Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Randomized Controlled Trial
. 2010 Sep 1;202(5):717-22.
doi: 10.1086/655470.

Effect of CYP2B6, ABCB1, and CYP3A5 polymorphisms on efavirenz pharmacokinetics and treatment response: an AIDS Clinical Trials Group study

Heather J Ribaudo  1 , Huan Liu, Matthias Schwab, Elke Schaeffeler, Michel Eichelbaum, Alison A Motsinger-Reif, Marylyn D Ritchie, Ulrich M Zanger, Edward P Acosta, Gene D Morse, Roy M Gulick, Gregory K Robbins, David Clifford, David W Haas
Affiliations
Randomized Controlled Trial

Effect of CYP2B6, ABCB1, and CYP3A5 polymorphisms on efavirenz pharmacokinetics and treatment response: an AIDS Clinical Trials Group study

Heather J Ribaudo et al. J Infect Dis. .

Abstract

In AIDS Clinical Trials Group protocols 384, A5095, and A5097s, we characterized relationships between 22 polymorphisms in CYP2B6, ABCB1, and CYP3A5; plasma efavirenz exposure; and/or treatment responses. A stepwise logistic regression procedure selected polymorphisms associated with reduced drug clearance adjusted for body mass index and the composite CYP2B6 516/983 genotype. Relationships between selected polymorphisms and treatment responses were characterized by competing risk methodology. Association analyses involved 821 individuals (317 for pharmacokinetics and 643 for treatment response). Models that included CYP2B6 516/983 genotype best predicted pharmacokinetics. Slow-metabolizer genotypes were associated with increased central nervous system events among white participants and decreased virologic failure among black participants.

PubMed Disclaimer

Figures

Figure 1
Figure 1. Relationships between genetic polymorphisms and plasma efavirenz
Panel A: Allelic frequencies among 489 participants genotyped for the pharmacokinetic analysis cohort. Panel B: Concentration-time relationships between plasma efavirenz concentrations and hours post-dose among all 489 participants. Some individuals contribute multiple datapoints to the figure. Bottom panels: Median time-adjusted concentration percentile ranks, stratified for composite CYP2B6 516/983 genotype, among the 317 pharmacokinetic modeling cohort participants, regardless of race/ethnicity. Each individual contributes a single datapoint to the figure. Separate displays generated for each race/ethnicity group were consistent (data not shown).
Figure 2
Figure 2. Cumulative incidence of CNS events and virologic failure over time adjusted for the competing event of efavirenz discontinuation
According to CYP2B6 516/983 genotype, within each panel the decreasing lines on the top display the estimates of cumulative probability of remaining on efavirenz; the cumulative incidence of grade 2 or higher CNS event (panels A-D) or virologic failure (panels E-H) by genotype are displayed at the base on the figure. The mid-area between the two curves represents the probability of remaining event free over time. P-values are given by Gray k-sample tests for comparing the cumulative incidence of competing risks. Solid lines represent extensive metabolizers; dashed lines intermediate metabolizers, and dotted lined slow metabolizers. Adverse events were graded using the National Institute of Allergy and Infectious Diseases Division of AIDS toxicity scale. AE, adverse events; VF, virologic failure.
See this image and copyright information in PMC

References

    1. Gulick RM, Ribaudo HJ, Shikuma CM, et al. Three- vs four-drug antiretroviral regimens for the initial treatment of HIV-1 infection: a randomized controlled trial. JAMA. 2006;296:769–781. - PubMed
    1. Clifford DB, Evans S, Yang Y, et al. Impact of efavirenz on neuropsychological performance and symptoms in HIV-infected individuals. Ann Intern Med. 2005;143:714–721. - PubMed
    1. Haas DW, Ribaudo HJ, Kim RB, et al. Pharmacogenetics of efavirenz and central nervous system side effects: an Adult AIDS Clinical Trials Group study. AIDS. 2004;18:2391–2400. - PubMed
    1. Haas DW, Smeaton LM, Shafer RW, et al. Pharmacogenetics of Long-Term Responses to Antiretroviral Regimens Containing Efavirenz and/or Nelfinavir: An Adult AIDS Clinical Trials Group Study. J Infect Dis. 2005;192:1931–1942. - PubMed
    1. Wang J, Sonnerborg A, Rane A, et al. Identification of a novel specific CYP2B6 allele in Africans causing impaired metabolism of the HIV drug efavirenz. Pharmacogenet Genomics. 2006;16:191–198. - PubMed

Publication types

MeSH terms

Grants and funding