Highlight
– Individual‑patient meta‑analysis of 6056 participants from 23 studies shows single low‑dose primaquine (0.25 mg/kg) added to artemisinin‑based combination therapy (ACT) markedly reduces day‑7 gametocyte positivity (aOR 0.34, 95% CI 0.22–0.52) and mosquito infectivity over time (aOR per day 0.02, 95% CI 0.01–0.07).
– The efficacy and safety profile is consistent across age groups (including children 25% haemoglobin declines or grade ≥2 adverse events was observed at the 0.25 mg/kg target dose.
– Study supports broader use of single low‑dose primaquine in regions threatened by artemisinin partial resistance and highlights the need for child‑friendly praziquant formulations and deployment strategies.
Background
Interrupting onward transmission of Plasmodium falciparum is a cornerstone of malaria control and elimination strategies. Mature gametocytes (sexual stage parasites circulating in human blood) are essential for infecting Anopheles mosquitoes; drugs that clear gametocytes can therefore reduce population‑level transmission. Primaquine, an 8‑aminoquinoline, is a potent gametocytocide against mature P. falciparum gametocytes. Because primaquine can cause haemolysis in people with glucose‑6‑phosphate dehydrogenase (G6PD) deficiency, safety considerations have constrained its programmatic uptake, particularly among young children and in high‑burden settings.
Since the World Health Organization recommended a single low dose (0.25 mg/kg) of primaquine as a gametocytocide in P. falciparum malaria (policy statements from WHO), there has been ongoing debate about safety in children, the need for routine G6PD testing, and whether benefits vary by transmission intensity or ACT partner drug. The Lancet Infectious Diseases 2025 individual patient data meta‑analysis led by the WWARN Paediatric Primaquine for P. falciparum Transmission Blocking Study Group addresses these questions by pooling data from prospective trials that evaluated single‑dose primaquine (≤0.75 mg/kg) plus ACT in patients with uncomplicated falciparum malaria.
Study design and methods
This work is a systematic review and individual patient data meta‑analysis. Databases were searched up to April 3, 2024, and prospective studies that enrolled at least one child <15 years and included a study arm receiving a single primaquine dose (≤0.75 mg/kg) plus ACT were eligible. Exclusions included mass drug administration studies, healthy volunteer studies, severe malaria, or mixed infections.
Investigators contributed de‑identified individual patient data. For efficacy analyses, studies required measurements of transmission potential (gametocytaemia by microscopy or molecular detection, mosquito feeding assays) at enrolment and at follow‑up (day 3, day 7, or day 14). Safety analyses required haemoglobin/haematocrit measurements or adverse event reporting by day 7 and onward. Primary analytic endpoints included day‑7 gametocyte carriage and probability of infecting a mosquito; safety endpoints included clinically relevant declines in haemoglobin (>25% decline) and adverse events up to day 28. Regression modelling used random study‑site intercepts to account for clustering. The analyses were registered with PROSPERO (CRD42021279363 safety; CRD42021279369 efficacy).
Population and interventions
Individual patient data were obtained from 23 of 30 eligible studies and included 6056 patients across 16 countries. Participant distribution by age: 1171 (19.3%) young children (<5 years), 2827 (46.7%) older children (5 to <15 years), and 2058 (34.0%) adults (≥15 years). Primaquine dosing regimens varied, but the principal comparison focused on a single low dose target of 0.25 mg/kg combined with commonly used ACTs (artemether‑lumefantrine [AL] or dihydroartemisinin‑piperaquine [DHA‑PPQ]). A subset received lower doses (<0.2 mg/kg) due to dosing variability.
Key findings: efficacy
Adding a single low dose of primaquine (0.2–0.25 mg/kg) to ACTs significantly reduced gametocyte carriage at day 7 (adjusted odds ratio [aOR] 0.34, 95% CI 0.22–0.52; p<0.001). Time‑to‑loss of infectivity to mosquitoes was also markedly reduced when primaquine was administered (aOR per day 0.02, 95% CI 0.01–0.07; p<0.001), indicating rapid interruption of transmissibility.
Importantly, subgroup analyses found no evidence that treatment effects differed by age. Comparisons of primaquine effect on day‑7 gametocyte positivity showed no significant difference between young children (<5 years) and older children (aOR 1.08, 95% CI 0.52–2.23; p=0.84) or adults (aOR 0.50, 95% CI 0.20–1.25; p=0.14). Similar nonsignificant differences were observed for infectivity outcomes (for example, young children vs older children aOR 1.36, 95% CI 0.07–27.71; p=0.84), although confidence intervals for infectivity comparisons were wide due to smaller numbers of mosquito feeding assays.
Transmission setting (low versus moderate‑to‑high) did not modify primaquine efficacy against gametocytaemia (aOR 1.07, 95% CI 0.46–2.52; p=0.86) or infectivity (aOR 0.18, 95% CI 0.01–2.95; p=0.23).
Comparisons across ACT partner drugs were generally reassuring: with a primaquine target dose of 0.25 mg/kg, gametocyte clearance was similar for DHA‑PPQ versus AL (aOR 1.56, 95% CI 0.65–3.79; p=0.32 at day 7). However, when primaquine doses were <0.2 mg/kg, patients treated with DHA‑PPQ were more likely to have persistent gametocytaemia than those treated with AL (aOR 5.68, 95% CI 1.38–23.48; p=0.016 at day 7), suggesting that underdosing primaquine may undermine its benefit, especially when combined with some ACTs.
Key findings: safety
Safety analyses focused on clinically important haemoglobin declines and adverse events. At the primaquine target dose of 0.25 mg/kg there was no increase in the risk of a >25% fall in haemoglobin concentration, regardless of age group, transmission setting, or G6PD status. Risks of grade ≥2 adverse events and serious adverse events were similar between primaquine and no‑primaquine groups, including in young children.
These findings provide reassuring evidence that a single low dose of primaquine at 0.25 mg/kg has an acceptable safety profile in the populations studied. Nonetheless, rare severe haemolysis cannot be definitively excluded because the pooled dataset—while large—may still be underpowered to detect very rare events and excluded severe malaria, neonates, and certain vulnerable populations.
Expert commentary and interpretation
This comprehensive individual‑patient meta‑analysis addresses a critical implementation question: can single‑dose primaquine be used safely and effectively in young children, and in routine programmatic settings without routine G6PD testing? The evidence supports that a 0.25 mg/kg single dose given with ACT rapidly clears gametocytes and reduces infectivity across ages and epidemiological contexts, with no signal for clinically important haemolysis in the populations included.
From a biological perspective, primaquine’s activity against mature gametocytes, which are less susceptible to most blood‑stage antimalarials, explains the rapid loss of infectivity after a single dose. The similar efficacy across transmission settings argues that the drug’s pharmacodynamic effect is consistent irrespective of background exposure or immunity.
Policy implications are important. These findings bolster WHO policy and support programmatic expansion of single low‑dose primaquine to reduce transmission and counter the spread of artemisinin partial resistance, including in moderate‑to‑high transmission settings. Operational deployment should prioritize accurate dosing (to achieve ~0.25 mg/kg), availability of child‑friendly formulations to avoid underdosing, and monitoring systems to detect rare adverse events.
Limitations
Key limitations include: (1) incomplete inclusion of all eligible studies (23 of 30 contributed data), which could introduce selection bias; (2) heterogeneity in how gametocytaemia and infectivity were measured across studies, and relatively small numbers for mosquito feeding assays resulting in wide confidence intervals for infectivity subgroup comparisons; (3) limited representation of neonates, pregnant women, and some high‑prevalence G6PD variant populations; and (4) the inability to exclude very rare severe haemolytic events given sample size and follow‑up. Programmatic safety monitoring remains warranted where primaquine is scaled up.
Clinical and policy implications
For clinicians and malaria programme managers, the main takeaways are: (1) a single low dose of primaquine (0.25 mg/kg) added to standard ACT can be used to reduce transmission and is effective in children and adults; (2) routine G6PD testing is not required for a single low dose in many settings per prior WHO guidance, but local policies should be followed and special caution used for neonates, pregnant women, and persons with known severe G6PD deficiency; (3) ensuring accurate dosing is critical—pediatric formulations or dispersible tablets will improve dosing accuracy and uptake; and (4) surveillance for haemolysis and adverse events should accompany rollout to detect rare safety signals.
Conclusion
This large individual‑patient meta‑analysis provides robust evidence that single low‑dose primaquine (0.25 mg/kg) is both efficacious and safe for reducing P. falciparum gametocytaemia and infectivity across age groups and transmission settings. These findings support wider programmatic use of single low‑dose primaquine to help interrupt malaria transmission and to limit the spread of artemisinin partial resistance, while underscoring the need for child‑compatible formulations and continued pharmacovigilance.
Funding and trial registrations
The meta‑analysis was funded by the European Union and the Bill & Melinda Gates Foundation. The safety and efficacy analyses were registered with PROSPERO (CRD42021279363 and CRD42021279369).
Selected references
1) Yilma D, Stepniewska K, Bousema T, Drakeley C, Eachempati P, Guerin PJ, Mårtensson A, Mwaiswelo R, Taylor WR, Barnes KI; WWARN Paediatric Primaquine for P falciparum Transmission Blocking Study Group. Safety and efficacy of single‑dose primaquine to interrupt Plasmodium falciparum malaria transmission in children compared with adults: a systematic review and individual patient data meta‑analysis. Lancet Infect Dis. 2025 Sep;25(9):965‑976. doi: 10.1016/S1473-3099(25)00078-7. PMID: 40286803; PMCID: PMC12353880.
2) World Health Organization. Single dose primaquine as a gametocytocide in Plasmodium falciparum malaria. WHO policy recommendation. 2012. (WHO technical documents on primaquine policy and safety.)
AI thumbnail prompt
Photorealistic scene in a tropical clinic: a nurse administering an oral pediatric tablet to a smiling toddler seated on a mother’s lap; background includes a stylized schematic overlay of P. falciparum gametocytes (red ovals) and a semi‑transparent Anopheles mosquito silhouette; warm natural lighting, clinical but compassionate atmosphere, high color fidelity, editorial style.
