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)的长期病毒抑制很难在 随着时间的推移，对ART的重大毒性可能会积累起来。维持艾滋病毒的新策略 在允许休假的同时抑制病毒-3-药物ART是必要的，概念验证研究证明 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 结果--是高度优先的。我们建议进行一项开放标签的1/2期研究，以评估该药物的疗效 广泛中和HIV-1单抗VRC01以在没有ART的情况下保持病毒抑制 在病毒抑制的艾滋病毒感染儿童中，他们在出生后96小时内(或很快)开始标准的抗逆转录病毒治疗 在产中感染之后)。所有儿童将从早期婴儿治疗(EIT)研究中招募 (U01AI114235)，从出生起就经常接受临床、病毒学和 免疫学特征。接受抗逆转录病毒治疗96-240周并符合病毒学入院条件的儿童 将提供加入拟议研究的标准。干预将包括正在进行的抗逆转录病毒治疗加 输注VRC01抗体6周，然后每月维持给药 单独接受VRC01治疗，最多可额外治疗24周。接受VRC01维持治疗的儿童将 密切监测，任何VL&GT；400份/毫升后立即重新启动抗逆转录病毒治疗。所有参与者将 在30周时恢复艺术。这项研究旨在评估VCR01治疗HIV-1的三种可能好处- 受感染的儿童：1)我们将描述VRC01可以维持的病毒学控制持续时间 遵循早期ART的治疗，提供VRC01可能作为替代方案的概念验证 病毒贮备量低的儿童的标准抗逆转录病毒治疗；2)我们将调查VRC01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，这将是 对于制定限制病毒持久性和破坏病毒库稳定的策略具有很高的信息量 儿科患者的体内平衡；以及3)我们将评估VRC01的治疗是否与 先天或适应性抗病毒免疫反应的质的或量的变化，如果它有助于 开发一种抗病毒免疫配置文件，可以实现治疗后自发的病毒控制。

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.