的富马酸替诺福韦酯对耐药性HBV克隆。

StephenW

J Infect. 2015 Oct 26. pii: S0163-4453(15)00339-4. doi: 10.1016/j.jinf.2015.09.038. [Epub ahead of print]
Effect of tenofovir disoproxil fumarate on drug-resistant HBV clones.Murakami E1, Tsuge M2, Hiraga N1, Kan H1, Uchida T1, Masaki K1, Nakahara T1, Ono A1, Miki D3, Kawaoka T1, Abe H1, Imamura M1, Aikata H1, Ochi H3, Hayes CN1, Akita T4, Tanaka J5, Kazuaki Chayama6.
Author information

• 1Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan.
• 2Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan; Natural Science Center for Basic Research and Development, Hiroshima University, Hiroshima, Japan.
• 3Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan; Laboratory for Digestive Diseases, Center for Genomic Medicine, The Institute of Physical and Chemical Research (RIKEN), Hiroshima, Japan.
• 4Department of Epidemiology, Infectious Disease Control and Prevention, Integrated Health Sciences, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan.
• 5Liver Research Project Center, Hiroshima University, Hiroshima, Japan; Department of Epidemiology, Infectious Disease Control and Prevention, Integrated Health Sciences, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan.
• 6Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan; Laboratory for Digestive Diseases, Center for Genomic Medicine, The Institute of Physical and Chemical Research (RIKEN), Hiroshima, Japan. Electronic address: [email protected].
  


AbstractBACKGROUND & AIMS: Tenofovir disoproxil fumarate (TDF) has been approved for chronic hepatitis B treatment, and favorable susceptibility of hepatitis B virus (HBV) has been indicated. However, differences in TDF susceptibility among HBV genotypes and drug-resistant strains are unclear. In this study, TDF susceptibilities between genotypes A and C were evaluated in vitro and in vivo using several drug-resistant HBV clones.
METHODS: HBV expression plasmids were constructed from sera of HBV carriers, and drug-resistant substitutions were introduced by site-directed mutagenesis. TDF susceptibility was evaluated by changes of core-associated HBV replication intermediates in vitro or by change of serum HBV DNA in human hepatocyte chimeric mice carrying each HBV clone in vivo.
RESULTS: TDF susceptibilities of lamivudine-resistant clones (rtL180M/M204V) and lamivudine plus entecavir-resistant clones (rtL180M/S202G/M204V) were similar to wild type clones in vitro. However, lamivudine plus adefovir-resistant clones (rtA181T/N236T) acquired tolerance to TDF, and the rtN236T mutation was considered to be a causal substitution for TDF resistance. Furthermore, genotypic differences in TDF susceptibility were also observed between genotypes A and C in vitro, and the differences could be confirmed in vivo (p=0.023).
CONCLUSIONS: The present study indicates that TDF susceptibility varies among HBV genotypes and drug-resistant HBV clones.
Copyright © 2015. Published by Elsevier Ltd.


KEYWORDS: HBV genotype; Hepatitis B virus; drug resistance; susceptibility; tenofovir disoproxil fumarate

PMID:26515673 [PubMed - as supplied by publisher]

StephenW

Ĵ传染。 2015年26月PII：S0163-4453（15）00339-4。 DOI：10.1016 / j.jinf.2015.09.038。 [打印EPUB提前]
的富马酸替诺福韦酯对耐药性HBV克隆。
村上E1，柘植M2，平贺N1，菅直人H1，内田T1，正树K1，中原T1，小野A1，三木D3，河冈T1，安倍晋三H1，今村M1，Aikata H1，越智H3，海耶斯CN1，秋田T4，田中J5 ，和明Chayama6。
作者信息

    教研室胃肠病学和代谢，应用生命科学，生物医学和健康科学，广岛大学，广岛，日本研究所;肝病研究项目中心，广岛大学，日本广岛。
    教研室胃肠病学和代谢，应用生命科学，生物医学和健康科学，广岛大学，广岛，日本研究所;肝病研究项目中心，广岛大学，日本广岛;自然科学中心的基础研究和开发，广岛大学，日本广岛。
    3Department胃肠病学和代谢，应用生命科学，生物医学和健康科学，广岛大学，广岛，日本研究所;肝病研究项目中心，广岛大学，日本广岛;实验室消化系统疾病，中心基因医学，物理和化学研究的研究所（RIKEN），日本广岛。
    4Department流行病学，传染病预防控制，综合保健科学，生物医学及健康科学研究所，广岛大学，广岛，日本。
    5Liver研究项目中心，广岛大学，日本广岛;流行病学，传染病预防控制，综合保健科学，生物医学及健康科学研究所，广岛大学，广岛，日本系。
    6Department胃肠病学和代谢，应用生命科学，生物医学和健康科学，广岛大学，广岛，日本研究所;肝病研究项目中心，广岛大学，日本广岛;实验室消化系统疾病，中心基因医学，物理和化学研究的研究所（RIKEN），日本广岛。电子地址：[email protected]。

抽象的
背景与目的：

富马酸替诺福韦酯（TDF）已被批准用于治疗慢性乙型肝炎治疗，和乙型肝炎病毒的有利易感性（HBV）已经指出。然而，HBV基因型和药物抗性株中在TDF敏感性的差异不明确。在这项研究中，基因型A和C之间的TDF磁化率使用几种药物耐药HBV克隆在体外和体内进行评价。
方法：

HBV的表达质粒从HBV携带者的血清构成，耐药取代通过定点诱变引入。 TDF的敏感性是由核相关的HBV复制中间体在体外或在履行体内各HBV克隆人类肝细胞嵌合体小鼠血清HBV DNA变化而变化评估。
结果：

拉米夫定耐药株（rtL180M / M204V）和拉米夫定加恩替卡韦耐药克隆（rtL180M / S202G / M204V）TDF敏感性是相似的体外野生型的克隆。然而，拉米夫定加阿德福韦耐药克隆（rtA181T / N236T）后天耐受TDF，并且rtN236T突变被认为是有因果取代TDF阻力。此外，也基因型A和C之间观察体外药敏TDF基因型差异，其差异可在体内（P = 0.023）得到证实。
结论：

目前的研究表明，TDF敏感性HBV基因型和耐药性HBV克隆的不同而不同。

版权所有©2015年出版Elsevier公司
关键词：

HBV基因型;乙型肝炎病毒;耐药性;敏感性;富马酸替诺福韦酯