aDepartment of HIV/GUM, Imperial College Healthcare NHS Trust bMRC Clinical Trials Unit, London cDepartment of Clinical Virology, Manchester Royal Infirmary, Manchester dResearch Department of Infection and Population Health, UCL Medical School, London eInstitute of Infection & Global Health, University of Liverpool, Liverpool, UK.
AIDS. 2013 Sep 10;27(14):2245-53. doi: 10.1097/QAD.0b013e3283636179.
HIV-1 genetic variability may influence antiretroviral therapy (ART) outcomes. The study aim was to determine the impact of polymorphisms in regions known to harbor major nonnucleoside reverse transcriptase inhibitor (NNRTI) resistance mutations (codons 90-108, 135-138, 179-190, 225-348) on virologic responses to first-line NNRTI-based ART.
Reverse transcriptase sequences from ART-naive individuals who commenced efavirenz (EFV) or nevirapine (NVP) with at least two nucleos(t)ide reverse transcriptase inhibitors (NRTIs) without major drug resistance mutations were analyzed. The impact of polymorphisms on week 4 viral load decrease and time to virologic failure was measured over a median 97 weeks.
Among 4528 patients, most were infected with HIV-1 subtype B (67%) and commenced EFV-based ART (84%). Overall, 2598 (57%) had at least one polymorphism, most frequently at codons 90, 98, 101, 103, 106, 135, 138, 179, and 238. Virologic failure rates were increased in patients with two (n = 597) or more than two (n = 72) polymorphisms [adjusted hazard ratio 1.43; 95% confidence interval (CI) 1.07-1.92; P = 0.016]. Polymorphisms associated with virologic failure occurred at codons 90 (mostly V90I), 98 (mostly A98S), and 103 (mostly K103R), with adjusted hazard ratios of 1.78 (1.15-2.73; P = 0.009), 1.55 (1.16-2.08; P = 0.003), and 1.75 (1.00-3.05: P = 0.049), respectively. Polymorphisms at codon 179, especially V179D/E/T, predicted reduced week 4 responses (P = 0.001) but not virologic failure.
The occurrence of multiple polymorphisms, though uncommon, was associated with a small increase in the risk of NNRTI treatment failure; significant effects were seen with polymorphisms at codon 90, 98, and 103. The mechanisms underlying the slower suppression seen with V179D/E/T deserve further investigation.
HIV-1 遗传变异性可能影响抗逆转录病毒治疗（ART）的效果。本研究旨在确定与主要非核苷类逆转录酶抑制剂（NNRTI）耐药突变（密码子 90-108、135-138、179-190、225-348）相关的区域中的多态性对基于 NNRTI 的一线 ART 的病毒学反应的影响。
分析了开始接受依非韦伦（EFV）或奈韦拉平（NVP）联合至少两种核苷（酸）逆转录酶抑制剂（NRTIs）且无主要耐药突变的 ART 初治个体的逆转录酶序列。中位 97 周内，测量多态性对第 4 周病毒载量下降和病毒学失败时间的影响。
在 4528 名患者中，大多数感染了 HIV-1 亚型 B（67%）并开始接受 EFV 为基础的 ART（84%）。总体而言，2598 名（57%）患者至少有一种多态性，最常见的是密码子 90、98、101、103、106、135、138、179 和 238。有两种（n=597）或两种以上（n=72）多态性的患者病毒学失败率增加[调整后的危险比 1.43；95%置信区间（CI）1.07-1.92；P=0.016]。与病毒学失败相关的多态性发生在密码子 90（主要是 V90I）、98（主要是 A98S）和 103（主要是 K103R），调整后的危险比分别为 1.78（1.15-2.73；P=0.009）、1.55（1.16-2.08；P=0.003）和 1.75（1.00-3.05：P=0.049）。密码子 179 的多态性，特别是 V179D/E/T，预测第 4 周反应降低（P=0.001），但不预测病毒学失败。
尽管不常见，但多种多态性的发生与 NNRTI 治疗失败的风险略有增加相关；在密码子 90、98 和 103 中观察到显著的影响。V179D/E/T 更快抑制的机制值得进一步研究。
