Hepatitis B is a Treatable Disease!

Hepatitis B is a Treatable Disease! Harry L.A. Janssen Dept. of Gastroenterology & Hepatology Erasmus University Medical Center Rotterdam The Netherlands Hepatitis Summit Brussels October 2010

Prevalence of Hepatitis B Role of Immigration in Europe China The Netherlands 8-10% 0.2-0.3% Annelot David

HBV Disease: Silent Killer Resolution Stabilization Compensated Acute infection Chronic Hepatitis Cirrhosis HCC Asymptomatic carrier 30 50 years Decompensation Transplantation Death

Hepatitis B under-diagnosed and under-treated Tested Active Inflammation (ALT) 94% 28% Viral Load 68% 27% Treatment - 4% Kim, Hepatology 2004

Hepatitis B: 1990 A preventable disease!

Treatment of Hepatitis B 1990-2010 1957 Discovery interferon 1990 Discovery PMEA 1991 Discovery lamivudine (3TC) 1998 Discovery entecavir 2001 Discovery telbivudine 2005 Peginterferon alfa-2a Peginterferon alfa-2b * licensed 2008 Tenofovir licensed 1991 Interferon alfa-2b licensed 1999 Lamivudine (3TC) licensed 2003 Adefovir dipivoxil (PMEA prodrug) licensed 2006 Entecavir licensed 2007 Telbivudine licensed Adapted from: ClinicalCareOptions.com * Specific countries only

Goals for treatment Long-term clinical goals Keep patient healthy for as long as possible Prevent hepatic decompensation Prevent progression to cirrhosis and liver cancer Prolong survival Fung S, Lok ASF. Clinical Gastroenterol Hepatol. 2004;2(10):839 848

Phases Of Infection HBeAg Anti-HBe HBV DNA ALT Immunotolerant Phase Immuno-active Phase Immune control Phase HBeAg-negative Chronic Hepatitis Treatment indicated Treatment indicated

What end points are used? HBeAg seroconversion Suppression in HBV DNA levels Histological improvement ALT normalization HBsAg seroconversion Studies have linked high HBV DNA levels with increased risk of: Development of HCC and cirrhosis Disease progression Keeffe EB, et al. Clin Gastroenterol Hepatol 2006, 4: 936-62. The EASL Jury. J Hepatol. 2003; 39:S3 S25 Chen CJ, et al. JAMA 2006; 295:65 73. Iloeje UH, et al. Gastroenterology 2006; 130:678 686

Treatment Options Immuno-modulators IFNα Peg IFN Nx cytokines Vaccine therapy T-cel HBV Antivirals Lamivudine Adefovir Entecavir Telbivudine Emtricitabine Treatment combinations

Concepts of Treatment Goals in Hepatitis B Sustained response = No need for antiviral drugs IMMUNE CONTROL Pegylated Interferon Maintained response = Continued need for antiviral drugs VIRAL CONTROL Nucleos(t)ide Analogues

Concepts of Treatment Goals in Hepatitis B Sustained response = No need for antiviral drugs IMMUNE CONTROL Pegylated Interferon Maintained response = Continued need for antiviral drugs VIRAL CONTROL Nucleos(t)ide Analogues

Patients (%) Response to PEG-IFN 6 months post treatment Lau, NEJM 2005; Janssen, Lancet 2005; Marcellin, NEJM 2004. Treatment duration 48 weeks

Percentage of initial responders (%) Follow-up of PEG-IFN α-2b in HBeAg (+) CHB: 3 years post-treatment among HBeAg responders 100 90 80 81% n=64 78% 70 60 58% 50 45% 40 30 30% 20 10 0 HBeAg negative HBV DNA <10,000 copies/ml HBV DNA <400 copies/ml ALT normal HBsAg negative Buster et al., Gastroenterology 2008

IFN -2b Treatment is Associated with Prolonged Survival Proportion of patients surviving 1.0 Cirrhosis at baseline 1.0 No cirrhosis at baseline 0.8 0.8 0.6 0.6 0.4 0.4 0.2 0.2 0 0 5 Years 10 15 Responders 0 0 5 Years 10 15 Non-responders v Zonneveld et al. Hepatology 2004

Concepts of Treatment Goals in Hepatitis B Sustained response = No need for antiviral drugs IMMUNE CONTROL Pegylated Interferon Maintained response = Continued need for antiviral drugs VIRAL CONTROL Nucleos(t)ide Analogues

Improving the long-term health of HBV patients with NA rests on these pillars Regression of disease Fibrosis Uncontrolled viral replication No/ineffective treatment Antiviral potency + High genetic barrier to resistance Improved liver histology + Cirrhosis/ HCC Favourable safety profile Adherence

Resistance rates through 6 years among nucleos(t)ide-naïve patients Year 1 Year 2 Year 3 Year 4 Year 5 Year 6 Drug Generation 72 Weeks 1 st LVD 1 23% 46% 55% 71% 80% 2 nd ADV 1 LdT 2,3 0% 5% 3% 25% 11% 18% 29% 3rd TDF 4 ETV* 5,6 0% <1% 0% <1% 0% 1.2% 0% 1.2% 1.2% 1.2%

Proportion of patients with HBV DNA <300 copies/ml (%) Chang TT et al. Hepatology 2010;51:422 30. Entecavir 5-year efficacy data HBeAg(+) ETV long-term cohort (ETV-022 ETV-901) 100 80 Year 1 Year 2 83% Year 3 89% Year 4 91% Year 5 94% 60 55% 40 20 n = 0 80/146 116/140 116/131 98/108 88/94

Proportion of patients (%) Tenofovir 3-year efficacy data 100 90 80 70 60 50 40 30 20 10 0 p<0.001 14 83 HBV DNA undetectable <400 copies/ml 91 95 p<0.001 97 68 100 84 160 82 141 117 241 110 223 Week 48 1 Week 144 2 Week 48 1 Week 144 3 HBeAg(+) HBeAg ( ) 99 ADV TDF TDF TDF Adapted from 1. Marcellin P et al. N Engl J Med 2008;359:2442 55. 2. Heathcote EJ et al. 60th AASLD Oct 30 Nov 3, 2009; Boston, USA. Poster 483. Available at http://www.natap.org/2009/aasld/aasld_35.htm. (Accessed April 2010). 3. Marcellin P et al. 60th AASLD Oct 30 Nov 3, 2009, Boston, USA. Poster 481. Available at http://www.natap.org/2009/aasld/aasld_36.htm (Accessed April 2010).

Patients (%) Antiviral treatment delays disease progression Patients with CHB and cirrhosis or advanced fibrosis 25 20 15 Placebo (n=215) ITT population Lamivudine (n=436) (n=43) 21% p=0.001 10 (n=173) 9% 5 (n=198) (n=385) (n=122) 0 (n=417) 0 6 12 18 24 30 36 Time to disease progression (months) Liaw et al. NEJM 2004; 351:1521

Who Should be Treated and With What? PEG-IFN or Nucleoside Analogues? Balancing the facts Benefits Likelihood of sustained response Severity of liver disease Patient s age Host genetics HBV genotype Patient s preference Co-morbid illness Costs Risks Side effects Drug resistance

Conclusions Major improvement in HBV therapy in last decades! Choice of therapy depends on individual patient characteristics: PEG-IFN in selected proportion of patients Choose most potent NA with highest genetic barrier Therapy with NA may be indefinite in many patients More than 95% of HBV in remission with current drugs

Issues for the Future Safety & efficacy of longterm therapy Response prediction: individualized therapy Role of combination therapy How to induce long-term cure (HBsAg loss) New agents with different sites of action

Hepatitis B: 2010 A treatable disease!