Prevalence Clotting Factor Treatment Prior to 1987 Blood Long-Term Transfusion Worldwide 170 Million ( 3%) Hemodialysis Or Organ Transplant Prior to 1992

Hepatitis C: Diagnosis and Natural History Risk Factors Tushar Patel, MBChB

Prevalence Clotting Factor Treatment Prior to 1987 Blood Long-Term Transfusion Worldwide 170 million ( 3%) Hemodialysis or Organ Transplant Prior to 1992

Risk Factors Multiple for Hepatitis C Injection United States Sexual Partners Drug Use Anti-HCV positive 3.9 million(1.8%)

HCV RNA positive 2.7 million(1.4%) Mass Injections Birth from and Traditional Infected Mother Practices

Alter MJ et al., New Engl J Med 1999; 341:556 Lavanchy D & McMahon B, In: Liang TJ & Hoofnagle JH (eds.) Hepatitis C. New York: Academic Press, 2000:185

1 Current Likelihood of Transmission Diagnostic Tests • Transfusion ~ 1 in 1,000,000 • Heterosexual partner ~1 in 1,000 per yr • Hepatitis C antibody tests • Needlestick injury • Qualitative HCV RNA tests ¾ HCV-positive source ~ 5% ¾ HCV status unknown ~ 1% • Quantitative HCV RNA tests • Maternal-Infant • Genotyping ¾ Mother HIV-negative ~ 5% ¾ Mother HIV-positive 15 - 20% • Liver biopsy

Terrault NA, Hepatology 2002 ;36(Suppl 1):S99 Roberts EA, Yeung L. Hepatology 2002 ;36(Suppl 1):S106

Acute Hepatitis C Infection

1000 HCV RNA positive 800 Anti-HCV ALT 600 Diagnosis and Evaluation (IU/L) 400 Symptoms

200

Normal 0 ALT 02468101224123456 7 Weeks Months Time After Exposure

Hoofnagle JH, Hepatology 1997; 26:15S

2 Antibody tests for HCV Genotypes hepatitis C • Six major genotypes found throughout • Indicates past or present infection the world • Inexpensive, sensitive and specific • Major determinant of response to • Poor positive predictive value in low antiviral therapy prevalence populations • In Europe and U.S., 60-70% of patients • Low sensitivity in immunosuppressed have genotype 1 infection patients

Qualitative tests for Virological Tests Do Not Predict HCV RNA Natural History of Disease • Confirms diagnosis of HCV infection • No correlation between genotype and • Useful in the early diagnosis of acute progression of disease hepatitis C • No correlation between HCV RNA level and • Demonstrates the presence of active progression of disease infection

• “Gold standard” for documenting response to treatment

3 Liver Biopsy

• Degree of fibrosis is most important predictor of prognosis

• Useful in determining need for anti-viral therapy Natural History

• Advanced cirrhosis associated with reduced response to treatment

Outcome Following Hepatitis C Infection Stages of Fibrosis In Chronic Hepatitis

Acute hepatitis C Portal Periportal 55 - 85% Chronic infection

70%

12 Chronic hepatitis 1 - 4%/yr 20% HCC 3 4 Cirrhosis Decompensation 4 - 5%/yr Time (yr) Septal Cirrhosis 10 20 30

4 Stage of Disease Correlates Hepatocellular Carcinoma With Duration of Infection Incidence in HCV-Positive Cirrhosis 60 Chronic hepatitis

% 40 Liver cirrhosis Cumulative incidence 20 Hepatocellular carcinoma Median 00 0205010 30 40 60 012345678910 Years of follow-up Years since transfusion

Kiyosawa K, et al., Hepatology 1990; 12:671 Adapted from Ikeda K et al, Hepatology 1993;18:47

Outlook for Those With Factors Associated Compensated Cirrhosis Study A Study B Study C With Fibrosis Number 384 112 103 Follow-up (yr) 5.0 4.5 3.3 • Duration of infection Decompensation (%/yr) 3.9 4.4 5.0 • Alcohol > 50 gm per day HCC (%/yr) 1.4 2.3 3.3 5-Year Survival (%) 91 83 84 • Age > 40 years at infection Post decompensation (%) 50 51 -- • Male gender

A: Fattovich G et al. Gastroenterology 1997;112:463 B: Hu K & Tong MJ. Hepatology 1999;29:1311 C: Serfaty L et al. Hepatology 1998;27:1435 Poynard T, et al., Lancet 1997; 349:825

5 Progression to Cirrhosis Can Be Estimated Fibrosis Rate Varies Among From Initial Stage of Liver Biopsy Fibrosis HCV-Infected Individuals

100 4 Men who drink > 50 gm Initial Stage 3+ 80 alcohol daily Initial Stage 2-2.9 3 % 60 Progression Initial Stage 0-1.9 to Cirrhosis40 Stage of 2 (stage 4) Fibrosis 20 1 Women who don’t drink 0 0 2 4 6 8 101214161820 Time (yr) 0 0 5 10 15 20 25 30 35 Duration of Infection (year) Yano M, et. al., Hepatology 1996; 23:1334

Fibrosis Risk Varies Among HIV Co-Infection May Accelerate Individuals Progression to Cirrhosis

Patient A Patient B 50 40 Age at infection 25 42 30 Alcohol use Seldom 3-4 drinks/day % HIV Positive With 20 N = 80 Sex Female Male Cirrhosis 10 HIV Negative Fibrosis stage/yr 0.10 0.25 N = 80 0 Years to cirrhosis 40 16 0 5 10 15 20 Duration of HCV Infection (years)

Poynard T, et al., Lancet 1997; 349:825 Adapted from Di Martino V et al. Hepatology 2001;34:1193

6 Should we treat Future Prevalence Hepatitis C? of HCV 4

3 • HCV is the only chronic virus infection that can Individuals infected be eradicated (cured) by antiviral therapy. at any time 2

• Cure of infection (SVR) essentially eliminates of Prevalence

risk of decompensation in patients with HCV Infections (%) 1 Individuals infected cirrhosis and dramatically reduces risk of HCC. For >20 years 0 1960 1970 1980 1990 2000 2010 2020 2030

Davis, et al. Liver Transplantation 2003. Armstrong GL et al. Hepatology 2000; 31:777-782

Liver-Related Mortality in HCV Related Complications Expected to Chronic Infection Increase Greatly in the Coming Years

Results of a Markov Model Based on HCV Natural History Studies* Middle-Aged Young Transfusion Recipients Air Force Recruits 6 HCC 81%

4 Cirrhosis 82% % HCV-Negative Mortality Controls Decompensation 106% From Liver HCV Positive Disease 2 Liver-Related 181% Deaths n=377 n=222 n=8551 n=17 0 0 20 40 60 80 100 120 140 160 180 200 25 Years 45 Years Duration of Follow-Up Estimated % Increase From 2000 to 2020

Seeff LB et al, Ann Intern Med 2000; 132:105 *Assumes no HCV treatment. Seeff LB et al, Hepatology 2001;33:455 Davis GL, et al. Liver Transpl. 2003;9:331-338.

7 Mental Health Evaluation • Psychopathology (e.g., substance abuse, depression, anxiety) is prominent in individuals with chronic HCV • Pegylated IFN, with or without ribavirin, is Pre-treatment evaluation associated with depression rates of 20%-34% • IFN-α and ribavirin can worsen and/or induce depression and other underlying psychiatric conditions Æ Patients should be screened and have any pre- existing psychiatric conditions treated before initiating HCV treatment

1. Asnis GM, De La Garza R II. J Clin Gastroenterol. 2006;40:322-335. 2. Rifai MA, et al. Curr Treat Options Gastroenterol. 2006;9:508-519.

Current Practice Predictors of Response to Antiviral Therapy in Chronic Hepatitis C HCV viral load Hepatitis A/ B immunizations Anti-HAV AFP HBsAg +/- US, EGD TSH • Genotype 1 and 4 are less responsive ALT Liver Biopsy than other genotypes CBC

Patient referral High viral load is less responsive Mental Health Evaluation • Counseling and review Consent to treat – Natural history of HCV Specialist review as appropriate – Treatment options (ID, optho, card etc) – Adverse effects of Rx • Advanced fibrosis is less responsive – Expected benefits of Rx – Duration of treatment

Treatment with regular follow-up visits

8 Hepatitis C Virologic Responses Current and Future 8 7 PegIFN/RBV

Treatment IU/mL) 5 10 EVR 2 log decline Maher Azzouz,MD 4 10 Associate Professor of Medicine 3 Director of Endoscopy 2 Slow virologic response Limit of detection Division of Gastroenterolgy Hepatolgy and Nutrition RNA HCV (log 1 RVR cEVR The Comprehensive Transplant Center SVR The Ohio State University 0 0 48 12 18 24 30 36 42 48 54 60 66 72 78 Weeks

Goals of HCV Therapy Suboptimal Virologic Responses

• Primary goal: eradicate the virus 8 7 PegIFN/RBV • Secondary goals Relapse 6 Null response 9 Slow disease progression IU/mL) 10 5 Partial response Breakthrough 2 log decline 9 Minimize risk of HCC 4 10 9 Improve liver histology 3 2 9 Enhance quality of life Limit of detection HCV RNA HCV (log 1 9 Prevent transmission of virus 0 9 Reduce extrahepatic manifestations 0 48 12 18 24 30 36 42 48 54 60 66 72 78 Weeks

Lindsay KL. Hepatology. 2002;36(suppl 1):S114-S120.

9 HCV Therapy IDEAL Trial SVR/Standard Interferon (IFN) Which PegIFN is better Genotype 1 US Patients 100 50

80 40 41 40 38

60 30

43 SVR % 20 40 SVR (%)

10 19 20 6 0 PEG-INTRON 1.0 mcg/kg PEG-INTRON 1.5 mcg/kg Pegasys 180mcg 0 IFN IFN IFN/RBV 24 Weeks 48 Weeks 48 Weeks There were no statistical differences between groups

McHutchison J, et al. N Engl J Med. 1998;339:1485-1492. Poynard T, et al. Lancet. 1998;352: 1426-1432. Sulkowski, M., et al. Presented at EASL 2008, Milan, Italy

HCV Therapy Peg-IFN + RBV SVR With PegIFN/Ribavirin Response Rates • > 50% of GT 1 Patients Do Not Respond 60 52-53 Naive • PegIFN alfa-2b 1.5 µg/kg/week + • PegIFN alfa-2a 180 µg/week + 50 Retreatment RBV 800 mg/day for 48 weeks[1] weight-based RBV (1000 or 1200 38-41 27-40 mg/day) for 48 weeks[2] 100 40 82 17-29 80 76 30

SVR (%) 19-26

60 56 20 54 46 42 10 2-4 SVR (%) 40

0 20 All Genotypes Genotype 1 HIV/HCV HIV/HCV African American Peg on Peg US Patient Genotype 1 Genotype 1 Non-Responders n = 511 n = 348 n = 163 n = 453 n = 298 n = 140 0 Overall GT 1 GT 2/3 Overall GT 1 GT 2/3 Manns MP, et al. Lancet. 2001;358:958-965. Torriani FJ, et al. N Engl J Med. 2004;351:438-450. Poynard T et al. J Hepatol. 2005:42(Suppl 2):40-41.:Shiffman M.L., et al. Gastroenterology 2004; 126:1015- Jeffers LJ, et al. Hepatology. 2004;39:1702-1708. 1023.:Boceprevir Update Press Release; Schering Plough Pharmaceuticals; Kenilworth, NJ: Oct 18, 2007. 1. Manns M, et al. Lancet. 2001;358:958-965. Carrat F, et al. JAMA. 2004;292:2839-2848. Afdhal N, et al. EASL, 2007; NM283 Control Arm Phase 2 Trial Abstract; Barcelona, Spain. McHutchison, Muir AJ, et al. N Engl J Med. 2004;350:2265-2271. J., et al AASLD, 2008; Telaprevir Control Arm Phase 2 Trial, Abstract; San Francisco:Schiff,.E., et al. EASL 2. Fried MW, et al. N Engl J Med. 2002;347:975-982. Fried MW, et al. N Engl J Med. 2002;347:975-982. 2008; Boceprevir Control Arm – Phase 2 trial, Milan Italy

10 HCV Treatment Longer Duration of Therapy Longer Therapy in GT 1 Pts Without cEVR but Week 24 Challenges Negative HCV RNA Post Hoc Analysis of Slow Responders Who Completed PegIFN • Difficult-to-Treat HCV Patient 100 alfa-2a 180 µg/week + RBV 800 mg/day and Follow-up 48 weeks (n = 147) 80 P = .02 • Preventing Relapse 72 weeks (n =158) 64 • Retreatment Options for Treatment 60 P = .04 40 Failure 40 Patients (%) Patients 29 • Maintenance Therapy 20 17 17/100 31/106 30/47 21/52 0 • Future Options for Treatment SVR Relapse

Berg T, et al. Gastroenterology. 2006;130:1086-1097.

Duration of Undetectability Ribavirin Dosage/Adherence

• Longer Duration of Undetectability on Treatment • Higher Ribavirin dose and cumulative dose are Increases Chance for SVR associated with increased SVR Retrospective analysis of GT 1 patients receiving 48 weeks Retrospective analysis of pegIFN alfa-2a/RBV phase III trials of pegIFN alfa-2a + RBV (N = 453) 100 SVR (P = .006) Relapse 100 91 80 80 67 66 62 57 60 60 54 45 40 40

SVR (%) 33 32 Patients (%) Patients 20 22 19 20 2 0 41224HCV RNA Positive 0 0-60 > 60-80 > 80-97 > 97 Week Became HCV RNA Negative at Week 24 Cumulative RBV Exposure

Ferenci P, et al. J Hepatol. 2005;43:425-433. Reddy KR, et al. Clin Gastroenterol Hepatol. 2007;5:124-129.

11 Steatosis in HCV Effect of Weight Loss

• Steatosis is a common comorbidity of HCV on Antiviral Response • Found in 50% to 60% of HCV-infected patients[1,2] vs 14% role of insulin 32 treatment-naive GT 1 to 30% in general population[3,4] HCV patients with sensitizers metabolic syndrome Proportion of Patients With Fatty Liver Disease Among 121 HCV-Infected Individuals With Available Liver Biopsies[1]

NASH (18%) 15 patients on No steatosis (41%) low-calorie diet: 17 control patients 10% ↓ in BMI

HOMA: 4.86-3.45 (P = .0018) pegIFN alfa-2b + RBV Steatosis (41%) Response: 60.0% Response: 17.6% 1. Younossi ZM, et al. J Clin Gastroenterol. 2004;38:705-709. 2. Asselah T, et al. Gut. 2006;55:123-130. 3. Browning JD, et al. Hepatology. 2004;40:1387-95. 4. Nomura H, et al. Jpn J Med. 1988;27:142-149. Tarantino G, et al. Gut. 2006;55:585.

Steatosis in HCV HCV Treatment: Key Predictors of Response 2 Types of Steatosis in Hepatitis C

Metabolic syndrom HCV 1995-2000 Current Insulin resistance • GT 2 or 3 • Lack of steatosis Viral steatosis Overweight • Absence of fibrosis • Adherence (viremia) Diabetes • Low HCV RNA • Early response • Younger age • RBV dosage Steatosis GT 3 • Female sex • Race • Weight •Co-infection viral steatosis may disappear following successful hepatitis C therapy Alcohol

Manns MP, et al. Lancet. 2001;358:958-965. Rubbia-Brandt L, et al. J Hepatol. 2000;33:106-115. Adinolfi LE, et al. Hepatology. 2001;33:1358-1364. Fried MW, et al. N Engl J Med. 2002;347:975-982. Serfaty L, et al. Am J Gastroenterol. 2002;97:1807-1812. Monto A, et al. Hepatology. 2002;36:729-736. Muir AJ, et al. N Engl J Med. 2004;350:2265-2271. Poynard T, et al. Hepatology. 2003;38:75-85. Conjeevaram HS, et al. Gastroenterology. 2006;131:470-477.

12 HCV Patient Projections HCV Retreatment Outcome in Nonresponders to IFN-Based Therapy 400 Study Treatment GT N (Previous SVR Rate Naïve Non-Responders Treatment) (Previous Treatment) 350 Jacobson[1] PegIFN alfa-2b 1 (89%) 47 (IFN) 21% (IFN) 300 + RBV x 48 weeks 2/3 (9%) 219 (IFN/RBV) 8% (IFN/RBV) Sherman[2] PegIFN alfa-2a 1 36 (IFN) 22% (IFN) 250 + RBV x 48 weeks 148 (IFN/RBV) 20% (IFN/RBV) 200 2/3 9 (IFN) 44% (IFN) 19 (IFN/RBV) 37% (IFN/RBV) 150 RENEW[3] PegIFN alfa-2b 1.5 or 1 (91%) 704 (IFN/RBV) 12% 3.0 µg/kg/week + RBV 17% HCV Patients (,000) Patients HCV 100 HALT-C[4] PegIFN alfa-2a All 604 18% 50 + RBV x 48 weeks EPIC3[5] PegIFN alfa-2b 1 (81%) 903 18% 0 + RBV x 48 weeks 2/3 (15%)

1. Jacobson IM, et al. Am J Gastroenterol. 2005;100:2453-2462. 2. Sherman M, et al. Gut. 2006;55:1631-1638. 3. Gross J, et al. AASLD 2005. Abstract 60. 4. Shiffman ML, et al. Gastroenterology. 2004;126:1015-1023. Decision Resources Hepatitis C Report & Interactive Forecast Tool 2005. 5. Poynard T, et al. EASL 2008. Abstract 988.

HCV Retreatment Outcomes in Nonresponders to PegIFN/RBV

Study Treatment GT N (Previous SVR Rate Treatment) (Previous Treatment) REPEAT[1] PegIFN alfa-2a + 1 (> 473 8% HCV Retreatment RBV x 48 weeks 90%) PegIFN alfa-2a + 1 (> 469 16% RBV x 72 weeks 90%) EPIC3[2] PegIFN alfa-2b + 1 196 (PegIFN alfa- 6% (PegIFN alfa-2a) RBV x 48 weeks (81%) 2a) 7% (PegIFN alfa-2b) 2/3 280 (PegIFN alfa- (15%) 2b)

1. Jensen DM, et al. AASLD 2007. Abstract LB4. 2. Poynard T, et al. EASL 2008. Abstract 988.

13 HCV Retreatment: DIRECT 8-Year Posttreatment Outcomes: Sustained Virologic Response in Nonresponders to PegIFN/Rib Patients With or Without SVR

25%

n=172 n=245 n=242 Liver-Related Death Liver Failure 20% 50 5-year occurrence 50 5-year occurrence 40 40 p = 0.002 p <0.001 SVR: 4.4% (CI: 0% to 12.9%) SVR: 0% 15% No SVR: 12.9% (CI: 7.7% to 18.0%) No SVR: 13.3% (CI: 8.4% to 18.2%) 30 P = .024 (log likelihood) 30 P = .001 (log likelihood) SVR (%) SVR 10.7 10% 20 20 6.9 5% 0 10 10 Liver Failure (%) 0 0 0% No Treatment 9mcg 15mcg 081 2 34567 012345678 Liver-Related Death (%) Death Liver-Related Year Year At risk 337 261 192 160 124 95 79 49 31 At risk 337 256 183 155 121 92 74 44 27 Study Treatment GT N SVR Rate Events 0 5 11 16 20 24 25 28 30 Events 0 8 21 24 27 29 31 35 35 No SVR At risk14276483525148 6 5 1 (95%) 245 6.9% SVR At risk14276483525148 6 5 DIRECT CIFN 9 µg/day + Events00000 1111 Events00000 1111 RBV CIFN 15 µg/day + 1 (96%) 242 10.7% RBV ANNALS OF INTERNAL MEDICINE. ONLINE by Veldt BJ, Heathcote EJ, Wedemeyer H, Reichen J, Hofmann WP, Zeuzem S, Manns MP, Hansen BE, Schalm SW, Janssen HL. Bacon B, et al. Hepatology 2009 Copyright 2007 by American College of Physicians

Antiviral Therapy for HCV-Related HCV Retreatment: Relapsers Cirrhosis: Prevention of HCC

Outcomes in Relapsers to PegIFN-Based Therapy • Does it prevent HCC? 9 Early studies suggested reduced risk of HCC Study Treatment GT N SVR Rate following IFN treatment, even if treatment was unsuccessful Kaiser CIFN 9 µg/day 1 120 69% 9 Later studies indicate some benefit but only in + RBV x 72 weeks noncirrhotic patients achieving SVR PegIFN alfa-2a 42% + RBV x 72 weeks 9 Studies in HCV patients with cirrhosis do not show significant reduction in HCC after antiviral treatment • Conclusion: If advanced fibrosis or cirrhosis is present, patients remain at risk for HCC, even after achieving SVR

Kaiser S, et al. AASLD 2007. Abstract 1310. Yu ML, et al. Oncology. 2007;72(suppl 1):16-23.

14 Maintenance Therapy: HALT-C

Long-term PegIFN alfa-2a 90 μg/week in Nonresponders

• No reduction in fibrosis and no difference between arms • No significant difference between arms in any primary outcome 9 34.1% vs 33.8% (HR: 1.01; 95% CI: 0.81-1.26) Maintenance Therapy 100 Outcomes at 3.5 Years (P = NS for all comparisons) 80 No treatment (n = 533) PegIFN alfa-2a 90 µg/week (n = 517)* 60 40 31.9 28.2

Patients (%) Patients 20 13.2 14.3 4.6 6.6 3.2 2.8 0 Death Decompensation HCC Increase in Fibrosis *17% discontinued at 1.0 year and 30% discontinued at 3.5 years.

Di Bisceglie A, et al. AASLD 2007. Abstract LB1.

Maintenance Therapy: COPILOT

Event-Free Survival With and Primary Endpoints (ITT) 49% of patients did not achieve 4-year event-free survival

Primary Endpoints at Year 4 Colchicine 0.6 mg twice daily (n = 55) 30 27 Future Options for PegIFN alfa-2b 0.5 µg/kg/week (n = 51) 23 22 20 Treatment 13 10 10

Events (No.) 4 4 11 1 0 Death OLT Variceal CTP > 2 HCC Bleed Primary endpoints more common in both colchicine and pegIFN arms in patients with portal HTN (32% and 23%, respectively) vs without portal HTN (9% and 13%, respectively)

Afdhal N, et al. EASL 2008. Abstract 3.

15 Timeline for New Therapies Boceprevir + PegIFN/RBV: Phase 1 Phase 2 Phase 3 Phase II Nonresponder Study, GT 1 Response dependent on IFN responsiveness GS 9190 F Polymerase inhibitor Patients With Detectable HCV RNA or < 2 log Decline in ITMN 191 TMC435350 D 10 Protease Inhibitor HCV RNA at ≥ 12 Weeks of Previous PegIFN + RBV (N = 357) Protease Inhibitor A GSK625433 VCH-759 Albuferon 100 Polymerase inhibitor Polymerase inhibitor Albumin Interferon GS-9190 Taribavirin R 80 Polymerase Inhibitor RBV Pro Drug Telaprevir Protease Inhibitor E R7128 BLX-883 60 Polymerase Inhibitor Locetron Interferon Boceprevir V Protease Inhibitor Bavituximab Nitazoxanide 40 Anti phospholipid Antiprotozoal agent I SVR (%) SCH 900518 E 7-14 Protease Inhibitor 20 W 2 0 PegIFN alfa-2b + RBV Boceprevir* + PegIFN alfa-2b + RBV (Various Arms) 1 Year 2‐3 Years 2‐3 Years *100, 200, 400, and 800 mg TID. http://www.hcvadvocate.org/hepatitis/hepC/hcvdrugs.html. Accessed January 2008 Schiff E, et al. EASL 2008. Abstract 104. Franciscus A. Hepatitis C Support Project. Dec. 28, 2006.

AlbIFN Retreatment of IFN/RBV and Telaprevir + PegIFN alfa-2a + RBV in PegIFN/RBV Nonresponders Nonresponders or Relapsers • Open-label treatment of patients from control arms of AlbIFN alfa-2b + RBV* PROVE1-3 trials Every 4 Every 2 Weeks Week 4 (RVR) Week 8 Week 12 SVR, % (n/N) Weeks 100 100 100 100 100100 100 100 1200 µg 900 µg 1200 µg 1500 µg 1800 µg 100 89 79 80 80 67 All patients 25 (6/24) 30 (7/23) 13 (3/24) 9 (2/22) 9 (2/22) 60 50 GT1, 40 33

pegIFN/RBV < 10 IU/mL (%) 20 15 (2/13) 15 (2/13) 13 (2/16) 7 (1/15) 6 (1/18) nonresponde

Undetectable HCV RNA, 0 rs Week 4 Null Week 12 Null Partial Week 20 Relapser Responder* Responder† Responder‡ Breakthrough

† ‡ • Overall SVR rate: 17.4% *< 1 log10 drop at Week 4. < 2 log10 drop at Week 12. ≥ 2 log10 drop at Week 12; detectable • GT1, pegIFN + RBV nonresponder SVR rate: 10.7% HCV RNA at Week 24.

Nelson D, et al. AASLD 2007. Abstract 51. Poordad F, et al. EASL 2008. Abstract 1000.

16 Discontinued Clinical Programs HCV Therapy Conclusion

COMPANY PRODUCT PHASE REASON FOR DESCRIPTION DISCONTINUATION Roche/ Levovirin Phase I Lack of activity and formulation issues L-isomer of RBV Ribapharm • Relapsers are good candidates for retreatment Boehringer Ingelheim BILN 2061 Phase II Cardiac toxicity in animals Protease inhibitor

Roche Phase II Safety Polymerase inhibitor • Nonresponders to suboptimal therapy (ie, R1626 standard IFN) more likely to respond to Vertex Pharmaceutical Merimepodib (MMPD) Phase II Lack of efficacy Polymerase inhibitor retreatment vs those previously treated with Maxim Pharmaceuticals Maxamine® Phase III Lack of efficacy Immune response modifier pegIFN/RBV Indevus IP 501 Phase III Unknown Antifibrotic

ACTILON Coley Pharmaceutical Phase I/II Lack of efficacy Toll-like receptor agonist • Nonresponders with negative predictors of (CPG 10101) response (ie, advanced fibrosis, insulin Achillion/Gilead ACH806 Phase II Safety Protease Inhibitor resistance) may not be good candidates for Valopicitabine Clinical development on hold per FDA Idenix/Novartis Phase II Polymerase Inhibitor NM283 request for safety reasons retreatment Anadys / Novartis ANA 975 Phase Ib Safety Toll-like receptor agonist

http://www.hcvadvocate.org/hepatitis/hepC/hcvdrugs.html. Accessed January 2008

HCV Therapy Conclusion HCV Therapy Conclusion Improving Outcome and Decreasing Relapse

• Importance of duration of HCV RNA negativity • Slow responders may require longer duration of • Maintenance therapy has not been shown therapy (GT 1) to be effective for reducing fibrosis progression, other disease outcomes • Weight based dose of RBV • Improving Compliance • Promising results with new compounds, even in the setting of null response 9 Better management of adverse effects to decrease dose reductions or interruptions • Steatosis and Insulin Resistance • Some patients may be inherently resistant to IFN

17 Hepatitis C Therapy HCV therapy Managing side effects • Pegylated interferon plus ribavirin • Consensus interferon plus ribavirin • Both regimens associated with possibly Pegi Linnabary MS, RN, CNP significant side effects. Ohio State University Medical Center • Front-load your patient education about side effects; it saves time later. Teach them what that might experience.

Multidisciplinary team Place side effects in Identify / incorporate resources perspective • Psych: psychiatrist, psychologist, psych CNP. • Patients get on the internet and read about • Substance abuse resources: Local / state AA other’s bad experiences. People with bad information. AlAnon for friends, family. City / county resources. CD counselors. experiences likely to be most outspoken. • Opthamology: pre-treatment eye exams, • Present frequency of SEs as bell curve: especially in diabetic patients. Urgent referral is vision changes in patient on Rx.70 9 Outliers left: no problems • Endocrinology: DM management. 9 Outliers right: must DC treatment • Cardiologist 9 Largest number in the middle: flu-like sx • Pharmacist around injection time, fatigue during • Weight management resources week, but still working, functioning.

18 Fatigue- most common Injection Site Reactions • Hgb / thyroid – both are monitored Æ ? EPO / ? thyroid med may be indicated • Determine if patient is using proper technique and proper site. • Interventions: 9 Energy conservation measures. Be • Apply cool pack / ice pack to area. efficient. • Use small amount of hydrocortisone 1% 9 Assess for sleep time / sleep hygiene ointment to site between cold packs. 9 Plan A, B and C Æ patients love this. • Reinforce site rotation. 9 Regular moderate exercise. Walking 20 minutes daily.

GI issues: N/V, Insomnia anorexia, diarrhea • Assess for sleep / nap patterns. • Encourage small, frequent meals. Some pts develop changes in smell /taste. • Sleep hygiene: dark, quiet room. Regular bedtime. • Intuitive eating. Oatmeal, peanut butter. • “Boost” or “Ensure” blended with ice. • As with fatigue – regular, moderate exercise helpful. • Diarrhea – can take OTC antidiarrheal. Avoid fatty foods. Pt to contact office if • Benadryl 25 or 50mg PO HS PRN. vomiting and / or diarrhea becomes severe.

19 Pruritus Rash, Dry skin, & Alopecia Psychiatric Issues Associated with both IFN and RIB • Patients should be screened for depression • Maintain adequate hydration, non- prior to initiation of therapy, and stabilized caffeinated beverages. on an antidepressant if indicated. Consider psych follow-along in marginal patients. • Use warm, not hot water for bathing. • Journaling: encourage! • Keep sleeping quarters cool enough to prevent perspiration. • Communication: encourage communication between patient, spouse, • Lotions: Sarna or Eucerin Calming cream. SO, friends and family. Oatmeal based lotions (Aveeno).

Pruritus Flu-like Symptoms Rash, Dry Skin, Alopecia HA, Chills, Myalgias

• Benadryl 25 mg tablets. • Interventions: 9 Drug is sedating. For daytime use, start at 9 If not contraindicated, ibuprofen 400mg 12.5mg PO q 4-6h. Increase as tolerated. 30 minutes before IFN injection and 9 50 mg HS. continue q8h PRN the next 48 hours. 9 If rash is severe, check for autoimmune component. 9 Tylenol, no more than 2,000mg daily. Educate re: acetaminophen in many 9 Rash can be associated with both IFN and OTCs. Read label. RIB. 9 Alopecia is reversible. Reassure patient. 9 Typically, these SEs improve over time.

20 Cough Red Flags • Usually associated with ribavirin. • Vision changes: Stop IFN - urgent optho • Interventions: referral 9 Maintain H2O intake. Hard candies. • Severe depression: SI, HI. Stop IFN! 9 OTC dextromethorphan. • Severe rash with intractable pruritus. 9 Heating pad to chest (patient recommendation) • Monitor thyroid before, during, after therapy. 9 Rx Tessalon Perles 100mg. One or two perles TID PRN cough. (benzonatate). • Check autoimmune markers before 9 CXR? starting.

Oral Problems

• Apthous ulcers, “sore mouth”. Try Magic mouthwash. =parts: Mylanta, Benadryl, lidocaine. • Oral / oropharyngeal candidiasis. Rare, but can be very uncomfortable: anti-fungal rinse or systemic med.