PROJECT SUMMARY Children who are HIV-exposed but uninfected (HEU) may have worse neurodevelopmental outcomes compared to their HIV-unexposed and uninfected (HUU) peers. However, the etiology of this potential association is unclear. With a growing population of children who are HIV-exposed, making up over 15% of children in some countries, there is a critical need to identify evidence-based risk factors associated with poor neurodevelopment to appropriately target interventions. The specific objectives of this application are: (1): to evaluate potential risk factors longitudinally over the first 2 years of life in children who are HEU and HUU and define those associated with worse neurodevelopmental outcomes at 24 months, and (2) to create a risk assessment tool to predict which children will have worse neurodevelopmental outcomes. The central hypothesis is that children who are HEU and HUU will have different neurodevelopmental outcomes; and that we can use risk factors to predict which children are at risk for worse outcomes before 2 years of age. The rationale for developing this tool is to identify children at risk for worse neurodevelopmental outcomes earlier to allow for targeted intervention. In Aim 1, we will evaluate the potential risk factors for poor neurodevelopment in young children. In Aim 2, we will compare neurodevelopmental outcomes between 24-month-old children who are HEU and those who are HUU in Kenya. In Aim 3, we will create a risk assessment tool to predict which children are at risk for worse neurodevelopmental outcomes at 24 months of age. This study will leverage an existing cohort to prospectively enroll 500 children who are HEU and 500 who are HUU and longitudinally follow them from birth to 24 months of age. Within the first aim, the following factors will be measured every 6 months: infectious morbidity, biological risk factors, and social risk factors (both sociodemographic and psychosocial). We will then compare these factors between children who are HEU and HUU. Within the second aim, we will measure neurodevelopment (cognition, language, motor, and behavior) in children at 24 months of age using the Child Behavior Checklist and the Bayley Scales of Infant and Toddler Development, 3rd edition, which our team has culturally-adapted and internally validated for use in Kenya. We will then compare neurodevelopmental outcomes between children who are HEU and HUU, providing well-powered data to determine whether differences truly exist between the groups. Finally, within the third aim, we will use generalized linear mixed modeling to quantify associations among multiple factors on child neurodevelopment and create a risk assessment tool for use in children <24 months. The proposed study is significant, as we will determine interconnected factors associated with worse neurodevelopmental outcomes in children who are HEU and HUU in Kenya. The resulting risk assessment tool will allow clinical providers to institute interventions for children at risk for worse neurodevelopmental outcomes earlier. This work will also create a longitudinal cohort of children exposed to antiretroviral therapy and HIV that may be monitored for future studies.

PROJECT NARRATIVE Despite the success of perinatal and postnatal HIV transmission prevention services, many children born to mothers with HIV are not thriving. The proposed research will explore the interaction between HIV and child neurodevelopment to create a risk assessment tool predicting worse neurodevelopmental outcomes in order to target appropriate interventions to those in need. Thus, the proposed research is relevant to the NIH’s mission, as it develops fundamental knowledge to enhance health and reduce the burdens of human disability.