Uhlmann Erik J, Tebas Pablo, Storch Gregory A, Powderly William G, Lie Yolanda S, Whitcomb Jeannette M, Hellmann Nicholas S, Arens Max Q
Department of Pathology, Box 8118, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA.
J Clin Virol. 2004 Nov;31(3):198-203. doi: 10.1016/j.jcv.2004.03.012.
Cross resistance is common among the non-nucleoside reverse transcriptase inhibitors (NNRTIs). G190A appears in 5-15% of the patients treated with nevirapine or efavirenz who develop clinical resistance.
In this study we investigated the effect of G190A and other NNRTI substitutions on the phenotypic susceptibility to this class of drugs.
We identified 15 individuals, who after treatment with NNRTIs (nevirapine or efavirenz; median exposure of 20 months), developed isolated G190A, G190A in combination with K103N, or K103N alone. Phenotypic and genotypic analyses of stored plasma specimens were performed before and after the mutations occurred to assess NNRTI susceptibility.
All isolates that developed only G190A substitution became less susceptible to nevirapine (median: 125-fold) and efavirenz (median: 10-fold) but were 2.5-fold more sensitive to delavirdine (Wilcoxon P = 0.06). In the group with only K103N substitution, acquisition of resistance to all NNRTIs was observed. In the group with the double substitutions, G190A and K103N, delavirdine susceptibility decreased 13-fold, while resistance to nevirapine and efavirenz decreased by 239- and 154-folds, respectively (Kruskal-Wallis H P = 0.009).
The data suggest that the presence of a G190A substitution attenuates the phenotypic resistance associated with a K103N substitution, although resistance is still present. The in vivo significance of the increased phenotypic susceptibility to delavirdine is not known but could be evaluated in a clinical trial.
非核苷类逆转录酶抑制剂（NNRTIs）之间普遍存在交叉耐药性。在接受奈韦拉平或依非韦伦治疗并出现临床耐药的患者中，5% - 15%会出现G190A突变。
在本研究中，我们调查了G190A及其他NNRTI替代突变对这类药物表型敏感性的影响。
我们确定了15名个体，他们在接受NNRTIs（奈韦拉平或依非韦伦；中位暴露时间为20个月）治疗后，出现了单独的G190A突变、G190A与K103N联合突变或单独的K103N突变。在突变发生前后，对储存的血浆样本进行表型和基因型分析，以评估NNRTI敏感性。
所有仅发生G190A替代突变的分离株对奈韦拉平（中位值：125倍）和依非韦伦（中位值：10倍）的敏感性降低，但对地拉韦定的敏感性提高了2.5倍（Wilcoxon检验P = 0.06）。在仅发生K103N替代突变的组中，观察到对所有NNRTIs均产生耐药。在G190A和K103N双重替代突变组中，地拉韦定敏感性降低了13倍，而对奈韦拉平和依非韦伦的耐药性分别降低了239倍和154倍（Kruskal - Wallis H检验P = 0.009）。
数据表明，尽管仍存在耐药性，但G190A替代突变的存在减弱了与K103N替代突变相关的表型耐药性。对地拉韦定表型敏感性增加的体内意义尚不清楚，但可在临床试验中进行评估。
