Virology analyses of HCV isolates from genotype 1-infected patients treated with simeprevir plus peginterferon/ribavirin in Phase IIb/III studies

J Hepatol. 2015 May;62(5):1008-14. doi: 10.1016/j.jhep.2014.11.032. Epub 2014 Nov 28.

Abstract

Background & aims: Simeprevir is an oral hepatitis C virus (HCV) NS3/4A protease inhibitor approved for treatment of chronic HCV infection. Baseline NS3 polymorphisms in all patients and emerging mutations in patients who failed to achieve sustained virologic response (SVR) with simeprevir plus peginterferon/ribavirin (PR) in Phase IIb/III studies are described.

Methods: Baseline sequencing data were available for 2007 genotype 1 (GT1)-infected patients. Post-baseline data were available for 197/245 simeprevir-treated patients who did not achieve SVR. In vitro simeprevir susceptibility was assessed in a transient replicon assay as site-directed mutants or in chimeric replicons with patient-derived NS3 protease sequences.

Results: Baseline NS3 polymorphisms at positions associated with reduced in vitro susceptibility to simeprevir (43, 80, 122, 155, 156, and/or 168; EC50 fold change >2.0) were uncommon (1.3% [26/2007]), with the exception of Q80K, which confers ∼10-fold reduction in simeprevir activity in vitro (13.7% [274/2007]; GT1a 29.5% [269/911], GT1b 0.5% [5/1096]). Baseline Q80K had minor effect on initial response to simeprevir/PR, but resulted in lower SVR rates. Overall, 91.4% of simeprevir-treated patients [180/197] without SVR had emerging mutations at NS3 positions 80, 122, 155, and/or 168 at failure (mainly R155K in GT1a with and without Q80K, and D168V in GT1b), conferring high-level resistance in vitro (EC50 fold change >50). Emerging mutations were no longer detectable by population sequencing at study end in 50% [90/180] of patients (median follow-up 28.4weeks).

Conclusions: Simeprevir treatment failure was usually associated with emerging high-level resistance mutations, which became undetectable over time in half of the patients.

Trial registration: ClinicalTrials.gov NCT00882908 NCT00980330 NCT01281839 NCT01289782 NCT01290679.

Keywords: Genotype 1; HCV NS3/4A protease inhibitor; Hepatitis C virus; Once-daily; Peginterferon; Polymorphism; Q80K; Ribavirin; Simeprevir.

Publication types

  • Clinical Trial, Phase II
  • Clinical Trial, Phase III
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antiviral Agents / pharmacology
  • Double-Blind Method
  • Drug Resistance, Viral / genetics
  • Drug Therapy, Combination / methods
  • Female
  • Hepacivirus* / drug effects
  • Hepacivirus* / genetics
  • Hepatitis C, Chronic* / drug therapy
  • Hepatitis C, Chronic* / virology
  • Humans
  • Interferon-alpha / pharmacology*
  • Male
  • Middle Aged
  • Polyethylene Glycols / pharmacology*
  • Polymorphism, Genetic
  • Recombinant Proteins / pharmacology
  • Ribavirin / pharmacology*
  • Simeprevir / pharmacology*
  • Time Factors
  • Treatment Failure
  • Viral Nonstructural Proteins* / antagonists & inhibitors
  • Viral Nonstructural Proteins* / genetics

Substances

  • Antiviral Agents
  • Interferon-alpha
  • NS3 protein, hepatitis C virus
  • Recombinant Proteins
  • Viral Nonstructural Proteins
  • Polyethylene Glycols
  • Ribavirin
  • Simeprevir
  • peginterferon alfa-2a

Associated data

  • ClinicalTrials.gov/NCT00882908
  • ClinicalTrials.gov/NCT00980330
  • ClinicalTrials.gov/NCT01281839
  • ClinicalTrials.gov/NCT01289782
  • ClinicalTrials.gov/NCT01290679