Tafenoquine and G6PD: a primer for clinicians

Abstract

Background: Tafenoquine, an 8-aminoquinoline, is now indicated for causal prophylaxis against all human malarias and as radical curative (anti-relapse) treatment against Plasmodium vivax and Plasmodium ovale. As with other 8-aminoquinolines, tafenoquine causes hemolysis in individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency (hemizygous males and homozygous females) and is contraindicated in this population. Those with intermediate G6PD activity (heterozygous females) are also at risk for hemolysis. Awareness of how to prescribe tafenoquine in relation to G6PD status is needed so it can be used safely.

Methods: A standard literature search was performed on varying combinations of the terms tafenoquine, Arakoda, Kodatef, Krintafel, Kozenis, primaquine, G6PD deficiency, malaria prophylaxis and radical cure. The data were gathered and interpreted to review how tafenoquine should be prescribed in consideration of the G6PD status of an individual and traveller.

Results: Tafenoquine should only be given to those with G6PD activity >70% of the local population median. Qualitative G6PD tests are sufficient for diagnosing G6PD deficiency in males. However, in females quantitative G6PD testing is necessary to differentiate deficient, intermediate and normal G6PD statuses. Testing for G6PD deficiency is mandatory before tafenoquine prescription. Measures can be taken to avoid tafenoquine administration to ineligible individuals (i.e. due to G6PD status, age, pregnancy and lactation). Primaquine is still necessary for some of these cases. This review provides actions that can be taken to diagnose and manage hemolysis when tafenoquine is given inadvertently to ineligible individuals.

Conclusion: Attention to G6PD status is required for safe prescription of tafenoquine. A high index of suspicion is needed if hemolysis occurs. Clinicians should seek evidence-based information for the management and treatment of iatrogenicy hemolysis caused by 8-aminoquinolines.

Keywords: 8-aminoquinolines; causal prophylaxis; glucose-6-phosphate dehydrogenase deficiency; malaria prophylaxis; presumptive anti-relapse treatment (PART); radical cure; tafenoquine.

Figure 1

The sexual gametocytes transmit infection and complete the life cycle from humans to mosquitoes. 2–6: The sporogonic stages are where gametes form oocysts in the mosquito mid-gut then proceed to become sporozoites in the salivary glands. 7: The infective sporozoites are inoculated into humans during a mosquito bite.8A and 9A: Sporozoites travel to the liver and pre-erythrocytic schizogony occurs here. The resulting tissue schizonts rupture and releases merozoites into the bloodstream; causal prophylactic drugs act here. 8B and 9B: In P. vivax and P. ovale, some sporozoites will separately differentiate into dormant hypnozoites. When triggered to ‘wake up’, the latent hypnozoites will undergo pre-erythrocytic schizogony; ‘radical cure’ targets this life-cycle stage. 10: Asexual intraerythrocytic schizogony is the blood stage of infection when symptoms occur and where blood schizontocidal drugs act.This figure was reproduced and modified from Figure 1 in Peters, 1999, ‘based on an original figure by Andrea Darlow’ under SAGE publications licence number 4519190237646.

Figure 2

The solid black line indicates the threshold for diagnosing G6PD deficiency (≲30% of the population median). Figure 2a shows 2 distinct populations in males (G6PD normal and deficient). Figure 2b shows that some females will have intermediate G6PD activity as seen by the continuous distribution. This figure was adapted from Oo et al.