Global evolutionary analysis of chronic hepatitis C patients revealed significant effect of baseline viral resistance, including novel non‐target sites, for DAA‐based treatment and retreatment outcome

Abstract

Direct-acting antivirals (DAAs) have proven highly effective against chronic hepatitis C virus (HCV) infection. However, some patients experience treatment failure, associated with resistance-associated substitutions (RASs). Our aim was to investigate the complete viral coding sequence in hepatitis C patients treated with DAAs to identify RASs and the effects of treatment on the viral population. We selected 22 HCV patients with sustained virologic response (SVR) to match 21 treatment-failure patients in relation to HCV genotype, DAA regimen, liver cirrhosis and previous treatment experience. Viral-titre data were compared between the two patient groups, and HCV | 303 FAHNØE Et Al.

Inferior cure rate in pilot study of 4‐week glecaprevir/pibrentasvir treatment with or without ribavirin of chronic hepatitis C

“…This suggests that NS5A RAS could be a concern for short‐term treatment, but testing for baseline RAS will not be a realistic option in a clinical setting. The most important baseline RAS associated with treatment failures are located in NS5A domain I 18 . These also affected RNA titer decline and quasi‐species composition after the end of treatment.…”

“…The most important baseline RAS associated with treatment failures are located in NS5A domain I. 18 These also affected RNA titer decline and quasi-species composition after the end of treatment.…”

“…The RNA was subsequently prepped for total RNA‐seq using the NEBNext Ultra II directional RNA library kit as described 17 and sequenced on an Illumina NextSeq platform. Data were analysed by de novo assembly and subsequent mapping as recently presented 16,18 . In order to identify RAS of the HCV NS3, NS5A and NS5B genome regions resistance analysis was performed using HCV‐GLUE offline software with a 5% sensitivity threshold 19 .…”

“…Data were analysed by de novo assembly and subsequent mapping as recently presented. 16,18 In order to identify RAS of the HCV NS3, NS5A and NS5B genome regions resistance analysis was performed using HCV-GLUE offline software with a 5% sensitivity threshold. 19 Sequencing was performed for all patients at baseline and at time of virological relapse in those with treatment failure.…”

Viral genome wide association study identifies novel hepatitis C virus polymorphisms associated with sofosbuvir treatment failure

“…This effect may be more evident in less potent treatments such as SOF + RBV ± INF and can efficiently be counteracted in pan-genotypic regimens that include several potent DAA that can more rapidly inhibit viral replication. Another study has also identified sites outside the NS5B associated with sofosbuvir-based treatment outcome, including sites in similar regions of the NS2 and NS3 protein 35 . However, this was in gt1a HCV and in a cohort with only 20 patients.…”