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

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

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: Shepard CW, et al. Lancet Infect Dis. 2005;5: IOM. Hepatitis and Liver Cancer. NA Press Mitchell AE, et al. Hepatology. 2010;51: Jacobson IM, et al. Clin Gastroenterol Hepatol. 2010;8:

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: Accessed February 1, 2006.

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

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

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

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

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.

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: Accessed on October 17, Liver Cancer Has the Fastest Growing Death Rate in the United States

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

Established Risk Factors for Progression of Fibrosis and Cirrhosis Poynard T, Lancet : Mathurin P, Hepatology : Benhamou J, Hepatology :  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

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

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:

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 Log HCV RNA (copies/mL) Ferreira-Gonzalez A, et al. Semin Liver Dis. 2004;24:9-18.

HCV and Alcohol Excessive alcohol intake characterized as > 40 g/day for women and > 60 g/day for men Years Following Exposure Cirrhosis (%) HCV HCV + alcohol Wiley TE, et al. Hepatology. 1998:28:

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

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, , 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, Ever HCV infected All chronic HCV Acute HCV infection Cirrhosis

HCV Life Cycle and DAA Targets Adapted from Manns MP, et al. Nat Rev Drug Discov. 2007;6: 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

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: Backus L, et al 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)

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: Fried MW, et al. N Engl J Med. 2002;347: OverallGT1GT2/ OverallGT1GT2/3 SVR (%) n = HCV Standard of Care Prior to May 2011  GT1 (most common in US, Europe) least responsive to pegIFN/RBV

Null response Suboptimal Virologic Responses Relapse Breakthrough PegIFN/RBV Partial response 2 log 10 decline Limit of detection Wks HCV RNA (log 10 IU/mL) Incomplete treatment McHutchison JG, et al. N Engl J Med. 2009;361:

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

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: Pearlman BL, et al. Hepatology. 2007;46: Sanchez-Tapias JM, et al. Gastroenterology. 2006;131: Buti M, et al. Hepatology. 2010;52: Poynard T, et al. Gastroenterology. 2009;136: Pearlman BL, et al. AASLD Abstract Jensen DM, et al. Ann Intern Med. 2009;150: Bacon BR, et al. Hepatology. 2009;49: Jacobson IM, et al. Hepatology. 2007;46: Huang CF, et al. J Infect Dis. 2010;201:

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: Mitra D, et al. Value Health. 2010;13: Raptopoulou M, et al. J Viral Hepat. 2005;12: Smith SR, et al. Ann Pharmacother. 2007;41:  Retrospective analysis of pegIFN alfa-2b/RBV trials (N = 511) [1] Adherence Rate (%) n = SVR (%)

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.

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

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 Telaprevir [package insert]. May

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

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: Bacon BR, et al. N Engl J Med. 2011;364: Jacobson IM, et al. N Engl J Med. 2011;364: Sherman KE, et al AASLD. Abstract LB2. 5. Zeuzem S, et al. N Engl J Med. 2011;364:

Telaprevir Monotherapy and Development of Resistance Kieffer TL, et al. Hepatology. 2007;46: Telaprevir Dosing 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

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 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:

SPRINT-2: Response Rates According to Race Patients (%) SVRRelapse 4-wk PR → 44-wk BOC + PR4-wk PR → response-guided BOC + PR48-wk PR Patients (%) SVRRelapse Nonblack Patients Black Patients P <.001 P =.04 P =.004 n = Poordad F, et al. N Eng J Med. 2011;364:

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 mg/day. † Follow-up for 24 wks after completion of therapy. Bacon BR, et al. N Engl J Med. 2011;364: PR* RVR No RVR Wk 4

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: RESPOND-2: SVR Rates With Boceprevir-Based Therapy by Previous Response

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 mg/day. † eRVR = undetectable HCV RNA at Wks 4 and 12. Jacobson IM, et al. N Engl J Med. 2011;364: Wk 24 PR* eRVR † : PR* PR* Follow-up  Randomized, placebo-controlled trial

ADVANCE: Overall SVR and Relapse Rates Patients (%) 69 SVR P <.0001 for both treatment arms vs control T12PR24/48 (n = 363) PR48 (n = 361) T8PR24/48 (n = 364) n = Relapse n = Jacobson IM, et al. N Engl J Med. 2011;364:

REALIZE: Telaprevir in GT1 Treatment- Experienced Patients Zeuzem S, et al. N Engl J Med. 2011;364: 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 mg/day. PR* Placebo + PR* 24-wk follow-up for SVR

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: SVR (%) 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/ * 88* 24 59* 54* 15 29* 33* 5 T12/PR48Pbo/PR48LI T12/PR48

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

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

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 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] *Treatment duration covered in detail in next section.

Telaprevir Regimens Treatment-naive patients and previous relapsers – Triple therapy with TVR 750 mg TID + pegIFN/RBV for 12 wks, followed by 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] *Treatment duration covered in detail in next section.

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

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 CROI. Abstract 146LB. Undetectable HCV RNA, Wk 4 (ITT) Undetectable HCV RNA (%) Telaprevir + PRPR 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) Telaprevir + PRPR n/N= 5/7 12/168/1425/37 1/61/8 3/22 Undetectable HCV RNA (%)

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

Points to remember Incidence is declining, but prevalence of HCV- related cirrhosis will markedly increase in next 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)