Reduced cytochrome P-450 (CYP) 2D6 activity and Plasmodium vivax malaria risk in Amazonians: A retrospective, population-based cohort study

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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.
Funding Information
  • Fundação de Amparo à Pesquisa do Estado de São Paulo (2016/18740-9)
  • Fundação de Amparo à Pesquisa do Estado de São Paulo (2022/11963-3)
  • Fundação de Amparo à Pesquisa do Estado de São Paulo (2024/04280-2)
  • National Institute of Allergy and Infectious Diseases (U19 AI089681)
  • Fundação para a Ciência e a Tecnologia (UID/04413/2020)
  • Fundação para a Ciência e a Tecnologia (LA-REAL LA/P/0117/2020)
  • Fundação de Amparo à Pesquisa do Estado de Minas Gerais (APQ-00516-21)
  • Conselho Nacional de Desenvolvimento Científico e Tecnológico
  • Conselho Nacional de Desenvolvimento Científico e Tecnológico
  • Eric and Wendy Schmidt AI in Science Global Faculty fellowship
  • Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (Finance Code 001)
  • Fundação de Amparo à Pesquisa do Estado de São Paulo (2024/10682-6))
  • Fundação de Amparo à Pesquisa do Estado de São Paulo (2023/15369-1)
  • Fundação de Amparo à Pesquisa do Estado de São Paulo (2018/03902-9)

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