The Role of Iron Deficiency in the Neurodevelopment of Children Perinatally Exposed to HIV

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ABSTRACT With antiretroviral therapy (ART) increasingly available in pregnancy and childhood in sub-Saharan African countries where human immunodeficiency virus (HIV) is most prevalent, both the number of children who are HIV-infected (HI) but reaching adulthood and the number of children exposed to HIV but uninfected themselves (HEU) are increasing, shifting the post-ART research agenda to improving the quality of life in children perinatally exposed to HIV. Both HI children established on ART and HEU children have persistent neurobehavioral (NB) deficits in the areas of global cognition, executive functioning, motor development, but the mechanism of this delay is unclear. Iron deficiency (ID) afflicts 30% of children younger than 59 months in sub-Saharan Africa and is an established cause of impaired child brain development, but to date, no study has examined a potential association for ID in the NB impairments described in children perinatally exposed to HIV. Building on existing collaboration and substantial multidisciplinary expertise, we will characterize iron status and determine the prevalence of ID in a cohort of HI (n=70), HEU (n=70), and HIV-unexposed, uninfected (HUU) children (n=70) (Aim 1) who attend the Joint Research Centre in Kampala, Uganda, and we will establish the relationship between ID and scores from a range of NB tests (Aim 2) that collectively assess global cognition, motor development, executive function, and behavior. Notably, our study will be the first to apply the Behavior Rating Scales, a test for deficits in socioemotional behavior that are secondary to the altered dopaminergic signaling in an iron-deficient brain, in the context of HIV. We hypothesize that HEU and HI children will have a higher prevalence of ID (soluble transferrin receptor > 8.3 mg/L) and poorer NB test scores than HUU children and that within each group, scores will be poorer in ID vs. non-ID children. However, this difference will be greater in HEU and HI than in HUU children. This pilot and feasibility study will demonstrate whether there is an association between childhood ID and NB deficits in HI and HEU children, while also establishing the capacity and intellectual infrastructure to carry out NB assessments at JCRC for future longitudinal studies that can establish the temporality of iron deficiency and other factors that may lead to NB deficits in the sizeable and growing group of children perinatally exposed to HIV.