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

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.gov NCT01640574.

Impact of common genetic determinants of Hemoglobin A1c on type 2 diabetes risk and diagnosis in ancestrally diverse populations: A transethnic genome-wide meta-analysis

“…Thus, asymptomatic individuals often remain unaware of their G6PD genotype status and screening for the G6PD genotype before using HbA1c to diagnose T2D may be warranted in populations or ethnic groups where G6PD deficiency is common. Similarly, a recent study identified a significant hemolytic risk in women heterozygous for the G6PD Mahidol variant when treated with primaquine who were not detected by current screening methods [ 42 ]. Rarer hematologic conditions that reduce erythrocyte lifespan, e.g., hereditary hemolytic anemias, hereditary spherocytosis, and hemoglobinopathies have also been shown to lower HbA1c [ 9 , 43 ], and should also be considered before using HbA1c in these patients.…”

Evaluation of the CareStart™ glucose-6-phosphate dehydrogenase (G6PD) rapid diagnostic test in the field settings and assessment of perceived risk from primaquine at the community level in Cambodia

“…The majority of persons residing in the community have a primary (Grade 1-6) or secondary (Grade 7-9) education and 81% of those 15 years or older are literate [18]. [15]. Only quantitative tests can identify G6PD deficient females with activity levels between 30-70% [13,19].…”

“…According to the WHO, G6PD point-of-care tests must be able to detect G6PDd in males with less than 30% of enzymatic activity, and have test sensitivity of at least 95% to guide primaquine treatment [4,13]. Despite positive results from laboratory settings, there is still insufficient data to determine if the CareStart™ RDT could achieve the WHO required thresholds for test sensitivity and negative predictive values, when the test is performed in field settings by the health care workers (HCWs) and/or village malaria workers (VMWs) [15]. Given the potential risks associated with misdiagnosed G6PD status, the use of G6PD RDT in a community setting will require community engagement and a careful assessment of risks [13].…”

Vivax malaria in pregnancy and lactation: a long way to health equity

“…The use of PMQ for radical cure is complicated by a few factors, including adherence to a 14-day course, commonly observed side effects such as abdominal pain and, specifically in G6PD-deficient individuals, the risk of drug-induced haemolysis [9][10][11][12]. TQ provides radical cure in a single dose, improving adherence, but has not yet been implemented widely since receiving approval from the US Food and Drug Administration (FDA) in 2018 [13].…”