Background

Although experts have recommended testing for pretreatment drug resistance (PDR) before antiretroviral therapy (ART) initiation, there is little evidence to support its implementation. We aimed to establish whether an inexpensive point mutation assay can improve virological suppression by identifying PDR to guide drug selection for ART in a lower-middle income country.

Methods

Investigators did an open-label, randomised controlled trial at three HIV treatment sites in Kenya: two in Nairobi and one in rural Maseno. Individuals (aged ≥2 years) were eligible to participate if they were confirmed HIV-seropositive, qualified for first-line ART, planned to reside in the area for more than 1 year, and provided informed consent. We randomly assigned participants (1:1) to either PDR testing by oligonucleotide ligation assay (OLA) to guide selection of ART or to standard of care, which did not include OLA testing. The OLA-guided therapy group had pre-ART peripheral blood mononuclear cells evaluated for drug resistance to non-nucleoside reverse transcriptase inhibitor (NNRTI) at codons Lys103Asn, Tyr181Cys, Gly190Ala, and to lamivudine at Met184Val, and when at least one drug-resistant codon was detected in a participant's pre-ART specimen, clinicians were directed to prescribe protease inhibitor-based second-line ART. Those without detected resistance and those who were randomised to standard of care received NNRTI-based first-line ART. The primary outcome was plasma HIV-1 RNA of at least 400 copies per mL at 4, 8, or 12 months after ART initiation, which defined virological failure, assessed in all participants who received treatment (data were censored for those lost-to-follow-up or who died). The study has been completed and is registered with ClinicalTrials.gov, NCT01898754.

Findings

We screened 1198 participants between May 28, 2013, and Nov 4, 2014, of whom 991 (83%) were enrolled (492 received OLA and 495 received standard of care; four did not begin treatment). 93 participants (prevalence 9·4%) had PDR (95% CI 7·7–11·4). 34 (8·5%) of 400 participants in the OLA group had virological failure at month 12 of ART (95% CI 6·0–11·7) compared with 39 (9·7%) of 402 (7·0–13·0) in the standard-of-care group (log-rank p=0·26). Among participants with PDR, virological failure was lower in the OLA-guided therapy group than in the standard-of-care group: five (14%) of 35 compared with 13 (50%) of 26; p=0·0020). Among those prescribed NNRTI-based ART, participants given efavirenz were less likely to have virological failure than were those receiving nevirapine (odds ratio 0·37, 95% CI 0·22–0·62; p<0·0001). The OLA-guided therapy group had 39 serious non-lethal adverse events and 34 deaths. The standard-of-care group had 34 severe adverse events and 43 deaths, differences that were not significant. Adverse events judged to potentially be due to ART were few and similar between groups, with 17 (16%) in the OLA-guided therapy group and 16 (16%) in the standard-of-care group (p=0·90).

Interpretation

Our finding that OLA testing for PDR reduced virological failure in only those with specific PDR mutations suggests that PDR poses less of a risk for virological failure than that predicted by past prevalence estimates, and that the value of PDR testing to reduce virological failure should be assessed for antiretroviral treatment regimens.

Funding

US National Institutes of Health.

中文翻译：

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通过寡核苷酸连接测定法评估治疗前HIV耐药性的管理：一项随机对照试验。

背景

尽管专家建议在开始抗逆转录病毒治疗（ART）之前先进行治疗前耐药性（PDR）的测试，但几乎没有证据支持其实施。我们的目标是通过鉴定PDR来指导中低收入国家抗逆转录病毒疗法的药物选择，从而确定廉价的点突变测定法是否可以改善病毒学抑制作用。

方法

研究人员在肯尼亚的3个HIV治疗地点进行了一项开放标签，随机对照试验：内罗毕的2个地点和马塞诺农村的1个地点。年龄≥2岁的个体如果被确认患有HIV血清阳性，符合一线抗病毒治疗的资格，计划在该地区居住1年以上并提供知情同意，则有资格参加。我们通过寡核苷酸连接测定法（OLA）将参与者（1：1）随机分配到PDR测试中，以指导ART的选择或护理标准，其中不包括OLA测试。OLA指导的治疗组已对ART前外周血单个核细胞进行了评估，其密码子Lys103Asn，Tyr181Cys，Gly190Ala对非核苷逆转录酶抑制剂（NNRTI）具有耐药性，在Met184Val对拉米夫定具有耐药性，并且当至少一种耐药时在参与者中检测到密码子 在ART之前的标本中，临床医生被指示开处方基于蛋白酶抑制剂的二线ART。没有发现耐药性的患者和随机分配到护理标准的患者接受了基于NNRTI的一线抗逆转录病毒疗法。主要结果是在接受抗逆转录病毒治疗后的第4、8或12个月，血浆HIV-1 RNA至少为400拷贝/ mL，这定义了病毒学衰竭，在接受治疗的所有受试者中进行了评估（对因失访而丢失的数据进行了审查后续行动或谁去世）。该研究已经完成，并已在ClinicalTrials.gov上注册，编号NCT01898754。在接受抗病毒治疗的所有参与者中评估了定义病毒学衰竭的抗病毒治疗开始后的8个月或12个月（对失访者或死亡者进行了数据审查）。该研究已经完成，并已在ClinicalTrials.gov上注册，编号NCT01898754。在接受抗病毒治疗的所有参与者中评估了定义病毒学衰竭的抗病毒治疗开始后的8个月或12个月（对失访者或死亡者进行了数据审查）。该研究已经完成，并已在ClinicalTrials.gov上注册，编号NCT01898754。

发现

我们筛选了2013年5月28日至2014年11月4日之间的1198位参与者，其中991位（83％）被纳入了研究（492位接受了OLA，495位接受了标准护理；四位未开始治疗）。93名参与者（患病率9·4％）患有PDR（95％CI 7·7-11·4）。在OLA组的400名参与者中，有34名（8·5％）在ART的第12个月出现病毒学衰竭（95％CI 6·0-11·7），而402名（7·0–39）中有39名（9·7％）护理标准组（log-rank p = 0·26）中为13·0）。在PDR参与者中，OLA指导治疗组的病毒学失败率低于护理标准组：35名中的5名（14％），而26名中的13名（50％）；p = 0·0020）。在那些基于NNRTI的抗逆转录病毒疗法中，接受依非韦伦治疗的受试者比接受奈韦拉平的受试者发生病毒学失败的可能性更小（几率0·37，95％CI 0·22-0·62； p <0·0001）。OLA指导的治疗组有39例严重的非致命不良事件和34例死亡。护理标准组有34例严重不良事件和43例死亡，差异不显着。在各组之间被判定为可能由ART引起的不良事件很少且相似，在OLA指导治疗组中为17（16％），在标准护理组中为16（16％）（p = 0·90） 。

解释

我们的发现表明，只有OLA检测PDR才能降低具有特定PDR突变的人的病毒学失败率，这表明PDR带来的病毒学失败风险要比过去的患病率预测所预测的要低，并且应该评估PDR测试降低病毒学失败率的价值用于抗逆转录病毒治疗方案。

资金

美国国立卫生研究院。