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Therapeutic Agents Used to Treat Hepatitis B

Therapeutic Agents Used to Treat Hepatitis B. Presentation Prepared by: Nina Kim, MD and David Spach, MD Last Updated: May 31, 2011. Timeline for FDA-Approved Agents used to Treat HBV. Tenofovir. Telbivudine. Entecavir. Peginterferon alpha-2b. Adefovir. Lamivudine.

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Therapeutic Agents Used to Treat Hepatitis B

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  1. Therapeutic Agents Used to Treat Hepatitis B Presentation Prepared by: Nina Kim, MD and David Spach, MDLast Updated: May 31, 2011

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

  3. Agents FDA-Approved for Treatment of Chronic HBV

  4. Agents used for Chronic HBV: Cautionary Notes

  5. Agents used for Chronic HBV: Adverse Effects

  6. Peginterferon alfa-2a vslamivudine vsPeginterferonalfa-2a + lamivudine in patients with HBeAg-negative chronic hepatitis B

  7. Peginterferon alfa-2a versus Lamivudine Alone or in Combination in HBeAg-Negative Patients Randomized Week 48 Week 72 Peginterferon alfa-2a:180 mcg SC 1x/week + Oral Placebo (n = 177) Peginterferon alfa-2a:180 mcg SC 1xweek + Lamivudine: 100 mg/day (n = 179) Lamivudine:100 mg/day (n = 181) Source: Marcellin P, et. al. N Engl J Med. 2004;351:1206-7.

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

  9. Source: Marcellin P, et. al. N Engl J Med. 2004;351:1206-7.

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

  11. Peginterferon alfa-2a versus Lamivudine Alone or in Combination in HBeAg-Positive Patients Randomized Week 48 Week 72 Peginterferon alfa-2a:180 mcg SC 1x/week + Oral Placebo (n = 271) Peginterferon alfa-2a:180 mcg SC 1x/week + Lamivudine: 100 mg/day (n = 271) Lamivudine:100 mg/day (n = 272) Source: Lau GKK, et. al. N Engl J Med. 2005;352:2682-95.

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

  13. Entecavirversus Lamivudine for up to 96 Weeks in Patients with HBeAg-Positive Chronic Hepatitis B

  14. Entecavir versus Lamivudine: 96 Week DataHBeAg-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. Entecavir versus Lamivudine: 96 Week DataHBeAg-Positive Patients: Study Design Week 0 Week 48 Week 96 FinalAnalysis Analysis for Virologic Response Randomized 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) Source: Gish RG, et. al. Gastroenterology. 2007;133:1437-44.

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

  17. Source: Gish RG, et. al. Gastroenterology. 2007;133:1437-44.

  18. Entecavirversus Lamivudine for 48 weeks in Patients with HBeAg-Negative Chronic Hepatitis B

  19. Entecavir versus Lamivudine: 48 Week DataHBeAg-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. Entecavir versus Lamivudine: 48 Week DataHBeAg-Negative Patients: Study Design Randomized Week 48 Entecavir: 0.5 mg/day (n = 325) Lamivudine:100 mg/day (n = 313) Source: Lai CL, et. al. N Engl J Med. 2006;354:1011-21.

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

  22. Entecavir versus Lamivudine: 48 Week DataHBeAg-Negative Patients: Conclusions Source: Lai CL, et. al. N Engl J Med. 2006;354:1011-21.

  23. Telbiviudine versus LamivudineGlobe Study: 52 Weeks

  24. Telbivudine versus LamivudineGlobe 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 withHBeAg 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. Telbivudine versus LamivudineGlobe Study: Design Week 0 Week 52 Randomized Analysis Telbivudine: 600 mg/day (n = 683) Lamivudine:100 mg/day (n = 687) Source: Lai CL, et. al. N Engl J Med. 2007;357:2576-88.

  26. Telbivudine versus LamivudineGlobe 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. Telbivudine versus LamivudineGlobe Study: Results HBeAg-Positive Patients: Week 52 Treatment Response Source: Lai CL, et al. N Engl J Med. 2007;357:2576-88.

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

  29. Telbivudine versus LamivudineUndetectable 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. Telbivudine versus LamivudineGlobe Study: Conclusions Source: Lai CL, et al. N Engl J Med. 2007;357:2576-88.

  31. Tenofovir versus Adefovir in Patients with Chronic HBV

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

  35. 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. 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. HBeSeroconversion after 1 Year of Therapy HBeAg-POSITIVE Patients at Baseline Source: EASL Clinical Practice Guidelines. J Hepatol. 2009:50:227-42.

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