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

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.

Methods for monitoring artemisinin-based combination therapies efficacy

“…The study realized in Myanmar indicated median parasite half-life was prolonged and clearance half-life was also greater than 5 h in 21% of enrolled patients. There were a significant association between delayed parasite clearance and polymorphisms in propeller kelch 13 region of P. falciparum (Tun et al, 2016).…”

“…This in vivo phenotype was not coupled with any in vitro resistance phenotype as per the standard in vitro susceptibility testing (Ashley et al, 2014;Dondorp et al, 2012;Takala-Harrison et al, 2014;Thriemer et al, 2014;Tun et al, 2016).…”

“…In vitro and exvivo RSA Dondorp et al (2009, , Thriemer et al (2014), Ashley et al (2014), Leang et al (2015) and Tun et al (2016) In vitro and ex-vivo RSA 0-3h can measure slow-clearing and fast-clearing P.…”

Role of K13 Mutations in Artemisinin-Based Combination Therapy

“…Unsurprisingly, ASMQ efficacy in 5 Cambodian provinces where DP was failing in 2014-2016 was 100% at day 42 (n = 305), even though 94.2% (278/295) of parasites carried the K13 C580Y mutation (Amaratunga et al, unpublished data; Rithea et al, unpublished data). High ACT efficacy despite high K13 mutation prevalence has also been reported in neighboring countries [4][5][6][7].…”

“…To this end, the World Health Organization has supported the development of a malaria elimination strategy for this region, and is currently integrating it into the national malaria control programs of all GMS countries [9]. Charlotte Rasmussen, 1 Frédéric Ariey, 2 Rick M. Fairhurst, 3 Pascal Ringwald, 1 and Didier Ménard 4,5,6 …”