摘要目的 评估100 mg或200 mg磷酸依米他韦与索磷布韦联合给药12周在基因1型、非肝硬化、初治或以干扰素为基础经治失败的慢性丙型肝炎患者中的抗病毒活性和安全性.方法 本研究为多中心、随机、平行、开放、连续给药的Ⅱ期临床试验.采用区组随机方法,以"初治"或"经治"为分层因素,按1∶1比例将患者随机分配到磷酸依米他韦100 mg+索磷布韦400 mg组(100 mg组)或磷酸依米他韦200 mg+索磷布韦400 mg组(200 mg组)中,连续给药12周,停药观察24周.测定受试者HCV RNA水平,对于接受研究药物治疗但未实现持续病毒应答( sustained virological response ,SVR)的受试者,监测并说明HCV耐药病毒株的比例及变化情况.研究期间通过监测不良事件、体格检查、安全性实验室检查、12-导联心电图,以及生命体征来评价安全性和耐受性.主要终点是停药后12周时的持续病毒学应答(SVR12)率.分类变量使用描述性统计量,连续变量使用8个要素描述性统计量;采用描述统计法并按照HCV基因亚型及治疗组进行总结;安全性数据都采用描述统计法并按照治疗组进行总结.结果 2017年7月31日至2018年9月26日共筛选174例受试者,成功入组129例受试者,127例完成研究. 100 mg组64例,200 mg组65例. 129例受试者中18.6%是经治患者,所有受试者HCV基因型均为1b型. 127例(98.4%)受试者在治疗结束后12周时HCV RNA均低于定量下限[95%可信区间(confidence interval,CI):94.51%～99.81%],其中100 mg组63例(98.40%,95%CI: 91.60%～99.96%), 200 mg组64 例(98.50%,95%CI:91.72%～99.96%),组间差异无统计学意义( χ2 ＝0.000 2, P ＝0.989 2).初治患者105例(98.10%)获得SVR12(95%CI:93.29%～99.77%),经治患者24例(100.00%)获得SVR12(95%CI:85.75%～100.00%).试验过程中未发生治疗期间病毒学失败(包括突破、反弹和疗效不佳)、治疗结束后复发等情况.基线Sanger测序结果显示,HCV NS5A的Y93位点仅见Y93H／Y或Y93H突变,其总发生率为11.6%(15／129),L31位点仅见L31M突变,其发生率为1.6%(2／129),未见同时存在Y93和L31位点的突变;HCV NS5B基因未见S282位点突变.共100例(77.5%)受试者发生不良事件,未发生与研究相关的≥3级的不良事件或严重不良事件,未出现受试者因为不良事件而终止治疗或导致死亡的情况.结论 磷酸依米他韦100 mg或200 mg与索磷布韦400 mg联合给药12周对基因1b型、非肝硬化、初治或以干扰素为基础经治失败的慢性丙型肝炎患者具有良好的疗效和安全性.

abstractsObjective To assess the efficacy and safety of 100 mg or 200 mg yimitasvir phosphate combined with sofosbuvir in patients with non-cirrhotic chronic hepatitis C virus ( HCV) genotype 1 infection who were treatment-na?ve or had a virologic failure to prior interferon-based treatment.Methods A multicenter, randomized, open-label, phase 2 clinical trial was conducted.The patients were randomly assigned to yimitasvir phosphate 100 mg+sofosbuvir 400 mg group (Group 100 mg) and yimitasvir phosphate 200 mg+sofosbuvir 400 mg group ( Group 200 mg) in a 1∶1 ratio with the stratified factors of " treatment-naive" or"treatment-experienced" for 12 weeks and followed up for 24 weeks after the end of treatment.During the clinical trial, HCV RNA was tested in all patients.Resistance of virus in patients who didn′t achieved sustained virological response (SVR) was monitored.Safety and tolerability were assessed by monitoring adverse events , physical examination , laboratory examination, electrocardiogram, and vital signs during the study.The primary end point was SVR12 after the end of therapy.Descriptive statistics were used for categorical variables and eight descriptive statistics were used for continuous variables.Descriptive statistics were used and summarized according to HCV genotypes and treatment groups.Safety data were presented using descriptive statistics and summarized according to treatment groups.Results A total of 174 subjects were screened from July 31, 2017 to September 26, 2018.One hundred and twenty-nine patients were successfully enrolled and received treatment , and 127 completed the study.There were 64 patients and 65 patients assigned to Group 100 mg and Group 200 mg, respectively.Among the 129 patients who underwent randomization and were treated , 18.6% were treatment-experienced and: 100%were HCV genotype 1b infection.The total SVR rate was 98.4%(127／129), with 98.4%(63／64, 95%confidence interval [CI]: 91.60%-99.96%) in the Group 100 mg, and 98.50%(64／65, 95%CI: 91.72%-99.96%) in the Group 200 mg.There was no significant difference between the two groups (χ2 ＝0.000 2, P＝0.989 2).The SVR rates in treatment-naive group and treatment-experienced group were 98.10%(95%CI: 93.29%-99.77%) and 100.00%(24／24, 95%CI: 85.75%-100.00%), respectively.Virological failure during treatment ( including breakthrough , rebound and poor efficacy) and relapse after treatment did not occur during the trial.By Sanger sequencing , 11.6%(15／129) patients had baseline NS5A Y93H／Y or Y93H resistance-associated substitutions ( RAS), 1.6%( 2／129) patients had baseline NS5A L31M RAS.No mutation was observed in NS5B S282 at baseline.There was no S282 mutation in HCV NS5B.A total of 100 (77.5%) subjects had adverse events.No adverse events ≥Grade 3 or severe adverse events related to the study treatment.No patient prematurely discontinued study treatment owing to an adverse event.No life-threatening adverse event was reported.Conclusion Twelve weeks of yimitasvir phosphate 100 mg or 200 mg combined with sofosbuvir 400 mg daily is a highly effective and safe regimen for patients without cirrhosis with HCV genotype 1b infection who had not been treated previously or had a virologic failure to prior interferon-based treatment.