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Overcoming the Barriers of Clinical Translation: The Abacavir Example

Overcoming the Barriers of Clinical Translation: The Abacavir Example. Elizabeth J. Phillips, MD, FRCPC, FRACP Professor & Director, Centre for Clinical Pharmacology & Infectious Diseases, Murdoch University Royal Perth Hospital, Sir Charles Gairdner Hospital Perth, Western Australia.

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Overcoming the Barriers of Clinical Translation: The Abacavir Example

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  1. Overcoming the Barriers of Clinical Translation: The Abacavir Example Elizabeth J. Phillips, MD, FRCPC, FRACP Professor & Director, Centre for Clinical Pharmacology & Infectious Diseases, Murdoch University Royal Perth Hospital, Sir Charles Gairdner Hospital Perth, Western Australia ASCEPT December 1, 2009

  2. Translation is an Active Process -Intepretable and cost-effective test -broad uptake in clinical practice -positive impact on patient effiacy and/or safety <1% Pharmacogenetic/genomic Discovery >99% “Lost in Translation” -improved understanding of pathophysiology of disease, mechanism of drug efficacy, toxicity -identification of new therapeutic targets

  3. T1T4: The Translational Paradigm Step 1 - A discovery with a potential application Step 2 - Generation of high-level clinical evidence - Basic science supports biological plausibility Step 3 - Delivery of research to the clinic - Quality assurance, valid, efficient and inexpensive lab testing and lab report easy to interpret Step 4 - Evaluation of test in real clinical practice

  4. ABACAVIR CLINICAL ROADMAP Abacavir causes abacavir hypersensitivity (ABC HSR) in 5-8% 1998 2002 2002 – 2004 2002- 2008 2002- 2005 2008 2008 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

  5. HLA-B*5701 & Abacavir Lancet March 2, 2002 Lancet March 30, 2002

  6. HLA-B*5701 and Abacavir Hypersensitivity: A Comparison of Two Studies Hetherington et al, 2002*HLA-B57 Mallal et al, 2002 HLA-B*5701 Pos Neg Pos Neg HSR 14 4 Sens 78% 36 29 Sens 55% No HSR 5 177 Spec 97% 8 649 Spec 99% Pos PV Neg PV Pos PV Neg PV 74% 98% 82% 96% *Caucasians only Observed sensitivity and specificity PV assumes prevalence of ~9% Mallal, et al. Lancet 2002;359:727-2. Hetherington, et al. Lancet 2002;359:1121-2.

  7. 78% 57% 48% 8% Early Problems with “Phenotype” • 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 100 80 60 Sensitivity of HLA-B*5701 40 20 0 Mallal CNA30027 CNA30032 Mallal et al. Lancet 2002 Hughes et al. Pharmacogenomics 2004 White Black

  8. Phenotypic Uncertainty of Abacavir HSR Cases in CNA30024 as reported by Investigators in the ABC HSR CRF Module Hernandez, et al. ADR/Lipodystrophy 2003.

  9. CD8+ Patch Testing Following Abacavir (ABC) Exposure Alcohol dehydrogenase (Abacavir) CYP450 Prior ABCingestion ABC  Reactive Metabolite (Antigen) Sensitization Conjugation with host protein in skin Presentation by epidermal Langerhans cells Local Reaction 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

  10. Patch testing ABC HSR 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 Previously assigned tolerant Carriers of 57.1 AH markers 0/5 ABC non-HSR Abacavir Skin Patch Testing 3 previously assigned cases had diagnosis revised (1) Concurrent NNRTI therapy (2) Negative patch test Martin, et al. PNAS 2004;23;101:4180-5.

  11. HLA-B*5701 and Abacavir Hypersensitivity HLA-B*5701 Pos Neg HSR 15 1* Sens 93.8% No HSR 4 180 Spec 97.8% Pos PV Neg PV 78.9% 99.4% Reclassified first 200 patients (*not available) Martin, et al. PNAS 2004;23;101:4180-5.

  12. First Randomised Study to Examine Utility of Pharmacogenetic Test to Decrease toxicity N Eng J Med 2008;358:568-79

  13. 100% 99% 96% 44% 14% CS-HSR (n=57/130) SPT-pos (n=42/42) Control (n=194/202) CS-HSR (n=10/69) SPT-pos (n=5/5) Control (n=204/206) High Negative Predictive Value of HLA-B*5701 Generalised Across Race 100% Sensitivity/Specificity of HLA-B*5701 and 95% CI White Black OR: White IC-HSR 1945 [110-34352]; CS-HSR 19[8-48] Black IC-HSR 900 [30-21045]; CS-HSR 17[4-164]

  14. Incorporation 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

  15. Incorporation of HLA-B*5701 Testing into Treatment Guidelines DHHS Guidelines: http://aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf: Jan 2008. IAS Guidelines: JAMA 2008;300(5):555-70

  16. Laboratory Translation* Phillips and Mallal, Mol Diag Ther 2009;13(1): 1-9 *Ongoing quality assurance program mediated by ASEATTA MDiviney@arcbs.redcross.org.au

  17. (1) Abacavir (1) Abacavir NH N N N H2N N R R R R R R R R R R R OH OH H H H H H H H H H O N H2N N N HO R= APC ADH Cytosol Abacavir (2) Metabolism APC Cytosol Reactive metabolite (3) Proteosome ADH? (7) Surface of APC Hsp-70? Unknown cytosolic protein? HLA-B*5701+ (4) Haptenated peptide abacavir hapten TcR (5) ER (8)Abacavir specific CD8+ T-cell HLA-B*5701 Class I MHC TAP N B2m Tapasin (6) Golgi (4) Haptenated peptide (9) Pro-inflammatory cytokines (7) Surface of APC Phillips E and Mallal S. Mol Diag Ther 2009;13(1): 1-9 (10)Hypersensitivity symptoms

  18. Number Needed to Test...

  19. Challenges to Translation – Beyond Abacavir • More prospective studies needed but difficulties in generating high level evidence for generic drugs (???funding) • Generalisation difficulties for other drugs (negative predictive value of HLA-B*5801 and HLA-B*1502 will be <<<100% in Caucasians) • Specificity of phenotype (lack of “patch test” equivalents) • Single gene/allele associations will be unlikely for most drugs

  20. Acknowledgments Participants and clinical staff involved in the Western Australian HIV Cohort Study Simon Mallal James McCluskey David Nolan Dianne Cheesman Ian James Tess Lethborg Mina John Tony Purcell Annalise Martin Emma Hammond Annette Patterson Mandvi Bharafway Campbell Witt Richard Harrigan Frank Christiansen Andri Rauch Rom Kreuger Amalio Telenti Susan Herrmann Hansjakob Furrer Coral-Ann Almeida Julio Montaner GSK and PREDICT-1 and SHAPE investigators and study teams National Health and Medical Research Council of Australia Canadian Foundation for AIDS Research Canadian Dermatology Foundation

  21. “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

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