Future studies of combination therapy for chronic hepatitis C: optimizing response rates for each hepatitis C population.

Interferon alfa, the only treatment currently approved for chronic hepatitis C virus infection, has a limited response rate (20-25%) in most patients. Ribavirin has also been used to treat hepatitis C virus infection, but treatment results in only a modest reduction in HCV-RNA levels; most patients relapse after the drug is discontinued. Combination therapy with ribavirin and interferon seems to be a logical approach to the treatment of hepatitis C virus infection. Small studies suggest that combination therapy results in improved sustained response rates compared with either interferon or ribavirin alone. In one study, 6 months of combination therapy was compared with 6 months of ribavirin monotherapy and 6 months of interferon alfa monotherapy. The sustained virologic response rates were 47% for combination therapy, 13% for interferon monotherapy, and 0% for ribavirin monotherapy. This study suggests that combination therapy can potentially double the sustained response rate, but larger studies are needed to evaluate this further. In trial design for clinical studies, many factors must be considered. Determining the response to interferon monotherapy might include establishing liver histology (especially in patients with cirrhosis) and hepatitis C virus genotype--types 1b and 4 are associated with a poor response, which is likely to affect the response to combination therapy. Patients in treatment trials should be followed long term at regular intervals; it is only with prolonged, detailed follow-up that the full effects of antiviral therapy on health and prevention of cirrhosis and hepatocellular carcinoma can be determined. Large multicenter studies are also needed to determine the effect of combination therapy in liver transplant patients. These studies must also address toxicity issues, as interferon may increase the risk of graft rejection post-transplant, and the low-grade hemolysis associated with ribavirin may stimulate hepatic iron deposition.