A clinical trial to evaluate the impact of broadly neutralizing antibody VRC01 on HIV viral reservoir and maintenance of suppression in a cohort of early-treated children in Botswana

摘要 抗逆转录病毒治疗（ART）的长期病毒抑制难以在治疗过程中维持。 整个生命周期，并且对ART的显著毒性可能随着时间的推移而累积。维持艾滋病毒的新策略 病毒抑制，同时允许时间关闭3药物ART是必要的，概念验证研究，以证明 这种策略的可行性-并研究其对病毒库，免疫反应和临床的影响 成果-具有高度优先地位。我们提出了一项开放标签的1/2期研究，以评估 广泛中和的HIV-1单克隆抗体VRC 01在没有ART的情况下维持病毒抑制 在出生后96小时内（或更短时间内）开始标准抗逆转录病毒治疗的病毒抑制HIV感染儿童中， 产后感染）。所有儿童将从早期婴儿治疗（EIT）研究中招募 （U 01 AI 114235），并且从出生起就对其临床、病毒学和 免疫学特征。接受96-240周抗逆转录病毒治疗并符合病毒学标准的儿童 将提供入组拟定研究的标准。干预措施将包括正在进行的抗逆转录病毒治疗加 持续6周的时间输注VRC 01抗体，随后每月维持施用VRC 01抗体。 VRC 01单独治疗长达24周。接受VRC 01维持治疗的儿童将 密切监测，在任何VL > 400拷贝/mL后立即重新开始ART。所有参与者将 在第30周恢复ART。该研究旨在评估VCR 01治疗HIV-1的三种可能益处， 感染儿童：1）我们将描述VRC 01可维持的病毒学控制持续时间 早期ART后的治疗，提供了概念验证，即VRC 01可以作为一种可能的替代方案， 低病毒库儿童的标准ART; 2）我们将研究VRC 01治疗是否与 随着残留病毒库的大小和/或细胞或克隆组成的变化， 对于开发限制病毒持久性和使病毒库不稳定的策略具有高度信息性 儿童患者的体内平衡; 3）我们将评估VRC 01治疗是否与 先天性或适应性抗病毒免疫应答的定性或定量变化，以及是否促进了 开发抗病毒免疫特征，能够实现自发的治疗后病毒控制。

Abstract Long-term viral suppression with antiretroviral treatment (ART) is difficult to maintain over the course of an entire lifetime, and significant toxicities to ART may accumulate with time. Novel strategies that maintain HIV viral suppression while allowing time off 3-drug ART are needed, and proof-of-concept studies to demonstrate the feasibility of such a strategy – and to study its impact on viral reservoir, immune responses, and clinical outcomes – are of high priority. We propose an open-label Phase 1/2 study to evaluate the efficacy of the broadly neutralizing HIV-1 monoclonal antibody VRC01 to maintain viral suppression in the absence of ART among virally suppressed HIV-infected children who started standard ART within 96 hours of birth (or soon after intrapartum infection). All children will be recruited from the Early Infant Treatment (EIT) study (U01AI114235), and have been followed from birth with frequent assessments of their clinical, virologic and immunologic characteristics. Children who have received 96-240 weeks of ART and meet virologic entry criteria will be offered enrollment into the proposed study. The intervention will consist of ongoing ART plus infusions of VRC01 antibodies for a period of 6 weeks, followed by monthly maintenance administration of VRC01 treatment alone for up to 24 additional weeks. Children receiving VRC01 maintenance therapy will be monitored closely, with immediate re-initiation of ART following any VL > 400 copies/mL. All participants will resume ART at week 30. The study is designed to evaluate three possible benefits of VCR01 therapy in HIV-1- infected children: 1) we will characterize the duration of virologic control that can be maintained with VRC01 treatment following early ART, providing proof-of-concept that VRC01 may serve as a possible alternative to standard ART in children with low viral reservoirs; 2) we will investigate whether VRC01 therapy is associated with changes in the size and/or the cellular or clonal composition of residual viral reservoirs, which will be highly informative for developing strategies to limit viral persistence and to destabilize viral reservoir homeostasis in pediatric patients; and 3) we will evaluate whether treatment with VRC01 is associated with qualitative or quantitative changes in innate or adaptive antiviral immune responses, and if it facilitates the development of an antiviral immune profile that can enable spontaneous post-treatment viral control.