Artesunate + amodiaquine versus artemether-lumefantrine for the treatment of uncomplicated Plasmodium falciparum malaria in the Colombian Pacific region: a noninferiority trial

Abstract

Introduction: In Colombia, there are no published studies for the treatment of uncomplicated Plasmodium falciparum malaria comparing artemisinin combination therapies. Hence, it is intended to demonstrate the non-inferior efficacy/safety profiles of artesunate + amodiaquine versus artemetherlumefantrine treatments. Methods: A randomized, controlled, open-label, noninferiority (Δ≤5%) clinical trial was performed in adults with uncomplicated P. falciparum malaria using the 28-day World Health Organization validated design/definitions. Patients were randomized 1:1 to either oral artesunate + amodiaquine or artemether-lumefantrine. The primary efficacy endpoint: adequate clinical and parasitological response; secondary endpoints: -treatment failures defined per the World Health Organization. Safety: assessed through adverse events. Results: A total of 105 patients was included in each group: zero censored observations. Mean (95%CI -Confidence interval) adequate clinical and parasitological response rates: 100% for artesunate + amodiaquine and 99% for artemether-lumefantrine; the noninferiority criteria was met (Δ=1.7%). There was one late parasitological therapeutic failure (1%; artemether-lumefantrine group), typified by polymerase chain reaction as the MAD20 MSP1 allele. The fever clearance time (artesunate + amodiaquine group) was significantly shorter (p=0.002). Respectively, abdominal pain for artesunate + amodiaquine and artemether-lumefantrine was 1.9% and 3.8% at baseline (p=0.68) and 1% and 13.3% after treatment (p<0.001). Conclusions: Uncomplicated P. falciparum malaria treatment with artesunate + amodiaquine is noninferior to the artemetherlumefantrine standard treatment. The efficacy/safety profiles grant further studies in this and similar populations.

Artemether–Lumefantrine Efficacy for the Treatment of Uncomplicated Plasmodium falciparum Malaria in Choco, Colombia after 8 Years as First-Line Treatment

“…In 2008, a randomized clinical trial with two treatment arms, artesunate plus amodiaquine and AL, reported ACPR rates of 100% and 99%, respectively. 10 In 2007-2008, ACPR rates with AL at days 28 and 42 were 98.7% and 97.5%, respectively, in a study conducted in Tumaco, Nariño Department on the Pacific coast of Colombia. 24 Contrary to previous studies in Colombia, which experienced challenges recruiting and retaining participants, 25 our study was able to reach the desired sample size in less than 8 months, and our loss to the follow-up rate was limited to only four participants in the 28-day follow-up.…”

“…Any person reporting the use of any medication with antimalarial effects in the past 4 weeks, with a history of hypersensitivity to the treatment being offered, or with heart, kidney, and liver diseases, and HIV infection were also ineligible. The required sample size was 78 participants based on the assumption of therapeutic failure of 5.3% (based on a previous study in Colombia) 10 in a population of infinite size with a level of significance of 5%, and a maximum tolerable error of ± 5%. We added 15% to account for loss to follow-up, with a final target of 90 participants.…”

“…9 Since the introduction of ACTs in Colombia, studies have shown treatment response rates greater than 95%. 10 Monitoring of drug resistance-associated genes among malaria parasites can be performed during TESs to determine the prevalence of parasites with resistance genotypes, which complements TES findings. Mutations in PfK13 propeller gene are considered molecular markers of artemisinin resistance in P. falciparum.…”

Artemeter-Lumefantrine therapeutic efficacy, safety and plasma levels in patients with uncomplicated falciparum malaria from the Colombian Pacific región

“…The detection of submicroscopic parasitemia in four cases (5%) on day 28 by PCR may reflect a reduction in susceptibility to AL in the region, however reinfections could not be ruled out as the cause for these findings. In the analysis, these cases were considered as therapeutic failures in accordance with findings in the same area in 2009 where a late failure of 1% was evidenced 9 . From the comparison of this data and the findings in the previous study, we infer that the crude and PCR-corrected ACPR rates found in the Colombian Pacific region 9 are similar.…”

“…Other studies conducted in the period 2010-2016 showed effective first-line treatment for P. falciparum (treatment failure rates 0%) (1). In Colombia a study in 2008 with Artesunate-Amodiaquine (AS-AQ) regimen vs. AL regimen, found no early treatment failure (ETF) or late clinical failures (LCF) in either group and one late parasitological treatment failure (LPTF) in the AL group 9 .…”