Effectiveness and safety of 3 and 5 day courses of artemether–lumefantrine for the treatment of uncomplicated falciparum malaria in an area of emerging artemisinin resistance in Myanmar

Abstract

BackgroundArtemisinin resistance in Plasmodium falciparum has emerged and spread in Southeast Asia. In areas where resistance is established longer courses of artemisinin-based combination therapy have improved cure rates.MethodsThe standard 3-day course of artemether–lumefantrine (AL) was compared with an extended 5-day regimen for the treatment of uncomplicated falciparum malaria in Kayin state in South-East Myanmar, an area of emerging artemisinin resistance. Late parasite clearance dynamics were described by microscopy and quantitative ultra-sensitive PCR. Patients were followed up for 42 days.ResultsOf 154 patients recruited (105 adults and 49 children < 14 years) 78 were randomized to 3 days and 76 to 5 days AL. Mutations in the P. falciparum kelch13 propeller gene (k13) were found in 46% (70/152) of infections, with F446I the most prevalent propeller mutation (29%; 20/70). Both regimens were well-tolerated. Parasite clearance profiles were biphasic with a slower submicroscopic phase which was similar in k13 wild-type and mutant infections. The cure rates were 100% (70/70) and 97% (68/70) in the 3- and 5-day arms respectively. Genotyping of the two recurrences was unsuccessful.ConclusionDespite a high prevalence of k13 mutations, the current first-line treatment, AL, was still highly effective in this area of South-East Myanmar. The extended 5 day regimen was very well tolerated, and would be an option to prolong the useful therapeutic life of AL.Trial registration NCT02020330. Registered 24 December 2013, https://clinicaltrials.gov/NCT02020330Electronic supplementary materialThe online version of this article (10.1186/s12936-018-2404-4) contains supplementary material, which is available to authorized users.

Efficacy of artemether-lumefantrine for treating uncomplicated Plasmodium falciparum cases and molecular surveillance of drug resistance genes in Western Myanmar

“…The artemisinin resistance phenotype was also documented in eastern (37.1%) [ 43 ] and northeastern (23.1%) [ 20 ] Myanmar after treatment with artesunate. In southeastern Myanmar, 20% of the cases were still parasitaemic on day 3 after treatment with AL [ 49 ]. Despite the presence of artemisinin resistance, ACT still demonstrated high therapeutic efficacies (95.9–100%) in the above areas.…”

“…To date, clinical studies to monitor the efficacies of artemisinins or ACT detected artemisinin-resistant P. falciparum only in southern and eastern Myanmar [ 43 , 44 ]. In comparison, ACT remained highly efficacious in northern, northeastern (at the China-Myanmar border) and western Myanmar [ 19 , 45 – 49 ]. Molecular surveillance also detected disparate distributions and prevalence of pfk13 mutations in different regions of Myanmar [ 29 , 30 , 46 – 48 , 50 ], providing a quick assessment of the artemisinin resistance situation.…”

Parasite clearance, cure rate, post-treatment prophylaxis and safety of standard 3-day versus an extended 6-day treatment of artemether–lumefantrine and a single low-dose primaquine for uncomplicated Plasmodium falciparum malaria in Bagamoyo district, Tanzania: a randomized controlled trial

“…However, studies from Africa are needed to evaluate efficacy, safety and tolerability of dose prolongation for the treatment of uncomplicated malaria. To date, there are two published studies on artemether-lumefantrine dosage extension to 5 days; one from Myanmar on non-pregnant adults and children [29], and the other on pregnant vs non-pregnant women in Congo [30], as the only study from Africa to evaluate artemether-lumefantrine dosage extension.…”

Electrocardiographic safety evaluation of extended artemether-lumefantrine treatment in patients with uncomplicated Plasmodium falciparum malaria in Bagamoyo District, Tanzania

“…Plasmodium falciparum resistance to artemisinin-based combination therapy (ACT) is an emerging threat to the improvements made for past decade in the strive to control and eliminate malaria [1]. Alternative strategies to protect the therapeutic lifespan of artemisinin-based combinations are being explored, such as extending the ACT treatment duration, optimizing drug dosing, new combinations and use of triple ACT as development of new anti-malarial drugs with comparable efficacy is underway [2][3][4][5][6]. Among studies that explored the efficacy and safety of extended ACT, such as artemether-lumefantrine, i.e.…”

“…Among studies that explored the efficacy and safety of extended ACT, such as artemether-lumefantrine, i.e. the most commonly used artemisinin-based combination for the treatment of uncomplicated P. falciparum malaria in Africa, few have electrocardiographic (ECG) parameters as part of safety reporting [4,6].…”