Growth faltering and developmental delay in HIV-exposed uninfected infants

Background Human Immunodeficiency Virus (HIV) is a major cause of mortality and morbidity globally. Vertical transmission is the primary mode of HIV acquisition among infants. Although successful interventions have reduced vertical transmission to less than <2.9% in low-to-middle income countries (LMIC), new concerns have emerged about the health outcomes of HIV-exposed uninfected (HEU) children. In 2018, there were an estimated 14.8 million children who were HEU, 90% of whom resided in Sub-Saharan Africa. HEU infants worldwide significantly outnumber infants that are infected with HIV and represent nearly 30% of the newborn population in certain HIV endemic nations. These HEU children have increased morbidity and mortality compared to HIV unexposed, uninfected (HUU) children. Among HEUs, studies have reported low birth weight (LBW), impaired early growth, impaired psychomotor and cognitive development, increased hearing loss, increased incidence of speech delay, immunological abnormalities, and increased susceptibility to infectious diseases. This thesis has two objectives: (1) review published data on circulating biomarkers that are associated with growth faltering and neurodevelopmental delay in HEU infants (Chapter 2); and (2) evaluate growth faltering and neurodevelopment in a Ugandan HEU infant cohort (Chapter 3). Methods In Chapter 2, we performed a systematic review of the literature of studies to identify biomarkers that are associated with growth faltering and neurodevelopmental delay in HEU infants. In Chapter 3, we prospectively followed a cohort of HEU infants from birth to 18 months of age, and measured growth parameters longitudinally. The Malawi Development Assessment Tool (MDAT) and the Color Object Association Test (COAT) were used for developmental assessments at 12 and 18 months of age. We examined the association between early growth faltering and subsequent neurodevelopment. Results In Chapter 2, we found that biomarkers of inflammation (acute phase reactant, proinflammatory cytokines, regulatory cytokines, chemokines), microbial translocation, growth factors, tissue remodelling, and neutrophil activation were associated with growth faltering and poor neurodevelopmental outcomes. In Chapter 3, we found that LBW and failure to thrive (FTT) were associated with a lower MDAT score at 18 months of age. Conclusion This thesis addresses growth faltering and neurodevelopmental outcomes in HEU infants and biomarkers associated with these outcomes. These findings may contribute to identifying HEU infants at risk of having poor growth and neurodevelopment and target interventions to mitigate these adverse outcomes.