A Meta-analysis Assessing Diarrhea and Pneumonia in HIV-Exposed Uninfected Compared With HIV-Unexposed Uninfected Infants and Children.
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ABSTRACT: Objective
Previous studies have demonstrated that HIV-exposed uninfected (HEU) infants and children experience morbidity and mortality at rates exceeding those of their HIV-unexposed uninfected (HUU) counterparts. We sought to summarize the association between HEU vs. HUU infants and children for the outcomes of diarrhea and pneumonia.Design
Meta-analysis.Methods
We reviewed studies comparing infants and children in the 2 groups for these infectious disease outcomes, in any setting, from 1993 to 2018 from 6 databases.Results
We included 12 studies, and 17,955 subjects total [n = 5074 (28.3%) HEU and n = 12,881 (71.7%) HUU]. Random-effects models showed HEU infants and children had a 20% increase in the relative risk of acute diarrhea and a 30% increase in the relative risk of pneumonia when compared with their HUU counterparts. When stratifying by time since birth, we showed that HEU vs. HUU children had a 50% and 70% increased risk of diarrhea and pneumonia, respectively, in the first 6 months of life.Conclusions
We show an increased risk of diarrhea and pneumonia for HEU vs. HUU infants and children. Although we acknowledge, and commend, the immense public health success of prevention of mother-to-child transmission, we now have an enlarging population of children that seem to be vulnerable to not only death, but increased morbidity. We need to turn our attention to understanding the underlying mechanism and designing effective public health solutions. Further longitudinal research is needed to elucidate possible underlying immunological and/or sociological mechanisms that explain these differences in morbidity.
SUBMITTER: Brennan AT
PROVIDER: S-EPMC8214449 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:We sought to determine if HIV-exposed uninfected (HEU) children had worse neurodevelopmental outcomes at 24 months compared with HIV-unexposed uninfected (HUU) children in Botswana. HIV-infected and uninfected mothers enrolled in a prospective observational study ("Tshipidi") in Botswana from May 2010 to July 2012. Child neurodevelopment was assessed at 24 months with the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III: cognitive, gross motor, fine motor, expressive language, and receptive language domains) and the Development Milestones Checklist (DMC), a caregiver-completed questionnaire (locomotor, fine motor, language and personal-social domains). We used linear regression models to estimate the association of in-utero HIV exposure with neurodevelopment, adjusting for socioeconomic and maternal health characteristics. We evaluated 670 children (313 HEU, 357 HUU) with ≥1 valid Bayley-III domain assessed and 723 children (337 HEU, 386 HUU) with a DMC. Among the 337 HEU children with either assessment, 122 (36%) were exposed in utero to maternal 3-drug antiretroviral treatment and 214 (64%) to zidovudine. Almost all HUU children (99.5%) breastfed, compared with only 9% of HEU children. No domain score was significantly lower among HEU children in adjusted analyses. Bayley-III cognitive and DMC personal-social domain scores were significantly higher in HEU children than in HUU children, but differences were small. HEU children performed equally well on neurodevelopmental assessments at 24 months of age compared with HUU children. Given the global expansion of the HEU population, results suggesting no adverse impact of in-utero HIV and antiretroviral exposure on early neurodevelopment are reassuring.
| S-EPMC5613819 | biostudies-literature
Project description:BackgroundHIV-uninfected infants of HIV-positive women may experience worse growth and health outcomes than infants of HIV-negative women, but this has not been thoroughly investigated under the World Health Organization's most recent recommendations to reduce vertical transmission.ObjectiveTo determine whether HIV-exposed and -uninfected (HEU) infants whose mothers received Option B+ have higher odds of experiencing suboptimal growth trajectories than HIV-unexposed, -uninfected infants, and if this relationship is affected by food insecurity.DesignRepeated anthropometric measures were taken on 238 infants (HEU = 86) at 1 week and 1, 3, 6, 9, and 12 months after delivery in Gulu, Uganda. Latent class growth mixture modeling was used to develop trajectories for length-for-age z-scores, weight-for-length z-scores, mid-upper arm circumference, sum of skinfolds, and arm fat area. Multinomial logistic models were also built to predict odds of trajectory class membership, controlling for socioeconomic factors.ResultsHEU infants had greater odds of being in the shortest 2 length-for-age z-scores trajectory classes [odds ratio (OR) = 3.80 (1.22-11.82), OR = 8.72 (1.80-42.09)] and higher odds of being in smallest sum of skinfolds trajectory class [OR = 3.85 (1.39-10.59)] vs. unexposed infants. Among HEU infants, increasing food insecurity was associated with lower odds of being in the lowest sum of skinfolds class [OR = 0.86 (0.76-0.98)].ConclusionsThere continues to be differences in growth patterns by HIV-exposure under the new set of World Health Organization guidelines for the prevention of mother-to-child transmission of HIV and the feeding of HEU infants in low-resource settings that are not readily identified through traditional mixed-effects modeling. Food insecurity was not associated with class membership, but differentially affected adiposity by HIV-exposure status.
| S-EPMC7492413 | biostudies-literature
Project description:OBJECTIVES:To assess neurodevelopment of breastfed HIV-exposed uninfected (HEU) and breastfed HIV-unexposed children in the context of universal maternal antiretroviral therapy (ART). DESIGN:Prospective study with antenatal enrolment and follow-up of breastfeeding HEU and HIV-unexposed mother-infant pairs through 12-18 months postpartum. SETTING:Peri-urban community, Cape Town, South Africa. PARTICIPANTS:HEU (n = 215) and HIV-unexposed (n = 306) children. MAIN OUTCOME MEASURES: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). RESULTS: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). CONCLUSION: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.
| S-EPMC6341164 | biostudies-literature
Project description:BACKGROUND: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. METHODS: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. RESULTS: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. CONCLUSIONS: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.
| S-EPMC7353328 | biostudies-literature
Project description:Objectives We evaluated the prevalence and risk factors for hepatic steatosis in South African children with perinatally acquired HIV (PHIV) who started treatment early and remain on long-term antiretroviral therapy (ART) compared to HIV-uninfected children. Design A cross-sectional study from April 2019 to October 2021. PHIV, HIV-exposed uninfected (HEU) and HIV-unexposed (HU) children were enrolled from an ongoing cohort study. Methods All children had transient elastography (TE) with controlled attenuation parameter (CAP). Liver enzymes, lipogram, insulin and glucose were sent after an overnight fast. Multivariable linear regression analyses identified predictors of CAP. Hepatic steatosis was defined as CAP>248kPa. Results 215 children (111 [52%] male; median age 14.1 years; IQR 12.7–14.9) participated in the study, 110 PHIV, 105 HIV-uninfected (36 HEU, 69 HU). PHIV initiated ART at a median age of 2.7 months (IQR 1.8–8.5). Hepatic steatosis prevalence was 9% in PHIV, 3% in HEU and 1% in HU children (p = 0.08). However, 8% of lean (body mass index z-score ≤ +1) PHIV had hepatic steatosis compared to zero lean HEU or HU children (p = 0.03). In multivariable linear regression analysis of all PHIV, body mass index (BMI) z-score was positively associated with CAP (p = 0.001) while CD4 count (p = 0.02) and duration of suppression of HIV viraemia (p = 0.009) were negatively associated with CAP, adjusting for age, sex and ethnicity. Conclusions Hepatic steatosis prevalence was higher in lean PHIV than lean HIV-uninfected South African children. Longer suppression of HIV viraemia and higher CD4 count were associated with lower CAP and might be protective factors for hepatic steatosis in PHIV children.
| S-EPMC9218275 | biostudies-literature
Project description:BackgroundVery few studies consider the oral health status and quality of life in HIV-1 exposed uninfected (HEU) children. The aim of this study was to estimate the prevalence of caries in primary teeth and its oral health related quality of life impacts in HEU children compared to HIV-unexposed-uninfected (HUU) children, whilst adjusting for confounding covariates.MethodsThis study uses data from the Ugandan site of the ANRS 121741 PROMISE- PEP trial (ClinicalTrials.gov, number NCT00640263) conducted in 2009-2013 that recruited mothers with HIV-1 and their uninfected children. Of 244 HEU-children-caretaker pairs available at the end of the one-year trial, 166 were re-enrolled in the ANRS 12341 PROMISE-PEP M&S study at 5-7 years and 164 were included in this study. These were age and sex-matched with 181 HUU children-caretaker comparators. Caries experience was recorded using World Health Organization's Decayed, Missed and Filled teeth (dmft/DMFT) indices. The Early Childhood Oral health Impact Scale (ECOHIS) was used for assessment of oral health related quality of life. Mixed effects logistic regression was conducted with dmft and ECOHIS scores as outcomes and HIV-1 exposure status as the main exposure.ResultsForty-eight percent of HEU children and 60% of HUU had dmft> 0. Corresponding figures for ECOHIS> 0 were 12% of HEU and 22% of HUU. The crude analysis showed differences related to HIV-1 exposure in caries experience and oral health related quality of life. Mixed effect logistic regression analyses were not significant when adjusted for use of dental care and toothache. If caregivers' DMFT> 0, the adjusted odds ratio for caries experience (dmft> 0) was 1.6 (95% CI: 1.0-2.8) while if dmft> 0 the adjusted odds ratio for quality of life impacts (ECOHIS> 0) was 4.6 (95% CI: 2.0-10.6).ConclusionThe prevalence of untreated caries in primary teeth and quality of life impacts was high in this study population. HIV-1 exposed uninfected children were not more likely than HUU children to experience dental caries or have impaired oral health related quality of life. Given the global expansion of the HEU child population, the present findings indicating no adverse effect of pre- and post-natal HIV-1 exposure on caries in deciduous teeth are reassuring.
| S-EPMC7106612 | biostudies-literature
Project description:ObjectivesInfants who are HIV exposed but uninfected (HEU) compared with HIV unexposed uninfected (HUU) have an increased risk of adverse birth outcomes, morbidity and hospitalization. In the era of universal maternal antiretroviral treatment, there are few insights into patterns of neonatal morbidity specifically.DesignA prospective cohort study.MethodsWe compared neonatal hospitalizations among infants who were HEU (n = 463) vs. HUU (n = 466) born between 2017 and 2019 to a cohort of pregnant women from a large antenatal clinic in South Africa. We examined maternal and infant factors associated with hospitalization using logistic regression.ResultsHospitalization rates were similar between neonates who were HEU and HUU (13 vs. 16%; P = 0.25). Overall, most hospitalizations occurred directly after birth (87%); infection-related causes were identified in 34%. The most common reason for hospitalization unrelated to infection was respiratory distress (25%). Very preterm birth (<32 weeks) (29 vs. 11%; P = 0.01) as well as very low birthweight (<1500 g) (34 vs. 16%; P = 0.02) occurred more frequently among hospitalized neonates who were HEU. Of those hospitalized, risk of intensive care unit (ICU) admission was higher in neonates who were HEU (53%) than HUU (27%) [risk ratio = 2.1; 95% confidence interval (95% CI) 1.3-3.3]. Adjusted for very preterm birth, the risk of ICU admission remained higher among neonates who were HEU (aRR = 1.8; 95% CI 1.1-2.9).ConclusionNeonates who were HEU (vs. HUU) did not have increased all-cause or infection-related hospitalization. However, very preterm birth, very low birthweight and ICU admission were more likely in hospitalized neonates who were HEU, indicating increased severity of neonatal morbidity.
| S-EPMC8076534 | biostudies-literature
Project description:BackgroundDiarrhea in infancy can compromise linear growth and this relationship is likely influenced by diarrhea severity, number of episodes, and the timing of those episodes. HIV exposed, uninfected infants (HEU) have higher risk of growth faltering, infectious morbidity and mortality than HIV-unexposed infants and may be representative of children particularly vulnerable to diarrhea-associated linear growth faltering.Methodology/principal findingsWe utilized data from a cohort of Kenyan HEU infants followed from birth to 12 months of age. Infant length and morbidity were ascertained at monthly study visits and sick visits. Longitudinal models estimated the association between diarrhea severity and length-for-age Z-score (LAZ) in the following month, at 12 months of age, and in 6-month intervals. The 372 enrolled infants experienced an average of 2.15 episodes (range: 0-8) of diarrhea and 0.54 episodes (0-4) of moderate-to-severe diarrhea (MSD) between birth and 12 months. Surviving infants had a mean LAZ of -0.97 (standard deviation: 1.2) at 12 months. MSD was significantly associated with an average loss of 0.14 (95% Confidence Interval [CI]: -0.24, -0.05, p = 0.003) in LAZ one month after the episode. Linear growth outcomes were not predicted by cumulative episodes of diarrhea, or timing of diarrhea during infancy.Conclusions/significanceDiarrhea severity influenced the relationship between diarrhea and subsequent linear growth. HEU infants with MSD may benefit from nutritional interventions following severe diarrhea to protect against linear growth faltering.
| S-EPMC7384652 | biostudies-literature
Project description:ObjectiveTo compare growth among antiretroviral drug and maternal HIV-exposed uninfected (AHEU) versus age-matched and sex-matched HIV-unexposed uninfected (HUU) children.DesignProspective cohort of AHEU children identified from the PROMISE trial (NCT01061151: clinicaltrials.gov registry) and age-matched and sex-matched HUU controls from child-wellness clinics, enrolled (September 2013 to October 2014) in Malawi and Uganda.MethodsWeight-for-age (WAZ), length-for-age (LAZ), weight-for-length (WLZ), and head-circumference-for-age (HCAZ) z-scores were derived at 12 months and 24 months of age. Wilcoxon Rank-Sum and Fisher's exact tests were used for unadjusted exposure group comparisons. Generalized Estimating Equations models estimated adjusted relative risks (aRR) for poor growth outcomes.ResultsOverall, 471 (50.5%) AHEU and 462 (49.5%) HUU children were assessed. Ugandan AHEU compared with HUU children had significantly lower mean LAZ (P < 0.001) and WAZ (P < 0.001) at 12 and 24 months of age and HCAZ (P = 0.016) at 24 months, with similar but not significant differences among Malawian AHEU and HUU children. The risk of stunting (more than two standard deviations below the WHO population LAZ median) was increased among AHEU versus HUU children: aRR = 2.13 (95% confidence interval (CI): 1.36-3.33), P = 0.001 at 12 months, and aRR = 1.67 (95% CI 1.16-2.41), P = 0.006 at 24 months of age in Uganda; and aRR = 1.32 (95% CI 1.10-1.66), P = 0.018, at 24 months of age in Malawi. The risk of HCAZ below WHO median was increased among AHEU versus HUU children at 24 months of age, aRR = 1.35 (95% CI 1.02-1.79), P = 0.038 in Uganda; and aRR = 1.35 (95% CI 0.91-2.02), P = 0.139 in Malawi.ConclusionPerinatal exposures to maternal HIV and antiretroviral drugs were associated with lower LAZ (including stunting), WAZ and HCAZ at 24 months of age compared with HUU children.
| S-EPMC7487261 | biostudies-literature
Project description:HIV-exposed uninfected infants (HEU) have abnormal immunologic functions and increased infectious morbidity in the first 6 months of life, which gradually decreases thereafter. The mechanisms underlying HEU immune dysfunctions are unknown. We hypothesized that unique characteristics of the HEU gut microbiota associated with maternal HIV status may underlie the HEU immunologic dysfunctions. We characterized the infant gut, maternal gut, and breast milk microbiomes of mother-infant pairs, including 123 with HEU and 117 with HIV-uninfected infants (HUU), from South Africa. Pan-bacterial 16S rRNA gene sequencing was performed on (i) infant stool at 6, 28, and 62 weeks; (ii) maternal stool at delivery and 62 weeks; and (iii) breast milk at 6 weeks. Infant gut alpha and beta diversities were similar between groups. Microbial composition significantly differed, including 12 genera, 5 families and 1 phylum at 6 weeks; 12 genera and 2 families at 28 weeks; and 2 genera and 2 families at 62 weeks of life. Maternal gut microbiomes significantly differed in beta diversity and microbial composition, and breast milk microbiomes differed in microbial composition only. Infant gut microbiotas extensively overlapped with maternal gut and minimally with breast milk microbiotas. Nevertheless, exclusively breastfed HEU and HUU had less divergent microbiomes than nonexclusively breastfed infants. Feeding pattern and maternal gut microbiome imprint the HEU gut microbiome. Compared to HUU, the HEU gut microbiome prominently differs in early infancy, including increased abundance of taxa previously observed to be present in excess in adults with HIV. The HEU and HUU gut microbiome compositions converge over time, mirroring the kinetics of HEU infectious morbidity risk. IMPORTANCE HIV-exposed uninfected infants (HEU) are highly vulnerable to infections in the first 6 months of life, and this vulnerability decreases to the age of 24 months. Because the microbiome plays a critical role in the education of the infant immune system, which protects them against infections, we characterized the gut microbiomes of HEU and HIV-unexposed infants (HUU) in the first year of life. The HEU and HUU gut microbiomes showed prominent differences at 6 and 28 weeks of life but converged at 62 weeks of life, mirroring the time course of the HEU excess infectious morbidity and suggesting a potential association between the infant gut microbiome structure and susceptibility to infections. Infant gut microbiotas extensively overlapped with maternal gut and minimally with breast milk microbiotas. Moreover, exclusively breastfed HEU and HUU had less divergent microbiomes at 6 and 28 weeks than nonexclusively breastfed HEU and HUU. The factors that affect the HEU gut microbiome, maternal gut microbiome and exclusive breastfeeding, may be targeted by interventions.
| S-EPMC9600264 | biostudies-literature