London School of Hygiene & Tropical Medicine

Scientists have identified genetic markers associated with resistance to the one of the most commonly used malaria drugs in Southeast Asia, according to two studies published in The Lancet Infectious Diseases.

Plasmodium falciparum, the most common species of malaria parasites, with multiple copies of the plasmepsin 2 and plasmepsin 3 genes and the exo-E415G variant, was found to be less sensitive to the antimalarial drug piperaquine. The researchers, from the Institut Pasteur in Cambodia and the National Institutes of Health, USA, could identify with high accuracy which patients would fail treatment. They believe the findings could be used to help track and contain the spread of drug-resistant disease in the region.

More than 200 million people are infected with P. falciparum, which kills around half a million people every year. Worldwide, antimalarial control efforts are mainly dependent on artemisinin-based combination treatments. Artemisinin resistance has been known about for years, but a recent rise in resistance to piperaquine as well means the main malaria treatment, taken both together, is starting to fail.

So how significant are the findings in the fight against malaria? David Conway, Professor of Biology at the London School of Hygiene & Tropical Medicine said:

"These two new independent studies are a big step forward in our understanding of the molecular determinants of resistance, which should guide the use of tools to diagnose and monitor its occurrence and spread, as well as strategies to contain it.

"They show novel parasite genetic changes associated with the recent emergence of resistance in Cambodia. This evolving parasite resistance is a major threat for malaria control internationally, because piperaquine is used as part of an artemisinin-based combination therapy, and we have already seen resistance to the artemisinin component become widespread in Southeast Asia over the past several years.

"Both of the studies analyse malaria parasite genome sequences from hundreds of patients, and show that piperaquine resistance is associated with two adjacent plasmepsin enzyme genes that have been duplicated. This leads to increased concentrations of vital enzymes which the parasite uses to metabolise the products of haemoglobin that it has digested. It is likely that the enhanced enzyme activity reduces the ability of the drug to sufficiently disrupt the metabolism.

"It is important to note that parasites resistant to piperaquine are sensitive to a different drug called mefloquine, which is also used as an alternative combination therapy in some areas, and the resistance mechanisms seem to be incompatible in the parasite. Therefore, it may be important to rotate the use of these different combinations or to use new triple drug combinations in order to prevent the further spread of resistance."

Related links:

• Paving the road to a malaria-free world
• Malaria Centre