Human Direct Skin Feeding Versus Membrane Feeding to Assess the Mosquitocidal Efficacy of High-Dose Ivermectin (IVERMAL Trial).

Menno R Smit,Teun Bousema,Bernard O Abong’O,Penelope A Phillips-Howard,Feiko O Ter Kuile,Titus K Kwambai,Eric O Ochomo,Ghaith Aljayyoussi,Stephen A Ward,John E Gimnig,Aaron M Samuels,Simon K Kariuki,David Waterhouse,Nabie M Bayoh,Duolao Wang,Meghna R Desai

doi:10.1093/cid/ciy1063

Abstract

BackgroundIvermectin is being considered for mass drug administration for malaria, due to its ability to kill mosquitoes feeding on recently treated individuals. In a recent trial, 3-day courses of 300 and 600 mcg/kg/day were shown to kill Anopheles mosquitoes for at least 28 days post-treatment when fed patients’ venous blood using membrane feeding assays. Direct skin feeding on humans may lead to higher mosquito mortality, as ivermectin capillary concentrations are higher. We compared mosquito mortality following direct skin and membrane feeding.MethodsWe conducted a mosquito feeding study, nested within a randomized, double-blind, placebo-controlled trial of 141 adults with uncomplicated malaria in Kenya, comparing 3 days of ivermectin 300 mcg/kg/day, ivermectin 600 mcg/kg/day, or placebo, all co-administered with 3 days of dihydroartemisinin-piperaquine. On post-treatment day 7, direct skin and membrane feeding assays were conducted using laboratory-reared Anopheles gambiae sensu stricto. Mosquito survival was assessed daily for 28 days post-feeding.ResultsBetween July 20, 2015, and May 7, 2016, 69 of 141 patients participated in both direct skin and membrane feeding (placebo, n = 23; 300 mcg/kg/day, n = 24; 600 mcg/kg/day, n = 22). The 14-day post-feeding mortality for mosquitoes fed 7 days post-treatment on blood from pooled patients in both ivermectin arms was similar with direct skin feeding (mosquitoes observed, n = 2941) versus membrane feeding (mosquitoes observed, n = 7380): cumulative mortality (risk ratio 0.99, 95% confidence interval [CI] 0.95–1.03, P = .69) and survival time (hazard ratio 0.96, 95% CI 0.91–1.02, P = .19). Results were consistent by sex, by body mass index, and across the range of ivermectin capillary concentrations studied (0.72–73.9 ng/mL).ConclusionsDirect skin feeding and membrane feeding on day 7 resulted in similar mosquitocidal effects of ivermectin across a wide range of drug concentrations, suggesting that the mosquitocidal effects seen with membrane feeding accurately reflect those of natural biting. Membrane feeding, which is more patient friendly and ethically acceptable, can likely reliably be used to assess ivermectin’s mosquitocidal efficacy.Clinical Trials RegistrationNCT02511353.

Highlights

Ivermectin is being considered for mass-drug-administration for malaria due to its ability to kill mosquitoes feeding on recently treated individuals
The proportion of mosquitoes that fully fed was higher for direct skin feeding (2,941/3,446; 85.3%) versus membrane feeding (7,380/10,368; 71.2%) (RR 1.20, 95% CI 1.12-1.28, p
Direct skin feeding was associated with similar 14-day post-feeding mosquito mortality when fed on blood 7 days post-treatment, both in terms of cumulative mortality

Summary

Introduction

Ivermectin is being considered for mass-drug-administration for malaria due to its ability to kill mosquitoes feeding on recently treated individuals. Methods We conducted a mosquito feeding study nested within a randomized, double-blind, placebo-controlled trial of 141 adults with uncomplicated malaria in Kenya comparing 3-day ivermectin 0 (n=46), 300 (n=48), or 600 mcg/kg/day (n=47), co-administered with dihydroartemisinin-piperaquine. The 14-day-post-feeding mortality for mosquitoes fed on blood 7-days post-treatment from patients in both ivermectin arms pooled was similar with direct-skin-feeding (n=2,941 mosquitoes) versus membrane-feeding (n=7,380 mosquitoes): cumulative-mortality (RR=0.99, 0.95-1.03, p=0.69) and survival-time (HR=0.96, 0.91-1.02, p=0.19). Conclusions Direct-skin-feeding and membrane-feeding on day 7 resulted in similar mosquitocidaleffects of ivermectin across a wide range of drug-concentrations, suggesting that the mosquitocidal-effects seen with membrane-feeding accurately reflect those of naturalbiting. Ivermectin is documented to be remarkably well tolerated, even up to doses of 2,000 mcg/kg [7, 8]

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