Decreased dihydroartemisinin-piperaquine protection against recurrent malaria associated with Plasmodium falciparum plasmepsin 3 copy number variation in Africa
Dihydroartemisinin-piperaquine (DHA-PPQ) is being recommended in Africa for the management of uncomplicated Plasmodium falciparum malaria and for chemoprevention strategies, based on the ability of piperaquine to delay re-infections. Although therapeutic resistance to piperaquine has been linked to increased copy number in plasmepsin-coding parasite genes (pfpm), their effect on the duration of the post-treatment prophylactic period remains unclear. Here, we retrospectively analyzed data from a randomized clinical trial, where patients received either DHA-PPQ or artesunate-amodiaquine for recurrent malaria episodes over two years. We observed an increase in the relative risk of re-infection among patients receiving DHA-PPQ compared to artesunate-amodiaquine after the first malaria season. This was driven by shorter average times to reinfection and coincided with an increased frequency of infections comprising pfpm3 multi-copy parasites. The decline in post-treatment protection of DHA-PPQ upon repeated use in a high transmission setting raises concerns for its wider use for chemopreventive strategies in Africa.
Authors
- José Pedro Gil (ORCID: https://orcid.org/0000-0002-6107-9379)
- Pedro Eduardo Ferreira (ORCID: https://orcid.org/0000-0002-2682-7722)
- Walter E. Haefeli (ORCID: https://orcid.org/0000-0003-0672-6876)
- Nouhoum Diallo (ORCID: https://orcid.org/0000-0003-0273-588X)
- Ulrika Morris (ORCID: https://orcid.org/0000-0003-4734-5754)
- Jürgen Burhenne (ORCID: https://orcid.org/0000-0002-2190-1698)
- Abdoulaye Djimdé (ORCID: https://orcid.org/0000-0003-0062-2283)
- María Isabel Veiga (ORCID: https://orcid.org/0000-0002-2205-8102)
- Issaka Sagara (ORCID: https://orcid.org/0000-0002-8555-9983)
- Leyre Pernaute-Lau (ORCID: https://orcid.org/0000-0002-7767-966X)
- Kassim Sanogo
- Taís Nóbrega de Sousa (ORCID: https://orcid.org/0000-0002-6874-9427)
- Anders Björkman (ORCID: https://orcid.org/0000-0002-8882-130X)
- Mamadou Teketé (ORCID: https://orcid.org/0000-0002-1395-0051)
- Mario Recker (ORCID: https://orcid.org/0000-0001-9489-1315)
- Juliana Inoue (ORCID: https://orcid.org/0000-0001-6786-5509)
- Bakary Fofana
- Steffen Borrmann (ORCID: https://orcid.org/0000-0001-9189-4393)
- Alassane Dicko
- Aliou Traoré
Institutions
- University of London (GB)
- University of Lisbon (PT)
- Heidelberg University (DE)
- University of Exeter (GB)
- Karolinska Institutet (SE)
- Centre de Recherche Médicales de Lambaréné (GA)
- German Center for Infection Research (DE)
- Fundação Oswaldo Cruz (BR)
- University of Tübingen (DE)
- University of Minho (PT)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-03-18
- DOI
- https://doi.org/10.1038/s41467-025-57726-5
- Citations
- 4
- Primary Topic
- Malaria Research and Control
- Type
- article
- Field-Weighted Citation Impact
- 7.51
Funders
- Deutsche Forschungsgemeinschaft
- Medicines for Malaria Venture
- Vetenskapsrådet
- European and Developing Countries Clinical Trials Partnership