Clinical performance validation of the STANDARD G6PD test: A multi-country pooled analysis

Abstract

Introduction: Screening for G6PD deficiency can inform disease management including malaria. Treatment with the antimalarial drugs primaquine and tafenoquine can be guided by point-of-care testing for G6PD deficiency.

Methods and findings: Data from similar clinical studies evaluating the performance of the STANDARD G6PD Test (SD Biosensor, South Korea) conducted in Bangladesh, Brazil, Ethiopia, India, Thailand, the United Kingdom, and the United States were pooled. Test performance was assessed in a retrospective analysis on capillary and venous specimens. All study sites used spectrophotometry for reference G6PD testing, and either the HemoCue or complete blood count for reference hemoglobin measurement. The sensitivity of the STANDARD G6PD Test using the manufacturer thresholds for G6PD deficient and intermediate cases in capillary specimens from 4212 study participants was 100% (95% Confidence Interval (CI): 97.5%-100%) for G6PD deficient cases with <30% activity and 77% (95% CI 66.8%-85.4%) for females with intermediate activity between 30%-70%. Specificity was 98.1% (95% CI 97.6%-98.5%) and 92.8% (95% CI 91.6%-93.9%) for G6PD deficient individuals and intermediate females, respectively. Out of 20 G6PD intermediate females with false normal results, 12 had activity levels >60% on the reference assay. The negative predictive value for females with G6PD activity >60% was 99.6% (95% CI 99.1%-99.8%) on capillary specimens. Sensitivity among 396 P. vivax malaria cases was 100% (69.2%-100.0%) for both deficient and intermediate cases. Across the full dataset, 37% of those classified as G6PD deficient or intermediate resulted from true normal cases. Despite this, over 95% of cases would receive correct treatment with primaquine, over 87% of cases would receive correct treatment with tafenoquine, and no true G6PD deficient cases would be treated inappropriately based on the result of the STANDARD G6PD Test.

Conclusions: The STANDARD G6PD Test enables safe access to drugs which are contraindicated for individuals with G6PD deficiency. Operational considerations will inform test uptake in specific settings.

Fig 1. Site-specific variation in G6PD activity among normal males on fresh capillary and venous specimens on A) the reference assay, and B) the STANDARD G6PD Test*.

* The UK study, which included newborns and samples with blood disorders, and the Thailand study, which was conducted on frozen samples, are not included in Figure 1.

Fig 2. G6PD activity classification of the STANDARD G6PD and reference assay for A) males and B) females.

G6PD status classification measured by the STANDARD G6PD Test is shown on the X-axis, for capillary (grey) and venous (black) specimens, respectively. Results are plotted by the reference G6PD percent activity (Y-axis). Shaded areas correspond to true G6PD normal (green), intermediate (yellow), and deficient (red) status classifications on the reference assay.

Fig 3. Participant eligibility and outcomes for radical cure treatment options based on the results of the STANDARD G6PD Test on capillary specimens.

Panels A and B represent eligibility and outcomes for daily primaquine regimen. Panels C and D represent eligibility and outcomes for tafenoquine and daily primaquine, with those who are considered ineligible for tafenoquine then considered for primaquine eligibility. Abbreviations: G6PD, glucose-6-phosphate-dehydrogenase; PQ, Primaquine; Hb, Hemoglobin; TQ, Tafenoquine. * No other treatment eligibility criteria (e.g., age, anemia status, pregnancy status) were considered as part of the calculation.