发现新的恩替卡韦抗性乙型肝炎病毒逆转录酶A181C替代综合基

StephenW

Hepatol Commun. 2018 Aug 21;2(9):1123-1135. doi: 10.1002/hep4.1231. eCollection 2018 Sep.
Discovery of the Novel Entecavir-Resistant Hepatitis B Virus Reverse Transcriptase A181C Substitution From an Integrated Genotypic Analysis.
Rose RE1, Hernandez D1, Falk PJ1, Ericson K1, Zhou N1, Thiry A1, McPhee F1.
Author information

1
    Bristol-Myers Squibb Pharmaceutical Research and Development Wallingford CT.

Abstract

Entecavir (ETV) is a first-line therapy for chronic hepatitis B virus (HBV), demonstrating potent suppression of HBV DNA and a high barrier to viral resistance. Previous studies revealed that ETV-resistant (ETVr) HBV DNA resulted from substitutions in the HBV reverse transcriptase (RT) at positions rtT184, rtS202, or rtM250 in combination with lamivudine resistance (LVDr) substitutions rtM204I/V±rtL180M. In vitro, viral variants exhibit varying degrees of ETV susceptibility and replication capacity depending on specific resistance substitutions. To explore the potential for additional pathways to ETVr, HBV RT sequences from 982 evaluable patients enrolled in 17 ETV clinical studies were analyzed. Thirty novel emergent substitutions at amino acid positions not previously associated with HBV nucleos(t)ide drug resistance were observed in at least 2 patients and were identified in patient-derived HBV with a wild-type, LVDr, or ETVr RT sequence. Phenotypic analysis of these substitutions indicated that they had no effect on ETV susceptibility. Phenotypic analysis was also performed on patient-derived HBV RT sequences from 10 LVD-naive and 13 LVD-experienced patients with virologic breakthrough and emergent novel substitutions while on ETV treatment. One LVD-experienced patient-derived HBV RT harboring LVDr substitutions rtL180M+rtM204V with rtA181C displayed reduced ETV susceptibility (122-fold greater than wild-type HBV) and remained susceptible to adefovir and tenofovir. HBV harboring the rtA181C substitution without LVDr substitutions rtL180M+rtM204V remained susceptible to inhibition by ETV, adefovir, and tenofovir, although cross-resistance to LVD and telbivudine was observed. Conclusion: An integrated genotypic analysis of HBV RT sequences from patients with chronic HBV treated with ETV led to the discovery of the novel ETVr substitution rtA181C. This substitution was always detected in combination with LVDr substitutions rtL180M+rtM204V in ETV-treated patients.

PMID:
    30202825
PMCID:
    PMC6128232
DOI:
    10.1002/hep4.1231

StephenW

Hepatol Commun。 2018年8月21日; 2（9）：1123-1135。 doi：10.1002 / hep4.1231。 eCollection 2018年9月
发现新的恩替卡韦抗性乙型肝炎病毒逆转录酶A181C替代综合基因型分析。
Rose RE1，Hernandez D1，Falk PJ1，Ericson K1，Zhou N1，Thiry A1，McPhee F1。
作者信息

1
    Bristol-Myers Squibb药物研究与开发Wallingford CT。

抽象

恩替卡韦（ETV）是慢性乙型肝炎病毒（HBV）的一线治疗药物，表现出对HBV DNA的有效抑制和对病毒抗性的高度屏障。先前的研究显示，ETV抗性（ETVr）HBV DNA是由于在rtT184，rtS202或rtM250位置的HBV逆转录酶（RT）中的取代与拉米夫定抗性（LVDr）取代rtM204I / V±rtL180M的组合而产生的。在体外，病毒变体表现出不同程度的ETV易感性和复制能力，这取决于具体的抗性替代。为了探索ETVr的其他途径的可能性，分析了参加17个ETV临床研究的982名可评估患者的HBV RT序列。在至少2名患者中观察到在先前未与HBV核（t）ide药物抗性相关的氨基酸位置处的30个新的紧急取代，并且在具有野生型，LVDr或ETVr RT序列的患者衍生的HBV中鉴定。这些取代的表型分析表明它们对ETV易感性没有影响。还对来自10名LVD初治患者和13名LVD患者的患者来源的HBV RT序列进行了表型分析，所述患者在ETV治疗时具有病毒学突破和新出现的新替代。一个LVD经历的患者来源的HBV RT携带LVDr替换rtL180M + rtM204V与rtA181C显示出降低的ETV易感性（比野生型HBV高122倍）并且仍然对阿德福韦和替诺福韦敏感。尽管观察到对LVD和替比夫定的交叉抗性，但在没有LVDr取代的情况下携带rtA181C替代的HBV rtL180M + rtM204V仍然易受ETV，阿德福韦和替诺福韦的抑制。结论：对ETV治疗的慢性HBV患者HBV RT序列进行综合基因型分析，发现了新的ETVr替代rtA181C。总是在ETV治疗的患者中结合LVDr取代rtL180M + rtM204V检测到该取代。

结论：
    30202825
PMCID：
    PMC6128232
DOI：
    10.1002 / hep4.1231

StephenW

https://aasldpubs.onlinelibrary. ... f/10.1002/hep4.1231