长期应用恩替卡韦治疗的慢性乙型肝炎患者耐药发生情况及原因分析:8年随访研究  

Drug resistance occurring in chronic hepatitis B patients receiving long-term entecavir treatment and analysis of its causes:an eight-year follow-up study

作　　者：田敬华[1] 徐飞[1] 刘亚楠[1] 宋淑静[1] 华文浩[1] 马秀云[2] 蔡晧东[2] 

机构地区：[1]首都医科大学附属北京地坛医院检验科,北京100015 [2]首都医科大学附属北京地坛医院门诊,北京100015

出　　处：《药物不良反应杂志》2011年第6期341-347,共7页Adverse Drug Reactions Journal

摘　　要：目的:了解慢性乙型肝炎患者长期应用恩替卡韦(ETV)治疗的耐药发生情况并探讨耐药原因。方法:对2003-2007年3月参加ETV剂量和疗效的随机双盲Ⅱ期临床试验、ETV与拉米夫定(LAM)治疗慢性乙型肝炎的随机双盲对照Ⅲ期临床试验、ETV治疗LAM失效的慢性乙型肝炎Ⅲ期临床试验及其后续ETV开放治疗临床试验的63例慢性乙型肝炎患者继续给予治疗和随访,计算截至2011年3月的累积耐药发生率,对临床耐药患者进行乙型肝炎病毒(HBV)逆转录酶区(RT)序列突变检测,并分析耐药原因。结果:63例患者中3例治疗2年后失访;1例治疗2.5年时转其他中心治疗;其他59例中16例用药4～6年,43例用药7～8年,随访4～8年,中位随访时间7年。13例患者发生临床耐药,累积耐药发生率为20.5%。9例耐药患者进行了HBV RT序列突变检测,其中5例检测出LAM耐药位点L180M和M204V突变和1～2个ETV耐药位点突变,符合ETV耐药特点;3例仅检出LAM耐药位点突变;1例检出2个ETV耐药位点突变和ADF耐药位点A181T突变。LAM经治、治疗前高病毒载量、治疗6个月病毒学应答不佳、治疗依从性差可能与耐药的发生有关。结论:长期应用恩替卡韦治疗慢性乙型肝炎耐药率较低。对治疗初期应答不佳患者,加强监测和提高治疗依从性可减少耐药的发生。Objective：To discuss the drug resistance occurring in chronic hepatitis B patients after an 8-year treatment with entecavir resistance.Methods： Sixty-three chronic hepatitis B patients were enrolled in the clinical trials（a randomised,double-blind,phase Ⅱ clinical trial of entecavir dosage and efficacy,a randomised,double-blind,phase Ⅲ clinical trial treating chronic hepatitis B patients with entecavir versus lamivudine,a phase Ⅲ clinical trial of entecavir for treating lamivudine-refractory patients with chronic hepatitis B,and a subsequent open-label clinical trial） from 2003 to March 2007,and then they continued therapy with continued follow-up.In the 8 years ending in March 2011,a cumulative incidence of entecavir resistance was calculated.Hepatitis B virus reverse transcriptase sequence mutations was detected and the causes of drug resistance were analysed.Results： Among 63 patients,3 patients lost from follow-up after a 2-year treatment.One patient was transferred to another medical centre after 2 years and a half of treatment.In addition,of 59 patient,16 received drug therapy for 4-6 years and 43 for 7-8 years.The duration of follow-up was 4-8 years and median follow-up duration was 7 years.Thirty patients developed clinical resistance to entecavir.Cumulative incidence of resistance was 20.5%.Nine patients with exhibiting drug resistance underwent the detection of HBV RT sequence mutations,5 of them had lamivudine resistance-associated mutations of L180M and M204V and 1-2 mutation site of ETV resistance and the findings were compatible with ETV resistance profile.Three patients only had lamivudine resistance mutations.One patient had mutation sites of ETV resistance and ADE resistance mutations of A181T.Drug resistance development may be related to prior therapy of lamivudine,high viral load before treatment,poor virological response after a 6-month treatment,and poor medication compliance.Conclusion： Entecavir has a low resistance rate after long-term use of entecavir for treating chroni

关 键 词：乙型肝炎 慢性 乙型肝炎病毒 恩替卡韦 耐药 

分 类 号：R512.62[医药卫生—内科学]