Variation in Glucose-6-Phosphate Dehydrogenase activity following acute malaria

Abstract

Primaquine and tafenoquine are the only licensed drugs with activity against Plasmodium vivax hypnozoites but cause haemolysis in patients with glucose–6–phosphate dehydrogenase (G6PD) deficiency. Malaria also causes haemolysis, leading to the replacement of older erythrocytes with low G6PD activity by reticulocytes and young erythrocytes with higher activity. Aim of this study was to assess the impact of acute malaria on G6PD activity. Selected patients with uncomplicated malaria were recruited in Bangladesh (n = 87), Indonesia (n = 75), and Ethiopia (n = 173); G6PD activity was measured at the initial presentation with malaria and a median of 176 days later (range 140 to 998) in the absence of malaria. Among selected participants (deficient participants preferentially enrolled in Bangladesh but not at other sites) G6PD activity fell between malaria and follow up by 79.1% (95%CI: 40.4 to 117.8) in 6 participants classified as deficient (<30% activity), 43.7% (95%CI: 34.2 to 53.1) in 39 individuals with intermediate activity (30% to <70%), and by 4.5% (95%CI: 1.4 to 7.6) in 290 G6PD normal (≥70%) participants. In Bangladesh and Indonesia G6PD activity was significantly higher during acute malaria than when the same individuals were retested during follow up (40.9% (95%CI: 33.4–48.1) and 7.4% (95%CI: 0.2 to 14.6) respectively), whereas in Ethiopia G6PD activity was 3.6% (95%CI: -1.0 to -6.1) lower during acute malaria. The change in G6PD activity was apparent in patients presenting with either P. vivax or P. falciparum infection. Overall, 66.7% (4/6) severely deficient participants and 87.2% (34/39) with intermediate deficiency had normal activities when presenting with malaria. These findings suggest that G6PD activity rises significantly and at clinically relevant levels during acute malaria. Prospective case-control studies are warranted to confirm the degree to which the predicted population attributable risks of drug induced haemolysis is lower than would be predicted from cross sectional surveys. Author summary Plasmodium vivax forms dormant liver stages in the human host that reactivate weeks to months after the first infection and cause significant morbidity and mortality in affected populations. The group of 8-aminoquinolines are the only class of licensed drugs that remove these liver stages from the human host but are contra-indicated in patients with low activities of the glucose-6-phosphate dehydrogenase enzyme (G6PD). The WHO therefore recommends testing G6PD activity prior to treatment to exclude individuals with low activities from standard treatment. We enrolled 335 patients with malaria in Bangladesh, Indonesia, and Ethiopia and measured G6PD activity in all participants. All participants were followed up and a second G6PD measurement was collected between 6 and 33 months after enrolment if participants were free of malaria. When comparing both measurements, G6PD activity was 10% higher during malaria. The increase in G6PD activity during malaria is probably triggered by the Plasmodium infection, the observed change in G6PD activity may alter the risk profile of standard malaria treatment with 8-aminoquinolines.