A combination of mefloquine associated with artesunate (AS-MQ) was the first widely deployed artemisinin-based combination therapy (ACT) for acute uncomplicated Plasmodium falciparum malaria. The WWARN AS-MQ Dose Impact Study Group conducted a systematic review with individual patient data meta-analysis to investigate how mefloquine mg/kg dosing influences clinical and parasitological outcomes, including recurrence and tolerability endpoints.
Individual patient data from 31 clinical studies of uncomplicated falciparum malaria treated with various AS-MQ regimens were pooled and analysed. The target mefloquine dose across those studies was 25 mg/kg, with regimens conducted in Asia, Africa and South America. The analysis evaluated associations between estimated mg/kg dosing of mefloquine and artesunate and outcomes such as PCR-corrected recrudescence within 42 days, and early tolerability events like vomiting. Adjustments were made for background artemisinin resistance where relevant.
A total of 6,761 patients enrolled between 1995 and 2018 contributed data. The majority (74%) were from Asia. The median age of participants was 18 years (interquartile range 8–30 years), and 13.5% (915/6,761) were aged less than 5 years. Participants received an estimated median total mg/kg dose of mefloquine of 25 (range 6.8–60) and of artesunate of 12 (range 3.6–33.3). Overall, 1,572 participants (23.4%) were treated with the coformulation.
Across regions and prior to the emergence of artemisinin resistance, the PCR-corrected recrudescence rate at 42 days after any AS-MQ treatment was low. Reported rates were 2.4% for patients enrolled in Asia and 2.5% in Africa. In South America there was one recrudescent infection reported. Age-specific rates in young children were slightly higher: in children aged 1 to <5 years the corresponding recrudescence rates were 2.9% (Asia) and 3.3% (Africa).
After adjusting for background artemisinin resistance, the hazard of recrudescence in Asia was significantly higher in children aged 1 to <5 years than in adults (adjusted hazard ratio [AHR] 3.01, 95% CI 1.60–5.64, p < 0.001). In Africa the adjusted hazard ratio for the same age comparison was 5.18 (95% CI 0.61–44.28, p = 0.133), which was not statistically significant in the dataset analysed.
A significant MQ dose–effect was observed in Asia among patients treated with three-day regimens. For this subgroup, each 1 mg/kg increase in mefloquine dose was associated with a reduced hazard of recrudescence (AHR 0.89, 95% CI 0.83–0.96, p = 0.003). This finding indicates a measurable association between higher mg/kg dosing and lower risk of recrudescence in that regional and regimen-specific context.
The pooled dataset allowed assessment of early tolerability, measured as vomiting within one hour of dosing. Vomiting rates per dose were highest in the youngest children: in children aged 1–5 years there were 13 vomiting events among 378 doses (3.4% per dose). In children aged 5–11 years the rate was 1.7% per dose (20/1,168), and in patients aged 12 years or older it was 1.1% per dose (47/4,191). A test for trend across age groups was statistically significant (p < 0.001), indicating that early vomiting after dosing was more frequent in younger children.
The pooled individual patient data demonstrate that AS-MQ administered over three days is a highly efficacious ACT in low-to-moderate transmission settings without artemisinin resistance. The analysis identified a significant dose–response relationship in Asia for three-day regimens, with higher mefloquine mg/kg associated with reduced recrudescence. Young children (1 to <5 years) had a higher adjusted hazard of recrudescence in Asia and experienced the highest rates of early vomiting, which may limit the feasibility of increasing mefloquine doses in that age group. The authors note that consideration of dose optimisation in young children could be weighed against the dose-related increase in early vomiting.
All included data were obtained in accordance with applicable laws and ethical approvals in the countries where the original studies were conducted, and with the knowledge and consent of participants. Pseudonymised data were shared with WWARN. The analysis did not require review by the Oxford Central University Research Ethics Committee per the authors. Competing interests reported in the source include that an author works for DNDi which developed the first coformulation of AS-MQ, an author had prior employment relevant to the field, and various authors had worked on studies used to register the fixed-dose combination formulation. One author served as Associate Editor at Malaria Journal between 2015 and 2025.