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 1 – Management of Hepatitis C: Updated Guidelines from the Canadian Association for the Study of the Liver (CASL) November 2012

2. Robert P. Myers, MD, MSc Associate Professor, Liver Unit Division of Gastroenterology University of Calgary Management of Hepatitis C: Updated Guidelines from the Canadian Association for the Study of the Liver (CASL)

3. 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.

4. Burden of HCV in Canada  Significant medical and economic burden  Seroprevalence unknown Risk GroupPopulationPrevalencePrevalent CasesProportion of Cases IDU, total268,20052%140,00058% Current IDU84,40062%52,50022% Previous IDU183,80048%87,50036% Transfusion3,325,7000.8%25,90011% Hemophilia2,20040%9000.4% Other27,624,3000.27%75,80031% Total31,220,5000.8%243,000100% Remis RS. PHAC 2007

5. Burden of HCV in Canada  ~8,000 incident cases annually (80% IDUs)  Proportion diagnosed unclear (<80%)  HCV-related complications rising  Insufficient manpower to treat all cases Remis et al. PHAC 2007 800 900 700 600 500 400 300 200 100 0 1967197219771982198719921997200220072012201720222027 Year Cirrhosis Decomp HCC Transplant Modelled incidence

6. Davis GL et al. Gastroenterology 2010; 138(2):513-21 * Assumes 30% Dx & up to 25% Rx’d in 2010. Outcomes at 2020.  Antiviral Therapy Must be Maximized to Make an Impact 30 20 40 50 60 70 80 90 100 Liver-related death vs. no treatment (%) 0Current*25%50%75%100% Proportion of population treated 80% SVR rate 60% SVR rate 40% SVR rate 68% ↓ 34% ↓

7. 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

8. Who Should Be Treated? CASL Recommendations Myers RP et al. Can J Gastro 2012; 26(6):359-75

9.  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. Who Should Be Treated? CASL Recommendations Myers RP et al. Can J Gastro 2012; 26(6):359-75

10.  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: Is Liver Biopsy Really Necessary?

11. 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 kPa67% / 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 ≥0.5856% / 83% FibroSpect II (Patel, 2004) α2M, HA, TIMP-1≥0.3677% / 73% Hepascore (Adams, 2005) α2M, HA, GGT, bilirubin≥0.5089% / 63% FibroMeter (Leroy, 2005) α2M, HA, AST, platelets, PT, urea ≥0.5075% / 78% Pre-Treatment Assessment: Non-invasive Measures of Fibrosis

12.  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. Pre-Treatment Assessment: CASL Recommendations Myers RP et al. Can J Gastro 2012; 26(6):359-75

13.  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 Pre-Treatment Assessment: CASL Recommendations Myers RP et al. Can J Gastro 2012; 26(6):359-75

14. Ge. Nature 2009. Suppiah. Nat Genet 2009. Tanaka. Nat Genet 2009. Thomas. Nature 2009.  Single-nucleotide polymorphisms (SNPs) on chromosome 19  Encodes IFN-λ3  Associated with viral clearance  ~50% of ethnic variation in SVR rates  Strongest pre-treatment predictor of SVR, but on-treatment response more important Interleukin 28B (IL28B) 80 100 60 40 20 0 T/T 102 T/C 433 C/C 336 European- Americans P=1.06x10 -25 SVR (%) 70 T/C 91 C/C 30 African- Americans 14 T/C 35 C/C 26 Hispanics P=2.06x10 -3 P=4.39x10 -3 P=1.37x10 -28 186 T/C 559 C/C 392 Combined rs12979860 SVR (%)Non-SVR (%) Numbers on bars represent n

15.  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 treatment- experienced patients and those with genotypes other than 1 and 4.  A non-favourable IL28B genotype does not preclude antiviral therapy. Pre-Treatment Assessment: CASL Recommendations Myers RP et al. Can J Gastro 2012; 26(6):359-75

16.  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. Antiviral Therapy for HCV Genotype 1: CASL Recommendations Myers RP et al. Can J Gastro 2012; 26(6):359-75

17.  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. Response-Guided Therapy (RGT): CASL Recommendations Myers RP et al. Can J Gastro 2012; 26(6):359-75

18.  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. Adherence to Antiviral Therapy: CASL Recommendations Myers RP et al. Can J Gastro 2012; 26(6):359-75

19.  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. Futility Rules: CASL Recommendations Myers RP et al. Can J Gastro 2012; 26(6):359-75

20. 1,230 Slide courtesy of Dr. J. Feld. 1 W0W1W2W3W4 If futility rules met, RNA is rising! Stop therapy! 10 6 10 5 10 4 10 3 10 2 10 10 7 1,800,000 99.9% reduction: Continue? 475 HCV RNA (IU/mL) Futility Rules Indicate Treatment Failure Even if the Viral Load Has Declined

21.  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%) Adverse Effects of the Protease Inhibitors (PIs) Myers RP et al. Can J Gastro 2012; 26(6):359-75

22.  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. Adverse Effects of the Protease Inhibitors (PIs): CASL Recommendations Myers RP et al. Can J Gastro 2012; 26(6):359-75

23.  Boceprevir and telaprevir are substrates and inhibitors of CYP3A4*  CYP3A4 metabolizes many common drugs  Potential increased drug concentrations with PI co- administration  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)

24.  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://www.hep-druginteractions.org/  http://medicine.iupui.edu/clinpharm/ddis/ http://medicine.iupui.edu/clinpharm/ddis/ Drug-Drug Interactions (DDIs): CASL Recommendations Myers RP et al. Can J Gastro 2012; 26(6):359-75

25.  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 Pawlotsky JM. Hepatology. 2011 May; 53(5):1742-51 Antiviral Resistance -5 -4 -3 -2 0 1 HCV RNA change from baseline (Log 10 IU/mL) Modest or null IFN  -ribavirin effect Study time Resistant HCV Wild-type, sensitive HCV

26.  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 Antiviral Resistance: CASL Recommendations

27.  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. Summary: CASL Guidelines for the Management of HCV

28. 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.