POTENTIAL MECHANISM FOR SUSTAINED ANTIRETROVIRAL EFFICACY OF AZT-3TC COMBINATION THERAPY
POTENTIAL MECHANISM FOR SUSTAINED ANTIRETROVIRAL EFFICACY OF AZT-3TC COMBINATION THERAPY
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DOI：
10.1126/science.7542804
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发表时间：
1995-08-04
期刊：
影响因子：
56.9
通讯作者：
HARRIGAN, PR
中科院分区：
文献类型：
--
作者：
LARDER, BA;KEMP, SD;HARRIGAN, PR
迫切需要能够预防或延缓耐药性人类免疫缺陷病毒1型（HIV - 1）突变体出现的抗逆转录病毒药物组合。对3'-叠氮胸苷（AZT，齐多夫定）有抗性的突变体，通过病毒逆转录酶的184位残基突变为缬氨酸，在体外表型上变得敏感，这一突变同时诱导了对（-）2'-脱氧-3'-硫代胞苷（3TC）的抗性。此外，在两种药物的大量体外筛选过程中未观察到AZT - 3TC的共抗性。在体内，AZT - 3TC联合疗法导致血清HIV - 1 RNA浓度的下降幅度明显大于单独使用AZT的治疗，尽管缬氨酸 - 184突变体迅速出现。联合治疗组中大多数在治疗24周时评估的样本仍对AZT敏感，这与体外突变研究结果一致。
Combinations of antiretroviral drugs that prevent or delay the appearance of drug-resistant human immunodeficiency virus-type 1 (HIV-1) mutants are urgently required. Mutants resistant to 3'-azidothymidine (ATT, zidovudine) became phenotypically sensitive in vitro by mutation of residue 184 of viral reverse transcriptase to valine, which also induced resistance to (-)2'-deoxy-3'-thiacytidine (3TC). Furthermore, AZT-3TC coresistance was not observed during extensive in vitro selection with both drugs. In vivo AZT-3TC combination therapy resulted in a markedly greater decrease in serum HIV-1 RNA concentrations than treatment with AZT alone, even though valine-184 mutants rapidly emerged. Most samples assessed from the combination group remained ATT sensitive at 24 weeks of therapy, consistent with in vitro mutation studies.