CYP2B6 genetic variants are associated with nevirapine pharmacokinetics and clinical response in HIV-1-infected children

AIDS. 2007 Oct 18;21(16):2191-9. doi: 10.1097/QAD.0b013e3282ef9695.

Abstract

Background: Cytochrome P450 2B6 (CYP2B6)-G516T genotype is associated with altered activity of hepatic CYP2B6 and efavirenz pharmacokinetics, but the relationship between the CYP2B6-G516T genotype and nevirapine (NVP) pharmacokinetics in plasma and cerebrospinal fluid (CSF) is limited.

Methods: In 126 children who received NVP and protease inhibitors from PACTG 366 and 377 cohorts, CYP2B6 and ATP-binding cassette, sub-family B, member 1 (ABCB1) gene polymorphisms were analyzed using real-time PCR. Plasma NVP pharmacokinetics and clinical data were collected and levels of NVP in CSF were evaluated in children with HIV-related neurologic diseases.

Results: NVP oral clearance in children with the CYP2B6-516-T/T genotype (homozygous variant, n = 14) was 1.6 l/h per m2, which was significantly decreased compared to 2.3 l/h per m2 in those with the -G/G (wild type, n = 49, P = 0.002) and 2.1 l/h per m2 in those with the -G/T genotype (heterozygous variants, n = 63, P = 0.008). Furthermore, children with the -T/T genotype had a significant increase in CD4+ T-cell percentage (+9.0%) compared with those with the -G/G (+3.2%, P = 0.01) and -G/T genotype (+5.0%, P = 0.04) from baseline to week 12. The same trend continued at week 24. Although ABCB1-C3435T genotypes did not affect plasma NVP pharmacokinetics (P = 0.39), the NVP CSF: plasma ratios were significantly higher in children with the ABCB1-3435-C/T or -T/T genotypes (0.62, n = 9) in comparison with those with the ABCB1-3435-C/C genotype (0.43, n = 5) (P = 0.01).

Conclusions: The CYP2B6-G516T genotype alters NVP pharmacokinetics and the immunologic response to NVP-containing HAART regimens in children. These data suggest that the CYP2B6-G516T is an important genetic variant that alters the pharmacokinetics and response to HAART regimens containing NVP.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics
  • Alkynes
  • Antiretroviral Therapy, Highly Active
  • Aryl Hydrocarbon Hydroxylases / genetics*
  • Benzoxazines / therapeutic use
  • CD4 Lymphocyte Count
  • Child, Preschool
  • Cyclopropanes
  • Cytochrome P-450 CYP2B6
  • Female
  • Gene Frequency
  • Genotype
  • HIV Infections / cerebrospinal fluid
  • HIV Infections / drug therapy
  • HIV Infections / genetics*
  • HIV Protease Inhibitors / therapeutic use
  • HIV-1*
  • Humans
  • Male
  • Multivariate Analysis
  • Nevirapine / cerebrospinal fluid
  • Nevirapine / pharmacokinetics*
  • Nevirapine / therapeutic use
  • Oxidoreductases, N-Demethylating / genetics*
  • Polymorphism, Genetic*
  • Retrospective Studies
  • Reverse Transcriptase Inhibitors / blood
  • Reverse Transcriptase Inhibitors / pharmacokinetics*
  • Reverse Transcriptase Inhibitors / therapeutic use
  • Treatment Outcome

Substances

  • ABCB1 protein, human
  • ATP Binding Cassette Transporter, Subfamily B
  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Alkynes
  • Benzoxazines
  • Cyclopropanes
  • HIV Protease Inhibitors
  • Reverse Transcriptase Inhibitors
  • Nevirapine
  • Aryl Hydrocarbon Hydroxylases
  • CYP2B6 protein, human
  • Cytochrome P-450 CYP2B6
  • Oxidoreductases, N-Demethylating
  • efavirenz