Protease Inhibitors in Chronic Hepatitis C:
An Update
Chapter 1 – Management of Hepatitis C: Updated Guidelines from the
Canadian Association for the Study of the Liver (CASL)
Edited by
Morris Sherman MD BCh PhD FRCP(C)
Associate Professor of Medicine
University of Toronto
November 2012
Management of Hepatitis C:
Updated Guidelines from the Canadian
Association for the Study of the Liver
(CASL)
Robert P. Myers, MD, MSc
Associate Professor, Liver Unit
Division of Gastroenterology
University of Calgary
Objectives: HCV Management
 Review updated CASL recommendations for
management of HCV genotype 1*
 Burden of HCV in Canada
 Pre-treatment assessment
 Triple therapy including boceprevir and telaprevir
 Adverse effects
 Drug-drug interactions
 Antiviral resistance
* Recommendations for non-1 genotypes are unchanged from the 2007 CASL HCV guidelines.
Burden of HCV in Canada
 Significant medical and economic burden
 Seroprevalence unknown
Risk Group
Population
Prevalence
Prevalent Cases
Proportion of Cases
268,200
52%
140,000
58%
Current IDU
84,400
62%
52,500
22%
Previous IDU
183,800
48%
87,500
36%
Transfusion
3,325,700
0.8%
25,900
11%
Hemophilia
2,200
40%
900
0.4%
Other
27,624,300
0.27%
75,800
31%
Total
31,220,500
0.8%
243,000
100%
IDU, total
Remis RS. PHAC 2007
Burden of HCV in Canada
Modelled incidence




~8,000 incident cases annually (80% IDUs)
Proportion diagnosed unclear (<80%)
HCV-related complications rising
Insufficient manpower to treat all cases
900
Cirrhosis
800
700
600
Decomp
500
400
HCC
300
Transplant
200
100
0
1967 1972 1977 1982 1987 1992 1997 2002 2007 2012 2017 2022 2027
Year
Remis et al. PHAC 2007
Liver-related death vs. no treatment (%)
Antiviral Therapy Must be Maximized
to Make an Impact

100
90
80% SVR rate
60% SVR rate
40% SVR rate
34% ↓
80
68% ↓
70
60
50
40
30
20
0
Current*
25%
50%
75%
100%
Proportion of population treated
* Assumes 30% Dx & up to 25% Rx’d in 2010. Outcomes at 2020.
Davis GL et al. Gastroenterology 2010; 138(2):513-21
Burden of HCV in Canada:
CASL Recommendations
 A large population-based seroprevalence survey should
be conducted to accurately define the prevalence of
hepatitis C in Canada. The design of the study should
include populations with an increased risk of hepatitis C,
particularly IDUs and immigrants from endemic
countries.
 Increased resources are necessary to improve hepatitis
C treatment capacity in Canada, including the training of
expert treaters and public funding for treatment nurses.
Myers RP et al. Can J Gastro 2012; 26(6):359-75
Who Should Be Treated?
CASL Recommendations
Myers RP et al. Can J Gastro 2012; 26(6):359-75
Who Should Be Treated?
CASL Recommendations
 All patients with chronic HCV, particularly those with liver fibrosis,
should be considered candidates for antiviral therapy.
 Patients with extrahepatic manifestations of HCV should be
considered for antiviral therapy.
 Persistently normal ALT does not exclude significant liver
disease nor preclude the need for antiviral therapy.
Myers RP et al. Can J Gastro 2012; 26(6):359-75
Pre-Treatment Assessment: Is Liver Biopsy
Really Necessary?
 Some fibrosis assessment necessary
 Prognosis
 Necessity of treatment
 Surveillance for HCC & varices
 F2 threshold less important with improved therapies
 Biopsy is imperfect
 Sampling error; variability in pathologic interpretation
 Numerous noninvasive alternatives to biopsy
Bedossa P et al. Hepatology 2003; 38(6):1449-57
Pre-Treatment Assessment:
Non-invasive Measures of Fibrosis
Test
(Reference)
Components
Cut-off
F2-F4 vs. F0-F1
Sensitivity/specificity
F2-F4 vs. F0-F1
FibroScan
(Castera, 2005)
Liver stiffness by transient
elastography
≥7.1 kPa
67% / 89%
APRI
(Shaheen, 2007)
AST/ULN x 100
Platelets
≥0.5
≥0.7
≥1.5
81% / 50%
84% / 70%
35% / 91%
FibroTest
(Poynard, 2004)
α2M, haptoglobin, apo-A1,
GGT, bilirubin
≥0.58
56% / 83%
α2M, HA, TIMP-1
≥0.36
77% / 73%
α2M, HA, GGT, bilirubin
≥0.50
89% / 63%
α2M, HA, AST, platelets, PT,
urea
≥0.50
75% / 78%
FibroSpect II
(Patel, 2004)
Hepascore
(Adams, 2005)
FibroMeter
(Leroy, 2005)
Pre-Treatment Assessment:
CASL Recommendations
 Assessment of Disease Severity
 All patients with HCV should have an assessment for the
severity of liver fibrosis. Acceptable methods include
liver biopsy, TE (FibroScan), and serum biomarker
panels (e.g. APRI, FibroTest, Fibrometer), either alone or
in combination.
 Alternatively, cirrhosis can be confidently diagnosed in
some patients with clear clinical or radiographic
evidence.
Myers RP et al. Can J Gastro 2012; 26(6):359-75
Pre-Treatment Assessment:
CASL Recommendations
 Virologic Testing
 HCV RNA and genotype testing are essential to the
management of patients with chronic hepatitis C.
 HCV RNA testing should be performed using a sensitive
quantitative assay (lower limit of detection ≤ 10-15 IU/mL)
with a broad dynamic range. Standardized results should
be expressed in IU/mL and be available within a maximum
of 7 days in order to facilitate management decisions.
 Although genotype 1b has higher response rates vs.
genotype 1a, testing for HCV subtype is not indicated
 This may change with newer DAAs available in the future
Myers RP et al. Can J Gastro 2012; 26(6):359-75
Interleukin 28B (IL28B)
 Associated with viral clearance
 ~50% of ethnic variation in SVR
rates
 Strongest pre-treatment predictor
of SVR, but on-treatment
response more important
100
P=1.06x10-25
80
SVR (%)
 Single-nucleotide polymorphisms
(SNPs) on chromosome 19
 Encodes IFN-λ3
P=2.06x10-3
P=4.39x10-3
P=1.37x10-28
Numbers on bars represent n
60
40
20
102 433 336
0
70
91
30
14
35
26
186 559 392
T/T T/C C/C
T/C C/C
T/C C/C
T/C C/C
EuropeanAmericans
AfricanAmericans
Hispanics
Combined
rs12979860
SVR (%)
Non-SVR (%)
Ge. Nature 2009. Suppiah. Nat Genet 2009. Tanaka. Nat Genet 2009. Thomas. Nature 2009.
Pre-Treatment Assessment:
CASL Recommendations
 IL28B Genotyping
 The IL28B genotype may provide valuable information
regarding the likelihood of SVR and the probability of
qualifying for shortened treatment duration in previously
untreated patients with genotype 1.
 The role of IL28B genotyping is limited in treatmentexperienced patients and those with genotypes other than
1 and 4.
 A non-favourable IL28B genotype does not preclude
antiviral therapy.
Myers RP et al. Can J Gastro 2012; 26(6):359-75
Antiviral Therapy for HCV Genotype 1:
CASL Recommendations
 Triple therapy including peginterferon (PEG-IFN), ribavirin
(RBV), and a protease inhibitor (telaprevir or boceprevir) is
the new standard of care in treatment-naïve and previous
treatment failures.
 Boceprevir (800 mg every 8 hours with food) is administered
after a 4-week lead-in period of PEG-IFN and RBV. Duration
of therapy depends on patient characteristics and treatment
response.
 Telaprevir (750 mg every 8 hours with non-low fat food)
should be started simultaneously with PEG-IFN and RBV and
given for the initial 12 weeks of therapy.
Myers RP et al. Can J Gastro 2012; 26(6):359-75
Response-Guided Therapy (RGT):
CASL Recommendations
 RGT - the tailoring of treatment duration based on early viral
kinetics - can be employed in selected patient subgroups.
 Boceprevir: HCV RNA negative at weeks 8 through 24
 Telaprevir: HCV RNA negative at weeks 4 through 12
 SVR rates of ~90% have been reported with 24 to 28 weeks
of therapy in patients qualifying for RGT.
 Partial responders treated with telaprevir, patients with
cirrhosis, and prior null responders should not receive RGT.
Myers RP et al. Can J Gastro 2012; 26(6):359-75
Adherence to Antiviral Therapy:
CASL Recommendations
 Adherence to treatment and to futility rules, and close
monitoring of concomitant drugs and side effects are
particularly important with PI-based therapy.
 Optimal management of this population should be
conducted by well-trained, experienced personnel.
Myers RP et al. Can J Gastro 2012; 26(6):359-75
Futility Rules:
CASL Recommendations
 Strict adherence to futility rules is vital to limit exposure to
potential side effects of these costly therapies that will not
achieve SVR, and to reduce emergence of antiviral
resistance.
 All therapy – including PEG-IFN and RBV – must be
discontinued if futility rules are met:
 Boceprevir: HCV RNA ≥100 IU/mL at week 12 or
detectable at week 24
 Telaprevir: HCV RNA >1,000 IU/mL at week 4 or 12, or
detectable at week 24
 Identical futility rules apply to treatment-naïve and
treatment-experienced patients.
Myers RP et al. Can J Gastro 2012; 26(6):359-75
Futility Rules Indicate Treatment Failure
Even if the Viral Load Has Declined
107
1,800,000
HCV RNA (IU/mL)
106
99.9% reduction:
Continue?
105
104
1,230
103
475
102
If futility rules met, RNA is rising!
Stop therapy!
10
1
W0
W1
W2
W3
W4
Slide courtesy of Dr. J. Feld.
Adverse Effects of the Protease Inhibitors (PIs)
 PI-based therapy associated with more adverse effects
than PEG-IFN and RBV dual therapy
 No data to support switching from one PI to another to
manage toxicity
 Major adverse effects differ by PI
 Boceprevir: anemia (~50%), dysgeusia (~40%)
 Telaprevir: anemia (~40%), rash (~40%), anorectal
symptoms (~30%)
Myers RP et al. Can J Gastro 2012; 26(6):359-75
Adverse Effects of the Protease Inhibitors (PIs):
CASL Recommendations
 Treatment with PIs should be supervised by experienced
personnel and adverse effects monitored closely.
 Close monitoring of hemoglobin levels is essential
during antiviral treatment for HCV, particularly during the
administration of PIs.
 Management of anemia may include any of the following
strategies: RBV dose reduction (first line), transfusion of
packed red blood cells, and/or erythropoietin
administration.
Myers RP et al. Can J Gastro 2012; 26(6):359-75
Drug-Drug Interactions (DDIs)
 Boceprevir and telaprevir are substrates and inhibitors of
CYP3A4*
 CYP3A4 metabolizes many common drugs
 Potential increased drug concentrations with PI coadministration
 Drugs that induced CYP3A4 may reduce PI concentration
(i.e. antiviral treatment efficacy)
 Numerous potential DDIs with PI-based therapy
 Antiarrhythmics, anticoagulants, anticonvulsants,
antihistamines, antibacterials, antiretrovirals, statins,
herbal products, immunosuppressants, OCPs,
phosphodiesterase inhibitors, and some
sedatives/hypnotics
* Minor elimination pathways include P-glycoprotein and aldoketoreductase.
Drug-Drug Interactions (DDIs):
CASL Recommendations
 Prior to the initiation of PIs, potential DDIs must be
considered, including those attributable to prescription
and over-the-counter pharmaceuticals and herbal
preparations.
 Review product monographs and useful online
resources for potential DDIs prior to initiating therapy.
 http://www.hep-druginteractions.org/
 http://medicine.iupui.edu/clinpharm/ddis/
Myers RP et al. Can J Gastro 2012; 26(6):359-75
Antiviral Resistance




HCV RNA change from
baseline (Log10 IU/mL)
All resistance variants pre-exist
Not caused by PIs, but unmasked by selective pressure
Reflect inadequate response to PEG-IFN/RBV
Predominant cause (80-90%) of incomplete viral suppression,
breakthrough, or relapse
 Genotype 1a > 1b
1
Modest or null IFNa-ribavirin effect
0
-1
-2
Resistant HCV
-3
-4
Wild-type, sensitive HCV
-5
Study time
Pawlotsky JM. Hepatology. 2011 May; 53(5):1742-51
Antiviral Resistance:
CASL Recommendations
 In order to reduce the development of antiviral
resistance to the PIs, patients who meet futility rules
indicating a high likelihood of treatment failure should
discontinue therapy immediately.
 Dosage reductions of boceprevir and telaprevir should
not be utilized to manage treatment-related side effects.
 To prevent resistance, PIs must be stopped if either
PEG-IFN or RBV are discontinued.
 There is no role for pre-treatment resistance testing.
Myers RP et al. Can J Gastro 2012; 26(6):359-75
Summary:
CASL Guidelines for the Management of HCV
 Must maximize case-finding, referral, and antiviral Rx to
reduce HCV burden in Canada.
 Barriers to treatment (e.g. need for biopsy) should be
minimized.
 New therapies (boceprevir and telaprevir) markedly
improve SVR rates in genotype 1 (treatment-naïve and
experienced), but are complex and have additional side
effects.
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.