Leen Vanheer & Almahamoudou Mahamar: Artemether–lumefantrine–amodiaquine or artesunate–amodiaquine combined with single low-dose primaquine to reduce Plasmodium falciparum malaria transmission in Ouélessébougou, Mali: a five-arm, phase 2, single-blind, ra

Methods

We did a five-arm, single-blind, phase 2 randomised controlled trial at the Ouélessébougou Clinical Research Unit of the Malaria Research and Training Centre of the University of Sciences, Techniques and Technologies of Bamako in Mali. Eligible participants were aged 10–50 years, with asymptomatic P falciparum microscopy-detected gametocyte carriage. Eligible participants were randomly allocated (1:1:1:1:1) to receive either artemether–lumefantrine, artemether–lumefantrine–amodiaquine, artemether–lumefantrine–amodiaquine plus primaquine, artesunate–amodiaquine, or artesunate–amodiaquine plus primaquine. Treatment regimens were administered on days 0, 1, and 2; primaquine was given as a single dose on day 0. All staff except the trial pharmacist and participants were masked to the treatment allocation. The primary outcome was the median percentage change in mosquito infection rate between pretreatment and 2 days after treatment initiation, assessed by direct membrane feeding assay. Data were analysed using a per-protocol analysis. This study is registered with ClinicalTrials.gov, NCT05550909.

Findings

Between Oct 16, 2022, and Dec 28, 2022, a total of 1249 individuals were screened; of whom, 100 were enrolled and randomly assigned to one of the five treatment groups (20 per group). Before treatment, 61 (61%) of 100 participants were infectious to mosquitoes, with a median of 7·3% (IQR 3·2 to 23·5) of mosquitoes becoming infected. Among infectious participants, the median percentage reduction in mosquito infection rate between pretreatment and 2 days after treatment was 100% (IQR 100 to 100) in the artemether–lumefantrine (p=0·0018), artemether–lumefantrine–amodiaquine (p=0·0018), and artemether–lumefantrine–amodiaquine plus primaquine (p=0·0009) treatment groups. In the artesunate–amodiaquine group the median percentage reduction in mosquito infection rate was only 32% (IQR –10·9 to 79·4; p=0·19), whereas a 100% median reduction was seen in the artesunate–amodiaquine plus primaquine group (IQR 100 to 100; p=0·0009). At day 2, two (10%) of 20 participants in the artemether–lumefantrine group, two (11%) of 19 in the artemether–lumefantrine–amodiaquine group, and 15 (75%) of 20 in the artesunate–amodiaquine group infected any number of mosquitoes whereas no infected mosquitoes were observed at this timepoint in the groups with primaquine. 85 (85%) of 100 participants had a total of 262 adverse events during follow-up; of which, 181 (69%) were categorised as mild and 81 (31%) as moderate. No serious adverse events were reported.

Interpretation

Our findings support the effectiveness of artemether–lumefantrine alone or as part of TACT for preventing nearly all human–mosquito malaria parasite transmission within 48 h. By contrast, substantial transmission was observed following treatment with artesunate–amodiaquine. The addition of a single low dose of primaquine blocks transmission to mosquitoes rapidly regardless of schizonticide.

Funding

Bill & Melinda Gates Foundation.

Introduction

Malaria morbidity and mortality remains unacceptably high.1 The emergence and spread of partial resistance against artemisinin derivatives, the main component of artemisinin-based combination therapies (ACTs), in southeast Asia2,3 and east Africa4,5 is threatening to increase malaria cases and deaths. Antimalarial treatments designed to slow the spread of resistance are therefore needed, either through novel combinations of existing drugs or supplementation with drugs that have specific effects on gametocytes, the sexual life stages responsible for maintaining parasite transmission. For optimal use, the understanding of how effective current and future antimalarials combat gametocytes is essential, and how this effect translates into reductions in transmission to mosquitoes.

Triple ACTs (TACTs) combine an existing ACT with a second partner drug that is slowly eliminated, to reduce the likelihood of incomplete parasite clearance and thus delay the spread of artemisinin resistance.6 Artemether–lumefantrine–amodiaquine is a TACT that has been proven safe, well tolerated, and efficacious for the treatment of uncomplicated Plasmodium falciparum malaria, including in areas with artemisinin and partner drug resistance.7,8 The effect of artemether–lumefantrine–amodiaquine on mature gametocytes and infectivity is unknown. Artesunate–amodiaquine is the first-line ACT for uncomplicated P falciparum malaria in many countries,9 but its efficacy in reducing transmission has not been directly tested. Studies assessing gametocyte carriage after artesunate–amodiaquine reported persistent gametocyte carriage after treatment for 21 days or more, but without transmission assays the infectivity of these persisting gametocytes cannot be confirmed.10, 11, 12

Although artemisinin-based treatments have superior gametocytocidal properties to non-artemisinin-based treatments,13 with artemether–lumefantrine being the most potent,14 the transmission-reducing activities of ACTs vary widely.14, 15, 16 By contrast, the 8-aminoquinoline primaquine is a potent gametocytocidal drug that, at a single low-dose (0·25 mg/kg), blocks transmission within 48 h of treatment. Since 2015, WHO recommends the addition of a single low-dose of primaquine to ACTs to reduce P falciparum transmission.17 The gametocytocidal and transmission-reducing activities of single low-dose primaquine have been assessed in combination with dihydroartemisinin–piperaquine, pyronaridine–artesunate, and artemether–lumefantrine,14, 15, 16,18,19; however, combining artemether–lumefantrine–amodiaquine or artesunate–amodiaquine with a single low-dose primaquine for P falciparum transmission reduction has not yet been tested.

In this study, we aimed to determine the safety and efficacy of artemether–lumefantrine–amodiaquine and artesunate–amodiaquine with and without single low-dose primaquine for reducing the transmission of P falciparum gametocytes.

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