By Philip R. Fischer, MD, DTM&H
Synopsis: Artemisinin resistance of Plasmodium falciparum is expanding in Southeast Asia and in parts of Africa. Among older children and adults in West Africa, the addition of low-dose primaquine to standard artemisinin combination therapy successfully blocked gametocyte survival and parasite transmission.
Source: Mahamar A, Vanheer LN, Smit MJ, et al. 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, randomised controlled trial. Lancet Microbe. 2025;6:100966.
Malaria still accounts for significant morbidity and mortality. The mainstay of treatment is artemisinin combination therapy (ACT), but partial resistance to artemisinins is spreading through Southeast Asia and east Africa. New therapeutic regimens are needed, especially those combatting the transmission of malaria via spread of the gametocyte stage of the parasite from infected humans to mosquitoes, which then can transmit malaria to other people.
The addition of a longer-lasting agent to ACT creates triple artemisinin combination therapy (TACT) with potential to reduce incomplete parasite clearance and, concurrently, to reduce increasing resistance to antimalarials. One such TACT includes artemether, lumefantrine, and amodiaquine; this treatment is effective against uncomplicated Plasmodium falciparum malaria, even in areas with emerging and persisting artemisinin resistance. However, the effect of this and other TACT medication combinations on the survival of gametocytes and, hence, ongoing malaria transmission, is unknown.
For the past decade, single doses of primaquine have been considered as adjuncts to ACT to block parasite transmission. The current study evaluated the safety and transmission-reducing efficacy of adding primaquine to various artemisinin-based medication regimens.
Malaria follows seasonal transmission patterns in rural Mali, with 20% to 25% of individuals harboring gametocytes during the rainy season. In this setting, a randomized, controlled, five-armed study was undertaken. Included subjects aged 10 to 50 years were asymptomatic for malaria and had P. falciparum gametocytemia without significant anemia; pregnant women were not included. Study subjects in the five treatment groups received: artemether-lumefantrine, artemether-lumefantrine-amodiaquine, artemether-lumefantrine-amodiaquine plus primaquine, artesunate-amodiaquine, or artesunate-amodiaquine plus primaquine. Medications were administered for three days, with primaquine (0.25 mg/kg) being given only on the first day of treatment. Clinical and parasitological evaluation was performed on days 2, 7, 14, 21, and 28 after the initiation of treatment. Anopheles mosquitoes were allowed to feed on venous blood samples.
In late 2022, 100 subjects were enrolled, with 20 assigned to each treatment group. Follow-up visits through 28 days were completed for 96% of study subjects.
At day 2 and following, no subject who had received primaquine was infectious to mosquitoes; 10% of those in the artemether-lumefantrine group, 11% in the artemether-lumefantrine-amodiaquine group, and 75% in the artesunate-amodiaquine group were infectious to mosquitoes. No study subject had a serious adverse reaction to treatment, although mild to moderate headache was identified in participants in each group.
The authors concluded that artemether-lumefantrine had potent transmission-blocking activity but that the effect on transmission was enhanced by including primaquine in the treatment regimen. Artesunate-amodiaquine, although widely used for treatment of uncomplicated malaria, was markedly less effective in blocking transmission of gametocytes.
Commentary
As resistance of P. falciparum to artemisinin derivatives increases, these new data provide reassurance that human-to-mosquito transmission of parasites can be blocked by the addition of primaquine to current artemisinin combination treatment regimens. This transmission-blocking effect is separate from the known effectiveness of these agents in treating symptomatic malaria infections.
An earlier (2020) multinational clinical trial of children and adults in eight countries of Africa and Asia showed that TACT was similarly effective to or more effective than ACT in the treatment of acute malaria as measured by a persisting lack of parasitemia until six weeks after treatment.1,2 In the Southeast Asia sites where artemisinin resistance is more common, the study showed that TACT was significantly more effective in clearing malaria infections than was ACT.1 As partial resistance to artemisinins expands, these data suggest that TACT will effectively enhance the therapeutic lifespan of current antimalarials.2
Rightly, clinicians have concern about using primaquine since it can provoke hemolytic crises in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. However, a 2022 meta-analysis involving 20 studies and 6,406 patients demonstrated that primaquine, when used as a single low dose (0.25 mg/kg), is safe without significant risk of severe hemolysis, even in patients with G6PD deficiency; pre-treatment testing for G6PD deficiency is not necessary when a single low dose of primaquine is to be used.3
Any future success in eliminating human malaria will require multifaceted interventions.4 Along the way toward the elimination of human malaria, primaquine can be helpful in reducing post-infection transmission. Ongoing implementation and improvements in vaccination also will be necessary. Resistance of Plasmodium to artemisinins is increasing, and new antimalarials still likely will be needed even if TACT is able to extend the effectiveness of ACT for the next several years.
Philip R. Fischer, MD, DTM&H, is Professor of Pediatrics, Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN.
References
1. van der Pluijm RW, Tripura R, Hoglund RM, et al. Triple artemisinin-based combination therapies versus artemisinin-based combination therapies for uncomplicated Plasmodium falciparum malaria: A multicentre, open-label, randomised clinical trial. Lancet. 2020;395(10233):1345-1360.
2. Kokori E, Olatunji G, Akinboade A, et al. Triple artemisinin-based combination therapy (TACT): Advancing malaria control and eradication efforts. Malar J. 2024;23(1):25.
3. Stepniewska K, Allen EN, Humphreys GS, et al. Safety of single-dose primaquine as a Plasmodium falciparum gametocytocide: A systematic review and meta-analysis of individual patient data. BMC Med. 2022;20(1):350.
4. Liu Y, Richardson S. Can malaria be eliminated? 15 years on. Trans R Soc Trop Med Hyg. 2025; Feb 17:traf018. doi: 10.1093/trstmh/traf018. [Online ahead of print].
Artemisinin resistance of Plasmodium falciparum is expanding in Southeast Asia and in parts of Africa. Among older children and adults in West Africa, the addition of low-dose primaquine to standard artemisinin combination therapy successfully blocked gametocyte survival and parasite transmission.
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