Kinetics of glucose-6-phosphate dehydrogenase (G6PD) activity during Plasmodium vivax infection: implications for early treatment of radical malaria | Malaria Magazine

This study showed that the level of G6PD activity varies between patients with P. vivax infection, but not over time in the same person (from day 1 to day 28 after starting chloroquine or ACT). Importantly, none of the patients with normal G6PD activity during the initial phase of the malaria episode (day 1) were categorized as having G6PD deficiency at day 14. Therefore, G6PD activity at baseline (day 1 ) could be used as a reference value to determine detect G6PD deficiency and start primaquine treatment early during P. vivax infection.

These results are consistent with the literature. The study by Taylor et al.. (15) in Cambodian patients showed that no patient with G6PD deficiency was misclassified as having normal G6PD during an acute episode of P. vivax malaria. They found that in men with G6PD deficiency, G6PD activity never reached the normal range and baseline G6PD activity was not affected by fever.

Furthermore, the present results show a direct link between G6PD activity and reticulocytosis, in agreement with the literature. In fact, in the same individual, G6PD activity varies depending on the age of the erythrocyte population. Specifically, G6PD activity peaks in reticulocytes and young red blood cells, and then declines as erythrocytes age (2, 14, 18).

Despite theoretical variations in G6PD activity during hemolysis, the present study showed that in each patient, G6PD activity remained stable during a malaria episode. Several hypotheses can be formulated. Firstly, this study focused on a sample of patients infected with P. vivax only, with few severe cases (4%) and low hemolysis (19). Second, changes in G6PD activity associated with acute hemolysis may differ from one variant to another. The African variant (A-), predominant in South America, causes mild deficiency and mild hemolysis in deficient individuals compared to other variants (8, 10, 20).

Among the 210 patients included in the prevalence analysis, none had G6PD activity <10% and 1.4% of patients had G6PD activity between 10 and 30%. However, because G6PD deficiency weakens red blood cells and provides protection against malaria (18, 21), the true prevalence of people with G6PD deficiency in the general population may have been underestimated (20). However, this finding is consistent with literature data showing a low prevalence of G6PD deficiency in the Americas (< 2%) (10, 22).

Law et al. (23). measured G6PD activity in patients from Bangladesh, Indonesia, and Ethiopia at the time of malaria infection and 6 to 33 months after infection. They found that G6PD activity was significantly higher during the malaria episode. They concluded that an individual’s G6PD status is not static and therefore the risk of drug-induced hemolysis in malaria cannot be predicted by enzyme activity far from the acute episode (i.e., during aparasitaemia). In another study conducted in Bangladesh, Ley et al. (24), showed that G6PD activity was higher in people with acute malaria than without it. Therefore, they suggested that 8-aminoquinoline treatment may be safer than expected in patients with clinical malaria.

The present study has several important limitations. First, its design (retrospective descriptive study) may involve several biases due to missing data. Furthermore, we did not include a control group (i.e., malaria-free controls) to compare changes in G6PD activity in the absence of malaria infection. This is important given the physiological variation in G6PD activity within a single day (25). Another limitation is the small sample size and, in particular, the small percentage of patients with G6PD deficiency. This is explained by the absence of patients with more than one G6PD test result before 2018 and the drastic decrease in malaria cases in our territory since 2020. In addition, it would have been important to compare G6PD activity with hexokinase activity. or pyruvate kinase. In fact, G6PD samples are shipped from French Guiana to mainland France and variable transit times can alter sample quality and affect results. However, these tests are not routinely performed and these data were not available. Finally, routine patient follow-up did not include a G6PD assay several months after the malaria episode, although it would have been very useful to determine the true baseline levels in the included patients (23).

Measurement of G6PD activity in the initial phase of a P. vivax The malaria episode could have a considerable impact in French Guiana. Using the measurement of G6PD activity on day 1 (instead of day 14) as a reference value, radical treatment with 8-aminoquinolines (primaquine or tafenoquine) could be started at least 14 days before, around the day 3 to day 7 instead of day 21. In the case of initial deficiency, the quantification of G6PD activity could be repeated in the aparasitemic phase and compared with a pyruvate kinase test to confirm or not the deficiency. In the present study, 30 patients were lost to follow-up before initiation of primaquine (i.e., 27% of the 113 patients in groups 1 and 2), a high proportion compared to the literature from neighboring countries ( 26, 27). This is a high percentage in view of the high incidence of P. vivax relapses (35% in this study), especially in the absence of radical treatment. Therefore, if clinical practice could be modified as proposed, it would be possible to avoid early relapses, reduce the number of patients lost to follow-up before initiation of primaquine, and decrease the risk of subsequent relapses. Reducing the incidence of relapses could have an impact on individual morbidity, but also on public health by reducing the number of hospitalizations, interindividual transmission and health care costs. However, this proposal needs to be confirmed in a prospective study with a control group to determine the safety of early introduction of primaquine.

This change in management could also have an impact on treatment adherence. Khanticul et al..(28) showed that 76.2% of patients with P. vivax malaria did not comply with antimalarial therapy. By starting primaquine earlier, total follow-up time would be reduced, which could contribute to improved adherence, especially in remote populations. A marketing authorization for tafenoquine, which is taken as a single dose (versus 14 days for primaquine), would also improve patient adherence and reduce the number of patients lost to follow-up before completing radical treatment. Several studies have demonstrated the efficacy and non-inferiority of tafenoquine compared to primaquine in patients without G6PD deficiency, but this molecule is not yet available in France (26, 29). These results are made even more relevant by the unexpected strong increase in new malaria cases in the Guiana Shield, particularly in the Brazilian state of Amapá and French Guiana, in 2023-2024 (30).

Optimization of radical treatment for P. vivax infections is essential to reduce parasite transmission and eradicate malaria. Early detection of G6PD deficiency and prompt administration of primaquine appear to be possible levers of action. Therefore, the development and validation of a tool for rapid quantitative assessment of G6PD activity is essential. It would drastically shorten the detection time of G6PD deficiency and the interval before initiation of radical treatment (Fig. 6) (31,32,33).

Finally, several studies suggest a synergy between primaquine and chloroquine (34,35,36,37). Therefore, implementation of rapid G6PD assays with early administration of primaquine, concomitantly with chloroquine treatment, could benefit the patient. This remains a hypothesis that needs to be confirmed.