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 journalArticlepeer-review

14 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

Bibliographical note

Funding Information:
Author contributions: Study concept and design: JJK, LL, JAP, DRN, MSS, IMJ, MWF. Acquisition of data: ASL, MSS, IW, KRR, MLS, MAH, BLP, FH, IMJ, GM, GPW. Analysis and interpretation of data: ASL, JJK, LL, JAP, GPW, DRN, MSS, LCM, IMJ, MV, MWF, WL. Drafting of manuscript: ASL. Critical revision of manuscript: JJK, JAP, GPW, DRN, MSS, LCM, KRR, IMJ, MWF, BLP, FH, MV, LCM, WL. Conflicts of interest These authors disclose the following: Anna S. Lok receives research support from Bristol-Myers Squibb, Gilead, and TARGET PharmaSolutions (paid to University of Michigan), and serves on advisory panel for Gilead and TARGET PharmaSolutions. Mark S. Sulkowski receives research support from AbbVie, AssemblyBio, Gilead, Proteus Digital Health (paid to Johns Hopkins University) and is a consultant for AbbVie and Gilead. K. Rajender Reddy is an ad-hoc advisor to AbbVie, Gilead, Merck, Shionogi, Dova, and Spark Therapeutics. He receives research support (paid to the University of Pennsylvania) from AbbVie, Gilead, Merck, Mallinckrodt, Conatus, Intercept, Exact Sciences, HCV-TARGET, NASH-TARGET, and HCC-TARGET. Mitchell L. Shiffman receives research support from AbbVie, BMS, Conatus, CymaBay, Exalenz, Galectin, Genfit, Gilead, Intercept, Immuron, Merck, NGMBio, Novartis, and Shire. He is a consultant for Optum Rx, gives sponsored lectures for AbbVie, BMS, Gilead, Intercept, and Merck and provides expert testimony/advisory board member for AbbVie, BMS, Gilead, Intercept, and Merck. Brian L. Pearlman receives grant/research support from AbbVie, Gilead, and Merck and gives sponsored lectures for AbbVie, Gilead, and Merck. Federico Hinestrosa receives grant/research support from AbbVie, Gilead, BMS, and Jansen. He gives sponsored lectures for AbbVie, Gilead, and Janssen and also provides expert testimony/advisory board member for Gilead. Ira M. Jacobson receives research support from Assembly, BMS, Enanta, Genfit, Gilead, Intercept, Janssen, and Merck. He is a consultant for AbbVie, BMS, Gilead, Janssen, Merck, Novo Nordisk, Siemens, and Springbank. GM receives research support from AbbVie, BMS, Gilead, Janssen, Merck, Conatus, and Salix. Michael W. Fried receives research grants paid to institution from AbbVie, BMS, Gilead, Merck, and NIH. He is an unpaid consultant to AbbVie, BMS, Merck, and TARGET PharmaSolutions. He also owns stock in TARGET PharmaSolutions, which is held in an independently managed trust. David R. Nelson receives research support from AbbVie, BMS, Gilead, and Merck and is a stockholder in TARGET PharmaSolutions. Jens J. Kort, Wenjing Lu, and Lois Larsen are AbbVie employees and may hold AbbVie stock. Joy A. Peter's domestic partner is an AbbVie employee who holds AbbVie stock. The remaining authors disclose no conflicts. Funding This study is a collaboration between AbbVie and the University of Florida. AbbVie provided funding and the study drug.

Publisher Copyright:
© 2019 AGA Institute

Keywords

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

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