Parasite clearance rates in Upper Myanmar indicate a distinctive artemisinin resistance phenotype: a therapeutic efficacy study.

Kyaw Myo Tun,Frank M Smithuis,Min Thein,Atthanee Jeeyapant,Nicholas P J Day,Arjen M Dondorp,Prayoon Yuentrakul,Cholrawee Promnarate,Mehul Dhorda,Elizabeth A Ashley,Tin Maung Hlaing,Charles J Woodrow,Sai Soe Moe Aung,Nicholas J White,Mallika Imwong

doi:10.1186/s12936-016-1240-7

Abstract

BackgroundArtemisinin resistance in Plasmodium falciparum extends across Southeast Asia where it is associated with worsening partner drug resistance and a decline in the efficacy of frontline artemisinin-based combination therapy. Dihydroartemisinin-piperaquine (DP) is an essential component of preventive and curative treatment in the region, but its therapeutic efficacy has fallen in Cambodia.MethodsA prospective clinical and parasitological evaluation of DP was conducted at two sites in Upper Myanmar between August 2013 and December 2014, enrolling 116 patients with acute uncomplicated falciparum malaria. Patients received DP orally for 3 days together with primaquine 0.25 mg/kg on admission. Parasite clearance half-lives based on 6 hourly blood smears, and day 42 therapeutic responses were assessed as well as parasite K13 genotypes.ResultsMedian parasite clearance half-life was prolonged, and clearance half-life was greater than 5 h in 21 % of patients. Delayed parasite clearance was significantly associated with mutations in the propeller region of the parasite k13 gene. The k13 F446I mutation was found in 25.4 % of infections and was associated with a median clearance half-life of 4.7 h compared with 2.7 h for infections without k13 mutations (p < 0.001). There were no failures after 42 days of follow-up, although 18 % of patients had persistent parasitaemia on day 3.ConclusionThe dominant k13 mutation observed in Upper Myanmar, F446I, appears to be associated with an intermediate rate of parasite clearance compared to other common mutations described elsewhere in the Greater Mekong Subregion. Discerning this phenotype requires relatively detailed clearance measurements, highlighting the importance of methodology in assessing artemisinin resistance.Electronic supplementary materialThe online version of this article (doi:10.1186/s12936-016-1240-7) contains supplementary material, which is available to authorized users.

Highlights

Artemisinin resistance in Plasmodium falciparum extends across Southeast Asia where it is associated with worsening partner drug resistance and a decline in the efficacy of frontline artemisinin-based combination therapy
Artemisinin resistance has steadily worsened along the Myanmar–Thailand border [17, 18] where the k13 C580Y mutation predominates, and is present in central and southern Myanmar where independent mutations have emerged [2, 3, 19]
Parasite clearance half-life is less prone to confounding by baseline parasitaemia than day 3 parasite positivity [28, 30, 31], and remains the gold-standard for determining resistance phenotypes needed for the characterization of artemisinin resistance [10, 32,33,34]

Summary

Introduction

Artemisinin resistance in Plasmodium falciparum extends across Southeast Asia where it is associated with worsening partner drug resistance and a decline in the efficacy of frontline artemisinin-based combination therapy. A recent molecular survey of k13 gene mutations, which obtained data from ten administrative regions, indicated that artemisinin resistance extends across much of Myanmar [1]. Several clinical studies have been undertaken at the border between Kachin State and Yunnan Province in China [20, 21]; based on a combination of day 3 parasite positivity rates and subsequent molecular and in vitro studies [4, 5, 22] it has been concluded that artemisinin resistance is present in this region

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Results

Conclusion