14th International HIV Drug Resistance Workshop 7-11 June 2005, Québec City, Canada

HCV RESISTANCE TO ANTIVIRAL AGENTS

Antivir Ther. 10, Suppl 1:P4 (abstract no. P2)

Giovanni Migliaccio and the HCV Antiviral Team
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. Among the various approaches being explored to identify novel therapies for HCV, the most advanced rely on the discovery of small molecules that inhibit HCV replication by targeting the viral enzymes. In fact, inhibitors of the viral 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. This pleanry talk will review advances in the emerging field of HCV antiviral resistance, focusing specifically on in vitro studies with prototypical inhibitors of the NS5B polymerase.

PRESENTING AUTHOR: Giovanni Migliaccio

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2005-06-07
P2

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