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63rd Annual Meeting of the American Association for the Study of the Liver Disease (63rd AASLD)

63rd Annual Meeting of the American Association for the Study of the Liver Disease (63rd AASLD). Boston, Massachusetts November 9-13, 2012. Epidemiology and Natural History of HBV Infection. Tram Tran, MD Cedars Sinai Medical Center Los Angeles, CA.

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63rd Annual Meeting of the American Association for the Study of the Liver Disease (63rd AASLD)

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  1. 63rd Annual Meeting of the American Association for the Study of the Liver Disease (63rd AASLD) Boston, Massachusetts November 9-13, 2012

  2. Epidemiology and Natural History of HBV Infection Tram Tran, MD Cedars Sinai Medical Center Los Angeles, CA

  3. HBV Discovered in Korean Mummy Dated to the 16th Century • Laparoscopic liver biopsies performed on mummified Korean child dated to 16 A.D. • Complete sequence of the oldest HBV isolate and the most ancient full viral genome known so far • Genome (3,215 base-pairs) analysis of the ancient HBV revealed a unique HBV genotype C2 (HBV/C2) sequence commonly spread in Southeast Asia • Comparison of the ancient genome with contemporary HBV/C2 DNA sequences from various regions in East Asia showed significant differences • Sequence likely dates back to 3,000-100,000 years ago Bar-Gal G, et al. 63rd AASLD; Boston, MA; November 9-13, 2012; Abst. 927.

  4. HBV DNA level: Most Important Predictor of HBV DNA and HBsAg Seroclearance HBV DNA Undetectable and HBsAg Loss at 1-2 Years by HBV DNA Level • Study to prospectively analyze factors for HBV DNA and HBsAg clearance in HBeAg-negative patients (N=163 pts; 2 year follow-up) • Cumulative HBsAg clearance 3% • Multivariate analysis showed HBV DNA level and APRI* score significantly associated (p<0.0001) with HBsAg clearance • Conclusion: HBV DNA level is the strongest predictor of HBV DNA and HBsAg seroclearance in HBV inactive carriers (untreated HBeAg-negative HBsAg carriers) Percent *APRI = AST-platelet ratio index Knop V, et al. 63rd AASLD; Boston, MA; November 9-13, 2012; Abst. 349.

  5. Predictors of HBsAg Seroclearance in CHB • 3, 014 patients in multicenter U.S. cohort retrospectively enrolled from 2001-2011 • HBsAg clearance in 26 patients over 11,751 person-years • 0.22% annual clearance and 0.86% overall rate • Higher annual clearance associated with male gender, HBeAg-negative and HBV DNA ≤ 10,000 IU/mL • Conclusion: HBsAg seroclearance rates may be lower than previously described, with or without treatment Annual Incidence of HBsAg Seroclearance by Various Patient Characteristics Among Treatment Naïve Patients p=0.11 Percent p=0.05 p=0.24 p=0.01 Nguyen LH, et al. 63rd AASLD; Boston, MA; November 9-13, 2012; Abst. 328.

  6. Long Term Follow-up of Inactive HBV Carriers and Relation with HBsAg Levels • HBeAg-negative, untreated, normal ALT level patients deemed “inactive carriers” with HBV DNA <2,000 IU/ml (N=170) followed for mean of 4.3 years • 1 year 13% became active 2 years 25%5 years 37% • Baseline HBV DNA <2000 IU/ml and HBsAg level <100 IU/ml predictive of remaining inactive • Conclusion: Combination of HBV DNA and HBsAg gave 100% prediction of remaining inactive carrier HBV DNA < 200 IU/ml HBsAg<1000 IU/ml HBV DNA > 200-2000 IU/ml HBsAg>1000 IU/ml P<0.001 P<0.001 Hansen BE, et al. 63rd AASLD; Boston, MA; November 9-13, 2012; Abst. 338.

  7. Lamivudine in pregnancy: Impact on HBV Flares and HBeAg Seroconversion Post Partum Maximum ALT post partum • Antiviral therapy useful in pregnant CHB patients to prevent flares and prevent mother to child transmission of HBV, but risks of therapy withdrawal unknown • 64 pregnant CHB patients recruited 2007-2011 • LAM offered 32 weeks until 2-4 weeks postpartum • Median age 29 years, f/u 11 months, baseline viral load >108 logs • 48 received LAM median treatment and 16 served as control • First 3 months postpartum 29% LAM vs. 18% control (p=NS) had flare (ALT >2XULN) • Seroconversion occurred in 5 patients • Postpartum flare not associated with seroconversion • Conclusion: Flares not higher after LAM use in pregnancy and are usually mild (3-18 months post partum) (0-3 months post partum) 1000- 900- 800- 700- 600- 500- 300 200 100 Seroconversion by Genotype Tan PK, et al. 63rd AASLD; Boston, MA; November 9-13, 2012; Abst. 335.

  8. Risk of HBV Vertical Transmission after Amniocentesis in Mothers with CHB Population Characteristics • 63 infants born to mothers who had amniocentesis compared to 198 matched controls • All infants had appropriate vaccinations • Level of maternal viremia predicts risk of transmission with amniocentesis: • No statistical difference in HBV transmission when maternal viremia <6.99 log copies/ml • Maternal viremia ≥107 log copies/ml: 50% amnio vs. 4% controls (p=0.006) • Amniocentesis performed on HBsAg-positive mothers with HBV DNA ≥ 107 log c/mL increased the risk of vertical transmission. • Conclusion: HBsAg-positive women who plan to have amniocentesis should be evaluated for the risk of vertical transmission and stratified by their HBV DNA levels Pan C, et al. 63rd AASLD; Boston, MA; November 9-13, 2012; Abst. 904.

  9. Hepatocellular carcinoma: Incidence and Risk for CHB patients on Antiviral therapy • In a large US observational cohort study, HBV antiviral therapy and HCC relationship was studied using ICD9 codes/tumor registry and chart review (2463 patients, follow-up 5 years) • 779 received antiviral therapy • 69 pts developed HCC • 27% of these received antiviral therapy • Factors associated with increased risk of HCC included no antiviral therapy, male gender, age >40 years at time of CHB diagnosis and higher comorbidity index. • Conclusion: Despite antiviral therapy, HCC can still occur, especially in an older, male CHB population Cox Multivariable Regression Model for Prediction of Hepatocellular Carcinoma Gordon SC, et al. 63rd AASLD; Boston, MA; November 9-13, 2012; Abst. 318.

  10. Hepatocellular Carcinoma: Risk Factors in CHB • 11-year retrospective analysis of 101 HCC patients and with viral suppression compared to matched cohort • 30% non-cirrhotic • Median follow-up 35 months • Multivariate analysis: age> 60, male gender, and LAM use associated with increased HCC risk • Conclusion: Association of lamivudine exposure with HCC raises the possibility of drug-induced mutations increasing HCC risk Ghaly S, et al. 63rd AASLD; Boston, MA; November 9-13, 2012; Abst. 332.

  11. Hepatocellular Carcinoma: Incidence and Risk for Patients with Family History of HCC • Study in Taiwan of 22,472 individuals with 18 year f/u and linkage to national cancer registry • 374 cases of HCC identified during 362,000 person/yrs of follow-up • Family history of HCC and HBsAg-positive had synergistic interaction with the risk of HCC in multivariable-adjusted analysis (age-sex-BMI-alcohol-smoking-ALT-DM)(HR: 32.33, 95% CI [20.8-50.3], p-value <0.01) • Conclusion: HBV patients with family history of HCC should be considered very high risk for HCC. Family History of HCC, HBsAg and HBeAg Serostatus, HBV DNA level, and Risk of Incident HCC 40.0% 19.1% 17.6% 10.3% 5.4% 2.5% 0.64% 0.62% Loomba R, et al. 63rd AASLD; Boston, MA; November 9-13, 2012; Abst. 598.

  12. Progression to Cirrhosis and Mortality with CHB Cumulative survival probability according to HBV replication during follow-up • Study examining natural history of untreated CHB patients over 25 years of follow-up • 105 untreated CHB patients enrolled • 76% male • Mean age 30 years • 64% HBeAg-positive • No evidence of cirrhosis • 43% became inactive carriers • 47% of these cleared HBsAg • 30% became HBeAg-negative • 30% developed cirrhosis (incidence rate 13/1000 person/years) • Older age, male sex, absence of sustained remission and sustained HBV replication predicted cirrhosis • Inactive Carriers and patients without cirrhosis had improved survival probability • Conclusion: In Caucasian patients with CHB without cirrhosis at presentation, progression to cirrhosis is relatively slow but cirrhosis occurrence strongly predict disease-related mortality 100% 79% Cumulative survival probability according to HBV cirrhosis occurrence 99% 79% Fattovich G, et al. 63rd AASLD; Boston, MA; November 9-13, 2012; Abst. 319.

  13. Epidemiology and Factors Related to Chronicity of Acute HBV • Study of 350 patients with acute HBV • 155 with one year f/u • Male 76%; mean age 38 years; 9 HIV+; 50% sexual risk factor • Results: • 96.7% resolution vs. 3.3% CHB • Median time from symptoms to clearance: HBeAg 23 days and HBsAg 111 days • Development of CHB following acute infection associated with lower ALT and bilirubin during acute HBV and HIV+ status at time of infection • Conclusion: HIV patients appear to evolve more frequently to CHB and lower values of biochemical markers appear related to the evolution of acute hepatitis B infection to CHB Dirchwolf M, et al. 63rd AASLD; Boston, MA; November 9-13, 2012; Abst. 320.

  14. Rheumatoid Factor in CHB Reflects Disease Activity and Stage • Study evaluating role of Rheumatoid Factor (RF) as marker of disease activity in CHB • RF available in 378 CHB pts • 53% Caucasian, 71% male, mean age 41 years • 35% had positive RF and more likely in: • Older (47 vs. 37 yrs) • Female • Lower platelet counts (183 vs. 214) • Higher AST/platelet ratio index • Increased histologic activity on biopsy • RF titers increased during flares and decreased on antiviral therapy • In CHB, RF may reflect disease activity and advanced fibrosis, and disappearance of RF correlates with virological response to therapy. R=0.94 R=0.98 RF (IU/mL) HBV DNA (Log IU/mL) Hernaez R, et al. 63rd AASLD; Boston, MA; November 9-13, 2012; Abst. 342.

  15. Performance of Transient Elastography for Staging Liver Fibrosis in CHB • Meta-analysis to assess performance of transient elastography for fibrosis in HBV patients • A total of 18 studies comprising 2,772 patients were analyzed • AUROC for diagnosis: • Significant fibrosis (F2): 0.859 (95% CI, 0.857–0.860) • Severe fibrosis (F3): 0.887 (95% CI, 0.886–0.887) • Cirrhosis (F4): 0.929 (95% CI, 0.928–0.929) • Conclusion: Transient elastography can be performed with good diagnostic accuracy for quantifying liver fibrosis in patients with CHB. Kim SU, et al. 63rd AASLD; Boston, MA; November 9-13, 2012; Abst. 1376.

  16. Staging Fibrosis in CHB Using APRI and FIB-4 • Large observational cohort study (Chronic Hepatitis B and C Cohort Study) of both treated and untreated CHB • 277 with lab and biopsy data available (1997-2010) • 64% male, 52% Asian • Median biopsy age 45 years • 25% F0, 25% F1, 21% F2, 15% F3, 14% F4 • AUC 0.84 APRI*, 0.82 FIB-4, 0.63 AST/ALT ratio • Both APRI* and FIB4 are useful markers for distinguishing severe fibrosis (F3-F4) from absent-to-moderate fibrosis (F0-F2). Mean (95% CI) APRI, FIB-4, and AST/ALT values by liver biopsy fibrosis stage *APRI = AST-platelet ratio index Lu M, et al. 63rd AASLD; Boston, MA; November 9-13, 2012; Abst. 346.

  17. Using Noninvasive Serum Markers to Predict Survival in CHB • Study of 600 patients who underwent FibroTest, APRI, biopsy, and FIB-4 on same day • Male 64%, age 42 years, 36% inactive carriers • Overall survival was very high at 5 years and predicted by liver stiffness and FibroTest: • 97.1% with liver stiffness ≤9 kPa vs. 61.5% with liver stiffness >20 kPa (p<0.01) • 96.8% with FibroTest ≤0.73 vs. 49.2% with FibroTest >0.85 (p<0.01) • Conclusion: Non-invasive diagnosis of liver fibrosis, either by liver stiffness measurement or FibroTest, can predict survival in chronic hepatitis B. ≤20kPa Liver Stiffness and FibroTest and Survival ≤0.85 >0.85 >20kPa P<0.001 P<0.001 de Ledinghen V, et al. 63rd AASLD; Boston, MA; November 9-13, 2012; Abst. 1321.

  18. Cost-Effectiveness of Universal HBV Vaccination in Adults with Diabetes Mellitus • Data show increased risk of HCC in diabetics and CDC recommends vaccinating adults with DM for HBV • Markov model of diabetic adults in US evaluated effect of HBV vaccine on morbidity and mortality • One-time HBVac program of 50,000 diabetic adults would be expected to prevent 423 cases of CHB and 4.7 cases of HCC death assuming annual progression rate of 0.33% in HBV liver disease to HCC • Model projected an estimated cost per Quality-adjusted life-year saved of $51,200 for diabetic adults who received HBVac. • Conclusion: This Markov model suggests that routine HBV vaccination in US adults with DM is cost effective and may be associated with decreased risk of HCC mortality Mortality by HBV Vaccine Status Njei B, et al. 63rd AASLD; Boston, MA; November 9-13, 2012; Abst. 343.

  19. Durability of Antibody Response Following HBV Vaccination in Healthcare Workers (HCW) • Study assessing durability of HBV vaccine in 159 Health care workers • Assessed 10-14 years (group 1), 15-19 years (group 2), and ≥20 years (group 3) after vaccination • Mean age at vaccination 31-34 years • Anti-HBs negativity was 16%, 26% and 25% among groups 1, 2 and 3, respectively. • HCWs without detectable anti-HBs were older (51 vs. 47 years; p=0.04), vaccinated at a later age (35 vs. 32 years; p=0.02) and non-smokers (92% vs. 76%; p=0.04) • Booster vaccination highly effective (94%) in HCWs with negative anti-HBs titers. • Conclusion: anti-HBs titers appear to wane over time in HCWs vaccinated as adults. Older age at vaccination was associated with negative anti-HBs titer. Efficacy of Booster HBV Vaccination Gara N, et al. 63rd AASLD; Boston, MA; November 9-13, 2012; Oral Presentation.

  20. Hepatitis B and C Association with Non-Hodgkin’s Lymphoma (NHL) Multivariate analysis results of the relationship between hepatitis status and NHL • Analysis of risk of NHL with HBV or HCV (2005-2009) • 1,055,912 patient discharges included: • HCV ICD-9: 45% • HBV ICD-9: 5% • No Hepatitis ICD-9: 50% • In multivariate analysis, hepatitis status was an independent risk factor for NHL with HBV having the largest effect size (OR=3.32, p<0.001) • Conclusion: This study confirms previous reports linking HBV and HCV and further elucidation of the mechanisms of the hepatitis and lymphoma relationship is needed Moehlen M, et al. 63rd AASLD; Boston, MA; November 9-13, 2012; Abst. 907.

  21. Pre-Immunosuppressant HBV Screening Practices • Survey distributed to 523 specialists (overall response rate was 79%): hematology (131), oncology (125), gastroenterology (102), rheumatology (68), dermatology (63), and other (34). • Physicians were predominantly women (54%) of average age 41 years, and with 14 years of professional experience. • 74% stated they were aware of recommendations for management of HBV reactivation risk • Trend stronger in gastroenterology and rheumatology (>80%) and weaker in oncology (56%), p<0.0001. • 37% never or only sometimes asked about HBV risk factors and 35% never or only sometimes requested HBsAg before starting treatment. • Conclusion: HBV screening practices vary among the medical specialties and depend on familiarity with the guidelines, particularly in high risk specialties such as oncology García-Bengoechea, M, et al. 63rd AASLD; Boston, MA; November 9-13, 2012; Abst. 915.

  22. Therapeutic Strategies for HBV Treatment S. Martin Cohen, MD Case Western Reserve University Cleveland, OH

  23. Continuing ETV with Partial Virologic Response is Beneficial Virologic Response for Patients Continued on ETV • Naïve HBV patients receiving ETV 0.5 mg daily • Partial Virologic Response (PVR) >1 log IU/ml decrease in HBV-DNA but still > 20 IU/ml at 48 weeks • Complete virologic response (CVR) < 20 IU/ml at 48 weeks • Viral Breakthrough: • Week 96: 1.6% CVR vs. 0% PVR (NS) • Week 144: 1.6% CVR vs. 5.9% PVR (p=0.092) • Cumulative Resistance: • 0% CVR vs. 5.9% PVR (p=0.067) • Conclusion: Long-term continuous ETV monotherapy in naïve patients with PVR at 48 weeks can achieve additional virologic response without significantly increasing antiviral resistance P <0.001 Kim IH, et al. 63rd AASLD; Boston, MA; November 9-13, 2012; Abst. 376.

  24. PEG-IFN Lambda for HBV is More Effective than PEG-IFN 2a • Phase 2B study of PEG-IFN Lambda vs. PEG-IFN alfa-2a n HBeAg-positive CHB patients • Baseline: IFN naïve, HBV-DNA > 105 copies/ml • 75% males, 90% Asians, 5% cirrhotics, 85% genotype B or C • 24 week interim data of planned 48 week treatment course • HBV-DNA dropped more at 12 and 24 weeks with Lambda • HBsAg dropped more with Lambda • HBeAg loss was equivalent • ALT normalized more with alfa-2a Serum HBV DNA Change From Baseline P=<0.0001 0.1203 0.0272 0.0018 -1.78 -2.28 -2.58 -2.77 Chan HLY, et al. 63rd AASLD; Boston, MA; November 9-13, 2012; Abst. LB-14.

  25. PEG-IFN Lambda has Fewer Adverse Events than PEG-IFN 2a • Adverse events • PEG-IFN alfa had more fever, headache, alopecia, myalgia, dizziness, rash, arthralgia, and dose-modifications due to hematologic AE’s • Lambda had more ALT flares • Conclusions: • PEG-Lambda had significantly better decrease in HBV-DNA at week 12, as well as better decreases in HBsAg levels • HBeAg seroconversion was equivalent between the 2 • PEG-alfa had better normalization of ALT at week 24 • PEG-Lambda had less flu-like symptoms and required less dose-modifications for hematologic side effects. Chan HLY, et al. 63rd AASLD; Boston, MA; November 9-13, 2012; Abst. LB-14.

  26. Tenofovir is Effective Salvage Therapy for NA-resistant HBV • Single center, retrospective, cohort study of TDF vs. TDF + nucleoside analog in NA-resistant CHB patients (N=148) • Study population • M204 – 62% • A181T or N236T – 2% • Viral breakthrough – 36% • 95.5% became HBV-DNA negative (mean 5.8 months) • 58 TDF monotherapy • 90 TDF + nucleoside analogue Conclusions: • TDF is effective salvage therapy for those who have failed other NA’s • No resistance was seen in this study • No advantage in adding a nucleoside analogue to TDF alone So J, et al. 63rd AASLD; Boston, MA; November 9-13, 2012; Abst. 364.

  27. PEG-IFN is Effective and Safe in Patients with HBV and Advanced Fibrosis/Compensated Cirrhosis • To evaluate efficacy and safety of PEG-IFN 2a in HBV patients with advanced fibrosis (Ishak 4-6) compared to Ishak 0-3 • PEG-2a X 48 weeks with 24 week follow-up • 13% of HBeAg+ and 21% of HBeAg- had Ishak 4-6 • For HBeAg+, the presence of advanced fibrosis had significantly better HBeAg seroconversion and DNA < 2,000, sAg loss, and ≥ 1 point decrease in Ishak fibrosis score • For HBeAg-, Overall response rates were similar • Safety • Overall no difference in med discontinuation rates • Advanced fibrosis HBeAg+ pts had more hematologic AE’s requiring dose reductions • Conclusions: • PEG-2a can be effectively and safely used in patients with compensated cirrhosis. Piratvisuth T, et al. 63rd AASLD; Boston, MA; November 9-13, 2012; Abst. 397.

  28. No Difference in Renal Toxicity with 2 years of Entecavir or Tenofovir • Single center, retrospective study of patients treated for at least 2 years with TDF, ETV, or nothing • Conclusions: • There was a slight decrease in GFR on TDF or ETV after 2 yrs (compared to controls) • There was no difference between ETV and TDF Baseline Characteristics Mean eGFR Over 24 Month Period Le ST, et al. 63rd AASLD; Boston, MA; November 9-13, 2012; Abst. 443.

  29. Long-term Entecavir Decreases Liver Stiffness Measurements • Liver stiffness measurements by transient elastography represent a non-invasive measure of liver fibrosis • 46 patients on ETV had a baseline and annual TE on Rx Conclusion: Long-term ETV improved liver stiffness beginning in year 1 and continuing through at least year 3 P=0.037 P=0.461 P=0.007 P=0.002 Papatheodoridia G, et al. 63rd AASLD; Boston, MA; November 9-13, 2012; Abst. 384.

  30. Tenofovir is Safe and Effective in Real-life Practice • 400 TDF-naïve patients treated with TDF, 2 year data • 46% were treated with TDF as 1st-line treatment • 54% were switched from another agent • 70% males, 76% white, 70% eAg-, 37% fibrosis score ≥2 • Naïve patients: 81% of HBeAg+ were HBV DNA negative, 88% for HBeAg- • Experienced: 84% of HBeAg+ were HBV DNA negative, 90% for HBeAg- • HBeAg loss and seroconversion was seen in 23% and 19% of HBeAg+ pts • HBsAg loss occurred in 5.1% of HBeAg+ and 1% of HBeAg- Petersen J, et al. 63rd AASLD; Boston, MA; November 9-13, 2012; Abst. 413.

  31. Tenofovir is Safe and Effective in Real-life Practice • No significant issues were seen at 96 weeks regarding phosphorus levels or CrCl • Conclusions: • TDF suppressed HBV DNA through 2 years in the majority of patients regardless of pre-treatment status • HBeAg loss/seroconversion was seen in 23%/19% of HBeAg+ patients • 5.1% of HBeAg+ patients lost HBsAg • Safety (including renal) was favorable in this real-life study Petersen J, et al. 63rd AASLD; Boston, MA; November 9-13, 2012; Abst. 413.

  32. HBIG-free Post-liver Transplant Regimen Using Oral Antiviral Therapy Alone Effectively Suppresses HBV-DNA • Retrospective review of 363 HBV OLT patients in Hong Kong • Non-randomized study • LAM (176), ETV (142), or LAM + ADV (44) • Mean follow-up 53 months Long Term HBsAg Seronegativity & HBV DNA Undetectability Pre-OLT Characteristics • 98% HBV DNA negative at 8 years • 88% HBsAg negative at 8 years Fung J, et al. 63rd AASLD; Boston, MA; November 9-13, 2012; Abst. 12.

  33. LAM Alone Without HBIG Should Probably be Avoided as Post-OLT HBV Treatment • Overall 8 year survival was 83%,with no difference between the 3 treatment groups (p=0.98) Conclusions: • Oral NA’s after OLT are associated with excellent HBV suppression and long-term survival • Agents with less resistance potential should be used to prevent development of virological rebound Virological Rebound (≥1 log IU/mL Increase) 42 Patients with VR Lamivudine Virologic rebound was significantly higher in the LAM group (36 total of which 25 had YMDD) The RR for viral rebound was 15.21 for the LAM group 17% Cumulative Rate of Virological Rebound Combination 9% P<0.001 7% 5% Entecavir 0% 0% Fung J, et al. 63rd AASLD; Boston, MA; November 9-13, 2012; Abst. 12.

  34. Adding PEG-IFN Alfa-2a to ETV Increases HBsAg Decline and HBeAg Clearance • PEG-IFN alfa-2a add-on strategy at weeks 24-48 to ETV in HBeAg+ pts • 48 weeks ETV (n=83) vs. 24 wks ETV + 24 wks ETV + PEG-IFN (n=77) • PEG-IFN 2a add-on group had significantly better HBV-DNA, HBeAg, and HBsAg responses • HBeAg loss at 48 weeks was 18% vs. 8% • 2 PEG add-on patients had grade 4 neutropenia • Conclusions: • Adding PEG-IFN 2a to ETV improves HBV-DNA, HBeAg, and HBsAg responses • PEG was reasonably well-tolerated • This might allow a more finite course of NA therapy for chronic HBV. ETV ETV ETV P<0.001 P<0.001 P<0.001 ETV+Peg-IFN ETV+Peg-IFN ETV+Peg-IFN HBV DNA HBeAg HBsAg 24 Sonneveld M, et al. 63rd AASLD; Boston, MA; November 9-13, 2012; Abst. 19.

  35. Sequential Therapy of ETV Followed by PEG-IFN 2a Showed No Difference vs. ETV Alone • HBeAg+ patients (n=146) received PEG-IFN for 48 weeks (conventional arm, n=74) or ETV for 12 weeks with a 48-week course of PEG-IFN starting at week 5 (sequential arm, n=74) • No differences of HBeAg seroclearance, normalization of aminotransferase, or HBV-DNA levels at EOT (6 month post-treatment data not yet available) Conclusion: PEG-IFN add-on to ETV therapy did not provide EOT benefit regarding HBV-DNA, eAg, or sAg levels Biochemical and Virological Response at 48 Weeks P=0.215 P=0.174 P=0.99 Jun DW, et al. 63rd AASLD; Boston, MA; November 9-13, 2012; Abst. 377.

  36. 5 Year ETV Effectively Suppresses HBV-DNA in Naïve HBV Patients • 418 consecutive naïve patients treated with ETV 0.5 mg for 52 months • Mean age 58 years; 76% males, 83% HBeAg-negative, HBV DNA 6.0 log IU/ml, 85% with elevated ALT, 49% cirrhotics Rate of Viral Suppression through 5 years was 100% in HBeAg-positive and negative Virological response by HBeAg Status (Undetectable HBV DNA) Lampertico P, et al. 63rd AASLD; Boston, MA; November 9-13, 2012; Abst. 366.

  37. HBsAg Loss Occurred in 33% of HBeAg+ Pts Treated With 5 Years of ETV HBsAg Loss in HBeAg-positive Patients • HCC developed at an yearly rate of 2.5% despite good viral suppression Conclusions: • Long-term ETV monotherapy efficiently suppressed HBV replication in naïve HBV patients • High rates of HBsAg loss can also be seen with this therapy 33% Months Lampertico P, et al. 63rd AASLD; Boston, MA; November 9-13, 2012; Abst. 366.

  38. Long-term De Novo LAM and ADV Combination Long-term Treatment is Effective • Retrospective study of naïve patients with CHB • HBeAg-positive (N=54), CHB-related cirrhosis (N=67) • 5 year data • No resistance was seen • No safety issues were reported Conclusion: De novo combination long-term therapy of LAM and ADV has a high virological and biochemical response rate without drug resistance emergence. Zhu B, et al. 63rd AASLD; Boston, MA; November 9-13, 2012; Abst. 437.

  39. Quantitative HBsAg Levels May be an Effective Indicator for Cessation of HBV Therapy • The usefulness of quantitative HBsAg (qHBsAg) level as an indicator for cessation of antiviral therapy. • 97 patients (with qHBsAg levels available) who had stopped HBV therapy  • 47 relapsed, 50 non-relapsers • Only significant variable predicting relapse was qHBsAg levels • qHBsAg < 567 IU/ml at treatment cessation had an 81% sensitivity and 70% specificity of predicting no relapse Conclusion: qHBsAg level might be a useful indicator of predicting relapse, and thus could provide a guide to determining if/when HBV therapy can be stopped. Patients with CHB who have stopped antivirals with measurement of qHBsAg level at the time of cessation from January 2008 to December 2011 (n = 306) Exclusion (n = 209) F/U loss or F/U < 6month Stopped NAs arbitrarily (HBV DNA (+) or abnormal ALT at the time of cessation) Acute hepatitis Patients with liver cirrhosis Patients with other comorbid medical conditions Analyzed (n = 97) Relapse:HBV DNA > 100IU.mL Non-Relapser (n = 50) Relapser (n = 47) Park UG, et al. 63rd AASLD; Boston, MA; November 9-13, 2012; Abst. 353.

  40. Viral Resistance Issues Kris Kowdley, MD Virginia Mason Medical Center Seattle, WA

  41. TDF/FTC vs. TDF Monotherapy for CHB Patients with LAM-R • Randomized, double-blind, phase IIIb trial • Chronic HBV with documented LAM-R (INNO-LiPA HBV) • N= 280 patients Dosing x 96 weeks TDF 300 mg once daily (N=141) Randomization 1:1 Further anti-HBV therapy at discretion of investigator – up to 24 weeks follow-up TDF 300 mg + FTC 200 mg once daily (N=139) Baseline Week 96 Primary Endpoint Fung S, et al. 63rd AASLD; Boston, MA; November 9-31, 2012; Abst. 20.

  42. Baseline Characteristics Fung S, et al. 63rd AASLD; Boston, MA; November 9-31, 2012; Abst. 20

  43. Results at Week 96:Primary Endpoint: HBV DNA <69 IU/mL Fung S, et al. 63rd AASLD; Boston, MA; November 9-31, 2012; Abst. 20

  44. TDF vs. FTC/TDF Conclusions • Nearly 90% of subjects with documented LAM-R achieved suppression to HBV DNA <400 cp/mL at week 96 with both TDF and FTC/TDF • No significant differences in efficacy were observed between monotherapy and combination therapy regimens • No detectable TDF resistance was observed with TDF or FTC/TDF through 96 weeks • TDF demonstrated favorable safety and tolerability with a low rate of renal events and no evidence of clinically relevant bone loss Fung S, et al. 63rd AASLD; Boston, MA; November 9-31, 2012; Abst. 20

  45. TDF vs. FTC/TDF Resistance • Analysis of amino acid changes within HBV polymerase /reverse transcriptase (pol/RT) after 96 weeks of TDF or FTC/TDF in 280 subjects with LAM-R mutations • Viremia at Week 96: • TDF arm = 7/133 subjects (5.3%) – 6 without virologic breakthrough • 2 had reversions toward consensus (rtM180L/M, rtV204M/V, rtI204M) or changes (rtV173L/V) at conserved sites • 2 had unique polymorphic site changes • 1 had no change • 2 had no genotype • FTC/TDF = 8/132 subjects (6.1%) – 4 without virologic breakthrough • 1 had unique polymorphic site change • 1 had no change • 1 was unable to genotype • 12/15 viremic subjects had genotype data at week 96 • 10/12 maintained baseline LAM-R mutations • Conclusions: no virologic resistance to TDF identified through 96 weeks in patients with LAM-R at baseline Croso AC, et al. 63rd AASLD; Boston, MA; November 9-31, 2012; Abst. 389

  46. DEFINE Trial: ETV/ADV vs. LAM/ADV vs. ETV for LAM-R HBeAg+ CHB • Randomized, open-label, comparative phase IIIb trial • Chronic HBV with documented LAM-R (rtM204V/I/S by INNO-Lipa) • N= 415 patients Dosing x 96 weeks ETV (1.0 mg) + ADV (10 mg) QD (N=138) Randomization 1:1:1 LAM (100 mg) + ADV (10 mg) QD (N=137) ETV (1.0 mg) QD (N=139) Baseline Week 96 Primary Endpoint Heo J, et al. 63rd AASLD; Boston, MA; November 9-31, 2012; Abst. 407.

  47. Baseline Characteristics Heo J, et al. 63rd AASLD; Boston, MA; November 9-31, 2012; Abst. 407.

  48. Results at Week 96:Primary Endpoint: HBV DNA <50 IU/mL Heo J, et al. 63rd AASLD; Boston, MA; November 9-31, 2012; Abst. 407.

  49. DEFINE Trial: Conclusions • Although the efficacy of ETV+ADV was comparable to that of LAM+ADV and ETV monotherapy at week 48, ETV+ADV was superior to LAM+ADV at week 96 • ALT normalization rates were comparable across all 3 treatment groups • Serologic responses were low with all 3 treatments, similar to previous reports with LAM+ADV or ETV in LAM-R CHB patients • Treatment with either ETV+ADV or LAM+ADV was associated with low rates of resistance development • Overall, ETV+ADV was well-tolerated and more effective than LAM+ADV for the treatment of LAM-R CHB over 96 weeks of treatment Heo J, et al. 63rd AASLD; Boston, MA; November 9-31, 2012; Abst. 407.

  50. Korean Study: ETV/ADV vs. ETV for ADV-refractory LAM-R CHB • Retrospective analysis of long-term efficacy of ETV/ADV or ETV at weeks 48 and 96 at one university liver center in Korea • Chronic HBV with documented LAM-R (rtM204V/I/S by INNO-Lipa) • N= 91 patients Dosing x 48-96 weeks ETV (1.0 mg) QD (N=46) Retrospective Observational ETV (1.0 mg) + ADV (10 mg) QD (N=45) Week 96 Baseline Kim IH, et al. 63rd AASLD; Boston, MA; November 9-31, 2012; Abst. 405.

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