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*

doi:10.3969/j.issn.1672-5069.2020.04.013

实用肝脏病杂志 ›› 2020, Vol. 23 ›› Issue (4): 504-507.doi: 10.3969/j.issn.1672-5069.2020.04.013

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^*

卓丽, 许敏, 邓浩辉

510317 广州市广东省第二人民医院感染病科(卓丽);广州市第八人民医院感染病中心(许敏,邓浩辉)

收稿日期:2019-11-18 发布日期:2020-07-15
通讯作者: 邓浩辉,E-mail:gz8hdhh@126.com
作者简介:卓丽,女,39岁,医学硕士,副主任医师。主要从事病毒性肝炎基础与临床诊治研究。E-mail: dorrina@163.com
基金资助:
*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)

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

Zhuo Li, Xu Min, Deng Haohui

Department of Infectious Disease, Second Provincial General Hospital, Guangzhou 510317, Guangdong Province, China

Received:2019-11-18 Published:2020-07-15

摘要/Abstract

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。

关键词: 肝硬化, 丙型肝炎, 阿舒瑞韦, 达拉他韦, 治疗, 准种

Abstract: 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 investigation.

Key words: Liver cirrhosis, Hepatitis C, Asunaprevir, Daclatasvirin, Therapy, Quasispecies

卓丽, 许敏, 邓浩辉. 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^*[J]. 实用肝脏病杂志, 2020, 23(4): 504-507.

Zhuo Li, Xu Min, Deng Haohui. 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[J]. Journal of Practical Hepatology, 2020, 23(4): 504-507.

参考文献

[1]Wei L,Zhang MX,Xu M, et al. A phase 3, open-label study of daclatasvir plus asunaprevir in Asian patients with chronic hepatitis C virus genotype 1b infection who are ineligible for or intolerant to interferon alfa therapies with or without ribavirin. J Gastroenterol Hepatol,2016,31(11):1860-1867.
[2]Shin SK,Lee JW,Ra H, et al. Durability of sustained virologic response and improvement of fibrosis markers after daclatasvir and asunaprevir treatment in genotype 1b hepatitis C virus-infected patients: a real life and multicenter study. J Korean Med Sci,2019,34(41):e264.
[3]Spengler U. Direct antiviral agents (DAAs) - A new age in the treatment of hepatitis C virus infection. Pharmacol Ther,2018,183:118-126.
[4]中华医学会肝病学分会和感染病学分会.丙型肝炎防治指南(2015年更新版).实用肝脏病杂志,2015,32(10):577-593.
[5]Deng H, Deng X, Liu Y, et al. Naturally occurring antiviral drug resistance in HIV patients who aremono-infected or co-infected with HBV or HCV in China. J Med Virol, 2018, 90(7):1246-1256.
[7]Wang X, Deng W, Qian K, et al. Quasispecies characters of hepatitis B virus in immunoprophylaxis failure infants.Eur J Clin Microbiol Infect Dis,2018,37(6):1153-1162.
[8]Ikegami T, Ueda Y, Akamatsu N, et al. Asunaprevir and daclatasvir for recurrent hepatitis C after liver transplantation: A Japanese multicenter experience. Clin Transplant,2017,31(11):e13109.
[9]Suda G, Furusyo N, Toyoda H, et al. Daclatasvir and asunaprevir in hemodialysis patients with hepatitis C virus infection: a nationwide retrospective study in Japan. J Gastroenterol,2018,53(1):119-128.
[10]Ikram A, Obaid A, Awan FM, et al. Identification of drug resistance and immune-driven variations in hepatitis C virus (HCV) NS3/4A, NS5A and NS5B regions reveals a new approach toward personalized medicine. Antiviral Res,2017,137:112-124.
[11]Liu F, Chen L, Yu D, et al. Evolutionary patterns of hepatitis B virus quasispecies under different selective pressures: correlation with antiviral efficacy.Gut,2011,60(9):1269-1277.
[12]Yang ZT,Huang SY,Chen L, et al. Characterization of full-length genomes of hepatitis B virus quasispecies in sera of patients at different phases of infection. J Clin Microbiol,2015,53(7):2203-2214.
[13]Mohd HK, Groeger J, Flaxman AD, et al. Global epidemiology of hepatitis C virus infection: new estimates of age-specific antibody to HCV seroprevalence. Hepatology,2013,57(4):1333-1342.
[14]Simmonds P, Holmes EC, Cha TA, et al. Classification of hepatitis C virus into six major genotypes and a series of subtypes by phylogenetic analysis of the NS-5 region. J Gen Virol,1993,74(11):2391-2399.

[1]	郝莎莎, 任晓静, 原丽莉, 姚佳. 肝硬化患者肠道微生态与肌量减少的相关性研究^*[J]. 实用肝脏病杂志, 2020, 23(4): 462-466.
[2]	汪可, 崔现平, 刘丽娟, 支庆江, 姜文营. 蓝莓花青素干预肝硬化大鼠肝组织凋亡蛋白表达的变化^*[J]. 实用肝脏病杂志, 2020, 23(4): 480-483.
[3]	徐金凤, 安红杰, 何文艳, 艾红, 赵崇山, 赵应飞, 董波, 周丽华, 吴晶. PR方案治疗慢性丙型肝炎患者ITPA基因rs1127354位点多态性与利巴韦林相关性溶血关系探讨^*[J]. 实用肝脏病杂志, 2020, 23(4): 500-503.
[4]	黄丽华, 杨正兵, 谭礼让. 熊去氧胆酸联合非诺贝特治疗PBC患者血清TGF-β、IFN-γ和IL-10水平变化^*[J]. 实用肝脏病杂志, 2020, 23(4): 520-523.
[5]	齐敬聪, 邢文静, 杜洋, 高辰玮. 熊去氧胆酸联合微生态制剂治疗原发性胆汁性胆管炎患者对肠道菌群的影响^*[J]. 实用肝脏病杂志, 2020, 23(4): 524-527.
[6]	侯光华, 胡启江, 徐美华, 朱绍咏, 黄波. 多烯磷脂酰胆碱联合二甲双胍和非诺贝特治疗NAFLD患者血清Pygo2和血脂水平变化^*[J]. 实用肝脏病杂志, 2020, 23(4): 528-531.
[7]	周娜, 蒋磊, 吴冰冰. 阿托伐他汀治疗NAFLD患者对肝脂肪变和外周血Treg/Th17细胞的影响^*[J]. 实用肝脏病杂志, 2020, 23(4): 532-535.
[8]	陈曦, 陈照林, 董静, 宋海燕, 刘波, 张骏飞, 陈从新. 脐带间充质干细胞联合双重血浆分子吸附治疗慢加急性肝衰竭患者临床效果初步观察[J]. 实用肝脏病杂志, 2020, 23(4): 544-547.
[9]	张静, 周新民. 应用重组人血小板生成素减少肝硬化患者术前血小板输注疗效初步研究^*[J]. 实用肝脏病杂志, 2020, 23(4): 552-555.
[10]	陈照林, 董静, 宋海燕, 刘波, 张骏飞. 特利加压素联合腹水浓缩回输术治疗肝硬化并发顽固性腹水患者临床研究[J]. 实用肝脏病杂志, 2020, 23(4): 556-559.
[11]	李娜, 郑少秋, 赵守松. FibroScan联合多种预测模型预测肝硬化患者食管静脉曲张程度应用价值探讨[J]. 实用肝脏病杂志, 2020, 23(4): 560-563.
[12]	汪志亮, 胡磊, 刘啸峰. 多层螺旋CT对比剂注射流率对肝硬化患者门静脉成像延迟时间的影响^*[J]. 实用肝脏病杂志, 2020, 23(4): 564-567.
[13]	宋丽俊, 袁雁, 王伟. 定量磁共振成像诊断原发性胆汁性肝硬化患者门静脉高压症价值分析^*[J]. 实用肝脏病杂志, 2020, 23(4): 568-571.
[14]	全亚宁, 商晓杰, 孟璇, 高榆秀. 实时超声造影和融合影像导航下微波消融与手术治疗小肝癌患者疗效比较^*[J]. 实用肝脏病杂志, 2020, 23(4): 581-584.
[15]	郑雪, 宣之东, 王玉, 张丽静. 超声联合CT检查在肝恶性肿瘤射频消融治疗中的应用价值探讨^*[J]. 实用肝脏病杂志, 2020, 23(4): 589-592.

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

PDF (PC)

可视化

摘要/Abstract

引用本文

使用本文

参考文献

相关文章 15

编辑推荐

Metrics

本文评价