprevir-based treatment. For patients known to be prior null responders, on-treatment response after a 4-week PegIFN/ribavirin lead-in may provide clinically useful prognostic information. However, withholding telaprevir-containing therapy in uncategorised treatment-experienced patient populations (i.e., that could include prior relapsers or partial responders), using response after a PegIFN/ribavirin lead-in could potentially exclude some patients with a high chance of SVR.

2013 - Virus-specific immune response in HBeAg-negative chronic hepatitis B: relationship with clinical profile and HBsAg serum levels [Articolo su rivista]
Loggi, Elisabetta; Bihl, Fk; Cursaro, C; Granieri, C; Galli, S; Brodosi, Lucia; Furlini, G; Bernardi, Mauro; Brander, C; Andreone, Pietro
abstract

Background & Aims: The immune impairment characterizing chronic hepatitis B (cHBV) infection is thought to be the consequence of persistent exposure to viral antigens. However, the immune correlates of different clinical stages of cHBV and their relation with different levels of HBsAg have not been investigated. The aim of the present study was to evaluate the relationship between HBV-specific T cells response and the degree of in vivo HBV control and HBsAg serum levels in HBeAg-HBeAb+ cHBV. Methods: Peripheral blood mononuclear cells from 42 patients with different clinical profiles (treatment-suppressed, inactive carriers and active hepatitis) of cHBV, 6 patients with resolved HBV infection and 10 HBV-uninfected individuals were tested with overlapping peptides spanning the entire HBV proteome. The frequency and magnitude of HBV-specific T cell responses was assessed by IFNc ELISPOT assay. Serum HBsAg was quantified with a chemiluminescent immunoassay. Results: The total breadth and magnitude of HBV-specific T cell responses did not differ significantly between the four groups. However, inactive carriers targeted preferentially the core region. In untreated patients, the breadth of the anti-core specific T cell response was inversely correlated with serum HBsAg concentrations as well as HBV-DNA and ALT levels and was significantly different in patients with HBsAg levels either above or below 1000 IU/mL. The same inverse association between anti-core T cell response and HBsAg levels was found in treated patients. Conclusions: Different clinical outcomes of cHBV infection are associated with the magnitude, breadth and specificity of the HBV-specific T cell response. Especially, robust anti-core T cell responses were found in the presence of reduced HBsAg serum levels, suggesting that core-specific T cell responses can mediate a protective effect on HBV control.

2012 - Antibodies against pegylated interferon-alpha affect response to treatment in patients with chronic hepatitis C [Abstract in Rivista]
Loggi, Elisabetta; Scuteri, Alessandra; MARTELLO PANNO, Arianna; Grandini, Elena; Cursaro, C.; Margotti, Marzia; Foglianti, G.; Bernardi, Mauro; Brillanti, Stefano; Andreone, Pietro
abstract

2012 - Balapiravir plus peginterferon alfa-2a (40KD)/ribavirin in a randomized trial of hepatitis C genotype 1 patients [Articolo su rivista]
Nelson, Dr; Zeuzem, S; Andreone, P; Ferenci, P; Herring, R; Jensen, Dm; Marcellin, P; Pockros, Pj; Rodríguez-Torres, M; Rossaro, L; Rustgi, Vk; Sepe, T; Sulkowski, M; Thomason, Ir; Yoshida, Em; Chan, A; Hill, G.
abstract

INTRODUCTION: Balapiravir (R1626, RG1626) is the prodrug of a nucleoside analogue inhibitor of the hepatitis C virus (HCV) RNA-dependent RNA polymerase (R1479, RG1479). This phase 2, double-blind international trial evaluated the optimal treatment regimen of balapiravir plus peginterferon alfa-2a (40KD)/ribavirin. MATERIAL AND METHODS: Treatment-naive genotype 1 patients (N = 516) were randomized to one of seven treatment groups in which they received balapiravir 500, 1,000, or 1,500 mg twice daily, peginterferon alfa-2a (40KD) 180 or 90 µg/week and ribavirin 1,000/1,200 mg/day or peginterferon alfa-2a (40KD)/ribavirin. The planned treatment duration with balapiravir was reduced from 24 to 12 weeks due to safety concerns. RESULTS: The percentage of patients with undetectable HCV RNA was consistently higher in all balapiravir groups from week 2 to 12. However, high rates of dose modifications and discontinuations of one/all study drugs compromised the efficacy assessment and resulted in similar sustained virological response rates in the balapiravir groups (range 32-50%) and the peginterferon alfa-2a (40KD)/ribavirin group (43%). Balapiravir was discontinued for safety reasons in 28-36% of patients (most often for lymphopenia) and the percentage of patients with serious adverse events (especially hematological, infection, ocular events) was dose related. Serious hematological adverse events (particularly neutropenia, lymphopenia) were more common in balapiravir recipients. Two deaths in the balapiravir/peginterferon alfa-2a/ribavirin combination groups were considered possibly related to study medication. CONCLUSION: Further development of balapiravir for the treatment of chronic hepatitis C has been halted because of the unacceptable benefit to risk ratio revealed in this study (www.ClinicalTrials.gov NCT 00517439).

2012 - CD 133+ stem cells for the treatment of end stage liver disease [Abstract in Atti di Convegno]
Brodosi, Lucia; Catani, Lucia; S., Lorenzini; R., Giordano; S., Rizzi; V., Giudice; Sollazzo, Daria; B., Nicolini; E., Montelatici; T., Montemurro; E., Dan; E., Massari; Baccarani, Michele; Bernardi, Mauro; Lemoli, ROBERTO MASSIMO; Andreone, Pietro
abstract

Previous studies have shown that bone marrow (BM) cells contribute to liver regeneration after tissue injury. The main objective of the present study was to evaluate the feasibility and the safety of the purification and intrahepatic reinfusion of increasing numbers of autologous BM-derived G-CSF-mobilized CD133+ stem cells (SCs) in patients with end-stage liver disease (ESLD). For this purpose, G-CSF at 7.5 µg/Kg/b.i.d. is administered subcutaneously (sc) from day 1 until the completion of peripheral blood stem cells (PBSC) collection. Collection of PBSC begin on day + 5 only if the concentration of CD133+ cells is > 8/µL. CliniMacs device is used for the positive selection of CD133+ SCs (under GMP conditions) from PB of mobilized standard-volume leukapheresis. At least 4 weeks after SC mobilization, collection and cryopreservation, highly purified autologous G-CSF-mobilized CD133+ cells are re-infused through the hepatic artery by transfemoral or transbrachial arteriography. CD133+ cells are administered to patients starting from 5x104/Kg patient’s body weight and increased every 3 patients up to 1x106/kg. G-CSF at 5µg/Kg/day is administered sc for 3 days after the reinfusion of SCs for their expansion and to induce a selective proliferative advantage of reinfused cells in vivo. Biological assays (phenotype of circulating SCs, clonogenic assays, serum cytokines) were done during the mobilization and re-infusion phases together with the phenotypic characterization of the isolated CD133+ SCs. The clinical trial is ongoing. Up to date, 9 patients have been successfully mobilized with G-CSF and highly purified autologous CD133+ SCs have been re-infused in 7 cases. Based on preliminary data, we suggest the feasibility and safety of intrahepatic reinfusion of highly purified CD133+ stem cells in patients with ESLD. Biological studies show that: 1) circulating hematopoietic and endothelial progenitors are increased after G-CSF treatment; 2) highly purified CD133+ cells express hematopoietic and endothelial markers; 3) serum concentration of HGF, SDF-1, VEGF and MMP9 and clonogenic capability of hematopoietic progenitors are increased during the mobilization and re-infusion phases; 4) clonogenic potential of endothelial progenitors shows variable expression.

2012 - Classical HLA-DRB1 and DPB1 alleles account for HLA associations with primary biliary cirrhosis [Articolo su rivista]
Invernizzi, P; Ransom, M; Raychaudhuri, S; Kosoy, R; Lleo, A; Shigeta, R; Franke, A; Bossa, F; Amos, Ci; Gregersen, Pk; Siminovitch, Ka; Cusi, D; de Bakker, Pi; Podda, M; Gershwin, Me; Seldin MFAlmasio, Pl; Alvaro, D; Andreone, P; Andriulli, A; Barlassina, C; Benedetti, A; Bernuzzi, F; Bianchi, I; Bragazzi, Mc; Brunetto, M; Bruno, S; Caliari, L; Casella, G; Civardi, F; Coco, B; Colli, A; Colombo, M; Colombo, S; Cursaro, C; Croce, Ls; Crosignani, A; Donato, F; Fabris, L; Ferrari, C; Floreani, A; Galli, A; Grattagliano, I; Lazzari, R; Macaluso, F; Marra, F; Marzioni, M; Mattalia, A; Montanari, R; Morini, L; Morisco, F; Moroni, L; Muratori, L; Muratori, P; Niro, G; Picciotto, A; Portincasa, P; Prati, D; Prisco, C; Rosina, F; Rossi, S; Selmi, C; Spinzi, G; Strazzabosco, M; Tarallo, S; Tiribelli, C; Toniutto, P; Vinci, M; Zuin, M.
abstract

Susceptibility to primary biliary cirrhosis (PBC) is strongly associated with human leukocyte antigen (HLA)-region polymorphisms. To determine if associations can be explained by classical HLA determinants, we studied Italian, 676 cases and 1440 controls, genotyped with dense single-nucleotide polymorphisms (SNPs) for which classical HLA alleles and amino acids were imputed. Although previous genome-wide association studies and our results show stronger SNP associations near DQB1, we demonstrate that the HLA signals can be attributed to classical DRB1 and DPB1 genes. Strong support for the predominant role of DRB1 is provided by our conditional analyses. We also demonstrate an independent association of DPB1. Specific HLA-DRB1 genes (*08, *11 and *14) account for most of the DRB1 association signal. Consistent with previous studies, DRB1*08 (P=1.59 × 10(-11)) was the strongest predisposing allele, whereas DRB1*11 (P=1.42 × 10(-10)) was protective. Additionally, DRB1*14 and the DPB1 association (DPB1*03:01; P=9.18 × 10(-7)) were predisposing risk alleles. No signal was observed in the HLA class 1 or class 3 regions. These findings better define the association of PBC with HLA and specifically support the role of classical HLA-DRB1 and DPB1 genes and alleles in susceptibility to PBC.Genes and Immunity advance online publication, 10 May 2012; doi:10.1038/gene.2012.17.

2012 - Combined blockade of programmed death-1 and activation of CD137 increase responses of human liver T cells against HBV, but not HCV [Articolo su rivista]
Fisicaro, Paola; Valdatta, Caterina; Massari, Marco; Loggi, Elisabetta; Ravanetti, Lara; Urbani, Simona; Giuberti, Tiziana; Cavalli, Albertina; Vandelli, Carmen; Andreone, Pietro; Missale, Gabriele; Ferrari, Carlo
abstract

In patients with chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infections, antiviral functions of T cells are impaired; these might be increased by blocking T-cell co-inhibitory pathways, such as preventing interaction between the receptor programmed death (PD)-1 and its ligand, PD-L1. We attempted to optimize the restoration of T-cell functions in patients with chronic HBV or HCV infection with a combination of reagents that block PD-1 interaction with PD-L1 and stimulate T-cell signaling via CD137, a member of the tumor necrosis factor-receptor family.

2012 - Eltrombopag before procedures in patients with cirrhosis and thrombocytopenia [Articolo su rivista]
Afdhal, Nh; Giannini, Eg; Tayyab, G; Mohsin, A; Lee, Jw; Andriulli, A; Jeffers, L; Mchutchison, J; Chen, Pj; Han, Kh; Campbell, F; Hyde, D; Brainsky, A; Theodore, D; ELEVATE Study Group, […; Akram, J; Andreone, P; Bessonova, E; Bilodeau, M; Bloomer, J; Botta-Fridlund, D; Bzowej, N; Calmus, Y; Carbonell, N; Caro Patón, A; Cholewinska, G; Chuang, Wl; Colombato, L; Colombo, M; Craxi, A; Di Leo, A; Diago, M; Dumortier, J; Elkasahab, M; Everson, G; Fallon, M; Fedeli, G; Finazzi, R; Fontanella, A; Francavilla, A; Gadano, A; Gambarin-Gelwan, M; Gordon, F; Graus Morales, J; Grieco, A; Gugenheim, J; Homenda, W; Iaquinto, G; Kang, H; Khan, Z; Kuliczkowski, K; Kwo, P; Lee, Jh; Lee, W; Lee, Ys; Mazur, W; Mazzella, G; Moreno, C; Morozov, V; Muñoz, A; Navasa Anadón, M; Nijhawan, S; Pinzello, G; Poordad, F; Prieto Castillo, M; Rafalsky, V; Rapaccini, G; Regenstein, F; Rewak, W; Riley, T; Ripoll Noiseux, C; Rizzetto, M; Rodrigo Lopez, J; Russo, M; Samuel, D; Sánchez Antolín, G; Satyanaryana, R; Savarino, V; Shiffman, M; Sigal, S; Solá Lamoglia, R; Sterling, R; Tanno, H; Te, H; Terg, R; Thuluvath, P; Trepo, C; Vargas, H; Xiol Quingles, X; Zaman, A; Fontana, R; Kim, K; Abrams, C; Gish, R; Cardenas, A; …],
abstract

BACKGROUND: Eltrombopag is an oral thrombopoietin-receptor agonist. This study evaluated the efficacy of eltrombopag for increasing platelet counts and reducing the need for platelet transfusions in patients with thrombocytopenia and chronic liver disease who are undergoing an elective invasive procedure. METHODS: We randomly assigned 292 patients with chronic liver disease of diverse causes and platelet counts of less than 50,000 per cubic millimeter to receive eltrombopag, at a dose of 75 mg daily, or placebo for 14 days before a planned elective invasive procedure that was performed within 5 days after the last dose. The primary end point was the avoidance of a platelet transfusion before, during, and up to 7 days after the procedure. A key secondary end point was the occurrence of bleeding (World Health Organization [WHO] grade 2 or higher) during this period. RESULTS: A platelet transfusion was avoided in 104 of 145 patients who received eltrombopag (72%) and in 28 of 147 who received placebo (19%) (P<0.001). No significant difference between the eltrombopag and placebo groups was observed in bleeding episodes of WHO grade 2 or higher, which were reported in 17% and 23% of patients, respectively. Thrombotic events of the portal venous system were observed in 6 patients who received eltrombopag, as compared with 1 who received placebo, resulting in the early termination of the study. The incidence and severity of other adverse events were similar in the eltrombopag and placebo groups. CONCLUSIONS: Eltrombopag reduced the need for platelet transfusions in patients with chronic liver disease who were undergoing elective invasive procedures, but it was associated with an increased incidence of portal-vein thrombosis, as compared with placebo.

2012 - Hepatitis C in the elderly: a multicenter cross-sectional study by the Italian Association for the Study of the Liver [Articolo su rivista]
Gramenzi, A; Conti, F; Cammà, C; Grieco, A; Picciotto, A; Furlan, C; Romagno, D; Rendina, M; Chiaramonte, M; Verucchi, G; Craxi, A; Bernardi, M; Andreone, P.
abstract

BACKGROUND: The prevalence of hepatitis C virus infection increases with advancing age, but elderly hepatitis C virus patients remain an understudied population. AIM: To define the virological, epidemiological and clinical profiles of Italian outpatients aged 65 years and over infected by hepatitis C virus. METHODS: We evaluated 1544 anti-hepatitis C virus positive patients aged ≥65 years referred to 34 Italian outpatient specialty clinics over a two-year period. RESULTS: The study population included 1134 (73%) early elderly (65-74 years) and 410 (27%) late elderly patients (≥75 years). Late elderly subjects were less likely to have their virus genotyped, their viral load assessed or a histological evaluation of liver disease. Overall, 30% of patients had advanced liver disease whose prevalence increased with increasing age. In both age groups, about 40% of patients had normal transaminase levels. Excluding patients with past infection, 51% had not received any antiviral treatment and only 25% were treated after the age of 65. Late elderly patients, women and patients with advanced liver diseases had been less frequently treated. The main reason for exclusion from treatment was age followed by the presence of comorbid conditions. CONCLUSIONS: Elderly hepatitis C virus patients referred to Italian specialty clinics have advanced and underestimated liver disease. Nevertheless, they are progressively understudied in parallel with increasing age.

2012 - Immunochip analyses identify a novel risk locus for primary biliary cirrhosis at 13q14, multiple independent associations at four established risk loci and epistasis between 1p31 and 7q32 risk variants [Articolo su rivista]
Juran, Bd; Hirschfield, Gm; Invernizzi, P; Atkinson, Ej; Li, Y; Xie, G; Kosoy, R; Ransom, M; Sun, Y; Bianchi, I; Schlicht, Em; Lleo, A; Coltescu, C; Bernuzzi, F; Podda, M; Lammert, C; Shigeta, R; Chan, Ll; Balschun, T; Marconi, M; Cusi, D; Heathcote, Ej; Mason, Al; Myers, Rp; Milkiewicz, P; Odin, Ja; Luketic, Va; Bacon, Br; Bodenheimer HC, Jr; Liakina, V; Vincent, C; Levy, C; Franke, A; Gregersen, Pk; Bossa, F; Gershwin, Me; Deandrade, M; Amos, Ci; Italian PBC Genetics Study, Group; Lazaridis, Kn; Seldin, Mf; Siminovitch, Ka; Almasio, Pl; Alvaro, D; Andreone, P; Andriulli, A; Barlassina, C; Battezzati, Pm; Benedetti, A; Bragazzi, M; Brunetto, M; Bruno, S; Caliari, L; Casella, G; Civardi, F; Coco, B; Colli, A; Colombo, M; Colombo, S; Cursaro, C; Crocè, Ls; Crosignani, A; Donato, F; Fabris, L; Ferrari, C; Floreani, A; Fontana, R; Galli, A; Grattagliano, I; Lazzari, R; Macaluso, F; Malinverno, F; Marra, F; Marzioni, M; Mascia, E; Mattalia, A; Montanari, R; Morini, L; Morisco, F; Muratori, L; Muratori, P; Niro, Ga; Picciotto, A; Portincasa, P; Prati, D; Rosina, F; Rossi, S; Selmi, C; Spinzi, G; Strazzabosco, M; Tarallo, S; Tiribelli, C; Toniutto, P; Vinci, M; Zuin, M.
abstract

To further characterize the genetic basis of primary biliary cirrhosis (PBC), we genotyped 2426 PBC patients and 5731 unaffected controls from three independent cohorts using a single nucleotide polymorphism (SNP) array (Immunochip) enriched for autoimmune disease risk loci. Meta-analysis of the genotype data sets identified a novel disease-associated locus near the TNFSF11 gene at 13q14, provided evidence for association at six additional immune-related loci not previously implicated in PBC and confirmed associations at 19 of 22 established risk loci. Results of conditional analyses also provided evidence for multiple independent association signals at four risk loci, with haplotype analyses suggesting independent SNP effects at the 2q32 and 16p13 loci, but complex haplotype driven effects at the 3q25 and 6p21 loci. By imputing classical HLA alleles from this data set, four class II alleles independently contributing to the association signal from this region were identified. Imputation of genotypes at the non-HLA loci also provided additional associations, but none with stronger effects than the genotyped variants. An epistatic interaction between the IL12RB2 risk locus at 1p31and the IRF5 risk locus at 7q32 was also identified and suggests a complementary effect of these loci in predisposing to disease. These data expand the repertoire of genes with potential roles in PBC pathogenesis that need to be explored by follow-up biological studies.

2012 - Infections and organ transplantation: new challenges for prevention and treatment--a colloquium [Articolo su rivista]
Grossi, P. A.; Costa, A. N.; Fehily, D.; Blumberg, E. A.; Kuehnert, M. J.; Fishman, J. A.; Ison, M. G.; Lattes, R.; Kotton, C. N.; Lilleri, D.; Kabanova, A.; Lanzavecchia, A.; Gerna, G.; Razonable, R. R.; Comoli, P.; Zecca, M.; Basso, S.; Ginevri, F.; Grossi, A.; Schena, F. P.; Rimola, A.; Burra, P.; De Martin, E.; Rodriguez Castro, K. I.; Fagiuoli, S.; Pasulo, L.; Bruno, R.; Andreone, Pietro; Loggi, Elisabetta; Arena, F.; Maria Rossolini, G.; Sganga, G.; Cozza, V.
abstract

2012 - Liver transplantation for hepatocellular carcinoma in clinical practice: the lesson from a 20-year multicentre experience in Italy [Articolo su rivista]
Farinati, Fabio; Giacomin, Anna; Vanin, Veronica; Sergio, Adriana; Burra, Patrizia; Cillo, Umberto; Di Nolfo, Annamaria; Del Poggio, Paolo; Benvegnu, Luisa; Zoli, Marco; Borzio, Franco; Giannini, Edoardo; Caturelli, Eugenio; Cazzagon, Nora; Rapaccini Gian, Ludovico; Trevisani, Franco; for the Italian Liver Cancer (ITA. LI., CA) group (; Andreone, P; Bernardi, M; Biselli, M; Caraceni, P; di Micoli, A; Domenicali, M; Magalotti, D; Cappa, Fm; Santi, V; Zambruni, A; Balsamo, C; Di Marco, M; Vavassori, E; Gilardoni, L; Mattiello, M; Alberti, A; Gatta, A; Gios, M; Molaro, M; Sala, M; Savarino, V; Risso, D; Ghittoni, G; Roselli, P; Grazi, Gl; Nardo, B; Ravaioli, M; Pinna, Ad; Giampalma, E; Golfieri, R; ),
abstract

INTRODUCTION: Hepatocellular carcinoma (HCC) is an established indication for liver transplantation (LT), but the selection criteria and priority are still debated. AIMS: To ascertain the number and features of patients with HCC who undergo transplantation in a Western country, the number of patients eligible for LT according to the American Association for the Study of Liver Diseases (AASLD) guidelines, the number of patients who actually undergo transplantation and whether adherence affects survival. METHODS: This is a retrospective analysis from a multicentre Italian database of 2042 cases of HCC, recruited prospectively and consecutively. Kaplan-Meier (log rank) and Cox multivariate analysis estimated survival. RESULTS: Patients who had undergone transplantation (50, 2.5%, with no change over time) had a median survival of 133 months, significantly influenced by the number of lesions and alpha-fetoprotein levels, which were found to be independent predictors of survival on multivariate analysis. Milan criteria were fulfilled in 68%, impacting on survival, whereas 48% fulfilled AASLD guidelines, without such an impact. Two hundred and twenty-eight (11%) patients were eligible for LT according to AASLD; in this group, alpha-fetoprotein levels and Child-Pugh class were independent predictors of survival. CONCLUSION: Among patients with HCC, those undergoing LT represent a small minority; even fewer (1%) are those who undergo transplantation according to AASLD guidelines, adherence to which only marginally affects survival. Overall, LT impact on HCC patients' treatment is very limited

2012 - Liver transplantation from hepatitis B surface antigen positive donors: a safe way to expand the donor pool [Articolo su rivista]
Loggi, Elisabetta; Micco, Lorenzo; Ercolani, Giorgio; Cucchetti, Alessandro; Bihl, Fk; Grazi, GIAN LUCA; Gitto, Stefano; Bontadini, Andrea; Bernardi, Mauro; Grossi, P; Nanni Costa, A; Pinna, ANTONIO DANIELE; Brander, C; Andreone, Pietro
abstract

BACKGROUND & AIMS: The main limitation of orthotopic liver transplantation (OLT) is the scarcity of available donor organs. A possibility to increase the organ pool is to use grafts from hepatitis B virus surface antigen (HBsAg) positive donors, but few data are currently available in this setting. We assessed the clinical, serovirological, and immunological outcomes of liver transplant from HBsAg positive donors in a single centre study. METHODS: From 2005 to 2009 10 patients underwent OLT from HBsAg positive donors, for HBV-related disease (n=6) or HBV-unrelated disease (n=4). The median follow-up was 42 months (range 12-60). All recipients were HBcAb positive and were given antiviral prophylaxis. RESULTS: Patients transplanted for HBV-related disease never cleared HBsAg. Two HBsAg negative patients never tested positive for HBsAg, whereas the others experienced an HBsAg appearance, followed by spontaneous production of anti-HBs, allowing HBsAg clearance. No patient ever had any sign of HBV hepatitis. HBV replication was effectively controlled by antiviral therapy. The immunologic sub-study showed that a most robust anti-HBV specific T cell response was associated with the control of HBV infection. CONCLUSIONS: OLT from HBsAg positive donors seems to be a safe procedure in the era of highly effective antiviral therapy.

2012 - Long-term antiviral treatment for recurrent hepatitis C after liver transplantation [Articolo su rivista]
Bertuzzo, VALENTINA ROSA; Cescon, Matteo; Morelli, M. C.; DI GIOIA, Paolo; Tame', Mariarosa; Lorenzini, S.; Andreone, Pietro; Ercolani, Giorgio; DEL GAUDIO, Massimo; Ravaioli, Matteo; Cucchetti, Alessandro; Dazzi, Alessandro; D'Errico, Antonietta; Pinna, ANTONIO DANIELE
abstract

Background and aims: The management of patients treated for hepatitis C recurrence after liver transplantation and not achieving virological response following treatment with interferon plus ribavirin is controversial. Methods: A retrospective analysis of the outcomes of 70 patients non-responders to antiviral treatment after liver transplantation was performed. Twenty-one patients (30.0%; Group A) were treated for ≤12 months and 49 (70.0%; Group B) for more than 12 months. Results: The 2 groups were comparable for main demographic, clinical and pathological variables. Median duration of antiviral treatment was 8.2 months in Group A and 33.4 months in Group B. No patient achieved a complete virological response. The 5-year patient hepatitis C-related survival rate was 49.2% in Group A and 88.3% in Group B (P = 0.002), while the 5-year graft survival rate was 49.2% in Group A and 85.9% in Group B (P = 0.007). The median yearly fibrosis progression rate was 1.21 per year in Group A and 0.40 per year in Group B (P = 0.001). Conclusions: Prolonged antiviral treatment showed an overall beneficial effect in transplanted patients with a recurrent hepatitis C infection and not responding to conventional therapy. The treatment should be continued as long as it is permitted, in order to improve clinical and histological outcomes.

2012 - Menopause, and not age, is a critical factor associated with a worse response to antiviral therapy in women affected by chronic hepatitis C [Articolo su rivista]
Gitto, S; Karampatou, A; Andreone, P; Villa, Erica
abstract

Letter commenting the fact that menopause and not age is a key factor for resistance to IFN

2012 - Randomized trial of albinterferon alfa-2b every 4 weeks for chronic hepatitis C virus genotype 2/3 [Articolo su rivista]
Pianko, S; Zeuzem, S; Chuang, Wl; Foster, Gr; Sarin, Sk; Flisiak, R; Lee, Cm; Andreone, P; Piratvisuth, T; Shah, S; Sood, A; George, J; Gould, M; Komolmit, P; Thongsawat, S; Tanwandee, T; Rasenack, J; Li, Y; Pang, M; Yin, Y; Feutren, G; Jacobson, Im; B2202 Study, Team.
abstract

Albinterferon alfa-2b (albIFN) is a fusion protein of recombinant human albumin/recombinant interferon (IFN)-α-2b, with ∼200-h half-life. Safety/efficacy of albIFN q4wk was evaluated in 391 treatment-naive patients with chronic hepatitis C virus (HCV) genotype 2/3. Patients were randomized 3:4:4:4 to one of four open-label treatment groups: pegylated IFN (Peg-IFN)-α-2a 180 μg qwk or albIFN 900, 1200 or 1500 μg q4wk, plus oral ribavirin 800 mg/day, for 24 weeks. Primary efficacy endpoint was sustained virologic response (SVR; HCV RNA <20 IU/mL 24 weeks post-treatment). SVR rates were as follows: 85%, 76%, 76% and 78% with Peg-IFNα-2a and albIFN 900, 1200 and 1500 μg, respectively (P = NS); corresponding rapid virologic response rates (HCV RNA <43 IU/mL at week 4) were as follows: 78%, 49% (P < 0.001), 60% (P = 0.01) and 71%. SVR rates were not influenced by interleukin 28B genotype, although rapid virologic response rates were greater with interleukin 28B CC (P = NS). Serious adverse event rates were as follows: 4%, 11%, 3% and 3% with Peg-IFNα-2a and albIFN 900, 1200 and 1500 μg, respectively. No increase in serious/severe respiratory events was noted with albIFN. Fewer absolute neutrophil count reductions <750/mm(3) occurred with albIFN (P = 0.03), leading to fewer IFN dose reductions. Haemoglobin reductions <10 g/dL were less frequent with albIFN 900 and 1200 μg vs 1500 μg and Peg-IFNα-2a (P = 0.02), leading to fewer ribavirin dose reductions. albIFN administered q4wk produced fewer haematologic reductions than Peg-IFNα-2a, but had numerically lower SVR rates (P = NS) in patients with chronic HCV genotype 2/3.

2012 - Relationship between hepatic hemodynamics assessed by Doppler ultrasound and liver stiffness [Articolo su rivista]
Salvatore, V; Borghi, A; Peri, E; Colecchia, A; Li Bassi, S; Montrone, L; Di Donato, R; Conti, F; Crespi, C; Festi, D; Bernardi, M; Andreone, P; Bolondi, L.
abstract

AIM: We tested the relationship between hepatic haemodynamics assessed by Doppler ultrasonography and liver stiffness assessed by Transient Elastography in hepatitis C related chronic liver disease. METHODS: Three liver Doppler ultrasound parameters (hepatic artery resistance index, splenic artery resistance index and waveform pattern in hepatic veins) and liver stiffness measured by Transient Elastography were analysed in one hundred consecutive patients affected by hepatitis C related chronic liver disease. RESULTS: Hepatic and splenic arteries resistance indexes correlate significantly (p<0.0001 for both) with liver stiffness. A hepatic artery resistance index cut-off value of 0.64 provided sensitivity and specificity respectively of 84.4% and 69.1% for predicting liver stiffness ≤or >13 kPa, whereas a splenic artery resistance index cut-off value of 0.56 provided sensitivity and specificity respectively of 81.3% and 48.5%. The coincidental finding of both resistance indexes above the respective cut-off values showed a good accuracy in identifying patients with liver stiffness values >13 kPa (accuracy=78%, +LR=2.90, -LR=0.31). A significant difference in liver stiffness values was evident between patients with triphasic and bi- or monophasic waveform pattern (p=0.005). CONCLUSIONS: Hepatic and splenic arteries resistance indexes and the hepatic veins waveform pattern assessed by Doppler ultrasound may provide information similar to that of Transient Elastography in hepatitis C related chronic liver disease.

2012 - Silybin combined with phosphatidylcholine and vitamin E in patients with nonalcoholic fatty liver disease: A randomized controlled trial [Articolo su rivista]
Loguercio, C.; Andreone, Pietro; Brisc, C.; Brisc, M. C.; Bugianesi, E.; Chiaramonte, M.; Cursaro, C.; Danila, M.; de Sio, I.; Floreani, A.; Freni, M. A.; Grieco, A.; Groppo, M.; Lazzari, R.; Lobello, S.; Lorefice, E.; Margotti, M.; Miele, L.; Milani, S.; Okolicsanyi, L.; Palasciano, G.; Portincasa, P.; Saltarelli, P.; Smedile, A.; Somalvico, F.; Spadaro, A.; Sporea, I.; Sorrentino, P.; Vecchione, R.; Tuccillo, C.; Blanco, C. D.; Federico, A.
abstract

The only currently recommended treatment for nonalcoholic fatty liver disease (NAFLD) is lifestyle modification. Preliminary studies of silybin showed beneficial effects on liver function. Realsil (RA) comprises the silybin phytosome complex (silybin plus phosphatidylcholine) coformulated with vitamin E. We report on a multicenter, phase III, double-blind clinical trial to assess RA in patients with histologically documented NAFLD. Patients were randomized 1:1 to RA or placebo (P) orally twice daily for 12 months. Prespecified primary outcomes were improvement over time in clinical condition, normalization of liver enzyme plasma levels, and improvement of ultrasonographic liver steatosis, homeostatic model assessment (HOMA), and quality of life. Secondary outcomes were improvement in liver histologic score and/or decrease in NAFLD score without worsening of fibrosis and plasma changes in cytokines, ferritin, and liver fibrosis markers. We treated 179 patients with NAFLD; 36 were also HCV positive. Forty-one patients were prematurely withdrawn and 138 patients analyzed per protocol (69 per group). Baseline patient characteristics were generally well balanced between groups, except for steatosis, portal infiltration, and fibrosis. Adverse events (AEs) were generally transient and included diarrhea, dysgeusia, and pruritus; no serious AEs were recorded. Patients receiving RA but not P showed significant improvements in liver enzyme plasma levels, HOMA, and liver histology. Body mass index normalized in 15% of RA patients (2.1% with P). HCV-positive patients in the RA but not the P group showed improvements in fibrogenesis markers. This is the first study to systematically assess silybin in NAFLD patients. Treatment with RA but not P for 12 months was associated with improvement in liver enzymes, insulin resistance, and liver histology, without increases in body weight. These findings warrant further investigation.

2012 - Sirolimus Conversion Regimen Versus Continued Calcineurin Inhibitors in Liver Allograft Recipients: A Randomized Trial [Articolo su rivista]
Abdelmalek, Mf; Humar, A; Stickel, F; Andreone, P; Pascher, A; Barroso, E; Neff, Gw; Ranjan, D; Toselli, Lt; Gane, Ej; Scarola, J; Alberts, Rg; Maller, Es; Lo, Cm; for the Sirolimus Liver Conversion Trial Study, Group.
abstract

A large prospective, open-label, randomized trial evaluated conversion from calcineurin inhibitor (CNI)- to sirolimus (SRL)-based immunosuppression for preservation of renal function in liver transplantation patients. Eligible patients received liver allografts 6-144 months previously and maintenance immunosuppression with CNI (cyclosporine or tacrolimus) since early posttransplantation. In total, 607 patients were randomized (2:1) to abrupt conversion (<24 h) from CNI to SRL (n = 393) or CNI continuation for up to 6 years (n = 214). Between-group changes in baseline-adjusted mean Cockcroft-Gault GFR at month 12 (primary efficacy end point) were not significant. The primary safety end point, noninferiority of cumulative rate of graft loss or death at 12 months, was not met (6.6% vs. 5.6% in the SRL and CNI groups, respectively). Rates of death at 12 months were not significantly different, and no true graft losses (e.g. liver transplantation) were observed during the 12-month period. At 52 weeks, SRL conversion was associated with higher rates of biopsy-confirmed acute rejection (p = 0.02) and discontinuations (p < 0.001), primarily for adverse events. Adverse events were consistent with known safety profiles. In conclusion, liver transplantation patients showed no demonstrable benefit 1 year after conversion from CNI- to SRL-based immunosuppression.

2012 - Thymosin alpha-1 with peginterferon alfa-2a/ribavirin for chronic hepatitis C not responsive to IFN/ribavirin: an adjuvant role? [Articolo su rivista]
Ciancio, A; Andreone, P; Kaiser, S; Mangia, A; Milella, M; Solà, R; Pol, S; Tsianos, E; De Rosa, A; Camerini, R; McBeath, R; Rizzetto, M.
abstract

This study was conducted to determine whether the adding thymosin alpha-1 to standard of care for re-treatment of nonresponding hepatitis C infections can improve sustained viral response (SVR) rates. Patients (n = 552) with hepatitis C infections not responding to the combination of Peginterferon alfa-2a or 2b with ribavirin (RBV)were randomized to receive peginterferon alfa-2a 180 mg/week with RBV 800-1200 mg/daily plus either thymosin alpha-1 1.6 mg SC twice weekly (n = 275) or placebo (n = 277) for 48 weeks. Eighty-eight per cent of patients had HCV genotype 1, 6.6% type 4, 2.2% type 2 and 3.6% type 3. SVR rates in the intention to treat population were similar between thymosin alpha-1 and placebo (12.7%vs 10.5%; P = 0.407). Among patients who completed all 48 weeks of therapy, the SVR rate was significantly higher in the thymosin alpha-1 group at 41.0% (34/83) compared with 26.3% (26/99) in the placebo group (P = 0.048). No significant difference was observed between treatment groups in the incidence of adverse events. The addition of thymosin alpha-1 to the standard of care did not increase the on-treatment HCV viral response. Thymosin alpha-1 seems to play no role in the primary therapy of the disease. This study raises the hypothesis that thymosin alpha-1 may have a secondary therapeutic role as an adjuvant in the prevention of relapses in patients achieving a virologic response during therapy.

2011 - Accuracy of VirtualTouch Acoustic Radiation Force Impulse (ARFI) imaging for the diagnosis of cirrhosis during liver ultrasonography [Articolo su rivista]
Piscaglia, Fabio; Salvatore, Veronica; Di Donato, Roberto; D'Onofrio, M; Gualandi, Silvia; Gallotti, A; Peri, E; Borghi, Alberto; Conti, Fabio; Fattovich, G; Sagrini, Elisabetta; Cucchetti, Alessandro; Andreone, Pietro; Bolondi, Luigi
abstract

PURPOSE: VirtualTouch is a new technique recently proposed to evaluate liver stiffness during B-mode ultrasonography. The goal of the present study was to analyze the diagnostic accuracy of VirtualTouch in the diagnosis of cirrhosis and its correlation with transient elastography (Fibroscan). MATERIALS AND METHODS: A total of 133 patients with chronic liver disease were enrolled. 90 of 133 underwent VirtualTouch and transient elastography and 70 patients assessed with VirtualTouch were submitted to liver biopsy. Stiffness was assessed by both techniques in the right liver lobe. The diagnostic accuracy for cirrhosis was first assessed in the 90 patients submitted to transient elastography with > 13 kPa (47 % of patients) as diagnostic for cirrhosis values. The best cut-off for cirrhosis with VirtualTouch was then tested in the 70 patients with biopsy (cirrhosis in 38 % of patients). 41 patients were assessed by VirtualTouch by two different operators. RESULTS: The VirtualTouch values in controls, chronic hepatitis and cirrhosis were respectively 113, 147 and 255 cm/sec. The AUROC of liver VirtualTouch for the diagnosis of cirrhosis (reference Fibroscan) was 0.941 with 175 cm/sec as the best cut-off (sensitivity 93.0 %; specificity 85.1 %). VirtualTouch confirmed good performance also in patients with bioptic diagnosis of cirrhosis (AUROC 0.908, sensitivity 81.5 %, specificity 88.4 %,). The correlation of VirtualTouch with transient elastography was strict (r = 0.891) and the correlation in VirtualTouch measurements between two operators was also good (r = 0.874). CONCLUSION: VirtualTouch is able to identify the presence of cirrhosis with good accuracy, shows good interobserver reproducibility and the correlation of its values with those obtained by transient elastography with Fibroscan is good.

2011 - Liver transplantation for patients with alcoholic liver disease: an open question [Articolo su rivista]
Gramenzi, Annagiulia; Gitto, Stefano; Caputo, Fabio; Biselli, Maurizio; Lorenzini, S; Bernardi, Mauro; Andreone, Pietro
abstract

End-stage alcoholic liver disease is a recognised indication for liver transplantation but some questions on the matter remain open. It is difficult to quantify alcohol consumption, and a single definition of post-transplant relapse is lacking. Moreover, there are no internationally accepted criteria for the selection of candidates for liver transplantation and the eligibility parameters for these patients are controversial. Additional clinical and psychological evaluations are necessary in this setting, especially to establish the risk of alcohol relapse. Nevertheless, patient and graft survival rates after liver transplantation in alcoholic liver disease are comparable to those after transplant for other aetiologies, alcohol consumption relapse being one of the most important problems in the post-transplant phase. In conclusion, alcohol-related liver disease is a good indication for liver transplantation. The main future goals are to formulate a well-defined pre-transplant approach and a single definition of alcohol relapse and to improve prevention strategies.

2011 - Metronomic capecitabine as second-line treatment for patients with hepatocellular carcinoma with preserved liver function: A phase II study [Abstract in Atti di Convegno]
DE ROSA, Francesco; Agostini, Valentina; S., Di Girolamo; Andreone, Pietro; Trevisani, Franco; Bolondi, Luigi; Pinna, ANTONIO DANIELE; C., Serra; Golfieri, Rita; Biasco, Guido; Brandi, Giovanni
abstract

Background: The antiangiogenic drug sorafenib is standard treatment for advanced hepatocellular carcinoma (HCC) not suitable for surgical or loco-regional therapies in patients with preserved liver function. Many second-line drugs are currently under investigation, but none has proven effective so far. Metronomic chemotherapy is characterized by antiangiogenic activity as well and good tolerability. Therefore we started a phase II clinical study to assess efficacy of metronomic capecitabine in advanced HCC patients. Methods: This phase II trial allowed inclusion of 90 HCC patients (pts) in two sub-studies: first-line systemic treatment (60 pts) and second-line after sorafenib (30 pts.) Main inclusion criteria were Child-Pugh liver function class A and progressive disease not candidate for surgery or loco-regional treatments. Treatment schedule was capecitabine 500 mg bid after meals continuously. In case of severe toxicity up to two weeks off-therapy were permitted for recovery; no dose adjustment was allowed. Primary endpoint is three-months progression-free survival rate (PFS3mo), assessed by RECIST 1.1. This preliminary analysis aims at evaluating efficacy and toxicity of metronomic capecitabine after progression on sorafenib treatment. Results: Patients’ accrual ended in December 2010. A total of 30 pts pre-treated with sorafenib have been included; of these, 12 had relapsed after surgery and 24 had been previously managed with percutaneous ablations or chemoembolizations. 23 pts are currently assessable for efficacy. We observed no objective responses, 9 stable disease and 14 progressive disease, for a PFS3mo of 39%. Overall and progression-free survival will be evaluated in a further analysis with longer follow-up. All patients are assessable for toxicity. The most common adverse events were asthenia, nausea, diarrhoea and pruritus, generally mild and tolerable. Conclusions: Metronomic capecitabine is well tolerated and can be active in HCC patients after progression under sorafenib treatment. The extent of clinical benefit will be determined in the final analysis.

2011 - Metronomic capecitabine in advanced hepatocellualr cacinoma patients who have failed sorafenib: a phase II study [Abstract in Atti di Convegno]
De Rosa, F; Di Girolamo, S; Corbelli, J; Longobardi, C; Agostini, V; Andreone, P; Serra, C; Piscaglia, F; Trevisani, F; Golfieri, R; Bolondi, L; Pinna, Ad; Biasco, G; Brandi, G
abstract

2011 - Prognostic value of a single HVPG measurement and Doppler-ultrasound evaluation in patients with cirrhosis and portal hypertension [Articolo su rivista]
Berzigotti, Annalisa; Rossi, Valentina; Tiani, Carolina; Pierpaoli, Lucia; Zappoli, Paola; Riili, A; Serra, C; Andreone, Pietro; Morelli, Mc; Golfieri, R; Rossi, C; Magalotti, Donatella; Zoli, Marco
abstract

Background In patients with cirrhosis the onset of clinically significant portal hypertension (CSPH; i.e., hepatic venous pressure gradient (HVPG) C 10 mmHg) is associated with an increased risk of complications. However, most cirrhotic patients already have CSPH at presentation, and limited information is available on further risk stratification in this population. This study assessed the prognostic value of a single HVPG measurement and Doppler-ultrasound (US) evaluation in patients with cirrhosis and CSPH. Methods Eighty-six consecutive patients with cirrhosis (73% compensated) and untreated CSPH (mean HVPG 17.8 ± 5.1 mmHg) were included. All were studied by paired HVPG and US, and followed up for a minimum of 12 months (mean 28 ± 20 months). Results Sixteen (25.3%) patients developed a first decompensation, and 11.6% died on follow-up. HVPG (per 1 mmHg increase OR 1.22, 95% CI 1.05–1.40, p = 0.007) and bilirubin (per 1 mg/ml increase OR 2.42, 95% CI 0.93–6.26, p = 0.06) independently predicted first decompensation, and Model for End-Stage Liver Disease (MELD) score (per 1 point increase OR 1.24, 95% CI 1.03–1.51, p = 0.03) and HVPG (per 1 mmHg increase OR 1.08, 95% CI 1.01–1.26, p = 0.05) independently predicted mortality. The best HVPG cutoff predicting these events was 16 mmHg. Ultrasonographic parameters lacked independent predictive value. The ultrasonographic detection of abdominal collaterals had a high positive likelihood ratio (7.03, 95% CI 2.23–22.16) for the prediction of HVPG C 16 mmHg, implying an increase of the probability of belonging to this higher-risk population from 58 to 91%. Conclusions HVPG holds an independent predictive value for first decompensation and death in patients with CSPH. The ultrasonographic detection of collaterals allows the non-invasive identification of patients with HVPG C 16 mmHg, who are at higher risk.

2011 - Serum hepatitis B surface antigen monitoring in long-term Lamivudine-treated hepatitis B virus patients [Articolo su rivista]
Gramenzi, Annagiulia; Loggi, Elisabetta; Micco, Lorenzo; Cursaro, C; Fiorino, S; Galli, S; Gitto, Stefano; Galli, C; Furlini, G; Bernardi, Mauro; Andreone, Pietro
abstract

Serum hepatitis B virus surface antigen (HBsAg) levels have been suggested to predict interferon response in chronic hepatitis B. A few data are available on the role of HBsAg measurement in nucleos(t)ide analogues (NA) treatment. We retrospectively investigated the relation between HBsAg changes and main treatment outcomes during long-term lamivudine treatment in hepatitis e antigen (HBeAg)-negative chronic hepatitis B. A total of 42 HBeAg-negative patients were consecutively enrolled in an open-label study on long-term lamivudine monotherapy (150 mg/die). Serum HBsAg levels were quantified every 6 months by Architect assay (Abbott Diagnostics). HBV-DNA was quantified quarterly by real-time PCR (Roche Diagnostics). The median duration of lamivudine treatment was 66 months (20-153). One patient (2%) was a primary nonresponder, 35 (83%) developed virological breakthrough (VB) and the remaining six patients (14%) were classified as long-term on-treatment responders. During treatment, HBsAg levels decreased only in long-term on-treatment responders, while no changes were observed in resistant patients. Failure to achieve a decrease of 0.7 log(10) IU/mL in serum HBsAg at month six of lamivudine had a positive predictive value of developing VB of 90% and a negative predictive value of 100%. These high predictive values were also maintained in the subgroup of patients negative for HBV-DNA at month six. The results of this study with a small sample size suggest a role of on-treatment HBsAg quantification in the management of lamivudine-treated patients. If validated prospectively in a larger patient cohort, HBsAg measurements would be a useful adjunct to optimize antiviral therapy.

2011 - Telaprevir for previously untreated chronic hepatitis C virus infection [Articolo su rivista]
Jacobson, I. M.; McHutchison, J. G.; Dusheiko, G.; Di Bisceglie, A. M.; Reddy, K. R.; Bzowej, N. H.; Marcellin, P.; Muir, A. J.; Ferenci, P.; Flisiak, R.; George, J.; Rizzetto, M.; Shouval, D.; Sola, R.; Terg, R. A.; Yoshida, E. M.; Adda, N.; Bengtsson, L.; Sankoh, A. J.; Kieffer, T. L.; George, S.; Kauffman, R. S.; Zeuzem, S.; ADVANCE Study Team: Gadano, A.; Terg, R.; Bell, S.; Cheng, W.; Crawford, D.; Dore, G.; George, J.; MacDonald, G.; Roberts, S.; Ferenci, P.; Gschwantler, M.; Laferl, H.; Maieron, A.; Heathcote, J.; Kaita, K.; Myers, R.; Sherman, M.; Yoshida, E.; Barange, K.; Couzigou, P.; Marcellin, P.; Pawlotsky, J. M.; Pol, S.; Serfaty, L.; Trépo, C.; Zarski, J. P.; Berg, T.; Buggisch, P.; Diepolder, H.; Goeser, T.; Mauss, S.; Rasenack, J.; Schmidt, W.; Wedemeyer, H.; Zeuzem, S.; Baruch, Y.; Ben Ari, Z.; Maor, Y.; Safadi, R.; Shouval, D.; Zuckerman, E.; Andreone, Pietro; Colombo, M.; Rizzetto, M.; Baka Cwierz, B.; Flisiak, R.; Gladysz, A.; Janczewska Kazek, E.; Jablkowski, M.; Krycka, W.; Diago, M.; Esteban Mur, R.; Sanchez Tapias, J.; Sola, R.; Brown, A.; Dusheiko, G.; Fox, R.; Afdhal, N.; Arora, S.; Bennett, M.; Bernstein, D.; Bloomer, J.; Bochan, M.; Bonkovsky, H.; Brady, C.; Brown, R.; Bzowej, N.; Cochran, J.; Chasen, R.; Davis, G.; De Jesus, E.; Di Bisceglie, A.; Dienstag, J.; Dieterich, D.; Etzkorn, K.; Everson, G.; Fried, M.; Freilich, B.; Ghalib, R.; Gitlin, N.; Godofsky, E.; Gordon, S.; Hassanein, T.; Jacobson, I.; Javadi, F.; Jonas, M.; Kilby, A.; Kwo, P.; Lawitz, E.; Lebovics, E.; Lee, W.; Luketic, V.; Maillard, M.; Monto, A.; Morgan, T.; Min, A.; Murphy, M.; Nelson, D.; Northup, P.; Nyberg, L.; Pockros, P.; Poordad, F.; Poulos, J.; Reddy, R.; Rodriguez Torres, M.; Satyanarayana, R.; Schiff, E.; Schwartz, H.; Shaikh, O.; Sheikh, M.; Sherman, K.; Smith, J.; Strohecker, J.; Sulkowski, M.; Szabo, G.; Te, H.; Terrault, N.; Tsai, N.; Vargas, H.; Vierling, J.; Wruble, L.; Younossi, Z.; Zein, N.
abstract

BACKGROUND: In phase 2 trials, telaprevir, a hepatitis C virus (HCV) genotype 1 protease inhibitor, in combination with peginterferon-ribavirin, as compared with peginterferon-ribavirin alone, has shown improved efficacy, with potential for shortening the duration of treatment in a majority of patients. METHODS: In this international, phase 3, randomized, double-blind, placebo-controlled trial, we assigned 1088 patients with HCV genotype 1 infection who had not received previous treatment for the infection to one of three groups: a group receiving telaprevir combined with peginterferon alfa-2a and ribavirin for 12 weeks (T12PR group), followed by peginterferon-ribavirin alone for 12 weeks if HCV RNA was undetectable at weeks 4 and 12 or for 36 weeks if HCV RNA was detectable at either time point; a group receiving telaprevir with peginterferon-ribavirin for 8 weeks and placebo with peginterferon-ribavirin for 4 weeks (T8PR group), followed by 12 or 36 weeks of peginterferon-ribavirin on the basis of the same HCV RNA criteria; or a group receiving placebo with peginterferon-ribavirin for 12 weeks, followed by 36 weeks of peginterferon-ribavirin (PR group). The primary end point was the proportion of patients who had undetectable plasma HCV RNA 24 weeks after the last planned dose of study treatment (sustained virologic response). RESULTS: Significantly more patients in the T12PR or T8PR group than in the PR group had a sustained virologic response (75% and 69%, respectively, vs. 44%; P<0.001 for the comparison of the T12PR or T8PR group with the PR group). A total of 58% of the patients treated with telaprevir were eligible to receive 24 weeks of total treatment. Anemia, gastrointestinal side effects, and skin rashes occurred at a higher incidence among patients receiving telaprevir than among those receiving peginterferon-ribavirin alone. The overall rate of discontinuation of the treatment regimen owing to adverse events was 10% in the T12PR and T8PR groups and 7% in the PR group. CONCLUSIONS: Telaprevir with peginterferon-ribavirin, as compared with peginterferon-ribavirin alone, was associated with significantly improved rates of sustained virologic response in patients with HCV genotype 1 infection who had not received previous treatment, with only 24 weeks of therapy administered in the majority of patients

2011 - Telaprevir for retreatment of HCV infection [Articolo su rivista]
Zeuzem, S; Andreone, P; Pol, S; Lawitz, E; Diago, M; Roberts, S; Focaccia, R; Younossi, Z; Foster, Gr; Horban, A; Ferenci, P; Nevens, F; Müllhaupt, B; Pockros, P; Terg, R; Shouval, D; van Hoek, B; Weiland, O; Van Heeswijk, R; De Meyer, S; Luo, D; Boogaerts, G; Polo, R; Picchio, G; Beumont, M; REALIZE Study, Team.
abstract

BACKGROUND: Up to 60% of patients with hepatitis C virus (HCV) genotype 1 infection do not have a sustained virologic response to therapy with peginterferon alfa plus ribavirin. METHODS: In this randomized, phase 3 trial, we evaluated the addition of telaprevir to peginterferon alfa-2a plus ribavirin in patients with HCV genotype 1 infection who had no response or a partial response to previous therapy or who had a relapse after an initial response. A total of 663 patients were assigned to one of three groups: the T12PR48 group, which received telaprevir for 12 weeks and peginterferon plus ribavirin for a total of 48 weeks; the lead-in T12PR48 group, which received 4 weeks of peginterferon plus ribavirin followed by 12 weeks of telaprevir and peginterferon plus ribavirin for a total of 48 weeks; and the control group (PR48), which received peginterferon plus ribavirin for 48 weeks. The primary end point was the rate of sustained virologic response, which was defined as undetectable HCV RNA 24 weeks after the last planned dose of a study drug. RESULTS: Rates of sustained virologic response were significantly higher in the two telaprevir groups than in the control group among patients who had a previous relapse (83% in the T12PR48 group, 88% in the lead-in T12PR48 group, and 24% in the PR48 group), a partial response (59%, 54%, and 15%, respectively), and no response (29%, 33%, and 5%, respectively) (P<0.001 for all comparisons). Grade 3 adverse events (mainly anemia, neutropenia, and leukopenia) were more frequent in the telaprevir groups than in the control group (37% vs. 22%). CONCLUSIONS: Telaprevir combined with peginterferon plus ribavirin significantly improved rates of sustained virologic response in patients with previously treated HCV infection, regardless of whether there was a lead-in phase. (Funded by Tibotec and Vertex Pharmaceuticals; REALIZE ClinicalTrials.gov number, NCT00703118.).

2011 - The pharmacology and activity of non-steroidal anti-inflammatory drugs (NSAIDs): a review of their use as an adjuvant treatment in patients with HBV and HCV chronic hepatitis [Articolo su rivista]
Fiorino, S; Cursaro, C; Lorenzini, S; Loggi, E; Brodosi, L; Cattani, L; Cuppini, A; Bernardi, M; Andreone, P.
abstract

Introduction Different DNA and RNA viruses exploit common strategies to support their persistence and replication in infected individuals. In particular, the hepatitis B virus (HBV) and the hepatitis C virus (HCV) cause major health problems worldwide. These pathogens exert an immunosuppressive role by inducing the persistent activation of cyclooxygenase-2 (COX-2) and an increased synthesis of prostaglandin E2 (PGE2). The suppression of this proinflammatory network by non-steroidal anti-inflammatory drugs (NSAIDs) has been proposed as a therapeutic approach to decrease viral replication. Materials and methods In this review, the role of inflammation in the support of viral replication and NSAIDs and ketoprofen pharmacology are briefly discussed. In addition, studies that have investigated the use of NSAIDs for the treatment of HBV and HCV chronic hepatitis, which were identified by a systematic literature search of PubMed and MEDLINE, are reported. Results To date, pegylated-interferon (PEG-IFN) and/or nucleot(s)ide analogues and PEG-IFN and ribavirin remain the standard therapy for HBV and HCV chronic hepatitis, respectively. Discussion The use of NSAIDs in patients with chronic viral hepatitis has only a “historical” interest. Nevertheless, the possible usefulness of ketoprofen with PEG-IFN and ribavirin for HCV-infected patients, non-responders to standard therapy or with genotype 1, should be evaluated in future clinical studies.

2011 - Vitamins in the treatment of chronic viral hepatitis [Articolo su rivista]
Fiorino, S; Conti, F; Gramenzi, A; Loggi, E; Cursaro, C; Di Donato, R; Micco, L; Gitto, S; Cuppini, A; Bernardi, M; Andreone, P.
abstract

Abstract: Hepatitis B virus (HBV)- and hepatitis C virus (HCV)-related chronic infections represent a major health problem worldwide. Although the efficacy of HBV and HCV treatment has improved, several important problems remain. Current recommended antiviral treatments are associated with considerable expense, adverse effects and poor efficacy in some patients. Thus, several alternative approaches have been attempted. To review the clinical experiences investigating the use of lipid-and water-soluble vitamins in the treatment of HBV- and HCV-related chronic infections, PubMed, the Cochrane Library, MEDLINE and EMBASE were searched for clinical studies on the use of vitamins in the treatment of HBV- and HCV-related hepatitis, alone or in combination with other antiviral options. Different randomised clinical trials and small case series have evaluated the potential virological and/or biochemical effects of several vitamins. The heterogeneous study designs and populations, the small number of patients enrolled, the weakness of endpoints and the different treatment schedules and follow-up periods make the results largely inconclusive. Only well-designed randomised controlled trials with well-selected endpoints will ascertain whether vitamins have any role in chronic viral hepatitis. Until such time, the use of vitamins cannot be recommended as a therapy for patients with chronic hepatitis B or C.

2010 - An in-depth psychosocial and biochemical evaluation in transplant recipients for alcoholic liver disease should be planned [Articolo su rivista]
Gitto, S; Biselli, M; Bernardi, M; Andreone, P.
abstract

2010 - Antiviral intrahepatic T-cell responses can be restored by blocking programmed death-1 pathway in chronic hepatitis B [Articolo su rivista]
Fisicaro, P; Valdatta, C; Massari, M; Loggi, E; Biasini, E; Sacchelli, L; Cavallo, Mc; Silini, Em; Andreone, P; Missale, G; Ferrari, C.
abstract

BACKGROUND & AIMS: The antiviral function of peripheral hepatitis B virus (HBV)-specific T cells can be increased in patients with chronic hepatitis B by blocking the interaction of programmed death (PD)-1 with its ligand PD-L1. However, no information is available about the effects of this blockade on intrahepatic lymphocytes. We studied T-cell exhaustion and the effects of PD-1/PD-L1 blockade on intrahepatic and circulating HBV-specific T cells in patients with chronic hepatitis B. METHODS: A total of 42 patients with chronic HBV infection who underwent liver biopsy were studied. The ex vivo phenotype of peripheral and intrahepatic HBV-specific CD8(+) T cells was assessed by flow cytometry with class I tetramers and antibodies to T-cell differentiation molecules. Functional recovery was evaluated by analyzing expansion and production of interferon (IFN)-gamma and interleukin (IL)-2 after short-term incubation of T cells with HBV peptides in the presence of anti-PD-L1 or control antibodies. RESULTS: Intrahepatic HBV-specific CD8(+) cells expressed higher levels of PD-1 and lower levels of CD127 than their peripheral counterparts. Blockade of PD-1/PD-L1 interaction increased CD8(+) cell proliferation and IFN-gamma and IL-2 production by circulating intrahepatic lymphocytes, even though anti-PD-L1 had a stronger effect on intrahepatic compared with peripheral T cells. CONCLUSIONS: T-cell exhaustion by high antigen concentrations promotes HBV-specific T-cell dysfunction by affecting phenotype and function of peripheral and intrahepatic T cells. By restoring antiviral T-cell functions, not only in peripheral but also in intrahepatic lymphocytes, anti-PD-L1 might be a good therapeutic candidate for chronic HBV infection.

2010 - Capitolo 14 "Epatiti Virali Croniche", Volume IX "Malattie del Fegato, delle Vie Biliari e del Pancreas", Trattato di Medicina Interna, fondato da Paolo Larizza [Monografia/Trattato scientifico]
Gramenzi, A.; Lorenzini, S.; Brodosi, L.; Andreone, P.
abstract

Manifestazioni cliniche, dati di laboratorio, caratteristiche istologiche delle epatiti croniche HBV, HDV e HCV relate. Storia naturale, diagnosi e terapia.

2010 - Characterization of a stereotypical cellular and extracellular adult liver progenitor cell niche in rodents and diseased human liver [Articolo su rivista]
Lorenzini, S; Bird, Tg; Clayton, E; Bellamy, C; Samuel, K; Aucott, R; Andreone, P; Bernardi, M; Golding, M; Alison, Mr; Iredale, Jp; Forbes, Sj.
abstract

Background Stem/progenitor cell niches in tissues regulate stem/progenitor cell differentiation and proliferation through local signalling. Objective To examine the composition and formation of stem progenitor cell niches. Methods The composition of the hepatic progenitor cell niche in independent models of liver injury and hepatic progenitor cell activation in rodents and humans was studied. To identify the origin of the progenitor and niche cells, sex-mismatched bone marrow transplants in mice, who had received the cholineeethionine-deficient-diet to induce liver injury and progenitor cell activation, were used. The matrix surrounding the progenitor cells was described by immunohistochemical staining and its functional role controlling progenitor cell behaviour was studied in cell culture experiments using different matrix layers. Results The progenitor cell response in liver injury is intimately surrounded by myofibroblasts and macrophages, and to a lesser extent by endothelial cells. Hepatic progenitor cells are not of bone marrow origin; however, bone marrow-derived cells associate intimately with these cells and are macrophages. Laminin always surrounds the progenitor cells. In vitro studies showed that laminin aids maintenance of progenitor and biliary cell phenotype and promotes their gene expression (Dlk1, Aquaporin 1, γGT) while inhibiting hepatocyte differentiation and gene expression (CEPB/α). Conclusions During liver damage in rodents and humans a stereotypical cellular and laminin niche forms around hepatic progenitor cells. Laminin helps maintenance of undifferentiated progenitor cells. The niche links the intrahepatic progenitor cells with bone marrow-derived cells and links tissue damage with progenitor cell-mediated tissue repair

2010 - Clinical Impact and behaviour of serum autoantibodies in adult liver transplantation [Abstract in Atti di Convegno]
Granito, Alessandro; Vannini, A.; Quarneti, Chiara; Muratori, Paolo; Muratori, Luigi; Pappas, G.; Piscaglia, Fabio; Andreone, Pietro; Bianchi, G.; Tame, M. R.; Morelli, C.; Bianchi, FRANCESCO BIANCO; Pinna, ANTONIO DANIELE; Lenzi, Marco
abstract

2010 - Criteria for diagnosing benign portal vein thrombosis in the assessment of patients with cirrhosis and hepatocellular carcinoma for liver transplantation [Articolo su rivista]
Piscaglia, Fabio; Gianstefani, Alice; Ravaioli, Matteo; Golfieri, Rita; Cappelli, A.; Giampalma, E.; Sagrini, Elisabetta; Imbriaco, Grazia; Pinna, ANTONIO DANIELE; Bolondi, Luigi; Andreone, Pietro; Bianchi, Giampaolo; Biselli, Maurizio; Cescon, Matteo; Colecchia, Antonio; Cucchetti, Alessandro; DEL GAUDIO, Massimo; Ercolani, Giorgio; Grazi, GIAN LUCA; Lenzi, Marco; Leoni, S.; Mazzella, Giuseppe; Morelli, M. C.; Tame', Mariarosa; Verucchi, Gabriella; Vivarelli, Marco
abstract

Malignant portal vein thrombosis is a contraindication for liver transplantation. Patients with cirrhosis and early hepatocellular carcinoma (HCC) may have either malignant or benign (fibrin clot) portal vein thrombosis. The aim of this study was to assess prospectively whether well-defined diagnostic criteria would enable the nature of portal vein thrombosis to be established in patients with HCC under consideration for liver transplantation. Benign portal vein thrombosis was diagnosed by the application of the following criteria: lack of vascularization of the thrombus on contrast-enhanced ultrasound and on computed tomography or magnetic resonance imaging, absence of mass-forming features of the thrombus, absence of disruption of the walls of veins, and, if uncertainty persisted, biopsy of the thrombus for histological examination. Patients who did not fulfill the criteria for benign thrombosis were not placed on the transplantation list. In this study, all patients evaluated at our center during 2001-2007 with a diagnosis of HCC in whom portal vein thrombosis was concurrently or subsequently diagnosed were discussed by a multidisciplinary group to determine their suitability for liver transplantation. The outcomes for 33 patients who met the entry criteria of the study were as follows: in 14 patients who were placed on the transplantation list and underwent liver transplantation, no malignant thrombosis was detected when liver explants were examined histologically; 5 patients who were placed on the transplantation list either remained on the list or died from causes unrelated to HCC; in 9 patients, liver transplantation was contraindicated on account of a strong suspicion, or confirmation, of the presence of malignant portal vein thrombosis; and 5 patients who were initially placed on the transplantation list were subsequently removed from it on account of progression of HCC in the absence of evidence of neoplastic involvement of thrombosis. In conclusion, for a patient with HCC and portal vein thrombosis, appropriate investigations can establish whether the thrombosis is benign; patients with HCC and benign portal vein thrombosis are candidates for liver transplantation.

2010 - Cryoglobulinemia in elderly patients with HCV-related chronic hepatitis [Articolo su rivista]
Foschi, Fg; Dall’Aglio, Ac; Lanzi, A; Marano, G; Savini, S; Andreone, P; Bernardi, M; Stefanini, Gf.
abstract

Hepatitis C virus (HCV) infection affects about 3% of the world’s population and often leads to chronic liver disease. In some industrialized countries, HCV prevalence increases with age, but the optimal management of older patients has not been accurately defined. HCV infection can also lead to lymphoproliferative disorders, the most common being mixed cryoglobulinemia (MC), and also for this condition that frequently affects elderly patients, the optimal therapeutic strategy is still debated. We report the case of a 77-year-old Caucasian woman with HCV-related chronic hepatitis and cutaneous manifestations consisting of urticaria and pruritus related to MC resistant to antihistamines. The patient underwent a treatment with interferon and ribavirin. Such a treatment led to early biochemical and virological response associated with the resolution of cryoglobulinemia and cutaneous symptoms. After the end of treatment, HCV replication relapsed, but cryoglobulinemia and cutaneous symptoms did not recur. In the absence of definite treatment guidelines in this particular context, our experience suggests that the presence of symptoms related to HCV-infection that deeply affect patient quality of life warrants antiviral therapy even beyond the age limits that currently exclude patients from treatment.

2010 - Genome-wide meta-analyses identify three loci associated with primary biliary cirrhosis [Articolo su rivista]
Liu, X; Invernizzi, P; Lu, Y; Kosoy, R; Lu, Y; Bianchi, I; Podda, M; Xu, C; Xie, G; Macciardi, F; Selmi, C; Lupoli, S; Shigeta, R; Ransom, M; Lleo, A; Lee, At; Mason, Al; Myers, Rp; Peltekian, Km; Ghent, Cn; Bernuzzi, F; Zuin, M; Rosina, F; Borghesio, E; Floreani, A; Lazzari, R; Niro, G; Andriulli, A; Muratori, Luigi; Muratori, Paolo; Almasio, Pl; Andreone, Pietro; Margotti, Marzia; Brunetto, M; Coco, B; Alvaro, D; Bragazzi, Mc; Marra, F; Pisano, A; Rigamonti, C; Colombo, M; Marzioni, M; Benedetti, A; Fabris, L; Strazzabosco, M; Portincasa, P; Palmieri, Vo; Tiribelli, C; Croce, L; Bruno, S; Rossi, S; Vinci, M; Prisco, C; Mattalia, A; Toniutto, P; Picciotto, A; Galli, A; Ferrari, C; Colombo, S; Casella, G; Morini, L; Caporaso, N; Colli, A; Spinzi, G; Montanari, R; Gregersen, Pk; Heathcote, Ej; Hirschfield, Gm; Siminovitch, Ka; Amos, Ci; Gershwin, Me; Seldin, M. F.
abstract

A genome-wide association screen for primary biliary cirrhosis risk alleles was performed in an Italian cohort. The results from the Italian cohort replicated IL12A and IL12RB associations, and a combined meta-analysis using a Canadian dataset identified newly associated loci at SPIB (P = 7.9 × 10−11, odds ratio (OR) = 1.46), IRF5-TNPO3 (P = 2.8 × 10−10, OR = 1.63) and 17q12-21 (P = 1.7 × 10−10, OR = 1.38).

2010 - Hepatitis C Virus-related chronic liver disease in elderly patients: an Italian cross-sectional study [Articolo su rivista]
Gramenzi, A; Conti, F; Felline, F; Cursaro, C; Riili, A; Salerno, M; Gitto, S; Micco, L; Scuteri, A; Andreone, P; Bernardi, M.
abstract

2010 - Immunological modifications during treatment with thymosin alpha 1 plus antiviral therapy in chronic hepatitis C [Articolo su rivista]
Grandini, Elena; Cannoletta, Francesca; Scuteri, Alessandra; Fortini, Cinzia; Loggi, Elisabetta; Cursaro, C; Riili, Anna; DI DONATO, Roberto; Gramenzi, Annagiulia; Bernardi, Mauro; Andreone, Pietro
abstract

The current standard therapy for the treatment of chronic hepatitis C virus (HCV) is the combination of peginterferon and ribavirin, although many patients fail to clear the virus and their retreatment options are still unsatisfactory. Thymosin alpha1 (Talpha1) is an immunomodulating agent that has been proposed as complementary therapy for chronic HCV, especially in the setting of difficult-to-treat patients. The aim of this study was to evaluate, in patients nonresponsive to previous Peg-based therapy, the effect of standard antiviral therapy with or without Talpha1 on peripheral lymphocyte subsets. Twenty-four patients, 12 receiving Talpha1 and 12 standard therapy, were enrolled. Peripheral subpopulations were analyzed by flow cytometry. Although the addition of Talpha1 did not seem to significantly modify the T-lymphocyte subpopulations, as comparable behaviors were observed in the CD4 and CD8 longitudinal evaluation, Talpha1 produced an earlier increase of natural killer cells. An accurate selection of HCV patients who can benefit from immunomodulation is needed

2010 - In response [Articolo su rivista]
Gitto, S.; Biselli, M.; Bernardi, M.; Andreone, P.
abstract

2010 - Long term follow-up and outcome of liver transplantation for alcoholic liver disease: a single center case-control study [Articolo su rivista]
Biselli, Maurizio; Gramenzi, Annagiulia; DEL GAUDIO, Massimo; Ravaioli, Matteo; Vitale, Giovanni; Gitto, Stefano; Grazi, GIAN LUCA; Pinna, ANTONIO DANIELE; Andreone, Pietro; Bernardi, Mauro; Bologna Liver Transplantation, Group; Bianchi, FRANCESCO BIANCO; Bolondi, Luigi; Cescon, Matteo; D'Errico, Antonietta; Ercolani, Giorgio; Grigioni, Franco; Lenzi, Marco; Lodato, Francesca; Mazzella, Giuseppe; Piscaglia, Fabio; Roda, Enrico; Sama, Claudia; Tame', Mariarosa
abstract

BACKGROUND: Alcoholic liver cirrhosis (ALC) is a leading indication for orthotopic liver transplantation (OLT). GOALS: To investigate the long-term outcome of OLT for ALC compared with patients transplanted for hepatitis C virus (HCV) infection. STUDY: From 1987 to 2001, 49 OLT were performed for ALC and 173 for HCV. From these contemporary groups we matched 1:2 ALC patients (cases) to 98 HCV (controls). The following variables were analyzed: survival, retransplantation, rejection, primary nonfunction, infections, de novo tumors, cardiovascular and neurologic complications, and alcoholic recurrence. RESULTS: Actuarial survival rate at 9 years was comparable for cases and controls. Actuarial graft survival rate at 9 years was significantly higher in cases (78% vs. 60%; P=0.026). The retransplantation rate was higher in controls (21% vs. 4%; P=0.007). Post-OLT complications were not significantly different. The alcoholic recidivism rate was 28% without influence on patients or graft survival, whereas relapse of HCV caused the majority of death in controls (30%; P=0.042). At multivariate analysis retransplantation was the only predictor of patient survival (odds ratio: 4.35; 95% confidence interval: 2.16-8.74; P<0.001), whereas HCV was associated with a 2-fold probability of graft failure (odds ratio: 1.97; 95% confidence interval: 1.02-3.81; P=0.032). CONCLUSIONS: The long-term outcome of OLT for ALC is comparable to that for HCV, even if graft survival is significantly better among ALC. These data support ALC as an excellent indication for OLT.

2010 - Pharmacokinetics and efficacy of intravenous or intramuscular hepatitis B immunoglobulins in prophylaxis of hepatitis B after liver transplantation [Articolo su rivista]
Marzano, A.; Marengo, A.; Andreone, P.; Volpes, R.; Canova, D.; Cursaro, C.; Riili, A.; Fiorentino, B.; Bacci, M.; Guazzini, S.; Burra, P.
abstract

AIM: The use of hepatitis B immunoglobulin (HBIg) combined with nucleos(t)ide analogues (NUCs) has improved outcomes in post-hepatitis B (PHB) liver transplant (LT), reducing the 1-year recurrence rate below 10%. The aim of this study was to evaluate efficacy and pharmacokinetics of prophylaxis with NUC(s) and intravenous (iv-) or intramuscular (im-) HBIg in 33 PHBLTs, transplanted for more than 1 year. METHODS: During the first six months of the study, 18 subjects received 5000 IU of iv-HBIg every four weeks and 15 patients 2160 IU/12 mL of im-HBIg every two weeks. In the following six months, 31 subjects were switched to two different concentrations of im-HBIg, 2160/12 mL (16 patients) or 2000 IU/6 mL every two weeks (15 patients). RESULTS: All patients remained HBsAg-negative and 30/31 maintained anti-HBs >100 IU/L. Overall mean anti-HBs titer during treatment was 363 IU/mL. Mean HBIg half-life was 21.4, 27.3 and 26 days with intravenous, diluted or concentrated im-preparations, respectively. CONCLUSION: These results confirm an analogue efficacy and tolerance of iv- and im-HBIg combined with antivirals in prophylaxis of hepatitis B after LT. Anti-HBs titers three times higher than aimed and four weeks mean half-life could suggest the reduction of doses and the elongation of the interval of administration of im-HBIg.

2010 - Practice guidelines for the treatment of hepatitis C: recommendations from an AISF/SIMIT/SIMAST Expert Opinion Meeting [Articolo su rivista]
Piscaglia, Fabio; Italian Society of Infectious, Tropical Diseases; Italian Society for the Study of Sexually Transmitted Diseases: Prati, D.; Gasbarrini, A.; Mazzotta, F.; Sagnelli, E.; Carosi, G.; Abrescia, N.; Alberti, A.; Ambu, S.; Andreone, Pietro; Andriulli, A.; Angelico, M.; Antonucci, G. F.; Ascione, A.; Belli, L. S.; Bruno, R.; Bruno, S.; Burra, P.; Cammà, C.; Caporaso, N.; Cariti, G.; Cillo, U.; Coppola, N.; Craxì, A.; De Luca, A.; De Martin, E.; Di Marco, V.; Fagiuoli, S.; Ferrari, C.; Gaeta, G. B.; Galli, M.; Grieco, A.; Grossi, P.; Licata, A.; Maida, I.; Mangia, A.; Marino, N.; Maserati, R.; Missale, G.; Mondelli, M.; Nasta, P.; Niro, G.; Persico, M.; Petrelli, E.; Picciotto, A.; Piscaglia, F.; Pollicino, T.; Puoti, C.; Puoti, M.; Raimondo, G.; Rumi, M. G.; Santantonio, T.; Smedile, A.; Squadrito, G.; Baroni, G. S.; Taliani, G.; Tavio, M.; Toti, M.; Bonino, F.; Brunetto, M. R.; Cacopardo, B.; Caremani, M.; Cauda, R.; Colombo, M.; Di Perri, G.; Donato, F.; Farci, P.; Fattovich, G.; Filice, G.; Ghinelli, F.; Guadagnino, V.; Lazzarin, A.; Levrero, M.; Licata, G.; Orani, A.; Paffetti, A.; Pastore, G.; Piccinino, F.; Pizzigallo, E.; Pontisso, P.; Portelli, V.; Rizzetto, M.; Rossi, A.; Stroffolini, T.; Ubaldi, E.
abstract

It is increasingly clear that a tailored therapeutic approach to patients with hepatitis C virus infection is needed. Success rates in difficult to treat and low-responsive hepatitis C virus patients are not completely satisfactory, and there is the need to optimise treatment duration and intensity in patients with the highest likelihood of response. In addition, the management of special patient categories originally excluded from phase III registration trials needs to be critically re-evaluated. This article reports the recommendations for the treatment of hepatitis C virus infection on an individual basis, drafted by experts of three scientific societies.

2010 - Role of Contrast-Enhanced Ultrasonography in Primary Hepatic Lymphoma [Articolo su rivista]
Foschi, Fg; Dall’Aglio, Ac; Marano, Gianfranco; Lanzi, A; Savini, P; Piscaglia, Fabio; Serra, Carla; Cursaro, C; Bernardi, Mauro; Andreone, Pietro; Stefanini, Gf
abstract

Objective. Ultrasonography is the first examination performed for screening of hepatocellular carcinoma (HCC); contrast-enhanced ultrasonography (CEUS) can help discriminate between HCC and other lesions. Primary hepatic lymphoma (PHL), even if rare, should be considered in the differential diagnosis of focal liver lesions (FLLs). Few data are available in the literature about the role of CEUS in the diagnosis of PHL; we tried to determine whether CEUS could have a role in this setting. Methods. we describe 2 cases of primary non-Hodgkin lymphoma of the liver associated with hepatitis B virus (HBV) infection. The first patient was a 62-year-old man who was an HBV-inactive carrier, and the second was a 58-year-old man with type 2 diabetes and chronic HBV hepatitis. Results. in both cases, ultrasonography showed a hypoechoic liver lesion (4 and 3 cm, respectively) with irregular margins in segment 4 of the liver. On CEUS, these lesions were inhomogeneously hyperenhanced in the arterial phase and hypoenhanced in the portal and late phases. Contrast-enhanced computed tomography (CT) in both patients showed slight hyperenhancement in the arterial phase and hypoenhancement in the remaining phases. Needle biopsy showed marginal zone B-cell lymphoma of the mucosa-associated lymphoid tissue type in both patients. Conclusions. Contrast-enhanced ultrasonography and CT did not help us differentiate PHL from HCC; in fact, in both cases we saw the characteristic findings of primary HCC. Primary hepatic lymphoma is a rare condition, but it should always be considered in the differential diagnosis of FLLs. We stress the important role of liver biopsy when imaging indicates HCC in patients without underlying cirrhosis.

2010 - Six score systems to evaluate candidates with advanced cirrhosis for orthotopic liver transplant: which is the winner? [Articolo su rivista]
Biselli, M; Gitto, S; Gramenzi, A; Di Donato, R; Brodosi, L; Ravaioli, M; Grazi, Gl; Pinna, Ad; Andreone, P; Bernardi, M.
abstract

2009 - Alcohol and viral hepatitis: a mini-review [Articolo su rivista]
Gitto, S; Micco, L; Conti, F; Andreone, P; Bernardi, M.
abstract

Due to their high prevalence in the general population, alcohol use and abuse can be associated with hepatitis B and C virus infections and it has been demonstrated that alcohol plays a role as a co-morbid factor in the development of liver disease. There is evidence that alcohol abuse accelerates the progression of liver fibrosis and affects the survival of patients with chronic hepatitis C. The mechanism by which alcohol worsens hepatitis C virus-related liver disease has not been fully clarified, but enhanced viral replication, increased oxidative stress, cytotoxicity and impairment of immune response could play a relevant role. Alcohol abuse also seems to reduce both sensitivity to interferon and adherence to treatment. It sounds reasonable to presume that the mechanisms enhancing liver damage in patients affected by hepatitis B are similar to those involved in hepatitis C virus infection. However, more studies are warranted to improve our knowledge about the interaction between alcohol intake and hepatitis B virus infection. In conclusion alcohol abuse is associated with an accelerated progression of liver injury, leading to an earlier development of cirrhosis, higher incidence of hepatocellular carcinoma, and higher mortality. Abstinence could reverse some of these deleterious effects.

2009 - Allocation priority in non urgent liver transplantation: an overview of proposed scoring systems [Articolo su rivista]
Gitto, S; Lorenzini, S; Biselli, M; Conti, F; Andreone, P; Bernardi, M.
abstract

Given the lack of donors, a correct organ allocation system for candidates to liver transplantation is essential to increase graft and patient survival. The most used organ allocation tools are Child-Turcotte-Pugh and model for end-stage liver disease. It is generally accepted that model for end-stage liver disease score is superior to the Child-Turcotte-Pugh classification in predicting the short-term survival of cirrhotic patients awaiting liver transplantation. Since 2002, model for end-stage liver disease is widely used for liver allocation. In recent years, to overcome limitations of the consolidated scores, some adjustments to the original model for end-stage liver disease formula and new scoring systems have been proposed. Published data suggest that integrating serum sodium and model for end-stage liver disease may improve the score prognostic accuracy but further studies are necessary to confirm this issue. The updated model for end-stage liver disease, obtained through a revision of traditional model for end-stage liver disease parameters and tested in a large cohort of patients, is of great interest at the moment. In conclusion, several scoring systems have been described for organ allocation, but today, none is definitely able to overcome the limitations of the Child-Turcotte-Pugh and model for end-stage liver disease systems

2009 - Anti-HBs re-seroconversion after liver transplantation in a patient with past HBV infection receiving a HBsAg positive graft [Articolo su rivista]
Loggi, Elisabetta; Bihl, F; Chisolm JV, 3rd; Biselli, Maurizio; Bontadini, A; Vitale, G; Ercolani, Giorgio; Grazi, GIAN LUCA; Pinna, ANTONIO DANIELE; Bernardi, Mauro; Brander, C; Andreone, Pietro
abstract

2009 - Assessment of liver fibrosis in trnsplant recipients with recurrent HCV infection: Usefulness of transient elastography [Articolo su rivista]
Corradi, F.; Piscaglia, Fabio; Flori, S.; D'Errico, Antonietta; Vasuri, F.; Tamè, M. R.; Andreone, Pietro; Boni, P.; Gianstefani, Alice; Bolondi, Luigi
abstract

BACKGROUND: Progression of recurrent hepatitis C is accelerated in liver transplant recipients, leading to special need of non-invasive validated methods to estimate liver fibrosis. AIM: To assess the efficacy of liver stiffness measurement by transient elastography (Fibroscan) and serum parameters in predicting fibrosis stage in HCV-infected transplant recipients. METHODS: The correlation between liver fibrosis, assessed at liver histology on bioptic specimens obtained for clinical indications, and stiffness or clinico-serological indexes (Benlloch, APRI, Forns, Fibrotest and Doppler resistance index), was investigated in transplant recipients with recurrence of HCV chronic hepatitis. A total of 56 patients (of which 36 with all clinico-serological indexes), presenting with the following METAVIR fibrosis stage F1=38, F2=9, F3=8, F4=1, were enrolled in the study population. Differences between fibrosis stages were calculated by non-parametric analysis. The best cut-off for identifying significant fibrosis (F2-F4) was assessed by ROC curve analysis. RESULTS: Stiffness (median and range) was 7.7 KPa (range 4.2-13.9) in F1 and 17.0KPa (range 6.8-36.3) in >or=F2 (p<0.001). A stiffness cut-off of 10.1 KPa revealed 94% Sensitivity, 89% Specificity, 81% PPV and 94% NPV in differentiating F1 from F2-F4. The area under the receiver operator curve in the assessment of fibrosis was significantly higher for Liver stiffness (AUROC 0.943) than for any of the other non-invasive indexes (AUROCs ranging 0.591-0.815). CONCLUSIONS: Transient elastography of the liver provides good accuracy in identifying patients with significant fibrosis and performs better than non-invasive indexes based on clinico-serological parameters in transplant recipients.

2009 - Early discontinuation of ribavirin in HCV-2 and HCV-3 patients responding to Peg-interferon alpha-2a and ribavirin [Articolo su rivista]
Andriulli, A; Cursaro, C; Cozzolongo, R; Iacobellis, A; Valvano, Mr; Mangia, A; Minerva, N; Bacca, D; Stanzione, M; Scuteri, A; Montalto, G; Andreone, P.
abstract

2009 - Evolving clinical landscape of chronic hepatitis B: A multicenter Italian study [Articolo su rivista]
Stroffolini, T.; Almasio, P. L.; Sagnelli, E.; Mele, A.; Gaeta, G. B.; Italian Hospitals' Collaborating, Group; Andreone, Pietro; Scuteri, A.; Antonucci, G.; Iacomi, F.; Babudieri, S.; Pintus, A.; Stornaiuolo, G.; Brancaccio, G.; Brunetto, M.; Sasso, R.; Caporaso, N.; Morisco, F.; Chiaramonte, M.; Lattanzi, E.; Di Marco, V.; Venezia, G.; Fagiuoli, S.; Boninsegna, S.; Fattovich, G.; Olivari, N.; Ferrari, C.; Giuberti, T.; Ferrigno, L.; Magnani, G.; Massari, M.; Mangano, C.; Caserta, C.; Messina, V.; Pastore, G.; Palattella, S.; Piccinino, F.; Stanzione, M.; Pinzello, G.; Vinci, M.; Raimondo, G.; Caccamo, G.; Roffi, L.; Bellia, V.; Rizzetto, M.; Smedile, A.; Ciancio, A.
abstract

The aim of the study was to evaluate the characteristics of chronic hepatitis B with special reference to the geographical origin of the patients and to the prevalence of HBeAg and viral and non-viral co-factors of liver disease. A cross-sectional multicenter survey was undertaken, which enrolled 1,386 HBsAg chronic carriers observed consecutively in 21 referral centers over a 6-month period. The prevalence of HBeAg in patients was 11%; the presence of HBeAg was associated independently with a younger age and co-infection with HIV. Anti-HDV, anti-HCV, or anti-HIV antibodies were detected in 8.1%, 6.5%, and 2%, respectively. However, among the patients first diagnosed during the study period (incident cases), 14.3% were anti-HDV positive. Seven percent of the patients were immigrants; they were younger than Italian patients and 18% were HBeAg positive; no difference was observed in the prevalence of anti-HDV, anti-HCV, or anti-HIV antibodies. The presence of cirrhosis was associated independently with an age >52 years, the presence of anti-HDV or anti-HCV, alcohol use >4 drinks/day, and a high BMI. The clinical epidemiology of chronic hepatitis B virus (HBV) infection shows a dynamic profile, with the potential for re-emergence of cases with HBeAg or anti-HDV and an emerging impact of metabolic factors on the evolution of liver disease

2009 - Hepatitis C virus (HCV) infection in elderly patients: A multicenter Italian cross-sectional study [Abstract in Rivista]
Conti, F.; Morieri, M. L.; Gramenzi, A.; Cammà, C.; Greco, A.; Picciotto, A.; Taliani, G.; Romano, D.; Costa, P.; Rendina, M.; Ancarani, F.; Chiaramente, M.; Verucchi, G.; Craxì, A.; Bernardi, M.; Andreone, P.; the AISF HepaElder Study, Group
abstract

2009 - Hepatocellular carcinoma in patients with cryptogenic cirrhosis [Articolo su rivista]
Edoardo Giovanni, Giannini; Elisa, Marabotto; Vincenzo, Savarino; Trevisani, Franco; Maria Anna di, Nolfo; Paolo Del, Poggio∥; Luisa, Benvegnù; Fabio, Farinati; Zoli, Marco; Franco, Borzio; Eugenio, Caturelli; Maria, Chiaramonte; Italian Liver Cancer Group, [. . .; Andreone, Pietro; Bernardi, Mauro; Caraceni, Paolo; Cursaro, C.; Di Micoli, A.; Domenicali, Marco; Gramenzi, Annagiulia; Frigerio, M.; Cappa, F. M.; Santi, V.; Zambruni, A.; Grazi, GIAN LUCA; Nardo, Bruno; Ravaioli, M.; Giampalma, E.; Golfieri, Rita; Di Marco, M.; Vavassori, E.; Gilardoni, L.; Mattiello, M.; Alberti, A.; Gatta, A.; Gios, M.; De Giorgio, M.; Gianni, S.; Rinaldi, M.; Roselli, P.; Ghittoni, G.; ], . .
abstract

BACKGROUND & AIMS: Patients with cryptogenic cirrhosis (CC) can develop hepatocellular carcinoma (HCC), although the clinical characteristics of HCC in these patients have not been completely defined. We aimed to characterize the clinical features of patients diagnosed with HCC after CC during a 15-year period (1992-2006). METHODS: The clinical characteristics of 45 consecutive CC patients with HCC were analyzed, along with modality of diagnosis, tumor stage, treatment, survival, and causes of death. Data were compared with those of 426 consecutive patients with HCC and only hepatitis C virus (HCV) infection, diagnosed during the same period at the Italian Liver Cancer group centers. RESULTS: HCC patients with CC had similar impairments in liver function as patients with HCV infection (Child-Pugh class A: 53% vs 65%; P = .141). However, the HCC patients with CC had lower aminotransferase levels (P < .001) and higher platelet counts (P < .001). HCC was significantly less likely to be diagnosed during surveillance in CC patients (29% vs 64%; P < .0001). Patients with CC had a significantly greater prevalence of advanced HCC stage, according to Milano criteria (69% vs 41%; P < .0005), larger HCC size (4.9 vs 3.0 cm; P = .0001), lower amenability to any treatment (27% vs 42%; P = .036), and shorter survival times (P = .009, log-rank test) compared with HCV patients. Causes of death were similar in the 2 groups. CONCLUSIONS: Compared with HCV patients, HCC in CC patients often is diagnosed at an advanced stage, probably owing to lack of surveillance; this leads to limited treatment options and shorter survival times.

2009 - In portal hypertensive cirrhotic patients abdominal porto-systemic collaterals at ultrasound identify a group of patients at high risk of death [Abstract in Rivista]
Tiani, C; Rossi, V; Berzigotti, A; Pierpaoli, L; Zappoli, P; Magalotti, D; Riili, A; Di Micoli, A; Andreone, P; Golfieri, R; Bernardi, M; Zoli, M
abstract

Background and aim: Abdominal porto-systemic collaterals (APC) on color-Doppler ultrasound are a frequent finding in portal hypertensive cirrhotic patients, but their prognostic significance is unclear. In cirrhosis, an HVPG≥16mmHg has been associated with high mortality in some series. Non-invasive indicators of HVPG≥16mmHg might define a subgroup of high-risk patients, but data on this aspect are lacking. We aimed to investigate the prognostic value of HVPG and of APC in patients with cirrhosis and portal hypertension.

2009 - Is female sex a significant favorable prognostic factor in hepatocellular carcinoma? [Articolo su rivista]
Farinati, F.; Sergio, A.; Giacomin, A.; Di Nolfo, M. A.; Del Poggio, P.; Benvegnù, L.; Rapaccini, G.; Zoli, Marco; Borzio, F.; Giannini, E. G.; Caturelli, E.; Trevisani, Franco; for the Italian Liver Cancer group, [; Andreone, Pietro; Bernardi, Mauro; Biselli, Maurizio; Caraceni, Paolo; Cantarin, M. C.; Casadio, R.; Frigerio, M.; Di Micoli, A.; Domenicali, M.; Li Bassi, S.; Magalotti, D.; Cappa, F. M.; Santi, V.; Zambruni, A.; Balsamo, C.; DI MARCO, Mariacristina; Vavassor, E.; Gilardon, L.; Mattiello, M.; Alberti, A.; Gatta, A.; Gios, M.; Covino, M.; Gasbarrini, G.; Baldan, A.; Cristofori, C.; Molaro, M.; Sala, M.; Risso, D. T. R.; Ghittoni, G.; Roselli, P.; Grazi, GIAN LUCA; Nardo, B.; Ravaioli, M.; Pinna, ANTONIO DANIELE; Rossi, C.; Giampalma, E.; Golfieri, R. ].; Domenicali, Marco
abstract

OBJECTIVE: As sex favorably modulates the natural history of chronic liver diseases and the risk for neoplastic evolution, our study aimed to ascertain whether female hepatocellular carcinoma (HCC) patients are also characterized by better prognosis. METHODS: The ITA.LI.CA (Italian Liver Cancer) database was used, including 1834 HCC patients (482 females, 1352 males) that were consecutively diagnosed. The following variables were considered: age, etiology, modality of diagnosis, earlier interferon treatment, bilirubin, alpha-fetoprotein levels, constitutional syndrome, portal thrombosis, metastasis, number and size of nodules, grading, Child-Pugh class, tumor-nodes-metastases and Cancer of the Liver Italian Program staging, and treatment. RESULTS: Female HCC patients were characterized by older age (P=0.0001), higher prevalence of HCV infection (P=0.0001), diagnosis more frequently by surveillance (P=0.003), higher alpha-fetoprotein levels (P=0.0055), lower prevalence of constitutional syndrome (P=0.03), portal thrombosis (P=0.04), and metastasis (P=0.0001). HCC in females was more frequently unifocal (P=0.0001), smaller (P=0.001), well differentiated (P=0.001), and of lower Cancer of the Liver Italian Program and tumor-nodes-metastases stage (P=0.0001 and 0.0001). However, females underwent curative treatments (transplantation, resection, percutaneous ablation) in the same percentage of cases as males. Finally, females had a significantly longer survival (median 29 [95% confidence interval (CI): 24-33] vs. 24 (22-25) months, P=0.0001). The difference was sharper [median 36 (CI: 31-41] vs. 17 (CI: 15-19)] when females undergoing surveillance were compared with males diagnosed incidentally or for symptoms. The Cox model also identified sex as an independent predictor of survival. When only patients undergoing surveillance were considered, no significant difference was observed. CONCLUSION: HCC in females has better prognosis, but this is possibly more because of higher compliance with surveillance than to real biological differences.

2009 - Ketoprofen, peginterferon-alpha2a and ribavirin for genotype 1 chronic hepatitis C: a phase II study [Articolo su rivista]
Gramenzi, Annagiulia; Cursaro, C; Margotti, Marzia; Balsano, C; Spaziani, A; Anticoli, S; Loggi, Elisabetta; Salerno, M; Galli, S; Furlini, G; Bernardi, Mauro; Andreone, Pietro
abstract

2009 - Polymorphism rtQ215H in primary resistance to adefovir dipivoxil in hepatitis B virus infection: a case report [Articolo su rivista]
Micco, L; Fiorino, S; Loggi, E; Lorenzini, S; Vitale, G; Cursaro, C; Riili, A; Bernardi, M; Andreone, P.
abstract

The benefit of lamivudine (LAM) in hepatitis B virus (HBV) infection is compromised by the progressively increasing emergence of drug-resistant mutant strains. Although the addition of adefovir dipivoxil (ADV) usually induces complete suppression of viral replication, primary non-response to ADV in LAM resistant patients has been reported in a variable percentage of cases. Here we report a case of a patient with HBV infection and hepatocellular carcinoma who started LAM therapy and subsequently developed virological breakthrough. The patient was given ADV, but HBV-DNA negativisation was not reached. However, HBV clearance was obtained when the patient was switched from ADV to tenofovir. Virological evaluations showed two well-known LAM-related mutations (rtL180M and rtM204I) in addition to reverse-transcriptase rtQ215H. This is the first case suggesting that this mutation may have an impact on viral replication. Finally, we also report that rtQ215H is responsive to tenofovir.

2009 - Re-treatment of patients with chronic hepatitis C who do not respond to peginterferon-alpha2b: a randomized trial [Articolo su rivista]
Jensen, Dm; Marcellin, P; Freilich, B; Andreone, P; Di Bisceglie, A; Brandão-Mello, Ce; Reddy, Kr; Craxi, A; Martin, Ao; Teuber, G; Messinger, D; Thommes, Ja; Tietz, A.
abstract

2009 - Role of hepatitis B virus infection in the prognosis after hepatectomy for hepatocellular carcinoma in patients with cirrhosis: a Western dual-center experience [Articolo su rivista]
Cescon, M.; Cucchetti, A.; Grazi, G. L.; Ferrero, A.; Viganò, L.; Ercolani, G.; Ravaioli, M.; Zanello, M.; Andreone, P.; Capussotti, L.; Pinna, A. D.
abstract

HYPOTHESIS: The role of hepatitis B virus (HBV) infection in determining the prognosis after hepatectomy for hepatocellular carcinoma (HCC) in patients with cirrhosis is controversial. DESIGN: Retrospective study based on multicenter prospectively updated databases. SETTING: Two tertiary referral centers specializing in hepatobiliary surgery. PATIENTS: Two hundred four consecutive patients with cirrhosis undergoing hepatectomy for single nodules of HCC of 5 cm or smaller from January 1, 1997, through September 30, 2006. INTERVENTIONS: Patients were divided into the following groups according to their preoperative viral status: HBV positive and hepatitis C virus (HCV) negative (group 1); HBV negative and HCV positive (group 2); HBV negative and HCV negative (group 3); and HBV positive and HCV positive (group 4). MAIN OUTCOME MEASURES: A multivariate analysis was performed to determine factors associated with recurrence-free survival (RFS) among demographic, clinical, pathological, and surgical variables. RESULTS: The 2 centers had comparable RFS and early and late recurrence rates. Five-year RFS was significantly higher in groups 2 and 3 compared with group 1 (38%, 34%, and 9%, respectively; P = .007 and P = .05). Factors independently associated with RFS were HBV infection (P = .009; odds ratio, 1.79; 95% confidence interval, 1.15-2.78) and poor tumor differentiation (P < .001; odds ratio, 2.01; 95% confidence interval, 1.36-2.96). The concomitance of 0, 1, or 2 risk factors led to 5-year RFS rates of 49%, 20%, and 8%, respectively (P < .001). CONCLUSIONS: Infection with HBV is a strong predictive factor for lower RFS after hepatectomy for a single nodule of HCC of 5 cm or smaller in patients with cirrhosis, providing a further basis for adjuvant antiviral treatment. Patients who are seropositive for HBV with poorly differentiated HCC should also be considered to be at a high risk of recurrence and possibly included in a policy of salvage liver transplantation.

2009 - Two yr mycophenolate mofetil plus low-dose calcineurin inhibitor for renal dysfunction after liver transplant [Articolo su rivista]
Biselli, Maurizio; Vitale, Giovanni; Gramenzi, Annagiulia; Riili, Anna; Berardi, Sonia; Cammà, C; Scuteri, Alessandra; Morelli, Mc; Grazi, Gian Luca; Pinna, Antonio Daniele; Andreone, Pietro; Bernardi, Mauro
abstract

2009 - Vitamin E activity in immune response: A possible immunohenancing role in chronic viral infections [Capitolo/Saggio]
Fiorino, S.; Bihl, F.; Gramenzi, A.; Lorenzini, S.; Cursaro, C.; Loggi, E.; Fortini, C.; Bernardi, M.; Andreone, P.
abstract

In recent years, many roles of Vitamin E have been demonstrated and include not only antioxidant functions, but also cell signaling and immunemodulatory functions. In this paper the experimental and clinical evidence of vitamin E immunomodulatory properties as well as the vitamin E biological activities able to stimulate and enhance immune activities are briefly reviewed. Several lines of evidence suggest that vitamin E might be useful to improve immune unresponsiveness induced by several pathological conditions such as chronic viral infections and make its use in this setting promising. Further studies investigating the effects of Vitamin E on are of interest as they might help to identify its therapeutic utility in chronic infections. © 2010 by Nova Science Publishers, Inc. All rights reserved.

2008 - Anti-synthetase syndrome with lung involvement associated with primary biliary cirrhosis: A case report [Articolo su rivista]
D'Avanzo, M.; Fasano, Luca; Pacilli, ANGELA MARIA GRAZIA; Carbonara, Paolo; DI SCIOSCIO, Valerio; Salfi, Nunzio; Vitale, Giovanni; Andreone, Pietro; Fabbri, Mario
abstract

2008 - Clinical trial: peg-interferon alfa-2b and ribavirin for the treatment of genotype-1 hepatitis C recurrence after liver transplantation [Articolo su rivista]
Lodato, F; Berardi, S; Gramenzi, A; Mazzella, G; Lenzi, M; Morelli, Mc; Tame, Mr; Piscaglia, F; Andreone, P; Bologna Liver Transplantation Group (BLTG), [. . .; Ballardini, G; Bernardi, M; Bianchi, Fb; Biselli, M; Bolondi, L; Cescon, M; Colecchia, A; D'Errico, A; Del Gaudio, M; Ercolani, G; Grazi, Gl; Grigioni, W; Lorenzini, S; Pinna, Ad; Ravaioli, M; Roda, E; Sama, C; Vivarelli, M.; ], . .
abstract

Background Treatment of hepatitis C virus (HCV) recurrence after liver transplantation (LT) is difficult with low response rates. Aim To assess the safety and efficacy of pegylated-interferon (PEG-IFN) alfa-2b + ribavirin (RBV) in patients with post-LT recurrent genotype-1 HCV and to establish stopping rules according to response. Methods Fifty-three patients with post-LT HCV recurrence were enrolled. Patients received PEG-IFN alfa-2b 1.0 μ/kg/week plus RBV 8–10 mg/kg/day for 24 weeks. Those with ‘early virological response at week 24’ (EVR24) continued treatment for 24 weeks (group A). Patients without EVR24 were randomized to continue (group B) or to discontinue (group C). Results Overall sustained virological response (SVR) was 26% (14/53). Alanine aminotransferase, rapid virological response, EVR12, EVR24, undetectable serum HCV-RNA at weeks 12 (cEVR12) and 24 (cEVR24) were related to SVR. cEVR12 and cEVR24 (OR: 14.7; 95% CI: 2.02–106.4) were independent predictors of SVR. All patients with SVR, had cEVR12. No patient in groups B and C achieved end-of-treatment response. One patient in group B had SVR. Conclusions Pegylated-interferon alfa-2b was effective in one of four of patients with HCV genotype 1 after LT. Treatment should be discontinued in patients with no virological response at week 12. Further studies are needed to evaluate whether a longer treatment period may be beneficial in patients with ≥2 log10 drop in HCV-RNA at week 24

2008 - Demographic, etiological and clinical features of liver cirrhosis at the onset of the first episode of clinical decompensation: Preliminary results of the “A.I.S.F.-EPASCO” [Articolo su rivista]
Bruno, S; Almasio, P; Saibeni, S; Vandelli, Carmen; Ascione, A; Felder, M; Tommasini, M; Andreone, P; Gaeta, Gb; Andriulli, A; Furlan, C; Salerno, F; Loguercio, C; Persico, M; Stroffolini, T; the A. I. S. F., EPASCO Collaborative Study Group
abstract

Not applicable

2008 - Demographic, etiological and clinical features of liver cirrhosis at the onset of the first episode of clinical decompensation: Preliminary results of the “A.I.S.F.-EPASCO” Study. [Articolo su rivista]
Bruno, S.; Almasio, P.; Saibeni, S.; Vandelli, Carmen; Ascione, A.; Felder, M.; Tommasini, M.; Andreone, P.; Gaeta, G. B.; Andriulli, A.; Furlan, C.; Salerno, F.; Loguercio, C.; Persico, M.; Stroffolini, T.; EPASCO COLLABORATIVE STUDY GROUP, A. I. S. F.
abstract

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2008 - Evaluation of the effects of Human leukocyte INF-alpha on the immune response to the HBV vaccine in healthy unvaccinated individuals [Articolo su rivista]
Rizza, P; Capone, I; Urbani, F; Montefiore, E; Rapicetta, M; Chionne, P; Candido, A; Tosti, Me; Grimaldi, M; Palazzini, E; Viscomi, G; Cursaro, C; Margotti, M; Scuteri, A; Andreone, P; Taylor, E; Haygreen, Ea; Tough, Df; Borrow, P; Selleri, M; Castilletti, C; Capobianchi, M; Belardelli, F.
abstract

2008 - G-CSF administration is not related to PEG-IFN alfa-213 treatment duration nor response in liver transplanted patients with HCV recurrence [Abstract in Atti di Convegno]
Lodato, F; Tame, Mr; Di Girolamo, M; Azzaroli, F; Gramenzi, A; Berardi, S; Andreone, P; Pinna, Ad; Roda, E; Mazzella G, .
abstract

2008 - G-CSF administration is not related to Peg-IFN alfa-2b treatment duration nor response in liver transplanted patients with HCV recurrence [Abstract in Atti di Convegno]
F., Lodato; M. R., Tamè; M., Di Girolamo; Azzaroli, Francesco; Gramenzi, Annagiulia; S., Berardi; Andreone, Pietro; Pinna, ANTONIO DANIELE; Roda, Enrico; Festi, Davide; Mazzella, Giuseppe
abstract

2008 - Hepatitis B virus and immune response [Monografia/Trattato scientifico]
Fiorino, S; Vukotic, R; Loggi, E; Vitale, G; Cursaro, C; Gramenzi, A; Micco, L; Fortini, C; Cuppini, A; Bernardi, M; Andreone, P.
abstract

This new book provides a comprehensive review of the studies concerning HBV epidemiology, pathogenesis and treatment. In addition, it describes recent advances in the knowledge of immune response function, promoting either viral control or persistence, and effects of antiviral therapy in patients with HBV acute or chronic infection are reported. Although mechanisms involved in inflammatory and immune response in acute and chronic HBV infections have been extensively studied, several questions remain unresolved. Moreover, in recent years several key steps in research have contributed to improve our present knowledge of immunopathogenesis of HBV infection.

2008 - Hepatitis B virus e antigen loss during adefovir dipivoxil therapy is associated with enhanced virus-specific CD4+ T-cell reactivity [Articolo su rivista]
Cooksley, H; Chokshi, S; Maayan, Y; Wedwmeyer, H; Andreone, P; Gilson, R; Warnes, T; Paganin, S; Zoulim, F; Frederick, D; Neumann, Au; Brosgart, Cl; Naoumov, Nv.
abstract

2008 - Hepatocellular carcinoma appearance in patients with hepatitis C virus-related chronic liver disease 90 and 70 months after sustained virological response to interferon and ribavirin [Articolo su rivista]
Vukotic, Ranka; Gramenzi, Annagiulia; Vitale, Giovanni; Cursaro, C; Serra, C; Biselli, Maurizio; Scuteri, Alessandra; Andreone, Pietro; Bernardi, Mauro
abstract

We report here two cases of hepatocellular carcinoma (HCC) 90 and 70 months, respectively, after successful treatment with interferon (IFN) and ribavirin for hepatitis C virus (HCV)-related cirrhosis. A 50-year-old Caucasian man and a 66-year-old Caucasian woman with HCV-related cirrhosis were treated with IFN and ribavirin and in both cases a sustained virological response (SVR) was obtained with persistent normalization of serum aminotransferases and continuous disappearance of serum HCV-RNA. Both patients were subsequently followed up within an HCC surveillance programme based on biochemical and ultrasound (US) evaluation every 6 months and the appearance of HCC was detected 90 and 70 months, respectively, after discontinuation of therapy. We introduce these two cases to call attention to the importance of not underestimating the risk of HCC development even many years after complete HCV eradication, especially in the presence of established cirrhosis and concomitance of other risk factors for HCC.

2008 - Host ethnicity and genotype shape the hepatitis B virus-specific T-cell repertoire [Articolo su rivista]
Tan, At; Loggi, Elisabetta; Boni, C; Chia, A; Gehring, Aj; Sastry, Ks; Goh, V; Fisicaro, P; Andreone, Pietro; Brander, C; Lim, Sg; Ferrari, C; Bihl, F; Bertoletti, A.
abstract

2008 - In vitro effect of thymosin-alpha1 and interferon-alpha on Th1 and Th2 cytokine synthesis in patients with eAg-negative chronic hepatitis B [Articolo su rivista]
Loggi, Elisabetta; Gramenzi, Annagiulia; Margotti, Marzia; Cursaro, C; Galli, S; Vitale, Giovanni; Grandini, Elena; Scuteri, Alessandra; Vukotic, Ranka; Andreone, Pietro; Bernardi, Mauro
abstract

2008 - Lack of correlation between serum anti-HBcore detectability and hepatocellular carcinoma in patients with HCV-related cirrhosis [Articolo su rivista]
Stroffolini, T; Almasio, Pl; Persico, M; Bollani, S; Benvegnù, L; Di Costanzo, G; Pastore, G; Aghemo, A; Stornaiuolo, G; Mangia, A; Andreone, P; Stanzione, M; Mazzella, G; Saracco, G; Del Poggio, P; Bruno, S; Italian Association of the Study of the Liver Disease, (AISF)
abstract

BACKGROUND: While the likelihood of developing hepatocellular carcinoma (HCC) in patients coinfected with both HBV and HCV is increased, the role of previous exposure to HBV as a risk factor associated with tumor occurrence in subjects with HCV-related cirrhosis has not been fully investigated. AIM: To assess whether serum anti-HBc positivity, as a marker of previous HBV exposure, is associated with HCC development in HCV-related positive, hepatitis B surface antigen (HBsAg) negative patients with cirrhosis treated with alfa-interferon (IFN) monotherapy. PATIENTS AND: A database including 883 consecutive patients (557 men, mean age 54.7 yr) with histologically METHODS: proven cirrhosis treated with IFN between 1992 and 1997 was analyzed. All subjects have been surveilled every 6 months by ultrasound. Independent predictors of HCC were assessed by Cox multiple regression analysis. RESULTS: Mean follow-up was 96.1 months. Anti-HBc testing was available in 693 cases and, among them, 303 patients (43.7%) were anti-HBc seropositive. Anti-HBc positive patients were more often men (67.0%vs 58.7%, P= 0.03), had lower transaminase levels (3.3 +/- 2.0 vs 3.8 +/- 2.5 u.l.n., P= 0.004), and had higher rate of alcohol intake (38.3%vs 22.5%, P < 0.001) than anti-HBc negative patients. Overall, the incidence rates of HCC per 100 person-years were 1.84 (95% CI 1.34-2.47) in the anti-HBc positive patients and 1.86 (95% CI 1.41-2.42) in anti-HBc negative ones. By Cox multiple regression, there was no association of serum anti-HBc with HCC development (HR 1.03, 95% CI 0.69-1.52) or liver-related deaths incidence (HR 1.21; 95% CI 0.76-1.95). CONCLUSIONS: In comparison with anti-HBc negative subjects, serum anti-HBc positive patients with HCV-related/HBsAg negative cirrhosis treated with IFN monotherapy did not show a greater risk of HCC.

2008 - Stem cell mobilization and collection in patients with liver cirrhosis [Articolo su rivista]
Lorenzini, S; Isidori, Alessandro; Catani, Lucia; Gramenzi, Annagiulia; Talarico, S; Bonifazi, Francesca; Giudice, V; Conte, R; Baccarani, Michele; Bernardi, Mauro; Forbes, Sj; Lemoli, Roberto Massimo; Andreone, Pietro
abstract

Background: Bone marrow-derived stem cells (BMSC) and granulocyte colony-stimulating factor (G-CSF) have been proved to contribute to tissue regeneration after liver injury. Aims: To test the safety of G-CSF and define the exact dose capable of mobilizing BMSC in the majority of patients with liver cirrhosis; and to assess the feasibility of leukapheresis to collect BMSC from peripheral blood. Methods: In this study, we treated 18 patients affected by liver cirrhosis with increasing doses of G-CSF to mobilize CD34+ and CD133+ BMSC into the peripheral blood. Results: The dose-finding phase demonstrated that 15 μg/kg/day of G-CSF is the optimal dose to mobilize both CD34+ and CD133+ stem cells. Circulating BMSC were collected by a single step leukapheresis in three patients and the mean number of CD34+ and CD133+ cells cryopreserved was 1.3 ± 0.7 and 1.2 ± 0.5 × 106/kg, respectively. No severe adverse events were observed during the drug administration and stem cell collection. Noteworthy is, none of the patients showed a significant modification of liver function. Conclusions: Our study demonstrates that G-CSF administration and BMSC collection from the peripheral blood is possible and safe in patients with liver cirrhosis. The optimal dose to mobilize BMSC in cirrhotics is 15 μg/kg/day. At this dose, G-CSF does not seem to modify the residual liver function in cirrhotic patients

2008 - Stem cells for end stage liver disease: How far have we got? [Articolo su rivista]
Lorenzini, S; Gitto, S; Grandini, E; Andreone, P; Bernardi, M.
abstract

End stage liver disease (ESLD) is a health problem worldwide. Liver transplantation is currently the only effective therapy, but its many drawbacks include a shortage of donors, operative damage, risk of rejection and in some cases recidivism of the pre-transplant disease. These factors account for the recent growing interest in regenerative medicine. Experiments have sought to identify an optimal source of stem cells, sufficient to generate large amounts of hepatocytes to be used in bioartificial livers or injected in vivo to repair the diseased organ. This update aims to give non-stem cell specialists an overview of the results obtained to date in this fascinating field of biomedical research

2008 - Sustained and focused HBV-nucleocapsid-specific T cell immunity in liver transplant recipients compared to individuals with chronic and self-limited HBV infection [Articolo su rivista]
Bihl, F; Loggi, E; Chisholm III, Jv; Biselli, M; Morelli, Mc; Terrault, Na; Bernardi, M; Bertoletti, A; Andreone, P; Brander, C.
abstract

2008 - Treatment of chronic hepatitis B: Recommendations from an Italian workshop [Articolo su rivista]
Carosi, G.; Rizzetto, M.; Andreone, P.; Angelico, M.; Ascione, A.; Caporaso, N.; Fagiuolim, S.; Fattovich, G.; Mondelli, M.; Niro, G. A.; Pontisso, P.; Bonino, F.; Perno, C. F.; Prati, D.; Andreoni, M.; Angarano, G.; Annicchiarico, E.; Boncoraglio, R.; Brustia, D.; Calabrese, N.; Carlotto, A.; Cavalletto, L.; Cavina, M.; Chessa, L.; Croce, G.; De Sanctis, G.; Di Candilo, F.; Fabris, P.; Fracassetti, O.; Lanza, A. G.; Giuberti, T.; Guazzotti, G.; Iacovazzi, T.; Iovinella, V.; Izzi, A.; Loperfido, P.; Magni, C. F.; Marino, N.; Messina, V.; Michelone, G.; Morante, R.; Moretti, A.; Nasta, P.; Nauri, L.; Paffetti, A.; Pasino, M.; Perboni, G.; Petrelli, E.; Picciotto, A.; Pozzi, M.; Purificato, F.; Re, T.; Rinaldi, R.; Sani, S.; Santoro, R.; Schioppa, O.; Scotto, G.; Siciliano, M.; Sorbello, O.; Squadrito, G.; Taddei, M. T.; Traversa, A.; Tundo, P.; Venezia, G.; Vilardo, L.; Zignego, A. L.; Zoncada, A.; Zuin, M.
abstract

The changing scenario of hepatitis B virus therapy has encouraged the organisation of a workshop, endorsed by three Italian scientific societies, aimed at defining the current recommendations for hepatitis B virus treatment. Liver histology and stage of disease remain fundamental for treatment decisions; interferon and nucleoside/nucleotide analogues-based therapy represent different strategies for different phases of the hepatitis B virus disease. The recommendations defined: new and lower cut-off of hepatitis B virus-DNA for eligibility to therapy according to disease stage, how to optimise the use of nucleoside/nucleotide analogues and to individualise the monitoring of response and what to do with treatment failures. Specific recommendations have also been given for cirrhosis patients, those immune suppressed and co-infected with HIV and other hepatitis viruses. © 2008 Editrice Gastroenterologica Italiana S.r.l.

2007 - A randomized trial of induction doses of interferon alone or in combination with ribavirin or ribavirin plus amantadine for treatment of non-responder patients with chronic hepatitic C [Articolo su rivista]
Gramenzi, A; Andreone, P; Cursaro, C; Verucchi, G; Boccia, S; Giacomoni, Pl; Galli, S; Furlini, G; Biselli, M; Lorenzini, S; Attard, L; Bonvicini, F; Bernardi, M.
abstract

Background: Efficacy and safety of interferon induction therapy alone or in combination with ribavirin or ribavirin plus amantadine were evaluated in chronic hepatitis C patients who were nonresponders to primary antiviral treatment. Methods: The study was designed to have 225 HCV nonresponder patients, but at an interim analysis the response rate difference between groups was lower than expected and the enrollment was stopped when 75 patients had been randomized to receive interferon-α2a (group A, n = 26), interferon-αa plus 15 mg/kg per day of ribavirin (group B, n = 24), or interferon-α2a plus ribavirin plus 200 mg/day of amantadine hydrochloride (group C, n = 25). Treatment duration was 48 weeks. The dose of interferon was 6 MU/day for 4 weeks followed by 3 MU/ day for the remaining 44 weeks. Results: On intention-to-treat, the sustained virological response at 24 weeks of follow-up was 11.5% in group A, 12.5% in group B, and 12% in group C. Therapy was discontinued because of adverse effects in three patients in group A (11.5%), three in group B (12.5%), and two in group C (8%). Conclusions: Nonresponders with chronic hepatitis C may achieve a sustained virological response rate of approximately 12% if retreated with interferon induction treatment followed by administration of a daily dose. The addition of ribavirin or amantadine did not seem to improve the response rates

2007 - Adefovir and lamivudine combination therapy is superior to ADV monotherapy for lamivudine-resistant patients with HBeAG-negative chronic hepatitis B [Abstract in Atti di Convegno]
Lampertico, P.; Marzano, A.; Levrero, M.; Santantonio, T.; Di Marco, V.; Brunetto, M.; Andreone, P.; Sagnelli, E.; Fagiuoli, S.; Mazzella, G.; Raimondo, G.; Gaeta, G. B.; Ascione and On behalf of the AISF Adefovir Study Group, A.
abstract

2007 - Adefovir dipivoxil for wait-listed and post-liver transplantation patients with lamivudine-resistant hepatitis B: Final long-term results [Articolo su rivista]
Schiff, E.; Lai, C. -L.; Hadziyannis, S.; Nuehaus, P.; Terrault, N.; Colombo, M.; Tillmann, H.; Samuel, D.; Zuezem, S.; Villenueve, J. -P.; Arteburn, S.; Borroto-Esoda, K.; Brosgart, C.; Chuck, S.; Shakil, A. O.; Fung, J.; Alberti, A.; Lok, A.; Picciotto, A.; Torre, F.; Riely, C.; Trepo, C.; Bizollon, T.; Bottaa-Fridlund, D.; Gerolami, R.; Douglas, D.; Ranjan, D.; Faust, D.; Trojan, J.; Gane, E.; Villa, E.; Boarino, M.; Sokal, E.; Starkel, P.; Bonino, F.; Maurizio, B.; Gordon, F.; Pratt, J.; Berr, F.; Schiefke, I.; McCaughan, G.; Strasser, S.; Dusheiko, G.; Pageaux, G. P.; Larrey, D.; Pastore, G.; Santantonio, T.; Alexander, G.; Woodall, T.; Van Vlierberghe, H.; Colle, I.; Harley, H.; Guggenheim, J.; Myx-Staccini, A.; Metreau, J. M.; Mavier, P.; Vierling, J.; Tran, T.; Girgrah, N.; Nyberg, L.; Yuen, M. -F.; Ma, M.; Balnco, M. D.; Merli, M.; Tanzilli, P.; Angelico, M.; Di Paolo, D.; Rizzetto, M.; Marzano, A.; Lampertico, P.; Prieto, M.; Berenguer, M.; Felder, M.; Sterneck, M.; Willems, M.; Charlton, M.; Gunneson, T.; Ritter, M.; Voight, M.; Swift, J.; Shiffman, M.; Tassopoulos, N.; Klissas, I.; Naourmov, N.; Chamouard, P.; Marcellin, P.; Durand, F.; Angus, P.; Nathan, C.; Toniutto, P.; Fumo, E.; Andreone, P.; Cursaro, C.; Barcena, R.; Hoz, F. G.; Zachoval, R.; Christina, M.; De Man, R. A.; Metselaar, H.
abstract

Wait-listed (n = 226) or post-liver transplantation (n = 241) chronic hepatitis B (CHB) patients with lamivudine-resistant hepatitis B virus (HBV) were treated with adefovir dipivoxil for a median of 39 and 99 weeks, respectively. Among wait-listed patients, serum HBV DNA levels became undetectable (

2007 - Clinical and serological profile of primary biliary cirrhosis in men [Articolo su rivista]
Muratori, Paolo; Granito, Alessandro; Pappas, G; Muratori, Luigi; Quarneti, Chiara; DE MOLO, Chiara; Cipriano, Valentina; Vukotic, Ranka; Andreone, Pietro; Lenzi, Marco; Bianchi, FRANCESCO BIANCO
abstract

2007 - Comparing and combining gamma-hydroxybutiric acid (GHB) and naltrexone in maintaining abstinence from alcohol: an open randomized comparative study [Articolo su rivista]
Caputo, Fabio; Addolorato, G; Stoppo, M; Francini, S; Vignoli, Teo; Lorenzini, F; Del Re, A; Comaschi, C; Andreone, Pietro; Trevisani, Franco; Bernardi, Mauro
abstract

2007 - Evolution of hepatitis C vitus non structural 5A gene (NS5A) in the progression of liver disease to hepatocellular carcinoma [Articolo su rivista]
DE MITRI, MARIA STELLA; Cassini, Romina; Bagaglio, S; Morsica, G; Andreone, Pietro; Marino, N; Bernardi, Mauro
abstract

2007 - High incidence of allograft dysfunction in liver transplant patients treated with PEG-Interferon alfa-2b and Ribavirin for hepatitis C recurrence: possible de novo autoimmune hepatitis? [Articolo su rivista]
Berardi, Sonia; Lodato, Francesca; Gramenzi, Annagiulia; D'Errico, Antonietta; Lenzi, Marco; Bontadini, Andrea; Morelli, Mc; Tamè, Mr; Piscaglia, Fabio; Biselli, Maurizio; Sama, Claudia; Mazzella, Giuseppe; Pinna, ANTONIO DANIELE; Bernardi, Mauro; Andreone, Pietro
abstract

2007 - Impact of etiology of cirrhosis on the survival of patients diagnosed with hepatocellular carcinoma during surveillance [Articolo su rivista]
Trevisani, Franco; Magini, Giulia; Santi, Valentina; Maria Morselli-Labate, Antonio; Chiara Cantarini, Maria; Anna Di Nolfo, Maria; Del Poggio, Paolo; Benvegnù, Luisa; Rapaccini, Gianludovico; Farinati, Fabio; Zoli, Marco; Borzio, Franco; Giovanni Giannini, Edoardo; Caturelli, Eugenio; Bernardi, Mauro; CA) Group, for the Italian Liver Cancer (ITA. LI.; Andreone, Pietro; Biselli, Maurizio; Caraceni, Paolo; Chiara Cantarini, Maria; Cursaro, Carmela; Domenicali, Marco; Gramenzi, Annagiulia; Silvia, Li Bassi; Magalotti, Donatella; Mirici Cappa, Federica; Zambruni, Andrea; Luca Grazi, Gian; Nardo, Bruno; Ravaioli, Matteo; Rossi, Cristina; Golfieri, Rita
abstract

OBJECTIVES: Although the etiology of liver disease affects the features of hepatocellular carcinoma (HCC) diagnosed during surveillance, it is not known whether it influences patients' survival. We analyzed the impact of etiology on the characteristics and outcome of HCC detected during surveillance. METHODS: In this cohort study, 742 patients with HCC detected during semiannual or annual surveillance were selected from the ITA.LI.CA database, including 1,834 consecutive patients observed in three primary and seven tertiary care settings for HCC. Patients were grouped according to etiology: hepatitis B virus (HBV, 87), hepatitis C virus (HCV, 461), alcohol (59), and multietiology (135). RESULTS: In all etiologic groups, most HCCs were unifocal (51-68%) and most of them were

2007 - Low replication and variability of HBV pre-core in concomitant infection with hepatitis B and hepatitis C viruses [Articolo su rivista]
De Mitri, Maria Stella; Morsica, G; Cassini, Romina; Bagaglio, S; Andreone, Pietro; Bianchi, Giampaolo; Loggi, Elisabetta; Bernardi, Mauro
abstract

2007 - Prophylaxis and treatment of hepatitis B in immunocompromised patients [Articolo su rivista]
Marzano, A.; Angelucci, E.; Andreone, Pietro; Brunetto, M.; Bruno, R.; Burra, P.; Caraceni, Paolo; Daniele, B.; Di Marco, V.; Fabrizi, F.; Fagiuoli, S.; Grossi, P.; Lampertico, P.; Meliconi, Riccardo; Mangia, A.; Puoti, M.; Raimondo, G.; Smedile, A.
abstract

2007 - Regenerative medicine and liver injury: what role for bone marrow derived stem cells? Curr Stem Cell Res Ther. 2007 Jan;2(1):83-8. Review. PMID: 18220893 [PubMed - indexed for MEDLINE [Articolo su rivista]
Lorenzini, S.; Andreone, Pietro
abstract

In recent years, great interest has been aroused by the discovery of the ability of adult stem cells to contribute to regeneration processes and repair of damaged tissues. In particular, bone marrow derived stem cells (BMSCs), the most well known population of multipotent stem cells in adults, have been shown to be able to generate many different committed cellular types. In this review, we systematically organize the numerous hypotheses emerging from the most recent studies, in animal and humans, which evaluated the potentiality of BMSCs to contribute to tissue repair in different types of liver damage. Our aim is to give scientists and clinicians who are interested in regenerative medicine the rational basis for planning future studies on stem cell therapy for liver diseases.

2007 - Stem cell therapy for human liver cirrhosis: a cautious analysis of the results [Articolo su rivista]
Lorenzini, S.; Andreone, P.
abstract

End-stage liver disease, and in particular human liver cirrhosis, represents a worldwide health problem. Currently, liver transplant is the only effective treatment, but it is affected by many problems, including relative lack of donors, operative damage, risk of rejection, and high costs. Stem cell therapy is very attractive in this setting because it has the potential to help tissue regeneration while providing minimally invasive procedures and few complications. Only a few clinical studies on the administration of bone marrow-derived stem cells to cirrhotic patients have been published up to now. Although preliminary results seem to be encouraging, the number of treated patients is too small and the study design not completely appropriate to demonstrate safety and efficacy of stem cell therapy in liver cirrhosis. Well designed, randomized, controlled studies are needed to confirm preliminary results and eventually clear doubts.

2007 - Sustained virological response to interferon-alpha is associated with improved outcome in HCV-related cirrhosis: a retrospective study [Articolo su rivista]
Bruno, S.; Stroffolini, T.; Colombo, M.; Bollani, S.; Benvegnu, L.; Mazzella, G.; Ascione, A.; Santantonio, T.; Piccinino, F.; Andreone, P.; Mangia, A.; Gaeta, G. B.; Persico, M.; Fagiuoli, S.; Almasio, P. L.
abstract

The effect of achieving a sustained virological response (SVR) following interferon-alpha (IFNalpha) treatment on the clinical outcomes of patients with HCV-related cirrhosis is unknown. In an attempt to assess the risk of liver-related complications, HCC and liver-related mortality in patients with cirrhosis according to the response to IFNalpha treatment, a retrospective database was developed including all consecutive patients with HCV-related, histologically proven cirrhosis treated with IFNalpha monotherapy between January 1992 and December 1997. SVR was an undetectable serum HCV-RNA by PCR 24 weeks after IFNalpha discontinuation. HCC was assessed by ultrasound every 6 months. Independent predictors of all outcomes were assessed by Cox regression analysis. Of 920 patients, 124 (13.5%) were classified as achieving a SVR. During a mean follow-up of 96.1 months (range: 6-167) the incidence rates per 100 person-years of liver-related complications, HCC and liver-related death were 0, 0.66, and 0.19 among SVR and 1.88, 2.10, and 1.44 among non-SVR (P<0.001 by log-rank test). Multivariate analyses found that non-SVR was associated with a higher risk of liver-related complications (hazard ratio, HR, not applicable), HCC (HR 2.59; 95% CI 1.13-5.97) and liver-related mortality (HR 6.97; 95% CI 1.71-28.42) as compared to SVR. CONCLUSION: Thus, in patients with HCV-related, histologically proven cirrhosis, achievement of a SVR after IFNalpha therapy was associated with a reduction of liver-related mortality lowering both the risk of complications and HCC development. Irrespective of SVR achievement, all patients should continue surveillance because the risk of occurrence of HCC was not entirely avoided.

2006 - Acquired intestinal lymphangiectasia successfully treated with a low fat and MCT-enriched diet in a patient with liver transplantation [Articolo su rivista]
Biselli, Maurizio; Andreone, Pietro; Gramenzi, Annagiulia; Cursaro, C; Lorenzini, S; Bonvicini, Fiorenza; Bernardi, Mauro
abstract

Intestinal lymphangiectasia is defined as a dilatation of small bowel lymphatic capillaries and a loss of lymph into the bowel lumen. Clinically it is characterized by hypoproteinaemia and oedema. We present here a case of protein-losing enteropathy due to intestinal lymphangiectasia after liver transplantation in a 57-year-old man who was transplanted for hepatitis C virus. Four years after liver transplantation, the patient developed hypoalbuminaemia and ascites associated with recurrence of cirrhosis. The sudden fall in serum albumin led us to look for a cause of reduction other than or in addition to cirrhosis. Duodenal biopsies showed tall villi with dilated lymphatic vessels and widening of the villi caused by oedema, demonstrating intestinal lymphangiectasia. In this case a low-fat diet supplemented with medium-chain triacylglycerols achieved an early clinical improvement with increased serum albumin levels and ascites disappearance. Intestinal lymphangiectasia should be suspected in liver-transplanted patients developing hypoproteinaemia and hypoalbuminaemia after the recurrence of cirrhosis

2006 - Detection of HCV antigens in liver graft: Relevance to the management of recurrent post-liver transplant hepatitis C [Articolo su rivista]
Grassi, Alberto; Quarneti, C; Ravaioli, Matteo; Bianchini, F; Susca, M; D'Errico, Antonietta; Piscaglia, Fabio; Tame', Mariarosa; Andreone, Pietro; Grazi, Gian Luca; Galli, S; Zauli, Daniela; Pinna, Antonio Daniele; Bianchi, Francesco Bianco; Ballardini, G.
abstract

The aim of this study was to evaluate how the immunohistochemical detection of liver hepatitis C virus (HCV) antigens (HCV-Ag) could support the histologic diagnosis and influence the clinical management of post-liver transplantation (LT) liver disease. A total of 215 liver specimens from 152 HCV-positive patients with post-LT liver disease were studied. Histologic coding was: hepatitis (126), rejection (34), undefined (24; coexisting rejection grade I and hepatitis), or other (31). The percentage of HCV-Ag infected hepatocytes were evaluated, on frozen sections, by an immunoperoxidase technique. HCV-Ag were detectable early in 57% of cases within 30 days post-LT, 92% of cases between 31 and 180 days, and 74% of cases after more than 180 days. Overall, HCV-Ag were detected more frequently in histologic hepatitis as compared to rejection (P < 0.0001) with a higher percentage of positive hepatocytes (P < 0.00001). In 16 patients with a high number of HCV-Ag-positive hepatocytes (65%; range 40-90%) a clinical diagnosis of recurrent hepatitis (RHC) was made despite inconclusive histopathologic diagnosis. Multivariate analysis identified the percentage of HCV-Ag-positive hepatocytes and the time post-LT as independent predictors for RHC (P = 0.008 and P = 0.041, respectively) and the number of HCV-Ag-positive hepatocytes >/=50% as the only independent predictor for nonresponse (P < 0.001) in 26 patients treated with alpha-interferon plus ribavirin. In conclusion, HCV reinfection occurs early post-LT, reaching its peak within 6 months. Immunohistochemical detection of post-LT HCV reinfection support the diagnosis of hepatitis when the histologic features are not conclusive. A high number of infected cells, independently from the genotype, represents a negative predictive factor of response to antiviral treatment.

2006 - Mobilization of bone marrow-derived hematopoietic and endothelial stem cells after orthotopic liver transplantation and liver resection [Articolo su rivista]
Lemoli, ROBERTO MASSIMO; Catani, Lucia; Talarico, S; Loggi, Elisabetta; Gramenzi, Annagiulia; Baccarani, U; Fogli, Miriam; Grazi, GIAN LUCA; Aluigi, Michela; Marzocchi, Giulia; Bernardi, Mauro; Pinna, ANTONIO DANIELE; Bresadola, F; Baccarani, Michele; Andreone, Pietro
abstract

2006 - Pegylated interferon plus ribavirin for recurrent Hepatitis C infection after liver transplantation in naive and non-responder patients on a stable immunosuppressive regimen [Articolo su rivista]
Biselli, M; Andreone, P; Gramenzi, A; Lorenzini, S; Loggi, E; Bonvicini, F; Cursaro, C; Bernardi, M.
abstract

Background: Hepatitis C virus recurrence after liver transplantation is universal, leading to chronic hepatitis and cirrhosis. Aims and patients: We evaluated the efficacy and safety of pegylated interferon and ribavirin in 20 patients with recurrent Hepatitis C virus after liver transplantation (10 naïve and 10 non-responders to a previous interferon course). Methods: Treatment consisted of pegylated interferon alfa-2b (1.0 μg/kg once weekly) and ribavirin (600 mg/daily) for at least 6 months. Therapy continued for an additional 6 months only in patients with undetectable serum Hepatitis C virus-RNA or >2 log drop from baseline levels. Results: Eleven out of 20 patients (55%) completed 1 year of treatment. Nine patients (45%) had undetectable Hepatitis C virus-RNA at the end of treatment, six of them were naïves and three non-responders. In all of them, virological response persisted 6 months after discontinuation of therapy, so the sustained virological response rate was 60% in naïve patients and 30% in non-responders. Conclusions: Our results suggest that pegylated interferon plus ribavirin combination therapy may be effective in patients with post-liver transplantation recurrent chronic Hepatitis C, even in those previously non-responders to interferon plus ribavirin. These results need to be confirmed by large studies

2006 - Post-transplantation lymphoproliferative disorders in liver transplanted patients: a report of four cases [Articolo su rivista]
Lorenzini, S; Andreone, P; Gramenzi, A; Morelli, C; Zinzani, Pl; Grazi, Gl; Pileri, S; Baccarani, M; Tura, S; Bernardi, M.
abstract

Background. Posttransplant lymphoproliferative disorders (PTLDs) are an uncommon but important cause of morbidity and mortality in solid organ transplant recipients. They are often the result of Epstein-Barr. virus (EBV)-induced proliferation of B-lymphocytes in the setting of immunosuppression. Patients and Methods. We retrospectively analyzed four cases of PTLD after liver transplantation. In all patients immunosuppression was reduced and anti-CD20 monoclonal antibody (rituximab) was administered. In two of four patients, EBV viral load was positive in the peripheral blood, and gancyclovir was therefore also prescribed. Chemotherapy (CHOP) was used as a rescue in the event of treatment failure. Results. Even if no severe adverse events were observed during the treatment period, our treatment approach to PTLD was not effective, and only one patient out of four is still alive. Conclusions. Well-designed clinical trials are necessary to evaluate the role of this combined approach in the treatment of PTLD in liver transplant recipients.

2006 - Primary prophylaxis with nadolol in cirrhotic patients: Doppler patterns of splanchnic hemodynamics in good and poor responders [Articolo su rivista]
Berzigotti, Annalisa; Rinaldi, MARIA FRANCESCA; Magalotti, Donatella; Morelli, M. C.; Zappoli, Paola; Andreone, Pietro; Rossi, Cristina; Zoli, Marco
abstract

2006 - Review article: Alcoholic liver disease - Pathophysiological aspects and risk factors [Articolo su rivista]
Gramenzi, Annagiulia; Caputo, Fabio; Biselli, Maurizio; Kuria, F; Loggi, Elisabetta; Andreone, Pietro; Bernardi, Mauro
abstract

2006 - Sensitive line probe assay that simultaneously detects mutations conveying resistance to lamivudine and adefovir [Articolo su rivista]
Hussain, M.; Fung, S.; Libbrecht, E.; Sablon, E.; Cursaro, C.; Andreone, Pietro; Lok, A. S.
abstract

The INNO-LiPA HBV DR v2 assay is designed to detect hepatitis B virus mutations conveying resistance to lamivudine and adefovir. Our study confirms that this assay can simultaneously detect the presence of lamivudine and adefovir resistance mutations in clinical samples, has a high degree of concordance with sequencing, and can detect mutants earlier.

2006 - Virological analysis, genotypes and mutational patterns of the HBV pre-core/core gene in HBV/HCV-related hepatocellular carcinoma [Articolo su rivista]
DE MITRI, MARIA STELLA; Cassini, Romina; Morsica, G; Bagaglio, S; Andreone, Pietro; Loggi, Elisabetta; Muratori, Paolo; Bernardi, Mauro
abstract

We investigated the replicative profile of hepatitis B (HBV) and hepatitis C (HCV) viruses and the mutational pattern of the HBV precore/core (pre-C/C) domain in hepatocellular carcinoma (HCC). Thirty-eight consecutive patients with HCC were included in the study - 18 of them with HBV/HCV co-infection and 20 with HBV single infection. Twenty-three additional patients with co-infection, without HCC were recruited as the control group. Replication activity was evaluated by detecting and quantitating both HBV and HCV genomes. The HBV pre-C/C region, encompassing the pregenome encapsidation signal involved in viral replication, was analysed by direct sequencing. HBV viraemia levels were significantly lower (P = 0.04) in patients with co-infection in comparison with single-infected HCC, whereas two different HBV viraemia profiles were detected in co-infection with or without circulating HCV. HBV genotype D was prevalent in the three groups and HCV genotype 1b was found to be the infecting strain in all patients. Lower variability in the pre-C/C region was found in co-infection in comparison with HBV single infection (P = 0.0004). A synonymous T1936C mutation was found in all co-infected HCC cases not related to the presence or absence of circulating HCV, and a hypermutated pre-C strain, characterized by the same mutational pattern, was identified in three HCC cases. The mutational pattern of the pre-C/C region was closely related to HBV replication efficiency, and specific HBV mutations selectively associated with HCV co-infection could be linked with accelerated HBV/HCV-related disease progression. © 2006 The Authors.

2006 - Vitamin E as treatment for chronic viral hepatitis: is it time to perform large clinical trials? [Capitolo/Saggio]
Fiorino, S; Andreone, P; Gramenzi, A; Lorenzini, S; Cursaro, C; Bernardi, M.
abstract

2005 - Adefovir-resistant hepatitis B can be associated with viral rebound and hepatic decompensation [Articolo su rivista]
Fung, S. K.; Andreone, Pietro; Han, S. H.; Rajender Reddy, K.; Regev, A.; Keeffe, E. B.; Hussain, M.; Cursaro, C.; Richtmyer, P.; Marrero, J. A.; Lok, A. S.
abstract

BACKGROUND/AIMS: The susceptibility of adefovir-resistant hepatitis B virus (HBV) mutants is only reduced by 3-10-fold in in vitro studies, suggesting that virologic breakthrough and clinical deterioration are unlikely. The aim of this study was to describe the clinical course of patients with adefovir-resistant HBV infection. METHODS: Testing for adefovir-resistant mutations was performed on patients who had a suboptimal response or virologic breakthrough on adefovir. Adefovir-resistant mutations were detected using a line probe assay and direct sequencing of the HBV P-gene. RESULTS: Eight male patients with pre-existing lamivudine resistance or breakthrough (mean age 47+/-13 years) were found to have adefovir-resistant mutations rtA181V/T or rtN236T. Baseline median ALT was 66IU/L (range, 27-1161) and median HBV DNA 7.9log(10) copies/ml (range, 6-8.3). At the time of adefovir resistance (mean of 20+/-9 months), HBV DNA increased to >/=5log(10) copies/ml in 7 patients. After detection of adefovir resistance, hepatic decompensation occurred in 2 patients, 1 of whom died. Salvage therapy with lamivudine, entecavir or tenofovir was given to 7 patients and a reduction in HBV DNA by >/=3log(10) was seen in 3 patients. CONCLUSIONS: In conclusion, adefovir resistance can be associated with significant viral rebound and hepatic decompensation which may be fatal.

2005 - Cytokine profile of peripheral blood mononuclear cells from patients with different outcomes of hepatitis C virus infection [Articolo su rivista]
Gramenzi, Annagiulia; Andreone, Pietro; Loggi, Elisabetta; Foschi, F. G.; Cursaro, C.; Margotti, Marzia; Biselli, Maurizio; Bernardi, Mauro
abstract

2005 - ECHO-COLOUR-DOPPLER CHARACTERIZATION OF CIRRHOTIC PATIENTS RESPONDERS AND NON-RESPONDERS TO NADOLOL AS PRIMARY PROPHYLAXIS [Abstract in Atti di Convegno]
Berzigotti, A.; Palamarini, D.; Dapporto, S.; Morelli, M. C.; Rossi, C.; Magalotti, D.; Andreone, Pietro; Bernardi, Mauro; Zoli, Marco
abstract

2005 - Effect of liver transplantation on tuftsin activity and phagocytic activity of neutrophyl granulocytes in patients with liver cirrhosis [Articolo su rivista]
Foschi, F. G.; Trevisani, Franco; Loggi, Elisabetta; Parazza, M.; Melotti, C.; Bedeschi, E.; Mingazzini, L.; MIRICI CAPPA, Federica; Cescon, Matteo; Andreone, Pietro; Grazi, GIAN LUCA; Stefanini, G. F.; Bernardi, Mauro
abstract

2005 - GRANULOCYTE COLONY STIMULATING FACTOR (G-CSF) ADMINISTRATION IN CIRRHOTIC PATIENTS: A PHASE II STUDY EVALUATING TOLERABILITY PROFILE AND MOBILIZATION OF HAEMATOPOIETIC STEM CELLS (HSCS) [Abstract in Atti di Convegno]
Lorenzini, S.; Isidori, A.; Loggi, Elisabetta; Gramenzi, Annagiulia; Catani, Lucia; Talarico, S.; Cursaro, C.; Biselli, Maurizio; Bonifazi, F.; Lemoli, R. M.; Baccarani, Michele; Bernardi, Mauro; Andreone, Pietro
abstract

2005 - Genetic variability of hepatitis C virus in HBV/HCV co-infection and HCV single-infection [Articolo su rivista]
De Mitri, Maria Stella; Morsica, G.; Cassini, Romina; Bagaglio, S.; Andreone, Pietro; Bianchi, Giampaolo; Margotti, Marzia; Bernardi, Mauro
abstract

2005 - Human herpesvirus-8-related Kaposi’s sarcoma after liver transplantation successfully treated with cidofovir and liposomal daunorubicin [Articolo su rivista]
Verucchi, Gabriella; Calza, Leonardo; Trevisani, Franco; Zambruni, Andrea; Tadolini, Marina; Giuliani, R.; Manfredi, Roberto; Andreone, Pietro; Chiodo, Francesco; Bernardi, Mauro
abstract

2005 - Juvenile hemochromatosis associated with pathogenic mutations of adult hemochromatosis genes [Articolo su rivista]
Pietrangelo, Antonello; Caleffi, Angela; Henrion, J.; Ferrara, F.; Corradini, Elena; Kulaksiz, H.; Stremmel, W.; Andreone, P.; Garuti, Cinzia
abstract

Background & Aims: Juvenile hemochromatosis is a severe form of hereditary iron overload that has thus far been linked to pathogenic mutations of the gene coding for hemojuvelin (HJV), on chromosome 1, or, more rarely, that coding for hepcidin (HAMP), on chromosome 19. A milder adult-onset form is due to pathogenic mutations of HFE or, rarely, serum transferrin receptor 2. Methods: We studied a pedigree with siblings affected by both juvenile and adult-onset hereditary hemochromatosis. Affected subjects underwent full clinical evaluation, as well as microsatellite and gene sequencing analysis. Results: Two siblings (male and female, aged 24 and 25 years, respectively) were hospitalized for severe endocrinopathy and cardiomyopathy. At age 18 and 17 years, they had presented with impotence and amenorrhea, respectively, and increased serum iron levels. Hypogonadotropic hypogonadism was confirmed in both, and liver biopsy showed marked hepatic iron accumulation and micronodular cirrhosis. Iron levels were normalized after 24 months (female) and 36 months (male) of weekly phlebotomies. Microsatellite analysis showed no linkage with chromosome I and 19, and gene sequencing showed no hemojuvelin or hepcidin gene mutations. Instead, combined mutations of HFE (C282Y/H63D compound heterozygosity) and serum transferrin receptor 2 (Q317X homozygosity) were found. A 21-year-old brother with a milder phenotype resembling classic adult-onset hereditary hemochromatosis carried only the Q317X serum transferrin receptor 2 homozygote mutation. Conclusions: Juvenile hereditary hemochromatosis is not a distinct monogenic disorder invariably due to hemojuvelin or hepcidin mutations: it may be genetically linked to the adult-onset form of hereditary hemochromatosis.

2005 - Juvenile hemocromatosis associated with pathogenetic mutations of adult hemocromatosis genes [Articolo su rivista]
Pietrangelo, A; Caleffi, A; Henrion, J; Ferrara, F; Corradini, E; Kulaksiz, H; Stremmel, W; Andreone, Pietro; Garuti, C.
abstract

2005 - MUTATIONAL ANALYSIS OF THE HBV PRE-CORE/CORE GENE IN HBV/HCV-RELATED HEPATOCELLULAR CARCINOMA [Abstract in Atti di Convegno]
Cassini, Romina; Bagaglio, S.; Morsica, G.; Andreone, Pietro; Bernardi, Mauro
abstract

2005 - Simultaneous assessment of cytotoxic T lymphocyte responses against multiple viral infections by combined usage of optimal epitope matrices, anti- CD3 mAb T-cell expansion and "RecycleSpot" [Articolo su rivista]
Bihl, F. K.; Loggi, Elisabetta; Chisholm, J. V.; Hewitt, H. S.; Henry, L. M.; Linde, C.; Suscovich, T. J.; Wong, J. T.; Frahm, N.; Andreone, Pietro; Brander, C.
abstract

The assessment of cellular anti-viral immunity is often hampered by the limited availability of adequate samples, especially when attempting simultaneous, high-resolution determination of T cell responses against multiple viral infections. Thus, the development of assay systems, which optimize cell usage, while still allowing for the detailed determination of breadth and magnitude of virus-specific cytotoxic T lymphocyte (CTL) responses, is urgently needed. This study provides an up-to-date listing of currently known, well-defined viral CTL epitopes for HIV, EBV, CMV, HCV and HBV and describes an approach that overcomes some of the above limitations through the use of peptide matrices of optimally defined viral CTL epitopes in combination with anti-CD3 in vitro T cell expansion and re-use of cells from negative ELISpot wells. The data show that, when compared to direct ex vivo cell preparations, antigen-unspecific in vitro T cell expansion maintains the breadth of detectable T cell responses and demonstrates that harvesting cells from negative ELISpot wells for re-use in subsequent ELISpot assays (RecycleSpot), further maximized the use of available cells. Furthermore when combining T cell expansion and RecycleSpot with the use of rationally designed peptide matrices, antiviral immunity against more than 400 different CTL epitopes from five different viruses can be reproducibly assessed from samples of less than 10 milliliters of blood without compromising information on the breadth and magnitude of these responses. Together, these data support an approach that facilitates the assessment of cellular immunity against multiple viral co-infections in settings where sample availability is severely limited.

2005 - Transcatheter arterial chemoembolization therapy for patients with hepatocellular carcinoma: a case controlled study [Articolo su rivista]
Biselli, Maurizio; Andreone, Pietro; Gramenzi, Annagiulia; Trevisani, Franco; Cursaro, C.; Rossi, Cristina; Ricca Rossellini, S.; Cammà, C.; Lorenzini, S.; Stefanini, G. F.; Gasbarrini, G.; Bernardi, Mauro
abstract

Background & Aims: Transcatheter arterial chemoembolization (TACE) currently is used as a palliative treatment for patients with unresectable hepatocellular carcinoma (HCC), but its efficacy still is debated. Our aim was to assess the impact of TACE on patient survival and to identify prognostic factors for survival. Methods: Fifty-six cirrhotic patients with unresectable HCC undergoing at least :1 course of TACE were matched 1:1. for sex, age (in 5-year periods), parameters of Child-Pugh score, Okuda stage, and tumor type with a control group who had received only supportive care. Results: The 2 groups were comparable for cause of cirrhosis, alpha-fetoprotein serum levels, and Cancer of the Liver Italian Program (CLIP) score. The 56 patients in the TACE group received a total of 123 treatment courses. The median follow-up period was 16 months (range, 1-67 mo) in the TACE group and 5 months (range, 1-77 mo) in the supportive care group. Survival rates at 12, 24, and 30 months in patients receiving TACE were 74.3%, 52.1%, and 38.8% respectively, with a median survival time of 25 month whereas in supportive care patients the rates we 39.4%, 25.4%, and 19%, respectively, with a median survival time of 7 months (P =.0004). At univariate analysis, TACE, tumor type, presence of ascites, alpha-fetoprotein serum level, CLIP score, and Okuda stage were associated significantly with survival. Only TACE and CLIP score proved to be independent predictors of survival at multivariate analysis. Conclusions: TACE is an effective therapeutic option for cirrhotic patients with unresectable HCC and a CLIP score of 3 or less

2005 - Trattamento dell’epatopatia alcolica [Capitolo/Saggio]
Caputo, F; Lorenzini, F; Vignoli, T; Biselli, M; Lorenzini, S; Andreone, P; Bernardi, M; Trevisani, F.
abstract

Il consumo eccessivo di alcol (>30 g/die) può essere la causa principale di una serie di danni epatici che, a loro volta, determinano diverse condizioni anatomo-cliniche, di cui una acuta, l'epatite alcolica, e le altre croncihe, quali la steatosi, la steatoepatite, la fibrosi/ cirrosi.

2004 - Clinical outcome of HBeAg-negative chronic hepatitis B in relation to virological response to lamivudine [Articolo su rivista]
Di Marco, V.; Marzano, A.; Lampertico, P.; Andreone, Pietro; Santantonio, T.; Almasio, P. L.; Rizzetto, M.; Craxì, A.; Italian Association for the Study of the Liver Lamivudine Study Group, Italy
abstract

The effect of lamivudine treatment on the outcome of patients with hepatitis B e antigen (HBeAg)-negative chronic hepatitis is unclear. In a retrospective multicenter study, we have analyzed the virological events observed during lamivudine therapy in patients with HBeAg-negative chronic hepatitis and evaluated the correlation between virological response and clinical outcomes. Among 656 patients (mean age 49.1 years) included in the database, 54% had chronic hepatitis, 30% had Child-Turcotte-Pugh (CTP) A cirrhosis, and 16% had CTP B/C cirrhosis. On therapy (median 22 months, range 1-66), a virological response was obtained in 616 patients (93.9%). The rate of maintained virological response was 39% after 4 years. During follow-up, 47 (7.2%) patients underwent liver transplantation, liver disease worsened in 31 (4.7%), hepatocellular carcinoma (HCC) developed in 31 (4.7%), and 24 patients (3.6%) died of liver-related causes. Patients who had cirrhosis and who maintained virological response were less likely than those with viral breakthrough to develop HCC (P <.001) and disease worsening (P <.001). Survival was better in CTP A patients with cirrhosis and maintained virological response (P =.01 by rank test). Multivariate analysis revealed that presence of cirrhosis and viral breakthrough were independently related to mortality and development of HCC. In conclusion, lamivudine is highly effective in reducing viral load in HBeAg-negative patients. After 4 years of therapy, 39% of patients maintain a virological and biochemical response. Loss of virological response may lead to clinical deterioration in patients with cirrhosis.

2004 - Comparison of IFN-alpha 2b with or without ribavirin for treatment of chronic hepatitis C in HIV-positive patients infected with hepatitis C virus genotype 3a [Articolo su rivista]
G., Morsica; R., Bruno; S., Bagaglio; De Mitri, Maria Stella; Andreone, Pietro; A., Lazzarin
abstract

2004 - Genetic heterogeneity of hepatitis C virus in HBV/HCV co-infection [Abstract in Atti di Convegno]
DE MITRI, MARIA STELLA; G., Morsica; Cassini, Romina; S., Bagaglio; Andreone, Pietro; Bianchi, Giampaolo; Margotti, Marzia; Bernardi, Mauro
abstract

2004 - Hepatic artery stenosis in liver transplanted patients treated with pegylated Interferon alpha-2b and Ribavirin [Articolo su rivista]
Biselli, M.; Lorenzini, S.; Gramenzi, A.; Andreone, P.; Bernardi, M.; Rossi, C.; Grazi, Gl.
abstract

2004 - High risk of hepatocellular carcinoma in anti-HBe positive liver cirrhosis patients developing Lamivudine resistance [Articolo su rivista]
Andreone, Pietro; Gramenzi, Annagiulia; Cursaro, C.; Biselli, Maurizio; Cammà, C.; Trevisani, Franco; Bernardi, Mauro
abstract

2004 - In vitro effect of indomethacin and interferon-alpha on Th1 and Th2 cytokine synthesis in patients with chronic hepatitis C [Articolo su rivista]
Andreone, Pietro; Gramenzi, Annagiulia; Loggi, Elisabetta; Favarelli, L.; Cursaro, C.; Margotti, Marzia; Biselli, Maurizio; Lorenzini, S.; Bernardi, Mauro
abstract

Current evidences suggest that non-steroidal anti-inflammatory drugs could enhance the antiviral activity of interferon-α in chronic HCV infection. In this study, we investigated the effect of indomethacin, a non-steroidal anti-inflammatory drug, and interferon-α on cytokine production by peripheral blood mononuclear cells from 12 untreated patients with chronic hepatitis C. We evaluated the effect of incubation with indomethacin, interferon-α or both on synthesis of Th1- (interleukin-2, interferon-γ) and Th2-associated cytokines (interleukin-4, interleukin-10), and of the antiviral protein 2′,5′-oligoadenylate synthetase. Interferon-α induced a significant increase in production of interleukin-2. Smaller increases were also seen in the presence of indomethacin, while incubation with both indomethacin and interferon-α leads to a synergistic effect. Incubation with indomethacin decreased both interleukin-4 and interleukin-10, whereas interferon-α increased these cytokines. The addition of indomethacin to interferon-α significantly reversed this interferon-induced increase. Finally, both indomethacin and the association interferon-α plus indomethacin determined a significant increase in 2′,5′-oligoadenylate synthetase production compared to both baseline and interferon-α alone. In conclusion, indomethacin was able to enhance the antiviral activity of interferon-α and to modulate the interferon-induced Th1 and Th2 cytokine response by increasing the Th1-response, fundamental for sustained clearance of HCV, and by decreasing the Th-2 type response, associated with HCV persistence

2004 - OUTCOME OF LIVER TRANSPLANT FOR ALCOHOLIC LIVER DISEASE [Abstract in Atti di Convegno]
Lorenzini, S.; Biselli, Maurizio; Gramenzi, Annagiulia; DEL GAUDIO, Massimo; Ravaioli, M.; Bollino, Francesco; Porzio, Federica; Cursaro, C.; Grazi, GIAN LUCA; Bernardi, Mauro; Andreone, Pietro
abstract

2004 - OUTCOME OF LIVER TRANSPLANT FOR ALCOHOLIC LIVER DISEASE [Abstract in Atti di Convegno]
Lorenzini, S.; Biselli, Maurizio; Gramenzi, Annagiulia; DEL GAUDIO, Massimo; Ravaioli, M.; Bollino, F.; Porzio, F.; Cursaro, C.; Grazi, GIAN LUCA; Bernardi, Mauro; Andreone, Pietro
abstract

2004 - PEGYLATED INTERFERON PLUS RIBAVIRIN FOR THE TREATMENT OF RECURRENT HCV INFECTION AFTER LIVER TRANSPLANTATION [Abstract in Atti di Convegno]
Lorenzini, S.; Biselli, Maurizio; Gramenzi, Annagiulia; Bollino, Francesco; Cursaro, C.; Bernardi, Mauro; Andreone, Pietro
abstract

2004 - SPONTANEOUS MOBILIZATIONOF BONE MARROW-DERIVED HEMATOPOIETIC AND ENDOTHELAIL PROGENITOR CELLS AFTER ORTHOTOPIC LIVER TRANSPALNTATION (OLT) [Abstract in Atti di Convegno]
Loggi, E.; Gramenzi, A.; Catani, L.; Talarico, S.; Lemoli, Rm.; Bacacrani, U.; Grazi, Gl.; Vetrone, G.; Fogli, M.; Lorenzini, S.; Baccarani, M.; Pinna, Ad.; Beranrdi, M.; Andreone, P.
abstract

2004 - Surveillance for hepatocellular carcinoma in elderly italian patients with cirrhosis. Effects on cancer staging and patients survival [Articolo su rivista]
Trevisani, Franco; Cantarini, MARIA CHIARA; MORSELLI LABATE, ANTONIO MARIA; DE NOTARIIS, Stefania; Rapaccini, G.; Farinati, F.; Del Poggio, P.; Di Nolfo, M. A.; Benvegnù, L.; Zoli, Marco; Borzio, F.; Bernardi, Mauro; Andreone, P.; Biselli, M.; Caraceni, Paolo; Cantarini, M.; Cursaro, C.; Domenicali, M.; Gramenzi, Annagiulia; Li Bassi, S.; Magalotti, D.; Zambruni, F. Mirici Cappa A.; DI MARCO, Mariacristina; Vavassori, E.; Gilardoni, L.; Mattiello, M.; Alberti, A.; Gatta, A.; Gios, M.; Covino, M.; Gasbarrini, G.; Baldan, A.; Marino, D.; Sergio, A.; Molaro, M.; Sala, M.; Grazi, GIAN LUCA; Nardo, Bruno; Ravaioli, M.; Rossi, C.; Golfieri, Rita; Italian Liver Cancer group,
abstract

2004 - Terapia cellulare in Epatologia [Monografia/Trattato scientifico]
Ascione, A.; Muraca, M.; Strazzabosco, M.; Pinzani, M.; Calise, F.; Freitas, I.; Spinelli, A.; Laconi, E.; Smedile, A.; Palu', G.; Pegoraro, L.; Quarta, M.; Burra, P.; SVEGLIATI BARONI, G.; Burlina, A.; Gerunda, G.; Perboni, G.; Costa, P.; LO IACONO, O.; Tomat, S.; Russo, F. P.; Manganaro, M.; Neri, D.; Caraceni, P.; Alonzi, T.; Azzaroli, F.; Andreone, P.; Mazzella, G.; Gaia, S.; Lorenzini, S.; Ballardini, G.; Merenda, R.; Poci, C.; Ferraresso, C.; Licata, A.; Galli, A.; Vilei, M. T.; Granato, A.; Pressato, L.; Cozzi, E.; Brillanti, S.
abstract

2004 - Thymosin-alpha 1 plus interferon-alpha for naive patients with chronic hepatitis C: results of a randomized controlled pilot trial [Articolo su rivista]
Andreone, Pietro; Gramenzi, Annagiulia; Cursaro, C.; Felline, FRANCESCO PALMIRO; Loggi, Elisabetta; D'Errico, Antonietta; Spinosa, M.; Lorenzini, S.; Biselli, Maurizio; Bernardi, Mauro
abstract

In this pilot study, we evaluated the efficacy of interferon-α (IFN) plus Thymosin-α 1 (TA1) to that of IFN alone in naive patients with chronic hepatitis C. Twenty-two patients were randomized to receive interferon-α2b (3 million units three times a week) plus thymosin-α 1 (900 μg/m2 body surface area) and 19 received interferon-α2b alone at the same dose. Patients were treated for 6 months and followed up for another 6 months. Biochemical (alanine aminotransferase values) and virological (hepatitis C virus-RNA) responses to treatment were determined. Combination treatment showed significantly higher efficacy than monotherapy in achieving virological end-of-treatment response (P = 0.03). At 6-month follow up, the sustained biochemical and virological response was not different between the two groups. Our results indicate that the immune modulator TA1 may enhance the end-of-treatment response in naive patients with chronic hepatitis C. Higher doses and/ore more prolonged courses as well as the association with new interferon formulation such as pegylated interferons could improve the sustained response rates to this treatment.

2003 - Genetic heterogeneity of hepatitis C virus (HCV) in clinical strains of HIV positive and HIV negative patients chronically infected with HCV genotype 3a [Articolo su rivista]
Bagaglio, S; Bruno, R; Lodrini, S; De Mitri, Ms; Andreone, P; Loggi, E; Galli, L; Lazzarin, A; Morsica, G.
abstract

2003 - Interferon-alpha combined with ketoprofen as treatment of naïve patients with chronic hepatitis C: a randomized controlled trial [Articolo su rivista]
Andreone, P; Gramenzi, A; Cursaro, C; Biselli, M; Lorenzini, S; Loggi, E; Felline, F; Fiorino, S; Di Giammarino, L; Porzio, F; Galli, S; Bernardi, M.
abstract

2003 - Posttransplantation lymphoproliferative disorders [Articolo su rivista]
Andreone, P; Gramenzi, A; Lorenzini, S; Biselli, M; Cursaro, C; Pileri, S; Bernardi, M.
abstract

2003 - Prophylaxis and treatment of hepatis B virus infection after liver transplantation [Articolo su rivista]
Andreone, P; Lorenzini, S; Gramenzi, A; Biselli, M; Cursaro, C; Bernardi, M.
abstract

2003 - Sequence analysis of NS3 protease gene in clinical strains of hepatitis C virus [Articolo su rivista]
Lodrini, S; Bagaglio, S; Canducci, F; De Mitri, Ms; Andreone, P; Loggi, E; Lazzarin, A; Clementi, M; Morsica, G.
abstract

2002 - Anti-hepatitis A virus seroprevalence and seroconversion in a cohort of patients with chronic viral hepatitis. [Articolo su rivista]
Stroffolini, T; Almasio, Pl; Di Stefano, R; Andreone, P; Di Gaetano, G; Fattovich, G; Gaeta, Gb; Morisco, F; Smedile, A; Tripi, S; Zignego, Al; Ferraro, D; Mele, A; Craxi, A.
abstract

2002 - Efficacy of lamivudine therapy for advanced liver disease in patients with precore mutant hepatitis B virus infection awaiting liver transplantation [Articolo su rivista]
Andreone, P; Biselli, M; Gramenzi, A; Cursaro, C; Morelli, Mc; Sama, C; Lorenzini, S; Spinucci, G; Porzio, F; Felline, F; DI GIAMMARINO, L; Bernardi, M
abstract

2002 - Retreatment with interferon plus ribavirin of chronic hepatitis C non-responders to interferon monotherapy: a meta-analysis of individual patient data. [Articolo su rivista]
Cammà, C.; Bruno, S.; Schepis, Filippo; Iacono, O. L.; Andreone, P.; Gramenzi, A. G.; Mangia, A.; Andriulli, A.; Puoti, M.; Spadaro, A.; Freni, M.; Marco, V. D.; Cino, L.; Saracco, G.; Chiesa, A.; Crosignani, A.; Caporaso, N.; Morisco, F.; Rumi, M. G.; Craxì, A.
abstract

BACKGROUND AND AIMS: Retreatment with a combination of alpha interferon (IFN) plus ribavirin of patients with chronic hepatitis C who did not respond to IFN monotherapy has not been assessed in large controlled studies. METHODS: To assess the effectiveness and tolerability of IFN/ribavirin retreatment of non-responders to IFN and to identify predictors of complete (biochemical and virological) sustained response, we performed a meta-analysis of individual data on 581 patients from 10 centres. Retreatment with various IFN schedules (mean total dose 544 mega units) and a fixed ribavirin dose (1000-1200 mg/daily depending on body weight) was given for 24-60 (mean 39.5) weeks. RESULTS: Biochemical end of treatment and sustained responses were observed in 271/581 (46.6\%; 95\% confidence interval (CI) 42.6-50.7\%) and in 109/581 (18.7\%; 95\% CI 15.6-22.0\%) cases, respectively. Two hundred and six of 532 patients (38.7\%; 95\% CI 34.6-42.9\%) had an end of treatment complete response to retreatment while a complete sustained response occurred in 88 of 559 (15.7\%; 95\% CI 12.8-18.8\%). Fifty four of 581 patients (9.2\%; 95\% CI 7.0-11.7\%) stopped retreatment due to adverse effects. By logistic regression, complete sustained response was predicted independently by age <45 years (p=0.04), by normal pretreatment gamma-glutamyltransferase levels (p=0.01), and by a second course total IFN dose of at least 432 mega units (p=0.008). CONCLUSIONS: The overall low probability of effectiveness argues against indiscriminate retreatment of all IFN monotherapy non-responders with IFN/ribavirin. Patients less than 45 years old with normal gamma-glutamyltransferase levels who were retreated with high dose long course combination therapy had a complete sustained response rate of 30\%.

2002 - Transarterial chemoembolization for unresectable hepatocellular carcinoma: Meta-analysis of randomized controlled trials [Articolo su rivista]
C., Cammà; Schepis, Filippo; A., Orlando; M., Albanese; L., Shahied; F., Trevisani; P., Andreone; A., Craxì; M., Cottone
abstract

PURPOSE: To review the available evidence of chemoembolization for unresectable hepatocellular carcinoma (HCC). MATERIALS AND METHODS: Computerized bibliographic searches with MEDLINE and CANCERLIT databases from 1980 through 2000 were supplemented with manual searches, with the keywords "hepatocellular carcinoma," "liver cell carcinoma," "randomized controlled trial [RCT]," and "chemoembolization." Studies were included if patients with unresectable HCC were enrolled and if they were RCTs in which chemoembolization was compared with nonactive treatment (five RCTs) or if different transarterial modalities of therapy (13 RCTs) were compared. Data were extracted from each RCT according to the intention-to-treat method. Five of the RCTs with a nonactive treatment arm were combined by using the random-effects model, whereas all 18 RCTs were pooled from meta-regression analysis. RESULTS: Chemoembolization significantly reduced the overall 2-year mortality rate (odds ratio, 0.54; 95\% CI: 0.33, 0.89; P =.015) compared with nonactive treatment. Analysis of comparative RCTs helped to predict that overall mortality was significantly lower in patients treated with transarterial embolization (TAE) than in those treated with transarterial chemotherapy (odds ratio, 0.72; 95\% CI: 0.53, 0.98; P =.039) and that there is no evidence that transarterial chemoembolization is more effective than TAE (odds ratio, 1.007; 95\% CI: 0.79, 1.27; P =.95), which suggests that the addition of an anticancer drug did not improve the therapeutic benefit. CONCLUSION: In patients with unresectable HCC, chemoembolization significantly improved the overall 2-year survival compared with nonactive treatment, but the magnitude of the benefit is relatively small.

2001 - Impact of interferon therapy on the natural history of hepatitis C virus related cirrhosis [Articolo su rivista]
Gramenzi, A.; Andreone, P.; Fiorino, S.; Camma, C.; Giunta, M.; Magalotti, D.; Cursaro, C.; Calabrese, C.; Arienti, V.; Rossi, C.; Di Febo, G.; Zoli, M.; Craxi, A.; Gasbarrini, G.; Bernardi, M.
abstract

Background - The role of interferon treatment on the natural history of hepatitis C virus related cirrhosis is under debate. Aim - To evaluate the effect of interferon on the clinical course of compensated hepatitis C virus related cirrhosis. Patients and methods - Seventy two cirrhotic patients treated with interferon and 72 untreated controls matched treated patients with for quinquennia of age, sex, and Child-Pugh's score were enrolled in a prospective non-randomised controlled trial. Treated patients received leucocytic interferon alfa, with an escalating schedule for 12 months. The incidence and risk (Gox regression analysis) of clinical complications (hepatocellular carcinoma, ascites, jaundice, variceal bleeding, and encephalopathy) and death were calculated. Results - Over median follow up periods of 55 months for treated and 58 for untreated subjects, seven and nine patients, respectively, died, and 20 and 32, respectively, developed at least one clinical complication (ns). Hepatocellular carcinoma developed in six treated and 19 untreated patients (p=0.018). Seven treated patients showed sustained aminotranferase normalisation and none died or developed complications. Clinical complications were significantly associated with low albumin, bilirubin, and prothrombin activity while hepatocellular carcinoma was significantly related to no treatment with interferon, oesophageal varices, and high a fetoprotein levels. By stratified analysis, the beneficial effect of interferon was statistically evident only in patients with baseline a fetoprotein levels ≥ 20 ng/ml. Conclusions - Interferon does not seem to affect overall or event free survival of patients with hepatitis G virus related cirrhosis while it seems to prevent the development of hepatocellular carcinoma. Patients who achieved sustained aminotransferase normalisation survived and did not develop any complications during follow up.

2001 - In vitro effect of thymosin-alpha1 and interferon-alpha on Th1 and Th2 cytokine synthesis in patients with chronic hepatitis C [Articolo su rivista]
Andreone, P; Cursaro, C; Gramenzi, A; Margotti, M; Ferri, E; Talarico, S; Biselli, M; Felline, F; Tuthill, C; Martins, E; Gasbarrini, G; Bernardi, M.
abstract

2001 - Interferon and prevention of hepatocellular carcinoma in viral cirrhosis: an evidence-based approach. [Articolo su rivista]
Cammà, C; Giunta, M; Andreone, P; Craxì, A.
abstract

2001 - Interferon-alpha plus ribavirin and amantadine in patients with post-transplant hepatitis C: results of a pilot study [Articolo su rivista]
Andreone, P; Gramenzi, A; Cursaro, C; Biselli, M; Di Giammarino, L; Grazi, Gl; Jovine, E; D'Errico, A; Galli, S; Mazziotti, A; Cavallari, A; Bernardi, M.
abstract

2001 - VITAMIN E AS TREATMENT FOR CHRONIC HEPATITIS B: RESULTS OF A RANDOMIZED CONTROLLED PILOT TRIAL [Articolo su rivista]
Andreone, P; Fiorino, S; Cursaro, C; Gramenzi, A; Margotti, M; Di Giammarino, L; Biselli, M; Miniero, R; Gasbarrini, G; Bernardi, M
abstract

2000 - EVOLUTION OF HEPATITIS B VIRUS POLYMERASE GENE MUTATIONS IN HEPATITIS B e ANTIGEN-NEGATIVE PATIENTS RECEIVING LAMIVUDINE THERAPY [Articolo su rivista]
Lok, Asf; Hussain, M; Cursaro, C; Margotti, M; Gramenzi, A; Grazi, Gl; Jovine, E; Bernardi, M; Andreone, P
abstract

2000 - Effect of increasing dose of interferon on the evolution of hepatitis C virus 1b quasispecies [Articolo su rivista]
De Mitri, Ms; Mele, L; Morsica, G; Chen, Ch; Sitia, G; Gramenzi, A; Andreone, P; Alberti, A; Bernardi, M; Pisi, E.
abstract

2000 - Inhibition of the cyclooxygenase/lipoxygenase pathways to improve interferon alpha efficacy in chronic hepatitis C: don't lose the tract! [Articolo su rivista]
Andreone, P; Gramenzi, A; Cursaro, C; Bernardi, M.
abstract

2000 - Lamivudine-associated remission of chronic hepatitis delta [Articolo su rivista]
Andreone, P; Spertini, F; Negro, F.
abstract

2000 - Soluble CD30 serum level in HCV-positive chronic active hepatitis: A surrogate marker of disease activity? [Articolo su rivista]
Foschi, Fg; Gramenzi, A; Castelli, E; Cursaro, C; Pagani, S; Margotti, M; D'Errico, A; Andreone, P; Stefanini, Gf; Bernardi, M.
abstract

1999 - Gross pathologic types of hepatocellular carcinoma in Italy. [Articolo su rivista]
Stroffolini, T; Andreone, P; Andriulli, A; Ascione, A; Craxì, A; Chiaramonte, M; Galante, D; Manghisi, Og; Mazzanti, R; Medaglia, C; Pilleri, G; Rapaccini, Gl; Albanese, M; Taliani, G; Tosti, Me; Villa, Erica; Gasbarrini, G.
abstract

The prevalence and independent predictors of the different macroscopic types of hepatocellular carcinoma (HCC) were assessed in 1,073 unselected patients of 14 hospitals in Italy from May 1996 to May 1997. Solitary HCC was the most common cancer type (44.6%), followed by multinodular (44.2%), diffuse (8.4%) and massive (2.8%) types. After adjustment for the influence of confounders by multiple logistic regression analysis, Child-Pugh grades B and C were found to be independent predictors of multinodular (odds ratio, OR, 2.0; 95% confidence interval (CI) = 1.5-2.6) and diffuse (OR 2.6; 95% CI = 1.6-4.4) HCC types. These findings indicate that the majority of HCC cases are not detected at a potentially treatable stage. Delayed detection of HCC is associated with a higher likelihood of the multinodular or diffuse gross pathologic type.

1999 - INTERFERON-ALPHA PLUS RIBAVIRIN IN CHRONIC HEPATITIS C RESISTANT TO PREVIOUS INTERFERON-ALPHA COURSE: RESULTS OF A RANDOMIZED MULTICENTRE TRIAL [Articolo su rivista]
Andreone, P; Gramenzi, A; Cursaro, C; Sbolli, G; Fiorino, S; DI GIAMMARINO, L; Miniero, R; D'Errico, A; Gasbarrini, G; Bernardi, M
abstract

1999 - Interferon alpha plus ketoprofen or interferon alpha plus ribavirin in chronic hepatitis C non-responder to interferon alpha alone: results of a pilot study. [Articolo su rivista]
Andreone, P; Cursaro, C; Gramenzi, A; Fiorino, S; Di Giammarino, L; Miniero, R; D'Errico, A; Grigioni, Wf; Gasbarrini, G; Bernardi, M.
abstract

1999 - Serum pancreatic enzyme concentrations in chronic viral liver diseases. [Articolo su rivista]
Pezzilli, R; Andreone, P; Morselli-Labate, Am; Sama, C; Billi, P; Cursaro, C; Barakat, B; Gramenzi, A; Fiocchi, M; Miglio, F; Bernardi, M.
abstract

1998 - Characteristics of hepatocellular carcinoma in Italy [Articolo su rivista]
Stroffolini, T; Andreone, P; Andriulli, A; Ascione, A; Craxì, A; Chiaramonte, M; Galante, D; Villa, Erica
abstract

This study aimed to assess the main features of hepatocellular carcinoma at the time of diagnosis in Italy, particularly in relation to the presence or absence of underlying cirrhosis, hepatitis virus marker patterns, age of the subjects and alpha-foetoprotein values.METHODS:A total of 1148 patients with hepatocellular carcinoma seen at 14 Italian hospitals in the 1-year period from May 1996 to May 1997 were the subjects of this prevalence study. Both newly diagnosed cases (incident cases) and cases diagnosed before May 1996 but still attending the hospitals during the study period (prevalent cases) were included.RESULTS:We found that 71.1% of cases were positive for hepatitis C virus antibodies but negative for HBsAg; in contrast, 11.5% were negative for anti-HCV but positive for HBsAg; 5.3% were positive for both markers; and 12.1% were negative for both viruses. The mean age of detection was over 60 years, with a younger mean age in HBsAg-positive compared to anti-HCV-positive patients (59.3 years vs. 65.6 years, p<0.01). The male-to-female ratio among HBsAg-positive patients was 10.4:1, in contrast to 2.8:1 among anti-HCV-positive patients (p<0.01). The majority of cases (93.1%) had underlying cirrhosis. Cirrhotic patients were more likely to be anti-HCV positive than non-cirrhotic cases (73.2% vs 43.9%; p<0.01); conversely, absence of hepatitis virus markers was more frequently observed in the non-cirrhotic than in the cirrhotic population (40.9% vs. 10.0%; p<0.01). Overall, the alpha-foetoprotein level was altered (>20 ng/ml) in 57.9% of patients; only 18% of cases presented diagnostic (>400 ng/ml) values. Anti-HCV positivity (O.R. 2.0; CI 95%=1.3-3.1) but not HBsAg positivity (O.R. 1.0; CI 95%=0.6-1.8) was shown to be an independent predictor of the likelihood of altered alpha-foetoprotein values by multivariate analysis.CONCLUSIONS:These findings point to differences in the characteristics of the populations infected by hepatitis B and hepatitis C. Factors other than the hepatitis viruses are important in non-cirrhotic patients. A change in the relative prevalence of hepatitis virus markers among hepatocellular carcinoma cases was demonstrated, reflecting a significant change in the rate of HBV endemicity in the Italian population. Finally, the increased trend in the mortality rate from liver cancer in Italy from 4.8 per 100,000 in 1969 to 10.9 in 1994 may reflect the large cohort of subjects infected with HCV via the iatrogenic route during 1950s and 1960s when glass syringes were commonly used for medical treatment

1998 - Effect of interferon-α on progression of cirrhosis to hepatocellular carcinoma: A retrospective cohort study [Articolo su rivista]
Brunetto, M. R.; Oliveri, F.; Koehler, M.; Zahm, F.; Bonino, F.; Darvich, J.; Findor, J. A.; Tanno, H.; Pinchuk, L.; Baldi, M.; Colombatto, P.; Colombo, M.; Del Ninno, E.; Fasani, P.; Rumi, M. G.; Tommasini, M.; Alberti, A.; Benvegnu, L.; Chemello, L.; De Salvo, G.; Awetta, M.; Antoniello, S.; Pardo, F.; Bruno, S.; Podda, M.; Andreone, P.; Bernardi, M.; Gasbarrini, G.; D'Aquino, M.; Tempesta, D.; Bottelli, R.; Devita, A.; Masucci, F.; Belloni, G.; Mangia, A.; Tappero, G.; Caporaso, N.; Mazzella, G.; Puoti, M.; Hoersch, S.; Al Traif, I.
abstract

Background. There is debate about whether interferon-α treatment lowers the risk of progression to hepatocellular carcinoma in patients with chronic viral hepatitis and cirrhosis and whether any effect is limited to certain subgroups. We investigated these issues by retrospective analysis of data for 913 patients from Italy and Argentina. Methods. 21 centres reported patients from their records who had chronic viral hepatitis and Child's A cirrhosis, were positive for HBsAg or hepatitis-C-virus antibodies (anti-HCV), and had been screened yearly for at least 3 years by ultrasonography and α-1-fetoprotein testing. Prognostic risk factors for hepatocellular carcinoma defined by multivariate Cox regression analysis and individual observation time were used for group matching and conditional logistic regression analysis of the independent interferon-α treatment effect. Findings. After group matching, the number of patients was reduced to 637. Age, male sex, and portal hypertension were significant risk factors for hepatocellular carcinoma (each p < 0.001); hepatic inflammation (p = 0.21) and iron storage (p = 0.18) were also included in the model. 66 (19%) of 356 untreated patients and 29 (10%) of 281 treated patients developed hepatocellular carcinoma (relative risk 1.99 [95% CI 1.09-3.64]); the corresponding proportions for anti-HCV-positive patients were 48 (18.5%) of 259 versus 21 (9.1%) of 232 (3.14 [1.46-6. 80]), and those for hepatitis-B-virus-infected (HBV) patients were 18 (10%) of 97 and eight (16%) of 49 (0.98 [0.33-2.92]). Among anti-HCV patients without HBV markers, 29 (20%) of 129 untreated and six (5%) of 116 treated patients developed hepatocellular carcinoma (6.28 [1.65-2.38]). Interpretation. Interferon treatment lowered the rate of progression to hepatocellular carcinoma two fold. The risk reduction was apparently greater for patients with chronic hepatitis C and no evidence of HBV infection. Future studies should stratify HCV-infected patients by HBV status.

1998 - LAMIVUDINE TREATMENT FOR ACUTE HEPATITIS B AFTER LIVER TRANSPLANTATION [Articolo su rivista]
Andreone, P; Caraceni, P; Grazi, Gl; Belli, L; Milandri, Gl; Ercolani, G; Jovine, E; D'Errico, A; DAL MONTE, Pr; Ideo, G; Forti, D; Mazziotti, A
abstract

1998 - PREVALENCE OF MONOCLONAL GAMMOPATHIES IN PATIENTS WITH HEPATITIS C VIRUS INFECTION [Articolo su rivista]
Andreone, P; Zignego, Al; Cursaro, C; Gramenzi, G; Gherlinzoni, F; Fiorino, S; Giannini, C; Boni, P; Sabatini, E; Pileri, S; Tura, S; Bernardi, M
abstract

1998 - The opiate antagonists in the treatment of intractable pruritus in a patient with cirrhosis [Articolo su rivista]
Andreone, Pietro
abstract

The treatment of pruritus in liver diseases, due to the poor knowledge of its exact etiology and pathogenesis, is difficult and often unsuccessful. Pruritus can determine a worsening of life quality and serious sleeping troubles, and is considered an indication for liver transplantation itself. The case of a 64-year-old female with post-C-hepatitis cirrhosis and incohercible pruritus, treated with opiate antagonists: naloxone and naltrexone is presented. The patient responded soon and positively to therapy and did not show any of the typical side-effects of opiergic tone inhibitors. The satisfying results of this experience demonstrate the predominant role of endogenous opioids in the genesis of pruritus of cholestasis and the efficacy of opiate antagonists in controlling the itching.

1998 - Thymalfasin: clinical pharmacology and antiviral applications [Articolo su rivista]
Gramenzi, A; Cursaro, C; Andreone, P; Bernardi, M.
abstract

1998 - Vitamin E for chronic hepatitis B. [Articolo su rivista]
Andreone, P; Gramenzi, A; Bernardi, M.
abstract

1997 - 6. A randomized controlled trial of leukocytic IFN-a vs leukocytic IFN-a plus ribavirin in chronic hepatitis C resistant to a previous recombinant or lymphoblastoid IFN treatment [Articolo su rivista]
Andreone, P.; Cursaro, C.; Gramenzi, A.; Di Giammarino, L.; Felline, F.; Miniero, R.; Bernardi, M.
abstract

1997 - Hepatitis c infection and peripheral neuropathy [Articolo su rivista]
Cordivari, C.; Prblogo, G.; Rinaldi, R.; Liguori, R.; Marulli, D.; Andreone, P.; D'Alessandro, R.
abstract

An association between Hepatitis C Virus infection (IICV) and Peripheral Neuropathy (PN) has recently been reported This association has been explained by the presence of essential mixed cryoglobulinaemia. However most studies were retrospective and performed on patients with long-standing hepatic injection Further, the frequency and risk factors for peripheral neuropathy in HCV patients are not well defined. We performed a prospecive study on the frequency of PN in a consecutive series of HCV patients Method. One hundred and forty-two consecutive patients with HCV diagnosed according to serological studies by detection of anti-HCV antibodies and viral RNA in serum, were recruited from a Hepatology Department between June 1996-March 1997. The patients (91 M, 51F, average of 49.4+14 years, range 22-78 years) showed a mean period of infection of 37.8 months (1-80 months). All patients underwent neurological examination. On this basis, they were divided into four groups as concerns possible PN: pts. with only symptoms (group I), pts. with only signs (group 2), pts. with both symptoms and signs (group 3) and pts. without symptoms and signs (group 4). All patients with signs and/or symptoms were invited to come forward for electrophysiological examination.Results. We found 23 pts. (16.2%) in group 1, 2 pts. (1.4%) in group 2; 19 pts. (14.1%) in group 3 and 97 pts. (68.3%) in group 4 Cryoglobulinaemia was present in 42 pts. (29.7%): 12 pts. of group I, 2 pts. of group 2, 7 pts. of group 3 and 20 pts. of group 4 KMG and ENG study is in progress. Comment Our results show that PN symptoms in HCV infection are rather common finding. Results, neurophysiological investigations and factors related to PN will be presented.

1996 - A double-blind, placebo-controlled, pilot trial of thymosin alpha 1 for the treatment of chronic hepatitis C. [Articolo su rivista]
Andreone, P; Cursaro, C; Gramenzi, A; Buzzi, A; Covarelli, Mg; Di Giammarino, L; Miniero, R; Arienti, V; Bernardi, M; Gasbarrini, G.
abstract

1996 - A randomized controlled trial of thymosin-alpha1 versus interferon alfa treatment in patients with hepatitis B e antigen antibody--and hepatitis B virus DNA--positive chronic hepatitis B. [Articolo su rivista]
Andreone, P; Cursaro, C; Gramenzi, A; Zavagliz, C; Rezakovic, I; Altomare, E; Severini, R; Franzone, Js; Albano, O; Ideo, G; Bernardi, M; Gasbarrini, G.
abstract

1996 - Incidence of hepatitis C virus infection in Italian patients with idiopathic pulmonary fibrosis. [Articolo su rivista]
Meliconi, R; Andreone, P; Fasano, L; Galli, S; Pacilli, A; Miniero, R; Fabbri, M; Solforosi, L; Bernardi, M.
abstract

1996 - Interferon and hepatocellular carcinoma. [Articolo su rivista]
Andreone, P; Cursaro, C; Gramenzi, A; Trevisani, F; Gasbarrini, G; Bernardi, M.
abstract

1996 - Interferon-α plus indomethacin combined therapy in HBeAg positive chronic hepatitis B non-responder to a previous IFNα course: Results of a pilot study [Articolo su rivista]
Andreone, P.; Cursaro, C.; Gramenzi, A.; Miniero, R.; Bernardi, M.; Gasbarrini, G.
abstract

Background: interferon-α is able to induce a sustained inhibition of hepatitis B virus replication in about 30-40% of patients with chronic hepatitis B. There is evidence that non-steroidal antiinflammatory drugs can enhance the synthesis of antiviral proteins induced by interferon-α. Aim: to evaluate the efficacy and tolerability of combined therapy with interferon-α plus indomethacin in HBeAg and HBV-DNA positive patients affected by chronic active hepatitis non-responders to a previous interferon-a treatment. Methods: after six months of retreatment with interferon-α (6 MU thrice weekly) six patients were enrolled, without stopping the therapy, to receive interferon-α (with the same schedule) plus indomethacin (25 mg orally twice daily) for an additional six month course. Results: at the end of treatment and after six months of follow-up alanine transaminase normalization was seen in three (50%) and four (66.7%) patients, HBV-DNA loss in one (17%) and three (50%), HBeAg/HBeAb serum conversion in one (17%) and two (33%), respectively. The combined therapy was well tolerated and no indomethacin side-effects were observed. The treatment was stopped in one patient after 4 months because of a remarkable increase of alanine transaminase levels, and in another after five months because of hyperthyroidism occurrence. Conclusions: the results of this study, even if obtained in a small number of patients, are encouraging and suggest a randomized controlled trial to be confirmed.

1996 - Monoclonal gammopathy in patients with chronic hepatitis C virus infection. [Articolo su rivista]
Andreone, P; Gramenzi, A; Cursaro, C; Bernardi, M; Zignego, Al.
abstract

1995 - Detection of hepatitis C virus by polymerase chain reaction and recombinant immunoblot assay 3.0 in porphyria cutanea tarda. [Articolo su rivista]
Andreone, P; Cursaro, C; Gramenzi, A; Guidetti, Ms; Bardazzi, F; Tosti, A; Miniero, R.
abstract

1995 - Hemodynamic and renal effects of ascites apheresis, concentration and reinfusion in advanced cirrhosis. [Articolo su rivista]
Bernardi, M; Gasbarrini, A; Trevisani, F; Caraceni, P; De Collibus, C; Colantoni, A; Andreone, P; Cursaro, C; Ligabue, A; Gasbarrini, G.
abstract

1995 - Hepatitis C virus infection and lymphoproliferative disorders. [Articolo su rivista]
Andreone, P; Gramenzi, A; Cursaro, C; Bernardi, M.
abstract

1994 - Familial cluster of hepatitis C virus type 1. [Articolo su rivista]
Andreone, P; Gramenzi, A; Cursaro, C; Bernardi, M; Gasbarrini, G; Pontisso, P; Alberti, A.
abstract

1994 - Indomethacin enhances serum 2'5'-oligoadenylate synthetase in patients with hepatitis B and C virus chronic active hepatitis. [Articolo su rivista]
Andreone, P; Cursaro, C; Gramenzi, A; Buzzi, A; Miniero, R; Sprovieri, G; Gasbarrini, G.
abstract

1994 - Indomethacin increases 2′,5′-oligoadenylate synthetase release by cultured liver tissue of patients with HCV chronic active hepatitis [Articolo su rivista]
Andreone, P.; Cursaro, C.; Gramenzi, A.; Buzzi, A.; Miniero, R.; Bernardi, M.; Gasbarrini, G.
abstract

Interferon-α (IFN-α) stimulates the synthesis of antiviral proteins, such as 2′,5′-oligoadenylate synthetase (2′5′-OAS), and activation of arachidonic acid (AA) metabolism seems to constitute the post-receptorial signal induced by this cytokine. We evaluated the in vitro effect of IFN-α, indomethacin (an inhibitor of cyclooxygenase pathway of AA) and IFN-α plus indomethacin on 2′5′-OAS release by cultured liver biopsies of patients with active or inactive HCV infection and uninfected patients with various liver diseases. The results demonstrated that basal 2′5′-OAS release was significantly higher in patients with active HCV infection with respect to uninfected ones. In two HCV-Ab positive but HCV-RNA negative patients, basal 2′5′-OAS was similar to uninfected patients. In HCV-RNA positive patients, indomethacin alone was able to significantly increase the 2′5′-OAS production in a similar fashion to IFN-α alone, while a synergistic effect on 2′5′-OAS increase was seen when biopsies were cultured with IFN-α plus indomethacin. A similar trend was observed in the uninfected and in the HCV-Ab positive but HCV-RNA negative patients, even if the increase did not reach statistical significance. These results confirm the interaction between IFN-α and AA metabolites and suggest an evaluation of the in vivo response of IFN-α plus nonsteroid antiinflammatory drugs combined therapy. © 1994.

1993 - Interferon-alpha increases prostaglandin E2 production by cultured liver biopsy in patients with chronic viral hepatitis: can non-steroidal anti-inflammatory drugs improve the therapeutic response to interferon? [Articolo su rivista]
Andreone, P; Cursaro, C; Gasbarrini, G.
abstract

1993 - Preliminary results of thymosin-α1 versus IFN-α treatment in patients with HBeAg negative and HBV-DNA positive chronic active hepatitis [Articolo su rivista]
Andreone, P.; Cursaro, C.; Gramenzi, A.; Miniero, R.; Manzin, A.; Severini, R.; Franzone, J. S.; Clementi, M.; Sprovieri, G.; Gasbarrini, G.
abstract

1993 - Renal sodium retention during upright posture in preascitic cirrhosis. [Articolo su rivista]
Bernardi, M; Di Marco, C; Trevisani, F; Fornalè, L; Andreone, P; Cursaro, C; Baraldini, M; Ligabue, A; Tamè, Mr; Gasbarrini, G.
abstract

1992 - Bed-rest-induced hypernatriuresis in cirrhotic patients without ascites: does it contribute to maintain 'compensation'? [Articolo su rivista]
Trevisani, F; Bernardi, M; Gasbarrini, A; Tamè, Mr; Giancane, S; Andreone, P; Baraldini, M; Cursaro, C; Ligabue, A; Gasbarrini, G.
abstract

1992 - Interferon treatment in unresectable hepatocellular carcinoma. [Articolo su rivista]
Stefanini, G; Celi, A; Amorati, P; Mucci, F; Biselli, M; Andreone, P; Gasbarrini, G.
abstract

1992 - Interferon-alpha therapy combined with nonsteroid antiinflammatory drugs for treatment of chronic viral hepatitis? [Articolo su rivista]
Andreone, P; Cursaro, C; Gasbarrini, G.
abstract

1992 - The hemodynamic status of preascitic cirrhosis: an evaluation under steady-state conditions and after postural change. [Articolo su rivista]
Bernardi, M; Di Marco, C; Trevisani, F; De Collibus, C; Fornalé, L; Baraldini, M; Andreone, P; Cursaro, C; Zacá, F; Ligabue, A; Et, Al.
abstract

1991 - Enhancement of ELISA cut-off reduces HCV-Ab false-positivity in patients with HBV, HDV and alcoholic liver disease. [Articolo su rivista]
Andreone, P; Cursaro, C; Miniero, R; Stefanini, Gf; Sprovieri, G; Gasbarrini, G.
abstract

1991 - Role of prostaglandin E2 on defective interferon-gamma production during type B acute viral hepatitis. [Articolo su rivista]
Baraldini, M; Andreone, P; Cursaro, C; Pasini, P; Verucchi, G; Mazzetti, M; Stefanini, Gf; Gasbarrini, G.
abstract

1990 - Antacids in gastric ulcer treatment: evidence of cytoprotection. [Articolo su rivista]
Gasbarrini, G; Andreone, P; Baraldini, M; Cursaro, C; Micaletti, E.
abstract

1990 - Protection of the upper gastrointestinal mucosa: the role of antacids. [Articolo su rivista]
Gasbarrini, G; Andreone, P; Baraldini, M; Bonvicini, F; Cursaro, C; Brocchi, E.
abstract

1989 - Influence of cimetidine in low doses (less than ED50) on prostanoid production by human gastric mucosa in vitro. [Articolo su rivista]
Andreone, P; Baraldini, M; Micaletti, E; Cursaro, C; Saggioro, A; Della Monica, A; Bortoluzzi, F; Miglio, F; Gasbarrini, G.
abstract

1988 - Clinical significance of antibodies to polymerized human albumin detected by enzyme-linked immunosorbent assay. [Articolo su rivista]
Baraldini, M; Miglio, F; Cursaro, C; Stefanini, Gf; Andreone, P; Micaletti, E; Gasbarrini, G.
abstract

1988 - Synthesis of prostanoids in the gastric and duodenal mucosa of healthy subjects]. [Articolo su rivista]
Baraldini, M; Andreone, P; Cursaro, C; Micaletti, E; Saggioro, A; Bortoluzzi, F; Miglio, F; Gasbarrini, G.
abstract

1987 - Prostanoids in peritoneal fluid of infertile women with pelvic endometriosis and PID. [Articolo su rivista]
Pungetti, D; Lenzi, M; Travisani, D; Cantiero, D; Maurizio, G; Sarti, G; Zanardi, E; Andreone, P; Baraldini, M; Gasbarrini, G.
abstract

1985 - Effects of indomethacin and polyunsaturated phosphatidylcholine on short-term control of renal water excretion. [Articolo su rivista]
Agnoli, Gc; Andreone, P; Cacciari, M; Garutti, C; Ikonomu, E.
abstract

1984 - Action and interaction between sulpiride and dopamine on renal hemodyinamics in man [Articolo su rivista]
Agnoli, G. C.; Andreone, P.; Cacciari, M.; Garutti, C.; Ikonomu, E.; Lenzi, P.
abstract

1984 - Action and interaction between sulpiride and dopamine on sodium tubular reabsorption [Articolo su rivista]
Agnoli, G. C.; Andreone, P.; Cacciari, M.
abstract

1984 - Relation between acute changes in diuresis and renal prostaglandins. I: Induced hypotonic polyuria]. [Articolo su rivista]
Agnoli, Gc; Andreone, P; Cacciari, M; Garutti, C; Ikonomu, E.
abstract

1984 - Relation between acute changes in diuresis and renal prostaglandins. II. Induced antidiuresis]. [Articolo su rivista]
Agnoli, Gc; Andreone, P; Cacciari, M; Garutti, C; Ikonomu, E.
abstract

1984 - [Sulpiride (stereoisomers, racemic) and dopamine: actions and interactions on renal circulation]. [Articolo su rivista]
Agnoli, Gc; Andreone, P; Cacciari, M; Garutti, C; Ikonomu, E; Lenzi, P.
abstract

1984 - [Sulpiride (stereoisomers, racemic) and dopamine: actions and interactions on renal excretion of hydro-saline]. [Articolo su rivista]
Agnoli, Gc; Andreone, P; Cacciari, M; Garutti, C; Ikonomu, E; Lenzi, P.
abstract

1984 - [Sulpiride (stereoisomers, racemic) and dopamine: actions and interactions on tubular reabsorption] [Articolo su rivista]
Agnoli, Gc; Andreone, P; Cacciari, M; Garutti, C; Ikonomu, E; Lenzi, P.
abstract

1983 - The effects of the indomethacin treatment on urinary hydrosaline and prostaglandin-E excretions in hypotonic polyuria and hypertonic olyguria respectively [Articolo su rivista]
Agnoli, G. C.; Andreone, P.; Cacciari, M.; Franceschetti, F.; Garutti, C.
abstract

1983 - [Catecholamine receptors and renal function]. [Articolo su rivista]
Agnoli, Gc; Andreone, P; Cacciari, M; Garutti, C; Ikonomu, E; Lenzi, P.
abstract

1983 - [Effects of acute changes in water balance on hydrosaluresis and on urinary excretion of prostaglandin E, in the presence and absence of a cyclooxygenase inhibitor] [Articolo su rivista]
Agnoli, Gc; Andreone, P; Cacciari, M; Franceschetti, F; Garutti, C.
abstract

1982 - [A possibility that tubulo-glomerular retrocontrol influences renal function in toto]. [Articolo su rivista]
Agnoli, Gc; Andreone, P; Cacciari, M; Cariani, A; Garutti, C; Ikonomu, E; Lenzi, P.
abstract

Università degli studi di Modena e Reggio Emilia

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