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 3 – Side Effects of Antiviral Therapy for Hepatitis C November 2012

2. Side Effects of Antiviral Therapy for Hepatitis C Dr. Mark Levstik, FRCP(C) Associate Professor Medicine Division of Gastroenterology Multiorgan Transplant Unit London Health Sciences Centre

3. Side Effects with Boceprevir and Telaprevir  Hematological: (common to both PIs)  Anemia, Neutropenia  Effect is additive with INF and RBV  Gastrointestinal  Dysgeusia (BOC)  Diarrhea (TVR & ? BOC)  Anorectal irritation (TVR)  Dermatological  Telaprevir specific rash

4. Side Effect Comparison of Phase III studies Adverse EffectPeg Interferon/ RBV Boceprevir/ P/R Peg Interferon/ RBV Telaprevir/ P/R Anemia <100g/dl30%50%17%36% Rash19%17%34%56% Fatigue59%58%50%56% Diarrhoea15%20%17%26% Nausea42%46%28%39% Dysgeusia16%35%3%10% Anorectal7%29% Dysgeusia and anemia increased with boceprevir; Rash, anorectal irritation and anemia increased with telaprevir. Victrelis Product Monograph, August 2012 Incivek Product Monograph, June 2012

5. Patients  HCV genotype 1 infection  Compensated cirrhosis (Child Pugh A)  Treatment-experienced  Relapsers  Partial responders ( >2 log 10 HCV RNA decline at Week 12 but never negative)  Null responders theoretically excluded  Treated in the French early access program (From February 2011) Safety of Protease Inhibitors in Real Life: CUPIC Study Hezode C et al. EASL 2012, Abstract 8

6. Peg-IFN α-2a + RBV TVR + Peg-IFN α-2a + RBV Follow-up CUPIC: Treatment Regimen 48 4 16012 8 Weeks 72 SVR assessment Follow-up Peg-IFN + RBV 36 Interim analysis Hezode C et al. EASL 2012, Abstract 8 BOC : 800 mg/8h; peg-IFNα-2b : 1,5 µg/kg/week; RBV : 800 -1400 mg/d BOC + Peg-IFN α-2b + RBV TVR : 750 mg/8h; peg-IFNα-2a : 180 µg/week; RBV : 1000- 1200 mg/d

7. CUPIC: Patients Characteristics  Baseline patient characteristics similar between BOC and TVR  The CUPIC cohort had more advanced liver disease than in registration trials.  In BOC arm 26% would not meet RESPOND-2 inclusion criteria  In TVR arm 34% would not meet REALIZE inclusion criteria  Previous treatment response (%)BOCTVR  Partial responders4952  Relapsers4840  Null responders 3 8 Hezode C et al. EASL 2012, Abstract 8

8. CUPIC: Preliminary Safety Findings (16-Week Interim Analysis) Patients, n (% patients with ≥ 1 event) Boceprevir n=159 Telaprevir n=296 Serious adverse events (%) 38.448.6 Premature discontinuation Due to SAEs (%) 23.9 7.4 26.0 14.5 Death (%) 1.32.0 Infection (Grade 3/4) (%) 2.58.8 Rash Grade 3 (%) Grade 4 (SCAR) (%) 0000 6.8 0.7 Pruritus (Grade 3/4) (%) 0.63.7 Hepatic decompensation (%) 4.4 Hezode C et al. EASL 2012, Abstract 8

9. Patients, n (% patients with ≥ 1 event) Boceprevir (n=159) Telaprevir (n=296) Anemia (%) Grade 2 (8.0 – <10.0 g/dL) Grade 3/4 (<8,0 g/dL) EPO use Blood transfusion 22.6 10.1 66.0 10.7 19.6 10.1 56.8 15.2 Neutropenia (%) Grade 3 (500 – <1000/mm 3 ) Grade 4 (<500/mm 3 ) G-CSF use 4.4 0.6 3.8 4.0 0.7 2.4 Thrombopenia (%) Grade 3 (25 000 – <50 000) Grade 4 (<25 000) Thrombopoïetin use 6.3 0.6 1.9 11.8 1.3 1.7 Hezode C et al. EASL 2012, Abstract 8 CUPIC: Preliminary Safety Findings (16-Week Interim Analysis)

10. Take Home Message from CUPIC  PI therapy in patients with cirrhosis is associated with more severe and more frequent AEs  Anemia  Increased EPO use, ribavirin dose reductions and transfusions  Increased risk of severe infection  Increased risk of hepatic decompensation

11. Boceprevir Specific Side Effects  Dysgeusia and decreased appetite more prevalent than control  Hematological side effects more prevalent than control in Phase 2/3 naïve studies:  Neutropenia (<0.75 x 10 9 /L): 31% vs. 18% in controls  Platelets (< 50 x 10 9 /L): 3% vs. 1 % in controls  Anemia: 50% vs. 30% in controls  Grade II (<100 g/L): 49% vs. 29%  Grade III (<85 g/L) : 6% vs. 3%  Erythropoietin use 47% vs. 24% and pRBC 3% vs. 1% Victrelis Product Monograph, August 2012

12. Telaprevir Specific Side Effects  Rash, anorectal disorders, diarrhea and anemia more common than control  Rash seen > 50%, leads to 6% discontinuations  Mild – 37%  Moderate – 14%  Severe – 5%  Anorectal disorders seen with increase in diarrhea, itching and burning: 29% vs. 7% in controls  Anemia: 32% vs. 15% in controls  Grade II (<9.0-9.9 g/dL): 27% vs. 27%  Grade III (7.0-8.9 g/dL) : 51% vs. 24% Incivek Product Monograph, June 2012

13. Anemia Management

14. Mechanism of RBV-Associated Anemia  RBV uptake into RBC  adenosine kinase  RBV-triphosphate  Erythrocytes lack enzymes to hydrolyze RBV phosphates  RBV-phosphates are “trapped”  Erythrocyte T 1/2 > 40 days  RBV concentration in RBC 60-fold higher than serum (60:1)  Marked depletion of RBC adenosine triphosphate (ATP)  Impairs anti-oxidant defense mechanisms  Induces RBC oxidative membrane damage  Premature extravascular RBC removal by the reticuloendothelial system De Franceschi L. Hepatology 2000; 31:997-1004

15. Ribavirin Dose Reduction vs. EPO ?  Retrospective analyses of Boceprevir phase III studies have suggested that reducing the dose of RBV did not alter the SVR rate.  In patients treated with PEG+RBV (dual therapy), the effect of RBV dose reduction ON SVR was minimal if occurring when HCV-RNA was undetectable. Sulkowski MS et al. J Hepatol 2011; 54:S194-5. Reddy KR et al. Clin Gastroenterol Hepatol 2007; 5:124-9

16. Boceprevir Anemia Management: Erythropoietin vs. Ribavirin Dose Reduction Study After completion of 4 week PEG-IFN/RBV lead-in, all patients initiated boceprevir Hemoglobin ≤100 g/L Ribavirin dose reduction (DR) n = 249 Erythropoietin (40,000 IU/wk SC) n = 251 Hemoglobin ≤ 85 g/L: Secondary Strategy (EPO, RBV DR, transfusion) EPO: erythropoietin PEG-IFN: peginterferon RBV: ribavirin Genotype 1 patients, naive of treatment, Hb < 150 g/L at baseline 687 patients treated with boceprevir RGT Poordad et al. EASL 2012, Abstract 1419 Randomisation

17. Results – Primary and Key Efficacy End Points Patients (%)  (95% CI) -0.7% (-8.6, 7.2)* End-of-treatment response, relapse, and SVR were comparable between RBV DR and EPO arms DR, dose reduction; EOT, end of treatment; EPO, erythropoietin; RBV, ribavirin; SVR, sustained virologic response. *The stratum-adjusted difference (EPO vs. RBV DR) in SVR rates, adjusted for stratification factors and protocol cohort. Poordad et al. EASL 2012, Abstract 1419 82 71 10 82 71 10 0 25 50 75 100 EOT ResponseSVRRelapse RBV DR EPO 205/251203/249 19/196 19/197 178/249 178/251

18. Summary - Anemia Management  Ribavirin dose reduction does not decrease SVR  No advantage to Erythropoietin use, but may be used  Consider pRBC transfusion to maintain safe Hb  DAA should not be reduced  DAA should not be restarted or continued without Peg/RBV  Ribavirin may be increased once Hb recovers

19. Protease Inhibitors: Management of Anemia Hb < 100 g/L any time during treatment BoceprevirTelaprevir RBV dose reduction Up to 3 x 200 mg increments* Reduce RBV to 600 mg/day Hb > 85 g/L Maintain RBV dose reduction * Note:First dose reduction of 400mg if patient receiving 1400mg/day RBV dose reduction to 600 mg can be used with Boceprevir as wel Hb < 85 g/L EPO: 40-60,000 IU/wk AND/OR Transfusion

20. Rash Management - Telaprevir

21. Rash  Rash more prevalent in DAA but >50% with Telaprevir  Rash can be categorized:  Mild to moderate: < 30% of skin area  Moderate: 30-50% of skin area  Severe: generalized rash may progress with bullae, vesicles < 5% of patients Incivek Product Monograph, 2012

22. Rash Management Recommendations  Mild: Watchful monitoring  Oral antihistamines, moisturizers, topical steroids  Moderate: < 50% body  Monitor closely for progression/systemic symptoms  Antihistamines, moisturizers, topical steroids  Worsening/Severe: > 50% body ( < 4% of patients )  Stop telaprevir, observe closely for 7 days  IF no better, stop Ribavirin, observe for 7 days.  IF no better, stop Pegylated Interferon Incivek Product Monograph, 2012 Hézode C. Liver International. 2012; 32 Suppl 1:32-8 Cacoub P et al. Journal of Hepatology. 2012; 56(2):455-63

23. Telaprevir Severe Rash < 1%  DRESS:  Drug rash with eosinophilia and systemic symptoms  Rash, fever, facial edema ± hepatitis/nephritis  Eosinophils may not be present  Stevenson-Johnson Syndrome  Fever, target lesions and mucosal erosions/ulcers  STOP ALL drugs  Requires hospitalization  May require systemic steroids Incivek Product Monograph, 2012 Hézode C. Liver International. 2012; 32 Suppl 1:32-8 Cacoub P et al. Journal of Hepatology. 2012; 56(2):455-63

24. Other Side Effects of Boceprevir and Telaprevir

25. Gastroenterological Side Effects  Nausea, vomiting, diarrhea  Small meals three times daily with PI dosing useful  Fiber, loperamide aid with loose stool  Dysgeusia noted in Boceprevir patients  Metallic taste, rarely leads to dose reduction or discontinuation  Improved with chocolate administration

26. Gastroenterological Side Effects: Telaprevir  Nausea, vomiting and diarrhea common with TPV/PEG/RBV  Anorectal irritation:  Anorectal burning, itch and hemorrhoidal irritation common: > 29%  Therapy:  Frequent small meals, 21g fat per dose  Fiber, loperamide and topical hydrocortisone therapy, help relieve symptoms Incivek Product Monograph, 2012 Hézode C. Liver International. 2012; 32 Suppl 1:32-8 Cacoub P et al. Journal of Hepatology. 2012; 56(2):455-63

27. Management of Depression  Occurs in up to 37% of patients  Conduct pre-therapy and routine assessments with CES-D or other depression scale  Adjust interferon dose or discontinue therapy according to depression severity  May warrant use of antidepressants  Recommended agents to use with BOC and TVR: Escitalopram, citalopram (see Dr. Tseng’s chapter on DDIs)

28. Direct-Acting Antiviral Therapy: Boceprevir and Telaprevir  Patient side-effect education is important to success  Pre-therapy recommendations include:  Multivitamin, hydration, acetaminophen analgesia  Dietary recommendations to decrease GI toxicity effects ( small meals, fiber, loperamide )  Skin care through moisturizers and antihistamines  Close patient and hepatitis team communication  Monitor and pre-empt severe side effects  Drug and duration specific

29. 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.