Ivermectin to reduce malaria transmission: a research agenda for a promising new tool for elimination

Carlos J Chaccour, Kevin C Kobylinski, Quique Bassat, Teun Bousema, Chris Drakeley, Pedro Alonso, Brian D Foy, Carlos J Chaccour, Kevin C Kobylinski, Quique Bassat, Teun Bousema, Chris Drakeley, Pedro Alonso, Brian D Foy

Abstract

Background: The heterogeneity of malaria transmission makes widespread elimination a difficult goal to achieve. Most of the current vector control measures insufficiently target outdoor transmission. Also, insecticide resistance threatens to diminish the efficacy of the most prevalent measures, indoor residual spray and insecticide treated nets. Innovative approaches are needed. The use of endectocides, such as ivermectin, could be an important new addition to the toolbox of anti-malarial measures. Ivermectin effectively targets outdoor transmission, has a novel mechanism of action that could circumvent resistance and might be distributed over the channels already in place for the control of onchocerciasis and lymphatic filariasis.

Methods: The previous works involving ivermectin and Anopheles vectors are reviewed and summarized. A review of ivermectin's safety profile is also provided. Finally three definitive clinical trials are described in detail and proposed as the evidence needed for implementation. Several smaller and specific supportive studies are also proposed.

Conclusions: The use of ivermectin solves many challenges identified for future vector control strategies. It is an effective and safe endectocide that was approved for human use more than 25 years ago. Recent studies suggest it might become an effective and complementary strategy in malaria elimination and eradication efforts; however, intensive research will be needed to make this a reality.

References

    1. Alonso PL, Brown G, Arevalo-Herrera M, Binka F, Chitnis C, Collins F, Doumbo OK, Greenwood B, Hall BF, Levine MM, Mendis K, Newman RD, Plowe CV, Rodriguez MH, Sinden R, Slutsker L, Tanner M. A research agenda to underpin malaria eradication. PLoS Med. 2011;8:e1000406. doi: 10.1371/journal.pmed.1000406.
    1. Greenwood BM, Fidock DA, Kyle DE, Kappe SH, Alonso PL, Collins FH, Duffy PE. Malaria: progress, perils, and prospects for eradication. J Clin Invest. 2008;118:1266–1276. doi: 10.1172/JCI33996.
    1. Djogbenou L, Labbe P, Chandre F, Pasteur N, Weill M. Ace-1 duplication in Anopheles gambiae: a challenge for malaria control. Malar J. 2009;8:70. doi: 10.1186/1475-2875-8-70.
    1. Ranson H, N’Guessan R, Lines J, Moiroux N, Nkuni Z, Corbel V. Pyrethroid resistance in African anopheline mosquitoes: what are the implications for malaria control? Trends Parasitol. 2011;27:91–98. doi: 10.1016/j.pt.2010.08.004.
    1. Dondorp AM, Nosten F, Yi P, Das D, Phyo AP, Tarning J, Lwin KM, Ariey F, Hanpithakpong W, Lee SJ, Ringwald P, Silamut K, Imwong M, Chotivanich K, Lim P, Herdman T, An SS, Yeung S, Singhasivanon P, Day NP, Lindegardh N, Socheat D, White NJ. Artemisinin resistance in Plasmodium falciparum malaria. N Engl J Med. 2009;361:455–467. doi: 10.1056/NEJMoa0808859.
    1. Dondorp AM, Yeung S, White L, Nguon C, Day NP, Socheat D, von Seidlein L. Artemisinin resistance: current status and scenarios for containment. Nat Rev Microbiol. 2010;8:272–280.
    1. Roll Back Malaria Partnership. The Global Malaria Action Plan. Geneva; 2008. (accessed 28/04/2013)
    1. Cotter C, Sturrock HJ, Hsiang MS, Liu J, Phillips AA, Hwang J, Gueye CS, Fullman N, Gosling RD, Feachem RG. The changing epidemiology of malaria elimination: new strategies for new challenges. Lancet. 2013. in press.
    1. The malERA Consultative Group on Vector Control. A research agenda for malaria eradication: vector control. PLoS Med. 2011;8:e1000401.
    1. Edi CV, Koudou BG, Jones CM, Weetman D, Ranson H. Multiple-insecticide resistance in Anopheles gambiae mosquitoes, Southern Cote d’Ivoire. Emerg Infect Dis. 2012;18:1508–1511. doi: 10.3201/eid1809.120262.
    1. Govella NJ, Ferguson H. Why use of interventions targeting outdoor biting mosquitoes will be necessary to achieve malaria elimination. Front Physiol. 2012;3:199.
    1. Kelly-Hope LA, McKenzie FE. The multiplicity of malaria transmission: a review of entomological inoculation rate measurements and methods across sub-Saharan Africa. Malar J. 2009;8:19. doi: 10.1186/1475-2875-8-19.
    1. Omura S. Ivermectin: 25 years and still going strong. Int J Antimicrob Agents. 2008;31:91–98.
    1. Fox LM. Ivermectin: uses and impact 20 years on. Curr Opin Infect Dis. 2006;19:588–593. doi: 10.1097/QCO.0b013e328010774c.
    1. Mectizan Donation Program. Annual Highlights. 2011. (accessed 28/04/2013)
    1. Kobylinski KC, Deus KM, Butters MP, Hongyu T, Gray M, da Silva IM, Sylla M, Foy BD. The effect of oral anthelmintics on the survivorship and re-feeding frequency of anthropophilic mosquito disease vectors. Acta Trop. 2010;116:119–126. doi: 10.1016/j.actatropica.2010.06.001.
    1. Tesh RB, Guzman H. Mortality and infertility in adult mosquitoes after the ingestion of blood containing ivermectin. AmJTrop Med Hyg. 1990;43:229–233.
    1. Wilson ML. Avermectins in arthropod vector management - prospects and pitfalls. Parasitol Today. 1993;9:83–87. doi: 10.1016/0169-4758(93)90210-7.
    1. Chaccour C, Lines J, Whitty CJ. Effect of ivermectin on Anopheles gambiae mosquitoes fed on humans: the potential of oral insecticides in malaria control. J Infect Dis. 2010;202:113–116. doi: 10.1086/653208.
    1. Foley DH, Bryan JH, Lawrence GW. The potential of ivermectin to control the malaria vector Anopheles farauti. Trans R Soc Trop Med Hyg. 2000;94:625–628. doi: 10.1016/S0035-9203(00)90211-6.
    1. Bockarie MJ, Hii JL, Alexander ND, Bockarie F, Dagoro H, Kazura JW, Alpers MP. Mass treatment with ivermectin for filariasis control in Papua New Guinea: impact on mosquito survival. Med Vet Entomol. 1999;13:120–123. doi: 10.1046/j.1365-2915.1999.00159.x.
    1. Kobylinski KC, Sylla M, Chapman PL, Sarr MD, Foy BD. Ivermectin mass drug administration to humans disrupts malaria parasite transmission in Senegalese villages. AmJTrop Med Hyg. 2011;85:3–5. doi: 10.4269/ajtmh.2011.11-0160.
    1. Sylla M, Kobylinski KC, Gray M, Chapman PL, Sarr MD, Rasgon JL, Foy BD. Mass drug administration of ivermectin in south-eastern Senegal reduces the survivorship of wild-caught, blood fed malaria vectors. Malar J. 2010;9:365. doi: 10.1186/1475-2875-9-365.
    1. Pampiglione S, Majori G, Petrangeli G, Romi R. Avermectins, MK-933 and MK-936, for mosquito control. Trans R Soc Trop Med Hyg. 1985;79:797–799. doi: 10.1016/0035-9203(85)90121-X.
    1. Iakubovich V, Zakharova NF, Alekseev AN, Alekseev EA. Evaluation of the action of ivermectin on blood-sucking mosquitoes. Med Parazitol (Mosk) 1989;3:60–64.
    1. Jones JW, Meisch MV, Meek CL, Bivin WS. Lethal effects of ivermectin on Anopheles quadrimaculatus. J Am Mosq Control Assoc. 1992;8:278–280.
    1. Gardner K, Meisch MV, Meek CL, Biven WS. Effects of ivermectin in canine blood on Anopheles quadrimaculatus, Aedes albopictus and Culex salinarius. J Am Mosq Control Assoc. 1993;9:400–402.
    1. Fritz ML, Siegert PY, Walker ED, Bayoh MN, Vulule JR, Miller JR. Toxicity of bloodmeals from ivermectin-treated cattle to Anopheles gambiae s.l. Ann Trop Med Parasitol. 2009;103:539–547. doi: 10.1179/000349809X12459740922138.
    1. Butters MP, Kobylinski KC, Deus KM, da Silva IM, Gray M, Sylla M, Foy BD. Comparative evaluation of systemic drugs for their effects against Anopheles gambiae. Acta Trop. 2012;121:34–43. doi: 10.1016/j.actatropica.2011.10.007.
    1. Fritz ML, Walker ED, Miller JR. Lethal and sublethal effects of avermectin/milbemycin parasiticides on the African malaria vector, Anopheles arabiensis. J Med Entomol. 2012;49:326–331. doi: 10.1603/ME11098.
    1. Hooghof J, Lindsay SW, Drakeley C, Churcher T, Verhave JP, Kocken C, Sauerwein RW, Bousema T. Bastiaens G vGG. Duration of the mosquitocidal effect of ivermectin. MW Journal. 2012;3:1–5.
    1. Kobylinski KC, Foy BD, Richardson JH. Ivermectin inhibits the sporogony of Plasmodium falciparum in Anopheles gambiae. Malar J. 2012;11:381. doi: 10.1186/1475-2875-11-381.
    1. Garrett-Jones C, Shidrawi GR. Malaria vectorial capacity of a population of Anopheles gambiae: an exercise in epidemiological entomology. Bull World Health Organ. 1969;40:531–545.
    1. Macdonald G. The analysis of equilibrium in malaria. Trop Dis Bull. 1952;49:813–829.
    1. Foy BD, Kobylinski KC, da Silva IM, Rasgon JL, Sylla M. Endectocides for malaria control. Trends Parasitol. 2011;27:423–428. doi: 10.1016/j.pt.2011.05.007.
    1. Mackenzie CD, Geary TG, Gerlach JA. Possible pathogenic pathways in the adverse clinical events seen following ivermectin administration to onchocerciasis patients. Filaria J. 2003;2(1):S5. doi: 10.1186/1475-2883-2-5.
    1. Njoo FL, Beek WM, Keukens HJ, van Wilgenburg H, Oosting J, Stilma JS, Kijlstra A. Ivermectin detection in serum of onchocerciasis patients: relationship to adverse reactions. AmJTrop Med Hyg. 1995;52:94–97.
    1. Gardon J, Gardon-Wendel N, Demanga N, Kamgno J, Chippaux JP, Boussinesq M. Serious reactions after mass treatment of onchocerciasis with ivermectin in an area endemic for Loa loa infection. Lancet. 1997;350:18–22. doi: 10.1016/S0140-6736(96)11094-1.
    1. Wanji S, Akotshi DO, Mutro MN, Tepage F, Ukety TO, Diggle PJ, Remme JH. Validation of the rapid assessment procedure for loiasis (RAPLOA) in the democratic republic of Congo. Parasit Vectors. 2012;5:25. doi: 10.1186/1756-3305-5-25.
    1. Duke BO, Pacque MC, Munoz B, Greene BM, Taylor HR. Viability of adult Onchocerca volvulus after six 2-weekly doses of ivermectin. Bull World Health Organ. 1991;69:163–168.
    1. Awadzi K, Opoku NO, Addy ET, Quartey BT. The chemotherapy of onchocerciasis. XIX: The clinical and laboratory tolerance of high dose ivermectin. Trop Med Parasitol. 1995;46:131–137.
    1. Guzzo CA, Furtek CI, Porras AG, Chen C, Tipping R, Clineschmidt CM, Sciberras DG, Hsieh JY, Lasseter KC. Safety, tolerability, and pharmacokinetics of escalating high doses of ivermectin in healthy adult subjects. J Clin Pharmacol. 2002;42:1122–1133. doi: 10.1177/009127002401382731.
    1. Kamgno J, Gardon J, Gardon-Wendel N, Demanga N, Duke BO, Boussinesq M. Adverse systemic reactions to treatment of onchocerciasis with ivermectin at normal and high doses given annually or three-monthly. Trans R Soc Trop Med Hyg. 2004;98:496–504. doi: 10.1016/j.trstmh.2003.10.018.
    1. Merck & Co. Stromectrol. Package insert. 2009. (Accessed 28/04/2013)
    1. Pacque M, Munoz B, Poetschke G, Foose J, Greene BM, Taylor HR. Pregnancy outcome after inadvertent ivermectin treatment during community-based distribution. Lancet. 1990;336:1486–1489. doi: 10.1016/0140-6736(90)93187-T.
    1. Chippaux JP, Gardon-Wendel N, Gardon J, Ernould JC. Absence of any adverse effect of inadvertent ivermectin treatment during pregnancy. Trans R Soc Trop Med Hyg. 1993;87:318. doi: 10.1016/0035-9203(93)90146-H.
    1. Doumbo O, Soula G, Kodio B, Perrenoud M. Ivermectin and pregnancy in mass treatment in Mali. Bull Soc Pathol Exot. 1992;85:247–251.
    1. Gyapong JO, Chinbuah MA, Gyapong M. Inadvertent exposure of pregnant women to ivermectin and albendazole during mass drug administration for lymphatic filariasis. Trop Med Int Health. 2003;8:1093–1101. doi: 10.1046/j.1360-2276.2003.01142.x.
    1. Ndyomugyenyi R, Kabatereine N, Olsen A, Magnussen P. Efficacy of ivermectin and albendazole alone and in combination for treatment of soil-transmitted helminths in pregnancy and adverse events: a randomized open label controlled intervention trial in Masindi district, western Uganda. AmJTrop Med Hyg. 2008;79:856–863.
    1. Brown KR. Changes in the use profile of Mectizan: 1987–1997. Ann Trop Med Parasitol. 1998;92(Suppl 1):S61–64.
    1. Ogbuokiri JE, Ozumba BC, Okonkwo PO. Ivermectin levels in human breastmilk. Eur J Clin Pharmacol. 1993;45:389–390.
    1. Gutman J, Emukah E, Okpala N, Okoro C, Obasi A, Miri ES, Richards FO Jr. Effects of annual mass treatment with ivermectin for onchocerciasis on the prevalence of intestinal helminths. AmJTrop Med Hyg. 2010;83:534–541. doi: 10.4269/ajtmh.2010.10-0033.
    1. Bousema JT, Schneider P, Gouagna LC, Drakeley CJ, Tostmann A, Houben R, Githure JI, Ord R, Sutherland CJ, Omar SA, Sauerwein RW. Moderate effect of artemisinin-based combination therapy on transmission of Plasmodium falciparum. J Infect Dis. 2006;193:1151–1159. doi: 10.1086/503051.
    1. Sutherland CJ, Ord R, Dunyo S, Jawara M, Drakeley CJ, Alexander N, Coleman R, Pinder M, Walraven G, Targett GA. Reduction of malaria transmission to Anopheles mosquitoes with a six-dose regimen of co-artemether. PLoS Med. 2005;2:e92. doi: 10.1371/journal.pmed.0020092.
    1. Okell LC, Griffin JT, Kleinschmidt I, Hollingsworth TD, Churcher TS, White MJ, Bousema T, Drakeley CJ, Ghani AC. The potential contribution of mass treatment to the control of Plasmodium falciparum malaria. PLoS One. 2011;6:e20179. doi: 10.1371/journal.pone.0020179.
    1. von Seidlein L, Greenwood BM. Mass administrations of antimalarial drugs. Trends Parasitol. 2003;19:452–460. doi: 10.1016/j.pt.2003.08.003.
    1. The malERA Consultative Group on Drugs. A research agenda for malaria eradication: drugs. PLoS Med. 2011;8:e1000402.
    1. Baird JK, Surjadjaja C. Consideration of ethics in primaquine therapy against malaria transmission. Trends Parasitol. 2011;27:11–16. doi: 10.1016/j.pt.2010.08.005.
    1. Brosseau L, Drame PM, Besnard P, Toto JC, Foumane V, Le Mire J, Mouchet F, Remoue F, Allan R, Fortes F, Carnevale P, Manguin S. Human antibody response to Anopheles saliva for comparing the efficacy of three malaria vector control methods in Balombo. Angola. PLoS One. 2012;7:e44189. doi: 10.1371/journal.pone.0044189.
    1. Stone W, Bousema T, Jones S, Gesase S, Hashim R, Gosling R, Carneiro I, Chandramohan D, Theander T, Ronca R, Modiano D, Arca B, Drakeley C. IgG responses to Anopheles gambiae salivary antigen gSG6 detect variation in exposure to malaria vectors and disease risk. PLoS One. 2012;7:e40170. doi: 10.1371/journal.pone.0040170.
    1. Stevenson J, St Laurent B, Lobo NF, Cooke MK, Kahindi SC, Oriango RM, Harbach RE, Cox J, Drakeley C. Novel vectors of malaria parasites in the western highlands of Kenya. Emerg Infect Dis. 2012;18:1547–1549. doi: 10.3201/eid1809.120283.
    1. Osei-Atweneboana MY, Awadzi K, Attah SK, Boakye DA, Gyapong JO, Prichard RK. Phenotypic evidence of emerging ivermectin resistance in Onchocerca volvulus. PLoS Negl Trop Dis. 2011;5:e998. doi: 10.1371/journal.pntd.0000998.

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