Artemisinin resistant falciparum malaria in Myanmar

Thesis

Artemisinin-based combination therapy (ACT) is first-line treatment for Plasmodium falciparum malaria globally but artemisinin resistance is now prevalent across Southeast Asia. Myanmar has the highest malaria burden in the region, and determining the prevalence of artemisinin resistance and current therapeutic efficacy of first-line antimalarial drugs is critical for both clinicians and policy makers planning malaria control and elimination programmes. The aim of this research was to study the geographical extent, prevalence, degree and optimum treatment of artemisinin-resistant falciparum malaria in Myanmar through a countrywide molecular survey and two multicentre clinical trials supported by parasitological and pharmacological investigations.

In a molecular survey of clinical falciparum malaria cases carried out in 55 sites across 10 administrative regions and border sites in neighbouring countries 39% of cases (371/940) were associated with parasites carrying a kelch13 propeller mutation. Kelch13 mutation prevalence exceeded 10% in much of the east and north of the country and was 47% in an area 25 km from the border with India.

In a trial conducted in central and northern Myanmar treatment efficacy of dihydroartemisinin-piperaquine (DP) was 100% but there was delayed parasite clearance associated with the kelch13 mutation F446I (median clearance half-life 4.7 hours, IQR, 3.7 to 6.2).

In a randomised controlled trial of 3-days versus 5-days artemether-lumefantrine (AL) treatment efficacy was 100% (95%CI, 94.9-100) and 97% (95%CI, 90-99.7) respectively and the two arms showed equal clearance rates (measured by an ultrasensitive quantitative polymerase chain reaction assay, uqPCR)..There was no association between the presence of kelch13 propeller mutations and residual parasite density at day 21, measured using uqPCR. Gametocyte carriage rates were high reinforcing the need to implement single low-dose primaquine (0.25 mg/kg) with ACTs to kill gametocytes in this area of artemisinin resistance.

In conclusion, artemisinin resistant falciparum malaria is widespread in Myanmar. While DP and AL remain efficacious, the partner drugs are vulnerable and if resistance develops treatment efficacy is likely to decline rapidly. Greater efforts are urgently needed to monitor treatment efficacy of first-line antimalarial drugs and develop alternative treatment regimens.

Authors: Tun, K

• Alternative title: Artemisinin resistant malaria
• DOI: 10.5287/ora-xqb7vepqn
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford