Combinations of adefovir with nucleoside analogs produce additive antiviral effects against hepatitis B virus in vitro
Combinations of adefovir with nucleoside analogs produce additive antiviral effects against hepatitis B virus in vitro
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DOI：
10.1128/aac.48.10.3702-3710.2004
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发表时间：
2004-10-01
影响因子：
4.9
通讯作者：
Xiong, S
中科院分区：
文献类型：
--
作者：
Delaney, WE;Yang, HL;Xiong, S
联合治疗可能需要长期管理的一些患者慢性感染B型肝炎病毒（HBV）。阿德福韦是一种核苷酸类似物，对野生型和拉米夫定耐药HBV具有相似的活性。与拉米夫定相反，对前体药物阿德福韦酯的临床耐药性很少出现。基于其临床疗效和低频率的耐药，阿德福韦酯可能成为联合治疗方案的重要组成部分。因此，我们研究了阿德福韦与其他核苷类似物（拉米夫定，恩替卡韦，恩曲他滨[FrC]和替比夫定[L-dT]）和核苷酸类似物替诺福韦的体外抗病毒疗效。使用一种表达高水平野生型HBV的新型稳定细胞系，我们测定了每种药物单独使用和与阿德福韦酯联合使用的抗病毒活性。所有的两种药物组合导致更大的抗病毒效果比单药治疗，并可以表征为加性的布利斯独立模型。使用Loewe加和模型分析表明，阿德福韦酯与拉米夫定，FTC，或L-dT联合使用时产生的抗病毒效果和中度协同作用时，与恩替卡韦或替诺福韦。在试验剂量下单独使用或联合使用时，任何药物均无细胞毒性证据。
Combination therapies may be required for long-term management of some patients chronically infected with hepatitis B virus (HBV). Adefovir is a nucleotide analog that has similar activity against wild-type and lamivudine-resistant HBV. In contrast to lamivudine, clinical resistance to the prodrug adefovir dipivoxil emerges infrequently. Based on its clinical efficacy and low frequency of resistance, adefovir dipivoxil may form an important component of combination regimens. We therefore investigated the in vitro antiviral efficacy of combinations of adefovir with other nucleoside analogs (lamivudine, entecavir, emtricitabine [FrC],and telbivudine [L-dT]) and the nucleotide analog tenofovir. Using a novel stable cell line that expresses high levels of wild-type HBV, we assayed the antiviral activity of each drug alone and in combination with adefovir. All two-drug combinations resulted in greater antiviral effects than treatments with single agents and could be characterized as additive by the Bliss independence model. Analysis using the Loewe additivity model indicated that adefovir exerted additive antiviral effects when combined with lamivudine, FTC, or L-dT and moderately synergistic effects when combined with entecavir or tenofovir. There was no evidence of cytotoxicity with any of the drugs when used alone or in combination at the tested doses.