Abstract:

As crucial factors in hepatitis C virus (HCV) management, resistance-associated substitutions (RASs) are associated with the treatment outcome of some direct-acting antiviral (DAA)-based regimens. In this study, we mainly analyzed the impact of baseline Y93H or Y93Y/H on the short-term efficacy after single administration of NS5A inhibitors in three phase Ib clinical trials (yimitasvir phosphate, KW-136 and fopitasvir), and analyzed the prevalence of baseline RASs and treatment-emergent RASs. A total of 94 treatment-na?ve HCV genotype (GT)-1b (n = 63) and GT-2a (n = 31) Chinese patients were enrolled in three phase 1b clinical trials. We investigated RASs in 77 patients with next generation or Sanger sequencing. In the 7-day trial of yimitasvir phosphate, the mean maximum HCV RNA decrease of patients with baseline Y93H or Y93Y/H was lower than that of patients without the mutation in the 30 mg and 200 mg cohorts (0.83 vs. 2.45 log₁₀ IU/mL and 1.92 vs. 2.63 log₁₀ IU/mL). In the 3-day trial of KW-136, the mean maximum HCV RNA decrease in patients with baseline Y93H or Y93Y/H was lower than that of patients without the mutation in the 30, 60 and 120 mg cohorts (1.58 vs. 2.89 log₁₀ IU/mL, 3.16 vs. 4.09 log₁₀ IU/mL and 3.00 vs. 5.04 log₁₀ IU/mL, respectively). In the 3-day trial of fopitasvir, only 30 mg group had baseline Y93H or Y93Y/H, and the average maximum HCV RNA decrease of patients with baseline Y93H or Y93Y/H was lower than that of patients without the mutation (1.45 vs. 3.59 log₁₀ IU/mL). In the three trials, baseline RASs were observed in 54 patients (70.1%; 54/77). The most prevalent baseline RASs were Y93H and Y93Y/H (18.2%; 14/77), followed by L31M (16.9%; 13/77). The most common RASs after single administration of DAA were Y93H and Y93Y/H. Our data could provide reference for future clinical treatment and clinical trial.

Key words: Direct acting antiviral agents, Resistance-associated substitutions, HCV sequencing, Genotype 1b and 2a, HCV NS5A inhibitors