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乙型肝炎病毒新型恩替卡韦耐药突变rtL180M+A186T+M204V的鉴定
作者:刘璐洁 刘妍 陈容娟 李晓东 罗丹 林亚云 黄碧霞 李奇 刘新光 徐东平 
单位:523808  广东东莞 广东医科大学分子诊断重点实验室/衰老研究所(刘璐洁、黄碧霞、刘新光、徐东平) 100039  北京 解放军总医院第五医学中心(原解放军第302医院)临床研究管理中心/全军传染病研究所(刘妍、陈容娟、李晓东、罗丹、林亚云、李奇、徐东平) 
关键词:肝炎病毒 乙型 恩替卡韦耐药 突变 rtA186T 
分类号:R512.62
出版年,卷(期):页码:2019,44(3):197-202
摘要:

 [摘要]  目的  对rtL180M+A186T+M204V是否为恩替卡韦(ETV)的新型耐药突变进行鉴定。方法  纳入2011 7月-20167月就诊于原解放军第302医院的12 708例慢性HBV感染患者,采用直接测序法检测反转录酶区(RT) 序列耐药突变,对检出rtL180M+A186T+M204V突变的样本克隆进行测序(20个克隆/样本),构建野生和突变基因的重组1.1HBV复制子,转染HepG2细胞进行表型分析。结果  12 708例慢性HBV感染患者中采用ETV治疗者4047 例,共检出经典ETV耐药突变患者795例,rtL180M+A186T+M204V突变患者7例,分别占ETV治疗患者的19.64%0.17%rtL180M+A186T+M204V突变符合ETV耐药突变的特征:检出rtA186T阳性突变的样本均为拉米夫定(LAM) 经治后ETV治疗的患者;突变的检出均与临床病毒学反跳或不完全应答密切相关;表型耐药分析显示患者来源的 rtL180M+A186T+M204V突变株复制力仅为野生株的13.3%,且对ETV的药物耐药倍数是野生株的210.2倍,但对替诺福韦酯仍敏感。结论  rtL180M+A186T+M204V突变是一种新型ETV耐药突变,但临床检出率低,与突变株复制力明显降低相关,临床可考虑用替诺福韦酯对检出rtL180M+A186T+M204V耐药突变的患者进行挽救治疗。

[Abstract]  Objective  To identify whether rtL180M+A186T+M204V mutation is a novel entecavir (ETV)-resistant mutation. Methods  A total of 12 708 patients in the Fifth Medical Center of Chinese PLA General Hospital from July 2011 to July 2016 were enrolled in this study. Drug resistance mutation in reverse transcriptase region (RT) were analyzed by direct sequencing and verified by clonal sequencing if rtL180M+A186T+M204V has been detected (20 clones/sample); 1.1-mer HBV replicons harboring wild-type or mutant RT gene were constructed respectively and transfected into HepG2 cells for phenotypic analysis. Results  ETV experienced patients were detected in 4047 of total patients. Among these patients, classical ETV-resistant mutation of HBV and rtL180M+A186T+M204V mutation were detected in 795(19.64%) and 7(0.17%), respectively. The rtL180M+A186T+M204V mutant was consistent with the features of ETV-resistant mutation: all the rtA186T-positive patients had a history of lamivudine exposure prior to ETV treatment; the emergence of the mutations was associated with virological breakthrough or inadequate virological response to ETV; phenotypic analysis showed that patient-derived rtL180M+A186T+M204V mutant exhibited 13.3% replication capacity and 210.2-fold decreased susceptibility to ETV compared to the wild-type strain, while the mutant remained sensitive to tenofovir (TDF). Conclusions  rtL180M+A186T+M204V as a novel ETV-resistance mutation has a low clinical detection rate, which is related to the markedly reduced replication capacity of the mutant. TDF-based rescue therapy should be considered for patients harboring rtL180M+A186T+M204V mutation in clinical practice.

基金项目:
国家自然科学基金(81572010,81573676,81371852)
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