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Despite progress in providing antiretroviral therapy to pregnant women living with HIV, a substantial number of vertical transmissions continue to occur. Novel approaches leveraging modern potent, safe, and well-tolerated antiretroviral drugs are urgently needed.

Background Globally, over 16 million children were exposed to HIV during pregnancy but remain HIV-free at birth and throughout childhood by 2022. Children born HIV-free (CBHF) have higher morbidity and mortality and poorer neurodevelopment in early life compared to children who are HIV-unexposed (CHU), but long-term outcomes remain uncertain. We characterised school-age growth, cognitive and physical function in CBHF and CHU previously enrolled in the Sanitation Hygiene Infant Nutrition Efficacy (SHINE) trial in rural Zimbabwe. Methods and findings The SHINE trial enrolled pregnant women between 2012 and 2015 across 2 rural Zimbabwean districts. Co-primary outcomes were height-for-age Z-score and haemoglobin at age 18 months (clinicaltrials.gov NCT01824940). Children were re-enrolled if they were aged 7 years, resident in Shurugwi district, and had known pregnancy HIV-exposure status. From 5,280 pregnant women originally enrolled, 376 CBHF and 2016 CHU reached the trial endpoint at 18 months in Shurugwi; of these, 264 CBHF and 990 CHU were evaluated at age 7 years using the School-Age Health, Activity, Resilience, Anthropometry and Neurocognitive (SAHARAN) toolbox. Cognitive function was evaluated using the Kaufman Assessment Battery for Children (KABC-II), with additional tools measuring executive function, literacy, numeracy, fine motor skills, and socioemotional function. Physical function was assessed using standing broad jump and handgrip for strength, and the shuttle-run test for cardiovascular fitness. Growth was assessed by anthropometry. Body composition was assessed by bioimpedance analysis and skinfold thicknesses. A caregiver questionnaire measured demographics, socioeconomic status, nurturing, child discipline, food, and water insecurity. We prespecified the primary comparisons and used generalised estimating equations with an exchangeable working correlation structure to account for clustering. Adjusted models used covariates from the trial (study arm, study nurse, exact child age, sex, calendar month measured, and ambient temperature). They also included covariates derived from directed acyclic graphs, with separate models adjusted for contemporary variables (socioeconomic status, household food insecurity, religion, social support, gender norms, caregiver depression, age, caregiver education, adversity score, and number of children's books) and early-life variables (length-for-age-Z-score) at 18 months, birthweight, maternal baseline depression, household diet, maternal schooling and haemoglobin, socioeconomic status, facility birth, and gender norms. We applied a Bonferroni correction for the 27 comparisons (0.05/27) with threshold of p < 0.00185 as significant. We found strong evidence that cognitive function was lower in CBHF compared to CHU across multiple domains. The KABC-II mental processing index was 45.2 (standard deviation (SD) 10.5) in CBHF and 48.3 (11.3) in CHU (mean difference 3.3 points [95% confidence interval (95% CI) 2.0, 4.5]; p < 0.001). The school achievement test score was 39.0 (SD 26.0) in CBHF and 45.7 (27.8) in CHU (mean difference 7.3 points [95% CI 3.6, 10.9]; p < 0.001); differences remained significant in adjusted analyses. Executive function was reduced but not significantly in adjusted analyses. We found no consistent evidence of differences in growth or physical function outcomes. The main limitation of our study was the restriction to one of two previous study districts, with possible survivor and selection bias. Conclusions In this study, we found that CBHF had reductions in cognitive function compared to CHU at 7 years of age across multiple domains. Further research is needed to define the biological and psychosocial mechanisms underlying these differences to inform future interventions that help CBHF thrive across the life-course. Trial registration ClinicalTrials.gov The SHINE follow-up study was registered with the Pan-African Clinical Trials Registry (PACTR202201828512110). The original SHINE trial was registered at NCT https://clinicaltrials.gov/study/NCT01824940., Author(s): Joe D Piper 1,2,3,*, Clever Mazhanga 1, Marian Mwapaura 1, Gloria Mapako 1, Idah Mapurisa 1, Tsitsi Mashedze 1, Eunice Munyama 1, Maria Kuona 1, Thombizodwa Mashiri 1, Kundai [...]

BackgroundMeta-analyses show that small-quantity lipid-based nutrient supplements (SQ-LNSs) reduce child wasting and stunting. There is little information regarding effects on severe wasting or stunting.ObjectivesWe aimed to identify the effect of SQ-LNSs on prevalence of severe wasting (weight-for-length z score < -3) and severe stunting (length-for-age z score < -3).MethodsWe conducted a 2-stage meta-analysis of individual participant data from 14 randomized controlled trials of SQ-LNSs provided to children 6-24 mo of age. We generated study-specific and subgroup estimates of SQ-LNS compared with control and pooled the estimates using fixed-effects models. We used random-effects meta-regression to examine study-level effect modifiers. In sensitivity analyses, we examined whether results differed depending on study arm inclusion criteria and types of comparisons.ResultsSQ-LNS provision led to a relative reduction of 31% in severe wasting [prevalence ratio (PR): 0.69; 95% CI: 0.55, 0.86; n = 34,373] and 17% in severe stunting (PR: 0.83; 95% CI: 0.78, 0.90; n = 36,795) at endline. Results were similar in most of the sensitivity analyses but somewhat attenuated when comparisons using passive control arms were excluded (PR: 0.74; 95% CI: 0.57, 0.96; n = 26,327 for severe wasting and PR: 0.88; 95% CI: 0.81, 0.95; n = 28,742 for severe stunting). Study-level characteristics generally did not significantly modify the effects of SQ-LNSs, but results suggested greater effects of SQ-LNSs in sites with greater burdens of wasting or stunting, or with poorer water quality or sanitation.ConclusionsIncluding SQ-LNSs in preventive interventions to promote healthy child growth and development is likely to reduce rates of severe wasting and stunting. This meta-analysis was registered at www.crd.york.ac.uk/PROSPERO as CRD42019146592.

BackgroundMeta-analyses show that small-quantity lipid-based nutrient supplements (SQ-LNSs) reduce child stunting and wasting. Identification of subgroups who benefit most from SQ-LNSs may facilitate program design.ObjectivesWe aimed to identify study-level and individual-level modifiers of the effect of SQ-LNSs on child growth outcomes.MethodsWe conducted a 2-stage meta-analysis of individual participant data from 14 randomized controlled trials of SQ-LNSs provided to children 6-24 mo of age (n = 37,066). We generated study-specific and subgroup estimates of SQ-LNS compared with control and pooled the estimates using fixed-effects models. We used random-effects meta-regression to examine study-level effect modifiers. In sensitivity analyses, we examined whether results differed depending on study arm inclusion criteria and types of comparisons.ResultsSQ-LNS provision decreased stunting (length-for-age z score < -2) by 12% (relative reduction), wasting [weight-for-length (WLZ) z score < -2] by 14%, low midupper arm circumference (MUAC) (

BackgroundSmall-quantity (SQ) lipid-based nutrient supplements (LNSs) provide many nutrients needed for brain development.ObjectivesWe aimed to generate pooled estimates of the effect of SQ-LNSs on developmental outcomes (language, social-emotional, motor, and executive function), and to identify study-level and individual-level modifiers of these effects.MethodsWe conducted a 2-stage meta-analysis of individual participant data from 14 intervention against control group comparisons in 13 randomized trials of SQ-LNSs provided to children age 6-24 mo (total n = 30,024).ResultsIn 11-13 intervention against control group comparisons (n = 23,588-24,561), SQ-LNSs increased mean language (mean difference: 0.07 SD; 95% CI: 0.04, 0.10 SD), social-emotional (0.08; 0.05, 0.11 SD), and motor scores (0.08; 95% CI: 0.05, 0.11 SD) and reduced the prevalence of children in the lowest decile of these scores by 16% (prevalence ratio: 0.84; 95% CI: 0.76, 0.92), 19% (0.81; 95% CI: 0.74, 0.89), and 16% (0.84; 95% CI: 0.76, 0.92), respectively. SQ-LNSs also increased the prevalence of children walking without support at 12 mo by 9% (1.09; 95% CI: 1.05, 1.14). Effects of SQ-LNSs on language, social-emotional, and motor outcomes were larger among study populations with a higher stunting burden (≥35%) (mean difference: 0.11-0.13 SD; 8-9 comparisons). At the individual level, greater effects of SQ-LNSs were found on language among children who were acutely malnourished (mean difference: 0.31) at baseline; on language (0.12), motor (0.11), and executive function (0.06) among children in households with lower socioeconomic status; and on motor development among later-born children (0.11), children of older mothers (0.10), and children of mothers with lower education (0.11).ConclusionsChild SQ-LNSs can be expected to result in modest developmental gains, which would be analogous to 1-1.5 IQ points on an IQ test, particularly in populations with a high child stunting burden. Certain groups of children who experience higher-risk environments have greater potential to benefit from SQ-LNSs in developmental outcomes.This trial was registered at www.crd.york.ac.uk/PROSPERO as CRD42020159971.

Background World Health Organization (WHO) guidelines recommend cotrimoxazole prophylaxis for children who are HIV-exposed until infection is excluded and vertical transmission risk has ended. While cotrimoxazole has benefits for children with HIV, there is no mortality benefit for children who are HIV-exposed but uninfected, prompting a review of global guidelines. Here, we model the potential impact of alternative cotrimoxazole strategies on mortality in children who are HIV-exposed. Methods and findings Using a deterministic compartmental model, we estimated mortality in children who are HIV-exposed from 6 weeks to 2 years of age in 4 high-burden countries: Côte d'Ivoire, Mozambique, Uganda, and Zimbabwe. Vertical transmission rates, testing rates, and antiretroviral therapy (ART) uptake were derived from UNAIDS data, trial evidence, and meta-analyses. We explored 6 programmatic strategies: maintaining current recommendations; shorter cotrimoxazole provision for 3, 6, 9, or 12 months; and starting cotrimoxazole only for children diagnosed with HIV. Modelled alternatives to the current strategy increased mortality to varying degrees; countries with high vertical transmission had the greatest mortality. Compared to current recommendations, starting cotrimoxazole only after a positive HIV test had the greatest predicted increase in mortality: Mozambique (961 excess annual deaths; excess mortality 339 per 100,000 HIV-exposed children; risk ratio (RR) 1.06), Uganda (491; 221; RR 1.04), Zimbabwe (352; 260; RR 1.05), and Côte d'Ivoire (125; 322; RR 1.06). Similar effects were observed for 3-, 6-, 9-, and 12-month strategies. Increased mortality persisted but was attenuated when modelling lower cotrimoxazole uptake, smaller mortality benefits, higher testing coverage, and lower vertical transmission rates. The study is limited by uncertain estimates of cotrimoxazole coverage in programmatic settings; an inability to model increases in mortality arising from antimicrobial resistance due to limited surveillance data in sub-Saharan Africa; and lack of a formal health economic analysis. Conclusions Changing current guidelines from universal cotrimoxazole provision for children who are HIV-exposed increased predicted mortality across the 4 modelled high-burden countries, depending on test-to-treat cascade coverage and vertical transmission rates. These findings can help inform policymaker deliberations on cotrimoxazole strategies, recognising that the risks and benefits differ across settings., Author(s): Shrey Mathur 1,*, Melanie Smuk 1, Ceri Evans 1,2,3, Catherine J. Wedderburn 4,5, Diana M. Gibb 4, Martina Penazzato 6, Andrew J. Prendergast 1,2 Introduction Vertical transmission of HIV [...]

BackgroundThree large new trials of unprecedented scale and cost, which included novel factorial designs, have found no effect of basic water, sanitation and hygiene (WASH) interventions on childhood stunting, and only mixed effects on childhood diarrhea. Arriving at the inception of the United Nations' Sustainable Development Goals, and the bold new target of safely managed water, sanitation and hygiene for all by 2030, these results warrant the attention of researchers, policy-makers and practitioners.Main bodyHere we report the conclusions of an expert meeting convened by the World Health Organization and the Bill and Melinda Gates Foundation to discuss these findings, and present five key consensus messages as a basis for wider discussion and debate in the WASH and nutrition sectors. We judge these trials to have high internal validity, constituting good evidence that these specific interventions had no effect on childhood linear growth, and mixed effects on childhood diarrhea. These results suggest that, in settings such as these, more comprehensive or ambitious WASH interventions may be needed to achieve a major impact on child health.ConclusionThese results are important because such basic interventions are often deployed in low-income rural settings with the expectation of improving child health, although this is rarely the sole justification. Our view is that these three new trials do not show that WASH in general cannot influence child linear growth, but they do demonstrate that these specific interventions had no influence in settings where stunting remains an important public health challenge. We support a call for transformative WASH, in so much as it encapsulates the guiding principle that - in any context - a comprehensive package of WASH interventions is needed that is tailored to address the local exposure landscape and enteric disease burden.

Child stunting is a global problem and is only modestly responsive to dietary interventions. Numerous observational studies have shown that water quality, sanitation, and handwashing (WASH) in a household are strongly associated with linear growth of children living in the same household. We have completed three randomised efficacy trials testing improved household-level WASH with and without improved infant and young child feeding (IYCF) on stunting and diarrhoea in Bangladesh, Kenya, and Zimbabwe. In all trials, improved IYCF had a statistically significant benefit, but WASH had no effect on linear growth. In observational analyses of data from the control groups of the three trials, baseline sanitation was a strong risk factor for stunting in the study populations, suggesting this frequently reported association might be confounded by unmeasured factors of household wellbeing. WASH interventions reduced diarrhoea in Bangladesh, but not in Kenya or Zimbabwe. Intervention promoters visited participants six times per month in Bangladesh compared with monthly in Kenya and Zimbabwe; a review of the literature shows that virtually all published studies that have reported an effect on diarrhoea through home-based water treatment and handwashing promotion achieved high adherence by visiting participants at daily to fortnightly intervals. Despite achieving substantial behavioural change and significant reduction in infection prevalence for some enteric pathogens, detection of enteropathogens among children in the WASH groups of the trials was typically at ten times higher prevalence compared with high-income countries. Considering these results, we recommend that future research in the WASH sector focus on developing and evaluating interventions that are radically more effective in reducing faecal contamination in the domestic environment than the interventions implemented in these trials.

Children hospitalised for severe acute malnutrition (SAM) have a high risk of mortality, relapse and rehospitalisation following hospital discharge. Current approaches fail to promote convalescence, or to address the underlying social determinants of SAM, meaning that restoration of long‐term health, growth and neurodevelopment is not achieved. Although guidelines recommend play and stimulation to promote recovery, most caregivers are not supported to do this at home. We set out to evaluate the feasibility and acceptability of a codesigned intervention package aimed at providing child stimulation through play, and strengthening caregiver capabilities through problem‐solving skills, peer support and income‐generating activities. We evaluated the intervention in two phases, enroling 30 caregiver–child pairs from paediatric wards in Harare, Zimbabwe, once children who had been hospitalised with SAM were ready for discharge. Children were median 17.8 months old, and 28.6% had human immunodeficiency virus. Trained intervention facilitators (IFs)—lay workers whose own children had previously had SAM—delivered the intervention over 12 weeks with nurse supervision. Qualitative interviews with caregivers and IFs showed that the intervention was feasible and acceptable. Participants reported benefiting from the psychosocial support and counselling, and several started income‐generating projects. Caregivers appreciated the concept of play and caregiver–child interaction, and all reported practising what they had learned. By Week 12, caregiver mental health and caregiver–child interaction improved significantly. Overall, the intervention was feasible, acceptable and showed promise in modifying caregiver knowledge, attitudes and practice. An efficacy trial is now needed to evaluate whether the intervention can improve child convalescence following complicated SAM. Key messages: A psychosocial intervention which enhances child play and promotes caregiver support may improve convalescence following severe acute malnutrition.We co‐designed a complex intervention, designed to provide child stimulation through play, and to strengthen caregiver and household capabilities through problem‐solving skills, peer support and income‐generating activities.The 12‐week intervention, delivered by trained lay workers whose own children had previously had SAM, was feasible and acceptable, and caregivers showed improvements in mental health and caregiver‐child interaction.This psychosocial support package should now be tested in a randomised trial to evaluate its efficacy in promoting convalescence. [ABSTRACT FROM AUTHOR]

Children born to mothers with HIV, who themselves remain HIV‐free, are at risk for poorer health outcomes compared to children born to mothers without HIV, including increased morbidity and mortality, [...]

: 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, [...]

Low birthweight (LBW) is when an infant is born too soon or too small, and it affects one in seven infants in low- and middle-income countries. LBW has a significant impact on short-term morbidity and mortality, and it impairs long-term health and human capital. Antenatal microbial and inflammatory exposure may contribute to LBW. Ovid-Medline, Embase and Cochrane databases were searched for English-language articles evaluating inflammatory, microbial or infective causes of LBW, small-for-gestational age, intra-uterine growth restriction or prematurity. Inclusion criteria were human studies including published data; conference abstracts and grey literature were excluded. A narrative synthesis of the literature was conducted. Local infections may drive the underlying causes of LBW: for example, vaginitis and placental infection are associated with a greater risk of prematurity. Distal infection and inflammatory pathways are also associated with LBW, with an association between periodontitis and preterm delivery and environmental enteric dysfunction and reduced intra-uterine growth. Systemic maternal infections such as malaria and HIV are associated with LBW, even when infants are exposed to HIV but not infected. This latter association may be driven by chronic inflammation, co-infections and socio-economic confounders. Antimicrobial prophylaxis against other bacteria in pregnancy has shown minimal impact in most trials, though positive effects on birthweight have been found in some settings with a high infectious disease burden. Maternal inflammatory and infective processes underlie LBW, and provide treatable pathways for interventions. However, an improved understanding of the mechanisms and pathways underlying LBW is needed, given the impact of LBW on life-course. [ABSTRACT FROM AUTHOR]

Introduction: Exposure to maternal HIV may affect early child development (ECD), although previous studies have reported heterogeneous findings. We evaluated ECD among children who were HIV-exposed uninfected (CHEU) and children who were HIV-unexposed (CHU) recruited to the SHINE trial in rural Zimbabwe. Methods: SHINE was a community-based cluster-randomized trial of improved infant feeding and/or improved water, sanitation and hygiene. Pregnant women were enrolled between 2012 and 2015. We assessed ECD in a sub-study at 24 months of age, between 2016 and 2017, using the Malawi Developmental Assessment Tool (MDAT; assessing motor, cognitive, language and social development); MacArthur-Bates Communicative Development Inventory (CDI) (assessing vocabulary and grammar); A-not-B test (assessing object permanence); and a self-control task. Mothers and infants were tested longitudinally for HIV. We used generalized estimating equations to compare ECD scores between CHEU and CHU, accounting for the cluster-randomized design. Primary results were adjusted for trial-related factors that could affect measurement reliability of ECD: study nurse, age of child, calendar month of birth, sex and randomized arm. Results: A total of 205 CHEU and 1175 CHU were evaluated. Mean total MDAT score was 90.6 (SD 8.7) in CHEU compared to 92.4 (9.1) in CHU (adjusted mean difference -1.3, 95% CI: -2.3, -0.3), driven mostly by differences in gross motor (-0.5, 95% CI: -0.9, -0.2) and language scores (-0.6, 95% CI: -1.1, -0.1). There was evidence that fine motor scores were lower in CHEU (adjusted mean difference -0.4, 95% CI: -0.8, 0.0) but no evidence of a difference in social scores (0.1, 95% CI: -0.2, 0.4). Mean MacArthur-Bates CDI vocabulary score was 57.9 (SD 19.2) in CHEU compared to 61.3 (18.8) in CHU (adjusted mean difference -2.9 words, 95% CI: -5.7, -0.1). Object permanence and self-control scores were similar between groups. Conclusions: CHEU in rural Zimbabwe had total child development and vocabulary scores that were approximately 0.15 standard deviations lower than CHU at two years of age. More detailed and specific studies are now needed to unravel the reasons for developmental delay in CHEU and the likelihood that these delays persist in the longer term. Keywords: child development; language; motor; self-control; HIV-exposed uninfected; Zimbabwe, 1 | INTRODUCTION The increasing coverage of prevention of mother-to-child transmission (PMTCT) interventions in sub-Saharan Africa has dramatically reduced the number of children with HIV infection. However, this success has [...]