Abstract and Introduction

Abstract

The goal of hepatitis C virus (HCV) therapy is permanent viral eradication. This requires the use of drug combinations with multiple modes of action. Steady-state HCV replication kinetics can be disrupted by drugs that inhibit virus production (antiviral molecules), inhibit de novo cell infection, and/or accelerate the clearance of infected cells. Pegylated interferon-α and ribavirin combine all of these mechanisms of action when used together, yet fail to clear HCV from a significant number of patients. New therapeutic approaches are needed. The next generation of anti-HCV therapeutic agents will fall into four main categories: new interferons and interferon inducers, alternatives to ribavirin, specific HCV inhibitors, and immune therapies. Ideally, these new treatments will increase the rate of sustained viral eradication and improve tolerability and acceptability. Drug combinations will be tailored to the individual patient, based on baseline parameters and viral kinetics during therapy.

Introduction

Hepatitis C virus (HCV) infection is curable. The main end point of treatment is a sustained virological response, defined as undetectable HCV RNA in peripheral blood 24 weeks after the end of treatment,^[1] which generally corresponds to permanent cure.^[2] Viral eradication results from reduced viral production and gradual clearance of infected cells.^[3] Treatment of chronic hepatitis C is currently based on a combination of pegylated interferon (IFN)-α and ribavirin.^[1] Even under the favorable conditions of clinical trials, failure of IFN-α-based treatment is relatively rare in patients with genotype 2 or 3 infection, but remains frequent in genotype 1 and 4 infection.^[4-6] The higher failure rate in patients with HCV genotype 1 and 4 infection appears to be due to multiple factors, including virological factors.^[7] The concepts underlying current and future treatments for HCV infection are discussed in this article.