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Ivermectin—now an anti-malarial, too

18 Jul 2011

Patrick Adams

Source: TropIKA.net

A new study by researchers from Senegal and Colorado State University has found that ivermectin, a cheap, common heartworm medication used to combat onchocerciasis (river blindness) and other parasitic diseases, could also dramatically interrupt transmission of malaria.

The study, published in the July issue of the American Journal of Tropical Medicine and Hygiene, found that transmission of malaria parasites by mosquitoes fell substantially among people living in several Senegalese villages over two weeks after they took the drug ivermectin as part of a campaign to fight onchocerciasis. The drug appeared to kill malaria-carrying mosquitos that fed on the blood of the villagers (1).

To assess ivermectin’s efficacy as an anti-malarial, researchers collected mosquitoes from villages where people were already taking the drug and compared them to collections gathered at the same time from villages where people were not taking the drug. Two weeks after the drug was administered to people in the former, there was a 79 percent decline in mosquitoes carrying Plasmodium falciparum. That contrast sharply with the 246 percent increase of malaria-infected mosquitoes over the same period in villages not treated with ivermectin.

Since 1987, the pharmaceutical company Merck has donated million of doses of ivermectin under the trade name Mectizan to treat river blindness, a disease that affects about 18 million people. The disease is spread by black flies that transmit worms that invade the skin and eyes; 270,000 of those suffering the disease have become blind as a result.

“In terms of river blindness, this drug has transformed lives,” said Peter Hotez, president of the Sabin Vaccine Institute. “To add malaria to its already impressive return on investment would be an incredible development.”

“There is no silver bullet for malaria control,” said Brian D. Foy, PhD, a vector biologist at Colorado State University and the article’s senior author. “But this could be an important tool that would also contribute to the fight against other neglected diseases. It’s clearly a multipurpose drug.” 

Ivermetcin (IVM) is one of the primary drugs used to control the filarial nematodes Onchocerca volvulus and Wuchereria bancrofti. In a recent opinion piece on the virtues of endectocides (2), Foy et al note that the drug has been widely distributed in malaria endemic areas for more than 15 years through human mass drug administration (MDA). “One might question,” they write, “why those areas have not seen obvious signs of reduced malaria parasite prevalence, incidence or associated disease.” The answer, they say, has mainly to do with timing.

For one, programs like the WHO’s Onchocerciasis Elimination Program for the Americas (OEPA) and African Programme for Onchocerciasis Control (APOC) administered MDAs only twice a year at most, too infrequently to result in a sustained interruption of the malaria transmission cycle. Seldom do those MDAs coincide with malaria transmission seasons in the same area. And asexual parasitemias in humans can be remarkably stable even in the absence of sporozoite transmission, as observed in parasitological surveys of humans over multiple transmission seasons (3).

While the most effective malaria vector control tools are long-lasting insecticide treated nets (LLITNs) and indoor residual spraying (IRS), both come with significant limitations, including that they almost exclusively target endophagic vectors, the so-called “low-hanging fruit” of malaria vector control.

According to Ferguson et al, (4) these measures alone “are not sufficient to eliminate transmission in large tracts of tropical Africa” where the entomological inoculation rate (EIR), the most direct measure of human exposure, can exceed a thousand infectious bites per person per year (5).

“Expressed in terms of the parasite’s reproductive number, this means that if the local parasite population were entirely eliminated by mass drug administration, for example, a single infected person moving into the area would give rise to as many as ten thousand new infections and readily re-establish stable transmission…In most settings,” they argue, “achieving elimination will require interventions which target mosquitoes outside of human habitations.”

Indeed, while the advent of ivermectin as an anti-malarial is “good news on several fronts,” as Hotez put it, it also underscores the need to shore up troubling gaps in knowledge with respect to the mosquito life cycle outside of houses, including larval growth and sugar feeding, oviposition and adult dispersal—the result, say Ferguson et al, of deficiencies in funding for basic ecological research.

“Most funding for ecological studies of malaria vectors in recent years has been driven by the needs of specific biotechnological interventions rather than by the pursuit of basic ecological knowledge…Ecology should be considered an enabling science essential for defining the target product profiles of completely new control technologies and delivery systems.”

Says Foy, “Only sustained reductions in malaria parasite transmission will eventually result in reductions of malaria prevalence or disease.” By its ability to synergize with existing tools and health infrastructures, IVM offers the malaria community a powerful new tool for integrated malaria and NTD control in defined areas.

So will integration of control efforts be forthcoming? In recent years, the malaria community has largely resisted calls for integration by the Global Programme to Eliminate Lymphatic Filariasis (GPELF), the NTD with which malaria shares perhaps the most in common, including geographic distribution, an anophelene vector and preventive measures like bed nets and IRS. Now the two share ivermectin as well.

“They really don’t seem to understand this,” Eric Ottesen, director of the Lymphatic Filariasis Support Center at the Task Force for Global Health in Atlanta, USA, said last year of the malaria community. “They have money and they have a major problem. But they can claim the elimination of filariasis as part of their malaria control.”

“What we’re trying to do now,” he said, “is when we stop the once yearly treatment, if we at the same time try to coordinate the malaria interventions in areas where we’ve stopped, all we’re going to do is consolidate the gains we’ve made in filariasis control and knock it out completely. So that coordinated thinking is key.”

With regard to malaria, further studies are needed to determine whether more frequent, perhaps monthly, doses of ivermectin during the malaria season in different parts of Africa have an important impact on the disease. If they do, those findings may help address arguments against the use of IVM/MDAs for malaria, including logistic difficulties and higher costs associated with more frequent MDAs, and the potential to foster endectocide resistance in helminth populations.

But Foy believes that intensive ivermectin might not lead to resistant mosquitoes due to the fact that the drug would only target “the tiny percentage of mosquitoes that manage to bite people.”

Their work was funded with grants from The National Institutes of Health (NIH), Colorado State University, and with a Grand Challenges Explorations grant from the Bill & Melinda Gates Foundation, which rewards creative thinking to scientifically address pressing global health problems.

References

1. Kobylinski KC, Sylla M, Chapman PL, Sarr MD, Foy BD. (2011) Ivermectin mass drug administration to humans disrupts malaria parasite transmission in Senegalese villages. Am J Trop Med Hyg 85(1):3-5. Available from: http://www.ncbi.nlm.nih.gov/pubmed/21734116

2. Foy B, et al. (2010) Endectocides for malaria control. Trends in Parasitology e-pub ahead of print. Available from: http://www.ncbi.nlm.nih.gov/pubmed/21727027

3. Smith T, et al. (1993) Absence of seasonal variation in malaria parasitaemia in an area of intense seasonal transmission. Acta Trop. 54: 55–72. Available from: http://www.ncbi.nlm.nih.gov/pubmed/8103627

4. Ferguson HM, et al. (2010) Ecology: a prerequisite for malaria elimination and eradication. PLoS Med 7(8): e1000303. Available from: http://www.ncbi.nlm.nih.gov/pubmed/20689800

5. Smith DI, et al. (2005). The entomological inoculation rate and p falciparum infection in African children. Nature 438: 492-495. Available from: http://www.nature.com/nature/journal/v438/n7067/full/nature04024.html

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