Efficacy of Glecaprevir and Pibrentasvir in Patients With Genotype 1 Hepatitis C Virus Infection With Treatment Failure After NS5A Inhibitor Plus Sofosbuvir Therapy

Gastroenterology. 2019 Dec;157(6):1506-1517.e1. doi: 10.1053/j.gastro.2019.08.008. Epub 2019 Aug 8.

Abstract

Background & aims: Treatment options are limited for patients with hepatitis C (HCV) infection with treatment failure after sofosbuvir plus an NS5A inhibitor. There are some data for the efficacy of glecaprevir/pibrentasvir (G/P) in these patients. We performed a randomized trial of the safety and efficacy of 12 and 16 weeks of G/P, with or without ribavirin, in patients with HCV genotype 1 infection with treatment failure after sofosbuvir and an NS5A inhibitor.

Methods: We performed a phase 3b, open-label study of patients with chronic HCV genotype 1 infection who received previous treatment with sofosbuvir plus an NS5A inhibitor. Patients without cirrhosis were randomly assigned to groups that received G/P for 12 weeks (n = 78, group A) or 16 weeks (n = 49, group B). Patients with compensated cirrhosis were randomly assigned to groups that received G/P and ribavirin for 12 weeks (n = 21, group C) or G/P for 16 weeks (n = 29, group D). The primary end point was a sustained virologic response 12 weeks after treatment. Samples collected at baseline and at time of treatment failure were sequenced for resistance-associated substitutions in NS3 and NS5A.

Results: Of the 177 patients in the 4 groups, 81% were men, 79% had HCV genotype 1a infection, and 44% were black. Proportions of patients with sustained virologic response 12 weeks after treatment in groups A, B, C, and D were 90%, 94%, 86%, and 97%, respectively. The treatment failed in 13 (7.3%) patients with HCV genotype 1a infection, 6 (7.9%) in group A, 3 (6.1%) in group B, 3 (6.1%) in group C (6.1%), and 1 (3.4%) in group D. Most patients had baseline resistance-associated substitutions in NS5A. Treatment-emergent resistance-associated substitutions in NS3 and NS5A were observed in 9 and 10 patients with treatment failure, respectively. G/P was well tolerated. Ribavirin increased adverse events but did not increase efficacy.

Conclusions: In a randomized study of patients with chronic HCV genotype 1 infection who received previous treatment with sofosbuvir plus an NS5A inhibitor, 16 weeks treatment with G/P produced sustained virologic response 12 weeks after treatment in >90% of patients, including those with compensated cirrhosis. ClinicalTrials.gov, Number: NCT03092375.

Keywords: Compensated Cirrhosis; DAA Experienced; Drug Resistance Variant; Protease Inhibitor.

Publication types

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

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antiviral Agents / pharmacology
  • Antiviral Agents / therapeutic use*
  • Benzimidazoles / pharmacology
  • Benzimidazoles / therapeutic use
  • Drug Combinations
  • Drug Resistance, Multiple, Viral / genetics
  • Drug Therapy, Combination
  • Female
  • Genotype
  • Hepacivirus / genetics*
  • Hepacivirus / isolation & purification
  • Hepatitis C, Chronic / drug therapy*
  • Hepatitis C, Chronic / virology
  • Humans
  • Male
  • Middle Aged
  • Pyrrolidines / pharmacology
  • Pyrrolidines / therapeutic use
  • Quinoxalines / pharmacology
  • Quinoxalines / therapeutic use
  • Ribavirin / pharmacology
  • Ribavirin / therapeutic use
  • Sofosbuvir / pharmacology
  • Sofosbuvir / therapeutic use
  • Sulfonamides / pharmacology
  • Sulfonamides / therapeutic use
  • Sustained Virologic Response
  • Treatment Failure
  • Viral Nonstructural Proteins / antagonists & inhibitors
  • Viral Nonstructural Proteins / genetics

Substances

  • Antiviral Agents
  • Benzimidazoles
  • Drug Combinations
  • NS-5 protein, hepatitis C virus
  • NS3 protein, hepatitis C virus
  • Pyrrolidines
  • Quinoxalines
  • Sulfonamides
  • Viral Nonstructural Proteins
  • glecaprevir and pibrentasvir
  • Ribavirin
  • Sofosbuvir

Associated data

  • ClinicalTrials.gov/NCT03092375