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Decreased susceptibility of Plasmodium falciparum to both dihydroartemisinin and lumefantrine in northern Uganda

Author

Listed:
  • Patrick K. Tumwebaze

    (Infectious Diseases Research Collaboration)

  • Melissa D. Conrad

    (University of California)

  • Martin Okitwi

    (Infectious Diseases Research Collaboration)

  • Stephen Orena

    (Infectious Diseases Research Collaboration)

  • Oswald Byaruhanga

    (Infectious Diseases Research Collaboration)

  • Thomas Katairo

    (Infectious Diseases Research Collaboration)

  • Jennifer Legac

    (University of California)

  • Shreeya Garg

    (University of California)

  • David Giesbrecht

    (Brown University)

  • Sawyer R. Smith

    (Brown University)

  • Frida G. Ceja

    (Dominican University of California)

  • Samuel L. Nsobya

    (Infectious Diseases Research Collaboration)

  • Jeffrey A. Bailey

    (Brown University)

  • Roland A. Cooper

    (Dominican University of California)

  • Philip J. Rosenthal

    (University of California)

Abstract

Artemisinin partial resistance may facilitate selection of Plasmodium falciparum resistant to combination therapy partner drugs. We evaluated 99 P. falciparum isolates collected in 2021 from northern Uganda, where resistance-associated PfK13 C469Y and A675V mutations have emerged, and eastern Uganda, where these mutations are uncommon. With the ex vivo ring survival assay, isolates with the 469Y mutation (median survival 7.3% for mutant, 2.5% mixed, and 1.4% wild type) and/or mutations in Pfcoronin or falcipain-2a, had significantly greater survival; all isolates with survival >5% had mutations in at least one of these proteins. With ex vivo growth inhibition assays, susceptibility to lumefantrine (median IC50 14.6 vs. 6.9 nM, p 20 nM (p = 0.0002). Targeted sequencing of 819 isolates from 2015–21 identified multiple polymorphisms associated with altered drug susceptibility, notably PfK13 469Y with decreased susceptibility to lumefantrine (p = 6 × 10−8) and PfCRT mutations with chloroquine resistance (p = 1 × 10−20). Our results raise concern regarding activity of artemether-lumefantrine, the first-line antimalarial in Uganda.

Suggested Citation

  • Patrick K. Tumwebaze & Melissa D. Conrad & Martin Okitwi & Stephen Orena & Oswald Byaruhanga & Thomas Katairo & Jennifer Legac & Shreeya Garg & David Giesbrecht & Sawyer R. Smith & Frida G. Ceja & Sam, 2022. "Decreased susceptibility of Plasmodium falciparum to both dihydroartemisinin and lumefantrine in northern Uganda," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-33873-x
    DOI: 10.1038/s41467-022-33873-x
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    References listed on IDEAS

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    2. Aurel Holzschuh & Anita Lerch & Inna Gerlovina & Bakar S. Fakih & Abdul-wahid H. Al-mafazy & Erik J. Reaves & Abdullah Ali & Faiza Abbas & Mohamed Haji Ali & Mohamed Ali Ali & Manuel W. Hetzel & Joshu, 2023. "Multiplexed ddPCR-amplicon sequencing reveals isolated Plasmodium falciparum populations amenable to local elimination in Zanzibar, Tanzania," Nature Communications, Nature, vol. 14(1), pages 1-16, December.

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