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.


CONCLUSIONS
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.
Koev
Gennadiy
G
Abbott Laboratories, Global Pharmaceutical Research and Development, Department R4CQ, Building AP52N, 200 Abbott Park Road, Abbott Park, IL 60064, USA. gennadiy.koev@abbott.com
Kati
Warren
W
D000998:Antiviral Agents / Q000494:pharmacology*; D001665:Binding Sites; D002986:Clinical Trials as Topic; D024882:Drug Resistance, Viral / Q000187:drug effects* / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D016174:Hepacivirus / Q000187:drug effects* / Q000201:enzymology; D006526:Hepatitis C / Q000188:drug therapy; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; D012324:RNA-Dependent RNA Polymerase
D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase