Abstract
BackgroundProspective efficacy monitoring of anti-malarial treatments is imperative for timely detection of resistance development. The in vivo efficacy of artesunate-amodiaquine (ASAQ) fixed-dose combination (FDC) was compared to that of artemether-lumefantrine (AL) among children aged six to 59 months in Nimba County, Liberia, where Plasmodium falciparum malaria is endemic and efficacy data are scarce.MethodsAn open-label, randomized controlled non-inferiority trial compared the genotyping adjusted day 42 cure rates of ASAQ FDC (ASAQ Winthrop®) to AL (Coartem®) in 300 children aged six to 59 months with uncomplicated falciparum malaria. Inclusion was between December 2008 and May 2009. Randomization (1:1) was to a three-day observed oral regimen (ASAQ: once a day; AL: twice a day, given with fatty food). Day 7 desethylamodiaquine and lumefantrine blood-concentrations were also measured.ResultsThe day 42 genotyping-adjusted cure rate estimates were 97.3% [95% CI: 91.6-99.1] for ASAQ and 94.2% [88.1-97.2] for AL (Kaplan-Meier survival estimates). The difference in day 42 cure rates was −3.1% [upper limit 95% CI: 1.2%]. These results were confirmed by observed proportion of patients cured at day 42 on the per-protocol population. Parasite clearance was 100% (ASAQ) and 99.3% (AL) on day 3. The probability to remain free of re-infection was 0.55 [95% CI: 0.46-0.63] (ASAQ) and 0.66 [0.57-0.73] (AL) (p = 0.017).ConclusionsBoth ASAQ and AL were highly efficacious and ASAQ was non-inferior to AL. The proportion of patients with re-infection was high in both arms in this highly endemic setting. In 2010, ASAQ FDC was adopted as the first-line national treatment in Liberia. Continuous efficacy monitoring is recommended.Trial registrationThe protocols were registered with Current Controlled Trials, under the identifier numbers ISRCTN51688713, ISRCTN40020296.
Highlights
Prospective efficacy monitoring of anti-malarial treatments is imperative for timely detection of resistance development
The primary objective was to evaluate the efficacy of amodiaquine-artesunate versus artemether-lumefantrine among children between six and 59 months old suffering from uncomplicated malaria defined as the genotype adjusted cure rates at day 42 [10]
Secondary objectives were: (a) to evaluate the genotypeunadjusted cure rates at day 42, genotype adjusted/ unadjusted cure rates at day 28, and re-infection rates at day 42; (b) to assess blood drug concentration differences possibly influencing efficacy by measuring drug concentrations of amodiaquine and lumefantrine at day 0 and day 7; (c) to assess the safety of amodiaquine-artesunate and artemether-lumefantrine treatment among children between 6 and 59 months by documenting adverse events that occurred during the study before day 28 and by documenting serious adverse events; (d) to formulate recommendations for adapted case management of malaria in Nimba County
Summary
Prospective efficacy monitoring of anti-malarial treatments is imperative for timely detection of resistance development. The in vivo efficacy of artesunate-amodiaquine (ASAQ) fixed-dose combination (FDC) was compared to that of artemether-lumefantrine (AL) among children aged six to 59 months in Nimba County, Liberia, where Plasmodium falciparum malaria is endemic and efficacy data are scarce. Potent artemisinin-containing combination therapy (ACT) is the recommended firstline treatment for uncomplicated falciparum malaria in most endemic countries [2]. This includes artesunateamodiaquine (AS + AQ), artemether-lumefantrine (AL), artesunate-mefloquine (AS-MQ), artesunate-sulfadoxinepyrimethamine (AS-SP) and dihydroartemisininpiperaquine (DHAPQ), which are considered efficacious and safe [2,3,4,5]. The first FDC of AS + AQ (ASAQ Winthrop®) was developed by the Drugs for Neglected Diseases initiative (DNDi), and is currently registered in 32 African countries. ASAQ FDC was shown to be efficacious, safe and well tolerated in previous studies [6,7,8,9]
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