The effect of mefloquine dose on outcome of uncomplicated falciparum malaria treated with artesunate-mefloquine: a WWARN systematic review and individual patient data meta-analysis
Abstract
Introduction: A combination of mefloquine associated with artesunate (AS-MQ) was the first artemisinin-based combination therapy (ACT) to be used widely for acute uncomplicated P. falciparum malaria. Methods: Individual patient data from 31 studies of patients with uncomplicated falciparum malaria treated with various AS-MQ regimens (target mefloquine dose 25 mg/kg), conducted in Asia, Africa and South America, were pooled and analysed to investigate the effects of MQ mg/kg dosing on malaria recurrence and other clinical, parasitological and tolerability endpoints. Results: A total of 6,761 patients were enrolled in clinical studies conducted between 1995 and 2018; the majority (74%) were from Asia. The median age of study participants was 18 years (interquartile range IQR 8-30 years), of whom 13.5% (915/6761) were aged less than 5 years old. Participants received an estimated median [range] total mg/kg dose of mefloquine and artesunate of 25 [6.8-60] and 12 [3.6-33.3] respectively, and 1,572 (23.4%) participants were treated with the coformulation. The PCR-corrected recrudescence rate 42 days after any ASMQ treatment was 2.4% for patients enrolled in Asia and 2.5% in Africa, before artemisinin resistance emerged. Corresponding rates in children aged 1 to < 5 years were 2.9% and 3.3%. After adjusting for background artemisinin resistance, the hazard of recrudescence was higher in children aged 1 to < 5 years than in adults in Asia, but not in Africa (Asia, HR 3.01, 95%CI 1.60-5.64, p < 0.001; Africa HR 5.18, 95% CI 0.61-44.28, p = 0.133). There was only one recrudescent infection in South America. A significant MQ dose-effect was observed in Asia in patients treated with 3-dose regimens (AHR 0.89, 95% CI 0.83-0.96, p = 0.003 for 1 mg/kg increase in dose). Vomiting rates within an hour of dosing were highest in children 1- 5 years of age (n = 140) at 3.4% doses (13/378) compared to 1.7% (20/1,168) in children 5-11 years (n = 476), and 1.1% (47/4,191) in patients 12 years of age or older (n = 2027) (p < 0.001, test for trend). Conclusion: AS-MQ administered over three days is a highly efficacious ACT in low to moderate transmission areas without artemisinin resistance. While further optimisation of the mefloquine dose in the coformulation in children aged 1-5 years could be considered, dose-related early vomiting is highest in this age group and may preclude this.
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BibTeX
@article{ashley2026effect,
title = {{The effect of mefloquine dose on outcome of uncomplicated falciparum malaria treated with artesunate-mefloquine: a WWARN systematic review and individual patient data meta-analysis}},
author = {Elizabeth A Ashley and Emmanuel Baron and Marielle K Bouyou Akotet and Rebekah Burrow and Gwenaelle Carn and Verena I Carrara and Emmanuelle Comets and Chantal Csajka and Umberto d'Alessandro and Nicholas P Day and Abdoulaye A. Djimde and Arjen Dondorp and Stephan Duparc and Mabul Faiz and Marcelo Urbano Ferreira and Lawrence Fleckenstein and Oumar Gaye and Blaise Genton and Philippe J Guerin and Eva Maria Hodel and Georgina S Humphreys and Peter G. Kremsner and Srivicha Krudsood and Simone Ladeia-Andrade and Gilbert Lefevre and Rashid Mansoor and Mayfong Mayxay and Paul N Newton and François Nosten and Aung Pyae Phyo and Ric N. Price and Sasithon Pukrittayakamee and Michael Ramharter and Ronnatrai Rueangweerayut and Issaka Sagara and Sodiomon B. Sirima and Frank M. Smithuis and Kasia Stepniewska and Walter R. J. Taylor and Innocent Valéa and Neena Valecha and Ingrid V. F. van den Broek and Rob W van Der Pluijm and Michele van Vugt and Stephen A. Ward and Nicholas J. White},
journal = {Malaria Journal},
year = {2026},
month = nov,
doi = {10.1186/s12936-026-05963-4},
url = {https://hal.science/hal-05855046v1},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - The effect of mefloquine dose on outcome of uncomplicated falciparum malaria treated with artesunate-mefloquine: a WWARN systematic review and individual patient data meta-analysis
AU - Elizabeth A Ashley
AU - Emmanuel Baron
AU - Marielle K Bouyou Akotet
AU - Rebekah Burrow
AU - Gwenaelle Carn
AU - Verena I Carrara
AU - Emmanuelle Comets
AU - Chantal Csajka
AU - Umberto d'Alessandro
AU - Nicholas P Day
AU - Abdoulaye A. Djimde
AU - Arjen Dondorp
AU - Stephan Duparc
AU - Mabul Faiz
AU - Marcelo Urbano Ferreira
AU - Lawrence Fleckenstein
AU - Oumar Gaye
AU - Blaise Genton
AU - Philippe J Guerin
AU - Eva Maria Hodel
AU - Georgina S Humphreys
AU - Peter G. Kremsner
AU - Srivicha Krudsood
AU - Simone Ladeia-Andrade
AU - Gilbert Lefevre
AU - Rashid Mansoor
AU - Mayfong Mayxay
AU - Paul N Newton
AU - François Nosten
AU - Aung Pyae Phyo
AU - Ric N. Price
AU - Sasithon Pukrittayakamee
AU - Michael Ramharter
AU - Ronnatrai Rueangweerayut
AU - Issaka Sagara
AU - Sodiomon B. Sirima
AU - Frank M. Smithuis
AU - Kasia Stepniewska
AU - Walter R. J. Taylor
AU - Innocent Valéa
AU - Neena Valecha
AU - Ingrid V. F. van den Broek
AU - Rob W van Der Pluijm
AU - Michele van Vugt
AU - Stephen A. Ward
AU - Nicholas J. White
PY - 2026
DA - 2026/11/06
JO - Malaria Journal
DO - 10.1186/s12936-026-05963-4
UR - https://hal.science/hal-05855046v1
AB - Introduction: A combination of mefloquine associated with artesunate (AS-MQ) was the first artemisinin-based combination therapy (ACT) to be used widely for acute uncomplicated P. falciparum malaria. Methods: Individual patient data from 31 studies of patients with uncomplicated falciparum malaria treated with various AS-MQ regimens (target mefloquine dose 25 mg/kg), conducted in Asia, Africa and South America, were pooled and analysed to investigate the effects of MQ mg/kg dosing on malaria recurrence and other clinical, parasitological and tolerability endpoints. Results: A total of 6,761 patients were enrolled in clinical studies conducted between 1995 and 2018; the majority (74%) were from Asia. The median age of study participants was 18 years (interquartile range IQR 8-30 years), of whom 13.5% (915/6761) were aged less than 5 years old. Participants received an estimated median [range] total mg/kg dose of mefloquine and artesunate of 25 [6.8-60] and 12 [3.6-33.3] respectively, and 1,572 (23.4%) participants were treated with the coformulation. The PCR-corrected recrudescence rate 42 days after any ASMQ treatment was 2.4% for patients enrolled in Asia and 2.5% in Africa, before artemisinin resistance emerged. Corresponding rates in children aged 1 to < 5 years were 2.9% and 3.3%. After adjusting for background artemisinin resistance, the hazard of recrudescence was higher in children aged 1 to < 5 years than in adults in Asia, but not in Africa (Asia, HR 3.01, 95%CI 1.60-5.64, p < 0.001; Africa HR 5.18, 95% CI 0.61-44.28, p = 0.133). There was only one recrudescent infection in South America. A significant MQ dose-effect was observed in Asia in patients treated with 3-dose regimens (AHR 0.89, 95% CI 0.83-0.96, p = 0.003 for 1 mg/kg increase in dose). Vomiting rates within an hour of dosing were highest in children 1- 5 years of age (n = 140) at 3.4% doses (13/378) compared to 1.7% (20/1,168) in children 5-11 years (n = 476), and 1.1% (47/4,191) in patients 12 years of age or older (n = 2027) (p < 0.001, test for trend). Conclusion: AS-MQ administered over three days is a highly efficacious ACT in low to moderate transmission areas without artemisinin resistance. While further optimisation of the mefloquine dose in the coformulation in children aged 1-5 years could be considered, dose-related early vomiting is highest in this age group and may preclude this.
SN - 1475-2875
ER -