1. Edited by Morris Sherman MD BCh PhD FRCP(C) Associate Professor of Medicine University of Toronto Protease Inhibitors in Chronic Hepatitis C: An Update Chapter 5 – Case Study: Cirrhosis November 2012

2. Case Study: Cirrhosis Nir Hilzenrat, MD Gastrointestinal Division, Department of Medicine, SMBD- Jewish General Hospital, Associate Professor of Medicine, McGill University, Montreal, Quebec

3. Case History  58 year old woman, acquired hepatitis C from blood transfusion 30 years prior  Symptoms – mild fatigue and depression  ALT 2xULN  Synthetic function normal  Viral load 3x10 5 IU/mL  Liver biopsy (2002)  F 3/4, activity 2/4

4. Case History  Previous treatment in 2000 with pegylated interferon and ribavirin  < 1 log drop at week 12  Treatment discontinued  Treatment-related side effects  Severe fatigue  Fall in Hb level (148 g/L to 108 g/L).

5. Comments Previous treatment failures classified into  Null responder  Viral load does not fall by 2 logs at week 12  Partial responder  Viral load falls by > 2 logs, but never negative  Relapser  Viral load negative on therapy but positive after therapy  Telaprevir (REALIZE study ) response in null responders was 29% (21/72)  Boceprevir (PROVIDE study) response in null responders was 40% (19/47) Zeuzem, S. et al. N Engl J Med 2011; 364: 2417-28 Bronowicki, JP., International Liver Congress 2012, Abstract 204, EASL 2012

6. Comments  Probability of response with F3 or F4 and prior treatment failure (48 weeks of therapy) TelaprevirBoceprevir %n%n Relapser8748/558315/18 Partial responder3411/32466/13 Null responder147/50-- Bruno,S., Boceprevir in Addition to Standard of Care Enhanced SVR in Hepatitis C Virus Genotype-1 With Advanced Fibrosis/Cirrhosis: Subgroup Analysis of SPRINT-2 and RESPOND-2 Studies, Oral Presentation, EASL 2011 Vertex Pharmaceutical (Canada) Incorporated. Product Monograph: Incivek (Telaprevir tablets). http://pi.vrtx.com/files/canadapm_telaprevir_en.pdf (Accessed February 1, 2012)http://pi.vrtx.com/files/canadapm_telaprevir_en.pdf

7. Case Continued  Patient made aware of low probability of cure (15-40%)  However, she was willing to start treatment  It was accepted that we will assess the continuity of the treatment based on the response rate, i.e., HCV-RNA level, and the severity of adverse effect during the treatment  Fibroscan prior suggested cirrhosis  ALT x 4 ULN  Liver synthetic function normal  Viral load 2.8x10 6 IU/ml

8. Case Continued  Treatment was started with Peg INF/RIBA and boceprevir  At week 4 viral load decline was 0.8 logs Question  How important is the magnitude of the decline in viral load following the lead-in phase (TW4) of the PR & BOC treatment?

9. Importance of 4-Week HCV RNA in Boceprevir Triple Therapy  In RESPOND-2 likelihood of SVR for relapsers and partial-responders was associated with response to interferon in the lead-in phase SVR in all patientsSVR in F3/F4 < 1 log drop at wk 433%14-25% > 1 log drop at wk 473%55-87% Bruno,S., Boceprevir in Addition to Standard of Care Enhanced SVR in Hepatitis C Virus Genotype-1 With Advanced Fibrosis/Cirrhosis: Subgroup Analysis of SPRINT-2 and RESPOND-2 Studies, Oral Presentation, EASL 2011 Bacon BR et al. N Engl J Med 2011;364:1207-17

10. Comments  In the PROVIDE study, the SVR for null responders was 40%  Week 4 HCV RNA < 1 log decline from baseline  SVR 36%  Week 4 HCV RNA >1 log decline from baseline  SVR 55% Bronowicki, JP., Sustained Virologic Response (SVR) in Prior PegInterferon/Ribavirin (PR) Treatment Failures After Retreatment with Boceprevir (BOC) + PR: PROVIDE Study Interim Results, International Liver Congress 2012, Abstract 204, EASL 2012

11. Case Continued  The result was discussed with the patient.  She was made aware that the likelihood of achieving SVR is poor.  However, the patient asked to reassess the probability of her success rate after 4W of PR & BOC treatment, i.e., 8W of the whole treatment.

12. Question  The HCV RNA at week 8 was undetectable  What is the likelihood of achieving SVR?

13. Question  How long should she be treated for?  At week 12 and 24 the HCV RNA remained undetectable  Usual side effects, anemia, fatigue and depression

14. Question  What are the recommended approaches for this patient (i.e. cirrhotic null responder to previous PR treatment) according to the American Association of the Study of Liver Diseases (AASLD) and Canadian Association of the Study of Liver Diseases (CASL) updated guidelines?

15. The Canadian Liver Foundation (CLF) was the first organization in the world devoted to providing support for research and education into the causes, diagnoses, prevention and treatment of all liver disease. Through its chapters across the country, the CLF strives to promote liver health, improve public awareness and understanding of liver disease, raise funds for research and provide support to individuals affected by liver disease. For more information visit www.liver.ca or call 1-800-563-5483.www.liver.ca This project made possible through the financial support of Merck Canada Inc. The views, information and opinions contained herein are those of the authors and do not necessarily reflect the views and opinions of Merck Canada Inc. The Canadian Liver Foundation gratefully acknowledges the participating health care professionals for their contributions to this project and for their commitment to the liver health of Canadians.