Maria Buti Hospital General Universitario Vall Hebron Barcelona-. Spain Relapser or Non Responder? Chronic Hepatitis C

36 years old male Blood transfusion in the infancy No diseases, no alcohol, no iv drugs Diagnosed with Hepatitis C 22 years ago by ALT elevation in a routine check up Relapser or Non Responder? Chronic Hepatitis C

In 1997, he was treated with Interferon 3 MU/ for 48 week without response In 2002 was referred to our hospital Asymptomatic Physical Examination Normal, Weight 89 kg, Height 1,75 ALT 44 UI/ml, Hb 17% gr>/dl, no hypergammaglobulinemia Genotype 1

Abdominal US : Normal Liver biopsy: Chronic Active Hepatitis, Metavir F3 1.5  g/kg/ week May 2002 PegInterferon alfa 2b 1.5  g/kg/ week and ribavirin 1,200 mg for 48 weeks HCV-RNA undetectable at the end of treatment and relapse in the follow-up

Follow-up Elevated ALT, HCV RNA positive Evaluation and Inclusion in the EPIC 3 study

HCV RNA negative at week 12 Subject continue for additional 36 weeks + 24 weeks follow-up EPIC 3 Program Design Non-Responder Trial : N=2200 CHC with fibrosis (F2, F3 or F4 METAVIR) who failed to respond any IFN alfa/alpha + Ribavirin PEG-INTRON® 1.5  g/kg/wk + REBETOL ® mg/d Evaluation of virological response at week 12 N=3136 screened*, 1843 treated* Chronic Suppression for Non-Cirrhotics, n=700 HCV RNA positive at week 12 METAVIR F2 or F3 subjects PEG-INTRON® 0.5  g/kg/wk vs. control Duration: 3 years Chronic Suppression for Cirrhotics, n=1000 HCV RNA positive at week 12 METAVIR F4 subjects PEG-INTRON® 0.5  g/kg/wk vs. control Max duration: 5 years * METAVIR F4 CHC subjects Non-responder to any IFN alfa/alpha + Ribavirin DIRECT ENROLLERS

March 2005 started PegIntron 1.5 mg/kg /week and Ribavirin 1,200 mg/day ALT 43 UI/ml, Hb 17.4 mg/dl, mm leukocytes platelets, HCV RNA UI/ml Week 12: ALT 24 UI/ml, Hb 14.5 mg/dl, leukocytes, platelets, HCV-RNA UI/ml

HCV RNA negative at week 12 Subject continue for additional 36 weeks + 24 weeks follow-up EPIC 3 Program Design Non-Responder Trial : N=2200 CHC with fibrosis (F2, F3 or F4 METAVIR) who failed to respond any IFN alfa/alpha + Ribavirin PEG-INTRON® 1.5  g/kg/wk + REBETOL ® mg/d Evaluation of virological response at week 12 N=3136 screened*, 1843 treated* Chronic Suppression for Non-Cirrhotics, n=700 HCV RNA positive at week 12 METAVIR F2 or F3 subjects PEG-INTRON® 0.5  g/kg/wk vs. control Duration: 3 years Chronic Suppression for Cirrhotics, n=1000 HCV RNA positive at week 12 METAVIR F4 subjects PEG-INTRON® 0.5  g/kg/wk vs. control Max duration: 5 years * METAVIR F4 CHC subjects Non-responder to any IFN alfa/alpha + Ribavirin DIRECT ENROLLERS

0.5  g/kg/week for 3 years July 2005 He started maintenance therapy with PegIntron 0.5  g/kg/week for 3 years ALT UI/ml, Hb mg/dl, HCV RNA UI/ml. Excellent tolerance June 2008 stop maintenance therapy ALT 33 UI/ml, HCV-RNA UI/ml US: Normal Liver biopsy: improvement of the inflammatory activity and F2

Non Responder to Interferon Relapser to PegInterferon and Ribavirin Non Responder to Maintenance therapy Lost of follow-up

Nov 2011 he return to our out patients clinic He would like to be treated with a Protease inhibitor Asymptomatic Hb 17.3, ALT 41 UI/ml, HCV-RNA 7x10 5 UI/mL Genotype 1

1. Relapser 2. Partial Responder 3. True Non-responder He is a previously treated patient Type of Response and SVR with PI?

What SVR rates were seen with telaprevir in REALIZE according to prior response type? SVR (%) Prior relapsersPrior partial responders Prior null responders * * * * * * Telaprevir EU SmPC *p<0.001 vs PR48 SVR, considered virologic cure, was defined as HCV RNA <25 IU/mL at last observation within the Week 72 visit window. In case of missing data, the last HCV RNA data point from Week 12 of follow-up onwards was used PR48 4/27 T12/ PR48 30/49 LI T12/ PR48 27/48 n/N= PR48 2/37 T12/ PR48 22/72 LI T12/ PR48 25/75 PR48 15/68 T12/ PR48 122/145 LI T12/ PR48 124/141

PR48 2/29 BOC44/ PR48 SVR (%) Prior relapsersPrior partial responders BOC RGT PR48 15/51 BOC RGT 72/105 Boceprevir EU SmPC What SVR rates were seen with boceprevir in RESPOND-2 and Provide studies? SVR was defined as undetectable HCV RNA at the last available value in the period at or after follow-up Week 24. If there was no such value, the follow-up Week 12 value was carried forward BOC44/ PR48 Prior Null responders 36

1.Liver biopsy or Fibroscan 2.IL28b 3.HCV Subtype Management of Patient?

Prior relapsers Prior partial responders Prior null responders 53/62 n/N= 2/1512/38145/16710/180/53/1736/4716/380/91/511/32 No, minimal or portal fibrosis Cirrhosis Stage Pbo/PR48 Pooled T12/PR48 SVR (%) 48/571/151/1824/591/107/50 Bridging fibrosis No, minimal or portal fibrosis CirrhosisBridging fibrosis No, minimal or portal fibrosis CirrhosisBridging fibrosis How effective was telaprevir in patients with bridging fibrosis or cirrhosis? Drugs/AntiviralDrugsAdvisoryCommittee/UCM pdf SVR was defined as HCV RNA <25 IU/mL at last observation within the Week 72 visit window. In case of missing data, the last HCV RNA data point from Week 12 of follow-up onwards was used

SVR by IL-28B Polymorphism % SVR *~80% eligible for short duration therapy *

1.Lead-in phase and then Triple therapy with BOC 2.Lead-in-phase and then Triple therapy with TVR 3.Triple therapy with TVR He likes to be treated What is the best strategy?

SVR by Week 4 PR Lead-In Response Poorly Responsive to IFN <1 log 10 viral load decline at treatment week 4 Responsive to IFN ≥1 log 10 viral load decline at treatment week SVR (%) PR 48 BOC RGT BOC/PR48

REALIZE (telaprevir): SVR by Week 4 response according to prior response category (LI T12PR48 arm) 137/168n/N= Foster GR, et al. J Hepatol 2011;54(Suppl. 1):S 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 Overall Prior relapsers 62 8/13 Prior partial responders 56 10/18 Prior null responders 15 6/41 10%40%59% Proportion of patients in each category with <1 log 10 HCV RNA reduction SVR was defined as undetectable HCV RNA 24 weeks after last planned dose

1. Assess drug-drug interactions 2.Abdominal US Anything else before treatment?

1.Assess drug-drug interaction 2.Abdominal US - Tumor 3 cm diameter in lobule right of the liver suggestive of HCC Anything else before treatment?

1. Importance of define the type of previous response 2.Appropriate pre-treatment evaluation 3.Discuss the usefulness of the predictive factors 4. Role of lead-in phase 5. Always exclude HCC Summary