Transcript Protease inhibitors in chronic hepatitis C

Protease Inhibitors in Chronic Hepatitis C:
An Update
Chapter 5 – Case Study: Cirrhosis
Edited by
Morris Sherman MD BCh PhD FRCP(C)
Associate Professor of Medicine
University of Toronto
November 2012
Case Study:
Cirrhosis
Nir Hilzenrat, MD
Gastrointestinal 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: 2417-28
Bronowicki, 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
-
-
Vertex Pharmaceutical (Canada) Incorporated. Product Monograph: Incivek (Telaprevir
tablets). http://pi.vrtx.com/files/canadapm_telaprevir_en.pdf (Accessed February 1, 2012)
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
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 gratefully acknowledges the participating health care professionals
for their contributions to this project and for their commitment to the liver health of Canadians.
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.