In Vitro Susceptibility of Hepatitis C Virus Genotype 1 through 6 Clinical Isolates to the Pangenotypic NS3/4A Inhibitor Voxilaprevir
- 1 April 2019
- journal article
- research article
- Published by American Society for Microbiology in Journal of Clinical Microbiology
- Vol. 57 (4)
- https://doi.org/10.1128/jcm.01844-18
Abstract
Voxilaprevir is a direct-acting antiviral agent (DAA) that targets the NS3/4A protease of hepatitis C virus (HCV). High sequence diversity of HCV and inadequate drug exposure during unsuccessful treatment may lead to the accumulation of variants with reduced susceptibility to DAAs including NS3/4A protease inhibitors such as voxilaprevir. The voxilaprevir susceptibility of clinical and laboratory strains of HCV was assessed. The NS3 protease regions of viruses belonging to 6 genotypes and 29 subtypes from 345 DAA-naïve or -experienced (including protease inhibitor) patients, and 344 genotype 1 to 6 replicons bearing engineered NS3 resistance-associated substitutions (RASs) were tested in transient transfection assays. Median voxilaprevir EC50 against NS3 from protease inhibitor-naïve patient samples ranged from 0.38 nM for genotype 1, to 5.8 nM for genotype 3. Voxilaprevir susceptibilities of HCV replicons with NS3 RASs were dependent on subtype background and the type and number of substitutions introduced. The majority of RASs known to confer resistance to other protease inhibitors had little to no impact on voxilaprevir susceptibility, except A156L, T or V in genotype 1 to 4 which conferred >100-fold reductions but exhibited low replication capacity in most genotypes. These data support the use of voxilaprevir in combination with other DAAs in DAA-naïve and DAA-experienced patients infected with any subtype of HCV.Keywords
Funding Information
- Gilead Sciences
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