1. VP, Clinical Development Laboratory Corporation of America
Abacavir Hypersensitivity - A model for Personalized Medicine Test Adoption
Hawazin Faruki, DrPH
VP, Clinical Development
Laboratory Corporation of America
10/27/09

2. 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

3. Clinical Reference Laboratory
Physicians
& Payors
Pharma/Biotech
& CROs
IVD
Companies
Academia,
Consortia, &
Genomics
Companies
PBM
And
DM Companies
Biomarker
Identification
Biomarker Validation
&
Clinical Trials
Market Adoption
Market Launch
Standard of Care &
Payer Adoption
Physician
Endorsement
Slide courtesy Tom Kaminski

4. 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 doi: /tpj

5. 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 doi: /tpj

6. 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: Phillips EJ et al. AIDS 2005; 19:979-87

7. Human Leukocyte Antigen (HLA)
Major Histocomaptibility Complex Genes on Chromosome 6
Multiple hypervariable regions within each gene.
Polymorphic loci in the human genome related to immune function

8. 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* High resolution (4 digit allele-level)
DRB1* Synonymous variation
and encode the same AA sequence
Additional digits indicate non-coding or expression variants

9. 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

10. 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:

11. 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

12. 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:

13. Prospective Randomized Trial of HLA-B*5701 Screening (PREDICT-1)
Multicenter study 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

14. 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 ( )
Saag M et al. Clin Infect Dis :1111-8
Mallal S et al. NEJM 2008; 358:

16. HLA-B*5701 At LabCorp
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.

17. 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

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

19. Other Potential Modifiers of Test Adoption Curve
Access to test (laboratory and/or specimen requirements)
Regulatory Approval
Reimbursement limitations
Physician group involved

20. 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

21. 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)

22. 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

23. 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

24. 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