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Penazzato M.,University College London | Penazzato M.,World Health Organization | Prendergast A.J.,University College London | Prendergast A.J.,Queen Mary, University of London | And 4 more authors.
AIDS | Year: 2014

Background: Treatment of young HIV-infected children is challenging because of rapid disease progression, high viral loads and few drug options. This review was undertaken to update evidence on the management of young HIV-infected children and to inform the development of the 2013 WHO guidelines for antiretroviral therapy (ART) in low and middle-income countries. Design: A systematic review and meta-analysis. Methods: We identified and critically assessed randomized controlled trials that evaluated treatment strategies in perinatally HIV-infected infants and young children (aged 3 years). Results: Eight studies were included. Antiretroviral therapy (ART) initiation in asymptomatic infants led to 74% reduction in mortality or disease progression [hazard ratio 0.36, 95% confidence interval (CI) 0.18-0.74, P=0.0002]. Regardless of previous exposure to prevention of mother to child transmission (PMTCT), treatment failure at 24 weeks was more likely in children starting nevirapine-based than in those starting lopinavir/ritonavir (lopinavir/r)-based ART (hazard ratio 1.79, 95% CI 1.33-2.41, P=0.0001). Infants starting lopinavir/r-based ART and substituting lopinavir/r with nevirapine once virologic suppressionwas achievedwere less likely to experience viral load more than 50 copies/ml (hazard ratio 0.62, 95%CI 0.41-0.92, P=0.02) butmore likely to have confirmed virologic failure (1000 copies/ml) than those remaining on lopinavir/r (hazard ratio 10.19, 95% CI 2.36-43.94, P=0.002). Children receiving induction-maintenance ART (four-drug NNRTIbased regimen for 36 weeks followed by three-drug ART) showed better short-term immunologic and virologic responses, but no long-termbenefits. The only trial comparing continuous ART from infancy with interrupted ART beyond infancy was terminated early because the duration of treatment interruption was less than 3 months in most infants. Conclusion: ART initiation in asymptomatic infants reduces morbidity and mortality. Lopinavir/r-based first-line ART is superior to nevirapine-based regimens in young children, regardless of PMTCT exposure, but lopinavir/r use is challenging. Substituting lopinavir/r with nevirapine following virologic suppression may be feasible where viral load testing is available. Considering current evidence, induction-maintenance and treatment interruption strategies are not recommended. This review contributed to the evidence base for the 2013 WHO guidelines on antiretroviral therapy, which recommend that all children below 3 years start lopinavir/r-based ART and that lopinavir/r can be substituted with nevirapine once sustained virologic suppression is achieved. © 2014 Wolters Kluwer Health. Source

Prendergast A.J.,Queen Mary, University of London | Prendergast A.J.,Zvitambo Institute for Maternal Child Health Research | Rukobo S.,Zvitambo Institute for Maternal Child Health Research | Chasekwa B.,Zvitambo Institute for Maternal Child Health Research | And 6 more authors.
PLoS ONE | Year: 2014

Background: Stunting affects one-third of children in developing countries, but the causes remain unclear. We hypothesized that enteropathy leads to low-grade inflammation, which suppresses the growth hormone-IGF axis and mediates stunting. Methods: We conducted a case-control study of 202 HIV-unexposed Zimbabwean infants who were stunted (height-for-age Z-score (HAZ) <-2; cases) or non-stunted (HAZ >-0.5; controls) at 18 months. We measured biomarkers of intestinal damage (I-FABP), inflammation (CRP, AGP, IL-6) and growth hormone-IGF axis (IGF-1, IGFBP3) in infant plasma at 6 weeks and 3, 6, 12 and 18 months, and in paired maternal-infant plasma at birth. Adjusted mean differences between biomarkers were estimated using regression models. Multivariate odds ratios of stunting were estimated by logistic regression. Results: At birth, cases were shorter (median (IQR) HAZ -1.00 (-1.53, -0.08) vs 0.03 (-0.57, 0.62,); P<0.001) than controls and their mothers had lower levels of IGF-1 (adjusted mean difference (95%CI) -21.4 (-39.8, -3.1) ng/mL). From 6 weeks to 12 months of age, levels of CRP and AGP were consistently higher and IGF-1 and IGFBP3 lower in cases versus controls; IGF-1 correlated inversely with inflammatory markers at all time-points. I-FABP increased between 3-12 months, indicating extensive intestinal damage during infancy, which was similar in cases and controls. In multivariate analysis, higher log10 levels of CRP (aOR 3.06 (95%CI 1.34, 6.99); P = 0.008) and AGP (aOR 7.87 (95%CI 0.74, 83.74); P = 0.087) during infancy were associated with stunting. There were no associations between levels of I-FABP, IL-6, sCD14 or EndoCAb and stunting. Conclusions: Stunting began in utero and was associated with low maternal IGF-1 levels at birth. Inflammatory markers were higher in cases than controls from 6 weeks of age and were associated with lower levels of IGF-1 throughout infancy. Higher levels of CRP and AGP during infancy were associated with stunting. These findings suggest that an extensive enteropathy occurs during infancy and that low-grade chronic inflammation may impair infant growth. © 2014 Prendergast et al. Source

Brigham T.,Highline Community College | Chasekwa B.,Zvitambo Institute for Maternal Child Health Research | Mbuya M.N.N.,Zvitambo Institute for Maternal Child Health Research | Tielsch J.M.,George Washington University | Prendergast A.J.,Queen Mary, University of London
American Journal of Tropical Medicine and Hygiene | Year: 2014

The cornerstone of schistosomiasis control is mass praziquantel treatment in high prevalence areas. Adults are an important target population, given increasing recognition of the burden of male and female genital schistosomiasis. However, use of weighing scales to calculate praziquantel dosing in rural areas can be challenging. For school-age children, the World Health Organization (WHO) has approved a dose pole to simplify praziquantel dosing based on height. We modified the pediatric dose pole by adding two height categories and incorporating a simple overweight/obesity adjustment, for simplified mass treatment of adults in sub-Saharan Africa. Using the rural Zimbabwean Demographic and Health Survey data, we show that the modified dose pole with body mass index adjustment would result in > 98% of adults receiving an acceptable dose (30-60 mg/kg), with only 1.4%and 0.3% receiving an inadequate dose (< 30 mg/kg) or high dose (> 60 mg/kg), respectively. An adult dose pole may provide a more feasible alternative to weighing scales in community-based praziquantel treatment programs. Copyright © 2014 by The American Society of Tropical Medicine and Hygiene. Source

Lindenmayer G.W.,Zvitambo Institute for Maternal Child Health Research | Stoltzfus R.J.,Cornell University | Prendergast A.J.,Zvitambo Institute for Maternal Child Health Research | Prendergast A.J.,Queen Mary, University of London
Advances in Nutrition | Year: 2014

Zinc deficiency affects one-fifth of the world's population and leads to substantial morbidity and mortality. Environmental enteropathy (EE), a subclinical pathology of altered intestinal morphology and function, is almost universal among people living in developing countries and affects long-termgrowth and health. This review explores the overlapping nature of these 2 conditions and presents evidence for their interaction. EE leads to impaired zinc homeostasis, predominantly due to reduced absorptive capacity arising from disturbed intestinal architecture, and zinc deficiency exacerbates several of the proposed pathways that underlie EE, including intestinal permeability, enteric infection, and chronic inflammation. Ongoing zinc deficiency likely perpetuates the adverse outcomes of EE by worsening malabsorption, reducing intestinal mucosal immune responses, and exacerbating systemic inflammation. Although the etiology of EE is predominantly environmental, zinc deficiency may also have a role in its pathogenesis. Given the impact of both EE and zinc deficiency on morbidity and mortality in developing countries, better understanding the relation between these 2 conditions may be critical for developing combined interventions to improve child health. © 2014 American Society for Nutrition. Source

Gough E.K.,McGill University | Moodie E.E.M.,McGill University | Prendergast A.J.,Zvitambo Institute for Maternal Child Health Research | Prendergast A.J.,Queen Mary, University of London | And 12 more authors.
BMJ (Online) | Year: 2014

Objective:s To determine whether antibiotic treatment leads to improvements in growth in prepubertal children in low and middle income countries, to determine the magnitude of improvements in growth, and to identify moderators of this treatment effect. Design: Systematic review and meta-analysis. Data sources: Medline, Embase, Scopus, the Cochrane central register of controlled trials, and Web of Science. Study selection: Randomised controlled trials conducted in low or middle income countries in which an orally administered antibacterial agent was allocated by randomisation or minimisation and growth was measured as an outcome. Participants aged 1 month to 12 years were included. Control was placebo or non-antimicrobial intervention. Results: Data were pooled from 10 randomised controlled trials representing 4316 children, across a variety of antibiotics, indications for treatment, treatment regimens, and countries. In random effects models, antibiotic use increased height by 0.04 cm/month (95% confidence interval 0.00 to 0.07) and weight by 23.8 g/month (95% confidence interval 4.3 to 43.3). After adjusting for age, effects on height were larger in younger populations and effects on weight were larger in African studies compared with other regions. Conclusion Antibiotics have a growth promoting effect in prepubertal children in low and middle income countries. This effect was more pronounced for ponderal than for linear growth. The antibiotic growth promoting effect may be mediated by treatment of clinical or subclinical infections or possibly by modulation of the intestinal microbiota. Better definition of the mechanisms underlying this effect will be important to inform optimal and safe approaches to achieving healthy growth in vulnerable populations. Source

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