In The News: Evidence of Resistance to Standard Malaria Therapy for Severe Cases

Medpage Today reports on small study research into malaria treatment resistance in Ugandan children with severe cases. The researchers found partial resistance to the recommended treatment for Plasmodium falciparum malaria, artemisinin, in children treated with the drug, and some had recurrence of infection. The 100-patient study saw artemisinin partial resistance in 11% of children with complicated malaria and 10.3% adjusted recurrence when treated.

Partial resistance was defined as half-life for parasite clearance of greater than five hours. Variations in the P. falciparum kelch 13 protein have been shown in prior research to be associated with this partial resistance. Eight of the current study participants 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.

Variation A675V was associated with longer time to parasite clearance, mean half-life of 4.9 hours versus 3.2 hours for wild-type Pfkelch13 and a higher odds of artemisinin partial resistance when compared with wild-type Pfkelch13. Both children who presented with the C469Y variation cleared parasitemia rapidly, mean half-lifeof 1.3 hours. Two children (one P. falciparum with the A675V variant and another with wild-type Pfkelch13)experienced early treatment failure, requiring prolonged treatment with a derivative of artemisinin, artesunate, that is used for severe disease.

Recurrent malaria caused by the same strain of P. falciparum as the initial infection after treatment with artesunate followed by artemether-lumefantrine combination therapy, recrudescence, was experienced by 10.3% of participants. Researchers noted there was an expectation of mutations, though not that level of resistance or recrudescence.

An accompanying editorial noted limitations of the study in size and outcomes. In part it mentioned the study was unable to answer questions concerning artemisinin partial resistance and severe malaria, such as “do patients infected with [resistant] parasites have poorer clinical outcomes after treatment with parenteral artesunate compared with patients infected with drug-sensitive parasites?”

The study was conducted from 2021-2022 with children ages six months-12 years with complicated malaria severe enough to require hospitalization. Study participants were febrile with microscopy-confirmed P. falciparum parasitemia. They received parenteral artesunate followed by oral artemether/lumefantrine. Results of the study were presented at the annual American Society of Tropical Medicine and Hygiene meeting.

PIDS member and study researcher Chandy John is quoted in the story. 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. Current drugs for severe malaria are working, but not as well as they should.”