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Associate Professor of Medicine Division of Gastroenterology & Hepatology

Post Conference Update: Highlights from the American Association for the Study of Liver Diseases. PAUL KWO, MD. Associate Professor of Medicine Division of Gastroenterology & Hepatology Indiana University School of Medicine Indianapolis, IN. Faculty: Content Development and Training.

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Associate Professor of Medicine Division of Gastroenterology & Hepatology

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  1. Post Conference Update: Highlights from the American Association for the Study of Liver Diseases PAUL KWO, MD Associate Professor of Medicine Division of Gastroenterology & Hepatology Indiana University School of Medicine Indianapolis, IN

  2. Faculty:Content Development and Training Douglas T. Dieterich, MD Professor of Medicine Division of Liver Diseases Mount Sinai School of Medicine New York, New York Paul Y. Kwo, MD Associate Professor of Medicine Division of Gastroenterology Indiana University School of Medicine Indianapolis, Indiana Mark S. Sulkowski, MD Associate Professor of Medicine Johns Hopkins University School of Medicine Medical Director, Viral Hepatitis Center Johns Hopkins Medical Institution Baltimore, Maryland Tram Tran, MD Medical Director Liver Transplantation Cedars Sinai Medical Center Associate Professor University of California Los Angeles School of Medicine Los Angeles, California

  3. Learning Objectives (CME, CE, CPE) At the completion of this educational activity, participants should be able to: Discuss significant developments in the diagnosis and management of hepatitis B Summarize new drugs and treatment strategies for hepatitis B Describe recent hepatitis therapy toxicity, drug interaction and side effect data and strategies for management Identify new therapeutic strategies to avoid or overcome antiviral resistance Highlight diagnosis and management approaches for hepatitis B in individuals co-infected with HIV

  4. Wait-list Mortality Among Liver Transplant Candidates with CHB Comparison of outcomes for CHB and other liver disease etiologies on LTx wait-list (1995-2006) CHB pts (N=2,236): 36% Asian Pacific; 15% HCC Wait-list Outcomes Comparison: CHB deaths significantly higher CHB LTx rates significantly lower Post- MELD: CHB higher death and lower LTx rates persisted Conclusions: CHB pts on wait-list have worse outcomes than other liver disease etiologies Early Diagnosis and intervention for CHB are essential to improve outcomes LTx Death 1.0 Cholestatic HCV Other CHB 0.8 0.6 Probability 0.4 0.2 0.0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 Months Post-Listing Kim W, et al. 60th AASLD; Boston, MA; October 30-November 3, 2009; Abst. 3.

  5. Hepatic Steatosis Associated with Severe Fibrosis in CHB Comparison of steatosis and insulin resistance (IR) in CHB and chronic hepatitis C (CHC) and effect on fibrosis (N=340) Steatosis prevalence similar IR rate higher in CHC For CHB, severe fibrosis (F3-F4) independently associated with: Older age (OR 1.054, p=0.02) Low platelet levels (OR 0.984, p=0.003) High Υ-GT (OR 1.019, p=0.04) Steatosis >10% (OR 3.601, p=0.01) Moderate-severe necroinflammatory activity (OR 8.111, p=0.005) Conclusion: CHB has high rate of steatosis, which is associated with fibrosis Comparison of patients with CHB and CHC Variable Chronic hepatitis B (n=170) Chronic hepatitis C (n=170) P Type 2 Diabetes present (%) 3.6% 8.8% 0.04 PLT (X 103/mm) 194.7 ± 49.1 213.6 ± 62.6 0.001 Υ-GT (IU) 39.8 ± 32.9 68.5 ± 62.2 <0.001 Cholesterol (mg/dL) 190.5 ± 44.4 171.1 ± 37.8 <0.001 HOMA (score) 2.38 ± 1.81 2.78 ± 1.80 0.04 Insulin Resistance (HOMA>2.7) (%) 25.9% 42.2% 0.002 Steatosis ≥10% (%) 31.2% 38.8% 0.14 Petta S, et al. 60th AASLD; Boston, MA; October 30-November 3, 2009; Abst. 1334.

  6. Risk of Liver Disease Progression to HCC Retrospective study comparing clinical outcomes of NAFLD and CHB ± NAFLD (N=700) Mean follow-up 7.6 years No survival difference (p>0.05) CHB plus NAFLD had higher risk of progression to HCC than CHB and NAFLD alone (p=0.001) Cumulative Risk of HCC CHB + NAFLD CHB NAFLD 0.125 0.100 0.075 Cumulative Hazard of Development to HCC 0.050 0.025 0.000 0.0 0.0 4.0 6.0 8.0 10.0 12.0 14.0 Time of Follow-up (Years) Ye D, et al. 60th AASLD; Boston, MA; October 30-November 3, 2009; Abst. 976.

  7. Quality of Care of CHB in a Managed Care Setting Retrospective study using database of pts in managed care from 2001-2007 (N=250,401) Epidemiology and quality of care for CHB pts evaluated (N=1,163) Finding: Significant numbers of CHB pts did not have appropriate follow-up, screening or testing For 2006 and 2007: No primary care follow-up in 31% and 26% No gastroenterology visit in 74% and 71% Conclusion: Significant deficiencies exist in quality of care for CHB in managed care setting Lack of Screening and Testing in CHB Patients 100 90 80 80 70 63 60 Percent of Patients 46 50 40 27 30 23 20 10 0 Without Screening for HCV Without Screening for HCC Without Documented HIV Testing Without Testing for HAV Immunity Without imaging Surveillance Sy T, et al. 60th AASLD; Boston, MA; October 30-November 3, 2009; Abst. 1341.

  8. Diagnosis and Management of CHB by Primary Care Physicians Online surveys of PCPs regarding CHB in Asian-American pts (N=393) Most PCPs consider CHB serious and prevalent, but many don’t screen all Asian-American pts for CHB PCPs diagnosed over half of CHB in their practice 50% monitored without Tx; ~33% received CHB Tx ALT and HBV DNA commonly used to determine whether to Tx ~62% not familiar with current CHB Tx guidelines PCPs likely to refer CHB pts with advanced disease, worsening rapidly, or with resistance to Tx Conclusion: PCPs would benefit from more education regarding CHB and Tx guidelines PCP Beliefs and Screening 100 97 88 80 60 Percent of providers 40 32 20 0 CHB Serious in Asian-Americans CHB Prevalent in Asian-Americans CHB Screening of all Asian-Americans Upadhyaya N, et al. 60th AASLD; Boston, MA; October 30-November 3, 2009; Abst. 394.

  9. Quantitative HBs Antigen Levels in CHB HBsAg quantified in 4 infection phases in HBV mono-infected, Tx-naïve pts (N=226) HBe (+) immune tolerance (IT) HBe(+) immune clearance (IC) HBe(-) low replicative (LR) HBe(-) hepatitis (ENH) Results: HBsAg varied in different HBV phases (p<0.001) HBsAg/HBV DNA ratio highest in LR HBsAg correlated with HBV DNA in persistent HBV, not in consecutive phases HBsAg correlated with HBV DNA (R=0.74, P<0.0001) HBsAg and HBV DNA correlated with HBV GT D Acute HBV baseline HBSAg correlated with HBV DNA Conclusion: Varying levels of HBsAg may represent natural course of infection Serum HBsAg in different phases of persistent HBV 300000 250000 200000 HBsAg [IU/mL] 150000 100000 50000 0 ENH IT IC LR Jaroszewicz J, et al. 60th AASLD; Boston, MA; October 30-November 3, 2009; Abst. 1482.

  10. Long-term Serial HBV-DNA Levels after Spontaneous HBeAg Seroconversion Assessment of serial HBV DNA levels in CHB pts by ALT levels after spontaneous HBeAg seroconversion Persistently normal ALT (PNALT, N=58) Minimally elevated ALT: ≥1 ALT 1-2 x ULN (MALT, N=52) MALT had significantly higher overall HBV DNA levels than PNALT (p=0.008) These data suggest that HBV DNA level <5 log10 copies/ml and PNALT are appropriate criteria for inactive HBV HBV DNA Levels (log10 c/mL) Mean level <4 log10 in all assays <5 log10 in all assays ≥5 log10 Only 1 assay ≥ 2 assays PNALT 3.00±1.48 20.7% 72.4% 20.7% 6.9% MALT 3.50±1.47 15.4% 51.9% 19.2% 28.9% p value <0.0001 0.636 0.043 1.000 0.005 Chen Y, et al. 60th AASLD; Boston, MA; October 30-November 3, 2009; Abst. 1499.

  11. HBeAg Seroconversion During Treatment Does Not Lead to Durable Remission of CHB Evaluation of pts with HBeAg seroconversion on nucleos(t)ide analog (NA) Tx (N=48) Median follow-up: 58 months (N=44) NA Tx Used: 27 LAM, 13 ADV, 5 ETV, 2 TDF, 1 ADV + LAM 74% with HBeAg seroreversion by 3 years after HBeAg seroconversion High HBV DNA independent predictor of seroreversion (HR 1.36 per, P=0.006) Virologic recurrence occurred in 66% Associated with drug resistance in 53% Conclusions: HBeAg seroconversion not durable in a majority of cases NA should be continued indefinitely or until HBsAg seroconversion Durable Remission after HBeAg Seroconversion HBeAg negative and HBV DNA < 10,000 copies/mL Percent of Patients 35% N=42 Treatment Month Reasons for Recurrence 67% 70% Resistance Treatment Discontinuation 60% 50% Non-compliance 50% Suboptimal Suppression 40% Proportion of Patients (%) 33% 30% 20% 17% 20% 7% 7% 10% 0% 0% Virologic Recurrence Serologic and Virologic Recurrence Perquin M, et al. 60th AASLD; Boston, MA; October 30-November 3, 2009; Abst. 219.

  12. Risk of HCC in CHB Retrospective-prospective study of CHB patients +/- cirrhosis (CI) on HBV therapy > 12 months (n=956) Cumulative HCC rate: 4.8% (46/956) within 3.9 yrs Cumulative HCC rate increases with CHB disease severity, older age and male gender HR (95% CI) P Severity of liver disease CHB only Referent --- Compensated CI 2.3 (1.2-4.6) 0.016 Decompensated CI 3.7 (1.3-10.0) 0.012 Age group at treatment onset (yrs) < 50 Referent --- 50-60 7.7 (1.7-34.5) 0.007 > 60 16.7 (3.9-72.1) <0.001 Gender Male Referent --- Female 0.3 (0.1-0.8) 0.003 Papatheodoridis G, et al. 60th AASLD; Boston, MA; October 30-November 3, 2009; Abst. 137.

  13. Causes of Death with CHB in US Cohort study of HMO members with CHB (n=6,689) 48% women; 68.3% Asian-Pacific, 11.8% White Minimal Exposure to HBV antivirals HBV related deaths 10 year death rates: women < men (1.2% vs 4.8%), except within ages 20-29 Predictors of death in both sexes: age, pre-existing decompensated cirrhosis, HCC, cancer and diabetes. White and unknown race were additional predictors in men. Causes of death by age group: CHB-related deaths: 40% Age Deaths Cause of death (% within age group) HBV: HCC HBV: DCC Cancer C-V Others/unknown N N % N % N % N % N % N % 0-19 473 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 0 0.0 20-29 745 5 0.7 1 0.1 0 0.0 3 0.4 0 0.0 1 0.1 30-39 1773 30 1.7 7 0.4 3 0.2 8 0.5 3 0.2 9 0.5 40-49 2019 86 4.3 31 1.5 15 0.7 15 0.7 10 0.5 15 0.7 50-64 1338 187 14.0 70 5.2 26 1.9 40 3.0 23 1.7 28 2.1 65 and over 341 131 38.4 28 8.2 24 7.0 27 7.9 27 7.9 25 7.3 TOTAL 6689 439 6.6 137 2.1 68 1.0 93 1.4 63 0.9 78 1.2 Szpakowski J and Tucker L. 60th AASLD; Boston, MA; October 30-November 3, 2009; Abst. 79.

  14. Simulation Modeling of CHB Progression in US Markov state transition model used to assess natural Hx of CHB across lifetime of 3 cohorts: no infection, immune, and CHB (HBsAg+) No infection and immune had higher life expectancies compared to CHB In CHB: HBeAg+ had shorter projected lifespans High HBV DNA most important factor associated with decreased life expectancy Spontaneous seroconversion rates significantly affect outcomes Group Cohort Years 1 No Infection 44.60 2 Immune 44.60 3 Chronic (weighted average of 6 subgroups) 37.71 3a HBeAg positive, high viral load, normal LFTs 27.54 3b HBeAg positive, low viral load, normal LFTs 34.52 3c HBeAg negative, high viral load, normal LFTs 33.27 3d HBeAg negative, low viral load, normal LFTs 34.92 3e HBeAg positive, normal LFTs (immune tolerant) 30.67 3f HBeAg negative, normal LFTs (chronic asymptomatic) 36.82 Kaiser TE, et al. 60th AASLD; Boston, MA; October 30-November 3, 2009; Abst. 420.

  15. CHB Burden in a Median Endemic Country A model to determine potential burden of CHB in Turkey Estimated 3.5 million people (4.8%) with CHB and 775, 170 (25%) with high HBV DNA and elevated ALT levels Estimated Outcomes (%) of CHB Pts over a 20-year period: CHB Stage at Entry n Cirrhosis Decompensated Cirrhosis HCC Liver transplant Death Total 858,121 36% 9% 10% 4% 22% No cirrhosis 748,147 33% 6% 8% 3.7% 15% HBeAg(+) 356,606 15% 3% 3% 1.7% 8% HBeAg(-) 391,541 46% 9% 13% 2.2% 31% Cirrhosis 109,973 100% 26% 23% 4% 77% HBeAg(+) 18,703 100% 31% 10% 2% 76% HBeAg(-) 91,270 100% 24% 26% 2% 77% Toy M, et al. 60th AASLD; Boston, MA; October 30-November 3, 2009; Abst. 404.

  16. CHB Mortality Affectedby Treatment Long term therapy with low resistance profile drug: 88% mortality reduction (17% to 2%) for non-cirrhotics and (77% to 26%) for cirrhotics Long term therapy with high resistance (Lamivudine) profile drug: 46% mortality reduction If salvage therapy liver related deaths will be prevented by 73% Mortality of CHB patients who are non-cirrhotic at entry 50% Natural History 40% High Resistance Drug 30% Salvage Treatment Death (%) Low Resistance Drug 20% 10% 0% 2008 2013 2018 2023 2028 Year Mortality of CHB patients who are Cirrhotic at entry 100% 80% 60% Death (%) 40% 20% 0% 2008 2013 2018 2023 2028 Year Toy M, et al. 60th AASLD; Boston, MA; October 30-November 3, 2009; Abst. 404.

  17. Who Should Perform Percutaneous Liver Biopsy? Prospective comparison of liver biopsies (LBx) by radiology residents (R) at single VA center or single hepatologist (H) Methods: R: CT guided, anterior, epigastric using 16-gauge automatic needle 115 LBx, 19 (16.5%) repeat Bx H: lateral approach within the anterior to mid-clavicular lines using 14 gauge tru-cut needle 127 LBx, no repeat Bx Results: Longer specimens for H than R More portal tracts for H than R Conclusions: LBx by lateral approach preferable Training programs should have formal requirements for LBx competence Comparison of Liver Biopsies Hepatology Radiology P Mean Bx Length (mm) 1.51 +/- 0.41 0.94 +/- 0.57 <0.001 Mean Number of Portal Tracts per Bx 16.05 +/- 0.77 7.49 +/- 0.65 <0.001 # of Specimens ≥10mm 93/100 43/100 <0.001 # of Specimens ≥15mm 52/100 17/100 <0.001 # of Specimens with ≥6 Portal Tracts 99/100 52/100 <0.001 Talwani R, et al. 60th AASLD; Boston, MA; October 30-November 3, 2009; Abst. 1651.

  18. Economic Advantages of Transient Elastography In CHB Study evaluating number of HBsAg+ patients (n=98) requiring liver biopsy (LBx) using international guidelines or Chan algorithm Chan algorithm: LBx only if intermediate liver Transient elastography Results: Fewer LBx if Chan algorithm used rather than APASL guidelines (20 vs. 84) Annual cost savings from reduced liver biopsy = $83,328 LBx according to Chan algorithm LBx According To APASL Guidelines Normal ALT AGE ≥40 (64) ≤5.0kPa Reassurance n=42 >5.0-6.0kPa Observe n=9 >6.0-9.0kPa LBx n=12 >9.0-12.0kPa Consider Tx n=5 >12.0kPa Consider Tx n=4 LBx (n=84) No LBx (n=14) Elevated ALT ALT ≥ HNALT DNA ≥2000 Age <40 (20) <5.0kPa Reassurance n=6 >5.0-7.5kPa Observe n=8 >7.5-12.0kPa LBx n=8 >12.0-13.4kPa Consider Tx n=0 >13.4kPa Consider Tx n=3 Guirgis M, et al. 60th AASLD; Boston, MA; October 30-November 3, 2009; Abst. 498.

  19. Prognostic Value of Non-invasive Diagnostics for Liver Fibrosis in CHB and CHC Liver fibrosis evaluated in pts with CHB and CHC (n=200) 3 study groups: Doppler Ultrasonography (DUS), transient elastography (TE) and FibroTest (FT) Liver biopsies in all pts on day of noninvasive test All found to be accurate in diagnosing severe fibrosis (F2-F4) in pts with CHB and CHC Conclusion: DUS, TE and FT all appear to be reliable in diagnosing severe fibrosis and to have clinical utility ROC-curves of Severe (F2-F4)Liver Fibrosis Diagnostics 1 0.8 0.6 Transient Elastography AUROC=0.888 (p<0.001) Sensitivity FibroTest AUROC=0.884 (p<0.001) 0.4 DUS SAPI AUROC=0.843 (p<0.001) DUS MVPV AUROC=0.695 (p=0.001) 0.2 0 0 0.2 0.4 0.6 0.8 1 Specificity SAPI: Splenic Artery Pulsatility Index. MVPV: Mean Velocity of Portal Vein blood flow. Pavlov C, et al. 60th AASLD; Boston, MA; October 30-November 3, 2009; Abst. 1660.

  20. CHB and Risk for Pancreatic Cancer? Retrospective study of pts who had HBV testing between 1995-2008 (n=95,920) Risks for pancreatic cancer assessed according to HBV status Univariate analysis found previous HBV exposure associated with pancreatic CA (HR 2.493, p<0.001), but multivariate model (which included race, sex and age) did not: When cohort analysis is adjusted for covariates, only age and diabetes are predictors of pancreatic cancer Variable Hazard Ratio 95% CI P – Value Previous HBV Exposure 1.411 0.877-2.271 0.156 Active HBV Infection 1.075 0.149-7.764 0.943 Race (African American) 1.134 0.755-1.704 0.943 Age 1.077 1.062-1.093 <0.001 Sex (male) 1.023 0.691-1.516 0.908 HIV 1.274 0.398-4.080 0.683 Diabetes 1.884 1.268-2.800 0.002 Tang J, et al. 60th AASLD; Boston, MA; October 30-November 3, 2009; Abst. 1486.

  21. Studies GS-102 and GS-103: Safety and Tolerability of TDF in Patients with CHB Randomized, Double-Blind, Comparison of TDF vs. ADV for CHB 1 Year 2 Years 5Years 8 Years Double Blind Open-label Tenofovir 300 mg TDF 300 mg RANDOMIZATION 2:1 Adefovir 10 mg TDF 300 mg Pre-treatment Liver Biopsy Week 48 Liver Biopsy Week 144 Week 240Liver Biopsy End of Study Week 72 HBV DNA ≥400 copies/mL: Option to add FTC) to TDF in a fixed dose tablet Patients (n=) HBeAg- (GS-102) TDF → TDF (n=250) 219 ADV → TDF (n=125) 109 HBeAg+ (GS-103) TDF → TDF (n=176) 136 ADV → TDF (n=90) 76 Marcellin P, et al. 44th EASL; Copenhagen, Denmark; April 22-26, 2009; Abst. 925.

  22. Study 102 (HBeAg Negative):HBV DNA <400 Copies/mL (ITT) Open-Label Double-Blind 93% 88% 87% P<0.001 63% Patients (%) TDF to TDF ADV to TDF 0 24 48 72 96 120 144 Weeks 18% of patients were lamivudine experienced and of these 93% and 96% of TDF to TDF and ADV to TDF patients had HBV DNA <400 copies/mL at week 96. Marcellin P, et al. Hepatology. 2009;50(suppl):532A-533A. Abstract 481.

  23. Study 103 (HBeAg Positive):HBV DNA <400 Copies/mL (ITT) Open-Label Double-Blind TDF to TDF ADV to TDF 76% 72% 71% P<0.001 Patients (%) 13% 0 24 48 72 96 120 144 Weeks Heathcote EJ, et al. Hepatology. 2009;50(suppl):533A-534A. Abstract 483.

  24. Study 103: Comparison of Long-term Outcomes of TDF and ADV Arms At Year 3 of Study 103, 80% of patients remained on treatment 93% had HBV DNA <400 copies/mL (OT) 8% cumulative probability of HBsAg loss No resistance to TDF Favorable tolerability profile with no change in creatinine levels Cumulative Probability of HBsAg Loss 0.10 8% At Week 48 all patientsinitiate Open-Label TDF Cumulative Probability Function Estimate 0.05 TDF-TDF ADV-TDF 0.00 0 12 24 36 48 60 72 84 96 108 120 132 144 Weeks on Study Heathcote E, et al. 60th AASLD; Boston, MA; October 30-November 3, 2009; Abst. 483.

  25. TDF in Asian Patients: 72 Week Results Efficacy and safety of TDF among Asian patients with HBeAg- (Study 102) or HBeAg+ (Study 103) CHB evaluated at week 72 Asians comprised ~30% of all patients No differences between Asian and non-Asian patients regarding TDF antiviral efficacy, safety or tolerability HBeAg loss and seroconversion are slowly increasing over time in Asian pts Serologic Response Among Asian Patients (OT) 50 HBeAg Loss Anti-Hbe 40 28 30 Percent of Patients 22 19 18 17 17 20 10 0 Week 48 Week 96 Week 144 Lee S, et al. 60th AASLD; Boston, MA; October 30-November 3, 2009; Abst. 490.

  26. Long-term follow-up of CHB Patients Treated with TDF Mono-infected CHB Patients treated with TDF (300 mg/day) at 19 centers from 2002-2009 (n=194) Majority with previous NA Tx, mainly LAM (57%) 75% achieved HBV DNA <400 copies/mL by 1 year 92% achieved HBV DNA <400 copies/mL by 2 years Pts with slow decrease in HBV DNA often had ADV resistance Small, significant decrease in HBsAg levels No resistance to TDF Probability of Achieving HBV DNA Level <400 copies/mL 100 80 60 Patients with HBV DNA < 400 copies/mL (%) 40 20 0 0 3 6 9 12 Months of TDF Treatment De Man A, et al. 60th AASLD; Boston, MA; October 30-November 2009; Abst. 221.

  27. ETV-022: Loss of HBsAg after Treatment with ETV or LAM Evaluation of HBsAg loss by HBV genotype in study ETV-022 HBeAg(+) nucleoside-naïve adults with CHB, elevated serum ALT, and compensated liver disease Randomized to double-blind treatment for up to 96 weeks with ETV (0.5 mg/day) or LAM (100 mg/day), with up to 24 weeks of off-treatment follow-up HBsAg was measured at regular intervals during on- and off-treatment follow-up Gish R, et al. 60th AASLD; Boston, MA; October 30-November 3, 2009; Abst. 388.

  28. ETV-022: Loss of HBsAg and HBV Genotypes 18 pts treated with entecavir had HBsAg loss 8.4% and 13.5% for genotype A and D, respectively Characteristics of Patients with and without HBsAg loss Proportion of Patients with HBsAg Loss by Genotype (Week 120) Patients with HBsAg Loss N=28 Patients without HBsAg Loss N=681 ETV LVD 16 13.5% 14 Male 82% 75% 12 Asian 14% 59% 10% % with HBsAg Loss 10 8.4% Caucasian 79% 38% 8 7.1% Mean Viral Load(log10 copies/mL) 9.8 9.6 6 5.1% 4.1% Mean Knodell macroinflammatory score 9.1 7.7 4 2.9% 2.8% 1.3% 2 Median serum ALT (U/L) 163 101 0.9% 0% 0% 0% 0% 0 A B C D F Other Total Genotype Gish R, et al. 60th AASLD; Boston, MA; October 30-November 3, 2009; Abst. 388.

  29. Entecavir Use in Nucleos(t)ide-naïve CHB: Clinical Experience Safety and efficacy of ETV examined in an Italian, multicenter cohort study (n=376) Age 58 yrs; Male 75%; HBeAg(-) 83%; Cirrhotics 47% Median follow-up: 21 months Results: High Virologic response rates through week 96 High baseline HBV DNA associated with partial virologic response at week 48 (> 8 log U=27% vs. < 8 log U=6%) Progressive decline of liver stiffness (9.3 to 7.0 kPa by Fibroscan) No resistance detected ETV effective in NA-naive pts in clinical practice Undetectable HBV DNA (LLQ <12 IU/mL) with ETV 95 100 90 65 Undetectable HBV DNA 50 0 Week 24 Week 48 Week 96 Lampertico P, et al. 60th AASLD; Boston, MA; October 30-November 3, 2009; Abst. 220.

  30. Efficacy and Safety of Long-term LdT for CHB Evaluation of efficacy and safety of 4 years of continuous LdT Open-label trial enrolling patients from GLOBE Study (n=399) 213 HBeAg-positive; 186 HBeAg-negative High rates of efficacy through 4 years of therapy Early virologic response (wk24) predictive of favorable outcome Safety profile unchanged CK elevation (16%), myalgia (6%), myopathy (0.5%), myositis (0.5%) • HBV DNA undetectable • ALT Normalization • HBeAg Seroconversion Efficacy at 4 years in patients with undetectable HBV DNA at Week 24 of GLOBE study 100 92 90 88 86 80 60 51 40 20 0 HBeAg-positive patients HBeAg-negative patients Four year cumulative seroconversion rate in HBeAg-positive patients 60 51 46 50 38 40 24 30 20 10 0 Year 1 Year 2 Year 3 Year 4 Liaw Y. et al. 60th AALD; Boston, MA; October 20-November 3, 2009; Abst. 482

  31. Lactic Acidosis in CHB PatientsTreated with ETV Evaluation of 16 patients with decompensated liver cirrhosis treated with ETV 5 developed lactic acidosis (LA), between 4 and 240 days after starting ETV LA correlated with MELD score, INR, bilirubin, and creatinine (p<0.005 each) Lactic Acidosis During Treatment with Entecavir MELD score ≥22 LA N=5 No LA N=11 MELD score < 22 Lange C, et al. 60th AASLD; Boston, MA; October 30-November 3, 2009; Abst. 217.

  32. Lactic Acidosis in CHB Patients Treated with ETV: Severity of Disease and Outcomes LA reversible after ETC D/C (n=4) 1 death due to LA Conclusion: ETV should be used cautiously in CHB pts with high MELD score Characteristics of Lactic Acidosis in 5 Patients Patient A pH 7.2, lactate 50 mg/dL OLT LA Patient B pH 7.1, lactate 200 mg/dL LA Patient C pH 7.4, lactate 35 mg/DL, BE – 5 mmol/L Lamivudine LA pH 7.3, lactate 65 mg/dL Patient D Tenofovir LA Patient E pH 7.4, lactate 26 mg/Dl, BE – 5 mmol/L Tenofovir LA 0 Day of entecavir-therapy 240 Lange C, et al. 60th AASLD; Boston, MA; October 30-November 3, 2009; Abst. 217.

  33. Sustained Response in CHB Patients Treated With Peginterferon Alfa-2a Study to evaluate relationship of on treatment decline in HBsAg and sustained response rates HBeAg-negative pts received peginterferon alfa-2a (180 ug/wk) +/- LAM (100 mg/day) for 48 wks and followed for 5 years post-Tx (N=230) Analysis at 6 months and 5 yrs post-Tx: Sustained immune control (HBV DNA  10,000 copies/mL) HBsAg clearance Brunetto M, et al. 60th AASLD; Boston, MA; October 30-November 2009; Abst. 452.

  34. HBsAg and Long-term Outcomes at 5 Years Post-Treatment On Tx HBsAg decline is associated with sustained post-Tx response Highest response (sustained immune and HBsAg clearance) with continuous decline in HBsAg levels Proportion of patients in either the 6 month or 5 year analysis populations in each of the HBsAg decline groups Proportion of patients achieving HBsAg clearance 5 years post-treatment according to HBsAg decline on-treatment • 6 Months (n=155) • 5 Years (n=120) 25 60 23% 52% 51% 50 20 17% 40 15 Patients with HBsAg clearance 5 yrs post-treatment (%) 29% Patients (%) 28% 11% 30 10 16% 20 15% 5 10 5% 5% 0% 23/61 4/19 1/6 80/155 61/120 23/155 19/120 7/155 61/120 45/155 34/120 0 0 Continuous Late Decline with No Decline Continuous Late Decline with No Decline Relapse Relapse Decline Pattern Decline Pattern Brunetto M, et al. 60th AASLD; Boston, MA; October 30-November 2009; Abst. 452.

  35. Extended Treatment With PegIFN in Patients With HBeAg-Positive CHB Study evaluating whether extending peginterferon alfa-2a to 72 weeks improves HBeAg seroconversion rate in partial responders (N=31) Partial responders: no HBeAg seroconversion at week 48, but HBV DNA <10,000 copies/mL Study Design Peginterferon alfa-2a(180 µg/week; n=16) Peginterferon alfa-2a(180 µg/week; n=65) Follow-up off Tx (n=15) 0 48 72 Zhu Y, et al. 60th AASLD; Boston, MA; October 30-November 2009; Abst. 453.

  36. Extended Treatment With Peginterferon Alfa-2a in Patients With HBeAg-Positive CHB: Results Through 72 Weeks With Extension Tx: HBeAg and HBsAg levels continued to decline Partial responders achieved HBeAg clearance (38%), HBeAg seroconversion (31%) and HBsAg clearance (19%) HBsAg levels continue to decrease during peginterferon alfa-2a extension HBeAg levels continue to decrease during peginterferon alfa-2a extension 1200 300 1061 >250 >250 1000 250 229 827 Quantitative HBeAg levels (s/co) 191 800 200 Quantitative HBsAg levels (IU/mL) 176 176 173 161 144 600 150 131 100 400 310 256 248 207 185 50 200 138 105 51 0 0 Baseline Week 12 Week 24 Week 48 Week 72 Baseline Week 12 Week 24 Week 48 Week 72 Follow-up Group (N=15) Extension Group (N=16) Zhu Y, et al. 60th AASLD; Boston, MA; October 30-November 2009; Abst. 453 .

  37. Capsid Assembly Inhibitors Active Against HBV Variants Resistant to Nucleos(t)ides HBV capsid is an icosahedral complex of 120 capsid protein dimers Phenylpropenamides (AT-61 & AT-130) and heteroaryl-dehydropyrimidines (BAY-41 4109) interfere with HBV capsid assembly In vitro study using HepG2 stable cell lines expressing HBV mutants resistant to Nucleos(t)ide analogs Treated twice a week with increasing concentrations of AT-61, AT-130 and BAY-41 4109 Encapsidated DNA was quantified to determine concentration of drug that inhibits 50% of viral genome replication (IC50) Replication of WT and resistant variants was suppressed by all 3 drugs without cytotoxicity Targeting HBV nucleocapsid assembly or stability may represent a novel approach for HBV treatment Billioud G, et al. 60th AASLD; Boston, MA; October 30-November 3, 2009; Abst 393.

  38. ADV + LAM Associated with Fewer Long-term Symptoms than ADV Alone in CHB patients NIH study: randomized, controlled trial evaluating ADV + LAM (N=22) or ADV alone (n=19) Data on 8 symptoms evaluated at baseline, one and four years fatigue, nausea, poor appetite, headaches, muscle aches, itching, irritability, depression/sadness 95% of pts reported one or more symptoms at baseline Baseline demographics and clinical characteristics Variables ADV + LAM (n=22) ADV (n=19) Age (yrs) 46.7 ± 13.7 45.6 ± 13.2 Male 72.7% 94.7% Race Asian 40.9% 52.6% White 40.9% 42.1% Black 18.2% 5.3% HBeAg positive 77.3% 73.7% Responders 63.6% 31.6% ALT (U/L) 181.4 ± 250.9 88.8 ± 55.2 HBV DNA log10 c/mL 8.0 ± 1.6 7.9 ± 2.0 HAI score (0-18) 8.1 ± 2.7 7.9 ± 2.4 Cirrhosis (0-6) 5 (22.7) 2 (10.5) Martino AC, et al. 60th AASLD; Boston, MA; October 30-November 3, 2009; Abst 473.

  39. ADV + LAM vs. ADV: Fewer Long-term Symptoms with Combination Therapy and Treatment Response Symptomatic improvement was observed at 1 yr ADV alone similar to ADV + LAM except more nausea reported with ADV alone (P <.006) At year 4, significantly more symptoms in the ADV group including fatigue, nausea, poor appetite, myalgia, and mood Non-responders (n=19) had less symptomatic improvement HBV therapy was associated with improvement in symptoms ADV/LAM was more effective than ADV likely due to higher response Fatigue By Tx Arm and Response 0.2 0.15 Patient Percent LAM/ADV 0.1 ADV 0.05 0 Baseline Week 48 Week 192 0.2 0.15 Responders Patient Percent 0.1 Non-responders 0.05 0 Baseline Week 48 Week 192 Martino AC, et al. 60th AASLD; Boston, MA; October 30-November 3, 2009; Abst 473.

  40. LAM + ADV vs. ETV in Treatment-naïve, CHB Patients Retrospective evaluation of a single center experience with combination therapy vs. monotherapy in CHB pts (N=256) Tx-naïve patients treated with: LAM (100 mg/day) + ADV (10 mg/day) (N=197) ETV (0.5 mg/day) (N=59) Patients had similar baseline characteristics Baseline clinical characteristics ETV (n=59) LAM+ADV (n=197) Males 79% 78% Median age (years) 39 40 HBeAg+ 29% 35% Cirrhosis 37% 34% Duration (months) 12.3 ± 0.5 17.9 ± 1.1 HBV DNA log10 (IU/ml) 5.3 ± 0.3 4.9 ± 0.1 HBV DNA >104 IU/ml 36% 38% ALT (IU/L) 90.0 ± 13.3 88.3 ± 15.2 Platelets (x109/ml) 208 ± 5 193 ± 8 Carey I, et al. 60th AASLD; Boston, MA; October 30-November 3, 2009; Abst 417.

  41. LAM + ADV vs. ETV in Treatment-naïve, CHB Patients: Efficacy and Safety Outcomes LAM + ADV and ETV had similar proportions achieve complete response (HBV DNA < 12 IU/mL) NR rates similar in each group 1 pt in each group developed VB No viral mutations with drug resistance; including those with VB or NR Safety was similar with no difference in serum creatinine or eGFR over time Serum phosphate levels fell significantly in the LAM+ADV group but not in the ETV group Proportion of Complete Responders (HBV DNA <12 IU/mL) 100 LAM + ADV ETV 74 72 75 71 69 61 60 56 55 % of Patients 48 50 43 25 0 3 6 9 12 18 Months Carey I, et al. 60th AASLD; Boston, MA; October 30-November 3, 2009; Abst. 417.

  42. ETV + TDF for patients with CHB, Advanced Fibrosis and Multiple Previous Treatment Failures Open-label cohort from 8 European sites evaluating ETV + TDF combination therapy in CHB pts (N=39) with: Chronic HBV and advanced fibrosis HBV drug resistance (LAM and/or ADV) or partial response 3 lines of prior antiviral Tx (median) Median TDF + ETV Tx of 10.5 months (range 1-42) Patient characteristics Median Age (years) 48 Male 90% Median ALT (x ULN) 1.2 HBeAg positive 59% Median HBV DNA (log10 IU/mL) 4.2 HBV genotype (A:B:C:D:E) 2:3:3:20:2 Previous therapy ADV + LAM ADV + ETV TDF + LAM LAM ADV ETV TDF 13 5 2 1 6 7 5 Petersen J, et al. 60th AASLD; Boston, MA; October 30-November 3, 2009; Abst. 405.

  43. ETV + TDF for patients with CHB, Advanced Fibrosis and Multiple Previous Treatment Failures: Outcomes Results: Median HBV DNA decline of 3.5 log10 copies/mL (P=0.0001) 79% HBV-DNA undetectable (< 80 IU/ml) 13% HBeAg and 2% HBsAg loss No safety concerns No report of increase creatinine No clinical decompensation No Deaths Conclusion: ETV + TDF an effective rescue therapy in Tx-experienced, CHB pts 1011 1010 1009 1008 1007 1006 1005 1004 1003 1002 HBV DNA Viremia 1 4 6 6 1 Log10 copies/mL 8 5 1 8 5 3 1 1 7 6 5 4 1 LLoD 19 17 17 16 15 10 1 Baseline 3 6 9 12 15 18 Time (month) HBeAg and HBsAg Loss 13% 2% HBeAg loss HBsAg loss Petersen J, et al. 60th AASLD; Boston, MA; October 30-November 3, 2009; Abst. 405.

  44. Treatment-induced and Vaccine Escape HBV Mutants in Patients with HIV/HBV HIV-HBV patients followed prospectively for 3 years (N=308) 3 – 6 month assessments of HBV DNA and clinical outcomes Positive HBV DNA samples sequenced every 12 months 221 patients had genotypic analysis 84% had prior LAM exposure HBV DNA suppression increased as TDF use (63%) increased in the cohort (18.1%  66.6% undetectable) HBV DNA Detection and Treatment Used During Follow-up HBV DNA > 194 UI/mL (%) 3TC or FTC TDF ADV 100 90 * p<0.001 * 80 70 Percent of Patients * 60 50 40 * 30 * 20 10 0 Inclusion 12 24 36 Month Lacombe K, et al. 60th AASLD; Boston, MA; October 30-November 3, 2009; Abst. 218.

  45. Treatment-induced and Vaccine Escape HBV Mutants in Patients with HIV/HBV: Findings Analysis of S gene sequence for vaccine escape mutations at positions 120 and 145 6% at the start of the cohort 12% at end-of-follow up (2.1% per patient year) Escape variants on S gene selected by LAM (E164D and I195M) were found in 18.8% at inclusion (Incidence 1.8 100/PY) Polymerase mutations conferring LAM resistance (M204I, M180L, V173L) were >50% and remained in viremic patients 4 patients on TDF had virologic failure; no clear evidence of genotypic resistance Lacombe K, et al. 60th AASLD; Boston, MA; October 30-November 3, 2009; Abst. 218.

  46. High Rates of HBeAg Seroconversion and HBsAg Loss in HIV/HBV Patients Treated with TDF + FTC Observational cohort 107 patients with HIV/HBV 78% Males 65% HBeAg(+) HBV DNA 4.35 log10 IU/L ART included TDF (62%), FTC (30%) and/or LAM (46%) Median follow-up of 61 months: ~90% with HBV DNA <350 IU/mL 56% HBeAg seroconversion 6.6 – 7.9% HBsAg loss Rates of seroconversion and HBsAg loss higher with TDF/FTC or LAM compared to TDF alone (P>0.05) Cumulative Annual Probability 12 9.75 10 8 7.4 Patient Percent 6.2 6 4 2 0 HBeAg SC HbsAg loss HbsAg loss (HBeAg+) (HBeAg-) Kosi L, et al. 60th AASLD; Boston, MA; October 30-November 3, 2009; Abst. 391.

  47. Entecavir in Patients with HBV/HDV Co-infection 15 patients in Turkey with detectable HDV RNA and elevated ALT treated with ETV (1mg) daily x 1 year Follow-up on 12 patients (2 D/C for non-safety reasons) All patients achieved undetectable HBV DNA HDV RNA level unchanged except in 2 pts with low HDV RNA/high HBV DNA prior to treatment who achieved undetectable HDV RNA No change observed in HBsAg level ETV may be effective in a subset of patients with HBV/HDV but many do not have an HDV response 4.5 4 3.5 3 2.5 2 1.5 1 0.5 0 Viral Load (log10 copies/mL) • HDV RNA • HBV DNA Basal 6 Months 12 Months Onder F, et al. 60th AASLD; Boston, MA; October 30-November 3, 2009; Abst 913.

  48. Management of HBV Disease in Asian Patients on Disease Modifying Anti-Rheumatic Drug Disease Modifying Anti-Rheumatic Drug (DMARD) therapy in patients with rheumatoid arthritis (RA) and HBV infection may lead to liver flare No guidelines for HBV screening in this population RA cohort of Asian patients (N=505) Mean age 46.3 years 79.5% Female ~75% not screened for HBV Among those screened, 2 pts HBsAg(+) Patient Testing For HBV in Asian DMARD Patients 505 Asian Patients 424 on DMARD 103 tested for HBV During ALT Flare N=2 HBsAg(+) (2%) N=101 HBsAg(-) (98%) Bebb O, et al. 60th AASLD; Boston, MA; October 30-November 3, 2009; Abst 1353.

  49. Management of HBV Disease in Asian Patients on Disease Modifying Anti-Rheumatic Drug ALT flares common in pts on DMARD and most unrelated to HBV: Of 2 pts found to be HBsAg+ on testing during flare: Both HBeAg negative with detectable HBV DNA Treated with LAM with successful outcome Conclusion: HBV screening should be routine prior to initiating DMARD in patient with RA, particularly high risk patient groups 10% 4% 1% ALT rise on DMARD 38% 13% 24% 48% • No ALT rise • No data • ALT rise on DMARD, HBV +ve • ALT rise not on DMARD • ALT rise on DMARD, no HBV test • ALT rise on DMARD, HBV -ve Bebb O, et al. 60th AASLD; Boston, MA; October 30-November 3, 2009; Abst. 1353.

  50. HBV Disease Reactivation in Cancer Patients Receiving Chemotherapy Retrospective review of all cancer patients at Memorial Sloan-Kettering (2003- 2009) who had HBV DNA > 1000 c/mL and acute ALT or AST flare 217 patients had HBV DNA > 1000 copies/mL 21 had concomitant abrupt increase in serum ALT and/or AST Median HBV DNA 7.2 log10 c/mL Most patients had lymphoma or leukemia Immunosuppressive therapy was initiated a median of 21 days (range 5-141) prior to reactivation Malignancy in Enrolled Patients 32% 10% 58% • Lymphoma • Leukemia • Solid Tumors Mendelsohn R, et al. 60th AASLD; Boston, MA; October 30-November 3, 2009; Abst. 1328.

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