The emerging field of HCV drug resistance

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.