背景:关于非核苷逆转录酶抑制剂(NNRTIs)失效后二线抗逆转录病毒治疗(ART)疗效和安全性的随机比较数据在不同的地理环境中很少。这项研究的目的是评估HIV感染者的最佳二线ART。
方法:D2EFT是一个完整的国际,随机化,开放标签,3b/4期试验评估了在一线NNRTI治疗失败的HIV-1成人(年龄≥18岁)中的三种二线ART策略.这项研究是在亚洲14个国家的28个地点进行的,非洲,和拉丁美洲。最初设计用于比较推荐的护理标准(利托那韦增强的达鲁那韦[每天一次800mg达鲁那韦加100mg利托那韦]加两种核苷逆转录酶抑制剂[NRTI;每天一次或两次给药])与新型核苷保留方案dolutegravir(每天一次50mg)与利托那韦增强的达鲁那韦。该研究在第一年进行了调整,增加了第三组dolutegravir(50毫克,每天一次)与固定的富马酸替诺福韦酯(300毫克,每天一次)加拉米夫定(300毫克,每天一次)或恩曲他滨(200毫克,每天一次)。参与者被随机分配了计算机生成的,按地点分层的分组随机化方案(块大小为两个),以前使用富马酸替诺福韦酯,和HIV病毒载量。该试验旨在评估任一干预组相对于病毒学抑制的主要结果的护理标准的非劣效性。根据48周时小于50个拷贝/mL的HIVRNA载量确定。预设的非劣效性为12%。与改良的意向治疗人群进行了比较,包括所有随机分配的参与者,但不包括行政撤回。这项研究在ClinicalTrials.gov注册,NCT03017872。
结果:对1190人进行了筛查;在2017年11月1日至2021年12月31日之间招募了828名参与者。两名参与者由于管理原因无法接受他们指定的治疗方案;826名参与者被纳入分析。中位年龄为39岁(IQR33-46),450名(54%)参与者为女性。基线中位CD4计数为206个细胞/μL(23-354),中位HIVRNA为15400个拷贝/mL(3600-65986)。在利托那韦增强的达鲁那韦加上两个NRTIs组中,48周时HIVRNA少于50个拷贝/mL的参与者比例为257人中的194人(75%),在利托那韦增强的darunavir+dolutegravir组中,264人中有222人(84%),和227(78%)的291与富马酸替诺福韦酯加任拉米夫定或恩曲他滨组。与利托那韦增强的达鲁那韦加上两个NRTI相比,dolutegravir+利托那韦增强的darunavir在病毒学抑制方面的差异为8·6%(95%CI1·7~15·5;p=0·016),dolutegravir+替诺福韦酯+富马酸替诺福韦酯+拉米夫定或伊曲他滨在病毒学抑制方面的差异为6·7%(-1·2~14·4;p=发生了6人死亡,这些都与治疗无关。19次怀孕(11次分娩),没有先天性缺陷。
结论:在经历基于NNRTI的一线ART失败的个体中,切换到dolutegravir加利托那韦增强darunavir或dolutegravir与替诺福韦酯富马酸酯加拉米夫定或恩曲他滨,如果没有普遍的基因分型,与利托那韦增强的达鲁那韦加上两个NRTIs相比,在实现病毒抑制方面并不逊色。这些全球数据支持最新的世卫组织治疗指南。
背景:UNITAID;国家过敏和传染病研究所,美国;国家卫生和医学研究委员会,澳大利亚;ViiVHealthcare;和Janssen。
BACKGROUND: Randomised comparative data on efficacy and safety of second-line antiretroviral therapy (ART) after failure of non-nucleoside reverse transcriptase inhibitors (NNRTIs) across diverse geographical settings are scarce. The aim of this study was to evaluate optimal second-line ART for people with HIV.
METHODS: D2EFT is a completed international, randomised, open-label, phase 3b/4 trial evaluating three second-line ART strategies in adults (aged ≥18 years) with HIV-1 for whom first-line NNRTI therapy has failed. The study was done at 28 sites across 14 countries in Asia, Africa, and Latin America. It was originally designed to compare recommended standard of care (ritonavir-boosted
darunavir [800 mg
darunavir plus 100 mg ritonavir once daily] plus two nucleoside reverse transcriptase inhibitors [NRTIs; dosed once or twice daily]) with a novel nucleoside sparing regimen of dolutegravir (50 mg once daily) with ritonavir-boosted darunavir. The study was adapted during the first year to add a third arm of dolutegravir (50 mg once daily) with fixed tenofovir disoproxil fumarate (300 mg once daily) plus either lamivudine (300 mg once daily) or emtricitabine (200 mg once daily). Participants were randomly assigned with a computer-generated, blocked randomisation scheme (block size of two) stratified by site, previous tenofovir disoproxil fumarate use, and HIV viral load. The trial was designed to evaluate non-inferiority of either interventional arm against standard of care for the primary outcome of virological suppression, as determined by HIV RNA load of less than 50 copies per mL at 48 weeks. The prespecified non-inferiority margin was 12%. Comparisons were made with a modified intention-to-treat population, including all participants randomly assigned but excluding administrative withdrawals. This study is registered with ClinicalTrials.gov, NCT03017872.
RESULTS: 1190 individuals were screened; 828 participants were enrolled between Nov 1, 2017, and Dec 31, 2021. Two participants were unable to receive their assigned regimen for administrative reasons; and 826 participants were included in analyses. Median age was 39 years (IQR 33-46), and 450 (54%) participants were female. Baseline median CD4 count was 206 cells per μL (23-354) and median HIV RNA was 15 400 copies per mL (3600-65 986). The proportion of participants with HIV RNA of less than 50 copies per mL at 48 weeks was 194 (75%) of 257 in the ritonavir-boosted darunavir plus two NRTIs group, 222 (84%) of 264 in the ritonavir-boosted
darunavir plus dolutegravir group, and 227 (78%) of 291 in the dolutegravir with tenofovir disoproxil fumarate plus either lamivudine or emtricitabine group. Compared with ritonavir-boosted
darunavir plus two NRTIs, the difference in virological suppression was 8·6% (95% CI 1·7 to 15·5; p=0·016) for dolutegravir plus ritonavir-boosted
darunavir and 6·7% (-1·2 to 14·4; p=0·093) for dolutegravir with tenofovir disoproxil fumarate plus either lamivudine or emtricitabine. Six deaths occurred, none of which were related to treatment. 19 pregnancies (11 livebirths) occurred with no congenital defects.
CONCLUSIONS: In individuals experiencing failure of an NNRTI-based first-line ART, a switch to either dolutegravir plus ritonavir-boosted darunavir or dolutegravir with tenofovir disoproxil fumarate plus either lamivudine or emtricitabine, without universal access to genotyping, was non-inferior in achieving viral suppression compared with ritonavir-boosted darunavir plus two NRTIs. These global data support the most recent WHO treatment guidelines.
BACKGROUND: UNITAID; National Institute of Allergy and Infectious Diseases, USA; National Health and Medical Research Council, Australia; ViiV Healthcare; and Janssen.