Prevalence of HCV resistance-associated substitutions among treatment-failure patients receiving direct-acting antiviral agents.

Direct-acting antiviral (DAA) failure, which is mainly associated with the selection of resistance-associated substitutions (RASs), is not rare in HCV treatment. RAS data collected from published literature and RAS prevalence were integrated using meta-analysis. DAA-failure-associated RASs were identified by comparing their prevalence between DAA-failure and DAA-naïve patients. Prevalences of emerging RASs that occurred during treatment were also estimated. A total of 2932 DAA-naïve patients and 1466 DAA-failure patients were included. Significant differences in the prevalence of RASs were found in 76 scenarios that involved 34 RASs (11 in NS3, 18 in NS5A and 5 in NS5B), 4 genotypes (GTs) (GT1a, GT1b and GT3-4) and 14 DAAs (6 NS3 protease inhibitors [PIs], 6 NS5A inhibitors and 2 NS5B inhibitors). For NS3, the DAA-failure-associated RASs included V36L, Y56H, Q80K/R, R155K, A156T and D168A/E/L/T/V/Y. Substitutions at R155 and D168 were dominant for most NS3 PIs. For NS5A, DAA-failure-associated RASs included K24R, Q30R, L31M, and P32L in GT1a; R30Q/H, L31F/I/M/V, P58S, and Y93H in GT1b; A30K, L31M and Y93H in GT3; and M31V and Y93H in GT4. Y93H was the most prevalent RAS for NS5A inhibitors. DAA-failure-associated RASs were found at only five positions in NS5B. The majority of DAA-failure patients relapsed. A significant difference was detected for only four RAS sites between relapse patients and nonresponse/breakthrough patients. The RAS prevalence in DAA-failure patients varied among the HCV GTs and DAA regimens. The identified treatment-selected resistance patterns for broadly used DAA regimens will enable the selection of optimized retreatment options.