Attempts to reduce the human immunodeficiency virus type 1 (HIV-1) reservoir and induce antiretroviral therapy (ART)-free virologic control have largely been unsuccessful. In this phase 1b/2a, open-label, randomized controlled trial using a four-group factorial design, we investigated whether early intervention in newly diagnosed people with HIV-1 with a monoclonal anti-HIV-1 antibody with a CD4-binding site, 3BNC117, followed by a histone deacetylase inhibitor, romidepsin, shortly after ART initiation altered the course of HIV-1 infection (NCT03041012). The trial was undertaken in five hospitals in Denmark and two hospitals in the United Kingdom. The coprimary endpoints were analysis of initial virus decay kinetics and changes in the frequency of CD4⁺ T cells containing intact HIV-1 provirus from baseline to day 365. Secondary endpoints included changes in the frequency of infected CD4⁺ T cells and virus-specific CD8⁺ T cell immunity from baseline to day 365, pre-ART plasma HIV-1 3BNC117 sensitivity, safety and tolerability, and time to loss of virologic control during a 12-week analytical ART interruption that started at day 400. In 55 newly diagnosed people (5 females and 50 males) with HIV-1 who received random allocation treatment, we found that early 3BNC117 treatment with or without romidepsin enhanced plasma HIV-1 RNA decay rates compared to ART only. Furthermore, 3BNC117 treatment accelerated clearance of infected cells compared to ART only. All groups had significant reductions in the frequency of CD4⁺ T cells containing intact HIV-1 provirus. At day 365, early 3BNC117 + romidepsin was associated with enhanced HIV-1 Gag-specific CD8⁺ T cell immunity compared to ART only. The observed virological and immunological effects of 3BNC117 were most pronounced in individuals whose pre-ART plasma HIV-1 envelope sequences were antibody sensitive. The results were not disaggregated by sex. Adverse events were mild to moderate and similar between the groups. During a 12-week analytical ART interruption among 20 participants, 3BNC117-treated individuals harboring sensitive viruses were significantly more likely to maintain ART-free virologic control than other participants. We conclude that 3BNC117 at ART initiation enhanced elimination of plasma viruses and infected cells, enhanced HIV-1-specific CD8⁺ immunity and was associated with sustained ART-free virologic control among persons with 3BNC117-sensitive virus. These findings strongly support interventions administered at the time of ART initiation as a strategy to limit long-term HIV-1 persistence.

减少人类免疫缺陷病毒 1 型 (HIV-1) 储存库和诱导无需抗逆转录病毒治疗 (ART) 的病毒学控制的尝试基本上不成功。在这项使用四组因子设计的 1b/2a 期开放标签随机对照试验中，我们研究了是否可以使用具有 CD4 结合位点的单克隆抗 HIV-1 抗体对新诊断的 HIV-1 患者进行早期干预，3BNC117，随后使用组蛋白脱乙酰酶抑制剂罗米地辛，在 ART 开始后不久改变了 HIV-1 感染的过程 (NCT03041012)。该试验在丹麦的五家医院和英国的两家医院进行。共同主要终点是分析初始病毒衰变动力学以及从基线到第 365 天含有完整 HIV-1 原病毒的 CD4 ⁺ T 细胞频率的变化。次要终点包括受感染的 CD4 ⁺ T 细胞和病毒特异性 CD8 的频率变化⁺从基线到第 365 天的 T 细胞免疫、ART 前血浆 HIV-1 3BNC117 敏感性、安全性和耐受性，以及从第 400 天开始的 12 周分析 ART 中断期间病毒学控制丧失的时间。在 55 名新诊断的患者中（5 名女性和 50 名男性）接受随机分配治疗的 HIV-1 患者，我们发现与仅接受 ART 相比，使用或不使用罗米地辛的早期 3BNC117 治疗可增强血浆 HIV-1 RNA 衰减率。此外，与单独的 ART 相比，3BNC117 治疗加速了感染细胞的清除。所有组中含有完整 HIV-1 原病毒的 CD4 ⁺ T 细胞的频率均显着降低。在第 365 天，与仅 ART 相比，早期 3BNC117 + romidepsin 与增强的 HIV-1 Gag 特异性 CD8 ⁺ T 细胞免疫相关。 观察到的 3BNC117 的病毒学和免疫学效应在 ART 前血浆 HIV-1 包膜序列对抗体敏感的个体中最为明显。结果未按性别分类。各组之间的不良事件为轻度至中度且相似。在对 20 名参与者进行为期 12 周的 ART 中断分析期间，接受 3BNC117 治疗的携带敏感病毒的个体比其他参与者更有可能维持无 ART 的病毒学控制。我们的结论是，在 ART 开始时 3BNC117 增强了血浆病毒和感染细胞的消除，增强了 HIV-1 特异性 CD8 ⁺免疫力，并与 3BNC117 敏感病毒患者持续的无 ART 病毒学控制相关。这些发现强烈支持在开始 ART 时进行干预，作为限制 HIV-1 长期持续存在的策略。