Effectiveness and safety of reactive focal mass drug administration (rfMDA) using dihydroartemisinin-piperaquine to reduce malaria transmission in the very low-endemic setting of Eswatini: a pragmatic cluster randomised controlled trial

Abstract

Introduction: To reduce malaria transmission in very low-endemic settings, screening and treatment near index cases (reactive case detection (RACD)), is widely practised, but the rapid diagnostic tests (RDTs) used miss low-density infections. Reactive focal mass drug administration (rfMDA) may be safe and more effective.

Methods: We conducted a pragmatic 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. 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.

Results: From September 2015 to August 2017, 222 index cases from 47 clusters triggered 46 RACD events and 64 rfMDA events. RACD and rfMDA were delivered to 1455 and 1776 individuals, respectively. Index case coverage was 69.5% and 62.4% for RACD and rfMDA, respectively. Adherence to DP was 98.7%. No serious adverse events occurred. For rfMDA versus RACD, cumulative incidences (per 1000 person-years) of all malaria were 2.11 (95% CI 1.73 to 2.59) and 1.97 (95% CI 1.57 to 2.47), respectively; and of locally acquired malaria, they were 1.29 (95% CI 1.00 to 1.67) and 0.97 (95% CI 0.71 to 1.34), respectively. Adjusting for imbalance in baseline incidence, incidence rate ratio for rfMDA versus RACD was 0.95 (95% CI 0.55 to 1.65) for all malaria and 0.82 (95% CI 0.40 to 1.71) for locally acquired malaria. Similar results were obtained in a per-protocol analysis that excluded clusters with <80% index case coverage.

Conclusion: In a very low-endemic, real-world setting, rfMDA using DP was safe, but did not lower incidence compared with RACD, potentially due to insufficient coverage and/or power. To assess impact of interventions in very low-endemic settings, improved coverage, complementary interventions and adaptive ring trial designs may be needed.

Trial registration number: NCT02315690.

Keywords: malaria; public health.

Conflict of interest statement

Competing interests: None declared.

© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.

Figures

Figure 1

Map of the study area. RACD, reactive case detection; rfMDA, reactive focal mass drug administration.

Figure 2

Trial profile showing randomisation and enrolment. *Not covered due to staff limitations, fuel shortages, weather conditions complicating transport, or no study participants being present. °Average per event. †RDT testing conducted in 227 of DP ineligibles (82.5%). As none tested positive, none were referred for treatment with AL. ‡LAMP result not available in 1/5 RDT positives. #Referred to health facilities. No symptomatic malaria cases were found. AL, artemether–lumefantrine; DP, dihydroartemisin-piperaquine; LAMP, loop-mediated isothermal amplification; RACD, reactive case detection; RDT, rapid diagnostic test; rfMDA, reactive focal mass drug administration.

Figure 3

Monthly incidence in each study arm prior to and during the intervention period. Black and red circles show the timing of separate RACD or rfMDA intervention events, respectively. RACD, reactive case detection; rfMDA, reactive focal mass drug administration.

Figure 4

Malaria-free survival curves for the outcomes of (A) all incident malaria cases and (B) local incident malaria cases. High transmission seasons occurred October to may each year. RACD, reactive case detection; rfMDA, reactive focal mass drug administration.