Artemether-lumefantrine with or without single-dose primaquine and sulfadoxine-pyrimethamine plus amodiaquine with or without single-dose tafenoquine to reduce Plasmodium falciparum transmission: a phase 2 single-blind randomised clinical trial in Ouelessebougou, Mali

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Summary Background Artemether-lumefantrine is widely used for uncomplicated Plasmodium falciparum malaria; sulfadoxine-pyrimethamine plus amodiaquine is used for seasonal malaria chemoprevention. We determined the efficacy of artemether-lumefantrine with and without primaquine and sulfadoxine-pyrimethamine plus amodiaquine with and without tafenoquine for reducing gametocyte carriage and transmission to mosquitoes. Methods In this phase 2, single-blind, randomised clinical trial conducted, asymptomatic individuals aged 10-50 years with P. falciparum gametocytaemia were randomised (1:1:1:1) to receive either artemether-lumefantrine, artemether-lumefantrine with a single dose of 0·25 mg/kg primaquine, sulfadoxine-pyrimethamine plus amodiaquine or sulfadoxine-pyrimethamine plus amodiaquine with a single dose of 1·66 mg/kg tafenoquine. All trial staff other than the pharmacist were blinded. The primary outcome was the median within person percent change in mosquito infection rate in infectious individuals from baseline to day 2 (artemether-lumefantrine groups) or 7 (sulfadoxine-pyrimethamine plus amodiaquine groups) post treatment, assessed by direct membrane feeding assay. This study is registered withClinicalTrials.gov, NCT05081089 . Findings Between 13 Oct and 16 Dec 2021, 1290 individuals were screened and 80 were enrolled and randomly assigned to one of the four treatment groups (20 per group). In individuals who were infectious before treatment, the median percentage reduction in mosquito infection rate 2 days after treatment was 100% (IQR 97·2-100; n=19, p=0·026) with artemether-lumefantrine and 100% (100-100; n=19, p=0·0001) with artemether-lumefantrine with primaquine. Only two individuals infected mosquitoes on day 2 after artemether-lumefantrine and none at day 5. In contrast, the median percentage reduction in mosquito infection rate 7 days after treatment was 63·60% (IQR 0·62 to 100, n=20, p=0·009) with sulfadoxine-pyrimethamine plus amodiaquine and 100% (100-100; n=19, p<0·0001) with sulfadoxine-pyrimethamine plus amodiaquine with tafenoquine. Interpretation These data support the effectiveness of artemether-lumefantrine alone for preventing nearly all mosquito infections. In contrast, there was considerable post-treatment transmission after sulfadoxine-pyrimethamine plus amodiaquine where the addition of a transmission-blocking drug may be beneficial in maximizing its community impact. Funding Bill & Melinda Gates Foundation Brief summary Sulfadoxine-pyrimethamine plus amodiaquine is commonly used for seasonal malaria chemoprevention. Artemether-lumefantrine is the most widely used treatment regimen for uncomplicated Plasmodium falciparum malaria, but studies to date have shown inconsistent activity of artemether-lumefantrine against P. falciparum gametocytes. This study shows considerable post-treatment transmission after sulfadoxine-pyrimethamine plus amodiaquine but near complete prevention of mosquito infection after artemether-lumefantrine, even without primaquine. The addition of 8-aminoquinolines reduced transmission with both combinations.

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