通过表型方法重新研究乙肝病毒对恩替卡韦的耐药性

StephenW

Revisiting HBV resistance to entecavir with a phenotypic approach
Julien Marlet  1 , Clément Lier  2 , Emmanuelle Roch  3 , Morgan Maugey  3 , Alain Moreau  3 , Benjamin Combe  3 , Sandrine Lefeuvre  4 , Louis d'Alteroche  5 , Didier Barbereau  5 , Xavier Causse  6 , Frédéric Bastides  7 , Marie-Nadege Bachelier  8 , Denys Brand  2 , Catherine Gaudy-Graffin  2
Affiliations

    PMID: 32735901 DOI: 10.1016/j.antiviral.2020.104869

Abstract

Treatment adaptation after hepatitis B virus (HBV) treatment failure relies on genotypic resistance testing. However, the results of such tests are not always consistent with treatment response. These discrepancies may be due to differences in resistance levels between isolates with the same genotypic resistance testing profiles. We explored this hypothesis by investigating six cases of entecavir treatment failure with an integrative strategy combining genotypic and phenotypic resistance testing, medical record review and therapeutic drug monitoring. Among isolates with genotypic reduced susceptibility to entecavir, one displayed a higher level of resistance to entecavir (mean fold change in entecavir IC50 of 1 508 ± 531 vs. 318 ± 53, p=0.008). This isolate harbored a substitution (rt250L) at a position reported to be associated with resistance (rt250V). Reversion to wild-type amino acid at this position partially restored susceptibility to entecavir, confirming that the rt250L mutation was responsible for the high level of resistance to entecavir. This is the first description of entecavir treatment failure associated with selection of the rt250L mutation without other entecavir resistance mutations. One isolate with genotypic resistance to entecavir, harboring the rt173L mutation, displayed a lower level of resistance than the other, harboring the rt202G mutation (mean fold change of 323 ± 124 vs. 6 036 ± 2 100, p=0.20). These results suggest that isolates harboring the rt250L mutations should be considered resistant to entecavir, whereas isolates harboring the rt173L mutations should be considered to display reduced susceptibility to entecavir. An integrative approach to antiviral drug resistance in HBV would provide a more accurate assessment of entecavir treatment failures and help to improve the accuracy of genotypic testing algorithms.

Keywords: HBV; antiviral; entecavir; phenotypic; polymerase; resistance.

Copyright © 2020 Elsevier B.V. All rights reserved.

StephenW

通过表型方法重新研究乙肝病毒对恩替卡韦的耐药性
朱利安·马勒（Julien Marlet）1，克莱门特·里尔（ClémentLier）2，艾曼纽·罗奇（Emmanuelle Roch）3，摩根·莫格（Morgan Maugey）3，阿兰·莫罗（Alain Moreau）3，本杰明·科姆（Benjamin Combe）3，桑德琳·列弗弗（Sandrine Lefeuvre）4，路易·达·阿尔泰罗什（Louis d'Alteroche）5，迪迪埃·巴贝罗（Didier Barbereau）5，泽维尔·考斯（6）丹尼斯品牌2，凯瑟琳·高迪·格拉芬2
隶属关系

    PMID：32735901 DOI：10.1016 / j.antiviral.2020.104869

抽象

乙型肝炎病毒（HBV）治疗失败后的治疗适应性取决于基因型耐药性测试。但是，此类测试的结果并不总是与治疗反应一致。这些差异可能是由于具有相同基因型抗性测试图谱的分离株之间的抗性水平差异所致。我们通过结合基因型和表型耐药性测试，病历审查和治疗药物监测的综合策略，调查了6例恩替卡韦治疗失败的病例，从而探索了这一假设。基因型对恩替卡韦敏感性降低的分离株中，对恩替卡韦的耐药性更高（恩替卡韦IC50的平均倍数变化为1 508±531对318±53，p = 0.008）。该分离株在据报道与抗性（rt250V）相关的位置带有一个替代（rt250L）。在此位置恢复为野生型氨基酸可部分恢复对恩替卡韦的敏感性，这证实rt250L突变是对恩替卡韦的高水平耐药性的原因。这是对恩替卡韦治疗失败的首次描述，该治疗失败与没有其他恩替卡韦耐药突变的rt250L突变的选择有关。带有rt173L突变的对恩替卡韦具有基因型抗性的分离株显示出比另一个带有rt202G突变的抗性低的分离株（平均倍数变化为323±124对6036±2 100，p = 0.20）。这些结果表明，携带rt250L突变的分离株应被视为对恩替卡韦具有抗性，而携带rt173L突变的分离株应被视为对恩替卡韦的敏感性降低。乙肝病毒抗病毒耐药性的综合方法将提供对恩替卡韦治疗失败的更准确评估，并有助于提高基因型测试算法的准确性。

关键字：HBV；抗病毒物质;恩替卡韦表型聚合酶抵抗性。

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