1. Slide 1 Treatment of Hepatitis B Marion Peters MD University of California San Francisco

2. Slide 2 HBV is a life long, dynamic disease Changes over time Risk of end stage liver disease and cancer increases with ongoing inflammation and viremia in adults Fibrosis can be reversible Drugs can decrease fibrosis progression HBV can be controlled but not cured Reactivation can occur even in those who have lost HBsAg

3. Slide 3 Who should be tested for HBV?new Blood and organs donors Hemodialysis patients Pregnant women Infants of HBsAg + mothers Behavioural contacts: o Household and sexual contacts o HIV+, MSM, IDU Individuals from countries where prevalence is 2% Patients receiving immunosuppressive therapy Abnormal ALT of unknown cause CDC 2008

4. Slide 4 1. WHO. Hepatitis B. 2002. 2. Custer B, et al. J Clin Gastroenterol. 2004;38(10 suppl):S158. 3. WHO/WPRO data. HBsAg Prevalence (%) 1 8: High 2–8: Intermediate <2: Low Geographic Distribution of Chronic HBV Infection

5. Slide 5 Overlapping HIV and HBV Epidemics 400 million 4 million HBsAg+ HIV HBV 350-400 million 35-40 million 3.5- 4 million

6. Slide 6 Geographic Distribution of HBV Genotypes AeAe B,C,A,D F2F2 AaAa E D D C B C G G H BaBa Bj AD B D Greenland: F & H F 1, H Ae, Bj, C, D, F A, B, D B, A/Bj B3B3

7. Slide 7 Natural history of HBV

8. Slide 8 Immune escape < <> > HBeAg+ve HBeAg–ve ALT HBV-DNA Inactive (carrier) state* HBeAg –ve active chronic hepatitis HBeAg +ve chronic hepatitis Immune tolerance Immune clearance Immune control The phases of chronic hepatitis B *Previously considered to be healthy carriers

9. Slide 9 HBV Control Inflammatory: normalize serum ALT, biopsy Virologic: decrease HBV DNA Immune: seroconversion o HBeAg to HBeAb o HBsAg to HBsAb HBV never cured but controlled

10. Slide 10 Therapeutic endpoints over time TIME Loss of HBeAg Loss of HBV DNA Anti-HBe+ Loss of HBsAg Anti-HBs+ Improved survival Improved histology

11. Slide 11 Who should be considered for treatment? Immune escape < <> > HBeAg+ve HBeAg–ve ALT HBV-DNA Inactive (carrier) state HBeAg –ve/+ve active chronic hepatitis HBeAg +ve chronic hepatitis Immune tolerance Immune clearance Immune control treat

12. Slide 12 Overview of Algorithm Used to Determine Need for Treatment of HBV Keeffe EB, et al. Clin Gastroenterol Hepatol. 2008 Lok AS et al Hepatology, 2009 HBeAg Positive Treat Monitor ALT Q3mos for 1y HBeAg Negative HBV DNA >20,000 IU/mL HBV DNA >2,000 IU/mL Normal ALT Consider Liver Biopsy If >40yrs Significant fibrosis or inflammation Elevated ALT ALT Level

13. Slide 13 Approved HBV treatments 2009 Interferon alfa-2b – 1991 Lamivudine – 1998 Adefovir – 2002 Entecavir – 2005 Peginterferon alfa-2a – 2005 Telbivudine – 2006 Tenofovir - 2008 For HIV: o Emtricitabine o Tenofovir + emtricitabine (single pill co-formulation)

14. Slide 14 Treatment Goals in CHB: Remission Differences between the two strategies On-therapy maintained response = Off-therapy sustained response = Low viremia ALT normalization Continued need for antiviral drugs Immune control, no antiviral drugs

15. Slide 15 HBV Nucs: Nonresponse, Suboptimal Response, and Virologic Breakthrough Lok AS, et al. Hepatology. 2007;45:507-539. 1 log Change in HBV DNA (log 10 IU/mL) 0 -2.0 -3.0 -4.0 1.0 Nadir Virologic breakthrough Antiviral Drug Months 601218 Primary nonresponse Suboptimal response

16. Slide 16 HBeAg Seroconversion Rates Over Time in HBeAg-Positive Patients *With sustained undetectable HBV DNA. Chang TT, et al. J Viral Hepat. 2009;16:784-789. Chang TT, et al. AASLD 2006. Abstract 109. Lau GK, et al. N Engl J Med. 2005;352:2682-2695. Marcellin P, et al. N Engl J Med. 2008;359:2442-2455. Buster EH, et al. Gastroenterology. 2008;135;459- 467. Heathcote J, et al. AASLD 2008. Abstract 158. Heathcote J, et al. AASLD 2009. Abstract 483. Janssen HL, et al. Lancet. 2005;365;123-129. CCO Hepatitis Extended Treatment With Nucleos(t)ide Analogues* vs 1 Yr Peginterferon Treatment Not head-to-head trials; different patient populations and trial designs Entecavir Tenofovir Peginterferon HBeAg Seroconversion (%) 2122 31 39 26 1.0 Yr1.5-2.0 Yrs3.0-4.0 Yrs 100 80 60 40 20 0 22-27 29-32 35

17. Slide 17 HBsAg Loss Over Time in HBeAg- Positive Patients Chang TT, et al. N Engl J Med. 2006;354:1001-1010. Marcellin P, et al. N Engl J Med. 2008;359:2442-2455. Buster EH, et al. Gastroenterology. 2008;135;459-467. Gish R, et al. Gastroenterology. 2007;133:1437-1444. Heathcote J. AASLD 2008. Abstract 158. Heathcote J, et al. AASLD 2009. Abstract 483. Janssen HL, et al. Lancet. 2005;365:123-129. CCO Hepatitis Not head-to-head trials; different patient populations and trial designs Extended Treatment With Nucleos(t)ide Analogues* vs 1 Yr Peginterferon Treatment HBsAg Loss (%) 2 3 66 100 80 60 40 20 0 5 8 8 NA Entecavir Tenofovir Peginterferon *With sustained undetectable HBV DNA. 1.0 Yr1.5-2.0 Yrs3.0-4.0 Yrs 5

18. Slide 18 Predictors of HBsAg Loss in HBeAg-Positive Patients Race: whites > nonwhites [1] Genotype [1-3] o Nucleos(t)ide analogues: A and D o Peginterferon: A Serum HBsAg decline during first 24 wks with nucleos(t)ide analogues [1] HBeAg negative at or within 26 wks of completing peginterferon treatment [3 ] 1. Heathcote EJ, et al. EASL 2009. Abstract 909. 2. Gish RG, et al. J Viral Hepat. 2010;17:16-22. 3. Buster EH, et al. Gastroenterology. 2008;135;459-467. CCO Hepatitis

19. Slide 19 Undetectable HBV DNA Over Time in HBeAg-Negative Patients Lok AS, et al. Hepatology. 2009;50:661-662. Marcellin P, et al. AASLD 2008. Abstract 146. Marcellin P, et al. AASLD 2009. Abstract 481. Marcellin P, et al. Gastroenterology. 2009;136:2169-2179. Baqai S, et al. AASLD 2009. Abstract 476. Lai CL, et al. Hong Kong International Liver Congress 2006. CCO Hepatitis Extended Treatment With Nucleos(t)ide Analogues vs 1 Yr Peginterferon Treatment Not head-to-head trials; different patient populations and trial designs Entecavir Tenofovir Peginterferon Undetectable HBV DNA (%) 90 93 87 91 1 Yr2 Yrs3 Yrs 100 80 60 40 20 0 63 1516 NA 100* *Single center study. 96

20. Slide 20 Lai CL, et al. N Engl J Med. 2006;354:1011-1020. Marcellin P, et al. N Engl J Med. 2008;359:2442-2455. Marcellin P, et al. AASLD 2008. Abstract 146. Shouval D, et al. J Hepatol. 2009;50:289-295. Marcellin P, et al. AASLD 2009. Abstract 481. Brunetto M, et al. EASL 2008. Abstract 683. CCO Hepatitis HBsAg Loss Over Time in HBeAg-Negative Patients Extended Treatment With Nucleos(t)ide Analogues* Vs 1 Yr Peginterferon Treatment Not head-to-head trials; different patient populations and trial designs Patients (%) < 10 4 0 100 80 60 40 20 0 < 1 9 NA 0 7 1.0 Yr1.5-2.0 Yrs3.0-4.0 Yrs *With sustained undetectable HBV DNA. Entecavir Tenofovir Peginterferon

21. Slide 21 HBsAg Levels at Wk 12 of PegIFN Predict Off-Therapy SVR in HBeAg-Negative Pts 48 pts pegIFN alfa-2a for 48 wks SVR: undetectable HBV DNA (< 29 IU/mL) at Wk 24 following treatment completion Change in HBsAg level from baseline to Wk 12 evaluated as predictor of SVR o Cutoff: 0.5 log 10 IU/mL decrease o PPV: 89% – NPV: 90% Outcome, % (n) Decrease in HBsAg From Baseline to Wk 12 0.5 log 10 IU/mL (n = 9) < 0.5 log 10 IU/mL (n = 39) SVR89 (8)10 (4) No SVR11 (1)90 (35) Moucari R, et al. Hepatology. 2009;49:1151-1157. CCO Hepatitis

22. Slide 22 NAs: Potency versus resistance Likelihood of resistance development Potency of HBV DNA suppression LAM LdT ETV TDF ADV Nucleoside analogue Nucleotide analogue

23. Slide 23 Selection of Entecavir vs Tenofovir Lok AS. Hepatology. 2010;52:743-747. 21 2 < 1 21 3 0 0 5 10 15 20 25 HBeAg seroconversion HBsAg loss Entecavir Tenofovir HBeAg Neg HBsAg loss HBeAg Positive Response at Wk 48-52 (%)

24. Slide 24 Efficacy of Entecavir vs Tenofovir in the Setting of Resistance Similar antiviral activity against nonresistant HBV; efficacy against drug-resistant strains differs Activity According to Resistance EntecavirTenofovir LAM/LdT resistanceDecreasedActive ETV resistance--Active ADV resistanceActiveDecreased TDF resistanceActive-- Lok AS. Hepatology. 2010;52:743-747.

25. Slide 25 Antiviral resistance increases over time 1 Lai, Clin Infect Dis 2003; 2 Westland, Hepatology 2003; 3 Colonno R, EASL 2007; 4 Gane, EASL 2006 Year 4Year 2 Lamivudine 1 0 20 40 60 80 Year 1Year 3 Incidence of resistance (%) Entecavir (LAM-resistant) 3 Telbivudine 4 Adefovir 2 0% 2% 11% 18% 29% 5% 15% Entecavir (naive) 3 *** Year 5 24% 42% 53% 70% 65% 0.3% 0.4% 0.1% 0.8% 12% 20% 25% 40% Resistance to NAs…is it just a matter of time??

26. Slide 26 Special Populations with HBV Cirrhosis Decompensated cirrhosis Organ transplantation Acute hepatitis B Pregnancy Co infection with HCV or HDV Chronic renal failure Children

27. Slide 27 Cirrhosis 5 y Survival 84% for compensated 5 y Survival 14-35% for decompensated 6 Interferons are safe and effective in compensated HBV cirrhosis only 1 (I) Nucleoside analogues have been shown prospectively to be safe, decrease rates of liver decompensation and to decrease the development of HCC 2 (I) All cirrhotic patients with HBV DNA>2000 IU/mL should be treated regardless of ALT 3-5 (III) Many experts recommend treating compensated cirrhotics with any detectable viral load 3 (III) 1 Buster, 2007; 2 Liaw, 2004; 3 Keeffe, 2008; 4 Liaw 2008 (APASL); 5 Lok 2007; 6 Kim 2004

28. Slide 28 Wild-type (n=221) YMDD mutants (n=209) (49%) Time after randomisation (months) 0 5 10 15 20 25 061218243036 Treatment decreases HBV disease progression even with YMDD mutant status Patients with disease progression (%) Placebo (n=215) 5% 13% 21% Liaw et al. N Engl J Med 2004

29. Slide 29 Yao FY, et al. Hepatology. 2001;34:411. 23 consecutive UCSF patients compared with 23 historical controls Cumulative probability of survival without liver transplantation Lamivudine in Decompensated Cirrhosis 0 6 12 18 24 30 36 42 48 P <.001 Lamivudine treated Controls Time (mo) Survival (%) 100 80 60 40 20 0

30. Slide 30 1 0.9 0.8 0.7 0.6 0.5 0 1 2 3 4 5 Survival % Era 3 (1997-2002) Time (years) P =.14 Other HBV 1 0.9 0.8 0.7 0.6 0.5 0 1 2 3 4 5 Survival % Era 1 (1987-1991) Time (years) P < 0.01 Other HBV Kim WR, et al. Liver Transpl. 2004;10:968. Liver Transplantation and HBV Progress in Past Decade 5-year survival rates ~50% Many centers consider HBV to be contraindication for LT 5-year survival rates as good or better than for other indications for LT HBIG LAM

31. Slide 31 Pregnancy Many patients with CHB are immune tolerant when pregnant Children born to HBsAg positive mothers should receive HBIG within 12 hours of birth and the first dose of HBV vaccination, with subsequent vaccination at 1 and 3-6 months of age 1 o > 95% of children then immune to HBV Vaccine failure associated with o inadequate therapy o infants of mothers with very high HBV DNA (>8 Log 10 IU/mL) Treatment to decrease mother to child transmission (MTCT) o Lam for one month decreased MTCT (12.5% cf 28% historical controls) in women with >10 9 g equiv/mL 2 (III) Pregnant women with chronic active hepatitis B should be treated per standard guidelines: o Category B: Telbivudine, TDF o Category C: Lam, ADV, ETV 1 Lok, 2007; 2 van Zonneveld, 2003

32. Slide 32 Reactivation of HBV High rate of reactivation in immunosuppressed patients o Chemotherapy o HIV after immune reconstitution o Post organ transplant o Biologic response modifiers: rituximab (anti- CD20), TNF- inhibitors: GI, hematologists, rheumatologists, dermatologists Reactivation can occur in immunocompetent treated with steroids, BRMs

33. Slide 33 Reactivation of HBV Highest in HBV active disease 1.HBsAg pos, HBeAg pos, high HBV DNA 2.HBsAg pos, HBeAb pos, low HBV DNA 3.HBsAg neg, anti-HBs pos, anti-HBc pos o Deaths occur in all groups ALL patients undergoing chemotherapy must have tested HBsAg, HBsAb and HBcAb prior to treatment

34. Slide 34 DHHS Guidelines for HIV HBV Patients DHHS Guidelines. 2007 www.aidsinfo.gov-UPDATED FOR ETV.www.aidsinfo.gov-UPDATED * to avoid development of HBV-resistant mutants

35. Slide 35 HBV is a dynamic disease Diagnose Initial evaluation includes education o Family and sexual contacts should be tested o counsel drugs to avoid- steroids, chemo, BRM Monitor as status changes over time Selection of patients to treat o Individualize treatment decisions o Change if no/ poor response Long term monitoring o HCC, special populations, reactivation

36. Slide 36 Require monitoring… Inactive disease may not remain inactive Liver damage may occur if HBV reactivates Require treatment 40% 60% HBV is a dynamic disease!!! HBV can be controlled but not cured HBV: The importance of monitoring