1. 1 3 rd Paris Hepatitis Congress, 20/1/09 HBeAg-positive patient: Why do I treat with nucleos/tide analogs? Samuel S. Lee University of Calgary Calgary, Canada

2. 2 Speaker declarations Research support: Microgenix, Roche, Schering, Johnson & Johnson, BMS, Gilead, Virochem, Vertex, Merck, GSK, Novartis Consultant: Genentech, Microgenix, Roche, BMS, Novartis, Virochem Speakers Bureau: Roche, Gilead Oui, I am a Francophile!

3. 3 A la recherche des nanas perdues

4. 4 Objectives of this presentation Why treat? Who and when to treat Nucleos/tide treatment o efficacy o monitoring

5. 5 Multiple sexual partners is a risk factor for HBV

6. 6 Natural History of HBV

7. 7 “It was like déjà vu all over again” - Yogi Berra

8. 8 NATURAL HISTORY OF CHRONIC HBV Initial stage of replicative immune- tolerant, 15-25 yrs (N-ALT, HBeAg+) second stage replicating but immune- intolerant (‘immune clearance’), 5-25 yrs (  ALT, HBeAg+) third stage ‘nonreplicative’, generally inactive, (N-ALT, HBeAg-)

9. 9 Natural history of chronic HBV carriage

10. 10 Disease Progression of HBV

11. 11 REVEAL: Relationship between baseline HBV-DNA level & cirrhosis risk Iloeje UH, et al. Gastroenterology 2006; 130:678–686. P value for log-rank test, <0.001 REVEAL *From original enrolment of 3653, 69 diagnosed with cirrhosis and 2 that died within 6 months of entry were removed.

12. 12 HBV and mortality from HCC and CLD: Haimen City population-based study 9 of 35 townships in Haimen, China Original cohort from 1992-93 3464 HBsAg+ inception 701 excluded (mostly lost f/u), younger, non- peasant men; 2763 for study HBV DNA from baseline; 1600cp/ml; 10 5 447 total deaths; 231 HCC, 85 CLD 2003 survivor assessment: 1791 (3/4) agreed Chen G et al. Am J Gastro 2006;101:1797

13. 13 Haimen City cohort: deaths due to HCC Chen G et al. Am J Gastro 2006;101:1797

14. 14 Haimen City cohort: deaths due to CLD Chen G et al. Am J Gastro 2006;101:1797

15. 15 Time after Randomization (months) Disease Progression, % 21% Wild-Type (n = 221) YMDDm (n = 209) 0 5 10 15 20 25 06121824 30 36 Placebo (n = 215) YMDDm WT Placebo 5% 13% Liaw et al. N Engl J Med. 2004;351:1521-1531. Viral suppression in compensated cirrhosis reduces HCC risk?

16. 16 HBV Natural history: conclusions Disease progression depends on several host and viral factors Whether longterm viral suppression by Rx decreases disease progression not proven Threshold levels of HBV DNA and ALT still unclear level of viremia is important

17. 17 Treatment

18. 18 HBV replication (see diagram) Virus penetrates hepatocyte dsDNA made in cytoplasm; cccDNA enters nucleus cccDNA template for RNA transcription pregenomic RNA + polymerase synthesizes neg- strand DNA +strand DNA follows virus packaged in ER, released from hepatocytes

19. 19

20. 20 Which HBeAg+ patients should be treated with nuc analogs?

21. 21 Management considerations Majority of carriers do not die of liver disease 10-25% develop cirrhosis or HCC Unable to reliably predict complications Suppressive vs ‘curative’ Rx Rx: immunostimulant vs viral-suppressive

22. 22 More management considerations ALT levels Biopsy: yes or no? Biopsy results: inflammation, fibrosis levels HCV, HDV or HIV coinfected

23. 23 Algorithm for Selecting HBeAg-Positive Patients for Treatment  Rule out other causes of liver disease HBeAg-positive ALT elevated ALT normal HBV DNA > 20,000 IU/mL HBV DNA > 20,000 IU/mL HBV DNA < 20,000 IU/mL HBV DNA < 20,000 IU/mL ALT elevated for 3-6 months ALT normal  No treatment  Monitor every 3 months with ALT and HBV DNA  No treatment  Monitor every 3 months with ALT and HBV DNA  Monitor every 3 months  Consider biopsy if > 35-40 years  Treat if significant disease  Monitor every 3 months  Consider biopsy if > 35-40 years  Treat if significant disease TREAT Adapted from CASL Consensus Guidelines. Can J Gastroenterol 2007;21(Suppl C):5C-24C.

24. 24 Role of Liver Biopsy Purpose: assess degree of liver damage and rule out other causes of liver disease Most useful in persons who do not meet clear-cut guidelines for treatment Decisions on liver biopsy should take into consideration: –Age –Upper limits of normal for ALT –HBeAg status –HBV DNA levels –Other clinical features suggestive of chronic liver disease or portal hypertension Lok AS, McMahon BJ. Hepatology 2007;45:507-39.

25. 25 Monitoring on Rx Liver chemistry, hemogram, HBVDNA, HBeAg, anti-HBe q-3mo

26. 26 Which nucleos/tide analog?

27. 27 Algorithm for Selection of Specific Treatments for HBeAg-Positive Patients HBeAg-positive High viral load HBV DNA > 20 million IU/mL High viral load HBV DNA > 20 million IU/mL Low viral load HBV DNA < 20 million IU/mL Low viral load HBV DNA < 20 million IU/mL  Standard interferon  Pegylated interferon  Lamivudine  Adefovir  Entecavir  Telbivudine  Tenofovir  Standard interferon  Pegylated interferon  Lamivudine  Adefovir  Entecavir  Telbivudine  Tenofovir  Entecavir  Telbivudine  Tenofovir  Entecavir  Telbivudine  Tenofovir Adapted from CASL Consensus Guidelines. Can J Gastroenterol 2007;21(Suppl C):5C-24C. † Tenofovir is not currently indicated for the treatment of hepatitis B in Canada. Please consult the product monograph for appropriate prescribing information.

28. 28 Relative Potency of Different Antivirals at 48 to 52 Weeks of Therapy Adapted from: 1. CASL Consensus Guidelines.. Can J Gastroenterol 2007;21(Suppl C):5C-24C; 2. Chang TT, et al. N Engl J Med 2006;354:1001-10; 3. Lai CL, et al. N Engl J Med 2006;354:1011-20; 4. Lai CL, et al. Gastroenterology 2005;129:528-36; 5. Marcellin P, et al. Presented at the 58th AASLD; Boston, MA, November 2-6, 2007; 6. Heathcote J, et al. Presented at the 58th AASLD; Boston, MA, November 2-6, 2007. Lamivudine has been compared with entecavir and to telbivudine in two separate randomized controlled trials. Tenofovir † has been compared with adefovir in two separate randomized controlled trials. % of patients with HBV DNA < 80 IU/mL †

29. 29 Relative Potency of Different Antivirals at 48 to 52 Weeks of Therapy Entecavir Lamivudine Telbivudine Lamivudine Adefovir Mean log 10 decline in HBV DNA Tenofovir Adapted from: 1. CASL Consensus Guidelines. Can J Gastroenterol 2007;21(Suppl C):5C-24C; 2. Chang TT, et al. N Engl J Med 2006;354:1001-10; 3. Lai CL, et al. N Engl J Med 2006;354:1011-20; 4. Lai CL, et al. Gastroenterology 2005;129:528-36; 5. Marcellin P, et al. Presented at the 58th AASLD; Boston, MA, November 2-6, 2007; 6. Heathcote J, et al. Presented at the 58th AASLD; Boston, MA, November 2-6, 2007. † Lamivudine has been compared with entecavir and to telbivudine in two separate randomized controlled trials. Tenofovir † has been compared with adefovir in two separate randomized controlled trials.

30. 30 HBeAg Seroconversion Rates with Hepatitis B Antiviral Therapy* Duration of treatment HBe seroconversion rate Standard interferon16-24 weeks33% (HBeAg loss) 1 Pegylated interferon24-48 weeks29-32% 2-4 Lamivudine1 year 3 years 17-20% 5-8 40% 9 Adefovir1 year 3 years 12% 10 43% 11 Entecavir1 year 3 years 21% 8 39% 12 Telbivudine1 year 2 years 22% 13 33% 14 Tenofovir48 weeks21% 15 Adapted from CASL Consensus Guidelines. Sherman M, et al. Can J Gastroenterol 2007;21(Suppl C):5C-24C. 1. Wong DK, et al. Ann Intern Med 1993;119:312-23; 2. Lok AS, et al. Gastroenterology 1987;92:1839-43; 3. Cooksley WG, et al. J Viral Hepat 2003;10:298-305; 4. Lau GK, et al. N Engl J Med 2005;352:2682-95.; 5. Lai CL, et al. N Engl J Med 1998;339:61- 8.; 6. Dienstag JL, et al. N Engl J Med 1999;341:1256-63; 7. Schalm SW, et al. Gut 2000;46:562-8; 8. Chang TT, et al; BEHoLD AI463022 Study Group. N Engl J Med 2006;354:1001-10; 9. Chang TT, et al. J Gastroenterol Hepatol 2004;19:1276-82; 10. Marcellin P, et al; N Engl J Med 2003;348:808-16; 11. Hadziyannis SJ, et al; Adefovir Dipivoxil 438 Study Group. Gastroenterology 2006;131:1743-51; 12. Chang TT, et al. Hepatology 2006;44(Suppl 1):66A. (Abst); 13. DiBisceglie A, et al; Study Group The GLOBE. Hepatology 2006;44(Suppl 1):230A. (Abst) 14. van Bommel F, et al. Hepatology 2006;44:318-25; 15. Heathcote J, et al. 58 th AASLD; Boston, MA, November 2-6, 2007. Lamivudine has been compared with entecavir and to telbivudine in two separate randomized controlled trials. Tenofovir † has been compared with adefovir in two separate randomized controlled trials.

31. 31  May choose to treat or observe  Treat with entecavir, telbivudine, adefovir, tenofovir  Consider combination therapy  May choose to treat or observe  Treat with entecavir, telbivudine, adefovir, tenofovir  Consider combination therapy  Treat with entecavir, telbivudine or tenofovir  Consider combination therapy  Treat with entecavir, telbivudine or tenofovir  Consider combination therapy HBV DNA (PCR) HBV DNA (PCR) HBV DNA < 2000 IU/mL HBV DNA < 2000 IU/mL HBV DNA ≥ 2000 IU/mL HBV DNA ≥ 2000 IU/mL Algorithm for the Management of Hepatitis B Cirrhosis Adapted from CASL Consensus Guidelines. Can J Gastroenterol 2007;21(Suppl C):5C-24C. Patients with cirrhosis who are on therapy should not have therapy withdrawn due to concerns of a hepatitis flare and decompensation

32. 32 CASL Consensus recommendations Resistance linked to insufficient early viral suppression; check HBVDNA at 6 mos, consider switch if detectable Naïve: LAM only for cost, and LVL. ADV <200,000 IU/ml. ETV, Telbivudine, TDF for HVL 6-12 months consolidation Rx after anti-HBe+

33. 33 My preferences HBeAg+: PEG-IFN x 1 yr in younger, low viral load (10 6 IU), and increased ALT Start NA if PEG-IFN unsuccessful NA for older, HVL, cirrhosis, longterm suppression

34. 34 Conclusions Selection of pts for Rx based on viral load, ALT, biopsy, age and other factors Cirrhosis: once you start, do not stop (unless HBsAg loss) Both IFN and NA have roles in Rx NA choice tailored according to cost/benefit and viral load