title: Genotypic and phenotypic analyses of hepatitis C virus variants observed in clinical studies of VX-222, a nonnucleoside NS5B polymerase inhibitor.
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.
authors: Vertex Pharmaceuticals Incorporated, Boston, Massachusetts, USA min_jiang@vrtx.com.
authors: Min
authors: M
authors: Jiang
authors: Vertex Pharmaceuticals Incorporated, Boston, Massachusetts, USA.
authors: Eileen Z
authors: EZ
authors: Zhang
authors: Vertex Pharmaceuticals Incorporated, Boston, Massachusetts, USA.
authors: Andrzej
authors: A
authors: Ardzinski
authors: Vertex Pharmaceuticals Incorporated, Boston, Massachusetts, USA.
authors: Ann
authors: A
authors: Tigges
authors: Vertex Pharmaceuticals Incorporated, Boston, Massachusetts, USA.
authors: Andrew
authors: A
authors: Davis
authors: Vertex Pharmaceuticals Incorporated, Boston, Massachusetts, USA.
authors: James C
authors: JC
authors: Sullivan
authors: Vertex Pharmaceuticals Incorporated, Boston, Massachusetts, USA.
authors: Michelle
authors: M
authors: Nelson
authors: Vertex Pharmaceuticals Incorporated, Boston, Massachusetts, USA.
authors: Joan
authors: J
authors: Spanks
authors: Vertex Pharmaceuticals Incorporated, Boston, Massachusetts, USA.
authors: Jennifer
authors: J
authors: Dorrian
authors: Vertex Pharmaceuticals Incorporated, Boston, Massachusetts, USA.
authors: Olivier
authors: O
authors: Nicolas
authors: Vertex Pharmaceuticals Incorporated, Boston, Massachusetts, USA.
authors: Doug J
authors: DJ
authors: Bartels
authors: Vertex Pharmaceuticals Incorporated, Boston, Massachusetts, USA.
authors: B Govinda
authors: BG
authors: Rao
authors: Vertex Pharmaceuticals Incorporated, Boston, Massachusetts, USA.
authors: Rene
authors: R
authors: Rijnbrand
authors: Vertex Pharmaceuticals Incorporated, Boston, Massachusetts, USA.
authors: Tara L
authors: TL
authors: Kieffer
mesh_terms: D000595:Amino Acid Sequence; D000998:Antiviral Agents / Q000494:pharmacology*; D001483:Base Sequence; D003511:Cyclohexanols / Q000494:pharmacology*; D024882:Drug Resistance, Viral / Q000187:drug effects / Q000235:genetics; D014644:Genetic Variation / Q000187:drug effects* / Q000235:genetics*; D005838:Genotype; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics*; D006526:Hepatitis C / Q000188:drug therapy; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation / Q000187:drug effects / Q000235:genetics; D009842:Oligopeptides / Q000494:pharmacology; D010641:Phenotype; D012093:Replicon / Q000187:drug effects / Q000235:genetics; D013876:Thiophenes / Q000494:pharmacology*; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D014779:Virus Replication / Q000187:drug effects / Q000235:genetics; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D003511:Cyclohexanols; D009842:Oligopeptides; D013876:Thiophenes; D017361:Viral Nonstructural Proteins; C000592793:lomibuvir; C486464:telaprevir; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase