Overcoming the Barriers of Clinical Overcoming the Barriers of Clinical

Translation: The Abacavir ExampleTranslation: The Abacavir Example

Elizabeth J. Phillips, MD, FRCPC, FRACPElizabeth J. Phillips, MD, FRCPC, FRACPProfessor & Director, Centre for Clinical Pharmacology Professor & Director, Centre for Clinical Pharmacology

& Infectious Diseases, Murdoch University& Infectious Diseases, Murdoch UniversityRoyal Perth Hospital, Sir Charles Gairdner HospitalRoyal Perth Hospital, Sir Charles Gairdner Hospital

Perth, Western AustraliaPerth, Western Australia

ASCEPT December 1, 2009

Translation is an Active ProcessTranslation is an Active Process

Pharmacogenetic/genomicDiscovery

-Intepretable and cost-effective test -broad uptake in clinical practice -positive impact on patient effiacy and/or safety

“Lost in Translation”

<1%

>99%

-improved understanding of pathophysiology of disease, mechanism of drug efficacy, toxicity-identification of new therapeutic targets

T1T1T4: The Translational ParadigmT4: The Translational Paradigm

Step 1 - A discovery with a potential applicationStep 1 - A discovery with a potential application

Step 2 - Generation of high-level clinical evidenceStep 2 - Generation of high-level clinical evidence

- Basic science supports biological - Basic science supports biological plausibility plausibility

Step 3 - Delivery of research to the clinicStep 3 - Delivery of research to the clinic

- Quality assurance, valid, efficient and - Quality assurance, valid, efficient and

inexpensive lab testing and lab

report easy to interpret

Step 4 - Evaluation of test in real clinical practice

Abacavir causes abacavir hypersensitivity (ABC HSR) in 5-8% 1998

Two independent groups describe strong association between ABC HSR and HLA-B*5701 in predominantly Caucasian populations

Apparent low sensitivity of HLA-B*5701 in non-white populations questions generalisability

Clarity added to the “False positive clinical diagnosis “ of ABC HSR, observational studies

Patch testing is a highly specific for “true” ABC HSR

Randomised clinic trial using patch testing confirms utility of HLA-B*5701 and case-control study generalisability across ethnicity

Widespread uptake into clinic in developed world, incorporation into treatment guidelines, test reimbursed

ABACAVIR CLINICAL ROADMAP

2002

2002 – 2004

2002- 2008

2002- 2005

2008

2008

HLA-B*5701 & Abacavir

Lancet March 30, 2002

Lancet March 2, 2002

HLA-B*5701HLA-B*5701 and Abacavir and Abacavir Hypersensitivity: A Comparison Hypersensitivity: A Comparison

of Two Studiesof Two Studies

*Caucasians only Observed sensitivity and specificity PV assumes prevalence of ~9%

Pos Neg

Mallal et al, 2002HLA-B*5701

Hetherington et al, 2002*HLA-B57

14 4

5 177

Pos PV Neg PV

74% 98%

HSR

No HSR

Sens 78%

Spec 97%

Pos Neg

36 29

8 649

Pos PV Neg PV

82% 96%

Sens 55%

Spec 99%

Mallal, et al. Lancet 2002;359:727-2.Hetherington, et al. Lancet 2002;359:1121-2.

Early Problems with “Phenotype” Early Problems with “Phenotype”

0

20

40

60

80

100

Mallal CNA30027 CNA30032

White Black

78%

57%

48%

8%

•Early studies have observed variable sensitivity of HLA-B*5701

-Definition of abacavir hypersensitivity reaction (ABC HSR) nonspecificity of clinical phenotyping false positive clinical diagnosis-Differences in white and nonwhite races

Sens

itivity

of H

LA-B

*570

1

Mallal et al. Lancet 2002Hughes et al. Pharmacogenomics 2004

Phenotypic Uncertainty of Abacavir HSRPhenotypic Uncertainty of Abacavir HSR

Blinded StudyBlinded Study Abacavir Abacavir GroupsGroups

Zidovudine or Zidovudine or indinavirindinavir

CNA3005CNA3005 19/268 (7%)19/268 (7%) 6/265 (2%)6/265 (2%)

CNA30024CNA30024 27/324 (8%)27/324 (8%) 10/325 (3%)10/325 (3%)

Total CasesTotal Cases 46/592 (7.8%)46/592 (7.8%) 16/590 (2.7%)16/590 (2.7%)

Cases in CNA30024 as reported by Investigators in the ABC HSR CRF Module

Hernandez, et al. ADR/Lipodystrophy 2003.

Patch Testing Following Abacavir (ABC) ExposurePatch Testing Following Abacavir (ABC) Exposure

Presentation by epidermal Langerhans cells

Sensitization

Local Reaction

ABC Reactive Metabolite (Antigen)

Alcohol dehydrogenase (Abacavir)

Conjugation with host protein in skin

CYP450

CD8+

Prior ABC ingestion

Day 0 >6 weeks later

Phillips et al AIDS 2002;16:223, Phillips et al AIDS 2005;19:979. Phillips E, Mallal S. Mol Diag Ther 2009;13:19

Abacavir Skin Patch TestingAbacavir Skin Patch Testing

3 previously assigned cases had diagnosis revised

(1) Concurrent NNRTI therapy

(2) Negative patch test

Patch testing

Previously assigned cases

Carriers of 57.1 AH markers 9/9

Non-57.1 carriers (NNRTI+) 0/3

Non-57.1 carriers (NNRTI-) 1 patient unavailable

ABC HSR

ABC non-HSR Previously assigned tolerant Carriers of 57.1 AH markers 0/5

Martin, et al. PNAS 2004;23;101:4180-5.

HLAHLA--BB**57015701 and Abacavir and Abacavir HypersensitivityHypersensitivity

Reclassified first 200 patients (*not available)

Martin, et al. PNAS 2004;23;101:4180-5.

Pos Neg

HLA-B*5701

15 1*

4 180

Pos PV Neg PV

78.9% 99.4%

Sens 93.8%

Spec 97.8%

HSR

No HSR

First Randomised Study to Examine Utility of First Randomised Study to Examine Utility of Pharmacogenetic Test to Decrease toxicityPharmacogenetic Test to Decrease toxicity

N Eng J Med 2008;358:568-79

High Negative Predictive Value of HLA-High Negative Predictive Value of HLA-B*5701 Generalised Across RaceB*5701 Generalised Across Race

SPT-pos(n=42/42)

100%

CS-HSR(n=57/130)

44%

Control(n=194/202)

96%

SPT-pos(n=5/5)

100%

CS-HSR(n=10/69)

14%

Control(n=204/206)

99%

White Black

Sens

itivity

/Spe

cifici

ty o

f HLA

-B*5

701

and

95%

CI

OR: White IC-HSR 1945 [110-34352]; CS-HSR 19[8-48] Black IC-HSR 900 [30-21045]; CS-HSR 17[4-164]

Incorporation of Screening into Clinical TrialsIncorporation of Screening into Clinical Trials

*All 4/725 (0.8%) patients in ARIES study clinical diagnosed with HSR were patch test negative

AIDS 2008;22(13):1673-5

DHHS Guidelines: http://aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf: Jan 2008.

IAS Guidelines: JAMA 2008;300(5):555-70

PreferredPreferred

NNRTINNRTI EFVEFV ABC/3TCABC/3TC (for (for HLA-B*5701HLA-B*5701 negative patients) or negative patients) or

TDF/FTCTDF/FTC

PIPI FPV/r BIDFPV/r BIDLPV/r BIDLPV/r BIDATV/rATV/r

ABC/3TCABC/3TC (for (for HLA-B*570HLA-B*5701 negative patients) or1 negative patients) or

TDF/FTCTDF/FTC

Incorporation of HLA-B*5701 Testing Incorporation of HLA-B*5701 Testing into Treatment Guidelinesinto Treatment Guidelines

Laboratory Translation*Laboratory Translation*

CostCost Turn-around-Turn-around-timetime

FeasibilityFeasibility

High resolution High resolution HLA B typingHLA B typing

HighHigh

(>$500 USD)(>$500 USD)

Long (2 weeks Long (2 weeks or more)or more)

Not feasible Not feasible unless specialty unless specialty

laboratorylaboratory

PCR-based PCR-based techniquestechniques

Moderate Moderate (<$100 USD)(<$100 USD)

Moderate (<2 Moderate (<2 week)week)

Feasible for labs Feasible for labs with molecular with molecular technologiestechnologies

B17-monoclonal B17-monoclonal Flow CytometryFlow Cytometry

LowLow

(<$50 USD)(<$50 USD)

Low (mandated Low (mandated by need for fresh by need for fresh

cells)cells)

For labs doing For labs doing CD4+/8 CD4+/8

*Ongoing quality assurance program mediated by ASEATTA

MDiviney@arcbs.redcross.org.au

Phillips and Mallal, Mol Diag Ther 2009;13(1): 1-9

Cytosol

(1) Abacavir

(5) ER

HLA-B*5701 Class I MHC

Tapasin

TAP

B2m

(1) Abacavir

H 2 N

H O

O NN

N

(9) Pro-inflammatory cytokines

(8)Abacavir specific CD8+ T-cell

(6) Golgi

N

Unknown cytosolic protein?

(3) Proteosome

(4) Haptenated peptide

(10) Hypersensitivity symptoms

Cytosol

Hsp-70?

ADH Abacavir(2) Metabolism

ADH?

Reactive metabolite

(7) Surface of APC

(7) Surface of APC

HLA-B*5701+

TcR

abacavir hapten

OH

R

R

H

R

H

R

H

R

H

R

H

R

HR

H

R

H

N

R

H(4) Haptenated peptide

OH

R R=

H2N N

NH

NN APC

APC

Phillips E and Mallal S. Mol Diag Ther 2009;13(1): 1-9

Number Needed to Test...Number Needed to Test...DRUG HLA

AlleleHLA

Carriage Rate

Prevalence of diagnosis

of HSR or SJS/TEN in

high risk populations

Negative Predictive

Value

Approx. Minimum Number

needed to test to

prevent “1”

Abacavir B*5701 6-8% Caucasian

<1% African/Asian2.5% African

American

5-8% (includes 3% true HSR

and 2-7% false positive

diagnosis)

100% for patch test confirmed

14

Allopurinol B*5801 9-11% Han Chinese

1-6% Caucasian

1/250 100% in Han

Chinese

250

Carbamazepine B*1502 10-15% Han Chinese<0.1%

Caucasian

1-6/1000 100% in Han

Chinese

200

Challenges to Translation – Challenges to Translation – Beyond AbacavirBeyond Abacavir

More prospective studies needed but difficulties in More prospective studies needed but difficulties in generating high level evidence for generic drugs (???generating high level evidence for generic drugs (???funding)funding)

Generalisation difficulties for other drugs (negative Generalisation difficulties for other drugs (negative predictive value of HLA-B*5801 and HLA-B*1502 will be predictive value of HLA-B*5801 and HLA-B*1502 will be <<<100% in Caucasians)<<<100% in Caucasians)

Specificity of phenotype (lack of “patch test” Specificity of phenotype (lack of “patch test” equivalents)equivalents)

Single gene/allele associations will be unlikely for most Single gene/allele associations will be unlikely for most drugsdrugs

AcknowledgmentsAcknowledgmentsAcknowledgmentsAcknowledgments

Simon Mallal Simon Mallal James McCluskeyJames McCluskey

David NolanDavid Nolan Dianne Cheesman Dianne Cheesman

IIan Jamesan James Tess Lethborg Tess Lethborg

Mina JohnMina John Tony PurcellTony Purcell

Annalise MartinAnnalise Martin Emma Hammond Emma Hammond

Annette Patterson Annette Patterson Mandvi Bharafway Mandvi Bharafway

Campbell WittCampbell Witt Richard Harrigan Richard Harrigan

Frank ChristiansenFrank Christiansen Andri Rauch Andri Rauch

Rom KreugerRom Kreuger Amalio Telenti Amalio Telenti

Susan HerrmannSusan Herrmann Hansjakob Furrer Hansjakob Furrer

Coral-Ann AlmeidaCoral-Ann Almeida Julio Montaner Julio Montaner

GSK and PREDICT-1 and SHAPE investigators and study teamsGSK and PREDICT-1 and SHAPE investigators and study teams

National Health and Medical Research Council of Australia National Health and Medical Research Council of Australia

Simon Mallal Simon Mallal James McCluskeyJames McCluskey

David NolanDavid Nolan Dianne Cheesman Dianne Cheesman

IIan Jamesan James Tess Lethborg Tess Lethborg

Mina JohnMina John Tony PurcellTony Purcell

Annalise MartinAnnalise Martin Emma Hammond Emma Hammond

Annette Patterson Annette Patterson Mandvi Bharafway Mandvi Bharafway

Campbell WittCampbell Witt Richard Harrigan Richard Harrigan

Frank ChristiansenFrank Christiansen Andri Rauch Andri Rauch

Rom KreugerRom Kreuger Amalio Telenti Amalio Telenti

Susan HerrmannSusan Herrmann Hansjakob Furrer Hansjakob Furrer

Coral-Ann AlmeidaCoral-Ann Almeida Julio Montaner Julio Montaner

GSK and PREDICT-1 and SHAPE investigators and study teamsGSK and PREDICT-1 and SHAPE investigators and study teams

National Health and Medical Research Council of Australia National Health and Medical Research Council of Australia

Participants and clinical staff involved in the Western Australian HIV Cohort Study

Western AustralianHIV Cohort Study

Western AustralianHIV Cohort Study

Canadian Foundation for AIDS Research

Canadian Dermatology Foundation

“In the middle of difficulty lies opportunity”

“We can’t solve problems by using the same kind of thinking we used when we created them”

Albert Einstein 1878-1955