Treatment Failure in a UK Malaria Patient Harboring Genetically Variant Plasmodium falciparum From Uganda With Reduced In Vitro Susceptibility to Artemisinin and Lumefantrine
© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:78 |
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| Enthalten in: |
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America - 78(2024), 2 vom: 17. Feb., Seite 445-452 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
van Schalkwyk, Donelly A [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 19.02.2024 Date Revised 29.03.2024 published: Print Citation Status MEDLINE |
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| doi: |
10.1093/cid/ciad724 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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NLM365111015 |
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| 100 | 1 | |a van Schalkwyk, Donelly A |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Treatment Failure in a UK Malaria Patient Harboring Genetically Variant Plasmodium falciparum From Uganda With Reduced In Vitro Susceptibility to Artemisinin and Lumefantrine |
| 264 | 1 | |c 2024 | |
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| 500 | |a Date Completed 19.02.2024 | ||
| 500 | |a Date Revised 29.03.2024 | ||
| 500 | |a published: Print | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. | ||
| 520 | |a BACKGROUND: Recent cases of clinical failure in malaria patients in the United Kingdom (UK) treated with artemether-lumefantrine have implications for malaria chemotherapy worldwide | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Plasmodium falciparum | |
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| 650 | 4 | |a treatment failure | |
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| 650 | 7 | |a F38R0JR742 |2 NLM | |
| 650 | 7 | |a Antimalarials |2 NLM | |
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| 650 | 7 | |a Artemisinins |2 NLM | |
| 650 | 7 | |a Protozoan Proteins |2 NLM | |
| 700 | 1 | |a Pratt, Sade |e verfasserin |4 aut | |
| 700 | 1 | |a Nolder, Debbie |e verfasserin |4 aut | |
| 700 | 1 | |a Stewart, Lindsay B |e verfasserin |4 aut | |
| 700 | 1 | |a Liddy, Helen |e verfasserin |4 aut | |
| 700 | 1 | |a Muwanguzi-Karugaba, Julian |e verfasserin |4 aut | |
| 700 | 1 | |a Beshir, Khalid B |e verfasserin |4 aut | |
| 700 | 1 | |a Britten, Dawn |e verfasserin |4 aut | |
| 700 | 1 | |a Victory, Emma |e verfasserin |4 aut | |
| 700 | 1 | |a Rogers, Claire |e verfasserin |4 aut | |
| 700 | 1 | |a Millard, James |e verfasserin |4 aut | |
| 700 | 1 | |a Brown, Michael |e verfasserin |4 aut | |
| 700 | 1 | |a Nabarro, Laura E |e verfasserin |4 aut | |
| 700 | 1 | |a Taylor, Andrew |e verfasserin |4 aut | |
| 700 | 1 | |a Young, Bernadette C |e verfasserin |4 aut | |
| 700 | 1 | |a Chiodini, Peter L |e verfasserin |4 aut | |
| 700 | 1 | |a Sutherland, Colin J |e verfasserin |4 aut | |
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