A single-nucleotide polymorphism in CYP2B6 leads to >3-fold increases in efavirenz concentrations in plasma and hair among HIV-infected women

Monica Gandhi, Ruth M. Greenblatt, Peter Bacchetti, Chengshi Jin, Yong Huang, Kathryn Anastos, Mardge Cohen, Jack A. Dehovitz, Gerald B. Sharp, Stephen J. Gange, Chenglong Liu, Susan C. Hanson, Bradley Aouizerat

Research output: Contribution to journalArticle

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Abstract

Background. Efavirenz exhibits marked interindividual variability in plasma levels and toxicities. Prior pharmacogenetic studies usually measure exposure via single plasma levels, examine limited numbers of polymorphisms, and rarely model multiple contributors. We analyzed numerous genetic and nongenetic factors impacting short-term and long-term exposure in a large heterogeneous population of human immunodeficiency virus (HIV)-infected women. Methods. We performed 24-hour intensive pharmacokinetic studies in 111 women receiving efavirenz under actual-use conditions and calculated the area-under-the-concentration-time curve (AUC) to assess short-term exposure; the efavirenz concentration in hair was measured to estimate long-term exposure. A total of 182 single-nucleotide polymorphisms (SNPs) and 45 haplotypes in 9 genes were analyzed in relationship to exposure by use of multivariate models that included a number of nongenetic factors. Results. Efavirenz AUCs increased 1.26-fold per doubling of the alanine aminotransferase level and 1.23-fold with orange and/or orange juice consumption. Individuals with the CYP2B6 516TT genotype displayed 3.5-fold increases in AUCs and 3.2-fold increases in hair concentrations, compared with individuals with the TG/GG genotype. Another SNP in CYP2B6 (983TT) and a p-glycoprotein haplotype affected AUCs without substantially altering long-term exposure. Conclusions. This comprehensive pharmacogenomics study showed that individuals with the CYP2B6 516TT genotype displayed >3-fold increases in both short-term and long-term efavirenz exposure, signifying durable effects. Pharmacogenetic testing combined with monitoring of hair levels may improve efavirenz outcomes and reduce toxicities.

Original languageEnglish (US)
Pages (from-to)1453-1461
Number of pages9
JournalJournal of Infectious Diseases
Volume206
Issue number9
DOIs
StatePublished - Nov 1 2012

Fingerprint

efavirenz
Hair
Single Nucleotide Polymorphism
HIV
Area Under Curve
Genotype
Haplotypes
Alanine Transaminase
Cytochrome P-450 CYP2B6
Glycoproteins
Pharmacokinetics

ASJC Scopus subject areas

  • Infectious Diseases
  • Immunology and Allergy

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A single-nucleotide polymorphism in CYP2B6 leads to >3-fold increases in efavirenz concentrations in plasma and hair among HIV-infected women. / Gandhi, Monica; Greenblatt, Ruth M.; Bacchetti, Peter; Jin, Chengshi; Huang, Yong; Anastos, Kathryn; Cohen, Mardge; Dehovitz, Jack A.; Sharp, Gerald B.; Gange, Stephen J.; Liu, Chenglong; Hanson, Susan C.; Aouizerat, Bradley.

In: Journal of Infectious Diseases, Vol. 206, No. 9, 01.11.2012, p. 1453-1461.

Research output: Contribution to journalArticle

Gandhi, M, Greenblatt, RM, Bacchetti, P, Jin, C, Huang, Y, Anastos, K, Cohen, M, Dehovitz, JA, Sharp, GB, Gange, SJ, Liu, C, Hanson, SC & Aouizerat, B 2012, 'A single-nucleotide polymorphism in CYP2B6 leads to >3-fold increases in efavirenz concentrations in plasma and hair among HIV-infected women', Journal of Infectious Diseases, vol. 206, no. 9, pp. 1453-1461. https://doi.org/10.1093/infdis/jis508
Gandhi, Monica ; Greenblatt, Ruth M. ; Bacchetti, Peter ; Jin, Chengshi ; Huang, Yong ; Anastos, Kathryn ; Cohen, Mardge ; Dehovitz, Jack A. ; Sharp, Gerald B. ; Gange, Stephen J. ; Liu, Chenglong ; Hanson, Susan C. ; Aouizerat, Bradley. / A single-nucleotide polymorphism in CYP2B6 leads to >3-fold increases in efavirenz concentrations in plasma and hair among HIV-infected women. In: Journal of Infectious Diseases. 2012 ; Vol. 206, No. 9. pp. 1453-1461.
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abstract = "Background. Efavirenz exhibits marked interindividual variability in plasma levels and toxicities. Prior pharmacogenetic studies usually measure exposure via single plasma levels, examine limited numbers of polymorphisms, and rarely model multiple contributors. We analyzed numerous genetic and nongenetic factors impacting short-term and long-term exposure in a large heterogeneous population of human immunodeficiency virus (HIV)-infected women. Methods. We performed 24-hour intensive pharmacokinetic studies in 111 women receiving efavirenz under actual-use conditions and calculated the area-under-the-concentration-time curve (AUC) to assess short-term exposure; the efavirenz concentration in hair was measured to estimate long-term exposure. A total of 182 single-nucleotide polymorphisms (SNPs) and 45 haplotypes in 9 genes were analyzed in relationship to exposure by use of multivariate models that included a number of nongenetic factors. Results. Efavirenz AUCs increased 1.26-fold per doubling of the alanine aminotransferase level and 1.23-fold with orange and/or orange juice consumption. Individuals with the CYP2B6 516TT genotype displayed 3.5-fold increases in AUCs and 3.2-fold increases in hair concentrations, compared with individuals with the TG/GG genotype. Another SNP in CYP2B6 (983TT) and a p-glycoprotein haplotype affected AUCs without substantially altering long-term exposure. Conclusions. This comprehensive pharmacogenomics study showed that individuals with the CYP2B6 516TT genotype displayed >3-fold increases in both short-term and long-term efavirenz exposure, signifying durable effects. Pharmacogenetic testing combined with monitoring of hair levels may improve efavirenz outcomes and reduce toxicities.",
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T1 - A single-nucleotide polymorphism in CYP2B6 leads to >3-fold increases in efavirenz concentrations in plasma and hair among HIV-infected women

AU - Gandhi, Monica

AU - Greenblatt, Ruth M.

AU - Bacchetti, Peter

AU - Jin, Chengshi

AU - Huang, Yong

AU - Anastos, Kathryn

AU - Cohen, Mardge

AU - Dehovitz, Jack A.

AU - Sharp, Gerald B.

AU - Gange, Stephen J.

AU - Liu, Chenglong

AU - Hanson, Susan C.

AU - Aouizerat, Bradley

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N2 - Background. Efavirenz exhibits marked interindividual variability in plasma levels and toxicities. Prior pharmacogenetic studies usually measure exposure via single plasma levels, examine limited numbers of polymorphisms, and rarely model multiple contributors. We analyzed numerous genetic and nongenetic factors impacting short-term and long-term exposure in a large heterogeneous population of human immunodeficiency virus (HIV)-infected women. Methods. We performed 24-hour intensive pharmacokinetic studies in 111 women receiving efavirenz under actual-use conditions and calculated the area-under-the-concentration-time curve (AUC) to assess short-term exposure; the efavirenz concentration in hair was measured to estimate long-term exposure. A total of 182 single-nucleotide polymorphisms (SNPs) and 45 haplotypes in 9 genes were analyzed in relationship to exposure by use of multivariate models that included a number of nongenetic factors. Results. Efavirenz AUCs increased 1.26-fold per doubling of the alanine aminotransferase level and 1.23-fold with orange and/or orange juice consumption. Individuals with the CYP2B6 516TT genotype displayed 3.5-fold increases in AUCs and 3.2-fold increases in hair concentrations, compared with individuals with the TG/GG genotype. Another SNP in CYP2B6 (983TT) and a p-glycoprotein haplotype affected AUCs without substantially altering long-term exposure. Conclusions. This comprehensive pharmacogenomics study showed that individuals with the CYP2B6 516TT genotype displayed >3-fold increases in both short-term and long-term efavirenz exposure, signifying durable effects. Pharmacogenetic testing combined with monitoring of hair levels may improve efavirenz outcomes and reduce toxicities.

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