A 3-day course of either 300 mcg/kg/day or 600 mcg/kg/day of ivermectin may have similar mosquitocidal effects for up to 28-days postfeeding through membrane or direct skin feeding, according to a study published in Clinical Infectious Diseases.
Mass drug administration for malaria is being evaluated in several countries in an attempt to reduce malaria transmission and accelerate malaria elimination. Mass drug administration is the treatment of an entire population in an endemic area, regardless of individual infection status or symptoms. Currently, the most common antimalarial drug used for mass drug administration is dihydroartemisinin-piperquine because of its slow elimination, which provides 4 to 6 weeks of posttreatment prophylaxis against new infections.
Ivermectin, an antiparasitic drug that also kills mosquitoes feeding on those who have been recently treated, is a proposed and innovative tool to pair with dihydroartemisinin-piperquine to increase the effect of mass drug administration by killing the mosquitoes before they become infective. Recent studies of ivermectin at lower doses and in animals have shown promise with mosquitocidal effects lasting >2 weeks. Therefore, this randomized, double-blind, placebo-controlled mosquito feeding study was undertaken to compare mosquito mortality following direct skin and membrane feeding after 3 days of ivermectin treatment (ClinicalTrials.gov identifier: NCT02511353).
In total, 141 Kenyan adults with uncomplicated malaria were included. For 3 days, participants were co-administered dihydroartemisinin-piperquine with either 300 mcg/kg/day of ivermectin (n=24), 600 mcg/kg/day of ivermectin (n=22), or placebo (n=23). On day 7, posttreatment membrane and direct skin feeding assays were conducted. Mosquito survival was assessed daily for 28 days postfeeding. The primary outcome for this study was cumulative mosquito mortality 14 days after feeding on blood from patients who had started the 3-day ivermectin regimen 7 days earlier. The secondary outcome of this study was the daily survival of mosquitoes to day 14 postfeeding.
Direct skin feeding had a higher proportion of mosquitoes being fully fed (85.3%) compared with membrane feeding (71.2%; P <.0001); however, there was no difference between the treatment groups for either of these methods. At the 7-day mark after receiving treatment, researchers demonstrated that between the 2 ivermectin groups, mosquito mortality rate 14 days postfeeding was similar for both mosquitos that fed by direct skin contact (n=2949), and those that fed by membrane (n=7380). In terms of cumulative mortality, study authors reported a relative risk of .98 (95% CI, 0.90-1.06; P =.69) for mosquito mortality from feeding on participants in the 600 mcg/kg/day ivermectin group and a relative risk of 1.01 (95% CI, 0.98-1.03; P = .69) for those that fed on participants in the 300 mcg/kg/day ivermectin group. Hazard ratios for survival time for direct-contact fed mosquitos and membrane-fed mosquitos were .93 and 1.01 for the 300-mcg and 600-mcg ivermectin groups, respectively
Further, these results were consistent by body mass index, gender, and across the range of ivermectin capillary concentrations studied (0.72 to 73.9 ng/mL).
Overall, the study authors concluded that, “Direct skin feeding and membrane feeding on day 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.”
Smit MR, Ochomo EO, Aljayyoussi G, et al. Human direct skin feeding versus membrane feeding to assess the mosquitocidal efficacy of high-dose ivermectin (IVERMAL trial) [published online April 16, 2019]. Clin Infect Dis. doi:10.1093cid/ciy1063