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: 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., INTRODUCTION Vertical transmission of HIV has declined enormously over recent years due to the widespread scale‐up of antiretroviral therapy (ART) among pregnant and breastfeeding women. However, despite this marked progress, [...]

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. [ABSTRACT FROM AUTHOR]

Introduction: Studies have reported a higher risk of suboptimal neurodevelopment among children who are HIV‐exposed uninfected (HEU) compared to children HIV‐unexposed uninfected (HUU). Actual academic performance among school‐aged children by HIV exposure status has not been studied. Methods: Academic performance in Mathematics, Science, English, Setswana and overall among children enrolled in the Botswana‐based FLOURISH study who were attending public primary school and ranging in age from 7.1 to 14.6 years were compared by HIV exposure status using a Cochran‐Mantel‐Haenszel test. Lower academic performance was defined as a grade of "C" or lower (≤60%). Unadjusted and adjusted logistic regression models were fit to assess for an association between HIV exposure and lower academic performance. Results: Between April 2021 and December 2022, 398 children attending public primary school enrolled in the FLOURSH study, 307 (77%) were HEU. Median age was 9.4 years (IQR 8.9–10.2). Only 17.9% of children HEU were breastfeed versus 100% of children HUU. Among children HEU, 80.3% had foetal exposure to three‐drug antiretroviral treatment, 18.7% to zidovudine only and 1.0% had no antiretroviral exposure. Caregivers of children HEU were older compared to caregivers of children HUU (median 42 vs. 36 years) and more likely to have no or primary education only (15.0% vs. 1.1%). In unadjusted analyses, children HEU were more likely to have lower overall academic performance compared to their children HUU (odds ratio [OR]: 1.96 [95% confidence interval (CI): 1.16, 3.30]), and lower performance in Mathematics, Science and English. The association was attenuated after adjustment for maternal education, caregiver income, breastfeeding, low birth weight and child sex (aOR: 1.86 [95% CI: 0.78, 4.43]). Conclusions: In this Botswana‐based cohort, primary school academic performance was lower among children HEU compared to children HUU. Biological and socio‐demographic factors, including child sex, appear to contribute to this difference. Further research is needed to identify modifiable contributors, develop screening tools to identify the risk of poor academic performance and design interventions to mitigate risk. [ABSTRACT FROM AUTHOR]

Abstract Introduction: With increasing survival of vertically HIV-infected children and ongoing new horizontal HIV infections, the population of adolescents (age 10-19 years) living with HIV is increasing. This review aims [...]

Keywords: HIV pre-exposure prophylaxis; pregnancy; prevention; children; women; infant; Africa, Pregnant and breastfeeding women in high HIV-incidence settings are at great risk for HIV-acquisition and stand to benefit tremendously from HIV pre-exposure prophylaxis (PrEP) scale-up [1]. The PrEP Implementation in [...]

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. [ABSTRACT FROM AUTHOR]

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., Author(s): The Collaborative Initiative for Paediatric HIV Education and Research (CIPHER) Global Cohort Collaboration, Amy L. Slogrove 1, Michael Schomaker 1, Mary-Ann Davies 1, Paige Williams 2, Suna Balkan 3, [...]

: Introduction: Eighty percent of adolescents living with perinatally and behaviourally acquired HIV live in sub‐Saharan Africa (SSA), a continent with marked economic inequality. As part of our global project describing adolescents living with perinatally acquired HIV (APH), we aimed to assess whether inequality in outcomes exists by country income group (CIG) for APH within SSA. Methods: Through the CIPHER cohort collaboration, individual retrospective data from 7 networks and 25 countries in SSA were included. APH were included if they entered care at age 10 years. World Bank CIG classification for median year of first visit was used. Cumulative incidence of mortality, transfer‐out and loss‐to‐follow‐up was calculated by competing risks analysis. Mortality was compared across CIG by Cox proportional hazards models. Results: A total of 30,296 APH were included; 50.9% were female and 75.7% were resident in low‐income countries (LIC). Median [interquartile range (IQR)] age at antiretroviral therapy (ART) start was 8.1 [6.3; 9.5], 7.8 [6.2; 9.3] and 7.3 [5.2; 8.9] years in LIC, lower‐middle income countries (LMIC) and upper‐middle income countries (UMIC) respectively. Median age at last follow‐up was 12.1 [10.9; 13.8] years, with no difference between CIG. Cumulative incidence (95% CI) for mortality between age 10 and 15 years was lowest in UMIC (1.1% (0.8; 1.4)) compared to LIC (3.5% (3.1; 3.8)) and LMIC (3.9% (2.7; 5.4)). Loss‐to‐follow‐up was highest in UMIC (14.0% (12.9; 15.3)) compared to LIC (13.1% (12.4; 13.8)) and LMIC (8.3% (6.3; 10.6)). Adjusted mortality hazard ratios (95% CI) for APH in LIC and LMIC in reference to UMIC were 2.50 (1.85; 3.37) and 2.96 (1.90; 4.61) respectively, with little difference when restricted only to APH who ever received ART. In adjusted analyses mortality was similar for male and female APH. Conclusions: Results highlight probable inequality in mortality according to CIG in SSA even when ART was received. These findings highlight that without attention towards SDG 10 (to reduce inequality within and among countries), progress towards ensuring healthy lives and promoting wellbeing for all at all ages (SDG 3) will be hampered for APH in LIC and LMIC., Introduction Sub‐Saharan Africa (SSA) is a complex region marked by diversity and inequality. Across the continent gross national income per capita varies almost thirty fold from 160/1000. Sub‐Saharan Africa is [...]

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. [ABSTRACT FROM AUTHOR]

After witnessing an episode of poor injection safety in large numbers of children in a rural under‐resourced hospital in Uganda, we briefly review our own experience and that of others in investigating HIV infection in children considered unlikely to be through commonly identified routes such as vertical transmission, sexual abuse or blood transfusion. In the majority of cases, parents are HIV uninfected. The cumulative experience suggests that the problem is real, but with relatively low frequency. Vertical transmission is the major route for HIV to children. However, factors such as poor injection safety, undocumented surrogate breast feeding, an HIV‐infected adult feeding premasticated food to a weaning toddler, poor hygienic practice in the home and using unsterilised equipment for minor surgical or traditional procedures are of cumulative concern., Introduction Mother to child transmssion (MTCT) of HIV occurs in utero, intra‐partum or later via breast milk and is the most important route for HIV infection in children. Major strides [...]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

As a response to the human immunodeficiency virus (HIV) epidemic and part of ­Canadian Institutes for Health Research’s mandate to support international health research capacity building, the Canadian Institutes for Health Research Canadian HIV Trial Network (CTN) developed an international postdoctoral fellowship award under the CTN’s Postdoctoral Fellowship Awards Program to support and train young HIV researchers in resource-limited settings. Since 2010, the fellowship has been awarded to eight fellows in Cameroon, China, Lesotho, South Africa, Uganda and Zambia. These fellows have conducted research on a wide variety of topics and have built a strong network of collaboration and scientific productivity, with 40 peer-reviewed publications produced by six fellows during their fellowships. They delivered two workshops at international conferences and have continued to secure funding for their research, using the fellowship as a stepping stone. The CTN has been successful in building local HIV research capacity and forming a strong network of like-minded junior low- and middle-income country researchers with high levels of research productivity. They have developed into mentors, supervisors and faculty members, who, in turn, build local capacity. The sustainability of this international fellowship award relies on the recognition of its strengths and the involvement of other stakeholders for additional resources. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Group B Streptococcus (GBS) is a major cause of neonatal sepsis and mortality worldwide. Studies from both developed and developing countries have shown that HIV-exposed but uninfected (HEU) infants are at increased risk of infectious morbidity, as compared to HIV-unexposed uninfected infants (HUU). A higher susceptibility to GBS infections has been reported in HEU infants, particularly late-onset diseases and more severe manifestations of GBS diseases. We review here the possible explanations for increased susceptibility to GBS infection. Maternal GBS colonization during pregnancy is a major risk factor for early-onset GBS invasive disease, but colonization rates are not higher in HIV-infected compared to HIV-uninfected pregnant women, while selective colonization with more virulent strains in HIV-infected women is suggested in some studies. Lower serotype-specific GBS maternal antibody transfer and quantitative and qualitative defects of innate immune responses in HEU infants may play a role in the increased risk of GBS invasive disease. The impact of maternal antiretroviral treatment and its consequences on immune activation in HEU newborns are important to study. Maternal immunization presents a promising intervention to reduce GBS burden in the growing HEU population. [ABSTRACT FROM AUTHOR]

The author comments on the study by Goetghebuer et al that investigated risks of infant infection-related hospitalization in a human immunodeficiency virus (HIV)-exposed uninfected infants (HEU) cohort compared to HIV-unexposed (HU). The study established that initiation of maternal antiretroviral therapy before pregnancy reduced these risks. It notes that this study in high-income country with low HIV prevalence can not be generalized among poorer countries where most HEU children are born.

Great gains were achieved with the introduction of the United Nations' Millennium Development Goals, including improved child survival. Transition to the Sustainable Development Goals (SDGs) focused on surviving, thriving, and transforming, representing an important shift to a broader public health goal, the achievement of which holds the promise of longer-term individual and societal benefits. A similar shift is needed with respect to outcomes for infants born to women living with HIV (WLHIV). Programming to prevent vertical HIV transmission has been successful in increasingly achieving a goal of HIV-free survival for infants born to WLHIV. Unfortunately, HIV-exposed uninfected (HEU) children are not achieving comparable health and developmental outcomes compared with children born to HIV-uninfected women under similar socioeconomic circumstances. The 3rd HEU Child Workshop, held as a satellite session of the International AIDS Society's 9th IAS Conference in Paris in July 2017, provided a venue to discuss HEU child health and development disparities. A summary of the Workshop proceedings follows, providing current scientific findings, emphasizing the gap in systems for long-term monitoring, and highlighting the public health need to establish a strategic plan to better quantify the short and longer-term health and developmental outcomes of HEU children.

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

New vertical HIV infections are declining and the numbers of HIV exposed but uninfected (HEU) infants and children are increasing. This positive trend is tempered by the realization that despite escaping HIV infection, the substantial population of HEU children bear consequences of being born to an HIV-infected mother. A structured approach to the care of these children may improve their long term health and well-being. We propose and discuss a 10-point care package for HEU infants centered on providing optimal basic child health management for all children both HIV-exposed and unexposed. Providing basic comprehensive child care interventions benefits all infants, both HIV-exposed and unexposed. For HEU infants, particular attention should be given to providing optimal vertical transmission prevention interventions and conducting appropriate HIV testing. Clinicians should be aware of the consequences of anti-retroviral (ARV) and HIV exposure on HEU infants. As vertical transmission prevention programs become more sophisticated there is a pressing need for the establishment of pharmacovigilance and long-term surveillance systems as well as affordable infant HIV diagnostic tests. [ABSTRACT FROM AUTHOR]

The Molteno Adapted Scale (MAS) is a developmental screening tool for children up to five years of age, used by medical practitioners in the Western Cape, South Africa. It generates subquotients for language, personal and social, fine and gross motor domains. The general quotient is the average of all four subquotients, with a score < 85 indicating risk for global developmental delay. The authors aimed to determine the concurrent validity of the MAS, using the Bayley Scales of Infant and Toddler Development-3rd edition (BSID) as a comprehensive assessment reference measure. A total of 103 (55 girls) participants were enrolled from a longitudinal cohort study, of which 90 (49 girls) were assessed on both the MAS and BSID at 11–14 months, 53 (27 girls) at 30–42 months of age and 44 (21 girls) at both timepoints. The low number of developmentally delayed children precluded estimation of diagnostic accuracy of the MAS. Therefore, the authors determined Pearson correlation coefficients (r) for the MAS and BSID across similar domains at 11–14 months (n = 90) and 30–42 months (n = 53) and used the Bland–Altman analysis to detect bias between the MAS and BSID domain scores. Correlation was moderate to high between MAS and BSID domains, except for fine motor in 1-year-olds (r = 0.23), but Bland–Altman analysis found discordance especially between the MAS and BSID language and motor scores at the upper and lower performance ranges. Future studies should aim to standardise the operational procedures of the MAS, validate it across a wider age-range, and include children with varying degrees of delay. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]