Resistance analysis of genotype 3 HCV indicates subtypes inherently resistant to NS5A inhibitors

Abstract

Background and aims: HCV genotype-3 (gt3) is highly prevalent globally, with non-gt3a subtypes common in Southeast Asia. Resistance-associated substitutions (RASs) have been shown to play a role in treatment failure. However, the role of RASs in gt3 is not well understood. We report the prevalence of RASs in a cohort of directly acting antivirals (DAA) treatment-naïve gt3 infected patients, including those with rarer subtypes and evaluate the effect of these RAS on DAAs in-vitro.

Methods: Baseline samples from 496 gt3 patients enrolled in the BOSON clinical trial were analysed by next-generation sequencing after probe-based enrichment for HCV. Whole viral genomes were analysed for the presence of RASs to approved DAAs. The resistance phenotype of RASs in combination to daclatasvir, velpatasvir, pibrentasvir, elbasvir and sofosbuvir was measured using the S52 ΔN gt3a replicon model.

Results: The NS5A A30K and Y93H substitutions were the most common at 8.8% (n=44) and 12.2% (n=61) respectively and showed a 10-fold and 11-fold increase in EC₅₀ for daclatasvir compared to the unmodified replicon. Paired RASs (A30K + L31M and A30K + Y93H) were identified in 18 patients (9 of each pair); these combinations were shown to be highly resistant to daclatasvir, velpatasvir, elbasvir and pibrentasvir. The A30K + L31M combination was found in all gt3b and gt3g samples.

Conclusion: Our study reveals high frequencies of RASs to NS5A Inhibitors in gt3 HCV. The paired A30K + L31M substitutions occur in all patients with gt3b and gt3g virus. In vitro analysis suggests that these subtypes may be inherently resistant to all approved NS5A Inhibitors for gt3 HCV. This article is protected by copyright. All rights reserved.

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