Virology analysis in HCV genotype 1-infected patients treated with the combination of simeprevir and TMC647055/ritonavir, with and without ribavirin, and JNJ-56914845

Virol J. 2017 May 31;14(1):101. doi: 10.1186/s12985-017-0760-2.

Abstract

Background: In study TMC647055HPC2001, a 3-direct-acting-antiviral (DAA) regimen combining NS3/4A protease inhibitor simeprevir (SMV), non-nucleoside NS5B inhibitor TMC647055/ritonavir (RTV) and NS5A inhibitor JNJ-56914845 resulted in high sustained virologic response 12 weeks after actual end of treatment (SVR12) in chronic hepatitis C virus (HCV) genotype 1-infected patients. SVR12 rates were generally lower in the 2-DAA regimen SMV + TMC647055/RTV with or without ribavirin. The objective of this study was to identify and characterise pre-existing and emerging resistance-associated variants (RAVs) in patients enrolled in study TMC647055HPC2001.

Methods: HCV population sequencing analyses were performed on baseline isolates from all patients (n = 90) and post-baseline isolates from patients with virologic failure (n = 22). In addition, deep sequencing and phenotypic analyses were performed on selected baseline and post-baseline isolates.

Results: The majority of patients with virologic failure had emerging RAVs to all study drugs at the time of failure: in all 22 patients SMV RAVs emerged at NS3 positions 80, 155, 156 and/or 168, consistent with the known SMV resistance profile. Emerging TMC647055 RAVs at NS5B position 495 were detected in the majority of patients (16/22), and all 5 patients who failed the 3-DAA regimen had emerging JNJ-56914845 RAVs at NS5A positions 30 and/or 31. While at the end of study emerging SMV and TMC647055 RAVs were no longer observed by population sequencing in 40% (8/20) and 62.5% (10/16) of patients with follow-up data available, respectively, emerging JNJ-56914845 RAVs were still detected in all (5/5) patients.

Conclusions: Virologic failure in the 2- and 3-DAA combinations was, in the majority of patients, associated with the emergence of RAVs to all study drugs. While emerging SMV and TMC647055 RAVs became undetectable during follow-up, JNJ-56914845 RAVs in NS5A were still observed at end of study.

Trial registration number: NCT01724086 (date of registration: September 26, 2012).

Keywords: Genotype 1; Hepatitis C virus; JNJ-56914845; Simeprevir; TMC647055/ritonavir.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antiviral Agents / therapeutic use*
  • Carbamates / therapeutic use
  • Drug Resistance, Viral
  • Genotype*
  • Genotyping Techniques
  • Hepacivirus / classification
  • Hepacivirus / genetics
  • Hepacivirus / isolation & purification*
  • Hepatitis C, Chronic / drug therapy*
  • Hepatitis C, Chronic / virology
  • Heterocyclic Compounds, 4 or More Rings / therapeutic use*
  • Humans
  • Ribavirin / therapeutic use
  • Ritonavir / therapeutic use*
  • Sequence Analysis, DNA
  • Simeprevir / therapeutic use*
  • Sulfonamides / therapeutic use*
  • Treatment Failure
  • Valine / analogs & derivatives
  • Valine / therapeutic use

Substances

  • 27-cyclohexyl-12,13,16,17-tetrahydro-22-methoxy-11,17-dimethyl-10,10-dioxide-2,19-methano-3,7:4,1-dimetheno-1H,11H-14,10,2,9,11,17-benzoxathiatetraazacyclo docosine-8,18(9H,15H)-dione
  • Antiviral Agents
  • Carbamates
  • GSK2336805
  • Heterocyclic Compounds, 4 or More Rings
  • Sulfonamides
  • Ribavirin
  • Simeprevir
  • Valine
  • Ritonavir

Associated data

  • ClinicalTrials.gov/NCT01724086