Reduced cytochrome P-450 (CYP) 2D6 activity and Plasmodium vivax malaria risk in Amazonians: A retrospective, population-based cohort study
Year: 2026
Type: article
Study design: Observational Study
Abstract: BACKGROUND: Primaquine (PQ) is the only widely available drug that eliminates latent hypnozoites, thereby preventing relapses of Plasmodium vivax malaria. Because PQ biotransformation mediated by the cytochrome P-450 (CYP) isoenzyme CYP2D6 is required for therapeutic activity, patients with reduced CYP2D6 activity can experience relapse despite treatment. The minimum level of CYP2D6 activity for adequate anti-relapse PQ efficacy is unknown. METHODS AND FINDINGS: We conducted a retrospective, population-based cohort study in the main malaria hotspot of Brazil. We fitted time-to-event data from cohort participants who experienced vivax malaria, using Cox proportional hazards models, to explore how genotype-determined CYP2D6 activity, expressed as activity scores (AS), modulates the risk of P. vivax recurrence within 6 months after treatment with chloroquine and PQ (total dose, 3.5 mg/kg). We analyzed community-wide P. vivax malaria incidence data, using a multivariable negative binomial regression model, to quantify the impact of reduced CYP2D6 activity on the overall risk of vivax malaria, whether from relapses or new infections. Among 466 P. vivax-infected cohort participants, those with null/low CYP2D6 activity (AS ≤ 0.25), but not participants with intermediate CYP2D6 activity (AS from 0.5 to 1.0), had twice the risk of recurrence compared to an AS > 1.0 (hazard ratio = 2.22, P = 0.004). However, vivax malaria incidence did not differ significantly across CYP2D6 activity levels during 5 years of follow-up of 997 Amazonians exposed to intense transmission (mean, 26.6 vivax malaria cases/100 person-years). These findings suggest that the excess of relapses among people with severely reduced CYP2D6 activity adds relatively little to the overall burden of vivax malaria episodes. CONCLUSION: Amazonians with an AS ≤ 0.25, but not necessarily those with intermediate CYP2D6 activity, have a greater risk of recurrence after a PQ-treated P. vivax infection and require alternative relapse suppression regimens for the radical cure of vivax malaria.
Source: PLoS neglected tropical diseases
Language: English
Topic: Malaria Research and Control
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,670
Funders: Yale University, Universidade Federal do Acre, Fundação de Amparo à Pesquisa do Estado de São Paulo, Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, Conselho Nacional de Desenvolvimento Científico e Tecnológico, Fundação de Amparo à Pesquisa do Estado de Minas Gerais, Universidade de São Paulo, Faculdade de Medicina de São José do Rio Preto, Fundação Oswaldo Cruz, National Institutes of Health, Fundação para a Ciência e a Tecnologia, National Institute of Allergy and Infectious Diseases
Awards: G1426168670, G159015987, G1868203827, G1982445703, G2032552029, G2845895381, Amazonian Center of Excellence in Malaria Research, Translação e Inovação para a Saúde Global, Scientific bases for residual malaria elimination in the Brazilian Amazon, G4198127487, FARMACOGENÉTICA NA MALÁRIA: ELUCIDANDO FATORES GENÉTICOS ASSOCIADOS À FALHA TERAPÊUTICA NA MALÁRIA POR PLASMODIUM VIVAX, Individual variation in malaria risk: causes and consequences in Amazonian populations, G7026247316, G8558890345, Exploring the dual role of CD98hc in human erythropoiesis and Vivax Malaria, G8955364043
OpenAlex ID: W7141545110