Trajectories, predictors, and neurocognitive impact of HIV viral control among children living with HIV in Kenya

肯尼亚艾滋病毒感染儿童艾滋病病毒控制的轨迹、预测因素和神经认知影响

基本信息

批准号：
10382259
负责人：
Jillian Neary
金额：
$ 4.68万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-03-16 至 2024-03-15
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10382259
关键词：
3 year old Address Adherence Adult Africa South of the Sahara Aftercare Age Area Attention CD4 Lymphocyte Count Caregivers Cells Child Childhood Cohort Studies Complex Cytomegalovirus Cytomegalovirus Infections DNA Data Data Analyses Delayed Memory Development Disclosure Dose Drug resistance Early treatment Enrollment Epidemiology Equation Evaluation Face Failure Gaussian model Goals Growth HIV HIV therapy Highly Active Antiretroviral Therapy Immunity Immunologic Factors Immunosuppression Impulsivity Incidence Individual Infant Inflammation Kenya Learning Life Literature Malawi Methods Modeling Molecular Epidemiology Motor Neuraxis Neurocognition Neurocognitive Neurocognitive Deficit Neurons Opportunistic Infections Outcome Perinatal Pharmaceutical Preparations Proviruses RNA Regimen Research Research Personnel Sampling Short-Term Memory Site South Africa Statistical Methods Study models Survival Analysis Testing Time Training Uganda Viral Viral Load result Viral reservoir Viremia Virus Latency Zimbabwe aged antiretroviral therapy co-infection cognitive ability cognitive testing cohort executive function experience follow-up improved pediatric human immunodeficiency virus performance tests pre-doctoral sample collection skills student training therapy adherence treatment optimization treatment strategy

项目摘要

Project summary / Abstract: The primary goal of this project is to characterize the trajectories, predictors, and neurocognitive impact of viral control among children living with HIV in Kenya. There are approximately 1.7 million children ages 0-14 years living with HIV globally. For children living with HIV, early initiation of antiretroviral therapy (ART) is crucial to suppress viral load and recover immunity, resulting in improved survival, growth, neurocognition, and reduced likelihood of opportunistic infections. To control HIV replication, lifelong ART adherence is required, and children face unique challenges, including inappropriate drug dosing, poor adherence, and drug resistance, that make them less likely than adults to remain virally suppressed. Despite viral suppression, the viral reservoir persists as replication-competent provirus in infected cells that can reactivate when individuals living with HIV discontinue ART, resulting in rebound viremia. The viral reservoir remains the greatest challenge to post-treatment viral control and HIV cure; however, few studies have evaluated viral control and reservoirs in children. By leveraging samples and results from neurocognitive assessments performed within the 5R01HD094718 study (MPI: Drs. Grace John-Stewart and Dara Lehman), which involves two cohorts of children living with HIV with 10 years of post-ART follow up in Kenya, this project will contribute to the understanding of post-ART viral control among children living with HIV. Aim 1a will determine longitudinal trajectories and predictors of decline in HIV DNA among perinatally infected children. HIV DNA decline will be modeled using nonlinear mixed effects models and predictors will include age at ART initiation, ART regimen, baseline HIV RNA, baseline CD4, and early cytomegalovirus coinfection. Aim 1b will determine predictors of high viral reservoir among perinatally infected children on ART using generalized estimating equations. Predictors will include age at ART initiation, ART regimen, baseline HIV RNA, baseline CD4, and early cytomegalovirus coinfection. Aim 2 will determine incidence and predictors of virologic failure (HIV RNA exceeding ≥1,000, ≥400, and ≥50 copies/ml) among children who are virally suppressed at two years post-ART initiation using Cox regression. Predictors will include age at ART initiation, baseline CD4, ART regimen, caregiver disclosure, and child adherence to ART. Lastly, this project will determine the impact of viral control on neurocognition among children living with HIV. Aim 3 will determine the association between CD4, HIV RNA, HIV DNA, and reservoir levels and neurocognitive outcomes using generalized estimating equations. Findings from this project will optimize early treatment and potentially contribute to HIV cure strategies. This research plan will provide the F31 candidate with rigorous predoctoral training, including 1) advanced epidemiologic statistical methods including analyses of complex longitudinal data, 2) experience with molecular epidemiology related to pediatric HIV, and 3) content-area expertise in neurocognition among children living with HIV.

项目概要/摘要：该项目的主要目标是描述病毒的轨迹、预测因素和神经认知影响肯尼亚艾滋病毒感染儿童的控制大约有 170 万 0-14 岁儿童。对于全球艾滋病毒感染者来说，尽早开始抗逆转录病毒治疗（ART）至关重要。抑制病毒载量并恢复免疫力，从而改善生存、生长、神经认知，并减少为了控制艾滋病毒复制，需要终生坚持抗逆转录病毒疗法，并且儿童。面临独特的挑战，包括药物剂量不当、依从性差和耐药性，这使得与成年人相比，他们不太可能保持病毒抑制尽管病毒受到抑制，但病毒库仍然存在。作为受感染细胞中具有复制能力的原病毒，当艾滋病毒感染者停止治疗时，可以重新激活 ART，导致病毒血症反弹，病毒库仍然是治疗后病毒的最大挑战。控制和艾滋病毒治疗；然而，很少有研究通过利用来评估儿童的病毒控制和储存库。 5R01HD094718 研究中进行的神经认知评估的样本和结果（MPI： Drs. （Grace John-Stewart 和 Dara Lehman），该项目涉及两组感染艾滋病毒的儿童，这些儿童已经接受了 10 年的治疗在肯尼亚的抗逆转录病毒治疗后后续行动中，该项目将有助于了解抗逆转录病毒治疗后病毒控制目标 1a 将确定 HIV DNA 下降的纵向轨迹和预测因素。将使用非线性混合效应模型对围产期感染的儿童中的 HIV DNA 下降进行建模。预测因素包括 ART 开始时的年龄、ART 方案、基线 HIV RNA、基线 CD4 和早期目标 1b 将确定围产期感染者中高病毒库的预测因子。使用广义估计方程进行 ART 的儿童将包括 ART 开始时的年龄、ART 的年龄。治疗方案、基线 HIV RNA、基线 CD4 和早期巨细胞病毒合并感染将确定目标 2。病毒学失败（HIV RNA 超过 ≥1,000、≥400 和 ≥50 拷贝/ml）的发生率和预测因素使用 Cox 预测因子在 ART 开始两年后病毒受到抑制的儿童将包括在内。开始 ART 时的年龄、基线 CD4、ART 治疗方案、护理人员披露以及儿童对 ART 的依从性。该项目将确定病毒控制对艾滋病毒感染儿童神经认知的影响，目标 3 将。确定 CD4、HIV RNA、HIV DNA 和储存水平与神经认知结果之间的关联使用广义估计方程将优化早期治疗并有可能。该研究计划将为 F31 候选人提供严格的博士前准备。培训，包括 1) 先进的流行病学统计方法，包括复杂纵向数据的分析， 2) 与儿科 HIV 相关的分子流行病学经验，以及 3) 相关领域的专业知识艾滋病毒感染者的神经认知。