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The findings of two studies, published in The Lancet Infectious Diseases journal, reveal that by 2016–2018 malaria parasites resistant to both artemisinin and its widely used partner drug piperaquine represented more than 80% of the parasites circulating in northeast Thailand and Vietnam, despite having only emerged in western Cambodia in 2008.

Mosquito © CDC James Gathany

23 July 2019 Bangkok (Thailand) – A rapidly evolving multi-drug resistant lineage of P. falciparum malaria parasites continues to spread in Southeast Asia, leading to alarmingly high treatment failure rates in Cambodia, Thailand and Vietnam for DHA-piperaquine, one of the world’s most important anti-malaria drugs, say University of Oxford researchers in a study published today in The Lancet Infectious Diseases.

Malaria maps: before 20122 and after 2016DHA-piperaquine should no longer be used to treat falciparum malaria in Cambodia, Vietnam and northeast Thailand as it is ineffective and thereby contributes to increased malaria transmission, according to the author of the study, which was funded with support from the: United Kingdom Department for International Development, UK (DfID); Wellcome Trust, UK; Bill & 78 Melinda Gates Foundation, USA; Medical Research Council, UK; and the National Institute of Health, USA.

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

"Resistance to our antimalarial drugs is worsening and spreading  in the eastern Greater Mekong Subregion," said study co-author University of Oxford Prof Sir Nick White. “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 antimalarial 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) – where artemisinin, our most effective drug against malaria –  is combined 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 malaria-causing parasite and the one most prevalent in Africa and Asia – was widespread across the Greater Mekong Subregion.

Since then, global progress against malaria has stalled. Indeed case numbers globally have risen steadily for the past three years, with an estimated 219 million malaria cases (up from 217m in 2016) and 435,000 related deaths in 2017, most of them children under the age of 5 five in sub-Saharan Africa, according to the WHO World Malaria Report 2018.

“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. This 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," said University of Oxford Prof Arjen Dondorp, study co-author and Deputy Director of the Bangkok-based Mahidol Oxford Tropical Medicine Research Unit (MORU).

DHA-piperaquine is an oral artemisinin combination treatment (ACT) medication that is on the WHO’s List of Essential Medicines. DHA-piperaquine is used to treat P. falciparum and P. vivax malaria in Africa and Asia and in large-scale pilot programmes to eliminate malaria in the Greater Mekong Subregion. 

Although there are as yet no reports of artemisinin resistance in Africa, researchers urge elimination of these highly drug-resistant P. falciparum parasites in Southeast Asia to preserve the effectiveness of DHA-piperaquine and other ACTs in Africa and elsewhere in Asia and so prevent a global health emergency.

“Southeast Asia is the cradle of antimalarial drug resistance. We must eliminate falciparum malaria before it becomes untreatable in the Greater Mekong Subregion and elsewhere in Asia. This is the third time that the P. falciparum parasite has developed resistance on a large scale to antimalarial 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,” said study co-author Dr Rob van der Pluijm, TRAC II coordinator.

In a companion paper in The Lancet Infectious Diseases, Wellcome Sanger Institute researchers report that the strain of P. 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 new mutations and have produced an even higher level of resistance, allowing their proliferation and spread across the Greater Mekong Subregion.

“Genetic surveillance data shows that resistant P. 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.”

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References

Determinants of dihydroartemisinin-piperaquine treatment failure in falciparum malaria in Cambodia, Thailand and Vietnam: a prospective clinical, pharmacological and genetic study. Rob van der Pluijm et al.(2019). The Lancet Infectious Diseases, 22 July 2019. https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(19)30391-3/fulltext

Evolution and expansion of multidrug resistant malaria in Southeast Asia: a genomic epidemiology study.  William Hamilton and Roberto Amato et al. (2019). The Lancet Infectious Diseases, 22 July 2019. https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(19)30392-5/fulltext

Commentary

Accelerated evolution and spread of multidrug-resistant Plasmodium falciparum takes down the latest first-line antimalarial drug in southeast Asia. Didier Ménard and David A Fidock (2019). The Lancet Infectious Diseases. https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(19)30394-9/fulltext

Notes for editors

Mahidol Oxford Tropical Medicine Research Unit (MORU, www.tropmedres.ac, @MORUBKK) is a research collaboration between Mahidol University (Thailand) and University of Oxford and Wellcome (UK).

The Wellcome Sanger Institute is a world leading genomics research centre that undertakes large-scale research that forms the foundations of knowledge in biology and medicine. Funded by Wellcome, we have the freedom and support to push the boundaries of genomics. Our findings are used to improve health and to understand life on Earth. Find out more at www.sanger.ac.uk or follow us on Twitter, Facebook, LinkedIn and on our Blog

Funders

This research was funded with support from the: United Kingdom Department for International Development, UK; Wellcome Trust, UK; Bill & 78 Melinda Gates Foundation, USA; Medical Research Council, UK; and the National Institute of Health, USA.

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