Living Science

Abacavir Hypersensitivity - A model for Personalized Medicine

Test Adoption

Hawazin Faruki, DrPH

VP, Clinical Development

Laboratory Corporation of America

10/27/09

Living Science

Profile of Laboratory Corporation of America

• National clinical reference laboratory • Offers more than 4,400 routine and esoteric/genomic

tests through a network of 36 primary testing locations and 1,600 patient service centers

• Conducts testing on more than 400,000 specimens daily and delivering >1.4 million tests results daily

• Provides quality lab services to more than 220,000 physicians and other health care providers

Living ScienceClinical Reference Laboratory

Standard of Care & Payer Adoption

Biomarker Validation &

Clinical Trials

Biomarker

Biomarker

Identification

Identification

Academia, Consortia, & Genomics Companies

PhysicianEndorsement

Pharma/Biotech& CROs

IVD Companies

PBMAnd

DM Companies

Market LaunchMarket Launch

Physicians& Payors

Slide courtesy Tom Kaminski

Living Science

Abacavir Hypersensitivity

• Abacavir (GSK) licensed for treatment of HIV in 1998

• Hypersensitivity (HSR) in 2-9% of patients characterized by fever, rash, GI, respiratory, and constitutional symptoms

• Abacavir HSR is treatment limiting and potentially life threatening (rechallenge rxn)

• GSK implemented a clinical risk management program including physician education to increase awareness and clinical vigilance

• Racial differences in risk of HSR

Hughes AR, et al. Pharmacogenomics Jrnl 2008. doi:10.1038/tpj.2008.3

Living Science

Abacavir Hypersensitivity and HLA- B*5701

• Association of HLA-B*5701 with abacavir hypersensitivity first identified in 2001

• Strength of association varied by geographic region and by race (Sensitivity 8-57% depending on racial group)

• Clinical utility of the test questioned (potential misuse of a negative result to justify rechallenge)

• Skin patch testing introduced and used to supplement clinical case ascertainment initially in Australia (2004)

Hughes AR, et al. Pharmacogenomics Jrnl 2008. doi:10.1038/tpj.2008.3

Living Science

Skin Patch Testing

• Confirmation of abacavir HSR in patients with clinically defined hypersensitivity

• Application of abacavir to the skin via a patch

• 24-48 hours later, cutaneous reaction at the patch site confirms an HSR case

• Useful only if the patient has already been exposed to abacavir

Phillips EJ et al. AIDS 2002; 16:2223-5 Phillips EJ et al. AIDS 2005; 19:979-87

Living Science

• Major Histocomaptibility Complex Genes on Chromosome 6

• Multiple hypervariable regions within each gene.

• Polymorphic loci in the human genome related to immune function

Human Leukocyte Antigen (HLA)

Living Science

Levels of Resolution

• DRB1*13XX Low resolution (serological equivalent)

• DRB1*13AB Intermediate resolution (1301 or 1302)

– results may be anywhere in a range of low/high resolution

• DRB1*1301 High resolution (4 digit allele-level)

• DRB1*130101 Synonymous variation

– 130101 and 130102 encode the same AA sequence

• Additional digits indicate non-coding or expression variants

Living Science

HLA Typing at LabCorp

• In-house molecular HLA assays performed since 1991

• High volume molecular HLA typing for the National Marrow Donor Program since 1992

• Blood or non-invasive buccal swab testing • Low, intermediate of high resolution testing• Fully accredited by CAP, ASHI, AABB, NYState• Millions of total molecular HLA typings

performed/yr

Living Science

HLA B*5701: Initial Testing Experience in U.S.

• Physician awareness limited in 2004

• A few HIV practitioners ordered generic HLA B typing

• The test was often ordered inappropriately (e.g., for African Americans, not for recommended screening application, confusion with HLA B*27 for ankylosing spondylitis,)

• LabCorp introduces a specific test for HLA-B*5701 in December 2004

Faruki H et al. Pharmacogenet Genomics 2007; 17:857-860

Living Science

HLA B*5701: Initial Testing Experience (cont.)

• Supportive tools for physicians were provided to ensure proper use and interpretation of test results:– Report format – variable sensitivity in different racial groups

– Educational materials – including need for clinical vigilance

– Genetic counselors contact physicians’ offices to ensure all results are accurately interpreted

• GSK continues to investigate the hypersensitivity cases looking for clinical or genetic predictors of risk.– Fail to identify universal markers with sufficient sensitivity

– Simultaneous independent studies from Australia

Living Science

HLA B*5701: Initial Testing Experience (cont.)

• 2004 First study using skin patch testing conducted in Australia – 78% sensitivity without skin patch testing and 94% sensitivity

with skin patch testing

• Differences in sensitivity possibly due to differences in hypersensitivity case definitions

• 2006 GSK Predict-1 clinical trial – LabCorp provides testing

• July 2007 preliminary data released – HLA-B*5701 screening universally applicable and effective

• August 2007 genetic counselor follow-up education call discontinued

Faruki H et al. Pharmacogenet Genomics 2007; 17:857-860

Living Science

Prospective Randomized Trial of HLA-B*5701 Screening (PREDICT-1)

• Multicenter study - 1956 HIV infected patients from 19 countries

• Screening pre-abacavir vs. no screen pre-abacavir • Immunologically confirmed abacavir hypersensititivity (skin

patch testing) – 0% of screened group vs. 2.7% of controls (p<0.001)

• Clinical diagnosis of abacavir hypersensitivity – 3.4% of screened group vs. 7.8% of controls (p<0.001)

• Negative predictive value was 100% • Positive predictive value was 47.9%

Mallal et al. NEJM 2008; 358:568-79

Living Science

Landmark Studies for HLA-B*5701 Acceptance

• PREDICT-1 study definitively demonstrating clinical utility in reducing risk of abacavir HSR

• SHAPE study indicating generalizability of HLA-B*5701 to non-white HIV patients - test universally applicable

• Other studies in Australia, UK, and France demonstrating similar results (2006-2007)

Saag M et al. Clin Infect Dis 2008 46:1111-8Mallal S et al. NEJM 2008; 358:568-579

Living Science

Living Science

HLA-B*5701 At LabCorp 2005-2008

• Positivity rate decreased from 7.1% in the first 6 months of 2005 to 3.65% in 2nd Qr 2008.

• Decreasing orders for evaluation of an allergic rxn and more screening orders.

Living Science

Following Establishment of Clinical Utility

• Practice guideline and/or consensus statement inclusion

• Government endorsement and inclusion - DHHS, CMS policy statements

• Payer policy statements - Insurance and managed care

• LabCorp experience with other examples – HIV genotyping – Viradapt & GART

– HPV testing - ALTS study

– HCV genotyping – Hepatitis Interventional Therapy Group

Living Science

Goldman & Faruki 2008 Genetics in Medicine 10:874-78

Living Science

Other Potential Modifiers of Test Adoption Curve

• Access to test (laboratory and/or specimen requirements)

• Regulatory Approval• Reimbursement limitations• Physician group involved

Living Science

Regulatory Factors Impacting Test Adoption

• Historically, FDA approval key to assay adoption• More recently FDA drug labeling changes and test kit

approvals have not resulted in test uptake– Warfarin, UGTA1A, Cytochrome P450 chip,

• Tests with established clinical utility have been adopted prior to specific FDA action– HLA-B*5701, HIV resistance testing in 2000, CF testing in

2001

• Abacavir drug labeling update July 2008

Living Science

Tests Where Adoption Has Not Yet Occurred

• Warfarin drug labeling (2007) and FDA cleared test kits (2008)– Questions of dosing

– Clinical utility still being established

• UGTA1A FDA cleared test in 2006– Questions of utility depending on irinotecan dose

– Variable performance in different racial and ethnic groups

• Cytochrome P450 amplichip FDA cleared in 2005– clinical utility not clearly established

– Drug application not yet fully defined (SSRI’s and EGAPP)

Living Science

Other Payer and Reimbursement Limitations

• Sometimes no applicable existing CPT code– New CPT code is a multi year process

• Multiples of the same CPT codes can be limited by payers denying payment

• Cost effectiveness data may suggest lower pricing• Licensing and royalty burden may be limiting• For HLA-B*5701 CPT coding already well

established • Cost effectiveness studies for HLA-B*5701

demonstrating effectiveness

Living Science

Test (HLA-B*5701) Adoption Influenced by Physician Group Involved

• HIV Practitioners– small closely-knit group– good education network already established– well versed in molecular diagnostics– accustomed to adjusting drug regimens based

on molecular viral load and resistance testing– Expected to incorporate new developments into

their practice on a regular basis

Living Science

HLA-B*5701 Test Adoption Summary

• Well controlled and adequately powered studies demonstrating definitive clinical utility drive test adoption.

• Label revisions and regulatory guidance accompanied test adoption but did not necessarily drive test adoption.

• Reimbursement limitations and CPT coding may slow adoption however reimbursement was well established in this case.

• Other considerations: test access, specimen requirements, and physician group involved, facilitated test adoption