乙型肝炎病毒突变模式rtL180M + A181C + M204V可能在临床实践中有

StephenW

Emerg Microbes Infect. 2019;8(1):354-365. doi: 10.1080/22221751.2019.1584018.
Hepatitis B virus mutation pattern rtL180M+A181C+M204V may contribute to entecavir resistance in clinical practice.
Liu Y1, Zhou Y2, Li X1, Niu M3, Chen R1, Shao J1, Si L1, Luo D2, Lin Y2, Li L1, Zhang K2, Xiao X3, Xu Z1, Liu M2, Lu M4, Zoulim F5,6, Xu D1.
Author information

1
    a Institute of Infectious Diseases , Beijing 302 Hospital , Beijing , People's Republic of China.
2
    b Department of Infectious Diseases , The First Affiliated Hospital of Xi'an Jiaotong University , Xi'an , People's Republic of China.
3
    c Institute of Chinese Medicine , Beijing 302 Hospital , Beijing , People's Republic of China.
4
    d Institute of Virology , University Hospital of Essen, University of Duisburg-Essen , Essen , Germany.
5
    e Univ Lyon, Universite Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Leon Berard, Centre de recherche en cancerologie de Lyon , Lyon , France.
6
    f Department of Hepatology, Groupement Hospitalier Nord , Hospices Civils de Lyon , Lyon , France.

Abstract
BACKGROUND AND AIMS:

Entecavir (ETV) resistance of hepatitis B virus (HBV) conventionally requires rt184, 202, or 250 mutations plus lamivudine-resistance mutation (rtM204V/I ± L180M). This study aimed to clarify whether rtL180M+A181C+M204V mutations may contribute to HBV ETV resistance.
METHODS:

Serum samples were collected from 22,009 patients who underwent resistance testing in Beijing 302 Hospital from 2007 to 2016. HBV reverse transcriptase (RT) gene was screened by direct sequencing and verified by clonal sequencing. Phenotypic analysis was performed for evaluating replication capacity and drug susceptibility.
RESULTS:

Classical ETV-resistance mutations of HBV were detected in 1252 patients who were receiving ETV therapy. The rtA181C mutation was detected with rtL180M+M204V mutations in 18 lamivudine-experienced ETV-treated patients, and the emergence of the mutations was associated with virological breakthrough or inadequate virological response to ETV. Patient-derived representative rtA181C-containing mutants, rtL180M+A181C+M204V, rtL180M+A181C+M204V+M250V, and rtL180M+A181C+S202G+M204V, exhibited 45.7%, 25.9%, and 25.0% replication capacity and 85.6-, 356.1-, and 307.1-fold decreased susceptibility to ETV respectively compared to the wild-type strain, while the three mutants remained sensitive to tenofovir (TDF). Artificial elimination of rtA181C largely restored the rtL180M+A181C+M204V mutant's sensitivity to ETV. Molecular modelling of viral RT binding to ETV showed that the rtL180M+A181C+M204V mutant had a less stable conformation compared to rtL180M+M204V mutant. In clinical practice, undetectable serum HBV DNA was achieved in two of five longitudinally followed rtA181C-positive patients who received switching-to TDF therapy, but not in the other three who received add-on adefovir therapy during observation.
CONCLUSIONS:

Both clinical and experimental data support rtL180M+A181C+M204V as a novel non-classical ETV-resistance mutation pattern.
KEYWORDS:

Hepatitis B virus; antiviral therapy; entecavir resistance; mutation; nucleoside/nucleotide analogues; rtA181C

PMID:
    30866789
DOI:
    10.1080/22221751.2019.1584018

StephenW

Emerg Microbes Infect。 2019; 8（1）：354-365。 doi：10.1080 / 22221751.2019.1584018。
乙型肝炎病毒突变模式rtL180M + A181C + M204V可能在临床实践中有助于恩替卡韦耐药。
Liu Y1，Zhou Y2，Li X1，Niu M3，Chen R1，Shao J1，Si L1，Luo D2，Lin Y2，Li L1，Zhang K2，Xiao X3，Xu Z1，Liu M2，Lu M4，Zoulim F5,6，许D1。
作者信息

1
中华人民共和国北京市302医院传染病研究所。
2
b西安交通大学第一附属医院传染病科，中华人民共和国西安。
3
c中华人民共和国北京302医院中医研究所。
4
d德国埃森杜伊斯堡 - 埃森大学埃森大学医院病毒学研究所。
五
e Univ Lyon，Universite Claude Bernard Lyon 1，INSERM 1052，CNRS 5286，Centre Leon Berard，Centre de recherche en cancerologie de Lyon，Lyon，France。
6
f法国里昂，里昂Civils de Lyon收容所，医院，肝病科。

抽象
背景和目的：

乙型肝炎病毒（HBV）的恩替卡韦（ETV）耐药性通常需要rt184,202或250个突变加拉米夫定耐药突变（rtM204V / I±L180M）。本研究旨在阐明rtL180M + A181C + M204V突变是否可能导致HBV ETV耐药。
方法：

从2007年至2016年在北京302医院接受耐药性检测的22,009名患者采集血清样本。通过直接测序筛选HBV逆转录酶（RT）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。
结果：

在1252例接受ETV治疗的患者中检测到HBV的经典ETV抗性突变。 18例拉米夫定经历过ETV治疗的患者rtL180M + M204V突变检测到rtA181C突变，突变的出现与病毒突破或患者代表的含rtA181C的突变体相关，rtL180M + A181C + M204V，rtL180M + A181C与野生型菌株相比，+ M204V + M250V和rtL180M + A181C + S202G + M204V表现出45.7％，25.9％和25.0％的复制能力以及对ETV的敏感性降低85.6倍，356.1倍和307.1倍，而三种突变体仍然对替诺福韦（TDF）敏感。人工消除rtA181C在很大程度上恢复了rtL180M + A181C + M204V突变体对ETV的敏感性。与ETV结合的病毒RT的分子模型显示，与rtL180M + M204V突变体相比，rtL180M + A181C + M204V突变体具有较不稳定的构象。在临床实践中，接受转换为TDF治疗的rtA181C阳性患者接受了两次纵向稳定性的未检测的Able血清HBV DNA，但在观察期间接受阿德福韦治疗的其他三名患者中没有。
结论：

临床和实验数据均支持rtL180M + A181C + M204V作为新型非经典ETV抗性突变模式。
关键词：

乙型肝炎病毒;抗病毒治疗;恩替卡韦耐药;突变;核苷/核苷酸类似物; rtA181C

结论：
30866789
DOI：
10.1080 / 22221751.2019.1584018