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AIDS CLINICAL ROUNDS

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.

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

Protease Inh. Amprenavir Atazanavir Darunavir Indinavir Lopinavir Nelfinavir Ritonavir Saquinavir Tipranavir

Fusion inhibitor Enfuvertide

Integrase inhibitor Dolutegravir Elvitegravir Raltegravir

CCR5 inhibitor Maraviroc

NNRTIs Efavirenz Etravirine Nevirapine Rilpivirine

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

Protease Inh. Amprenavir Atazanavir Darunavir Indinavir Lopinavir Nelfinavir Ritonavir Saquinavir Tipranavir

Fusion inhibitor Enfuvertide

Integrase inhibitor Dolutegravir Elvitegravir Raltegravir

CCR5 inhibitor Maraviroc

NNRTIs Efavirenz Etravirine Nevirapine Rilpivirine

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

HSR No HSR

Pos Neg

Immunologically Confirmed HSR1

HLA-B*5701

23 0 25 794

Pos PV

48%

Neg PV 100%

Sens 100% Spec 97%

Clinically Suspected HSR1

HLA-B*5701

Pos Neg

30 36 19 762

Pos PV Neg PV

62% 96%

Sens 46% Spec 98%

1 Control Arm Data Only 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... HLA-B*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

Nolan et al J HIV Ther 2003;8:36

INDIA 5-20%

JAPAN 0%

CHINA 0% (NB 2.5% N.E.

provinces)

UK ~8%

MIDDLE EAST 1-2% (NB 5-7% Ashkenazi Jews)

AUSTRALIA ~8%

US Caucasian

~8% US Asian

~1%

US African-

American ~2.5%

W. EUROPE 5-7%

THAILAND 4-10%*

*THAILAND B*57 carriage: Urban Bangkok 3.6%

Thai Dai Lue (NE Thai) ~11% Southern Thai Muslim 3%

MEDITERRANEAN 1-2%

S. AMERICAN Caucasian

5-7%

US Hispanic

~2%

Subsaharan AFRICA

<1%

Drug X

OH

Drug X

O

Drug X

R

Phase 1 enzymes

(e.g. CYPs)

Phase 2 enzymes

(e.g. UGTs)

Hydrophobic Hydrophilic

Drug Metabolism and Elimination Nuclear receptor genes that

control ADME expression

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

Holzinger et al, Pharmacogenet Genom 2012; 22:858

(516G→T, 983T→C, 15582C→T)

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)

(Haas et al, submitted)

CYP2A6 -48T→G

26

CYP2B6 Haplotype and Virologic Response to Efavirenz-containing Regimens in Port-au-Prince, Haiti (n=360):

Haas et al, CROI 2013, Abstract 518

Gatanaga Clin Inf Dis 2007;45:1230

Efavirenz Dose Reduction by CYP2B6 Genotype

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

(EFV400=89%, EFV600=88%). Puls et al. Presented at IAS Conference 2013, abstract WELBB01

Estimated Cmin by CYP2B6 Haplotype

Holzinger et al, Pharmacogenet Genom 2012; 22:858

(516G→T, 983T→C, 15582C→T)

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

Kwara et al AIDS 2011, 25

Unexpected Interaction between Efavirenz and Rifampin-containing TB Therapy

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

Yuan et al AIDS 2011; 25:1271

CYP2B6

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

Rodríguez-Nóvoa et al, Pharmacogenomics J 2006;6,234

UDP-glucuronosyltransferase (UGT1A1) and Jaundice with Atazanavir

UGT1A1 promoter with 7 TA repeats is less active *28 allele, “Gilbert’s trait”

Rotger et al, J Inf Dis 2005;192,1381

UGT1A1*28 and Bilirubin Levels

ATV or IDV

*28/*28

Lubomirov et al J Inf Dis 2011;203:246

UGT1A1*28, *37 and Atazanavir Discontinuation (Swiss Cohort, N = 121, 80% Caucasian)

(HR = 9.13, 95% CI 3.4–25)

Schackman et a. Antiviral Ther 18: 399, 2013

Cost Effectiveness Analysis of UGT1A1 Genotyping to Prevent Atazanavir Discontinuation

UGT1A1*28, *37 and Atazanavir Discontinuation (ACTG protocol A5202, N = 646)

Ribaudo et al J Inf Dis 2012; 207:420-5

All White

Black Hispanic

X

46

Atazanavir and Bilirubin >3.0 mg/dL (ACTG protocol A5202)

Johnson et al. CROI 2013, Abstract 520

Baseline bilirubin, hemoglobin

UGT1A1

Baseline bilirubin, hemoglobin, UGT1A1

Lopinavir &

SLCO1B1 (OATP-1B1)

Giacomini et al, Nature Rev Drug Discov JID 2010;9,215

Transporters for drugs and endogenous substances

Lubomirov et al Pharmacogenet Genom 2010:20,217

SLCO1B1 and Lopinavir Clearance

SLCO1B1*5

Etravirine &

CYP2C19, CYP2C9

Lubomirov et al Pharmacogenet Genom 2013, 23:9

CYP2C19, CYP2C9 and Etravirine Clearance

Tenofovir, Renal Toxicity

Giacomini et al, Nature Rev Drug Discov JID 2010;9,215

Transport proteins for drugs and endogenous substances

CrCl change (ml/min/1.73m2)

Study weeks

0 24 48 72 96

-20

-15

-10

-5

0

5

LPV/r+TDF

EFV+TDF

LPV/r or EFV +2NRTIs

LPV/r+EFV

Time on study (weeks)

Goicoechea et al. IAS Meeting 2010

A5142: Regimen Type and Change in CrCl

• Only association was PRESERVED CrCl with rs2273697 • Did not replicate A5142 associations • May depend upon concomitant ART? (markers: black = efavirenz; grey = atazanavir)

ABCC2 variant (from Genome-wide Data) and Change in Creatinine Clearance with TDF (A5202)

Ribaudo et al, CROI 2011

Ruby Amanfu Anna Haas

Acknowledgements

• Individuals who volunteered for these studies.

• Funding • NIAID - ACTG (AI-068636 ) • NIAID - RO1 (AI-077505) • NCATS - Vanderbilt CTSA (TR-

000445 ) • Collaborators and colleagues. • Chip Schooley and Connie Benson