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April 26-30, 2006 Vienna, Austria

Updates in HBV Management CCO Independent Conference Coverage of the 2006 Annual Meeting of the European Association for the Study of the Liver* April 26-30, 2006 Vienna, Austria

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April 26-30, 2006 Vienna, Austria

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  1. Updates in HBV ManagementCCO Independent Conference Coverage of the 2006 Annual Meeting of the European Association for the Study of the Liver* April 26-30, 2006 Vienna, Austria *CCO is an independent medical education company that provides state-of-the-art medical information to healthcare professionals through conference coverage and other educational programs. This program is supported by an educational grant from

  2. About These Slides • These slides accompany CCO’s comprehensive online Independent Conference Coverage of the 2006 Annual Meeting of the European Association for the Study of the Liver • The full program is available on the Clinical Care Options for Hepatitis Web site: clinicaloptions.com/vienna2006 • Users are encouraged to use these slides in their own presentations, but we ask that content and attribution not be changed. Users are asked to honor this intent • These slides may not be published or posted online without permission from Clinical Care Options • We are grateful to Stephanos J. Hadziyannis, MD, Henry Dunant Hospital, Athens, Greece, who aided in the content creation of these slides DisclaimerThe materials published on the Clinical Care Options Web site reflect the views of the authors, not those of Clinical Care Options, LLC, the CME providers, or the companies providing educational grants. The materials may discuss uses and dosages for therapeutic products that have not been approved by the United States Food and Drug Administration. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or using any therapies described in these materials.

  3. Chronic Hepatitis B Treatment:Investigational Agents

  4. Phase II randomized, open-label, multicenter trial of adefovir-naive patients (N = 244) Patients received adefovir 10 mg/day or pradefovir 5, 10, 20, or 30 mg/day for 48 weeks Mean baseline HBV DNA: 7.9-8.2 log10 copies/mL Mean baseline ALT: 2.6-3.3 x ULN Genotype C: 67% – Asian: 100% – HBeAg(+): 70% Pradefovir for Chronic Hepatitis B: Week 48 Analysis Lee KS, et al. EASL 2006. Abstract 741.

  5. Pradefovir for Chronic Hepatitis B: Week 48 Analysis 0 Pradefovir 5 mg/day (n = 47) Pradefovir 10 mg/day (n = 49) Pradefovir 20 mg/day (n = 48) Pradefovir 30 mg/day (n = 48) -1 Adefovir 10 mg/day (n = 50) -2 Mean (SE) Change in HBV DNA From Baseline (log10 copies/mL) -3 -4.09 (P = .827 vs ADV) -4 -4.19 -4.84 (P = .007 vs ADV) -5 -4.89 (P = .007 vs ADV) -5.54 (P = .001 vs ADV) -6 0 4 12 18 24 36 48 Week Lee KS, et al. EASL 2006. Abstract 741.

  6. GLOBE: Predictors of Response to Telbivudine • Retrospective subanalysis of GLOBE trial: international, randomized phase III trial Thongsawat S. EASL 2006. Abstract 110.

  7. Telbivudine vs Adefovir in HBeAg-Positive Patients: Week 24 Analysis • Randomized, multicenter open-label study • Serum HBV DNA: > 105 copies/mL • ALT: 1.3-10.0 x ULN Week 52 Preliminary Analysis Week 24 Telbivudine 600 mg/day(n = 45) Telbivudine 600 mg/day(n = 45) HBeAg-positive, treatment-naive chronic hepatitis B patients with compensated liver disease (N = 135) Adefovir 10 mg/day(n = 45) Adefovir 10 mg/day(n = 45) Adefovir 10 mg/day(n = 45) Telbivudine 600 mg/day(n = 45) Chan HLY, et al. EASL 2006. Abstract 52.

  8. Telbivudine vs Adefovir in HBeAg-Positive Patients: Week 24 Analysis Weeks 0 4 8 12 16 20 24 0 - 1 Telbivudine (n = 45)Adefovir (n = 90) - 2 Mean Serum HBV DNAChange From Baseline (log10 copies/mL) - 3 - 4 - 5 - 6 - 7 NS, not significant. Chan HLY, et al. EASL 2006. Abstract 52.

  9. Phase III, multicenter, dose-escalating study (N = 65) HBeAg-positive Asian patients HBV DNA > 106 copies/mL ALT 1.5-10.0 x ULN Confirmed YMDD mutations 5 dose escalation groups ANA380 (30, 60, 90, 150, or 240 mg/day) + lamivudine for 4 weeks followed by 8 weeks ANA380 monotherapy ANA380 (LB80380) in HBeAg-Positive Patients With Lamivudine Resistance • ALT normalization: 12 of 36 individuals in 90, 150, or 240 mg/day arms by Week 12 • Significant viral suppression ANA380 Dosing Group, mg/day 30 (n = 13) 60 (n = 14) 90 (n = 14) 150 (n = 12) 240 (n = 12) 0 -1 -2 Reduction in HBV DNA by Week 12, log10 copies/mL -3 -2.8 -3.2 -4 -3.9 -3.9 -4.1 -5 Lai CL, et al. EASL 2006. Abstract 6.

  10. Open-Label, Phase III Study of Clevudine: Year 1 results • Clevudine 30 mg/day for 24 weeks, then 10 mg/day through Week 48, then 12 weeks follow-up off treatment (N = 55) • Median baseline HBV DNA for HBeAg(+) patients (n = 40): 8.10 log10 copies/mL • Median baseline HBV DNA for HBeAg(-) patients (n = 15): 4.91 log10 copies/mL • All patients with HBV DNA < 300 copies/mL at Week 24 had sustained virologic, biochemical responses through Week 48 Baseline (Week 0) Treatment End (Week 48) Follow-up (Week 60) 100 100 100 100 100 100 89 86 80 80 68 60 60 Percentage With Normal Serum ALT Percentage WithHBV DNA < 300 copies/mL 40 40 27 25 23 20 20 0 0 0 0 HBeAg-Positive Patients (n = 40) HBeAg-Negative Patients (n = 15) HBeAg-Positive Patients (n = 40) HBeAg-Negative Patients (n = 15) Chung YH, et al. EASL 2006. Abstract 53.

  11. Chronic Hepatitis B Treatment:Adefovir

  12. Adefovir Resistance Analysis • Incidence of HBV RT resistance mutations evaluated in 29 HBeAg(-) patients treated with ADV for 5 years • Majority of patients with adefovir resistance acquired N236T mutation • Mutation frequency by Year 5 • N236T > A181V > A181V/N236T > A181T/N236T Borroto-Esoda K, et al. EASL 2006. Abstract 483.

  13. Adefovir vs Adefovir + Lamivudine in Patients With Lamivudine Resistance • Multicenter prospective/retrospective analysis of patients in Italian Expanded Access Program (N = 738) • Factors associated with lower risk of virologic rebound in multivariate analysis at mean follow-up of 24 months • Receiving ADV plus LAM vs ADV alone • HR: 0.34 (95% CI: 0.15-0.71; P = .009) • Achieving HBV DNA negativity by Week 24 • HR: 0.05 (95% CI: 0.01-0.35; P = .003) *HBV DNA increase > 1 log10 vs nadir. †Evidence of resistance: N236T (n = 9), A181T/V (n = 9), N236T + A181V (n = 3), ALT increase (n = 30; 57%). Lampertico P, et al. EASL 2006. Abstract 116.

  14. Adefovir Therapy in Genotype C Patients • Single-arm study: 96 HBV genotype C patients treated for > 12 months • Cumulative rates of viral resistance • Defined as HBV DNA level elevated > 10-fold in ≥ 2 consecutive visits • Month 12: 23% • Month 24: 31% Lee YS, et al. EASL 2006. Abstract 500.

  15. Chronic Hepatitis B Treatment:Entecavir

  16. Responders(n = 275; 85%) Responders(n = 8; 29%) Responders(n = 245; 78%) Responders(n = 11; 42%) Virologic-onlyresponders(n = 34; 11%) Virologic-onlyresponders(n = 15; 54%) Virologic-onlyresponders(n = 34; 10%) Virologic-onlyresponders(n = 15; 58%) ETV-027: Entecavir in Nucleoside-Naive HBeAg(-) Patients: Week 96 Week 52: Management Decision Week 96 Week 48* Continue to Yr 2† (n = 26; 76%) Entecavir (n = 325) Nonresponders(n = 3; 1%) Nonresponders(n = 0; 0%) Continue to Yr 2† (n = 28; 82%) Lamivudine(n = 313) Nonresponders(n = 18; 6%) Nonresponders(n = 5; 18%) *Data missing at Week 48 for 13 entecavir- and 6 lamivudine-treated individuals. †Those responding after Week 48 and those not responding could discontinue before Week 96. Nonresponse, HBV DNA ≥ 0.7 MEq/mL by bDNA;Response, HBV DNA < 0.7 MEq/mL by bDNA and ALT < 1.25 x ULN; Virologic Response, HBV DNA < 0.7 MEq/mL by bDNA but ALT > 1.25 x ULN. Shouval D, et al. EASL 2006. Abstract 45.

  17. Cumulative response outcomes superior with entecavir Cumulative confirmed response defined as 2 sequential measurements of success ETV-027: Entecavir in Nucleoside-Naive HBeAg(-) Patients: Week 96 Cumulative Response Outcomes P < .0001 P = .05 P < .0001 100 94 90 P = .045 89 84 78 77 80 72 Entecavir 71 Lamivudine 60 Percentage of Patients 40 20 0 Wk 48 Wk 96 Wk 48 Wk 96 HBV DNA < 300 copies/mL ALT ≤ 1 x ULN Shouval D, et al. EASL 2006. Abstract 45.

  18. Responders(n = 0; 0%) Responders(n = 9; 12%) Responders(n = 13; 9%) Responders(n = 1; < 1%) Virologic-onlyresponders(n = 0; 0%) ETV-026: Entecavir in LAM-Refractory HBeAg(+) Patients: Week 96 Week 48* Week 52: Management Decision Week 96 Continue to Yr 2† (n = 77; 96%) Virologic-onlyresponders(n = 80; 55%) Virologic-onlyresponders(n = 57; 74%) Entecavir (n = 145) Nonresponders(n = 11; 14%) Nonresponders(n = 40; 28%) Continue to Yr 2† (n = 3; 43%) Virologic-onlyresponders(n = 7; 5%) Lamivudine(n = 141) Nonresponders(n = 121; 86%) Nonresponders(n = 3; 100%) *Data missing for 8 entecavir- and 16 lamivudine-treated individuals at Week 48. †Those responding after Week 48 and those not responding could discontinue before Week 96. Response, HBV DNA < 0.7 MEq/mL by bDNA and HBeAg loss; Virologic Response, HBV DNA < 0.7 MEq/mL by bDNA but HBeAg positive; Nonresponse, HBV DNA ≥ 0.7 MEq/mL by bDNA. Yurdaydin C, et al. EASL 2006. Abstract 80.

  19. ETV-026: Entecavir in LAM-Refractory HBeAg(+) Patients: Week 96 • Safety profile similar for entecavir, lamivudine • Entecavir superior to lamivudine across subgroups • ALT levels ≥ 2 x ULN at baseline associated with higher rates of histologic improvement in entecavir patients ETV, entecavir; LVD, lamivudine; NA, not available. *Cumulative percentage of patients achieving treatment endpoint for 2 sequential time points or at last observation. †ALT > 2 x baseline and > 10 x ULN while on treatment. Yurdaydin C, et al. EASL 2006. Abstract 80. Yurdaydin C, et al. EASL 2006. Abstract 512.

  20. Entecavir Treatment in Advanced Fibrosis Patients: Week 48 • Entecavir randomized phase III trials: ETV-022, ETV-027, ETV-026 Nucleoside-Naive Patients With Advanced Fibrosis or Cirrhosis Lamivudine-Refractory Patients With Advanced Fibrosis or Cirrhosis Missing data Worsening No change Improvement HBeAg Positive HBeAg Negative 8 100 100 8 17 19 24 22 2 6 80 80 0 35 31 5 19 28 35 18 60 60 Percentage of Patients Percentage of Patients 29 40 40 59 57 53 49 43 20 20 33 0 0 ETV (n = 46) LAM (n = 47) ETV (n = 51) LAM (n = 57) ETV (n = 23) LAM (n = 21) Advanced fibrosis, Ishak fibrosis score of 4, 5 or 6; fibrosis improvement, ≥ 1 point decline in Ishak fibrosis score from baseline; fibrosis worsening, ≥ 1 point increase in Ishak fibrosis score from baseline. Simsek H, et al. EASL 2006. Abstract 513.

  21. Analysis of Entecavir Resistance: Nucleoside-Naive Individuals • No evidence of ETV resistance mutations (substitutions decreasing ETV susceptibility > 3-fold) in any ETV-treated patients with • Virologic rebound (n = 18) at Year 1 or Year 2 • Suboptimal responses (HBV DNA > 105 copies/mL at Week 48; n = 5) • HBV DNA > 300 copies/mL at Week 96 or end of dosing (n = 33) • ETV susceptibility similar at baseline and at time of rebound or suboptimal responses in 23 evaluated patients • No patients with virologic rebound had substitutions decreasing ETV susceptibility • 90 substitutions at 76 residues of the RT gene emerged on ETV • None resulted in reduced susceptibility to ETV > 3-fold Colonno R, et al. EASL 2006. Abstract 490.

  22. Chronic Hepatitis B Treatment:Peginterferon

  23. Sustained Responses in HBeAg(-) Patients Treated With Peginterferon • Long-term follow-up of a phase III, randomized trial • Only sustained biochemical responders at 6 months in PEG monotherapy group evaluated (n = 116) Months 36* Randomization Month 12 Lamivudine 100 mg/day (n = 181) HBeAg-negativepatients with chronic HBV infection (N = 537) Follow-up Peginterferon alfa-2a 180 µg/week + Placebo once daily (n = 177) Peginterferon alfa-2a 180 µg/week + Lamivudine 100 mg/day (n = 179) *Current analysis. Marcellin P, et al. EASL 2006. Abstract 743.

  24. Sustained Responses in HBeAg(-) Patients Treated With Peginterferon • 66% of patients from original study eligible for follow-up study • Biochemical response defined as ALT < 50 IU/L • Complete response: ALT normal at all time points • Partial response: ALT at times elevated but never > 50 IU/L *4 patients reverted to HBsAg positivity. †Development of anti-HBs antibody. Marcellin P, et al. EASL 2006. Abstract 743.

  25. NO 60% (n = 103) YES 40% (n = 69) Sustained Responses in HBeAg(+) Patients Treated With Peginterferon 172 Patients Treated With Peginterferon alfa-2a Monotherapy for 48 Weeks HBeAg Seroconversion by Month 6 Off Treatment? Outcome at Month 12 Off Treatment? Durability of HBeAg Seroconversion, Month 12 Posttreatment Development of HBeAg Seroconversion, Months 6-12 100 100 91% HBeAg seroconversion 85 Maintained 80 80 Lost No HBeAg seroconversion 60 60 Percentage of Patients (n = 69) Percentage of Patients (n = 103) 40 40 15 20 20 9% 0 0 Lau GK, et al. EASL 2006. Abstract 50.

  26. Hepatitis B Treatment:Predictors of Response

  27. Early Virologic Suppression as a Predictor of Year 1 Response • Retrospective analysis of GLOBE trial (N = 1367) • Data from lamivudine- and telbivudine-treated patients pooled Proportion of Patients With Normalized ALT at Week 52 Proportion of Patients With Undetectable Viral Load at Week 52 HBeAg positive HBeAg negative 100 100 94 91 90 89 83 80 80 80 74 69 67 63 60 60 54 Percentage of Patients Percentage of Patients 40 36 40 40 30 20 20 10 5 0 0 < 300 300-3 log 3-4 log > 4 log < 300 300-3 log 3-4 log > 4 log Viral Load at Week 24 (copies/mL) Viral Load at Week 24 (copies/mL) Zeuzem S, et al. EASL 2006. Abstract 51.

  28. Early Virologic Suppression as a Predictor of Year 1 Response • HBV DNA < 300 copies/mL at Week 24 had high positive predictive value (PPV) for maintained suppression at Week 52 with telbivudine • PPV lower with lamivudine *Pooled data from telbivudine- and lamivudine-treated individuals. Zeuzem S, et al. EASL 2006. Abstract 51.

  29. Transplantation

  30. Adefovir ± ongoing lamivudine (N = 57) HBIG administration posttransplant (n = 34) Median adefovir treatment Prior to transplant: 15 wks Posttransplant: 36 wks Cumulative probability of ADV resistance measured from annual rates in larger study Week 48: 0% Week 96: 2% Week 144: 2% 7% discontinued due to adverse event (not ADV related) Highest serum creatinine posttransplant Normal/grade 1: 84% Grade 2: 7% Grade 3: 7% Grade 4: 2% Adefovir in Lamivudine-Resistant Hepatitis B Transplant Patients Schiff E, et al. EASL 2006. Abstract 2.

  31. LAM ± HBIG for Preventing HBV Recurrence After Transplant: Year 5 • 29 liver transplant patients • HBsAg positive, HBeAg positive, or anti-HBe positive • HBV DNA negative on lamivudine or spontaneously • Recurrence at Months 23, 24, 44, and 48 posttransplant • 3 of 4 individuals did not receive lamivudine pretransplant • Additional 5 patients HBV DNA positive but not HBsAg positive • 3/5 received lamivudine + HBIG for entire treatment duration • 5-year survival rate: 90% HBIG + Lamivudine (n = 9) HBIG + Lamivudine (n = 15) No recurrence Recurrence (n = 4) HBsAg positive and HBV DNA positive Lamivudine (n = 20) Lamivudine (n = 14) Buti M, et al. EASL 2006. Abstract 129.

  32. Nonliver Transplantation From anti-HBc–Positive Organ Donors • Virologic and serologic outcomes of anti-HBc(-) patients who received transplants from anti-HBc(+), HBsAg(-) donors assessed (N = 60) • 5/7 who developed anti-HBc antibodies were anti-HBs negative at time of transplant • No patients became HBsAg positive following transplant • HBV DNA undetectable in 10 of 43 kidney patients with negative or low anti-HBs titers Fytili P, et al. EASL 2006. Abstract 140.

  33. HBV Vaccination

  34. Relationship Between HBV Vaccination and HCC Incidence • 3,855,485 newborns vaccinated in Taiwan (1984-2000) • 43,134,217 person-years of follow-up • 158 cases of newly diagnosed HCC during follow-up • Rates higher in girls vs boys • Receiving 4 vs 1-2 doses increased preventive effects against HCC 1.0 Girls (n = 2,009,182) 0.74 (n = 15) Boys (n = 1,846,303) 0.8 0.51 (n = 49) HCC Incidence/ 100,000 Person-Years 0.6 0.44 (n = 98) 0.43 (n = 8) 0.37 (n = 33) 0.31 (n = 34) 0.29 (n = 60) 0.4 0.19 (n = 19) 0.2 0 Chien YC, et al. EASL 2006. Abstract 247.

  35. Go Online for More CCO Coverage of This Conference! Capsule Summaries of all the key data, plus Expert Analysis panel discussions exploring the clinical implications Expert Recap (slides and audio) plus your own copy of this PowerPoint deck clinicaloptions.com/vienna2006

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