The metabolism, pharmacokinetics and mechanisms of antiviral activity of ribavirin against hepatitis C virus

Ribavirin, a broad spectrum antiviral agent, in conjunction with interferon forms the current standard of treatment for hepatitis C virus (HCV) infection in humans. While ribavirin alone fails to induce a significant antiviral response, in combination with interferon, ribavirin dramatically improves the long-term outcome of therapy. The predominant mechanism(s) of ribavirin action against HCV, are yet to be established. In this review, we examine the current status of our understanding of the metabolism, pharmacokinetics and mechanisms of the antiviral activity of ribavirin against HCV, all of which are central to the rational identification of improved treatment protocols. Received 30 September 2005; received after revision 20 November 2005; accepted 7 December 2005     

Modelling how ribavirin improves interferon response rates in hepatitis C virus infection

Nearly 200 million individuals worldwide are currently infected with hepatitis C virus (HCV). Combination therapy with pegylated interferon and ribavirin, the latest treatment for HCV infection, elicits long-term responses in only about 50% of patients treated. No effective alternative treatments exist for non-responders. Consequently, significant efforts are continuing to maximize response to combination therapy. However, rational therapy optimization is precluded by the poor understanding of the mechanism(s) of ribavirin action against HCV. Ribavirin alone induces either a transient early decline or no decrease in HCV viral load, but in combination with interferon it significantly improves long-term response rates. Here we present a model of HCV dynamics in which, on the basis of growing evidence, we assume that ribavirin decreases HCV infectivity in an infected individual in a dose-dependent manner. The model quantitatively predicts long-term response rates to interferon monotherapy and combination therapy, fits observed patterns of HCV RNA decline in patients undergoing therapy, reconciles conflicting observations of the influence of ribavirin on HCV RNA decline, provides key insights into the mechanism of ribavirin action against HCV, and establishes a framework for rational therapy optimization.