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 sulfadoxinepyrimethamine (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 PQinduced hemolysis.

Epidemiology and Infectivity of Plasmodium falciparum and Plasmodium vivax Gametocytes in Relation to Malaria Control and Elimination

“…At an individual level, concerns with drug use are particularly acute for PQ. As discussed above, this drug is unique in it that it has a strong gametocytocidal effect (363,412,438), but it also induces hemolysis that is related to G6PD deficiency (20,92,381,414). Hemolysis may occur after a single dose in G6PD-deficient individuals (381,412,414) and may be particularly severe in individuals with the Mediterranean (BϪ) G6PD genotype (20,158).…”

“…As discussed above, this drug is unique in it that it has a strong gametocytocidal effect (363,412,438), but it also induces hemolysis that is related to G6PD deficiency (20,92,381,414). Hemolysis may occur after a single dose in G6PD-deficient individuals (381,412,414) and may be particularly severe in individuals with the Mediterranean (BϪ) G6PD genotype (20,158). Although the effect of PQ on hemoglobin levels is generally mild (412,414) and self-limiting (110,412), severe and life-threatening hemolysis may occur in some individuals (158,381).…”

Malaria elimination: needs assessment and priorities for the future

“…However, the effects of both on P. vivax and P. ovale liver hypnozoites are variable [27]. Moreover, they may cause hemolysis in glucose-6-phosphate dehydrogenase (G6PD)-deficient patients [28], even at low doses and with mild G6PD deficiency [6,29]. Feachem et al (2010) indicated thata the unavailability of a quick, point-of-care G6PD test for persons at risk of hemolysis is a challenge [9]; diagnostic trials of such tests have recently started.…”

TargetingPlasmodium falciparumtransmission with primaquine: same efficacy, improved safety with a lower dose?

“…In two recently published studies, children in Tanzania were given a 0.75 mg/kg dose of primaquine with sulphadoxine pyrimethamine and artesunate. The first study entailed mass drug administration, where mean hemoglobin concentrations dropped most significantly in G6PD A-hemi/homozygotes (-2.5 g/dl, 95% CI: -1.2 to -3.8 g/dl) [34]. In this study, a 5-year-old with the wildtype G6PD B variant had severe anemia (Hb drop from 8.3 to 4.8 g/dl) that was asymptomatic and recovered after being given hematinic drugs [34].…”

“…The first study entailed mass drug administration, where mean hemoglobin concentrations dropped most significantly in G6PD A-hemi/homozygotes (-2.5 g/dl, 95% CI: -1.2 to -3.8 g/dl) [34]. In this study, a 5-year-old with the wildtype G6PD B variant had severe anemia (Hb drop from 8.3 to 4.8 g/dl) that was asymptomatic and recovered after being given hematinic drugs [34]. The second study, which entailed the treatment of children with P. falciparum malaria, again did not result in symptomatic hemolysis.…”