Management of Chronic Hepatitis C in Cirrhosis and Liver Transplant Population

Shahid Habib, MD, Obaid Shakil Shaikh, MD

Abstract


Hepatitis C treatment has evolved tremendously since the discovery of the virus 24 years ago. Patients with cirrhosis, metabolic syndrome, co-infection with HIV, end stage renal disease and liver allograft recipients are particularly difficult to treat. At the same time, such patients often suffer from significant morbidity and mortality. This review primarily focuses on treatment of HCV infection in patients with cirrhosis and liver allograft recipients. First generation HCV protease inhibitors, boceprevir and telaprevir, improved sustained virologic response rates in both treatment naive and treatment experienced patients. However, both drugs are associated with significant adverse events and drug-drug interactions, thus limiting their use in patients with advanced liver disease and allograft recipients. The advent of highly effective and better tolerated oral anti-virals have dramatically enhanced treatment efficacy with response rates exceeding 90%. It is expected that such agents will significantly alter the outlook for difficult to treat HCV infected populations.


Keywords


outcome, prognosis, graft survival, patient survival, liver allograft, fibrosis, cirrhosis, interferon, ribavirin, telaprevir, boceprevir, sofosbuvir, simeprevir

Full Text:

PDF

References


Mohd Hanafiah K, Groeger J, Flaxman AD, Wiersma ST. Global epidemiology of hepatitis C virus infection: new estimates of age-specific antibody to HCV seroprevalence. Hepatology. 2013;57(4):1333-1342.

Hoofnagle JH, Mullen KD, Jones DB, et al. Treatment of chronic non-A,non-B hepatitis with recombinant human alpha interferon. A preliminary report. N Engl J Med. 1986;315(25):1575-1578.

Liang TJ, Ghany MG. Current and future therapies for hepatitis C virus infection. N Engl J Med. 2013;368(20):1907-1917.

Martel-Laferriere V, Dieterich DT. Update on combinations of DAAs with and without pegylated-interferon and ribavirin: triple and quadruple therapy more than doubles SVR. Clin Liver Dis. 2013;17(1):93-103.

Poordad F, McCone J Jr, Bacon BR, et al. Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med. 2011;364(13):1195-1206.

Jacobson IM, McHutchison JG, Dusheiko G, et al. Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med. 2011;364(25):2405-2416.

Lawitz E, Mangia A, Wyles D, et al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med. 2013;368(20):1878-1887.

Fried MW, Buti M, Dore GJ, et al. Once-daily simeprevir (TMC435) with pegylated interferon and ribavirin in treatment-naive genotype 1 hepatitis C: the randomized PILLAR study. Hepatology. 2013;58(6):1918-1929.

Fattovich G, Giustina G, Degos F, et al. Effectiveness of interferon alfa on incidence of hepatocellular carcinoma and decompensation in cirrhosis type C. European Concerted Action on Viral Hepatitis (EUROHEP). J Hepatol. 1997;27(1):201-205.

Hu KQ, Tong MJ. The long-term outcomes of patients with compensated hepatitis C virus-related cirrhosis and history of parenteral exposure in the United States. Hepatology. 1999;29(4):1311-1316.

Wright TL, Donegan E, Hsu HH, et al. Recurrent and acquired hepatitis C viral infection in liver transplant recipients. Gastroenterology. 1992;103(1):317-322.

Berenguer M, Schuppan D. Progression of liver fibrosis in post-transplant hepatitis C: mechanisms, assessment and treatment J Hepatol. 2013;58:1028-1041.

Seeff LB. Sustained virologic response: is this equivalent to cure of chronic hepatitis C? Hepatology. 2013;57(2):438-440.

Poynard T, McHutchison J, Manns M, et al. Impact of pegylated interferon alfa-2b and ribavirin on liver fibrosis in patients with chronic hepatitis C. Gastroenterology. 2002;122(5):1303-1313.

D'Ambrosio R, Aghemo A, Rumi MG, et al. A morphometric and immunohistochemical study to assess the benefit of a sustained virological response in hepatitis C virus patients with cirrhosis. Hepatology. 2012;56(2):532-543.

George SL, Bacon BR, Brunt EM, Mihindukulasuriya KL, Hoffmann J, Di Bisceglie AM. Clinical, virologic, histologic, and biochemical outcomes after successful HCV therapy: a 5-year follow-up of 150 patients. Hepatology. 2009;49(3):729-738.

Marcellin P, Boyer N, Gervais A, et al. Long-term histologic improvement and loss of detectable intrahepatic HCV RNA in patients with chronic hepatitis C and sustained response to interferon-alpha therapy. Ann Intern Med. 1997;127(10):875-881.

Mallet V, Gilgenkrantz H, Serpaggi J, et al. Brief communication: the relationship of regression of cirrhosis to outcome in chronic hepatitis C. Ann Intern Med. 2008;149(6):399-403.

Bruno S, Stroffolini T, Colombo M, et al. Sustained virological response to interferon-alpha is associated with improved outcome in HCV-related cirrhosis: a retrospective study. Hepatology. 2007;45(3):579-587.

Veldt BJ, Saracco G, Boyer N, et al. Long term clinical outcome of chronic hepatitis C patients with sustained virological response to interferon monotherapy. Gut. 2004;53(10):1504-1508.

Bruno S, Crosignani A, Facciotto C, et al. Sustained virologic response prevents the development of esophageal varices in compensated, Child-Pugh class A hepatitis C virus-induced cirrhosis. A 12-year prospective follow-up study. Hepatology. 2010;51(6):2069-2076.

Rincon D, Ripoll C, Lo Iacono O, et al. Antiviral therapy decreases hepatic venous pressure gradient in patients with chronic hepatitis C and advanced fibrosis. Am J Gastroenterol. 2006;101(10):2269-2274.

Saab S, Hunt DR, Stone MA, McClune A, Tong MJ. Timing of hepatitis C antiviral therapy in patients with advanced liver disease: a decision analysis model. Liver Transpl. 2010;16(6):748-759.

van der Meer AJ, Veldt BJ, Feld JJ, et al. Association between sustained virological response and all-cause mortality among patients with chronic hepatitis C and advanced hepatic fibrosis. JAMA. 2012;308(24):2584-2593.

Bruno S, Shiffman ML, Roberts SK, et al. Efficacy and safety of peginterferon alfa-2a (40KD) plus ribavirin in hepatitis C patients with advanced fibrosis and cirrhosis. Hepatology. 2010;51(2):388-397.

Bota S, Sporea I, Sirli R, et al. Severe adverse events during antiviral therapy in hepatitis C virus cirrhotic patients: A systematic review. World J Hepatology. 2013;5(3):120-126.

Fernandez-Rodriguez CM, Alonso S, Martinez SM, et al. Peginterferon plus ribavirin and sustained virological response in HCV-related cirrhosis: outcomes and factors predicting response. Am J Gastroenterol. 2010;105(10):2164-2172; quiz 2173.

Bota S, Sporea I, Popescu A, et al. Response to standard of care antiviral treatment in patients with HCV liver cirrhosis - a systematic review. JGLD. 2011;20(3):293-298.

Kwo PY, Lawitz EJ, McCone J, et al. Efficacy of boceprevir, an NS3 protease inhibitor, in combination with peginterferon alfa-2b and ribavirin in treatment-naive patients with genotype 1 hepatitis C infection (SPRINT-1): an open-label, randomised, multicentre phase 2 trial. Lancet. 2010;376(9742):705-716.

Bacon BR, Gordon SC, Lawitz E, et al. Boceprevir for previously treated chronic HCV genotype 1 infection. N Engl J Med. Mar 31 2011;364(13):1207-1217.

Sherman KE, Flamm SL, Afdhal NH, et al. Response-guided telaprevir combination treatment for hepatitis C virus infection. N Engl J Med. 2011;365(11):1014-1024.

McHutchison JG, Manns MP, Muir AJ, et al. Telaprevir for previously treated chronic HCV infection. N Engl J Med. 2010;362(14):1292-1303.

Zeuzem S, Andreone P, Pol S, et al. Telaprevir for retreatment of HCV infection. N Engl J Med. 2011;364(25):2417-2428.

Antaki N, Craxi A, Kamal S, et al. The neglected hepatitis C virus genotypes 4, 5 and 6: an international consensus report. Liver Int. 2010;30(3):342-355.

Mira JA, Garcia-Rey S, Rivero A, et al. Response to pegylated interferon plus ribavirin among HIV/hepatitis C virus-coinfected patients with compensated liver cirrhosis. Clin Infect Dis. 2012;55(12):1719-1726.

D'Heygere F, George C, Van Vlierberghe H, et al. Efficacy of interferon-based antiviral therapy in patients with chronic hepatitis C infected with genotype 5: a meta-analysis of two large prospective clinical trials. J Med Virol. 2011;83(5):815-819.

Ji F, Zhang S, Huang N, Deng H, Li Z. Splenectomy prior to antiviral therapy in patients with hepatitis C virus related decompensated cirrhosis. Braz J Infect Dis. 2013;17(5):601-605.

Di Marco V, Almasio PL, Ferraro D, et al. Peg-interferon alone or combined with ribavirin in HCV cirrhosis with portal hypertension: a randomized controlled trial. J Hepatol. 2007;47(4):484-491.

Di Marco V, Calvaruso V, Grimaudo S, et al. Role of IL-28B and inosine triphosphatase polymorphisms in efficacy and safety of Peg-Interferon and ribavirin in chronic hepatitis C compensated cirrhosis with and without oesophageal varices. J Viral Hepat. 2013;20(2):113-121.

Danish FA, Koul SS, Subhani FR, Rabbani AE, Yasmin S. Considerations in the management of hepatitis C virus-related thrombocytopenia with eltrombopag. Saudi j. 2010;16(1):51-56.

McHutchison JG, Dusheiko G, Shiffman ML, et al. Eltrombopag for thrombocytopenia in patients with cirrhosis associated with hepatitis C. N Engl J Med. 2007;357(22):2227-2236.

Kowdley KV, Lawitz E, Crespo I, et al. Sofosbuvir with pegylated interferon alfa-2a and ribavirin for treatment-naive patients with hepatitis C genotype-1 infection (ATOMIC): an open-label, randomised, multicentre phase 2 trial. Lancet. 2013;381(9883):2100-2107.

Lawitz E, Lalezari JP, Hassanein T, et al. Sofosbuvir in combination with peginterferon alfa-2a and ribavirin for non-cirrhotic, treatment-naive patients with genotypes 1, 2, and 3 hepatitis C infection: a randomised, double-blind, phase 2 trial. Lancet Infect Dis. 2013;13(5):401-408.

Osinusi A, Meissner EG, Lee Y-J, et al. Sofosbuvir and ribavirin for hepatitis C genotype 1 in patients with unfavorable treatment characteristics: a randomized clinical trial. JAMA. 2013;310(8):804-811.

Schluger LK, Sheiner PA, Thung SN, et al. Severe recurrent cholestatic hepatitis C following orthotopic liver transplantation. Hepatology. 1996;23(5):971-976.

Carrion JA, Torres F, Crespo G, et al. Liver stiffness identifies two different patterns of fibrosis progression in patients with hepatitis C virus recurrence after liver transplantation. Hepatology. 2010;51(1):23-34.

Firpi RJ, Clark V, Soldevila-Pico C, et al. The natural history of hepatitis C cirrhosis after liver transplantation. Liver Transpl. 2009;15(9):1063-1071.

Valadao RM, Terrault NA. Older donors: mounting risks for the hepatitis C-infected liver transplant recipient? Liver Transpl. 2009;15(7):677-681.

Berenguer M, Roche B, Aguilera V, et al. Efficacy of the retreatment of hepatitis C virus infections after liver transplantation: role of an aggressive approach. Liver Transpl. 2013;19(1):69-77.

Habib S, Chang CCH, De Vera M, Rana AA, Shaikh OS. Interferon Treatment Improves Survival among Liver Transplant Recipients with Recurrent Hepatitis C. J Surgery. 2013;1(1).

Belli LS, Volpes R, Graziadei I, et al. Antiviral therapy and fibrosis progression in patients with mild-moderate hepatitis C recurrence after liver transplantation. A randomized controlled study. Dig Liver Dis. 2012;44(7):603-609.

Terrault NA. Prophylactic and preemptive therapies for hepatitis C virus-infected patients undergoing liver transplantation. Liver Transpl. 2003;9(11):S95-S100.

Chalasani N, Manzarbeitia C, Ferenci P, et al. Peginterferon alfa-2a for hepatitis C after liver transplantation: two randomized, controlled trials. Hepatology. 2005;41(2):289-298.

Bzowej N, Nelson DR, Terrault NA, et al. PHOENIX: A randomized controlled trial of peginterferon alfa-2a plus ribavirin as a prophylactic treatment after liver transplantation for hepatitis C virus. Liver Transpl. 2011;17(5):528-538.

Wang CS, Ko HH, Yoshida EM, Marra CA, Richardson K. Interferon-based combination anti-viral therapy for hepatitis C virus after liver transplantation: a review and quantitative analysis. Am J Transplant. 2006;6(7):1586-1599.

Berenguer M. Systematic review of the treatment of established recurrent hepatitis C with pegylated interferon in combination with ribavirin. J Hepatol. 2008;49(2):274-287.

Xirouchakis E, Triantos C, Manousou P, et al. Pegylated-interferon and ribavirin in liver transplant candidates and recipients with HCV cirrhosis: systematic review and meta-analysis of prospective controlled studies. J Viral Hepat. 2008;15(10):699-709.

Pillai AA, Lee VS, Wang E, Rinella ME, Levitsky J. Factors associated with sustained virological response in liver transplant recipients with recurrent hepatitis C. Transplant Proc. 2010;42(9):3647-3651.

Coilly A, Roche B, Dumortier J, et al. Safety and efficacy of protease inhibitors to treat hepatitis C after liver transplantation: a multicenter experience. J Hepatol. 2014;60(1):78-86.

Verna EC, Burton JR, O'Leary JG. A multicenter study of protease inhibitor-triple therapy in HCV-infected liver transplant recipients: report from the CRUSH-C group. 48th Annual Meeting of the European Association for the Study of the Liver (EASL 2013). Amsterdam2013:Abstract 23.

Hulskotte E, Gupta S, Xuan F, et al. Pharmacokinetic interaction between the hepatitis C virus protease inhibitor boceprevir and cyclosporine and tacrolimus in healthy volunteers. Hepatology. 2012;56(5):1622-1630.

Garg V, van Heeswijk R, Lee JE, Alves K, Nadkarni P, Luo X. Effect of telaprevir on the pharmacokinetics of cyclosporine and tacrolimus. Hepatology. 2011;54(1):20-27.

Stravitz R, Levitsky J, Parikh ND, et al. Higher Sustained Virologic Response (SVR-12) Achievable in Liver Transplant (LT) Recipients with Hepatitis C (HCV) Treated with Protease Inhibitor (PI) Triple Therapy (TT). Hepatology. 2013;58(S1):Abstract 461.

Forns X, Fontana RJ, Moonka D, et al. Initial Evaluation of the Sofosbuvir Compassionate Use Program for Patients with Severe Recurrent HCV Following Liver Transplantation. Hepatology. 2013;58(S1):Abstract 1084.


Refbacks

  • There are currently no refbacks.