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.

Genotypes and phenotypes of G6PD deficiency among Indonesian females across diagnostic thresholds of G6PD activity guiding safe primaquine therapy of latent malaria

“…Varied national drug regulators have registered tafenoquine as a single-dose alternative to the standard 14 days daily dosing with primaquine for presumptive anti-relapse therapy (PART) following a diagnosis of P. vivax malaria [32,33]. The administration of tafenoquine is not recommended in patients having <70% of normal G6PD activity; thus, imposing quantitative testing as a necessity corroborated by our findings from females residing in Sumba.…”

Usability of a point-of-care diagnostic to identify glucose-6-phosphate dehydrogenase deficiency: a multi-country assessment of test label comprehension and results interpretation

“…For this, biosensors show particular promise for their ability to distinguish between the clinically relevant classifications of G6PD status and provide reliable results in both male and female populations [ 17 – 19 ]. Kozenis is indicated for individual with normal G6PD activity (greater than 70%) and, therefore, requires a G6PD test that can differentiate individuals with intermediate activity from those with normal activity [ 20 , 21 ].…”

Prevalence and Molecular Characterization of Glucose-6-Phosphate Dehydrogenase (G6pd) Deficiency in Females From Previously Malaria Endemic Regions in Northeastern Thailand and Identification of a Novel G6pd Variant

“…FST, the most commonly performed qualitative test, underestimates the prevalence of heterozygous G6PD deficiency; 28 in the present study, about half of females with intermediate G6PD activity were misclassified by FST having normal G6PD activity ( Table 2 ). These falsely normal females are thus vulnerable to oxidative hemolysis.…”