Gennadiy Koev1, Warren Kati. 1. Abbott Laboratories, Global Pharmaceutical Research and Development, Department R4CQ, Building AP52N, 200 Abbott Park Road, Abbott Park, IL 60064, USA. gennadiy.koev@abbott.com
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 drugs 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.
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 drugs 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.
Authors: Oliver Lenz; Thierry Verbinnen; Tse-I Lin; Leen Vijgen; Maxwell D Cummings; Jimmy Lindberg; Jan Martin Berke; Pascale Dehertogh; Els Fransen; Annick Scholliers; Katrien Vermeiren; Tania Ivens; Pierre Raboisson; Michael Edlund; Susan Storm; Lotta Vrang; Herman de Kock; Gregory C Fanning; Kenneth A Simmen Journal: Antimicrob Agents Chemother Date: 2010-02-22 Impact factor: 5.191
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