Effectiveness and Safety of Reactive Focal Mass Drug Administration versus Reactive Case Detection to Reduce Malaria Transmission in Very Low-Endemic Setting of Eswatini: A Pragmatic Cluster Randomised Controlled Trial

Abstract

Background: Screening and treatment near malaria index cases (reactive case detection (RACD)), is widely practiced, but the rapid diagnostic tests (RDTs) used miss low density infections. Presumptive treatment near index cases (reactive focal mass drug administration (rfMDA)) may be safe and more effective but has not been evaluated in very low-endemic settings. Methods: A cluster-randomised controlled trial was conducted in Eswatini, a very low -endemic setting. 77 clusters were randomised to rfMDA using dihydroartemisinin-piperaquine (DP) or RACD involving RDTs and artemether lumefantrine (AL), administered within 200 or 500 m of index cases, respectively. Interventions were delivered by the local programme, and evaluated using an intention-to-treat analysis. Findings: From Sept 2015–Aug 2017, 220 index cases from 47 clusters triggered 49 RACD events and 68 rfMDA events. RACD and rfMDA were delivered to 1 696 and 1 932 individuals, respectively. For rfMDA versus RACD, cumulative incidences (per 1 000 person-years) of all malaria were 2·11 (95% CI 1·73–2·59) and 1·97 (1·57–2·47), respectively; and of locally acquired malaria, they were 1·29 (95% CI 1·00–1·67) and 0·97 (0·71–1·34), respectively. Adjusting for imbalance in baseline incidence, incidence rate ratio (aIRR) for rfMDA versus RACD was 0·93 (95% CI 0·54–1·60) for all malaria and 0·77 (95% CI 0·38–1·56) for locally acquired malaria. No serious adverse events occurred. Interpretation: In a very low-endemic, real-world setting, rfMDA was safe. There was limited statistical power to estimate its effectiveness compared to RACD. Trial Registration: This trial is registered with the ClinicalTrials.gov (NCT02315690). Funding Statement: This study was supported by the Bill & Melinda Gates Foundation (A122394) and the Horchow Family Fund (5300375400). Declaration of Interests: The authors have no competing interests to report. Ethics Approval Statement: Ethics approval was obtained from Eswatini Ministry of Health (MOH) (MH/599C) and University of California San Francisco (14-15226). Written informed consent was obtained from individual participants. For children less than 18 years, written informed consent from a parent or guardian was required, as was written assent for children 12–17 years.