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Primary B-cell immunodeficiencies are risk factors for the generation of vaccine-derived polioviruses. We report immunodeficiency-associated vaccine-derived poliovirus serotype 3 in an 11-week-old boy with X-linked agammaglobulinemia. Unique characteristics of this case include early age of presentation, high viral evolutionary rate, and the child’s perinatal exposure to human immunodeficiency virus.

Improvements in administration and efficacy of antiretroviral therapy (ART) have reduced rates of mother‐to‐child transmission (MTCT) of human immunodeficiency virus (HIV) to < 2%. However, in utero exposure to antiretrovirals (ARVs) leads to abnormalities in HIV‐exposed uninfected (HEU) infants. We determined the effect of five ARVs on human umbilical cord blood (UCB)‐derived haematopoietic stem/progenitor cells (HSPC) with the aim of exploring a potential causal relationship with haematological abnormalities. Efavirenz (EFV) was cytotoxic to HSPCs alone and in combination with tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC). Dolutegravir (DTG) had a biphasic effect on HSPC expansion. Immunophenotypic analysis showed increased erythroid and granulocyte precursors after 7‐day culture with these drugs. Finally, using colony forming unit (CFU) assays, we observed impairment in the formation of CFU‐GEMM and CFU/Burst forming unit (BFU) erythroid (E) in the presence of DTG, lamivudine (3TC) and TDF, both visually and immunophenotypically. We conclude that multiple potential HSPC toxicities exist with ARVs commonly used in pregnancy, prompting the need for further research to confirm the safety of these drugs in this vulnerable group.

Introduction Studies have reported a higher risk of suboptimal neurodevelopment among children who are HIV‐exposed uninfected (HEU) compared to children HIV‐unexposed uninfected (HUU). Actual academic performance among school‐aged children by HIV exposure status has not been studied. Methods Academic performance in Mathematics, Science, English, Setswana and overall among children enrolled in the Botswana‐based FLOURISH study who were attending public primary school and ranging in age from 7.1 to 14.6 years were compared by HIV exposure status using a Cochran‐Mantel‐Haenszel test. Lower academic performance was defined as a grade of “C” or lower (≤60%). Unadjusted and adjusted logistic regression models were fit to assess for an association between HIV exposure and lower academic performance. Results Between April 2021 and December 2022, 398 children attending public primary school enrolled in the FLOURSH study, 307 (77%) were HEU. Median age was 9.4 years (IQR 8.9–10.2). Only 17.9% of children HEU were breastfeed versus 100% of children HUU. Among children HEU, 80.3% had foetal exposure to three‐drug antiretroviral treatment, 18.7% to zidovudine only and 1.0% had no antiretroviral exposure. Caregivers of children HEU were older compared to caregivers of children HUU (median 42 vs. 36 years) and more likely to have no or primary education only (15.0% vs. 1.1%). In unadjusted analyses, children HEU were more likely to have lower overall academic performance compared to their children HUU (odds ratio [OR]: 1.96 [95% confidence interval (CI): 1.16, 3.30]), and lower performance in Mathematics, Science and English. The association was attenuated after adjustment for maternal education, caregiver income, breastfeeding, low birth weight and child sex (aOR: 1.86 [95% CI: 0.78, 4.43]). Conclusions In this Botswana‐based cohort, primary school academic performance was lower among children HEU compared to children HUU. Biological and socio‐demographic factors, including child sex, appear to contribute to this difference. Further research is needed to identify modifiable contributors, develop screening tools to identify the risk of poor academic performance and design interventions to mitigate risk.

The impact of maternal factors on the size of HIV‐exposed‐uninfected (HEU) infants and breast milk composition is poorly understood. Anthropometry, bio‐electrical impedance, haemoglobin and HIV viral load data of women living with HIV (WLWH) and without HIV (WLWOH) were compared and related to their infants' anthropometric Z‐scores and breast milk macronutrients 6 weeks and 6 months postnatally. At both time points, WLWH (6‐week: n = 83; 6‐month: n = 63) had lower reactance (measure of body cell mass) (6‐week: p = 0.016; 6‐month: p < 0.001), phase angle (PhA) (measure of cell health) (6‐week: p = 0.001; 6‐month: p = 0.002) and haemoglobin (6‐week: p = 0.002; 6‐month: p = 0.004) than WLWOH (6‐week: n = 90; 6‐month: n = 73). HEU infants had lower weight‐for‐age Z‐scores (WAZ) (6‐week: p = 0.010; 6‐month: p = 0.005). Breast milk composition did not differ between groups. At 6 weeks, HEU infants had lower head circumference‐for‐age Z‐scores (HCAZ) (p = 0.014). Bivariate regression demonstrated maternal HIV predicted lower infant WAZ (ß = −0.442; p = 0.011) and HCAZ (ß = −0.445; p = 0.014). Maternal body mass index (BMI) and mid‐upper arm circumference were positively associated with breast milk protein content (ß = 0.018; p = 0.014 and ß = 0.025; p = 0.002, respectively). At 6 months (bivariate regression) maternal HIV predicted lower infant WAZ (ß = −0.609; p = 0.005) and length‐for‐age Z‐scores (ß = −0.741; p = 0.018). Higher maternal BMI and PhA were associated with higher infant WAZ (ß = 0.622; p = 0.015 and ß = 0.055; p = 0.017, respectively). On multivariable analysis, maternal HIV remained a predictor of lower WAZ (ß = −0.568; p = 0.024). In conclusion, maternal HIV infection and phenotype predict the size of infants and breast milk composition up to 6 months postnatally. Women living with HIV had infants with a lower weight for age up to 6 months, compared to women living without HIV. Maternal mid‐upper arm circumference and body mass index were positively associated with breast milk protein content at 6 weeks. Summary Maternal HIV status predicted a lower infant weight‐for‐age Z‐score at 6 weeks and 6 months, which necessitates close monitoring of HIV‐exposed‐uninfected (HEU) infants in the first 6 months of life. Maternal body mass index and phase angle, an indicator of cell membrane health, were lower in WLWH and these two measures were positively associated with infant weight‐for‐age Z‐scores at 6 months, confirming the association of maternal health with infant growth and supporting the need to perform prepregnancy screening and intervention. Maternal body mass index and mid‐upper arm circumference of WLWH and WLWOH related positively to breast milk protein content at 6 weeks. These maternal measurements are easily performed and could be utilised as a screening tool when breastfed infants show suboptimal growth.

Introduction Exposure to maternal HIV may affect early child development (ECD), although previous studies have reported heterogeneous findings. We evaluated ECD among children who were HIV‐exposed uninfected (CHEU) and children who were HIV‐unexposed (CHU) recruited to the SHINE trial in rural Zimbabwe. Methods SHINE was a community‐based cluster‐randomized trial of improved infant feeding and/or improved water, sanitation and hygiene. Pregnant women were enrolled between 2012 and 2015. We assessed ECD in a sub‐study at 24 months of age, between 2016 and 2017, using the Malawi Developmental Assessment Tool (MDAT; assessing motor, cognitive, language and social development); MacArthur‐Bates Communicative Development Inventory (CDI) (assessing vocabulary and grammar); A‐not‐B test (assessing object permanence); and a self‐control task. Mothers and infants were tested longitudinally for HIV. We used generalized estimating equations to compare ECD scores between CHEU and CHU, accounting for the cluster‐randomized design. Primary results were adjusted for trial‐related factors that could affect measurement reliability of ECD: study nurse, age of child, calendar month of birth, sex and randomized arm. Results A total of 205 CHEU and 1175 CHU were evaluated. Mean total MDAT score was 90.6 (SD 8.7) in CHEU compared to 92.4 (9.1) in CHU (adjusted mean difference −1.3, 95% CI: −2.3, −0.3), driven mostly by differences in gross motor (−0.5, 95% CI: −0.9, −0.2) and language scores (−0.6, 95% CI: −1.1, −0.1). There was evidence that fine motor scores were lower in CHEU (adjusted mean difference −0.4, 95% CI: −0.8, 0.0) but no evidence of a difference in social scores (0.1, 95% CI: −0.2, 0.4). Mean MacArthur‐Bates CDI vocabulary score was 57.9 (SD 19.2) in CHEU compared to 61.3 (18.8) in CHU (adjusted mean difference −2.9 words, 95% CI: −5.7, −0.1). Object permanence and self‐control scores were similar between groups. Conclusions CHEU in rural Zimbabwe had total child development and vocabulary scores that were approximately 0.15 standard deviations lower than CHU at two years of age. More detailed and specific studies are now needed to unravel the reasons for developmental delay in CHEU and the likelihood that these delays persist in the longer term.

Introduction Predictors of neurodevelopment among children who are HIV‐exposed uninfected (CHEU) are poorly understood. Methods 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. Results 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. Conclusions 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.

Introduction Medical challenges, including perinatally acquired HIV (PHIV), can be considered adversity with the potential to compromise individuals’ ability to meet societal expectations across the lifespan. Studies suggest that resilience, defined as positive adaptation in the context of adversity, helps individuals overcome challenges and improve their quality of life. Few longitudinal studies have examined resilience in young adults with perinatally acquired HIV (YAPHIV) or perinatal HIV exposure, uninfected (YAPHEU). We examined three young adult milestones, which can affect the life‐long quality of life, as markers of resilience: high school graduation, postsecondary education and current employment. Methods Analyses included YAPHIV and YAPHEU, ages 19–27 years, followed in longitudinal cohort studies: Pediatric HIV/AIDS Cohort Study Adolescent Master Protocol (AMP) (7–17 years) and AMP Up (≥18 years). Factors known to influence the attainment of milestones (outcomes) were examined: executive function, cognitive efficiency (working memory and processing speed), behavioural/social‐emotional functioning, parent/caregiver mental/physical health and cumulative risk. HIV disease markers for YAPHIV were examined. The most recent AMP assessment was used for each factor; outcomes were measured at AMP Up 1‐year follow‐up. Separate robust Poisson regression models were used to assess associations of each factor with each outcome; PHIV status was explored as an effect modifier of each association. Results Participants (N = 315; YAPHIV = 228): 58% female, 67% Black and 27% Hispanic. Compared to YAPHEU, YAPHIV were older and from families with higher median income and fewer symptoms of parent/caregiver mental health/substance use disorders. Proportions of YAPHIV and YAPHEU, respectively, who achieved each milestone were comparable: 82% versus 78% for high school graduation (p = 0.49), 45% versus 51% for postsecondary education (p = 0.35) and 48% versus 54% for current employment (p = 0.32). Higher cognitive efficiency was positively associated with postsecondary education and current employment. Higher executive function, age‐appropriate behavioural/social‐emotional functioning and lower cumulative risk were associated with academic milestones. Among YAPHIV, positive associations were: higher current CD4 with postsecondary education and lower nadir CD4 with current employment. PHIV status did not modify any association. Conclusions YAPHIV and YAPHEU demonstrated resilience, attaining at least one young adult milestone. Cognitive, behavioural and social resources to support resilience in childhood and adolescence may provide the foundation for continued achievement throughout adulthood.

Introduction 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. Discussion 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. Conclusions 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.

Introduction The number of children exposed to HIV and possibly to antiretroviral therapy (ART) in utero and during breastfeeding and are uninfected (HEU) globally will continue to increase from the estimated 15.9 million in 2021. Discussion There are still significant gaps in our understanding of the impact of HIV and/or ART exposure in children who are HEU, in terms of prevalence/incidence and severity on health and wellbeing, and long after exposure has ended. While there have been substantial programmatic efforts to support the elimination of vertical transmission of HIV, additional rigorous research is needed to better understand the biological, (psycho)social and structural factors contributing to optimal health for populations who are HEU. Furthermore, the best approaches to address and study the gaps in understanding also need to be explored. Given the scope of the problem including the large numbers of affected people as well as the often limited and competing in‐country resources for populations affected by HIV, novel methodologies, including multi‐level approaches and advanced analytics, need to be considered. Conclusions A growing population of children who are HEU are maturing into adolescence and young adulthood. Research to advance understanding of the possible negative long‐term effects of HIV and/or ART exposure in these youth is supported by the US National Institutes of Health. Both large epidemiological studies and smaller more comprehensive cohort studies may be required to address the complexity of the issue. Integrating both types of studies could allow the establishment of more reliable and validated predictions of which youth who are HEU are at the highest risk for specific negative health outcomes, such as mental health and neurocognitive disorders, and which interventional approaches may be most successful to address specific deficits both in terms of prevention and treatment. Finally, these goals can be more rapidly achieved with data science efforts, data harmonisation between studies and with sustainable data‐sharing practices. It is important to expand the commitment to research to identify biological, social and structural drivers, to develop screening tools, and impactful and contextually appropriate interventions to address the health and wellbeing of children who are HEU from birth through adulthood.

Introduction HIV‐exposed uninfected (HEU) newborns suffer from higher risks of opportunistic infections during the first months of life compared to HIV‐unexposed uninfected (HUU) newborns. Alterations in thymic mass, amounts of T helper (Th) cells, T‐cell receptor diversity, and activation markers have been found in HEU newborns, suggesting alterations in T cell ontogeny and differentiation. However, little is known about the ability of these cells to produce specialized Th responses from CD4+ T cells. Method To characterize the Th cell profile, we evaluated the frequency of Th1 (CD183+CD194−CD196−/CXCR3+CCR4−CCR6−), Th2 (CD183−CD194+CD196−/CXCR3−CCR4+CCR6−), Th17 (CD183−CD194+CD196+/CXCR3−CCR4+CCR6+), and CD4+CD25++ blood T‐cell phenotypes in 50 HEU and 25 HUU newborns. Early activation markers on CD4+ T cells and the Th cytokine profile produced from mononuclear cells under polyclonal T cell stimulation were also studied. Additionally, we probed the ability of CD4+ T cells to differentiate into interferon (IFN)‐γ‐producing Th1 CD4+ T cells in vitro. Results Lower percentages of differentiated Th1, Th2, Th17, and CD4+CD25++ T cells were found in blood from HEU newborns than in blood from HUU newborns. However, polyclonally stimulated Th cells showed a similar ability to express CD69 and CD279 but produced less secreted interleukin (IL)‐2 and IL‐4. Interestingly, under Th1 differentiation conditions, the percentages of CD4+IFN‐γ+ T cells and soluble IFN‐γ were higher in HEU newborns than in HUU newborns. Conclusion HEU neonates are born with reduced proportions of differentiated Th1/Th2/Th17 and CD4+CD25++ T cells, but the intrinsic abilities of CD4+ T cells to acquire a Th1 profile are not affected by the adverse maternal milieu during development. The frequency of differentiated peripheral Th cells in HIV‐exposed uninfected (HEU) newborns is reduced compared to control newborns. The consequences of this poorly differentiated pool of Th cells in HEU newborns could contribute to the high susceptibility to infections during the first months of life