How to manage G1 relapsers and non-responders George V. Papatheodoridis, MD Associate Professor in Medicine & Gastroenterology 2nd Department of Internal Medicine, Athens University Medical School, Hippokration General Hospital, Athens, Greece

Case 1 - AM 01/2008 Male, 42 y.o., H: 1.75 m, W 77 Kg, BMI 25.1 Kg/m 2, no other disease G1a, HCV RNA 1,200,000 IU/mL, Fibroscan 6.3 (0.9) kPa Peg-IFNa-2a (180 μg/wk) + RBV (1.2 g/d) x48 wks HCV RNA (-) at 12 & 48 wks, (+) at 72 wks No therapy - Transient, mild ALT elevations 12/2011 HCV RNA 2,200,000 IU/mL, Fibroscan 6.0 (1.0) kPa

Case 1 – AM – Question 1 Would you retreat this patient today? (BOC/TPV available) 1.No 2.Yes a. Peg-IFN + RBV b. Peg-IFN + RBV + BOC/TPV

SVR (%) 4-wk PR + 44-wk BOC+PR All relapsers 48-wk PR4-wk PR + 32-wk BOC+PR ± 12-wk PR RESPOND-2: SVR after ΒΟC based therapy in G1 relapsers Bacon BR et al. ΝΕJM 2011; 364: Ν= FO/F1/F2/F3 Relapsers F4 N=

PROVE 3 / REALIZE: SVR under TPV based therapy in G1 relapsers SVR (%) McHutchison JG et al. NEJM 2010;362: Zeuzem S et al. NEJM 2011;364: wk TPV+PR 24-wk TPV+PR 48-wk PR + 12-wk PR + 24-wk PR PROVE 3 trial P < wk TPV+PR 4-wk PR + 48-wk PR + 36-wk PR 12-wk TPV+PR + 32-wk PR REALIZE trial P <.0001

REALIZE: SVR in G1 prior relapsers by baseline fibrosis stage Stage No, minimal or portal Bridging fibrosis Cirrhosis fibrosis Patients with SVR, % Pooled T12/PR48 Pbo/PR48 n/N 145/167 12/38 53/62 2/15 48/57 1/15 Pol S et al. Hepatology 2011;54(Suppl. S1): 374A-375A.

Case 1 – AM – Question 2 If you retreat this patient with a triple combination, do you think that the virological response during a 4-week lead-in period with only Peg-IFN+RBV might offer useful information even in case of TPV based triple therapy? 1.No 2.Yes

REALIZE (telaprevir): SVR by Week 4 on-treatment response according to prior response category SVR (%) <1 log 10 HCV RNA reduction after 4-week Peg-IFN/RBV lead-in phase ≥1 log 10 HCV RNA reduction after 4-week Peg-IFN/RBV lead-in phase n/N = Foster GR et al. J Hepatol 2011; 54 (Suppl.): S3. Prior relapsers 8/13 Prior partial responders 10/18 Prior null responders 6/41 Prior relapsers 106/113 Prior partial responders 16/27 Prior null responders 15/28 P=0.001

SVR by Week 4 on-treatment response in the LI T12/PR48 arm in prior relapsers SVR (%) Zeuzem S et al. Hepatology 2011; 54 (Suppl. S1): 986A-987A. Reduction in HCV RNA at Week 4, log 10 IU/mL >2.0 n/N= 2/3 6/10 11/12 16/18 79/83 Proportions of patients in each group 2% 8% 10% 14% 66%

Case 1 – AM – Question 3 If you retreat this patient with a triple combination, would the induction of early virological response affect the continuation of therapy? 1.No 2.Yes

RESPOND-2 - RGT & BOC/PR48: SVR in G1 Relapsers by METAVIR Fibrosis Score & Early/Late response HCV-RNA undetectable at TW8* or detectable at TW8** All patients HCV RNA undetectable at TW12 and received at least 36 weeks of therapy. F0/1/2/3 F4 Early responders* Late responders** RGT BOC/PR48 Patients with SVR (%) n/N 46/50 37/39 1/2 14/14 15/16 18/21 5/7 1/2

Prior relapsers Prior partial responders Patients with SVR (%) Prior null responders REALIZE: SVR among TVR-treated patients with RVR and eRVR, according to previous response (N=465) Prior relapsers Prior partial responders Prior null responders SVR for patients achieving eRVR Berg T et al. Hepatology 2011;54(Suppl. S1): Abstr /193 n/N= 183/20138/5538/5628/4227/38 (80%) (67%) (32%) (77%) (65%) (29%) Proportion of patients with RVR Proportion of patients with eRVR SVR for patients achieving RVR

Case 1 – AM – Question 4 Would you retreat this patient with? 1.BOC based triple therapy 2.TPV based triple therapy 3.Any of the above combinations

BOC or TPV in G1 prior relapsers without cirrhosis Boceprevir, Telaprevir EU SmPC Weeks TPV + PR PR if RNA detectable at Week 4 or 12 HCV RNA Stop treatment at Week 24 if RNA undetectable at Week 4 and 12 If >1000 IU/mL at Week 4 or 12: discontinue all drugs If detectable at Week 24 or 36: discontinue PR PR lead-in BOC + PR PR If ≥100 IU/mL:If detectable: Discontinue all drugs HCV RNA Weeks

Case 2 - GS 02/2009 Female, 58 years, H 1.60 m, W 70 Kg, BMI 27.3 Kg/m 2, Diabetes G1b, HCV RNA 2,000,000 IU/mL, Fibroscan 14.3 (1.9) kPa Peg-IFNa-2b (100 μg/wk) +RBV (1.0 g/d) HCV RNA 1,200,000 IU/mL at 12 wks – stop treatment 05/ /2011 Moderate ALT elevations, increased γ-globulin 12/2011 HCV RNA 1,000,000 IU/mL, Fibroscan 17.5 (2.5) kPa

Would you retreat this patient today? (BOC/TPV available) 1.No 2.Yes a. Peg-IFN + RBV b. Peg-IFN + RBV + BOC/TPV Case 2 – GS – Question 1

REALIZE: SVR under TPV based therapy in G1 null responders Zeuzem S et al. NEJM 2011;364: Patients with SVR, % 12-wk TPV+PR 4-wk PR + 48-wk PR + 36-wk PR 12-wk TPV+PR + 32-wk PR P<0.001 n/N 21/72 25/37 2/37

REALIZE: SVR in G1 prior null responders by baseline fibrosis stage Stage No, minimal or portal Bridging fibrosis Cirrhosis fibrosis Patients with SVR, % Pooled T12/PR48 Pbo/PR48 n/N 24/59 1/18 16/38 0/9 7/50 1/10 Pol S et al. Hepatology 2011;54(Suppl. S1): 374A-375A.

BOC in G1 null responders to PR PROVIDE study: prospective, one arm Patients Ν= 37 from SPRINT-2 (naive) N= 11 from RESPOND-2 N= 42 HCV RNA > IU/ml N=31 G1a Duration of PR discontinuation: wks Vierling J et al. Hepatology 2011; 54 (Suppl. S1): 796A-797A. n/N= 20/43 16/42 3/19 Patients, %

PROVIDE: SVR rates by baseline patient characteristics* n/m (%)SVR, % (n/N) Male Female 27 (4/15) 44 (12/27) Black Non-black 27 (3/11) 42 (13/31) Age <50 years Age ≥50 years 50 (9/18) 29 (7/24) Weight <75 kg Weight ≥75 kg 25 (4/16) 46 (12/26) Baseline viral load ≤800,000 IU/mL Baseline viral load >800,000 IU/mL 67 (4/6) 33 (12/36) F0/1/2/3 † F4 † 38 (15/39) 50 (1/2) Platelets † <200,000 Platelets † ≥200,000 0 (0/8) 48 (16/33) ALT normal ALT elevated 50 (5/10) 34 (11/32) HCV genotype 1a ‡ HCV genotype 1b ‡ 41 (11/27) 33 (5/15) Vierling J et al. Hepatology 2011; 54 (Suppl. S1): 796A-797A.

Case 2 – GS – Question 2 If you retreat this patient with a triple combination, do you think that the virological response during a 4-week lead-in period with only Peg-IFN+RBV might offer useful information even in case of TPV based triple therapy? 1.No 2.Yes

SVR rates of null responders to PR under BOC+PR in relation to virological response during the lead-in period Vierling J et al. Hepatology 2011; 54 (Suppl. S1): 796A-797A. Proportions of patients in each group 76% 24% 38% 38% 21% 3% <1.0 ≥1.0 < < < Reduction in HCV RNA at Week 4, log 10 IU/mL n/N= 11/32 5/10 6/16 5/16 5/9 0/1 SVR (%)

REALIZE (telaprevir): SVR by Week 4 on-treatment response according to prior response category SVR (%) <1 log 10 HCV RNA reduction after 4-week Peg-IFN/RBV lead-in phase ≥1 log 10 HCV RNA reduction after 4-week Peg-IFN/RBV lead-in phase n/N = Foster GR et al. J Hepatol 2011; 54 (Suppl.): S3. Prior relapsers 8/13 Prior partial responders 10/18 Prior null responders 6/41 Prior relapsers 106/113 Prior partial responders 16/27 Prior null responders 15/28 P=0.001

SVR by Week 4 on-treatment response in the LI T12/PR48 arm in prior null responders SVR (%) Zeuzem S et al. Hepatology 2011; 54 (Suppl. S1): 986A-987A. Reduction in HCV RNA at Week 4, log 10 IU/mL 2.0 n/N= 1/16 5/25 8/18 3/5 4/5 Proportions of patients in each group 23% 36% 26% 7% 7%

Case 2 – GS – Question 3 Would you retreat this patient with? 1.BOC based triple therapy 2.TPV based triple therapy 3.Any of the above combinations

BOC or TPV in G1 prior null responders Weeks TPV + PR PR HCV RNA If >1000 IU/mL at Wk 4 or 12: discontinue all drugs If detectable at Wk 24 or 36: discontinue PR PR lead-in BOC + PR If ≥100 IU/mLIf detectable Discontinue all drugs HCV RNA Weeks Boceprevir, Telaprevir EU SmPC