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

Date Published: February 7, 2017

Publisher: Public Library of Science

Author(s): Cindy S. Chu, Germana Bancone, Kerryn A. Moore, Htun Htun Win, Niramon Thitipanawan, Christina Po, Nongnud Chowwiwat, Rattanaporn Raksapraidee, Pornpimon Wilairisak, Aung Pyae Phyo, Lily Keereecharoen, Stéphane Proux, Prakaykaew Charunwatthana, François Nosten, Nicholas J. White, Paul Garner

Abstract: BackgroundRadical cure of Plasmodium vivax malaria with 8-aminoquinolines (primaquine or tafenoquine) is complicated by haemolysis in individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency. G6PD heterozygous females, because of individual variation in the pattern of X-chromosome inactivation (Lyonisation) in erythroid cells, may have low G6PD activity in the majority of their erythrocytes, yet are usually reported as G6PD “normal” by current phenotypic screening tests. Their haemolytic risk when treated with 8-aminoquinolines has not been well characterized.Methods and FindingsIn a cohort study nested within a randomised clinical trial that compared different treatment regimens for P. vivax malaria, patients with a normal standard NADPH fluorescent spot test result (≳30%–40% of normal G6PD activity) were randomised to receive 3 d of chloroquine or dihydroartemisinin-piperaquine in combination with primaquine, either the standard high dose of 0.5 mg base/kg/day for 14 d or a higher dose of 1 mg base/kg/d for 7 d. Patterns of haemolysis were compared between G6PD wild-type and G6PD heterozygous female participants. Between 21 February 2012 and 04 July 2014, 241 female participants were enrolled, of whom 34 were heterozygous for the G6PD Mahidol variant. Haemolysis was substantially greater and a larger proportion of participants reached the threshold of clinically significant haemolysis (fractional haematocrit reduction >25%) in G6PD heterozygotes taking the higher (7 d) primaquine dose (9/17 [53%]) compared with G6PD heterozygotes taking the standard high (14 d) dose (2/16 [13%]; p = 0.022). In heterozygotes, the mean fractional haematocrit reductions were correspondingly greater with the higher primaquine dose (7-d regimen): −20.4% (95% CI −26.0% to −14.8%) (nadir on day 5) compared with the standard high (14 d) dose: −13.1% (95% CI −17.6% to −8.6%) (nadir day 6). Two heterozygotes taking the higher (7 d) 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%) (nadir day 3) compared with −5.5% (95% CI −7.4% to −3.7%) (nadir day 4), respectively. Limitations to this nested cohort study are that the primary objective of the trial was designed to measure efficacy and not haemolysis in relation to G6PD genotype and that the heterozygote groups were small.ConclusionHigher daily doses of primaquine have the potential to cause clinically significant haemolysis in G6PD heterozygous females who are reported as phenotypically normal with current point of care tests.Trial RegistrationClinicalTrials.govNCT01640574.

Partial Text: Primaquine is the only widely available drug that is effective against P. vivax hypnozoites, the latent forms that emerge from the liver to produce relapses of P. vivax malaria. The recommended regimen to prevent relapse of P. vivax malaria (called radical treatment) is primaquine given for 14 d at a daily dose of 0.25 to 0.5 mg base/kg. However, although widely recommended for radical treatment of P. vivax and P. ovale infections, primaquine is often not given. This is because primaquine causes haemolysis in glucose-6-phosphate dehydrogenase (G6PD)-deficient individuals [1]. While G6PD deficiency is very common in malaria-endemic areas, G6PD testing is generally unavailable because the standard point-of-care test requires appropriate reagents, electricity, trained staff, and quality controls.

Between March 2012 and July 2014, 680 patients with acute P. vivax malaria and a normal G6PD FST were enrolled in the main trial. Details of all participants and the therapeutic outcomes will be reported elsewhere. Of the 241 female participants recruited, 34 (14%) were subsequently found to be G6PD Mahidol heterozygotes. One withdrew from the trial, leaving 33 with evaluable data (Fig 1). Symptoms, vital signs, and laboratory indices were similar in all treatment groups. G6PD heterozygous female participants taking PMQ-0.5 were younger (median 12 y [interquartile range (IQR) 7 to 27.5; range 1.5 to 45]) than heterozygous female participants taking PMQ-1 (19 y [IQR 14 to 27; range 6 to 38]) or wild-type female participants taking PMQ-1 (17 y [IQR 10.5 to 35; range 2 to 63]) or PMQ-0.5 (21 years [IQR 11 to 38; range 3 to 60]) (Table 1). Children less than 5 y old were under-represented in the heterozygous female PMQ-1 group.

These results show that the standard high dose primaquine regimen given over 14 d (0.5 mg base/kg/d) is reasonably well tolerated by G6PD Mahidol heterozygous female participants, whereas significant haematocrit reductions (fractional haematocrit reduction >25%) were observed in those taking the higher daily dose (same total dose) given over 7 d (1 mg base/kg/d). Two heterozygous participants receiving the higher primaquine dose given over 7 d (1 mg base/kg/d) required transfusion. G6PD Mahidol wild-type female participants did not have an increased risk of primaquine-induced haemolysis when taking the same dose. Irrespective of primaquine regimen and despite continued dosing, haematocrits increased by day 7. The lack of subjective complaints and change in vital signs suggests that haematocrit declines were tolerated and these symptoms and signs did not identify moderate or even severe degrees of haemolysis [11].



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