Malaria study finds evidence of artemisinin resistance in Rwanda

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New research by scientists in Africa and the United States has found evidence of the emergence of artemisinin-resistant malaria in Rwanda.

In a study published this week in the Lancet Infectious Diseases, a team including researchers from The Rwanda Biomedical Centre, the US Centers for Disease Control and Prevention, and the US Agency for International Development found that an artemisinin combination therapy (ACT) used in Rwanda for treatment of malaria caused by the Plasmodium falciparum parasite remains highly effective. Efficacy rates from a therapeutic study conducted among children at three sites in Rwanda were above 90%.

But the study also found evidence of delayed parasite clearance, which can be a sign of partial resistance to the artemisinin component of ACT, and identified mutations in P falciparum genes that have been associated with delayed parasite clearance and artemisinin resistance. It's the first documented evidence of partial artemisinin resistance in Africa.

ACTs are currently the most effective and widely used treatments for uncomplicated malaria caused by P falciparum. But widespread artemisinin resistance has emerged in the Greater Mekong Subregion of southeast Asia, and experts say that if resistance to ACTs were to spread widely in Africa, the results could be devastating.

Resistance mutations linked to delayed parasite clearance

The routine therapeutic efficacy study was conducted by the Malaria and Other Parasitic Diseases Division of the Rwanda Biomedical Centre in 2018 per World Health Organization (WHO) guidelines to do periodic antimalarial efficacy monitoring. Children ages 6 to 59 months with P falciparum monoinfection and fever were treated at three sites—Masaka, Rukara, and Bugarama—with a 3-day course of artemether-lumefantrine (a form of ATC), and researchers monitored treatment response for 28 days using weekly microscopy screenings of blood samples for P falciparum.

The primary endpoint was polymerase chain reaction (PCR)-corrected parasitological cure on day 28, per WHO protocol. The researchers also assessed parasitemia on day 3 of treatment and conducted molecular analysis on samples collected pre-treatment and during follow-up to identify and characterize mutations in the pfkelch13 and P falciparum multidrug resistance-1 (pfmdr1) genes.

A total of 228 children with symptomatic uncomplicated P falciparum malaria were enrolled in the three sites: 88 in Rukara, 52 in Masaka, and 88 in Bugarama. The per-protocol PCR-corrected drug efficacies were 93.8% in Rukara, 97% in Masaka, and 97.2% in Bugarama. The WHO only recommends replacement of antimalarial therapy if efficacy falls below 90%.

The pfkelch13 gene was successfully sequenced from 254 of 265 samples (218 pre-treatment and 36 post-treatment), and 38 (15%) of the 254 samples had one of the mutations that have been validated as molecular markers for artemisinin partial resistance: 36 with a R561H mutation, and 2 with a P574L mutation. Thirty of those mutations were present in the pre-treatment samples.

Eight of the 51 participants in Masaka (16%) and 12 of 82 participants in Rukara (12%) had detectable parasitemia by microscopy on day 3 post-treatment, a WHO criterion for artemisinin partial resistance. Delayed parasite clearance was associated with the pre-treatment presence of the pfkelch13 R561H mutation in Masaka but not in Rukara.

Further genetic analysis of the pfkelch13 R561H mutations suggested a common ancestry and independent origin in Rwanda.

"This study confirms that artemether–lumefantrine remains highly efficacious in all three study sites, with PCR-corrected efficacy of 94–97%," the study authors wrote. "However, the presence of two validated markers of artemisinin partial resistance, R561H and P574L, and delayed parasite clearance (parasitaemia at day 3) in more than 10% of the study participants in Masaka and Rukara are of some concern."

They also noted that the prevalence of the pfkelch13 R561H mutation found in the Masaka site in this study was higher than found in a study that analyzed samples collected from Masaka from 2013 to 2015.

Call for 'heightened vigilance'

The authors said that ACTs can remain effective even if partial artemisinin resistance is found as long as the partner drug is effective. But as evidence from the Greater Mekong Subregion has shown, once artemisinin resistance becomes prevalent, resistance to the partner drug often follows.

"Heightened vigilance for artemether–lumefantrine efficacy and the evaluations of the efficacy of other ACTs in Rwanda should be considered," they wrote.

In an accompanying commentary, Philip Rosenthal, MD, a professor of medicine at the University of California San Francisco who studies malaria, warned that these findings and other recent data suggest Africa is on the verge of clinically meaningful artemisinin resistance.

"Loss of efficacy of key ACTs, particularly artemether–lumefantrine, the most widely used antimalarial, could have dire consequences, as occurred when chloroquine resistance led to enormous increases in malaria deaths in the late twentieth century," he wrote. "Although it is impossible to predict the pace of progression of drug resistance in Africa, close surveillance for genotypic and phenotypic evidence of artemisinin and partner drug resistance, with prompt replacement of failing regimens, could save many lives."

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