North Africa) The prevalence of CHB varies widely across EMEA (Europe, Middle East & 8% High 2 8% Intermediate <2% Low

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1 The prevalence of CHB varies widely across EMEA (Europe, Middle East & North Africa) 8% High 2 8% Intermediate <2% Low

2 Immune tolerance Immune clearance Immune control Reactivation phase HBeAg +ve HBeAg -ve/ anti-hbe +ve < > < > HBV-DNA cp/ml cp/ml <10 5 cp/ml >10 5 cp/ml ALT Normal/ mild CH Moderate/severe CH Cirrhosis Normal/mild CH Inactive cirrhosis Moderate/severe CH Cirrhosis HBeAg +ve CHB Inactive-carrier state HBeAg ve CHB Fattowich, J Hepatol 2003; 39: S50-S58

3 Natural progression of CHB Liver Cancer (HCC) 25 40% lifetime risk for death due to HCC or liver failure 5 10% 10 15% in 5 yr Chronic Infection 30% Cirrhosis Liver Transplantation Death 23% in 5 yr Acute flare Liver Failure 25 40% lifetime risk for death due to HCC or liver failure Adapted from: Fattovich, et al. Gastroenterology. 2004;127:S Torresi, et al. Gastroenterology. 2000;118:S Fattovich, et al. Hepatology. 1995;21: Perrillo, et al. Hepatology. 2001;33:424-32

4 Who should be treated? Benefits Risks Severity of liver disease/likelihood of disease progression to cirrhosis and liver cancer Probability of treatment response Treatment considerations Age of patient Gender Co-morbidities Viral load HBeAg status ALT Previous treatment HBV genotype Liver histology Adverse effects Drug resistance Adapted from Lok A. Clin Gastroenterol Hepatol. 2004;2(10):

5 Goals of Therapy: 2 Distinct Patient Populations HBeAg positive (wild type) HBeAg loss ± seroconversion Suppression of HBV DNA ALT normalization HBeAg negative (precore and core promoter mutants) HBeAg seroconversion not an endpoint Suppression of HBV DNA ALT normalization Keeffe EB, et al. Clin Gastroenterol Hepatol. 2008;6:

6 Current Guideline Recommendations for First-line Therapy Peginterferon alfa-2a Exceptions: pregnancy, chemotherapy prophylaxis, decompensated cirrhosis, acute infection Entecavir Tenofovir EASL. J Hepatol. 2009;50: Liaw YF, et al. Hepatol Int. 2008;2: Lok AS, et al. Hepatology. 2009;50:

7 AASLD Guideline Recommendations for Duration of NA Treatment 32. Duration of nucleoside analogue treatment a. HBeAg-positive chronic hepatitis B Treatment should be continued until the patient has achieved HBeAg seroconversion and undetectable serum HBV DNA and completed at least 6 mos of additional treatment after appearance of anti-hbe. (I) Close monitoring for relapse is needed after withdrawal of treatment. (I) b. HBeAg-negative chronic hepatitis B Treatment should be continued until the patient has achieved HBsAg clearance. (I) Lok AS, et al. Hepatology. 2009;50:

8 Impact of HBV treatment Decrease in the rate of decompensation Decrease in liver transplantation Absence of good data demonstrating an effect on livercancer occurrence in the contextof HBV (recent KCE report)

9 HBV vaccination: recommendations Universal in babies «Rescue» in children and teenagers People at risk: Newborns from carriers Health professionals Contacts, chronic liver disease, stay in endemic countries [

10 Hepatitis C virus: The major causative agent of viral non-a, non-b hepatitis A blind recombinant immunoscreening approach,of general application to studies of infectious diseases, wasused to clone and identify the genome of the previously uncharacterizednon-a, non-b hepatitis (NANB) virus. This agent is a positive-strandedrna virus that appears to be distantly related to the flaviviridae family. Data obtained usingthis assay indicate that this agent, termed the hepatitis Cvirus (HCV), is the major cause of post-transfusion, community-acquiredand cryptogenic, NANB. QL Choo, et al. Chiron Corporation, Emeryville California, USA

11 Hepatitis C Virus Single stranded, positive sense, RNA Flaviviridae family Spherical, enveloped Great genetic diversity Six genotypes: 1 through 6 Multiple subtypes: a, b, c, etc Viral sequences can be used to track a common source of infection ~ 50 nm

12 HCV: A Global Health Problem 170 Million Carriers Worldwide, 3-4 MM new cases/year 3% of World Population CANADA 300,000 U.S.A. 4 M WEST EUROPE 9 M EAST MEDITERRANEAN 20M AFRICA 32 M FAR EAST ASIA 60 M SOUTH EAST ASIA 30 M SOUTH AMERICA 10 M AUSTRALIA 0.2 M SOURCE, WHO 1999

13 Detection Infection: HCV Ab, PCR (quantitative) if HCV Ab + Hepatitis: serum transaminases

14 FIBROTIC PROGRESSION Mild Moderate 15-33% Severe fibrosis Cirrhosis- mild Cirrhosis - severe HCC % Years adapted from Afdhal, Sem Liver Disease, 2004

15 Natural History Acute HCV Resolved 15% Chronic HCV 85% Stable 75% to 95% Cirrhosis 5% to 25% Stable 97% to 99%/yr HCC or Decompensation 1% to 3%/yr Thomas DL, et al. Clin Liver Dis. 2005;9: Strader DB, et al. Eur J Gastroenterol Hepatol. 1996;8: Seeff LB, et al. Hepatology. 2002;36(suppl):S1-S2. Seeff LB, et al. Hepatology. 2002;36(suppl):S35-S46. Liang TJ, et al. Ann Intern Med. 2000;132: Fattovich G, et al. Gastroenterology. 1997;112:

16 Modes of HCV Transmission HCV can probably survive on environmental surfaces at room temperature for hours Do not exchange blood Razors, toothbrushes, nail clippers Sexual transmission rate is low Condoms recommended for multiple sexual partners Not transmitted by casual contact (eg, hugging)

17 HCV Infection: High-Risk Populations in Which Screening Is Indicated Injection drug use Nasal inhalation of cocaine Chronic renal failure on dialysis Incarceration Multiple sexual partners, MSM, HIV positive Transplantation or transfusion of blood products before 1992 Occupational exposure to blood products Body piercing and possibly tattoo Children born to HCVpositive women Centers for Disease Control and Prevention. April 10, Verucchi G, et al. Infection. 2004;32:33-46.

18 Large Population Underscreenedand HCV Patients Underdiagnosed Current screening practices fail to identify a large proportion of patients with chronic HCV infection [1] As few as 25% of patients are diagnosed Survey of 4000 primary care physicians [2] Only 59% of 1412 respondents asked all patients about HCV risk factors AASLD recommends that as part of a comprehensive health evaluation, all persons should be screened for behaviors that place them at high risk for HCV infection [3] CDC recommends to screen all baby-boomerspatientsborn between 1945 and Kim WR. Hepatology. 2002;36:S30-S Shehab TM, et al. J Viral Hepat. 2001;8: Ghany MG, et al. Hepatology. 2009;49:

19 HCV therapy Goals: viral eradication Duration: limited in time depending on genotype Whom?: active hepatitis and/or fibrosis compensated cirrhosis - normal ALT? (15 to 20% progressive disease)

20 Standard Therapy for HCV SVR naïve patients (%) No therapy Monotherapy 24 weeks Monotherapy 48 weeks Combination therapy 48 weeks 41% PEG-IF 48 weeks 54,56,61,76% 39% PEG-IF + RIBA 48 weeks Genotype sp 20 16% 10 6% 0 0% Combined data :Poynard et al (1998), McHutchison et al (1998), Zeuzem et al (2000), Fried et al (2002)

21 SVR Rates With BOC or TVR in Genotype 1 Treatment-Naive Patients SVR (%) PegIFN/RBV BOC or TVR + PegIFN/RBV Poordad F, et al. N Engl J Med. 2011;364: Jacobson IM, et al. N Engl J Med. 2011;364:

22 Evolving Landscape to "IFN-free" Therapies EU Approval Timelines for Key DAAs with 1st indication 1 st Market Approval NOT EXHAUSTIVE DCV + PR TN 1b TMC-435 +PR TN, Relapsers ASU +DCV ±PR TN, TE, IFN intol/inel TVR BOC GS-7977+R (G2/3, G1?) TN BI PR TN, TE ABT-450/r/ABT ABT-333 ±R cirrhotics GS GS-5885 ±R TN Wave 1: Triple (Launched) Wave 2: Triple Wave 3: Oral Combinations, IFN Free & QUAD Only molecules in phase 3 shown. Vaniprevir not included as ph3 is in Japanese patients. Alisporivir not included as on hold Dates estimated by end of phase 3 (primary objective completion date) + approx. 1 year (clinicaltrials.gov) DCV: daclatasvir; ASU: asunaprevir (BMS)

23 NEUTRINO: SVR12 With Sofosbuvir + P/R According to Genotype and Fibrosis Level SVR12 According to Genotype SVR12 According to Fibrosis Level SVR12 (%) SVR12 (%) n/n = 261/292 27/28 7/7 GT 1 GT 4 GT 5, /273 43/54 No Cirrhosis Cirrhosis Lawitz E, et al. EASL Abstract

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25 TURQUOISE II:Abbvie3 DAAs+ RBV in Cirrhotic Pts by HCV Subtype GT1a wks 24 wks GT1b SVR12 (%) / 64 52/ 56 Naive 14/ 15 13/ 13 11/ 11 10/ 10 Relapse Partial Response Null Response Poordad F, et al. EASL Abstract O163. Reproduced with permission. 40/ 50 39/ 42 Naive Relapse Partial Response Null Response Virologic failure in 17/380 pts (4.5%); relapse more frequent with 12-wk vs 24-wk treatment (12 vs 1 pt), 7/12 relapsers by posttreatment Wk 12 were GT1a null responders 0 22/ 22 18/ 18 25/ 25 20/ 20 6/7 3/3 14/ 10/ 14 10

26 Conclusions HCV It willbepossible in a nearfuture to cure all HCV patients Difficulties will be to diagnose all patients