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 *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

clinicaloptions.com/hep Updates in HBV Management 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 Users are asked to honor this intent  These slides may not be published or posted online without permission from Clinical Care Options  We are grateful to Stephanos J. Hadziyannis, MD, Henry Dunant Hospital, Athens, Greece, who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 Disclaimer The 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.

Chronic Hepatitis B Treatment: Investigational Agents

clinicaloptions.com/hep Updates in HBV Management Pradefovir for Chronic Hepatitis B: Week 48 Analysis Lee KS, et al. EASL Abstract 741.  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: log 10 copies/mL –Mean baseline ALT: x ULN –Genotype C: 67% – Asian: 100% – HBeAg(+): 70% Week 48 Outcome Pradefovir Adefovir (n = 50) 5 mg/day (n = 47) 10 mg/day (n = 49) 20 mg/day (n = 48) 30 mg/day (n = 48) HBV DNA < 400 copies/mL, % ALT normalized  HBeAg-positive patients  HBeAg-negative patients HBeAg seroconversion, %

clinicaloptions.com/hep Updates in HBV Management Pradefovir for Chronic Hepatitis B: Week 48 Analysis Lee KS, et al. EASL Abstract (P =.827 vs ADV) (P =.001 vs ADV) Pradefovir 5 mg/day (n = 47) (P =.007 vs ADV) (P =.007 vs ADV) Week Mean (SE) Change in HBV DNA From Baseline (log 10 copies/mL) Adefovir 10 mg/day (n = 50) Pradefovir 10 mg/day (n = 49) Pradefovir 20 mg/day (n = 48)Pradefovir 30 mg/day (n = 48) Mean Change in HBV DNA from Baseline, log 10 copies/mL PradefovirAdefovir 5 mg/day10 mg/day20 mg/day30 mg/day10 mg/day HBeAg Positive Patients (n = 33) (n = 33) (n = 31) (n = 36) (n = 36) HBeAg Negative Patients (n = 14) (n = 16) (n = 17) (n = 12) (n = 14)

clinicaloptions.com/hep Updates in HBV Management GLOBE: Predictors of Response to Telbivudine  Retrospective subanalysis of GLOBE trial: international, randomized phase III trial Thongsawat S. EASL Abstract 110. Factors Associated With Undetectable Viral Load at Year 1 (Stepwise Logistic Regression) Factor Odds Ratio for Undetectable HBV DNA HBeAg Positive (n = 921) HBeAg Negative (n = 446) Telbivudine treatment High ALT Prior interferon use2.16NS High Knodell score (> median)2.22NS Asian race vs other3.33 Asian vs white raceNS2.44 Asia region vs other2.63NS Asia region vs North America2.70NS HBV DNA, middle vs highest tertile HBV DNA, lowest vs highest tertile

clinicaloptions.com/hep Updates in HBV Management Telbivudine vs Adefovir in HBeAg- Positive Patients: Week 24 Analysis Chan HLY, et al. EASL Abstract 52. HBeAg-positive, treatment-naive chronic hepatitis B patients with compensated liver disease (N = 135) Preliminary Analysis Week 24  Randomized, multicenter open-label study –Serum HBV DNA: > 10 5 copies/mL –ALT: x ULN Week 52 Telbivudine 600 mg/day (n = 45) Adefovir 10 mg/day (n = 45) Telbivudine 600 mg/day (n = 45)

clinicaloptions.com/hep Updates in HBV Management Weeks Telbivudine vs Adefovir in HBeAg- Positive Patients: Week 24 Analysis Week 24 Outcome Telbivudine, % (n = 45) Adefovir, % (n = 90) P Value Serum HBV DNA, copies/mL  < 300  log 10  3-4 log 10  > 4 log <.01 NS <.01 ALT normalization6163 HBeAg loss1610 NS, not significant Telbivudine (n = 45) Adefovir (n = 90) Mean Serum HBV DNA Change From Baseline (log 10 copies/mL) Chan HLY, et al. EASL Abstract 52.

clinicaloptions.com/hep Updates in HBV Management ANA380 (LB80380) in HBeAg-Positive Patients With Lamivudine Resistance Lai CL, et al. EASL Abstract (n = 13) 60 (n = 14) 90 (n = 14) 150 (n = 12) 240 (n = 12) Reduction in HBV DNA by Week 12, log 10 copies/mL ANA380 Dosing Group, mg/day  Phase III, multicenter, dose- escalating study (N = 65)  HBeAg-positive Asian patients –HBV DNA > 10 6 copies/mL –ALT 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  ALT normalization: 12 of 36 individuals in 90, 150, or 240 mg/day arms by Week 12  Significant viral suppression

clinicaloptions.com/hep Updates in HBV Management 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 log 10 copies/mL –Median baseline HBV DNA for HBeAg(-) patients (n = 15): 4.91 log 10 copies/mL  All patients with HBV DNA < 300 copies/mL at Week 24 had sustained virologic, biochemical responses through Week 48 Chung YH, et al. EASL Abstract 53. Percentage With HBV DNA < 300 copies/mL Percentage With Normal Serum ALT HBeAg-Negative Patients (n = 15) HBeAg-Positive Patients (n = 40) Baseline (Week 0)Treatment End (Week 48)Follow-up (Week 60) HBeAg-Negative Patients (n = 15) HBeAg-Positive Patients (n = 40)

Chronic Hepatitis B Treatment: Adefovir

clinicaloptions.com/hep Updates in HBV Management  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 Adefovir Resistance Analysis Borroto-Esoda K, et al. EASL Abstract 483. Virologic Resistance (VR) Analysis in HBeAg(-) Patients With ADV Resistance Mutations by Year 5 Cumulative Probability of Outcome, Year Genotypic Resistance, % Genotypic Resistance + VR, % Genotypic Resistance + VR + ALT Elevation, %

clinicaloptions.com/hep Updates in HBV Management 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: ; P =.009) –Achieving HBV DNA negativity by Week 24 –HR: 0.05 (95% CI: ; P =.003) Lampertico P, et al. EASL Abstract 116. Outcome Virologic Rebound and Adefovir Resistance Adefovir, % (n = 277)Adefovir + Lamivudine, % (n = 294)P Value Virologic rebound*154<.001 Adefovir resistance † 80<.001 *HBV DNA increase > 1 log 10 vs nadir. † Evidence of resistance: N236T (n = 9), A181T/V (n = 9), N236T + A181V (n = 3), ALT increase (n = 30; 57%).

clinicaloptions.com/hep Updates in HBV Management 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 Abstract 500. Outcome Months After Starting Adefovir Median change in serum HBV DNA, log 10 copies/mL HBV DNA < 100 copies/mL, % ALT normalization, % HBeAg loss, %

Chronic Hepatitis B Treatment: Entecavir

clinicaloptions.com/hep Updates in HBV Management ETV-027: Entecavir in Nucleoside- Naive HBeAg(-) Patients: Week 96 Responders (n = 275; 85%) Virologic-only responders (n = 34; 10%) Entecavir (n = 325) Lamivudine (n = 313) Continue to Yr 2 † (n = 26; 76%) Continue to Yr 2 † (n = 28; 82%) Nonresponders (n = 3; 1%) *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 1.25 x ULN. Week 48* Week 96 Week 52: Management Decision Shouval D, et al. EASL Abstract 45. Responders (n = 11; 42%) Virologic-only responders (n = 15; 58%) Nonresponders (n = 0; 0%) Responders (n = 245; 78%) Virologic-only responders (n = 34; 11%) Nonresponders (n = 18; 6%) Responders (n = 8; 29%) Virologic-only responders (n = 15; 54%) Nonresponders (n = 5; 18%)

clinicaloptions.com/hep Updates in HBV Management ETV-027: Entecavir in Nucleoside- Naive HBeAg(-) Patients: Week 96  Cumulative response outcomes superior with entecavir –Cumulative confirmed response defined as 2 sequential measurements of success Shouval D, et al. EASL Abstract 45. P <.0001 P =.045 P =.05 Entecavir Lamivudine Wk 48Wk 96Wk 48Wk 96 Percentage of Patients Cumulative Response Outcomes ALT ≤ 1 x ULN HBV DNA < 300 copies/mL

clinicaloptions.com/hep Updates in HBV Management Week 96 ETV-026: Entecavir in LAM-Refractory HBeAg(+) Patients: Week 96 Yurdaydin C, et al. EASL Abstract 80. Continue to Yr 2 † (n = 77; 96%) Continue to Yr 2 † (n = 3; 43%) *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. Week 48*Week 52: Management Decision Responders (n = 13; 9%) Entecavir (n = 145) Lamivudine (n = 141) Nonresponders (n = 40; 28%) Responders (n = 1; < 1%) Virologic-only responders (n = 7; 5%) Nonresponders (n = 121; 86%) Responders (n = 9; 12%) Virologic-only responders (n = 57; 74%) Nonresponders (n = 11; 14%) Responders (n = 0; 0%) Virologic-only responders (n = 0; 0%) Nonresponders (n = 3; 100%) Virologic-only responders (n = 80; 55%)

clinicaloptions.com/hep Updates in HBV Management 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 Yurdaydin C, et al. EASL Abstract 80. Yurdaydin C, et al. EASL Abstract 512. Outcome, Week 96 LVD, n (%) (n = 145) ETV, n (%) (n = 141) P Value Cumulative confirmed undetectable HBV DNA* (< 300 copies/mL) 1 (< 1)42 (30)<.0001 Cumulative confirmed normal ALT* (≤ 1 x ULN) 42 (29)120 (85)<.0001 HBeAg seroconversion8 (6)24 (17).0011 ALT flare † 16 (11)1(1)NA 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.

clinicaloptions.com/hep Updates in HBV Management Entecavir Treatment in Advanced Fibrosis Patients: Week 48  Entecavir randomized phase III trials: ETV-022, ETV-027, ETV-026 Simsek H, et al. EASL Abstract ETV (n = 46) Missing dataWorseningNo changeImprovement LAM (n = 47) Percentage of Patients HBeAg NegativeHBeAg Positive Nucleoside-Naive Patients With Advanced Fibrosis or Cirrhosis ETV (n = 51) LAM (n = 57) ETV (n = 23) LAM (n = 21) Percentage of Patients Lamivudine-Refractory Patients With Advanced Fibrosis or Cirrhosis 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.

clinicaloptions.com/hep Updates in HBV Management 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 > 10 5 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 Abstract 490.

Chronic Hepatitis B Treatment: Peginterferon

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

clinicaloptions.com/hep Updates in HBV Management 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 Marcellin P, et al. EASL Abstract 743. Sustained Response Outcomes at 24 Months Off-Treatment Follow-up Response Criteria Peginterferon Alfa-2a Responders, n (%) (N = 116) Biochemical response69 (59) Complete biochemical response44 (38) Partial biochemical response25 (22) Combination response (biochemical + HBV DNA levels < 100 x 10 3 copies/mL) 47 (41) HBsAg loss11 (9)* HBsAg seroconversion † 6 (5) *4 patients reverted to HBsAg positivity. † Development of anti-HBs antibody.

clinicaloptions.com/hep Updates in HBV Management 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? YES 40% (n = 69) Durability of HBeAg Seroconversion, Month 12 Posttreatment 91% 9% Percentage of Patients (n = 69) Maintained Lost Outcome at Month 12 Off Treatment? Development of HBeAg Seroconversion, Months Percentage of Patients (n = 103) HBeAg seroconversion No HBeAg seroconversion NO 60% (n = 103) Lau GK, et al. EASL Abstract 50.

Hepatitis B Treatment: Predictors of Response

clinicaloptions.com/hep Updates in HBV Management Early Virologic Suppression as a Predictor of Year 1 Response Zeuzem S, et al. EASL Abstract < log3-4 log Viral Load at Week 24 (copies/mL) Percentage of Patients HBeAg positive HBeAg negative > 4 log Proportion of Patients With Undetectable Viral Load at Week < log3-4 log> 4 log Viral Load at Week 24 (copies/mL) Proportion of Patients With Normalized ALT at Week 52 Percentage of Patients  Retrospective analysis of GLOBE trial (N = 1367) –Data from lamivudine- and telbivudine-treated patients pooled

clinicaloptions.com/hep Updates in HBV Management 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 Zeuzem S, et al. EASL Abstract 51. Outcomes at Week 52* Week 24 Viral Load, % < 300 copies/mL copies/mL ,000 copies/mL > 10,000 copies/mL Virologic breakthrough  HBeAg-positive patients  HBeAg-negative patients HBeAg seroconversion (HBeAg-positive patients) *Pooled data from telbivudine- and lamivudine-treated individuals.

Transplantation

clinicaloptions.com/hep Updates in HBV Management Adefovir in Lamivudine-Resistant Hepatitis B Transplant Patients  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% Schiff E, et al. EASL Abstract 2. Detection of HBV Markers Posttransplant MarkerHBIG, n (%) (n = 34) No HBIG, n (%) (n = 23) Serum HBV DNA > 1000 copies/mL  Confirmed  Single positive test 2 (6) 4 (12) 0 (0) 3 (13) HBsAg positive  Confirmed  First test was only positive 0 (0) 2 (6) 0 (0) 2 (9)

clinicaloptions.com/hep Updates in HBV Management  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% LAM ± HBIG for Preventing HBV Recurrence After Transplant: Year 5 Buti M, et al. EASL Abstract 129. HBIG + Lamivudine (n = 15) Lamivudine (n = 14) HBIG + Lamivudine (n = 9) Lamivudine (n = 20) No recurrence Recurrence (n = 4) HBsAg positive and HBV DNA positive

clinicaloptions.com/hep Updates in HBV Management 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 Abstract 140. Transplanted OrganAnti-HBc Positive After Transplant, n (%) Lung (n = 17)  Anti-HBs < 100 IU/L at transplant (n = 11)  Anti-HBs > 100 IU/L at transplant (n = 6) 4 (24) 3 (27) 1 (17) Kidney (n = 43)  Anti-HBs < 100 IU/L at transplant (n = 20)  Anti-HBs > 100 IU/L at transplant (n = 23) 3 (7) 2 (10) 1 (4)

HBV Vaccination

clinicaloptions.com/hep Updates in HBV Management Relationship Between HBV Vaccination and HCC Incidence  3,855,485 newborns vaccinated in Taiwan ( ) –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 Chien YC, et al. EASL Abstract 247. All Participants, n1-2 Vaccine Doses, n3 Vaccine Doses, n4 Vaccine Doses, n Girls2,009,182217,7681,061,759729,655 Boys1,846,303197,921979,213669, (n = 98) 0.74 (n = 15) 0.51 (n = 49) 0.31 (n = 34) 0.29 (n = 60) 0.43 (n = 8) 0.37 (n = 33) 0.19 (n = 19) Girls (n = 2,009,182) Boys (n = 1,846,303) HCC Incidence/ 100,000 Person-Years

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