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Abstract Details
Linkage of resistance-associated substitutions in GT1 sofosbuvir+NS5A inhibitor failures treated with glecaprevir/pibrentasvir
J Hepatol. 2021 May 20;S0168-8278(21)00339-1. doi: 10.1016/j.jhep.2021.04.057.Online ahead of print.
Gary P Wang1, Gretja L Schnell2, Jens J Kort3, Gurjit S Sidhu4, Layla Schuster4, Rakesh L Tripathi2, Lois Larsen2, Larry C Michael5, Ken Bergquist5, Ashley Magee5, Chandni B Patel4, Joan A Whitlock4, Ryan Tamashiro4, Joy A Peter6, Michael W Fried7, David R Nelson8
Author information
1Division of Infectious Diseases and Global Medicine, Department of Medicine, University of Florida, Gainesville, FL, USA; Infectious Disease Section, Medical Service, North Florida/South Georgia Veterans Health System, Gainesville, FL, USA. Electronic address: gary.wang@medicine.ufl.edu.
2AbbVie Inc, North Chicago, IL, USA.
3AbbVie Inc, Mettawa, IL, USA.
4Division of Infectious Diseases and Global Medicine, Department of Medicine, University of Florida, Gainesville, FL, USA.
5HCV-Target Data Coordinating Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
6Hepatology Research, University of Florida, Gainesville, FL, USA.
7Division of Gastroenterology and Hepatology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
8Department of Medicine, University of Florida, Gainesville, FL, USA.
Abstract
Background/aims: Re-treatment with glecaprevir/pibrentasvir (G/P) resulted in >90% SVR12 rate 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 3 b, 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 15% cutoff.
Results: 169 of 177 (95.5%) patients were PI-naïve. All 33 GT1b 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 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. Re-treatment 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. Here, 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 #: NCT03092375.