Reduced cytochrome P-450 (CYP) 2D6 activity and Plasmodium vivax malaria risk in Amazonians: a retrospective, population-based cohort study
File(s)
Published version (uncorrected proof)
Author(s)
Type
Journal Article
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.
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.
Editor(s)
Markus, Miles B
Date Issued
2026-03-27
Date Acceptance
2026-03-18
Citation
PLoS Neglected Tropical Diseases, 2026, 20 (3)
ISSN
1935-2727
Publisher
Public Library of Science (PLoS)
Journal / Book Title
PLoS Neglected Tropical Diseases
Volume
20
Issue
3
Copyright Statement
© 2026 Corder et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
License URL
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/41894411
PII: PNTD-D-25-01961
Subjects
Mâncio Lima Cohort Study Working Group
Publication Status
Published online
Coverage Spatial
United States
Article Number
e0014160
Date Publish Online
2026-03-27