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TUPDB0104

TUPDB0104. A single nucleotide polymorphism in CYP2B6 leads to >3-fold increases in efavirenz concentrations in intensive pharmacokinetic curves and hair samples.

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TUPDB0104

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  1. TUPDB0104 A single nucleotide polymorphism in CYP2B6 leads to >3-fold increases in efavirenz concentrations in intensive pharmacokinetic curves and hair samples • M. Gandhi, R.M. Greenblatt, P. Bacchetti, C. Jin, Y. Huang, M. Cohen, J. Dehovitz, K. Anastos, S.J. Gange, C. Liu, S. Hanson, B. Aouizerat • for the Women’s Interagency HIV Study (WIHS) • Pharmacokinetics and Pharmacogenomics of ART: Coming of Age • Oral poster discussion, AIDS 2012, Washington DC, July 24

  2. Background • EFV mainstay of current cART, high rates of AEs • Pharmacogenomics (PG) “personalize” selection, dosing; optimize outcomes • Studies investigating PG & EFV exposure limited by • Single plasma levels of EFV as exposure measure • Small # single nucleotide polymorphisms (SNPs) examined • Failure to model non-genetic contributors Women’s Interagency HIV Study (WIHS): Multicenter prospective cohort study HIV-infected and at-risk women

  3. Methods: EFV AUC- “Short-term exposure” • 24 hour intensive PK studies performed in 111 WIHS women on EFV under conditions of actual use • Areas under the curve (AUCs) calculated Efavirenz concentration (mg/ml) Median PK curve Time of blood draw (hours)

  4. Hair EFV levels: “Long-term exposure” • Average exposure over time • Not snapshot (AUC of AUC) • Easy and cheap to collect • Stored at room temp • Shipped without biohazard • Not subject to white coat effects • Integrates behavior (adherence) and biology (PK)

  5. Methods (cont.) • Multivariate linear regression between predictors and short/long-term exposure • Genetic predictors: 182 SNPs/ 45 haplotypes in 9 genes (ABCB1, ABCC2, CYP2B6, CYP2C19, CYP2D6, CYP3A5, CYP3A4, SCL22A6, UGT1A1) • Literature-based: SNPs -EFV absorption, distribution, metabolism, elimination (ADME) • Tag SNPs: Neighboring regions in high LD across coding/noncoding regions of ADME genes • Non-genetic: Diet, age, race, HepB/C status, smoking, substance use, hepatic, renal function, etc.

  6. Results

  7. Results

  8. Conclusions • Individuals homozygous CYP2B6 516 rare (TT) allele >3-fold increases in short-term (AUCs) and long-term (hair) EFV exposure in this diverse cohort of HIV-infected women • AUCs more robust than single plasma levels (and self-reported adherence) as short-term measures, cumbersome • Hair levels better in averaging exposure over time • Effect of CYP2B6 516 TT on long-term exposure signifies durable effects • Genetic testing coupled with hair measurement may enable EFV dosing optimization in clinical setting, especially when non-genetic risk factors for high exposure are present

  9. Acknowledgements • Participants and staff of the WIHS • Funding • NIAID/NIH RO1 AI065233 (Greenblatt); UO1 AI034989 (Greenblatt); NIAID ARRA 3U01AI034989-17S1 (Greenblatt, Aouizerat); K23 AI067065 (Gandhi) THANK YOU!

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