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

一项临床试验，旨在评估广泛中和抗体 VRC01 对博茨瓦纳早期治疗儿童队列中 HIV 病毒库的影响以及维持抑制

• 批准号: 10092914
• 负责人: Daniel R. Kuritzkes
• 金额: $ 199.9万
• 依托单位: HARVARD SCHOOL OF PUBLIC HEALTH
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-02-20 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10092914
• 关键词: Address; Adult; Adverse event; Aftercare; Anti-Retroviral Agents; Antibodies; Antiviral Agents; Autologous; Biological Assay; Birth; Botswana; CD4 Positive T Lymphocytes; Cells; Characteristics; Child; Chromosomes; Clinical; Clinical Data; Clinical Research; Clinical Trials; Clinical Virology; Complex; Control Groups; Coupled; DNA; Data; Development; Developmental Delay Disorders; Drug Kinetics; Enrollment; Evolution; Frequencies; Gene Expression; Growth; HIV; HIV Genome; HIV-1; Homeostasis; Hour; Immune; Immune response; Immunologic Markers; Immunologics; Immunotherapy; Infant; Infection; Infusion procedures; Injections; Intervention; Kinetics; Length; Life; Maintenance; Maintenance Therapy; Measurement; Monitor; Monoclonal Antibodies; Morbidity - disease rate; Outcome; Participant; Pharmaceutical Preparations; Phase; Phenotype; Plasma; Population; RNA; Research Infrastructure; Residual state; Safety; Severities; Site; T-Lymphocyte; Therapeutic; Time; Toxic effect; Variant; Viral; Viral reservoir; Withdrawal; adaptive immune response; anti-viral efficacy; antiretroviral therapy; base; cohort; design; efficacy evaluation; immune activation; improved; infant infection; intrapartum; mortality; neutralizing antibody; novel; novel strategies; open label; pediatric human immunodeficiency virus; pediatric patients; primary endpoint; recruit; research clinical testing; transcriptome sequencing; treatment effect; treatment response; viral rebound; virology

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.

抽象的 在抗逆转录病毒治疗（ART）的长期病毒抑制（在 整个生命周期和对艺术的重大毒性可能会随着时间而积累。维持艾滋病毒的新型策略 抑制病毒，同时需要休假3毒品，并进行概念证明研究以证明 这种策略的可行性 - 并研究其对病毒储层，免疫调查和临床的影响 结果 - 优先考虑。我们提出了一项开放标签期1/2研究，以评估 在没有ART的情况下，广泛中和HIV-1单克隆抗体VRC01维持病毒抑制 在病毒抑制的艾滋病毒感染的儿童中，他们在出生后96小时内开始了标准艺术（或很快 产前感染后）。所有儿童将从早期婴儿治疗（EIT）研究中招募 （U01AI114235），从出生开始就经常评估其临床，病毒学和 免疫学特征。接受过96-240周艺术并符合病毒学入学的孩子 将向拟议的研究提供标准。干预措施将包括持续的艺术和 VRC01抗体的输注为6周，然后每月维护给药 仅VRC01治疗多达24周。接受VRC01维护疗法的儿童将是 密切监视，并在任何VL> 400副本/毫升之后立即重新启动艺术。所有参与者都会 该研究旨在评估VCR01治疗在HIV-1-- 感染儿童：1）我们将表征可以使用VRC01维持的病毒控制持续时间 早期艺术后的治疗，提供概念证明VRC01可能是可能的替代方案 病毒储存率低的儿童的标准艺术； 2）我们将研究VRC01治疗是否相关 随着残留病毒储层的大小和/或细胞或克隆组成的变化，这将是 有足够的信息来制定限制病毒持久性并破坏病毒式稳定的策略的信息 小儿患者的稳态； 3）我们将评估VRC01治疗是否与 先天或适应性抗病毒免疫调查的定性或定量变化，如果它有助于 开发抗病毒免疫特征，该抗病毒型可以实现赞助后治疗病毒控制。