Hepatitis C genotype 4R resistance‐associated polymorphisms: The achilles heel of the nonstructural 5A inhibitors?

Abstract

Potential conflict of interest: Dr. Abergel consults for, is on the speakers' bureau of, and received grants from Gilead and MSD. He consults for and received grants from Janssen and Roche. He consults for AbbVie and Bristol‐Myers Squibb. TO THE EDITOR: We read with interest the review article reported by Lontok et al. on hepatitis C virus (HCV) resistance to direct antiviral agents (DAAs).1 Nonstructural 5A (NS5A) class resistance‐associated variants (RAVs; variants at any position associated with resistance to any NS5A inhibitor) may be associated with virological treatment failure (Fig. 1). Studies performed on NS5A RAVs in genotype (G) 4 patients who received a regimen based on sofosbuvir and NS5A inhibitors are very limited. In a recent multicenter study, it was shown that 2 of 3 patients who did not respond to sofosbuvir and ledipasvir combination had a G4‐r subtype.2 This result suggests that some subtypes have a different susceptibility to antiviral treatment. This loss of susceptibility could be attributed to the number of basal NS5A RAVs.Figure 1: NS5A class RAVs: variants at any position associated with resistance to any NS5A inhibitor.We aimed to demonstrate that NS5A RAVs number is more prevalent in certain HCV‐specific subtypes. We collected from the NCBI, European, and Japanese HCV databases, 47 HCV‐NS5A‐G4 sequences, and proceeded to multiple sequence alignment using Clustal W2. We analyzed 16 subtypes 4a, seven 4b, three 4d, two 4m, three 4o, and 16 4r. We assessed prevalence by subtype of the main RAVs: L28M, L30R, L31M, P58T, and Y93H. Among the G4 subtypes, the subtype 4r is the only one with 75% of the strains having two or three RAVs. The predominance of certain NS5A polymorphisms depending on G4 subtype was also reported by Zhou et al.3 Indeed, 52 of 54 genotype 4d NS5A sequences harbored L30R, whereas L30Q was observed only in genotype 4f NS5A sequences. Only a few patients with treatment failure to sofosbuvir plus daclatasvir were available for resistance analysis.3 Because of the broad use of NS5A inhibitors as first‐line DAA regimens, together with the high likeliness of selection of NS5A RAVs and persistence of these RAVs, a large prospective study on the respective role of the subtypes and of NS5A and NS5B RAVs on SVR12 should be conducted in patients treated with any Nucs or protease inhibitors and NS5A inhibitors combination.4