在一大群中国乙型肝炎病毒患者中，恩替卡韦耐药诱导突变rt

StephenW

Antiviral Res. 2019 Feb 20. pii: S0166-3542(18)30667-3. doi: 10.1016/j.antiviral.2019.02.012. [Epub ahead of print]
Prevalence of the entecavir-resistance-inducing mutation rtA186T in a large cohort of Chinese hepatitis B virus patients.
Liu L1, Liu Y2, Chen R2, Li X2, Luo D2, Zhao Y1, Li Q2, Huang B1, Wang FS2, Liu X3, Xu D4.
Author information

1
    Institute of Infectious Diseases, Beijing 302 Hospital/The Fifth Medical Center of PLA General Hospital, Beijing 100039, China; Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics/Institute of Biochemistry & Medical Molecular Biology, Guangdong Medical University, Dongguan 523808, Guangdong Province, China.
2
    Institute of Infectious Diseases, Beijing 302 Hospital/The Fifth Medical Center of PLA General Hospital, Beijing 100039, China.
3
    Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics/Institute of Biochemistry & Medical Molecular Biology, Guangdong Medical University, Dongguan 523808, Guangdong Province, China. Electronic address: [email protected].
4
    Institute of Infectious Diseases, Beijing 302 Hospital/The Fifth Medical Center of PLA General Hospital, Beijing 100039, China; Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics/Institute of Biochemistry & Medical Molecular Biology, Guangdong Medical University, Dongguan 523808, Guangdong Province, China. Electronic address: [email protected].

Abstract

This study aimed to clarify whether rtA186T and rtI163V substitutions of hepatitis B virus (HBV) contributed to entecavir (ETV) resistance. A total of 22,009 Chinese patients with chronic HBV infection who received resistance testing at Beijing 302 Hospital from 2007 to 2016 were enrolled. Among them, 6170 patients had been treated with ETV. The HBV reverse transcriptase gene was screened by direct sequencing and verified by clonal sequencing. Phenotypic analysis was performed for evaluating replication capacity and drug susceptibility. Classical ETV-resistance mutations rtT184/S202/M250substitution+rtM204V/I±L180M (LAM-r), rtA186T, and rtI163V were detected in 1252 (5.69%), 14 (0.06%), and 230 (1.06%) of the 22,009 patients, respectively. The rtA186T mutation always coexisted with LAM-r, but not with rtI163V. The 14 rtA186T-positive patients were all treated with LAM and ETV, and the emergence of the rtA186T+LAM-r was closely associated with virological breakthrough or inadequate virological response to ETV. By contrast, the emergence of rtI163V was not related to ETV treatment. Six rtA186T-positive patients were followed up longitudinally, showing that these patients all had received sequential adefovir and LAM monotherapies prior to ETV treatment. Compared to wild-type strain, two patient-derived mutants' rtL180M+A186T+M204V and rtL180M+T184S+A186T+M204V had 86.7% and 89.2% decreased replication capacity, 210- and 555-fold increased ETV resistance, respectively; and artificial elimination of rtA186T largely restored their ETV sensitivity. The rtA186T mutants remained sensitive to tenofovir. In conclusion, our study confirmed that rtA186T plus LAM-r is a novel ETV-resistance mutation pattern which conferred ETV resistance in multiple Chinese patients.

Copyright © 2019. Published by Elsevier B.V.
KEYWORDS:

Entecavir; Hepatitis B virus; Mutation; Resistance; rtA186T; rtI163V

PMID:
    30796932
DOI:
    10.1016/j.antiviral.2019.02.012

StephenW

抗病毒药物2019年2月20日.pii：S0166-3542（18）30667-3。 doi：10.1016 / j.antiviral.2019.02.012。 [印刷前的电子版]
在一大群中国乙型肝炎病毒患者中，恩替卡韦耐药诱导突变rtA186T的患病率。
Liu L1，Liu Y2，Chen R2，Li X2，Luo D2，Zhao Y1，Li Q2，Huang B1，Wang FS2，Liu X3，Xu D4。
作者信息

1
    中国人民解放军总医院第五医疗中心北京302医院感染科学研究所，北京100039;广东医科大学广东省医学分子诊断重点实验室/生物化学与医学分子生物学研究所，广东省东莞市523808
2
    中国人民解放军总医院第五医疗中心北京302医院感染科学研究所，北京100039
3
    广东医科大学广东省医学分子诊断重点实验室/生物化学与医学分子生物学研究所，广东省东莞市523808电子地址：[email protected]。
4
    中国人民解放军总医院第五医疗中心北京302医院感染科学研究所，北京100039;广东医科大学广东省医学分子诊断重点实验室/生物化学与医学分子生物学研究所，广东省东莞市523808电子地址：[email protected]。

抽象

本研究旨在阐明乙型肝炎病毒（HBV）的rtA186T和rtI163V取代是否有助于恩替卡韦（ETV）耐药。共纳入22,009名中国慢性HBV感染患者，他们于2007年至2016年在北京302医院接受了耐药性检测。其中，6170例患者接受过ETV治疗。通过直接测序筛选HBV逆转录酶基因并通过克隆测序验证。进行表型分析以评估复制能力和药物敏感性。经典ETV抗性突变rtT184 / S202 / M250substitution + rtM204V / I±L180M（LAM-r），rtA186T和rtI163V在22,009中检测到1252（5.69％），14（0.06％）和230（1.06％）患者，分别。 rtA186T突变始终与LAM-r共存，但不与rtI163V共存。 14例rtA186T阳性患者均接受LAM和ETV治疗，rtA186T + LAM-r的出现与病毒学突破或对ETV的病毒学应答反应密切相关。相比之下，rtI163V的出现与ETV治疗无关。对6名rtA186T阳性患者进行纵向随访，显示这些患者在ETV治疗前均接受了顺序阿德福韦和LAM单药治疗。与野生型菌株相比，两个源自患者的突变体'rtL180M + A186T + M204V和rtL180M + T184S + A186T + M204V分别具有86.7％和89.2％的复制能力下降，ETV抗性分别增加210和555倍;人工消除rtA186T在很大程度上恢复了他们的ETV敏感性。 rtA186T突变体对替诺福韦仍然敏感。总之，我们的研究证实rtA186T加LAM-r是一种新的ETV抗性突变模式，它赋予多名中国患者ETV耐药性。

版权所有©2019。Elsevier B.V.
关键词：

恩替卡韦;乙型肝炎病毒;突变;抵抗性; rtA186T; rtI163V

结论：
    30796932
DOI：
    10.1016 / j.antiviral.2019.02.012

左罗

看来要对自己负责，还是用TAF比较靠普

newchinabok

左罗 发表于 2019-2-26 10:20
看来要对自己负责，还是用TAF比较靠普

taf ，替诺，恩替 包括核衣壳抑制剂都有耐药，只不过不太容易发生

左罗

请问专家们：包括taf在内的替诺如果有朝一日遭遇耐药，可否有应对之策？谢谢！

newchinabok

左罗 发表于 2019-2-26 13:58
请问专家们：包括taf在内的替诺如果有朝一日遭遇耐药，可否有应对之策？谢谢！  ...

我不是专家，我是个患者，我个人认为乙肝就是个单行道，乙肝不是治好，就是最后挂了。不敢往下想。实在不好意思说出事情真像，让很多人恐慌。替诺耐药有核衣壳，核衣壳耐药有其它核衣壳，在往下就不知道了

hchu

“人工消除rtA186T在很大程度上恢复了他们的ETV敏感性。”

人工消除是什么意思？

ivanich

回复 hchu 的帖子

这句话有意思，是不是让他变得不耐药了？

pourvivre

回复 newchinabok 的帖子

乙肝如不治好，还可能随着年纪增大自愈。和基因，生活习惯有关系。乙肝研究几十年，没有几百年，很多原理有待发现。