Decreased dihydroartemisinin-piperaquine protection against recurrent malaria associated with Plasmodium falciparum plasmepsin 3 copy number variation in Africa

Leyre Pernaute-Lau, Mario Recker, Mamadou Tékété, Tais Nóbrega Sousa, Aliou Traore, Bakary Fofana, Kassim Sanogo, Ulrika Morris, Juliana Inoue, Pedro E. Ferreira, Nouhoum Diallo, Jürgen Burhenne, Issaka Sagara, Alassane Dicko, Maria I. Veiga, Walter Haefeli, Anders Björkman, Abdoulaye A. Djimde, Steffen Borrmann and José Pedro Gil ()
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Leyre Pernaute-Lau: Karolinska Institutet
Mario Recker: University of Exeter, Penryn Campus
Mamadou Tékété: University of Science, Techniques and Technologies of Bamako
Tais Nóbrega Sousa: Karolinska Institutet
Aliou Traore: University of Science, Techniques and Technologies of Bamako
Bakary Fofana: University of Science, Techniques and Technologies of Bamako
Kassim Sanogo: University of Science, Techniques and Technologies of Bamako
Ulrika Morris: Karolinska Institutet
Juliana Inoue: University of Tübingen
Pedro E. Ferreira: University of Minho, Campus de Gualtar
Nouhoum Diallo: University of Science, Techniques and Technologies of Bamako
Jürgen Burhenne: German Center for Infection Research (DZIF)
Issaka Sagara: University of Science, Techniques and Technologies of Bamako
Alassane Dicko: University of Science, Techniques and Technologies of Bamako
Maria I. Veiga: University of Minho, Campus de Gualtar
Walter Haefeli: German Center for Infection Research (DZIF)
Anders Björkman: Karolinska Institutet
Abdoulaye A. Djimde: University of Science, Techniques and Technologies of Bamako
Steffen Borrmann: University of Tübingen
José Pedro Gil: Karolinska Institutet

Nature Communications, 2025, vol. 16, issue 1, 1-7

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-57726-5

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