Effectiveness of reactive focal mass drug administration and reactive focal vector control to reduce malaria transmission in the low malaria-endemic setting of Namibia: a cluster-randomised controlled, open-label, two-by-two factorial design trial

Abstract

Background: In low malaria-endemic settings, screening and treatment of individuals in close proximity to index cases, also known as reactive case detection (RACD), is practised for surveillance and response. However, other approaches could be more effective for reducing transmission. We aimed to evaluate the effectiveness of reactive focal mass drug administration (rfMDA) and reactive focal vector control (RAVC) in the low malaria-endemic setting of Zambezi (Namibia).

Methods: We did a cluster-randomised controlled, open-label trial using a two-by-two factorial design of 56 enumeration area clusters in the low malaria-endemic setting of Zambezi (Namibia). We randomly assigned these clusters using restricted randomisation to four groups: RACD only, rfMDA only, RAVC plus RACD, or rfMDA plus RAVC. RACD involved rapid diagnostic testing and treatment with artemether-lumefantrine and single-dose primaquine, rfMDA involved presumptive treatment with artemether-lumefantrine, and RAVC involved indoor residual spraying with pirimiphos-methyl. Interventions were administered within 500 m of index cases. To evaluate the effectiveness of interventions targeting the parasite reservoir in humans (rfMDA vs RACD), in mosquitoes (RAVC vs no RAVC), and in both humans and mosquitoes (rfMDA plus RAVC vs RACD only), an intention-to-treat analysis was done. For each of the three comparisons, the primary outcome was the cumulative incidence of locally acquired malaria cases. This trial is registered with ClinicalTrials.gov, number NCT02610400.

Findings: Between Jan 1, 2017, and Dec 31, 2017, 55 enumeration area clusters had 1118 eligible index cases that led to 342 interventions covering 8948 individuals. The cumulative incidence of locally acquired malaria was 30·8 per 1000 person-years (95% CI 12·8-48·7) in the clusters that received rfMDA versus 38·3 per 1000 person-years (23·0-53·6) in the clusters that received RACD; 30·2 per 1000 person-years (15·0-45·5) in the clusters that received RAVC versus 38·9 per 1000 person-years (20·7-57·1) in the clusters that did not receive RAVC; and 25·0 per 1000 person-years (5·2-44·7) in the clusters that received rfMDA plus RAVC versus 41·4 per 1000 person-years (21·5-61·2) in the clusters that received RACD only. After adjusting for imbalances in baseline and implementation factors, the incidence of malaria was lower in clusters receiving rfMDA than in those receiving RACD (adjusted incidence rate ratio 0·52 [95% CI 0·16-0·88], p=0·009), lower in clusters receiving RAVC than in those that did not (0·48 [0·16-0·80], p=0·002), and lower in clusters that received rfMDA plus RAVC than in those receiving RACD only (0·26 [0·10-0·68], p=0·006). No serious adverse events were reported.

Interpretation: In a low malaria-endemic setting, rfMDA and RAVC, implemented alone and in combination, reduced malaria transmission and should be considered as alternatives to RACD for elimination of malaria.

Funding: Novartis Foundation, Bill & Melinda Gates Foundation, and Horchow Family Fund.

Copyright © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.

Figures

Figure 1

Two-by-two factorial study design of reactive focal interventions Reactive case detection involved administering rapid diagnostic tests for malaria to individuals living within a 500-m radius of an index case, and treating individuals who tested positive with artemether-lumefantrine and single-dose primaquine. Reactive focal mass drug administration involved presumptively treating individuals living within a 500-m radius of an index case with artemether-lumefantrine, without testing for malaria beforehand. Reactive focal vector control involved spraying the long-lasting insecticide, pirimiphos-methyl, to the interior walls of households located within a seven-household radius of an index case. The effectiveness of three interventions were compared to three respective controls: (1) rfMDA versus RACD (B and D vs A and C); (2) RAVC versus no RAVC (C and D vs A and B); and (3) rfMDA plus RAVC versus a RACD only (D vs A).

Figure 2

Trial profile RACD=reactive case detection. RAVC=reactive vector control. rfMDA=reactive focal mass drug administration. AL=artemether-lumefantrine. RDT=rapid diagnostic test. *Eligible cases were not covered because the study team was unable to respond within 5 weeks of the index case being reported because of a high case load.