在替诺福韦恩替卡韦联合治疗期间，选择两例慢性乙型肝炎

StephenW

Jibatuat. 2017 Apr 6.论坛 pii: S0168-8278 (17) 30198-8. Doi: 10.1016 / j.jhep.2017.03.027. [Epub ahead of print]
Selection of the highly replicative and partially multidrug resistant rtS78T polymerase mutation in two patients with chronic hepatitis B virus infection during tenofovir-entecavir combination therapy.
Shirvani-Dastgerdi E1, Winer BY2, Celia-Terrassa A2, Kang Y2, Tabernero D3, Yagmur E4, Rodríguez-Frías F3, Gregori J5, Luedde T6, Trautwein C6, Ploss A2, Tacke F7.
Author information

1
    Department of Medicine III, RWTH-University Hospital Aachen, Aachen, Germany .; Department of Molecular Biology, Princeton University, Princeton, NJ, USA.
2
    Department of Molecular Biology, Princeton University, Princeton, NJ, USA.
3
    Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain; Liver Unit, Vall d'Hebron Institute of Research (VHIR), Universitat Autònoma de Barcelona (UAB), Barcelona, Spain The
4
    Medical Care Center, Dr Stein and Colleagues, Mönchengladbach, Germany.
5
    Roche Diagnostics SL, Sant Cugat del Vallès, Spain
6
    Department of Medicine III, RWTH-University Hospital Aachen, Aachen, Germany.
7
    Department of Medicine III, RWTH-University Hospital Aachen, Aachen, Germany .. Electronic address: [email protected].

Abstract

Patients with chronically infected with the hepatitis B virus (HBV) that are on long-term treatment with nucleoside or nucleotide analogues are at risk of selecting HBV strains with complex mutational patterns. We here report two cases of HBV- Dual antiviral therapy with entecavir (ETV) and tenofovir (TDF), of which one patient died from aggressive hepatocellular carcinoma (HCC). Ultra-deep pyrosequencing analyses revealed the selection of the rtS78T polymerase mutation in both cases that creates a premature stop codon at SC69 and thereby deletes  almost the entire small HBV surface protein. One of the patients had an additional 261-bp deletion in the preS1 / S2 region. Functional analyses of the mutations in vitro revealed that the rtS78T / sC69 * mutation, but not the preS1 / S2 deletion, greatly enhanced viral replication and conferred a reduced susceptibility to ETV and TDF. This partial resistance to antiviral favouring long-term persistence of these isolates, along with increased production of HBV transcripts and the sustained secretion of viral particles in the absence of antigenic domains of S protein, may predispose carcinogenic effects
LAY SUMMARY:

Long-term treatment with antiviral products with the risk of selecting mutations in the hepatitis B virus (HBV). We here report two cases of patients with insufficient response to dual tenofovir and entecavir therapy. Molecular analyses identified a clear mutation, rtS78T / sC69 * That is abolishes HBsAg detection, enhanced replication, sustained exosome-mediated virion secretion and decreased susceptibility to antivirals, thereby representing a potential high-risk mutation for HBV-infected individuals.
Copyright © 2017 European Association for the Study of the Liver. All rights reserved.
KEYWORDS:

HBV; HBsAg; HCC; drug resistance; exosome; mutations

PMID:
    28392234
DOI:
    10.1016 / j.jhep.2017.03.027

StephenW

基巴图特2017年4月6日。pii：S0168-8278（17）30198-8。 Doi：10.1016 / j.jhep.2017.03.027。 [提前印刷]
在替诺福韦恩替卡韦联合治疗期间，选择两例慢性乙型肝炎病毒感染患者的高度复制和部分多药耐药rtS78T聚合酶突变。
Shirvani-Dastgerdi E1，Winer BY2，Celia-Terrassa A2，Kang Y2，Tabernero D3，Yagmur E4，Rodríguez-FríasF3，Gregori J5，Luedde T6，Trautwein C6，Ploss A2，Tacke F7。
作者信息

1德国亚琛亚琛大学医院第三医学系;普林斯顿大学分子生物系，普林斯顿，新泽西州，美国。
2普林斯顿大学分子生物系，普林斯顿，新泽西州，美国。
3 Centro deInvestigaciónBiomédicaen Red de EnfermedadesHepáticasy Digestivas（CIBERehd），Instituto de Salud Carlos III，Madrid，Spain;肝脏单位，Vall d'Hebron研究所（VHIR），巴塞罗那自治大学（UAB），西班牙巴塞罗那
4医疗中心，Stein博士和同事，德国门兴格拉德巴赫。
5 Roche Diagnostics SL，Sant Cugat delVallès，西班牙
6德国亚琛亚琛大学医院第三医学系。
7德国亚琛亚琛大学附属医院三医院电子地址：[email protected]。

抽象

患有长期治疗核苷或核苷酸类似物的乙型肝炎病毒（HBV）长期感染的患者有选择具有复杂突变型HBV病毒株的风险。本文报道了两例乙型肝炎病毒感染患者，尽管采用恩替卡韦（ETV）和替诺福韦（TDF）进行双重抗病毒治疗，其中一例患者死于侵袭性肝细胞癌（HCC）。超深度焦磷酸测序分析显示在两种情况下选择rtS78T聚合酶突变，在sC69中产生过早终止密码子，从而几乎消除了整个小的HBV表面蛋白。其中一名患者在preS1 / S2区域内还有261 bp的缺失。体外突变的功能分析显示，rtS78T / sC69 *突变，但不是preS1 / S2缺失，显着增强病毒复制，并赋予对ETV和TDF的易感性降低。这种对抗病毒治疗的部分抗性有利于这些分离株的长期持续性，以及在没有S蛋白的抗原结构域的情况下HBV转录物的产生增加和病毒颗粒的持续分泌可能会导致致癌作用。
总结

用抗病毒药物进行长期治疗具有选择乙型肝炎病毒（HBV）突变的风险。我们在这里报告了两例对双重替诺福韦和恩替卡韦治疗反应不足的患者。分子分析确定了一个不同的突变，rtS78T / sC69 *，其消除HBsAg检测，增强复制，持续的外来体介导的病毒体分泌和降低对抗病毒药物的易感性，从而代表HBV感染个体潜在的高风险突变。

版权所有©2017欧洲肝脏研究协会。版权所有。
关键词：

HBV; HBsAg;肝癌;耐药性;外来体突变

PMID：
28392234
DOI：
10.1016 / j.jhep.2017.03.027

neilhbver

没看太明白，联合用药都耐药了？

StephenW

回复 neilhbver 的帖子

只有两个病人.联合用药不能完全病毒抑制 (10 - 100 copies/ml).

我个人的意见:
这个"部分"耐药性,长期结果不明, 因为一名病人死于HCC(联合用药之前有过HCC), 另一名病人自己停止治疗.