Cytochrome P450 2D6 (CYP2D6) and glucose-6-phosphate dehydrogenase (G6PD) genetic variations in Thai vivax malaria patients: Implications for 8-aminoquinoline radical cure

Abstract

Background Primaquine and tafenoquine are the only licensed drugs that effectively kill the hypnozoite stage and are used to prevent Plasmodium vivax malaria relapse. However, both primaquine and tafenoquine can cause acute hemolysis in glucose-6-phosphate dehydrogenase (G6PD)-deficient people with varying degrees of severity depending on G6PD variants. Additionally, primaquine efficacy against malaria parasites was decreased in individuals with impaired cytochrome P450 2D6 (CYP2D6) activity due to genetic polymorphisms. This study aimed to characterize G6PD and CYP2D6 genetic variations in vivax malaria patients from Yala province, a malaria-endemic area along the Thai–Malaysian border, and determine the biochemical properties of identified G6PD variants. Methodology/Principle findings Multiplexed high-resolution melting assay and DNA sequencing detected five G6PD variants, including G6PD Kaiping, G6PD Vanua Lava, G6PD Coimbra, G6PD Mahidol, and G6PD Kerala-Kalyan. Biochemical and structural characterization revealed that G6PD Coimbra markedly reduced catalytic activity and structural stability, indicating a high susceptibility to drug-induced hemolysis. While Kerala-Kalyan had minor effects, it is possible to develop mild adverse effects when receiving radical treatment. CYP2D6 genotyping was performed using long-range PCR and DNA sequencing, and the phenotypes were predicted using the combination of allelic variants. Decreased and no-function alleles were detected at frequencies of 53.4% and 14.2%, respectively. The most common alleles were CYP2D*36+*10 (25.6%), *10 (23.9%), and *1 (22.2%). Additionally, 51.1% of the intermediate metabolizers showed CYP2D6*10/*36+*10 as the predominant genotype (15.9%). Conclusions/Significance Our findings provide insights about genetic variations of G6PD and CYP2D6 in 88 vivax malaria patients from Yala, which may influence the safety and effectiveness of radical treatment. Optimization of 8-aminoquinoline administration may be required for safe and effective treatment in the studied population, which could be a significant challenge in achieving the goal of eliminating malaria.

Influence of CYP2C19, CYP2D6 and CYP3A4 genetic variants on the biological effect of malaria treatment with primaquine in G6PD- deficient and G6PD-normal patients

“…A study with 88 patients infected with vivax malaria from the province of Yala. in Thailand, identi ed that about 51.1% of these patients were intermediate metabolizers of CYP2D6 and had reduced enzymatic activity, thus putting them at risk of therapeutic failure and reinforcing the need to implement G6PD and CYP2D6 testing as an aid in the use of 8-aminoquinolines for the elimination of vivax malaria (14,35). In gUM, the clinical outcome with PQ remains undetermined (14); however, it is suggested that the CYP2D6 ultra-rapid phenotype is less susceptible to recurrence and PQ failure (18).…”

Association of CYP2C19, CYP2D6 and CYP3A4 Genetic Variants on Primaquine Hemolysis in G6PD-Deficient Patients

“…In gIMs, the active metabolites may not achieve the desired response, and the clinical picture would depend on the severity of the CYP2D6 enzymatic alteration, body weight and the total dose administered. A study with 88 patients infected with vivax malaria from Thailand identified that about 51.1% of these patients were intermediate metabolizers of CYP2D6 and had reduced enzymatic activity, thus putting them at risk of therapeutic failure and reinforcing the need to implement G6PD and CYP2D6 testing as an aid in the use of 8-aminoquinolines for the elimination of vivax malaria [ 15 , 35 ]. In gUM, the clinical outcome with PQ remains undetermined [ 17 ]; however, it is suggested that the CYP2D6 ultra-rapid phenotype is less susceptible to recurrence and PQ failure [ 21 ].…”

“…This study had some limitations, such as the low number of patients included, due to the scarcity of well-described severe hemolytic cases followed up with exams and updated phone contact record; clinical and laboratory data were collected retrospectively. The future implementation of pharmacogenetic testing for better patient management is needed, The implementation of pharmacogenetic tests would help in better patient management, as the metabolism of PQ by different enzymatic phenotypes of CYPs can contribute to severe hemolysis, thus increasing the risks of hospitalizations [ 5 , 21 , 34 , 35 ], in addition to the importance of diagnosing G6PDd before treatment with any of the 8-aminoquinolines [ 36 , 37 ].…”