Edited byMorris Sherman MD BCh PhD FRCP(C)

Associate Professor of MedicineUniversity of Toronto

Protease Inhibitors in Chronic Hepatitis C:An Update

Chapter 5 – Case Study: Cirrhosis

November 2012

Case Study:

Cirrhosis

Nir Hilzenrat, MDGastrointestinal Division, Department of Medicine,

SMBD- Jewish General Hospital,Associate Professor of Medicine,

McGill University, Montreal, Quebec

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 3x105 IU/mL Liver biopsy (2002)

F 3/4, activity 2/4

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).

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: 2417-28Bronowicki, JP., International Liver Congress 2012, Abstract 204, EASL 2012

Comments

Probability of response with F3 or F4 and prior treatment failure (48 weeks of therapy)

Telaprevir Boceprevir

% n % n

Relapser 87 48/55 83 15/18

Partial responder 34 11/32 46 6/13

Null responder 14 7/50 - -

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)

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 2.8x106 IU/ml

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?

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 patients SVR in F3/F4

< 1 log drop at wk 4 33% 14-25%

> 1 log drop at wk 4 73% 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

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

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.

Question

The HCV RNA at week 8 was undetectable

What is the likelihood of achieving SVR?

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

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?

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.

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.