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

• Published in: Journal of hepatology Vol. 75; no. 4; pp. 820 - 828
• Main Authors: Wang, Gary P., Schnell, Gretja L., Kort, Jens J., Sidhu, Gurjit S., Schuster, Layla, Tripathi, Rakesh L., Larsen, Lois, Michael, Larry C., Bergquist, Ken, Magee, Ashley, Patel, Chandni B., Whitlock, Joan A., Tamashiro, Ryan, Peter, Joy A., Fried, Michael W., Nelson, David R.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.10.2021; Elsevier Science Ltd
• Subjects: Adult; Antiviral agents; Antiviral Agents - administration & dosage; Antiviral Agents - metabolism; Benzimidazoles - pharmacology; Benzimidazoles - therapeutic use; Chronic infection; Cirrhosis; Drug Combinations; Drug Resistance - immunology; Female; Genotypes; Glecaprevir/Pibrentasvir; Hepatitis C; Hepatitis C - drug therapy; Hepatitis C - epidemiology; Hepatitis C - physiopathology; Hepatitis C therapy; Humans; Liver cirrhosis; Longitudinal Studies; Male; Middle Aged; Multiple-linked substitutions; Mutation; Next-generation sequencing; NS5A resistance; Patients; Persistence of treatment-emergent substitutions; Pyrrolidines - pharmacology; Pyrrolidines - therapeutic use; Quinoxalines - administration & dosage; Quinoxalines - pharmacology; Quinoxalines - therapeutic use; Resistance-associated substitutions; Ribavirin; RNA-Dependent RNA Polymerase - antagonists & inhibitors; RNA-Dependent RNA Polymerase - pharmacology; Sofosbuvir - administration & dosage; Sofosbuvir - metabolism; Sulfonamides - pharmacology; Sulfonamides - therapeutic use; Treatment failure; Treatment-emergent RASs; United States - epidemiology; Viral Nonstructural Proteins - antagonists & inhibitors; Viral Nonstructural Proteins - pharmacology; United States; Next-generation sequencing; NS5A resistance; Glecaprevir/Pibrentasvir; Treatment-emergent RASs; Treatment failure; Persistence of treatment-emergent substitutions; Resistance-associated substitutions; Multiple-linked substitutions; Hepatitis C therapy
• ISSN: 0168-8278; 1600-0641
• DOI: 10.1016/j.jhep.2021.04.057

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. 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. 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. 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. 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. NCT03092375. [Display omitted] •Primer-ID NGS tracked multiply linked NS5A RASs in GT1 failures re-treated with G/P.•Decreasing SVR12 rates with double- or triple-linked NS5A RASs.•No single GT1a NS5A RAS or NS3 RAS was associated with a reduced SVR12.•Among 13 failures, 4 had treatment-emergent NS3 RASs; 10 had additional NS5A RASs.•85% of GT1a with double- or triple-linked NS5A RASs achieved SVR12 with 16 weeks G/P.