In the Journals

Antimalarial resistance spread undetected for 5 years in Cambodia

A genomic analysis of malaria parasites in Cambodia revealed that resistance to first-line treatment with dihydroartemisinin-piperaquine emerged as early as 2008 — 5 years before it was first reported in the region in 2013.

Robert Amato, PhD , of the Wellcome Sanger Institute, and colleagues identified a specific Plasmodium falciparum parasite lineage that was responsible for the majority of dihydroartemisinin-piperaquine resistance.

“Our study has provided the most comprehensive analysis by far of the parasites responsible for the outbreak of drug-resistant malaria in Cambodia,” Amato said in a press release. “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.”

The researchers examined 1,492 P. falciparum samples collected from 11 locations across southeast Asia, including 464 samples from western Cambodia between 2007 and 2013. They identified 38 independent origins of artemisinin resistance. However, a single epidemiological origin — the KEL1 lineage — accounted for 91% of parasites with resistance to dihydroartemisinin-piperaquine.

Parasites in the KEL1 lineage were first detected in low frequencies in 2007. During this time, the parasites exhibited markers of resistance to the first-line drug mefloquine. After artesunate-mefloquine was replaced as the recommended therapy with dihydroartemisinin-piperaquine in 2008, the KEL1 lineage merged with another major lineage known as PLA1, which is associated with piperaquine resistance. By 2013, the KEL1/PLA1 colineage was prevalent in 63% of parasites in western Cambodia and had spread to the northern region of the country.

Over time, resistance to mefloquine decreased from 59% in 2007 to 6% in 2013. Meanwhile, resistance to dihydroartemisinin-piperaquine increased from 16% to 68%.

“At present, parasites resistant to dihydroartemisinin-piperaquine are sensitive to mefloquine, and artesunate-mefloquine is now being used successfully as first-line antimalaria treatment in Cambodia,” the researchers wrote. “Evidence also suggests that parasites resistant to dihydroartemisinin-piperaquine are responsive to artesunate-pyronaridine, a new artemisinin combination therapy.”

Although malaria remains treatable in Cambodia, the researchers warned that the situation is “extremely fragile,” and it would be “catastrophic” if resistance were to spread among the last effective antimalarial drugs.

“There is now an urgent need to provide national malaria control programs 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,” study author Dominic Kwiatkowski, FRCP, professor at the Wellcome Sanger Institute and the University of Oxford, said in the release. – by Stephanie Viguers

Disclosures: The authors report no relevant financial disclosures.

A genomic analysis of malaria parasites in Cambodia revealed that resistance to first-line treatment with dihydroartemisinin-piperaquine emerged as early as 2008 — 5 years before it was first reported in the region in 2013.

Robert Amato, PhD , of the Wellcome Sanger Institute, and colleagues identified a specific Plasmodium falciparum parasite lineage that was responsible for the majority of dihydroartemisinin-piperaquine resistance.

“Our study has provided the most comprehensive analysis by far of the parasites responsible for the outbreak of drug-resistant malaria in Cambodia,” Amato said in a press release. “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.”

The researchers examined 1,492 P. falciparum samples collected from 11 locations across southeast Asia, including 464 samples from western Cambodia between 2007 and 2013. They identified 38 independent origins of artemisinin resistance. However, a single epidemiological origin — the KEL1 lineage — accounted for 91% of parasites with resistance to dihydroartemisinin-piperaquine.

Parasites in the KEL1 lineage were first detected in low frequencies in 2007. During this time, the parasites exhibited markers of resistance to the first-line drug mefloquine. After artesunate-mefloquine was replaced as the recommended therapy with dihydroartemisinin-piperaquine in 2008, the KEL1 lineage merged with another major lineage known as PLA1, which is associated with piperaquine resistance. By 2013, the KEL1/PLA1 colineage was prevalent in 63% of parasites in western Cambodia and had spread to the northern region of the country.

Over time, resistance to mefloquine decreased from 59% in 2007 to 6% in 2013. Meanwhile, resistance to dihydroartemisinin-piperaquine increased from 16% to 68%.

“At present, parasites resistant to dihydroartemisinin-piperaquine are sensitive to mefloquine, and artesunate-mefloquine is now being used successfully as first-line antimalaria treatment in Cambodia,” the researchers wrote. “Evidence also suggests that parasites resistant to dihydroartemisinin-piperaquine are responsive to artesunate-pyronaridine, a new artemisinin combination therapy.”

Although malaria remains treatable in Cambodia, the researchers warned that the situation is “extremely fragile,” and it would be “catastrophic” if resistance were to spread among the last effective antimalarial drugs.

“There is now an urgent need to provide national malaria control programs 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,” study author Dominic Kwiatkowski, FRCP, professor at the Wellcome Sanger Institute and the University of Oxford, said in the release. – by Stephanie Viguers

Disclosures: The authors report no relevant financial disclosures.