HIV-exposed But Uninfected Children Research Articles

A Retrospective Observational Study of the Impact of HIV Status on the Outcome of Paediatric Intensive Care Unit Admissions at a Tertiary Hospital in South Africa (2015-2019).

HIV-infected and HIV-exposed but uninfected (HEU) children have unique health risks. Our study looked at how HIV exposure and infection impact presentation and outcomes in PICU in an era of improved ART. A retrospective analysis of children admitted to PICU was performed. The sample was divided into HIV negative, HEU and HIV infected, and presentation and outcomes were compared with a significance level set at α = 0.05. Our study showed that 16% (109/678) of children admitted to PICU were HEU and 5.2% (35/678) were HIV infected. HIV-infected children were admitted at a younger age (median two months) with an increased incidence of lower respiratory infections than HIV-negative children (p < 0.001); they also required longer ventilation and admission (p < 0.001). HIV-infected children had a higher mortality (40%) (p = 0.02) than HIV-negative (22.7%) children; this difference was not significant when comparing only children with a non-surgical diagnosis (p = 0.273). HEU children had no significant difference in duration of ICU stay (p = 0.163), ventilation (p = 0.443) or mortality (p = 0.292) compared to HIV-negative children. In conclusion, HIV-infected children presented with more severe disease requiring longer ventilation and admission. HEU had similar outcomes to HIV-negative children.

Supragingival mycobiome of HIV-exposed-but-uninfected children reflects a stronger correlation with caries-free-associated taxa compared to HIV-infected or uninfected children.

Highly active antiretroviral treatment (HAART) has greatly reduced opportunistic infections in HIV-infected individuals. However, even with the use of HAART, HIV-infected individuals are still at an increased risk of oral diseases, including dental caries. Dental caries development is associated with microbial community shifts leading to community dysbiosis. HIV infection can significantly alter the bacteriome and mycobiome composition in the oral cavity; however, these impacts have not been assessed for caries initiation and progression. The aim of this study was to characterize the mycobiome for supragingival plaque samples from HIV-infected (HI), HIV-exposed-but-uninfected (HEU), and HIV-unexposed-and-uninfected (HUU) children with and without caries. To accomplish this, ITS1 amplicons of 127 samples were sequenced. We found that HIV infection and exposure resulted in changes to the supragingival plaque mycobiome for both health and caries. Overall, a reduction in community diversity as caries progressed was observed, with HI children having the lowest diversity and HEU children the highest. Candida albicans was the most abundant species identified, with 177 different amplicon sequence variants (ASVs). Two C. albicans ASVs dominated the data (53.0% and 38.5% of all taxonomic assignments). The more frequent ASV dominated HI and HUU communities, whereas the second dominated HEU communities. HEU children also had the lowest abundance of C. albicans and the highest number of health-associated taxa (taxa statistically associated with caries-free teeth).IMPORTANCEGlobally, caries is among the most frequent chronic childhood disease, and the fungal component of the microbial community responsible is poorly studied despite evidence that fungi contribute to increased acid production exacerbating enamel demineralization. HIV infection is another global health crisis. Perinatal HIV exposure with infection are caries risk factors; however, the caries experience in the context of perinatal HIV exposure without infection is less clear. Using high-throughput amplicon sequencing, we find taxonomic differences that become pronounced during late-stage caries. Notably, we show a stronger correlation with health-associated taxa for HIV-exposed-but-uninfected children when compared to unexposed and uninfected children. This aligns with a lower incidence of caries in primary teeth at age 6 or less for exposed yet uninfected children. Ultimately, these findings could contribute to improved risk assessment, intervention, and prevention strategies such as biofilm disruption and the informed design of pro-, pre-, and synbiotic oral therapies.

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

ABSTRACT 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.

In-utero HIV exposure and cardiometabolic health among children 5-8 years: findings from a prospective birth cohort in South Africa.

To evaluate if in-utero HIV exposure is associated with adverse cardiometabolic health outcomes at 5-8 years of age. Prospective cohort study. We enrolled a random sample of HIV-exposed but uninfected (HEU) and HIV-unexposed children from the Drakenstein Child Health study, a longitudinal birth cohort study in Cape Town, South Africa, in a cardiometabolic health pilot study. Outcomes were assessed by trained study staff and included: anthropometry, body composition and size, blood pressure, fasting plasma glucose, HbA1c, lipids, and insulin resistance using HOMA-IR. We used multivariable linear and log-binomial regression to estimate associations between HIV-exposure and cardiometabolic outcomes, adjusted for child age, sex, height, body size, and maternal factors as appropriate. We included 260 children (HEU n = 100, HIV-unexposed n = 160). HEU children had older mothers (median age 30 vs. 26 years), with minimal differences in gestational age and size at birth by HIV-exposure status. In multivariable analyses, HEU children had lower weight-for-age (mean difference -0.35, 95% confidence interval -0.66, -0.05), and height-for-age (mean difference -0.29, 95% confidence interval -0.56, -0.03; z-scores). There were no differences in adiposity, impaired glucose metabolism, or lipid levels by HIV-exposure status. Overall, 12% of children had blood pressure more than 90th percentile, with no differences by HIV-exposure status. Overall, there were few differences in cardiometabolic outcomes between HEU and HIV-unexposed children in this South African cohort. Although these findings are reassuring, monitoring of cardiometabolic health is important as HEU and HIV-unexposed children enter adolescence and cardiometabolic risk trajectories become established.

The Danish HIV Birth Cohort (DHBC) - a nationwide, prospective cohort

PurposeThe purpose of the Danish HIV Birth Cohort (DHBC) is to investigate the significance of HIV-1 infection in pregnancy and after delivery in women living with HIV (WLWH) in Denmark...

#33: A Tale of Two Pneumos: the Impact of HIV Exposure or Infection Status on Pediatric Carriage of Streptococcus pneumoniae and Pneumocystis jirovecii, a Nested Case–control Analysis from the Pneumonia Etiology Research in Child Health (PERCH) study in Zambia

Abstract Background Most pediatric HIV cases in Africa reflect maternal to child transmission (MTCT). The persistently high seroprevalence of HIV in pregnant women (16.6%) and the low rates of mother to child HIV transmission (~2%) have resulted in a high number of children who are HIV exposed but uninfected (HEU). HIV exposed but uninfected (HEU) children have increased rates of morbidity and mortality vs. HIV unexposed and uninfected (HUU). Methods To explore the mechanisms behind this phenomenon, each case and control was sampled using a nasopharyngeal NP swab and an oropharyngeal (OP). A multiplex real-time polymerase chain reaction (PCR) assay was used to determine the presence of Streptococcus pneumoniae and Pneumocystis jirovecii in the NP/OP specimens. We compared nasopharyngeal carriage rates of S. pneumoniae and P. jirovecii between HIV-infected, HEU, or HUU case (pneumonia) and control (without pneumonia) children. In bivariate analyses, using carriage as a dichotomous outcome, proportions we compared using chi-square or odds ratios with 95% confidence intervals. In multivariate models, we created logistic and linear regression models adjusting for nutritional status as possible mediators of carriage status. Results SP carriage rates were similar between cases and controls. However, density was increased among HIV-infected children vs. HEU or HUU children (15.8 vs. 4.7 vs. 3.6 × 105 copies/mL, respectively). Among cases, PJ carriage among HIV positive, HEU and HUU children was 31%, 15% and 10%,, respectively, (P &amp;lt; 0.05) and carriage density was 63.9, 20.9, and 4.8 × 103 copies/mL, respectively (P &amp;lt; 0.05). In adjusted logistic regression models, HIV-infected cases were slightly more likely to be an S. pneumoniae carrier compared with HUU cases (aOR = 1.1; 95% CI: 0.57–2.14). In contrast, all other case/exposure combinations were less likely to be S. pneumoniae carriers with the lowest adjusted odds among HIV-infected controls children (aOR = 0.34; 95% CI: 0.17–0.71). The odds of being a PJ carrier was almost 6 times higher in HIV-infected cases than in HIV unexposed cases (aOR = 6.63; 95% CI: 3.24–13.54). Conclusions We demonstrate that HIV infection and HIV exposure without infection each have an impact on carriage rates and density for S. pneumoniae and P. jirovecii, though the magnitude and nature of these effects differs substantially between the two pathogens. This may be explained in part by differences in immune responses to these two different pathogens. Our analysis provides further evidence of fundamental differences in immune function among HIV exposed but uninfected infants compared with HIV unexposed, uninfected infants.

Immune status, and not HIV infection or exposure, drives the development of the oral microbiota

Even with antiretroviral therapy, children born to HIV-infected (HI) mothers are at a higher risk of early-life infections and morbidities including dental disease. The increased risk of dental caries in HI children suggest immune-mediated changes in oral bacterial communities, however, the impact of perinatal HIV exposure on the oral microbiota remains unclear. We hypothesized that the oral microbiota of HI and perinatally HIV-exposed-but-uninfected (HEU) children will significantly differ from HIV-unexposed-and-uninfected (HUU) children. Saliva samples from 286 child-participants in Nigeria, aged ≤ 6 years, were analyzed using 16S rRNA gene sequencing. Perinatal HIV infection was significantly associated with community composition (HI vs. HUU—p = 0.04; HEU vs. HUU—p = 0.11) however, immune status had stronger impacts on bacterial profiles (p < 0.001). We observed age-stratified associations of perinatal HIV exposure on community composition, with HEU children differing from HUU children in early life but HEU children becoming more similar to HUU children with age. Our findings suggest that, regardless of age, HIV infection or exposure, low CD4 levels persistently alter the oral microbiota during this critical developmental period. Data also indicates that, while HIV infection clearly shapes the developing infant oral microbiome, the effect of perinatal exposure (without infection) appears transient.

Children Exposed or Unexposed to Human Immunodeficiency Virus: Weight, Height, and Body Mass Index During the First 5 Years of Life-A Danish Nationwide Cohort.

Exposures to human immunodeficiency (HIV) and antiretroviral therapy in utero may have adverse effects on infant growth. Among children born in Denmark and aged 0-5 years, we aimed to compare anthropometric outcomes in HIV-exposed but uninfected (HEU) children with those in children not exposed to HIV. In a nationwide register-based study we included all singleton HEU children born in Denmark in 2000-2016. HEU children were individually matched by child sex, parity, and maternal place of birth to 5 singleton controls born to mothers without HIV. Weight-for-age z (WAZ) scores, length-for-age z (LAZ) scores, and weight-for-length or body mass index-for-age z scores were generated according to the World Health Organization standards and the Fenton growth chart for premature infants. Differences in mean z scores were analyzed using linear mixed models, both univariate and adjusted for social and maternal factors. In total, 485 HEU children and 2495 HIV-unexposed controls were included. Compared with controls, HEU children were smaller at birth, with an adjusted difference in mean WAZ and LAZ scores of -0.29 (95% confidence interval [CI], -.46 to -.12) and -0.51 (95% CI, -.71 to -.31), respectively (both P ≤ .001). Over time, there was a trend toward increasing WAZ and LAZ scores in HEU children, and there was no significant difference in adjusted WAZ scores after age 14 days (-0.13 [95% CI, -.27 to .01]; P = .07) and LAZ scores after age 6 months (-0.15 [95% CI, -.32 to .02]; P = .08). Compared with a matched control group, HEU children were smaller at birth, but this difference decreased with time and is not considered to have a negative effect on the health and well-being of HEU children during early childhood.

SAT-256 Obesity and Reactive Airway Disease Are Increased Among HIV-Exposed Uninfected Adolescents

Background: Worldwide, over 1 million babies are born to mothers with HIV each year. With the advent of prenatal antiretroviral therapy (ART), the vast majority of these individuals are HIV-exposed but uninfected (HEU). HEU infants and children exhibit impaired growth, mitochondrial toxicity, and immune activation compared to HIV-unexposed peers. Nonetheless, the long-term sequelae of in utero HIV and ART exposure have never before been examined. We hypothesized that in utero HIV/ART exposure may condition fetal development in a manner that predisposes to obesity and reactive airway disease (RAD) later in life. Methods: We leveraged a patient database registry at a U.S. academic health system to compare long-term health outcomes among HEU adolescents and matched controls, and to determine maternal factors associated with adverse HEU outcomes. HEU individuals born since 1990 with medical records available at age ≥ 13 y were identified. Over 200,000 controls also were retrieved from RPDR and matched up to 3:1 on birthdate (±5 y), age of last encounter (±2 y), sex, race, and zip code (SAS 9.4). Charts were manually reviewed to confirm HEU status and to extract health information. BMI was adjusted for age and sex per CDC growth charts. Obesity was defined as BMI ≥ 30 kg/m2 or ≥ 95 percentile. RAD was by clinical report. Results: 50 HEU adolescents (18 [15, 20] y, 54% male) and 141 matched controls (19 [16, 21] y, 55% male) were compared. Mothers of HEU adolescents were 30 ± 4 years old with BMI 26 [24, 30] kg/m2. Mothers had HIV for 4 [1, 7] years with CD4 count 405 [222, 615]/mm3, and 93% received prenatal ART. Obesity was seen in 42% of HEU adolescents compared to 25% of controls (P = 0.04). The prevalence of RAD also was higher among HEU than controls (40% vs. 24%, P = 0.04). Within the HEU group, there was a strong inverse correlation between maternal third trimester CD4 count and adolescent BMI z-score (r = -0.47, P = 0.01). This relationship persisted upon adjustment for prenatal maternal factors including age, BMI, ART, and HIV duration as well as median household income (P < 0.05). Lower third trimester CD4 count also was strongly associated with higher birth weight (r = -0.56, P = 0.006) and placental weight (r = -0.58, P = 0.006). Prenatal maternal CD4 nadir, peak HIV viral load, HIV duration, and ART were not associated with adolescent BMI z-score. Unlike obesity, maternal factors did not relate to RAD among HEU. Conclusions: In utero exposure to HIV/ART may predispose to obesity and RAD in adolescence. Lower prenatal maternal CD4 count – indicative of more severe immune dysfunction – was associated with higher adolescent BMI. Prospective studies are needed to further characterize metabolic and immune dysregulation among the aging and expanding HEU population. Insights learned from these individuals may have implications for other groups exposed to maternal inflammation in utero, including individuals born to obese mothers.

PG-1 Compromised growth among HIV exposed compared to unexposed children in Nigeria

Introduction: HIV exposed but uninfected (HEU) children may be at an increased risk of impaired growth and development when compared to their unexposed and uninfected (HUU) counterparts. We compared growth pattern between HEU and HUU children in Nigeria. Methods: HIV infected and uninfected pregnant women were enrolled at the Plateau State Specialist Hospital (PSSH) Jos Nigeria. Babies born to these mothers were recruited at birth and the mother-infant pairs followed up until 18 months. Weight, length, and head circumference of the babies were measured at each study visit. Age and gender standardized z scores were generated for each anthropometric measure using the World Health Organization Child Growth Standards. Children with length for age (LAZ), weight for age (WAZ) and weight for length (WLZ) z scores &lt;−2 were classified as stunted, underweight, and wasted respectively. Results: A total of 415 children (307 HEU and 108 HUU) were included in this analysis. At birth, 117 (28.4%), 9 (2.2%) and 32 (7.8%) babies were stunted, underweight and wasted respectively. In a multivariable longitudinal analysis, the odds of stunting was higher among HEU as compared to HUU children (OR: 2.4 [95% CI: 1.4 to 4.1]; P = 0.001). Similarly, odds of being underweight was higher among the HEU children (OR: 1.6 [95% CI: 1.1 to 2.2]; P = 0.009). While the odds of wasting appeared higher for the HEU children (OR: 1.5 [95% CI: 0.9 to 2.4]; P = 0.128), the difference did not reach statistical significance. Conclusions: We found strong evidence of greater impairment of linear and ponderal growth among HEU as compared to HUU children during the first 18 months of life in Nigeria. Further studies are needed to explore the causal basis for these differences.

Risk for Speech and Language Impairments in Preschool Age HIV-exposed Uninfected Children With In Utero Combination Antiretroviral Exposure.

Perinatally HIV-exposed but uninfected (HEU) children have elevated risk of late language emergence at 1 year of age, with possible links to in utero antiretroviral (ARV) exposure. We investigated possible risks for speech impairments (SIs) and language impairments (LI) in preschool monolingual HEU children in the United States. Speech and language assessments were conducted as part of the Pediatric HIV/AIDS Cohort Study Surveillance Monitoring of ART Toxicities study at ages 3 (N = 208) and 5 (N = 429) years. Domains of speech, overall language, vocabulary and grammar were assessed. SI and LI were defined by standardized scores <15th percentile and categorized as primary (normal nonverbal IQ ≥ 85 without hearing loss) and concomitant (low nonverbal IQ and/or presence of hearing loss). Logistic regression models were used to estimate odds of SI and LI for different ARV exposures, adjusted for confounding variables. The risk for language impairments in HEU children was higher than population norms; risk for SIs was not elevated. Risk factors for impairments included male sex, black race and other socioeconomic measures, although these varied by age, primary (P) versus concomitant (C) impairment and by speech or language measure. Adjusted logistic regression models revealed lower and increased risk for specific ARVs. Tenofovir exposure was associated with increased risk for SI at 3 years of age but was associated with decreased risk for concomitant language impairment at 5 years of age. Further investigation of combination ARV exposure and speech/language impairment among preschool children is needed to confirm associations.

Neurodevelopment in Young Children Born to HIV-Infected Mothers: A Meta-analysis.

HIV-infected (HIV+) children have worse neurodevelopmental outcomes compared with HIV-uninfected children. However, little is known regarding the differences in neurodevelopment between young HIV+ children, HIV-exposed but uninfected (HEU) children, and HIV-unexposed and uninfected (HUU) children. To systematically review and meta-analyze data on neurodevelopmental performance between young HIV+, HEU, and HUU children. 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. Titles, abstracts, and full texts were assessed by 2 independent reviewers. Data were extracted by 2 independent reviewers and cross-checked by 2 additional reviewers. Forty-five studies were identified for inclusion in the systematic review, and of these, 11 were included in the meta-analysis on the basis of availability of Bayley Scales of Infant and Toddler Development scores. Within the meta-analysis, when compared with their HUU peers, HIV+ and HEU children had lower cognitive and motor scores. HIV+ and HEU children with antiretroviral (ARV) exposure had lower cognitive and motor scores compared with those without ARV exposure. We were unable to control adequately for intravenous drug use, geographic location, or quality of the assessment independently. Both HIV+ and HEU children had worse developmental outcomes compared with HUU children. HIV+ and HEU children with ARV exposure also had worse developmental outcomes compared with those without exposure; however, these results should be interpreted with caution. More research is needed to identify the impact of ARV exposure on young children.

Effect of co-trimoxazole on mortality in HIV-exposed but uninfected children in Botswana (the Mpepu Study): a double-blind, randomised, placebo-controlled trial.

Co-trimoxazole prophylaxis reduces mortality among HIV-infected children, but efficacy in HIV-exposed but uninfected (HEU) children in a non-malarial, low-breastfeeding setting with a low risk of mother-to-child transmission of HIV is unclear. HEU children in Botswana were randomly assigned to receive co-trimoxazole (100 mg/20 mg once daily until age 6 months and 200 mg/40 mg once daily thereafter) or placebo from age 14-34 days to age 15 months. Mothers chose whether to breastfeed or formula feed their children. Breastfed children were randomly assigned to breastfeeding for 6 months (Botswana guidelines) or 12 months (WHO guidelines). The primary outcome, analysed by a modified intention-to-treat approach, was cumulative child mortality from treatment assignment to age 18 months. We also assessed HIV-free survival by duration of breastfeeding. This trial is registered with ClinicalTrials.gov, number NCT01229761. From June 7, 2011, to April 2, 2015, 2848 HEU children were randomly assigned to receive co-trimoxazole (n=1423) or placebo (n=1425). The data and safety monitoring board stopped the study early because of a low likelihood of benefit with co-trimoxazole. Only 153 (5%) children were lost to follow-up (76 in the co-trimoxazole group and 77 in the placebo group), and 2053 (72%) received treatment continuously to age 15 months, death, or study closure. Mortality after the start of study treatment was similar in the two study groups: 30 children died in the co-trimoxazole group, compared with 34 in the placebo group (estimated mortality at 18 months 2·4% vs 2·6%; difference -0·2%, 95% CI -1·5 to 1·0, p=0·70). We saw no difference in hospital admissions between groups (12·5% in the co-trimoxazole group vs 17·4% in the placebo group, p=0·19) or grade 3-4 clinical adverse events (16·5% vs 18·4%, p=0·18). Grade 3-4 anaemia did not differ between groups (8·1% vs 8·3%, p=0·93), but grade 3-4 neutropenia was more frequent in the co-trimoxazole group than in the placebo group (8·1% vs 5·8%, p=0·03). More co-trimoxazole resistance in commensal Escherichia coli isolated from stool samples was seen in children aged 3 or 6 months in the co-trimoxazole group than in the placebo group (p=0·001 and p=0·01, respectively). 572 (20%) children were breastfed. HIV infection and mortality did not differ significantly by duration of breastfeeding (3·9% for 6 months vs 1·9% for 12 months, p=0·21). Prophylactic co-trimoxazole seems to offer no survival benefit among HEU children in non-malarial, low-breastfeeding areas with a low risk of mother-to-child transmission of HIV. US National Institutes of Health.

Health and survival of HIV perinatally exposed but uninfected children born to HIV-infected mothers.

The number of HIV-exposed but uninfected (HEU) infants exposed to both HIV and multiple antiretroviral drugs in utero and during prolonged breastfeeding is increasing in low-income countries where HIV prevalence is the highest. We review recent evidence on the effects of perinatal/postnatal exposure to maternal HIV and combined antiretroviral therapy (cART) on health outcomes of HEU children (mitochondrial and metabolic toxicity, adverse pregnancy outcomes, neurodevelopment, growth, infectious morbidity, and mortality). Several studies have reported ART-associated mitochondrial toxicity and metabolic disorders with conflicting results on adverse pregnancy outcomes, underscoring the need to conduct further investigations on these questions. Studies about congenital abnormalities report no significant differences between HEU exposed to ART and HIV-unexposed (HUU) children. Updated French data showed no significant difference in cancer incidence between HEU cART-exposed children and the general paediatric population. Furthermore, HEU children exposed to maternal cART have modest but significant impairment of development and a higher risk of growth impairment. Finally, HEU have higher risks of infections (mainly low respiratory tract infections and diarrhoea) and malaria than HUU children, particularly in children not breastfed or after early weaning. Higher mortality risk from infectious disease is reported in HEU compared to HUU children. As we move toward the elimination of mother-to-child transmission of HIV, HEU children are an emerging population whose health outcomes remain to be fully described. Future large cohorts of HEU children using careful comparison groups of HUU in the post-ART era are needed to better understand their long-term health outcomes.

Pattern of Infectious Morbidity in HIV-Exposed Uninfected Infants and Children.

Almost 30% of children in Southern Africa are HIV exposed but uninfected (HEU) and experience exposures that could increase vulnerability to infectious diseases compared to HIV unexposed (HU) children. The mechanisms of HEU infant vulnerability remain ill-defined. This review seeks to appraise the existing clinical evidence of the pattern of HEU infant infectious morbidity to aid understanding of the potential mechanism of susceptibility. A systematic search was conducted of scientific literature databases and conference proceedings up to December 2015 for studies comparing adequately defined HEU (in whom HIV-infection had been excluded through age-appropriate testing) and HU infants for all-cause mortality, all-cause hospitalization, or an infection-related morbidity. The systematic review was complemented by a narrative review of additional studies detailing the pattern of infectious morbidity experienced by HEU children without comparison to HU children or without conclusive exclusion of HIV-infection in HIV-exposed infants. Only 3 of 22 eligible identified studies were designed to primarily compare HEU and HU infants for infectious morbidity. Fourteen were conducted prior to 2009 in the context of limited antiretroviral interventions. Three patterns emerge: (1) causes of morbidity and mortality in HEU infants are consistent with the common causes of childhood morbidity and mortality (pneumonia, diarrheal disease, and bacterial sepsis) but occur with greater severity in HEU infants resulting in higher mortality, more frequent hospitalization, and more severe manifestations of disease; (2) the greatest relative difference between HEU and HU infants in morbidity and mortality occurs beyond the neonatal period, during mid-infancy, having waned by the second year of life; and (3) HEU infants are at greater risk than HU infants for invasive streptococcal infections specifically Group B Streptococcus and Streptococcus pneumonia. To definitively understand HEU infant infectious morbidity risk, substantially larger prospective studies with appropriate HU infant comparison groups are necessary. HEU children would benefit from collaboration among researchers to achieve the quality of evidence required to improve HEU infant outcomes globally. HEU infant health and well-being, beyond avoiding HIV-infection, deserves a more prominent position in the local and international HIV research agendas.

In Utero Exposure to Antiretroviral Drugs: Effect on Birth Weight and Growth Among HIV-exposed Uninfected Children in Brazil.

There are concerns about the effects of in utero exposure to antiretroviral drugs (ARVs) on the development of HIV-exposed but uninfected (HEU) children. The aim of this study was to evaluate whether in utero exposure to ARVs is associated with lower birth weight/height and reduced growth during the first 2 years of life. This cohort study was conducted among HEU infants born between 1996 and 2010 in Tertiary children's hospital in Rio de Janeiro, Brazil. Weight was measured by mechanical scale, and height was measured by measuring board. Z-scores for weight-for-age (WAZ), length-for-age (LAZ) and weight-for-length were calculated. We modeled trajectories by mixed-effects models and adjusted for mother's age, CD4 cell count, viral load, year of birth and family income. A total of 588 HEU infants were included of whom 155 (26%) were not exposed to ARVs, 114 (19%) were exposed early (first trimester) and 319 (54%) later. WAZ were lower among infants exposed early compared with infants exposed later: adjusted differences were -0.52 (95% confidence interval [CI]: -0.99 to -0.04, P = 0.02) at birth and -0.22 (95% CI: -0.47 to 0.04, P = 0.10) during follow-up. LAZ were lower during follow-up: -0.35 (95% CI: -0.63 to -0.08, P = 0.01). There were no differences in weight-for-length scores. Z-scores of infants exposed late during pregnancy were similar to unexposed infants. In HEU children, early exposure to ARVs was associated with lower WAZ at birth and lower LAZ up to 2 years of life. Growth of HEU children needs to be monitored closely.

Proportions of CD4+, CD8+ and B cell subsets are not affected by exposure to HIV or to Cotrimoxazole prophylaxis in Malawian HIV-uninfected but exposed children.

BackgroundAs a result of successful PMTCT programs, children born from HIV-infected mothers are now effectively protected from contracting the infection. However, it is not well known whether in utero exposure to the virus and the subsequent exposure to Cotrimoxazole (CTX) prophylaxis affect the cell mediated immune system of the children. This observational prospective study was aimed at determining how CD4+ T, CD8+ T and B cell subsets varied in HIV-exposed but uninfected (HEU) children at different ages.MethodsWe recruited HEU and HIV-unexposed and uninfected (HUU) children from 6 months of age and followed them up until they were 18 months old. HEU children received daily CTX prophylaxis beginning at 6 weeks of age until when 12 months of age. Venous blood samples were collected 6 monthly and analysed for different subsets of CD8+ T, B cells and totalCD4+ T cells.ResultsAt 6 months of age, HEU children had a lower percentage of total CD4+ T cells compared to HUU children and a lower proportion of naïve CD8+ T cells but higher percentage of effector memory CD8+ T cells compared to HUU children. HEU and HUU children had similar proportions of all B cell subsets at all ages.ConclusionsThe study showed that the subtle variations in CD4+ and CD8+ T cell subsets observed at 6 months do not last beyond 12 months of age, suggesting that HEU children have a robust cell-mediated immune system during first year of life.Trial registrationThis article report is not based on results of a controlled health-care intervention

Immunity to Measles, Mumps, and Rubella in US Children With Perinatal HIV Infection or Perinatal HIV Exposure Without Infection.

Children with perinatal human immunodeficiency virus (HIV) infection (PHIV) may not be protected against measles, mumps, and rubella (MMR) because of impaired initial vaccine response or waning immunity. Our objectives were to estimate seroimmunity in PHIV-infected and perinatally HIV-exposed but uninfected (HEU) children and identify predictors of immunity in the PHIV cohort. PHIV and HEU children were enrolled in the Pediatric HIV/AIDS Cohort Study (PHACS) at ages 7-15 years from 2007 to 2009. At annual visits, demographic, laboratory, immunization, and clinical data were abstracted and serologic specimens collected. Most recent serologic specimen was used to determine measles seroprotection by plaque reduction neutralization assay and rubella seroprotection and mumps seropositivity by enzyme immunoassay. Sustained combination antiretroviral therapy (cART) was defined as taking cART for at least 3 months. Among 428 PHIV and 221 HEU PHACS participants, the prevalence was significantly lower in PHIV children for measles seroprotection (57% [95% confidence interval {CI}, 52%-62%] vs 99% [95% CI, 96%-100%]), rubella seroprotection (65% [95% CI, 60%-70%] vs 98% [95% CI, 95%-100%]), and mumps seropositivity (59% [95% CI, 55%-64%] vs 97% [95% CI, 94%-99%]). On multivariable analysis, greater number of vaccine doses while receiving sustained cART and higher nadir CD4 percentage between last vaccine dose and serologic testing independently improved the cumulative prediction of measles seroprotection in PHIV. Predictors of rubella seroprotection and mumps seropositivity were similar. High proportions of PHIV-infected children, but not HEU children, lack serologic evidence of immunity to MMR, despite documented immunization and current cART. Effective cART before immunization is a strong predictor of current seroimmunity.

Cardiac effects of in-utero exposure to antiretroviral therapy in HIV-uninfected children born to HIV-infected mothers.

We evaluated the potential cardiac effects of in-utero exposures to antiretroviral drugs in HIV-exposed but uninfected (HEU) children. We compared echocardiographic parameters of left ventricular function (ejection fraction, fractional shortening, and stress-velocity index) and structure (left ventricular dimension, posterior wall/septal thickness, mass, thickness-to-dimension ratio, and wall stress) (expressed as Z-scores to account for age and body surface area) between HEU and HIV-unexposed cohorts from the Pediatric HIV/AIDS Cohort Study's Surveillance Monitoring for ART Toxicities study. Within the HEU group, we investigated the associations between the echocardiographic Z-scores and in-utero exposures to maternal antiretroviral drugs. There were no significant differences in echocardiographic Z-scores between 417 HEU and 98 HIV-unexposed children aged 2-7 years. Restricting the analysis to HEU children, first-trimester exposures to combination antiretroviral therapy (a regimen including at least three antiretroviral drugs) and to certain specific antiretroviral drugs were associated with significantly lower stress-velocity Z-scores (mean decreases of 0.22-0.40 SDs). Exposure to combination antiretroviral therapy was also associated with lower left ventricular dimension Z-scores (mean decrease of 0.44 SD). First-trimester exposure to combination antiretroviral therapy was associated with higher mean left ventricular posterior wall thickness and lower mean left ventricular wall stress Z-scores. There was no evidence of significant cardiac toxicity of perinatal combination antiretroviral therapy exposure in HEU children. Subclinical differences in left ventricular structure and function with specific in-utero antiretroviral exposures indicate the need for a longitudinal cardiac study in HEU children to assess long-term cardiac risk and cardiac monitoring recommendations.

Pubertal onset in children with perinatal HIV infection in the era of combination antiretroviral treatment.

To evaluate associations of perinatal HIV infection, HIV disease severity, and combination antiretroviral treatment with age at pubertal onset. Analysis of data from two US longitudinal cohort studies (IMPAACT 219C and PHACS AMP), conducted during 2000-2012, including perinatally HIV-infected (PHIV) and HIV-exposed but uninfected (HEU) youth. Tanner stage assessments of pubertal status (breast and pubic hair in girls; genitalia and pubic hair in boys) were conducted annually. We compared the timing of pubertal onset (Tanner stage ≥2) between PHIV and HEU youth using interval-censored models. For PHIV youth, we evaluated associations of HIV disease severity and combination antiretroviral treatment with age at pubertal onset, adjusting for race/ethnicity and birth cohort. The mean age at pubertal onset was significantly later for the 2086 PHIV youth compared to the 453 HEU children (10.3 vs. 9.6, 10.5 vs. 10.0, 11.3 vs. 10.4, and 11.5 vs. 10.7 years according to female breast, female pubic hair, male genitalia, and male pubic hair staging, respectively, all P < 0.001). PHIV youth with HIV-1 RNA viral load above 10, 000 copies/ml (vs. ≤10, 000 copies/ml) or CD4% below 15% (vs. ≥15%) had significantly later pubertal onset (by 4-13 months). Each additional year of combination antiretroviral treatment was associated with a 0.6-1.2-month earlier mean age at pubertal onset, but this trend did not persist after adjustment for birth cohort. Pubertal onset occurs significantly later in PHIV than in HEU youth, especially among those with more severe HIV disease. However, in the current era, combination antiretroviral treatment may result in more normal timing of pubertal onset.