Mayers D
Walter Reed Army Institute of Research, Rockville, Maryland, USA.
AIDS. 1996 Nov;10 Suppl 1:S9-13.
To review knowledge of drug-resistance patterns to nucleoside HIV reverse transcriptase inhibitors and how this can be used to advantage in patient management.
The speed of emergence of HIV-1 drug resistance is dependent on host, viral and drug factors. Resistance to zidovudine develops over months to years, and is associated with mutations in HIV reverse transcriptase at positions 41, 67, 70, 215 and 219. Reductions in susceptibility to didanosine, zalcitabine and stavudine develop more slowly and are lower than those seen with zidovudine. Resistance to lamivudine develops rapidly, in weeks to months; selection of a pre-existing mutated viral strain results in a 1000-fold reduction in susceptibility. There is some cross-resistance between nucleoside antiretroviral agents, particularly among didanosine, zalcitabine and lamivudine.
Some agents induce mutations that reverse or suppress zidovudine resistance; combination therapy with these drugs may delay the emergence of multidrug-resistance, but the mutational flexibility of the HIV-1 virus means that drug resistant isolates will eventually develop. Combining HIV protease inhibitors that strongly suppress viral replication with nucleoside inhibitors also delays the emergence of resistance.
Widespread use of nucleoside HIV reverse transcriptase inhibitors that incompletely suppress viral replication has led to the emergence of resistant viral strains, with a consequent risk of transmission of drug-resistant virus. Combinations of protease inhibitors and reverse transcriptase inhibitors may slow viral replication sufficiently to prevent generation of resistant virus, to extend the duration of antiviral activity and increase the benefit to patients.
回顾对核苷类HIV逆转录酶抑制剂耐药模式的认识，以及如何在患者管理中利用这一知识。
HIV-1耐药性出现的速度取决于宿主、病毒和药物因素。对齐多夫定的耐药性在数月至数年的时间里逐渐形成，与HIV逆转录酶第41、67、70、215和219位的突变有关。对去羟肌苷、扎西他滨和司他夫定的敏感性降低发展较为缓慢，且低于齐多夫定。对拉米夫定的耐药性在数周至数月内迅速出现；选择预先存在的突变病毒株会导致敏感性降低1000倍。核苷类抗逆转录病毒药物之间存在一些交叉耐药性，尤其是在去羟肌苷、扎西他滨和拉米夫定之间。
一些药物可诱导逆转或抑制齐多夫定耐药性的突变；与这些药物联合治疗可能会延迟多药耐药性的出现，但HIV-1病毒的突变灵活性意味着最终仍会产生耐药毒株。将强烈抑制病毒复制的HIV蛋白酶抑制剂与核苷抑制剂联合使用也可延迟耐药性的出现。
广泛使用不能完全抑制病毒复制的核苷类HIV逆转录酶抑制剂已导致耐药病毒株的出现，从而带来耐药病毒传播的风险。蛋白酶抑制剂和逆转录酶抑制剂联合使用可能会充分减缓病毒复制，以防止产生耐药病毒，延长抗病毒活性的持续时间并增加对患者的益处。
