Resistance to the world's most effective anti-malarial drug, artemisinin, is now widespread across mainland Southeast Asia, seriously threatening global malaria control and elimination, according to a study led by Oxford University researchers based in Thailand.
The study, which analysed blood samples from 1241 malaria patients in 10 countries across Asia and Africa, found that artemisinin resistance in the malaria parasite Plasmodium falciparum is now firmly established in Western Cambodia, Thailand, Vietnam, Eastern Myanmar and Northern Cambodia. There are also signs of emerging resistance in Central Myanmar, Southern Laos and Northeastern Cambodia.
Reassuringly, there are no signs of resistance in the three African sites included in the study: in Kenya, Nigeria and Democratic Republic of the Congo.
The study also suggests that extending the course of antimalarial treatment in areas with established resistance – for six days rather than the standard three days – could offer a temporary solution to this worsening problem.
'It may still be possible to prevent the spread of artemisinin-resistant malaria parasites across Asia and then to Africa by eliminating them, but that window of opportunity is closing fast,' says senior author Professor Nicholas White, Professor of Tropical Medicine at the University of Oxford and Chair of the Worldwide Antimalarial Resistance Network. 'Conventional malaria control approaches won't be enough – we will need to take more radical action and make this a global public health priority without delay.'
The study was conducted by an international team, the Tracking Resistance to Artemisinin Collaboration (TRAC), and their results are published in the New England Journal of Medicine.
Led by Wellcome Trust-funded researchers at the Mahidol Oxford Tropical Medicine Research Unit (MORU) in Bangkok, the scientists enrolled malaria-infected adults and children at 15 trial sites in 10 countries between May 2011 and April 2013.
Patients received a six-day antimalarial treatment, three days of an artemisinin derivative and a three day course of artemesinin combination treatment (ACT). The researchers examined the different responses of the patients to artemisinin treatment. Blood samples were analysed to measure the rate at which the parasites were cleared from a patient's blood, or the 'parasite clearance half-life'.
Conventional malaria control approaches won't be enough – we will need to take more radical action and make this a global public health priority without delay
Professor Nick White
Results showed that the median parasite clearance half-life ranged from 1.8 hours in the Democratic Republic of the Congo to 7 hours at the Thailand-Cambodia border, where artemisinin resistance has been known about since 2005.
The proportion of patients with parasites in their blood 72 hours after treatment, a widely used test for artemisinin resistance, ranged from 0% in Kenya to 68% in Eastern Thailand.
Malaria infections that were slow to clear were also strongly associated with a single mutation in a gene in the parasite called kelch 13. This confirms that mutations in kelch 13 are a reliable marker of resistance, and will make future efforts to monitor the spread of resistance easier.
Researchers also found that patients who had slow-clearing infections were also more likely to have parasite stages which can infect mosquitoes. This suggests that artemisinin-resistant malaria parasites have a transmission advantage over parasites that are not resistant, which drives their spread.
'Frontline ACTs are still very effective at curing the majority of patients. But we need to be vigilant as cure rates have fallen in areas where artemisinin resistance is established,' says Dr Elizabeth Ashley, lead scientist of the TRAC study and a clinical researcher at the Mahidol Oxford Tropical Medicine Research Unit (MORU). 'Action is needed to prevent the spread of resistance from Myanmar into neighbouring Bangladesh and India.'
Professor Jeremy Farrar, director of the Wellcome Trust, comments: 'If resistance spreads out of Asia and into Africa much of the great progress in reducing deaths from malaria will be reversed. Our ability to respond to these rapidly emerging health problems depends on swift gathering of evidence, which can be quickly translated into public health and clinical interventions that are then implemented. Antimicrobial resistance is happening now. This is not just a threat for the future, it is today's reality.'
Currently over half of the world's population are at risk of malaria infection. Although there has been a substantial reduction in the number of people falling ill and dying from malaria – with approximately 3.3 million deaths prevented since 2000 – it is estimated that more than 600,000 people still die from the disease each year, most of them children under five years of age living in Africa.
• Two other studies published today involving Oxford University researchers show promising results in efforts to come up with new drugs and vaccines against malaria.
Over on the Oxford Science Blog there are descriptions of results from a clinical trial of a potential new anti-malarial drug in development at Novartis – a trial also carried out by MORU researchers in Thailand. And in Kenya, a study of children’s immune responses to proteins from the malaria parasite has identified many more candidates for developing new vaccines against the disease.
While promising, neither the new anti-malarial drug nor the novel vaccines would be available for many years – showing how much action is needed now to contain drug resistance to artemisinin.
'The artemisinin drugs are arguably the best antimalarials we have ever had. We need to conserve them in areas where they are still working well,' says Dr Ashley.
The study on the spread of artemisinin resistance was coordinated by MORU, the Mahidol Oxford Tropical Medicine Research Unit, which is funded by the Wellcome Trust. The TRAC project was funded by the UK Department for International Development. Additional support was given by the Worldwide Antimalarial Resistance Network (WWARN), the National Institute of Allergy and Infectious Diseases (NIAID) and the Bill & Melinda Gates Foundation.