1. Genetik og bivirkninger til antiretroviral terapi (HLA, HIV & abacavir hypersensitivity) Thomas Benfield Overlæge, dr.med. Infektionsmedicinsk afdeling Hvidovre Hospital

2. Antiretrovirale stoffer T-20 (’04) Maraviroc (’06) Tipranavir (’05) Darunavir (’06) Etavicrine (’07) Raltegravir (’07) Emtricitabine Entry inhibitors:Integration:

3. EuroSIDA: Mocroft et al. Lancet 2003

5. Association between presence of HLA-B*5701, HLA-DR7, and HLA-DQ3 and hypersensitivity to HIV-1 reverse-transcriptase inhibitor abacavir Mallal et al. Lancet 2002; 359: 727 185 patients with either reaction or > 6 weeks exposure PPV 100% NPV 97%

6. Genetic variations in HLA-B region and hypersensitivity reactions to abacavir Hetherington et al. Lancet 2002; 359: 1121 Case-control study of 85 patients with ABC reaction and 115 controls with > 6 weeks ABC exposure Sensitivity 33-55%

7. Martin et al. PNAS2004

8. Predisposition to abacavir hypersensitivity conferred by HLA-B*5701 and a haplotypic Hsp70- Hom variant Martin et al. PNAS2004

10. Original Article HLA-B*5701 Screening for Hypersensitivity to Abacavir Simon Mallal, M.B., B.S., Elizabeth Phillips, M.D., Giampiero Carosi, M.D., Jean- Michel Molina, M.D., Cassy Workman, M.B., B.S., Janez Tomažič, M.D., Eva Jägel- Guedes, M.D., Sorin Rugina, M.D., Oleg Kozyrev, M.D., Juan Flores Cid, M.D., Phillip Hay, M.B., B.S., David Nolan, M.B., B.S., Sara Hughes, M.Sc., Arlene Hughes, Ph.D., Susanna Ryan, Ph.D., Nicholas Fitch, Ph.D., Daren Thorborn, Ph.D., Alastair Benbow, M.B., B.S., for the PREDICT-1 Study Team N Engl J Med Volume 358(6):568-579 February 7, 2008

11. Eligibility Criteria  Key inclusion criteria: –Naïve to ABC –Pre-study need for ABC treatment  Key exclusion criteria: –Contraindications to ABC –Known HLA-B*5701 status

12. Double-Blind Study Design 6-Week Observation Period ABC-naïve subjects ABC-containing regimen HSR monitoring according to Standard of Care plus HLA-B*5701 screening 2 (screening arm) ABC-containing regimen HSR monitoring according to Standard of Care 1 (control arm) Randomise (1:1) HLA-B*5701 positive subjects excluded HLA-B*5701 negative subjects continued 1. retrospective high resolution typing 2. prospective high resolution typing

13. Blinded Independent Skin Patch Testing  Immune cell-mediated reaction  Research tool used to identify patients with immune-mediated abacavir HSR Adhesive surface Petrolatum control Excipient control 1% abacavir 10% abacavir Phillips et al. AIDS 2002 and 2005 Phillips et al. IAS 2007 Abstract MOPEB001 24-hour reading(48 hour reading)

14. Analysis Populations  ITT (n=1956) – number of subjects randomised  ITT exposed (n=1772) – number of subjects with at least one dose of ABC-containing medication Primary population for analysis  ITT evaluable (n=1650) – all randomised patients who started abacavir and either completed the six-week observation period or stopped ABC early due to HSR

15. 0 1 2 3 4 5 6 7 8 9 Incidence (%) 3.4% (27/803) 7.8% (66/847) 2.7% (23/842) OR 0.40 P < 0.0001 OR 0.03 P < 0.0001 Control arm Prospective HLA-B*5701 screening arm Clinically Suspected HSR Immunologically Confirmed HSR Clinically Suspected and Immunologically Confirmed HSR in ITT evaluable population 0.0% (0/802) (0.25, 0.62) (0, 0.18)

16. Multivariate Analysis of Covariates associated with HSR (Odds Ratio) CovariatesClinically suspected Immunologically -confirmed* Clinically suspected but not immunologically- confirmed † Prospective HLA-B*5701 screening vs control 0.40 P<0.0001 0.03 P<0.000001 0.69 P=0.1513 White vs non-white2.19 P=0.0242 4.21 P=0.1139 2.00 P=0.0879 ART-naïve vs ART- experienced 1.37 P=0.2611 1.20 P=0.6637 1.49 P=0.2213 Introduction of NNRTI: yes vs no 3.19 P=0.0011 1.45 P=0.5693 4.04 P=0.0008 Concurrent PI use: yes vs no 1.86 P=0.0094 1.05 P=0.9123 2.38 P=0.0031 * For the analysis of immunologically-confirmed HSR the same covariates were used as those found to be important for clinically diagnosed HSR. † Clinically diagnosed cases with negative EPT results.

17. Performance Characteristics of HLA-B*5701 Screening for HSR HSR No HSR PosNeg Immunologically Confirmed HSR 1 HLA-B*5701 230 25794 Pos PV 48% Neg PV 100% Sens 100% Spec 97% Clinically Suspected HSR 1 HLA-B*5701 PosNeg 3036 19762 Pos PVNeg PV 62%96% Sens 46% Spec 98% 1 Control Arm Data Only

18. Screening Implications Test 100 subjects: –Treat 94 subjects at low risk for ABC HSR –Prevent 4 ABC HSR events –Inappropriately exclude ABC in 2 subjects –Open screening may also reduce clinical overdiagnosis of HSR Do not treat with ABC Appropriate to treat with ABC Example shown is based upon PPV calculated from PREDICT-1 HLA-B*5701 test 94 Negative 6 Positive PREDICT-1 Population n = 100

19. Conclusion HLA-B*5701 screening reduced the risk of hypersensitivity reaction to abacavir In predominantly white populations, similar to the one in this study, 94% of patients do not carry the HLA-B*5701 allele and are at low risk for hypersensitivity reaction to abacavir Our results show that a pharmacogenetic test can be used to prevent a specific toxic effect of a drug

20. The prevalence of HLA-B*5701 in different parts of the world Phillips et al. CID2006 Nolan et al. J HIV Ther 2003

21. Ingelman-Sundberg. NEJM 2008

22. Baggrund: Codon 244-252 præsenteres af HLA-B5701 RT og pol sekventeres rutinemæssigt

24. Prevalence of HLA-B*5701 and substitutions at RT codon 245 at baseline. HLA-B5701Non-B5701 RT 245V (wild type)1/24 (4%)278/368 (76%) RT 245E/M/L23/24 (96%)90/368 (14%) Sensitivity: 96% Specificity: 76% PPV: 20% NPV: 99% P < 0.001

25. http://www.ebi.ac.uk/imgt/hla/ http://www.allelefrequencies.net HLA nomenclature