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

Anna S. Lok, Mark S. Sulkowski, Jens J. Kort, Ira Willner, K. Rajender Reddy, Mitchell L. Shiffman, Mohamed A. Hassan, Brian L. Pearlman, Federico Hinestrosa, Ira M. Jacobson, Giuseppe Morelli, Joy A. Peter, Monika Vainorius, Larry C. Michael, Michael W. Fried, Gary P. Wang, Wenjing Lu, Lois Larsen, David R. Nelson

Research output: Contribution to journalArticle

9 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1506-1517.e1
JournalGastroenterology
Volume157
Issue number6
DOIs
StatePublished - Dec 2019

Keywords

  • Compensated Cirrhosis
  • DAA Experienced
  • Drug Resistance Variant
  • Protease Inhibitor

PubMed: MeSH publication types

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

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    Lok, A. S., Sulkowski, M. S., Kort, J. J., Willner, I., Reddy, K. R., Shiffman, M. L., Hassan, M. A., Pearlman, B. L., Hinestrosa, F., Jacobson, I. M., Morelli, G., Peter, J. A., Vainorius, M., Michael, L. C., Fried, M. W., Wang, G. P., Lu, W., Larsen, L., & Nelson, D. R. (2019). Efficacy of Glecaprevir and Pibrentasvir in Patients With Genotype 1 Hepatitis C Virus Infection With Treatment Failure After NS5A Inhibitor Plus Sofosbuvir Therapy. Gastroenterology, 157(6), 1506-1517.e1. https://doi.org/10.1053/j.gastro.2019.08.008