The population of 16 million children exposed to HIV and uninfected (CHEU) under 15 years of age continues to expand rapidly, and the estimated prevalence of CHEU exceeds 20% in several countries in sub-Saharan Africa with high HIV prevalence. Some evidence suggests that CHEU experience suboptimal neurodevelopmental outcomes compared to children born to women without HIV. In this commentary, we discuss the latest research on biologic and socio-behavioural factors associated with neurodevelopmental outcomes among CHEU.
Some but not all studies have noted that CHEU are at risk of poorer neurodevelopment across multiple cognitive domains, most notably in language and motor skills, in diverse settings, ages and using varied assessment tools. Foetal HIV exposure can adversely influence infant immune function, structural brain integrity and growth trajectories. Foetal exposure to antiretrovirals may also influence outcomes. Moreover, general, non-CHEU-specific risk factors for poor neurodevelopment, such as preterm birth, food insecurity, growth faltering and household violence, are amplified among CHEU; addressing these factors will require multi-factorial solutions. There is a need for rigorous harmonised approaches to identify children at the highest risk of delay. In high-burden HIV settings, existing maternal child health programmes serving the general population could adopt structured early child development programmes that educate healthcare workers on CHEU-specific risk factors and train them to conduct rapid neurodevelopmental screening tests. Community-based interventions targeting parent knowledge of optimal caregiving practices have shown to be successful in improving neurodevelopmental outcomes in children and should be adapted for CHEU.
CHEU in sub-Saharan Africa have biologic and socio-behavioural factors that may influence their neurodevelopment, brain maturation, immune system and overall health and wellbeing. Multidisciplinary research is needed to disentangle complex interactions between contributing factors. Common environmental and social risk factors for suboptimal neurodevelopment in the general population are disproportionately magnified within the CHEU population, and it is, therefore, important to draw on existing knowledge when considering the socio-behavioural pathways through which HIV exposure could impact CHEU neurodevelopment. Approaches to identify children at greatest risk for poor outcomes and multisectoral interventions are needed to ensure optimal outcomes for CHEU in sub-Saharan Africa.

Children who are HIV-exposed and uninfected (CHEU) are a growing population at potential risk of poor neurocognitive development. We tested a nurturing care intervention on children\'s neurocognitive development and maternal depressive symptoms (primary) with mediation through caregiving activities (secondary).
This study was conducted among six intervention and nine comparison antenatal-care/prevention of vertical transmission (ANC/PVT) HIV clinics in eSwatini. We enrolled pregnant women and measured infant development at 9 and 18 months. mothers2mothers (m2m) designed and implemented the clinic-home-community-based intervention. We measured infants\' neurodevelopment, maternal depressive symptoms and caregiving activities with the Mullen Scales of Early Learning (MSEL), Edinburgh Postnatal Depression Scale, HOME Inventory and Family Care Indicators. We fitted linear mixed effects regression models with clinic random effects to compare intervention versus comparison arms, and generalised structural equation models to evaluate mediation, adjusting for confounders.
Mother-infant pairs (n = 429) participated between January 2016 through May 2018. Socio-demographic characteristics were balanced between arms except for higher rates of peri-urban versus rural residence and single versus married mothers in the comparison group. The 18 month retention was 82% (180/220) intervention, 79% (166/209) comparison arm, with 25 infant deaths. Intervention MSEL scores were significantly, and modestly, higher in receptive language (55.7 [95% CI 54.6, 56.9] vs. 53.7 [95% CI 52.6, 54.8]), expressive language (42.5 [95% CI 41.6, 39.8] vs. 40.8 [95% CI 39.8, 41.7]) and composite MSEL (85.4 [95% CI 83.7, 84.5] vs. 82.7 [95% CI 81.0, 84.5]), with no difference in maternal depressive symptoms or in observations of mother-child interactions. Intervention book-sharing scores were higher (0.63 vs. 0.41) and mediated the effect on MSEL scores (indirect effect, p-values ≤ 0.024). The direct effects on visual reception and expressive language scores were significantly higher in the intervention compared to the comparison arm (coefficients 1.93 [95% CI 0.26, 3.60] and 1.66 [95% CI 0.51, 2.79, respectively]).
Nurturing care interventions can be integrated into ANC/PVT clinic-home-community programmes. The intervention, mediated through interactive caregiving activities, increased language development scores among CHEU. Partnering with a local team, m2m, to design and implement a culturally relevant intervention illustrates the ability to impact parent-child play and learning activities that are associated with children\'s neurodevelopment.

Predictors of neurodevelopment among children who are HIV-exposed uninfected (CHEU) are poorly understood.
Mothers with and without HIV and their children were enrolled during 6-week postnatal care visits across seven sites in Kenya between March 2021 and June 2022. Infant neurodevelopment was assessed using the Malawi Developmental Assessment Tool, including social, language, fine motor and gross motor domains. We used multivariate linear mixed effects models to identify associations between 1-year neurodevelopment scores, HIV and antiretroviral therapy (ART) exposures, and household factors, adjusted for potential confounders and clustered by the site.
At 1-year evaluation, CHEU (n = 709) and children who are HIV-unexposed uninfected (CHUU) (n = 715) had comparable median age (52 weeks) and sex distribution (49% vs. 52% female). Mothers living with HIV were older (31 vs. 27 years), had lower education (50% vs. 26% primary) and were more likely to be report moderate-to-severe food insecurity (26% vs. 9%) (p < 0.01 for all). Compared to CHUU, CHEU had higher language scores (adjusted coeff: 0.23, 95% CI: 0.06, 0.39) and comparable social, fine and gross motor scores. Among all children, preterm birth was associated with lower gross motor scores (adjusted coeff: -1.38, 95% CI: -2.05, -0.71), food insecurity was associated with lower social scores (adjusted coeff: -0.37, 95% CI: -0.73, -0.01) and maternal report of intimate partner violence (IPV) was associated with lower fine motor (adjusted coeff: -0.76, 95% CI: -1.40, -0.13) and gross motor scores (adjusted coeff: -1.07, 95% CI: -1.81, -0.33). Among CHEU, in utero efavirenz (EFV) exposure during pregnancy was associated with lower gross motor scores compared to dolutegravir (DTG) exposure (adjusted coeff: -0.51, 95% CI: -1.01, -0.03). Lower fine and gross motor scores were also associated with having a single or widowed mother (adjusted coeff: -0.45, 95% CI: -0.87, -0.03) or a deceased or absent father (adjusted coeff: -0.81, 95% CI: -1.58, -0.05), respectively.
Biologic and social factors were associated with child neurodevelopment. Despite socio-demographic differences between CHEU and CHUU, 1-year neurodevelopment was similar. Addressing IPV and food insecurity may provide benefits regardless of maternal HIV status. DTG use was associated with higher neurodevelopmental scores in CHEU, compared to EFV regimens, potentially contributing to a lack of neurodevelopmental difference between CHEU and CHUU.

Children who are HIV-exposed but uninfected (CHEU) are at risk of linear growth faltering and neurodevelopmental delay. Circulating biomarkers associated with these adverse outcomes may elucidate pathways of injury.
To identify biomarkers associated with growth faltering and neurodevelopmental delay in CHEU.
We performed a systematic review of electronic databases MEDLINE (1946-April 2021), EMBASE (1974-April 2021), Scopus (2004-April 2021), and PubMed (1985-April 2021), following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The systematic review was registered on the International Prospective Register of Systematic Reviews (PROSPERO, registration number CRD42021238363).
We found seven studies associating biomarker abnormalities and growth outcomes in CHEUs and two studies on biomarker abnormalities and neurodevelopmental delay. Biomarker abnormalities associated with growth restriction were: C-reactive protein (CRP), tumour necrosis factor (TNF), interferon-gamma (IFN-γ), interleukin (IL)-12p70, IFN-γ-induced protein-10 (CXCL10/IP-10), lipopolysaccharide binding protein (LBP), insulin-like growth factor-1 (IGF-1), and IGF-binding protein-1 (IGFBP-1). Biomarkers associated with motor, language, and cognitive delay were CRP, IFN-γ, IL-1β, -2, -4, -6, -10, -12p70, neutrophil gelatinase-associated lipocalin (NGAL), granulocyte-macrophage colony-stimulating factor (GM-CSF), and matrix metalloproteinase- 9 (MMP-9).
Elevated markers of inflammation (acute phase reactants, pro-inflammatory cytokines, chemokines) and intestinal microbial translocation are associated with growth faltering. Elevated markers of inflammation are associated with adverse neurodevelopment.

With the global rollout of mother-to-child prevention programs for women living with HIV, vertical transmission has been all but eliminated in many countries. However, the number of children who are exposed in utero to HIV and antiretroviral therapy (ART) is ever-increasing. These children who are HIV-exposed-but-uninfected (CHEU) are now well recognized as having persistent health disparities compared to children who are HIV-unexposed-and-uninfected (CHUU). Differences reported between these two groups include immune dysfunction and higher levels of inflammation, cognitive and metabolic abnormalities, as well as increased morbidity and mortality in CHEU. The reasons for these disparities remain largely unknown. The present review focuses on a proposed link between immunometabolic aberrations and clinical pathologies observed in the rapidly expanding CHEU population. By drawing attention, firstly, to the significance of the immune and metabolic alterations observed in these children, and secondly, the impact of their healthcare requirements, particularly in low- and middle-income countries, this review aims to sensitize healthcare workers and policymakers about the long-term risks of in utero exposure to HIV and ART.

UNASSIGNED: With the implementation of lifelong antiretroviral therapy (ART) for HIV treatment and prevention, the proportion of children exposed to ART in utero from conception is increasing. We estimated the effect of timing of ART exposure on growth of children HIV-exposed and uninfected (CHEU) up to Up to 24 months of age in Malawi.
UNASSIGNED: Data were collected from a prospective cohort of infants HIV-exposed aged 1-6 months (enrollment) and their mothers with HIV enrolled in the National Evaluation of Malawi\'s Prevention of Mother-to-Child Transmission of HIV Programme (2014-2018). Anthropometry was measured at enrollment, visit 1 (approximately 12 months), and visit 2 (approximately 24 months). Weight-for-age (WAZ) and length-for-age (LAZ) were calculated using the WHO Growth Standards. Multivariable mixed-effects models with linear splines for age were used to examine differences in growth by timing of ART exposure (from conception, first/second trimester, or third trimester/postpartum). Models were adjusted for confounders selected a priori guided by a conceptual framework. Hypothesized interactions and potential mediators were explored, and interactions with splines were included in final models if P < 0.1.
UNASSIGNED: A total of 1,206 singleton CHEU and their mothers were enrolled and 563 completed the follow-up through 24 months of age. Moreover, 48% of CHEU were exposed to ART from conception, 40% from first/second trimester, and 12% from third trimester/postpartum. At enrollment, 12% of infants had low birthweight (LBW), 98% had been breastfed in past 7 days, and 57% were enrolled in an HIV care clinic. CHEU growth trajectories demonstrated cohort-wide growth faltering after the age of 12 months. Of 788 and 780 CHEU contributing to WAZ and LAZ multivariable models, respectively, there was no evidence of differences in mean WAZ or LAZ among those exposed from conception or first/second trimester vs. third trimester/postpartum and no evidence of a difference in WAZ or LAZ rate of change by timing of ART exposure (all interactions P > 1.0).
UNASSIGNED: Reassuringly, ART exposure from conception was not associated with decreased WAZ or LAZ in CHEU Up 24 months of age. Overall growth trajectories suggest CHEU experience growth faltering after 12 months of age and may need support through and beyond the first 2 years of life.

Studies focusing on children affected by HIV have shown that they have generally lower academic performance, however, few studies separate children who are HIV exposed and infected (CHEI) and those who are HIV exposed but uninfected (CHEU). Importantly, in rural sub-Saharan Africa, the majority of studies on CHEI and CHEU examine academic performance indirectly based on cognitive test scores. Therefore, studies assessing the effects of HIV on academic achievement directly for CHEI and CHEU are needed. This article evaluates the effects of HIV-infection on cognitive and academic performance by comparing CHEI (n = 82) and CHEU (n = 1045) aged 7-17 years old using cross-sectional data from an ongoing longitudinal study in a rural area of Zambia. Youth completed cognitive and academic assessments; their height and weight were assessed to generate Body Mass Index (BMI). Caregiver questionnaires provided information on youths\' years in school and household socio-economic status (SES). Results indicated that while HIV infection status did explain some of the variance in performance between CHEI and CHEU, age, BMI, years of schooling and SES accounted for additional variance. The effect of years of schooling on both cognitive and academic performance demonstrated that CHEI\'s performance may be greatly improved by consistent school enrollment.