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

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

Abstract

Background: Artemisinin 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.

Methods: The 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.

Results: Of 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.

Conclusion: Despite 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://ichgcp.net/clinical-trials-registry/NCT02020330.

Keywords: Artemether–lumefantrine; Artemisinin resistance; Myanmar; Plasmodium falciparum; kelch13 mutation.

Figures

Fig. 1
Fig. 1
Clearance of P. falciparum parasitaemia assessed by quantitative uPCR. One circle represents one patient, red circles are treated by AL5, blue circles are treated by AL3
Fig. 2
Fig. 2
Clearance of P. falciparum parasitaemia assessed by quantitative uPCR. One circle represents one patient, red circles are infections with kelch13 mutations after position 440, blue circles represent infections with kelch wild types alleles

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