Public health authorities have long worried that the emergence in Africa of malaria resistant to artemisinin was only a matter of time. Parasites that can thwart this key component of front-line treatments appeared in Southeast Asia in the early 2000s and eventually led to clinical failures. The stakes are higher for Africa, which in 2019 saw 94% of both malaria cases and deaths worldwide—estimated at 229 million and 409,000, respectively. Two recent papers provide evidence that the dreaded resistance now has a foothold on the continent.
The findings are “a game changer,” says malaria researcher Philip Rosenthal of the University of California, San Francisco. For now, there’s no evidence that current treatments are failing outright; patients with the resistant parasites simply take longer to clear them. “I don’t think this is a reason to panic,” Rosenthal says, “but we should be very concerned that things may be changing, and we definitely need new drugs.”
The mosquito-borne parasite Plasmodium falciparum, which causes most malaria in Africa, mutates rapidly. It developed resistance to once potent drugs such as chloroquine in the 1950s and ’60s, leading to a surge in the world’s malaria burden. The arrival in the 1990s of artemisinin, derived from a Chinese herbal remedy, reduced the toll. Artemisinin is now typically paired with one of several secondary drugs in orally administered artemisinin-based combination therapies (ACTs) that deliver a one-two punch to the parasites. It’s also administered alone intravenously for severe disease.
By the mid-2000s, the malaria parasite had developed resistance to ACTs in Southeast Asia. Studies traced the resistance to mutations in a gene known as kelch13. Several groups launched surveys to watch for these mutations in Africa and in recent years have documented them in parasites isolated from African patients. The two recent studies show those mutations are slowing the rate at which drug treatment eliminates the parasite from patients’ bodies.
The first study, published in April in The Lancet Infectious Diseases, focused on children brought to three health centers in Rwanda with fevers in 2018. Those confirmed to have malaria were treated with a 3-day course of artemether-lumefantrine, an ACT. After 3 days, most patients had cleared the parasites. But more than 10% of the patients were still infected, and their parasites carried the telltale kelch13 mutations. The authors, led by Naomi Lucchi, a malaria specialist at the U.S. Centers for Disease Control and Prevention, called their finding “the first documented evidence of artemisinin partial resistance in Africa.”
The second team, led by malaria specialist Toshihiro Mita of Juntendo University, has tracked malaria in northern Uganda since 2013. From 2017 through 2019, the team studied the response of malaria patients treated at St. Mary’s Hospital Lacor in Gulu with intravenous artesunate, a water-soluble artemisinin derivative. In this study, researchers collected patient blood samples several times a day and checked how quickly the number of parasites declined. In 14 out of 230 patients, it took longer than 5 hours to halve the parasite load, which is a standard indication of delayed clearance. Thirteen of those patients had parasites with kelch13 mutations, the team reported on 23 September in The New England Journal of Medicine (NEJM).
“These results are quite obviously important given that artemisinin combination therapies are the only category of drugs currently available for the treatment of falciparum malaria,” says Ivo Mueller, an infectious disease epidemiologist at the Walter and Eliza Hall Institute of Medical Research.
The genetic details of the two new studies suggest the drug-evading mutations developed locally and were not imported from Southeast Asia. Drawing on previous studies of blood samples from malaria patients, both research groups found that kelch13 mutations appeared in the mid-2010s and increased by the late 2010s, going from 7.4% to 20% in Rwanda and from 3.9% to 19.8% in Uganda. This suggests artemisinin resistance emerged several years ago, Mita says. But its geographic spread remains unclear. “It is a possibility that this parasite migrated from other regions near northern Uganda,” he says, “but we don’t have any data from those regions.” Also unclear is whether overuse or misuse of artemisinin has driven resistance in Africa, researchers say.
“Fortunately, despite observed delay in parasite clearance, patients eventually clear their infections as long as the ACT partner drug remains effective, and resistance to partner drugs has not been confirmed in Africa,” says Betty Balikagala, a Juntendo University epidemiologist and first author of the NEJM paper. Only when such resistance emerged did clinical failures start to occur in Southeast Asia, Mueller notes. “The public health relevance of these findings should not be overly dramatized,” he says of the new studies.
Still, with few potential new drugs in the pipeline, he and others are urging new treatment strategies. Doctors in Southeast Asia have managed to maintain the efficacy of combination therapies by cycling through different partner drugs. “And if two drugs don’t work, try three,” Rosenthal says, referring to recent interest in adding another secondary drug to ACTs. The approach “has shown good efficacy in clinical trials,” he says.
Artemisinin’s diminishing efficacy is a “serious warning sign that we need to react to,” says Abdoulaye Djimdé, a genetic epidemiologist at the University of Science, Techniques and Technology of Bamako. “We should not wait until kids start dying from resistant parasites before tackling this problem.”