Antimicrobial Chemotherapy
Review
15 October 2024

Artemisinin-resistant malaria

SUMMARY

The artemisinin antimalarials are the cornerstone of current malaria treatment. The development of artemisinin resistance in Plasmodium falciparum poses a major threat to malaria control and elimination. Recognized first in the Greater Mekong subregion of Southeast Asia nearly 20 years ago, artemisinin resistance has now been documented in Guyana, South America, in Papua New Guinea, and most recently, it has emerged de novo in East Africa (Rwanda, Uganda, South Sudan, Tanzania, Ethiopia, Eritrea, and eastern DRC) where it has now become firmly established. Artemisinin resistance is associated with mutations in the propeller region of the PfKelch gene, which play a causal role, although the parasites’ genetic background also makes an important contribution to the phenotype. Clinically, artemisinin resistance manifests as reduced parasiticidal activity and slower parasite clearance and thus an increased risk of treatment failure following artemisinin-based combination therapy (ACT). This results from the loss of artemisinin activity against the younger circulating ring stage parasites. This loss of activity is likely to diminish the life-saving advantage of artesunate in the treatment of severe falciparum malaria. Gametocytocidal and thus transmission blocking activities are also reduced. At current levels of resistance, artemisinin-resistant parasites still remain susceptible at the trophozoite stage of asexual development, and so, artemisinin still contributes to the therapeutic response. As ACTs are the most widely used antimalarial drugs in the world, it is essential from a malaria control perspective that ACT cure rates remain high. Better methods of identifying uncomplicated hyperparasitemia, the main cause of ACT treatment failure, are required so that longer courses of treatment can be given to these high-risk patients. Reducing the use of artemisinin monotherapies will reduce the continued selection pressure which could lead potentially to higher levels of artemisinin resistance. Triple artemisinin combination therapies should be deployed as soon as possible to protect the ACT partner drugs and thereby delay the emergence of higher levels of resistance. As new affordable antimalarial drugs are still several years away, the control of artemisinin resistance must depend on the better use of available tools.

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[This article was published on 15 October 2024 with a labeling error in Fig. 2. The figure was corrected in the current version, posted on 22 October 2024.]

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Author Bios

Mahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
N. J. White is Professor of Tropical Medicine at the Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand and at Oxford University, UK. He is also a Consultant Physician in acute general medicine at the John Radcliffe Hospital, Oxford. He chairs the Wellcome Trust Tropical Medicine Research Programmes in South East Asia where he has conducted research across a broad range of infectious diseases, particularly on malaria. He co-chaired the WHO antimalarial treatment guidelines committee for twelve years. He currently chairs the Scientific Advisory Committee of the Drugs for Neglected Diseases initiative and the Coalition for Equitable Research in Low Resource Settings.
Mahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
K. Chotivanich is a Professor at the Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand and she is an Associate Fellow of the Royal Society of Thailand. She is a malariologist with over twenty years of clinical and laboratory experience leading and conducting malaria research studies. Her primary research focus is on malaria pathophysiology and antimalarial drug resistance.

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Published In

cover image Clinical Microbiology Reviews
Clinical Microbiology Reviews
Online First
eLocator: e00109-24
Editor: Ferric C. Fang, University of Washington School of Medicine, Seattle, Washington, USA
PubMed: 39404268

History

Published online: 15 October 2024

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Keywords

  1. malaria
  2. antimalarial agents
  3. artemisinin
  4. Plasmodium falciparum
  5. drug resistance evolution

Contributors

Authors

Mahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
Author Contributions: Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Visualization, Writing – original draft, and Writing – review and editing.
Mahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
Author Contributions: Investigation, Methodology, Project administration, Validation, Visualization, and Writing – review and editing.

Editor

Ferric C. Fang
Editor
University of Washington School of Medicine, Seattle, Washington, USA

Reviewer

Sunil Parikh
Peer Reviewer
Yale School of Public Health, New Haven, Connecticut, USA

Notes

The authors declare no conflict of interest.

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