Resistant Malaria Parasite Mutations Observed in Rwanda

A new study from Rwanda indicated that drug-resistant mutations in the malaria parasite are becoming more prevalent, and difficult to mitigate, throughout Africa.

The new research, published in The Lancet Infectious Diseases, show Plasmodium falciparum mutations are associated with delayed parasite clearance—or, the persistence of parasitemia after 3 days of treatment—in a nature first observed in artemisinin-resistant malaria prevalence in Southeast Asia.

The international team of investigators additionally uncovered indications that mutation transmission is likely more prevalent than previously reported in research, and could precede greater geographical spread of treatment-resistant malaria.

As they noted, Plasmodium falciparum kelch13 (Pfkelch13) R561H and P574L have been previously reported in Rwanda as in southeast Asia, but no clinical association to parasite clearance has been established in assessment.

“We aimed to establish the efficacy of artemether–lumefantrine and genetic characterization of Pfkelch13 alleles and their association with treatment outcomes,” investigators wrote.

The team conducted its open-label, single-arm, multi-center, therapeutic efficacy trial across 3 Rwandan clinical sites in 2018, assessing three-day artemether-lumefantrine in children aged 6-59 months with P falciparum monoinfection and fever.

Investigators observed treatment response for 28 days via weekly blood sample microscopy screenings for the malaria-driving parasite. Pfkelch13 and P falciparum multidrug resistance-1 (Pfmdr1) genes were characterized in collected patients’ parasites. The team sought a primary endpoint of PCR-corrected parasitological cure of malaria risk on day 28.

Of the 228 patients enrolled, 224 reached the trial endpoint. Investigators observed PCR-corrected curative treatment efficacies in 97.0% (95% CI, 88 – 100), 93.8% (95% CI, 85 – 98), and 97.2% (95% CI, 91 – 100) of patients from the 3 Rwandan sites.

Pfkelch12 R561H mutations were observed in 28 (13%) of 218 pre-treatment patient samples; P574L mutations were present in just 2 (1%) samples. A combined 20 participants from 2 of the Rwandan sites were microscopically positive 3 days following treatment initiation, which was associated with pre-treatment presence of Pfkelch13 R561H in one of the sites (P = .005).

“Genetic analysis of Pfkelch13 R561H mutations suggest their common ancestry and local origin in Rwanda,” investigators wrote.

In a statement accompanying the study, lead author Dr. Aline Uwimana, of the Rwanda Biomedical Center in Kigali, noted that mutations can often emerge spontaneously, and in isolated instances of treatment-resistant burden.

“However, our new study shows that resistant isolates are starting to become more common and most importantly, are associated with clinical implications (delayed parasite clearance),” Uwimana said.

Co-author Dr. Naomi Lucci, Centers for Disease Control and Prevention (CDC) Resident Advisor for the US President’s Malaria Initiative did note the positive outcome of 94% overall treatment efficacy of malaria in Rwanda, “but new studies and ongoing monitoring are urgently needed,” she added.