1. Hepatitis web study H EPATITIS W EB S TUDY Therapeutic Agents Used to Treat Hepatitis B Presentation Prepared by: Nina Kim, MD and David Spach, MD Last Updated: May 31, 2011

2. Hepatitis web study Timeline for FDA-Approved Agents used to Treat HBV Lamivudine Telbivudine Entecavir Adefovir Interferon alpha-2a Peginterferon alpha-2b Tenofovir

3. Hepatitis web study Agents FDA-Approved for Treatment of Chronic HBV MedicationTrade NameDose Interferon alfa-2bIntron A 5 million IU sq once daily or 10 million IU sq 3x/week Peginterferon alfa-2aPegasys180 mcg sq once weekly Lamivudine (3TC) Epivir-HBV (100 mg) Epivir 100 mg PO once daily 300 mg PO once daily for HIV-infected Adefovir (ADV)Hepsera10 mg PO once daily Entecavir (ETV)Baraclude 0.5 mg PO once daily: treatment-naïve 1 mg PO once daily: lamivudine resistance Telbivudine (LdT)Tyzeka600 mg PO once daily Tenofovir (TDF)Viread300 mg PO once daily Abbreviations: IU = international units; sq = subcutaneously qd = once dailybid = twice daily

4. Hepatitis web study Agents used for Chronic HBV: Cautionary Notes MedicationCautionary Note Interferon alfa-2b and Peginterferon alfa-2a Contraindicated in patients with: Uncontrolled major depression (especially with past suicide attempts) Autoimmune hepatitis or other autoimmune diseases Severe cardiovascular disease (e.g. uncontrolled hypertension, coronary artery disease, congestive heart failure) Decompensated cirrhosis or hepatocellular carcinoma Uncontrolled seizure disorder Lamivudine (3TC) Not recommended for first-line anti-HBV therapy because of high resistance rates Adefovir (ADV) Caution in patients with baseline renal insufficiency Entecavir (ETV) Taken on empty stomach (>2 hours before or after a meal); should not use without HIV therapy in HIV-HBV co-infected patients Telbivudine (LdT) Creatine kinase elevation 8%, symptomatic myopathy rare Tenofovir (TDF) Caution in patients with baseline renal insufficiency

5. Hepatitis web study Agents used for Chronic HBV: Adverse Effects

6. Hepatitis web study Hepatitis web study Peginterferon alfa-2a vs lamivudine vs Peginterferon alfa-2a + lamivudine in patients with HBeAg-negative chronic hepatitis B

7. Hepatitis web study Source: Marcellin P, et. al. N Engl J Med. 2004;351:1206-7. Peginterferon alfa-2a versus Lamivudine Alone or in Combination in HBeAg-Negative Patients Peginterferon alfa-2a:180 mcg SC 1x/week + Oral Placebo (n = 177) Lamivudine:100 mg/day (n = 181) Study Features Randomized 1:1:1 HBeAg-negative (N=537) HBV DNA > 10 5 copies/mL ALT > 1-10x ULN Treatment x 48 weeks Peginterferon alfa-2a:180 mcg SC 1xweek + Lamivudine: 100 mg/day (n = 179) Week 48Week 72Randomized

8. Hepatitis web study Peginterferon alfa-2a versus Lamivudine Alone or in Combination in HBeAg-Negative Patients HBeAg-N EGATIVE Patients: Week 72 Treatment Response Source: Marcellin P, et. al. N Engl J Med. 2004;351:1206-7. P=0.007 P=0.003P=0.849 P=0.004 P=0.003P=0.915

9. Hepatitis web study Source: Marcellin P, et. al. N Engl J Med. 2004;351:1206-7. Conclusions: “Patients with HBeAg-negative chronic hepatitis B had significantly higher rates of response, sustained for 24 weeks after the cessation of therapy, with peginterferon alfa-2a than with lamivudine. The addition of lamivudine to peginterferon alfa-2a did not improve post- therapy response rates.”

10. Hepatitis web study Hepatitis web study Peginterferon alfa-2a versus Lamivudine Alone or in Combination in HBeAg-Positive Patients

11. Hepatitis web study Source: Lau GKK, et. al. N Engl J Med. 2005;352:2682-95. Peginterferon alfa-2a versus Lamivudine Alone or in Combination in HBeAg-Positive Patients Week 48Week 72Randomized Peginterferon alfa-2a:180 mcg SC 1x/week + Oral Placebo (n = 271) Lamivudine:100 mg/day (n = 272) Study Features Randomized 1:1:1 HBeAg-positive (N=814) HBV DNA > 5x10 5 copies/mL ALT > 1-10x ULN Peginterferon alfa-2a:180 mcg SC 1x/week + Lamivudine: 100 mg/day (n = 271)

12. Hepatitis web study Peginterferon alfa-2a versus Lamivudine Alone or in Combination in HBeAg-Positive Patients HBeAg-P OSITIVE Patients: Week 72 Treatment Response Source: Lau GKK, et. al. N Engl J Med. 2005;352:2682-95. P < 0.001 P = 0.006 P = 0.002 P = 0.02 P < 0.001

13. Hepatitis web study Hepatitis web study Entecavir versus Lamivudine for up to 96 Weeks in Patients with HBeAg-Positive Chronic Hepatitis B

14. Hepatitis web study Entecavir versus Lamivudine: 96 Week Data HBeAg-Positive Patients: Study Design Background - Phase 3, randomized double-blind controlled trial - 146 centers in Europe, Asia, N. & S. America, Australia & Middle East - BeHold Study Group Subjects - N = 709 with chronic hepatitis B eAg-positive; 57% White, 40% Asian - Excluded: prior lamivudine therapy x >12 weeks or any prior entecavir - Week 52 “virologic responders”: continue blinded treatment to week 96 Regimens - Entecavir 0.5 mg qd (n = 354 at week 52; n = 243 up to week 96) - Lamivudine 100 mg qd (n = 355 at week 52; n = 164 up to week 96) Study End-Points - Response: HBV DNA to <700,000 copies/mL & HBeAg loss - Virologic responders: HBV DNA <700,000 copies/mL Source: Gish RG, et. al. Gastroenterology. 2007;133:1437-44.

15. Hepatitis web study Source: Gish RG, et. al. Gastroenterology. 2007;133:1437-44. Entecavir versus Lamivudine: 96 Week Data HBeAg-Positive Patients: Study Design Entecavir: 0.5 mg mg/day (n = 354 at week 52) (n = 243 at week 96) Lamivudine: 100 mg/day (n = 355 at week 52) (n = 164 at week 96) Study Features Randomized, double-blinded HBeAg-positive (N=709) Treatment-naïve HBV DNA > 10 6 copies/mL Week 48Week 96Week 0 Analysis for Virologic Response Final Analysis Randomized

16. Hepatitis web study Entecavir versus Lamivudine: 96 Week Data HBeAg-Positive Patients: Study Design HBeAg-P OSITIVE Patients: Week 96 Treatment Response Source: Gish RG, et. al. Gastroenterology. 2007;133:1437-44.

17. Hepatitis web study Source: Gish RG, et. al. Gastroenterology. 2007;133:1437-44. Conclusions: “Entecavir treatment through 96 weeks results in continued benefit for patients with HBeAg-positive chronic hepatitis B.”

18. Hepatitis web study Hepatitis web study Entecavir versus Lamivudine for 48 weeks in Patients with HBeAg-Negative Chronic Hepatitis B

19. Hepatitis web study Entecavir versus Lamivudine: 48 Week Data HBeAg-Negative Patients: Study Design Background - Phase 3, randomized, double-blind, controlled trial - 146 centers in Europe, Asia, N. & S. America, Australia & Middle East Subjects - N = 648 with chronic hepatitis B eAg-negative randomized - Race/Ethnicity: 58% White, 39% Asian - Excluded: prior lamivudine therapy x >12 weeks or any prior entecavir Regimens - Entecavir 0.5 mg qd x > 52 weeks - Lamivudine 100 mg qd > 52 weeks Study End-Points - Primary: HBV DNA suppression to <700,000 copies/mL - Follow-up at 48 weeks Source: Lai CL, et. al. N Engl J Med. 2006;354:1011-21.

20. Hepatitis web study Source: Lai CL, et. al. N Engl J Med. 2006;354:1011-21. Entecavir versus Lamivudine: 48 Week Data HBeAg-Negative Patients: Study Design Entecavir: 0.5 mg/day (n = 325) Lamivudine:100 mg/day (n = 313) Study Features Randomized, double-blinded HBeAg-negative (N=648) HBV DNA > 7x10 5 copies/mL ALT 1.3 to 10 X ULN Week 48Randomized

21. Hepatitis web study Entecavir versus Lamivudine: 48 Week Data HBeAg-Negative Patients: Results HBeAg-N EGATIVE Patients: Week 48 Treatment Response Source: Lai CL, et. al. N Engl J Med. 2006;354:1011-21. P<0.001 P=0.045 P=0.01

22. Hepatitis web study Source: Lai CL, et. al. N Engl J Med. 2006;354:1011-21. Entecavir versus Lamivudine: 48 Week Data HBeAg-Negative Patients: Conclusions Conclusions: “Among patients with HBeAg-negative chronic hepatitis B who had not previously been treated with a nucleoside analogue, the rates of histologic improvement, virologic response, and normalization of alanine aminotransferase levels were significantly higher at 48 weeks with entecavir than with lamivudine. The safety profile of the two agents was similar, and there was no evidence of viral resistance to entecavir.”

23. Hepatitis web study Hepatitis web study Telbiviudine versus Lamivudine Globe Study: 52 Weeks

24. Hepatitis web study Telbivudine versus Lamivudine Globe Study: Design Background - Phase 3, randomized double-blind controlled trial - Performed at Asia, Europe, N. America, Australia & New Zealand Subjects - N = 1370 with chronic hepatitis B; 76% Asian - Treatment naïve - HBeAg-positive (N=921) and HBeAg-negative (N=446) Regimens - Telbivudine: 600 mg qd - Lamivudine: 100 mg qd Study End-Points - Primary: HBV DNA suppression to <5 log copies/mL, along with HBeAg loss or normalization of ALT levels - Follow-up at 52 weeks Source: Lai CL, et. al. N Engl J Med. 2007;357:2576-88.

25. Hepatitis web study Source: Lai CL, et. al. N Engl J Med. 2007;357:2576-88. Telbivudine versus Lamivudine Globe Study: Design Telbivudine: 600 mg/day (n = 683) Lamivudine:100 mg/day (n = 687) Study Features Randomized, double-blinded HBeAg-positive (N=921) HBeAg-negative (N=446) Treatment-naïve HBV DNA > 10 6 copies/mL Week 52Week 0 Randomized Analysis

26. Hepatitis web study Telbivudine versus Lamivudine Globe Study: Results Serum HBV DNA Levels after 24 Weeks of Therapy Source: Lai CL, et al. N Engl J Med. 2007;357:2576-88.

27. Hepatitis web study Telbivudine versus Lamivudine Globe Study: Results HBeAg-P OSITIVE Patients: Week 52 Treatment Response Source: Lai CL, et al. N Engl J Med. 2007;357:2576-88.

28. Hepatitis web study Telbivudine versus Lamivudine Globe Study: Results HBeAg-NEGATIVE Patients: Week 52 Treatment Response Source: Lai CL, et al. N Engl J Med. 2007;357:2576-88.

29. Hepatitis web study Telbivudine versus Lamivudine Undetectable HBV DNA Levels, Through 52 Weeks HBeAg-Positive Patients at Baseline Source: Lai CL, et al. N Engl J Med. 2007;357:2576-88.

30. Hepatitis web study Source: Lai CL, et al. N Engl J Med. 2007;357:2576-88. Telbivudine versus Lamivudine Globe Study: Conclusions Conclusions: “Among patients with HBeAg-positive chronic hepatitis B, the rates of therapeutic and histologic response at 1 year were significantly higher in patients treated with telbivudine than in patients treated with lamivudine. In both the HBeAg-negative and the HBeAg- positive groups, telbivudine demonstrated greater HBV DNA suppression with less resistance than did lamivudine.”

31. Hepatitis web study Hepatitis web study Tenofovir versus Adefovir in Patients with Chronic HBV

32. Hepatitis web study Tenofovir versus Adefovir in Patients with Chronic HBV Combined Data from Studies 102 and 103 Source: Marcellin P, et al. N Engl J Med. 2008;359:2442-55.

33. Hepatitis web study Tenofovir in Patients with Chronic HBV Combined Data from Studies 102 and 103 Source: Marcellin P, et al. N Engl J Med. 2008;359:2442-55.

34. Hepatitis web study Response Rate, 3 Years After Stopping Therapy HBeAg-NEGATIVE Patients at Baseline Source: Marcellin P, et al. Gastroenterology. 2009;136:2169-79.

35. Hepatitis web study Undetectable HBV DNA Levels after 1 Year of Therapy HBeAg-POSITIVE Patients at Baseline Source: EASL Clinical Practice Guidelines. J Hepatol. 2009:50:227-42.

36. Hepatitis web study Undetectable HBV DNA Levels after 1 Year of Therapy HBeAg-NEGATIVE Patients at Baseline Source: EASL Clinical Practice Guidelines. J Hepatol. 2009:50:227-42.

37. Hepatitis web study HBe Seroconversion after 1 Year of Therapy HBeAg-POSITIVE Patients at Baseline Source: EASL Clinical Practice Guidelines. J Hepatol. 2009:50:227-42.