Developmental challenges in infants who are HIV-exposed uninfected

The global HIV epidemic continues to affect millions of people and significantly affects children. Approximately 16 million children born to HIV-positive women, categorized as HIV-exposed uninfected (HEU), face unique developmental hurdles despite not contracting the virus. These children are more likely to experience developmental issues due to factors such as exposure to maternal HIV, antiretroviral therapy (ART), nutritional shortages, and adverse social conditions. Research indicates that children who are HIV-exposed but uninfected (HEU) may have subpar neurodevelopmental outcomes compared to those born to HIV-negative women. Despite the growing awareness of HEU children's challenges, there remains a gap in comprehensive reviews that synthesize knowledge about the influences on their development, especially with current ART protocols. This review examines these developmental challenges, focusing on growth and neurodevelopmental outcomes; the effects of maternal HIV infection and ART; and the influence of nutrition, socio-environmental factors, and biological mechanisms on health outcomes in HEU infants.

Children with HEU are at higher risk of growth deficits and neurodevelopmental delays. Maternal health issues, such as poor nutrition and mental health disorders, adversely affect fetal and postnatal development. Socioenvironmental conditions also shape the developmental outcomes of HEU children. In-utero exposure to HIV and antiretroviral drugs (ARVs), along with neonatal ARV exposure during breastfeeding, can negatively affect an infant's immune function, brain structure, growth patterns, and neurodevelopment. While studies have shown differences between children born HIV-uninfected but exposed to HIV/ARV and their unexposed peers, several limitations have been noted. Much of the immunological, neurological, and mortality data in children born HIV-uninfected but exposed to HIV/ARV lacks non-HIV-exposed and ARV-exposed controls, making it challenging to distinguish between the effects of ARVs and HIV exposure. These limitations emphasize the need for future studies with well-defined control groups to isolate the effects of ARVs from HIV exposure better.

HEU infants face multifactorial developmental challenges arising from the interplay of biological factors, including maternal immune activation, systemic inflammation, ART-related mitochondrial toxicity, and altered infant immune function and socio-environmental determinants such as nutritional deficiencies, food insecurity, and maternal mental health disorders. These interacting factors collectively impair growth, neurodevelopment, and immune competence. To mitigate these adverse outcomes, targeted interventions are urgently needed, including optimizing ART regimens to reduce infant toxicity, implementing comprehensive nutritional and food security support for mothers and children, addressing maternal mental health and psychosocial wellbeing, and strengthening early childhood development programs alongside improved healthcare access. Future research must employ rigorous longitudinal designs with well-matched control groups to disentangle the effects of HIV and ART exposure and to inform effective, integrated strategies that promote optimal health and development in HEU children.