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Polymorphisms in cytochrome P450 are associated with extensive efavirenz pharmacokinetics and CNS toxicities in an HIV cohort in Botswana

The Pharmacogenomics Journalvolume 18pages678688 (2018) | Download Citation

Abstract

Inter-individual variability in efavirenz (EFV) pharmacokinetics and dynamics is dominantly driven by the polymorphism in cytochrome P450 (CYP) isoenzyme 2B6 516G>T. We hypothesized that additional CYP polymorphisms mediate the relationship between CYP2B6 516G>T, EFV metabolism, and clinical events. We investigated 21 SNPs in 814 HIV-infected adults initiating EFV-based therapy in Botswana for population pharmacokinetics, CNS toxicities, and treatment outcomes. Two SNPs (rs28399499 and rs28399433) showed reduced apparent oral EFV clearance. Four SNPs (rs2279345, rs4803417, rs4802101, and rs61663607) showed extensive clearance. Composite CYP2B-mediated EFV metabolism was significantly associated with CNS toxicity (p = 0.04), with extensive metabolizers reporting more and slow and very slow metabolizers reporting less toxicity after 1 month compared to intermediate metabolizers. Composite CYP2B6 metabolism was not associated with composite early treatment failure. In conclusion, our data suggest that CNS-related toxicities might not be solely the result of super-therapeutic parent EFV concentrations in HIV-infected individuals in patients of African ancestry.

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Acknowledgements

We thank the medical staff at the Bontleng, BH3, Broadhurst Traditional Area, Morwa, Nkoyaphiri, Phase II, and Village Infectious Diseases Care Clinics for their assistance with carrying out this study. We also thank the Ministry of Health of Botswana for supporting the project and the patients who participated.

Author contributions

MV wrote the article; RG, GPB, MV, BLS, and MM designed the research; MV, SLB, AFZ, MRG, BR, XH, APS, MM, BLS, GPB, RA, and RG performed the research; MV analyzed the data. The final manuscript reviewed and approved by all authors.

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Affiliations

  1. Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA

    • Marijana Vujkovic
    • , Xiaoyan Han
    • , Gregory P. Bisson
    •  & Robert Gross
  2. Department of Epidemiology and Biostatistics, Dornsife School of Public Health, Drexel University, Philadelphia, PA, USA

    • Scarlett L. Bellamy
  3. Department of Anesthesiology and Critical Care Medicine, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA

    • Athena F. Zuppa
    • , Ganesh S. Moorthy
    •  & Andrew P. Steenhoff
  4. Metrum Research Group, Tariffville, CT, USA

    • Marc R. Gastonguay
  5. Botswana UPenn Partnership, Gaborone, Botswana

    • Bakgaki Ratshaa
  6. Division of Infectious Diseases, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA

    • Bakgaki Ratshaa
  7. Faculty of Medicine, University of Botswana, Gaborone, Botswana

    • Mosepele Mosepele
  8. Rutgers Biomedical and Health Sciences, Newark, NJ, USA

    • Brian L. Strom
  9. Department of Medicine (Infectious Diseases), University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA

    • Gregory P. Bisson
    •  & Robert Gross
  10. Division of Oncology, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA

    • Richard Aplenc

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The authors declare that they have no conflict of interest.

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Correspondence to Robert Gross.

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https://doi.org/10.1038/s41397-018-0028-2