在189个月的抗HBV治疗期间，患者的HBV相关S区变体的耐药突变

StephenW

Antivir Ther. 2019 Mar 18. doi: 10.3851/IMP3305. [Epub ahead of print]
Molecular cloning and phenotypic analysis of drug-resistance mutants with relevant S-region variants of HBV for a patient during 189-month anti-HBV treatment.
Liu Y1, Wu C2, Chen R1, Li X1, Xu Z1, Li Q1, Li L1, Wang FS1, Yang D3, Lu M4, Xu D1.
Author information

1
    Institute of Infectious Diseases, Beijing 302 Hospital, Beijing, China.
2
    State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China.
3
    Department of Infectious Disease, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
4
    Institute of Virology, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany.

Abstract
BACKGROUND:

A unique chronic hepatitis B patient was followed over 189 months of nucleoside/nucleotide analogue (NAs) therapies with the analysis of multiple drug-resistance HBV mutants.
METHODS:

Clonal sequencing (≥ 20 clones/sample) was performed on sera sampled at 41 time-points, and the phenotypic features of eight representative mutants were analyzed.
RESULTS:

Lamivudine (LAM)-, adefovir dipivoxil (ADV)-, entecavir (ETV)-, and repeat ADV-resistance mutants emerged upon individual sequential NA monotherapy. The efficacy of NA combination rescue therapies ranked as LAM+ADV < ETV+ADV < ETV+tenofovir disoproxil fumarate (TDF). Specifically, LAM+ADV and ETV+ADV suppressed viral loads to < 100 IU/mL for a long period of time, either with or without late stage HBV DNA fluctuations. Furthermore, ETV+TDF suppressed the viral load to < 10 IU/mL. During the LAM+ADV and ETV+ADV combination therapies, ETV-resistance mutants dominated at most time-points, and MDR mutants that harbored LAM-, ETV- and ADV-resistance mutations were intermittently detected. Interestingly, the rtA181T-causative sW172stop to sW172non-stop mutation transition was observed at HBV DNA fluctuations. In a phenotypic analysis, two MDR strains had cross-resistance to LAM, ETV, and ADV, and a lower susceptibility to TDF (< 10-fold decrease compared to the wild-type strain). In contrast, the natural replication capacity was inversely associated with the number of primary resistant mutations which would limit MDR mutant development.
CONCLUSIONS:

Taken together, viral drug susceptibility, replication capacity, and perhaps immunological adaptation may play coordinated roles in the fitness of drug-resistance mutants. ETV+TDF therapy is the preferred option for treating chronic hepatitis B patients with multiple drug failure.

PMID:
    30882363
DOI:
    10.3851/IMP3305

StephenW

Antivir Ther。 2019年3月18日doi：10.3851 / IMP3305。 [印刷前的电子版]
在189个月的抗HBV治疗期间，患者的HBV相关S区变体的耐药突变体的分子克隆和表型分析。
Liu Y1，Wu C2，Chen R1，Li X1，Xu Z1，Li Q1，Li L1，Wang FS1，Yang D3，Lu M4，Xu D1。
作者信息

1
北京302医院传染病研究所，北京
2
中国科学院武汉病毒研究所病毒学国家重点实验室，武汉
3
华中科技大学同济医学院附属协和医院传染病科，武汉
4
德国埃森杜伊斯堡 - 埃森大学埃森大学医院病毒学研究所。

抽象
背景：

一项独特的慢性乙型肝炎患者接受了超过189个月的核苷/核苷酸类似物（NAs）治疗，并对多种耐药性HBV突变体进行了分析。
方法：

对在41个时间点取样的血清进行克隆测序（≥20个克隆/样品），并分析8个代表性突变体的表型特征。
结果：

拉米夫定（LAM） - 阿德福韦酯（ADV） - ，恩替卡韦（ETV） - ，重复ADV耐药突变出现在个别连续NA单药治疗。 NA组合的救援治疗的排名为LAM + ADV <ETV + ADV <ETV +富马酸替诺福韦酯（TDF）的功效。具体而言，LAM + ADV和ETV + ADV抑制病毒载量为<100 IU / mL的的很长一段时间，或者具有或不具有晚期HBV DNA的波动。此外，ETV + TDF将病毒载量抑制到<10 IU / mL。在LAM + ADV和ETV + ADV组合疗法，ETV-抗性突变体至多时间点为主，有趣的是间歇地检测到时，rtA181T-致病sW172stop到sW172non窝藏LAM-，ETV-和ADV-抗性突变的突变体MDR在HBV DNA波动时观察到停止突变。在一个表型分析中，两个MDR菌株不得不LAM，ETV和ADV交叉耐药性，和更低的易感性TDF（<10  - 对比度下降相比于野生型菌株）。 ，天然复制能力与限制MDR突变体发育的初级抗性突变的数量成反比关联。
结论：

总之，病毒药物敏感性，复制能力和可能的免疫适应可能在耐药突变体的适应性中起协调作用。 ETV + TDF治疗是治疗多种药物治疗失败的慢性乙型肝炎患者的首选方案。

结论：
30882363
DOI：
10.3851 / IMP3305