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

博茨瓦纳早期治疗儿童中三种广泛中和抗体和分析治疗中断的临床试验

• 批准号: 10764517
• 负责人: Daniel R. Kuritzkes
• 金额: $ 179.91万
• 依托单位: HARVARD SCHOOL OF PUBLIC HEALTH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-05 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10764517
• 关键词: Adherence; Adolescent; Adult; Aftercare; Antibody Therapy; Biological Assay; Birth; Botswana; CD4 Lymphocyte Count; Characteristics; Child; Child Development; Childhood; Clinical; Clinical Markers; Clinical Trials; DNA; Data; Dose; Drug Kinetics; Ensure; Genome; Growth and Development function; HIV; HIV Seronegativity; HIV serology; HIV-1; Immune response; Immunotherapy; Infection; Innate Immune Response; Interruption; Intervention; Maintenance; Measures; Monitor; Morbidity - disease rate; Outcome; Outcome Study; Participant; Pattern; Pediatrics; Population; Protocols documentation; RNA; Research; Residual state; Rotation; Safety; Serology test; Specific qualifier value; Testing; Time; Training; Treatment-related toxicity; Use Effectiveness; Vaccines; Viral; Viral reservoir; Visit; adaptive immune response; antibody immunotherapy; antiretroviral therapy; appropriate dose; cohort; critical period; design; follow-up; improved; innovation; mortality; neutralizing antibody; novel; novel strategies; pediatric human immunodeficiency virus; preservation; small molecule; success; treatment response; treatment strategy

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.

项目总结/摘要 新的HIV-1治疗策略，维持病毒抑制，同时允许时间关闭小分子 抗逆转录病毒治疗是高度优先事项。使用强效和长期的抗逆转录病毒治疗干预， 在生长的关键时期，作用广泛的中和抗体（bNAb）可以减少直接的ART毒性。 艾滋病毒感染儿童的健康和发展，将确保坚持，并可能比ART对病毒储存库有益 减少和后处理控制。bNAb与病毒库的减少有关，最近 研究支持一种潜在的疫苗样作用，可以训练免疫反应， 结果。像早期治疗的成年人一样，早期治疗的儿童可能有最好的机会成为治疗后 控制器，但需要进一步的研究-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，表明每月接受双重治疗， 在44%的早期ART治疗儿童中，bNAb可以在没有ART的情况下维持病毒抑制24周。我们也 表明成功的特定标志物是可识别的，并且标准ART的中断可以安全地进行。 在我们的研究中。在拟定的研究（Tatelo Plus）中，我们将进行多步介入治疗。 临床试验，使该领域更进一步。使用新颖的逐步设计和创新的bNAb旋转 策略，我们将首先确定长效三联疫苗的安全性、药代动力学、剂量和储库影响 当添加到现有有效的bNAb免疫治疗中时，使用VRC 07 - 523 LS、PGDM 1400 LS和PGT 121 - 414 LS进行bNAb免疫治疗 条在选定的具有成功有利标志物的参与者中，我们接下来将测量三联bNAb治疗 停止抗逆转录病毒治疗后取得成功。最后，我们将测试ATI期间病毒学控制的维持情况 在一个更严格选择的参与者群体中--那些病毒储存量极低或有证据表明 HIV整合在基因组的非编码区。本研究的具体目的是（1）确定 在以下情况下，伴随使用三联bNAb免疫治疗长达24周的安全性、药代动力学和给药 在博茨瓦纳35例早期治疗的HIV-1感染儿童中，将抗逆转录病毒治疗添加到抗逆转录病毒治疗中;（2）确定 维持三重bNAb治疗24周的病毒学抑制和CD 4细胞计数保持 在选定的早期治疗儿童中停止标准ART后;和（3）为了确定安全性， 在两组中维持24周ATI的病毒学抑制和CD 4细胞计数：a） 具有最低病毒储库的标记的那些，和B）具有HIV-1整合的证据的那些，所述整合主要在 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细胞组成。 残余病毒库，以及抗病毒先天性和适应性免疫应答的程度和质量。这 这项研究将代表儿童bNAb联合治疗的一个飞跃， 通过仔细进行ATI的治疗议程。