Linked-evidence modelling of qualitative G6PD testing to inform low- and intermediate-dose primaquine treatment for radical cure of Plasmodium vivax

Background: Radical cure of Plasmodium vivax infections is key to the control of vivax malaria. However, the standard doses of 8-aminoquinoline drugs used for radical cure can cause severe haemolysis in G6PD-deficient patients. The availability of near-patient G6PD tests could increase use of primaquine (PQ), however direct evidence of the impacts that G6PD testing has on downstream patient outcomes, such as haemolysis and recurrence is lacking. Methodology/Principle findings: A linked-evidence model was created to investigate changes in the number of severe haemolysis events and P. vivax recurrences within 6 months of treatment when qualitative G6PD testing was used to guide PQ treatment (0.25mg/kg/day for 14 days and 0.5mg/kg/day for 7 days), compared to prescribing 14-day PQ with no G6PD testing. In the model patients identified as G6PD-deficient received 8-week PQ (0.75mg/kg/week). The model was used to simulate scenarios with 1%, 5% and 10% prevalence of G6PD-deficiency (G6PDd) in theoretical populations of 10,000 male and female P. vivax patients and initially assumed 100% adherence to the prescribed PQ regiment. Results illustrate that G6PD testing to guide the 14-day PQ regiment reduced severe haemolysis by 21–80% and increased recurrences by 3–6%, compared to applying the 14-day PQ regiment without G6PD testing. Results for the 7-day PQ regiment informed by G6PD testing were mixed, dependent on G6PDd prevalence and sex. When adherence to the PQ regiments was less than perfect the model predicted reductions in the number of recurrences at all prevalence levels, provided adherence to 7-day PQ was 5–10% higher than adherence to the 14-day regiment. Conclusions/Significance: Introduction of G6PD testing to guide PQ treatment reduces severe haemolysis events for the 14-day regiment, and the 7-day regiment in higher G6PDd prevalence settings, compared to use of 14-day PQ without G6PD testing when all patients adhere to the prescribed PQ treatment. At a population level, there were increases in recurrences, but this could be resolved when the 7-day regiment was used and had superior adherence compared to the 14-day regiment. Author summary: To eliminate vivax malaria treatment is required that cures the blood infection and also kills any dormant parasites in the liver (called hypnozoites). Unfortunately, drugs currently available to treat hypnozoites such as primaquine can cause severe haemolysis when given to patients who have glucose-6-phosphate dehydrogenase (G6PD) deficiency, a common human enzyme polymorphism. The author created a mathematical model that compares the number of severe haemolysis events and vivax recurrences within 6 months of treatment in a theoretical population when qualitative G6PD tests are used to guide primaquine treatment versus the use of primaquine without consideration of the G6PD status of the patient. The results demonstrate that adding G6PD tests into the clinical pathway can reduce the number of severe haemolysis events, but may increase the number of recurrences, with specific results determined by the prevalence of G6PD deficiency, the dosing regiment and adherence to the prescribed primaquine treatment.