The fight against the parasites that cause malaria is proving tricky in Southeast Asia. Researchers say a rapidly evolving variant of falciparum malaria is proving resistant to key medicines.

This has led to “alarmingly high treatment failure rates in Cambodia, Thailand and Vietnam” for DHA-piperaquine, one of the world’s most important anti-malaria drugs.

The discovery was documented by University of Oxford researchers in a study published today in The Lancet Infectious Diseases.

Authors of the study say DHA-piperaquine should no longer be used to treat falciparum malaria in Cambodia, Vietnam and northeastern Thailand because it is ineffective and will actually contribute to increased malaria transmission.

The researchers want urgent action to eliminate falciparum malaria from the Greater Mekong Subregion to prevent a local increase of multiple resistant strains and their further spread to other parts of Asia and Africa and avoid a potential global health emergency.

Resistance spreading

“Resistance to our anti-malarial drugs is worsening and spreading in the eastern Greater Mekong Subregion,” a co-author of the study, Sir Nick White, who is a professor with Oxford University.

“We need urgently to eliminate malaria in this region and act now to prevent the spread of these multi-drug resistant parasites to other parts of Asia and Sub-Saharan Africa. When resistance to previous anti-malarial drugs arose in Southeast Asia and spread to Africa-millions of children died as a consequence.”

Malaria deaths dropped significantly after the introduction in the late 1990s of artemisinin-combination therapy (ACT) – which combines artemisinin, the most effective drug against malaria, with another anti-malaria drug such as piperaquine.

However, in 2014, the Tracking Resistance to Artemisinin Collaboration (TRAC) study reported in the New England Journal of Medicine (NEJM) that artemisinin resistance in Plasmodium falciparum – the most deadly form of parasite causing malaria and the one most prevalent in Africa and Asia – was widespread across the Greater Mekong Subregion.

Since then, global progress against malaria has stalled.

In fact, the number of cases globally has risen steadily for the past three years, with an estimated 219 million malaria cases (up from 217 million in 2016) and 435,000 related deaths in 2017. Most of these were children under the age of five in sub-Saharan Africa, according to the WHO World Malaria Report 2018.

Prof Arjen Dondorp, study co-author and deputy director of the Bangkok-based Mahidol Oxford Tropical Medicine Research Unit (MORU), said: “DHA-piperaquine is failing and should no longer be used to treat falciparum malaria across the eastern Greater Mekong Subregion. It provides ineffective treatment for the patient and thereby contributes to increased malaria transmission.

“his has immediate public health importance, so we felt we should not wait to report this until we published our full TRAC II results later this year,” he said

DHA-piperaquine is a drug used in artemisinin combination treatment that is on the WHO’s List of Essential Medicines. It is used to treat falciparum and vivax malaria in Africa and Asia and in large-scale pilot programs to eliminate malaria in the Greater Mekong Subregion.

Researchers have said that although there have yet to be reports of artemisinin resistance in Africa, they want to eliminate these highly drug-resistant falciparum parasites in Southeast Asia to preserve the effectiveness of DHA-piperaquine and other ACTs in Africa and elsewhere in Asia – to prevent a global health emergency.

‘Cradle of drug-resistance’

“Southeast Asia is the cradle of anti-malarial drug resistance. We must eliminate falciparum malaria before it becomes untreatable in the Greater Mekong Subregion and elsewhere in Asia,” study co-author and TRAC II coordinator Dr Rob van der Pluijm said.

“This is the third time that the falciparum parasite has developed resistance on a large scale to anti-malarial drugs: First, chloroquine and sulphadoxine-pyrimethamine arose and spread in the 60s and 70s, and now resistance has emerged to artemisinins and ACT partner drugs. We must get rid of these parasites once and for all,” he said

In a companion paper in The Lancet Infectious Diseases, Wellcome Sanger Institute researchers report that the strain of falciparum malaria which has become DHA-piperaquine resistant, which they call KEL1/PLA1, has evolved and spread widely in recent years after it was first found in Cambodia.

The parasites have acquired mutated and produced an even higher level of resistance, allowing them to spread across the Greater Mekong Subregion.

“Genetic surveillance data shows that resistant falciparum parasites are evolving further, developing new mutations that make them fitter and more resistant, and enabling them to spread regionally, and take over entire parasite populations,” said University of Oxford Prof Olivo Miotto, study co-author and Senior Informatics Fellow at MORU.

We must act quickly to stop the situation getting worse.”