HIV-unexposed Children Research Articles

Neurodevelopment of HIV-exposed uninfected children in South Africa: outcomes from an observational birth cohort study

SummaryBackgroundHIV infection is known to cause developmental delay, but the effects of HIV exposure without infection during pregnancy on child development are unclear. We compared the neurodevelopmental outcomes of HIV-exposed uninfected and HIV-unexposed children during their first 2 years of life.MethodsPregnant women (>18 years of age) at 20–28 weeks' gestation were enrolled into the Drakenstein Child Health cohort study while attending routine antenatal appointments at one of two peri-urban community-based clinics in Paarl, South Africa. Livebirths born to enrolled women during follow-up were included in the birth cohort. Mothers and infants received antenatal and postnatal HIV testing and antiretroviral therapy per local guidelines. Developmental assessments on the Bayley Scales of Infant and Toddler Development, third edition (BSID-III), were done in a subgroup of infants at 6 months of age, and in the full cohort at 24 months of age, with assessors masked to HIV exposure status. Mean raw scores and the proportions of children categorised as having a delay (scores <–2 SDs from the reference mean) on BSID-III were compared between HIV-exposed uninfected and HIV-unexposed children.Findings1225 women were enrolled between March 5, 2012, and March 31, 2015. Of 1143 livebirths, 1065 (93%) children were in follow-up at 6 months and 1000 (87%) at 24 months. Two children were diagnosed with HIV infection between birth and 24-month follow-up and were excluded from the analysis. BSID-III assessments were done in 260 (24%) randomly selected children (61 HIV-exposed uninfected, 199 HIV-unexposed) at 6 months and in 732 (73%) children (168 HIV-exposed uninfected, 564 HIV-unexposed) at 24 months. All HIV-exposed uninfected children were exposed to antiretrovirals (88% to maternal triple antiretroviral therapy). BSID-III outcomes did not significantly differ between HIV-exposed uninfected and HIV-unexposed children at 6 months. At 24 months, HIV-exposed uninfected children scored lower than HIV-unexposed for receptive language (adjusted mean difference −1·03 [95% CI −1·69 to −0·37]) and expressive language (−1·17 [–2·09 to −0·24]), whereas adjusted differences in cognitive (−0·45 [–1·32 to 0·43]), fine motor (0·09 [–0·49 to 0·66]), and gross motor (−0·41 [–1·09 to 0·27]) domain scores between groups were not significant. Correspondingly, the proportions of HIV-exposed uninfected children with developmental delay were higher than those of HIV-unexposed children for receptive language (adjusted odds ratio 1·96 [95% CI 1·09 to 3·52]) and expressive language (2·14 [1·11 to 4·15]).InterpretationUninfected children exposed to maternal HIV infection and antiretroviral therapy have increased odds of receptive and expressive language delays at 2 years of age. Further long-term work is needed to understand developmental outcomes of HIV-exposed uninfected children, especially in regions such as sub-Saharan Africa that have a high prevalence of HIV exposure among children.FundingBill & Melinda Gates Foundation, SA Medical Research Council, Wellcome Trust.

Rates of Hospitalization and Infection-Related Hospitalization Among Human Immunodeficiency Virus (HIV)-Exposed Uninfected Children Compared to HIV-Unexposed Uninfected Children in the United States, 2007-2016.

Studies from multiple countries have suggested impaired immunity in perinatally human immunodeficiency virus (HIV)-exposed uninfected children (HEU), with elevated rates of all-cause hospitalization and infections. We estimated and compared the incidence of all-cause hospitalization and infection-related hospitalization in the first 2 years of life among HEU and HIV-unexposed uninfected children (HUU) in the United States. Among HEU, we evaluated associations of maternal HIV disease-related factors during pregnancy with risk of child hospitalization. HEU data from subjects enrolled in the Surveillance Monitoring for Antiretroviral Therapy Toxicities Study (SMARTT) cohort who were born during 2006-2017 were analyzed. HUU comparison data were obtained from the Medicaid Analytic Extract database, restricted to states participating in SMARTT. We compared rates of first hospitalization, total hospitalizations, first infection-related hospitalization, total infection-related hospitalizations, and mortality between HEU and HUU using Poisson regression. Among HEU, multivariable Poisson regression models were fitted to evaluate associations of maternal HIV factors with risk of hospitalization. A total of 2404 HEU and 3 605 864 HUU were included in the analysis. HEU children had approximately 2 times greater rates of first hospitalization, total hospitalizations, first infection-related hospitalization, and total infection-related hospitalizations compared with HUUs. There was no significant difference in mortality. Maternal HIV disease factors were not associated with the risk of child infection or hospitalization. Compared with HUU, HEU children in the United States have higher rates of hospitalization and infection-related hospitalization in the first 2 years of life, consistent with studies in other countries. Closer monitoring of HEU infants for infection and further elucidation of immune mechanisms is needed.

Neurodevelopmental and behavioural outcomes of HIV-exposed uninfected and HIV-unexposed children at 2–3 years of age in Cape Town, South Africa

ABSTRACTSuccessful vertical HIV transmission prevention programmes (VTP) have resulted in an expanding population of HIV-exposed uninfected (HEU) infants whose growth, health and neurodevelopmental outcomes could have consequences for future resource allocation. We compared neurodevelopmental and behavioural outcomes in a prospective cohort of 2–3 year old HEU and HIV-unexposed uninfected (HU) children.Women living with and without HIV and their infants were enrolled within three days of birth from a low-risk midwife obstetric unit in Cape Town, South Africa during 2012 and 2013, under WHO Option A VTP guidelines. HIV-uninfected children aged 30–42 months were assessed using the Bayley scales of Infant Development-Third edition (BSID) and Strengths and Difficulties questionnaire (SDQ).Thirty-two HEU and 27 HU children (mean birth weight 3048g vs 3096g) were assessed. HEU children performed as well as HU children on BSID cognitive, language and motor domains. Mean scores fell within the low average range. Mothers of HEU children reported fewer conduct problems but stunting was associated with increased total difficulties on the SDQ.HEU and HU children’s performance on the BSID was similar. In this low-risk cohort, HIV exposure did not confer additional risk. Stunting was associated with increased behavioural problems irrespective of HIV exposure.

Immunogenicity and Safety of an Early Measles Vaccination Schedule at 6 and 12 Months of Age in Human Immunodeficiency Virus (HIV)-Unexposed and HIV-Exposed, Uninfected South African Children.

Measles morbidity and mortality rates are greatest in children <12 months old, with increased susceptibility in human immunodeficiency virus (HIV)-exposed children. We evaluated the immunogenicity and safety of an early 2-dose measles vaccine regimen administered at 6 and 12 months of age in South Africa. HIV-unexposed (HU) (n = 212) and HIV-exposed, uninfected (HEU) (n = 71) children received measles vaccination (CAM-70) at 6 and 12 months of age. Measles immunoglobulin G titers were measured by means of enzyme-linked immunosorbent assay before and 1 month after each vaccine dose. The majority of children (88.2% HU and 95.8% HEU; P = .04) were seronegative (<150 mIU/mL) to measles at 4.2 months of age. This was particularly evident among infants of mothers born from 1992 onwards (year of public nationwide measles vaccine availability). One month after the first measles vaccine, 42.3% of HU and 46.4% of HEU children were seropositive (≥330 mIU/mL). After the second dose, the proportion seropositive increased to 99.0% in HU and 95.3% in HEU children. Safety profiles were similar between HU and HEU children. Early 2-dose measles vaccination at 6 and 12 months of age was safe and induced antibody responses in HU and HEU children, which could partly offset the early loss of maternally derived antibodies in infants born to predominantly measles-vaccinated mothers. NCT03330171.

Altered Intestinal Permeability and Fungal Translocation in Ugandan Children With Human Immunodeficiency Virus.

Children with perinatally acquired human immunodeficiency virus (HIV; PHIVs) face a lifelong cumulative exposure to HIV and antiretroviral therapy (ART). The relationship between gut integrity, microbial translocation, and inflammation in PHIV is poorly understood. This is a cross-sectional study in 57 PHIVs, 59 HIV-exposed but uninfected children, and 56 HIV-unexposed and -uninfected children aged 2-10 years old in Uganda. PHIVs were on stable ART with HIV-1 RNA <400 copies/mL. We measured markers of systemic inflammation, monocyte activation, and gut integrity. Kruskal-Wallis tests were used to compare markers by group and the Spearman correlation was used to assess correlations between biomarkers. The mean age of all participants was 7 years and 55% were girls. Among PHIVs, the mean CD4 % was 34%, 93% had a viral load ≤20 copies/mL, and 79% were on a nonnucleoside reverse transcriptase inhibitor regimen. Soluble cluster of differentiation 14 (sCD14), beta-D-glucan (BDG), and zonulin were higher in the PHIV group (P ≤ .01). Intestinal fatty acid binding protein (I-FABP) and lipopolysaccharide binding protein (LBP) did not differ between groups (P > .05). Among PHIVs who were breastfed, levels of sCD163 and interleukin 6 (IL6) were higher than levels in PHIV who were not breastfed (P < .05). Additionally, in PHIVs with a history of breastfeeding, sCD14, BDG, LBP, zonulin, and I-FABP correlated with several markers of systemic inflammation, including high-sensitivity C-reactive protein, IL6, d-dimer, and systemic tumor necrosis factor receptors I and II (P ≤ .05). Despite viral suppression, PHIVs have evidence of altered gut permeability and fungal translocation. Intestinal damage and the resultant bacterial and fungal translocations in PHIVs may play a role in the persistent inflammation that leads to many end-organ diseases in adults.Despite viral suppression, children with perinatally acquired human immunodeficiency virus (HIV) in Uganda have evidence of alterations in intestinal permeability and fungal translocation, compared to HIV-exposed but uninfected and HIV-unexposed children, which may play a role in HIV-associated chronic inflammation.

Effect of in utero exposure to HIV and antiretroviral drugs on growth in HIV-exposed uninfected children: a systematic review and meta-analysis protocol

IntroductionHIV-exposed uninfected (HEU) children have higher morbidity and mortality compared with HIV unexposed uninfected children. Despite the fact that malnutrition contributes to about half of all infant deaths below 5...

Vaccination among HIV-infected, HIV-exposed uninfected and HIV-uninfected children: a systematic review and meta-analysis of evidence related to vaccine efficacy and effectiveness

ABSTRACTEvidence-based approaches were used in making recommendations for vaccination against vaccine-preventable diseases for HIV-infected and HIV-exposed individuals but with limited substantiation. We conducted a systematic review and meta-analysis with randomized-controlled trials (RCTs), cohort and case–control studies that have efficacy and effectiveness of vaccines in HIV-infected and HIV-exposed children as outcomes. Web of Science, Cochrane Library, PubMed and Scopus databases were searched for articles. Efficacy of 9-valent pneumococcal conjugate vaccine (PCV9) against total vaccine serotype invasive pneumococcal disease was 32% in HIV-infected children and 78% among HIV-uninfected children. Vaccine effectiveness of Bacillus Calmette–Guérin vaccine in preventing tuberculosis in HIV-infected children was zero compared to 59% protection in HIV-unexposed children. Likewise, HIV-uninfected children have better protection against invasive Haemophilus influenzae type b disease than the HIV-infected children. Effectiveness studies of rotavirus vaccines show that HIV-exposed uninfected children have similar protection against rotavirus gastroenteritis compared to the non-exposed children. Children who are severely immunosuppressed are poorly protected against invasive pneumococcal diseases. HIV-infected children tend to have lesser vaccine protection against vaccine-preventable diseases when compared to unexposed children. HIV-infected children who are immunocompetent are more likely to have better vaccine protection against vaccine-preventable diseases than those who are immunosuppressed. The overall quality of the observational studies was very low with very little confidence in the effect estimate. The overall quality of evidence for the RCT outcomes was mainly high. This study reveals a dearth of efficacy and effectiveness studies among HIV-infected and exposed children.

Neurodevelopmental effects of ante-partum and post-partum antiretroviral exposure in HIV-exposed and uninfected children versus HIV-unexposed and uninfected children in Uganda and Malawi: a prospective cohort study

Antiretroviral medication during pregnancy and breastfeeding substantially decreases the risk of HIV transmission from mothers to infants, but its effects on the child's neurodevelopment are unknown. This study compared neurodevelopmental outcomes of ante-partum and post-partum antiretroviral exposure in HIV-exposed and uninfected children with HIV-unexposed and uninfected children at ages 12, 24, 48, and 60 months. For this study, a prospective cohort of HIV-exposed and uninfected children was identified from two research sites in the PROMISE-BF trial (at Blantyre, Malawi, and Kampala, Uganda), in which pregnant HIV-infected mothers were randomly assigned to triple antiretroviral prophylaxis (lopinavir-ritonavir plus either lamivudine and zidovudine or emtricitabine and tenofovir), versus zidovudine alone. Post partum, the mother-infant pairs were randomly assigned to maternal triple antiretroviral treatment or infant nevirapine during breastfeeding. HIV-unexposed and uninfected children matched for age, sex, and socioeconomic background were enrolled at vaccination and well-child clinics at the study sites. We included only children without a history of documented brain infection or injury or substantial malnutrition, and whose mothers were randomly assigned and maintained within their assigned ante-partum and post-partum phases throughout their treatment arm periods. Primary outcomes were the Mullen Scales of Early Learning (MSEL) cognitive composite score at age 12 months, 24 months, and 48 months; and the mental processing index for the Kaufman Assessment Battery for Children, second edition (KABC-II) global score at 48 months and 60 months. Repeated measures were analysed using a linear mixed-effects model controlling for data collection site. Between Aug 23, 2013, and Dec 17, 2014, we co-enrolled 861 children. For MSEL assessments, 738 were eligible for inclusion at age 12 months, 790 at age 24 months, and 692 at age 48 months. For KABC-II assessments, 685 were eligible for inclusion at age 48 months and 445 at age 60 months. There were no differences in MSEL cognitive composite scores according to exposure at age 12 and 24 months (p=0·19 and 0·24, respectively, for comparison of all groups). At 48 months, MSEL cognitive composite scores were worse for children of mothers who did not remain on triple antiretroviral treatment throughout both the ante-partum and post-partum treatment phases (adjusted means 80·64 [95% CI 77·74-83·54] and 81·34 [78·19-84·48], respectively), compared with those who did remain on triple treatment (adjusted mean 85·93, 95% CI 83·05-88·80; p=0·0486 for the comparison of all groups). The KABC-II composite scores (mental processing index) did not differ at 48 or 60 months according to exposure (p=0·81 and 0·89, respectively, for comparison of all groups). Scores for MSEL and KABC-II for children of mothers on triple antiretrovirals in both the ante-partum and post-partum treatment phases were similar to those for children in the HIV-unexposed and uninfected reference group at all timepoints. Maternal triple antiretroviral exposure during both the ante-partum and post-partum phases did not result in greater developmental risks for the mothers' HIV-exposed and uninfected children through age 60 months, compared with children who were HIV-unexposed and uninfected. This might be because ante-partum triple antiretroviral protection of the health of mothers with HIV during pregnancy might be neuroprotective for the child, and when continued post partum, could enhance the quality of caregiving for the child through better clinical care for the mother. National Institutes of Health and Eunice Kennedy Shriver National Institute of Child Health and Human Development.

Independent and combined effects of improved water, sanitation, and hygiene (WASH) and improved complementary feeding on early neurodevelopment among children born to HIV-negative mothers in rural Zimbabwe: Substudy of a cluster-randomized trial.

BackgroundGlobally, nearly 250 million children (43% of all children under 5 years of age) are at risk of compromised neurodevelopment due to poverty, stunting, and lack of stimulation. We tested the independent and combined effects of improved water, sanitation, and hygiene (WASH) and improved infant and young child feeding (IYCF) on early child development (ECD) among children enrolled in the Sanitation Hygiene Infant Nutrition Efficacy (SHINE) trial in rural Zimbabwe.Methods and findingsSHINE was a cluster-randomized community-based 2×2 factorial trial. A total of 5,280 pregnant women were enrolled from 211 clusters (defined as the catchment area of 1–4 village health workers [VHWs] employed by the Zimbabwean Ministry of Health and Child Care). Clusters were randomly allocated to standard of care, IYCF (20 g of small-quantity lipid-based nutrient supplement per day from age 6 to 18 months plus complementary feeding counseling), WASH (ventilated improved pit latrine, handwashing stations, chlorine, liquid soap, and play yard), and WASH + IYCF. Primary outcomes were child length-for-age Z-score and hemoglobin concentration at 18 months of age. Children who completed the 18-month visit and turned 2 years (102–112 weeks) between March 1, 2016, and April 30, 2017, were eligible for the ECD substudy. We prespecified that primary inferences would be drawn from findings of children born to HIV-negative mothers; these results are presented in this paper. A total of 1,655 HIV-unexposed children (64% of those eligible) were recruited into the ECD substudy from 206 clusters and evaluated for ECD at 2 years of age using the Malawi Developmental Assessment Tool (MDAT) to assess gross motor, fine motor, language, and social skills; the MacArthur–Bates Communicative Development Inventories (CDI) to assess vocabulary and grammar; the A-not-B test to assess object permanence; and a self-control task. Outcomes were analyzed in the intention-to-treat population. For all ECD outcomes, there was not a statistical interaction between the IYCF and WASH interventions, so we estimated the effects of the interventions by comparing the 2 IYCF groups with the 2 non-IYCF groups and the 2 WASH groups with the 2 non-WASH groups. The mean (95% CI) total MDAT score was modestly higher in the IYCF groups compared to the non-IYCF groups in unadjusted analysis: 1.35 (0.24, 2.46; p = 0.017); this difference did not persist in adjusted analysis: 0.79 (−0.22, 1.68; p = 0.057). There was no evidence of impact of the IYCF intervention on the CDI, A-not-B, or self-control tests. Among children in the WASH groups compared to those in the non-WASH groups, mean scores were not different for the MDAT, A-not-B, or self-control tests; mean CDI score was not different in unadjusted analysis (0.99 [95% CI −1.18, 3.17]) but was higher in children in the WASH groups in adjusted analysis (1.81 [0.01, 3.61]). The main limitation of the study was the specific time window for substudy recruitment, meaning not all children from the main trial were enrolled.ConclusionsWe found little evidence that the IYCF and WASH interventions implemented in SHINE caused clinically important improvements in child development at 2 years of age. Interventions that directly target neurodevelopment (e.g., early stimulation) or that more comprehensively address the multifactorial nature of neurodevelopment may be required to support healthy development of vulnerable children.Trial registrationClinicalTrials.gov NCT01824940

Caregiver socioemotional health as a determinant of child well-being in school-aged and adolescent Ugandan children with and without perinatal HIV exposure.

Caregiver socio-emotional attributes are major determinants of child well-being. This investigation in vulnerable school-aged Ugandan children estimates relationships between children's well-being and their caregiver's anxiety, depression and social support. Perinatally HIV-infected, HIV-exposed uninfected and HIV-unexposed Ugandan children and their caregivers were enrolled. Perinatal HIV status was determined by 18months of age using DNA-polymerase chain-reaction test; status was confirmed via HIV rapid diagnostic test when children were 6-18years old. Five indicators of child well-being (distress, hopelessness, positive future orientation, esteem and quality of life (QOL)) and caregivers' socioemotional status (depressive symptoms, anxiety and social support) were measured using validated, culturally adapted and translated instruments. Categories based on tertiles of each caregiver psychosocial indicator were defined. Linear regression analyses estimated percent differences (β) and corresponding 95% confidence intervals (CI) for child well-being in relation to caregiver's psychosocial status. As per tertile increment, caregiver anxiety was associated with 2.7% higher distress (95%CI:0.2%, 5.3%) and lower self-esteem/QOL (β=-1.3%/-2.6%; 95%CI: -5.0%,-0.2%) in their children. Child distress/hopelessness increased (β=3.3%/7.6%; 95%CI:0.4%, 14.7%) and self-esteem/QOL decreased 2.3% (β=-2.3%/-4.4%; 95%CI: -7.2%, -1.3%) as per tertile increment in caregiver depression. Higher caregiver social support was associated with lower distress and higher positive outlook (β=3%; 95%CI:1.4%, 4.5%) in their children. HIV-infected/exposed children had most caregiver depression-related QOL deficit (β=-5.2%/-6.8%; 95%CI: -12.4%, -0.2%) and HIV-unexposed children had most caregiver social support-related enhancements in positive outlook (β=4.5%; 95%CI:1.9%, 7.1%). Caregiver anxiety, depressive symptoms and low social support were associated with worse well-being in school-aged and adolescent children. Improvement of caregiver mental health and strengthening caregiver social support systems may be a viable strategy for improving well-being of vulnerable children and adolescents in this setting.

Growth trajectories of breastfed HIV-exposed uninfected and HIV-unexposed children under conditions of universal maternal antiretroviral therapy: a prospective study

Over 1 million HIV-exposed uninfected (HEU) children are born in sub-Saharan Africa annually. Little data exist on the risk of impaired growth in this population under current policies of universal maternal antiretroviral therapy (ART) with breastfeeding. We aimed to study the growth of breastfed HEU children born to women who initiated ART during pregnancy and compare their growth with that of breastfed HIV-unexposed (HU) children drawn from the same community. A prospective cohort of HIV-uninfected and HIV-infected pregnant women, who were initiating ART, were enrolled at their first antenatal care visit in a primary care centre in Gugulethu, Cape Town, South Africa. HIV infected women were participants of the Maternal Child Health Antiretroviral Therapy (MCH-ART) study, and HIV-uninfected pregnant women were participants in the HIV-Unexposed-Uninfected (HU2) study. All women were followed up during pregnancy, through delivery, to the early postnatal visit, which was scheduled for the first week after birth. At this visit, eligible breastfeeding mother-child pairs were recruited for continuation of postnatal follow-up until approximately age 12 months. Child anthropometry was measured at around 6 weeks, and every 3 months from month 3 to month 12. Weight-for-age (WAZ), length-for-age (LAZ), weight-for-length (WLZ), head circumference-for-age, and body-mass index-for-age Z scores were compared between HEU and HU children longitudinally using mixed effects linear regression. At 12 months, proportions of HEU and HU children with moderate or severe malnutrition were compared cross-sectionally using logistic regression. MCH-ART is registered with ClinicalTrials.gov, number NCT01933477. Between June, 2013, and April, 2016, 884 breastfeeding mothers and their newborn babies (HEU, n=471; HU, n=413) were enrolled into postnatal follow-up. Excluding 12 children who tested HIV positive during follow-up, 461 HEU and 411 HU children attended 4511 study visits in total, with a median of 6 visits (IQR 5-6) per child. Birth characteristics were similar (overall, 94 [11%] of 872 preterm [<37 weeks] and 90 [10%] small-for-gestational age [birthweight <10th percentile]). Median duration of breastfeeding was shorter among HEU than HU children (3·9 months [IQR 1·4-12·0] vs 9·0 months [IQR 3·0-12·0]). Although WAZ scores increased over time in both groups, HEU children had consistently lower mean WAZ scores than HU children (overall β -0·34, 95% CI -0·47 to -0·21). LAZ scores decreased in both groups after 9 months. At 12 months, HEU children had lower mean LAZ scores than HU children (β -0·43, -0·61 to -0·25), with a higher proportion of children stunted (LAZ score <-2: 35 [10%] of 342 HEU vs 14 [4%] of 342 HU children; odds ratio [OR] 2·67, 95% CI 1·41 to 5·06). Simultaneously, overweight (WLZ score >2) was common in both groups of children at 12 months (54 [16%] of 342 HEU vs 60 [18%] of 340 HU children; OR 0·87, 95% CI 0·58 to 1·31). Compared with HU children, HEU children have small deficits in early growth trajectories under policies of universal maternal ART and breastfeeding. Large proportions of both HEU and HU children were overweight by 12 months, indicating substantial risks for early onset obesity among South African children. Although the longer-term metabolic effects of ART exposure in the context of childhood obesity warrants further investigation, addressing childhood obesity should be an urgent public health priority in this setting. Eunice Kennedy Shriver National Institute of Child Health and Human Development, Elizabeth Glaser Pediatric AIDS Foundation, South African Medical Research Council, and the Fogarty Foundation.

The impact of in utero HIV exposure on gut microbiota, inflammation, and microbial translocation

ABSTRACTHIV-exposed but uninfected (HEU) children represent a growing population and show a significantly higher number of infectious diseases, several immune alterations, compromised growth, and increased mortality rates when compared to HIV-unexposed children. Considering the impact that the gut microbiota has on general host homeostasis and immune system development and modulation, we hypothesized that HEU children present altered gut microbiota that is linked to the increased morbidity and the immune system disorders faced by them. Our experiments revealed no differences in beta and alpha diversity of the gut microbiota between HEU and unexposed children or between HIV-infected and uninfected mothers. However, there were differences in the abundance of several taxa from the gut microbiota between HEU and unexposed children and between HIV-infected and uninfected mothers. Functional prediction based on 16S rRNA sequences also indicated differences between HEU and unexposed children and between infected and uninfected mothers. In addition, we detected no differences between HEU and unexposed children in relation to weight, weight-for-age z scores, albumin serum levels, or microbial translocation and inflammation markers. In summary, HIV-infected mothers and their HIV-exposed children present alterations in the abundance of several taxa in the gut microbiome and the predicted functional metagenome when compared to uninfected mothers and unexposed children. Knowledge about the gut microbiome of HEU children in different settings is essential in order to determine better treatments for this susceptible population.

Nutritional, Socioeconomic, and Delivery Characteristics Are Associated with Neurodevelopment in Tanzanian Children

To evaluate the hypothesis that various maternal, socioeconomic, delivery, and infant nutritional characteristics are associated with early childhood development in young Tanzanian children. We performed a prospective cohort study among 206 HIV-exposed, uninfected and 247 HIV-unexposed Tanzanian infants who had been enrolled in 2 separate micronutrient trials (NCT00197730 and NCT00421668). Trained nurses administered culturally modified Bayley Scales of Infant and Toddler Development, 3rd edition (BSID-III), to evaluate cognitive, motor, and language development at 15 months of age. This analysis explored predictors of BSID-III z-scores using multivariable linear regression. Among maternal determinants, we found that low maternal height predicted all BSID-III domains in HIV-unexposed children; low maternal education predicted lower cognitive (standardized mean difference, -0.41; 95% CI, -0.74 to -0.08) and lower gross motor scores (standardized mean difference, -0.32; 95% CI, -0.61 to -0.04) in HIV-exposed children. Among delivery characteristics, facility delivery predicted higher cognitive scores (standardized mean difference, 1.36; 95% CI, 0.26-2.46); and oxytocin administration predicted lower fine motor scores (standardized mean difference, -0.48; 95% CI, -0.87 to -0.09) in HIV-exposed children. Higher length-for-age z-scores at 6 weeks of age predicted better cognitive (standardized mean difference, 0.15; 95% CI, 0.01-0.29) and expressive language scores (standardized mean difference, 0.16; 95% CI, 0.02-0.29) at 15 months in HIV-exposed infants. This hypothesis-generating study found significant associations between nutritional status and health of the mother and child, and maternal educational attainment, with direct measures of early childhood development at 15 months of age. In addition, several aspects of delivery (facility birth and oxytocin administration) were associated with early childhood development. Future intervention trials should focus on modifiable maternal, infant, and obstetric factors to strengthen the evidence base concerning early childhood development. ClinicalTrials.gov: NCT00197730 and NCT00421668.

Neurodevelopmental outcomes in HIV-infected and uninfected African children.

HIV infection is associated with cognitive impairments, but outcomes are poorly explored in children starting antiretroviral therapy (ART) early or in those exposed but uninfected. Nested cross-sectional evaluation of the neurocognitive and behavioural outcomes of HIV-infected, HIV-exposed uninfected (HEU) and HIV-unexposed (HUU) Cameroonian children at age 4-9 years prospectively followed. Cognitive development was assessed in 127 HIV-infected, 101 HEU, 110 HUU children using the KABC-II, neurologic dysfunction using the Touwen examination and behavioural difficulties using the Strength and Difficulties Questionnaire (SDQ). Analyses were adjusted for children age, sex and primary language. Contextual factors were included in a second step to assess their effects on outcomes. All HIV-infected children were treated before 12 months. There was a negative linear gradient in KABC-II scores from HUU children to HEU and HIV-infected children [gradient: -6.0 (-7.7; -4.3) for nonverbal index, NVI, and -8.8 (-10.7; -6.8) for mental processing index, MPI]. After adjusting for contextual factors, scores of HEU children were not significantly different from those of HUU children (all P > 0.1) and differences between HIV-uninfected and HUU children reduced [NVI: from -11.9 (-15.3; -8.5) to -3.4 (-6.8; -0.01), MPI: from -17.6 (-21.3; -13.8) to -5.5 (-9.3; -1.7)]. Compared with uninfected children, HIV-infected children had more neurological dysfunctions and higher SDQ scores (P = 0.002). Despite early ART, perinatal-HIV infection is associated with poorer neurocognitive scores and increased behavioural difficulties during childhood. Contextual factors play an important role in this association, which emphasizes the need for early nutritional and developmental interventions targeting both HIV-affected infants and their relatives.

Effect of HIV exposure and timing of antiretroviral therapy initiation on immune memory responses to diphtheria, tetanus, whole cell pertussis and hepatitis B vaccines

ABSTRACT Objectives: We evaluated memory responses and antibody persistence to diphtheria-toxoid, tetanus-toxoid, whole-cell-pertussis (DTwP), and Hepatitis-B vaccines in HIV-unexposed, HIV-exposed-uninfected and HIV-infected children previously randomized to initiate time-limited ART at 6–10 weeks (ART-Immed) or when clinically/immunologically indicated (ART-Def). Methods: All children received DTwP booster at 15–18 months. Antibodies were measured for pertussis-toxoid, filamentous haemagglutinin (FHA), diphtheria-toxoid, tetanus-toxoid, and hepatitis-B prior to booster, 1–2 weeks post-booster and at 24 months of age. Results: Pre-booster antibody GMC were lower in HIV-infected groups than HIV-unexposed children for all epitopes. Post-booster and at 24 months of age, the ART-Def group had lower GMCs and antibody proportion ≥0.1 IU/ml for tetanus-toxoid and diphtheria-toxoid compared to HIV-unexposed children. At 24 months of age, the ART-Immed group had higher GMCs, and more likely to maintain antibody titres ≥1.0 IU/ml to tetanus-toxoid and diphtheria-toxoid compared to HIV-unexposed children. Compared to HIV-unexposed children, at 15 and 24 months of age, persistence of antibody to HBsAg of ≥10 mIU/ml was similar in the ART-Immed group but lower among the ART-Def group. Antibody kinetics indicated more robust memory responses in HIV-exposed-uninfected than HIV-unexposed children to diphtheria-toxoid and wP. Conclusion: HIV-infected children not on ART at primary vaccination had poorer memory responses, whereas HIV-exposed-uninfected children mounted robust memory responses.

Measles Immunity at 4.5 Years of Age Following Vaccination at 9 and 15-18 Months of Age Among Human Immunodeficiency Virus (HIV)-infected, HIV-exposed-uninfected, and HIV-unexposed Children.

Human immunodeficiency virus (HIV)-infected and HIV-exposed-uninfected (HEU) children may be at increased risk of measles infection due to waning of immunity following vaccination. We evaluated persistence of antibodies to measles vaccination at 4.5 years of age in HIV-unexposed, HEU, and HIV-infected children with CD4+ ≥25% previously randomized to immediate antiretroviral therapy (ART) interrupted at 12 months (HIV/Immed-ART-12), 24 months (HIV/Immed-ART-24), or when clinically/immunologically indicated (HIV/Def-ART). The HIV/Def-ART group initiated ART by median 5.8 (interquartile range, 4.4-10.3) months of age. In this study, HIV-unexposed (n = 95), HEU (n = 84), HIV/Immed-ART-12 (n = 70), HIV/Immed-ART-24 (n = 70), and HIV/Def-ART (n = 62) children were scheduled to receive measles vaccination at age 9 and 15-18 months. Antimeasles serum immunoglobulin G titers were quantified using enzyme-linked immunosorbent assay at 4.5 years. Compared with HIV-unexposed children (2860 mIU/mL), measles antibody geometric mean titers (GMTs) were significantly lower in both HIV/Immed-ART-12 (571; P < .001) and HIV/Immed-ART-24 (1136; P < .001) but similar in the HIV/Def-ART (2777) and HEU (3242) groups. Furthermore, compared with HIV-unexposed, antibody titers ≥330 mIU/mL (ie, presumed serocorrelate for protection; 99%) were also significantly lower in HIV/Immed-ART-12 (70%; P < .001) and HIV/Immed-ART-24 (83%; P < .001) but similar in the HIV/Def-ART (90%) and HEU (98%) groups. HIV-infected children in whom ART was interrupted at either 12 or 24 months had lower GMTs and lower proportions with seroprotective titers than HIV-unexposed children, indicating a potential downside of ART treatment interruption. NCT00099658 and NCT00102960.

Interventions for developmental delays in children born to HIV-infected mothers: a systematic review

ABSTRACTChildren born to HIV-infected mothers have worse developmental outcomes compared to HIV-unexposed children. However, little is known about interventions to improve developmental outcomes in this population. This study systematically reviews the literature on interventions to improve development in children born to HIV-infected mothers. We systematically searched the following electronic bibliographic databases: Ovid MEDLINE, Embase, PsycINFO, Education Resources Information Center, and the Cochrane Database of Systematic Reviews. Studies were selected on the basis of defined inclusion criteria and excluded if antiretroviral medication was the only intervention. Titles, abstracts, and full texts were assessed by 2 independent reviewers. Data were collected on characteristics of the study design, intervention, and developmental outcomes measured. Risk of bias and strength of evidence were assessed on all included articles. Our search resulted in 11,218 records. After our initial review, 43 records were appraised in their entirety and 9 studies met all inclusion criteria. Six were performed in sub-Saharan Africa, while the remaining 3 were performed in the United States. Eight were randomized-controlled trials and one was a retrospective chart review. Four studies focused on caregiver-training, 2 studied massage therapy, and the remaining studies focused on maternal vitamin supplementation, video-based cognitive therapy, or center-based interventions. Massage therapy had the most consistent improvements in the domains measured, while caregiver training and cognitive therapy interventions had limited benefits. The center-based intervention showed no benefit. Only 3 studies had a low risk of bias, and 4 studies had good strength of evidence. Most studies found some benefit. However, these findings are limited by the quality of the study designs, small sample size, and heterogeneity of the interventions and assessments used to measure outcomes. There is a critical need for the creation of evidence-based interventions to promote development in this vulnerable population.

HIV Exposure and Formula Feeding Predict Under-2 Mortality in HIV-Uninfected Children, Botswana

To prospectively assess rates and detailed predictors of morbidity and mortality among HIV-exposed uninfected children and HIV-unexposed children in Botswana in a more recent era. We enrolled HIV-infected and HIV-uninfected mothers and their children in the prospective observational Tshipidi study at 2 sites (1 city and 1 village) in Botswana from May 2010-July 2012. Live-born children and their mothers were followed for 24 months postpartum. Detailed sociodemographic data, health, and psychosocial characteristics were collected at baseline and prospectively, and health outcomes ascertained. Mothers chose infant feeding method with counselling. A total of 893 live-born HIV-uninfected children (436 HIV-exposed uninfected, 457 HIV-unexposed) were followed. HIV-infected mothers had a median CD4 count of 410 cells/mm3, 32% took 3-drug antiretroviral treatment during pregnancy, 67% took only zidovudine, and 1% took <2 weeks of any antiretrovirals antepartum. Twenty four-month vital status was available for 888 (99.4%) children. HIV-exposed uninfected children had a significantly higher risk of death compared with children of HIV-uninfected mothers (5.0% vs 1.8%) (adjusted hazard ratio 3.27, 95% CI 1.44-7.40). High collinearity between maternal HIV status and child feeding method precluded analysis of these factors as independent predictors of mortality. Preterm birth, low birth weight, and congenital anomaly were also associated with mortality (in separate analyses), but maternal socioeconomic factors, depression, substance use, and social support were not significant predictors. The strongest predictors of 24-month mortality among children in Botswana were HIV exposure and formula feeding, although the relative contribution of these factors to child health could not be separated.

The sex gap in neonatal mortality and the AIDS epidemic in sub-Saharan Africa

The sex gap in early-age death is one of the most important sources of child inequality in all societies, and it carries negative social consequences in the long run. In...

Neurodevelopment of breastfed HIV-exposed uninfected and HIV-unexposed children in South Africa.

To assess neurodevelopment of breastfed HIV-exposed uninfected (HEU) and breastfed HIV-unexposed children in the context of universal maternal antiretroviral therapy (ART). Prospective study with antenatal enrolment and follow-up of breastfeeding HEU and HIV-unexposed mother-infant pairs through 12-18 months postpartum. Peri-urban community, Cape Town, South Africa. HEU (n = 215) and HIV-unexposed (n = 306) children. Cognitive, motor and language development at median 13 (interquartile range 12-14) months of age: continuous and dichotomous Bayley Scales of Infant and Toddler Development Third Edition (delay defined as composite score <85). Incidence of preterm delivery (<37 weeks) was similar among HEU and HIV-unexposed children (11 vs. 9%, P = 0.31; median gestation 39 weeks); 48% were boys. Median breastfeeding duration was shorter among HEU vs. HIV-unexposed children (6 vs. 10 months). All HIV-infected mothers initiated lifelong ART (tenofovir-emtricitabine-efavirenz) antenatally. HEU (vs. HIV-unexposed) children had higher odds of cognitive delay [odds ratio (OR) 2.28 (95% confidence interval (CI) 1.13-4.60)] and motor delay [OR 2.10 (95% CI 1.03-4.28)], but not language delay, in crude and adjusted analysis. Preterm delivery modified this relationship for motor development: compared with term HIV-unexposed children, term HEU children had similar odds of delay, preterm HIV-unexposed children had five-fold increased odds of delay (adjusted OR 4.73, 95% CI 1.32; 16.91) and preterm HEU children, 16-fold increased odds of delay (adjusted OR 16.35, 95% CI 5.19; 51.54). Young HEU children may be at increased risk for cognitive and motor delay despite universal maternal ART and breastfeeding; those born preterm may be particularly vulnerable.