Malaria that is resistant to standard artemisinin treatment has been extensively reported along the Cambodia-Thailand border. New research published Online First by The Lancet shows that this resistant malaria has emerged and increased rapidly along the Thailand-Myanmar border, some 800km westward. The study was led by Professor François Nosten and Professor Nicholas White, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand, and Centre for Tropical Medicine (Oxford University), Oxford, UK, and colleagues and was conducted at the Shoklo Malaria Research Unit in Thailand, and by Dr Tim Anderson's group at the Texas Biomedical Research Institute, in San Antonio, TX, USA. The study was funded by The Wellcome Trust and the US National Institutes of Health.
Since artemisinin-resistant malaria was confirmed in Cambodia in 2006 there has been a concerted international effort to control P. falciparum malaria in this region to prevent resistance spreading. However, this containment strategy is dependent on whether or not resistance has spread or appeared elsewhere. In this study, the authors analysed data from patients in malaria clinics of the Shoklo Malaria Research Unit located along the northwestern border of Thailand treated between 2001 and 2010. They measured six-hourly parasite counts in patients with uncomplicated hyperparasitaemic falciparum malaria (≥4% infected red blood cells) who had been given various oral artesunate-containing regimens since 2001. Parasite clearance half-lives (a measure of treatment resistance) were estimated and parasites were genotyped.
3202 patients were studied between 2001 and 2010. Parasite clearance half-lives lengthened from a mean of 2.6 hours in 2001 to 3.7 hours in 2010, compared with a mean of 5.5 hours in 119 patients in Western Cambodia measured between 2007 and 2010. The proportion of slow-clearing infections, with a half life equal to or great than 6.2 hours, increased from 0.6% in 2001 to 20% in 2010. This slowing of parasite clearance was shown to result from a genetic trait. The authors say more genetic analysis is needed to know whether the parasites from the 2 regions have a common origin.
The authors say: "Genetically determined artemisinin resistance in P. falciparum emerged along the Thailand–Myanmar border at least 8 years ago and has since increased substantially. At this rate of increase, resistance will reach rates reported in western Cambodia in 2-6 years."
The artesunate–mefloquine combination has been the first-line treatment for falciparum malaria on the western border of Thailand since 1994. Artesunate was added to a failing mefloquine regimen, and the high effectiveness of the combination (>90% day 42 cure rates) has been sustained since then, although evidence suggests that effectiveness is decreasing, with a day 42 cure rate in 86 patients in 2010 of 89%. The authors point out that the declining artemisinin effectiveness will have an adverse effect on the treatment of uncomplicated falciparum malaria by slowing therapeutic responses and increasing treatment failure rates and will reduce the remarkable life-saving effectiveness of artesunate in the treatment of severe malaria and hyperparasitaemic patients.
The authors say: "A potential radical approach to containment of artemisinin resistance is to try to eliminate P. falciparum malaria from western Cambodia, but would this strategy be justified if resistance has already spread or emerged elsewhere? Genetically determined resistance to artemisinins is now prevalent on the Thailand–Myanmar border, contiguous with a malaria endemic area in which a large burden of uncontrolled disease exists, so containment efforts will need to be expanded and surveillance and control strategies re-examined."
They conclude: "Identification of a molecular marker will be crucial to monitor the distribution and spread of resistance and to understand the evolution of this trait and the mechanism of action of artemisinin. The large numbers of patients infected with malaria, high heritability, and the broad range of parasite clearance half-lives make the Thailand–Myanmar border region ideal for powerful association studies. Clinical studies are needed urgently to map further spread and to establish the effect of different degrees of artemisinin resistance on treatment effectiveness and transmissibility."
In a linked Comment, Dr Anne-Catrin Uhlemann, and Dr David A Fidock, Columbia University College of Physicians and Surgeons, New York, USA, say: "Containment efforts should no longer be restricted to Cambodia, because resistance could be starting to emerge in various parts of southeast Asia, including Myanmar where the malaria burden is high and public health infrastructure weak."
They conclude: "Antimalarial control efforts are vitally dependent on artemisinin combination treatments. Should these regimens fail, no other drugs are ready for deployment, and drug development efforts are not expected to yield new antimalarials until the end of this decade. Whether initial signs of decreased parasite responsiveness will result in high-grade resistance and a loss of clinical effectiveness cannot yet be judged. Nor is it clear if forms of resistance will emerge that are sufficiently viable to compete with drug-sensitive organisms in high-transmission settings in sub-Saharan Africa, where the effect of malaria is greatest. The importance of artemisinin combination treatments nonetheless emphasises the need to both monitor for signs of emerging resistance and implement all available measures towards malaria elimination while we can."
Professor Nicholas J White, Mahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand, and Centre for Tropical Medicine, University of Oxford, UK. T) +662 203 6301 / +6689 203 7200) nickwdt@tropmedres.ac
Professor François Nosten, Mahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand, and also the Shoklo Malaria Research Unit, Thailand. T) +6655 545 021 / +6681 881 33 50 E) francois@tropmedres.ac
Dr David A Fidock, Columbia University College of Physicians and Surgeons, New York, USA. T) +1 212-305-0816 E) df2260@columbia.edu
Journal
The Lancet