In Tanzania, hemolysis after a single dose of primaquine coadministered with an artemisinin is not restricted to glucose-6-phosphate dehydrogenase-deficient (G6PD A-) individuals

Abstract

The current interest in malaria elimination has led to a renewed interest in drugs that can be used for mass administration to minimize malaria transmission. Primaquine (PQ) is the only generally available drug with a strong activity against mature Plasmodium falciparum gametocytes, the parasite stage responsible for transmission. Despite concerns about PQ-induced hemolysis in glucose-6-phosphate dehydrogenase (G6PD)-deficient individuals, a single dose of PQ may be safe and efficacious in clearing gametocytes that persist after conventional treatment. As part of a mass drug intervention, we determined the hemolytic effect of sulfadoxine-pyrimethamine (SP) plus artesunate (AS) plus a single dose of primaquine (PQ; 0.75 mg/kg of body weight) in children aged 1 to 12 years. Children were randomized to receive SP+AS+PQ or placebo; those with a hemoglobin (Hb) level below 8 g/dl were excluded from receiving PQ and received SP+AS. The Hb concentration was significantly reduced 7 days after SP+AS+PQ treatment but not after placebo or SP+AS treatment. This reduction in Hb was most pronounced in G6PD-deficient (G6PD A-) individuals (-2.5 g/dl; 95% confidence interval [95% CI], -1.2 to -3.8 g/dl) but was also observed in heterozygotes (G6PD A) (-1.6 g/dl; 95% CI, -0.9 to -2.2 g/dl) and individuals with the wild-type genotype (G6PD B) (-0.5 g/dl; 95% CI, -0.4 to -0.6 g/dl). Moderate anemia (Hb level of <8 g/dl) was observed in 40% (6/15 individuals) of the G6PD A-, 11.1% (3/27 individuals) of the G6PD A, and 4.5% (18/399 individuals) of the G6PD B individuals; one case of severe anemia (Hb level of <5 g/dl) was observed. PQ may cause moderate anemia when coadministered with artemisinins, and excluding individuals based on G6PD status alone may not be sufficient to prevent PQ-induced hemolysis.

Trial registration: ClinicalTrials.gov NCT00509015.

FIG. 1.

Hb concentration on day 7 after treatment with SP+AS+PQ, shown as a percentage of the baseline value in relation to G6PD genotype. There was a significant reduction in Hb concentration in G6PD B (P < 0.0001), G6PD A (P < 0.0001), and G6PD A− (P = 0.001) individuals on day 7 after treatment compared to that on day 0 (d0).

FIG. 2.

Hb concentrations before and after SP+AS+PQ treatment for those individuals who became moderately anemic (Hb level of <8 g/dl) after the intervention. On the x axis is the hemoglobin concentration in g/dl; on the y axis are individual observations for G6PD homo-/hemizygous individuals (6 of 15 individuals treated [40%] became moderately anemic), heterozygotes (3 of 27 individuals [11.1%]), and wild-type individuals (18 of 399 individuals [4.5%]). Arrows represent individual baseline (right) and postintervention (left) hemoglobin measurements. Dashed lines represent the values below which individuals are considered to have severe (5 g/dl) or moderate (8 g/dl) anemia.

FIG. 3.

Hb concentration on day 7 after treatment with SP+AS+PQ, shown as a percentage of the baseline value in relation to α⁺-thalassemia genotype (A) or GSTM1 genotype (B). The reduction in Hb concentration was not related to α⁺-thalassemia genotype (P = 0.23) or GSTM1 genotype (P = 0.50).