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

项目摘要/摘要： 这个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。 肯尼亚艾滋病毒携带者儿童的控制。大约有170万0-14岁的儿童 全球艾滋病毒携带者。对于感染艾滋病毒的儿童来说，及早开始抗逆转录病毒治疗(ART)对 抑制病毒载量和恢复免疫力，从而改善生存、生长、神经认知和减少 机会性感染的可能性。为了控制艾滋病毒的复制，需要终身坚持艺术，而儿童 面临独特的挑战，包括不适当的药物剂量，依从性差，以及抗药性，这些都使 与成年人相比，他们保持病毒抑制的可能性更小。尽管病毒受到抑制，但病毒库仍然存在 作为感染细胞中具有复制能力的前病毒，当艾滋病毒携带者停止感染时，该前病毒可以重新激活 ART，导致反跳性病毒血症。病毒库仍然是治疗后病毒感染的最大挑战 控制和治愈艾滋病毒；然而，很少有研究对儿童的病毒控制和宿主进行评估。通过利用 5R01HD094718研究中进行的神经认知评估的样本和结果(MPI：Dr. 格雷斯·约翰-斯图尔特和达拉·雷曼)，涉及两组携带艾滋病毒的儿童，他们有10年的 在肯尼亚的抗逆转录病毒治疗后的后续行动，该项目将有助于了解抗逆转录病毒治疗后病毒控制在 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的下降将使用非线性混合效应模型和 预测因素将包括开始抗逆转录病毒治疗时的年龄、抗逆转录病毒治疗方案、基线HIV RNA、基线CD4和早期。 巨细胞病毒合并感染。目标1b将确定围产期感染人群中高病毒蓄积量的预测因素 儿童使用广义估计方程进行抗逆转录病毒治疗。预测因素将包括艺术入门年龄、艺术 治疗方案、基线HIV RNA、基线CD4和早期巨细胞病毒合并感染。目标2将决定 病毒学失败的发生率和预测因素(艾滋病毒RNA超过≥1,000，≥400和≥50拷贝/毫升) 对接受抗逆转录病毒治疗后两年被病毒抑制的儿童进行COX回归分析。预测者将包括 接受抗逆转录病毒治疗的年龄、基线CD4、抗逆转录病毒治疗方案、照顾者披露情况以及儿童对抗逆转录病毒治疗的依从性。最后，这一点 该项目将确定病毒控制对艾滋病毒携带者儿童神经认知的影响。目标3将 确定CD4、HIVRNA、HIVDNA和储存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，并有可能 为艾滋病毒治疗战略作出贡献。这项研究计划将为F31候选人提供严格的博士前培训 培训，包括1)先进的流行病学统计方法，包括分析复杂的纵向数据， 2)具有与儿童艾滋病毒相关的分子流行病学经验，以及3)内容领域的专业知识 艾滋病毒携带者儿童的神经认知。

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.