Standardized Definitions of In Utero Human Immunodeficiency Virus and Antiretroviral Drug Exposure Among Children.

In countries with high human immunodeficiency virus (HIV) prevalence, up to 30% of pregnant women are living with HIV, with fetal exposure to both HIV and antiretroviral therapy during pregnancy. In addition, pregnant women without HIV but at high risk of HIV acquisition are increasingly receiving HIV preexposure antiretroviral prophylaxis (PrEP). Investments are being made to establish and follow cohorts of children to evaluate the long-term effects of in utero HIV and antiretroviral exposure. Agreement on a key set of definitions for relevant exposures and outcomes is important both for interpreting individual study results and for comparisons across cohorts. Harmonized definitions of in utero HIV and antiretroviral drug (maternal treatment or PrEP) exposure will also facilitate improved classification of these exposures in future observational studies and clinical trials. The proposed definitions offer a uniform approach to facilitate the consistent description and estimation of effects of HIV and antiretroviral exposures on key child health outcomes.

Innate Immune Responses and Gut Microbiomes Distinguish HIV-Exposed from HIV-Unexposed Children in a Population-Specific Manner.

In both high- and low-income countries, HIV-negative children born to HIV-positive mothers (HIV exposed, uninfected [HEU]) are more susceptible to severe infection than HIV-unexposed, uninfected (HUU) children, with altered innate immunity hypothesized to be a cause. Both the gut microbiome and systemic innate immunity differ across biogeographically distinct settings, and the two are known to influence each other. And although the gut microbiome is influenced by HIV infection and may contribute to altered immunity, the biogeography of immune-microbiome correlations among HEU children have not been investigated. To address this, we compared the innate response and the stool microbiome of 2-y-old HEU and HUU children from Belgium, Canada, and South Africa to test the hypothesis that region-specific immune alterations directly correlate to differences in their stool microbiomes. We did not detect a universal immune or microbiome signature underlying differences between HEU versus HUU that was applicable to all children. But as hypothesized, population-specific differences in stool microbiomes were readily detected and included reduced abundances of short-chain fatty acid-producing bacteria in Canadian HEU children. Furthermore, we did not identify innate immune-microbiome associations that distinguished HEU from HUU children in any population. These findings suggest that maternal HIV infection is independently associated with differences in both innate immunity and the stool microbiome in a biogeographical population-specific way.

Growth patterns of infants with in- utero HIV and ARV exposure in Cape Town, South Africa and Lusaka, Zambia.

BACKGROUND: Infants born HIV-exposed yet remain uninfected (HEU) are at increased risk of poorer growth and health compared to infants born HIV-unexposed (HU). Whether maternal antiretroviral treatment (ART) in pregnancy ameliorates this risk of poorer growth is not well understood. Furthermore, whether risks are similar across high burden HIV settings has not been extensively explored. METHODS: We harmonized data from two prospective observational studies conducted in Cape Town, South Africa, and Lusaka, Zambia, to compare weight-for-age (WAZ), length-for-age (LAZ) and weight-for-length (WLZ) Z-scores between infants who were HEU and HU, converting infant anthropometric measures using World Health Organisation Growth Standards adjusted for age and sex. Linear mixed effects models were fit to identify risk factors for differences in anthropometrics at 6-10 weeks and 6 months by infant HIV exposures status and by timing of exposure to maternal ART, either from conception or later in gestation. RESULTS: Overall 773 mother-infant pairs were included across two countries: women living with HIV (WLHIV), 51% (n = 395) with 65% on ART at conception and 35% initiating treatment in pregnancy. In linear mixed effects models, WAZ and WLZ at 6-10 weeks were lower among infants who were HEU vs HU [ß = - 0.29 (95% CI: - 0.46, - 0.12) and [ß = - 0.42 (95% CI: - 0.68, - 0.16)] respectively after adjusting for maternal characteristics and infant feeding with a random intercept for country. At 6 months, LAZ was lower [ß = - 0.28 CI: - 0.50, - 0.06)] among infants who were HEU, adjusting for the same variables, with no differences in WAZ and WLZ. Within cohort evaluations identified different results with higher LAZ among infants who were HEU from Zambia at 6-10 weeks, [ß = + 0.34 CI: + 0.01, + 0.68)] and lower LAZ among infants who were HEU from South Africa [ß = - 0.30 CI: - 0.59, - 0.01)] at 6 months, without other anthropometric differences at either site. CONCLUSION: Infant growth trajectories differed by country, highlighting the importance of studying contextual influences on outcomes of infants who were HEU.

Severe acute malnutrition outcomes for children of South African compared to foreign-born parents admitted to a rural regional hospital in South Africa: a retrospective cohort study.

BACKGROUND: Children of foreign-born parents with vulnerable legal status, limited economic rights and exclusion from national social interventions may be at higher risk for severe acute malnutrition (SAM). We evaluated the relationship between parent status (foreign-born vs. South African) and outcomes for children with SAM admitted to a rural regional hospital in the Western Cape, South Africa. METHODS: A retrospective cohort study was conducted including children <5 years admitted to Worcester Provincial Hospital during 2015-17 with SAM (WHO weight-for-height Z score <-3, presence of nutritional oedema, mid-upper-arm-circumference of <11.5 cm or visible severe wasting). Exposures, including parent status, and outcomes including in-hospital death were determined from hospital and regional dietician records. RESULTS: Of 95 children included, 31 (33%) were of foreign-born and 64 (67%) of South African parents. Median (interquartile range) age at admission was 12 (8-18) vs. 10 (8-13) months in children of South African vs. foreign-born parents with no difference in preterm birth, concurrent illnesses or admission duration. Age, HIV status and breastfeeding practices were no different in foreign-born compared to South African mothers. In-hospital deaths occurred in 3/64 (5%) and 6/31 (19%) children of South African vs. foreign-born parents (p = 0.01). Children of foreign-born compared to South African parents had an odds ratio of 4.88 (95% CI 1.13-21.06) for in-hospital SAM-associated mortality. CONCLUSION: In this rural setting, 33% of children admitted with SAM were of foreign-born parents and experienced in-hospital SAM-associated mortality at least four times higher than children of South African parents. This illustrates the extreme vulnerability of these children.

In some contexts children of foreign-born parents may experience vulnerable legal status putting them at higher risk for food insecurity and severe malnutrition in their early years of life, compared to children of native-born parents. In a rural region of the Western Cape of South Africa, we observed that children of foreign-born parents were four times more likely to die of malnutrition than children of South African parents. This was so even though these children did not display other expected risk factors for malnutrition such as being born preterm, not breastfeeding or being HIV-exposed. To achieve the Sustainable Developmental Goals, policy makers and healthcare systems will need to cater for all children in the country, including asylum seekers and children of foreign-born parents. The South African Constitution and Refugee Act are in support of this. However, the findings of this study illustrate the extent of vulnerability of children living in South Africa born to foreign-born parents and calls for an evaluation of the services made available to support their health and well-being.

Lower birth weight-for-age and length-for-age z-scores in infants with in-utero HIV and ART exposure: a prospective study in Cape Town, South Africa.

BACKGROUND: Successful scale-up of antiretroviral therapy (ART) during pregnancy has minimized infant HIV acquisition, and over 1 million infants are born HIV-exposed but uninfected (HEU), with an increasing proportion also exposed in utero to maternal ART. While benefits of ART in pregnancy outweigh risks, some studies have reported associations between in utero ART exposure and impaired fetal growth, highlighting the need to identify the safest ART regimens for use in pregnancy. METHODS: We compared birth anthropometrics of infants who were HEU with those HIV-unexposed (HU) in Cape Town, South Africa. Pregnant women had gestational age assessed by ultrasound at enrolment. Women living with HIV were on ART (predominately tenofovir-emtricitabine-efavirenz) either prior to conception or initiated during pregnancy. Birth weights and lengths were converted to weight-for-age (WAZ) and length-for-age (LAZ) z-scores using Intergrowth-21st software. Linear regression was used to compare mean z-scores adjusting for maternal and pregnancy characteristics. RESULTS: Among 888 infants, 49% (n = 431) were HEU and 51% (n = 457) HU. Of 431 HEU infants, 62% (n = 268) were exposed to HIV and antiretrovirals (ARVs) from conception and 38% (n = 163) were exposed to ARVs during gestation but after conception (median fetal ARV exposure of 21 weeks [IQR; 17-26]). In univariable analysis, infants who were HEU had lower mean WAZ compared with HU [ß = - 0.15 (95% Confidence Interval (CI): - 0.28, - 0.020)]. After adjustment for maternal age, gravidity, alcohol use, marital and employment status the effect remained [adjusted ß - 0.14 (95%CI: - 0.28, - 0.01]. Similar differences were noted for mean LAZ in univariable [ß - 0.20 (95%CI: - 0.42, - 0.01] but not multivariable analyses [adjusted ß - 0.18 (95%CI: - 0.41, + 0.04] after adjusting for the same variables. Mean WAZ and LAZ did not vary by in utero ARV exposure duration among infants who were HEU. CONCLUSION: In a cohort with high prevalence of ART exposure in pregnancy, infants who were HEU had lower birth WAZ compared with those HU. Studies designed to identify the mechanisms and clinical significance of these disparities, and to establish the safest ART for use in pregnancy are urgently needed.

Population-level Mortality Associated with HIV Exposure in HIV-uninfected Infants in Botswana and South Africa: A Model-based Evaluation.

We aimed to quantify the contribution of excess mortality in HIV-exposed uninfected (HEU) infants to total mortality in HIV-uninfected infants in Botswana and South Africa in 2013. Population attributable fractions (PAFs) and excess infant deaths associated with HIV exposure in HIV-uninfected infants were estimated. Additionally, the Thembisa South African demographic model estimated the proportion of all infant mortality associated with excess mortality in HEU infants from 1990 to 2013. The PAF (lower bound; upper bound) of mortality associated with HIV exposure in HIV-uninfected infants was 16.8% (2.5; 31.2) in Botswana and 15.1% (2.2; 28.2) in South Africa. Excess infant deaths (lower bound; upper bound) associated with HIV exposure in 2013 were estimated to be 5.6 (0.5; 16.6)/1000 and 4.9 (0.6; 11.2)/1000 HIV-uninfected infants in Botswana and South Africa, respectively. In South Africa, the proportion of all infant (HIV-infected and HIV-uninfected) mortality associated with excess HEU infant mortality increased from 0.4% in 1990 to 13.8% in 2013.

Factors Associated with Severe Dehydrating Diarrhoea in the Rural Western Cape, South Africa.

Background: Acute diarrhoea (AD) remains a leading cause of childhood death. We evaluated whether delayed healthcare seeking was associated with severe dehydration in rural South Africa. Methods: In a prospective cohort study of children with AD admitted to a secondary-level hospital, data were collected through structured caregiver interviews and hospital record review. The primary outcome was severe dehydration/death, and the primary determinant was delay >12 h between AD symptom onset and healthcare facility presentation. Results: Total 68% (71 of 104) of children experienced a delay, and 51% (54 of 104) had severe dehydration with no in-hospital deaths. There was no difference in children with (35 of 71) or without (19 of 33) delay for severe dehydration. Mothers of children with severe dehydration tended to be younger [median (interquartile range) 24 (21-28) vs. 27 (23-30) years, p = 0.07] and used less oral rehydration solution (63 vs. 80%, p = 0.08). Conclusion: Delay of >12 h in seeking healthcare for AD was not associated with severe dehydration.

The epidemiology of adolescents living with perinatally acquired HIV: A cross-region global cohort analysis.

BACKGROUND: Globally, the population of adolescents living with perinatally acquired HIV (APHs) continues to expand. In this study, we pooled data from observational pediatric HIV cohorts and cohort networks, allowing comparisons of adolescents with perinatally acquired HIV in "real-life" settings across multiple regions. We describe the geographic and temporal characteristics and mortality outcomes of APHs across multiple regions, including South America and the Caribbean, North America, Europe, sub-Saharan Africa, and South and Southeast Asia. METHODS AND FINDINGS: Through the Collaborative Initiative for Paediatric HIV Education and Research (CIPHER), individual retrospective longitudinal data from 12 cohort networks were pooled. All children infected with HIV who entered care before age 10 years, were not known to have horizontally acquired HIV, and were followed up beyond age 10 years were included in this analysis conducted from May 2016 to January 2017. Our primary analysis describes patient and treatment characteristics of APHs at key time points, including first HIV-associated clinic visit, antiretroviral therapy (ART) start, age 10 years, and last visit, and compares these characteristics by geographic region, country income group (CIG), and birth period. Our secondary analysis describes mortality, transfer out, and lost to follow-up (LTFU) as outcomes at age 15 years, using competing risk analysis. Among the 38,187 APHs included, 51% were female, 79% were from sub-Saharan Africa and 65% lived in low-income countries. APHs from 51 countries were included (Europe: 14 countries and 3,054 APHs; North America: 1 country and 1,032 APHs; South America and the Caribbean: 4 countries and 903 APHs; South and Southeast Asia: 7 countries and 2,902 APHs; sub-Saharan Africa, 25 countries and 30,296 APHs). Observation started as early as 1982 in Europe and 1996 in sub-Saharan Africa, and continued until at least 2014 in all regions. The median (interquartile range [IQR]) duration of adolescent follow-up was 3.1 (1.5-5.2) years for the total cohort and 6.4 (3.6-8.0) years in Europe, 3.7 (2.0-5.4) years in North America, 2.5 (1.2-4.4) years in South and Southeast Asia, 5.0 (2.7-7.5) years in South America and the Caribbean, and 2.1 (0.9-3.8) years in sub-Saharan Africa. Median (IQR) age at first visit differed substantially by region, ranging from 0.7 (0.3-2.1) years in North America to 7.1 (5.3-8.6) years in sub-Saharan Africa. The median age at ART start varied from 0.9 (0.4-2.6) years in North America to 7.9 (6.0-9.3) years in sub-Saharan Africa. The cumulative incidence estimates (95% confidence interval [CI]) at age 15 years for mortality, transfers out, and LTFU for all APHs were 2.6% (2.4%-2.8%), 15.6% (15.1%-16.0%), and 11.3% (10.9%-11.8%), respectively. Mortality was lowest in Europe (0.8% [0.5%-1.1%]) and highest in South America and the Caribbean (4.4% [3.1%-6.1%]). However, LTFU was lowest in South America and the Caribbean (4.8% [3.4%-6.7%]) and highest in sub-Saharan Africa (13.2% [12.6%-13.7%]). Study limitations include the high LTFU rate in sub-Saharan Africa, which could have affected the comparison of mortality across regions; inclusion of data only for APHs receiving ART from some countries; and unavailability of data from high-burden countries such as Nigeria. CONCLUSION: To our knowledge, our study represents the largest multiregional epidemiological analysis of APHs. Despite probable under-ascertained mortality, mortality in APHs remains substantially higher in sub-Saharan Africa, South and Southeast Asia, and South America and the Caribbean than in Europe. Collaborations such as CIPHER enable us to monitor current global temporal trends in outcomes over time to inform appropriate policy responses.

Neurodevelopmental outcome of HIV-exposed but uninfected infants in the Mother and Infants Health Study, Cape Town, South Africa.

OBJECTIVES: To compare neurodevelopmental outcomes of HIV-exposed uninfected (HEU) and HIV-unexposed uninfected (HUU) infants in a peri-urban South African population. HEU infants living in Africa face unique biological and environmental risks, but uncertainty remains regarding their neurodevelopmental outcome. This is partly due to lack of well-matched HUU comparison groups needed to adjust for confounding factors. METHODS: This was a prospective cohort study of infants enrolled at birth from a low-risk midwife obstetric facility. At 12 months of age, HEU and HUU infant growth and neurodevelopmental outcomes were compared. Growth was evaluated as WHO weight-for-age, length-for-age, weight-for-length and head-circumference-for-age Z-scores. Neurodevelopmental outcomes were evaluated using the Bayley scales of Infant Development III (BSID) and Alarm Distress Baby Scale (ADBB). RESULTS: Fifty-eight HEU and 38 HUU infants were evaluated at 11-14 months of age. Performance on the BSID did not differ in any of the domains between HEU and HUU infants. The cognitive, language and motor scores were within the average range (US standardised norms). Seven (12%) HEU and 1 (2.6%) HUU infant showed social withdrawal on the ADBB (P = 0.10), while 15 (26%) HEU and 4 (11%) HUU infants showed decreased vocalisation (P = 0.06). There were no growth differences. Three HEU and one HUU infant had minor neurological signs, while eight HEU and two HUU infants had macrocephaly. CONCLUSIONS: Although findings on the early neurodevelopmental outcome of HEU infants are reassuring, minor differences in vocalisation and on neurological examination indicate a need for reassessment at a later age.

Unknown Antenatal HIV-Infection Status Has Declined Over Time in British Columbia, Canada.

OBJECTIVES: The objective was to determine whether the proportion of pregnant women with unknown antenatal HIV-infection status is declining over time in British Columbia (BC) and whether associated factors are amenable to intervention. METHODS: Through a retrospective cohort study of all deliveries in the British Columbia Perinatal Data Registry from 2005 to 2011, we examined the association between year of delivery and no recorded antenatal HIV test result. The trend in unknown antenatal HIV-infection status over time was evaluated by the Cochran-Mantel-Haenzsel test and multivariable logistic regression was used to determine the odds of unknown antenatal HIV-infection status by year of delivery. RESULTS: A total of 299 771 deliveries were included; 9.1% had unknown antenatal HIV-infection status with a declining trend from 12.7% to 5.5% from 2005 to 2011 (P <0.0001). Adjusted for maternal age, parity, gestation, and number of antenatal visits, pregnant women were 64% less likely to not have antenatal HIV testing in 2011 compared to 2005 (adjusted odds ratio [aOR] 0.36; 95% CI 0.34-0.38). The odds of no antenatal HIV testing were 54% higher in multiparous compared to primiparous women (aOR 1.54; 95% CI 1.49-1.58), and each additional antenatal visit reduced the odds of no antenatal HIV testing by 8% (aOR 0.92; 95% CI 0.92-0.93). CONCLUSION: The declining trend in unknown antenatal HIV-infection status in BC is encouraging. Consistent with Canadian and BC HIV testing guidelines, further strengthening of routine testing at the first antenatal visit in all pregnancies irrespective of previous HIV testing, particularly in multiparous women, could achieve universal pregnancy HIV testing in BC.

Maternal and birth outcomes in pregnant people with and without HIV in the Western Cape, South Africa.

INTRODUCTION: We evaluated associations of HIV and antiretroviral therapy (ART) with birth and maternal outcomes at a province-wide-level in the Western Cape, South Africa, in a recent cohort before dolutegravir-based first-line ART implementation. METHODS: This retrospective cohort study included pregnant people delivering in 2018-2019 with data in the Western Cape Provincial Health Data Centre which integrates individual-level data on all public sector patients from multiple electronic platforms using unique identifiers. Adverse birth outcomes (stillbirth, low birth weight (LBW), very LBW (VLBW)) and maternal outcomes (early and late pregnancy-related deaths, early and late hospitalizations) were compared by HIV/ART status and adjusted prevalence ratios (aPRs) calculated using log-binomial regression. RESULTS: Overall 171,960 pregnant people and their singleton newborns were included, 19% (N = 32 015) identified with HIV. Amongst pregnant people with HIV (PPHIV), 60% (N = 19 157) were on ART preconception, 29% (N = 9276) initiated ART during pregnancy and 11% (N = 3582) had no ART. Adjusted for maternal age, multiparity, hypertensive disorders and residential district, stillbirths were higher only for PPHIV not on ART [aPR 1.31 (95%CI 1.04-1.66)] compared to those without HIV. However, LBW and VLBW were higher among all PPHIV, with aPRs of 1.11-1.22 for LBW and 1.14-1.54 for VLBW. Pregnancy-initiated ART was associated with early pregnancy-related death (aPR 3.21; 95%CI 1.55-6.65), and HIV with or without ART was associated with late pregnancy-related death (aPRs 7.89-9.01). CONCLUSIONS: Even in the universal ART era, PPHIV experienced higher rates of LBW and VLBW newborns, and higher late pregnancy-related death regardless of ART status than pregnant people without HIV.

Adverse birth outcome case definitions associated with maternal HIV and antiretroviral drug use in pregnancy: a scoping review protocol.

INTRODUCTION: The global antiretroviral therapy era has led to a decline in the number of children newly acquiring HIV and an increase in the number of children who are HIV-exposed and uninfected (HEU). This shift has prompted extensive research focussing on health and survival outcomes of children who are HEU. Study findings, particularly in relation to adverse birth outcomes, have been disparate, inconclusive and have not always been generalisable. Thus, the objectives of this scoping review are (1) to identify and extract definitions used for the adverse birth outcome terms 'low birth weight', 'small for gestational age', 'stillbirth' and 'preterm birth'; (2) to compare the characteristics of studies from which birth outcome definitions were extracted by (a) temporal periods and (b) study country setting (high-income vs low-income and middle-income countries); (3) to use content analysis to map and describe the temporal and geographic distribution of the definitions used and construct a logical model of their evolution. METHODS AND ANALYSIS: The online databases of PubMed/MEDLINE, Scopus, Web of Science, Cochrane Library and CINHAL/EBSCOhost will be used to identify published and grey literature from 2011 to 2022 to identify definitions for the adverse birth outcome terms 'low birth weight', 'small for gestational age', 'stillbirth' and 'preterm birth'. A three-step process of (1) duplicate removal, (2) title and abstract screening and (3) full text screening will be used to select included studies. The extracted data will be used to conduct a comparative analysis, content analysis and construct a logic model. ETHICS AND DISSEMINATION: This review will be used to inform a consensus process around the development of harmonised definitions for the specified adverse birth outcomes. Our dissemination plan includes presentations, publications as well as the development infographics and a resource hub. The study is approved by the Human Research Ethics Committee of Stellenbosch University.

Hypertensive disorders of pregnancy and HIV: analysis of a province-wide cohort during 2018 and 2019.

OBJECTIVE: We evaluated the prevalence of de novo hypertensive disorders of pregnancy (dnHDP) in pregnant people with HIV (PPHIV) in the Western Cape Province, South Africa in 2018-2019 by HIV and antiretroviral therapy (ART) status. METHODS: All people with a pregnancy outcome from 1 January 2018 to 31 December 2019 in the Western Cape Provincial Health Data Centre (WCPHDC) were included. The WCPHDC integrates data from multiple electronic platforms according to unique identifiers. dnHDP was classified by ICD-10 code or first-time prescription of antihypertensive drugs less than 140 days before delivery. Pregnant people with preexisting hypertension without superimposed preeclampsia/eclampsia were not considered to have dnHDP. Adjusted prevalence ratios (aPR) for dnHDP by HIV/ART status were calculated using Poisson regression with robust variance. RESULTS: Among 180 553 pregnant people studied, 13 677 (7.6%) had dnHDP and 33 978 (18.8%) were PPHIV. Among PPHIV, 11.3% ( N  = 3827) had no evidence of ART, 59.7% ( N  = 20 283) initiated ART preconception and 29.0% ( N  = 9868) had ART initiated during pregnancy. Compared to those without HIV (7.7%), dnHDP prevalence was lower in PPHIV with preconception [6.9%; aPR 0.78; 95% confidence interval (CI) 0.74-0.83] or pregnancy-initiated ART (7.0%; aPR 0.83; 95% CI 0.75-0.92) and higher in PPHIV without ART (9.8%; aPR 1.17; 95% CI 1.06-1.29) adjusted for maternal age, multiparity, multigestation pregnancy and preexisting hypertension. ART duration by delivery of at least 100 weeks versus pregnancy-initiated ART of 20-<40 weeks was protective (aPR 0.88; 95% CI 0.78-0.98). CONCLUSIONS: In the context of universal ART, these findings are reassuring for most PPHIV. ART was not associated with increased dnHDP prevalence and longer ART duration was protective.

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

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

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

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

Feasibility Study of a Powder-Based Supplement Intervention for a future Synbiotic Trial in Breastfed Children from South Africa.

Background: Children who are HIV-exposed uninfected (HEU), i.e., born to mothers living with HIV despite not acquiring HIV infection themselves, have increased morbidity and mortality. Data suggests that the breastmilk profile, and more specifically human milk oligosaccharide (HMO) composition, differ by maternal HIV status and may partly help explain this increased risk. We are currently conducting an HMO-based synbiotic randomized trial in breastfed children HEU, the MIGH-T MO study (ClinicalTrials.gov Identifier: NCT05282485), to assess the impact on health outcomes of children HEU. Here, we report our experience from a study of the feasibility and acceptability of a powder-based intervention given to breastfeeding children, conducted prior to the initiation of MIGH-T MO. Methods: 10 mothers living with HIV and their breastfeeding children HEU accessing care at Tygerberg Hospital, in Cape Town, South Africa were enrolled. A powder-based product, potato maltodextrin, was mixed with expressed breast milk and administered to the infants daily for 4 weeks. Data on feasibility, acceptability, adherence, and health outcomes were assessed at the enrollment visit and at the 4 week visit, along with weekly telephone calls. Results: 10 mother-infant pairs were enrolled in this study, with infant age ranging from 6-20 months of age. Among the mothers who met the eligibility criteria, all of them enrolled into the study suggesting high acceptability. While there was some Ioss-to-follow-up after the first visit, among the mothers who remained, there were no major feasibility concerns related to study procedures, product administration, adherence, tolerance, and health outcome assessment. Conclusion: Our pilot study demonstrated that a powder-based intervention for breastfeeding children HEU in South Africa is acceptable and feasible. This suggests potential feasibility and acceptability for other larger studies, including our ongoing MIGH-T MO study, that use similar powder-based interventions such as probiotics, prebiotics, or synbiotics, in breastfed infants from similar settings.

Preferences for onward health data use in the electronic age among maternity patients and providers in South Africa: a qualitative study.

Despite the expanding digitisation of individual health data, informed consent for the collection and use of health data is seldom explicitly sought in public sector clinics in South Africa. This study aims to identify perceptions of informed consent practices for health data capture, access, and use in Gauteng and the Western Cape provinces of South Africa. Data collection from September to December 2021 included in-depth interviews with healthcare providers (n = 12) and women (n = 62) attending maternity services. Study findings suggest that most patients were not aware that their data were being used for purposes beyond the individualised provision of medical care. Understanding the concept of anonymised use of electronic health data was at times challenging for patients who understood their data in the limited context of paper-based folders and booklets. When asked about preferences for electronic data, patients overwhelmingly were in favour of digitisation. They viewed electronic access to their health data as facilitating rapid and continuous access to health information. Patients were additionally asked about preferences, including delivery of health information, onward health data use, and recontacting. Understanding of these use cases varied and was often challenging to convey to participants who understood their health data in the context of information inputted into their paper folders. Future systems need to be established to collect informed consent for onward health data use. In light of perceived ties to the care received, these systems need to ensure that patient preferences do not impede the content nor quality of care received.