Data characterising the long-term use and safety of emtricitabine plus tenofovir disoproxil fumarate as daily oral pre-exposure prophylaxis (PrEP) are scarce and there are uncertainties regarding the value of routine HIV-1 RNA testing during oral PrEP follow-up. The DISCOVER trial was a randomised, controlled, phase 3 trial in which cisgender men and transgender women aged 18 years and older with a high likelihood of acquiring HIV were recruited from 94 clinics in Europe and North America and randomly assigned to receive either emtricitabine plus tenofovir disoproxil fumarate (200/25 mg) tablets daily, with matched placebo tablets, or emtricitabine plus tenofovir alafenamide (200/300 mg) tablets daily, with matched placebo tablets, for at least 96 weeks. After completion of the trial, participants were offered enrolment in this 48-week open-label extension study of emtricitabine plus tenofovir alafenamide. In participants diagnosed with HIV during the randomised and open-label phases of the study, we characterised HIV-1 test results and measured HIV-1 RNA viral load retrospectively when available. Adherence based on tenofovir diphosphate concentrations in dried blood spots and genotypic resistance were assessed in participants diagnosed with HIV. Safety assessments included adverse events, laboratory parameters, and, in a subset of participants, bone mineral density. HIV-1 incidence in participants initially randomly assigned to receive emtricitabine plus tenofovir alafenamide was estimated using a Poisson distribution. Changes from baseline in safety endpoints were described in participants assigned to received emtricitabine plus tenofovir alafenamide and in those who switched from emtricitabine plus tenofovir disoproxil fumarate during the open-label phase. This trial is registered with , , and is ongoing. Between Sept 13, 2016, and June 30, 2017, 5399 participants were enrolled and randomly assigned in DISCOVER. 2699 were assigned to receive emtricitabine plus tenofovir disoproxil fumarate and 2700 were assigned to receive emtricitabine plus tenofovir alafenamide, of whom 2693 and 2694, respectively, received at least one dose of study drug. 2115 (79%) assigned to emtricitabine plus tenofovir disoproxil fumarate switched to emtricitabine plus tenofovir alafenamide in the open-label phase, and 2070 (77%) continued with emtricitabine plus tenofovir alafenamide in the open-label phase. As of data cutoff (Dec 10, 2020), after 15 817 person-years of follow-up, 27 new HIV-1 diagnoses were observed across the total study period, with three occurring during the open-label phase. In participants who were initially assigned to emtricitabine plus tenofovir alafenamide, the incidence was 0·13 per 100 person-years (95% CI 0·061–0·23; ten of 2670). Stored plasma samples were available for 23 of 27 participants, including 22 with incident infection. In four (17%) of 23 participants, retrospective testing detected HIV-1 RNA before serological HIV-1 test positivity; one was a suspected baseline infection. Of the three incident cases, all three were non-adherent to PrEP and none developed drug resistance. Among participants taking emtricitabine plus tenofovir alafenamide for up to 144 weeks, markers of glomerular filtration and proximal renal tubule dysfunction (β2-microglobulin to creatinine ratio and retinol-binding protein to creatinine ratio) improved or remained stable at 144 weeks compared with baseline, bone mineral density in hip and lumbar spine increased or remained stable from baseline to week 144 (n=191), cholesterol and glucose concentrations remained stable, and median bodyweight increased by less than 1 kg per year. In participants who switched from emtricitabine plus tenofovir disoproxil fumarate during the open-label phase (2115 [79%] of 2693), markers of glomerular filtration and proximal renal tubule dysfunction improved or remained stable, bone mineral density increased, cholesterol concentrations increased, glucose concentrations were similar, and median bodyweight increased more compared with those who remained on emtricitabine and tenofovir alafenamide. Routine HIV-1 RNA testing for follow-up of individuals on daily oral PrEP provides modest additional clinical benefit. Long-term use of emtricitabine and tenofovir alafenamide as daily oral PrEP is safe and well tolerated and can be an especially appropriate choice for people with bone or renal morbidities. Gilead Sciences.

中文翻译：

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HIV-1 感染动力学、耐药性和恩曲他滨联合替诺福韦艾拉酚胺暴露前预防的长期安全性（DISCOVER）：随机对照 3 期试验的第 144 周开放标签扩展


描述恩曲他滨联合富马酸替诺福韦二吡呋酯每日口服暴露前预防 (PrEP) 的长期使用和安全性的数据很少，并且口服 PrEP 随访期间常规 HIV-1 RNA 检测的价值存在不确定性。 DISCOVER 试验是一项随机对照 3 期试验，从欧洲和北美的 94 家诊所招募了年龄在 18 岁及以上且极有可能感染 HIV 的顺性别男性和跨性别女性，并随机分配接受恩曲他滨加替诺福韦治疗每日富马酸二吡呋酯 (200/25 mg) 片剂，搭配匹配的安慰剂片剂，或每日恩曲他滨加替诺福韦艾拉酚胺 (200/300 mg) 片剂，搭配匹配的安慰剂片剂，持续至少 96 周。试验完成后，参与者被邀请参加这项为期 48 周的恩曲他滨加替诺福韦艾拉酚胺的开放标签扩展研究。在研究的随机和开放标签阶段期间诊断出 HIV 的参与者中，我们对 HIV-1 检测结果进行了表征，并在可用时回顾性测量了 HIV-1 RNA 病毒载量。根据干血斑中的替诺福韦二磷酸盐浓度和基因型耐药性，对诊断为艾滋病毒的参与者进行了评估。安全性评估包括不良事件、实验室参数以及一部分参与者的骨矿物质密度。使用泊松分布估计最初随机分配接受恩曲他滨加替诺福韦艾拉酚胺治疗的参与者的 HIV-1 发病率。分配接受恩曲他滨加替诺福韦艾拉酚胺的参与者以及在开放标签阶段从恩曲他滨加富马酸替诺福韦酯转为接受治疗的参与者描述了安全性终点相对于基线的变化。 该试验已在 、 、 注册，并且正在进行中。 2016年9月13日至2017年6月30日期间，共有5399名参与者注册并随机分配到DISCOVER中。 2699 人被分配接受恩曲他滨加富马酸替诺福韦二吡呋酯治疗，2700 人被分配接受恩曲他滨加替诺福韦艾拉酚胺治疗，其中分别有 2693 人和 2694 人接受至少一剂研究药物。在开放标签阶段，分配至恩曲他滨加富马酸替诺福韦二吡呋酯的 2115 名患者 (79%) 转为恩曲他滨加替诺福韦艾拉酚胺，2070 名患者 (77%) 在开放标签阶段继续使用恩曲他滨加替诺福韦艾拉酚胺。截至数据截止（2020 年 12 月 10 日），经过 15817 人年的随访，在整个研究期间观察到 27 例新的 HIV-1 诊断，其中 3 例发生在开放标签阶段。在最初分配至恩曲他滨加替诺福韦艾拉酚胺治疗的参与者中，发病率为每 100 人年 0·13 例（95% CI 0·061–0·23；2670 人中的 10 人）。 27 名参与者中的 23 名获得了储存的血浆样本，其中 22 名是意外感染者。在 23 名参与者中，有 4 名 (17%) 在 HIV-1 血清学检测呈阳性之前进行了回顾性检测，检测到了 HIV-1 RNA；一种是疑似基线感染。在这三起事件病例中，三人均未遵守 PrEP，且没有一人出现耐药性。 在服用恩曲他滨加替诺福韦艾拉酚胺长达 144 周的参与者中，与基线相比，肾小球滤过和近端肾小管功能障碍的标志物（β2-微球蛋白与肌酐比值和视黄醇结合蛋白与肌酐比值）在 144 周时与基线相比有所改善或保持稳定。髋部和腰椎的矿物质密度从基线到第 144 周有所增加或保持稳定（n=191），胆固醇和葡萄糖浓度保持稳定，中位体重每年增加不到 1 公斤。在开放标签阶段从恩曲他滨加富马酸替诺福韦酯转为替诺福韦二吡呋酯的参与者中（2115 名 [2693 名中的 79%]），肾小球滤过和近端肾小管功能障碍的标志物改善或保持稳定，骨矿物质密度增加，胆固醇浓度增加，血糖水平升高。与继续服用恩曲他滨和替诺福韦艾拉酚胺的患者相比，浓度相似，中位体重增加更多。对每日口服 PrEP 个体进行常规 HIV-1 RNA 检测可提供一定程度的额外临床益处。长期使用恩曲他滨和替诺福韦艾拉酚胺作为每日口服 PrEP 是安全且耐受性良好的，对于患有骨骼或肾脏疾病的患者来说是特别合适的选择。吉利德科学。