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)(1). Combination therapy with pegylated interferon and ribavirin, the latest treatment for HCV infection, elicits long-term responses in only about 50% of patients treated(2-4). No effective alternative treatments exist for non-responders(5). Consequently, significant efforts are continuing to maximize response to combination therapy(6,7). However, rational therapy optimization is precluded by the poor understanding of the mechanism(s) of ribavirin action against HCV8. Ribavirin alone induces either a transient early decline or no decrease in HCV viral load(9-12), but in combination with interferon it significantly improves long-term response rates(2-4,13-15). Here we present a model of HCV dynamics in which, on the basis of growing evidence(16-21), 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.