Optimizing G6PD testing for Plasmodium vivax case management and beyond: why sex, counseling, and community engagement matter

Abstract

Safe access to the most effective treatment options for Plasmodium vivax malaria are limited by the absence of accurate point-of-care testing to detect glucose-6-phosphate dehydrogenase (G6PD) deficiency, the most common human genetic disorder. G6PD-deficient patients are at risk of life-threatening hemolysis when exposed to 8-aminoquinolines, the only class of drugs efficacious against P. vivax hypnozoites. Until recently, only qualitative tests were available in most settings. These can identify patients with severe G6PD deficiency (mostly male) but not patients with intermediate G6PD deficiency (always female). This has led to and reinforced a gap in awareness in clinical practice of the risks and implications of G6PD deficiency in females-who, unlike males, can have a heterozygous genotype for G6PD. Increasing recognition of the need for radical cure of P. vivax, first for patients' health and then for malaria elimination, is driving the development of new point-of-care tests for G6PD deficiency and their accessibility to populations in low-resource settings. The availability of user-friendly, affordable, and accurate quantitative point-of-care diagnostics for the precise classification of the three G6PD phenotypes can reduce sex-linked disparities by ensuring safe and effective malaria treatment, providing opportunities to develop supportive counseling to enhance understanding of genetic test results, and improving the detection of all G6PD deficiency phenotypes in newborns and their family members.

Keywords: G6PD deficiency; G6PD heterozygous females; G6PD testing; Plasmodium vivax; disparity; gender; genetic counselling; haemolysis; neonatal hyperbilirubinaemia; primaquine; sex; tafenoquine.

Figure 1.. Schematic of population histograms demonstrating the relationship between phenotype and genotype in G6PD deficiency in males (left panel) and females (right panel).

The G6PD gene is located on the X chromosome, such that females have two genes and males have only one. Males with a mutated G6PD allele (in red, G6PD _DEF) that expresses a compromised (deficient) G6PD enzyme protein typically have a blood G6PD value of less than 30% of normal. Females with two mutated G6PD-deficient alleles (in red, G6PD _{DEF1, DEF2}) also typically have a blood G6PD value of less than 30% of normal. Males with a wild type G6PD allele (in green, G6PD _WT) that expresses a fully functional enzyme have G6PD activity in an approximate normal distribution around the 100% median, as do females with two wild type G6PD alleles (in green, G6PD _{WT1, WT2}). Heterozygous females with both wild type and mutated G6PD alleles (in yellow, G6PD _{WT, DEF1}) can express a spectrum of whole blood G6PD activity, ranging from severely deficient (<30%) to beyond the World Health Organization definition of normal for females (>80%), with the majority in the intermediate (30% to 80%) activity range. The colored zones indicate the distribution of enzymatic activities associated with the genotypes as described above; the blue line represents the cumulative G6PD activity-based histogram.