Linkage of resistance-associated substitutions in GT1 sofosbuvir + NS5A inhibitor failures treated with glecaprevir/pibrentasvir

Abstract

Background & aims: Retreatment with glecaprevir/pibrentasvir (G/P) resulted in a rate of sustained virologic response 12 weeks after treatment completion (SVR12) of >90% in HCV genotype 1 (GT1) patients who previously failed a regimen of sofosbuvir plus an NS5A inhibitor (NS5Ai). This study investigated the prevalence and impact of baseline NS3 and NS5A resistance-associated substitutions (RASs) on the efficacy of G/P in prior GT1 sofosbuvir+NS5Ai failures and the persistence of treatment-emergent RASs.

Methods: Longitudinal samples from 177 patients enrolled in a phase IIIb, randomized pragmatic clinical trial were analyzed. Patients without cirrhosis were randomized to 12 or 16 weeks of G/P, and patients with compensated cirrhosis were randomized to G/P and ribavirin for 12 weeks or G/P for 16 weeks. Linkage of RAS was identified using Primer-ID next-generation sequencing at a 15% cut-off.

Results: Of 177 patients, 169 (95.5%) were PI-naïve. All 33 GT1b-infected patients achieved SVR12. In GT1a-infected patients, baseline NS5A RASs were prevalent (74.5%, 105/141) but NS3 RASs were uncommon. Baseline NS3 RASs had no impact on G/P efficacy and patients with baseline NS5A RASs showed a numerically but not statistically significantly lower SVR12 rate compared to those without NS5A RASs (89% vs. 97%). SVR12 was achieved in 34 of 35 (97%) patients without NS5A baseline substitution, and 53 of 57 (93%), 35 of 40 (88%), 5 of 8 (63%) with single, double-linked, and triple-linked NS5A substitutions, respectively. Among 13 patients with virologic failure, 4 acquired treatment-emergent NS3 RASs and 10 acquired NS5A RASs.

Conclusion: Baseline NS5A RASs were highly prevalent. The presence of an increasing number of linked NS5A RASs in GT1a showed a trend in decreasing SVR12 rates, although no specific NS5A RASs or their linkage pattern were associated with lower SVR12 rates.

Lay summary: Direct-acting antivirals have revolutionized the treatment of chronic hepatitis C infection, but treatment failure occurs in some patients. Retreatment of patients who previously failed a regimen consisting of sofosbuvir and an NS5A inhibitor with a regimen of glecaprevir and pibrentasvir (G/P) is >90% effective. Herein, we analyzed samples from these patients and showed that retreatment efficacy with G/P is lower in patients with double- or triple-linked NS5A resistance mutations than in patients with single or no NS5A resistance mutations.

Clinical trial number: NCT03092375.

Keywords: Glecaprevir/Pibrentasvir; Hepatitis C therapy; Multiple-linked substitutions; NS5A resistance; Next-generation sequencing; Persistence of treatment-emergent substitutions; Resistance-associated substitutions; Treatment failure; Treatment-emergent RASs.

Conflict of interest statement

Conflict of interest Gary Wang: Has a patent issued. Gretja Schnell: Personal fees from AbbVie, during the conduct of the study; Personal Fees and other from AbbVie, outside the submitted work. Jens Kort: Personal fees from AbbVie; Personal fees and other from AbbVie, outside the submitted work; has a patent issued. Gurjit Sidhu: Nothing to disclose. Layla Schuster: Nothing to disclose. Rakesh Tripathi: Personal fees and other from AbbVie, outside the submitted work. Lois Larsen: Personal fees from AbbVie, during the conduct of the study; Personal Fees and other from AbbVie, outside the submitted work. Larry Michael: Nothing to disclose. Ken Bergquist: Nothing to disclose. Ashley Magee: Nothing to disclose. Chandni Patel: Nothing to disclose. Joan Whitlock: Nothing to disclose. Joy Peter: Domestic Partner is an AbbVie Stockholder. Michael Fried: Grants from AbbVie, Bristol-Myers Squibb, Merck, and Gilead; Personal Fees from AbbVie, Bristol-Myers Squibb, Merck, Roche; Personal fees and other from TARGET PharmaSolutions, outside the submitted work. David Nelson: Grants from AbbVie, Gilead and Merck during the conduct of the study; Stockholder of TARGET PharmaSolutions, outside the submitted work. Please refer to the accompanying ICMJE disclosure forms for further details.

Published by Elsevier B.V.