A Clinical Trial of Three Broadly Neutralizing Antibodies and Analytic Treatment Interruption in Early-Treated Children in Botswana

项目摘要/摘要 新的HIV-1治疗策略，在保持病毒抑制的同时允许小分子停药 抗逆转录病毒治疗(ART)是高度优先的。一种节省艺术的治疗干预，使用有效和长期的- 广谱中和抗体(BNAbs)可在生长的关键时期减少ART的直接毒性。 对于艾滋病毒携带者的儿童和发展，将确保依从性，并可能比病毒宿主的ART有好处 复位和后处理控制。BNAbs与病毒库的减少有关，最近 研究支持一种潜在的疫苗样效应，可能训练免疫反应并改善长期疗效 结果。像接受早期治疗的成人一样，接受早期治疗的儿童可能有最好的机会成为治疗后患者。 控制剂，但还需要进一步的研究--包括利用分析治疗中断(ATI)的研究。 我们最近完成了Tatelo研究，这是一项概念验证试验，表明每月治疗Dual 在早期接受抗逆转录病毒治疗的儿童中，44%的患者在没有抗逆转录病毒治疗的情况下，bNAbs可以维持病毒抑制24周。我们也 表明成功的特定标志是可以识别的，标准艺术的中断是安全的 在我们的研究环境中进行。在拟议的研究(Tatelo Plus)中，我们将进行多步骤干预 将这一领域推向更远的临床试验。使用新的分步设计和创新的bNAb旋转 策略，我们将首先确定长效三联制剂的安全性、药代动力学、剂量和对患者的影响。 在现有有效基础上加用VRC07-523LS、PGDM1400LS和PGT121-414LS进行bNab免疫治疗 艺术。在选定的成功标志良好的参与者中，我们接下来将测量三重bNAb治疗 艺术中断后的成功。最后，我们将测试ATI期间病毒控制的维护情况 在一组更精选的参与者中--那些病毒储备量极低或有证据表明 HIV在基因组非编码区的整合。这项研究的具体目的是(1)确定 联合使用三联bNAb免疫治疗24周的安全性、药代动力学和剂量 在博茨瓦纳早期治疗的35名艾滋病毒感染儿童中加入抗逆转录病毒治疗；(2)确定安全性、维持性 对病毒学的抑制作用，以及维持24周的CD4细胞计数维持三联bNAb治疗 在选定的早期治疗的儿童中停止标准的ART之后；以及(3)确定安全性， 维持病毒学抑制，并在两组中保存24周ATI的CD4细胞计数：a) 那些具有最低病毒库标志的人，以及b)那些有证据表明HIV-1整合的人，主要是 基因组的非编码区。在每个研究步骤中，我们将测量细胞的大小和组成 残留的病毒库，以及抗病毒先天和获得性免疫反应的大小和质量。这 这项研究将代表着儿童联合bNAb治疗的飞跃，并将推动儿科 通过仔细进行的ATI治疗议程。

Project Summary/Abstract Novel HIV-1 treatment strategies that maintain viral suppression while allowing time off small molecule antiretroviral treatment (ART) are of high priority. An ART-sparing treatment intervention using potent and long- acting broadly neutralizing antibodies (bNAbs) may reduce direct ART toxicities during critical periods of growth and development for children with HIV, will ensure adherence, and may have benefits over ART for viral reservoir reduction and post-treatment control. bNAbs have been associated with reduction in viral reservoirs, and recent studies support a potential vaccine-like effect that may train immune responses and improve long-term outcomes. Like early-treated adults, early-treated children may have the best chance to become post-treatment controllers, but further studies are needed -- including studies that utilize an analytic treatment interruption (ATI). We recently completed the Tatelo Study, a proof-of-concept trial demonstrating that monthly treatment with dual bNAbs could maintain viral suppression for 24 weeks without ART in 44% of early-ART treated children. We also showed that specific markers for success were identifiable, and that interruption of standard ART could be safely performed in our study setting. In the proposed study (Tatelo Plus), we will perform a multi-step interventional clinical trial that advances the field farther. Using a novel step-wise design and an innovative bNAb rotation strategy, we will first determine the safety, pharmacokinetics, dosing, and reservoir impact of long-acting triple bNAb immunotherapy with VRC07-523LS, PGDM1400LS and PGT121-414LS when added to existing effective ART. In selected participants with favorable markers for success, we will next measure triple-bNAb treatment success following ART discontinuation. Finally, we will test for the maintenance of virologic control during an ATI in an even more highly selected group of participants -- those with extremely low viral reservoir or evidence of HIV integration in non-encoding regions of the genome. The specific aims of this study are (1) to determine the safety, pharmacokinetics and dosing of up to 24 weeks of concomitant use of triple bNAb immunotherapy when added to ART in 35 early-treated children living with HIV-1 in Botswana; (2) to determine the safety, maintenance of virologic suppression, and CD4 cell count preservation of 24 weeks of maintenance triple bNAb treatment following the discontinuation of standard ART in selected early-treated children; and (3) to determine the safety, maintenance of virologic suppression, and CD4 cell count preservation of a 24 week ATI among two groups: a) those with markers for the lowest viral reservoir, and b) those with evidence of HIV-1 integration in predominantly non-encoding regions of the genome. At each study step, we will measure the size and cellular composition of residual viral reservoirs, and the magnitude and quality of antiviral innate and adaptive immune responses. This study will represent a leap forward for combination bNAb treatment in children, and will advance the pediatric cure agenda through a carefully conducted ATI.