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Common anti-parasitic could be new tool for malaria control

High doses of ivermectin kills mosquitoes feeding on humans for a month after treatment

Mark Gould

Wednesday, 28 March 2018

A drug commonly used to treat parasitic diseases could become a new tool for malaria control. A randomised trial* published in The Lancet Infectious Diseases shows that multiple, high doses of ivermectin are well tolerated and able to kill mosquitoes feeding on humans for at least 28 days after treatment. Up to now, the mosquito-killing effects of lower doses of this ‘repurposed’ drug had been short-lived.

Transmission modelling to predict the potential impact of this approach indicates that pairing high-dose ivermectin with a standard malaria treatment (dihydroartemisinin-piperaquine) in community-wide campaigns, such as mass drug administration, could reduce malaria prevalence by up to 61% more than campaigns with only antimalarials. In areas of low prevalence, where 10% of the population is infected, adding ivermectin could reduce prevalence to less than 0.1% for more than six months.

Ivermectin was discovered 30 years ago, and to date more than 2.5 billion doses have been given across Africa and Latin America to kill parasitic worms, including those that cause river blindness and lymphatic filariasis, and has been shown to be safe.

In a randomised trial conducted at the Jaramogi Oginga Odinga Teaching and Referral Hospital in Kisumu, Kenya, 141 adults with uncomplicated malaria were randomly assigned to receive dihydroartemisinin-piperaquine (DP) plus either three days of 600 µg/kg ivermectin per day (47 participants), ivermectin 300 µg/kg per day (48), or a placebo (46).

The researchers fed the patients’ blood at regular intervals to laboratory-reared Anopheles mosquitoes and assessed mosquito survival every day for 28 days after feeding. 128 participants (91%) attended a visit seven days after treatment and were included in the main analysis.

Seven days after treatment, mosquitoes died four times faster after being fed blood from participants who received the lower dose ivermectin treatment compared to those fed on blood from participants given placebo. This mosquito mortality rate was six times higher after treatment with the higher dose of ivermectin than placebo.

During the two weeks after feeding, 41% of mosquitoes died in the placebo arm, compared to 93% and 97% of mosquitoes killed in the 300 and 600 µg/kg/day arms, respectively. The effect on mosquito mortality remained significantly higher 28 days after treatment with both ivermectin doses compared with placebo.

The authors note several limitations, including that the study only included individuals with symptomatic malaria, so the findings might not be generalisable to mass drug administration campaigns that target the entire population—most of whom are either asymptomatic or uninfected. They also note that standard laboratory-reared mosquitoes are known to be sensitive to pyrethroids and other classes of insecticides, which might not reflect wild populations. Lastly, they highlight that studies of the safety, tolerability, and efficacy of high doses of the drug will need to be done in children, and as multiple rounds, before its effect on malaria transmission can be assessed in community-wide campaigns.

“This is the first study to show the safety and efficacy of multiple high-doses of ivermectin on mosquito mortality”, says Dr Menno Smit from the Liverpool School of Tropical Medicine, Liverpool, UK, who led the study.

“Our results suggest that a 300 µg/kg dose of ivermectin each day for three days would provide a good balance between efficacy and tolerability.”

“Despite these encouraging findings, further rigorous safety and efficacy trials in younger age groups are needed before high-dose ivermectin can be administered at scale to assess its impact on malaria transmission and human health”, says Smit, adding that, “high-dose ivermectin may also have potential applications in other vector-borne diseases transmitted by mosquitoes including Zika virus, dengue, and West Nile fever, as well as insect- and tick-borne disease like sleeping sickness and Lyme disease. Further studies should be done to assess the use of high-dose ivermectin against these insects.”

*Smit RM, Ochomo OE, Aljayyoussi G, et al. Safety and mosquitocidal efficacy of high-dose ivermectin when co-administered with dihydroartemisinin-piperaquine in Kenyan adults with uncomplicated malaria (IVERMAL): a randomised, double-blind, placebo-controlled trial. The Lancet, March 2018; DOI:10.1016/S1473-3099(18)30163-4

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