HIV-exposed Uninfected Children Research Articles

Diagnosis and management of community-acquired pneumonia in children: South African Thoracic Society guidelines.

Background Pneumonia remains a major cause of morbidity and mortality amongst South African children. More comprehensive immunisation regimens, strengthening of HIV programmes, improvement in socioeconomic conditions and new preventive strategies have impacted on the epidemiology of pneumonia. Furthermore, sensitive diagnostic tests and better sampling methods in young children improve aetiological diagnosis. Objectives To produce revised guidelines for pneumonia in South African children under 5 years of age. Methods The Paediatric Assembly of the South African Thoracic Society and the National Institute for Communicable Diseases established seven expert subgroups to revise existing South African guidelines focusing on: (i) epidemiology; (ii) aetiology; (iii) diagnosis; (iv) antibiotic management and supportive therapy; (v) management in intensive care; (vi) prevention; and (vii) considerations in HIV-infected or HIVexposed, uninfected (HEU) children. Each subgroup reviewed the published evidence in their area; in the absence of evidence, expert opinion was accepted. Evidence was graded using the British Thoracic Society (BTS) grading system. Sections were synthesized into an overall guideline which underwent peer review and revision. Recommendations Recommendations include a diagnostic approach, investigations, management and preventive strategies. Specific recommendations for HIV infected and HEU children are provided. Validation The guideline is based on available published evidence supplemented by the consensus opinion of SA paediatric experts. Recommendations are consistent with those in published international guidelines.

Association of maternal and infant inflammation with neurodevelopment in HIV-exposed uninfected children in a South African birth cohort

HIV-exposed uninfected (HEU) children may have altered immune regulation and poorer neurodevelopment outcomes compared to their HIV-unexposed (HU) counterparts. However, studies investigating the association of maternal and infant inflammation with neurodevelopment in HEU children are limited and longitudinal data are lacking. This study investigated serum inflammatory markers in women living with HIV vs. HIV-uninfected women during pregnancy and in their children, as well as associations with neurodevelopmental outcomes at two years of age in an African birth cohort study. A sub-group of mother–child dyads from the Drakenstein Child Health Study had serum inflammatory markers measured at ≈26 week’s gestation (n = 77 HIV-infected mothers; n = 190 HIV-uninfected mothers), at 6–10 weeks (n = 63 HEU infants and n = 159 HU infants) and at 24–28 months (n = 77 HEU children and n = 190 HU children). Serum inflammatory markers [granulocyte–macrophage colony-stimulating factor (GM-CSF), interferon-γ (IFN-γ), interleukin IL-1β, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12p70, IL-13, tumor necrosis factor-α (TNF-α), neutrophil gelatinase-associated lipocalin (NGAL) and metalloproteinase-9 (MMP-9)] were analyzed with a multiplex bead array and ELISA assays. The Bayley Scales of Infant and Toddler Development, third edition, was used to assess neurodevelopment at 24–28 months. After correcting for multiple comparisons, HIV infection during pregnancy was associated with lower serum levels of inflammatory markers in mothers at 26 weeks gestation (GM-CSF and MMP-9, p < 0.05) and HEU children at 6–10 weeks (IFN-γ and IL-1β, p < 0.01), and at 24–28 months (IFN-γ, IL-1β, IL-2 and IL-4, p < 0.05) compared to HIV-uninfected mothers and HU children. In HEU infants at 6–10 weeks, inflammatory markers (GM-CSF, IFN-γ, IL-10, IL-12p70, IL-1β, IL-2, IL-4, IL-6 and NGAL, all p < 0.05) were associated with poorer motor function at two years of age. This is the first study to evaluate the associations of follow-up immune markers in HEU children with neurodevelopment. These findings suggest that maternal HIV infection is associated with immune dysregulation in mothers and their children through two years of age. An altered immune system in HEU infants is associated with poorer follow-up motor neurodevelopment. These data highlight the important role of the immune system in early neurodevelopment and provide a foundation for future research.

Child HIV Exposure and CMV Seroprevalence in Botswana: No Associations With 24-Month Growth and Neurodevelopment.

BackgroundWe sought to identify predictors of child cytomegalovirus (CMV) infection overall and by maternal HIV status and to assess associations of child CMV status with growth and neurodevelopmental outcomes at 24 months of age in Botswana.MethodsData and samples were used from the Botswana-based observational Tshipidi study (2010–2014), enrolling pregnant women living with and without HIV and following their infants through 2 years of age. Child plasma samples were tested at 18 months of age for anti-CMV immunoglobulin G (IgG). Associations were assessed between detectable anti-CMV IgG and growth (using the World Health Organization Child Growth Standards) and neurodevelopment (using the Bayley Scales of Infant and Toddler Development III and the Developmental Milestones Checklist) at 24 months of age.ResultsOf 317 children, 215 (68%) had detectable anti-CMV IgG at 18 months of age. Comparatively, 83% (n = 178) of HIV-unexposed uninfected (HUU) children had positive CMV serology vs 47% (n = 139) of HIV-exposed uninfected (HEU) children (P < .01); 100% of HUU vs 10.5% of HEU children breastfed. Child CMV infection was not associated with weight-for-age, weight-for-length, or length-for-age z-scores at 24 months. In HUU children, CMV infection was associated with smaller head circumference (P < .01). No difference was observed by child CMV status in any neurodevelopmental domain at 24 months.ConclusionsWe observed high CMV seropositivity in 18-month-old children in Botswana, with higher seropositivity among breastfed (HUU) children. Positive CMV serostatus was not associated with 24-month child growth or neurodevelopmental outcomes, with the exception of smaller head circumference among HUU CMV-positive children.

Cerebrovascular Disease in Children Perinatally Infected With Human Immunodeficiency Virus in Zambia

BackgroundHigh rates of cerebrovascular disease (CVD) have previously been described in pediatric human immunodeficiency virus (HIV). However, little is known about pediatric CVD in the era of antiretroviral therapy or about the contribution of CVD to HIV-associated neurocognitive disorders. MethodsWe completed a neuroimaging substudy of the HIV-Associated Neurocognitive Disorders in Zambia study, a prospective cohort study of neurocognitive complications of pediatric HIV. Brain magnetic resonance imaging (1.5 T) was acquired for 34 HIV+ children on antiretroviral therapy and 17 HIV-exposed uninfected children (aged eight to 17 years). Demographics, medical history, neurological examination, and neuropsychologic testing results were collected. Two neuroradiologists, unaware of HIV status and clinical course, read the scans. ResultsCVD was identified in seven of 34 children with HIV (HIV+ CVD+) and no HIV-exposed uninfected children (21% vs 0%, P = 0.05). Three participants had white matter changes suggestive of small vessel disease, four had infarcts, and two had evidence of intracranial artery stenosis. Age of antiretroviral therapy initiation and exposure to protease inhibitors or efavirenz was not significantly different between children with and without CVD. HIV+ CVD+ children had significantly worse scores on a summary measure of cognition than the HIV+ CVD− group (NPZ8 score −0.57 vs 0.33, P = 0.04). ConclusionsThis study demonstrates high rates of CVD in children with HIV despite antiretroviral therapy, and worse cognitive performance in children with CVD. Longitudinal studies are necessary to determine the mechanisms and incidence of new-onset CVD in children with HIV.

Management of community-acquired pneumonia in children: South African oracic Society guidelines (part 3)

Background. Pneumococcal conjugate vaccine (PCV) administration and other advances have been associated with a shift in the aetiological spectrum of community-acquired pneumonia, necessitating reconsideration of empiric antibiotic treatment guidelines. Management strategies have also evolved in the last decade. Objectives. To produce revised guidelines for the treatment of pneumonia in South African (SA) children, including ambulatory, hospital and intensive care management. Methods. An expert subgroup, reviewing evidence on the management of childhood pneumonia, was convened as part of a broader group revising SA guidelines. Evidence was graded using the British Thoracic Society (BTS) grading system and recommendations were made. Results. Antibiotic treatment depends on the child’s age, possible aetiology, antimicrobial resistance patterns, previous treatment, as well as factors affecting host susceptibility, including HIV, and nutritional and vaccination status. All children with signs of severe pneumonia should receive antibiotics. Children 1 month of age, high-dose amoxicillin remains the preferred antibiotic. For severe pneumonia in this age group, hospitalisation and empiric treatment with amoxicillin-clavulanate orally is recommended; if oral therapy is not tolerated, intravenous therapy is recommended. Generally, 5 days of therapy is proposed, but longer duration may be needed in cases of severe or complicated disease. A macrolide antibiotic should be used if pertussis, mycoplasma or chlamydia pneumonia is suspected. Most hypoxic children can receive oxygen via nasal cannulae, but respiratory support should be individualised and extends to non-invasive and invasive ventilation in some cases. Children should be fed enterally; if this is not possible, administer intravenous isotonic fluids at <80% of maintenance, with monitoring of sodium levels. Empiric antibiotic treatment is the same in HIV-infected, HIV-exposed uninfected and HIV-uninfected children, although treatment for pneumocystis pneumonia and/or cytomegalovirus pneumonia should be considered in HIV-infected infants, especially in the absence of combination antiretroviral therapy. Conclusions. Updated guidelines optimise the management of childhood pneumonia in the context of changing epidemiology, improvements in HIV prevention and new evidence on management.

Fractures in children and adolescents living with perinatally acquired HIV.

Across numerous settings, bone mineral density for age and sex is lower in children/adolescents living with perinatally-acquired HIV (PHIV) compared to uninfected peers. We assessed incidences of any fracture/any long bone fracture, and osteoporosis prevalence in PHIV and HIV-exposed uninfected (PHEU) participants in the Pediatric HIV/AIDS Cohort Study (PHACS). Lifetime history of fracture events from birth up to age 20years was obtained by chart review and/or interview, including age at fracture, mechanism, and bone(s) fractured. Poisson regression models were fit comparing fracture incidence by HIV status adjusted for age, sex, and race, with effect modification by age (<6, ≥6yr). PHIV (N=412) were older (median 17.5 vs 16.7yr) and more frequently reported black race (72% vs 61%) than PHEU children/adolescents (N=206). 17% of PHIV and 12% of PHEU ever reported a fracture. Among children <6yr, the adjusted incidence rate ratio of ≥1 fracture was higher (7.23; 95% CI 0.98, 53.51) in PHIV than PHEU, but similar among children/adolescents ≥6years (1.20; 95% CI: 0.77, 1.87). Results were similar for long bone fracture. The most common fracture mechanisms were falling to the ground from a standing height (23.6% PHIV vs 8.8% PHEU) and sports injuries (21.3% vs 32.4%), and the most commonly fractured sites were the forearm and small bones of the wrist/hands. None of the children had osteoporosis. Among children/adolescents ≥6yr of age, fractures were similar by perinatal HIV status. Prospective, targeted collection of fracture history will be necessary to determine rates of fracture as PHIV and PHEU age into adulthood. Lifetime fracture history was collected in children/adolescents living with perinatally-acquired HIV (PHIV) and HIV-exposed uninfected (PHEU) children from birth up to age 20years. Fracture incidence was higher in PHIV compared to PHEU among children <6years old, but not among older children/adolescents.

Neurodevelopment of HIV-Exposed Uninfected Infants Born to Women With Perinatally Acquired HIV in the United States

Lifelong HIV and antiretroviral therapy may confer neurodevelopmental risk on the children of women with perinatally acquired HIV infection (PHIV). We analyzed data from HIV-exposed uninfected (HEU) infants born to women with PHIV vs. non-perinatally acquired HIV (NPHIV) enrolled in the Surveillance Monitoring for Antiretroviral Therapy Toxicities (SMARTT) study. Using the Bayley Scales of Infant and Toddler Development, third Ed. (Bayley-III), we compared neurodevelopmental outcomes at the age of 1 year in HEU infants born to women with PHIV vs. NPHIV. Those with valid Bayley-III data at the age of 1 year and a mother born after 1982 were included. Cognitive, language, and motor domains were assessed as continuous composite scores. Linear mixed effects models were fit to estimate the mean difference in Bayley-III scores between groups, adjusting for confounders. Five hundred fifty women with HIV gave birth to 678 HEU children (125 and 553 born to women with PHIV and NPHIV, respectively). Mean scores for each of the Bayley-III domains were not significantly different between infants born to women with PHIV vs. NPHIV in unadjusted models. After adjustment, infants of women with PHIV had lower language (91.9 vs. 94.8, P = 0.05) and motor (93.7 vs. 96.8, P = 0.03) composite scores, but no differences in cognitive composite scores. Cognitive domain outcomes of infants born to women with PHIV vs. NPHIV are reassuring. Differences in early language and motor functioning, while of modest clinical significance, highlight the importance of long-term monitoring of neurodevelopment in children of women with PHIV.

Immune checkpoint dysregulation and immune activation in HIV-exposed uninfected children

Abstract Children who are HIV-exposed uninfected (CHEU) are a growing population worldwide. CHEU suffer greater morbidity and mortality from infectious diseases, likely due to their impaired cell-mediated immunity (CMI) and hyper-inflammatory responses. As CMI and inflammatory responses are regulated by immune checkpoints (ICPs) that play a key role in maintaining immune homeostasis, we determined whether CHEU had altered expression of the ICP axes. We used multiplex immunoassays to quantify plasma levels of 16 soluble ICPs (sBTLA, sCD27, sCD28, sCD40, sCD80, sCTLA-4, sGITR, sGITRL, sHVEM, sICOS, sLAG-3, sLIGHT, sPD-1, sPD-L1, sTIM-3, and sTLR-2) from 46 CHEU and 37 children who are HIV-unexposed uninfected (CHUU) from AMPATH in western Kenya. We demonstrated that all ICPS except GITR were detected in all samples. Compared to CHUU, CHEU had significantly higher levels of 2 sICPs: soluble CD40 (sCD40) and soluble TIM-3 (sTIM-3). As CD40 plays an essential role in antigen-presenting cell functions, while TIM-3 is a key member of immunosuppressive ICPs that inactivate T cell activity, the dysregulated sCD40 and sTIM-3 could play a role in the impaired CMI in CHEU and can be explored as biomarkers for adverse health outcomes in CHEU. A previous study showed that the percentage of activated CD8 T cells (CD8+CD38high) was increased in Canadian CHEU. Therefore, we also studied the activation of T cells in PBMCs from Kenya and found that CHEU had higher percentages of activated CD4 (CD4+CD38+HLA-DR+) and CD8 (CD8+CD38+HLA-DR+) T cells in the peripheral blood compared to CHUU. Our study demonstrated that the ICP axes were dysregulated in CHEU, and we provided additional support to the notion that the immune system in CHEU is altered.

Psychosocial Adjustment in Ugandan Children: Coping With Human Immunodeficiency Virus Exposure, Lifetime Adversity, and Importance of Social Support.

Cumulative lifetime adversity and social support were investigated as determinants of psychosocial adjustment (esteem, distress, hopefulness, positive outlook/future aspirations, and sense of purpose) over 12 months in 6-10-years-old HIV-infected, HIV-exposed uninfected and HIV-unexposed uninfected children from Uganda. Each determinant and psychosocial adjustment indicator was self-reported using standardized questionnaires administered at baseline, 6, and 12 months. Linear mixed effects models were used to relate time-varying lifetime adversity and social support to psychosocial adjustment over 12 months. Regardless of HIV status, higher adversity predicted lower esteem (coefficient b= -2.98, 95% confidence interval (CI): [-4.62, -1.35]) and increased distress (b=3.96, 95% CI: [1.29, 6.62]) but was not associated with hopefulness, positive outlook or sense of purpose. Low social support predicted higher distress (b=9.05, 95% CI: [7.36, 10.73]), lower positive outlook (b= -10.56, 95% CI: [-2.34, -8.79]) and low sense of purpose (b= -9.90, 95% CI: [-11.44, -8.36]) over 12 months. Pragmatic interventions that enhance coping with adversity and provide emotional/instrumental support should be tested for effectiveness in promoting resilient psychosocial adjustment trajectory in vulnerable children.

Toxic Stress and Quality of Life in Early School-Aged Ugandan Children With and Without Perinatal Human Immunodeficiency Virus Infection.

Caregiver's and child's self-reported quality of life (QOL) was defined using standardized questionnaires in a sample (N = 277) of 6-10 years old HIV-infected, HIV-exposed uninfected, and HIV-unexposed uninfected children from Uganda. Psychosocial stress (acute stress and cumulative lifetime adversity) and physiologic stress (dysregulations across 13 biomarkers), perinatal HIV status, and their interaction were related to child QOL via general linear models. Lower child- and caregiver-reported psychosocial stress were dose-dependently associated with higher QOL (acute stress: mean difference coefficient b = 8.1-14.8, effect size [ES] = 0.46-0.83). Lower allostasis was dose-dependently associated with higher QOL (b = 6.1-9.7, ES = 0.34-0.54). Given low caregiver acute stress, QOL for HIV-infected was similar to HIV-uninfected children; however, given high caregiver acute stress, a QOL disadvantage (b = -7.8, 95% CI: -12.8, -2.8; ES = -0.73) was evident for HIV-infected versus uninfected children. Testing of caregiver stress reduction interventions is warranted to increase wellbeing in dependent children.

Micronutrients, Metabolic Complications, and Inflammation in Ugandan Children With HIV.

Selenium, zinc, and chromium are essential micronutrients. Their alterations have been associated with HIV disease progression, metabolic complications, and mortality. This is a cross-sectional study in children with perinatally acquired HIV (PHIV, n = 57), HIV-exposed uninfected (HEU, n = 59), and HIV-unexposed uninfected (HIV-, n = 56) children aged 2 to 10 years old, age- and sex-matched, enrolled in Uganda. PHIV were on stable antiretroviral therapy (ART) with undetectable viral load. We measured plasma concentrations of selenium, zinc, and chromium as well as markers of systemic inflammation, monocyte activation, and gut integrity. Among PHIV children, 93% had viral load ≤20 copies/mL, median CD4 was 37%, and 77% were receiving a nonnucleotide reserve transcriptase regimen. Median age of all participants was 8 years and 55% were girls. Median selenium concentrations were higher in PHIV compared with the HEU and HIV groups (P < 0.001), 46% of children overall had low zinc status (P = 0.18 between groups). Higher selenium, but not chromium or zinc, was associated with lower IL6, sTNFRI and II, and higher beta d glucan, a marker of fungal translocation, zonulin, a marker of gut permeability, oxidized LDL and insulin resistance (P ≤ 0.01). In this cohort of PHIV on ART in Uganda, there is a high prevalence of low zinc status overall. Higher plasma selenium concentrations were associated with lower systemic inflammation and higher gut integrity markers. Although our findings do not support the use of micronutrient supplementation broadly for PHIV in Uganda, further studies are warranted to assess the role of selenium supplements in attenuating heightened inflammation.

Short-term immunogenicity and safety of hepatitis-A and varicella vaccines in HIV-exposed uninfected and HIV-unexposed South African children

BackgroundHIV-exposed uninfected (HEU) children have increased risk of infectious morbidity during early childhood. We evaluated the short-term immunogenicity and safety of single dose inactivated hepatitis-A virus (HAV) vaccine and live attenuated varicella zoster virus (VZV) vaccine in South African children. Methods195 HIV-unexposed and 64 HEU children received either one dose of HAV or VZV vaccine at 18 months of age. Blood samples were tested for hepatitis-A or VZV antibodies before and one month after vaccination by chemiluminescent microparticle immunoassay and enzyme-linked immunosorbent assay, respectively. All children were evaluated for solicited adverse events (AEs). ResultsOne-month post-vaccination, a similar percentage of HIV-unexposed (91.8%) and HEU (82.9%) children were seropositive for hepatitis-A (p = 0.144). VZV antibody geometric mean fold-rise was also similar in HIV-unexposed (5.6; 95%CI: 4.6–6.7) and HEU children (5.1; 95%CI: 3.7–7.2); however, only 44% HIV-unexposed and HEU seroconverted (titers > 50 mIU/ml). AEs occurred with similar frequency and severity between groups, except for more systemic AEs after VZV vaccination in HEU than HIV-unexposed children. ConclusionsSingle dose HAV and VZV vaccine was similarly immunogenic in HIV-unexposed and HEU children. We did not identify differences in short-term humoral immunity after administration of either a live attenuated or inactivated vaccine. Seroconversion rates after a single dose of VZV vaccine were, however, lower compared to reports from previous studies (85–89%).Clinical trials registration: NCT03330171.

Response to Zhao and Zhou: Diagnosis of HIV infection in breastfed infants of mothers on antiretroviral therapy.

We thank Zhao and Zhou [1] for their thoughtful comments on our report of two infants born to women with HIV who had unusual trajectories of diagnostic tests. The two HIV-exposed infants were initially positive on nucleic acid amplification tests in the first month of life but had multiple negative tests during breastfeeding and presented with definitive evidence of HIV infection around the time of breastfeeding cessation. We hypothesize that constituents of breast milk, or processes induced by breastfeeding, most likely in combination with antiviral effects of maternal antiretroviral therapy, led to the undetectable test results that we observed in already infected infants until breastfeeding ended. We considered the alternative explanation of postnatal transmission proposed by Zhao and Zhou [1], but this explanation requires dismissing the initial positive test results on the early samples as transient infections or false-positive results. A rigorous investigation of 42 cases of suspected transient infection, failed to confirm a single one, despite the plausibility of this concept [2]. In one of the infants in our report, virus was detected in peripheral blood mononuclear cells (PBMCs) from three separate blood samples collected over the first month of life making laboratory errors an unlikely explanation. In this same case, CD4+ T cells from one of these early age time points were found to be positive for 2-LTR episomal HIV-1 DNA. Detection of 2-LTR episomal DNA in CD4+ T cells, although at low levels, provides evidence of viral replication as these episomal circles are a by-product thereof [3]. We acknowledge that early samples were not available for the second case making the alternative explanation of an initial false-positive result followed by postnatal infection a possible explanation of this second case. It should be noted that current birth testing and early treatment guidelines in South Africa would provide indefinite treatment to transient infections should they occur [4]. We would like to clarify the implications of our observations in the context of current guidance around antiretroviral use for women and their children to prevent vertical transmission of HIV. Maintenance of maternal therapeutic antiretroviral drug regimens over the full duration of breastfeeding and beyond is now considered standard of care for prevention of HIV transmission to children. This recommendation is consistent with clinical trials demonstrating exceptionally low rates of postnatal transmission if effective maternal antiretroviral drug treatment is in place [5]. Longer term infant prophylaxis is recommended only for infants whose mothers initiated treatment late and/or who are nonadherent with treatment. In both cases, maternal viral loads through the breastfeeding period were less than 1000 RNA copies/ml and in-country treatment guidelines were followed in terms of prophylactic regimens [6]. Because of concerns that infant prophylaxis may mask underlying HIV infections, some have encouraged repeat testing after prophylaxis has ended [7]. What distinguishes our cases is that the pattern of negative results was observed after discontinuation of antiretrovirals given to the infants but during continuation of maternal antiretroviral treatment and breastfeeding. Although the profile of the results that we observed is rare, we support repeat testing of HIV-exposed breastfed infants after complete cessation of all breastfeeding. The profile of HIV antibodies is of great interest, but it is unlikely that changes in standard anti-HIV IgG antibody titres over time in these infants will be helpful to resolve the timing of transmission. Infant antiretroviral prophylaxis. and on-going antiretroviral exposure via breast milk, like early treatment, may lead to undetectable antibodies [8]. The ability to detect HIV antibody would probably be at the time when these factors are no longer in place and viral levels rise and drive antibody production. Thus, a rise in antibodies, only once breastfeeding has stopped, might not necessarily mean the children were infected later. More sensitive assays differentiating antibody isotypes and antigen specificity may be more informative but will need comparison with the usual profile of antibodies in HIV-exposed uninfected children. The utility of HIV antibodies as markers of viral processes is well appreciated and this is likely to be a productive, albeit complex, line of research. Acknowledgements Conflicts of interest There are no conflicts of interest.

Caries experience and oral health related quality of life in a cohort of Ugandan HIV-1 exposed uninfected children compared with a matched cohort of HIV unexposed uninfected children

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.

A description of early neurodevelopment in a cohort of HIV-exposed uninfected children

ABSTRACT Introduction: Successful strategies preventing mother-to-child HIV transmission have resulted in increasing numbers of uninfected children exposed to maternal HIV and ART in-utero, and while breastfeeding. Some reports describe exposure as impacting neurodevelopment. Methods: This cross-sectional analysis included 49 of the 70 HIV-exposed uninfected (HEU) birth-enrolled children as the control arm of an observational cohort study of early treatment in HIV-infected infants in Johannesburg, South Africa. We used the Bayley Scales of Infant and Toddler Development-3rd Edition (BSID-III) to assess neurodevelopment at 12 months of age. Cognitive, language and motor subscale composite scores and performance categories were analysed. We evaluated associations between BSID-III performance categories and cohort variables. Results: Evaluating composite scores according to performance categories showed a higher percentage of scores in the average, high average and superior categories as compared to test reference norms. Maternal BMI ≥ 25 kg/m2 and mid-upper arm circumference ≥ 32 cm were associated with higher than average infant language scores. Six children scored below average (<90) – three in the cognitive and three in the language subscale. Conclusion: No developmental delay was found in ART-exposed HEU children at 12 months of age. A small number of at-risk children suggest ongoing screening, referral and follow-up is needed.

Maternal Diarrhea and Antibiotic Use are Associated with Increased Risk of Diarrhea among HIV-Exposed, Uninfected Infants in Kenya.

.HIV-exposed, uninfected (HEU) children are a growing population at particularly high risk of infection-related death in whom preventing diarrhea may significantly reduce under-5 morbidity and mortality in sub-Saharan Africa. A historic cohort (1999–2002) of Kenyan HEU infants followed from birth to 12 months was used. Maternal and infant morbidity were ascertained at monthly clinic visits and unscheduled sick visits. The Andersen–Gill Cox model was used to assess maternal, environmental, and infant correlates of diarrhea, moderate-to-severe diarrhea (MSD; diarrhea with dehydration, dysentery, or related hospital admission), and prolonged/persistent diarrhea (> 7 days) in infants. HIV-exposed, uninfected infants (n = 373) experienced a mean 2.09 (95% CI: 1.93, 2.25) episodes of diarrhea, 0.47 (95% CI: 0.40, 0.55) episodes of MSD, and 0.34 (95% CI: 0.29, 0.42) episodes of prolonged/persistent diarrhea in their first year. Postpartum maternal diarrhea was associated with increased risk of infant diarrhea (Hazard ratio [HR]: 2.09; 95% CI: 1.43, 3.06) and MSD (HR: 2.89; 95% CI: 1.10, 7.59). Maternal antibiotic use was a risk factor for prolonged/persistent diarrhea (HR: 1.63; 95% CI: 1.04, 2.55). Infants living in households with a pit latrine were 1.44 (95% CI: 1.19, 1.74) and 1.49 (95% CI: 1.04, 2.14) times more likely to experience diarrhea and MSD, respectively, relative to those with a flush toilet. Current exclusive breastfeeding was protective against MSD (HR: 0.30; 95% CI: 0.15, 0.58) relative to infants receiving no breast milk. Reductions in maternal diarrhea may result in substantial reductions in diarrhea morbidity among HEU children, in addition to standard diarrhea prevention interventions.

Streptococcus pneumoniae colonization in pneumococcal vaccine-naïve human immunodeficiency virus-exposed infected and -uninfected South African children.

Pneumococcal nasopharyngeal colonization is a pre-requisite for pneumococcal disease; the risk for pneumococcal disease is high in children born to women living with human immunodeficiency virus (HIV). We investigated pneumococcal colonization, serotype distribution and antibiotic susceptibility of Streptococcus pneumoniae isolates carried by perinatal HIV-infected and HIV-exposed-uninfected (HEU) children.Serial nasopharyngeal swabs were collected from 331 HIV-infected and 491 HEU children, at up to 6 scheduled timepoints, between median ages of 25 to 181 weeks. Pneumococcus was identified by culture; serotyping and antibiotic susceptibility testing were done by conventional methods. No pneumococcal vaccine was given.HIV-infected children were less likely to be colonized with 7-valent pneumococcal conjugate vaccine 7 serotypes than HEU at a median of 25 weeks of age (23% vs 36%; P < .001); however, no differences in colonization between the 2 groups were observed at subsequent study-visits. Over the 36-months study-period pneumococcal colonization increased in both HIV-infected (from 45% to 77%) and HEU (from 57% to 61%) children. Over the study-period, pneumococcal isolates non-susceptible to cotrimoxazole decreased from 92% to 57% and had a similar trend to penicillin (from 65% to 42%) in HIV-infected children. Similarly, pneumococcal nonsusceptible to cotrimoxazole decreased from 93% to 57% and to penicillin from 69% to 37% in HEU children.Vaccine serotype colonization was common in this population and similar rates were observed in HIV-infected and HEU children. The prevalence of pneumococcal isolates non-susceptible to cotrimoxazole and penicillin decreased with age.

Impact of HIV status and vaccination schedule on bacterial nasopharyngeal carriage following infant immunisation with the pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine in South Africa

BackgroundNasopharyngeal carriage (NPC) of Streptococcus pneumoniae is a precondition for pneumococcal disease and a source of transmission. This trial evaluated NPC of S. pneumoniae and other pathogens post-vaccination with the pneumococcal non-typeable Haemophilus influenzae (NTHi) protein D conjugate vaccine (PHiD-CV) in human immunodeficiency virus (HIV)-infected (HIV+), HIV-exposed-uninfected (HEU), and HIV-unexposed-uninfected (HUU) South African children. MethodsIn this phase III, open, single‐centre, controlled study (ClinicalTrials.gov: NCT00829010), 484 children were stratified by HIV status: 83 HIV+, 101 HEU, and 300 HUU. HIV+ and HEU children received a 3 + 1 PHiD-CV vaccination schedule: primary vaccination, age 6/10/14 weeks, and booster dose, age 9–10 months. HUU infants were randomised (1:1:1) to 3-dose priming and booster (HUU/3+1); 3-dose priming without booster (HUU/3+0); or 2-dose priming and booster (HUU/2+1). Bacterial NPC was assessed 8 times up to 24–27 months of age. ResultsOverall pneumococcal carriage rates were similar across 3+1 groups irrespective of HIV status; trends towards higher carriage rates in the HIV+ than HEU and HUU/3+1 groups were observed at 24–27 months of age. In HUU children, carriage of any pneumococcal serotype was similar for the three different dosing schedules at all timepoints; carriage of vaccine-type pneumococci tended to be lower at 16–19 months and 24–27 months of age in children who had received a booster dose (HUU/2+1 and HUU/3+1 groups) than in the HUU/3+0 group. Carriage rates of NTHi, Staphylococcus aureus and Moraxella catarrhalis were comparable between all groups. ConclusionsHIV infection or exposure did not seem to alter the effect of PHiD-CV on pneumococcal NPC in children during their first 2 years of life. NPC prevalence of vaccine-type pneumococci following vaccination series tended to be lower in children who had received a booster dose in comparison to those who had not.

Association of maternal HIV-1 severity with dental caries: an observational study of uninfected 5- to 7-yr-old children of HIV-1-infected mothers without severe immune suppression.

Treatment programs to prevent perinatal and postnatal HIV-1 transmission have become available in sub-Saharan Africa, leading to an emerging population of HIV-1 exposed uninfected (HEU) children. Exposure to HIV-1 in utero and during breastfeeding may increase the risk of morbidity and mortality in HEU children. This study estimated the association of the severity of maternal HIV-1 infection as assessed by CD4 count and viral load at baseline (7d postpartum), with dmft count of their 5- to 7-yr-old HEU offspring. A follow-up study was conducted of HIV-1-infected mother-HEU children pairs (n=164) from the Ugandan site of the ANRS 12341-PROMISE- PEP trial (ClinicalTrials.gov, number NCT00640263). HIV-1-infected mothers were interviewed and the HEU children were examined for caries using the World Health Organization's survey methods for field conditionsand the dmft index. Directed acyclic graphs and negative binomial regression were used for analyses. The prevalence of 1 or more dmft was 48%. Negative binomial regression showed no association between the dmft count and maternal CD4 counts 7d postpartum but a 10% lower dmft count with longer breastfeeding duration was found. Maternal CD4 count at birth was not associated with the dental caries experience in uninfected children born to women without severe immune suppression, while there appeared to be a protective effect of high viral load and breastfeeding duration.

Multiple Concurrent Illnesses Associated with Anemia in HIV-Infected and HIV-Exposed Uninfected Children Aged 6-59 Months, Hospitalized in Mozambique.

.Anemia is an increasingly recognized problem in sub-Saharan Africa. To determine the magnitude, severity, and associated factors of anemia among hospitalized children aged 6–59 months, HIV-infected and HIV-exposed uninfected children (a child born to a known HIV-infected mother) with a documented fever or history of fever within the prior 24 hours of hospital admission (N = 413) were included in this analysis. Of 413 children enrolled, 364 (88%) were anemic, with 53% classified as mild anemia (hemoglobin [Hb] 7–9.9 g/dL). The most common diagnoses associated with hospital admission included acute respiratory illness (51%), malnutrition (47%), gastroenteritis/diarrhea (25%), malaria (17%), and bacteremia (13%). A diagnosis of malaria was associated with a decrease in Hb by 1.54 g/dL (P < 0.001). In HIV-infected patients, malaria was associated with a similar decrease in Hb (1.47 g/dL), whereas a dual diagnosis of bacteremia and malaria was associated with a decrease in Hb of 4.12 g/dL (P < 0.001). No difference was seen in Hb for patients on antiretroviral therapy versus those who were not. A diagnosis of bacteremia had a roughly 4-fold increased relative odds of death during hospitalization (adjusted odds ratio = 3.97; 95% CI: 1.61, 9.78; P = 0.003). The etiology of anemia in high-burden malaria, HIV, tuberculosis, and poor nutrition countries is multifactorial, and multiple etiologies may be contributing to one’s anemia at any given time. Algorithms used by physician and nonphysician clinicians in Mozambique should incorporate integrated and non–disease specific approaches to pediatric anemia management and should include improved access to blood culture.