Cross-Resistance Testing of Next-Generation Nucleoside and Nucleotide Analogues against Lamivudine-Resistant HBV
Cross-Resistance Testing of Next-Generation Nucleoside and Nucleotide Analogues against Lamivudine-Resistant HBV
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DOI：
10.1177/135965350501000507
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发表时间：
2005-07
影响因子：
1.2
通讯作者：
Huiling Yang;X. Qi;Alex Sabogal;Michael I. Miller;S. Xiong;W. Delaney
中科院分区：
文献类型：
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作者：
Huiling Yang;X. Qi;Alex Sabogal;Michael I. Miller;S. Xiong;W. Delaney
几种新一代核苷和核苷酸类似物目前正在临床开发中，用于治疗慢性乙型肝炎。然而，新药物对拉米夫定耐药乙型肝炎病毒（HBV）的疗效尚未得到充分探索。为了在体外研究这一点，我们产生了一种新的稳定的表达HBV的细胞系，该细胞系编码拉米夫定耐药突变的四种主要模式（rtL180M+rtM204V, rtV173L+rtL180M+rtM204V， rtM204I和rtL180M+ rtM204I）。利用这些细胞系，我们评估了所有4株拉米夫定耐药HBV在临床发展的不同阶段对11种核苷类似物的敏感性。我们的研究表明，拉米夫定耐药HBV对无环膦酸盐核苷酸（阿德福韦、替诺福韦和阿拉米福韦）仍然敏感，对恩替卡韦的敏感性降低，并且对所有l -核苷（包括恩曲他滨、替比夫定、克利夫定和托西他滨）具有高水平的交叉耐药。
Several next-generation nucleoside and nucleotide analogues are currently in clinical development for the treatment of chronic hepatitis B. However, the efficacy of newer agents against lamivudine-resistant hepatitis B virus (HBV) has not been fully explored. To investigate this in vitro, we generated novel stable cell lines expressing HBV encoding the four major patterns of lamivudine resistance mutations (rtL180M+rtM204V, rtV173L+rtL180M+rtM204V, rtM204I and rtL180M+ rtM204I). Using these cell lines, we assessed the susceptibility of all four strains of lamivudine-resistant HBV to eleven nucleoside analogues in various stages of clinical development. Our studies indicate that lamivudine-resistant HBV remain sensitive to acyclic phosphonate nucleotides (adefovir, tenofovir, and alamifovir), have reduced susceptibility to entecavir, and have high-level cross-resistance to all L-nucleosides tested including emtricitabine, telbivudine, clevudine, and torcitabine.