Early prevention interventions towards ART-free pediatric HIV remission

早期预防干预措施以实现免抗逆转录病毒疗法儿童艾滋病毒缓解

• 批准号: 10700531
• 负责人: Huanbin Xu
• 金额: $ 78.12万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-16 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10700531
• 关键词: Acceleration; Address; Adult; Affect; Aftercare; Age; Anatomy; Animals; Anti-Retroviral Agents; Antiviral Agents; Birth; Breast Feeding; Cells; Child; Childhood; Clinical Data; Clinical Trials; Data; Development; Disease remission; Drug Kinetics; Early Intervention; Early treatment; Equilibrium; Evaluation; Exposure to; Formulation; Genetic; HIV; HIV Infections; HIV therapy; HIV-1; Half-Life; Immune; Immune system; Immunologics; Infant; Infection; Injectable; Integrase; Interruption; Intervention; Intravenous; Knowledge; Lymphoid Tissue; Macaca; Metabolism; Modeling; Molecular; Monitor; Neonatal; Newborn Infant; Outcome; Pathogenicity; Penetration; Perinatal; Pharmaceutical Preparations; Prevention; Preventive treatment; Primates; Principal Investigator; Publishing; Recommendation; Regenerative capacity; Regimen; Residual state; SIV; Safety; Sampling; Site; Tissue Sample; Treatment Protocols; Treatment outcome; Viral; Viral Genome; Viral Load result; Viral Physiology; Viral reservoir; Viremia; Virus Integration; Withholding Treatment; analog; comparative; efficacy evaluation; high risk; infancy; infant infection; inhibitor; insight; neonate; pediatric human immunodeficiency virus; pediatric human immunodeficiency virus infection; preclinical trial; prevent; preventive intervention; prophylactic; simian human immunodeficiency virus; transmission process; treatment duration; treatment strategy; truvada; viral rebound

Principal Investigators (Last, first, middle): Xu, Huanbin PROJECT SUMMARY/ABSTRACT: Despite remarkable advances in prevention of vertical HIV-1 transmission, however, there is little data to guide the optimal early treatment regimens in vulnerable neonates with high risk of MTCT. Current recommended antiretroviral regimens for children are extrapolated from clinical trial in adults. Most recently, our studies show that a short-term combined ART (cART) incorporating an integrase strand transfer inhibitor (INSTI), initiated at 3 days post infection (dpi) but not one day beyond, can rapidly suppress viremia to undetectable levels in neonates, and a prolonged 9-month-early intervention of this regimen results in sustained virologic remission in 4 of 5 infants for more than 2.5 years after treatment cessation. Surprisingly, our further preliminary data showed that delaying treatment (e.g., newborn macaques inoculated with SIV/SHIV AD8 and cART initiated at 5dpi) or treating older infants (e.g., 1.5-month old infant macaques exposed to SIV with cART initiated at 3dpi) drastically altered the outcomes after interruption of the same 9-month-early intervention, as indicated by viral rebound in 4/5 and 3/3 animals, respectively. These findings suggest that outcome of pediatric sustained virologic remission appears to be very sensitive to the age of infants (e.g., newborn versus infants) and the timing (e.g., proviral reservoir seeding?) of intervention initiation, yet the exact mechanisms of viral remission remain elusive. New antivirals are also emerging and a once-monthly analog of DTG called cabotegravir (CAB) shows even greater potential for preventing HIV acquisition and replication in recent adult clinical trials, yet its efficacy and safety in pediatric HIV therapy have not been examined. Given newborn neonates lack well-organized lymphoid tissues (sanctuary sites for antiretrovirals penetration and viral reservoirs) while possessing more dynamic and regenerative capacity than an adult, prophylactic intervention in infants may be unique in that it may have more effective antiviral activity for ART-free HIV remission, resulting in more replenishment of key immune cells and normal development of the immune system. In this proposal, we hypothesize that early prevention interventions, based on appropriate initial timing, duration and INSTI combination, could effectively block viral genome integration and completely eliminate early viral reservoirs, resulting in a sustained state of ART-free virologic remission in infants exposed to or infected with HIV, and subsequently, normal immune development throughout infancy. Utilizing the pediatric NHP model of HIV, our overarching objective is address: SA1, the impact of proviral reservoirs on prophylactic intervention outcomes in infants while assessing the efficacy and safety of cabotegravir in a preclinical trial; SA2, the optimum prevention intervention strategy for achieving pediatric HIV remission, and; SA3, the pharmacokinetics and immunological alterations of ART in the unique infant primate host. Overall, these studies will provide insight into the optimal prevention intervention that achieves a sustained state of ART-free virologic remission for infants exposed to or infected with HIV at birth, which will have significant translational significance towards the treatment of HIV infection of infants in general.

首席研究人员（最后，第一，中间）：Xu，Huanbin 项目摘要/摘要： 尽管预防垂直HIV-1传输方面取得了显着进步，但几乎没有数据可以指导 MTCT高风险的脆弱新生儿的最佳早期治疗方案。推荐电流 儿童的抗逆转录病毒方案在成年人的临床试验中被外推。最近，我们的研究表明 在启动的短期合并艺术（CART）纳入了整合酶链抑制剂（Insti） 感染后3天（DPI），但没有一天，可以迅速抑制病毒血症 新生儿，该方案的长时间长时间的9个月介入导致持续的病毒学缓解 5个婴儿中有4个在治疗后2。5年以上。令人惊讶的是，我们进一步的初步数据显示 延迟治疗（例如，接种SIV/SHIV AD8和CART的新生猕猴在5DPI上启动）或 急剧治疗年龄较大的婴儿（例如，在3DPI启动的CART上暴露于SIV的1.5个月大的猕猴）急剧 相同9个月的干预中断后，结果改变了结果，如病毒反弹所示 分别为4/5和3/3动物。这些发现表明，小儿持续病毒学缓解的结果 似乎对婴儿的年龄（例如，新生儿与婴儿）和时间（例如，前病毒）非常敏感 干预开始的储层播种？但是病毒缓解的确切机制仍然难以捉摸。新的 抗病毒药也正在出现，并且一个月一次的DTG类似物称为cabotegravir（Cab）显示出更大的 在最近的成人临床试验中预防艾滋病毒收购和复制的潜力，但其功效和安全性 尚未检查小儿艾滋病毒疗法。鉴于新生儿新生儿缺乏组织良好的淋巴组织 （抗逆转录病毒侵入和病毒储层的避难所），同时拥有更具动态性和动态性 比成人的再生能力，预防性干预婴儿可能是独一无二的，因为它可能具有更多 无艺术HIV缓解的有效抗病毒活性，导致更多的关键免疫细胞和 免疫系统的正常发展。在此提案中，我们假设早期预防干预措施， 基于适当的初始计时，持续时间和Insti组合，可以有效阻断病毒基因组 整合并完全消除早期病毒储存库，导致持续的无效病毒学状态 暴露于或感染HIV的婴儿的缓解，随后在整个过程中进行正常免疫发育 婴儿期。利用艾滋病毒的儿科NHP模型，我们的总体目标是地址：SA1， 对婴儿预防性干预结果的前疾病，同时评估的疗效和安全性 在临床前试验中的Cabotegravir； SA2，实现小儿艾滋病毒的最佳预防干预策略 缓解，并且； SA3，独特的婴儿灵长类动物的药代动力学和免疫学改变 主持人。总体而言，这些研究将提供有关实现持续的最佳预防干预措施的见解 暴露于或感染HIV的婴儿的无效病毒缓解状态，这将具有重要的 一般来说，对婴儿的艾滋病毒感染的治疗意义。