Despite mutations in the Plasmodium falciparum kelch13 (Pfkelch13) allele leading to emerging artemisinin resistance in Rwanda, artemether-lumefantrine shows high efficacy in treating malaria, according to study results published in The Lancet Infectious Diseases. The study authors also reported that as long as the partner drug to artemisinin-based combined therapies is effective, combined therapies will still be efficacious despite delayed parasite clearance.
For uncomplicated malaria infections caused by P falciparum, the most effective treatments are currently artemisinin-based combination therapies. In Rwanda, first-line treatment is artemether-lumefantrine combination therapy, and although there have been reports of validated markers for resistance in Rwanda, an association with parasite clearance has not yet been observed.
A team of investigators conducted an open-label, single-arm, multicenter, therapeutic efficacy analysis to determine the efficacy of artemether-lumefantrine and if treatment outcomes are linked to genetic traits in the Pfkelch13 alleles.
Children aged 6 to 59 months who had a P falciparum monoinfection with fever were enrolled in the study and treated with a 3-day course of artemether-lumefantrine. Treatment response was assessed for 28 days during which time blood samples were screened for the presence of P falciparum. Extracted parasite genomic DNA was assessed for molecular antimalarial drug resistance and microsatellite markers. Pfkelch13 propeller domain and P falciparum multidrug resistance-1 genes (Pfmdr1) were analyzed for single nucleotide polymorphisms.
The primary outcome was polymerase chain reaction (PCR)-corrected parasitologic cure on day 28 (using World Health Organization protocol), and secondary outcomes included parasitemia on the third day of treatment.
Of the 228 children enrolled in the study, 4 withdrew between days 4 and 6 and 1 withdrew on day 28. At the 3 sites in Rwanda that were included in the study, PCR-corrected efficacies in Masaka, Rukara, and Bugarama were 97.0%, 93.8%, and 97.2%, respectively.
There were 254 samples that successfully sequenced Pfkelch13 (218 pretreatment samples, 36 posttreatment samples). Of these, 38 samples had the validated artemisinin partial resistance marker; 36 had an R561H mutation, and 2 had a P574L mutation.
Pfmdr1 was successfully sequenced in 243 samples: 208 pretreatment samples and 35 posttreatment samples. Haplotype N84Y, Y194F, and D1246Y was seen in 48% of the 240 pretreatment samples and 50% of the 40 posttreatment samples. In addition, 43% of the pretreatment and 40% of the posttreatment total observed haplotypes had N86, 184F, and D1246 haplotypes.
Three days after treatment initiation, parasitemia was detected via microscopy in 20 of the participants, 11 of whom carried the Pfklech13 R561H mutation. After stratifying data by site, the association between day-3 parasitemia and R561H mutation was significant to Masaka origin (P =.0005) but not to Rukara (P =.063), suggesting a common ancestry and local origin of this mutation.
“These results highlight the importance of additional [therapeutic efficacy studies] to confirm the current findings and collect additional evidence for the presence of delayed parasite clearance by more frequent monitoring (every 8 h) of [parasitemia] within the first 3 days following treatment,” the investigators noted. “Additional molecular surveillance in different parts of the country and in bordering countries will help monitor the extent of spread of the mutant parasites to inform public health actions to mitigate the spread of this mutation.”
Uwimana A, Umulisa N, Venkatesan M, et al. Association of Plasmodium falciparum kelch13 R561H genotypes with delayed parasite clearance in Rwanda: an open-label, single-arm, multicentre, therapeutic efficacy study. Lancet Infect Dis. Published online April 14, 2021. doi:10.1016/S1473-3099(21)00142-0