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Multiple genetic variants predict steady-state nevirapine clearance in HIV-infected Cambodians

Julie Bertrand1, Monidarin Chou, Danielle M Richardson

  • 1UMR 738, French National Institute of Health and Medical Research, Paris Diderot University, Paris, France. j.bertrand@ucl.ac.uk

Pharmacogenetics and Genomics
|October 30, 2012
PubMed

Insights

Several CYP2B6 gene variants, including CYP2B6 516G→T, independently influence nevirapine clearance in HIV-infected Cambodians. Combining these genetic factors improves predictions of nevirapine clearance variability.

Area of Science:

  • Pharmacogenetics
  • HIV/AIDS Treatment
  • Drug Metabolism

Background:

  • Interindividual variability in nevirapine clearance exists among HIV-infected Cambodians.
  • Previous studies identified CYP2B6 516G→T (CYP2B6*6) as a partial predictor of this variability.

Purpose of the Study:

  • To investigate additional genetic variants that predict steady-state nevirapine clearance in HIV-infected Cambodian patients.
  • To enhance the prediction model for nevirapine clearance by incorporating multiple genetic factors.

Main Methods:

  • Analysis of genetic polymorphisms in ABCB1, CYP2A6, CYP2B6, CYP2C19, CYP3A4, CYP3A5, and NR1I2 in the Phnom Penh ESTHER cohort.
  • Estimation of mean individual nevirapine clearance from a population model using drug concentrations at 18 and 36 months.
  • Application of bivariate and multivariate linear regression to identify associations between genetic variants and nevirapine clearance.

Main Results:

  • CYP2B6 516G→T was significantly associated with lower nevirapine clearances (P=3.5×10⁻⁶).
  • Independent associations were found with CYP2B6 rs7251950 and CYP2B6 rs2279343.
  • A combined model including CYP2B6 516G→T, rs7251950, and rs2279343 explained 11% of interindividual variability in nevirapine clearance.

Conclusions:

  • Multiple CYP2B6 polymorphisms are independently associated with nevirapine clearance in HIV-infected Cambodians.
  • Incorporating several genetic polymorphisms in combination improves the prediction of nevirapine clearance variability.
Abstract

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