Effectiveness and safety of reactive focal mass drug administration (rfMDA) using dihydroartemisinin-piperaquine to reduce malaria transmission in very low-endemic setting of Eswatini: a pragmatic cluster randomised controlled trial
Authors: Vilakati Sibonakaliso , Mngadi Nontokozo , Benjamin-Chung Jade , Dlamini Nomcebo , Dufour Mi-Suk Kang , Whittemore Brooke , Bhangu Khayelihle , Prach Lisa M. , Baltzell Kimberly , Nhlabathi Nomcebo , Malambe Calisile , Dlamini Bongani , Helb Danica , Greenhouse Bryan , Maphalala Gugu , Pindolia Deepa , Kalungero Muhindo , Tesfa Getahun , Gosling Roly , Ntshalintshali Nyasatu , Kunene Simon , Hsiang Michelle S. 
Published: March 2021

AbstractIntroductionTo reduce malaria transmission in very low-endemic settings, screening and treatment near 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.MethodsWe conducted a cluster-randomised controlled trial in Eswatini, a very low-endemic setting. 77 clusters were randomised to rfMDA using dihydroartemisin-piperaquine (DP) or RACD involving RDTs and artemether lumefantrine (AL). Interventions were delivered by the local programme. An intention-to-treat analysis was used to compare cluster-level cumulative confirmed malaria incidence among clusters with cases. Secondary outcomes included safety and adherence.ResultsFrom Sept 2015–Aug 2017, 220 index cases from 47 clusters triggered 49 RACD events and 68 rfMDA events. RACD and rfMDA were delivered to 1696 and 1932 individuals, respectively. Index case and target population intervention coverages for both arms were 75.6%–81.4% and adherence to DP was 98.7%. For rfMDA versus RACD, cumulative incidences (per 1000 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.ConclusionIn a very low-endemic, real-world setting, this trial is the first to evaluate rfMDA using DP. rfMDA was safe and resulted in lower cumulative incidence compared to RACD, but we were unable to confirm its effectiveness, potentially due to insufficient power. To assess impact of interventions in very low-endemic settings, multi-site, adaptive trials and use of complementary interventions may be needed.What is already known?Reactive case detection (RACD), or malaria testing and treatment in the vicinity of passively detected malaria cases, is a standard of care intervention used in low and very low transmission settings aiming for malaria elimination.Despite the use of RACD, progress toward malaria elimination has stalled in many countries and new strategies are needed.Reactive focal mass drug administration (rfMDA) is a transmission reducing strategy that has been shown to be effective in a low transmission setting, but there are no trial data from a very low transmission setting.What are the new findings?In a pragmatic, cluster-randomised controlled trial of rfMDA using dihydroartemisinin-piperaquine compared to RACD, we found that rfMDA was safe.rfMDA resulted in lower cumulative incidence, but we were unable to confirm its effectiveness compared to RACD, potentially due to insufficient power (we expected 63 total clusters would have incident cases, but observed 47).What do the new findings imply?When implemented in a real-world, very low transmission setting, rMDA was safe but evidence regarding its effectiveness to reduce transmission was weak.The challenge to show a statistically significant impact of a targeted community-based intervention in a very low transmission setting highlights the need for such trials to be multi-site, adaptive, and consider use of complementary interventions.