A study today in the New England Journal of Medicine reports evidence of emerging artemisinin-resistant malaria in Uganda, a potentially worrisome development for Africa.
Conducted at a hospital in Northern Uganda, where malaria transmission is high, the study found that 5.8% of malaria patients treated with an artemisinin derivative from 2017 through 2019 had evidence of slow parasite clearance, which can be a sign of partial resistance to artemisinin. Further analysis of parasite DNA samples from patient blood samples identified genetic mutations associated with delayed parasite clearance and artemisinin resistance.
Artemisinin and artemisinin combination therapies (ACTs) are the most effective and widely used treatment for malaria caused by the Plasmodium falciparum parasite and have greatly contributed to global reductions in malaria deaths and complications. While artemisinin resistance is widespread in the Greater Mekong Subregion of Southeast Asia, experts fear it could have a devastating impact in Africa, where 90% of malaria cases and deaths are reported.
"Our findings suggest a potential risk of cross-border spread across Africa and highlight the need to perform large-scale surveys," the team of researchers from Uganda and Japan wrote.
Clinical, molecular signs of resistance
Out of 247 patients who received intravenous artesunate and were enrolled in the study, the researchers were able to determine parasite clearance half-life in 240. Parasites were rapidly cleared in most patients, with a median half-life of 1.9 hours, but 14 patients had evidence of slow parasite clearance (defined as a half-life of more than 5 hours) and were considered to have in vivo artemisinin resistance.
Genotyping of parasite DNA in blood samples from the 14 patients revealed that 13 were infected with P falciparum parasites with mutations in the A675V or C469Y allele in the kelch13 gene, which is used to validate artemisinin resistance. Both mutations have also been detected in Southeast Asia and are among the mutations listed by the World Health Organization as potential molecular markers for artemisinin resistance.
Multivariable analysis showed they were both associated with prolonged parasite clearance half-lives, and were the only significant predictors of prolonged parasite clearance.
When the researchers conducted genotyping of parasite DNA from all 240 patients, along with an additional 195 malaria patients treated at the hospital from 2015 through 2019, they found that the prevalence of parasites with kelch13 mutations increased from 3.9% in 2015 to 19.8% in 2019.
This increase was primarily due to the significant increase in the frequency of the A675V and C469Y alleles, which reached a prevalence of 11.5% and 4.2%, respectively, in 2019. The genetic data also suggest the mutations emerged independently in Uganda.
"The association that we found between clinical artemisinin resistance and the presence of the A675V and C469Y mutations raises the possibility that these resistance markers can be used to assist in the detection of artemisinin resistance among patients with P. falciparum infection in Africa," the researchers wrote.
Major threat to malaria control in Africa
The findings come on the heels of a study published in April that detected partial artemisinin resistance in the neighboring country of Rwanda. That was the first documented report of artemisinin resistance in Africa.
In an editorial that accompanies today's study, Nicholas White, of Mahidol University in Thailand, says the findings are concerning because artesunate is the drug of choice for severe malaria, and reduced susceptibility to the artemisinin component of ACT puts greater pressure on the partner drug.
"East Africa is reliant on a single drug, artemether–lumefantrine, to treat falciparum malaria. Fortunately, artemether–lumefantrine has held up well, even in the Greater Mekong Subregion of Southeast Asia, where other artemisinin combination therapies have faltered," he writes. "High-grade lumefantrine resistance has not yet emerged, but if it did, it would be a major threat to current control and elimination efforts."
White said that, with new malaria drugs several years away, health officials in East Africa should begin looking at strategies to contain artemisinin resistance, such as including additional partner drugs or using two different ACTs to treat malaria patients.
"Whichever approach is chosen, it would be much better to act now rather than wait for years while the situation deteriorates and higher levels of resistance develop," he wrote.