Drug-resistant malaria has spread to critical border regions of Southeast Asia
31 July 2014
Bangkok: Drug-resistant malaria parasites have spread to critical border regions of Southeast Asia, seriously
threatening global malaria control and elimination programmes, according to a study published in the New England Journal
of Medicine.
The study confirms that resistance to the world’s most effective antimalarial drug, artemisinin, is now widespread in
Southeast Asia. This is not the first, or even the second time the malaria parasite has developed resistance to front
line drugs, and each time resistance has emerged from the same corner of Asia on the Cambodia-Thailand border.
The study, which analysed blood samples from 1241 malaria patients in 10 countries across Asia and Africa, found that
artemisinin resistance in Plasmodium falciparum - the most deadly form of malaria-causing parasite – 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, located 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.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," said
Professor Nicholas White, senior author of the study and Chairman of the Welcome Trust-funded Mahidol Oxford Tropical
Medicine Research Unit (MORU), Professor of Tropical Medicine at the University of Oxford, and Chair of the Worldwide
Antimalarial Resistance Network.
The study was conducted by the Tracking Resistance to Artemisinin Collaboration (TRAC) which enrolled infected adults
and children at 15 trial sites in 10 malaria-endemic countries between May 2011 and April 2013. The TRAC partners
examined the different responses in malaria infected patients to artemisinin treatment. Patients received a six-day
antimalarial treatment, three days of an artemisinin derivative and a three day course of artemesinin combination
treatment (ACT). Patients’ blood was analysed to measure the ‘parasite clearance half-life’ or rate at which the
parasites are cleared from a patient’s blood.
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 aboutsince 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 point mutation in a P. falciparum gene called kelch 13, an important validation of the
recently discovered genetic marker (k13) in the DNA of the malaria parasite.
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 P. falciparum 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,” said Dr Elizabeth Ashley, lead scientist of the TRAC
study and Clinical Researcher at the Mahidol Oxford Tropical Medicine Research Unit (MORU), University of Oxford.
“Action is needed to prevent the spread of resistance from Myanmar into neighbouring Bangladesh and India.”
Dr Jeremy Farrar, Director of the Wellcome Trust says: “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’spopulation 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.1
While new antimalarial medicines are indevelopment, and another paper published in the New England Journal of Medicine
has shown some promising trial results for a potential new antimalarial drug in development at Novartis, they are
unlikely to be available for widespread distribution for several years.
“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,” concluded Dr Ashley.
Publication details: Elizabeth A Ashley et al. Spread of Artemisinin Resistance in Plasmodium falciparum Malaria. Advanced online publication
in New England Journal of Medicine. July 31 2014; 371:411-23. DOI: 10.1056/NEJMoa1314981.
Notes to editors
•From the late 1950s to the 1970s chloroquine resistant malaria parasites spread across Asia to Africa, resulting in a
resurgence of malaria infections and millions of deaths. Chloroquine was replaced by sulphadoxine-pyrimethamine (SP),
but resistance to SP also emerged in Western Cambodia and spread to Africa. SP was replaced by ACTs, and now we face the
prospect of history repeating itself for a third time.
•Artemisinin is the most effective drug against malaria. Artemisinin derivatives, such as artesunate, have several
advantages over other antimalarial drugs such as chloroquine and mefloquine: the artemisinin derivatives act more
rapidly and they have fewer side-effects. Although artemisinin derivatives can be used on their own - as a monotherapy -
fears about the possible development of resistance led to recommendations that they should only be used in conjunction
with one or more other drugs - as artemisinin combination therapies (ACTs).
•ACTs are now recommended by the World Health Organization as the firstline treatment for uncomplicated falciparum
malaria, and they have contributed substantially to the recent decline in malaria cases in most tropical endemic
regions.
•Some of key drivers of resistance in the malaria parasites are counterfeit or substandard treatments, unregulated
antimalarial drug use, using artemisinin without a partner antimalarial as part of a combination treatment, and the
unusual genetic structure of malaria parasites in Western Cambodia.
•The presence of kelch 13 mutations was strongly associated with a delayed parasite clearance from the patient’s system
during treatment, and thus has been confirmed as a reliable marker of resistance. This will facilitate surveillance
efforts going forward.
•Patients with slower parasite clearance are more likely to transmit their drug resistant strain to others.
•Treatment failure rates with artesunate-mefloquine in Thailand and with DHA-piperaquine in Cambodia have now risen more
than fivefold.
•1 Malaria burden estimates from the WHO World Malaria Report 2013.
Funding
The TRAC project was funded by the UK Department for International Development (DFID). Additional support was given by
the Worldwide Antimalarial Resistance Network (WWARN), the Intramural Research Program of the National Institute of
Allergy and Infectious Diseases (NIAID) at the National Institutes of Health (NIH), and the Bill & Melinda Gates Foundation. The study was coordinated by MORU, the Mahidol Oxford Research Programme funded by the
Wellcome Trust.
ENDS