The emerging field of HCV drug resistance

Abstract

Background: With 170 million people infected worldwide and an inadequate current standard of care, hepatitis C virus (HCV) infection represents a major unmet medical need. Multiple companies are working on the discovery and development of specific HCV antiviral drugs, including inhibitors of HCV polymerase, protease and NS5A. Because of the error-prone nature of viral RNA replication, resistance mutants will develop that could present a potentially significant challenge to developing antiviral treatment regimens. Objective: Here, we review the major drug classes currently in preclinical and clinical development and the resistance mutations specific for each class that have been identified from cell culture and/or in vivo studies. Methods: We have analyzed currently available scientific literature to create a comprehensive review of the current state of the art in the field of HCV resistance to specific antiviral agents, in vitro and in vivo. Results/conclusion: Most specific HCV inhibitors described in the literature can select resistant viral variants in cell culture and in the clinic. Interplay of a mutant's fitness and its level of resistance will determine its clinical importance. Combinations of non-cross-resistant classes of dugs will be key to successful antiviral therapy. The number of drugs in a combination as well as the optimal duration of antiviral treatment, are important issues that need to be addressed in future studies.

Keywords::

• antiviral therapy
• drug discovery
• HCV
• HCV drug resistance
• HCV polymerase inhibitors
• HCV protease inhibitors
• HCV replicon
• NS3
• NS5A
• NS5B
• small molecule antivirals

Acknowledgements

We thank Akhter Molla (Abbott Antiviral Research) for critical reading of the manuscript and helpful suggestions. We are also very grateful to Kenton Longenecker (Abbott Advanced Technology) for providing original artwork for Figure 1.