1. Updates in Treatment of Hepatitis C Gene LeSage, MD, FACP, AGAF

2. Objectives HCV epidemiology, risk factors, diagnosis and prognosis Interferon (IFN) and Ribavirin (RBV) based therapy Direct acting anti-viral (DAA) therapies

3. HCV Epidemiology Nearly 3% of worldwide population has chronic HCV infection [1,2] – Most common blood-borne infection in United States [3] Up to 75% unaware of HCV infection until liver disease or cancer develops many yrs later [4] HCV infection associated with multiple disease processes [5] – Including liver disease, diabetes, B-cell proliferative disorders, depression, and cognitive disorders Diminishing HCV infection rates, morbidity through prevention an important ongoing public health initiative 1. Lavanchy D. Liver Int. 2009;29:74-81. 2. Shepard CW, et al. Lancet Infect Dis. 2005;5:558-567. 3. IOM. Hepatitis and Liver Cancer. NA Press. 2010. 4. Mitchell AE, et al. Hepatology. 2010;51:729-733. 5. Jacobson IM, et al. Clin Gastroenterol Hepatol. 2010;8:1017-1029.

4. Hepatitis C Virus Infection Population at Risk Transfusion of blood products before 1992 Intravenous drug use Nasal inhalation of cocaine Chronic renal failure on dialysis Incarceration Occupational exposure to blood products Transplantation of an organ/tissue graft from an HCV- positive donor Body piercing and potentially tattoo Centers for Disease Control and Prevention. Hepatitis C fact sheet. Available at: http://www.cdc.gov/ncidod/diseases/hepatitis/c/fact.htm. Accessed February 1, 2006.

6. Hepatitis C Virus Diagnostic Testing Diagnostic Test Type SpecificationsSerologicVirologic Mode of detectionAntibodiesVirus Sensitivity> 95%> 98% SpecificityVariable> 98% Detection postexposure2-6 months2-6 weeks UseScreeningConfirmation

7. HCV Infection - Liver Biopsy Only test that can accurately assess – Severity of inflammation – Degree of fibrosis Determines the following – Risk for developing cirrhosis in future – Need for therapy – Need for ongoing therapy when initial treatment has failed

8. HCV RNA 0 50 100 150 200 06121824 Month ALT (IU/l) Resolution Chronic + +- Hepatitis C Virus Response to Acute Infection Illustration by Mitchell L. Shiffman, MD.

9. Prevalence of Anti-HCV, United States, 1999-2002 (NHANES) Armstrong et al. AASLD 2004. Overall prevalence: 1.6% (4.1 million) Born ~1945-1965

10. HCV Infection Chronic Hepatitis Cirrhosis HCC 1%(1%–3%/y) 100% 25 y 90% (60%–95%/y) 15% (10%–30%/y) HCV to HCC Pyramid Graphic courtesy of Dr. H.B. El-Serag.

11. -2-1.5-1-0.500.511.52 All Other Cancers (Average) Liver Thyroid Esophagus Lung & Bronchus (Female) Testis Corpus & Uterus, NOS Trends in US Cancer Mortality Rates Annual Percent Change (1994–2003) NOS = not otherwise specified. National Cancer Institute. Seer Summary Figures and Tables. Available at: http://seer.cancer.gov/csr/1975_2003/results_merged/topic_graph_trends.pdf. Accessed on October 17, 2008. Liver Cancer Has the Fastest Growing Death Rate in the United States

12. Chronic Hepatitis C Infection Progression to Cirrhosis 20%-33%15%-33% 01020304050 HCC Cirrhosis C Cirrhosis A Severe Moderate Mild Years Shiffman ML. Viral Hepatitis Rev. 1999;5:27-43.

13. Established Risk Factors for Progression of Fibrosis and Cirrhosis Poynard T, Lancet 1997 349:825-32 Mathurin P, Hepatology 1998 27:868-72 Benhamou J, Hepatology 1999 30:1054-8  Male gender  Longer duration of infection  Age >40 years at time of infection  Alcohol excess  >50 gm/day - men  >30 gm/day - women  Persistently elevated ALT levels  HIV, HBV coinfections  Organ transplantation

14. Newly-Recognized Risk Factors for HCV Disease Progression  Menopausal status  Cannabis  Insulin resistance  Obesity, metabolic syndrome

15. Chronic HCV Infection Normal vs Elevated Serum ALT Normal ALTElevated ALT Portal 26% No fibrosis 23% Mild 39% Cirrhosis 6% Bridging 6% Portal 20% No fibrosis 16% Mild 33% Cirrhosis 18% Bridging 13% Shiffman ML, et al. J Infect Dis. 2000;182:1595-1601.

16. HCV RNA effect on Liver Histology & Fibrosis Genotype No Fibrosis Portal Fibrosis Bridging Fibrosis Cirrhosis  Serum HCV RNA does not correlate with level of fibrosis 0 2 4 6 8 Log HCV RNA (copies/mL) 1 2 3 4 Ferreira-Gonzalez A, et al. Semin Liver Dis. 2004;24:9-18.

17. HCV and Alcohol Excessive alcohol intake characterized as > 40 g/day for women and > 60 g/day for men. 0 20 40 60 80 100 10203040 Years Following Exposure Cirrhosis (%) HCV HCV + alcohol Wiley TE, et al. Hepatology. 1998:28:805-809.

18. Past and Future (Estimated) US Incidence and Prevalence of HCV Infection Graphic courtesy of Centers for Disease Control and Prevention. Decline among IDUs Overall incidence

19. Persons (n) Peak incidence Peak cirrhosis Reprinted from Gastroenterology, 138, Davis GL, et al, Aging of hepatitis C virus (HCV)-infected persons in the United States: a multiple cohort model of HCV prevalence and disease progression, 513-521, Copyright 2010, with permission from Elsevier. The Changing Face of HCV in the US Yr 6,000,000 5,000,000 4,000,000 3,000,000 2,000,000 1,000,000 0 195019601970198019902000201020302020 Ever HCV infected All chronic HCV Acute HCV infection Cirrhosis

20. HCV Life Cycle and DAA Targets Adapted from Manns MP, et al. Nat Rev Drug Discov. 2007;6:991-1000. Receptor binding and endocytosis Fusion and uncoating Transport and release (+) RNA Translation and polyprotein processing RNA replication Virion assembly Membranous web ER lumen LD ER lumen LD NS3/4 protease inhibitors NS5B polymerase inhibitors Nucleoside/nucleotide Nonnucleoside *Role in HCV life cycle not well defined NS5A* inhibitors

21. Sustained virologic response (SVR) as Clinical Endpoint SVR used as endpoint of successful HCV treatment – Defined as undetectable serum HCV RNA levels 24 wks after end of treatment Achieving SVR results in significant reduction of HCV-associated complications and mortality [1,2] 1. Morgan TR, et al. Hepatology. 2010;52:833-844. 2. Backus L, et al. 2010 AASLD. Abstract 213. SVR betterNo SVR better Genotype 1 Genotype 2 Genotype 3 P <.0001 P =.004 P <.0001 All-Cause Mortality HR (95% CI) 00.20.40.60.81.01.21.41.61.82.0

22. PegIFN alfa-2b 1.5 µg/kg/wk + RBV 800 mg/day for 48 Wks [1] PegIFN alfa-2a 180 µg/wk + Weight-Based RBV (1000 or 1200 mg/day) for 48 Wks [2] 1. Manns MP, et al. Lancet. 2001;358:958-965. 2. Fried MW, et al. N Engl J Med. 2002;347:975-982. 46 76 56 OverallGT1GT2/3 298140453 42 82 100 80 60 40 20 0 54 OverallGT1GT2/3 SVR (%) 348147511 100 80 60 40 20 0 n = HCV Standard of Care Prior to May 2011  GT1 (most common in US, Europe) least responsive to pegIFN/RBV

23. Null response Suboptimal Virologic Responses Relapse Breakthrough PegIFN/RBV Partial response 2 log 10 decline Limit of detection Wks 0412182430364248546066728 78 HCV RNA (log 10 IU/mL) 0 1 2 3 4 5 6 7 8 Incomplete treatment McHutchison JG, et al. N Engl J Med. 2009;361:580-593.

24. Development of Viral Resistance Treatment begins Viral LoadTime Selection of resistant quasispecies Incomplete suppression  Inadequate potency  Inadequate drug levels  Inadequate adherence  Preexisting resistance Drug-susceptible quasispecies Drug-resistant quasispecies

25. Limitations of PegIFN/RBV In GT1/4 slow responders variable results achieved by extending therapy to 72 wks [1-4] Few options available for patients who fail pegIFN/RBV [5-8] SVR rates consistently lower among blacks, older patients, individuals with advanced cirrhosis [9,10] 1. Berg T, et al. Gastroenterology. 2006;130:1086-1097. 2. Pearlman BL, et al. Hepatology. 2007;46:1688-1694. 3. Sanchez-Tapias JM, et al. Gastroenterology. 2006;131:451-460. 4. Buti M, et al. Hepatology. 2010;52:1201-1207. 5. Poynard T, et al. Gastroenterology. 2009;136:1618-1628. 6. Pearlman BL, et al. AASLD 2009. Abstract 815. 7. Jensen DM, et al. Ann Intern Med. 2009;150:528-540. 8. Bacon BR, et al. Hepatology. 2009;49:1838-1846. 9. Jacobson IM, et al. Hepatology. 2007;46:982-990. 10. Huang CF, et al. J Infect Dis. 2010;201:751-759.

26. Adherence to PegIFN/RBV: Essential but Challenging Only ~ 60% of US patients adhere to HCV therapy [2] Drug exposure correlates with SVR; ≥ 80% adherence correlates with SVR [1,3] Patient self-report overestimates adherence [4] Adherence wanes over time [4] 1. McHutchison JG, et al. Gastroenterology. 2002;123:1061-1069. 2. Mitra D, et al. Value Health. 2010;13:479-486. 3. Raptopoulou M, et al. J Viral Hepat. 2005;12:91-95. 4. Smith SR, et al. Ann Pharmacother. 2007;41:1116-1123.  Retrospective analysis of pegIFN alfa-2b/RBV trials (N = 511) [1] Adherence Rate (%) 0 20 40 60 80 100 35 10 n = SVR (%) 24 17 307050 72 54 75 53 90 305 63

27. Limitations of IFN-based therapy 2. Tolerability and acceptance 100 HCV RNA+ Patients 40 Eligible Patients 28 Start Therapy 5 Cures Eligible patient refusal, 30% Patient dropout or nonresponse, 75% Ineligible patients, 60% Modeled on Falck-Ytter Y. Annals 2002.

28. IL28B Genotype a Strong Predictor of SVR With PegIFN/RBV in Genotype 1 HCV Ge D, et al. Nature. 2009;461:399-401. Factor Associated With SVROdds Ratio (95% CI) Baseline HCV RNA (< vs ≥ 600,000 IU/mL) 1.010.00.1 IL28B rs12979860 genotype (CC vs TT) 7.3 Baseline fibrosis (METAVIR F0-F2 vs F3-F4) Whites (n = 871)Blacks (n = 191)Hispanics (n = 75) 4.2 3.0 6.1 5.1 1.1 5.6 2.4 4.1

29. Direct-Acting Antiviral Agents Directly target HCV Improve virological response when combined with pegIFN/RBV HCV NS3/4A protease inhibitors (PI) boceprevir and telaprevir approved by FDA, May 2011 [1,2] – Indicated in combination with pegIFN/RBV for treatment of GT1 HCV–infected patients who are untreated or who have failed previous therapy 1. Boceprevir [package insert]. May 2011. 2. Telaprevir [package insert]. May 2011. 3.

30. Key Factors for Considering Treatment Candidacy for PI-Based Therapy FactorRole Genotype  Boceprevir and telaprevir licensed only for patients with genotype 1 HCV Fibrosis stage  Individuals with mild or moderate fibrosis have better rates of SVR with PI-based triple therapy than those with advanced fibrosis or cirrhosis  SVR rates for individuals with cirrhosis are markedly improved with PI-based therapy vs pegIFN/RBV alone, but SVR rates are still lower than for individuals with F0-F3 fibrosis Treatment experience  Treatment-naive patients and previous relapsers or partial responders to IFN-based therapy have excellent response rates with PI-based therapy  Both previous partial responders and previous null responders have lower SVR rates with triple therapy than treatment-naive patients or relapsers. Previous null responders have the lowest SVR rates with triple therapy

31. Boceprevir and Telaprevir Clinical Trials Phase III trials leading to approval – Boceprevir plus pegIFN/RBV SPRINT-2: treatment-naive patients [1] RESPOND-2: treatment-experienced patients [2] – Telaprevir plus pegIFN/RBV ADVANCE: treatment-naive patients [3] ILLUMINATE: treatment-naive patients [4] REALIZE: treatment-experienced patients [5] 1. Poordad F, et al. N Engl J Med. 2011;364:1195-1206. 2. Bacon BR, et al. N Engl J Med. 2011;364:1207-1217. 3. Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416. 4. Sherman KE, et al. 2010 AASLD. Abstract LB2. 5. Zeuzem S, et al. N Engl J Med. 2011;364:2417-2428.

32. Telaprevir Monotherapy and Development of Resistance Kieffer TL, et al. Hepatology. 2007;46:631-639. Telaprevir Dosing 0 2 4 6 8 0 2 4 6 8 Log 10 HCV RNA (IU/mL) HCV RNA (>100 IU/mL) Wild type T54A V36A/M R155K/T 36/155 A156V/T 36/156 Days Patient 1002Patient 1018 LOD 114 1

33. Phase III SPRINT-2: Boceprevir + PegIFN/RBV in GT 1 Tx-Naive Patients Treatment-naive patients with genotype 1 HCV (2 cohorts: N = 938 nonblack and 159 black) PR* (n = 316, 52) PR* (n = 311 nonblack, 52 black) Wk 72 Wk 48 Follow-up Wk 28 Follow-up Wk 4 BOC + PR* (n = 316 nonblack, 52 black) BOC + PR* (n = 311 nonblack, 55 black) PR* (n = 311, 55) PR* *BOC 800 mg q8h; pegIFN alfa-2b 1.5 µg/kg/wk; weight-based RBV 600-1400 mg/day. † Undetectable HCV RNA at Wk 4 of BOC treatment (ie, at Wk 8) and at all subsequent assays. Follow-up RVR † No RVR  Randomized, placebo-controlled trial Poordad F, et al. N Eng J Med. 2011;364:1195-1206.

34. SPRINT-2: Response Rates According to Race 0 20 40 60 80 100 Patients (%) SVRRelapse 4-wk PR → 44-wk BOC + PR4-wk PR → response-guided BOC + PR48-wk PR 67 68 40 8 23 9 0 20 40 60 80 100 Patients (%) SVRRelapse 42 53 23 17 14 12 Nonblack Patients Black Patients P <.001 P =.04 P =.004 n =211 213125 21 183722 2912 362 Poordad F, et al. N Eng J Med. 2011;364:1195-1206.

35. Phase III RESPOND-2: Boceprevir in GT 1 Previous Nonresponders to PegIFN/RBV PR* (n = 80) PR* (n = 161) BOC + PR* (n = 161) BOC + PR* (n = 162) PR* (n = 162) Treatment- experienced patients with GT 1 HCV (N = 403) Wk 48 Wk 8 Wk 36 Follow-up † *BOC 800 mg TID; pegIFN alfa-2b 1.5 µg/kg/wk; weight-based RBV 600-1400 mg/day. † Follow-up for 24 wks after completion of therapy. Bacon BR, et al. N Engl J Med. 2011;364:1207-1217. PR* RVR No RVR Wk 4

36. 40 52 7 69 75 29 0 20 40 60 80 100 BOC RGTBOC/PR48PR48 Previous partial response Previous relapse n/N = 23/57 72/105 30/58 77/103 2/29 15/51 SVR (%)  SVR rates with boceprevir-based triple therapy higher among previous relapsers vs previous partial responders to pegIFN/RBV therapy (previous null responders excluded from study) – Both groups had higher SVR rates vs pegIFN/RBV alone Bacon BR, et al. N Engl J Med. 2011;364:1207-1217. RESPOND-2: SVR Rates With Boceprevir-Based Therapy by Previous Response

37. Phase III ADVANCE: Telaprevir + PegIFN/RBV in GT 1 Tx-Naive Patients Treatment-naive patients with GT 1 HCV (N = 1088) Wk 12 TVR + PR* (n = 364) TVR + PR* (n = 363) PR* (n = 361) eRVR † : PR* Wk 72 Wk 48 Wk 8 Follow-up *TVR 750 mg q8h; pegIFN alfa-2a 180 µg/wk; weight-based RBV 1000-1200 mg/day. † eRVR = undetectable HCV RNA at Wks 4 and 12. Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416. Wk 24 PR* eRVR † : PR* PR* Follow-up  Randomized, placebo-controlled trial

38. ADVANCE: Overall SVR and Relapse Rates 0 20 40 60 80 100 Patients (%) 69 SVR 75 44 P <.0001 for both treatment arms vs control T12PR24/48 (n = 363) PR48 (n = 361) T8PR24/48 (n = 364) n = 250 271 158 Relapse 99 28 n =28 27 64 Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416.

39. REALIZE: Telaprevir in GT1 Treatment- Experienced Patients Zeuzem S, et al. N Engl J Med. 2011;364:2417-2428. Patients with GT1 HCV who previously failed pegIFN/RBV (N = 632) Telaprevir 750 mg q8h + PR* (n = 266) Placebo + PR* (n = 264) Placebo + PR* (n = 132) Wk 4 Telaprevir 750 mg q8h + PR* PR* Wk 12Wk 16 Wk 48 Randomized 2:2:1; stratified by HCV RNA and previous response *PegIFN alfa-2a 180 µg/wk + RBV 1000-1200 mg/day. PR* Placebo + PR* 24-wk follow-up for SVR

40. REALIZE: SVR Rates With Telaprevir- Based Therapy by Previous Response  SVR rates with telaprevir-based triple therapy higher among previous relapsers vs previous partial responders vs null responders to pegIFN/RBV – All groups had higher SVR rates vs pegIFN/RBV alone Zeuzem S, et al. N Engl J Med. 2011;364:2417-2428. 100 0 60 SVR (%) 80 40 Previous RelapsersPrevious Partial Responders n/N= Previous Null Responders *P <.001 vs Pbo/PR48 4/2729/4926/48 2/37 21/7225/7516/68121/145124/141 20 83* 88* 24 59* 54* 15 29* 33* 5 T12/PR48Pbo/PR48LI T12/PR48

41. Patients Who Are Not Candidates for PI-Based Therapy Patients with previous serious adverse events leading to premature pegIFN/RBV treatment discontinuation Contraindications for boceprevir and telaprevir therapy – Pregnant women or men whose female partners are pregnant – Coadministration with other drugs highly dependent on CYP3A4/5 for clearance and for which elevated plasma concentrations associated with serious/life-threatening events – When coadministered with potent CYP3A4/5 inducers where significantly reduced boceprevir or telaprevir plasma concentrations may be associated with reduced efficacy Safety and pharmacokinetics of the PIs have not been studied in patients with decompensated cirrhosis or in liver transplant recipients

42. Resistance to Protease Inhibitors Resistance may develop rapidly with protease inhibitors It is ESSENTIAL that patients take pegIFN/RBV with protease inhibitors NEVER dose reduce a protease inhibitor Always STOP the protease inhibitor if HCV RNA begins to increase

43. Boceprevir Regimens Treatment-naive patients – 4-wk lead-in period of pegIFN/RBV alone, then triple therapy with BOC 800 mg TID + pegIFN/RBV for 24-32 wks Duration dependent on treatment response* Followed by additional 12 wks of pegIFN/RBV alone for slow responders Previous partial responders and relapsers – 4-wk lead-in period of pegIFN/RBV alone, then triple therapy with BOC 800 mg TID + pegIFN/RBV for 32 weeks Followed by additional 12 wks of pegIFN/RBV alone for slow responders Previous null responders and all cirrhotic patients – 4-wk lead-in period of pegIFN/RBV alone, then triple therapy with BOC 800 mg TID + pegIFN/RBV for 44 weeks Boceprevir [package insert]. 2011. *Treatment duration covered in detail in next section.

44. Telaprevir Regimens Treatment-naive patients and previous relapsers – Triple therapy with TVR 750 mg TID + pegIFN/RBV for 12 wks, followed by 12-36 wks of pegIFN/RBV alone Duration of pegIFN/RBV dependent on treatment response* (except cirrhotics may benefit from full 48-wk course) Previous partial and null responders – Triple therapy with TVR 750 mg TID + pegIFN/RBV for 12 wks, followed by 36 wks of pegIFN/RBV alone Telaprevir [package insert]. 2011. *Treatment duration covered in detail in next section.

45. Treat Pros and Cons of Treating vs Deferring Therapy Once PIs Are Available  Protease inhibitors substantially increase chance of SVR  Successful treatment may arrest progression of liver disease (including potential for cirrhosis, HCC, etc)  Many patients already “warehoused” awaiting DAAs, but when is the right time to exit the warehouse?  Current regimens complex, challenging adverse events  Potential for better treatment options in future, eg, better response rates, fewer adverse events, shorter duration  Risk of resistance if therapy fails; impact on future options? Defer

46. Study 110: Preliminary Data in HIV/HCV Coinfection Higher rates of undetectable HCV RNA at Wks 4 and 12 with telaprevir plus pegIFN/RBV vs pegIFN/RBV alone – Similar results regardless of use of concurrent ART Sulkowski M, et al. 2011 CROI. Abstract 146LB. Undetectable HCV RNA, Wk 4 (ITT) 100 80 60 40 20 0 Undetectable HCV RNA (%) Telaprevir + PRPR 0 12 5 0 71 75 64 70 n/N= 5/7 12/169/1426/37 0/61/80/81/22 No ART EFV-based ART ATV/RTV-based ART Total Undetectable HCV RNA, Wk 12 (ITT) 100 80 60 40 20 0 Telaprevir + PRPR 17 12 14 12 71 75 57 68 n/N= 5/7 12/168/1425/37 1/61/8 3/22 Undetectable HCV RNA (%)

47. Select DAAs in Clinical Development Phase IPhase IIPhase III Protease InhibitorsABT-450 ACH-1625 GS 9451 MK-5172 VX-985 BMS-650032 CTS-1027 Danoprevir GS 9256 IDX320 Vaniprevir BI 201335 Boceprevir Telaprevir TMC435 Nonnucleoside polymerase inhibitors BI 207127 IDX375 ABT-333 ABT-072 ANA598 BMS-791325 Filibuvir Tegobuvir VX-759 VX-222 Nucleoside polymerase inhibitors IDX184 PSI-7977 RG7128 NS5A inhibitorsA-831 PPI-461 BMS-790052 BMS-824393 CF102

49. Points to remember Incidence is declining, but prevalence of HCV- related cirrhosis will markedly increase in next 10-20 years HCV treatment can induce permanent remission and reduces mortality and morbidly DAAs markedly increases effectiveness of treatment in difficult to treat patients (genotype 1, advanced fibrosis, previously treated and African Americans)