Measuring effects of ivermectin-treated cattle on malaria vectors in Vietnam: a village-randomized trial

Background Malaria elimination using current tools has stalled in many areas. Ivermectin (IVM) is a broad-antiparasitic drug and mosquitocide that has been proposed as a tool for reaching malaria elimination. Under laboratory conditions, IVM has been shown to reduce the survival of Anopheles populations that have fed on IVM-treated mammals. Treating cattle with IVM has been proposed as an important contribution to malaria vector management, however, the impacts of IVM in this animal health use-case had been untested in field trials in Southeast Asia. Methods Through a randomized village-based trial, this study aimed to quantify the effect of IVM-treated cattle on anopheline populations in treated vs. untreated villages in Central Vietnam. Local zebu cattle in six rural villages were included in this study. Cattle were treated with IVM at established veterinary dosages in three villages and in three additional villages, cattle were untreated as controls. The mosquito populations in all villages were sampled using cattle-baited traps for six days before, and six days after a 2-day treatment IVM-administration (intervention) period. Vector species were characterized using taxonomic keys. The impact of the intervention was analyzed using a difference-in-differences (DID) approach with generalized estimating equations (Poisson distribution with bootstrapped errors). Results Across the treated villages, 1,112 of 1,527 censused cows (73% overall; range 67% to 83%) were treated with IVM. In both control and treated villages, there was a 30% to 40% decrease in total anophelines captured in the post-intervention period as compared to the pre-intervention period. In the control villages, there were 1873 captured pre-intervention and 1079 captured during the post-intervention period. In the treated villages, there were 1594 captured pre-intervention, and 1101 captured during the post-intervention period. The DID model analysis comparing total captures between arms was not statistically significant (p = 0.67). Secondary outcomes of vector diversity found that in four villages (two treated and two control) there were statistically significant changes in the anopheline population diversity (p < 0.05) based on Shannon’s diversity index. Two villages (one treated and one control) had a statistically significant increase in diversity and two villages (one treated and one control) had a significant decrease in population diversity (p < 0.05). There were no clear trends in treated or untreated vector population evenness or richness estimates. Conclusions Unexpectedly large decreases in trapping counts post-intervention across all study villages impacted the ability of this study to quantify any differential impacts. As such, the results of this study do not provide evidence that treating cattle in villages with IVM reduces nightly captures from cattle-baited traps of female anopheles mosquitoes when compared to control villages. The lack of differential impacts may be due to several factors including the short half-life of IVM, crossover in mosquito populations between treated and control villages, feeding preferences of the mosquitoes, and mass-action effects from extensive mosquito trapping. Future studies should plan to treat at least 80% of the cattle in the village and evaluate the relationship between dose-density and mosquito prevalence. Additional studies should investigate whether IVM differentially impacts vector species at a population level. ### Competing Interest Statement JCH is a military service member of the United States government. This work was prepared as part of his official duties. Title 17 U.S.C. 105 provides that `copyright protection under this title is not available for any work of the United States Government.' Title 17 U.S.C. 101 defines a U.S. Government work as work prepared by a military service member or employee of the U.S. Government as part of that person's official duties. The views expressed in this article reflect the results of research conducted by the authors and do not necessarily reflect the official policy or position of the Department of the Navy, Defense Health Agency, Department of Defense, nor the United States Government. ### Clinical Trial This was a randomized entomological trial with only entomological outcomes. ### Funding Statement This study was supported by the Defense Malaria Assistance Program with funds from the Defense Health Agency Research and Development Program (work unit number D1428) ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. 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