Hepatitis C virus Resistance to Protease Inhibitors

[Guest guest]

J Hepatol. 2011 Jan 29. [Epub ahead of print]

Hepatitis C virus Resistance to Protease Inhibitors.

Halfon P, Locarnini S.

Virological Departement Laboratoire Alphabio, Hôpital Ambroise Paré, Marseille,

France.

Abstract

Recent advances in molecular biology have led to the development of novel small

molecules that target specific viral proteins of the hepatitis C virus (HCV)

life cycle. These drugs, collectively termed directly acting antivirals (DAA)

against HCV, include a range of non-structural (NS) 3/NS4A protease, NS5B

polymerase and NS5A inhibitors at various stages of clinical development. The

rapid replication rate of HCV, along with the low fidelity of its polymerase,

gives rise to the generation of mutations throughout the viral genome resulting

in remarkable sequence variation in the HCV population, known as a quasispecies.

The efficacy of DAAs is limited by the presence of these mutations resulting in

amino-acid substitutions within the targeted proteins which affect viral

sensitivity to these compounds. Thus, due to the high genetic variability of

HCV, variants with reduced susceptibility to DAA can occur naturally even before

treatment begins, but usually at low levels. Not surprisingly then, these

changes are selected in patients either breaking through or not responding to

potent DAA treatment. Six major position mutations in the NS3 HCV Protease (36,

54, 155, 156, 168, and 170) have now been reported in vitro or in vivo

associated with different levels of resistance. The amino acid composition at

several of the drug resistance sites can vary between the HCV genotypes/

subtypes, resulting in different consensus amino acids leading to a reduction in

replicative fitness as well as reduced DAA sensitivity. Different amino acid

diversity profiles for HCV genotypes/subtypes suggest differences in the

position/ type of immune escape and drug resistance mutations. Also, different

pathways of resistance profiles based on the chemical scaffold (linear or

macrocyclic) of the protease inhibitors have been described. This review first

describes how resistance to a protease inhibitor can develop and then provides

an overview of the mechanism of how particular mutations confer varying levels

of resistance to protease inhibitor, which have been identified and

characterized using both genotypic and phenotypic tools. Future potential

therapeutic strategies to assist patients who do develop resistance to protease

inhibitors are also outlined. The challenge developing new HCV protease

inhibitors should take in consideration not only the antiviral potency of the

drugs, the occurrence and importance of side effects, the frequency of oral

administration, but also the resistance profiles of these agents.

Copyright © 2011. Published by Elsevier B.V.

PMID: 21284949 [PubMed - as supplied by publisher]