Thierry Poynard, MD, PhD, is Professor of Medicine at the University of Paris VI, Hopital Pitie-Salpetriere in Paris, France, and Co-Director of the CNRS 1484 Research Unit. He is a member of the French Association for the Study of the Liver, the French National Society of Gastroenterology, the European Association for the Study of the Liver, the French National Society of Gastroenterology, the European Association for the Study of the Liver, and the American Association for the Study of Liver Disease. Dr. Poynard served as Chief Editor of Gastroenterologic and Biologic Clinic and has served on the editorial boards of Journal of Hepatology, Antiviral Therapy, and Hepatology. He has published more than 500 articles and communications on subjects such as detection of liver disease in alcoholics, alcoholic hepatitis, viral hepatitis, and the prevention of recurrent gastrointestinal bleeding in patients with cirrhosis.
Multiple options are now available for treating hepatitis C virus (HCV) infection. Based on recent data, previously untreated patients with HCV infection are most likely to achieve sustained virological, histological, and biochemical benefit when treated with interferon plus ribavirin rather than with interferon alone. Ribavirin is a synthetic guanosine analogue. The exact mechanism of action has not been established but may involve antiviral and immunomodulatory actions. Ribavirin, when given alone, decreases ALT levels transiently, but has no antiviral effects.
To date, five randomized, controlled trials of interferon plus ribavirin as initial treatment for chronic HCV infection have been published. All have demonstrated that the combination of interferon plus ribavirin significantly increases sustained loss of HCV RNA post-treatment over that seen with interferon alone. A subsequent meta-analysis of individual patient data from most published European studies of combination therapy found that the efficacy of interferon/ribavirin is enhanced two – to threefold over interferon alone in all patient groups studied, including treatment naïve patients.
Results of two large multicenter studies of combination therapy in over 1700 treatment-naïve patients, conducted in the United States and internationally, have recently been published. Patients were randomized to receive 24 or 48 weeks of interferon monotherapy or 24 or 48 weeks of interferon plus ribavirin. These studies confirm the significant benefit of combination therapy in terms of virological, histological, and biochemical improvement 24 weeks after cessation of therapy. Patients with genotype I infection benefited most from 48 weeks of combination therapy. The benefit of combination therapy was extended to all patients, especially those with high viral burden, advanced fibrosis or cirrhosis, and genotype I infection. Stepwise logistic regression analyses indicated that, in addition to combination therapy and 48 weeks of therapy, greater efficacy was associated with non-genotype I infection, low pretreatment viral burden, absence of extensive fibrosis, and female sex.
Important issues raised by these studies include whether HCV genotyping should be performed prior to therapy to determine the duration of combination therapy (i.e., 24 weeks for non-genotype 1 [genotypes 2 and 3] patients and 48 weeks for genotype 1-infected patients). Also, it appears that late clearance of HCV RNA during therapy (i.e., after week 12) and a subsequent sustained response with combination therapy occurs in 10% to 15% of patients. Thus, the optimal time to measure HCV RNA during therapy with interferon plus ribavirin is at 24 weeks rather than at 12 weeks, which is the rule used for interferon monotherapy. If a patient has undetectable serum HCV RNA at week 24 of interferon plus ribavirin therapy, then therapy should be continued for an additional 24 weeks, especially for genotype I patients. Patients with persistent viremia at week 24 can cease combination therapy and may still have a subsequent sustained response.
Combination therapy is generally well-tolerated, but dosage modification and discontinuation of treatment are more frequent than with interferon monotherapy. Side effects of the combination regimen are additive but not synergistic and generally do not limit the safety of its use. Adverse effects specific to ribavirin include dose-dependent reversible hemolytic anemia, cough, pruritus, rash, and insomnia.
Additional studies in treatment-naïve patients are required to determine the optimal duration of therapy, the optimal dose of ribavirin, and factors that accurately predict response.
– Chemello L, Cavalletto L, Bernardinello E, et al. The effect of interferon-alfa and ribavirin combination therapy in naïve patients with chronic hepatitis C. J. Hepatol. 1995;23(suppl2):8-12.
– Hoofnagle J, Di Bisceglie A. The treatment of chronic viral hepatitis. N Engl J Med. 1997;336:347-356.
– Lai MY, Kao JH, Yang PM, et al. Long-term efficacy of ribavirin plus interferon-alfa in the treatment of chronic hepatitis. Gastroenterology. 1996;111:1307-1312.
– McHutchison JG, Gordon SC, Schiff ER, et al. interferon-a-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C N Engl J Med. 1998;339:1485-1492.
– Poynard T, Leroy V, Cohard M, et al. Meta-analysis of interferon randomized trials in the treatment of viral hepatitis: effect of dose and duration. Hepatology. 1996;24:788-789.
– Poynard T, Marcellin P, Lee SS, et al. Randomized trial of interferon-a-2b plus ribavirin for 48 weeks or for 24 weeks versus interferon-a-2b plus placebo for 48 weeks for treatment of chronic infection with hepatitis C virus. Lancet. 1990;352:1426-1432.
– Reichard 0, Norkraus E, Fryden A, Braconier J-H, Sonnerborg A, Weiland 0. Randomized, double-blind, placebo-controlled trial of interferon-a-2b with and without ribavirin for chronic hepatitis C. Lancet. 1998;351:83-87.
– Schalm S, Hansen B, Chemello L, et al. Ribavirin enhances the efficacy but not the adverse effects in interferon in chronic hepatits C. J. Hepatol. 1997;26:961-966.