阿舒瑞韦联合达拉他韦治疗慢性丙型肝炎患者初步疗效及其病毒准种变化和耐药变异特征分析  

Preliminaryobservation of asunaprevir and daclatasvirin combination therapy in patients with chronic hepatitis C and hepatitis C liver cirrhosis and the resistance mutations and quasispecies changes

作　　者：卓丽 许敏[2] 邓浩辉[2] Zhuo Li;Xu Min;Deng Haohui(Department of Infectious Disease,Second Provincial General Hospital,Guangzhou 510317,Guangdong Province,China)

机构地区：[1]广东省第二人民医院感染病科,广州市510317 [2]广州市第八人民医院感染病中心

出　　处：《实用肝脏病杂志》2020年第4期504-507,共4页Journal of Practical Hepatology

基　　金：广东省医学科学技术研究基金资助项目(编号:A2017142);广州市卫生健康科技项目(编号:20191A011037)。

摘　　要：目的观察应用阿舒瑞韦(ASV)联合达拉他韦(DCV)治疗慢性丙型肝炎(CHC)或代偿期丙型肝炎肝硬化患者的初步疗效,并分析复发患者丙型肝炎病毒(HCV)耐药变异和准种变化特征。方法27例CHC和13例丙型肝炎肝硬化患者接受ASV联合DCV治疗24周,随访12周。纳入患者均为HCV 1b基因型感染。结果在随访结束时,38例(95.0%)获得持续病毒学应答(SVR),2例治疗失败的患者基线均存在NS5A抑制剂相关的耐药变异;在治疗过程中有7例(17.5%)患者出现血清谷丙转氨酶或尿酸升高和血小板或血红蛋白下降;1例治疗失败的患者基线和复发时均存L31V+Y93H NS5A抑制剂相关的耐药变异,但复发时血清耐药株的比例显著高于基线时(100.0%+100.0%对2.1%+56.2%),复发血清HCV各基因片段准种复杂度(Sn为0.91±0.02对0.40±0.07,t=19.127,P<0.001)和多样性(d为17.70±6.63对1.65±0.36,t=6.75,P<0.001;dN为3.55±2.18对1.37±0.41,t=2.801,P=0.026;dS为48.11±10.06对2.06±0.90,t=13.598,P<0.001)均显著低于基线血清,Tajima中性检验提示复发时血清HCV各基因片段的D值显著低于基线血清(1.84±1.20对-2.30±0.18,t=10.352,P<0.001)。结论ASV联合DCV治疗HCV 1b基因型感染的CHC和丙型肝炎肝硬化患者具有良好的近期疗效和安全性,存在NS5A抑制剂相关耐药变异者可能导致治疗失败。Objective The aim of this study was to investigate the preliminary efficacy of asunaprevir(ASV)and daclatasvirin(DCV)combination therapy in patients with chronic hepatitis C and hepatitis C liver cirrhosis and the resistance mutations and quasispecies changes.Methods 27 patients with CHC and 13 with hepatitis C-induced liver cirrhosis were recruited in this study,and all patients received ASV and DCV combination therapy for 24 weeks.All the patients were followed-up for 12 weeks.Serum HCV gene regions,including core,E1,E2,NS2,NS3,NS4,NS5A and NS5B were sequenced by using second-generation sequencing and the difference of resistance mutations,HCV quasispecies and Tajima test were analyzed.Results At the end of 12-week follow-up,the sustained virological response was achieved in 38 patients(95.0%),and one patient had Y93H and another one had L31V+Y93H NS5A resistance-associated mutations(RAVs)in the two failed patients;during the period of treatment,7 patients(17.5%)had abnormal laboratory examinations,including serum alanine aminotransferase or uric acide elevation or platelet counts or hemoglobin decrease;in a recurrent patient,L31V+Y93H RAVs was found at baseline and recurrent blood samples,however,the percentage of L31V+Y93H RAVs in recurrent sample was significantly higher than that at baseline;the HCV quasispecies complexity(Sn:0.91±0.02 vs.0.40±0.07,t=19.127,P<0.001)and diversity(d:17.70±6.63 vs.1.65±0.36,t=6.75,P<0.001;dN:3.55±2.18 vs.1.37±0.41,t=2.801,P=0.026;dS:48.11±10.06 vs.2.06±0.90,t=13.598,P<0.001,respectively)in recurrent sample were significantly decreased as compared to those at baseline;in addition,the result of Tajima test showed that the D<0 in amplified HCV regions from recurrent sample,and the D value was significantly lower in recurrent sample(1.84±1.20 vs.-2.30±0.18,t=10.352,P<0.001).Conclusion Excellent clinical efficacy and safety were observed in our series of patients with CHC or hepatitis C liver cirrhosis with HCV 1b genotype infection,which warrants further and long-term in

关 键 词：肝硬化 丙型肝炎 阿舒瑞韦 达拉他韦 治疗 准种 

分 类 号：R512.63[医药卫生—内科学]