Cozzi-Lepri Alessandro, Noguera-Julian Marc, Di Giallonardo Francesca, Schuurman Rob, Däumer Martin, Aitken Sue, Ceccherini-Silberstein Francesca, D'Arminio Monforte Antonella, Geretti Anna Maria, Booth Clare L, Kaiser Rolf, Michalik Claudia, Jansen Klaus, Masquelier Bernard, Bellecave Pantxika, Kouyos Roger D, Castro Erika, Furrer Hansjakob, Schultze Anna, Günthard Huldrych F, Brun-Vezinet Francoise, Paredes Roger, Metzner Karin J
University College London, London, UK.
Institut de Recerca de la SIDA IrsiCaixa i Unitat VIH, Universitat Autònoma de Barcelona, Universitat de Vic, Catalonia, Spain.
J Antimicrob Chemother. 2015 Mar;70(3):930-40. doi: 10.1093/jac/dku426. Epub 2014 Oct 21.
It is still debated if pre-existing minority drug-resistant HIV-1 variants (MVs) affect the virological outcomes of first-line NNRTI-containing ART.
This Europe-wide case-control study included ART-naive subjects infected with drug-susceptible HIV-1 as revealed by population sequencing, who achieved virological suppression on first-line ART including one NNRTI. Cases experienced virological failure and controls were subjects from the same cohort whose viraemia remained suppressed at a matched time since initiation of ART. Blinded, centralized 454 pyrosequencing with parallel bioinformatic analysis in two laboratories was used to identify MVs in the 1%-25% frequency range. ORs of virological failure according to MV detection were estimated by logistic regression.
Two hundred and sixty samples (76 cases and 184 controls), mostly subtype B (73.5%), were used for the analysis. Identical MVs were detected in the two laboratories. 31.6% of cases and 16.8% of controls harboured pre-existing MVs. Detection of at least one MV versus no MVs was associated with an increased risk of virological failure (OR = 2.75, 95% CI = 1.35-5.60, P = 0.005); similar associations were observed for at least one MV versus no NRTI MVs (OR = 2.27, 95% CI = 0.76-6.77, P = 0.140) and at least one MV versus no NNRTI MVs (OR = 2.41, 95% CI = 1.12-5.18, P = 0.024). A dose-effect relationship between virological failure and mutational load was found.
Pre-existing MVs more than double the risk of virological failure to first-line NNRTI-based ART.
既往存在的少数耐药HIV-1变异株（MVs）是否会影响含一线非核苷类逆转录酶抑制剂（NNRTI）的抗逆转录病毒治疗（ART）的病毒学结局仍存在争议。
这项欧洲范围内的病例对照研究纳入了经群体测序显示感染药物敏感HIV-1的初治受试者，这些受试者在含一种NNRTI的一线ART治疗中实现了病毒学抑制。病例组经历了病毒学失败，对照组是来自同一队列的受试者，自ART开始后在匹配时间其病毒血症仍被抑制。在两个实验室采用盲法、集中的454焦磷酸测序及平行生物信息学分析来鉴定频率在1%-25%范围内的MVs。根据MV检测情况通过逻辑回归估计病毒学失败的比值比（OR）。
260份样本（76例病例和184例对照）用于分析，大部分为B亚型（73.5%）。在两个实验室检测到相同的MVs。31.6%的病例和16.8%的对照携带既往存在的MVs。检测到至少一种MV与未检测到MV相比，病毒学失败风险增加（OR = 2.75，95%置信区间[CI] = 1.35 - 5.60, P = 0.005）；对于至少一种MV与未检测到非核苷类逆转录酶抑制剂（NRTI）MVs相比（OR = 2.27，95% CI = 0.76 - 6.77, P = 0.140）以及至少一种MV与未检测到NNRTI MVs相比（OR = 2.41，95% CI = 1.12 - 5.18, P = 0.024），观察到类似的关联。发现病毒学失败与突变负荷之间存在剂量效应关系。
既往存在的MVs使基于一线NNRTI的ART发生病毒学失败的风险增加一倍以上。
