Abstract
Although Plasmodium vivax relapses are classically associated with hypnozoite activation, it has been proposed that a proportion of these cases are due to primaquine (PQ) treatment failure caused by polymorphisms in cytochrome P-450 2D6 (CYP2D6). Here, we present evidence that CYP2D6 polymorphisms are implicated in PQ failure, which was reinforced by findings in genetically similar parasites, and may explain a number of vivax relapses. Using a computational approach, these polymorphisms were predicted to affect the activity of CYP2D6 through changes in the structural stability that could lead to disruption of the PQ-enzyme interactions. Furthermore, because PQ is co-administered with chloroquine (CQ), we investigated whether CQ-impaired metabolism by cytochrome P-450 2C8 (CYP2C8) could also contribute to vivax recurrences. Our results show that CYP2C8-mutated patients frequently relapsed early (<42 days) and had a higher proportion of genetically similar parasites, suggesting the possibility of recrudescence due to CQ therapeutic failure. These results highlight the importance of pharmacogenetic studies as a tool to monitor the efficacy of antimalarial therapy.
Highlights
Several factors have highlighted the importance of malaria caused by Plasmodium vivax, such as the spread of parasites that are resistant to available drugs [1]
To investigate whether variants of the cytochrome P-450 2D6 enzyme are associated with an increased risk of P. vivax relapse, five polymorphisms known to be responsible for low or null metabolic activity of CYP2D6 were analyzed in 46 patients who had relapsed P. vivax infections
Many factors may contribute to the success of drug therapies, including adherence to the prescribed therapy, correct or optimal dosing, general health status of the patient, interactions with other drugs, and the contribution of the parasite genetics related to drug resistance
Summary
Several factors have highlighted the importance of malaria caused by Plasmodium vivax, such as the spread of parasites that are resistant to available drugs [1]. The concept of vivax malaria as a benign disease has changed due to the description of severe cases and even deaths [2, 3]. Dormant forms of the parasite that reside in the liver, i.e., hypnozoites, act as a reservoir for the disease and have hindered the control of malaria caused by P. vivax. It has been estimated that relapses cause between 50 and 80% of P. vivax infections in children living in areas with hyperendemic transmission [4,5,6].
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