Evaluation of seasonal malaria chemoprevention in two areas of intense seasonal malaria transmission: Secondary analysis of a household-randomised, placebo-controlled trial in Hounde District, Burkina Faso and Bougouni District, Mali

Background Seasonal malaria chemoprevention (SMC) is now widely deployed in the Sahel, including several countries that are major contributors to the global burden of malaria. Consequently, it is important to understand whether SMC continues to provide a high level of protection and how SMC might be improved. SMC was evaluated using data from a large, household-randomised trial in Hounde, Burkina Faso and Bougouni, Mali. Methods and findings The parent trial evaluated monthly SMC plus either azithromycin (AZ) or placebo, administered as directly observed therapy 4 times per year between August and November (2014-2016). In July 2014, 19,578 children aged 3-59 months were randomised by household to study group. Children who remained within the age range 3-59 months in August each year, plus children born into study households or who moved into the study area, received study drugs in 2015 and 2016. These analyses focus on the approximately 10,000 children (5,000 per country) under observation each year in the SMC plus placebo group. Despite high coverage and high adherence to SMC, the incidence of hospitalisations or deaths due to malaria and uncomplicated clinical malaria remained high in the study areas (overall incidence rates 12.5 [95% confidence interval (CI): 11.2, 14.1] and 871.1 [95% CI: 852.3, 890.6] cases per 1,000 person-years, respectively) and peaked in July each year, before SMC delivery began in August. The incidence rate ratio comparing SMC within the past 28 days with SMC more than 35 days ago-adjusted for age, country, and household clustering-was 0.13 (95% CI: 0.08, 0.20), P < 0.001 for malaria hospitalisations and deaths from malaria and 0.21 (95% CI 0.20, 0.23), P < 0.001 for uncomplicated malaria, indicating protective efficacy of 87.4% (95% CI: 79.6%, 92.2%) and 78.3% (95% CI: 76.8%, 79.6%), respectively. The prevalence of malaria parasitaemia at weekly surveys during the rainy season and at the end of the transmission season was several times higher in children who missed the SMC course preceding the survey contact, and the smallest prevalence ratio observed was 2.98 (95% CI: 1.95, 4.54), P < 0.001. The frequency of molecular markers of sulfadoxine-pyrimethamine (SP) and amodiaquine (AQ) resistance did not increase markedly over the study period either amongst study children or amongst school-age children resident in the study areas. After 3 years of SMC deployment, the day 28 PCR-unadjusted adequate clinical and parasitological response rate of the SP + AQ regimen in children with asymptomatic malaria was 98.3% (95% CI: 88.6%, 99.8%) in Burkina Faso and 96.1% (95% CI: 91.5%, 98.2%) in Mali. Key limitations of this study are the potential overdiagnosis of uncomplicated malaria by rapid diagnostic tests and the potential for residual confounding from factors related to adherence to the monthly SMC schedule. Conclusion Despite strong evidence that SMC is providing a high level of protection, the burden of malaria remains substantial in the 2 study areas. These results emphasise the need for continuing support of SMC programmes. A fifth monthly SMC course is needed to adequately cover the whole transmission season in the study areas and in settings with similar epidemiology. Author summaryWhy was this study done? Seasonal malaria chemoprevention (SMC) is recommended for children under 5 years of age in countries of the Sahel and sub-Sahel. Many countries in West and Central Africa now have large-scale SMC programmes. The malaria burden remains high in several countries that have introduced SMC, including Burkina Faso and Mali, which are amongst the most important contributors to the global burden of malaria cases and deaths. It is important to understand whether SMC retains a high level of protection in these areas and how its impact might be improved. What did the researchers do and find? In this study, the level of protection provided by SMC was investigated using data from a large but closely supervised clinical trial in 2 districts in southern Burkina Faso and Mali. SMC was delivered 4 times per year over 3 years, reaching a very high percentage of children. All the daily doses of SMC were supervised by the study team. Specific substudies showed that molecular markers of resistance to the combination of antimalarials used for SMC were rare amongst malaria parasites and that the SMC combination was highly effective in curing infections detected at the end of the rainy season. Malaria incidence was markedly reduced in the period immediately after each SMC course. In the first 4 weeks after SMC, malaria cases were reduced by 78%, and malaria hospitalisations and deaths from malaria were reduced by 87%. Despite the benefits of SMC, the number of malaria cases, hospital admissions for malaria, and deaths from malaria remained very high in the study areas. There was a large peak in July each year, coinciding with the beginning of the rainy season, before SMC delivery began in August. What do these findings mean? SMC is likely to be averting a very large number of malaria cases, hospitalisations, and deaths in the study areas, but malaria has still not been brought under control. At least one additional monthly course of SMC is needed to address the high burden of malaria, including malaria deaths, that currently occurs outside the peak transmission season. This is likely to be the case in other areas of the Sahel that have a longer transmission season than can be covered by a 4-month SMC programme. Additional new tools are needed urgently to further reduce malaria in these districts and areas with similar epidemiology.