Plasma folate dynamics in Plasmodium falciparum-infected African children treated with artemisinin combination therapy and single low-dose primaquine or placebo

Abstract

Background: Adding single low-dose (0.25 mg/kg) primaquine (SLDPQ) to block Plasmodium falciparum transmission is now a WHO recommendation. Whether SLDPQ increases haemolysis in glucose-6-phosphate dehydrogenase deficient (G6PDd) patients, leading to increased folate demand and impaired haemoglobin (Hb) recovery is unknown. This study sought to answer this question. Methods: This randomized, placebo-controlled trial measured serial plasma folate concentrations [Day (D) 0, 3, 7 and 28] in falciparum-infected Ugandan and Congolese children (6 months to 11 years), treated with age-dosed SLDPQ/placebo and artemether-lumefantrine/dihydroartemisinin-piperaquine. Genotyping defined G6PD (G6PD c.202T allele) status. Multiple linear and non-linear, mixed effects, cubic spline regression were fitted to identify factors significantly associated with plasma folate at baseline and over time, respectively. Results: 408 children (3 had missing D0 values) had ≥ 1 plasma folate value. Of these, 66 (16.2%) were G6PD-deficient, 51 (12.5%) heterozygous females, 283 normal and 8 unknown. Mean baseline folate concentrations were 10.83 [standard deviation (SD) 3.58, SLDPQ] vs 10.92 (SD 4.54, placebo) ng/ml, associated independently with baseline Hb [estimate: 0.52 ng/ml (95% CI: 0.26 to 0.79, p = 0.0001)] and baseline parasitaemia [estimate: − 0.18 ng/ml (− 0.32 to − 0.05, p = 0.007)]. For all patients, mean plasma folate concentration paralleled mean haemoglobin concentration with an initial mean fall of 1.65 ng/ml (p < 0.0001 vs. baseline), followed by a sustained rise achieving a mean D28 concentration of 11.04 (SD 4.45) ng/ml. Over time, only age (p = 0.0001), male sex (p = 0.017) and baseline parasitaemia (p = 0.029) were significantly associated with a reduced plasma folate. Conclusion: SLDPQ and G6PD status did not compromise posttreatment plasma folate concentrations in young children with acute uncomplicated falciparum malaria, providing additional evidence of SLDPQ safety and supporting its use without G6PD testing. Trial registration The trial is registered, reference number ISRCTN11594437.