HIV Exposure Without Infection Impacts Early Language Development: Outcomes from a South African Birth Cohort Study

Background:  Whereas HIV infection is known to cause developmental delay, effects of HIV and antiretroviral drugs (ARVs) in HIV-exposed uninfected (HEU) children are unclear. We compared developmental outcomes of HEU and HIV-unexposed uninfected (HUU) children during their first 2 years of life in the South African population-based Drakenstein Child Health cohort study. Methods:  Between 2012-2015, pregnant women were enrolled antenatally in a peri-urban setting. Mothers and children received HIV testing and ARVs per local guidelines. Developmental assessments were conducted blinded to HIV/ARV status, using the Bayley-III Scales of Infant and Toddler Development(BSID-III). Of 1143 live births, 1065(93%) children were in follow-up at 6 months and 1000(87%) at 24 months excluding two HIV-infected children. 260(24%) randomly selected children (61 HEU, 199 HUU) had BSID-III assessments at 6 months and 732(73%)(168 HEU, 564 HUU) at 24 months. All HEU children were exposed to ARVs (88% to maternal triple antiretroviral therapy). Outcomes were similar for HEU and HUU children at 6 months (p>0·10). At 24 months, HEU children scored lower than HUU in receptive language (adjusted difference -1·03, 95% confidence interval[CI] -1·69 to -0·37) and expressive language (-1·17, 95%CI -2·09 to -0·24); in contrast, cognitive, fine and gross motor domains were similar (all p>0·24). Corresponding to this, HEU children had higher proportions of developmental delay (score<-2SD) compared to HUU in receptive (14%vs7%, adjusted odds ratio[aOR] 1·96, 95%CI 1·09 to 3·52) and expressive language(11%vs6%, aOR 2·14, 95%CI 1·11 to 4·15).   Interpretation:  We found uninfected children exposed to maternal HIV and ARVs had two-fold increased odds of receptive and expressive language delay at two years. Given almost a quarter of South African children are HIV-exposed, and the importance of language in society, further long-term work to understand developmental outcomes of HEU children is needed.   Funding Statement: The study was funded by the Bill & Melinda Gates Foundation [OPP 1017641]. Additional support for HJZ, DJS and KAD was provided by the South African Medical Research Council. CJW is supported by the Wellcome Trust through a Research Training Fellowship [203525/Z/16/Z]. KAD is additionally supported by the NRF, an Academy of Medical Sciences Newton Advanced Fellowship (NAF002/1001) funded by the UK Government’s Newton Fund, by NIAAA via (R21AA023887), by the Collaborative Initiative on Fetal Alcohol Spectrum Disorders (CIFASD) developmental grant (U24 AA014811), and by the US Brain and Behaviour Foundation Independent Investigator grant (24467). AMR is additionally supported by the UK Medical Research Council (MRC) and the UK Department for International Development (DFID) under the MRC/DFID Concordat agreement which is also part of the EDCTP2 programme supported by the European Union grant reference (MR/R010161/1). WB is supported by the SAMRC National Health Scholars programme. Declaration of Interests: The authors state: "No conflicts of interest." Ethics Approval Statement: The study was approved by the Faculty of Health Sciences, Human Research Ethics Committee, University of Cape Town (401/2009 and 044/2017) and the London School of Hygiene & Tropical Medicine Observational/Interventions Research Ethics committee (11903).