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Wellcome Sanger Institute researchers find resistance to anti-malarial drugs was under-reported for years

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A mosquito sucking blood
A mosquito sucking blood

Team has conducted most comprehensive genetic study of malaria parasites in South-East Asia

The study showed resistance to malaria drugs was under-reported in Cambodia
The study showed resistance to malaria drugs was under-reported in Cambodia

Resistance to anti-malarial drugs was under-reported for years in Cambodia, researchers from the Wellcome Sanger Institute at Hinxton and their collaborators have shown.

Their findings have significant implications for the management of the global health risk associated with the disease, which killed nearly half a million people and infected more than 200 million in 2016. Delays in detecting the spread of resistance could undermine global efforts to eliminate marlaria.

The research team conducted the most comprehensive genetic study of malaria parasites in South-East Asia.

It revealed that the parasites developed multi-drug resistance to first-line treatments extremely rapidly. One main resistant strain spread aggressively in the five years before clinical resistance was reported, they found.

A map of countries affected by malaria, as of March 2015. Image: Petaholmes.
A map of countries affected by malaria, as of March 2015. Image: Petaholmes.

Malaria is caused by Plasmodium parasites and is spread through the bite of infected female Anopheles mosquitoes. Children under five years of age are most at risk, with 95 per cent of deaths occurring in this age group in sub-Saharan Africa. Malaria is also found in the tropical and sub-tropical areas of South America and Asia.

The first-line treatment for malaria in many parts of the world is a combination of two powerful drugs – dihydroartemisinin and piperaquine – known as the DHA-PPQ treatment.

This was introduced into Cambodia in 2008 and was initially effective, but in 2013 clinical trials showed malaria parasites were resistant to both drugs. Subsequent studies reported that resistance has since spread to Thailand, Laos and Vietnam.

Studying the initial emergence and spread of resistance was important to understand the future risks, so researchers analysed DNA sequence data from nearly 1,500 Plasmodium falciparum parasites from South-East Asia, including more than 450 collected in Cambodia during 2007-13. This effectively allowed them to look back in time to see how the malaria parasites treated with DHA-PPQ evolved resistance.

The malaria transmission cycle
The malaria transmission cycle

The study showed that a single multi-drug resistant strain of the Plasmodium parasite emerged in the same year that DHA-PPQ became the official first-line antimalarial treatment in Cambodia. The strain spread aggressively, outcompeting all other resistant malaria parasites, which led to the complete failure of treatment in Cambodia. While other drugs may be effective at the moment, the situation there is extremely fragile, with resistance spreading and uncertainty over how malaria parasites will respond to current treatments.

Dr Roberto Amato, first author on the paper from the Wellcome Sanger Institute, said: “Our study has provided the most comprehensive analysis by far of the parasites responsible for the outbreak of drug resistant malaria in Cambodia.

“It reveals that resistance to the combination therapy appeared almost as soon as that treatment was introduced as the official first-line therapy and that it spread steadily and aggressively after that.

“Various factors allowed the extent of this outbreak to stay under the radar for years, but we show it is now possible to use modern genomic technologies to get a full picture of an outbreak.”

The symptoms of malaria
The symptoms of malaria

Professor Mike Turner, head of infections and immunobiology at Wellcome, added: “This study confirms earlier observations that a strain of malaria, resistant to our most effective drugs, has emerged in the Greater Mekong sub-region. If this parasite strain keeps spreading and becomes dominant further afield it could devastate vulnerable populations globally.

“It is surprising to see that the parasites developed resistance so rapidly. Co-ordinated actions by governments and organisations to control and eliminate this parasite population are urgently needed.

“Real-time genetic sequencing would allow regional malaria control programmes to respond immediately to evolutionary changes in the parasite population.”

Death rates from malaria have fallen globally by 47 per cent since 2000, with huge investment in mosquito nets and the spraying of insecticide.

The Anopheles mosquito spreads malaria
The Anopheles mosquito spreads malaria

Dominic Kwiatkowski, a corresponding author on the paper from the Wellcome Sanger Institute and the University of Oxford, added: “Our study shows that modern genomic surveillance can detect patterns of resistance much sooner than was possible in the past, providing vital information and allowing public health officials to respond as soon as possible.

“There is now an urgent need to provide national malaria control programmes with the tools for active genomic surveillance that will help to detect new emergences of resistance as soon as they arise and thereby reduce the risk of a major global outbreak.”

The Welcome Sanger Institute has also sequenced the DNA of 765 wild mosquitoes in Africa, and found 52 million small differences in their genomes. This means they are able to evolve rapidly and develop insecticide resistance, as the Cambridge Independent reported in December.

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Malaria kills a child every two minutes - and now mosquitoes are becoming resistant to insecticide

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