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

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.