Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD, USA.
Critical Care Medicine Department, Clinical Center, NIH, Bethesda, MD, USA.
Nature. 2022 Jun;606(7913):375-381. doi: 10.1038/s41586-022-04797-9. Epub 2022 Jun 1.
Antiretroviral therapy is highly effective in suppressing human immunodeficiency virus (HIV). However, eradication of the virus in individuals with HIV has not been possible to date. Given that HIV suppression requires life-long antiretroviral therapy, predominantly on a daily basis, there is a need to develop clinically effective alternatives that use long-acting antiviral agents to inhibit viral replication. Here we report the results of a two-component clinical trial involving the passive transfer of two HIV-specific broadly neutralizing monoclonal antibodies, 3BNC117 and 10-1074. The first component was a randomized, double-blind, placebo-controlled trial that enrolled participants who initiated antiretroviral therapy during the acute/early phase of HIV infection. The second component was an open-label single-arm trial that enrolled individuals with viraemic control who were naive to antiretroviral therapy. Up to 8 infusions of 3BNC117 and 10-1074, administered over a period of 24 weeks, were well tolerated without any serious adverse events related to the infusions. Compared with the placebo, the combination broadly neutralizing monoclonal antibodies maintained complete suppression of plasma viraemia (for up to 43 weeks) after analytical treatment interruption, provided that no antibody-resistant HIV was detected at the baseline in the study participants. Similarly, potent HIV suppression was seen in the antiretroviral-therapy-naive study participants with viraemia carrying sensitive virus at the baseline. Our data demonstrate that combination therapy with broadly neutralizing monoclonal antibodies can provide long-term virological suppression without antiretroviral therapy in individuals with HIV, and our experience offers guidance for future clinical trials involving next-generation antibodies with long half-lives.
抗逆转录病毒疗法在抑制人类免疫缺陷病毒（HIV）方面非常有效。然而，迄今为止，尚未能够在 HIV 感染者中彻底清除该病毒。鉴于 HIV 抑制需要终身接受抗逆转录病毒治疗，主要是每天接受治疗，因此需要开发使用长效抗病毒药物抑制病毒复制的临床有效替代品。在这里，我们报告了一项由两部分组成的临床试验结果，该试验涉及两种 HIV 特异性广泛中和单克隆抗体 3BNC117 和 10-1074 的被动转移。第一部分是一项随机、双盲、安慰剂对照试验，招募了在 HIV 感染的急性/早期阶段开始接受抗逆转录病毒治疗的参与者。第二部分是一项开放标签的单臂试验，招募了对 HIV 有病毒学控制且对 HIV 无抗药性的治疗药物的参与者。在 24 周的时间内，最多输注 8 次 3BNC117 和 10-1074，耐受性良好，没有与输注相关的任何严重不良事件。与安慰剂相比，组合广泛中和单克隆抗体在分析性治疗中断后仍能保持完全抑制血浆病毒血症（长达 43 周），前提是在研究参与者的基线时没有检测到具有抗药性的 HIV。同样，在基线时携带敏感病毒且对 HIV 无抗药性治疗药物的治疗药物的参与者中，也观察到了强大的 HIV 抑制作用。我们的数据表明，在 HIV 感染者中，联合使用广泛中和单克隆抗体可以在不使用抗逆转录病毒治疗的情况下提供长期的病毒学抑制作用，我们的经验为涉及半衰期较长的下一代抗体的未来临床试验提供了指导。
