Subcortical Brain Volumes and Neurocognitive Function in Children With Perinatal HIV Exposure: A Population-Based Cohort Study in South Africa.

Background: Children who are HIV-exposed and uninfected (HEU) are at risk for early neurodevelopmental impairment. Smaller basal ganglia nuclei have been reported in neonates who are HEU compared to HIV-unexposed (HU); however, neuroimaging studies outside infancy are scarce. We examined subcortical brain structures and associations with neurocognition in children who are HEU. Methods: This neuroimaging study was nested within the Drakenstein Child Health Study birth cohort in South Africa. We compared (T1-weighted) magnetic resonance imaging-derived subcortical brain volumes between children who were HEU (n = 70) and HU (n = 92) at age 2-3 years using linear regression. Brain volumes were correlated with neurodevelopmental outcomes measured with the Bayley Scales of Infant and Toddler Development III. Results: Compared to HU children, on average children who were HEU had 3% lower subcortical grey matter volumes. Analyses of individual structures found smaller volume of the putamen nucleus in the basal ganglia (-5% difference, P = .016) and the hippocampus (-3% difference, P = .044), which held on adjustment for potential confounders (P < .05). Maternal viremia and lower CD4 count in pregnancy were associated with smaller child putamen volumes. Children who were HEU had lower language scores than HU; putamen and hippocampus volumes were positively correlated with language outcomes. Conclusions: Overall, children who are HEU had a pattern of smaller subcortical volumes in the basal ganglia and hippocampal regions compared to HU children, which correlated with language function. Findings suggest that optimizing maternal perinatal HIV care is important for child brain development. Further studies are needed to investigate underlying mechanisms and long-term outcomes.

Perceived risk for HIV acquisition and sexual HIV exposure among sexual and gender minorities: a systematic review.

We conducted a systematic review to explore the relationship between perceived risk for HIV acquisition and sexual HIV exposure among sexual and gender minorities. We included 39 studies divided into (i) correlations or associations, (ii) models using sexual HIV exposure as the outcome, and (iii) models using perceived risk for HIV acquisition as the outcome. The sample size range was from 55 to 16,667 participants, primarily cisgender men who have sex with men (73.3%) and White (51.3%). Sexual HIV exposure and perceived risk for HIV acquisition assessments and recall time frames across studies differed markedly. Most of studies (84.6%) found significant correlations, comparisons, or associations between different levels of perceived risk for HIV acquisition and high sexual HIV exposure. In addition, 51.3% of studies reported other variables associated with high sexual HIV exposure (i.e., misuse of substances or alcohol) or with high perceived risk for HIV acquisition (i.e., younger age). In conclusion, the association between perceived risk for HIV acquisition and sexual HIV exposure has shown to be consistent. However, the assessment for perceived risk for HIV acquisition should include more components of perception (i.e., an affective component), or for sexual HIV exposure should consider the different estimated sexual per-acts probability of acquiring HIV.

Impact of perinatal HIV exposure and infection on salivary properties among Nigerian children.

BACKGROUND: There is growing evidence that perinatal HIV infection and exposure affect salivary pH and flow rate in children in most parts of the world, but not against the background of caries and the African demographic. This study aimed to evaluate the impact of HIV infection as well as exposure on salivary properties and their influence upon the dental caries experience among school-aged children in Nigeria. METHOD: This cross-sectional study assessed the salivary flow rates and salivary pH of HIV infected and exposed school-aged (4-11) children receiving care at a Nigerian tertiary hospital. A total of 266 consenting participants which comprised of three groups as follows: (1) HIV Infected (HI) (n = 87), (2) HIV Exposed and Uninfected (HEU) (n = 82) and (3) HIV Unexposed and Uninfected (HUU) (n = 97) were recruited for the study. Questionnaires completed by parents/guardians were used for data collection. Three calibrated dentists performed oral examinations for dental caries. International Caries Detection and Assessment Scores (ICDAS) was used and presented as dmft/DMFT. Salivary pH was measured using MColourpHast™ pH indicator strips, while salivary flow rate was determined by collecting unstimulated whole saliva using the suction method. Data analysis relied on comparative statistics to determine the correlation between HIV exposure and infection on salivary pH and flow rates. RESULT: Across the groups, (HI, HEU, and HUU) mean pH of the HI was significantly less than that of HEU and HUU. Similarly, there was a statistically significant difference in the SFR across the three groups (p = 0.004). Other variables such as gender, age and oral hygiene status expressed by the gingival inflammatory scores had no significant influence on the pH and SFR of study participants. There was a rather unexpected positive correlation of DMFT of HI and HEU groups with increasing salivary flow rate; though, the relationship was weak and not significant. CONCLUSION: Perinatal HIV exposure and infection significantly impact salivary pH and flow rate among school-aged children in Nigeria. The findings of this study imply that HIV infection influenced the salivary pH, while HIV maternal exposure (without infection) impacted salivary flow rates when compared to the controls.

Lower Insulin Sensitivity Through 36 Months of Life With in Utero HIV and Antiretroviral Exposure in Botswana: Results From the Tshilo Dikotla Study.

BACKGROUND: There are little data on changes in insulin sensitivity during the first few years of life following in utero human immunodeficiency virus (HIV) and antiretroviral (ARV) exposure. METHODS: The Tshilo Dikotla study enrolled pregnant persons with HIV (PWH) (receiving tenofovir/emtricitabine or lamivudine plus dolutegravir or efavirenz) and pregnant individuals without HIV, as well as their liveborn children. Newborns were randomized to receive either zidovudine (AZT) or nevirapine (NVP) postnatal prophylaxis. Homeostasis Model Assessment for Insulin Resistance (HOMA-IR) was assessed at birth and 1, 18, 24, and 36 months of life. We fit linear mixed-effects models to evaluate the association between in utero HIV/ARV exposure and average HOMA-IR from birth through 36 months of life, adjusting for confounders. RESULTS: A total of 419 children were included (287 with in utero HIV/ARV exposure and uninfected [CHEU] and 132 without in utero HIV/ARV exposure [CHUU]). CHEU were born to older women (29.6 vs 25.3 years of age) with higher gravidity (3 vs 1). HOMA-IR was persistently higher in CHEU versus CHUU in adjusted analyses (mean difference of 0.07 in log10 HOMA-IR, P  = .02) from birth through 36 months of life. Among CHEU, no differences in HOMA-IR were observed from birth through 36 months by in utero ARV exposure status or between AZT and NVP infant prophylaxis arms. CONCLUSIONS: In utero HIV/ARV exposure was associated with lower insulin sensitivity throughout the first 36 months of life, indicating persistent early life metabolic disturbances which may raise concern for poorer metabolic health later in life.

Change in HIV-related characteristics of children hospitalised with infectious diseases in Western Cape, South Africa, 2008-2021: a time trend analysis.

INTRODUCTION: With the scaling up of vertical HIV transmission prevention programmes, the HIV-related population profile of children in South Africa has shifted. We described temporal changes in HIV-related characteristics of children, aged ≤3 years (up to the third birthday), with infectious disease hospitalisations across the Western Cape province. METHODS: We used routinely collected electronic data to identify children born in the Western Cape with infectious disease hospital records for lower respiratory tract infections, diarrhoea, meningitis and tuberculous meningitis, from 2008 to 2021. Linked maternal and child unique identifiers were used to extract pregnancy, HIV-related, laboratory, pharmacy and hospitalisation data. We described temporal changes in child HIV exposure and acquisition status, timing of maternal HIV diagnosis and antiretroviral therapy (ART) start, infant exposure to maternal ART and timing thereof, and maternal CD4 and HIV viral load closest to delivery. We used logistic and multinomial regression to assess changes in characteristics between the Pre-Option B+ (2008-2013), Option B+ (2013-2016) and Universal ART periods (2016-2021). RESULTS: Among 52,811 children aged ≤3 years with hospitalisations, the proportion living with HIV dreased from 7.0% (2008) to 1.1% (2021), while those exposed to HIV and uninfected increased from 14.0% (2008) to 16.1% (2021) with a peak of 18.3% in 2017. Among mothers with HIV (n = 9873), the proportion diagnosed with HIV and starting ART before pregnancy increased from 20.2% to 69.2% and 5.8% to 59.0%, respectively, between 2008 and 2021. Children hospitalised during the Universal ART period had eight times higher odds (Odds Ratio: 8.41; 95% CI: 7.36-9.61) of exposure to maternal ART versus children admitted Pre-Option B+. Among mothers of children exposed to HIV and uninfected with CD4 records (n = 7523), the proportion with CD4 <350 cells/µl decreased from 90.6% (2008) to 27.8% (2021). CONCLUSIONS: In recent years, among children hospitalised with infectious diseases, there were fewer children with perinatally acquired HIV, while an increased proportion of those without HIV acquisition are exposed to maternal HIV and ART. There is a need to look beyond paediatric HIV prevalence and consider child exposure to HIV and ART among children without HIV, when assessing the HIV epidemic's impact on child health services.

Neurodevelopment of children who are HIV-exposed and uninfected in Kenya.

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.

Neurodevelopment among children exposed to HIV and uninfected in sub-Saharan Africa.

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.

The role of internalised HIV stigma in disclosure of maternal HIV serostatus to children perinatally HIV-exposed but uninfected: a prospective study in the United States.

INTRODUCTION: Decisions to disclose HIV serostatus may be complicated by internalised HIV stigma. We evaluated the association of internalised HIV stigma in biological mothers living with HIV with disclosure of their serostatus to their children perinatally HIV-exposed but uninfected (CHEU). METHODS: Mothers and their CHEU were enrolled in the United States (U.S.)-based Surveillance Monitoring for Antiretroviral Therapy (ART) Toxicities (SMARTT) study of the Pediatric HIV/AIDS Cohort Study (PHACS), a longitudinal study of outcomes related to in utero exposure to HIV and ART among CHEU. Mothers completing at least one stigma and disclosure assessment starting at the child's age 11-, 13-, 15- and/or 17-year study visits between 16 August 2016 and 1 October 2020 were eligible. Stigma was measured with the 28-item Internalised HIV Stigma Scale (IHSS). Mean stigma scores were linearly transformed to a range of 0-100, with higher scores indicating greater levels of stigma. At each visit, mothers were asked if their child was aware of their HIV diagnosis and at what age the child became aware. The Kaplan-Meier estimator evaluated the cumulative probability of disclosure at each child age. Logistic regression models with generalised estimating equations to account for repeated measures were fit to examine the association between stigma and disclosure, controlling for relevant socio-demographic variables. RESULTS: Included were 438 mothers of 576 children (mean age 41.5 years, 60% U.S.-born, 60% Black/African American and 37% with household income ≤$10,000). The prevalence of disclosure across all visits was 29%. Mothers whose children were aware versus not aware of their serostatus reported lower mean IHSS scores (38.2 vs. 45.6, respectively). The cumulative proportion of disclosure by age 11 was 18.4% (95% CI: 15.5%, 21.8%) and 41% by age 17 (95% CI: 35.2%, 47.4%). At all child ages, disclosure was higher among children of U.S.-born versus non-U.S.-born mothers. After adjusting for age, marital status and years since HIV diagnosis, higher IHSS scores were associated with lower odds of disclosure (OR = 0.985, 95% CI: 0.975, 0.995). CONCLUSIONS: Providing support to women as they make decisions about serostatus disclosure to their children may entail addressing internalised HIV stigma and consideration of community-level factors, particularly for non-U.S.-born mothers.

Association of HIV Exposure and HIV Infection With In-hospital Mortality Among Hospitalized Infants <1 Year of Age, South Africa, 2016-2018.

We enrolled 1323 hospitalized infants aged <1 year in 2016-2018, and examined the association between HIV status and in-hospital mortality. After controlling for confounders, HIV-exposed uninfected infants did not have an increased risk of mortality, whereas infants living with HIV had 4 times greater risk compared with HIV-uninfected infants.

Bifidobacterium infantis supplementation versus placebo in early life to improve immunity in infants exposed to HIV: a protocol for a randomized trial.

INTRODUCTION: Infants who are born from mothers with HIV (infants who are HIV exposed but uninfected; iHEU) are at higher risk of morbidity and display multiple immune alterations compared to infants who are HIV-unexposed (iHU). Easily implementable strategies to improve immunity of iHEU, and possibly subsequent clinical health outcomes, are needed. iHEU have altered gut microbiome composition and bifidobacterial depletion, and relative abundance of Bifidobacterium infantis has been associated with immune ontogeny, including humoral and cellular vaccine responses. Therefore, we will assess microbiological and immunological phenotypes and clinical outcomes in a randomized, double-blinded trial of B. infantis Rosell®-33 versus placebo given during the first month of life in South African iHEU. METHODS: This is a parallel, randomised, controlled trial. Two-hundred breastfed iHEU will be enrolled from the Khayelitsha Site B Midwife Obstetric Unit in Cape Town, South Africa and 1:1 randomised to receive 8 × 109 CFU B. infantis Rosell®-33 daily or placebo for the first 4 weeks of life, starting on day 1-3 of life. Infants will be followed over 36 weeks with extensive collection of meta-data and samples. Primary outcomes include gut microbiome composition and diversity, intestinal inflammation and microbial translocation and cellular vaccine responses. Additional outcomes include biological (e.g. gut metabolome and T cell phenotypes) and clinical (e.g. growth and morbidity) outcome measures. DISCUSSION: The results of this trial will provide evidence whether B. infantis supplementation during early life could improve health outcomes for iHEU. ETHICS AND DISSEMINATION: Approval for this study has been obtained from the ethics committees at the University of Cape Town (HREC Ref 697/2022) and Seattle Children's Research Institute (STUDY00003679). TRIAL REGISTRATION: Pan African Clinical Trials Registry Identifier: PACTR202301748714019. TRIALS: gov: NCT05923333. PROTOCOL VERSION: Version 1.8, dated 18 July 2023.

1H-MRS neurometabolite profiles and motor development in school-aged children who are HIV-exposed uninfected: a birth cohort study.

Objective: Alterations in regional neurometabolite levels as well as impaired neurodevelopmental outcomes have previously been observed in children who are HIV-exposed uninfected (CHEU). However, little is known about how neurometabolite profiles may relate to their developmental impairment. This study aimed to compare neurometabolite concentrations in school-aged CHEU and children who are HIV-unexposed (CHU) and to explore associations of neurometabolite profiles with functional neurodevelopment in the context of perinatal HIV exposure. Methods: We used 3 T single voxel proton magnetic resonance spectroscopy (1H-MRS) to quantify absolute and relative neurometabolites in the parietal gray and parietal white matter in school-aged CHEU and aged- and community-matched CHU. Functional neurodevelopmental outcomes were assessed using the early learning outcome measure (ELOM) tool at 6 years of age. Results: Our study included 152 school-aged children (50% males), 110 CHEU and 42 CHU, with an average age of 74 months at the neuroimaging visit. In an adjusted multiple linear regression analysis, significantly lower glutamate (Glu) concentrations were found in CHEU as compared to CHU in the parietal gray matter (absolute Glu, p = 0.046; Glu/total creatine (Cr+PCr) ratios, p = 0.035) and lower total choline to creatine ratios (GPC+PCh/Cr+PCr) in the parietal white matter (p = 0.039). Using factor analysis and adjusted logistic regression analysis, a parietal gray matter Glu and myo-inositol (Ins) dominated factor was associated with HIV exposure status in both unadjusted (OR 0.55, 95% CI 0.17-0.45, p = 0.013) and adjusted analyses (OR 0.59, 95% CI 0.35-0.94, p = 0.031). With Ins as one of the dominating metabolites, this neurometabolic factor was similar to that found at the age of two years. Furthermore, this factor was also found to be correlated with ELOM scores of gross motor development in CHEU (Pearson's r = -0.48, p = 0.044). In addition, in CHEU, there was a significant association between Ins/Cr+PCr ratios in the parietal white matter and ELOM scores of fine motor coordination and visual motor integration in CHEU (Pearson's r = 0.51, p = 0.032). Conclusion: Reduced Glu concentrations in the parietal gray matter may suggest regional alterations in excitatory glutamatergic transmission pathways in the context of perinatal HIV and/or antiretroviral therapy (ART) exposure, while reduced Cho ratios in the parietal white matter suggest regional myelin loss. Identified associations between neurometabolite profiles and gross and fine motor developmental outcomes in CHEU are suggestive of a neurometabolic mechanism that may underlie impaired motor neurodevelopmental outcomes observed in CHEU.

Impact of HIV on the Oral Microbiome of Children Living in Sub-Saharan Africa, Determined by Using an rpoC Gene Fragment Metataxonomic Approach.

Children living with HIV have a higher prevalence of oral diseases, including caries, but the mechanisms underlying this higher prevalence are not well understood. Here, we test the hypothesis that HIV infection is associated with a more cariogenic oral microbiome, characterized by an increase in bacteria involved in the pathogenesis of caries. We present data generated from supragingival plaques collected from 484 children representing three exposure groups: (i) children living with HIV (HI), (ii) children who were perinatally exposed but uninfected (HEU), and (iii) unexposed and therefore uninfected children (HUU). We found that the microbiome of HI children is distinct from those of HEU and HUU children and that this distinction is more pronounced in diseased teeth than healthy teeth, suggesting that the impact of HIV is more severe as caries progresses. Moreover, we report both an increase in bacterial diversity and a decrease in community similarity in our older HI cohort compared to our younger HI cohort, which may in part be a prolonged effect of HIV and/or its treatment. Finally, while Streptococcus mutans is often a dominant species in late-stage caries, it tended to be found at lower frequency in our HI cohort than in other groups. Our results highlight the taxonomic diversity of the supragingival plaque microbiome and suggest that broad and increasingly individualistic ecological shifts are responsible for the pathogenesis of caries in children living with HIV, coupled with a diverse and possibly severe impact on known cariogenic taxa that potentially exacerbates caries. IMPORTANCE Since its recognition as a global epidemic in the early 1980s, approximately 84.2 million people have been diagnosed with HIV and 40.1 million people have died from AIDS-related illnesses. The development and increased global availability of antiretroviral treatment (ART) regimens have dramatically reduced the mortality rate of HIV and AIDS, yet approximately 1.5 million new infections were reported in 2021, 51% of which are in sub-Saharan Africa. People living with HIV have a higher prevalence of caries and other chronic oral diseases, the mechanisms of which are not well understood. Here, we used a novel genetic approach to characterize the supragingival plaque microbiome of children living with HIV and compared it to the microbiomes of uninfected and perinatally exposed children to better understand the role of oral bacteria in the etiology of tooth decay in the context of HIV exposure and infection.

The impact of HIV and ART exposure during pregnancy on fetal growth: a prospective study in a South African cohort.

BACKGROUND: In utero exposure to human immunodeficiency virus (HIV) and antiretroviral (ART) is associated with adverse birth outcomes, which are often attributed to alterations in placental morphology. This study used structural equation models (SEMs) to examine the impact of HIV and ART exposure on fetal growth outcomes and whether these associations are mediated by placental morphology in urban-dwelling Black South African women. METHODS: This prospective cohort study included pregnant women living with HIV (WLWH, n = 122) and not living with HIV (WNLWH, n = 250) that underwent repeated ultrasonography during pregnancy, and at delivery, to determine fetal growth parameters in Soweto, South Africa. The size and the velocity of fetal growth measures (i.e., head and abdominal circumference, biparietal diameter, and femur length) were calculated using the Superimposition by Translation and Rotation. Placenta digital photographs taken at delivery were used to estimate morphometric parameters and trimmed placental weight was measured. All WLWH were receiving ART for the prevention of vertical transmission of HIV. RESULTS: A trend towards a lower placental weight and significantly shorter umbilical cord length was reported in WLWH compared to their counterparts. After sex stratification, umbilical cord length was significantly shorter in males born to WLWH than in male fetuses born to WNLWH (27.3 (21.6-32.8) vs. 31.4 (25.0-37.0) cm, p = 0.015). In contrast, female fetuses born to WLWH had lower placental weight, birth weight (2.9 (2.3-3.1) vs. 3.0 (2.7-3.2) kg), and head circumference (33 (32-34) vs. 34 (33-35) cm) than their counterparts (all p ≤ 0.05). The SEM models showed an inverse association between HIV and head circumference size and velocity in female fetuses. In contrast, HIV and ART exposure was positively associated with femur length growth (both size and velocity) and abdominal circumference velocity in male fetuses. None of these associations appeared to be mediated via placental morphology. CONCLUSION: Our findings suggest that HIV and ART exposure directly affects head circumference growth in females and abdominal circumference velocity in male fetuses; but may improve femur length growth in male fetuses only.

Co-trimoxazole prophylaxis for children who are HIV-exposed and uninfected: a systematic review.

INTRODUCTION: Co-trimoxazole prophylaxis is recommended for children born to women with HIV to protect those who acquire HIV from opportunistic infections, severe bacterial infections and malaria. With scale-up of maternal antiretroviral therapy, most children remain HIV-exposed uninfected (HEU) and the benefits of universal co-trimoxazole are uncertain. We assessed the effect of co-trimoxazole on mortality and morbidity of children who are HEU. METHODS: We performed a systematic review (PROSPERO number: CRD42021215059). We systematically searched MEDLINE, Embase, Cochrane CENTRAL, Global Health, CINAHL Plus, Africa-Wide Information, SciELO and WHO Global Index Medicus for peer-reviewed articles from inception to 4th January 2022 without limits. Ongoing randomized controlled trials (RCTs) were identified through registries. We included RCTs reporting mortality or morbidity in children who are HEU receiving co-trimoxazole versus no prophylaxis/placebo. The risk of bias was assessed using the Cochrane 2.0 tool. Data were summarized using narrative synthesis and findings were stratified by malaria endemicity. RESULTS: We screened 1257 records and included seven reports from four RCTs. Two trials from Botswana and South Africa of 4067 children who are HEU found no difference in mortality or infectious morbidity in children randomized to co-trimoxazole prophylaxis started at 2-6 weeks of age compared to those randomized to placebo or no treatment, although event rates were low. Sub-studies found that antimicrobial resistance was higher in infants receiving co-trimoxazole. Two trials in Uganda investigating prolonged co-trimoxazole after breastfeeding cessation showed protection against malaria but no other morbidity or mortality differences. All trials had some concerns or a high risk of bias, which limited the certainty of evidence. DISCUSSION: Studies show no clinical benefit of co-trimoxazole prophylaxis in children who are HEU, except to prevent malaria. Potential harms were identified for co-trimoxazole prophylaxis leading to antimicrobial resistance. The trials in non-malarial regions were conducted in populations with low mortality potentially reducing generalizability to other settings. CONCLUSIONS: In low-mortality settings with few HIV transmissions and well-performing early infant diagnosis and treatment programmes, universal co-trimoxazole may not be required.

Disrupted memory T cell expansion in HIV-exposed uninfected infants is preceded by premature skewing of T cell receptor clonality.

While preventing vertical HIV transmission has been very successful, the increasing number of HIV-exposed uninfected infants (iHEU) experience an elevated risk to infections compared to HIV-unexposed and uninfected infants (iHUU). Immune developmental differences between iHEU and iHUU remains poorly understood and here we present a longitudinal multimodal analysis of infant immune ontogeny that highlights the impact of HIV/ARV exposure. Using mass cytometry, we show alterations and differences in the emergence of NK cell populations and T cell memory differentiation between iHEU and iHUU. Specific NK cells observed at birth were also predictive of acellular pertussis and rotavirus vaccine-induced IgG and IgA responses, respectively, at 3 and 9 months of life. T cell receptor Vß clonotypic diversity was significantly and persistently lower in iHEU preceding the expansion of T cell memory. Our findings show that HIV/ARV exposure disrupts innate and adaptive immunity from birth which may underlie relative vulnerability to infections.

T-SPOT.TB Reactivity in Southern African Children With and Without in Utero Human Immunodeficiency Virus Exposure.

Infants who are human immunodeficiency virus (HIV)-exposed uninfected (iHEU) experience higher risk of infectious morbidity than infants HIV-unexposed uninfected (iHUU). We compared tuberculosis (TB) infection prevalence in 418 Bacillus Calmette-Guérin vaccinated sub-Saharan African iHEU and iHUU aged 9-18 months using T-SPOT.TB. Prevalence of TB infection was low and did not differ by HIV exposure status.

Comparison of Feeding Practices and Growth of Urbanized African Infants Aged 6-12 Months Old by Maternal HIV Status in Gauteng Province, South Africa.

Appropriate feeding practices are protective against malnutrition and poor growth. We compared feeding practices and growth in HIV-exposed-uninfected (HEU) and HIV-unexposed-uninfected (HUU) between 6-12 months of age in urbanized African infants in South Africa. A repeated cross-sectional analysis was used to determine differences in infant feeding practices and anthropometric measures by HIV exposure status at 6, 9, and 12 months in the Siyakhula study. The study included 181 infants (86 HEU; 95 HUU). Breastfeeding rates were lower in HEU vs. HUU infants at 9 (35.6% vs. 57.3%; p = 0.013) and 12 months (24.7% vs. 48.0%; p = 0.005). Introduction to early complementary foods was common (HEU = 16.2 ± 11.0 vs. HUU = 12.8 ± 9.3 weeks; p = 0.118). Lower weight-for-age Z-scores (WAZ) and head circumference-for-age Z-scores (HCZ) were found in HEU infants at birth. At 6 months, WAZ, length-for-age Z-scores (LAZ), HCZ, and mid-upper-arm circumference-for-age Z-scores (MUACAZ) were lower in HEU vs. HUU infants. At 9 months, lower WAZ, LAZ, and MUACAZ were found in HEU vs. HUU infants. At 12 months, lower WAZ, MUACAZ, and weight-for-length Z-scores (-0.2 ± 1.2 vs. 0.2 ± 1.2; p = 0.020) were observed. HEU infants had lower rates of breastfeeding and poorer growth compared to HUU infants. Maternal HIV exposure affects the feeding practices and growth of infants.

Maternal ART throughout gestation prevents caudate volume reductions in neonates who are HIV exposed but uninfected.

Introduction: Successful programmes for prevention of vertical HIV transmission have reduced the risk of infant HIV infection in South Africa from 8% in 2008 to below 1% in 2018/2019, resulting in an increasing population of children exposed to HIV perinatally but who are uninfected (HEU). However, the long-term effects of HIV and antiretroviral treatment (ART) exposure on the developing brain are not well understood. Whereas children who are HEU perform better than their HIV-infected counterparts, they demonstrate greater neurodevelopmental delay than children who are HIV unexposed and uninfected (HUU), especially in resource-poor settings. Here we investigate subcortical volumetric differences related to HIV and ART exposure in neonates. Methods: We included 120 infants (59 girls; 79 HEU) born to healthy women with and without HIV infection in Cape Town, South Africa, where HIV sero-prevalence approaches 30%. Of the 79 HEU infants, 40 were exposed to ART throughout gestation (i.e., mothers initiated ART pre conception; HEU-pre), and 39 were exposed to ART for part of gestation (i.e., mothers initiated ART post conception; HEU-post). Post-conception mothers had a mean (± SD) gestational age (GA) of 15.4 (± 5.7) weeks at ART initiation. Mothers with HIV received standard care fixed drug combination ART (Tenofovir/Efavirenz/Emtricitabine). Infants were imaged unsedated on a 3T Skyra (Siemens, Erlangen, Germany) at mean GA equivalent of 41.5 (± 1.0) weeks. Selected regions (caudate, putamen, pallidum, thalamus, cerebellar hemispheres and vermis, and corpus callosum) were manually traced on T1-weighted images using Freeview. Results: HEU neonates had smaller left putamen volumes than HUU [ß (SE) = -90.3 (45.3), p = 0.05] and caudate volume reductions that depended on ART exposure duration in utero. While the HEU-pre group demonstrated no caudate volume reductions compared to HUU, the HEU-post group had smaller caudate volumes bilaterally [ß (SE) = -145.5 (45.1), p = 0.002, and -135.7 (49.7), p = 0.008 for left and right caudate, respectively]. Discussion: These findings from the first postnatal month suggest that maternal ART throughout gestation is protective to the caudate nuclei. In contrast, left putamens were smaller across all HEU newborns, despite maternal ART.

Psychiatric disorders in perinatally HIV-exposed, uninfected children: a systematic review.

The population of perinatally HIV-exposed but uninfected (HEU) children is growing rapidly globally. However, perinatal HIV and antiretroviral (ARV) medicine exposure in HIV-uninfected children has raised concerns about HEU children's mental well-being. The objective of this study was to systematically review the literature on psychiatric disorders in HEU children. The PRISMA guideline was used as a methodical frame of reference. A systematic search was conducted in 5 databases. Data from the included studies were extracted, and the results were summarized qualitatively. The search identified 1,976 articles of which 105 were eligible for full-text analysis. 13 studies met the inclusion criteria. Eight studies compared psychiatric disorder prevalence in perinatally HIV-infected children with HEU children, and only one study found a difference between the two groups. Three studies found that HEU children had a higher prevalence of psychiatric disorders compared with HIV-unexposed, uninfected (HUU) children. These findings indicate that factors such as psychosocial stress, socioeconomic status, and stigma contribute to the increased risk of mental disorders in HEU children. More research is needed comparing HEU children with HUU children adjusting for potential confounders that might partially explain the higher rates seen in the HIV-exposed population.Prospero ID: CRD42020212420.

Lower Insulin Sensitivity in Newborns With In Utero HIV and Antiretroviral Exposure Who Are Uninfected in Botswana.

BACKGROUND: Few data exist on early-life metabolic perturbations in newborns with perinatal HIV and antiretroviral (ARV) exposure but uninfected (HEU) compared to those perinatally HIV unexposed and uninfected (HUU). METHODS: We enrolled pregnant persons with HIV (PWH) receiving tenofovir (TDF)/emtricitabine or lamivudine (XTC) plus dolutegravir (DTG) or efavirenz (EFV), and pregnant individuals without HIV, as well as their liveborn infants. Newborns were randomized to receive either zidovudine (AZT) or nevirapine (NVP) postnatal prophylaxis. Preprandial homeostasis model assessment for insulin resistance (HOMA-IR) was assessed at birth and 1 month. Linear mixed models were fit to assess the association between in utero HIV/ARV exposure and average HOMA-IR from birth to 1 month, adjusting for confounders. RESULTS: Of 450 newborns, 306 were HEU. HOMA-IR was higher in newborns HEU versus HUU after adjusting for confounders (mean difference of 0.068 in log HOMA-IR, P = .037). Among newborns HEU, HOMA-IR was not significantly different between TDF/XTC/DTG versus TDF/XTC/EFV in utero ARV exposure and between AZT versus NVP newborn postnatal prophylaxis arms. CONCLUSIONS: Newborns HEU versus HUU had lower insulin sensitivity at birth and at 1 month of life, raising potential concern for obesity and other metabolic perturbations later in life for newborns HEU. CLINICAL TRIALS REGISTRATION: NCT03088410.