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

• 批准号: 10159497
• 负责人: Jillian Neary
• 金额: $ 4.6万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 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/10159497
• 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; virology

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： 这个项目的主要目标是描述病毒的轨迹，预测因子和神经认知影响。 控制肯尼亚艾滋病毒感染儿童。大约有170万0-14岁的儿童 在全球范围内感染艾滋病毒。对于感染艾滋病毒的儿童，尽早开始抗逆转录病毒治疗至关重要， 抑制病毒载量和恢复免疫力，从而改善生存、生长、神经认知， 机会性感染的可能性。为了控制艾滋病毒复制，需要终身坚持抗逆转录病毒治疗， 面临独特的挑战，包括不适当的药物剂量，依从性差和耐药性， 他们比成年人更不可能保持病毒抑制。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前病毒，当艾滋病毒感染者停止使用时， 抗逆转录病毒治疗，导致病毒血症反弹。病毒库仍然是治疗后病毒感染的最大挑战。 控制和艾滋病毒治愈;然而，很少有研究评估了儿童的病毒控制和水库。通过利用 在5 R 01 HD 094718研究中进行的神经认知评估的样本和结果（MPI：Drs. Grace John-Stewart和达拉雷曼），该研究涉及两组患有10年艾滋病的儿童。 在肯尼亚，该项目将有助于了解抗逆转录病毒治疗后的病毒控制， 感染艾滋病毒的儿童。目标1a将确定艾滋病毒DNA下降的纵向轨迹和预测因素 在围产期感染的儿童中。HIV DNA下降将使用非线性混合效应模型进行建模， 预测因素包括ART开始时的年龄、ART治疗方案、基线HIV RNA、基线CD 4和早期 巨细胞病毒合并感染。目的1b将确定围产期感染者中高病毒储库的预测因子 儿童ART使用广义估计方程。预测因素将包括ART开始时的年龄、ART 方案、基线HIV RNA、基线CD 4和早期巨细胞病毒合并感染。目标2将决定 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， 使用考克斯回归分析在ART开始后两年病毒抑制的儿童。预测因素将包括 ART开始时的年龄、基线CD 4、ART方案、护理人员披露和儿童对ART的依从性。最后， 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CD 4、HIV RNA、HIV DNA和储库水平与神经认知结果之间的关系 使用广义估计方程。该项目的发现将优化早期治疗， 有助于艾滋病毒治疗战略。该研究计划将为F31候选人提供严格的博士预科课程。 培训，包括1）先进的流行病学统计方法，包括复杂的纵向数据分析， 2)与儿科HIV相关的分子流行病学经验，以及3）内容领域的专业知识， 艾滋病病毒感染儿童的神经认知能力。