Hepatitis C virus (HCV) genotype 4 is known to be highly heterogeneous. Previous studies have suggested that HCV subtype 4r is less responsive to directly-acting antiviral (DAA) drug treatment than other genotype 4 subtypes. The authors found that, among 537 DAA-treated patients who experienced a virologic failure (VF) in France between 2015–2018, 22.5% were infected with genotype 4 and 22.3% of them with subtype 4r. Therefore subtype 4r is over-represented when compared with its prevalence in the French population. Population sequencing of nonstructural protein (NS) 3, NS5A and NS5B genes was performed in all subtype 4r patients at treatment failure and in six of them at baseline. Whole HCV genome sequencing was performed in two baseline and three treatment failure samples. The authors found that at treatment failure, all subtype 4r patients had two to three dominant NS5A resistance-associated substitutions (RASs), including at least L28A/C/I/M/V and L30R. Among the 13 patients who had been exposed to sofosbuvir and an NS5A inhibitor (daclatasvir, ledipasvir or velpatasvir), 38.5% also had NS5B S282C/T RASs at treatment failure. One additional patient had S282C/T RASs at treatment failure. The prevalence of S282C/T RASs at treatment failure was found to be significantly higher in patients infected with genotype 4r than with other genotypes, including other subtypes of genotype 4. Therefore the lower observed rates of sustained virologic response in patients infected with subtype 4r are related to the frequent pre-existence at treatment baseline, and subsequent selection by DAA treatment, of both NS5A and NS5B S282 RASs. These patients should therefore be identified and given a triple DAA combination regimen as first-line treatment.
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