Venturi G, Romano L, Catucci M, Riccio M L, De Milito A, Gonnelli A, Rubino M, Valensin P E, Zazzi M
Dipartimento di Biologia Molecolare, Università di Siena, Italy.
Eur J Clin Microbiol Infect Dis. 1999 Apr;18(4):274-82. doi: 10.1007/s100960050276.
To define factors predictive of failure to respond to nucleoside reverse-transcriptase inhibitors in human immunodeficiency virus type-1 (HIV-1)-infected subjects pretreated with zidovudine (ZDV), three groups of subjects shifted to double therapy with ZDV plus didanosine (ddI, n = 13), zalcitabine (ddC, n = 14), or lamivudine (3TC, n = 12) were retrospectively evaluated, with respect to addition of the second NRTI, at week 0 and week 24. Factors considered included duration of ZDV pretreatment, CD4+ cell counts, plasma HIV-1 RNA load, peripheral blood mononuclear cell HIV-1 DNA load, and HIV-1 DNA genotypic resistance to nucleoside reverse-transcriptase inhibitors. The three groups were well matched for baseline characteristics and did not differ significantly in virological and immunological response to the different combination treatments. Drug-specific resistance mutations were selected in more than half the cases by 3TC, but not by ddI and ddC. Low-level and substantial genotypic resistance to ZDV was detected 13 (33.3%) and in 19 (48.7%) patients at baseline, respectively, and evolved through week 24 in several patients. When subjects were divided into responders and nonresponders to the second nucleoside reverse-transcriptase inhibitor on the basis of a decrease of more than 0.5 log10 (n = 15) or less than 0.5 log10 (n = 21) in HIV-1 RNA, respectively, baseline genotypic ZDV resistance was the only independent predictor of failure in a logistic regression model (P = 0.003 or P = 0.024, depending on whether low-level resistance was considered or not, respectively). Thus, selection of ZDV resistance mutations may impair subsequent use of different nucleoside reverse-transcriptase inhibitor compounds.
为了确定在接受齐多夫定（ZDV）预处理的1型人类免疫缺陷病毒（HIV-1）感染受试者中，对核苷类逆转录酶抑制剂无反应的预测因素，我们对三组转而接受ZDV加去羟肌苷（ddI，n = 13）、扎西他滨（ddC，n = 14）或拉米夫定（3TC，n = 12）联合治疗的受试者进行了回顾性评估，评估内容为在第0周和第24周添加第二种核苷类逆转录酶抑制剂（NRTI）的情况。考虑的因素包括ZDV预处理的持续时间、CD4 +细胞计数、血浆HIV-1 RNA载量、外周血单个核细胞HIV-1 DNA载量以及HIV-1 DNA对核苷类逆转录酶抑制剂的基因型耐药性。三组受试者的基线特征匹配良好，对不同联合治疗的病毒学和免疫学反应无显著差异。超过半数的病例中由3TC选择出了药物特异性耐药突变，但ddI和ddC未出现这种情况。基线时分别在13例（33.3%）和19例（48.7%）患者中检测到对ZDV的低水平和显著基因型耐药，并且在数例患者中持续到了第24周。当根据HIV-1 RNA下降超过0.5 log10（n = 15）或低于0.5 log10（n = 21）将受试者分为对第二种核苷类逆转录酶抑制剂有反应者和无反应者时，在逻辑回归模型中，基线基因型ZDV耐药是无反应的唯一独立预测因素（P = 0.003或P = 0.024，分别取决于是否考虑低水平耐药）。因此，ZDV耐药突变的选择可能会损害后续不同核苷类逆转录酶抑制剂化合物的使用。
