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      Novel Insights into Plasmodium vivax Therapeutic Failure: CYP2D6 Activity and Time of Exposure to Malaria Modulate the Risk of Recurrence

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          Abstract

          Plasmodium vivax relapse is one of the major causes of sustained global malaria transmission. Primaquine (PQ) is the only commercial drug available to prevent relapses, and its efficacy is dependent on metabolic activation by cytochrome P450 2D6 (CYP2D6). Impaired CYP2D6 function, caused by allelic polymorphisms, leads to the therapeutic failure of PQ as a radical cure for P. vivax malaria. Here, we hypothesized that the host immune response to malaria parasites modulates susceptibility to P. vivax recurrences in association with CYP2D6 activity.

          ABSTRACT

          Plasmodium vivax relapse is one of the major causes of sustained global malaria transmission. Primaquine (PQ) is the only commercial drug available to prevent relapses, and its efficacy is dependent on metabolic activation by cytochrome P450 2D6 (CYP2D6). Impaired CYP2D6 function, caused by allelic polymorphisms, leads to the therapeutic failure of PQ as a radical cure for P. vivax malaria. Here, we hypothesized that the host immune response to malaria parasites modulates susceptibility to P. vivax recurrences in association with CYP2D6 activity. We performed a 10-year retrospective study by genotyping CYP2D6 polymorphisms in 261 malaria-exposed individuals from the Brazilian Amazon. The immune responses against a panel of P. vivax blood-stage antigens were evaluated by serological assays. We confirmed our previous findings, which indicated an association between impaired CYP2D6 activity and a higher risk of multiple episodes of P. vivax recurrence (risk ratio, 1.75; 95% confidence interval [CI], 1.2 to 2.6; P = 0.0035). An important finding was a reduction of 3% in the risk of recurrence (risk ratio, 0.97; 95% CI, 0.96 to 0.98; P < 0.0001) per year of malaria exposure, which was observed for individuals with both reduced and normal CYP2D6 activity. Accordingly, subjects with long-term malaria exposure and persistent antibody responses to various antigens showed fewer episodes of malaria recurrence. Our findings have direct implications for malaria control, since it was shown that nonimmune individuals who do not respond adequately to treatment due to reduced CYP2D6 activity may present a significant challenge for sustainable progress toward P. vivax malaria elimination.

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          Author and article information

          Journal
          Antimicrob Agents Chemother
          Antimicrob. Agents Chemother
          aac
          aac
          AAC
          Antimicrobial Agents and Chemotherapy
          American Society for Microbiology (1752 N St., N.W., Washington, DC )
          0066-4804
          1098-6596
          2 March 2020
          21 April 2020
          May 2020
          : 64
          : 5
          : e02056-19
          Affiliations
          [a ] Molecular Biology and Malaria Immunology Research Group, Instituto René Rachou, Fundação Oswaldo Cruz (FIOCRUZ), Belo Horizonte, Minas Gerais, Brazil
          [b ] Universidade Federal de Minas Gerais, Departamento de Engenharia de Produção, Belo Horizonte, Minas Gerais, Brazil
          [c ] Hospital Julio Muller, Universidade Federal de Mato Grosso, Cuiabá, Mato Grosso, Brazil
          [d ] Departamento de Análises Clínicas e Toxicológicas, Faculdade de Ciências Farmacêuticas, Universidade de São Paulo, São Paulo, Brazil
          Author notes
          Address correspondence to Luzia Helena Carvalho, luzia.carvalho@ 123456fiocruz.br , or Tais Nobrega Sousa, tais.sousa@ 123456fiocruz.br .

          Citation Silvino ACR, Kano FS, Costa MA, Fontes CJF, Soares IS, de Brito CFA, Carvalho LH, Sousa TN. 2020. Novel insights into Plasmodium vivax therapeutic failure: CYP2D6 activity and time of exposure to malaria modulate the risk of recurrence. Antimicrob Agents Chemother 64:e02056-19. https://doi.org/10.1128/AAC.02056-19.

          Author information
          https://orcid.org/0000-0002-6874-9427
          Article
          PMC7179649 PMC7179649 7179649 02056-19
          10.1128/AAC.02056-19
          7179649
          32122891
          40abba4c-6228-443e-b30d-6e071f1e1d93
          Copyright © 2020 American Society for Microbiology.

          All Rights Reserved.

          History
          : 11 October 2019
          : 8 December 2019
          : 24 February 2020
          Page count
          supplementary-material: 1, Figures: 4, Tables: 4, Equations: 0, References: 68, Pages: 14, Words: 10275
          Funding
          Funded by: Programa PrInt-Fiocruz-CAPES;
          Award Recipient :
          Funded by: Programa Estratégico de Apoio à Pesquisa em Saúde;
          Award Recipient :
          Funded by: Fundação de Amparo à Pesquisa do Estado de Minas Gerais (FAPEMIG Foundation), https://doi.org/10.13039/501100004901;
          Award Recipient :
          Funded by: MCTI | Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), https://doi.org/10.13039/501100003593;
          Award Recipient :
          Categories
          Epidemiology and Surveillance
          Custom metadata
          May 2020

          immune response,primaquine,cytochrome P-450,pharmacogenetics,treatment failure,recurrence, Plasmodium vivax ,malaria

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