Effectiveness and safety of 3 and 5\xa0day courses of artemether\u2013lumefantrine for the treatment of uncomplicated falciparum malaria in an area of emerging artemisinin resistance in Myanmar

Kyaw Myo Tun,Elizabeth A Ashley,Thar Htun Kyaw,Atthanee Jeeyapant,Mavuto Mukaka,Phaik Yeong Cheah,Thaung Hlaing,Nicholas P J Day,Nicholas J White,Mehul Dhorda,Arjen Dondorp,Aung Hpone Myint,Frank Smithuis,Mallika Imwong,Zwe Thiha Kyaw

doi:10.1186/s12936-018-2404-4

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/NCT02020330

Highlights

Artemisinin resistance in Plasmodium falciparum has emerged and spread in Southeast Asia
Artemisinin resistance has been followed by partner drug resistance in the eastern Greater Mekong sub-region, and this has resulted in a precipitous decline in the efficacy of dihydroartemisinin–piperaquine [4, 9]
Falciparum malaria was routinely treated with 3 days artemether–lumefantrine and a single gametocytocidal dose of primaquine according to national policy

Summary

Introduction

Artemisinin resistance in Plasmodium falciparum has emerged and spread in Southeast Asia. Artemisinin resistance in Plasmodium falciparum has emerged in South-East Asia and extends over a large area of the Greater Mekong sub-region from the coast of Vietnam to the Eastern border of India [1,2,3,4,5,6]. Artemisinin resistance results in delayed parasite clearance leaving a larger residual number of parasites after a 3-day artemisinin-based combination therapy (ACT) course for the slowly eliminated partner drug to remove [7, 8]. This increases the probability that some parasites will survive to recrudesce. In the absence of new drugs, strategies to counter the loss of ACT efficacy rely on adapted regimens of existing artemisinin-based combinations to optimize efficacy against resistant parasite strains, such as longer courses or triple drug combinations [1, 4, 13]

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Discussion

Conclusion