Estimating the impact of alternative programmatic cotrimoxazole strategies on mortality among children born to mothers with HIV: A modelling study.

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.

Parental and health visitor perceptions on growth screening in early childhood: a qualitative study.

BACKGROUND: Growth screening in early childhood can help identify children with a range of medical and psychosocial vulnerabilities. In the UK, childhood growth and development up to age 5 years are assessed through the Healthy Child Programme, delivered by health visitors. However, formal criteria to trigger referrals for onward investigation are unclear. There is a lack of qualitative data on the acceptability and feasibility of formal growth screening programmes. This study aimed to build understanding of the perceptions and motivations of caregivers and health visitors in relation to child growth and growth screening. METHODS: This longitudinal observational study was part of a larger study piloting an automated growth screening algorithm in Tower Hamlets, London. We conducted three separate qualitative focus group interviews with health visitors (n=10), English-speaking parents (n=6), and Sylheti-speaking parents (n=5). Participants were purposively sampled, and written informed consent was obtained. A bilingual researcher facilitated each group, using a semi-structured interview guide. Data were analysed by two researchers using thematic analysis and assessed for intercoder reliability. The interview guide was translated into Sylheti, and data from the Sylheti group were translated into English by the same bilingual researcher. FINDINGS: Findings suggest that parents desire holistic care in which health visitors are empowered to refer to other health professionals and council services. Parents also want easier access to health visitors, frequent visits with the same health-care provider, and advice on raising their children. Health visitors were seen as well positioned to play an essential role in educating parents on health and developmental milestones and in helping them identify when their child might need additional support. Both parents and health visitors stressed that resources need to be in place not only to assess children but also to provide access to services when problems are identified. INTERPRETATION: These findings suggest that implementing growth screening through health visitors is feasible and acceptable, provided health visitors are given the resources and capabilities to refer children to appropriate services. Interpretation is limited by the purposive nature of the sampling and possible response bias. FUNDING: Barts Charity.

Biological and pathological mechanisms leading to the birth of a small vulnerable newborn.

The pathway to a thriving newborn begins before conception and continues in utero with a healthy placenta and the right balance of nutrients and growth factors that are timed and sequenced alongside hormonal suppression of labour until a mature infant is ready for birth. Optimal nutrition that includes adequate quantities of quality protein, energy, essential fats, and an extensive range of vitamins and minerals not only supports fetal growth but could also prevent preterm birth by supporting the immune system and alleviating oxidative stress. Infection, illness, undernourishment, and harmful environmental exposures can alter this trajectory leading to an infant who is too small due to either poor growth during pregnancy or preterm birth. Systemic inflammation suppresses fetal growth by interfering with growth hormone and its regulation of insulin-like growth factors. Evidence supports the prevention and treatment of several maternal infections during pregnancy to improve newborn health. However, microbes, such as Ureaplasma species, which are able to ascend the cervix and cause membrane rupture and chorioamnionitis, require new strategies for detection and treatment. The surge in fetal cortisol late in pregnancy is essential to parturition at the right time, but acute or chronically high maternal cortisol levels caused by psychological or physical stress could also trigger labour onset prematurely. In every pathway to the small vulnerable newborn, there is a possibility to modify the course of pregnancy by supporting improved nutrition, protection against infection, holistic maternal wellness, and healthy environments.

Formulation and acceptability of local nutrient-dense foods for young children: A formative study for the Child Health, Agriculture and Integrated Nutrition (CHAIN) Trial in rural Zimbabwe.

Stunting affects almost one-quarter of children globally, leading to reduced human capacity and increased long-term risk of chronic disease. Despite intensive infant and young child feeding (IYCF) interventions, many children do not meet their requirements for essential nutrients. This study aimed to assess the feasibility of implementing an IYCF intervention utilizing nutrient-dense powders from egg, biofortified sugar beans and Moringa oleifera leaf in rural Zimbabwe. A mixed-methods formative study was conducted comprising the following: (i) a recipe formulation trial, (ii) trials of improved practices to assess acceptability of the intervention, and (iii) a participatory message formulation process to develop counselling modules for the IYCF-plus intervention. Twenty-seven mother-baby pairs were recruited between November 2019 and April 2020. Key domains affecting IYCF practices that emerged were time, emotional and physical space, cultural and religious beliefs, indigenous knowledge systems and gender dynamics. Household observations and sensory evaluation indicated high acceptability of the new ingredients. Recipe formulation and participatory message formulation by participants instilled community ownership and served to demystify existing misconceptions about the new food products. Families noted the potential for intervention sustainability because the foods could be grown locally. Supplementing complementary foods with nutrient-dense local food ingredients as powders has the potential to sustainably address nutrient-gaps in the diets of young children living in rural lower- and middle-income countries. Comprehensive IYCF counselling utilizing a gender-lens approach, family support and indigenous knowledge systems or resources are key elements to support positive behaviour change in complementary feeding interventions.

Understanding the interaction between cytomegalovirus and tuberculosis in children: The way forward.

Over 1 million children develop tuberculosis (TB) each year, with a quarter dying. Multiple factors impact the risk of a child being exposed to Mycobacterium tuberculosis (Mtb), the risk of progressing to TB disease, and the risk of dying. However, an emerging body of evidence suggests that coinfection with cytomegalovirus (CMV), a ubiquitous herpes virus, impacts the host response to Mtb, potentially influencing the probability of disease progression, type of TB disease, performance of TB diagnostics, and disease outcome. It is also likely that infection with Mtb impacts CMV pathogenesis. Our current understanding of the burden of these 2 diseases in children, their immunological interactions, and the clinical consequence of coinfection is incomplete. It is also unclear how potential interventions might affect disease progression and outcome for TB or CMV. This article reviews the epidemiological, clinical, and immunological literature on CMV and TB in children and explores how the 2 pathogens interact, while also considering the impact of HIV on this relationship. It outlines areas of research uncertainty and makes practical suggestions as to potential studies that might address these gaps. Current research is hampered by inconsistent definitions, study designs, and laboratory practices, and more consistency and collaboration between researchers would lead to greater clarity. The ambitious targets outlined in the World Health Organization End TB Strategy will only be met through a better understanding of all aspects of child TB, including the substantial impact of coinfections.

Fat and lean mass predict time to hospital readmission or mortality in children treated for complicated severe acute malnutrition in Zimbabwe and Zambia.

HIV and severe wasting are associated with post-discharge mortality and hospital readmission among children with complicated severe acute malnutrition (SAM); however, the reasons remain unclear. We assessed body composition at hospital discharge, stratified by HIV and oedema status, in a cohort of children with complicated SAM in three hospitals in Zambia and Zimbabwe. We measured skinfold thicknesses and bioelectrical impedance analysis (BIA) to investigate whether fat and lean mass were independent predictors of time to death or readmission. Cox proportional hazards models were used to estimate the association between death/readmission and discharge body composition. Mixed effects models were fitted to compare longitudinal changes in body composition over 1 year. At discharge, 284 and 546 children had complete BIA and skinfold measurements, respectively. Low discharge lean and peripheral fat mass were independently associated with death/hospital readmission. Each unit Z-score increase in impedance index and triceps skinfolds was associated with 48 % (adjusted hazard ratio 0·52, 95 % CI (0·30, 0·90)) and 17 % (adjusted hazard ratio 0·83, 95 % CI (0·71, 0·96)) lower hazard of death/readmission, respectively. HIV-positive v. HIV-negative children had lower gains in sum of skinfolds (mean difference -1·49, 95 % CI (-2·01, -0·97)) and impedance index Z-scores (-0·13, 95 % CI (-0·24, -0·01)) over 52 weeks. Children with non-oedematous v. oedematous SAM had lower mean changes in the sum of skinfolds (-1·47, 95 % CI (-1·97, -0·97)) and impedance index Z-scores (-0·23, 95 % CI (-0·36, -0·09)). Risk stratification to identify children at risk for mortality or readmission, and interventions to increase lean and peripheral fat mass, should be considered in the post-discharge care of these children.

Short stature and language development in the United Kingdom: a longitudinal analysis of children from the Millennium Cohort Study.

BACKGROUND: In low- and middle-income countries, poverty and impaired growth prevent children from meeting their cognitive developmental potential. There are few studies investigating these relationships in high-income settings. METHODS: Participants were 12,536 children born between 2000 and 2002 in the UK and participating in the Millennium Cohort Study (MCS). Short stature was defined as having a height-for-age 2 or more standard deviations below the median (≤ - 2 SDS) at age 3 years. Standardized British Abilities Scales II (BAS II) language measures, used to assess language development at ages 3, 5, 7 and 11 years, were the main outcome assessed. RESULTS: Children with short stature at age 3 years (4.1%) had language development scores that were consistently lower from ages 3 to 11 years (- 0.26 standard deviations (SD) (95% CI - 0.37, - 0.15)). This effect was attenuated but remained significant after adjustment for covariates. Trajectory analysis produced four distinct patterns of language development scores (low-declining, low-improving, average and high). Multinomial logistic regression models showed that children with short stature had a higher risk of being in the low-declining group, relative to the average group (relative risk ratio (RRR) = 2.11 (95% CI 1.51, 2.95)). They were also less likely to be in the high-scoring group (RRR = 0.65 (0.52, 0.82)). Children with short stature at age 3 years who had 'caught up' by age 5 years (height-for-age ≥ 2 SDS) did not have significantly different scores from children with persistent short stature, but had a higher probability of being in the high-performing group than children without catch-up growth (RRR = 1.84 (1.11, 3.07)). CONCLUSIONS: Short stature at age 3 years was associated with lower language development scores at ages 3 to 11 years in UK children. These associations remained significant after adjustment for socioeconomic, child and parental factors.

Antenatal and delivery practices and neonatal mortality amongst women with institutional and non-institutional deliveries in rural Zimbabwe: observational data from a cluster randomized trial.

BACKGROUND: Despite achieving relatively high rates of antenatal care, institutional delivery, and HIV antiretroviral therapy for women during pregnancy, neonatal mortality has remained stubbornly high in Zimbabwe. Clearer understanding of causal pathways is required to inform effective interventions. METHODS: This study was a secondary analysis of data from the Sanitation Hygiene Infant Nutrition Efficacy (SHINE) trial, a cluster-randomized community-based trial among pregnant women and their infants, to examine care during institutional and non-institutional deliveries in rural Zimbabwe and associated birth outcomes. RESULTS: Among 4423 pregnant women, 529 (11.9%) delivered outside a health institution; hygiene practices were poorer and interventions to minimise neonatal hypothermia less commonly utilised for these deliveries compared to institutional deliveries. Among 3441 infants born in institutions, 592 (17.2%) were preterm (< 37 weeks gestation), while 175/462 (37.9%) infants born outside health institutions were preterm (RR: 2.20 (1.92, 2.53). Similarly, rates of stillbirth [1.2% compared to 3.0% (RR:2.38, 1.36, 4.15)] and neonatal mortality [2.4% compared to 4.8% (RR: 2.01 1.31, 3.10)] were higher among infants born outside institutions. Among mothers delivering at home who reported their reason for having a home delivery, 221/293 (75%) reported that precipitous labor was the primary reason for not having an institutional delivery while 32 (11%), 34 (12%), and 9 (3%), respectively, reported distance to the clinic, financial constraints, and religious/personal preference. CONCLUSIONS: Preterm birth is common among all infants in rural Zimbabwe, and extremely high among infants born outside health institutions. Our findings indicate that premature onset of labor, rather than maternal choice, may be the reason for many non-institutional deliveries in low-resource settings, initiating a cascade of events resulting in a two-fold higher risk of stillbirth and neonatal mortality amongst children born outside health institutions. Interventions for primary prevention of preterm delivery will be crucial in reducing neonatal mortality in Zimbabwe. TRIAL REGISTRATION: The trial is registered with ClinicalTrials.gov, number NCT01824940.

Recovery of children following hospitalisation for complicated severe acute malnutrition.

Nutritional recovery and hospital readmission following inpatient management of complicated severe acute malnutrition (SAM) are poorly characterised. We aimed to ascertain patterns and factors associated with hospital readmission, nutritional recovery and morbidity, in children discharged from hospital following management of complicated SAM in Zambia and Zimbabwe over 52-weeks posthospitalization. Multivariable Fine-Gray subdistribution hazard models, with death and loss to follow-up as competing risks, were used to identify factors associated with hospital readmission; negative binomial regression to assess time to hospitalisation and ordinal logistic regression to model factors associated with nutritional recovery. A total of 649 children (53% male, median age 18.2 months) were discharged to continue community nutritional rehabilitation. All-cause hospital readmission was 15.4% (95% CI 12.7, 18.6) over 52 weeks. Independent risk factors for time to readmission were cerebral palsy (adjusted subhazard ratio (aSHR): 2.96, 95% CI 1.56, 5.61) and nonoedematous SAM (aSHR: 1.64, 95%CI 1.03, 2.64). Unit increases in height-for-age Z-score (HAZ) (aSHR: 0.82, 95% CI 0.71, 0.95) and enrolment in Zambia (aSHR: 0.52, 95% CI 0.28, 0.97) were associated with reduced subhazard of time to readmission. Young age, SAM at discharge, nonoedematous SAM and cerebral palsy were associated with poor nutritional recovery throughout follow-up. Collectively, nonoedematous SAM, ongoing SAM at discharge, cerebral palsy and low HAZ are independent risk factors for readmission and poor nutritional recovery following complicated SAM. Children with these high-risk features should be prioritised for additional convalescent care to improve long-term outcomes.

Determinants of Urogenital Schistosomiasis Among Pregnant Women and its Association With Pregnancy Outcomes, Neonatal Deaths, and Child Growth.

BACKGROUND: Schistosoma haematobium is a parasitic helminth that causes urogenital pathology. The impact of urogenital schistosomiasis during pregnancy on birth outcomes and child growth is poorly understood. METHODS: Risk factors for urogenital schistosomiasis were characterized among 4437 pregnant women enrolled in a cluster-randomized community-based trial in rural Zimbabwe. Infection was defined via urine microscopy (≥1 S. haematobium egg) and urinalysis (hematuria). Associations between infection and pregnancy outcomes were assessed in case-control analyses using conditional logistic regression. The association of maternal infection with birthweight and length-for-age Z scores (LAZ) at 1 and 18 months of age were assessed using generalized estimating equations. RESULTS: Urogenital schistosomiasis (egg positive and/or hematuria positive) was detected in 26.8% of pregnant women. Risk factors significantly associated with infection were maternal age, education, marital status, and religion; household drinking water source and latrine; study region; and season. Urogenital schistosomiasis was not significantly associated with adverse pregnancy outcomes (miscarriage, stillbirth, preterm, and small-for-gestational age), birthweight, neonatal death, or LAZ. CONCLUSIONS: Including pregnant women in antihelminthic treatment programs would benefit a large number of women in rural Zimbabwe. However, clearance of the low-intensity infections that predominate in this context is unlikely to have additive benefits for pregnancy outcomes or child growth. CLINICAL TRIALS REGISTRATION: NCT01824940.

Mortality, Human Immunodeficiency Virus (HIV) Transmission, and Growth in Children Exposed to HIV in Rural Zimbabwe.

BACKGROUND: Clinical outcomes of children who are human immunodeficiency virus (HIV)-exposed in sub-Saharan Africa remain uncertain. METHODS: The Sanitation Hygiene Infant Nutrition Efficacy (SHINE) trial evaluated improved infant and young child feeding (IYCF) and/or improved water, sanitation, and hygiene in 2 rural Zimbabwean districts with 15% antenatal HIV prevalence and > 80% prevention of mother-to-child transmission (PMTCT) coverage. Children born between February 2013 and December 2015 had longitudinal HIV testing and anthropometry. We compared mortality and growth between children who were HIV-exposed and HIV-unexposed through 18 months. Children receiving IYCF were excluded from growth analyses. RESULTS: Fifty-one of 738 (7%) children who were HIV-exposed and 198 of 3989 (5%) children who were HIV-unexposed (CHU) died (hazard ratio, 1.41 [95% confidence interval {CI}, 1.02-1.93]). Twenty-five (3%) children who were HIV-exposed tested HIV positive, 596 (81%) were HIV-exposed uninfected (CHEU), and 117 (16%) had unknown HIV status by 18 months; overall transmission estimates were 4.3%-7.7%. Mean length-for-age z score at 18 months was 0.38 (95% CI, .24-.51) standard deviations lower among CHEU compared to CHU. Among 367 children exposed to HIV in non-IYCF arms, 147 (40%) were alive, HIV-free, and nonstunted at 18 months, compared to 1169 of 1956 (60%) CHU (absolute difference, 20% [95% CI, 15%-26%]). CONCLUSIONS: In rural Zimbabwe, mortality remains 40% higher among children exposed to HIV, vertical transmission exceeds elimination targets, and half of CHEU are stunted. We propose the composite outcome of "alive, HIV free, and thriving" as the long-term goal of PMTCT programs. CLINICAL TRIALS REGISTRATION: NCT01824940.

Regional differences in short stature in England between 2006 and 2019: A cross-sectional analysis from the National Child Measurement Programme.

BACKGROUND: Short stature, defined as height for age more than 2 standard deviations (SDs) below the population median, is an important indicator of child health. Short stature (often termed stunting) has been widely researched in low- and middle-income countries (LMICs), but less is known about the extent and burden in high-income settings. We aimed to map the prevalence of short stature in children aged 4-5 years in England between 2006 and 2019. METHODS AND FINDINGS: We used data from the National Child Measurement Programme (NCMP) for the school years 2006-2007 to 2018-2019. All children attending state-maintained primary schools in England are invited to participate in the NCMP, and heights from a total of 7,062,071 children aged 4-5 years were analysed. We assessed short stature, defined as a height-for-age standard deviation score (SDS) below -2 using the United Kingdom WHO references, by sex, index of multiple deprivation (IMD), ethnicity, and region. Geographic clustering of short stature was analysed using spatial analysis in SaTScan. The prevalence of short stature in England was 1.93% (95% confidence interval (CI) 1.92-1.94). Ethnicity adjusted spatial analyses showed geographic heterogeneity of short stature, with high prevalence clusters more likely in the North and Midlands, leading to 4-fold variation between local authorities (LAs) with highest and lowest prevalence of short stature. Short stature was linearly associated with IMD, with almost 2-fold higher prevalence in the most compared with least deprived decile (2.56% (2.53-2.59) vs. 1.38% (1.35-1.41)). There was ethnic heterogeneity: Short stature prevalence was lowest in Black children (0.64% (0.61-0.67)) and highest in Indian children (2.52% (2.45-2.60)) and children in other ethnic categories (2.57% (2.51-2.64)). Girls were more likely to have short stature than boys (2.09% (2.07-2.10) vs. 1.77% (1.76-1.78), respectively). Short stature prevalence declined over time, from 2.03% (2.01-2.05) in 2006-2010 to 1.82% (1.80-1.84) in 2016-2019. Short stature declined at all levels of area deprivation, with faster declines in more deprived areas, but disparities by IMD quintile were persistent. This study was conducted cross-sectionally at an area level, and, therefore, we cannot make any inferences about the individual causes of short stature. CONCLUSIONS: In this study, we observed a clear social gradient and striking regional variation in short stature across England, including a North-South divide. These findings provide impetus for further investigation into potential socioeconomic influences on height and the factors underlying regional variation.

Revisiting Koch's postulate to determine the plausibility of viral transmission by human milk.

As breastfeeding is of utmost importance for child development and survival, identifying whether breast milk is a route of transmission for human viruses is critical. Based on the principle of Koch's postulate, we propose an analytical framework to determine the plausibility of viral transmission by breast milk. This framework is based on five criteria: viral infection in children receiving breast milk from infected mothers; the presence of virus, viral antigen, or viral genome in the breast milk of infected mothers; the evidence for the virus in breast milk being infectious; the attempts to rule out other transmission modalities; and the reproduction of viral transmission by oral inoculation in an animal model. We searched for evidence in published reports to determine whether the 5 criteria are fulfilled for 16 human viruses that are suspected to be transmissible by breast milk. We considered breast milk transmission is proven if all 5 criteria are fulfilled, as probable if 4 of the 5 criteria are met, as possible if 3 of the 5 criteria are fulfilled, and as unlikely if less than 3 criteria are met. Only five viruses have proven transmission through breast milk: human T-cell lymphotropic virus 1, human immunodeficiency virus, human cytomegalovirus, dengue virus, and Zika virus. The other 11 viruses fulfilled some but not all criteria and were categorized accordingly. Our framework analysis is useful for guiding public health recommendations and for identifying knowledge gaps amenable to original experiments.

Maternal caregiving capabilities are associated with child linear growth in rural Zimbabwe.

Between birth and 2 years, children's well-being depends on the quality of care they receive from caregivers, primarily their mothers. We developed a quantitative survey instrument to assess seven psychosocial characteristics of women that determine their caregiving ability ('maternal capabilities': physical health, mental health, decision-making autonomy, social support, mothering self-efficacy, workload and time stress, and gender norm attitudes). We measured maternal capabilities in 4,025 mothers and growth in their 4,073 children participating in the Sanitation Hygiene Infant Nutrition Efficacy (SHINE) trial in rural Zimbabwe. We used generalized estimating equation models with exchangeable correlation structure to test the association between each maternal capability during pregnancy, and infant length-for-age Z (LAZ) at 18 months, accounting only for within-cluster correlation and intervention arms in unadjusted analyses and for potential confounders in adjusted analyses to examine the association between each capability, assessed during pregnancy, with child LAZ at 18 months of age. In adjusted models, each unit increase in gender norm attitudes score (reflecting more equitable gender norm attitudes) was associated with +0.09 LAZ (95% CI: 0.02, 0.16) and a decreased odds of stunting (adjusted odds ratio [AOR]: 0.86; 95% CI: 0.74, 1.01); each unit increase in social support score was associated with +0.11 LAZ (95% CI: 0.05, 0.17, p < 0.010) and decreased odds of stunting (AOR: 0.83; 95% CI: 0.73, 0.96). Each unit increase in decision-making autonomy was associated with a 6% reduced odds of stunting (AOR: 0.94; 95% CI: 0.89, 0.996, p = 0.04). Interventions and social programming that strengthen these maternal capabilities may improve child nutritional status.

Impact of Water Quality, Sanitation, Handwashing, and Nutritional Interventions on Enteric Infections in Rural Zimbabwe: The Sanitation Hygiene Infant Nutrition Efficacy (SHINE) Trial.

BACKGROUND: We assessed the impact of water, sanitation, and hygiene (WASH) and infant and young child feeding (IYCF) interventions on enteric infections in the Sanitation Hygiene Infant Nutrition Efficacy (SHINE) trial in rural Zimbabwe. METHODS: We tested stool samples collected at 1, 3, 6, and 12 months of age and during diarrhea using quantitative molecular diagnostics for 29 pathogens. We estimated the effects of the WASH, IYCF, and combined WASH + IYCF interventions on individual enteropathogen prevalence and quantity, total numbers of pathogens detected, and incidence of pathogen-attributable diarrhea. RESULTS: WASH interventions decreased the number of parasites detected (difference in number compared to non-WASH arms, -0.07 [95% confidence interval, -.14 to -.02]), but had no statistically significant effects on bacteria, viruses, or the prevalence and quantity of individual enteropathogens after accounting for multiple comparisons. IYCF interventions had no significant effects on individual or total enteropathogens. Neither intervention had significant effects on pathogen-attributable diarrhea. CONCLUSIONS: The WASH interventions implemented in SHINE (improved pit latrine, hand-washing stations, liquid soap, point-of-use water chlorination, and clean play space) did not prevent enteric infections. Transformative WASH interventions are needed that are more efficacious in interrupting fecal-oral microbial transmission in children living in highly contaminated environments.

Enhanced Prophylaxis plus Antiretroviral Therapy for Advanced HIV Infection in Africa.

BACKGROUND: In sub-Saharan Africa, among patients with advanced human immunodeficiency virus (HIV) infection, the rate of death from infection (including tuberculosis and cryptococcus) shortly after the initiation of antiretroviral therapy (ART) is approximately 10%. METHODS: In this factorial open-label trial conducted in Uganda, Zimbabwe, Malawi, and Kenya, we enrolled HIV-infected adults and children 5 years of age or older who had not received previous ART and were starting ART with a CD4+ count of fewer than 100 cells per cubic millimeter. They underwent simultaneous randomization to receive enhanced antimicrobial prophylaxis or standard prophylaxis, adjunctive raltegravir or no raltegravir, and supplementary food or no supplementary food. Here, we report on the effects of enhanced antimicrobial prophylaxis, which consisted of continuous trimethoprim-sulfamethoxazole plus at least 12 weeks of isoniazid-pyridoxine (coformulated with trimethoprim-sulfamethoxazole in a single fixed-dose combination tablet), 12 weeks of fluconazole, 5 days of azithromycin, and a single dose of albendazole, as compared with standard prophylaxis (trimethoprim-sulfamethoxazole alone). The primary end point was 24-week mortality. RESULTS: A total of 1805 patients (1733 adults and 72 children or adolescents) underwent randomization to receive either enhanced prophylaxis (906 patients) or standard prophylaxis (899 patients) and were followed for 48 weeks (loss to follow-up, 3.1%). The median baseline CD4+ count was 37 cells per cubic millimeter, but 854 patients (47.3%) were asymptomatic or mildly symptomatic. In the Kaplan-Meier analysis at 24 weeks, the rate of death with enhanced prophylaxis was lower than that with standard prophylaxis (80 patients [8.9% vs. 108 [12.2%]; hazard ratio, 0.73; 95% confidence interval [CI], 0.55 to 0.98; P=0.03); 98 patients (11.0%) and 127 (14.4%), respectively, had died by 48 weeks (hazard ratio, 0.76; 95% CI, 0.58 to 0.99; P=0.04). Patients in the enhanced-prophylaxis group had significantly lower rates of tuberculosis (P=0.02), cryptococcal infection (P=0.01), oral or esophageal candidiasis (P=0.02), death of unknown cause (P=0.03), and new hospitalization (P=0.03). However, there was no significant between-group difference in the rate of severe bacterial infection (P=0.32). There were nonsignificantly lower rates of serious adverse events and grade 4 adverse events in the enhanced-prophylaxis group (P=0.08 and P=0.09, respectively). Rates of HIV viral suppression and adherence to ART were similar in the two groups. CONCLUSIONS: Among HIV-infected patients with advanced immunosuppression, enhanced antimicrobial prophylaxis combined with ART resulted in reduced rates of death at both 24 weeks and 48 weeks without compromising viral suppression or increasing toxic effects. (Funded by the Medical Research Council and others; REALITY Current Controlled Trials number, ISRCTN43622374 .).

Microbial Translocation Does Not Drive Immune Activation in Ugandan Children Infected With HIV.

Objective: Immune activation is associated with morbidity and mortality during human immunodeficiency virus (HIV) infection, despite receipt of antiretroviral therapy (ART). We investigated whether microbial translocation drives immune activation in HIV-infected Ugandan children. Methods: Nineteen markers of immune activation and inflammation were measured over 96 weeks in HIV-infected Ugandan children in the CHAPAS-3 Trial and HIV-uninfected age-matched controls. Microbial translocation was assessed using molecular techniques, including next-generation sequencing. Results: Of 249 children included, 142 were infected with HIV; of these, 120 were ART naive, with a median age of 2.8 years (interquartile range [IQR], 1.7-4.0 years) and a median baseline CD4+ T-cell percentage of 20% (IQR, 14%-24%), and 22 were ART experienced, with a median age of 6.5 years (IQR, 5.9-9.2 years) and a median baseline CD4+ T-cell percentage of 35% (IQR, 31%-39%). The control group comprised 107 children without HIV infection. The median increase in the CD4+ T-cell percentage was 17 percentage points (IQR, 12-22 percentage points) at week 96 among ART-naive children, and the viral load was <100 copies/mL in 76% of ART-naive children and 91% of ART-experienced children. Immune activation decreased with ART use. Children could be divided on the basis of immune activation markers into the following 3 clusters: in cluster 1, the majority of children were HIV uninfected; cluster 2 comprised a mix of HIV-uninfected children and HIV-infected ART-naive or ART-experienced children; and in cluster 3, the majority were ART naive. Immune activation was low in cluster 1, decreased in cluster 3, and persisted in cluster 2. Blood microbial DNA levels were negative or very low across groups, with no difference between clusters except for Enterobacteriaceae organisms (the level was higher in cluster 1; P < .0001). Conclusion: Immune activation decreased with ART use, with marker clustering indicating different activation patterns according to HIV and ART status. Levels of bacterial DNA in blood were low regardless of HIV status, ART status, and immune activation status. Microbial translocation did not drive immune activation in this setting. Clinical Trials Registration: ISRCTN69078957.

The Impact of Improved Water, Sanitation, and Hygiene on Oral Rotavirus Vaccine Immunogenicity in Zimbabwean Infants: Substudy of a Cluster-randomized Trial.

BACKGROUND: Oral vaccines have lower efficacy in developing compared to developed countries. Poor water, sanitation, and hygiene (WASH) may contribute to reduced oral vaccine immunogenicity. METHODS: We conducted a cluster-randomized 2 × 2 factorial trial in rural Zimbabwe. Pregnant women and their infants were eligible if they lived in clusters randomized to (1) standard of care (52 clusters); (2) improved infant feeding (53 clusters); (3) WASH: ventilated improved pit latrine, 2 hand-washing stations, liquid soap, chlorine, infant play space, and hygiene counseling (53 clusters); or (4) feeding plus WASH (53 clusters). This substudy compared oral rotavirus vaccine (RVV) seroconversion (primary outcome), and seropositivity and geometric mean titer (GMT) (secondary outcomes), in WASH vs non-WASH infants by intention-to-treat analysis. RESULTS: We included 801 infants with documented RVV receipt and postvaccine titer measurements (329 from 84 WASH clusters; 472 from 102 non-WASH clusters); 328 infants with prevaccination titers were included in the primary outcome. Thirty-three of 109 (30.3%) infants in the WASH group seroconverted following rotavirus vaccination, compared to 43 of 219 (19.6%) in the non-WASH group (absolute difference, 10.6% [95% confidence interval {CI}, .54%-20.7%]; P = .031). In the WASH vs non-WASH groups, 90 of 329 (27.4%) vs 107 of 472 (22.7%) were seropositive postvaccination (absolute difference, 4.7% [95% CI, -1.4% to 10.8%]; P = .130), and antirotavirus GMT was 18.4 (95% CI, 15.6-21.7) U/mL vs 14.9 (95% CI, 13.2-16.8) U/mL (P = .072). CONCLUSIONS: Improvements in household WASH led to modest but significant increases in seroconversion to RVV in rural Zimbabwean infants. CLINICAL TRIALS REGISTRATION: NCT01824940.

Independent and combined effects of improved water, sanitation, and hygiene (WASH) and improved complementary feeding on early neurodevelopment among children born to HIV-negative mothers in rural Zimbabwe: Substudy of a cluster-randomized trial.

BACKGROUND: Globally, nearly 250 million children (43% of all children under 5 years of age) are at risk of compromised neurodevelopment due to poverty, stunting, and lack of stimulation. We tested the independent and combined effects of improved water, sanitation, and hygiene (WASH) and improved infant and young child feeding (IYCF) on early child development (ECD) among children enrolled in the Sanitation Hygiene Infant Nutrition Efficacy (SHINE) trial in rural Zimbabwe. METHODS AND FINDINGS: SHINE was a cluster-randomized community-based 2×2 factorial trial. A total of 5,280 pregnant women were enrolled from 211 clusters (defined as the catchment area of 1-4 village health workers [VHWs] employed by the Zimbabwean Ministry of Health and Child Care). Clusters were randomly allocated to standard of care, IYCF (20 g of small-quantity lipid-based nutrient supplement per day from age 6 to 18 months plus complementary feeding counseling), WASH (ventilated improved pit latrine, handwashing stations, chlorine, liquid soap, and play yard), and WASH + IYCF. Primary outcomes were child length-for-age Z-score and hemoglobin concentration at 18 months of age. Children who completed the 18-month visit and turned 2 years (102-112 weeks) between March 1, 2016, and April 30, 2017, were eligible for the ECD substudy. We prespecified that primary inferences would be drawn from findings of children born to HIV-negative mothers; these results are presented in this paper. A total of 1,655 HIV-unexposed children (64% of those eligible) were recruited into the ECD substudy from 206 clusters and evaluated for ECD at 2 years of age using the Malawi Developmental Assessment Tool (MDAT) to assess gross motor, fine motor, language, and social skills; the MacArthur-Bates Communicative Development Inventories (CDI) to assess vocabulary and grammar; the A-not-B test to assess object permanence; and a self-control task. Outcomes were analyzed in the intention-to-treat population. For all ECD outcomes, there was not a statistical interaction between the IYCF and WASH interventions, so we estimated the effects of the interventions by comparing the 2 IYCF groups with the 2 non-IYCF groups and the 2 WASH groups with the 2 non-WASH groups. The mean (95% CI) total MDAT score was modestly higher in the IYCF groups compared to the non-IYCF groups in unadjusted analysis: 1.35 (0.24, 2.46; p = 0.017); this difference did not persist in adjusted analysis: 0.79 (-0.22, 1.68; p = 0.057). There was no evidence of impact of the IYCF intervention on the CDI, A-not-B, or self-control tests. Among children in the WASH groups compared to those in the non-WASH groups, mean scores were not different for the MDAT, A-not-B, or self-control tests; mean CDI score was not different in unadjusted analysis (0.99 [95% CI -1.18, 3.17]) but was higher in children in the WASH groups in adjusted analysis (1.81 [0.01, 3.61]). The main limitation of the study was the specific time window for substudy recruitment, meaning not all children from the main trial were enrolled. CONCLUSIONS: We found little evidence that the IYCF and WASH interventions implemented in SHINE caused clinically important improvements in child development at 2 years of age. Interventions that directly target neurodevelopment (e.g., early stimulation) or that more comprehensively address the multifactorial nature of neurodevelopment may be required to support healthy development of vulnerable children. TRIAL REGISTRATION: ClinicalTrials.gov NCT01824940.

The implications of three major new trials for the effect of water, sanitation and hygiene on childhood diarrhea and stunting: a consensus statement.

BACKGROUND: Three 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 BODY: Here 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. CONCLUSION: These 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.