Second Generation Protease Inhibitors and Nucleotide Inhibitors

Abstract

The hepatitis C virus (HCV) protease and polymerase inhibitors are in rapid phases of development. Following closely behind the approval of the inhibitors of the HCV RNA NS3/4A protease, boceprevir and telaprevir, include both a) more potent protease inhibitors and b) the development of the viral NS5B RNA-dependent RNA polymerase inhibitors. Protease inhibitors generally have a low barrier to resistance and extensive cross-resistance between agents. NS5B polymerase inhibitors are generally considered to have a high barrier to resistance and the potential for use across all genotypes. However, in the absence of ribavirin or of other direct-acting antivirals these agents may predispose to the selection of resistant variants or for viral relapse following treatment completion. Optimal combination of agents and therapy durations remain major challenges in clinical research.