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耐药相关突变(Resistance-associated substitutions,RASs)是丙型肝炎病毒(Hepatitis C virus,HCV)治疗的关键因素,并与一些直接抗病毒药物(Direct acting antivirals,DAAs)为基础的治疗方案的治疗结果相关.在本研究中,我们主要分析了三个Ⅰb期临床试验(磷酸依米他韦、KW-136和福比他韦)中,基线Y93H或Y93Y/H耐药突变对NS5A抑制剂单药给药后短期疗效的影响,并且分析了基线RASs、给药后出现的RASs的发生率.共94例HCV基因型(Genotype,GT)1b(n=63)和HCV GT-2a(n=31)的中国初治慢性丙型肝炎(Chronic hepatitis c,CHC)患者被纳入三个Ⅰb期临床试验.本研究中使用Sanger测序法(Sanger sequencing)和二代测序法(Next generation sequencing,NGS)检测了77例患者的耐药突变情况.磷酸依米他韦7天给药试验中,在30和200 mg剂量组中,存在基线期Y93H或Y93Y/H突变的患者,平均最大HCV RNA下降值低于无该突变的患者,分别为0.83 vs.2.45 log10 IU/mL和1.92 vs.2.63 log10 IU/mL.在KW-136 3天给药试验中,在30、60和120 mg剂量组中,存在基线期Y93H或Y93Y/H突变的患者,平均最大HCV RNA下降值低于无该突变的患者,分别为1.58 vs.2.89 log10IU/mL、3.16 vs.4.09 log10 IU/mL和3.00vs.5.04 log10 IU/mL.在福比他韦3天单药给药试验中,只有30 mg剂量组存在基线期Y93H或Y93Y/H突变,其中存在基线期Y93H或Y93Y/H突变的患者,平均最大HCV RNA下降值低于无该突变的患者,为1.45 vs.3.59 log10IU/mL.三个试验中,共54例(70.1％;54/77)患者被检测到了基线期RASs.最普遍的基线RASs是Y93H和Y93Y/H,为18.2％(14/77),其次为L31M(16.9％;13/77).DAA单药给药后最普遍出现的RASs是Y93H和Y93Y/H.我们的数据可为以后的临床治疗及临床试验提供参考.“,”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 effiicacy 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-naive HCV genotype(GT)-lb(n=63)and GT-2a(n=31)Chinese patients were enrolled in three phase lb 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 logio 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.