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

1. AIDS CLINICAL ROUNDS
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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
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audience. They may not be used for other purposes without the
presenter’s express permission.

2. Pharmacogenomics
of HIV Therapy
David W. Haas, M.D.
Division of Infectious Diseases
Vanderbilt University School of Medicine

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.

5. Evans et al. Ann Rev Gen Hum Genet 2:9, 2001.

6. A global view of HIV infection in 2011
43 million people living with HIV

7. 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

8. 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

9. 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

10. 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

11. 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

12. Abacavir
&
HLA-B*5701

13. Abacavir Hypersensitivity Reaction

14. 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

15. 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

16. 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….”

17. 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

18. 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

19. Efavirenz
&
CYP2B6

20. Efavirenz Metabolism by CYP2B6
Ward et al. J Pharmacol Exp Ther 2003:306,287.

21. CYP2B6 516G>T and
Efavirenz Plasma Levels: A5097s
Haas et al, AIDS 2004;18:2391

22. Estimated Cmin by CYP2B6 Haplotype
(516G→T, 983T→C, 15582C→T)
Holzinger et al, Pharmacogenet Genom 2012; 22:858

23. Genome-wide Association of Efavirenz Plasma Levels
(ACTG384, A5095, A5142, A5202)
CYP2B6, P = 10-40
Holzinger et al, Pharmacogenet Genom 2012; 22:858

24. Human Genetics and Efavirenz Discontinuation in
Swiss HIV Cohort Study
Lubomirov et al, J infect Dis 2011;203:246

25. CYP2A6 -48T→G and Efavirenz Levels
in CYP2B6 Slow Metabolizers (N=84)
(Haas et al, submitted)

26. Q-Q Plot for Efavirenz in CYP2B6 Slow Metabolizers
(103 ADME Polymorphisms)
CYP2A6 -48T→G
(Haas et al, submitted)

27. CYP2B6 Haplotype and Virologic Response to Efavirenzcontaining Regimens in Port-au-Prince, Haiti (n=360):
Haas et al, CROI 2013, Abstract 518
26

28. Efavirenz Dose Reduction by CYP2B6 Genotype
Gatanaga Clin Inf Dis 2007;45:1230

29. 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%).

30. Estimated Cmin by CYP2B6 Haplotype
(516G→T, 983T→C, 15582C→T)
Holzinger et al, Pharmacogenet Genom 2012; 22:858

31. 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

32. Unexpected Interaction between Efavirenz
and Rifampin-containing TB Therapy
Kwara et al AIDS 2011, 25

33. Nevirapine
&
HLA, CYP2B6

34. Nevirapine
Biotransformation
in Humans
Riska et al. Drug Metab Dispo
1999:27,895
CYP2B6

35. CYP2B6
516G>T and
Nevirapine
Clearance in
Children
Saitoh et al
AIDS 2007:21,2191

36. Nevirapine Toxicity: ADME and Immune SNPs
(B-I protocol 1100.1452)
Yuan et al AIDS 2011; 25:1271

37. Nevirapine Toxicity: ADME and Immune SNPs
(B-I protocol 1100.1452, N = 863)
CYP2B6
CYP2B6
Yuan et al AIDS 2011; 25:1271

38. Nevirapine Toxicity: ADME and Immune SNPs
(B-I protocol 1100.1452, N = 863)
Yuan et al AIDS 2011; 25:1271

39. 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.

40. Atazanavir
&
UGT1A1

42. 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

43. UGT1A1*28 and Bilirubin Levels
ATV or IDV
*28/*28
Rotger et al, J Inf Dis 2005;192,1381

44. 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

45. Cost Effectiveness Analysis of UGT1A1 Genotyping
to Prevent Atazanavir Discontinuation
Schackman et a. Antiviral Ther 18: 399, 2013

46. 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

47. 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

48. Lopinavir
&
SLCO1B1
(OATP-1B1)

49. Transporters for drugs and endogenous substances
Giacomini et al, Nature Rev Drug Discov JID 2010;9,215

50. SLCO1B1 and Lopinavir Clearance
SLCO1B1*5
Lubomirov et al Pharmacogenet Genom 2010:20,217

51. Etravirine
&
CYP2C19, CYP2C9

52. CYP2C19, CYP2C9 and Etravirine Clearance
Lubomirov et al Pharmacogenet Genom 2013, 23:9

53. Tenofovir, Renal
Toxicity

54. Transport proteins for drugs and endogenous substances
Giacomini et al, Nature Rev Drug Discov JID 2010;9,215

55. 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

56. 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

60. Anna Haas
Ruby Amanfu

61. 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