HCV resistance to antiviral agents

Poster number: 0

Giovanni Migliaccio & the HCV antiviral team

  1. IRBM P. Angeletti - Merck Research Laboratories, Pomezia (Roma) ITALY

With an estimated 170 million chronically infected individuals worldwide, Hepatitis C virus (HCV) exacts a heavy toll on public health. The high prevalence of the disease and the limited efficacy of current therapies based on interferon-alpha have stimulated the search for safer and more effective drugs. The most direct route to identify novel therapies for HCV is undoubtedly the development of inhibitors that block viral enzymes required in the viral replication cycle Among the HCV encoded enzymes, the NS3/4A serine protease and the NS5B RNA-dependent RNA polymerase have emerged as proper targets for small molecule inhibitors. In fact, inhibitors of the NS3 protease and NS5B RNA polymerase have just started to show encouraging results in clinical trials. Similarly to HIV, the high genetic diversity, mutation rate and turnover of HCV are expected to favour the emergence of drug-resistance, potentially limiting the clinical usefulness of these novel drugs. Indeed, preclinical evidence is accumulating that resistance development might eventually restrict the efficacy of enzyme inhibitors. Although in vitro systems for HCV antiviral resistance studies are less advanced than for HIV, recent progress in biochemical and tissue culture assays have laid the foundations for resistance testing during drug-development and hopefully for therapy management. These studies are providing a wealth of information, ranging from the understanding of the mechanism of inhibition to the definition of the resistance determinants, and suggest that viruses resistant to these novel drugs might exist or arise in vivo. Moreover, initial structure-activity relationship studies suggest possible approaches to the design of inhibitors with improved resistance profiles. Lastly, preliminary cross-resistance analysis indicates that structurally different inhibitors elicit distinct resistance profiles and might therefore be used in combination therapy.

Iíll review the advances in the emerging field of HCV antiviral resistance, focusing specifically on in vitro studies with prototypical inhibitors of the NS5B polymerase.