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Haemolysis in G6PD Heterozygous Females Treated with Primaquine for Plasmodium vivax Malaria: A Nested Cohort in a Trial of Radical Curative Regimens

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Background: The radical curative efficacy of the 8-aminoquinolines in vivax malaria has been recognized for over 75 years. However, treatmentwith primaquine or tafenoquine against the hypnozoites of Plasmodium vivax malaria is complicated by haemolysis in individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency. G6PD heterozygous females may have low G6PDactivity levels,yet are usuallyreported as G6PD “normal”by current phenotypic screening tests.Their haemolytic risk when treated with 8-aminoquinolines has not been well characterized. Methods and Findings: In a randomised clinical trial comparing different treatment regimens in Plasmodium vivax malaria, patients with a normal G6PD fluorescent spot test(≳30%–40% of normal G6PD activity) were randomised to receive 3 days of chloroquine or dihydroartemisinin-piperaquine in combination with primaquine, either the standard high dose of 0.5 mg base/kg/day for 14 daysor a higher dose of 1 mg base/kg/dayfor 7 days. Within a subgroup of females, patterns of haemolysis were compared between G6PD wild-type and G6PD heterozygous participants. Results: Between 21 February 2012 and 04 July 2014, 241 female participantswere enrolled, of whom 34 were heterozygous for the G6PD Mahidol variant. Haemolysis was substantially greaterin G6PD heterozygotes taking the higher (7 days) primaquine dose (9/17 [53%]) compared with G6PD heterozygotes taking the standard high (14 days) dose(2/16 [13%]; p= 0.022). In heterozygotes, the mean fractional haematocrit reductions were correspondingly greater with the higher primaquine dose (7-dayregimen): −20.4% (95% CI −26.0 % to −14.8%) compared with the standard high (14 days) dose: −13.1% (95% CI−17.6%to −8.6%). Two heterozygotes taking the higher (7 days) primaquine dose required blood transfusion. In wild-type participants, mean haematocrit reductions were clinically insignificant and similar with both doses: −5.8 (95% CI −7.2%to −4.4%) compared with −5.5% (95% CI −7.4%to −3.7%), respectively. Conclusion: Higher daily doses of primaquinegreater than 0.5mg/kg/day are potentially dangerous in G6PD heterozygous females who screen as “normal” with current point of care tests.