Impact of Pre-existing Hepatitis C Virus Genotype 6 NS3, NS5A and NS5B Polymorphisms on Their In Vitro Susceptibility to Inhibition by Direct-Acting Antiviral Agents [Antiviral Agents]

HCV genotype (GT)-6 is found predominantly in East and Southeast Asia. Clinical studies have focused on patients infected with HCV GT-6a where high response rates to direct-acting antivirals (DAAs) have been achieved. However, GT-6 is highly diverse with 29 reported subtypes. We explored the diversity of GT-6 polymorphisms at residues associated with DAA resistance, their impact on DAA in vitro potency when evaluated in a GT-6a consensus replicon and their association with specific GT-6 subtypes. GT-6 sequences from 25 patient-derived samples and 105 sequences from the US HCV database were compared and substitutions at resistance-associated residue positions were phenotyped against different DAAs. Pre-existing resistance-associated substitutions (RASs) to NS3 protease (A156V, D168E) and NS5B nucleotide (L159F, S282C) inhibitors were rare (<4%). Pre-existing RASs to NS5A inhibitors were common, especially at L28 (A/F/G/M/T/V) and R30 (E/N/S). In vitro susceptibilities of NS5A-L28A and -L28T were dramatically reduced against all tested NS5A drugs (EC₉₀ range 119-2032nM) compared with susceptibilities against a GT-6a consensus replicon (EC₉₀ range 0.1-19nM). These L28 RASs pre-existed in combination with R30S (EC₉₀[lsqb]L28A-R30S[rsqb] ≥720nM or EC₉₀[lsqb]L28T-R30S[rsqb] ≥128nM against tested DAAs) or as L28T-L31I (EC₉₀[lsqb]tested DAAs[rsqb] >5000nM) and were detected in evaluated GT-6b or -6f sequences. NS5A-L28A-R30A, observed in GT-6r, did not replicate. In conclusion, HCV GT-6b, GT-6f and GT-6r sequences harbored highly resistant RASs to all evaluated NS5A drugs. Monitoring of response rates in patients infected with these GT-6 subtypes treated with NS5A drug-containing regimens is therefore suggested to confirm any association between noted NS5A polymorphisms and treatment failure.

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