1. HLA Testing: A Single Centre Experience Laura Waters, Andrea Gritz, Desmond Maitland, Brian Gazzard & Mark Nelson. Research Fellow PKR/SSR St. Stephen’s Centre Chelsea & Westminster Hospital, London

2. Introduction Guidelines recommend 3 fixed dose NRTI combinations for initial therapy: - Tenofovir + emtricitabine - Abacavir* + lamivudine - Zidovudine + lamivudine Combivir ® less attractive due to twice daily dosing and probable association with lipoatrophy *ABC

3. Introduction Adverse events are a common cause of treatment discontinuation 1,2 ABC HSR occurs in 5-8% individuals 3,4 Strong association between ABC HSR and HLA B*5701 positivity 5,6 Prospective testing has reduced ABC HSR in two cohorts 7,8 1. Monforte et al 2000; 2. O’Brien et al 2003; 3. European SPC; 4. US SPC; 5. Mallal et al 2002; 6. Hetherington et al 2002; 7. Rauch et al 2006; 8. Reeves et al 2006.

4. 0.0 0.05 0.10 0.15 0.20 1998/19992000/20012002/20032004–7/2005 Possible ABC- related symptoms Definite ABC HSR # 2 patients results not reviewed prior to therapy $ 1 patient with informed choice/incomplete haplotype Proportion of ABC-naïve patients discontinuing ABC within 6 weeks n=68n=131n=107n=60 # Before genetic screening After genetic screening #$#$ *p<0.05 Rauch A et al 2006. Fall in early ABC discontinuation with genetic screening

5. 0.0 0.05 0.10 0.15 0.20 1998/19992000/20012002/20032004–7/2005 Possible ABC- related symptoms Definite ABC HSR # 2 patients results not reviewed prior to therapy $ 1 patient with informed choice/incomplete haplotype Proportion of ABC-naïve patients discontinuing ABC within 6 weeks n=68n=131n=102n=49 # Before genetic screening After genetic screening #$#$ *p<0.05 Rauch A et al 2006. Fall in early ABC discontinuation with genetic screening

6. Clinician assessed HSR pre and post-B*5701 0.5% (0.1-3.0%) 6.2% (4.1-9.4%) p = 0.001 total HSR Number of subjects Pre B*5701Post B*5701 0 50 100 150 200 250 300 350 Reeves I et al. ADRL 2006

7. Aims To describe the frequency of the HLA B*5701 allele in our clinic cohort To assess the rate of ABC discontinuation with prospective HLA testing To compare ABC HSR rates before and after the introduction of routine HLA B*5701 screening

8. Methods HLA screening was introduced in August 2005 for: - all treatment-naïve subjects commencing therapy - treatment-experienced patients considering a switch to ABC ABC avoided if B*5701 positive All individuals undergoing HLA testing between 1/8/05 and 1/7/06 were reviewed

9. Methods Data collected: - gender, ethnicity - treatment history - adverse events Detailed case note review of all subjects discontinuing ABC Suspected ABC HSR rate with prospective B*5701 screening compared with historical ABC HSR rate (1/8/04 – 1/8/05)

10. Statistical Methods ABC HSR rates before and after the use of prospective HLA B*5701 testing: Chi-squared test with Yates’ correction ABC HSR rates between groups: Chi-squared test with Yates’ correction or Fisher’s exact test

11. Results 739 HLA B*5701 tests performed: - 735 successful - 4 test failures 54/735 tested HLA B*5701 positive = 7.3% 11/111 females HLA B*5701 positive = 9.9% # 43/624 males HLA B*5701 positive = 6.9% # # p-value 0.35, Yates’ Correction

12. Results EthnicityTotal number HLA B*5701+; number (%) White52340 (7.6%) Black13412 (9.0%) Other612 (3.3%) Unknown170 TOTAL74154 (7.3%)

13. Results Subjects testing HLA B*5701 positive (n=54) Naïve (n=25) - 14 did not commence therapy - 9 commenced non-ABC cART - 2 commenced ABC; both HSR Experienced (n=29) - None commenced ABC - 7 history of ABC exposure - 4/7 symptoms of HSR - 2/6 tolerated ABC (for 6 W & 5 Y) - 1/6 switched at 9/7 with result

14. Results Subjects testing HLA B*5701 negative (n=681) Naïve (n=285) - 163 remain off therapy - 122 commenced cART - 47 commenced ABC with no discontinuations Experienced (n=396) - 151 switched to ABC - 8 discontinued ABC (5.3%) - 4/8 suspected HSR (2.6%)

15. B*5701- Suspected HSR Clinical FeaturesSPP 1 Increasing fever, myalgia, rash, nausea & SOB 8 weeks into ABC therapy POSITIVE + systemic symptoms 2 Nausea, fever, myalgia 3 weeks into ABC; resolve with cessation NEGATIVE 3 Fatigue & GI symptoms 10 days into ABC; resolve with cessation REFUSED 4 Fever, dizziness & GI symptoms 2 weeks into ABC; resolve with cessation PENDING SPP = Skin Patch Testing

16. 0 20 40 60 80 100 120 140 160 180 200 Number individuals 134 10 6 201 Pre-B*5701 testing Pre-B*5701 testing Starting ABC Suspected HSR 7.5% 3.0% p = 0.10 Suspected HSR Pre & Post Prospective B*5701 Testing

17. 0 20 40 60 80 100 120 140 160 180 200 Number individuals 134 10 4 199 Pre-B*5701 testing Pre-B*5701 testing Starting ABC Suspected HSR 7.5% 2.0% p = 0.03 Suspected HSR Pre & Post Prospective B*5701 Testing

18. 0 20 40 60 80 100 120 140 160 Naïve individuals Experienced individuals 47 0 151 4 p = 0.57* 2.6% ABC HSR Rates in Treatment- Naïve & Experienced Subjects Starting ABC Suspected HSR *by Fisher’s exact test

19. Conclusions The introduction of prospective HLA B*5701 screening reduced the incidence of ABC HSR in our cohort Despite testing HLA B*5701 negative, 4 individuals (2.0%) discontinued ABC for suspected HSR

20. Conclusions 1 HLA B*5701 negative subject developed HSR with a positive SPP and systemic symptoms Our data highlight the importance of maintaining clinical vigilance when prescribing ABC regardless of the HLA B*5701 result

21. Acknowledgements Sundhiya Mandalia Marta Boffito St Stephen’s Centre staff & patients