1. Sunday, November 1, 2009 Back Bay Ballroom Sheraton Boston Hotel Boston, Massachusetts Beyond the Tip of the Iceberg: Strategies to Ensure Optimal HBV Screening, Diagnosis, and Initial Therapy This program is supported by an educational grant from

2. clinicaloptions.com/hepatitis Beyond the Tip of the Iceberg Program Faculty Chair Norah Terrault, MD, MPH Associate Professor of Medicine Director, Viral Hepatitis Center Department of Medicine, Division of Gastroenterology University of California, San Francisco San Francisco, California Faculty Jules L. Dienstag, MD Carl W. Walter Professor of Medicine Dean for Medical Education Harvard Medical School Physician, Gastrointestinal Unit Massachusetts General Hospital Boston, Massachusetts Faculty W. Ray Kim, MD Associate Professor of Medicine Division of Gastroenterology and Hepatology Mayo Clinic Rochester, Minnesota Albert D. Min, MD Director of Hepatitis Research Professor of Clinical Medicine Division of Digestive Diseases Beth Israel Medical Center New York, New York

3. clinicaloptions.com/hepatitis Beyond the Tip of the Iceberg About These Slides  Our thanks to the presenters who gave permission to include their original data  Users are encouraged to use these slides in their own noncommercial 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 Users are asked to honor this intent  These slides may not be published or posted online without permission from Clinical Care Options Disclaimer The materials published on the Clinical Care Options Web site reflect the views of the authors of the CCO material, 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.

4. clinicaloptions.com/hepatitis Beyond the Tip of the Iceberg Burden of Chronic HBV Disease  ~ 400 million people worldwide living with chronic HBV infection [1] –Yearly, ~ 500,000 people die of HBV-related cirrhosis and HCC –> 1 million US residents have chronic HBV infection –Up to two thirds are unaware of their infection [2] –Less than one half of patients with known HBV infection referred to specialist for evaluation [3]  To reduce disease complications, need to –Identify infected individuals –Assess disease status and need for treatment and other monitoring –Optimize treatment outcomes: issues of who, when, and how to treat 1. Sorrell MF, et al. Ann Intern Med. 2009;150:104-110. 2. Lin SY, et al. Hepatology. 2007;46:1034-1040. 3. CDC. MMWR. 2007;56:446-448.

5. W. Ray Kim, MD Associate Professor of Medicine Division of Gastroenterology and Hepatology Mayo Clinic Rochester, Minnesota HBV Screening and Diagnosis: Are Current Practices Effective at Identifying Patients at Risk and Evaluating Patients for HBV Treatment?

6. clinicaloptions.com/hepatitis Beyond the Tip of the Iceberg 2008 CDC Guidelines for HBV Screening: New Recommendations  Persons born in countries with ≥ 2% HBsAg prevalence  US-born persons not vaccinated as infants whose parents were born in regions with high HBV endemicity (≥ 8% HBsAg prevalence)  Persons with behavioral exposures to HBV –Injection drug users, MSM  Persons needing immunosuppressive therapy –Chemotherapy, organ transplantation, immunosuppression for rheumatologic or gastroenterologic disorders  Persons with elevated ALT/AST of unknown etiology Weinbaum CM, et al. MMWR Recomm Rep. 2008;57(RR-8);1-20. http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5708a1.htm http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5708a1.htm

7. clinicaloptions.com/hepatitis Beyond the Tip of the Iceberg Global Distribution of HBV Centers for Disease Control and Prevention. CDC Health Information for International Travel 2010. Prevalence of HBsAg High ≥ 8% Intermediate 2% to 7% Low < 2%

8. clinicaloptions.com/hepatitis Beyond the Tip of the Iceberg New HBV Cases Diagnosed in Olmsted County, Minnesota: 1994-2000 Kim WR, et al. Hepatology. 2004;39:811-816. Foreign Born (%) 100 80 60 40 20 0 WhiteAfricanAsianOther/ Unknown 15 91 99 100 n = 25 n = 55 n = 102 n = 9

9. clinicaloptions.com/hepatitis Beyond the Tip of the Iceberg Noninvasive Assessment of Fibrosis  No large-scale validation specific to hepatitis B patients  Elastography data (n = 173) –Liver stiffness measure able to detect significant cirrhosis and fibrosis –Correlation with METAVIR and Ishak scoring systems demonstrated (P <.001) –Optimal cutoff for cirrhosis: 11.0 kPa –Sensitivity: 93% – Specificity: 87% Marcellin P, et al. Liver Int. 2009;29:242-247.

10. clinicaloptions.com/hepatitis Beyond the Tip of the Iceberg Liver Stiffness in Acute Hepatitis  Acute hepatitis without obvious evidence of chronic liver disease – 18 total patients; 8 with HBV infection Arena U, et al. Hepatology. 2008;47:380-384. Cutoff for prediction of cirrhosis 0 1000 2000 3000 4000 5000 6000 ALT (U/L) OnsetRecovery 0 5 10 15 20 25 35 Liver Stiffness (kPa) OnsetRecovery 30

11. clinicaloptions.com/hepatitis Beyond the Tip of the Iceberg Serum Markers of Fibrosis in Hepatitis B  FibroTest [1]  APRI vs LSM [2] AUROC: FibroTest = 0.78 LSM = 0.84APRI = 0.78 1. Reprinted from J Hepatol, 39, Myers RP et al, Prediction of liver histological lesions with biochemical markers in patients with chronic hepatitis B, 222-230, Copyright 2003, with permission from Elsevier. 2. Kim SU, et al. J Clin Gastroenterol. Liver Stiffness Measurement in Combination With Noninvasive Markers for the Improved Diagnosis of B-viral Liver Cirrhosis.2009;43(3):267-271. Reproduced with permission. LSM APRI 0.0 0.2 0.4 0.6 0.8 1.0 FibroTest Fibrosis Stage Donors01234 0.0 0.2 0.4 0.6 0.8 1.0 Sensitivity 0.00.20.40.60.81.0 1-Specificity LSM AAR API APRI

12. clinicaloptions.com/hepatitis Beyond the Tip of the Iceberg HCC Surveillance: AASLD Practice Guideline Recommendations  Hepatitis B –Cirrhosis regardless of age –Asian males 40 yrs of age or older –Asian females 50 yrs of age or older –HCC in first-degree relative (start before 40 yrs of age) –African older than 20 yrs of age  Cirrhosis from other causes Bruix J, et al. Hepatology. 2005;42:1208-1236.

13. clinicaloptions.com/hepatitis Beyond the Tip of the Iceberg Risk of HCC According to Baseline Factors  REVEAL: long-term follow-up (mean, 11.4 yrs) of untreated HBsAg positive individuals in Taiwan (N = 3653) HBV DNA (copies/mL) HCC (% per Yr) Chen CJ, et al. JAMA. 2006;295:65-73. < 300 300-9999 10,000-99,999 100,000-999,999 ≥ 1 million 1.4 1.2 1.0 0.8 0.6 0.4 0.2 0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0 No cirrhosis Cirrhosis

14. clinicaloptions.com/hepatitis Beyond the Tip of the Iceberg Surveillance Interval  Optimal interval not known  Randomized trial: decreased mortality based on 6-mo surveillance intervals (vs no screening) [1]  Retrospective data: equivalence between 6- and 12-mo intervals [2] Absolute risk of HCC Whether to perform surveillance Rate of tumor growth Surveillance interval 1. Zhang GH, et al. J Cancer Res Clin Oncol. 2004;130:417-422. 2. Trevisani F, et al. Am J Gastroenterol. 2002;97:734-744.

15. clinicaloptions.com/hepatitis Beyond the Tip of the Iceberg Take Home Points  HBV screening in the target population highly justified –Data indicate correlation between HBV DNA and long-term outcome –Antiviral therapy able to alter natural history  Target population –Patients from areas with projected prevalence 2% or higher including unvaccinated US born children of immigrants from endemic areas  Other groups –Immunosuppressive therapy –Abnormal aminotransferases

16. clinicaloptions.com/hepatitis Beyond the Tip of the Iceberg  Emerging data on noninvasive markers of fibrosis in HBV –LSM probably more accurate than existing serum panel –Acute flare may lead to false elevations of LSM  Cirrhosis is by far the largest risk factor for HCC  Correlation between HBV DNA and HCC risk well known –Uncertain how that info is incorporated into surveillance strategy Take Home Points (cont’d)

17. Albert D. Min, MD Director of Hepatitis Research Professor of Clinical Medicine Division of Digestive Diseases Beth Israel Medical Center New York, New York After Diagnosis: Given the Benefits of HBV Treatment, Why Do So Few Patients Initiate Therapy When Indicated?

18. clinicaloptions.com/hepatitis Beyond the Tip of the Iceberg Liver Society Guidelines* HBeAg PositiveHBeAg Negative HBV DNA, IU/mL ALTHBV DNA, IU/mL ALT EASL 2009 [1] > 2000> ULN † > 2000> ULN † APASL 2008 [2] ≥ 20,000> 2 x ULN † ≥ 2000> 2 x ULN † AASLD 2009 [3] > 20,000 > 2 x ULN ‡ or (+) biopsy ≥ 20,000** ≥ 2 x ULN ‡ or (+) biopsy 1. EASL. J Hepatol. 2009;50:227-242. 2. Liaw YF, et al. Hepatol Int. 2008;3:263-283. 3. Lok ASF, McMahon BJ. Hepatology. 2009;50:661-662. Treatment Criteria for Chronic Hepatitis B  Recommended HBV DNA and ALT levels outlined in the following table *Although ALT and HBV DNA are primary tests used to determine treatment candidacy, the levels of elevation that warrant consideration of treatment are not universally agreed upon. † Laboratory normal. ‡ 30 U/L for men and 19 U/L for women. **In patients older than 40 yrs of age, 2000 IU/mL should be considered as a cutoff for treatment.

19. clinicaloptions.com/hepatitis Beyond the Tip of the Iceberg What Is a “Normal” ALT Level?  9221 first-time potential blood donors  74% suitable donors after exclusion of anemia, seizure, sexual, and other risk –57% determined to be at “low risk” for liver disease –Negative viral serology –BMI < 25 –Normal serum cholesterol, triglycerides, and glucose levels –Absence of concurrent medication use  Updated healthy ALT ranges determined from the group of low-risk individuals –Males: 30 IU/L –Females: 19 IU/L Prati D, et al. Ann Intern Med. 2002;137:1-10.

20. clinicaloptions.com/hepatitis Beyond the Tip of the Iceberg  1387 asymptomatic HBsAg-positive patients with ≥ 1-yr follow-up –189 with persistently normal ALT (PNALT)* included in analysis (HBeAg negative: 116 /189, 61%)  21% of HBeAg-negative patients with PNALT and HBV DNA < 5 log copies/mL had HAI ≥ 3 and/or fibrosis stage ≥ 2 Kumar M, et al. Gastroenterology. 2008;134:1376-1384. *≥ 3 ALT values in the previous 1 yr prior to baseline liver biopsy that were all ≤ 40 IU/L and remained so until the start of treatment or the last follow-up. 60.3 39.7 35.3 13.8 0 20 40 60 80 100 HBV DNA ≥ 5 log copies/mLHistologic Fibrosis Stage ≥ 2 HBeAg positive HBeAg negative Patients (%) Patients With Normal ALT May Have Significant Fibrosis

21. clinicaloptions.com/hepatitis Beyond the Tip of the Iceberg Favorable Short-term Outcomes in Patients With High HBV DNA, Normal ALT  240 HBeAg-positive individuals (male 130, female 110); mean age: 27.6 yrs  Mean follow-up: 10.5 yrs (range: 3-20)  Spontaneous HBeAg seroconversion in 85% between the ages of 20 and 39 yrs  Reactivation of hepatitis after HBeAg seroconversion in 2.2% per yr  Progression to cirrhosis in 5.4% after 10 yrs  HCC: none Chu CM, et al. Am J Med. 2004;116:829-834.

22. clinicaloptions.com/hepatitis Beyond the Tip of the Iceberg Cumulative Risk of Liver-Related Complications in Chronic Hepatitis B  Long-term follow-up of 3233 patients with chronic hepatitis B in Hong Kong –Risk of developing ascites, SBP, esophageal varices, encephalopathy, or HCC determined –Reference group: ALT < 0.5 x ULN  Persons with ALT 0.5-1.0 x ULN and 1.0-2.0 x ULN had an increased risk of developing liver disease complications (P <.0001 vs reference group) Yuen M-F et al. Gut. 2005;54:1610-1614.

23. clinicaloptions.com/hepatitis Beyond the Tip of the Iceberg HBeAg-Negative DiseaseInactive Carrier HBsAg positive Anti-HBe positive Anti-HBc positive HBV DNA> 2000 IU/mL*< 2000 IU/mL ALTElevated † Normal *Fluctuations to < 2000 IU/mL can occur. † May be elevated either persistently or intermittently. Keeffe EB, et al. Clin Gastroenterol Hepatol. 2008;6:1315-1341. HBeAg-Negative Chronic HBV vs Inactive Carrier State

24. clinicaloptions.com/hepatitis Beyond the Tip of the Iceberg Hadziyannis SJ, et al. Semin Liver Dis. 2006;26:130-141. HBeAg-Negative Patients Require Frequent Monitoring Mos 500 300 200 100 0 0612183336 ALT (U/L) HBV DNA (copies/mL) 400 50 x 10 6 30 x 10 6 20 x 10 6 10 x 10 6 0 40 x 10 6 212427301593 ALT HBV DNA

25. clinicaloptions.com/hepatitis Beyond the Tip of the Iceberg Hui CK, et al. Hepatology. 2007;46:395-401. Fibrosis Stage Disease Progression Minimal During Immune-Tolerant Phase  57 patients with high HBV DNA levels in immune-tolerant phase –48 remained in immune tolerant phase at 5-year follow-up Follow-up Liver Biopsy 100 60 40 20 0 80 Initial Liver Biopsy Fibrosis Stage on Initial and Follow-up Liver Biopsy, % P =.58 02 F2 F1 F0 6965 3133

26. clinicaloptions.com/hepatitis Beyond the Tip of the Iceberg Chen CJ, et al. JAMA. 2006;295:65-73. *Cox proportional hazards models. Risk is relative to < 10 4 copies/mL at entry/not tested at follow-up. Data adjusted for sex, age, cigarette smoking, and alcohol consumption. HBV DNA (copies/mL) Adjusted Hazard Ratio* for HCC Low < 10 4 Mid 10 4 - 10 5 High ≥ 10 5 DNA at entry: DNA at follow-up: 10.1 7.3 3.8 0 4 8 12 16 n =146120537 Persistently Elevated HBV DNA Associated With Increased HCC Risk

27. clinicaloptions.com/hepatitis Beyond the Tip of the Iceberg Take Home Points  ALT is an imperfect measure of liver histology –“Normal” levels should be lower than the current reference range  HBeAg-negative CHB patients require frequent monitoring –Severity of liver disease may not be evident from occasional testing  Short-term outcome is favorable in CHB patients in immune-tolerant phase  Active viral replication in CHB patients is associated with long-term risk of cirrhosis and HCC

28. Norah Terrault, MD, MPH Associate Professor of Medicine Director, Viral Hepatitis Center Department of Medicine, Division of Gastroenterology University of California, San Francisco San Francisco, California Current Options for First-line HBV Treatment

29. clinicaloptions.com/hepatitis Beyond the Tip of the Iceberg Goals of Hepatitis B Treatment  Prevention of long-term negative clinical outcomes (eg, cirrhosis, HCC, death) by durable suppression of HBV DNA  Primary treatment endpoint –Sustained decrease in serum HBV DNA level to low or undetectable  Secondary treatment endpoints –Decrease or normalize serum ALT –Improve liver histology –Induce HBeAg loss or seroconversion –Induce HBsAg loss or seroconversion

30. clinicaloptions.com/hepatitis Beyond the Tip of the Iceberg Interferon alfa-2b Lamivudine Adefovir Peginterferon alfa-2a Telbivudine Tenofovir 199019982002200520062008 Entecavir HBV Treatment Landscape in 2009

31. clinicaloptions.com/hepatitis Beyond the Tip of the Iceberg Factors Driving Selection of Initial Therapy Nucleos(t)ide AnaloguesPeginterferon Safety & tolerability Efficacy (potency) Barrier to resistance (durability) Safety & tolerability

32. clinicaloptions.com/hepatitis Beyond the Tip of the Iceberg Undetectable* HBV DNA in HBV Patients After 1 Year of Treatment *By PCR-based assay (LLD ~ 50 IU/mL) except for some LAM studies. Lok AS, et al. Hepatology. 2007;45:507-539. Lok AS, et al. Hepatology. 2009;50:661-662. HBeAg PositiveHBeAg Negative Undetectable* HBV DNA (%) 100 80 60 40 20 0 LAMADVETVTBVTDF 40-44 13-21 67 60 76 60-73 51-63 90 88 93 100 80 60 40 20 0 LAMADVETVTBVTDF Peg- IFN 25 63 Not head-to-head trials; different patient populations and trial designs

33. clinicaloptions.com/hepatitis Beyond the Tip of the Iceberg HBeAg Loss and Seroconversion in HBeAg+ Patients After 1 Year of Treatment Outcome (%) Lok AS, et al. Hepatology. 2007;45:507-539. Lau GK, et al. N Engl J Med. 2005;352:2682-2695. Marcellin P, et al. N Engl J Med. 2003;348:808-816. Chang TT, et al. N Engl J Med. 2006;354:1001-1010. Lai CL, et al. N Engl J Med. 2007;357:2576-2588. Marcellin P, et al. N Engl J Med. 2008;359:2442-2455. Janssen HL, et al, Lancet. 2005;365;123-129. Heathcote J, et al. AASLD 2009. Abstract 483. HBeAg LossHBeAg Seroconversion 100 80 60 40 20 0 17-32 24 22 26 22 12-18 21 23 22 100 80 60 40 20 0 30 NA 22-27 Not head-to-head trials; different patient populations and trial designs LAMADVETVTBVTDF Peg- IFN LAMADVETVTBVTDF Peg- IFN

34. clinicaloptions.com/hepatitis Beyond the Tip of the Iceberg 0% 24%49%67% 38% 0%3%11%18% 70% 4%17% 29% 0.2% 1.2% 0.5%1.2% Yr 3Yr 4Yr 2Yr 1Yr 5 Yr 6 LAM ETV TBV ADV TDF EASL HBV Guidelines. J Hepatol. 2009;50:227-242. Tenny DJ, et al. EASL 2009. Abstract 20. Marcellin P, et al. AASLD 2009. Abstract 481. Heathcote E, et al. Abstract 483. Not head-to-head trials; different patient populations and trial designs Cumulative Rates of Resistance With Oral Agents in Nucleos(t)ide-Naive Patients Drug Generation 1st 2nd 3rd

35. clinicaloptions.com/hepatitis Beyond the Tip of the Iceberg Tolerability and Safety: Nucleos(t)ide Analogues vs Peginterferon Nucleos(t)ide Analogues  Safe at all stages of disease, including decompensated cirrhosis  Safe in immunocompromised populations –Selected drugs probably safe in pregnancy  Reported toxicities are rare Peginterferon  Contraindications –Decompensated cirrhosis –Pregnancy –Significant cardiopulmonary disease –Uncontrolled seizures, psychiatric disease –Autoimmune diseases  Not recommended –Cirrhosis  Adverse effects common Lok AS, et al. Hepatology. 2007;45:507-539. Lok AS, et al. Hepatology. 2009;50:661-662.

36. clinicaloptions.com/hepatitis Beyond the Tip of the Iceberg Current Guideline Recommendations for First-line Therapy  Peginterferon alfa-2a –Exceptions: pregnancy, chemotherapy prophylaxis, decompensated cirrhosis  Entecavir  Tenofovir EASL. J Hepatol. 2009;50:227-242. Liaw YF, et al. Hepatol Int. 2008;2:263-283. Lok AS, et al. Hepatology. 2009;50:661-662.

37. clinicaloptions.com/hepatitis Beyond the Tip of the Iceberg HBeAg Seroconversion Rates Over Time in HBeAg-Positive Patients *With sustained undetectable HBV DNA. Chang TT, et al. J Viral Hepat. 2009;16:784-789. Chang TT, et al. AASLD 2006. Abstract 109. Lau GK, et al. N Engl J Med. 2005;352:2682-2695. Marcellin P, et al. N Engl J Med. 2008;359:2442-2455. Buster EH, et al. Gastroenterology. 2008;135;459-467. Heathcote J, et al. AASLD 2008. Abstract 158. Heathcote J, et al. AASLD 2009. Abstract 483. Janssen HL, et al. Lancet. 2005;365;123-129. Extended Treatment With Nucleos(t)ide Analogues* vs Limited Duration (1 Yr) Peginterferon Treatment Not head-to-head trials; different patient populations and trial designs Entecavir Tenofovir Peginterferon HBeAg Seroconversion (%) 2122 31 39 26 1.0 Yr1.5-2.0 Yrs3.0-4.0 Yrs 100 80 60 40 20 0 22-27 29-32 35

38. clinicaloptions.com/hepatitis Beyond the Tip of the Iceberg HBsAg Loss Over Time in HBeAg-Positive Patients Chang TT, et al. N Engl J Med. 2006;354:1001-1010. Marcellin P, et al. N Engl J Med. 2008;359:2442-2455. Buster EH, et al. Gastroenterology. 2008;135;459-467. Gish R, et al. Gastroenterology. 2007;133:1437-1444. Heathcote J. AASLD 2008. Abstract 158. Heathcote J, et al. AASLD 2009. Abstract 483. Janssen HL, et al. Lancet. 2005;365:123-129. Not head-to-head trials; different patient populations and trial designs Extended Treatment With Nucleos(t)ide Analogues* vs Limited Duration (1 Yr) Peginterferon Treatment HBsAg Loss (%) 2 3 66 100 80 60 40 20 0 5 8 8 NA Entecavir Tenofovir Peginterferon *With sustained undetectable HBV DNA. 1.0 Yr1.5-2.0 Yrs3.0-4.0 Yrs 5

39. clinicaloptions.com/hepatitis Beyond the Tip of the Iceberg Predictors of HBsAg Loss in HBeAg- Positive Patients  Race: whites > nonwhites [1]  Genotype [1-3] –Nucleos(t)ide analogues: A and D –Peginterferon: A  Decline in HBsAg level during first 24 wks with nucleos(t)ide analogues [1]  HBeAg negative at or within 26 wks of completing peginterferon treatment [3] 1. Heathcote EJ, et al. EASL 2009. Abstract 909. 2. Gish RG, et al. J Viral Hepat. 2009;[Epub ahead of print]. 3. Buster EH, et al. Gastroenterology. 2008;135;459-467.

40. clinicaloptions.com/hepatitis Beyond the Tip of the Iceberg Undetectable HBV DNA Over Time in HBeAg-Negative Patients Lok AS, McMahon BJ. Hepatology. 2009;50:661-662. Marcellin P, et al. AASLD 2008. Abstract 146. Marcellin P, et al. AASLD 2009. Abstract 481. Marcellin P, et al. Gastroenterology. 2009;136:2169-2179. Baqai S, et al. AASLD 2009. Abstract 476. Extended Treatment With Nucleos(t)ide Analogues vs Limited Duration (1 Yr) Peginterferon Treatment Not head-to-head trials; different patient populations and trial designs Entecavir Tenofovir Peginterferon Undetectable HBV DNA (%) 90 93 87 91 1 Yr2 Yrs3 Yrs 100 80 60 40 20 0 87 1516 NA 100* *single center study.

41. clinicaloptions.com/hepatitis Beyond the Tip of the Iceberg Lai CL, et al. N Engl J Med. 2006;354:1011-1020. Marcellin P, et al. N Engl J Med. 2008;359:2442-2455. Marcellin P, et al. AASLD 2008. Abstract 146. Marcellin P, et al. APASL 2009. Abstract PE086. Shouval D, et al. J Hepatol. 2009;50:289-295. Marcellin P, et al. AASLD 2009. Abstract 481. HBsAg Loss Over Time in HBeAg-Negative Patients On Extended Treatment With Nucleos(t)ide Analogues* vs Limited Duration (1 yr) Peginterferon Treatment Not head-to-head trials; different patient populations and trial designs Patients (%) < 10 4 0 100 80 60 40 20 0 < 1 12 NA Entecavir Tenofovir Peginterferon 0 6 1.0 Yr1.5-2.0 Yrs3.0-4.0 Yrs *With sustained undetectable HBV DNA.

42. clinicaloptions.com/hepatitis Beyond the Tip of the Iceberg Wk 12 HBsAg Levels Predict Outcomes in HBeAg-negative Patients  48 patients consecutively treated with pegIFN alfa-2a for 48 weeks  SVR defined as undetectable serum HBV DNA (< 70 copies/mL) 24 weeks after treatment cessation  Change in HBsAg level from baseline to Week 12 evaluated as predictor of SVR –Cutoff of 0.5 log 10 IU/mL used –PPV = 89%– NPV = 90% Moucari R, et al. Hepatology. 2009;49:1151-1157. Outcome, % (n) Change in HBsAg from Baseline to Week 12 ≥ 0.5 log 10 IU/mL (n = 9) < 0.5 log 10 IU/mL (n = 39) SVR89 (8)10 (4) No SVR11 (1)90 (35)

43. clinicaloptions.com/hepatitis Beyond the Tip of the Iceberg Summary of Therapy for CHB in Treatment-Naive Patients  Tenofovir, entecavir, and peginterferon are preferred first-line drugs –First decision is between NAs vs peginterferon –3rd generation NAs have high efficacy, very low rates of resistance, and excellent safety record –Peginterferon offers finite therapy, some evidence of off-treatment benefits  HBeAg seroconversion –Increases over time with NAs –Approximately same after 3 yrs continuous treatment with NAs vs 1 yr of peginterferon  HBsAg loss –Infrequent and increases slowly (< 10% at 3-4 yrs) –Rare in HBeAg-negative CHB with NAs –After 3-4 yrs follow-up, somewhat higher with peginterferon than NAs

44. Jules L. Dienstag, MD Carl W. Walter Professor of Medicine Dean for Medical Education Harvard Medical School Physician, Gastrointestinal Unit Massachusetts General Hospital Boston, Massachusetts Tip of the Iceberg: Is Determining “How to Treat” a Barrier to Initiating HBV Therapy?

45. clinicaloptions.com/hepatitis Beyond the Tip of the Iceberg Decision to treat PegIFN Nucleos(t)ide analogues The First Branch Point in Choosing Treatment for Hepatitis B

46. clinicaloptions.com/hepatitis Beyond the Tip of the Iceberg Nucleos(t)ide Analogues vs PegIFN  Use of pegIFN in younger patients –Very small proportion will benefit –Most will require longer treatment with nucleos(t)ide analogues  PegIFN better in genotype A > B > C > D –Favorable genotypes growing vanishingly rare –This relationship between genotype and response seen for pegIFN alfa-2b but not with pegIFN alfa-2a –HBeAg seroconversion with pegIFN alfa-2a according to genotype –A: 52%; B: 30%; C: 31%; D: 22% (not significant)  Predictors of HBeAg response same for pegIFN and nucleos(t)ide analogues (eg, high ALT, low HBV DNA) Flink HJ, et al. Am J Gastro. 2006;101:297-303. Lau GK, et al. N Engl J Med. 2005;352:2682-2695.

47. clinicaloptions.com/hepatitis Beyond the Tip of the Iceberg Long-term Outcomes With pegIFN alfa-2a in HBeAg-Negative Chronic Hepatitis B  5 yrs posttreatment follow-up in patients treated with pegIFN ± LAM vs LAM alone for 48 wks Marcellin P, et al. ILC 2009. Abstract 924. *vs 3.5% for LAM alone at Yr 5 (P =.022). Outcomes With PegIFN ± LAM (n = 230 [65%] of original 356) Patients (%) 0 HBsAg Loss 100 60 80 20 ALT Normalization HBV DNA < 400 copies/mL Yr 1 Yr 3 13.5 15.7 Yr 5 16.5 47.4 30.9 22.2 4.8 8.7 12.2* 40

48. clinicaloptions.com/hepatitis Beyond the Tip of the Iceberg HBV DNA During Follow-up After Stopping Adefovir  Patients receiving 4-5 years continuous adefovir followed long-term off treatment –33 patients who had sustained undetectable HBV DNA on treatment followed –HBV DNA levels followed in 18 off-treatment sustained biochemical responders  All patients initially rebounded to detectable HBV DNA  Proportion of patients with HBV DNA < 1000 copies/mL –1 month after adefovir discontinuation: 5.6% –12 months after adefovir discontinuation: 55.6% –48 months after adefovir discontinuation: 66.7% Hadziyannis SJ, et al. EASL 2009. Abstract 18.

49. clinicaloptions.com/hepatitis Beyond the Tip of the Iceberg HBsAg Loss (n) Hadziyannis SJ, et al. EASL 2009. Abstract 18. Used with permission. 18 16 14 12 10 8 6 4 2 0 EOTYr 1Yr 2Yr 3Yr 4 Time Off Treatment HBsAg Loss (%) 100 80 60 40 20 0 EOTYr 1Yr 2Yr 3Yr 4 Time Off Treatment Sustained Biochemical Responders, % (n = 18) Total, % (n = 33) 2 3 5 7 10 11.11 16.66 27.77 38.88 55.55 30.30 21.21 15.15 6.069.09 HBsAg Loss Off Treatment After 4-5 Years of Continuous Adefovir

50. clinicaloptions.com/hepatitis Beyond the Tip of the Iceberg Lok AS, et al. Hepatology. 2007;45:507-539. 1 log Change in HBV DNA (log 10 IU/mL) 0 -2.0 -3.0 -4.0 1.0 Nadir Virologic breakthrough Antiviral Drug Mo 601218 Primary nonresponse Suboptimal response “Undesirable” Virologic Responses to Oral Therapy

51. clinicaloptions.com/hepatitis Beyond the Tip of the Iceberg Does the Roadmap Concept Apply to ETV or TDF During First Yr?  1.2% resistance to ETV at 6 yrs in nucleos(t)ide-naive patients [1]  No resistance to TDF seen to date through 3 yrs in HBeAg- negative patients and 2 yrs in HBeAg-positive patients [2,3] –Patients with positive HBV DNA at 24 and 48 wks often negative subsequently  Tentative conclusion: for patients with positive HBV DNA at 48 wks on ETV or TDF, it may still be appropriate to continue monotherapy—especially if HBV DNA is still declining  More data needed 1. Tenny D, et al. EASL 2009. Abstract 20. 2. Heathcote E, et al. AASLD 2009. Abstract 483. 3. Marcellin P, et al. AASLD 2009. Abstract 481.

52. clinicaloptions.com/hepatitis Beyond the Tip of the Iceberg Take Home Points  For pegIFN: finite treatment for 48 wks –Some consider in young, noncirrhotic patients with low HBV DNA, high ALT, favorable genotypes  For nucleos(t)ide analogues –Select entecavir or tenofovir in most cases –HBeAg-positive chronic hepatitis B: treat until HBeAg seroconversion, stop after consolidation period –HBeAg-negative chronic hepatitis B: treat indefinitely

53. clinicaloptions.com/hepatitis Beyond the Tip of the Iceberg Take Home Points (cont’d)  In the case of incomplete response to entecavir or tenofovir –Distinguish between noncompliance, breakthrough resistance, and suboptimal response –“Roadmap” approach does not apply well –Suboptimal response: approach remains to be defined

54. Go Online for More From this Program! Downloadable Slides for use in your own noncommercial presentations Downloadable Worksheet: quick reference guide for HBV screening and evaluation available in English or simplified Chinese clinicaloptions.com/HBViceberg