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Genotypic and phenotypic analyses of hepatitis C virus variants observed in clinical studies of VX-222, a nonnucleoside NS5B polymerase inhibitor
Journal article   Open access   Peer reviewed

Genotypic and phenotypic analyses of hepatitis C virus variants observed in clinical studies of VX-222, a nonnucleoside NS5B polymerase inhibitor

Min Jiang, Eileen Z Zhang, Andrzej Ardzinski, Ann Tigges, Andrew Davis, James C Sullivan, Michelle Nelson, Joan Spanks, Jennifer Dorrian, Olivier Nicolas, …
Antimicrobial agents and chemotherapy, Vol.58(9), pp.5456-5465
09/2014
DOI: 10.1128/AAC.03052-14
PMCID: PMC4135882
PMID: 24982088
url
https://europepmc.org/articles/pmc4135882View
Published (Version of record) Open Access

Abstract

VX-222, a thiophene-2-carboxylic acid derivative, is a selective nonnucleoside inhibitor of the hepatitis C virus (HCV) NS5B RNA-dependent RNA polymerase. In phase 1 and 2 clinical studies, VX-222 demonstrated effective antiviral efficacy, with substantial reductions in plasma HCV RNA in patients chronically infected with genotype 1 HCV. To characterize the potential for selection of VX-222-resistant variants in HCV-infected patients, the HCV NS5B gene was sequenced at baseline and during and after 3 days of VX-222 dosing (monotherapy) in a phase 1 study. Variants with the substitutions L419C/I/M/P/S/V, R422K, M423I/T/V, I482L/N/T, A486S/T/V, and V494A were selected during VX-222 dosing, and their levels declined over time after the end of dosing. Phenotypic analysis of these variants was conducted using HCV replicons carrying site-directed mutations. Of the 17 variants, 14 showed reduced susceptibility to VX-222 compared with the wild type, with the L419C/S and R422K variants having higher levels of resistance (>200-fold) than the rest of the variants (6.8- to 76-fold). The M423I and A486S variants remained susceptible to VX-222. The 50% effective concentration (EC50) for the L419P variant could not be obtained due to the poor replication of this replicon. The majority of the variants (15/17) were less fit than the wild type. A subset of the variants, predominately the L419S and R422K variants, were observed when the efficacy and safety of VX-222- and telaprevir-based regimens given for 12 weeks were investigated in genotype 1 HCV-infected patients in a phase 2 study. The NS3 and NS5B variants selected during the dual combination therapy showed reduced susceptibility to both telaprevir and VX-222 and had a lower replication capacity than the wild type. The phase 1b study has the ClinicalTrials.gov identifier NCT00911963, and the phase 2a study has ClinicalTrials.gov identifier NCT01080222.
 Amino Acid Sequence Antiviral Agents - pharmacology Base Sequence Cyclohexanols - pharmacology Drug Resistance, Viral - drug effects Drug Resistance, Viral - genetics Genetic Variation - drug effects Genetic Variation - genetics Genotype Hepacivirus - drug effects Hepacivirus - genetics Hepatitis C - drug therapy Humans Molecular Sequence Data Mutation - drug effects Mutation - genetics Oligopeptides - pharmacology Phenotype Replicon - drug effects Replicon - genetics Thiophenes - pharmacology Viral Nonstructural Proteins - antagonists & inhibitors Virus Replication - drug effects Virus Replication - genetics

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