In Vitro Antiviral Activity and Resistance Profile of the Next-Generation Hepatitis C Virus NS3/4A Protease Inhibitor Glecaprevir

Abstract

Glecaprevir (formerly ABT-493) is a novel hepatitis C virus (HCV) NS3/4A protease inhibitor (PI) with pangenotypic activity. It inhibited the enzymatic activity of purified NS3/4A proteases from HCV genotypes 1 to 6 in vitro (half-maximal [50%] inhibitory concentration = 3.5 to 11.3 nM) and the replication of stable HCV subgenomic replicons containing proteases from genotypes 1 to 6 (50% effective concentration [EC50] = 0.21 to 4.6 nM). Glecaprevir had a median EC50 of 0.30 nM (range, 0.05 to 3.8 nM) for HCV replicons containing proteases from 40 samples from patients infected with HCV genotypes 1 to 5. Importantly, glecaprevir was active against the protease from genotype 3, the most-difficult-to-treat HCV genotype, in both enzymatic and replicon assays demonstrating comparable activity against the other HCV genotypes. In drug-resistant colony selection studies, glecaprevir generally selected substitutions at NS3 amino acid position A156 in replicons containing proteases from genotypes 1a, 1b, 2a, 2b, 3a, and 4a and substitutions at position D/Q168 in replicons containing proteases from genotypes 3a, 5a, and 6a. Although the substitutions A156T and A156V in NS3 of genotype 1 reduced susceptibility to glecaprevir, replicons with these substitutions demonstrated a low replication efficiency in vitro. Glecaprevir is active against HCV with most of the common NS3 amino acid substitutions that are associated with reduced susceptibility to other currently approved HCV PIs, including those at positions 155 and 168. Combination of glecaprevir with HCV inhibitors with other mechanisms of action resulted in additive or synergistic antiviral activity. In summary, glecaprevir is a next-generation HCV PI with potent pangenotypic activity and a high barrier to the development of resistance.

Evolutionary Pathways to Persistence of Highly Fit and Resistant Hepatitis C Virus Protease Inhibitor Escape Variants

“…This suggested that NS3P position 156 is the only position mediating major resistance to these PIs. In accordance with our findings, Ng et al reported that A156T selected under glecaprevir in the 1a(H77) subgenomic replicon resulted in high resistance and severe reduction in replication efficacy . However, fitness‐compensating substitutions were not identified and effects on viral assembly, as described in our study, cannot be studied in replicons.…”

Advanced liver fibrosis effects on the response to sofosbuvir‐based antiviral therapies for chronic hepatitis C

“…Among these 67 patients with DAA treatment history, 58 (86.6%) were able to achieve SVR. The recently approved combination of glecaprevir, an NS3/4A inhibitor, and pibrentasvir, an NS5A inhibitor, have different resistance profiles than previous DAAs . Therefore, the combination of these drugs resulted in a high SVR rate for patients with prior DAA treatment failure in a phase 3 clinical trial conducted in Japan .…”

HCV genotype 4, 5 and 6: Distribution of viral subtypes and sustained virologic response rates in clinical trials of approved direct‐acting antiviral regimens

“…Cell culture studies demonstrated antiviral activity of each drug component against each approved GT, with data generally demonstrating consistent activity across several representative subtypes of GT 4 and 6. Although it is not feasible to capture all of the genetic diversity of GT 4 and 6 subtypes in cell culture studies and clinical trials, antiviral activity generally has been demonstrated, at minimum, across the most common representative subtypes of GT 4 and 6…”