1. Choosing First-Line Therapy in Chronic Hepatitis B This program is supported by an unrestricted educational grant from

2. clinicaloptions.com/hep Choosing First-Line Therapy in Chronic Hepatitis B About These Slides  Users are encouraged to include these slides in their own 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  These slides may not be published or posted online or used for any other commercial purpose without written permission from Clinical Care Options.  We are grateful to Emmet B. Keeffe, MD, MACP, with the Stanford University Medical Center in Palo Alto, California, for aiding in the content development of these slides. Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patient’s conditions and possible contraindications on dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities.

3. clinicaloptions.com/hep Choosing First-Line Therapy in Chronic Hepatitis B Outline  Introduction: Considerations for Selecting Initial HBV Therapy  Case Vignette: First-line Treatment in an HBeAg-Positive Patient –Review of key factors in determining initial therapy in HBeAg-positive patients  Case Vignette: First-line Treatment in an HBeAg-Negative Patient –Review of key factors in determining initial therapy in HBeAg-negative patients  Case Vignette: First-line Treatment in a Cirrhotic Patient With Hepatitis B –Review of key factors in determining initial therapy in cirrhotics

4. clinicaloptions.com/hep Choosing First-Line Therapy in Chronic Hepatitis B Considerations for Selecting First-Line Therapy in Hepatitis B  Goals of therapy  Candidacy for therapy  Baseline patient factors –HBeAg positive vs HBeAg negative –HBV genotype –HBV DNA level –ALT level –Presence or absence of cirrhosis –Significant patient comorbidities (ie, depression, kidney disease)  Treatment factors –Expected duration of therapy –Efficacy of available therapies –Resistance profiles of available therapies

5. Case 1: Choosing First-Line Therapy in an HBeAg-Positive Patient

6. clinicaloptions.com/hep Choosing First-Line Therapy in Chronic Hepatitis B History  36-year-old male with HBV infection diagnosed 6 years ago at time of blood donation –Currently asymptomatic  Born in Taiwan and immigrated to United States at age 24 –Works as a software engineer  Recent death of his mother, an HBsAg carrier, prompted referral –Died at 64 years of age from complications of cirrhosis  Brother and sister are both HBsAg carriers  No family history of liver cancer  No current alcohol or tobacco use

7. clinicaloptions.com/hep Choosing First-Line Therapy in Chronic Hepatitis B Current Presentation  Patient presents for evaluation of his HBV-positive status  Laboratory results –ALT: 56 IU/L– AST: 44 IU/L –HBeAg positive – Anti-HBe negative –HBV DNA: 32,000 IU/mL –Anti-HAV IgG positive –HCV/HIV/HDV negative –Alpha-fetoprotein: 3.2 ng/mL  HBV genotyping: wild-type virus, genotype B  Liver ultrasound: normal  Liver biopsy: grade 2, stage 1

8. clinicaloptions.com/hep Choosing First-Line Therapy in Chronic Hepatitis B Key Questions  Does this patient meet standard criteria for treatment with antiviral therapy?  Which treatment options are available? –What are the advantages and disadvantages of these drugs?

9. clinicaloptions.com/hep Choosing First-Line Therapy in Chronic Hepatitis B Phases of Chronic HBV Infection: Candidates for Therapy Phases of Chronic HBV Infection Immune Tolerance Immune Clearance/ HBeAg-Positive CHB Nonreplicative (Inactive Carrier) Reactivation/ HBeAg-Negative CHB HBV DNA, IU/mL 10 5 - 10 10 10 4 - 10 10 < 10 4 10 3 - 10 8 HBeAgHBeAg+ HBeAg- ALTNormalHigh or fluctuatingNormalHigh or fluctuating Other-- Active inflammation on liver biopsy HBsAg may become undetectable Active inflammation on liver biopsy Candidates for therapy? NoYesNoYes Yim HJ, et al. Hepatology. 2006;43:S173-S181.

10. clinicaloptions.com/hep Choosing First-Line Therapy in Chronic Hepatitis B 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 –Decrease 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 –Clinical trials only; not routinely assessed in practice

11. clinicaloptions.com/hep Choosing First-Line Therapy in Chronic Hepatitis B ≥ 100,000 10,000- 99,999 HBV DNA Associated With Increased Risk of HCC and Cirrhosis  REVEAL: Long-term follow-up of untreated HBsAg positive individuals in Taiwan Baseline HBV DNA (copies/mL) Patients (%) Cumulative Incidence of HCC at Year 13 Follow-up [1] (N = 3653) 50 40 30 20 10 0 1.3 1.4 3.6 12.2 14.9 Cumulative Incidence of Cirrhosis at Year 13 Follow-up [2] (N = 3582) 4.5 5.9 9.8 23.5 36.2 < 300 300- 999 1000- 9999 < 300 300- 9999 10,000- 99,999 100,000- 999,999 ≥ 1 million 1. Chen CJ, et al. JAMA. 2006;295:65-73. 2. Iloeje UH, et al. Gastroenterology. 2006;130:678-686.

12. clinicaloptions.com/hep Choosing First-Line Therapy in Chronic Hepatitis B Chen CJ, et al. JAMA. 2006;295:65-73. Persistently Elevated HBV DNA Associated With Increased HCC Risk *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 (95% CI) 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

13. clinicaloptions.com/hep Choosing First-Line Therapy in Chronic Hepatitis B HBV DNA Associated With Increased Risk of HCC and Cirrhosis  Serum HBV DNA  10 4 copies/mL (~ 2000 IU/mL) independent predictor of cirrhosis and HCC development [1] –Dose-response relationship between level of HBV DNA and relative risk –Unknown if results can be generalized to all HBV carriers worldwide  Sustained suppression of HBV replication may prevent long-term risk of cirrhosis and HCC [2] –Hypothesis needs to be proven prospectively 1. Chen CJ, et al. JAMA. 2006;295:65-73. 2. Iloeje UH, et al. Gastroenterology. 2006;130:678-686.

14. clinicaloptions.com/hep Choosing First-Line Therapy in Chronic Hepatitis B 1957 Interferon discovered 1991 Interferon alfa-2b approved for HBV 1998 Lamivudine (3TC) approved as first nucleoside analogue for HBV 1991 3TC anti-HBV and anti-HIV activity discovered 1990 PMEA anti-HBV activity discovered 2002 Adefovir dipivoxil (PMEA prodrug) approved for HBV 1998 Entecavir anti-HBV activity discovered 2005 Entecavir and peginterferon alfa-2a approved for HBV 2006 Telbivudine approved for HBV 2001 Telbivudine anti-HBV activity discovered HBV Treatment in the United States: 2007

15. clinicaloptions.com/hep Choosing First-Line Therapy in Chronic Hepatitis B Treatment of Chronic Hepatitis B: Efficacy of Current Regimens HBeAg-Positive Patients Drug Duration of Treatment HBeAg Seroconversion at Yr 1, % HBV DNA Negative at Yr 1,* % Off-Treatment Durability of HBeAg Seroconversion, † % Interferon4-6 mos~ 183780-90 Lamivudine≥ 1 yr1740-4450-80 Adefovir≥ 1 yr122191 Entecavir≥ 1 yr216776 Peginterferon alfa-2a1 yr2725NA Telbivudine≥ 1 yr2360  80 *Interferon and lamivudine: hybridization assay; adefovir, entecavir, and peginterferon: PCR assay. † 24 weeks posttreatment. Dienstag JL, et al. N Engl J Med. 1999;341:1256-1263. Wong DK, et al. Ann Intern Med. 1993;119:312- 323. Marcellin P, et al. N Engl J Med. 2004;351:1206-1217. Lau GK, et al. N Engl J Med. 2005;352:2682- 2695. Baraclude (entecavir) [package insert]. Bristol-Myers Squibb; 2005. Tyzeka (telbivudine) [package insert]. Idenix/Novartis; 2006. Lai CL, et al. AASLD 2006. Abstract 91.

16. clinicaloptions.com/hep Choosing First-Line Therapy in Chronic Hepatitis B Treatment of Chronic Hepatitis B: Efficacy of Current Regimens (cont’d) HBeAg-Negative Patients Drug Duration of Treatment HBV DNA Negative at Yr 1,* % Off-Treatment Durability of HBV DNA Negativity,* † % Interferon1 yr60-7010-20 LamivudineIndefinite60-70< 10 AdefovirIndefinite51  5 EntecavirIndefinite90NA Peginterferon alfa-2a1 yr6319 TelbivudineIndefinite88NA *Interferon and lamivudine: hybridization assay; adefovir, entecavir, and peginterferon: PCR assay. † 24 weeks posttreatment. Hadziyannis S, et al. J Hepatol 1990;11(Suppl 1):S133-S136. Hadziyannis SJ, et al. N Engl J Med. 2003;348:800-807. Marcellin P, et al. N Engl J Med. 2004;351:1206-1217. Pastore G, et al. J Hepatol. 1992;14:221-225. Baraclude (entecavir) [package insert]. Bristol-Myers Squibb; 2005. Tyzeka (telbivudine) [package insert]. Idenix/Novartis; 2006. Lok AS, et al. Hepatology. 2000;32:1145-1153. Hadziyannis SJ, et al. Hepatology. 2000;32:847-851.

17. clinicaloptions.com/hep Choosing First-Line Therapy in Chronic Hepatitis B Treatment of Chronic Hepatitis B: Additional Treatment Factors Other Treatment Factors DrugOral/SC Adverse Effects Contra- indications Resistance, %Cost* InterferonSCMany++NoneHigh LamivudineOralNegligible-  23 at Yr 1  71 at Yr 4 Low AdefovirOralNegligible-  0 at Yr 1  30 at Yr 5 Intermediate EntecavirOralNegligible-  < 1 in naive at Yr 4  ~ 40 in LAM-r at Yr 4 Intermediate Peginterferon alfa-2aSCMany++NoneHigh TelbivudineOralNegligible-  22 in HBeAg+ at Wk 92  9 in HBeAg- at Wk 92 Intermediate *Based on 1-year treatment duration. Lai CL, et al. Clin Infect Dis. 2003;36:687-696. Lok AS, et al. Gastroenterology. 2003;125:1714-1722. Borroto-Esoda K, et al. EASL 2006. Abstract 483. Colonno RJ, et al. EASL 2007. Abstract 781. Marcellin P, et al. N Engl J Med. 2004;351:1206-1217. Lau GK, et al. N Engl J Med. 2005;352:2682-2695. Tyzeka (telbivudine) [PI]. Idenix/Novartis; 2006. Hepsera (adefovir) [PI]. Gilead; 2002. Lai CL, et al. AASLD 2006. Abstract 91. Wong DK, et al. Ann Intern Med. 1993;119:312-323.

18. clinicaloptions.com/hep Choosing First-Line Therapy in Chronic Hepatitis B Factors Influencing Choice of Therapy  Primary decision: peginterferon alfa-2a vs oral agent  Peginterferon an option in a patient with –Genotype A –Low HBV DNA –High ALT –No comorbidities –Desire for a fixed duration of therapy and avoidance of resistance  Choice of oral agent dependent on –Potency: highest with entecavir and telbivudine –Rate of resistance: lowest with entecavir –Cost: lowest with lamivudine and lower with telbivudine –Safety: good for all oral agents –Special circumstances, eg, pregnancy (telbivudine class B and lamivudine good safety experience), HIV coinfection, presence of cirrhosis, etc

19. clinicaloptions.com/hep Choosing First-Line Therapy in Chronic Hepatitis B Treatment Recommendations for HBeAg-Positive Patients 2007 AASLD Guidelines  Who to treat? –HBV DNA > 20,000 IU/mL and ALT > 2 x ULN* –Consider biopsy if age > 40 yrs, ALT 1-2 x ULN, or family history of HCC; treat as needed  Preferred drug(s) –Adefovir, entecavir, or peginterferon  Duration of therapy –Continue 6 mo after HBeAg → anti- HBe 2006 US Algorithm  Who to treat? –HBV DNA ≥ 20,000 IU/mL and ALT > ULN* –Consider biopsy if ALT normal and age > 35-40 yrs; treat if disease  Preferred drug(s) –Adefovir, entecavir, or peginterferon  Duration of therapy –Continue 6-12 mos after HBeAg → anti-HBe and HBV DNA- *ULN = 30 IU/mL for men and 19 IU/mL for women. Lok AS, et al. Hepatology. 2007;45:507-539. Keeffe EB, et al. Clin Gastroenterol Hepatol. 2006;4:936-962.

20. clinicaloptions.com/hep Choosing First-Line Therapy in Chronic Hepatitis B Updated from Keeffe EB, et al. Clin Gastroenterol Hepatol. 2006;4:936-962. Treatment Algorithm for HBeAg- Positive Patients  No treatment  Monitor every 6-12 mos  Monitor ALT every 3-12 mos (immune tolerant)  Consider biopsy if age > 35-40 yrs and treat if significant disease  Treat  Adefovir, entecavir, peginterferon, and possibly telbivudine are first-line options HBeAg Positive ALT elevated ALT normal HBV DNA ≥ 20,000 IU/mL HBV DNA < 20,000 IU/mL

21. clinicaloptions.com/hep Choosing First-Line Therapy in Chronic Hepatitis B Case 1 Recommendations  Patient with HBeAg-positive chronic hepatitis B recommended to undergo treatment based on –Serum HBV DNA > 20,000 IU/mL (32,000 IU/mL), elevated ALT > 30 IU/L (56 IU/L) and inflammation (grade 2) and fibrosis (stage 1) on biopsy  Adefovir 10 mg/day, entecavir 0.5 mg/day, telbivudine 600 mg/day (if serum HBV DNA undetectable at Week 24 of therapy), or peginterferon alfa-2a 180 μg/wk are all treatment options  Patient preference for oral vs peginterferon alfa-2a should be assessed

22. Case 2: Choosing First-Line Therapy in an HBeAg-Negative Patient

23. clinicaloptions.com/hep Choosing First-Line Therapy in Chronic Hepatitis B History  54-year-old male born in China  HBV infection diagnosed 6 years ago –Currently asymptomatic and not taking any medications  Works as a marketing manager  2 brothers are both HBsAg positive  No family history of liver cancer

24. clinicaloptions.com/hep Choosing First-Line Therapy in Chronic Hepatitis B Referral Records  Referral records –Elevated ALT levels (60-180 IU/mL) over the 6 months prior to his consultation visit –HBeAg, anti-HBe, and HBV DNA were not assessed  Physical examination unremarkable

25. clinicaloptions.com/hep Choosing First-Line Therapy in Chronic Hepatitis B Laboratory Results: July 2005  ALT: 26 IU/mL  AST: 22 IU/mL  HBeAg negative  Anti-HBe positive  HBV DNA: 800 IU/mL  Anti-HAV IgG positive  HCV/HDV/HIV antibodies negative

26. clinicaloptions.com/hep Choosing First-Line Therapy in Chronic Hepatitis B Questions  In which phase of chronic HBV infection is this patient?  Does this patient meet standard criteria for treatment with antiviral therapy?

27. clinicaloptions.com/hep Choosing First-Line Therapy in Chronic Hepatitis B Initial Impressions  Nonreplicative/inactive HBsAg carrier phase after recent HBeAg seroconversion or  Reactivation/HBeAg-negative chronic hepatitis B phase currently quiescent with minimal viral replication and necroinflammation

28. clinicaloptions.com/hep Choosing First-Line Therapy in Chronic Hepatitis B Management Options  Follow-up with repeated ALT and HBV DNA testing to properly classify phase of infection  Liver biopsy to assess presence and degree of necroinflammation and fibrosis  Noninvasive test for necroinflammation and fibrosis  HBV mutation test for the presence of precore and core promoter mutants

29. clinicaloptions.com/hep Choosing First-Line Therapy in Chronic Hepatitis B December 2005  Patient seen for new fatigue and pain in right upper quadrant  Mild liver tenderness on examination  Laboratory results –ALT: 142 IU/L –AST: 126 IU/L –HBeAg negative –Anti-HBe positive –HBV DNA: 52,000 IU/mL  Liver biopsy: grade 2, stage 2 disease

30. clinicaloptions.com/hep Choosing First-Line Therapy in Chronic Hepatitis B Management Questions  What is this patient’s diagnosis and phase of chronic HBV infection?  Does this patient meet criteria for treatment?  How long should treatment be administered?  Which agents are the best options?

31. clinicaloptions.com/hep Choosing First-Line Therapy in Chronic Hepatitis B Yim HJ, et al. Hepatology. 2006;43:S173-S181. Phases of Chronic HBV Infection: Candidates for Therapy Phases of Chronic HBV Infection Immune Tolerance Immune Clearance/ HBeAg-Positive CHB Nonreplicative (Inactive Carrier) Reactivation/ HBeAg-Negative CHB HBV DNA, IU/mL 10 5 - 10 10 10 4 - 10 10 < 10 4 10 3 - 10 8 HBeAgHBeAg+ HBeAg- ALTNormalHigh or fluctuatingNormalHigh or fluctuating Other-- Active inflammation on liver biopsy HBsAg may become undetectable Active inflammation on liver biopsy Candidates for therapy? NoYesNoYes

32. clinicaloptions.com/hep Choosing First-Line Therapy in Chronic Hepatitis B Chu CJ, et al. Hepatology. 2002;36:1408-1415. Appropriate HBV DNA Level for Treatment in HBeAg-negative Patients  Retrospective analysis of 165 hepatitis B patients in Taiwan –1/3 of HBeAg-negative patients had HBV > 10 5 copies/mL –2/3 of HBeAg-negative patients and all inactive carriers had HBV DNA levels < 10 5 copies/mL  Conclusions regarding HBeAg-negative chronic hepatitis B –Not possible to define single cutoff for HBV DNA to distinguish inactive carrier from HBeAg-negative disease –HBV DNA threshold of > 10 5 copies/mL too high for determining treatment candidacy

33. clinicaloptions.com/hep Choosing First-Line Therapy in Chronic Hepatitis B When to Stop Therapy: 2 Distinct Patient Populations  HBeAg positive (wild type) –HBeAg loss  seroconversion –Durable suppression of HBV DNA to low or undetectable –Therapy discontinued 6-12 months after HBeAg seroconversion; durability of response ~ 80%  HBeAg negative (precore and core promoter mutants) –HBeAg seroconversion not an endpoint –Durable suppression of HBV DNA to low or undetectable –Relapse common after stopping oral therapy –Therapy usually administered long term; several years of undetectable HBV DNA may decrease the relapse rate

34. clinicaloptions.com/hep Choosing First-Line Therapy in Chronic Hepatitis B Treatment Recommendations for HBeAg-Negative Patients 2007 AASLD Guidelines  Who to treat? –HBV DNA > 20,000 IU/mL and ALT > 2 x ULN* –HBV DNA ≥ 2000 IU/mL and ALT 1- 2 x ULN: consider biopsy and treat as needed  Preferred drug(s) –Adefovir, entecavir, or peginterferon  Duration of therapy –Peginterferon x 1 yr –Treat long term with oral agents 2006 US Algorithm  Who to treat? –HBV DNA ≥ 2000 IU/mL and ALT > ULN* –Consider biopsy if ALT normal and age > 35-40 yrs; treat if disease  Preferred drug(s) –Adefovir, entecavir, or peginterferon  Duration of therapy –Peginterferon x 1 yr –Treat long term with oral agents *ULN = 30 IU/mL for men and 19 IU/mL for women. Lok AS, et al. Hepatology. 2007;45:507-539. Keeffe EB, et al. Clin Gastroenterol Hepatol. 2006;4:936-962.

35. clinicaloptions.com/hep Choosing First-Line Therapy in Chronic Hepatitis B Updated from Keeffe EB, et al. Clin Gastroenterol Hepatol. 2006;4:936-962. Treatment Algorithm for HBeAg- Negative Patients  No treatment  Monitor every 6-12 mos  Monitor ALT and HBV DNA or  Consider biopsy since ALT often fluctuates and treat if significant disease  Treat  Adefovir, entecavir, peginterferon, and possibly telbivudine are first-line options  Long-term treatment required (oral agents) HBeAg Negative ALT elevated HBV DNA ≥ 2000 IU/mL HBV DNA < 2000 IU/mL ALT normal

36. clinicaloptions.com/hep Choosing First-Line Therapy in Chronic Hepatitis B Conclusions  Patient has HBeAg-negative chronic hepatitis B, which often has a fluctuating course  Need exists to treat long term using agent with low resistance rates –Adefovir or entecavir are preferred oral treatment options over lamivudine or telbivudine because of resistance rates –Peginterferon alfa-2a is an alternative option

37. Case 3: First-Line Treatment in a Cirrhotic Patient With Hepatitis B

38. clinicaloptions.com/hep Choosing First-Line Therapy in Chronic Hepatitis B History  46-year-old female born in Taiwan and emigrated to United States at 26 years of age  HBV infection diagnosed 8 years ago after other family members were found to be HBsAg carriers –Mother died from complications of liver disease –Details not available –Brother and sister both HBsAg carriers –No family history of liver cancer  Currently asymptomatic  Works part time from home while caring for 2 children  No use of tobacco or alcohol

39. clinicaloptions.com/hep Choosing First-Line Therapy in Chronic Hepatitis B Initial Evaluation  HBeAg positive  Anti-HBe negative  HBV DNA: 4000 IU/mL  ALT: 88 IU/L  AST: 86 IU/L  Complete blood count –Hematocrit: 38% –White blood cells: 3400/mm 3 –Platelet count: 140,000/mm 3  Albumin: 3.6 g/dL  Bilirubin: 1.0 mg/dL  International normalized ratio: 1.0

40. clinicaloptions.com/hep Choosing First-Line Therapy in Chronic Hepatitis B Further Tests  Alpha-fetoprotein: 18 ng/mL  Liver ultrasound –Coarse liver with nodular surface –Mild splenomegaly  Liver biopsy: grade 2, stage 4 disease

41. clinicaloptions.com/hep Choosing First-Line Therapy in Chronic Hepatitis B Questions  Is this patient a candidate for hepatitis B therapy?  What are the most optimal treatment options?  How long should treatment be continued?

42. clinicaloptions.com/hep Choosing First-Line Therapy in Chronic Hepatitis B Keeffe EB, et al. Clin Gastroenterol Hepatol. 2006;4:936-962. Treatment Algorithm: Patients With Compensated Cirrhosis  No treatment  May choose to treat or observe  If treat: adefovir, entecavir, or combination treatment  May be a role for combination therapy  Treat with adefovir or entecavir  May be a role for combination therapy  Significant clinical consequences associated with lamivudine resistance in this population HBV DNA (PCR) HBV DNA ≥ 2000 IU/mL HBV DNA < 2000 IU/mL

43. clinicaloptions.com/hep Choosing First-Line Therapy in Chronic Hepatitis B Liaw YF, et al. N Engl J Med. 2004;351:1521-1531. Delayed Disease Progression With Continued Suppression: Cirrhotics  651 cirrhosis patients from Taiwan with evidence of viral replication Patients With Disease Progression at Follow-up (%) 25 20 15 10 5 0 Placebo (n = 215) 21 P =.001 9 Lamivudine (n = 436)

44. clinicaloptions.com/hep Choosing First-Line Therapy in Chronic Hepatitis B Liaw YF, et al. N Engl J Med. 2004;351:1521-1531. Disease Progression & HCC in LAM Recipients With Advanced Disease  Decreased incidence of HCC at Yr 3 in LAM patients –HCC occurred in 3.9% of LAM patients vs 7.4% of placebo patients –Hazard ratio: 0.49; P =.047  Time to disease progression affected by YMDD status –49% of LAM patients had evidence of YMDD mutations during therapy –Incidence of disease progression in placebo group, 21% vs 13% for LAM patients with YMDD mutations vs 5% for LAM patients with wild-type virus

45. clinicaloptions.com/hep Choosing First-Line Therapy in Chronic Hepatitis B Treatment Recommendations Compensated Cirrhosis 2007 AASLD Guidelines  Who to treat? –HBeAg positive or negative –HBV DNA > 2000 IU/mL; no ALT specified –HBV DNA < 2000 IU/mL; consider treating if ALT elevated –HBV DNA negative; observe  Preferred drug(s) –Adefovir or entecavir 2006 US Algorithm  Who to treat? –HBeAg positive or negative –HBV DNA ≥ 2000 IU/mL; no ALT specified –HBV DNA < 2000 IU/mL; may choose to treat or observe  Preferred drug(s) –Adefovir, entecavir –May be role for combination therapy –May be role for peginterferon in very early cirrhosis Lok AS, et al. Hepatology. 2007;45:507-539. Keeffe EB, et al. Clin Gastroenterol Hepatol. 2006;4:936-962.

46. clinicaloptions.com/hep Choosing First-Line Therapy in Chronic Hepatitis B Lok AS, et al. Hepatology. 2007;45:507-539. Keeffe EB, et al. Clin Gastroenterol Hepatol. 2006;4:936-962. Treatment Recommendations Decompensated Cirrhosis 2007 AASLD Guidelines  Who to treat? –HBeAg positive or negative –Any HBV DNA level  Preferred drug(s) –Lamivudine + adefovir or entecavir monotherapy  Duration of therapy –Long term  Other recommendations –Refer for transplantation 2006 US Algorithm  Who to treat? –HBeAg positive or negative –Any HBV DNA level  Preferred drug(s) –Lamivudine + adefovir or entecavir monotherapy  Duration of therapy –Long term  Other recommendations –Refer for transplantation

47. clinicaloptions.com/hep Choosing First-Line Therapy in Chronic Hepatitis B Potential Role of Combination Therapy  Advantages –Reduced rate of resistance –Potential for added efficacy  Disadvantages –Greater cost –Potential for increased toxicity  Potential patient populations –Patients with HBV antiviral drug resistance –Patients with cirrhosis –After liver transplantation –All patients?

48. clinicaloptions.com/hep Choosing First-Line Therapy in Chronic Hepatitis B Conclusions  Patient has HBeAg-positive chronic hepatitis B with compensated cirrhosis  Based on the need for long-term therapy and lower rates of resistance –Adefovir or entecavir preferred vs lamivudine or telbivudine –Combination therapy with 2 oral agents is an option  Peginterferon alfa-2a is an alternative option but may be less desirable in presence of cirrhosis

49. clinicaloptions.com/hep Choosing First-Line Therapy in Chronic Hepatitis B Summary: Treatment of Chronic Hepatitis B When to start therapy  Elevated serum HBV DNA plus elevated ALT and/or significant disease on liver biopsy –HBeAg-positive CHB: HBV DNA > 20,000 IU/mL –HBeAg-negative CHB: HBV DNA > 2000 IU/mL –CHB with cirrhosis: HBV DNA > 2000 IU/mL or any detectable When to stop or alter therapy  HBeAg-positive CHB: HBeAg seroconversion and undetectable HBV DNA  HBeAg-negative CHB: long-term therapy  Development of antiviral drug resistance  Inadequate virologic response (  2000 IU/mL) at Week 24

50. clinicaloptions.com/hep Choosing First-Line Therapy in Chronic Hepatitis B Summary: Selection of Initial Therapy  Primary decision: peginterferon alfa-2a vs oral agent  Peginterferon an option in a patient with –Genotype A –Low HBV DNA –High ALT –No comorbidities –Desire for a fixed duration of therapy and avoidance of resistance  Choice of oral agent dependent on –Potency: highest with entecavir and telbivudine –Rate of resistance: lowest with entecavir –Cost: lowest with lamivudine and lower with telbivudine –Safety: good for all oral agents –Special circumstances, eg, pregnancy (telbivudine class B and lamivudine good safety experience), HIV coinfection, presence of cirrhosis, etc

51. CME-certified Module of all the key factors influencing decisions regarding choice of first-line therapy in hepatitis B Interactive Case Challenges: review challenging cases and compare your answers to those of your peers Virtual Presentation (slides and audio) plus downloadable PowerPoint slides clinicaloptions.com/FirstLineHBV Go Online for More of This Program!