The potential impact of adding ivermectin to a mass treatment intervention to reduce malaria transmission: a modelling study.

BACKGROUND Ivermectin (IVM), used alongside mass treatment strategies with an artemisinin combination therapy, has been suggested as a possible tool for reducing malaria transmission. Mosquitoes ingesting a bloodmeal containing IVM have increased mortality, reducing the probability that the parasite completes sporogony. METHODS Human pharmacokinetic data and mortality data for mosquitoes taking bloodmeals containing IVM are used to quantify the mosquitocidal effect of IVM. These are incorporated into a transmission model to estimate the impact of IVM in combination with mass treatment strategies with artemether-lumefantrine on transmission metrics. RESULTS Adding IVM increases the reductions in parasite prevalence achieved and delays the reemergence of parasites compared to mass treatment alone. This transmission effect is obtained through its effect on vector mortality. IVM effectiveness depends on coverage with the highest impact achieved if given to the whole population rather than only those with existing detectable parasites. Our results suggest that including IVM in a mass treatment strategy can reduce the time taken to interrupt transmission as well as help to achieve transmission interruption in transmission settings in which mass treatment strategies alone would be insufficient. CONCLUSIONS Including IVM in mass treatment strategies could be a useful adjunct to reduce and interrupt malaria transmission.

[1]  P. Diggle,et al.  The Geographic Distribution of Loa loa in Africa: Results of Large-Scale Implementation of the Rapid Assessment Procedure for Loiasis (RAPLOA) , 2011, PLoS neglected tropical diseases.

[2]  Safety, Tolerability, and Pharmacokinetics of Escalating High Doses of Ivermectin in Healthy Adult Subjects , 2002, Journal of clinical pharmacology.

[3]  Teun Bousema,et al.  Factors determining the occurrence of submicroscopic malaria infections and their relevance for control , 2012, Nature Communications.

[4]  M. Alpers,et al.  Mass treatment with ivermectin for filariasis control in Papua New Guinea: impact on mosquito survival , 1999, Medical and veterinary entomology.

[5]  Wes Hinsley,et al.  Reducing Plasmodium falciparum Malaria Transmission in Africa: A Model-Based Evaluation of Intervention Strategies , 2010, PLoS medicine.

[6]  M. Elkassaby Ivermectin uptake and distribution in the plasma and tissue of Sudanese and Mexican patients infected with Onchocerca volvulus. , 1991, Tropical medicine and parasitology : official organ of Deutsche Tropenmedizinische Gesellschaft and of Deutsche Gesellschaft fur Technische Zusammenarbeit.

[7]  U. Klotz,et al.  Protein binding and ivermectin estimations in patients with onchocerciasis , 1993, Clinical pharmacology and therapeutics.

[8]  B. Sharp,et al.  Indoor residual spraying for preventing malaria. , 2010, The Cochrane database of systematic reviews.

[9]  David L. Smith,et al.  Malaria resurgence: a systematic review and assessment of its causes , 2012, Malaria Journal.

[10]  P. Martin,et al.  Cumulative mortality rates in Aedes polynesiensis after feeding on polynesian Wuchereria bancrofti carriers treated with single doses of ivermectin, diethylcarbamazine and placebo. , 1991, Tropical medicine and parasitology : official organ of Deutsche Tropenmedizinische Gesellschaft and of Deutsche Gesellschaft fur Technische Zusammenarbeit.

[11]  C. Lengeler,et al.  Insecticide-treated bed nets and curtains for preventing malaria. , 2004, The Cochrane database of systematic reviews.

[12]  M. Malecela,et al.  Lymphatic filariasis control in Tanzania: effect of six rounds of mass drug administration with ivermectin and albendazole on infection and transmission , 2010, BMC Infectious Diseases.

[13]  A. Hoerauf,et al.  Lymphatic fi lariasis and onchocerciasis , 2010 .

[14]  Kevin C. Kobylinski,et al.  Mass drug administration of ivermectin in south-eastern Senegal reduces the survivorship of wild-caught, blood fed malaria vectors , 2010, Malaria Journal.

[15]  C. Meek,et al.  Lethal effects of ivermectin on Anopheles quadrimaculatus. , 1992, Journal of the American Mosquito Control Association.

[16]  Kevin C Kobylinski,et al.  Ivermectin inhibits the sporogony of Plasmodium falciparum in Anopheles gambiae , 2012, Malaria Journal.

[17]  U. Klotz,et al.  Determination of ivermectin in human plasma by high-performance liquid chromatography. , 1993, Arzneimittel-Forschung.

[18]  B. Greenwood,et al.  Mass administrations of antimalarial drugs. , 2003, Trends in parasitology.

[19]  E. Walker,et al.  Toxicity of bloodmeals from ivermectin-treated cattle to Anopheles gambiae s.l. , 2009, Annals of tropical medicine and parasitology.

[20]  C. Macauley Aggressive active case detection: a malaria control strategy based on the Brazilian model. , 2005, Social science & medicine.

[21]  Longkai Qi Human Pharmacokinetics of Orally Taking Ivermectin , 2001 .

[22]  Shen Wei,et al.  Liquid chromatographic assay of ivermectin in human plasma for application to clinical pharmacokinetic studies. , 2006, Journal of pharmaceutical and biomedical analysis.

[23]  Tanya L Russell,et al.  Increased proportions of outdoor feeding among residual malaria vector populations following increased use of insecticide-treated nets in rural Tanzania , 2011, Malaria Journal.

[24]  A. Breckenridge,et al.  The relative systemic availability of ivermectin after administration as capsule, tablet, and oral solution , 2004, European Journal of Clinical Pharmacology.

[25]  H. Guzmán,et al.  Mortality and infertility in adult mosquitoes after the ingestion of blood containing ivermectin. , 1990, The American journal of tropical medicine and hygiene.

[26]  Richard J Maude,et al.  The last man standing is the most resistant: eliminating artemisinin-resistant malaria in Cambodia , 2009, Malaria Journal.

[27]  T. Geary,et al.  Ivermectin distribution in the plasma and tissues of patients infected with Onchocerca volvulus , 1996, European Journal of Clinical Pharmacology.

[28]  Kevin C. Kobylinski,et al.  Ivermectin mass drug administration to humans disrupts malaria parasite transmission in Senegalese villages. , 2011, The American journal of tropical medicine and hygiene.

[29]  S. Njenga,et al.  Impact of two rounds of mass treatment with diethylcarbamazine plus albendazole on Wuchereria bancrofti infection and the sensitivity of immunochromatographic test in Malindi, Kenya. , 2008, Transactions of the Royal Society of Tropical Medicine and Hygiene.

[30]  M. Bockarie,et al.  Impact of Three Rounds of Mass Drug Administration on Lymphatic Filariasis in Areas Previously Treated for Onchocerciasis in Sierra Leone , 2013, PLoS neglected tropical diseases.

[31]  Nicolas Moiroux,et al.  Pyrethroid resistance in African anopheline mosquitoes: what are the implications for malaria control? , 2011, Trends in Parasitology.

[32]  W. Takken Do insecticide‐treated bednets have an effect on malaria vectors? , 2002, Tropical medicine & international health : TM & IH.

[33]  K. Singh,et al.  Epidemiological study of focal outbreak of malaria in consolidation phase area and evaluation of remedial measures in Uttar Pradesh (India). , 1966 .

[34]  Akira Kaneko,et al.  Malaria eradication on islands , 2000, The Lancet.

[35]  D. Foley,et al.  The potential of ivermectin to control the malaria vector Anopheles farauti. , 2000, Transactions of the Royal Society of Tropical Medicine and Hygiene.

[36]  M. Malecela,et al.  Lymphatic Filariasis Control in Tanzania: Effect of Repeated Mass Drug Administration with Ivermectin and Albendazole on Infection and Transmission , 2010, PLoS neglected tropical diseases.

[37]  C. Meek,et al.  Effects of ivermectin in canine blood on Anopheles quadrimaculatus, Aedes albopictus and Culex salinarius. , 1993, Journal of the American Mosquito Control Association.

[38]  Cees Leeuwis,et al.  The SolarMal Project: innovative mosquito trapping technology for malaria control , 2012, Malaria Journal.

[39]  K. R. Brown Changes in the use profile 1987-1997 of Mectizan: , 1998 .

[40]  S. Lindsay,et al.  Duration of the mosquitocidal effect of ivermectin , 2012 .

[41]  Bernhards Ogutu,et al.  A controlled, parallel, cluster-randomized trial of community-wide screening and treatment of asymptomatic carriers of Plasmodium falciparum in Burkina Faso , 2013, Malaria Journal.

[42]  T. Déirdre Hollingsworth,et al.  The Potential Contribution of Mass Treatment to the Control of Plasmodium falciparum Malaria , 2011, PloS one.

[43]  Massamba Sylla,et al.  The effect of oral anthelmintics on the survivorship and re-feeding frequency of anthropophilic mosquito disease vectors. , 2010, Acta tropica.

[44]  J. Lines,et al.  Effect of ivermectin on Anopheles gambiae mosquitoes fed on humans: the potential of oral insecticides in malaria control. , 2010, The Journal of infectious diseases.

[45]  Achim Hoerauf,et al.  Lymphatic filariasis and onchocerciasis , 2010, The Lancet.

[46]  G. Kafuko,et al.  A MALARIA ERADICATION EXPERIMENT IN THE HIGHLANDS OF KIGEZI (UGANDA). , 1964, East African medical journal.

[47]  Q. Bassat,et al.  Ivermectin to reduce malaria transmission: a research agenda for a promising new tool for elimination , 2013, Malaria Journal.