1. Understanding and Implementing the AASLD’s HBV Practice Guidelines* and Other Recent Guidelines and Recommendations on the Diagnosis, Management, and Treatment of Hepatitis B This program is supported by educational grants from Image: Pavelk/Copyright©2010 Shutterstock Images LLC. All Rights Reserved *The AASLD 2010 Practice Guidelines were developed solely by AASLD without industry funding or influence.

2. Nezam H. Afdhal, MD, FRCPI Associate Professor of Medicine Harvard Medical School Chief of Hepatology Beth Israel Deaconess Medical Center Boston, Massachusetts Using HBV Treatment Guidelines in Determining How to Treat

3. clinicaloptions.com/hepatitis AASLD HBV Guidelines: An Update Program Faculty Program Director W. Ray Kim, MD Associate Professor of Medicine Division of Gastroenterology and Hepatology Mayo Clinic Rochester, Minnesota Faculty Nezam H. Afdhal, MD, FRCPI Associate Professor of Medicine Harvard Medical School Chief of Hepatology Beth Israel Deaconess Medical Center Boston, Massachusetts

4. clinicaloptions.com/hepatitis AASLD HBV Guidelines: An Update AASLD Practice Guidelines: Chronic Hepatitis B—Update 2009  AASLD: leading medical organization for advancing science and practice of hepatology  AASLD guidelines a key reference on best practices for care of patients with hepatitis B –Previous edition in 2007 –Current edition in 2009 –Evidence-based recommendations approved by the AASLD and endorsed by the Infectious Diseases Society of America Lok AS, et al. Hepatology. 2009;50:661-662.

5. clinicaloptions.com/hepatitis AASLD HBV Guidelines: An Update Grading System for Quality of Evidence on Which Recommendation Is Based  Grade I: based on randomized, controlled trials  Grade II-1: based on controlled trials without randomization  Grade II-2: based on cohort or case-control analytic studies  Grade II-3: based on multiple time series, dramatic uncontrolled experiments  Grade III: based on opinions of respected authorities, descriptive epidemiology Lok AS, et al. Hepatology. 2009;50:661-662.

6. Goals and Endpoints of Therapy

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

8. clinicaloptions.com/hepatitis AASLD HBV Guidelines: An Update Goals of Therapy: 2 Distinct Patient Populations HBeAg positive (wild type)  HBeAg loss  seroconversion  Suppression of HBV DNA  ALT normalization HBeAg negative (precore and core promoter mutants)  HBeAg seroconversion not an endpoint  Suppression of HBV DNA  ALT normalization Keeffe EB, et al. Clin Gastroenterol Hepatol. 2008;6:1315-1341.

9. Treatment Options for Hepatitis B

10. clinicaloptions.com/hepatitis AASLD HBV Guidelines: An Update Interferon alfa-2b Lamivudine Adefovir Peginterferon alfa-2a Telbivudine Tenofovir 199019982002200520062008 Entecavir HBV Treatment Landscape in 2010

11. clinicaloptions.com/hepatitis AASLD HBV Guidelines: An Update Recommended Dosing of Anti-HBV Agents Agent Rou te Recommended Dosing AdultChildren Interferon alfaSQ5 MU daily or 10 MU 3 x per wk 6 MU/m 2 3 x per wk (max: 10 MU) Peginterferon alfa-2a SQ180 µg/wkNot approved LamivudinePO100 mg QD* † 3 mg/kg/day (max: 100 mg/day) AdefovirPO10 mg QD*Not approved ‡ EntecavirPO  0.5 mg QD (no previous LAM)  1.0 mg QD (if refr/resist to LAM)* Not approved TelbivudinePO600 mg QD*Not approved TenofovirPO300 mg QD*Not approved *Dose adjustment needed if eGFR < 50 mL/min. † Persons coinfected with HIV should receive 150 mg BID. Should only be used in combination with other antiretrovirals. ‡ Approved for ages 12 and older. Lok AS, et al. Hepatology. 2009;50:661-662.

12. clinicaloptions.com/hepatitis AASLD HBV Guidelines: An Update Undetectable* HBV DNA After 1 Yr 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 LAMADVETVLdTTDF 40-44 13-21 67 60 76 60-73 51-63 90 88 93 100 80 60 40 20 0 LAMADVETVLdTTDF Peg- IFN 25 63 Not head-to-head trials; different patient populations and trial designs

13. clinicaloptions.com/hepatitis AASLD HBV Guidelines: An Update HBeAg Loss and Seroconversion in HBeAg+ Patients After 1 Yr 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. HBeAg LossHBeAg Seroconversion 100 80 60 40 20 0 17-32 24 21 26 22 12-18 21 23 21 100 80 60 40 20 0 30 NA 22-27 Not head-to-head trials; different patient populations and trial designs LAMADVETVLdTTDF Peg- IFN LAMADVETVLdTTDF Peg- IFN

14. clinicaloptions.com/hepatitis AASLD HBV Guidelines: An Update Durability of HBeAg Seroconversion AgentnPosttreatment Time Point Sustained HBeAg Seroconversion, % Peginterferon [1] 7224 wks82 Lamivudine [1-4] 55 61 43 39 24 wks 52 wks 40.7 mos* 58 72 93 77 Adefovir [5] 45150 wks*91 Telbivudine [3] 5552 wks86 Entecavir [2] 7024 wks77 1. Lau GKK, et al. N Engl J Med. 2005;352:2682-2695. 2. Gish RG, et al. Gastroenterology. 2007;133:1437- 1444. 3. Poynard T, et al. EASL 2008. Abstract 706. 4. Dienstag JL, et al. Hepatology. 2003; 37:748-755. 5. Wu IC, et al. Clin Infect Dis. 2008;47:1305-1311. Not head-to-head trials; different patient populations and trial designs *Median follow-up.

15. clinicaloptions.com/hepatitis AASLD HBV Guidelines: An Update Other Outcomes in HBeAg-Positive Patients After 1 Yr of Treatment Outcome (%) Not head-to-head trials; different patient populations and trial designs Lok AS, et al. Hepatology. 2009;50:661-662. *No/short duration consolidation treatment among LAM- and ETV-treated patients; most patients treated with ADV and LdT had consolidation. 0 20 40 60 80 100 ALT Normalization Histologic Improvement Response Durability* HBsAg Loss 41-75 49-56 50-80 1 48 53 ~ 90 0 77 65 ~ 80 0 68 72 69 2 68 74 NA 3.2 39 38 NA 3 LAM ADV LdT ETV TDF PegIFN

16. clinicaloptions.com/hepatitis AASLD HBV Guidelines: An Update Other Outcomes in HBeAg-Negative Patients After 1 Yr of Treatment Not head-to-head trials; different patient populations and trial designs 60-79 60-66 < 10 72 64 ~ 5 74 67 NA 78 70 3 76 72 NA 38 48 ~ 20 0 20 40 60 80 100 ALT Normalization Histologic Improvement Response Durability Outcome (%) LAM ADV LdT ETV TDF PegIFN Lok AS, et al. Hepatology. 2009;50:661-662.

17. clinicaloptions.com/hepatitis AASLD HBV Guidelines: An Update 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 LdT ADV TDF EASL. 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. AASLD 2009. 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

18. clinicaloptions.com/hepatitis AASLD HBV Guidelines: An Update 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 –Chemotherapy prophylaxis –Acute HBV infection  Not recommended –Cirrhosis  Adverse effects common Lok AS, et al. Hepatology. 2007;45:507-539. Lok AS, et al. Hepatology. 2009;50:661-662.

19. Selecting Optimal First-line Therapy

20. clinicaloptions.com/hepatitis AASLD HBV Guidelines: An Update Current Guideline Recommendations for First-line Therapy  Peginterferon alfa-2a –Exceptions: pregnancy, chemotherapy prophylaxis, decompensated cirrhosis, acute infection  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.

21. clinicaloptions.com/hepatitis AASLD HBV Guidelines: An Update Factors Driving Selection of Initial Therapy Nucleos(t)ide AnaloguesPeginterferon Efficacy (potency) Barrier to resistance (durability) Safety & tolerability Efficacy (potency) Finite duration

22. clinicaloptions.com/hepatitis AASLD HBV Guidelines: An Update 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

23. clinicaloptions.com/hepatitis AASLD HBV Guidelines: An Update 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

24. clinicaloptions.com/hepatitis AASLD HBV Guidelines: An Update 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. 2010;17:16-22. 3. Buster EH, et al. Gastroenterology. 2008;135;459-467.

25. clinicaloptions.com/hepatitis AASLD HBV Guidelines: An Update Undetectable HBV DNA Over Time in HBeAg-Negative Patients Lok AS, et al. 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. Lai CL, et al. Hong Kong International Liver Congress 2006. 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 63 1516 NA 100* *Single center study. 96

26. clinicaloptions.com/hepatitis AASLD HBV Guidelines: An Update 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. Shouval D, et al. J Hepatol. 2009;50:289-295. Marcellin P, et al. AASLD 2009. Abstract 481. Brunetto M, et al. EASL 2008. Abstract 683. HBsAg Loss Over Time in HBeAg-Negative Patients 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 9 NA 0 7 1.0 Yr1.5-2.0 Yrs3.0-4.0 Yrs *With sustained undetectable HBV DNA. Entecavir Tenofovir Peginterferon

27. clinicaloptions.com/hepatitis AASLD HBV Guidelines: An Update HBsAg Levels at Wk 12 of PegIFN Predict Off-Therapy SVR in HBeAg-Negative Pts  48 pts consecutively treated with pegIFN alfa-2a for 48 wks  SVR definition: undetectable serum HBV DNA (< 70 copies/mL) at Wk 24 following treatment completion  Change in HBsAg level from baseline to Wk 12 evaluated as predictor of SVR –Cutoff: 0.5 log 10 IU/mL decrease –PPV: 89%– NPV: 90% Outcome, % (n) Decrease in HBsAg From Baseline to Wk 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) Moucari R, et al. Hepatology. 2009;49:1151-1157.

28. clinicaloptions.com/hepatitis AASLD HBV Guidelines: An Update Decision to treat IFN (PegIFN alfa-2a) Nucleos(t)ide analogues The First Branch Point in Choosing With What to Treat

29. clinicaloptions.com/hepatitis AASLD HBV Guidelines: An Update PegIFN vs Nucleos(t)ide Analogues PegIFNNucleos(t)ide Analogues ProConProCon  Finite course of therapy  No resistance  Higher rate of HBeAg loss in 1 yr  Higher rate of HBsAg loss with short duration therapy*  SQ administration  Frequent AEs  Contraindicated in patients with cirrhosis, in pregnancy, with acute hepatitis B, and who are immunosuppressed  PO administration  Infrequent AEs  Safe for patients with decompensated disease †  Need for long- term or indefinite therapy  Potential for drug resistance *Particularly for HBeAg-positive patients with genotype A infection. † Recent case report of lactic acidosis in severe liver failure. Lok AS. Hepatology. 2010;52:743-747. Buster EH, et al. Gastroenterology. 2008;135:459-467. Lange CM, et al. Hepatology. 2009;50:2001-2006.

30. clinicaloptions.com/hepatitis AASLD HBV Guidelines: An Update Limitations of Response to Finite-Duration PegIFN Therapy  HBeAg seroconversion in HBeAg-positive patients treated with pegIFN for 1 yr –25% to 35% after 3-5 yrs posttreatment follow-up  HBV DNA ≤ 400 copies/mL in HBeAg-negative patients treated with pegIFN for 1 yr –13% to 18% after 3-5 yrs posttreatment follow-up Lok AS. Hepatology. 2010;52:743-747.

31. clinicaloptions.com/hepatitis AASLD HBV Guidelines: An Update  Favorable predictors of response [1,2] –Low HBV DNA* –High ALT* –Genotype A or B > C or D [3-5] When to Consider PegIFN 1. Lok AS, et al. Hepatology. 2009;50:661-662. 2. Lok AS. Hepatology. 2010;52:743-747. 3. Janssen HL, et al, Lancet. 2005;365;123-129. 4. Lau GK, et al. N Engl J Med. 2005;352:2682-2695. 5. Flink HJ, et al. Am J Gastroenterol. 2006;101:297-303.  Specific patient demographics [1,2] –Generally young people –Young women wanting pregnancy in near future –Absence of comorbidities  Patient preference [1,2]  Concomitant HCV infection *Also predictive of response to nucleos(t)ide analogues.

32. clinicaloptions.com/hepatitis AASLD HBV Guidelines: An Update Nucleos(t)ide analogues LamivudineAdefovir The Second Branch Point in Choosing With What to Treat EntecavirTelbivudineTenofovir

33. clinicaloptions.com/hepatitis AASLD HBV Guidelines: An Update AASLD Guideline Preferred Agents HBeAg-positive adults with indications for treatment: “Treatment may be initiated with any of the 7 approved antiviral medications, but pegIFN-α, tenofovir, or entecavir are preferred (I).” HBeAg-negative adults with indications for treatment: “Treatment may be initiated with any of the 7 approved antiviral medications but pegIFN-α, tenofovir, or entecavir are preferred in view of the need for long-term treatment. (I for pegIFN-α, tenofovir, or entecavir and II-1 for IFN-α, adefovir, telbivudine, and lamivudine).” Lok AS, et al. Hepatology. 2009;50:661-662.

34. clinicaloptions.com/hepatitis AASLD HBV Guidelines: An Update Selection of Entecavir vs Tenofovir EntecavirTenofovir Log HBV DNA ↓ at Wk 48-52  HBeAg positive6.96.2  HBeAg negative5.04.6 Genotypic resistance, %  NA naive1.2 (Yr 5)0 (Yr 3)  Lamivudine experienced 51 (Yr 5)NR Pregnancy ratingClass CClass B AEsNone Renal toxicity; ↓ BMD Lok AS. Hepatology. 2010;52:743-747. 21 2 < 1 21 3 0 0 5 10 15 20 25 HBeAg seroconversion HBsAg loss Entecavir Tenofovir HBeAg Negative HBsAg loss HBeAg Positive Response at Wk 48-52 (%)

35. clinicaloptions.com/hepatitis AASLD HBV Guidelines: An Update Efficacy of Entecavir vs Tenofovir in the Setting of Resistance  Similar antiviral activity against nonresistant HBV; efficacy against drug-resistant strains differs Activity According to Resistance EntecavirTenofovir LAM/LdT resistanceDecreasedActive ETV resistance--Active ADV resistanceActiveDecreased TDF resistanceActive-- Lok AS. Hepatology. 2010;52:743-747.

36. On-Treatment Monitoring and Response Evaluation

37. clinicaloptions.com/hepatitis AASLD HBV Guidelines: An Update Monitoring of Patients Receiving (Peg)IFN Therapy Lok AS, et al. Hepatology. 2009;50:661-662. Time PointMonitoring During treatment Every 4 wks  Blood counts  Liver panel Every 12 wks  TSH  HBV DNA levels Every 24 wks  HBeAg/anti-HBe (if initially HBeAg positive) Posttreatment Every 12 wks during first 24 wks  Blood counts  Liver panel  TSH  HBV DNA  HBeAg/anti-HBe (if initially HBeAg positive)

38. clinicaloptions.com/hepatitis AASLD HBV Guidelines: An Update Monitoring of Patients Receiving Nucleos(t)ide Analogue Therapy Time PointMonitoring Every 12 wks  Liver panel  Serum creatinine (if receiving TDF or ADV) Every 12-24 wks  HBV DNA levels Every 24 wks  HBeAg/anti-HBe (if initially HBeAg positive) Every 6-12 mos  HBsAg in HBeAg-negative patients with persistently undetectable HBV DNA Lok AS, et al. Hepatology. 2009;50:661-662.

39. clinicaloptions.com/hepatitis AASLD HBV Guidelines: An Update AASLD Guideline Recommendations for Duration of NA Treatment “32. Duration of nucleoside analogue treatment a. HBeAg-positive chronic hepatitis B—Treatment should be continued until the patient has achieved HBeAg seroconversion and undetectable serum HBV DNA and completed at least 6 mos of additional treatment after appearance of anti-HBe. (I) ● Close monitoring for relapse is needed after withdrawal of treatment. (I) b. HBeAg-negative chronic hepatitis B—Treatment should be continued until the patient has achieved HBsAg clearance. (I)” Lok AS, et al. Hepatology. 2009;50:661-662.

40. clinicaloptions.com/hepatitis AASLD HBV Guidelines: An Update Definition of Response to Antiviral Therapy ResponseDefinition Primary nonresponse* ↓ in serum HBV DNA by < 2 log 10 IU/mL after ≥ 24 wks of therapy Biochemical response↓ in serum ALT to within the normal range Virologic response ↓ in serum HBV DNA to undetectable levels by PCR and loss of HBeAg in patients who were initially HBeAg positive Virologic relapse ↑ in serum HBV DNA of 1 log 10 IU/mL after discontinuation of treatment in ≥ 2 determinations > 4 wks apart Histologic response ↓ in histology activity index by ≥ 2 points and no worsening of fibrosis score compared to pretreatment liver biopsy Complete response Fulfill criteria of biochemical and virologic response and HBsAg loss Lok AS, et al. Hepatology. 2009;50:661-662. Chronic Hepatitis B: Update 2009, Lok ASF, McMahon BJ, www.aasld.org. Copyright@2009. American Association for the Study of Liver Diseases. Reproduced with permission of the American Association for the Study of Liver Diseases. *Not applicable to interferon therapy.

41. clinicaloptions.com/hepatitis AASLD HBV Guidelines: An Update Definitions Related to Antiviral Resistance to Nucleos(t)ide Analogues TermDefinition Virologic breakthrough ↑ HBV DNA by 1 log 10 (10-fold) above nadir after achieving virologic response, during continued tx Viral rebound ↑ HBV DNA to > 20,000 IU/mL or above pre-tx level after achieving virologic response, during continued tx Biochemical breakthrough ↑ ALT to above ULN after achieving normalization, during continued tx Genotypic resistance Detection of mutations shown by in vitro studies to confer resistance to the NA administered Phenotypic resistance In vitro confirmation that mutation detected decreases susceptibility (as demonstrated by increase in inhibitory concentrations) to the NA administered Lok AS, et al. Hepatology. 2009;50:661-662. Chronic Hepatitis B: Update 2009, Lok ASF, McMahon BJ, www.aasld.org. Copyright@2009. American Association for the Study of Liver Diseases. Reproduced with permission of the American Association for the Study of Liver Diseases. Manifestations of Antiviral Resistance Antiviral Treatment Virologic rebound Virologic breakthrough Genotypic resistance Hepatitis flare Biochemical breakthrough ULN HBV DNA (log 10 IU/mL) ALT (U/L) Yrs 8 6 4 2 0 0123

42. clinicaloptions.com/hepatitis AASLD HBV Guidelines: An Update Prevention and Monitoring of Resistance Prevention Avoid unnecessary treatment Initiate potent antiviral that has low rate of drug resistance or use combination therapy Switch to alternative therapy in patients with primary nonresponse Monitoring Test for serum HBV DNA (PCR) every 3-6 mos during tx Check for medication compliance in patients with virologic breakthrough Confirm antiviral resistance with genotypic testing Lok AS, et al. Hepatology. 2009;50:661-662. Chronic Hepatitis B: Update 2009, Lok ASF, McMahon BJ, www.aasld.org. Copyright@2009. American Association for the Study of Liver Diseases. Reproduced with permission of the American Association for the Study of Liver Diseases.

43. clinicaloptions.com/hepatitis AASLD HBV Guidelines: An Update AASLD Guideline Recommendations for Managing IFN Failure “17. Patients who failed to respond to prior IFN-α (standard or pegylated) therapy may be retreated with nucleoside analogues (NA) if they fulfill the [treatment candidacy] criteria. (I)” Lok AS, et al. Hepatology. 2009;50:661-662.

44. clinicaloptions.com/hepatitis AASLD HBV Guidelines: An Update AASLD Guideline Recommendations for Managing Primary Nonresponse to NA “18. Patients who failed to achieve primary response as evidenced by < 2 log decrease in serum HBV DNA level after at least 6 mons of NA therapy should be switched to an alternative treatment or receive additional treatment. (III)” Lok AS, et al. Hepatology. 2009;50:661-662.

45. clinicaloptions.com/hepatitis AASLD HBV Guidelines: An Update AASLD Guideline Recommendations for Managing Breakthrough “19. Patients who develop breakthrough infection while receiving NA therapy ● Compliance should be ascertained, and treatment resumed in patients who have had long lapses in medications. (III) ● A confirmatory test for antiviral-resistant mutation should be performed if possible to differentiate primary nonresponse from breakthrough infection and to determine if there is evidence of multidrug resistance (in patients who have been exposed to more than 1 NA treatment). (III) ● All patients with virologic breakthrough should be considered for rescue therapy. (II-2) ● For patients in whom there was no clear indication for hepatitis B treatment and who continue to have compensated liver disease, withdrawal of therapy may be considered, but these patients need to be closely monitored and treatment reinitiated if they experience severe hepatitis flares. (III)” Lok AS, et al. Hepatology. 2009;50:661-662.

46. clinicaloptions.com/hepatitis AASLD HBV Guidelines: An Update Management of Antiviral-Resistant HBV TreatmentStrategy Lamivudine resistance  Add adefovir or tenofovir  Stop lamivudine and switch to tenofovir/emtricitabine* Adefovir resistance  Add lamivudine †  Stop adefovir and switch to tenofovir/emtricitabine*  Switch to or add entecavir* † Entecavir resistance  Switch to tenofovir or tenofovir/emtricitabine* Telbivudine resistance ‡  Add adefovir or tenofovir  Stop telbivudine and switch to tenofovir/emtricitabine Tenofovir resistance §  May add entecavir, telbivudine, lamivudine, or emtricitabine *In HIV-coinfected patients; scant in vivo data in non-HIV–coinfected patients. † Durability of viral suppression unknown, especially in patients with previous lamivudine resistance. ‡ Clinical data not available. § Not addressed in AASLD guidelines; EASL 2009 HBV guidelines recommend genotypic and phenotypic testing by expert lab to establish cross-resistance profile. Lok AS, et al. Hepatology. 2009;50:661-662. EASL. J Hepatol. 2009;50:227-242. Chronic Hepatitis B: Update 2009, Lok ASF, McMahon BJ, www.aasld.org. Copyright@2009. American Association for the Study of Liver Diseases, Reproduced with permission of the American Association for the Study of Liver Diseases.

47. Treatment of Special Populations

48. clinicaloptions.com/hepatitis AASLD HBV Guidelines: An Update Management of Patients With Compensated Cirrhosis Preferred therapies  ETV or TDF –NAs should be used; IFN can be associated with hepatitis flare Treatment duration  Long-term treatment –Can discontinue in HBeAg-positive patients with confirmed HBeAg seroconversion and ≥ 6 mos consolidation therapy –Can discontinue in HBeAg-negative patients with confirmed HBsAg clearance  Treatment discontinuation requires close monitoring for flare or relapse Lok AS, et al. Hepatology. 2009;50:661-662.

49. clinicaloptions.com/hepatitis AASLD HBV Guidelines: An Update Management of Patients With Decompensated Cirrhosis Lok AS, et al. Hepatology. 2009;50:661-662. Preferred therapies  (LAM or LdT) + (ADV or TDF); TDF or ETV monotherapy* –Treatment should be coordinated with transplantation center –IFNs should not be used in decompensated cirrhosis Treatment duration  Lifelong treatment recommended *Clinical data documenting safety and efficacy of TDF or ETV monotherapy in decompensated cirrhosis are lacking.

50. clinicaloptions.com/hepatitis AASLD HBV Guidelines: An Update Management of Patients With HIV Coinfection 1. Lok AS, et al. Hepatology. 2009;50:661-662. 2. DHHS Adults and Adolescents Guidelines. 2009.  HBV/HIV-coinfected patients who require HBV therapy should be treated [1] –Liver biopsy should be considered in patients with fluctuating or mildly elevated ALT (1-2 x normal) Not on or Anticipating Antiretroviral Therapy* Planning Antiretroviral Therapy Already Receiving Antiretroviral Therapy  Treat with antiviral therapy that is not active vs HIV, such as pegIFN or ADV 10 mg  Although LdT does not target HIV, it should not be used in this circumstance  Treat with therapies that are effective against both viruses: TDF + (FTC or LAM) preferred (plus ≥ 1 other anti-HIV agent)  If regimen does not include drug active against HBV, may add pegIFN or ADV  If LAM resistance, add TDF *DHHS guidelines recommend that any HBV/HIV-coinfected patient in whom HBV treatment is indicated should initiate a fully suppressive antiretroviral regimen containing 2 drugs with anti-HBV activity. [2]

51. clinicaloptions.com/hepatitis AASLD HBV Guidelines: An Update Management of Patients With HIV Coinfection Lok AS, et al. Hepatology. 2009;50:661-662. “38. When HAART regimens are altered, drugs that are effective against HBV should not be discontinued without substituting another drug that has activity against HBV, unless the patient has achieved HBeAg seroconversion and has completed an adequate course of consolidation treatment. (II-3)”

52. clinicaloptions.com/hepatitis AASLD HBV Guidelines: An Update Management of HBV During Chemotherapy or Immunosuppression  Reactivation of HBV replication common during immunosuppression/chemotherapy (20% to 50%)  Prophylactic antiviral therapy recommended in HBV carriers at onset of cancer chemotherapy or immunosuppressive therapy –If baseline HBV DNA < 2000 IU/mL, continue treatment for 6 mos after –If baseline HBV DNA > 2000 IU/mL, continue treatment until they reach treatment endpoints for hepatitis B  Tenofovir or entecavir preferred if treatment for > 12 mos Lok AS, et al. Hepatology. 2009;50:661-662.

53. Go Online to Access More of the 2009 AASLD HBV Guidelines Program! 1 additional Interactive Virtual Presentation and downloadable slidesets 3 Interactive Case Challenges clinicaloptions.com/GuidelinesHBV

54. Go Online to Access All of AASLD’s Practice Guidelines!* AASLD promotes preferable methods of approaching diagnostic, therapeutic, and preventive aspects of care through the development of practice guidelines  Portal Hypertension Guidelines  Viral Hepatitis Guidelines  Metabolic/Genetic/Autoimmune Liver Disease Guidelines  End-Stage Liver Disease/Surgery Guidelines  Position Papers on Other Disorders aasld.org/practiceguidelines *AASLD guidelines represent the official opinion of the Association, as reflected in the evidence-based reviews and recommendations of the individuals involved in developing the guidelines.