In what scientists call a “sinister development,” a malaria parasite resistant to a widely used drug combination is on the march in Southeast Asia. It has rapidly made its way in an arc from western Cambodia, through northeastern Thailand, to southern Laos; now it has landed in southern Vietnam, where it is causing alarming rates of treatment failure.
What’s more, the team from the Mahidol Oxford Tropical Medicine Research Unit in Bangkok writes in the October issue of The Lancet Infectious Diseases, this strain, resistant to an artemisinin combination therapy (ACT), is outcompeting others and becoming dominant in parts of what is known as the Greater Mekong subregion. That's not only bad news for the region, the researchers say; should this bug spread to Africa, where more than 90% of malaria deaths occur, the consequences could be disastrous. The outspoken head of the Mahidol group, Nicholas White, has urged the World Health Organization (WHO) in Geneva, Switzerland, to declare a Public Health Emergency of International Concern, a designation reserved for the most serious outbreaks that pose a global threat.
But the letter—which triggered media stories warning of a "superbug" on the loose—and White’s warning irked many in the famously contentious malaria research community, where personal animosities and longstanding grudges run deep. WHO experts dismissed the report as “nothing new” and decried what they see as overblown claims from a group that they say has cried wolf before. "Parasite resistance to antimalarial medicines is a serious problem. But we must not create unnecessary alarm," the head of WHO's Global Malaria Programme, Pedro Alonso, said in a 29 September statement.
The critics don’t question the group's genetic studies of the malaria parasite, Plasmodium falciparum, but they dispute the interpretation that they spell disaster. “This is not a superstrain,” asserts Dyann Wirth, a malaria researcher at Harvard University who chaired a WHO panel that reviewed the group’s earlier data in December. "It has not reached the proportion where the world should panic.”
In May, the group described the strain’s spread to Thailand and Laos in an extensive analysis in the same journal; now, in a one-page letter, they report that it has reached Bình Phước province in southern Vietnam. “We wanted to publish this quickly,” says co-author Arjen Dondorp of the Mahidol group.
ACTs pair the drug artemisinin or one of its derivatives with one of five partner drugs; different combinations are used in different parts of the world. They all pack a one-two punch: Artemisinin hits hard and fast, wiping out malaria parasites in hours , while the longer-acting partner drug mops up any stragglers. White has long been one of the strongest proponents of ACTs, which are now the gold standard.
Around 2008, two teams, including one led by Dondorp, found that parasites were developing resistance to artemisinin in western Cambodia. White warned, too loudly some say, that the loss of artemisinin could cause a repeat of the chloroquine disaster of the 1980s, when resistant parasites spread from the Greater Mekong to Africa and millions died. He repeatedly slammed WHO for its slow, bureaucratic response to the threat.
Things got worse in 2015, when scientists found that the partner drug used in Cambodia, piperaquine, was failing, too. When parasites are resistant to the artemisinin component, the drug still works, but more slowly. When piperaquine resistance emerges as well, treatment fails: Patients get better, but a month later they are sick again. The failure rate for this ACT has now reached 90% in western Cambodia; in Vietnam, it has already hit 30%.
Researchers have been tracking the spread of artemisinin-resistant parasites first by looking for signs in patients, and later by using multiple mutations in the parasite’s Kelch13, or K13, gene, as molecular markers for resistance. When multidrug-resistant malaria was detected, researchers were initially handicapped by the lack of a marker for piperaquine resistance; now, they have one, the presence of multiple copies of the plasmepsin 2 gene. (Both markers were discovered by Didier Ménard, who previously worked in Phnom Penh at the Pasteur Institute in Cambodia and is now at its counterpart in Paris.)
With that tool in hand, the Mahidol group says it has detected an ominous pattern. One strain carrying a mutation named C580Y in the K13 gene is pushing out the others; in the process, it has acquired piperaquine resistance as well. The group traced this lineage back to one that was first detected in Pailin, a sleepy town in western Cambodia on the Thai border.
The new evidence is solid and "very alarming," says Chris Plowe, who runs the Institute for Global Health at the University of Maryland’s School of Medicine in Baltimore. For reasons still unclear, resistance to older malaria drugs—including chloroquine and sulfadoxine-pyrimethamine—emerged in Pailin as well and then spread broadly, Plowe points out. "If multidrugresistance can spread from Cambodia to Vietnam, it can and will spread elsewhere," he says.
The pattern is all too familiar, says Philippe Guérin, director of the WorldWide Antimalarial Resistance Network in London. “The theoretical risk is becoming real.”
But WHO's expert group, assembled after White’s December presentation, took issue with many of the claims. Although the K13 C580Y strain is becoming dominant in parts of the region, the group said in a carefully worded report in March, that is not the case everywhere in the Greater Mekong, where several lineages are circulating more or less in equilibrium. The risk of spread to Africa “cannot be discounted,” they acknowledged, but they deemed it fairly low because various genetic factors decrease the chance that the parasite could take off in a new environment. And if it somehow did, Africa is much better equipped to deal with than it was in the 1980s when chloroquine resistance hit, WHO experts say, with strong national malaria programs in place and increased monitoring of drug efficacy.
Besides, the panel said, a plan WHO and the six countries of the Greater Mekong launched in 2015 to eliminate P. falciparum malaria by 2025 should halt the spread of resistant strains, and the project just got a $242 million boost from the Global Fund to Fight AIDS, Tuberculosis and Malaria. “We are winning the battle,” Alonso asserted in his statement.
Malaria experts have been encouraged because so far, parasites resistant to piperaquine are still susceptible to an older drug, mefloquine, that has regained its efficacy after years on the shelf. The Cambodian government has already switched to an ACT that contains mefloquine instead of piperaquine, and Vietnam is doing the same. The expert group recommends increased surveillance in the Mekong, Africa, and elsewhere specifically for the K13 C580Y strain, so other countries can act quickly and switch drugs if needed. But Dondorp and others predict that "mefloquine resistance will emerge quickly,” as will resistance to other partner drugs—raising the prospect of untreatable malaria.
Dondorp fears the constant bickering and conflicting statements will confuse participating countries and lower the sense of urgency. “The landscape is very politically charged,” agrees Guérin. “We need more attention to the data and less attention to the politics.”