1. HLA-B*5701 and Abacavir Alec Walker October 2014

2. Part I. Discovery 2 Association between presence of HLAB*5701, HLA-DR7, and HLA-DQ3 and hypersensitivity to HIV-1 reverse-transcriptase inhibitor abacavir S Mallal, D Nolan, C Witt, G Masel, A M Martin, C Moore, D Sayer, A Castley, C Mamotte, D Maxwell, I James, F T Christiansen Lancet 2002; 359: 727–32

3. Living with Cost and Benefit 3 Background The use of abacavir—a potent HIV-1 nucleoside- analogue reverse-transcriptase inhibitor—is complicated by a potentially life- threatening hypersensitivity syndrome in about 5% of cases. Genetic factors influencing the immune response to abacavir might confer susceptibility. We aimed to find associations between MHC alleles and abacavir hypersensitivity in HIV-1 positive individuals treated with abacavir. 1.Why use abacavir, ever? 2.How would knowledge of a predictor of hypersensitivity affect the cost-benefit profile?

4. Translating into Formal Structure 4 Methods MHC region typing was done in the first 200 Western Australian HIV Cohort Study participants exposed to abacavir. Definite abacavir hypersensitivity was identified in 18 cases, and was excluded in 167 individuals with more than 6 weeks’ exposure to the drug (abacavir tolerant). 15 individuals experienced some symptoms but did not meet criteria for abacavir hypersensitivity. p values were corrected for comparisons of multiple HLA alleles (p c ) by multiplication of the raw p value by the estimated number of HLA alleles present within the loci examined. 3. What is the study design (e.g. cohort, case- control, case-crossover, cross-sectional, other?)

5. What is the Risk Associated with … 5

6. Which Genotype? 6 4.(Note that Predictive Value = Risk.) How do you balance Sensitivity (displayed) and Predictive Value in choosing a criterion?

7. Graphical Presentation 7 5. What does this chart convey that the tabulations miss?

8. Many Comparators 8 6. What information do other comparators offer? Do they tell you about risk?

9. Part II. Assessment 9 Prospective Genetic Screening Decreases the Incidence of Abacavir Hypersensitivity Reactions in the Western Australian HIV Cohort Study A. Rauch, D. Nolan, A. Martin, E. McKinnon, C. Almeida, and Simon Mallal Clinical Infectious Diseases 2006;43:99–102

10. Design: Screen All Patients Treat with Abacavir only Those Who are Negative 10 Any symptoms Hypersensitivity 7. Why does screening reduce the occurrence of symptoms other than those of hyper- sensitivity?

11. When HLA-B*5701 Patients Were Treated with Abacavir 11 Of the 9 ART-naive, HLA-B*5701–positive patients identified by genetic screening, 1 patient started abacavir treatment before the review of HLA results. This 48-year- old white man subsequently developed a typical abacavir hyper-sensitivity reaction, characterized by the development of a widespread maculopapular rash, fever, and constitutional symptoms 6 days after commencing abacavir therapy. Of the 14 ART-experienced, HLA-B*5701–positive patients who were screened, 2 started abacavir therapy. In 1 case, HLA test results were not reviewed before drug prescription, and 1 patient made an informed choice to initiate abacavir therapy because … of previous treatment complications)... Both of these white patients experienced abacavir hypersensitivity reactions….

12. What More Information is Needed? An RCT of abacavir screening was undertaken. Suggest:  Exposure measure  Outcomes  Necessity for blinding  Generalizability  Ethical justification. 12

13. 13 Mallal S, et al for the PREDICT-1 Study Team. HLA-B*5701 screening for hypersensitivity to abacavir. N Engl J Med. 2008 Feb 7;358(6):568-79

14. Exposures  Prospective HLA-B*5701 pharmacogenetic screening followed by combination active antiretroviral therapy that included abacavir (the prospective-screening group), or  Combination active antiretroviral therapy that included abacavir, followed by retrospective HLA- B*5701 pharmacogenetic screening (the control group). 14

15. Endpoints  Risk of clinically diagnosed hypersensitivity reaction to abacavir during the 6-week observation period  Risk of immunologically confirmed hypersensitivity reaction (defined as a clinically diagnosed reaction that was confirmed by a positive result on epicutaneous patch testing 6 to 10 weeks after clinical diagnosis). 15

16. Endpoints 16 Note that the clinically diagnosed events that were not confirmed were fewer in the prospective screening group (27 or 3.4% vs. 43 or 5.1%). Why? Granting that these are unrelated to HLA- B*5701, would you still count this difference as an effect of screening?

17. Ethics, revisited “The strength of the existing evidence, the availability of patch testing as a research tool for the identification of patients who could have had a hypersensitivity reaction, and widespread acknowledgment that definitive prospective data are required to include HLA- B*5701 screening in the standard of care provide the rationale for our study.” The justification rests on a belief that the observational data were not definitive. Do you agree? 17

18. 18 From the 9/11/2013 label http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Sear ch.Label_ApprovalHistory#apphist

19. Thank You!