Pre-existing minor variants with NS5A L31M/V-Y93H double substitution are closely linked to virologic failure with asunaprevir plus daclatasvir treatment for genotype 1b hepatitis C virus infection

Abstract

Background L31 and Y93 in the NS5A region of the hepatitis C virus (HCV) are the most important substitution positions associated with resistance to direct-acting antiviral (DAA) treatment. Methods We analyzed the frequency of NS5A L31M/V and Y93/H in NS5A inhibitor-naive HCV genotype 1 patients who received asunaprevir plus daclatasvir combination treatment using a conventional sequencing method and a deep sequencing method that can distinguish a single substitution at either position and a double substitution at both positions with a 0.1% detection threshold. Results The frequency of substitutions at both sites using the conventional method was very low, with 1 in 14 non-responders and 0 in 42 randomly selected responder patients. On the other hand, for the deep sequencing method, cases with double substitutions in the tandem sequence were detected in 8/14 non-responders and 1/42 responders (p<0.0001). For the conventional method, substitutions were detected at any position in 6/14 non-responders and 2/42 responders (p = 0.0019), with a clear difference between the two groups. The difference was also clear with the deep sequencing method, with 11/14 non-responders and 8/ 42 responders. Interestingly, for the deep sequencing method, the single substitution of L31

Efficacy decrease of antiviral agents when administered to ongoing hepatitis C virus infections in cell culture

“…Selection of RAS is responsible for a large proportion of HCV treatment failures (Di Maio et al, 2017 , 2021 ; Kai et al, 2017 ; Ceccherini-Silberstein et al, 2018 ; Dietz et al, 2018 ; Perpinan et al, 2018 ; Sorbo et al, 2018 ; Lombardi et al, 2019 ; Chen et al, 2020 ; Malandris et al, 2021 ; Sarrazin, 2021 ). RASs have been identified in treatment-naive patients (Costantino et al, 2015 ; Kai et al, 2017 ; Li et al, 2017a , b ; Esposito et al, 2018 ; Perales et al, 2018 ; Yang et al, 2018 ; Morishita et al, 2020 ), reflecting the impact of the basal HCV mutation rate and viral population dynamics on the response to antiviral agents.…”