MOSQUITOCIDAL EFFECTS OF ORALLY ADMINISTERED IVERMECTIN AGAINST ANOPHELES GAMBIAE SENSU STRICTO

Abstract

Introduction: The progress towards malaria elimination has relatively stagnated since 2015 attributed in part to the over reliance on insecticide-based vector control methods and ensuing selective pressure that has led to increased insensitivity of vectors to insecticides and behavioral changes that contribute to the persistence of malaria transmission. New and improved vector control approaches are needed to supplement existing tools. Endectocides and ivermectin is one such tool. This current study was undertaken to evaluate the mosquitocidal effect of different ivermectin oral regimens on Anopheles gambiae s.s mosquitoes with the aim of gathering evidence on most advantageous dose regimen for mass drug administration campaigns for malaria vector control. Methods: A Phase II open-label randomised controlled trial was carried out as part of the Broad One-Health Endectocide-based Malaria initiative in Africa project (BOHEMIA). Sixteen healthy human subjects were recruited from Ngerenya village (Kilifi) and randomized into three groups: 1) single dose 400mcg/Kg; 2) 300mcg/Kg given once a day for three consecutive days; and 3) control (no treatment). Participants were enrolled in four permuted cohorts of four participants each (3 participants were assigned to an ivermectin-treatment and 1 to control). Participants were followed up for 28 days during which blood was withdrawn at different time’s points (Day 0+4hrs, D7, D10, D14, D21, and D28) and fed to mosquitoes to assess mosquitocidal effect post-treatment. Mosquito blood feeding was done by direct membrane feeding assay (DMFA), where a total of 150 insectary reared female An. gambiae s.s Kilifi strain (2-5 days old) were fed on each participant blood collected at the different timepoints. After blood feeding mosquitoes were kept under standard insectary conditions and monitored for daily survival for 28 days. Data was analyzed with STATA Version 17 software using Kaplan Meier curves for survival curve estimation, log rank test for a statistical comparison and Cox proportional hazard regressions to show the variability in the drug effect. Results: Ivermectin at a dose of 400mcg/kg given once was effective for 21 days (HR=1.80 (1.46-2.23), p<0.0001) while 300mcg/kg given thrice taking 28 days (HR=2.53 (2.06-3.10), P<0.0001). Mosquitoes fed on 400mcg/kg blood at 0+4hrs (HR=22.14 (17.07-28.72), p<0.0001) to day 7 (HR=4.56 (3.8-5.45), p<0.0001) post treatment and 300mcg/kg blood at 0+4hrs (HR=8.72 (7.25-10.49), p<0.0001) was unlikely to survive for more than 10 days. Overall, the median mosquito survival time was 17 and 23 days for ivermectin 400mcg/kg and 300mcg/kg respectively. Conclusion: Single high dose ivermectin 400mcg/kg was more hazardous to mosquitoes than 300mcg/kg given thrice. Sustained mosquitocidal effect was observed for both doses for a period of 21 days’ post treatment. Ivermectin 400mcg/kg is a good candidate for MDA against malaria vectors. The dose regime provides adequate mosquitocidal effect for 21 days. Furthermore, 400mcg/Kg is already approved for human use in countries with stringent regulatory approvals (SRA) and is likely to be more feasible to administer in an MDA campaign ensuring higher levels of compliance compared to a 3-day regimen. Keywords: Malaria, An. gambiae s.s, ivermectin, endectocide, direct membrane feeding assay, randomised controlled trial, Kilifi