Identifying an optimal dihydroartemisinin-piperaquine dosing regimen for malaria prevention in young Ugandan children

Erika Wallender, Ali Mohamed Ali, Emma Hughes, Abel Kakuru, Prasanna Jagannathan, Mary Kakuru Muhindo, Bishop Opira, Meghan Whalen, Liusheng Huang, Marvin Duvalsaint, Jenny Legac, Moses R. Kamya, Grant Dorsey, Francesca Aweeka, Philip J. Rosenthal and Rada M. Savic ()
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Erika Wallender: University of California, San Francisco
Ali Mohamed Ali: University of California, San Francisco
Emma Hughes: University of California, San Francisco
Abel Kakuru: Infectious Diseases Research Collaboration
Prasanna Jagannathan: Stanford University
Mary Kakuru Muhindo: Infectious Diseases Research Collaboration
Bishop Opira: Infectious Diseases Research Collaboration
Meghan Whalen: University of California, San Francisco
Liusheng Huang: University of California, San Francisco
Marvin Duvalsaint: University of California, San Francisco
Jenny Legac: University of California, San Francisco
Moses R. Kamya: Infectious Diseases Research Collaboration
Grant Dorsey: University of California, San Francisco
Francesca Aweeka: University of California, San Francisco
Philip J. Rosenthal: University of California, San Francisco
Rada M. Savic: University of California, San Francisco

Nature Communications, 2021, vol. 12, issue 1, 1-13

Abstract: Abstract Intermittent preventive treatment (IPT) with dihydroartemisinin-piperaquine (DP) is highly protective against malaria in children, but is not standard in malaria-endemic countries. Optimal DP dosing regimens will maximize efficacy and reduce toxicity and resistance selection. We analyze piperaquine (PPQ) concentrations (n = 4573), malaria incidence data (n = 326), and P. falciparum drug resistance markers from a trial of children randomized to IPT with DP every 12 weeks (n = 184) or every 4 weeks (n = 96) from 2 to 24 months of age (NCT02163447). We use nonlinear mixed effects modeling to establish malaria protective PPQ levels and risk factors for suboptimal protection. Compared to DP every 12 weeks, DP every 4 weeks is associated with 95% protective efficacy (95% CI: 84–99%). A PPQ level of 15.4 ng/mL reduces the malaria hazard by 95%. Malnutrition reduces PPQ exposure. In simulations, we show that DP every 4 weeks is optimal across a range of transmission intensities, and age-based dosing improves malaria protection in young or malnourished children.

Date: 2021
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DOI: 10.1038/s41467-021-27051-8

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