Mass drug administration to reduce malaria incidence in a low-to-moderate endemic setting: short-term impact results from a cluster randomised controlled trial in Senegal

BackgroundIn Africa, the scale-up of malaria control interventions, including seasonal malaria chemoprevention (SMC), has dramatically reduced malaria burden, but progress toward malaria elimination has stalled. We evaluated mass drug administration (MDA) as a strategy to accelerate reductions in malaria incidence in Senegal. MethodsWe conducted an open-label, cluster-randomised controlled trial in a low-to-moderate transmission setting of Tambacounda, Senegal. Eligible villages had a population size between 200-800. All villages received pyrethroid-piperonyl butoxide bednets and proactive community case management of malaria at baseline. Sixty villages were randomised 1:1 to either three cycles of MDA with dihydroartemisinin-piperaquine+single-low dose primaquine administered to individuals aged [&ge;]3 months, six-weeks apart starting the third week of June (intervention), or standard-of-care, which included three monthly cycles of SMC with sulfadoxine-pyrimethamine+amodiaquine administered to children aged 3-120 months starting end of July (control). MDA and SMC were delivered door-to-door. The primary outcome was clinical malaria incidence in all ages assessed during the peak transmission season (July-December), the year after intervention. Here, we report safety, coverage, and impact outcomes during the intervention year. The trial is registered at ClinicalTrials.Gov (NCT04864444). FindingsBetween June 21, 2021 and October 3, 2021, 6505, 7125, and 7250 participants were administered MDA and 3202, 3174, and 3146 participants were administered SMC across cycles. Coverage of [&ge;]1 dose of MDA drugs was 79%, 82%, and 83% across cycles. During the transmission season of the intervention year, MDA was associated with a 55% [95% CI: 28%- 72%] lower incidence of malaria compared to control (MDA: 93 cases/1000 population; control: 173 cases/1000 population). No serious adverse events were reported in either arm. InterpretationIn low-to-moderate malaria transmission settings with scaled-up malaria control interventions, MDA with dihydroartemisinin-piperaquine+single-low dose primaquine is effective and well-tolerated for reducing malaria incidence. Further analyses will focus on the sustainability of this reduction. FundingUnited States Presidents Malaria Initiative Research in contextO_ST_ABSEvidence before this studyC_ST_ABSThe current World Health Organization (WHO) guidelines recommend that malaria programmes consider mass drug administration (MDA) for Plasmodium falciparum transmission reduction in low-to-very low transmission settings (broadly defined as parasite prevalence <10% or annual malaria incidence of <250 cases per population). In moderate-to-high transmission areas, MDA is recommended for rapid reduction of disease burden, but not for transmission reduction due to the lack of published studies demonstrating its short- or long-term benefits. Among the numerous studies that contributed to this recommendation, five evaluated the antimalarial combination, dihydroartemisinin-piperaquine + single low-dose primaquine. However, none of the studies were conducted in countries implementing seasonal malaria chemoprevention as part of their routine malaria control strategy. On January 23, 2024, we conducted a PubMed search using the following term: "mass drug administration" AND "dihydroartemisinin-piperaquine". We found one additional cluster randomised controlled trial conducted in a moderate transmission setting of The Gambia (an SMC-implementing country), that evaluated mass drug administration with the antimalarial combination, dihydroartemisinin-piperaquine + ivermectin. This study demonstrated that MDA was associated with a 70% reduction in the odds of PCR-confirmed malaria two months after the last round of MDA. However, given the study demonstrated little evidence on entomological outcomes, authors concluded that much of the observed effect of MDA was likely attributable to the antimalarial efficacy of dihydroartemisinin-piperaquine. Added value of this studyOur study adds to the current evidence base demonstrating the benefits of MDA with dihydroartemisinin-piperaquine + single-dose primaquine on malaria burden reduction and may have impacts on short-term transmission. Combined with The Gambia trial results, our study provides new evidence demonstrating that MDA with dihydroartemisinin-piperaquine can have short-term benefits on transmission in low and moderate transmission settings where malaria transmission is highly seasonal. Implications of all the available evidenceAs countries in sub-Sahelian and Sahelian Africa progressively scale-up their malaria control interventions, they will reach a plateau where no further gains can be made. In low and moderate transmission settings, MDA is a well-tolerated and effective intervention for rapidly reducing malaria burden and may have an impact on transmission in the short-term.