Abstract
Glecaprevir (an NS3/4A protease inhibitor) and pibrentasvir (an NS5A inhibitor) are potent and pangenotypic hepatitis C virus (HCV) direct-acting antivirals. This report describes the baseline polymorphisms and treatment-emergent substitutions in NS3 or NS5A detected in samples from HCV genotype 1-infected patients receiving 3-day monotherapy of glecaprevir or pibrentasvir, respectively. None of the NS3 polymorphisms detected in the 47 baseline samples collected prior to glecaprevir monotherapy conferred reduced susceptibility to glecaprevir. The NS3 A156T substitution, which conferred resistance to glecaprevir but had low replication efficiency, emerged in one genotype 1a-infected patient among the 35 patients with available post-baseline sequence data. Baseline NS5A polymorphisms were detected in 12 of 40 patients prior to pibrentasvir monotherapy; most polymorphisms were single-position NS5A amino acid substitutions that did not confer resistance to pibrentasvir. Among the 19 patients with available post-baseline NS5A sequence data, 3 had treatment-emergent NS5A substitutions during pibrentasvir monotherapy. All treatment-emergent NS5A substitutions were linked multiple-position, almost exclusively double-position, substitutions that conferred resistance to pibrentasvir. Replicons engineered with these double-position substitutions had low replication efficiency. In conclusion, resistance-conferring substitutions emerged in a small number of genotype 1-infected patients during glecaprevir or pibrentasvir monotherapy; unlike other NS5A inhibitors, pibrentasvir did not select single-position NS5A substitutions during monotherapy.
Highlights
Hepatitis C virus (HCV) infection is a major public health problem, with a recent report estimating that approximately 70 million individuals are chronically infected with hepatitis C virus (HCV) worldwide [1]
Forty out of 47 (85%) and 33 out of 40 (83%) patients in the glecaprevir and pibrentasvir monotherapy studies, respectively, were infected with HCV genotype 1a; the rest of the patients were infected with HCV genotype 1b
Resistance analysis was conducted on all baseline and post-baseline samples with sufficient viral titer from genotype 1-infected patients who received 3 days of glecaprevir or pibrentasvir monotherapy
Summary
Hepatitis C virus (HCV) infection is a major public health problem, with a recent report estimating that approximately 70 million individuals are chronically infected with HCV worldwide [1]. Newer DAA combinations are highly efficacious in many HCV-infected populations, a number of them are not effective for all HCV genotypes [8,9,10,11]; some of them have reduced activity against certain baseline resistance-associated polymorphisms [12,13,14,15], and DAA resistance-conferring substitutions often emerge in patients who experience virologic failure [11,16,17,18]. This report describes the prevalence of baseline polymorphisms and treatment-emergent substitutions in NS3 or NS5A in samples from patients who received 3-day monotherapy of either glecaprevir or pibrentasvir, respectively. The changes in susceptibility conferred by these baseline polymorphisms and treatment-emergent substitutions in NS3 or NS5A to glecaprevir or pibrentasvir, respectively, were determined
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