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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.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec002\">\n                    <jats:title>Methods and findings<\/jats:title>\n                    <jats:p>\n                      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\n                      <jats:italic>P. vivax<\/jats:italic>\n                      recurrence within 6 months after treatment with chloroquine and PQ (total dose, 3.5\u2009mg\/kg). We analyzed community-wide\n                      <jats:italic>P. vivax<\/jats:italic>\n                      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\n                      <jats:italic>P. vivax<\/jats:italic>\n                      -infected cohort participants\n                      <jats:italic>,<\/jats:italic>\n                      those with null\/low CYP2D6 activity (AS \u2264 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 &gt; 1.0 (hazard ratio\u2009=\u20092.22,\n                      <jats:italic>P<\/jats:italic>\n                      \u2009=\u20090.004). 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.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec003\">\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      Amazonians with an AS \u2264 0.25, but not necessarily those with intermediate CYP2D6 activity, have a greater risk of recurrence after a PQ-treated\n                      <jats:italic>P. vivax<\/jats:italic>\n                      infection and require alternative relapse suppression regimens for the radical cure of vivax malaria.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1371\/journal.pntd.0014160","type":"journal-article","created":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T17:40:19Z","timestamp":1774633219000},"page":"e0014160","update-policy":"https:\/\/doi.org\/10.1371\/journal.pntd.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Reduced cytochrome P-450 (CYP) 2D6 activity and Plasmodium vivax malaria risk in Amazonians: A retrospective, population-based cohort study"],"prefix":"10.1371","volume":"20","author":[{"given":"Rodrigo M.","family":"Corder","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria Carolina S. 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