Differential impact of Tafenoquine and Primaquine on Plasmodium vivax recurrence: the role of CYP2D6 variants.

Malaria, particularly by Plasmodium vivax, remains a significant public health challenge in endemic regions. P. vivax has the dormant liver-stage hypnozoites that can reactivate, causing relapses, even after the initial blood-stage infection has been cleared. The prevention of these relapses hinges on the use of 8-aminoquinolines such as primaquine (PQ) and tafenoquine (TQ). However, the efficacy of these treatments is associated with Cytochrome P450 2D6 (CYP2D6) activity, which influences drug metabolism. This case-control study aimed to evaluate the relationship between CYP2D6 activity and the efficacy of TQ and PQ in preventing P. vivax relapses. Patients with P. vivax malaria were included in a nested case-control cohort study conducted at the Fundação de Medicina Tropical Dr. Heitor Vieira Dourado (Manaus, AM, Brazil). Participants were classified as cases (recurrent malaria within 180 days) or controls (patients without recurrence). They were treated with PQ or TQ. Epidemiological data were collected from participants, and blood samples were obtained for CYP2D6 genotyping by real-time PCR. The results showed that CYP2D6 polymorphisms did not affect TQ efficacy (P = 0.172). However, participants treated with PQ had a higher risk of recurrence until six months (P = 0.016). Those with a predicted intermediate or poor metabolizer phenotype (gIM + gPM) were more likely to experience recurrence compared to normal metabolizers (gNM) (P = 0.036). Our findings indicate that CYP2D6 does not impact the efficacy of TQ, whereas P. vivax recurrence is associated with predicted metabolic phenotype, with increased risk among patients treated with PQ, suggesting that CYP2D6 variability influences treatment response, particularly in intermediate/poor metabolizers.