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Cell culture studies of the efficacy and barrier to resistance of sofosbuvir/velpatasvir and glecaprevir/pibrentasvir against hepatitis C virus genotypes 2a, 2b and 2c

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Introduction of highly efficient therapies with direct-acting antivirals (DAA) for patients with chronic hepatitis C virus (HCV) infection offers exceptional opportunities to globally control this deadly disease. For achieving this ambitious goal, it is essential to prevent antiviral resistance against the most optimal first-line and retreatment DAA choices. We performed independent comparisons of the efficacy and barrier to resistance of pangenotypic DAA regimens for HCV genotype 2 infections, using previously, and newly developed efficient cell culture adapted strains of subtypes 2a, 2b and 2c. With applied experimental cell culture conditions, combination treatment with sofosbuvir/velpatasvir or glecaprevir/pibrentasvir DAA-regimens was efficient in eradicating HCV infections, in contrast to single drug treatments frequently leading to viral escape. Sequence analysis of drug targets from recovered viruses revealed known resistance associated substitutions (RAS) emerging in the NS3 protease or NS5A after treatment failure, which were genetically stable after viral passage and exhibited significant phenotypic resistance. After sofosbuvir treatment failure, only a genotype 2a virus harbored NS5B-RAS S282T and thus had decreased susceptibility to nucleotide analogs (nucs). However, in most cases viral escape from sofosbuvir led to other NS5B substitutions with maintained drug susceptibility, and in one case no changes in NS5B were detected. For a genotype 2b virus, after treatment failure with sofosbuvir/velpatasvir, retreatment with glecaprevir/pibrentasvir maintained efficacy due to the high barrier to resistance and low cross-resistance of pibrentasvir. Our findings suggest slight superiority of glecaprevir/pibrentasvir for genotype 2b in culture, which could have potential therapeutic interest meriting more definitive investigations in the clinic.

Original languageEnglish
JournalAntimicrobial Agents and Chemotherapy
Volume64
Issue number3
ISSN0066-4804
DOIs
Publication statusPublished - 21 Feb 2020

ID: 58597351