Emtricitabine and tenofovir alafenamide vs emtricitabine and tenofovir disoproxil fumarate for HIV pre-exposure prophylaxis (DISCOVER): primary results from a randomised, double-blind, multicentre, active-controlled, phase 3, non-inferiority trial.
Emtricitabine and tenofovir alafenamide vs emtricitabine and tenofovir disoproxil fumarate for HIV pre-exposure prophylaxis (DISCOVER): primary results from a randomised, double-blind, multicentre, active-controlled, phase 3, non-inferiority trial.
复制标题
DOI：
10.1016/s0140-6736(20)31065-5
复制
发表时间：
2020-07-25
期刊：
影响因子：
168.9
通讯作者：
Hare, C. Bradley
中科院分区：
文献类型：
--
作者：
Mayer, Kenneth H.;Molina, Jean-Michel;Thompson, Melanie A.;Anderson, Peter L.;Mounzer, Karam C.;De Wet, Joss J.;DeJesus, Edwin;Jessen, Heiko;Grant, Robert M.;Ruane, Peter J.;Wong, Pamela;Ebrahimi, Ramin;Zhong, Lijie;Mathias, Anita;Callebaut, Christian;Collins, Sean E.;Das, Moupali;McCallister, Scott;Brainard, Diana M.;Brinson, Cynthia;Clarke, Amanda;Coll, Pep;Post, Frank A.;Hare, C. Bradley
当用于艾滋病毒治疗时，与富马酸替诺福韦二吡呋酯相比，替诺福韦艾拉酚胺显示出较高的抗病毒功效，并改善了肾脏和骨骼安全性。在这里，我们报告了一项盲法 3 期研究的主要结果，该研究评估了恩曲他滨和替诺福韦艾拉酚胺与恩曲他滨和富马酸替诺福韦二吡呋酯预防 HIV 的暴露前预防 (PrEP) 的有效性和安全性。这项研究是一项正在进行的、随机、双盲、多中心、主动对照、3 期非劣效性试验，在欧洲和北美地区的 94 个社区、公共卫生和医院相关诊所进行，这些地区的艾滋病毒发病率或艾滋病毒感染者患病率较高，或两者兼而有之。我们招募了与男性发生性行为的成年顺性别男性和与男性发生性行为的跨性别女性，根据他们在过去 12 周内自我报告的性行为或最近（入组后 24 周内）的细菌性传播感染史，两者都具有感染 HIV 的高风险。不排除当前或之前使用恩曲他滨和富马酸替诺福韦二吡呋酯的 PrEP 的参与者。我们使用计算机生成的随机分配序列随机分配（1:1）参与者每天接受恩曲他滨（200 mg）和替诺福韦艾拉酚胺（25 mg）片剂，以及匹配的安慰剂片剂（恩曲他滨和替诺福韦艾拉酚胺组），或每天接受恩曲他滨（200 mg）和富马酸替诺福韦二吡呋酯（300 mg）片剂，以及匹配的安慰剂片剂（恩曲他滨和替诺福韦艾拉酚胺组）。和富马酸替诺福韦二吡呋酯组）。因此，所有参与者都获得了两片平板电脑。提供研究药物、评估结果和收集数据的试验申办者、研究者、参与者和研究人员均不参与分组。主要疗效结果是 HIV 感染事件，在所有参与者完成 48 周的随访以及一半参与者完成 96 周的随访后进行评估。这个完整的分析集包括所有随机分配的参与者，他们接受了至少一剂指定的研究药物，并且至少进行了一次基线后 HIV 检测。如果 HIV 发病率比 (IRR) 的 95·003% CI 上限小于预先指定的非劣效界值 1·62，则恩曲他滨和替诺福韦艾拉酚胺相对于恩曲他滨和富马酸替诺福韦二吡呋酯的非劣效性成立。我们预先指定了六个次要骨矿物质密度和肾脏生物标志物安全终点，以使用安全分析集进行评估。该分析集包括所有随机分配的至少接受一剂指定研究药物的参与者。该试验已在 ClinicalTrials.gov 注册，NCT02842086，并且不再招募。 2016年9月13日至2017年6月30日期间，5857名参与者中的5387名（92%）被随机分配并接受恩曲他滨和替诺福韦艾拉酚胺（n=2694）或恩曲他滨和富马酸替诺福韦二吡呋酯（n=2693）治疗。在主要疗效分析时（即，当所有参与者完成 48 周，50% 完成 96 周时），恩曲他滨和替诺福韦艾拉酚胺在 HIV 预防方面不劣于恩曲他滨和富马酸替诺福韦二吡呋酯，因为 IRR 的 95% CI 上限小于预先指定的非劣效界值 1·62 (IRR) 0·47 [95% CI 0·19–1·15]）。经过 8756 人年的随访后，22 名参与者被诊断为 HIV，其中恩曲他滨和替诺福韦艾拉酚胺组有 7 名参与者（每 100 人年 0·16 例感染 [95% CI 0·06–0·33]），恩曲他滨和富马酸替诺福韦二吡呋酯组有 15 名参与者（每 100 人年 0·34 例感染） [0·19–0·56]）。两种治疗方案均具有良好的耐受性，报告不良事件导致停止研究药物的受试者人数较少（恩曲他滨和替诺福韦艾拉酚胺组的 2694 名受试者中有 36 名 [1%]，而恩曲他滨和富马酸替诺福韦二吡呋酯组的 2693 名受试者中有 49 名 [2%]）。恩曲他滨和替诺福韦艾拉酚胺在所有六个预先指定的骨矿物质密度和肾脏生物标志物安全终点方面均优于恩曲他滨和富马酸替诺福韦二吡呋酯。每日恩曲他滨和替诺福韦艾拉酚胺对于预防 HIV 的疗效不逊于每日恩曲他滨和富马酸替诺福韦二吡呋酯，并且两种方案的不良事件数量都很低。恩曲他滨和替诺福韦艾拉酚胺对骨密度和肾脏安全生物标志物的影响比恩曲他滨和富马酸替诺福韦二吡呋酯更有利。吉利德科学。
Tenofovir alafenamide shows high antiviral efficacy and improved renal and bone safety compared with tenofovir disoproxil fumarate when used for HIV treatment. Here, we report primary results from a blinded phase 3 study evaluating the efficacy and safety of pre-exposure prophylaxis (PrEP) with emtricitabine and tenofovir alafenamide versus emtricitabine and tenofovir disoproxil fumarate for HIV prevention. This study is an ongoing, randomised, double-blind, multicentre, active-controlled, phase 3, non-inferiority trial done at 94 community, public health, and hospital-associated clinics located in regions of Europe and North America, where there is a high incidence of HIV or prevalence of people living with HIV, or both. We enrolled adult cisgender men who have sex with men and transgender women who have sex with men, both with a high risk of acquiring HIV on the basis of their self-reported sexual behaviour in the past 12 weeks or their recent history (within 24 weeks of enrolment) of bacterial sexually transmitted infections. Participants with current or previous use of PrEP with emtricitabine and tenofovir disoproxil fumarate were not excluded. We used a computer-generated random allocation sequence to randomly assign (1:1) participants to receive either emtricitabine (200 mg) and tenofovir alafenamide (25 mg) tablets daily, with matched placebo tablets (emtricitabine and tenofovir alafenamide group), or emtricitabine (200 mg) and tenofovir disoproxil fumarate (300 mg) tablets daily, with matched placebo tablets (emtricitabine and tenofovir disoproxil fumarate group). As such, all participants were given two tablets. The trial sponsor, investigators, participants, and the study staff who provided the study drugs, assessed the outcomes, and collected the data were masked to group assignment. The primary efficacy outcome was incident HIV infection, which was assessed when all participants had completed 48 weeks of follow-up and half of all participants had completed 96 weeks of follow-up. This full analysis set included all randomly assigned participants who had received at least one dose of the assigned study drug and had at least one post-baseline HIV test. Non-inferiority of emtricitabine and tenofovir alafenamide to emtricitabine and tenofovir disoproxil fumarate was established if the upper bound of the 95·003% CI of the HIV incidence rate ratio (IRR) was less than the prespecified non-inferiority margin of 1·62. We prespecified six secondary bone mineral density and renal biomarker safety endpoints to evaluate using the safety analysis set. This analysis set included all randomly assigned participants who had received at least one dose of the assigned study drug. This trial is registered with ClinicalTrials.gov, NCT02842086, and is no longer recruiting. Between Sept 13, 2016, and June 30, 2017, 5387 (92%) of 5857 participants were randomly assigned and received emtricitabine and tenofovir alafenamide (n=2694) or emtricitabine and tenofovir disoproxil fumarate (n=2693). At the time of the primary efficacy analysis (ie, when all participants had completed 48 weeks and 50% had completed 96 weeks) emtricitabine and tenofovir alafenamide was non-inferior to emtricitabine and tenofovir disoproxil fumarate for HIV prevention, as the upper limit of the 95% CI of the IRR, was less than the prespecified non-inferiority margin of 1·62 (IRR 0·47 [95% CI 0·19–1·15]). After 8756 person-years of follow-up, 22 participants were diagnosed with HIV, seven participants in the emtricitabine and tenofovir alafenamide group (0·16 infections per 100 person-years [95% CI 0·06–0·33]), and 15 participants in the emtricitabine and tenofovir disoproxil fumarate group (0·34 infections per 100 person-years [0·19–0·56]). Both regimens were well tolerated, with a low number of participants reporting adverse events that led to discontinuation of the study drug (36 [1%] of 2694 participants in the emtricitabine and tenofovir alafenamide group vs 49 [2%] of 2693 participants in the emtricitabine and tenofovir disoproxil fumarate group). Emtricitabine and tenofovir alafenamide was superior to emtricitabine and tenofovir disoproxil fumarate in all six prespecified bone mineral density and renal biomarker safety endpoints. Daily emtricitabine and tenofovir alafenamide shows non-inferior efficacy to daily emtricitabine and tenofovir disoproxil fumarate for HIV prevention, and the number of adverse events for both regimens was low. Emtricitabine and tenofovir alafenamide had more favourable effects on bone mineral density and biomarkers of renal safety than emtricitabine and tenofovir disoproxil fumarate. Gilead Sciences.