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58th Annual Meeting of the American Association for the Study of Liver Diseases

58th Annual Meeting of the American Association for the Study of Liver Diseases. Boston, MA November 2-6, 2007. Epidemiology and Natural History of HBV Infection. Douglas Dieterich MD Mount Sinai School of Medicine New York, NY. How Old is HBV?.

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58th Annual Meeting of the American Association for the Study of Liver Diseases

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  1. 58th Annual Meeting of the American Association for the Study of Liver Diseases Boston, MA November 2-6, 2007

  2. Epidemiology and Natural History of HBV Infection Douglas Dieterich MD Mount Sinai School of Medicine New York, NY

  3. How Old is HBV? • HBV associated with humans for >1,000 years but no definitive evidence • Recent evidence establishes ≥500 years • Naturally mummified body of a Korean child found virtually intact • Laparoscopy: Large organ in RUQ and biopsies sent for pathology and HBV DNA testing • HBV DNA genotype C isolated from the liver • Pathology: Appeared to be normal liver Klein A, et al. 58th AASLD; Boston, MA; November 2-6, 2007. Poster 925.

  4. Viral Load Predicts Disease Progression:The REVEAL Study Risk Evaluation of Viremia Elevation & Associated Liver Disease Prospective, multicenter, observational cohort study 7 Taiwanese townships aged 30–65 years (n=89,293) 1991-1992 Recruitment Baseline HBsAg+ (n=9800) • 24% PCR neg • 85% HBeAg(-) • 94% ALT<45 IU/L • 98% non-cirrhotic (on Ultrasound) Baseline HBV DNA (n=3851) Follow-up analysis for cirrhosis/HCC (n=3774) June 2004: 43,993 PYs follow-up Chen CJ. JAMA. 2006;295:65-73.

  5. Effect of Chronic Elevations of HBV DNA Level on HCC Risk Impact of increasing HBV DNA levels was assessed Subset with HBV DNA ≥104 c/mL, no cirrhosis, anti-HCV negative 71 new cases of HCC (n=1,289; 15,508 PY) 69% males Risk of HCC was strongly associated with increasingHBV DNA level in a dose dependent fashion: REVEAL Study *P value for trend <0.001 Chen C, et al. 58th AASLD; Boston, MA; November 2-6, 2007. Poster 920.

  6. Changes in HBV DNA Using a Trajectory Model Increased HCC Risk Cumulative Incidence of HCC by HBV DNA Trajectory Classes 0.09 Reference Group: HBV DNA < 104 at enrollment Class I: Medium to Low Class II: Medium to Medium Class III: High to High Class IV: Persistently Very High 0.08 0.07 0.06 0.05 Cumulative Incidence of HCC 0.04 0.03 0.02 0.01 0.00 0 1 2 3 4 5 6 7 8 9 10 11 12 13 Year of Follow-up • Compared to HBsAg (-) patients: • Increasing HBV from one level to another was also a risk for HCC Chen C, et al. 58th AASLD; Boston, MA; November 2-6, 2007. Poster 906; Iloeje U, et al. Ibid. Poster 907.

  7. HBV DNA Levels Predict HCC Recurrence After RFA 66 pts with HBV and HCC were treated with RFA* Recurrence rates on follow up (mean 3.2 year): One year 30% Two year 60% Three year 74.3% Multivariate Analysis for risk of recurrence Risk FactorRisk ratio (95% CI, p value)Platelet count (<150,000/mm3) 3.74 (1.56-8.97, 0.003) HBV DNA level (≥10,000 c/mL) 2.87 (1.16-7.09, 0.023) *Radio-Frequency Ablation Goto T, et al. 58th AASLD; Boston, MA; November 2-6, 2007. Poster 917.

  8. Serial HBV Measurements Predict Disease Progression • Study from Thrace, Greece evaluated risk factors for CHB disease progression • 257 CHB pts enrolled: 14 HBeAg(+), 243 HBeAg(-) • F/U 12.5 years (mean) • Viral markers, liver biochemistry and PE every 6 mos. • Liver Bx and abdominal U/S every 2-4 years • 27% of HBeAg(-) pts intermittently had HBV DNA <104 • Serial measurements are necessary to find real HBV DNA levels • Multivariate Odds Ratio (OR) of fibrosis risk: Zacharakis G, et al. 58th AASLD; Boston, MA; November 2-6, 2007. Poster 898.

  9. Significant Liver Disease in Asymptomatic Patients 105 treatment-naïve patients with CHB HBV DNA > 105 c/ml, ALT ≤ 2x ULN x 12 mos, mean age 37 years Significant fibrosis in 60% and histology in 66% Compared to patients < 20 years of age: Conclusion: A large portion of patients with ALT< 2x ULN have significant fibrosis on liver biopsy Park JY, et al. 58th AASLD; Boston, MA; November 2-6, 2007. Poster 942.

  10. Significant Histological Findings in Patients with Normal ALT Study comparing liver histology in CHB pts with persistently normal (n=139) and abnormal (n=135) ALT Normal ALT group: 24% significant fibrosis, 9.4% cirrhosis Within normal ALT range, fibrosis rate higher in pts with higher ALT Age >40 years significant risk for fibrosis No correlation with HBeAg status or HBV DNA level P=0.029 Patient Percent Gui H, et al. 58th AASLD; Boston, MA; November 2-6, 2007. Poster 936.

  11. HBeAg Seroconversion is a Poor Clinical Endpoint 298 patients with documented HBeAg seroconversion 116 treatment-induced, 182 spontaneous Reactivation in 71 patients (39%) Older age, male gender and higher ALT at seroconversion were risks for reactivation (all p<0.006) No difference between IFN, ADV, LAM treatment Treatment induced seroconversion less durable than spontaneous Remission of ALT shorter (14 vs 22 mos., p=0.037) More likely to have HBeAg reactivation at 48 mos. (38% vs 25%, p=0.048) Lim, GL et al. 58th AASLD; Boston, MA; November 2-6, 2007. Poster 937.

  12. Longitudinal Study of HBsAg Seroclearance 298 patients with HBsAg clearance 71% male, med. age 43.1 Med. F/U 36 mos after HBsAg clearance 29 liver biopsies: 44% anti-HBs(+) 100% detectable HBV DNA 79% cccDNA 7 pts with HCC and 9 with liver decompensation ↑risk with age ≥50 at HBeAg seroconversion for HCC and significant fibrosis (p=0.001) 20 * p = 0.004 15 HBsAg seroclearance at age ≥ 50* 10 Cumulative Risk of HCC (%) 5 HBsAg seroclearance at age < 50* 0 0 12 24 26 48 60 72 84 96 108 120 Follow-up (month) Age of HBsAgseroclearance No. ofpatientsat risk <50 151 124 102 87 71 56 47 37 21 15 10 ≥50 147 120 86 63 51 46 38 31 24 18 12 Wong, D et al. 58th AASLD; Boston, MA; November 2-6, 2007. Poster 900.

  13. HBV and Gender Longitudinal study to assess gender and natural course of HBeAg(+) CHB (1977-1998) 454 males, 110 females Mean F/U 12 yrs No differences in: Hepatitis B flares Spontaneous HBeAg seroconversion ↑Risk persistent ALT elevation in males (47% vs. 15%, p<0.0001) May be cause of faster progression to cirrhosis Lin E, et al. 58th AASLD; Boston, MA; November 2-6, 2007. Poster 928.

  14. Liver Transplants for HBV Declining All LTx candidates newly registered to the Organ Procurement and Transplantation Network (UNOS) (1985-2006) Unique individual patient for primary LTx All diagnostic information used to identify patients with HBV or HCV: Diagnostic codes and written-in diagnosis Laboratory data HBsAg, HBV-DNA, anti-HCV, HCV-RNA Kim WR, et al. 58th AASLD; Boston, MA; November 2-6, 2007. Poster 12.

  15. Therapeutic Strategies for HBV Treatment Emmet Keeffe MD Stanford University School of Medicine Palo Alto, CA

  16. Effect of Lamivudine and Adefovir on Development of HCC • Evaluation of LAM and ADV effect on HCC in pts with HBV-related cirrhosis • Retrospective study: 111 pts on oral antiviral and 111 untreated pts randomly selected and matched according to age, gender, Child-Pugh class A, and HBeAg(+) LAM LAM Untreated LAM Continued (n=590) LAM switched (n=284) (n=1592) Treat (n=111) Control (n=111) Eun J, et al. 58th AASLD; Boston, MA; November 2-6, 2007. Poster 961.

  17. Baseline Characteristics Eun J, et al. 58th AASLD; Boston, MA; November 2-6, 2007. Poster 961.

  18. Cumulative Incidence of HCC 40 Log-rank, p<0.003 Control (32.4%) (n=104) Cumulative Incidence of HCC (%) 20 Treated (4.5%) (n=111) 0 0 5 10 15 20 Years Elapsed Conclusion: Oral antiviral agents, such as LAM and ADV, mayreduce the incidence of HCC in patients with HBV-related liver cirrhosis Eun J, et al. 58th AASLD; Boston, MA; November 2-6, 2007. Poster 961.

  19. Entecavir Therapy in HBeAg(+) CHB Study Design Week 48 Week 96 Week 144 Week 192 11 RespondersAt Week 48 or who became responders during Year 2 who relapsed during off-treatment follow-up R=74 R=37 ETVN=354 243 151 Virologic RespondersAt Week 96 VR=247 VR=198 21 Non-respondersAt Week 48 or who became non-responders during Year 2 NR=19 NR=8 Non-responders [NR]HBV DNA ≥0.7 MEq/mL by bDNA Responders [R]HBV DNA <0.7 MEq/mL by bDNA and HBeAg loss Virologic Responders [VR]HBV DNA <0.7 MEq/mL by bDNA and HBeAg(+) Han S, et al. 58th AASLD; Boston, MA; November 2-6, 2007. Poster 938.

  20. Baseline Characteristics ETV-022 and ETV-901 A B C D Other Nucleoside-naïve HBeAg(+) ETV 4 year Treatment Cohort HBV Genotype (%) Han S, et al. 58th AASLD; Boston, MA; November 2-6, 2007. Poster 938.

  21. Outcomes and Conclusions ETV-022 and ETV-901 • 91% nucleoside-naïve HBeAg(+) on ETV for 4 years had undetectable HBV DNA • 86% maintenance of normal ALT levels • Additional patients in year 3 and 4 had HBeAg loss and HBeAg seroconversion • Only one patient developed resistance * Denominator represent patients with available samples ** Numbers/proportions represent additional patients achieving HBeAg loss or HBeAg seroconversion during treatment in ETV-901 Han S, et al. 58th AASLD; Boston, MA; November 2-6, 2007. Poster 938.

  22. Long-term Follow-up on ETV Nonresponders Study Design Cumulative response outcomes Patients who enrolled in ETV-901 Week 48 Week 96 R R Responders 397 Responders 105 ETV Virologic Responders 225 Virologic Responders 166 VR VR NR NR Non-responders 30 Non-responders 21 Sherman M, et al. 58th AASLD; Boston, MA; November 2-6, 2007. Poster 997.

  23. Baseline Characteristics ETV-901: ETV Nonresponders A B C D Other Baseline Characteristics of All Treated Patients in ETV-022 vs. Protocol-Defined Nonresponders Who Subsequently Entered ETV-901 Sherman M, et al. 58th AASLD; Boston, MA; November 2-6, 2007. Poster 997.

  24. Long-term Outcomes ETV-901: ETV Nonresponders • Four patients experienced a virologic breakthrough; none developed ETV resistance • No patients discontinued due to adverse events Sherman M, et al. 58th AASLD; Boston, MA; November 2-6, 2007. Poster 997.

  25. Conclusions Fewer than 5% of nucleoside-naïve patients treated with ETV in studies ETV-022 and ETV-027 met protocol-defined criteria of “Non-Response” Most “non-responders” who continued to receive ETV treatment in rollover study ETV-901 achieved HBV DNA <300 copies/mL and ALT normalization 4 patients experienced virologic breakthrough during treatment in ETV-901; however, genotypic and phenotypic analysis failed to show evidence of ETV resistance Treatment compliance should be evaluated in patientswith non-response ETV-901: ETV Nonresponders Sherman M, et al. 58th AASLD; Boston, MA; November 2-6, 2007. Poster 997.

  26. Telbivudine Therapy:Baseline Variables Predict Outcomes Randomization 1:1 Telbivudine (n=680) Lamivudine (n=687) 0 52 weeks (Primary Endpoint) 104 Weeks (Final Analysis) • Entry criteria: • Nucleos(t)ide-naïve patients, aged 16-70, with HBeAg(+) (n=921) or HBeAg(-) (n=446) CHB and compensated liver disease • Serum HBV DNA >6 log10 copies/mL • Serum ALT ≥1.3-10 x ULN • Pretreatment liver biopsy consistent with CHB Zeuzem S, et al. 58th AASLD; Boston, MA; November 2-6, 2007. Poster 994.

  27. Methods Baseline variables included in the model age, body mass index (BMI), serum ALT, Ishak fibrosis score, serum HBV DNA level, Knodell histologic activity index (HAI) score, gender, and HBV genotype For analysis of on-treatment predictive factors, patients were categorized according to serum HBV DNA level at Weeks 12 and 24: PCR-negative; <3 log10 copies/mL; 3-4 log10 copies/mL, and ≥4 log10 copies/mL baseline ALT level: <2 x ULN, 2-5 x ULN, and >5 x ULN For stepwise multiple regression analyses, patients were categorized as HBV DNA PCR-negative or not PCR-negative at Weeks 12 and 24 GLOBE Substudy Zeuzem S, et al. 58th AASLD; Boston, MA; November 2-6, 2007. Poster 994.

  28. Baseline Variables and On-Treatment(Week 24) Predictors of Week 104 Outcomes GLOBE Substudy 5.66 Week 24 PCR- negative (P<0.001) 2.00 Baseline HBV DNA (P=0.015) Serum HBV DNA PCR-negative 2.00 Baseline ALT (P=0.005) 1.73 BMI (P=0.021) 2.61 Week 24 PCR-negative (P<0.001) HBeAgseroconversion 2.80 Week 24 PCR-negative (P<0.001) 9.76 24.4 Baseline ALT (P=0.001) Serum HBV DNAPCR-negative 3.79 2.69 BMI (P=0.010) Week 24 PCR-negative (P<0.001) 3.98 2.49 Week 24 PCR-negative (P=0.002) ALT normalization BMI (P<0.001) ALT normalization 3.74 1.93 Age (P=0.004) Age (P=0.013) 0.06 Week 24 PCR-negative (P<0.001) 0.16 0.10 Week 24 PCR-negative (P<0.001) Baseline Ishak fibrosis score (P=0.002) 0.40 Resistance 0.23 Resistance Age (P<0.001) BMI (P=0.039) 0.49 0.23 Gender (P=0.028) Age (P=0.047) 0 1 2 3 4 5 6 7 8 9 10 11 0 1 2 3 4 5 6 7 8 9 10 11 Odds ratio ± 95% CI HBeAg(-) HBeAg(+) Odds ratio ± 95% CI Zeuzem S, et al. 58th AASLD; Boston, MA; November 2-6, 2007. Poster 994.

  29. Week 104 Outcomes With Telbivudine: HBeAg(+) Globe Substudy Baseline ALT ≥2 x ULN, HBV DNA <9 log10 (n=80) 71% of telbivudine treated patients achieved PCR negativity at Week 24 (n=57/80) 89% PCR-negative at Week 104 (n=51/57) 1.8% Resistance at Week 104 (n=1/57) 81% ALT normalat Week 104 (n=46/57) 52% Seroconversion at Week 104 (n=25/48) Zeuzem S, et al. 58th AASLD; Boston, MA; November 2-6, 2007. Poster 994.

  30. Week 104 Outcomes With Telbivudine: HBeAg(-) Globe Substudy Baseline HBV DNA <7 log10 (n=91) 95% of telbivudine treated patients achieved PCR negativityat Week 24 (n=86/91) 91% PCR-negative at Week 104 (n=78/86) 2% Resistance at Week 104 (n=2/86) 83% ALT normal at Week 104 (n=57/69) Zeuzem S, et al. 58th AASLD; Boston, MA; November 2-6, 2007. Poster 994.

  31. Conclusions GLOBE Substudy • High rates of efficacy and low resistance occurred after 2 years telbivudine treatment in patients with: • HBeAg(+) and elevated ALT and HBV DNA <9 log10 c/mL • HBeAg(-) and <7 log10 c/mL at baseline • Optimal viral load reduction at week 24 • These parameters may contribute to on-treatment patient management strategies Zeuzem S, et al. 58th AASLD; Boston, MA; November 2-6, 2007. Poster 994.

  32. Chronic Telbivudine Therapy: Creatine Kinase Elevations and Muscle Toxicity FDA review of the telbivudine approval database for CK elevations and adverse event patterns consistent with muscle toxicity Data reviewed from trials that prospectively measured CK levels and recorded clinical adverse events, and in which LdT was used in at least one arm Time to onset and frequency of CK elevations from the pivotal phase 3 trial (52 week data) were assessed Time-to-Onset (days) of New-Onset CK Elevations (Grade 1-4) in NV-02B-007* 1.00 0.75 0.50 0.25 0 LAM Survival Distribution Function LdT 0 100 200 300 400 500 600 700 800 * Grade 1–2 CK elevations are only counted for subjects who did not have Grade 3–4 CK elevation Brown C, et al. 58th AASLD; Boston, MA; November 2-6, 2007. Poster 940.

  33. Conclusions Emerging pattern of a myopathy with chronic telbudine therapy Unknown if associated with mitochondrial toxicity Imperfect relationship between the timing and severity of CK elevations and myopathy and variable demography and symptom presentation Further characterization of toxicity, including mechanism and predisposing factors, warranted Myopathy may occur more frequently in the population treated longer-term with telbivudine LdT Myopathy Brown C, et al. 58th AASLD; Boston, MA; November 2-6, 2007. Poster 940.

  34. Model for Predicting Sustained HBeAg Loss with Peginterferon Alfa-2b 233 pts randomized to PEG-IFN α-2b 100 μg ± LAM100 mg for 52 weeks Univariate logistic regression analysis, followed by backward stepwise selection used to identify predictors of HBeAg loss at 26 weeks Model based on HBV genotype, serum HBV DNA, ALT, GGT and previous IFN therapy provided an adequate prediction of PEG-IFN induced HBeAg loss Nomogram was generated from the logistic regression formula 1 2 3 4 5 10 20 30 40 50 60 70 80 90 95 Points 0 1 2 3 4 5 6 7 8 9 10 A B C D Probability of sustained HBeAg loss: Calculated by drawing a vertical line to the top points axis through each variable. Sum points for each variable and locate on Total score axis. A vertical line is projected from Total score axis to the bottom scale to get predicted probability 1 4 ALT (x ULN)by Genotype 1 3 4 n14 HBV DNA (log) 11 10 9 8 7 6 5 GGT (x ULN) 1 2 3 5 Previous IFN Yes No Total Score 0 2 4 6 8 10 12 14 16 18 20 22 Chance HBeAg Loss (%) log it (p) – 3.3861 -42854 *(geno-B) -26463 *(geno-C) -0.4907 * (geno-D) +1.4497 *log ALT -0.8043 * previous IFN -0.3849 *log HBV DNA +1.2644 * log GGT +6.8256 *log ALT *(geno-B) +2.3102 *log ALT *(geno-C) -0.3586 –log ALT *(geno-D). Buster E, et al. 58th AASLD; Boston, MA; November 2-6, 2007. Poster 1002.

  35. Cases Demonstrating Use of Nomogram Buster E, et al. 58th AASLD; Boston, MA; November 2-6, 2007. Poster 1002.

  36. Effect of Lamivudine ± Adefovir on Esophageal Varices (EV) Open-label, prospective cohort study 123 HBeAg(-), cirrhotic pts on LAM (100 mg/d)  ADV (10 mg/d) Intensive F/U LFTs and HBV DNA every 2 mos. Drug-resistance test, AFP and US scan every 6 mos. Upper GI endoscopy at baseline and every other year for pts without EV and every year for pts with EV Multiple Endpoints Assessed Iavarone M, et al. 58th AASLD; Boston, MA; November 2-6, 2007. Poster 775.

  37. Baseline Characteristics *median (range) Iavarone M, et al. 58th AASLD; Boston, MA; November 2-6, 2007. Poster 775.

  38. EV During 76 Months of LAM±ADV Follow-up* F0 N=84 F0 N=32 Unchanged 75 (89%) Worsened 9 (11%) Improved 16 (50%) Unchanged 13 (41%) Worsened 3 (9%) Development Rate 2.0% X year Due to decompensation, HCC Progression Rate 2.0% X year Due to thrombosis, HCC *Median of 76 mos. (range 11-126 mos.) Iavarone M, et al. 58th AASLD; Boston, MA; November 2-6, 2007. Poster 775.

  39. Changes in Size of EV with LAM±ADV EV worsened in 3% with long-term HBV suppression with LAM±ADV vs. 25% with LAM+ADV after clinical resistance (p=0.0003) Overall, yearly rates of development and progression of EV were 2.0 and 2.0, respectively, both lower than expected in cohort of untreated virologic cirrhosis Regression Stable Progression (p=0.0003) 100 90 80 70 60 50 40 30 20 10 0 Response* N=81 Resistance** N=42 *HBV-DNA persistently < 3.3 log10 copies/ml on therapy with LAM or LAM+ADV for virological resistance **HBV DNA10 > 6 log and ALT > ULN, confirmed by molecular analysis. Iavarone M, et al. 58th AASLD; Boston, MA; November 2-6, 2007. Poster 775.

  40. New Therapies for HBV Treatment Mark Sulkowski MD Johns Hopkins School of Medicine Baltimore, MD

  41. Novel HBV Therapy HBV replication is closely linked to the life-time risk of disease outcomes (HCC, ESLD) New treatment paradigm = long-term suppression of HBV replication: ↓ hepatic inflammation and fibrosis ↓ risk of hepatic decompensation and/or HCC Increasing recognition of resistant HBV variants in previously treated persons Role of new anti-HBV therapies Tenofovir Clevudine α-glalactosylceramide Combination antiviral therapy

  42. Tenofovir DF is a Nucleotide Analogue Inhibitor of HBV DNA Polymerase TDF is a nucleotide analogue Inhibits HIV-1 RNA transcriptase and HBV DNA polymerase Obligate chain terminator TDF shown to have activity in patients mono-infected with HBV and co-infected with HIV/HBV TDF is approved for the treatment of HIV-1 infection 1.3 million patient years safety exposure in HIV and 6 years clinical safety data Two pivotal HBV trials

  43. Study GS-US-174-0103:TDF vs. ADV in HBeAg(+) Pts Randomized, Double-Blind, Comparison of Tenofovir vs. Adefovir for HBeAg(+) Chronic Hepatitis B Treatment naïve, HBeAg(+),18-69 years of age with compensated liver disease HBV DNA >106 c/mL and ALT ≥ 2x and < 10xULN Knodell Necroinflammatory score ≥ 3 HIV, HDV, HCV negative 5 Years Double Blind Open-label Tenofovir 300 mg (n =176) Tenofovir 300 mg RANDOMIZATION 2:1 Adefovir 10 mg (n = 90) Pre-treatment Liver Biopsy Week 48 Liver Biopsy Week 240 Liver Biopsy • Primary Endpoint of Complete Response: • HBV DNA <400 copies/mL AND Histologic improvement (at least a 2-point reduction in the Knodell necroinflammatory score without worsening in fibrosis) Heathcote J, et al. 58th AASLD; Boston, MA; November 2-6, 2007. Poster LB6.

  44. Baseline Characteristics GS-US-174-0103 Heathcote J, et al. 58th AASLD; Boston, MA; November 2-6, 2007. Poster LB6.

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