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AIDS CLINICAL ROUNDS
The UC San Diego AntiViral Research Center sponsors weekly
presentations by infectious disease clinic...
Pharmacogenomics
of HIV Therapy

David W. Haas, M.D.
Division of Infectious Diseases
Vanderbilt University School of Medic...
Objectives
• To discuss current knowledge
regarding HIV pharmacogenomics.
• To consider implications for HIV care
in the U...
Evans et al. Ann Rev Gen Hum Genet 2:9, 2001.
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

...
Question 1: In your “clinical sphere of
influence”, about what % of active HIV+
patients have ever had a human genetic tes...
Question 2: In your “clinical sphere of
influence”, about what % of active HIV+
patients have ever had a human genetic tes...
Question 3: Of the 25 different anti-HIV
drugs, how many have been definitively
shown to be affected by human genetic
poly...
US FDA-Approved Antiretrovirals (2014)
NRTIs
Abacavir
Didanosine
Emtricitabine
Lamivudine
Stavudine
Tenofovir
Zidovudine

...
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 abacav...
Performance of HLA-B*5701 Screening
for Abacavir HSR
Clinically Suspected HSR1
HLA-B*5701
Pos
HSR
No HSR

36
762

Pos PV N...
DHHS Panel Guidelines (12/07)
(http://aidsinfo.nih.gov)

“The Panel recommends HLA-B*5701 testing
prior to initiating abac...
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...
Drug Metabolism and Elimination
Nuclear receptor genes that
control ADME expression
Phase 1
enzymes
(e.g. CYPs)

Drug X

P...
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, Phar...
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, CRO...
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 ...
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...
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 patien...
Atazanavir
&
UGT1A1
UDP-glucuronosyltransferase (UGT1A1) and
Jaundice with Atazanavir

UGT1A1
promoter with
7 TA repeats is
less active
*28 al...
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)

Lubomiro...
Cost Effectiveness Analysis of UGT1A1 Genotyping
to Prevent Atazanavir Discontinuation

Schackman et a. Antiviral Ther 18:...
UGT1A1*28, *37 and Atazanavir Discontinuation
(ACTG protocol A5202, N = 646)
All

White

X
Black

Hispanic

Ribaudo et al ...
Atazanavir and Bilirubin >3.0 mg/dL
(ACTG protocol A5202)
Baseline
bilirubin,
hemoglobin,
UGT1A1

UGT1A1

Baseline
bilirub...
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
L...
ABCC2 variant (from Genome-wide Data) and Change in
Creatinine Clearance with TDF (A5202)
• Only association was PRESERVED...
Anna Haas

Ruby Amanfu
Acknowledgements
• Individuals who volunteered for these
studies.
• Funding
• NIAID - ACTG (AI-068636 )
• NIAID - RO1 (AI-...
Pharmacogenomics of HIV Therapy
Pharmacogenomics of HIV Therapy
Pharmacogenomics of HIV Therapy
Pharmacogenomics of HIV Therapy
Pharmacogenomics of HIV Therapy
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Pharmacogenomics of HIV Therapy

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

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Transcript of "Pharmacogenomics of HIV Therapy"

  1. 1. 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.
  2. 2. Pharmacogenomics of HIV Therapy David W. Haas, M.D. Division of Infectious Diseases Vanderbilt University School of Medicine
  3. 3. 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.
  4. 4. Evans et al. Ann Rev Gen Hum Genet 2:9, 2001.
  5. 5. A global view of HIV infection in 2011 43 million people living with HIV
  6. 6. 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
  7. 7. 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
  8. 8. 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
  9. 9. 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
  10. 10. 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
  11. 11. Abacavir & HLA-B*5701
  12. 12. Abacavir Hypersensitivity Reaction
  13. 13. 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
  14. 14. 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
  15. 15. 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….”
  16. 16. 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
  17. 17. 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
  18. 18. Efavirenz & CYP2B6
  19. 19. Efavirenz Metabolism by CYP2B6 Ward et al. J Pharmacol Exp Ther 2003:306,287.
  20. 20. CYP2B6 516G>T and Efavirenz Plasma Levels: A5097s Haas et al, AIDS 2004;18:2391
  21. 21. Estimated Cmin by CYP2B6 Haplotype (516G→T, 983T→C, 15582C→T) Holzinger et al, Pharmacogenet Genom 2012; 22:858
  22. 22. Genome-wide Association of Efavirenz Plasma Levels (ACTG384, A5095, A5142, A5202) CYP2B6, P = 10-40 Holzinger et al, Pharmacogenet Genom 2012; 22:858
  23. 23. Human Genetics and Efavirenz Discontinuation in Swiss HIV Cohort Study Lubomirov et al, J infect Dis 2011;203:246
  24. 24. CYP2A6 -48T→G and Efavirenz Levels in CYP2B6 Slow Metabolizers (N=84) (Haas et al, submitted)
  25. 25. Q-Q Plot for Efavirenz in CYP2B6 Slow Metabolizers (103 ADME Polymorphisms) CYP2A6 -48T→G (Haas et al, submitted)
  26. 26. CYP2B6 Haplotype and Virologic Response to Efavirenzcontaining Regimens in Port-au-Prince, Haiti (n=360): Haas et al, CROI 2013, Abstract 518 26
  27. 27. Efavirenz Dose Reduction by CYP2B6 Genotype Gatanaga Clin Inf Dis 2007;45:1230
  28. 28. 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%).
  29. 29. Estimated Cmin by CYP2B6 Haplotype (516G→T, 983T→C, 15582C→T) Holzinger et al, Pharmacogenet Genom 2012; 22:858
  30. 30. 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
  31. 31. Unexpected Interaction between Efavirenz and Rifampin-containing TB Therapy Kwara et al AIDS 2011, 25
  32. 32. Nevirapine & HLA, CYP2B6
  33. 33. Nevirapine Biotransformation in Humans Riska et al. Drug Metab Dispo 1999:27,895 CYP2B6
  34. 34. CYP2B6 516G>T and Nevirapine Clearance in Children Saitoh et al AIDS 2007:21,2191
  35. 35. Nevirapine Toxicity: ADME and Immune SNPs (B-I protocol 1100.1452) Yuan et al AIDS 2011; 25:1271
  36. 36. Nevirapine Toxicity: ADME and Immune SNPs (B-I protocol 1100.1452, N = 863) CYP2B6 CYP2B6 Yuan et al AIDS 2011; 25:1271
  37. 37. Nevirapine Toxicity: ADME and Immune SNPs (B-I protocol 1100.1452, N = 863) Yuan et al AIDS 2011; 25:1271
  38. 38. 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.
  39. 39. Atazanavir & UGT1A1
  40. 40. 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
  41. 41. UGT1A1*28 and Bilirubin Levels ATV or IDV *28/*28 Rotger et al, J Inf Dis 2005;192,1381
  42. 42. 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
  43. 43. Cost Effectiveness Analysis of UGT1A1 Genotyping to Prevent Atazanavir Discontinuation Schackman et a. Antiviral Ther 18: 399, 2013
  44. 44. 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
  45. 45. 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
  46. 46. Lopinavir & SLCO1B1 (OATP-1B1)
  47. 47. Transporters for drugs and endogenous substances Giacomini et al, Nature Rev Drug Discov JID 2010;9,215
  48. 48. SLCO1B1 and Lopinavir Clearance SLCO1B1*5 Lubomirov et al Pharmacogenet Genom 2010:20,217
  49. 49. Etravirine & CYP2C19, CYP2C9
  50. 50. CYP2C19, CYP2C9 and Etravirine Clearance Lubomirov et al Pharmacogenet Genom 2013, 23:9
  51. 51. Tenofovir, Renal Toxicity
  52. 52. Transport proteins for drugs and endogenous substances Giacomini et al, Nature Rev Drug Discov JID 2010;9,215
  53. 53. 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
  54. 54. 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
  55. 55. Anna Haas Ruby Amanfu
  56. 56. 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
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