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Samuel S. Lee University of Calgary Calgary, Canada

Understand the rationale, timing, and efficacy of nucleoside analog therapy in HBeAg-positive HBV patients. Explore disease progression, monitoring, and treatment considerations. Learn about the CASL guidelines for selecting and monitoring treatments.

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Samuel S. Lee University of Calgary Calgary, Canada

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

  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. A la recherche des nanas perdues

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

  5. Multiple sexual partners is a risk factor for HBV

  6. Natural History of HBV

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

  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. Natural history of chronic HBV carriage

  10. Disease Progression of HBV

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

  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; <105; >105 • 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. Haimen City cohort: deaths due to HCC Chen G et al. Am J Gastro 2006;101:1797

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

  15. Viral suppression in compensated cirrhosis reduces HCC risk? 25 Placebo (n = 215) 21% YMDDm (n = 209) 20 Wild-Type (n = 221) Placebo 15 13% Disease Progression, % YMDDm 10 WT 5% 5 0 36 0 6 12 18 24 30 Time after Randomization (months) Liaw et al. N Engl J Med. 2004;351:1521-1531.

  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. Treatment

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

  20. 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

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

  22. Algorithm for Selecting HBeAg-Positive Patients for Treatment HBeAg-positive HBV DNA > 20,000IU/mL HBV DNA < 20,000IU/mL ALT normal ALT elevated ALT elevated for 3-6 months ALT normal • Monitor every3 months • Consider biopsy if > 35-40 years • Treat if significant disease TREAT • Rule out other causes of liver disease • No treatment • Monitor every3 months with ALT and HBV DNA Adapted from CASL Consensus Guidelines. Can J Gastroenterol 2007;21(Suppl C):5C-24C.

  23. 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.

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

  25. Which nucleos/tide analog?

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

  27. Relative Potency of Different Antivirals at 48 to 52 Weeks of Therapy % of patients with HBV DNA < 80 IU/mL † 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. 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. Gastroenterology2005;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.

  28. Relative Potency of Different Antivirals at 48 to 52 Weeks of Therapy Lamivudine Telbivudine Entecavir Lamivudine Adefovir Tenofovir Mean log10 decline in HBV DNA † 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. 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 JMed 2006;354:1011-20; 4. Lai CL, et al. Gastroenterology2005;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.

  29. HBeAg Seroconversion Rates with Hepatitis B Antiviral Therapy* 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. 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 Med1993;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 Med2005;352:2682-95.; 5. Lai CL, et al. N Engl J Med1998;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 Hepatol2004;19:1276-82; 10. Marcellin P, et al; N Engl J Med 2003;348:808-16; 11. Hadziyannis SJ, et al; Adefovir Dipivoxil 438Study 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. Hepatology2006;44(Suppl 1):230A.(Abst) 14. van Bommel F, et al. Hepatology 2006;44:318-25; 15. Heathcote J, et al. 58th AASLD; Boston, MA, November 2-6, 2007.

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

  31. 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+

  32. My preferences • HBeAg+: PEG-IFN x 1 yr in younger, low viral load (106 IU), and increased ALT • Start NA if PEG-IFN unsuccessful • NA for older, HVL, cirrhosis, longterm suppression

  33. 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

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