Larder B A, Kemp S D, Harrigan P R
Antiviral Therapeutic Research Unit, Wellcome Research Laboratories, Beckenham, Kent, UK.
Science. 1995 Aug 4;269(5224):696-9. doi: 10.1126/science.7542804.
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 (AZT, 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 decreased 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 AZT sensitive at 24 weeks of therapy, consistent with in vitro mutation studies.
迫切需要能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）耐药的突变体，通过病毒逆转录酶第184位残基突变为缬氨酸，在体外表现出敏感性，这也诱导了对（-）2'-脱氧-3'-硫代胞苷（3TC）的耐药性。此外，在两种药物的广泛体外筛选过程中未观察到AZT-3TC交叉耐药。在体内，AZT-3TC联合治疗导致血清HIV-1 RNA浓度的下降幅度明显大于单独使用AZT治疗，尽管缬氨酸-184突变体迅速出现。联合治疗组在治疗24周时评估的大多数样本仍对AZT敏感，这与体外突变研究一致。
