Metabolic disruptions in P. vivax malaria: Insights from four antimalarial treatment regimens.

Understanding how antimalarial regimens affect host metabolism could inform more effective Plasmodium vivax control strategies. This study investigated plasma metabolic alterations in P. vivax-infected patients treated with four antimalarial regimens using ultra-high-performance liquid chromatography-mass spectrometry. Patients received: (T1) chloroquine (CQ) for 3 days + primaquine (PQ) for 14 days; (T2) dihydroartemisinin-piperaquine (DHA-PPQ) for 3 days + PQ for 14 days; (T3) CQ + PQ42 (from day 42); or (T4) DHA-PPQ + PQ42 (from day 42). CQ-based regimens (T1, T3) caused broad metabolic perturbations involving arginine/proline, aspartate/asparagine, glutamate, nitrogen, pyrimidine, and vitamin B3 metabolism pathway. TI specifically affected alanine/aspartate, and methionine/cysteine metabolisms, while T3 influenced aminosugar, butanoate, glutathione metabolisms, glycine, serine, alanine, threonine metabolisms, tyrosine, and ubiquinone metabolisms. These disruptions have the potential to impair vascular function and immune responses, and affect redox balance and energy production, vital in parasite clearance and host recovery. Contrastingly, DHA-PPQ-based regimens (T2, T4) had distinct effects. T2 altered histidine metabolism, while T4 disrupted the carnitine shuttle, porphyrin metabolism, and plasma lipid levels; changes that may potentially impact energy homeostasis during infection, hemoglobin turnover and oxidative stress responses. Regimens lacking PQ (T3, T4) affected androgen/estrogen biosynthesis, implicating PQ to modulate hormone-related responses during treatment. These findings suggest antimalarial regimens exert regimen-specific metabolic effects, with CQ-based therapies broadly impacting amino acid and redox metabolism, and DHA-PPQ-based therapies affecting lipid and mitochondrial pathways. Mapping these metabolic signatures reveals the profound impact of these interventions on patients and support host-directed strategies for optimized vivax malaria management.