In the Journals Plus

Drug-resistant P. falciparum spreads in Greater Mekong subregion

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February 9, 2017

A dominant artemisinin-resistant Plasmodium falciparum lineage has spread from western Cambodia to Thailand and Laos, displacing other malaria parasites and acquiring piperaquine resistance, according to recent study findings. Researchers reported that the parasite lineage is causing high treatment failure rates with artemisinin combination therapies and threatens global efforts to control and eliminate malaria.

 “We are losing a dangerous race to eliminate artemisinin-resistant falciparum malaria before widespread resistance to the partner antimalarials make that impossible,” Sir Nicholas J White, MD, DSc, FRS, of the Mahidol-Oxford Tropical Medicine Research Unit, said in a press release. “The consequences of resistance spreading further into India and Africa could be grave if drug resistance is not tackled from a global public health emergency perspective.”

Existing evidence suggests that PfKelch13 mutations mediating artemisinin resistance in falciparum malaria have emerged across the Greater Mekong subregion (GMS) independently on multiple occasions. Previously, P. falciparum with resistance to the antimalarial therapies chloroquine and sulfadoxine-pyrimethamine also emerged on multiple occasions in the GMS. A pyrimethamine-resistant parasite lineage eventually dominated other lineages in a “hard selective sweep,” spreading across India and Africa, according to the researchers.

Mallika Imwong, PhD, of the Mahidol-Oxford Tropical Medicine Research Unit, White and colleagues hypothesized that a dominant lineage of artemisinin-resistant P. falciparum lineage is now spreading through the GMS. To investigate their theory, the researchers tested 434 P. falciparum isolates collected between January 2008 and December 2015 from Myanmar, northeastern Thailand, southern Laos and western Cambodia for PfKelch13 mutations, indicating artemisinin resistance, and Pfplasmepsin2 gene amplification, indicating piperaquine resistance. They used microsatellite genotyping to determine genetic relatedness.

In 2014 and 2015, a single long PfKelch13 C580Y haplotype lineage that emerged in western Cambodia in 2008 was identified in 65 of 88 isolates collected from Thailand, 86 of 111 isolates from Laos, and in all 14 isolates collected from Cambodia. Pfplasmepsin2 amplification was observed only in parasites within the PfKelch13 C580Y lineage and was found in 10 of 14 isolates collected from Cambodia and all 15 isolates collected from northeastern Thailand in 2015. 

According to the researchers, the C580Y mutation does not confer a higher level of artemisinin resistance compared with other PfKelch13 mutations; however, it appears to be fitter and more transmissible.

“It isn’t that the C580Y mutation itself makes the malaria parasites fitter, it is the other genetic changes that go along with it — hence the critical emphasis on the term ‘lineage.’ This is what makes superbugs — the evolution of multiple factors that make them fitter and more transmissible,” White explains in the release. “The spread and emergence of drug-resistant malaria parasites across Asia into Africa has occurred before. Last time it killed millions. We need to work with our policy, research and funding partners to respond to this threat in Asia urgently to avoid history repeating itself.”

In a related editorial, Elizabeth Hemming-Schroeder, PhD student, and Eugenia Lo, PhD, of the University of California at Irvine, agreed that the findings underscore the need to contain and eliminate malaria in the region. The spread of the artemisinin-resistant lineage, they added, emphasizes the importance of developing a new antimalarial drug or implementing alternative treatment regimens of available drugs.

“This study fills an important knowledge gap about the evolution of [artemisinin combination therapy (ACT)] resistance in the GMS,” they wrote. “Although the observed evolutionary pattern should not be surprising, we anticipate the findings to be highly impactful to malaria control policy. Imwong and colleagues provide substantial evidence that history is repeating itself with regard to antimalrial drug resistance in the case of ACT resistance.” – by Stephanie Viguers

Disclosure: The researchers report no relevant financial disclosures.