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

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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.