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  1. 1. White Nights of Hepatology 2010, an EASL endorsed conference Conference proceedings: www.elsevier.ru/WNH EASL endorsed conference “White nights of hepatology” Saint-Petersburg, June 10-11, 2010 IFN therapy prospects of chronic hepatitis B K. ZHDANOV
  2. 2. White Nights of Hepatology 2010, an EASL endorsed conference Conference proceedings: www.elsevier.ru/WNH 25-year survival rates in untreated CHB 100 Inactive CHB Survival probability 80 60 HBeAg-/HBV DNA+ or HBeAg reversion 40 HBeAg+ persistence 20 0 0 5 10 15 20 25 Time (years) Fattovich et al. Gut 2008
  3. 3. White Nights of Hepatology 2010, an EASL endorsed conference Conference proceedings: www.elsevier.ru/WNH HBsAg clearance – Improves survival Survival in patients with and without HBsAg seroconversion Retrospective study of 309 cirrhotic patients over mean follow-up of 5.7 years 100 With HBsAg clearance 80 Survival (%) P<0.001 60 No HBsAg 40 clearance 20 0 2 4 6 8 10 12 14 Time (years) Fattovich et al. Am J Gastroenterol 1998
  4. 4. White Nights of Hepatology 2010, an EASL endorsed conference Conference proceedings: www.elsevier.ru/WNH When should we treat? Anti-HBe HBV DNA ALT Immune Immune clearance Inactive Reactivation tolerant HBeAg +ve CHB CHB HBeAg –ve CHB ? Lok et al. Arch Intern Med 2006
  5. 5. White Nights of Hepatology 2010, an EASL endorsed conference Conference proceedings: www.elsevier.ru/WNH Treatment options in CHB IFN: immune stimulation and antiviral action • Effect usually sustained off therapy/post- treatment Nucleos(t)ide analogs: antiviral action only • Effect maintained on therapy unless resistance • Effect may not be sustained off treatment
  6. 6. White Nights of Hepatology 2010, an EASL endorsed conference Conference proceedings: www.elsevier.ru/WNH
  7. 7. White Nights of Hepatology 2010, an EASL endorsed conference Conference proceedings: www.elsevier.ru/WNH
  8. 8. White Nights of Hepatology 2010, an EASL endorsed conference Conference proceedings: www.elsevier.ru/WNH Effect of ETV treatment discontinuation on viral load in CHB (HBeAg-) Percentage of protocol-defined responders who had achieved HBV DNA <300 copies/mL at Week 48 59% ETV (n=257) LVD (n=201) 14% 4% 5% 3% 5% 8 16 24 Follow-up weeks Shouval D. et al. J Hepatol 50 (2009) 289-295
  9. 9. clinical undetectable White Nights of Hepatology 2010, an EASL endorsed conference histological survival Conference proceedings: www.elsevier.ru/WNH remission HBV DNA improvement ALT - N HBeAg HBsAg seroconversion seroconversion 1980 1990 2000 2010 Peg-IFN alfa IFN ADV ETV LDT LVD TDF 18% (HBeAg+) 10-47% (HBeAg-)
  10. 10. White Nights of Hepatology 2010, an EASL endorsed conference Conference proceedings: www.elsevier.ru/WNH
  11. 11. White Nights of Hepatology 2010, an EASL endorsed conference Conference proceedings: www.elsevier.ru/WNH IFN LONG-TERM OUTCOMES HBeAg-positive: follow-up of 11 years IFN Control (n=233) (n=233) 18% 34% Cirrhosis p = 0.041* 3% 13% HCC p = 0.011* 98% 53% Survival p = 0.003* *p vs control Lin et al. EASL 2005 and J Hepatol 2007
  12. 12. White Nights of Hepatology 2010, an EASL endorsed conference Conference proceedings: www.elsevier.ru/WNH HBsAg clearance increases over time in responders to IFN-based therapy Patients with HBeAg seroconversion and undetectable HBV DNA 48 weeks post-treatment with IFN 90 80 80 Cumulative rate of HBsAg 70 60 clearance (%) 60 50 40 40 30 20 10 0 5 10 15 Years post treatment Moucari et al. J Hepatol 2009
  13. 13. White Nights of Hepatology 2010, an EASL endorsed conference Conference proceedings: www.elsevier.ru/WNH HBsAg clearance increases over time in sustained responders to IFN 100 HBsAg-negative patients (%) 80 Sustained responders* 60 45% 40 IFN All patients 20 18% Treatment failures 0 0 12 24 36 48 60 72 84 96 108 120 Months *ALT normal and HBV DNA undetectable <1pg/mL Lampertico et al. Hepatology 2003
  14. 14. White Nights of Hepatology 2010, an EASL endorsed conference Conference proceedings: www.elsevier.ru/WNH 1 year of PEG-IFN (± LAM) in HBeAg +ve CHB HBeAg seroconversion 6 months On-therapy post-treatment Janssen 25% 29% Lau 27–24% 32–27% Chan 38% 36% Response is sustained post-treatment Janssen et al. Lancet 2005; Lau et al. N Eng J Med 2005; Chan et al. Ann Intern Med 2005
  15. 15. White Nights of Hepatology 2010, an EASL endorsed conference Conference proceedings: www.elsevier.ru/WNH Responders* to Peg-IFN α-2b therapy in HBeAg-positive CHB: 3-year follow up Patients treated with PEG-IFN ± LAM for 1 year 100 81% 80 77% 58% Patients (%) 60 40 30% 20 0 HBeAg ALT HBV DNA HBsAg cleared normal <10,000 cleared cp/mL *HBeAg loss at 6 months post-treatment Buster et al. Gastroenterology 2008
  16. 16. White Nights of Hepatology 2010, an EASL endorsed conference Conference proceedings: www.elsevier.ru/WNH HBsAg clearance rate increases post- treatment with PEGASYS (± lamivudine) 15 N=230 13 12% HBsAg clearance (%) 11% 11 Patients with 9% 9 7 6% 5 3% 3 1 Years after EOT 1 2 3 4 5 HBeAg-negative patients Marcellin et al. APASL 2009
  17. 17. White Nights of Hepatology 2010, an EASL endorsed conference Conference proceedings: www.elsevier.ru/WNH PEGASYS demonstrated sustained immune control up to 5 years 88% of PEGASYS patients who achieved HBV DNA 50 ≤10,000 copies/mL at Year 1 post-treatment % patients with HBV DNA 40 maintained that response 31% ≤10,000 cp/mL up to year 5 (N=36/41) 30 20 28% of PEGASYS patients who achieved HBV DNA 10 ≤10,000 copies/mL at Year 1 post-treatment N=72 0 cleared HBsAg at year 5 Post-treatment (N=20/72*) * 54% of PEGASYS patients Y1 who achieved HBsAg clearance also achieved HBsAg seroconversion Marcellin et al. AASLD 2009 poster
  18. 18. White Nights of Hepatology 2010, an EASL endorsed conference Conference proceedings: www.elsevier.ru/WNH Efficacy of PEGASYS in patients who failed prior treatment HBeAg-positive/negative disease
  19. 19. White Nights of Hepatology 2010, an EASL endorsed conference Conference proceedings: www.elsevier.ru/WNH Comparing PEGASYS with ADV in HBeAg- positive LAM-resistant patients (China) HBeAg-positive, LAM-resistant (YMDD+), on lamivudine for ≥6 months and still on Rx, N=235 PEGASYS 180 µg N=155 Follow-up LAM 100 mg Adefovir 10 mg N=80 LAM 100 mg 0 12 24 48 72 Study Weeks Randomization 2:1 Hou et al. AASLD 2008; Hou et al. APASL 2009
  20. 20. White Nights of Hepatology 2010, an EASL endorsed conference Conference proceedings: www.elsevier.ru/WNH Better HBsAg decline with PEGASYS vs ADV in patients who failed prior NAs Mean reduction in HBsAg from baseline LAM-YMDD mutation patients 0 -0.31 -0.35 Quantitative HBsAg ADV (N=80) (log10 IU/mL) -0.5 P<0.001 PEGASYS -1 -0.75 (N=155) -0.92 -1.5 BL 24 48 Weeks Hou et al. AASLD 2008; Hou et al. APASL 2009
  21. 21. White Nights of Hepatology 2010, an EASL endorsed conference Conference proceedings: www.elsevier.ru/WNH PEGASYS is superior to ADV in patients with YMDD mutations 16 PEGASYS P=0.045 14 13.6% Adefovir 12 11.6% Patients (%) 10 8.8% 8 6 4 3.8% 3.2% 2 1.9% 0% 0% 0 HBeAg HBeAg HBsAg HBsAg clearance seroconversion clearance seroconversion Hou J et al. APASL 2009; EASL 2009
  22. 22. White Nights of Hepatology 2010, an EASL endorsed conference Conference proceedings: www.elsevier.ru/WNH Potential ways to increase rates of sustained immune control 1. Extending PEGASYS therapy 2. Combining PEGASYS with NAs
  23. 23. White Nights of Hepatology 2010, an EASL endorsed conference Conference proceedings: www.elsevier.ru/WNH Extended treatment duration N=49 HBeAg-positive patients treated for 96 weeks • Week 48: – HBeAg loss = 37% (18/49) • Week 96: – HBeAg loss increased to 53% (26/49); HBsAg cleared in 10% (5/49) 60 53% 51% HBeAg loss (%) 50 Cumulative 35% 37% 40 30% 30 18% 20 10 0 12 24 36 48 72 96 Weeks of PEGASYS treatment Wu. APASL 2008
  24. 24. White Nights of Hepatology 2010, an EASL endorsed conference Conference proceedings: www.elsevier.ru/WNH Extended treatment is associated with better virologic response at week 72 Extension group Follow-up group 100% P=0.14 81% 80% 60% 53% P=0.043 38% P=0.23 40% 19% 20% 0% 0% 0% HBV DNA HBeAg HBsAg clearance undetectable seroconversion Jiang et al. data on file
  25. 25. White Nights of Hepatology 2010, an EASL endorsed conference Conference proceedings: www.elsevier.ru/WNH Italian PegBeLiver study: Patients with HBeAg-negative disease A PEGASYS 180 µg Follow-up HBeAg-negative B N=122 PEGASYS 180 µg PEGASYS 135 µg Follow-up PEGASYS 180 µg plus PEGASYS 135 µg Follow-up LAM 100 mg C qHBsAg 0 48 96 144 Study Weeks Randomization 2:2:1
  26. 26. White Nights of Hepatology 2010, an EASL endorsed conference Conference proceedings: www.elsevier.ru/WNH HBsAg(-) HBsAg(-) 0% 9% (n=3) + 6% (n=2) <10IU/ml n=51 n=52 n=51 n=52
  27. 27. White Nights of Hepatology 2010, an EASL endorsed conference Conference proceedings: www.elsevier.ru/WNH Potential ways to increase rates of sustained immune control 1. Extending PEGASYS therapy 2. Combining PEGASYS with NAs • Sequential PEGASYS + • Concomitant ETV, ADV or TDF • Nested
  28. 28. White Nights of Hepatology 2010, an EASL endorsed conference Conference proceedings: www.elsevier.ru/WNH High rates of sustained immune control and HBsAg clearance with PEGASYS + ADV PEGASYS 180 μg/week + ADV 10 mg/d 48 weeks HBeAg seroconversion 6 months post-treatment 10/28 36% HBeAg-positive patients (N=41) HBsAg clearance up to 5 Y post-treatment* 4/28 14% HBV DNA suppression 6 months post-treatment 14/30 47% HBeAg-negative (<2,000 IU/mL) patients (N=45) HBsAg clearance up to 5 Y post-treatment* 7/30 23% *Patients who completed 6 months of post-treatment follow up were followed for up to 5 years Takkenberg et al. AASLD 2009
  29. 29. White Nights of Hepatology 2010, an EASL endorsed conference Conference proceedings: www.elsevier.ru/WNH Combination study: PEGASYS + nested ETV in HBeAg-negative CHB STUDY WEEK BL 12 24 36 48 48 60 72 84 96 108 120 132 144 PEGASYS 180 µg sc/Wk (GENOTYPES: B=30%; C=30%; D=30%, Other=10%) A ENTECAVIR FOLLOW UP PERIOD placebo oral od PEGASYS Duration Code break PEGASYS 180 µg sc/Wk HBeAg Negative B ENTECAVIR FOLLOW UP PERIOD 0.5mg oral od N=400 PEGASYS 180 µg sc/Wk C ENTECAVIR PEGASYS 180 µg sc/Wk FOLLOW UP PERIOD placebo oral od PEGASYS 180 µg sc/Wk D ENTECAVIR PEGASYS 180 µg sc/Wk FOLLOW UP PERIOD 0.5mg oral od RANDOMIZATION & DOUBLE BLIND 1ry END POINT: HBV DNA <10,000 copies/ml ENTECAVIR TREATMENT ALLOCATION at 48 weeks post treatment Planned 1st patient in for screening: July 2010 Planned 1st patient enrolled: September 2010
  30. 30. White Nights of Hepatology 2010, an EASL endorsed conference Conference proceedings: www.elsevier.ru/WNH Switch study: UK NA Follow up NA 3Y PEGASYS Follow up 3 years 0 48 weeks 144 Endpoints: 2 years post-treatment • Sustained immune control (HBV DNA <10,000 copies/mL) • Clearance of HBsAg Parallel immunology/biomarkers substudy
  31. 31. White Nights of Hepatology 2010, an EASL endorsed conference Conference proceedings: www.elsevier.ru/WNH
  32. 32. Sustained immune control through IFN-based White Nights of Hepatology 2010, an EASL endorsed conference Conference proceedings: www.elsevier.ru/WNH therapy is the critical step towards HBsAg clearance Clinical benefit (↓HCC/↓cirrhosis) & improved survival POST-TREATMENT HBsAg clearance SUSTAINED IMMUNE CONTROL* *POST-TREATMENT HBV DNA ≤10,000 copies/mL ON-TREATMENT in HBeAg-negative disease HBV DNA suppression HBsAg decline
  33. 33. White Nights of Hepatology 2010, an EASL endorsed conference Conference proceedings: www.elsevier.ru/WNH Treatment costs for PEGASYS vs NAs 40,000 Cumulative costs of treatment (US$) 30,000 NAs 20,000 PEGASYS 10,000 1 2 3 4 Years Source: Costs of Antiviral Therapy of Chronic Hepatitis B,” an abstract by John B. Wong, M.D., Tufts New England Medical Center, Boston, MA presented at the NIH Meeting; Management of Hepatitis B on April 7, 2006
  34. 34. White Nights of Hepatology 2010, an EASL endorsed conference Conference proceedings: www.elsevier.ru/WNH CONCLUSIONS 1. Sustained immune control through IFN-based therapy in CHB (HBeAg+ and HBeAg-) is the critical step towards HBsAg clearance. Thus Peg-IFN can be used as first-line monotherapies. 2. Peg-IFN is effective in NAs resistance and can be used in patients who failed prior NAs. 3. HBV genotype has a poor individual predictive value and currently, genotype alone should not override the choice of treatment. 4. Extending Peg-IFN therapy improves SVR rate and HBsAg clearance. 5. Combining Peg-IFN with NAs is potential way to increase rates of sustained immune control.

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