Resistance analysis of a 3-day monotherapy study with glecaprevir or pibrentasvir in patients with chronic hepatitis C virus genotype 1 infection

Teresa I. Ng, Tami Pilot-Matias, Rakesh Tripathi, Gretja Schnell, Preethi Krishnan, Thomas Reisch, Jill Beyer, Tatyana Dekhtyar, Michelle Irvin, Liangjun Lu, Armen Asatryan, Andrew Campbell, Betty Yao, Sandra Lovell, Federico Mensa, Eric J. Lawitz, Jens Kort, Christine Collins

Research output: Contribution to journalArticle

1 Scopus citations

Abstract

Glecaprevir (an NS3/4A protease inhibitor) and pibrentasvir (an NS5A inhibitor) are potent and pangenotypic hepatitis C virus (HCV) direct-acting antivirals. This report describes the baseline polymorphisms and treatment-emergent substitutions in NS3 or NS5A detected in samples from HCV genotype 1-infected patients receiving 3-day monotherapy of glecaprevir or pibrentasvir, respectively. None of the NS3 polymorphisms detected in the 47 baseline samples collected prior to glecaprevir monotherapy conferred reduced susceptibility to glecaprevir. The NS3 A156T substitution, which conferred resistance to glecaprevir but had low replication efficiency, emerged in one genotype 1a-infected patient among the 35 patients with available post-baseline sequence data. Baseline NS5A polymorphisms were detected in 12 of 40 patients prior to pibrentasvir monotherapy; most polymorphisms were single-position NS5A amino acid substitutions that did not confer resistance to pibrentasvir. Among the 19 patients with available post-baseline NS5A sequence data, 3 had treatment-emergent NS5A substitutions during pibrentasvir monotherapy. All treatment-emergent NS5A substitutions were linked multiple-position, almost exclusively double-position, substitutions that conferred resistance to pibrentasvir. Replicons engineered with these double-position substitutions had low replication efficiency. In conclusion, resistance-conferring substitutions emerged in a small number of genotype 1-infected patients during glecaprevir or pibrentasvir monotherapy; unlike other NS5A inhibitors, pibrentasvir did not select single-position NS5A substitutions during monotherapy.

Original languageEnglish (US)
Article number462
JournalViruses
Volume10
Issue number9
DOIs
StatePublished - Sep 2018

Keywords

  • ABT-493
  • ABT-530
  • Glecaprevir
  • HCV
  • Monotherapy
  • Pibrentasvir
  • Resistance

ASJC Scopus subject areas

  • Infectious Diseases
  • Virology

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