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Dominic Chavez, World Bank
The study, published in The Lancet Infectious Diseases, has confirmed the safety and efficacy of single low-dose primaquine in reducing malaria transmission in young children, who bear the highest malaria burden globally.
This approach has mostly been used in older children and adults, as the tablets currently available are not easy to use in young children. The lack of a child-friendly formulation limits the potential of primaquine to play a role in global elimination efforts. This work also quantifies primaquine efficacy in areas with a high malaria burden, suggesting a potential role for the drug in limiting the selection and spread of drug-resistant malaria in Africa.
Primaquine is the only widely available antimalarial that kills Plasmodium falciparum gametocytes. This is important because the P. falciparum parasite spreads from people to mosquitoes at the gametocyte stage in their life cycle. These gametocytes are the sexual stages of the parasite, and are picked up by mosquitoes during a blood meal from an infected person. Inside the mosquito, they develop further, eventually leading to the production of sporozoites, which infects a new human host when the mosquito bites that person. Although young children account for over two-thirds of malaria deaths in Africa, a paediatric formulation of primaquine is not yet marketed.
Currently, the World Health Organization (WHO) recommends a single low dose of primaquine (0.25 mg/kg) only in areas with low malaria transmission. However, resistance to artemisinin—the main malaria treatment—is spreading, including in African regions with moderate-to-high transmission. Artemisinin (partial) resistance slows parasite clearance, leading to higher gametocyte levels and potentially increasing the spread of drug-resistant malaria.
Researchers, led by Dr Daniel Yilma of Jimma University, Ethiopia, conducted an individual patient data meta-analysis using data shared with the WWARN repository. They analysed data from 23 studies across 16 countries, including 6,056 patients (19.3% under 5 years old and 46.7% aged 5 to <15 years). Dr Yilma said “This is the first large-scale comparison of a single low-dose primaquine’s impact across different age groups and transmission settings”.
Prof Karen Barnes, at the University of Cape Town, South Africa, and the Lead for WWARN’s Antimalarial Resistance Theme, added: “This analysis demonstrates the potential of combining all available individual patient data to inform regulatory and policy decisions, saving the time and substantial expense of conducting new clinical trials in over 1000 young children.”
The study results show that before treatment, gametocytes are more common in young compared to older children and adults. They are also more frequent in areas with moderate-to-high malaria transmission than in low-transmission regions. Adding a single low dose of primaquine to standard malaria treatment (Artemisinin-based Combination Treatments, ACTs) was found to be both safe and effective across all ages and transmission settings.
Dr Yilma added: “The effectiveness of single low-dose primaquine in reducing P. falciparum transmission depends on achieving a high coverage at population level. Since young children are more likely to carry gametocytes, it is crucial to develop a child-friendly, affordable primaquine formulation to maximise the benefit of primaquine in blocking malaria transmission”.
Prof Karen Barnes noted: “The study also shows the potential for expanding the use of single low-dose primaquine to areas with moderate-to-high malaria transmission, to limit the selection and spread of drug-resistant malaria. Large-scale rollout in these settings should be carefully monitored to better understand its impact on malaria transmission and resistance.”
The study also shows that gametocyte clearance rates differ with different ACTs. Without primaquine or with a very low (<0.2mg/kg) primaquine dose, patients treated with dihydroartemisinin-piperaquine were more likely to carry gametocytes than those treated with artemether-lumefantrine. This is an important consideration when selecting malaria treatments, as it could impact significantly on the spread of malaria and drug resistance. Fortunately, gametocyte clearance was similar across ACTs when combined with the WHO-recommended 0.25 mg/kg primaquine target dose.
The finding that single low-dose primaquine is safe and efficacious across all age groups and malaria transmission settings provides supportive evidence to expand single low-dose primaquine use to advance malaria elimination and in areas threatened by drug-resistant malaria, including moderate-to-high transmission areas in sub-Saharan Africa.