Section of Retroviral Therapeutics, Brigham and Women's Hospital, Harvard Medical School, Harvard University, Boston, Massachusetts 02139, USA.
JAMA. 2011 Apr 6;305(13):1327-35. doi: 10.1001/jama.2011.375.
Presence of low-frequency, or minority, human immunodeficiency virus type 1 (HIV-1) drug resistance mutations may adversely affect response to antiretroviral treatment (ART), but evidence regarding the effects of such mutations on the effectiveness of first-line ART is conflicting.
To evaluate the association of preexisting drug-resistant HIV-1 minority variants with risk of first-line nonnucleoside reverse transcriptase inhibitor (NNRTI)-based antiretroviral virologic failure.
Systematic review of published and unpublished studies in PubMed (1966 through December 2010), EMBASE (1974 through December 2010), conference abstracts, and article references. Authors of all studies were contacted for detailed laboratory, ART, and adherence data.
Studies involving ART-naive participants initiating NNRTI-based regimens were included. Participants were included if all drugs in their ART regimen were fully active by standard HIV drug resistance testing. Cox proportional hazard models using pooled patient-level data were used to estimate the risk of virologic failure based on a Prentice weighted case-cohort analysis stratified by study.
Individual data from 10 studies and 985 participants were available for the primary analysis. Low-frequency drug resistance mutations were detected in 187 participants, including 117 of 808 patients in the cohort studies. Low-frequency HIV-1 drug resistance mutations were associated with an increased risk of virologic failure (hazard ratio (HR], 2.3 [95% confidence interval {CI}, 1.7-3.3]; P < .001) after controlling for medication adherence, race/ethnicity, baseline CD4 cell count, and plasma HIV-1 RNA levels. Increased risk of virologic failure was most strongly associated with minority variants resistant to NNRTIs (HR, 2.6 [95% CI, 1.9-3.5]; P < .001). Among participants from the cohort studies, 35% of those with detectable minority variants experienced virologic failure compared with 15% of those without minority variants. The presence of minority variants was associated with 2.5 to 3 times the risk of virologic failure at either 95% or greater or less than 95% overall medication adherence. A dose-dependent increased risk of virologic failure was found in participants with a higher proportion or quantity of drug-resistant variants.
In a pooled analysis, low-frequency HIV-1 drug resistance mutations, particularly involving NNRTI resistance, were significantly associated with a dose-dependent increased risk of virologic failure with first-line ART.
低频或少数人 HIV-1 耐药突变可能会对艾滋病抗病毒治疗（ART）的反应产生不利影响，但关于这些突变对一线 ART 效果的影响的证据存在冲突。
评估预先存在的抗 HIV-1 少数耐药变体与一线非核苷逆转录酶抑制剂（NNRTI）为基础的抗逆转录病毒病毒学失败的风险。
在 PubMed（1966 年至 2010 年 12 月）、EMBASE（1974 年至 2010 年 12 月）、会议摘要和文章参考文献中进行了发表和未发表研究的系统评价。所有研究的作者均被联系以获取详细的实验室、ART 和依从性数据。
纳入了开始接受 NNRTI 为基础方案的无 ART 经验的参与者的研究。如果参与者的 ART 方案中的所有药物都能通过标准的 HIV 耐药性检测完全有效，则将其纳入研究。使用合并的患者水平数据的 Cox 比例风险模型，根据 Prentice 加权病例对照分析，按研究分层，估计病毒学失败的风险。
主要分析中，可获得 10 项研究和 985 名参与者的个体数据。在 187 名参与者中检测到低频耐药突变，包括队列研究中的 808 名患者中的 117 名。在控制药物依从性、种族/民族、基线 CD4 细胞计数和血浆 HIV-1 RNA 水平后，低频 HIV-1 耐药突变与病毒学失败的风险增加相关（危险比（HR），2.3 [95%置信区间（CI），1.7-3.3]；P <.001）。病毒学失败的风险增加与对 NNRTI 耐药的少数耐药变体最密切相关（HR，2.6 [95% CI，1.9-3.5]；P <.001）。在队列研究参与者中，与没有少数耐药变体的参与者相比，35%的可检测到少数耐药变体的参与者经历了病毒学失败，而 15%的参与者没有少数耐药变体。少数变体的存在与 95%或更高或低于 95%的总体药物依从性下病毒学失败的风险增加 2.5 至 3 倍相关。在具有更高比例或数量的耐药变异体的参与者中，发现病毒学失败的风险呈剂量依赖性增加。
在一项合并分析中，低频 HIV-1 耐药突变，特别是涉及 NNRTI 耐药的突变，与一线 ART 病毒学失败的风险呈剂量依赖性增加显著相关。
