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- Title
Treatment Failure in a UK Malaria Patient Harboring Genetically Variant Plasmodium falciparum From Uganda With Reduced In Vitro Susceptibility to Artemisinin and Lumefantrine.
- Authors
Schalkwyk, Donelly A van; Pratt, Sade; Nolder, Debbie; Stewart, Lindsay B; Liddy, Helen; Muwanguzi-Karugaba, Julian; Beshir, Khalid B; Britten, Dawn; Victory, Emma; Rogers, Claire; Millard, James; Brown, Michael; Nabarro, Laura E; Taylor, Andrew; Young, Bernadette C; Chiodini, Peter L; Sutherland, Colin J
- Abstract
Background Recent cases of clinical failure in malaria patients in the United Kingdom (UK) treated with artemether-lumefantrine have implications for malaria chemotherapy worldwide. Methods Parasites were isolated from an index case of confirmed Plasmodium falciparum treatment failure after standard treatment, and from comparable travel-acquired UK malaria cases. Drug susceptibility in vitro and genotypes at 6 resistance-associated loci were determined for all parasite isolates and compared with clinical outcomes for each parasite donor. Results A traveler, who returned to the UK from Uganda in 2022 with Plasmodium falciparum malaria, twice failed treatment with full courses of artemether-lumefantrine. Parasites from the patient exhibited significantly reduced susceptibility to artemisinin (ring-stage survival, 17.3% [95% confidence interval {CI}, 13.6%–21.1%]; P <.0001) and lumefantrine (effective concentration preventing 50% of growth = 259.4 nM [95% CI, 130.6–388.2 nM]; P =.001). Parasite genotyping identified an allele of pfk13 encoding both the A675V variant in the Pfk13 propeller domain and a novel L145V nonpropeller variant. In vitro susceptibility testing of 6 other P. falciparum lines of Ugandan origin identified reduced susceptibility to artemisinin and lumefantrine in 1 additional line, also from a 2022 treatment failure case. These parasites did not harbor a pfk13 propeller domain variant but rather the novel nonpropeller variant T349I. Variant alleles of pfubp1 , pfap2mu , and pfcoronin were also identified among the 7 parasite lines. Conclusions We confirm, in a documented case of artemether-lumefantrine treatment failure imported from Uganda, the presence of pfk13 mutations encoding L145V and A675V. Parasites with reduced susceptibility to both artemisinin and lumefantrine may be emerging in Uganda.
- Subjects
UNITED Kingdom; DRUG therapy for malaria; GENETIC variation; TREATMENT failure; ANTIMALARIALS
- Publication
Clinical Infectious Diseases, 2024, Vol 78, Issue 2, p445
- ISSN
1058-4838
- Publication type
Article
- DOI
10.1093/cid/ciad724