NEW YORK (Reuters Health) – The current outbreak of multidrug-resistant malaria in Southeast Asia originated in western Cambodia soon after dihydroartemisinin-piperaquine became the first-line antimalarial drug there, according to a new genetic study.
Since 2013, the rate of complete treatment failure in patients receiving dihydroartemisinin-piperaquine has increased rapidly in Cambodia, northeast Thailand and Vietnam.
Dr. Dominic P. Kwiatkowski from Wellcome Singer Institute, in Hinxton, UK, and colleagues conducted an in-depth genetic analysis of the epidemiological origins and early history of this outbreak using genome sequence data on P. falciparum samples collected in Cambodia from 2007 to 2013.
The 580Tyr mutation of kelch13, associated with artemisinin resistance, accounted for nearly half (48%) of the artemisinin-resistant samples. The frequency of this KEL1 lineage in western Cambodia increased from 4% in 2007 to 63% in 2013, the researchers report in The Lancet Infectious Diseases, online February 1.
Amplifications of plasmepsin 2-3, markers of piperaquine resistance, were observed in 41% of samples from western Cambodia, but only 1% of samples from elsewhere. Most samples had strong evidence of recent shared ancestry in a lineage the researchers called PLA1.
These amplifications were absent in 2007, but increased rapidly to 79% frequency in western Cambodia by 2013.
Resistance to dihydroartemisinin-piperaquine was present in western Cambodia as early as 2008 and then rapidly increased from 16% to 68% by 2013.
Not until 2012 were similar samples identified in northern Cambodia, and the findings together indicate that emergence of dihydroartemisinin-piperaquine resistance in northern Cambodia in 2012 was the result of migration of parasites from western Cambodia.
Increasing piperaquine resistance in western Cambodia has been matched by decreasing resistance to mefloquine. As the KEL1 lineage increased in frequency, it progressively lost mdr1 amplifications associated with mefloquine resistance as it gained plasmepsin 2-3 amplifications.
“Therefore, at present, parasites resistant to dihydroartemisinin-piperaquine are sensitive to mefloquine, and artesunate-mefloquine is now being used successfully as first-line antimalarial treatment in Cambodia,” the researchers note. “Evidence also suggests that parasites resistant to dihydroartemisinin-piperaquine are responsive to artesunate-pyronaridine, a new artemisinin combination therapy.”
“Unlike the situation in 2008, provision of national malaria control programs, with tools for high-resolution genetic surveillance of all observed malaria cases in the most vulnerable locations, is now technically feasible,” they add. “We propose that this strategy should be used as part of the regional malaria elimination policy because it would enable malaria control programs to respond as soon as possible to evolutionary changes in the parasite population, and thereby reduce uncertainty and risk.”
“We also suggest that these data should be made openly available, so that all countries in the region and the international malaria community can cooperate to find a solution if a particular intervention strategy starts to fail,” the authors conclude. “With use of appropriate technologies and concerted action, major outbreaks of resistance should not go unnoticed in the future and the risk of a global health emergency should be reduced.”
Dr. Kwiatkowski did not respond to a request for comment.
SOURCE: http://bit.ly/2BfGslC
Lancet Infect Dis 2018.
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