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

Abstract

Background Plasmodium vivax occurs as a latent infection of liver and a patent infection of red blood cells. Radical cure requires both blood schizontocidal and hypnozoitocidal chemotherapies. The hypnozoitocidal therapies available are primaquine and tafenoquine, 8-aminoquinoline drugs that can provoke threatening acute hemolytic anemia in patients having an X-linked G6PD-deficiency. Heterozygous females may screen as G6PD-normal prior to radical cure and go on to experience hemolytic crisis. Methods & findings This study examined G6PD phenotypes in 1928 female subjects living in malarious Sumba Island in eastern Indonesia to ascertain the prevalence of females vulnerable to diagnostic misclassification as G6PD-normal. All 367 (19%) females having <80% G6PD normal activity were genotyped. Among those, 103 (28%) were G6PD wild type, 251 (68·4%) were heterozygous, three (0·8%) were compound heterozygotes, and ten (2·7%) were homozygous deficient. The variants Vanua Lava, Viangchan, Coimbra, Chatham, and Kaiping occurred among them. Below the 70% of normal G6PD activity threshold, just 18 (8%) were G6PD-normal and 214 (92%) were G6PD-deficient. Among the 31 females with <30% G6PD normal activity were all ten homozygotes, all three compound heterozygotes, and just 18 were heterozygotes (7% of those). Conclusions In this population, most G6PD heterozygosity in females occurred between 30% and 70% of normal (69·3%; 183/264). The prevalence of females at risk of G6PD misclassification as normal by qualitative screening was 9·5% (183/1928). Qualitative G6PD screening prior to 8-aminoquinoline therapies against P. vivax may leave one in ten females at risk of hemolytic crisis, which may be remedied by point-of-care quantitative tests.

Reference and point-of-care testing for G6PD deficiency: Blood disorder interference, contrived specimens, and fingerstick equivalence and precision

“…The results from this study identified (i) confirmed hemizygous males with G6PD activity as low as 68% and (ii) confirmed homozygous females with G6PD activity below 80%. These observations are supported by a recent large US based study correlating percent activity against reference range [ 39 ] and a study with females in Indonesia [ 40 ]. Establishing a performance threshold for intermediates at 80% G6PD activity will result in (i) a significant lowering of the positive predictive power of the test for G6PD intermediate cases due to the lower AUC and (ii) a significantly higher proportion of females with homozygous G6PD normal alleles included in the intermediate group, if they have equivalent activity distributions to hemizygous normal males.…”

ABO blood group antigens and differential glycan expression: Perspective on the evolution of common human enzyme deficiencies

“…Glucose-6-phosphate dehydrogenase deficiency is one of the most common human enzyme deficiencies, affecting approximately 500 million people worldwide or 6.3% of the estimated 7.9 billion persons alive ( Cappellini and Fiorelli, 2008 ; Frank, 2005 ; Louicharoen et al., 2009 ; Luzzatto et al., 2020 ; Nkhoma et al., 2009 ; Satyagraha et al., 2021 ; WHO, 2019 ). G6PD deficiency, an X-linked recessive condition, makes RBCs more vulnerable to oxidative stress ( Cappellini and Fiorelli, 2008 ; Frank, 2005 ; Louicharoen et al., 2009 ; Satyagraha et al., 2021 ; WHO, 2019 ). G6PD is the rate-limiting enzyme of the pentose phosphate pathway, which produces NADPH that, in turn, maintains glutathione in a reduced state, thereby protecting cells from reactive oxygen species ( Ravikumar and Greenfield, 2020 ).…”

A Review of the Current Status of G6PD Deficiency Testing to Guide Radical Cure Treatment for Vivax Malaria

“…Most hemi- and homozygous individuals have G6PD activities below 30% (G6PD deficient) or above 70% to 80% of normal activity (G6PD normal) [ 36 ]. Conversely heterozygous females have enzyme activities ranging from close to 0% to almost normal activities, with activities of the majority of heterozygous females clustering around the 50% mark [ 37 ].…”