Preventive malaria treatment among school-aged children in sub-Saharan Africa: a systematic review and meta-analyses.

BACKGROUND: The burden of malaria infection in sub-Saharan Africa among school-aged children aged 5-15 years is underappreciated and represents an important source of human-to-mosquito transmission of Plasmodium falciparum. Additional interventions are needed to control and eliminate malaria. We aimed to assess whether preventive treatment of malaria might be an effective means of reducing P falciparum infection and anaemia in school-aged children and lowering parasite transmission. METHODS: In this systematic review and two meta-analyses, we searched the online databases PubMed, Embase, Cochrane CENTRAL, and Clinicaltrials.gov for intervention studies published between Jan 1, 1990, and Dec 14, 2018. We included randomised studies that assessed the effect of antimalarial treatment among asymptomatic school-aged children aged 5-15 years in sub-Saharan Africa on prevalence of P falciparum infection and anaemia, clinical malaria, and cognitive function. We first extracted data for a study-level meta-analysis, then contacted research groups to request data for an individual participant data meta-analysis. Outcomes of interest included prevalence of P falciparum infection detected by microscopy, anaemia (study defined values or haemoglobin less than age-adjusted and sex-adjusted values), clinical malaria (infection and symptoms on the basis of study-specific definitions) during follow-up, and code transmission test scores. We assessed effects by treatment type and duration of time protected, and explored effect modification by transmission setting. For study-level meta-analysis, we calculated risk ratios for binary outcomes and standardised mean differences for continuous outcomes and pooled outcomes using fixed-effect and random-effects models. We used a hierarchical generalised linear model for meta-analysis of individual participant data. This study is registered with PROSPERO, CRD42016030197. FINDINGS: Of 628 studies identified, 13 were eligible for the study-level meta-analysis (n=16 309). Researchers from 11 studies contributed data on at least one outcome (n=15 658) for an individual participant data meta-analysis. Interventions and study designs were highly heterogeneous; overall risk of bias was low. In the study-level meta-analysis, treatment was associated with reductions in P falciparum prevalence (risk ratio [RR] 0·27, 95% CI 0·17-0·44), anaemia (0·77, 0·65-0·91), and clinical malaria (0·40, 0·28-0·56); results for cognitive outcomes are not presented because data were only available for three trials. In our individual participant data meta-analysis, we found treatment significantly decreased P falciparum prevalence (adjusted RR [ARR] 0·46, 95% CI 0·40-0·53; p<0·0001; 15 648 individuals; 11 studies), anaemia (ARR 0·85, 0·77-0·92; p<0·0001; 15 026 individuals; 11 studies), and subsequent clinical malaria (ARR 0·50, 0·39-0·60; p<0·0001; 1815 individuals; four studies) across transmission settings. We detected a marginal effect on cognitive function in children older than 10 years (adjusted mean difference in standardised test scores 0·36, 0·01-0·71; p=0·044; 3962 individuals; five studies) although we found no significant effect when combined across all ages. INTERPRETATION: Preventive treatment of malaria among school-aged children significantly decreases P falciparum prevalence, anaemia, and risk of subsequent clinical malaria across transmission settings. Policy makers and programme managers should consider preventive treatment of malaria to protect this age group and advance the goal of malaria elimination, while weighing these benefits against potential risks of chemoprevention. FUNDING: US National Institutes of Health and Burroughs Wellcome Fund/ASTMH Fellowship.

Effect of intermittent preventive treatment of malaria on health and education in schoolchildren: a cluster-randomised, double-blind, placebo-controlled trial.

BACKGROUND: Malaria is a major cause of morbidity and mortality in early childhood, yet its consequences for health and education during the school-age years remain poorly understood. We examined the effect of intermittent preventive treatment (IPT) in reducing anaemia and improving classroom attention and educational achievement in semi-immune schoolchildren in an area of high perennial transmission. METHODS: A stratified, cluster-randomised, double-blind, placebo-controlled trial of IPT was done in 30 primary schools in western Kenya. Schools were randomly assigned to treatment (sulfadoxine-pyrimethamine in combination with amodiaquine or dual placebo) by use of a computer-generated list. Children aged 5-18 years received three treatments at 4-month intervals (IPT n=3535, placebo n=3223). The primary endpoint was the prevalence of anaemia, defined as a haemoglobin concentration below 110 g/L. This outcome was assessed through cross-sectional surveys 12 months post-intervention. Analysis was by both intention to treat, excluding children with missing data, and per protocol. This study is registered with ClinicalTrials.gov, number NCT00142246. FINDINGS: 2604 children in the IPT group and 2302 in the placebo group were included in the intention-to-treat analysis of the primary outcome; the main reason for exclusion was loss to follow-up. Prevalence of anaemia at 12 months averaged 6.3% in the IPT group and 12.6% in the placebo group (adjusted risk ratio 0.52, 95% CI 0.29-0.93; p=0.028). Significant improvements were also seen in two of the class-based tests of sustained attention, with a mean increase in code transmission test score of 6.05 (95% CI 2.83-9.27; p=0.0007) and counting sounds test score of 1.80 (0.19-3.41; p=0.03), compared with controls. No effect was shown for inattentive or hyperactive-compulsive behaviours or on educational achievement. The per-protocol analysis yielded similar results. 23 serious adverse events were reported within 28 days of any treatment (19 in the IPT group and four in the placebo group); the main side-effects were problems of balance, dizziness, feeling faint, nausea, and/or vomiting shortly after treatment. INTERPRETATION: IPT of malaria improves the health and cognitive ability of semi-immune schoolchildren. Effective malaria interventions could be a valuable addition to school health programmes.

Costs and cost-effectiveness of delivering intermittent preventive treatment through schools in western Kenya.

BACKGROUND: Awareness of the potential impact of malaria among school-age children has stimulated investigation into malaria interventions that can be delivered through schools. However, little evidence is available on the costs and cost-effectiveness of intervention options. This paper evaluates the costs and cost-effectiveness of intermittent preventive treatment (IPT) as delivered by teachers in schools in western Kenya. METHODS: Information on actual drug and non-drug associated costs were collected from expenditure and salary records, government budgets and interviews with key district and national officials. Effectiveness data were derived from a cluster-randomised-controlled trial of IPT where a single dose of sulphadoxine-pyrimethamine and three daily doses of amodiaquine were provided three times in year (once termly). Both financial and economic costs were estimated from a provider perspective, and effectiveness was estimated in terms of anaemia cases averted. A sensitivity analysis was conducted to assess the impact of key assumptions on estimated cost-effectiveness. RESULTS: The delivery of IPT by teachers was estimated to cost US$ 1.88 per child treated per year, with drug and teacher training costs constituting the largest cost components. Set-up costs accounted for 13.2% of overall costs (equivalent to US$ 0.25 per child) whilst recurrent costs accounted for 86.8% (US$ 1.63 per child per year). The estimated cost per anaemia case averted was US$ 29.84 and the cost per case of Plasmodium falciparum parasitaemia averted was US$ 5.36, respectively. The cost per case of anaemia averted ranged between US$ 24.60 and 40.32 when the prices of antimalarial drugs and delivery costs were varied. Cost-effectiveness was most influenced by effectiveness of IPT and the background prevalence of anaemia. In settings where 30% and 50% of schoolchildren were anaemic, cost-effectiveness ratios were US$ 12.53 and 7.52, respectively. CONCLUSION: This study provides the first evidence that IPT administered by teachers is a cost-effective school-based malaria intervention and merits investigation in other settings.

Relationships between anaemia and parasitic infections in Kenyan schoolchildren: a Bayesian hierarchical modelling approach.

Anaemia is multi-factorial in origin and disentangling its aetiology remains problematic, with surprisingly few studies investigating the relative contribution of different parasitic infections to anaemia amongst schoolchildren. We report cross-sectional data on haemoglobin, malaria parasitaemia, helminth infection and undernutrition among 1523 schoolchildren enrolled in classes 5 and 6 (aged 10-21 years) in 30 primary schools in western Kenya. Bayesian hierarchical modelling was used to investigate putative relationships. Children infected with Plasmodium falciparum or with a heavy Schistosoma mansoni infection, stunted children and girls were found to have lower haemoglobin concentrations. Children heavily infected with S. mansoni were also more likely to be anaemic compared with uninfected children. This study further highlights the importance of malaria and intestinal schistosomiasis as contributors to reduced haemoglobin levels among schoolchildren and helps guide the implementation of integrated school health programmes in areas of differing parasite transmission.