Evidence of Resistance to Standard Malaria Therapy for Severe Cases

Partial resistance to artemisinin, the recommended treatment for Plasmodium falciparum malaria, occurred in Ugandan children with severe disease who were treated with the drug, and some treated patients had recurrence of their infection, according to a small prospective study.

Artemisinin partial resistance — defined as a half-life for parasite clearance of greater than 5 hours — was seen in 11% of children with complicated malaria, and an adjusted 10.3% experienced recurrence after being treated, reported Chandy John, MD, MS, of the Ryan White Center for Pediatric Infectious Diseases and Global Health in Indianapolis, and colleagues in JAMA.

Prior research has shown that variations in the P. falciparum kelch 13 protein are associated with artemisinin partial resistance and infections with these variants are on the rise.

Of 100 children in the current study, eight had infections with the A675V variation, two had the C4692Y variation, and none had the R5661H variation. Approximately 20 kelch 13 variants are associated with delayed parasite clearance after infection.

The A675V variation was associated with longer time to parasite clearance, with a mean half-life of 4.9 hours versus 3.2 hours for wild-type Pfkelch13 (P=0.005) as well as a higher odds of artemisinin partial resistance when compared with wild-type Pfkelch13 (OR 6.2, 95% CI 1.2-30.6, P=0.04). Both children with the C469Y variation cleared parasitemia rapidly, with a mean half-lifeof 1.3 hours.

Two children — one that had P. falciparum with the A675V variant and another with wild-type Pfkelch13 — experienced early treatment failure and required prolonged treatment with artesunate, a derivative of artemisinin used for severe disease.

The 10.3% of participants that experienced recrudescence — recurrent malaria caused by the same strain of P. falciparum as the initial infection after treatment with artesunate followed by artemether-lumefantrine combination therapy — was also notable John told MedPage Today.

“We expected to find some parasites with [Pfkelch13] mutations, but didn’t expect to find 11% artemisinin partial resistance or 10% recrudescence,” he said.

“If the children at highest risk for death from malaria have partial resistance to the best drugs for treatment of severe malaria, this may lead to difficulty in treating severe malaria if resistance becomes widespread or more pronounced,” John added. “Current drugs for severe malaria are working, but not as well as they should.”

“This treatment efficacy is unexpectedly poor compared with that in numerous studies of artemisinin-based combination therapy for uncomplicated malaria, but experience with the long-term efficacy of treatment for severe malaria is limited,” wrote Philip Rosenthal, MD, of the University of California San Francisco, in an accompanying editorial.

Rosenthal continued that because of its small sample size and limited characterization of treatment outcomes, “the study was unable to answer the most important question concerning [artemisinin partial resistance] and severe malaria: do patients infected with [resistant] parasites have poorer clinical outcomes after treatment with parenteral artesunate compared with patients infected with drug-sensitive parasites?”

“Poorer outcomes associated with [artemisinin partial resistance] would not be surprising because children often present for care with advanced disease, and rapid action of artesunate is likely critical to provide speedy resolution of life-threatening effects of severe falciparum malaria,” Rosenthal wrote. “If [resistance] is indeed associated with poorer outcomes, changes in management strategies may be needed.”

The study, conducted from 2021-2022, enrolled children ages 6 months to 12 years with complicated malaria, defined as febrile, microscopy-confirmed P. falciparum parasitemia severe enough to require hospitalization. Children were treated with parenteral artesunate followed by oral artemether/lumefantrine.

Researchers evaluated the presence of Pfkelch13 variations and analyzed outcomes for each variation separately. They also determined the estimated parasitemia half-life, partial resistance to artemisinin, early treatment failure (defined as persistence of parasitemia of 72 hours or greater after initial treatment), and polymerase chain reaction (PCR)-adjusted recrudescence within 28 days of treatment.

Results of the study were also simultaneously presented at this year’s annual meeting of the American Society of Tropical Medicine and Hygiene, held in New Orleans.

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