Pharmacogenomics of HIV Therapy
Upcoming SlideShare
Loading in...5
×
 

Pharmacogenomics of HIV Therapy

on

  • 539 views

David Haas, MD, professor at Vanderbilt University School of Medicine, presents "Pharmacogenomics of HIV therapy" for AIDS Clinical Rounds at UC San Diego

David Haas, MD, professor at Vanderbilt University School of Medicine, presents "Pharmacogenomics of HIV therapy" for AIDS Clinical Rounds at UC San Diego

Statistics

Views

Total Views
539
Views on SlideShare
538
Embed Views
1

Actions

Likes
0
Downloads
29
Comments
0

1 Embed 1

http://www.slideee.com 1

Accessibility

Categories

Upload Details

Uploaded via as Adobe PDF

Usage Rights

© All Rights Reserved

Report content

Flagged as inappropriate Flag as inappropriate
Flag as inappropriate

Select your reason for flagging this presentation as inappropriate.

Cancel
  • Full Name Full Name Comment goes here.
    Are you sure you want to
    Your message goes here
    Processing…
Post Comment
Edit your comment

Pharmacogenomics of HIV Therapy Pharmacogenomics of HIV Therapy Presentation Transcript

  • AIDS CLINICAL ROUNDS The UC San Diego AntiViral Research Center sponsors weekly presentations by infectious disease clinicians, physicians and researchers. The goal of these presentations is to provide the most current research, clinical practices and trends in HIV, HBV, HCV, TB and other infectious diseases of global significance. The slides from the AIDS Clinical Rounds presentation that you are about to view are intended for the educational purposes of our audience. They may not be used for other purposes without the presenter’s express permission.
  • Pharmacogenomics of HIV Therapy David W. Haas, M.D. Division of Infectious Diseases Vanderbilt University School of Medicine
  • Objectives • To discuss current knowledge regarding HIV pharmacogenomics. • To consider implications for HIV care in the US and worldwide. • To suggest strategies to continue advancing the field. View slide
  • Evans et al. Ann Rev Gen Hum Genet 2:9, 2001. View slide
  • A global view of HIV infection in 2011 43 million people living with HIV
  • US FDA-Approved Antiretrovirals (2014) NRTIs Abacavir Didanosine Emtricitabine Lamivudine Stavudine Tenofovir Zidovudine NNRTIs Efavirenz Etravirine Nevirapine Rilpivirine Fusion inhibitor Enfuvertide CCR5 inhibitor Maraviroc Integrase inhibitor Dolutegravir Elvitegravir Raltegravir Protease Inh. Amprenavir Atazanavir Darunavir Indinavir Lopinavir Nelfinavir Ritonavir Saquinavir Tipranavir
  • Question 1: In your “clinical sphere of influence”, about what % of active HIV+ patients have ever had a human genetic test? 1. less than 5% 2. 5-50% 3. 50-100% 4. don’t know, or not applicable
  • Question 2: In your “clinical sphere of influence”, about what % of active HIV+ patients have ever had a human genetic test – not counting HLA-B*5701? 1. less than 5% 2. 5-50% 3. 50-100% 4. don’t know, or not applicable
  • Question 3: Of the 25 different anti-HIV drugs, how many have been definitively shown to be affected by human genetic polymorphisms (levels, efficacy, or toxicity)? 1. 0-5 2. 6-10 3. 11-15 4. 16-25
  • US FDA-Approved Antiretrovirals (2014) NRTIs Abacavir Didanosine Emtricitabine Lamivudine Stavudine Tenofovir Zidovudine NNRTIs Efavirenz Etravirine Nevirapine Rilpivirine Fusion inhibitor Enfuvertide CCR5 inhibitor Maraviroc Integrase inhibitor Dolutegravir Elvitegravir Raltegravir Protease Inh. Amprenavir Atazanavir Darunavir Indinavir Lopinavir Nelfinavir Ritonavir Saquinavir Tipranavir
  • Abacavir & HLA-B*5701
  • Abacavir Hypersensitivity Reaction
  • PREDICT-1: a novel randomised prospective study to determine the clinical utility of HLA-B*5701 screening to reduce abacavir hypersensitivity in HIV-1 infected subjects Mallal et al; NEJM 2008; 358:568
  • Performance of HLA-B*5701 Screening for Abacavir HSR Clinically Suspected HSR1 HLA-B*5701 Pos HSR No HSR 36 762 Pos PV Neg PV 62% 1 Pos Neg 30 19 Control Arm Data Only 96% Immunologically Confirmed HSR1 HLA-B*5701 Sens 46% Spec 98% Neg 23 25 0 794 Sens 100% Spec 97% Pos PV Neg PV 48% 100% Mallal et al; NEJM 2008
  • DHHS Panel Guidelines (12/07) (http://aidsinfo.nih.gov) “The Panel recommends HLA-B*5701 testing prior to initiating abacavir therapy... HLAB*5701-positive patients should not be prescribed abacavir…, positive status should be recorded as an abacavir allergy in the patient’s medical record….”
  • Frequency of HLA-B*5701 W. EUROPE 5-7% US Caucasian ~8% US Asian ~1% MEDITERRANEAN UK 1-2% ~8% MIDDLE EAST 1-2% (NB 5-7% Ashkenazi Jews) INDIA 5-20% CHINA 0% (NB 2.5% N.E. provinces) US AfricanAmerican ~2.5% JAPAN 0% US Hispanic ~2% AUSTRALIA ~8% THAILAND 4-10%* S. AMERICAN Caucasian 5-7% Subsaharan AFRICA <1% *THAILAND B*57 carriage: Urban Bangkok 3.6% Thai Dai Lue (NE Thai) ~11% Southern Thai Muslim 3% Nolan et al J HIV Ther 2003;8:36
  • Drug Metabolism and Elimination Nuclear receptor genes that control ADME expression Phase 1 enzymes (e.g. CYPs) Drug X Phase 2 enzymes (e.g. UGTs) Drug X Drug X OH O R Hydrophobic Hydrophilic
  • Efavirenz & CYP2B6
  • Efavirenz Metabolism by CYP2B6 Ward et al. J Pharmacol Exp Ther 2003:306,287.
  • CYP2B6 516G>T and Efavirenz Plasma Levels: A5097s Haas et al, AIDS 2004;18:2391
  • Estimated Cmin by CYP2B6 Haplotype (516G→T, 983T→C, 15582C→T) Holzinger et al, Pharmacogenet Genom 2012; 22:858
  • Genome-wide Association of Efavirenz Plasma Levels (ACTG384, A5095, A5142, A5202) CYP2B6, P = 10-40 Holzinger et al, Pharmacogenet Genom 2012; 22:858
  • Human Genetics and Efavirenz Discontinuation in Swiss HIV Cohort Study Lubomirov et al, J infect Dis 2011;203:246
  • CYP2A6 -48T→G and Efavirenz Levels in CYP2B6 Slow Metabolizers (N=84) (Haas et al, submitted)
  • Q-Q Plot for Efavirenz in CYP2B6 Slow Metabolizers (103 ADME Polymorphisms) CYP2A6 -48T→G (Haas et al, submitted)
  • CYP2B6 Haplotype and Virologic Response to Efavirenzcontaining Regimens in Port-au-Prince, Haiti (n=360): Haas et al, CROI 2013, Abstract 518 26
  • Efavirenz Dose Reduction by CYP2B6 Genotype Gatanaga Clin Inf Dis 2007;45:1230
  • ENCORE1 Trial - Efavirenz 400 mg vs. 600 mg (a “non-genetic” study) Study design • Randomized ART-naive to TDF/FTC + EFV (400mg vs. 600mg). • Primary endpoint VL< 200 copies/mL at 48 weeks. • N=630 (EFV400=321; EFV600=310). 37% African, 33% Asian, 30% Caucasian. Results • Fewer side-effects attributed to EFV, esp. CNS with EFV400 (37% vs. 47%). • Fewer treatment discontinuations for adverse events with EFV400 (2% vs. 6%). • No difference in VL< 200 copies/mL at 48 weeks (EFV400=94%, EFV600=92%) by modified ITT. • No difference in overall adverse event frequency Puls et al. Presented at IAS Conference 2013, abstract WELBB01 (EFV400=89%, EFV600=88%).
  • Estimated Cmin by CYP2B6 Haplotype (516G→T, 983T→C, 15582C→T) Holzinger et al, Pharmacogenet Genom 2012; 22:858
  • Precision Dose Reduction of Efavirenz Pros: • Improve neurocognitive function • Improve tolerability • Improve prescribing of generic efavirenz • Many patients on efavirenz • Extend role of efavirenz as first-line agent • Reduce drug cost • Inform drug interactions • Impetus to co-formulate • >50% of patients eligible to dose reduce Cons: • • • • • Increase number of pills Selective non-adherence Copays Requires genotyping Virologic control
  • Unexpected Interaction between Efavirenz and Rifampin-containing TB Therapy Kwara et al AIDS 2011, 25
  • Nevirapine & HLA, CYP2B6
  • Nevirapine Biotransformation in Humans Riska et al. Drug Metab Dispo 1999:27,895 CYP2B6
  • CYP2B6 516G>T and Nevirapine Clearance in Children Saitoh et al AIDS 2007:21,2191
  • Nevirapine Toxicity: ADME and Immune SNPs (B-I protocol 1100.1452) Yuan et al AIDS 2011; 25:1271
  • Nevirapine Toxicity: ADME and Immune SNPs (B-I protocol 1100.1452, N = 863) CYP2B6 CYP2B6 Yuan et al AIDS 2011; 25:1271
  • Nevirapine Toxicity: ADME and Immune SNPs (B-I protocol 1100.1452, N = 863) Yuan et al AIDS 2011; 25:1271
  • Severe Nevirapine Reactions (summary) In patients with high CD4 counts (>250 women, >400 men)… • Genotypes identify patients at increased risk for severe toxicity with nevirapine initiation. • Genotype cannot yet identify patients at acceptably low risk.
  • Atazanavir & UGT1A1
  • UDP-glucuronosyltransferase (UGT1A1) and Jaundice with Atazanavir UGT1A1 promoter with 7 TA repeats is less active *28 allele, “Gilbert’s trait” Rodríguez-Nóvoa et al, Pharmacogenomics J 2006;6,234
  • UGT1A1*28 and Bilirubin Levels ATV or IDV *28/*28 Rotger et al, J Inf Dis 2005;192,1381
  • UGT1A1*28, *37 and Atazanavir Discontinuation (Swiss Cohort, N = 121, 80% Caucasian) (HR = 9.13, 95% CI 3.4–25) Lubomirov et al J Inf Dis 2011;203:246
  • Cost Effectiveness Analysis of UGT1A1 Genotyping to Prevent Atazanavir Discontinuation Schackman et a. Antiviral Ther 18: 399, 2013
  • UGT1A1*28, *37 and Atazanavir Discontinuation (ACTG protocol A5202, N = 646) All White X Black Hispanic Ribaudo et al J Inf Dis 2012; 207:420-5
  • Atazanavir and Bilirubin >3.0 mg/dL (ACTG protocol A5202) Baseline bilirubin, hemoglobin, UGT1A1 UGT1A1 Baseline bilirubin, hemoglobin Johnson et al. CROI 2013, Abstract 520 46
  • Lopinavir & SLCO1B1 (OATP-1B1)
  • Transporters for drugs and endogenous substances Giacomini et al, Nature Rev Drug Discov JID 2010;9,215
  • SLCO1B1 and Lopinavir Clearance SLCO1B1*5 Lubomirov et al Pharmacogenet Genom 2010:20,217
  • Etravirine & CYP2C19, CYP2C9
  • CYP2C19, CYP2C9 and Etravirine Clearance Lubomirov et al Pharmacogenet Genom 2013, 23:9
  • Tenofovir, Renal Toxicity
  • Transport proteins for drugs and endogenous substances Giacomini et al, Nature Rev Drug Discov JID 2010;9,215
  • A5142: Regimen Type and Change in CrCl 5 LPV/r or EFV +2NRTIs EFV+TDF 0 CrCl -5 change (ml/min/1.7-10 3m2) LPV/r+EFV LPV/r+TDF -15 -20 0 24 48 72 Study weeks Time on study (weeks) Goicoechea et al. IAS Meeting 2010 96
  • ABCC2 variant (from Genome-wide Data) and Change in Creatinine Clearance with TDF (A5202) • Only association was PRESERVED CrCl with rs2273697 • Did not replicate A5142 associations • May depend upon concomitant ART? (markers: black = efavirenz; grey = atazanavir) Ribaudo et al, CROI 2011
  • Anna Haas Ruby Amanfu
  • Acknowledgements • Individuals who volunteered for these studies. • Funding • NIAID - ACTG (AI-068636 ) • NIAID - RO1 (AI-077505) • NCATS - Vanderbilt CTSA (TR000445 ) • Collaborators and colleagues. • Chip Schooley and Connie Benson