Neurodevelopment of Children Exposed to HIV But Uninfected in Zambia: Outcomes From Prospective Birth Cohort Study.

INTRODUCTION: Children exposed to HIV but uninfected (CHEU) number approximately 15.7 million globally. In Zambia, an estimated 56,000 CHEU are born annually, representing a substantial proportion of the national birth cohort. CHEU experience a higher risk of neurodevelopmental delay compared to their peers born HIV-unexposed. It is unknown whether the increased neurodevelopment delay burden of CHEU has been diminished by maternal combination antiretroviral therapy. METHODS: This prospective observational study analysed a subset of participants from the Zambian Infant Cohort Study (ZICS), which included 1500 pregnant women-infant dyads enrolled at a peri-urban hospital in Zambia. Infants aged 6-24 months were enrolled in a 1:1 ratio of CHEU to CHU and were followed for 18 months. Neurodevelopment was evaluated using the Malawi Developmental Assessment Tool (MDAT) at 6- and 18-month follow-ups. Anthropometrics, Caregiver-Reported Early Development Instruments assessments, eye-tracking and additional assessments were conducted at 6-, 12- and 18-month follow-ups. The primary outcomes were MDAT domain-specific Z-scores for gross motor, fine motor, language and social-adaptive. A series of regression models were fitted with MDAT domain-specific Z-scores as dependent variables, and CHEU versus CHU status as the primary independent variable. All models were adjusted for child birth year, age at assessment, sex, mother's age, education, household size and socioeconomic status. RESULTS: Between March 2022 and October 2024, a total of 316 mother-infant pairs were enrolled in the study (CHEU, n = 155; CHU, n = 161). MDAT assessments at the 18-month follow-up were done for a total of 286 infants (139 CHEU [89.7%] and 147 CHU [91.3%]). The mean age at 18-month follow-up was comparable between CHEU and CHU (29.1 vs. 28.0 months, respectively). Mean MDAT Z-scores were comparable between CHEU and CHU for all domains, with adjusted mean differences in Z-scores of 0.00 (95% CI: -0.23, 0.23) for gross motor, 0.00 (95% CI: -0.28, 0.27) for fine motor, -0.10 (95% CI: -0.48, 0.28) for language and -0.01 (95% CI: -0.32, 0.30) for social-adaptive. CONCLUSIONS: Neurodevelopmental outcomes at endline were comparable between CHEU and CHU across all the MDAT domains in this peri-urban Zambian cohort.