1. IL28B polymorphism and SVR Do IL28B or not do IL28B? Donald M. Jensen, MD, FACP Professor of Medicine Director, Center for Liver Diseases University of Chicago, USA Stanislas Pol, MD, PhD Unité d’Hépatologie, Hôpital Cochin 27 Rue du Faubourg Saint-Jacques 75014Paris France

2. O’Brian TR et al. Nat Genet 2009 IL28B polymorphism

3. Ge et al. Nature 2009;461:399-401 Anatomy of the IL28B gene

4. Global prevalence of C/T Alleles at SNP rs 12979860 may explain recognized geographical variation in SVR rates Thomas DL, et al. Nature. 2009;461:798-802 IL28B polymorphism

5. Tillmann HL et al. Gastroenterology 2011 Genetic variation in IL28B (rs 12979860) RR 2.63 (CI: 1.8-3.9) Percent of patients achieving spontaneous clearance p = 0.021 p = 4.0*10 -8 ; RR 10.6 (CI: 2.7 – 41.1) p = 5.8*10 -78 German anti-D cohort infected with HCV genotype 1 (N=194) RR 2.63 IC: 1.8-3.9 6.1 24.4 64.2 0 10 20 30 40 50 60 70 T/T (n=2/33)C/T (n=22/90)C/C (n=43/67) IL28B polymorphism and HCV spontaneous clearance

6. Predictors of chronic vs. spontaneously cleared HCV infection 1362 individuals 1015 HCV infected 347 who cleared the virus spontaneously 448 HCV/HIV co-infected Rauch A et al. Gastroenterology. 2010;15:1338-1345 Rs 8099917 G-risk allele is associated with progression to chronicity in either HCV or HCV/HIV co-infected patients. Genetic variation in IL28B (rs 8099917) IL28B polymorphism and HCV spontaneous clearance

7. Matsuura K. Abstract 1171. EASL 2010. TT 94.4 TT 89.2 TT 23.4 TG 5.6 TG 10.8 TG 72.7 GG 3.9 0 20 40 60 80 100 Spontaneous clearance (n=107) SVR (n=185)Non response (n=128) GG TG TT Genetic variation in IL28B (Rs 8099917) IL28B polymorphism and HCV spontaneous clearance

8. IL28B polymorphism could be used in acute hepatitis C in order to: – Select patients who needed to be treated rapidly (TT or asymptomatic CT rs 12979860 and GT or GG rs 8099917) – Follow and delay treatment in patients with expected high spontaneous clearance IL28B polymorphism and HCV spontaneous clearance Practical Implications

9. IL28B polymorphism and SVR Ge D et al. Nature 2009 Genetic variation in IL28B (rs 12979860)

10. IL28B polymorphism and SVR Ge D et al. Nature 2009 Genetic variation in IL28B (rs 12979860)

11. IL28B CC genotype predict both RVR and SVR in Caucasians without RVR p>0.25 CC vs. non-CC p<0.0001 CTCCTT RVR=14% 4 % 19 % 77 % Non-RVR=86% 13 % 56 % 31 % 100% 76% 85% SVR 24% 31% 66% SVR CC CT TT IL28B polymorphism and RVR Genetic variation in IL28B (rs 12979860) Thompson AJ et al. AASLD 2009

12. Logistic regression, backward selection Covariates: rs 12979860 (2-level), ethnicity (4-level), age (>40), gender, BMI (>30), VL (>600,000), ALT (>ULN), fasting glucose (≥5.6), hepatic steatosis (>0%), fibrosis (METAVIR F34), RBV (≤13 mg/kg/d) Odds ratio95% Confidence intervalp-value CC genotype vs. non-CC5.24.16.7<0.001 VL ≤600,000 IU/mL3.12.34.1<0.001 Caucasian vs. AA ethnicity2.82.04.0<0.001 Hispanic vs. AA ethnicity2.11.33.60.004 METAVIR F0122.61.84.0<0.001 Fasting blood sugar <5.6 mmol/L1.71.32.2<0.001 IL28B polymorphism and SVR Genetic variation in IL28B (rs 12979860) Thompson AJ et al. AASLD 2009

13. Mangia A et al. Abstract 126. EASL 2010. 0 15 30 45 60 75 90 TT 88% 74% 72% 73% 79% 84% 29% 67% 87% TT CT CC SVR % 24 Weeks (n=68) 12 Weeks If RVR (n=122) 24 Weeks If no RVR (n=78) p=0.45p=0.34p=0.0002 SVR: 57% (TT), 75% (CT), 82% (CC); p=0.005 Genotype 2/3 Patients IL28B polymorphism and SVR Genetic variation in IL28B (rs 12979860)

14. CC genotype is associated with SVR only in genotype 1/4 patients. IL28B polymorphism and SVR Genetic variation in IL28B (rs 12979860) Rallon NI, et al. AIDS. 2010;15:F23-29 164 HCV/HIV co-Infected patients treated by PR

15. Reduction of viral load is independently associated with IL28B genotypes and ethnicity (p<0.0001). Thompson AJ et al. AASLD 2009 IL28B polymorphism and viral kinetics Genetic variation in IL28B (rs 12979860)

16. IL28B polymorphism and hepatic ISG Genetic variation in IL28B (rs 8099917) Honda M, et al. Gastroenterology 2010 91 patients, gene expression profile in the liver Expression of IFN stimulated gene (ISG) in relation to IL28B (Rs 8099917) Patients with up-regulated ISGs are associated with NR. IL28B polymorphisms are strongly associated with SVR (TT: 86% vs. GG: 65%; p<0.001) Hepatic ISGs were strongly associated with IL28B polymorphism; its expression was higher in patients with minor genotypes (TG or GG) The different expression of hepatic ISGs before treatment may be due to polymorphisms in IL28B

17. Dual vs. Triple therapy Duration of therapy IL28B polymorphism and SVR Practical Implications

18. IL28B polymorphism and SVR Practical Implications Dual vs. Triple therapy Duration of therapy

19. RVS (%) PR48 50/64 n/N= CCTT BOC44/ PR48 44/55 CT BOC RGT 63/77 PR48 33/116 BOC44/ PR48 82/115 BOC RGT 67/103 PR48 10/37 BOC RGT 23/42 78 82 80 28 65 71 27 55 59 0 20 40 60 80 100 BOC44/ PR48 26/44 Poordad F, et al. N Engl J Med 2011;364:1195-206 Impact of IL28B on SVR with DAAs CC patients with non extensive fibrosis (F0-2) and RVR have the same rate of SVR with dual vs. triple therapy SPRINT-2

20. Vierling JM. et al. EASL 2011. (abstract 481) % SVR All the patients (cohort 1 and cohort 2) Indétectable Impact of IL28B on SVR with DAAs CC patients with non extensive fibrosis (F0-2) and RVR have the same rate of SVR with dual vs. triple therapy

21. Dual vs. Triple therapy Duration of therapy IL28B polymorphism and SVR Practical Implications

22. Retrospective analysis of randomized comparing PEG-IFNα-2a 180 μg/w. + RBV 1000-1200 mg/j 24 w. vs 48 w. in Taïwan 662 genotype 1-infected patients Liu CH et al. AASLD 2011, Abs. 414 0 20 40 60 80 100 IL28B rs8099917 TT ARN < 600 000 UI/ml IL28B rs8099917 TT ARN > 600 000 UI/ml 24 w. 48 w. 95 99 70 97 % SVR if RVR p = 0.21p < 0.001 Impact of IL28B on SVR

23. RVS (%) PR48 50/64 n/N= CCTT BOC44/ PR48 44/55 CT BOC RGT 63/77 PR48 33/116 BOC44/ PR48 82/115 BOC RGT 67/103 PR48 10/37 BOC RGT 23/42 78 82 80 28 65 71 27 55 59 0 20 40 60 80 100 BOC44/ PR48 26/44 RVS (%) PR48 35/55 n/N= CCTT T12PR 45/50 PR48 6/26 T12PR 16/22 PR48 20/80 T12PR 48/68 CT 64 90 25 71 23 73 0 20 40 60 80 100 Impact of IL28B on SVR with DAAs Poordad F, et al. N Engl J Med 2011;364:1195-206; Jacobson IM, et al. N Engl J Med 2011;364:2405­16 Higher rate of SVR in CC vs. CT/TT

24. PILLAR study with TMC435 0 20 40 60 80 100 % SVR CC 100 97 84 CT/TT 50 78 73 123531347278n = P/RTMC435 150 mgTMC435 75 mg Fried MW et al. AASLD 2011, Abs. LB5 Impact of IL28B on SVR with DAAs Higher rate of SVR in CC vs. CT/TT

25. (SPRINT-2: Boceprevir in naïve patients) RVS (%) 50 54 27 28 78 55 65 82 59 71 80 0 10 20 30 40 50 60 70 80 90 100 CCCTTT PR48BOC TGRBOC/PR48 50 64 63 77 44 55 33 116 67 103 82 115 10 37 23 42 26 44 Poordad F, et al. N Engl J Med 2011;364:1195-206 Impact of IL28B on SVR with DAAs Higher rate of « short » treatments in CC vs. CT/TT : ~ 80 % of CC naïve patients are eligible

26. 50 17 46 55 61 79 72 73 77 0 10 20 30 40 50 60 70 80 90 100 CCCTTT 6 13 22 28 17 22 5 29 38 62 48 66 13 18 6 11 5 10 PR48BOC TGRBOC/PR48 Bacon BR et al. N Engl J Med 2011;364:1207-17 RVS (%) (RESPOND-2: Boceprevir in experienced patients) Impact of IL28B on SVR with DAAs Higher rate of « short » treatments in CC vs. CT/TT : ~ 80 % of CC experienced patients are eligible

27. SVR Rates by IL28B Genotype and Prior Response Prior relapsers Patients achieving SVR (%) Prior partial responders Prior null responders CCCT TT CCCT TT CCCT TT Pooled T12/PR48 (n=209) Pbo/PR48 (n=52) Pooled T12/PR48 (n=79) Pbo/PR48 (n=20) Pooled T12/PR48 (n=134) Pbo/PR48 (n=33) 51/58 4/12100/117 6/3029/34 3/105/81/5 33/57 2/1010/14 0/5 4/1027/92 1/1810/32 1/150/0 n/N= Impact of IL28B on SVR with DAAs Pol S, et al. EASL 2011

28. Phase II, randomized controlled trial in genotype 1 naïve patients in 323 patients Telaprevir (TVR) 750 mg/8 h, PEG-IFN 180 µg/w, RBV 1 000-1 200 mg/d Phase II, randomized controlled trial in genotype 1 naïve patients in 323 patients Telaprevir (TVR) 750 mg/8 h, PEG-IFN 180 µg/w, RBV 1 000-1 200 mg/d PR48 (n = 82) T12/PR24 (n = 81) T12/PR12 (n = 82) T12/P12 (n = 78) TVR + PEG-IFNα-2a Placebo + PEG-IFNα-2a + ribavirin (RBV) PEG-IFNα-2a + RBV TVR + PEG-IFNα-2a + RBV Hezode C et al. NEJM 2009 Impact of IL28B on SVR with DAAs Prove 2 sub-analysis

29. Hezode C et al. NEJM 2009 Virologic Response after treatment Relapse (%) 0 20 40 60 80 PR48T12/PR24T12/PR12 T12/P12 (No RBV) 48 % 68 62 36 39/8255/8151/8228/78 NS* p = 0.01* p = 0.08* SVR * vs PR48 0 10 20 30 50 PR48T12/PR24T12/PR12 T12/P12 (No RBV) 20 % 14 29 48 9/458/5618/6322/46 40 RVS 12 Impact of IL28B on SVR with DAAs Prove 2 sub-analysis

30. Virologic Response after treatment 0 20 40 60 80 PR48T12/PR24T12/PR12 T12/P12 (No RBV) 48 % 68 62 36 39/8255/8151/8228/78 NS* p = 0.01* p = 0.08* SVR * vs PR48 RVS 12 Impact of IL28B on SVR with DAAs Prove 2 sub-analysis TPR 12w : 100% CC SVR < 50% CT/TT By courtesy of J-P. Bronowicki

31. Early treatment of acute hepatitis Dual vs. Triple therapy: PR vs. BOC/TVR PR Duration of therapy: 12w/24w/36 w or 48w IL28B polymorphism Practical Implications The “Pro” summary

32. IL28B in the Era of DAA Therapy: What’s not to like? Can we avoid the toxicity of DAAs and use dual therapy in IL28B CC patients? Is knowledge of IL28B CC status helpful in encouraging patients to be treated with the hope of eRVR+ RGT? Can we use IL28B TT or CT information in patients with “mild” disease to wait for newer therapies with better outcomes?

33. Dual versus Triple Therapy The argument: Dual therapy for IL28B CC is more cost-effective than triple therapy: – For patients with IL28B CC: SVR rates (~90%) are about the same with P/R as if T/P/R was used right from the start – It is more cost-effective to treat IL28B CC subjects initially with PEG/RBV and reserve TVR-based triple therapy to those who do not respond. Gellad et al: AASLD 2011

34. Dual versus Triple Therapy However,…. – This two step strategy means that at least 36% of patients will require a subsequent course of triple therapy – It assumes that 100% of P/R failures will undergo re- treatment - not supported by clinical experience data. – Evolution of therapy may demonstrate that these uniquely responsive patients may achieve a comparably high rate of SVR with only 12 weeks of triple therapy without the need for a PEG/RBV tail (trial in progress) – Finally, patients may refuse a non-DAA containing therapy

35. Duration of Therapy: 24 vs 48 weeks The argument: Those with geno-1, IL28B CC are more likely to have an eRVR and qualify for 24 weeks (RGT) therapy. However,…. – Regardless of IL28B status, an eRVR still requires actual measurement of undetectable HCV RNA at weeks 4 and 12 – Therefore, it’s on-treatment virologic responses that really matter, not pre-treatment dispositions

36. Selecting Candidates for Therapy Argument: IL28B CT or TT with ‘mild disease’ may be able to wait for future therapies However,… – How do we define ‘mild’? What is the accuracy? E.g. Liver bx: 25-30% may miss cirrhosis – Should all ‘mild’ cases be deferred given the toxicity of DAA triple therapy? – When is IFN-free therapy anticipated?

37. Selecting Candidates for Therapy Argument: IL28B may identify a cohort of uniquely sensitive subjects for short course IFN-free therapy However,…. – As therapies become more effective (>90% SVR), the role of IL28B will decline as a predictor (e.g. PILLAR) – In the absence of IFN, is there even a role for - IFN responsiveness? (e.g. PROTON)

38. Summary How will IL28B be utilized in the era of DAA triple therapy? – Predict shorter treatment duration – Identify patients who may benefit from dual therapy However,… – True utilization may depend upon real life clinical experience with triple therapy and retrospective analysis of IL28B Ten years too late????