BACKGROUND: The World Health Organization has yet to endorse deployment of topical repellents for malaria prevention as part of public health campaigns. We aimed to quantify the effectiveness of repellent distributed by the village health volunteer (VHV) network in the Greater Mekong Subregion (GMS) in reducing malaria in order to advance regional malaria elimination. METHODS AND FINDINGS: Between April 2015 and June 2016, a 15-month stepped-wedge cluster randomised trial was conducted in 116 villages in Myanmar (stepped monthly in blocks) to test the effectiveness of 12% N,N-diethylbenzamide w/w cream distributed by VHVs, on Plasmodium spp. infection. The median age of participants was 18 years, approximately half were female, and the majority were either village residents (46%) or forest dwellers (40%). No adverse events were reported during the study. Generalised linear mixed modelling estimated the effect of repellent on infection detected by rapid diagnostic test (RDT) (primary outcome) and polymerase chain reaction (PCR) (secondary outcome). Overall Plasmodium infection detected by RDT was low (0.16%; 50/32,194), but infection detected by PCR was higher (3%; 419/13,157). There was no significant protection against RDT-detectable infection (adjusted odds ratio [AOR] = 0.25, 95% CI 0.004-15.2, p = 0.512). In Plasmodium-species-specific analyses, repellent protected against PCR-detectable P. falciparum (adjusted relative risk ratio [ARRR] = 0.67, 95% CI 0.47-0.95, p = 0.026), but not P. vivax infection (ARRR = 1.41, 95% CI 0.80-2.47, p = 0.233). Repellent effects were similar when delayed effects were modelled, across risk groups, and regardless of village-level and temporal heterogeneity in malaria prevalence. The incremental cost-effectiveness ratio was US$256 per PCR-detectable infection averted. Study limitations were a lower than expected Plasmodium spp. infection rate and potential geographic dilution of the intervention. CONCLUSIONS: In this study, we observed apparent protection against new infections associated with the large-scale distribution of repellent by VHVs. Incorporation of repellent into national strategies, particularly in areas where bed nets are less effective, may contribute to the interruption of malaria transmission. Further studies are warranted across different transmission settings and populations, from the GMS and beyond, to inform WHO public health policy on the deployment of topical repellents for malaria prevention. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry (ACTRN12616001434482).
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We would like to thank local communities and VHVs for their participation in the research; KMSS staff Win Tun Kyi, Augustine Tual Sian Piang, Min Thant Zin Latt, Nwe Ni Aye, and Khine Zar Lwin (KMSS National Office, Yangon, Myanmar); Joseph Maung Win, Tun Tun Aung, Richard Joseph, Shine Thu Aung, and Thet Naing, Myo Tint (KMSS Yangon, Yangon, Myanmar); Ludovico Saw Piko, Benedetta, Win Win Aye, Ngo Petru, Maurice Nyo, Daniel Win, and Saw Golbert (KMSS Taunggo, Taunggo, Myanmar); Albino Htwe Win, Tin Aung, Perpetua Aye Aye Mu, Mu Paula, John Bosco, Alfred, John Min Aung, and Poe Reh (KMSS Loikaw, Loikaw, Myanmar); and Paul Thar San, Saw Isidore, Theresa, Saw Michael, and Saw Pho Mue (KMSS Hpa An, Hpa An, Myanmar) for the local advocacy, coordination, and preliminary planning and implementation of field work; Burnet Institute staff Toe Than Tun, Phone Myint Win, Lia Burns, Ricardo Ataide, Alissa Robertson, Josh Charles, and Nicole Romero for contributing towards technical, coordination, and management support and/or contextual inputs; Thaung Hlaing and Thandar Lwin (Myanmar Ministry of Health and Sports) for provision of policy guidance; and Department of Medical Research Ethics Review Committee for their technical guidance in planning of the field implementation of the study.