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

Children with HIV have poorer viral control than adults. Early initiation of effective antiretroviral therapy (ART) is essential for suppressing virus and recovering immunity; however, children are less likely to attain viral suppression than adults due to inadequate treatment dosing for weight, drug resistance, and barriers to adherence. Similar to adults, during viral suppression replication-competent HIV persists in infected cells that can reactivate after discontinuation or interruption of ART. Understanding predictors and trajectories of HIV viral control and the effect of HIV viral control on neurocognitive outcomes can inform cure and differentiated care strategies for children with HIV and identify children who could benefit from interventions to improve neurocognitive outcomes. Methods: We used samples, responses to questionnaires, and results from neurocognitive and neuropsychological assessments from the Optimizing Pediatric HAART study (5R01HD094718; MPIs: Drs. Grace John-Stewart and Dara Lehman), which enrolled a cohort of children with HIV who initiated ART by 12 months of age and have been followed for >10 years post-ART in Kenya. For Chapter 1, we used linear mixed effects models to determine predictors of HIV DNA levels. Chapter 2 involved group-based trajectory models to determine HIV viral load trajectories and Fisher’s exact tests and t-tests to determine correlates of HIV viral load trajectories. For Chapter 3, we assessed the relationship between HIV viral load, HIV DNA, and cytomegalovirus (CMV) DNA and neurocognitive and neuropsychological outcomes using generalized linear models. Results: In Chapter 1, children with 10% higher pre-ART CD4 percent had 13% and 24% lower total and intact HIV DNA levels, respectively, in adjusted models. One-log higher pre-ART HIV viral load was significantly associated with 21% higher total HIV DNA levels. Children on protease inhibitor-based first-line regimens had higher intact HIV DNA compared to children on non-nucleoside reverse transcriptase inhibitor-based regimens. One-log higher CMV DNA copies/ml was significantly associated with 16% higher intact HIV DNA levels. In Chapter 2, nearly two-thirds (63%) of children were in the sustained-low HIV, and 16% were in the sustained-very-high, 9% were in the sustained-high viral load group during the 6-24 month time period. Children in the sustained-high viral load group were more frequently on a first-line protease inhibitors and had younger caregivers compared to children in the sustained-low viral load group. From 48-96 months post-ART, 76% of children were in the sustained-low viral load group, and children in the high-to-low viral load group had younger caregivers compared to children in the sustained-low viral load group. In Chapter 3, higher pre-ART viral load, total HIV DNA levels, and intact DNA levels were associated with lower mean executive function z-score. Higher CMV DNA levels were associated with lower cognitive ability and motor z-scores. Higher total HIV DNA was associated with higher motor z-scores and higher intact HIV DNA was associated with higher attention z-scores. Conclusions: Early initiation of effective and palatable ART is crucial for improving viral control and neurocognitive outcomes for children with HIV. Further studies investigating the link between CMV DNAemia and HIV DNA levels as well as impact of CMV prevention or suppression therapy on neurocognitive outcomes in children living with HIV are needed. Leveraging advanced epidemiologic methods to assess longitudinal viral control could inform approaches to target children with different patterns of HIV viral control. Children with higher levels of pre-ART viral load and early HIV DNA and CMV DNA levels may benefit from targeted and effective strategies to improve long-term neurocognitive outcomes.