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Introduction Eugene R. Schiff, MD
Introduction Eugene R. Schiff, MD
Introduction Eugene R. Schiff, MD
Introduction Eugene R. Schiff, MD
Introduction Eugene R. Schiff, MD
Introduction Eugene R. Schiff, MD
Introduction Eugene R. Schiff, MD
Introduction Eugene R. Schiff, MD
Introduction Eugene R. Schiff, MD
Introduction Eugene R. Schiff, MD
Introduction Eugene R. Schiff, MD
Introduction Eugene R. Schiff, MD
Introduction Eugene R. Schiff, MD
Introduction Eugene R. Schiff, MD
Introduction Eugene R. Schiff, MD
Introduction Eugene R. Schiff, MD
Introduction Eugene R. Schiff, MD
Introduction Eugene R. Schiff, MD
Introduction Eugene R. Schiff, MD
Introduction Eugene R. Schiff, MD
Introduction Eugene R. Schiff, MD
Introduction Eugene R. Schiff, MD
Introduction Eugene R. Schiff, MD
Introduction Eugene R. Schiff, MD
Introduction Eugene R. Schiff, MD
Introduction Eugene R. Schiff, MD
Introduction Eugene R. Schiff, MD
Introduction Eugene R. Schiff, MD
Introduction Eugene R. Schiff, MD
Introduction Eugene R. Schiff, MD
Introduction Eugene R. Schiff, MD
Introduction Eugene R. Schiff, MD
Introduction Eugene R. Schiff, MD
Introduction Eugene R. Schiff, MD
Introduction Eugene R. Schiff, MD
Introduction Eugene R. Schiff, MD
Introduction Eugene R. Schiff, MD
Introduction Eugene R. Schiff, MD
Introduction Eugene R. Schiff, MD
Introduction Eugene R. Schiff, MD
Introduction Eugene R. Schiff, MD
Introduction Eugene R. Schiff, MD
Introduction Eugene R. Schiff, MD
Introduction Eugene R. Schiff, MD
Introduction Eugene R. Schiff, MD
Introduction Eugene R. Schiff, MD
Introduction Eugene R. Schiff, MD
Introduction Eugene R. Schiff, MD
Introduction Eugene R. Schiff, MD
Introduction Eugene R. Schiff, MD
Introduction Eugene R. Schiff, MD
Introduction Eugene R. Schiff, MD
Introduction Eugene R. Schiff, MD
Introduction Eugene R. Schiff, MD
Introduction Eugene R. Schiff, MD
Introduction Eugene R. Schiff, MD
Introduction Eugene R. Schiff, MD
Introduction Eugene R. Schiff, MD
Introduction Eugene R. Schiff, MD
Introduction Eugene R. Schiff, MD
Introduction Eugene R. Schiff, MD
Introduction Eugene R. Schiff, MD
Introduction Eugene R. Schiff, MD
Introduction Eugene R. Schiff, MD
Introduction Eugene R. Schiff, MD
Introduction Eugene R. Schiff, MD
Introduction Eugene R. Schiff, MD
Introduction Eugene R. Schiff, MD
Introduction Eugene R. Schiff, MD
Introduction Eugene R. Schiff, MD
Introduction Eugene R. Schiff, MD
Introduction Eugene R. Schiff, MD
Introduction Eugene R. Schiff, MD
Introduction Eugene R. Schiff, MD
Introduction Eugene R. Schiff, MD
Introduction Eugene R. Schiff, MD
Introduction Eugene R. Schiff, MD
Introduction Eugene R. Schiff, MD
Introduction Eugene R. Schiff, MD
Introduction Eugene R. Schiff, MD
Introduction Eugene R. Schiff, MD
Introduction Eugene R. Schiff, MD
Introduction Eugene R. Schiff, MD
Introduction Eugene R. Schiff, MD
Introduction Eugene R. Schiff, MD
Introduction Eugene R. Schiff, MD
Introduction Eugene R. Schiff, MD
Introduction Eugene R. Schiff, MD
Introduction Eugene R. Schiff, MD
Introduction Eugene R. Schiff, MD
Introduction Eugene R. Schiff, MD
Introduction Eugene R. Schiff, MD
Introduction Eugene R. Schiff, MD
Introduction Eugene R. Schiff, MD
Introduction Eugene R. Schiff, MD
Introduction Eugene R. Schiff, MD
Introduction Eugene R. Schiff, MD
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  • 1. Introduction Eugene R. Schiff, MD Leonard Miller Professor of Medicine Chief, Division of Hepatology Director, Center for Liver Disease University of Miami School of Medicine Miami, Florida
  • 2. HBV DNA >10 4-5 c/mL ALT 1–2 x ULN When Do You Start Therapy?
  • 3. Adefovir Entecavir Peginterferon Lamivudine? What Are the First-Line Therapeutic Options? HBV DNA >10 4-5 c/mL ALT 1–2 x ULN When Do You Start Therapy?
  • 4. Choice of drug Monitor patient status Switch or add-on therapy Compliance How Do You Manage Resistance, Breakthrough, and Suboptimal Response? Adefovir Entecavir Peginterferon Lamivudine? What Are the First-Line Therapeutic Options? HBV DNA >10 4-5 c/mL ALT 1–2 x ULN When Do You Start Therapy?
  • 5. HBeAg seroconversion? HBV DNA <10 4-5 c/mL? Normalization of ALT? When Do You Stop Therapy? Choice of drug Monitor patient status Switch or add-on therapy Compliance How Do You Manage Resistance, Breakthrough, and Suboptimal Response? Adefovir Entecavir Peginterferon Lamivudine? What Are the First-Line Therapeutic Options? HBV DNA >10 4-5 c/mL ALT 1–2 x ULN When Do You Start Therapy?
  • 6. When Do You Initiate HBV Therapy? Kris V. Kowdley, MD Professor of Medicine School of Medicine University of Washington Medical Center Seattle, Washington
  • 7. Natural Progression of HBV Chronic Infection Cirrhosis Death <ul><li>Torresi J, et al. Gastroenterology . 2000;118:S83. 2. Fattovich G, et al. Hepatology . 1995;21:77. </li></ul><ul><li>3. Perrillo RP, et al. Hepatology . 2001;33:424. </li></ul>5%–10% 1 Liver Failure 30% 1 23% in 5 y 2 Liver Cancer (HCC) Chronic HBV is the 6th leading indication of liver transplantation in the US 3 ( ~ 5%) Liver Transplantation Acute flare 6% in 5 y 2
  • 8. Treatment Endpoints in Chronic Hepatitis B Undetectable Serum HBV DNA HBeAg Loss or Seroconversion HBsAg Clearance Treatment Endpoints Decreased HAI and Fibrosis <ul><li>0 </li></ul>Normal ALT cccDNA Clearance
  • 9. Objectives of Therapy <ul><li>Decrease hepatic inflammation </li></ul><ul><li>Decrease rate of progression to fibrosis </li></ul><ul><li>Decrease incidence of long-term sequelae (cirrhosis, end-stage liver disease, hepatocellular carcinoma) </li></ul>
  • 10. Goals of Treatment in HBV <ul><ul><li>Suppression of viral replication </li></ul></ul><ul><ul><li>Eradication of serum HBV DNA </li></ul></ul><ul><ul><li>HBeAg seroconversion </li></ul></ul><ul><ul><li>Liver histology improvement or stabilization </li></ul></ul><ul><ul><li>HBsAg loss </li></ul></ul>
  • 11. Anti-HBV Treatment Guidelines *New published reports coming out soon. 1. Lok ASF, et al. Hepatology. 2001;34:1225. 2. Lok ASF, et al. Hepatology. 2004;39:857. 3. Lok ASF, et al. Gastroenterology. 2001;120:1828. 4. Keeffe EB, et al. Clin Gastroenterol Hepatol. 2004;2:87. 5. de Franchis R, et al. J Hepatol. 2003;39:S3. 6. Liaw YF, et al. J Gastroenterol Hepatol. 2003;18:239. Keeffe EB, et al 4 2004 Position paper US Algorithm* Lok ASF, et al 3 2000/2001 Position paper NIH conference* (US) Liaw YF, et al 6 2003 Consensus statement APASL (Asia) de Franchis R, et al 5 2003 Evidence-based EASL (Europe) Lok ASF, et al 1,2 2001; updated 2004 Evidence-based AASLD (US) Author Year Type
  • 12. Accepted Criteria for Therapy <ul><li>For patients without cirrhosis </li></ul><ul><ul><li>HBV DNA >10 5 copies/mL 1,2 </li></ul></ul><ul><ul><li>ALT >2 x ULN 1,2 </li></ul></ul><ul><li>For patients with cirrhosis </li></ul><ul><ul><li>ALT criteria not necessary 1-3 </li></ul></ul><ul><ul><li>HBV DNA thresholds are variable 1-3 </li></ul></ul>1. Lok ASF, et al. Hepatology. 2004;39:857. 2. de Franchis, et al. J Hepatol. 2003;39:S3. 3. Liaw YF, et al. J Gastroenterol Hepatol. 2003;18:239.
  • 13. Which Patients Should Be Treated? AASLD Guidelines 1 HBV DNA HBeAg (copies/mL) ALT Management + >10 5 ≤2 x ULN Follow + >10 5 >2 x ULN Treat – >10 5 >2 x ULN Treat – – ≤ 2 x ULN Follow +/– >10 5 Cirrhosis If compensated, treat; if decompensated*, refer for liver transplant +/– – Cirrhosis If compensated, observe; if decompensated*, refer for liver transplant 1. Lok ASF, et al. Hepatology. 2004;39:857. 2. INTRON® A (interferon alfa-2b) Product Information. Kenllworth, NJ: Schering Corporation: 2004. 3. PEGASYS® (peginterferon alfa-2a) Product Information. Nutley, NJ: Hoffmann-La Roche Inc.: 2004. * Do not use interferon or peginterferon if the patient has decompensated cirrhosis. 2,3 Specific treatment recommendations are made elsewhere in this activity.
  • 14. US Treatment Algorithm Update HBeAg+ Compensated Disease <ul><li>No treatment </li></ul><ul><li>Monitor every 6 – 12 mo </li></ul><ul><li>Monitor every 3–12 mo (immune tolerant) </li></ul><ul><li>Consider biopsy, if age >35–40 y, and treat if significant disease </li></ul>Treat HBeAg Positive ALT Elevated ALT Normal HBV DNA ≥ 10 5 c/mL HBV DNA <10 5 c/mL Courtesy of Emmet Keeffe, MD. Keeffe EB, et al. Clin Gastroenterol Hepatol. 2006: In press.
  • 15. US Treatment Algorithm Update HBeAg– Compensated Disease <ul><li>No treatment </li></ul><ul><li>Monitor every 6 – 12 mo </li></ul><ul><li>Monitor ALT, or </li></ul><ul><li>Consider biopsy, since ALT often fluctuates, and treat if significant disease </li></ul><ul><li>Long-term treatment required </li></ul><ul><li>Treat </li></ul><ul><li>Long-term treatment required </li></ul>HBeAg Negative ALT Elevated ALT Normal HBV DNA ≥ 10 4 c/mL HBV DNA <10 4 c/mL Courtesy of Emmet Keeffe, MD. Keeffe EB, et al. Clin Gastroenterol Hepatol. 2006: In press.
  • 16. US Treatment Algorithm Update Compensated Cirrhosis May Choose to Treat or Observe Treat HBV DNA (PCR) HBV DNA <10 4 c/mL HBV DNA ≥ 10 4 c/mL Courtesy of Emmet Keeffe, MD. Keeffe EB, et al. Clin Gastroenterol Hepatol. 2006: In press.
  • 17. US Treatment Algorithm Update Decompensated Cirrhosis <ul><li>Observe </li></ul><ul><li>Wait list for transplant </li></ul><ul><li>Treat </li></ul><ul><li>Wait list for transplant </li></ul>HBV DNA Detectable by PCR? No Yes Courtesy of Emmet Keeffe, MD. Keeffe EB, et al. Clin Gastroenterol Hepatol. 2006: In press.
  • 18. Prevalence of Fibrosis Among Patients with Immunotolerance <ul><li>14 immunotolerant individuals recruited </li></ul><ul><ul><li>HBV DNA ≥10 6 copies/mL (median 5.1 x 10 7 ; range 4.5 x 10 3 –3.4 x 10 8 ) </li></ul></ul><ul><ul><li>2 normal ALT measurements within 2 years prior to liver biopsy (median 28 U/L; range 13–77 U/L) </li></ul></ul><ul><ul><li>Liver histology measured with Batts and Ludwig scoring </li></ul></ul><ul><li>79% of individuals had fibrosis </li></ul><ul><ul><li>Stage 1, 36%—Stage 2, 43% </li></ul></ul><ul><ul><li>No cirrhosis or septal fibrosis </li></ul></ul><ul><li>Baseline mean ALT poorly correlated with liver biopsy stage </li></ul><ul><ul><li>R 2 coefficient = .08 </li></ul></ul>Wang C, et al. Hepatology. 2005;42:573A.
  • 19. Role of Liver Biopsy in Patients with Normal ALT and High Viral Load <ul><li>190 individuals with HBV DNA >10,000 copies/mL </li></ul><ul><ul><li>Persistently normal ALT*, n = 57 </li></ul></ul><ul><li>24% of individuals with persistently normal ALT levels had stage 2–4 fibrosis </li></ul>*Persistently normal ALT, 2 measurements 6 months apart. Courtesy of M. Lai, MD. Lai M, et al. Hepatology. 2005;42:720A. Multiple Regression Analysis for Stage ≥ 2 Fibrosis .0216 1.160–6.476 2.741 Alcohol intake <.0001 1.027–1.080 1.053 Age <.0001 4.010–11.500 6.790 Inflammation grade .0020 1.235–2.558 1.778 ALT P Value 95% CI OR Parameter
  • 20. Clinical Significance of Viral Replication Worsening Histology, Including Cirrhosis HCC Viral Replication Elevated ALT
  • 21. Baseline HBV DNA Level and Relative Risk of HCC <ul><li>Multivariate-adjusted relative risk of HCC by cohort (N = 3653) entry serum HBV DNA level (94% of subjects with ALT <1 x ULN) </li></ul><ul><li>Adjusted for gender, age, smoking, alcohol consumption </li></ul>0 7 <300 300–9.9x10 3 1.0–9.9x10 4 1.0–9.9x10 5 >10 5 Relative Risk 1 1.1 2.3 6.6 6.1 HBV DNA (copies/mL) 6 5 4 3 2 1 Chen C-J, et al. JAMA. 2006;295:65.
  • 22. Baseline HBV DNA Level and Cumulative Incidence of HCC 0 2 4 6 8 10 12 14 16 <300 300–<10 4 10 4 –<10 5 10 5 –<10 6 ≥ 10 6 N = 3653, 11-y follow-up Cumulative Incidence of HCC Chen C-J, et al. JAMA. 2006;295:65. HBV DNA (copies/mL) 1.3 1.37 3.57 12.17 14.89
  • 23. Baseline HBV DNA Level and Relative Risk of Cirrhosis Iloeje UH, et al, Gastroenterology. 2006;130:678. 0 10 <300 300–9.9x10 3 1.0–9.9x10 4 1.0–9.9x10 5 >10 5 N = 3653, 11-y follow-up Relative Risk 1 1.4 2.5 5.9 9.8 Adjusted for gender, age, smoking, alcohol consumption HBV DNA (copies/mL) 7 6 5 4 3 2 1 9 8
  • 24. Effect of Lamivudine on Incidence of HCC Time of Diagnosis of HCC Reprinted with permission, from Liaw YF, et al. N Engl J Med. 2004;351:1521. Copyright © 2004 Massachusetts Medical Society. All rights reserved. Months Lamivudine Placebo Diagnosis of HCC (%) 0 10 6 0 12 18 24 30 36 P = .047
  • 25. Effective Viral Suppression Reduces Level of Inflammation on Biopsy Mommeja-Marin H, et al. Serum HBV DNA as a marker of efficacy during therapy for chronic HBV infection: analysis and review of the literature. Hepatology. 2003;37:1309. Reprinted with permission of Wiley-Liss, Inc., a subsidiary of John Wiley & Sons, Inc. Review of 26 prospective studies (3428 patients) Median Improvement in HAI HBV DNA Median log 10 Decrease r = 0.96 P < .000003 N = 3428 Post-treatment vs baseline 0 1 2 3 4 5 1 2 3 4 5 -1 -2
  • 26. Goals of Treatment Are Changing! 1980s: Reduce severity of liver disease
  • 27. Goals of Treatment Are Changing! 1980s: Reduce severity of liver disease 1990s: Reduce viral replication
  • 28. Goals of Treatment Are Changing! 1980s: Reduce severity of liver disease 1990s: Reduce viral replication 2000s: Prevent cancer?
  • 29. Initial Therapy: What Are the Therapeutic Options and Considerations? Robert G. Gish, MD Medical Director Liver Transplant Program California Pacific Medical Center San Francisco, California
  • 30. Current FDA-Approved Anti-HBV Therapies <ul><li>Interferon alfa-2b </li></ul><ul><li>Lamivudine </li></ul><ul><li>Peginterferon alfa-2a </li></ul><ul><li>Adefovir </li></ul><ul><li>Entecavir </li></ul>
  • 31. Lamivudine
  • 32. Lamivudine Considerations for Use <ul><li>Short-term therapy </li></ul><ul><ul><li>Chemotherapy </li></ul></ul><ul><ul><li>Immune suppressants </li></ul></ul><ul><ul><li>Pregnancy </li></ul></ul><ul><li>Cost </li></ul><ul><li>Lamivudine no longer a first-choice therapy due to high rate of resistance 1 </li></ul>1. Keeffe EB, et al. Clin Gastroenterol Hepatol. 2006: In press.
  • 33. Peginterferon
  • 34. Peginterferon Considerations for Use <ul><li>HBeAg+ </li></ul><ul><ul><li>Genotype A 1,2 </li></ul></ul><ul><ul><li>ALT >80 IU/mL 2 </li></ul></ul><ul><ul><li>HBV DNA <10 8 copies/mL 2 </li></ul></ul><ul><ul><li>Compensated liver disease guidelines 3-6 </li></ul></ul><ul><ul><li>Monoinfected </li></ul></ul><ul><ul><li>No psychiatric or medical contraindications </li></ul></ul><ul><li>HBeAg- </li></ul><ul><ul><li>No specific populations that benefit over others 7 </li></ul></ul><ul><ul><li>Modest number of patients negative by PCR long-term 7 </li></ul></ul><ul><li>Consider PEG IFN before nucleos(t)ide therapy due to defined treatment intervals and high HBeAg seroconversion rates </li></ul><ul><li>Should not be used in decompensated cirrhosis 8 </li></ul>1. Janssen HL, et al. Lancet. 2005;365:123. 2. Lau G, et al. N Engl J Med. 2005;352:2682. 3. Liaw YF, et al. J Gastroenterol Hepatol. 2003;18:239. 4. De Franchis R, et al. J Hepatol. 2003;39:S3. 5. Lok AS, et al. Gastroenterology. 2001;120:1828. 6. Lok ASF, et al. Hepatology. 2004;39:957. 7. Marcellin P, et al. Hepatology. 2005;42:580A. 8. PEGASYS® (peginterferon alfa-2a) Product Information. Nutley, NJ: Hoffmann-La Roche Inc.: 2004.
  • 35. Peginterferon alfa-2a ± Lamivudine 24-Weeks Posttreatment, Overall 32% 32% 27% 34% 19% 22% 0 20 40 60 HBeAg Seroconversion HBV DNA <100,000 copies/mL PEG IFN (n = 271) PEG IFN + lamivudine (n = 271) Patients (%) With permission from Chow WC, et al. Hepatology. 2005;42:576A. P < .001 P < .012 Lamivudine (n = 272)
  • 36. Peginterferon alfa-2a ± Lamivudine at 24-Weeks Posttreatment HBeAg Seroconversion, by Genotype 52% 30% 31% 22% 22% 29% 28% 18% 20% 23% 18% 18% 0 20 40 60 A B C D 12/23 4/18 3/15 23/76 24/82 17/73 50/162 43/156 29/162 2/9 2/11 3/17 Patients with HBeAg Seroconversion (%) P = .002* Genotype P = .002* *Mantel Haenszel Chi Square test stratified for the effect of HBV genotype With permission from Chow WC, et al. Hepatology. 2005;42:576A. PEG IFN (n = 271) PEG IFN + lamivudine (n = 271) Lamivudine (n = 272)
  • 37. Adefovir 5-Year Data Now Available
  • 38. Adefovir Considerations for Use <ul><li>HBeAg+ and HBeAg- infection </li></ul><ul><li>Continued use if 1-log reduction every 3 mo and HBV PCR negative at 12–15 mo 1,2 </li></ul><ul><ul><li>If resistant to adefovir, switch to or add lamivudine, or switch to entecavir 3 </li></ul></ul>1. Locarnini S, et al. 40th EASL. April 13–17, 2005. Abstract 36. 2. Unpublished expert opinion. 3. Keeffe EB, et al. Clin Gastroenterol Hepatol. 2006: In press.
  • 39. The Efficacy of Adefovir Dipivoxil is Sustained in HBeAg- Patients Over 5 Years 68% 75% 71% 72% 77% 67% 78% 75% 0 20 40 60 80 100 Patients % Serum HBV DNA < 1000 copies/mL ALT Normalization Treatment Duration (Weeks) 48 96 144 192 48 96 144 192 67% 240 69% 240 5-year cohort of patients Hadziyannis S, et al. Management of Hepatitis B: 2006: NIH. April 6–8, 2006.
  • 40. Long-Term Adefovir in HBeAg- Infection Proportion of Patients with Improved Ishak Fibrosis Scores Over Time 8/24 (33%) 11/24 (46%) † 17/24 (71%) P = .005* *Cochran-Armitage exact test of trend over time for 5-y cohort. † LOCF (no improvement) n = 9 for 4-y cohort; n = 15 for 5-y. ‡ 1 patient received concomitant lamivudine. 7/22 (32%) † 12/22 (55%) ‡ 5-y cohort 4-y cohort 0 10 20 30 40 50 60 70 80 0 1 2 3 4 5 Years of Adefovir Treatment Ishak Fibrosis Reduced ≥ 1 Point (%) Hadziyannis S, et al. Hepatology. 2005;42:754A. Reprinted with permission.
  • 41. Safety of Adefovir Dipivoxil Over 4–5 Years <ul><li>Renal safety </li></ul><ul><ul><li>No on-treatment hypophosphatemia </li></ul></ul><ul><ul><li>4 patients (3%) had confirmed increases in creatinine ≥0.5 mg/dL </li></ul></ul><ul><ul><ul><li>Maximum value 1.5 mg/dL </li></ul></ul></ul><ul><ul><ul><li>Maximum increase 0.8 mg/dL </li></ul></ul></ul><ul><li>Adverse events </li></ul><ul><ul><li>3 patients permanently discontinued adefovir due to an adverse event </li></ul></ul><ul><ul><li>Serious adverse events occurred in 24 patients (19%) </li></ul></ul><ul><ul><ul><li>None were related to adefovir </li></ul></ul></ul><ul><ul><ul><li>3 patients developed hepatocellular carcinoma </li></ul></ul></ul>Hadziyannis S, et al. Hepatology. 2005;42:754A.
  • 42. Entecavir 2-Year Data Now Available
  • 43. Entecavir Considerations for Use <ul><li>Nucleoside-naive infection </li></ul><ul><ul><li>HBeAg+ </li></ul></ul><ul><ul><li>HBeAg- </li></ul></ul><ul><li>Lamivudine-resistant infection </li></ul><ul><li>Continued use if 1-log reduction every 3 months 1,2 </li></ul><ul><ul><li>If not, add tenofovir or adefovir </li></ul></ul>1. Locarnini S, et al. 40th EASL. April 13–17, 2005. Abstract 36. 2. Unpublished expert opinion.
  • 44. Entecavir Phase 3 Studies Histologic Endpoints – Primary Efficacy Endpoint Primary analysis: only patients with evaluable baseline biopsy included; missing/inadequate week-48 biopsy counted as failures. *Treatment for 52 weeks up to 96 weeks for partial responders. †Treatment for 48 weeks for up to 96 weeks for partial responders. FDA. Entecavir briefing document. February 10, 2005. ETV = entecavir; LVD = lamivudine. 16% 34% 38% 36% 35% 39% Ishak fibrosis score improvement 32% 55% 64% 73% 64% 74% Necroinflammatory > 2-point decrease 70% 87% 79% 84% 82% 89% Fibrosis no worse 28% 55% 61% 70% 62% 72% Overall histologic improvement LVD 100 mg (n = 116) ETV 1 mg (n =1 24) LVD 100 mg (n =2 87) ETV 0.5 mg (n = 296) LVD 100 mg (n = 314) ETV 0.5 mg (n = 314) Study 026 † LVD-Refractory Study 027* HBeAg– Study 022* HBeAg+
  • 45. Entecavir Phase 3 Studies Selected Secondary Efficacy Endpoints FDA. Entecavir briefing document. February 10, 2005. ETV = entecavir; LVD = lamivudine. *Treatment for 52 weeks up to 96 weeks for partial responders. †Treatment for 48 weeks for up to 96 weeks for partial responders. 17% 65% 71% 78% 61% 69% ALT normalization (<1 x ULN) 3% 8% NA NA 18% 21% HBeAg seroconversion -0.5 -5.1 -4.7 -5.2 -5.5 -7.0 Log HBV DNA by PCR (mean change from baseline) 1% 22% 77% 95% 42% 72% HBV DNA PCR <400 copies/mL LVD 100 mg ETV 1 mg LVD 100 mg ETV 0.5 mg LVD 100 mg ETV 0.5 mg Study 026 † LVD-Refractory Study 027* HBeAg– Study 022* HBeAg+
  • 46. Entecavir vs Lamivudine in HBeAg+ Infection* Virologic Response at Week 48 and Through Week 96 *Nucleoside-naive infection. † EOD (end of dosing) is defined as the last observation on-treatment. 64% 40% 0 20 40 60 80 100 Entecavir % HBV DNA <300 copies/mL 156/243 66/164 Lamivudine Week 48 Week 48 81% 39% 197/243 64/164 EOD* EOD † Gish RG, et al. Hepatology. 2005;42:267A. Entecavir (n = 354) Lamivudine (n = 355)
  • 47. Entecavir vs Lamivudine in HBeAg+ Infection* Serologic Response at Week 48 and Through Week 96 50 31% 26% 5% 3% 110/354 92/355 18/354 10/355 0 10 20 30 40 HBeAg Seroconversion HBsAg Loss % Patients Entecavir (n = 354) Lamivudine (n = 355) Gish RG, et al. Hepatology. 2005;42:267A. *Nucleoside-naive infection.
  • 48. All Treated HBeAg- Patients: Cumulative Confirmed HBV DNA Undetectable by PCR Through Week 96 0 10 20 30 40 50 60 70 80 90 100 Entecavir Lamivudine ALT  1 x ULN HBV DNA < 300 copies/mL 89% 84% 94% 77% P < .0001 P < .05 With permission from Shouval D, et al. 41st EASL. April 26–30, 2006. Abstract 45. Patients (%)
  • 49. Tenofovir A Medication in Evolution
  • 50. Tenofovir Potential Role <ul><li>We need phase 3 trial results </li></ul><ul><li>Coinfected patients </li></ul><ul><li>Lamivudine-resistant infection (HIV negative) </li></ul><ul><ul><li>Yes, if the patient fails </li></ul></ul><ul><ul><ul><li>Adefovir </li></ul></ul></ul><ul><ul><ul><ul><li>and </li></ul></ul></ul></ul><ul><ul><ul><li>Entecavir </li></ul></ul></ul><ul><li>Adefovir partial responder = incomplete responder </li></ul><ul><ul><li>Yes, if fails entecavir </li></ul></ul>
  • 51. Telbivudine <ul><li>Awaiting final results </li></ul><ul><li>Robust viral suppression </li></ul><ul><li>High HBeAg seroconversion </li></ul><ul><li>Good safety profile </li></ul><ul><li>5%+? resistance: need all patients who are DNA positive on treatment, screened for mutations </li></ul>
  • 52. Summary of Three Recent International Meetings <ul><li>HBV DNA quantification is emerging as the best single indicator of patient prognosis, including HCC 1,2 </li></ul><ul><li>Use the anti-HBV agent with the highest rate of HBV DNA suppression/negativity 1 </li></ul><ul><li>For HBeAg+ patients, also consider the rate of HBeAg seroconversion and durability of seroconversion (PEG IFN) 3 </li></ul><ul><li>Resistance is bad and has multiple implications 1 </li></ul><ul><li>Liver biopsy still has a role in selecting patients for treatment 1 </li></ul><ul><li>Long-term data are available on entecavir (2 years) and adefovir (5 years) in terms of safety and efficacy 1,3 </li></ul><ul><li>New data from China have shown equal efficacy for both adefovir and entecavir compared with data from licensing studies 2 </li></ul>1. NIH - Management of Hepatitis B: 2006. 2. 2006 Shanghai-Hong Kong International Liver Congress: 2006. 3. 41st EASL: 2006.
  • 53. Experts’ Approach to Managing Resistance, Breakthrough, and Suboptimal Response Norah A. Terrault, MD, MPH Assistant Professor of Medicine Department of Gastroenterology University of California, San Francisco San Francisco, California
  • 54. Definitions of Resistance <ul><li>Genotypic resistance </li></ul><ul><ul><li>Mutations in HBV genome that occur during therapy and confer drug resistance </li></ul></ul><ul><li>Virologic breakthrough </li></ul><ul><ul><li>Rebound of serum HBV DNA levels by ≥1 log after prior decline </li></ul></ul><ul><ul><li>Follows development of genotypic resistance </li></ul></ul><ul><li>Clinical breakthrough </li></ul><ul><ul><li>Virologic breakthrough with increase in ALT levels, worsening histology, or liver function </li></ul></ul><ul><li>Phenotypic resistance </li></ul><ul><ul><li>Decreased in vitro susceptibility to antiviral drugs associated with genotypic resistance </li></ul></ul>
  • 55. Dynamics of Drug Resistance Pallier C, et al. J Virology. 2006;80:643. Reprinted with permission from American Society of Microbiology. Lamivudine, 100 mg/day HBV DNA ALT AST HBV-DNA (IU/mL) ALT/AST (IU/mL) Lamivudine-sensitive Lamivudine-resistant Real-time PCR cutoff bDNA cutoff 10 9 10 6 10 3 500 400 300 200 100 M0 M2 M4 M6 M8 M10 M12 M14 M16 M18 M20 M22 M24 M26 M28 M30 M32 M34 M36 0%/100% 50 100%/0%
  • 56. Manifestations of Drug Resistance <ul><li>Relapse of HBV DNA </li></ul><ul><li>ALT elevation </li></ul><ul><li>Decline in liver synthetic function </li></ul><ul><li>Worsening of liver decompensation </li></ul><ul><ul><li>Can be acute presentation </li></ul></ul><ul><li>Liver-related death </li></ul><ul><li>Need for liver transplantation </li></ul>Lok AS, et al. Gastroenterology. 2003;125:1714.
  • 57. Incidence of Resistance in Nucleos(t)ide-Naive Patients Viral mutations conferring resistance are less frequent & delayed in onset with adefovir and entecavir versus lamivudine 24% 2% 42% 11% 53% 70% 0 10 20 30 40 50 60 70 80 Year 1 Year 2 Year 3* Year 4* Incidence of Resistance (%) Lamivudine 1 (YMDD) Adefovir (N236T+A181V) 2 0% 18% Entecavir 3 0% 0% 1. Lai C-L, et al. Clin Infect Dis. 2003;36:687. 2. Locarnini S, et al. 40th EASL. April 13–17, 2005. Abstract 36. 3. Colonno R, et al. Hepatology. 2005;42:573A. Note: Agents were not compared in head-to-head trial *No 3- or 4-year resistance data available for entecavir
  • 58. Predictors of Genotypic Resistance <ul><li>Lamivudine </li></ul><ul><ul><li>Baseline HBV DNA level 1,2 </li></ul></ul><ul><ul><li>HBV DNA >10 3 IU/mL at 24 weeks 3 </li></ul></ul><ul><ul><li>Male gender, higher HAI grade, higher BMI 1 </li></ul></ul><ul><li>Adefovir </li></ul><ul><ul><li>HBV DNA >10 3 IU/mL at 48 weeks 4 </li></ul></ul><ul><ul><li>Older age, genotype D, adefovir monotherapy (vs adefovir plus lamivudine) 5 </li></ul></ul><ul><li>Entecavir? </li></ul>1. Lai C-L, et al. Clin Infect Dis. 2003;36:687. 2. Zoulim F, et al. J Viral Hepatitis. 2006;13:278. 3. Yuen MF, et al. Hepatology. 2001;34:785. 4. Locarnini S, et al. 40th EASL. April 13–17, 2005. Abstract 36. 5. Fung SK, et al. J Hepatol. 2006;44:283.
  • 59. Risk of Resistance Predicted by HBV DNA Levels During Treatment 8% 13% 32% 64%  200  10 3  10 4 >10 4 HBV DNA L evels (c/mL) at 24 wk Patients with Resistance (%) 4% 26% 67% HBV DNA Levels (c/mL) at 48 wk Patients with Resistance (%) 0 20 40 60 80 100 <10 3 10 3 –10 6 >10 6 Lamivudine 1 Adefovir 2 1. Yuen et al. Hepatology . 2001;34:785. 2. Locarnini S, et al. 40th EASL. April 13–17, 2005. Abstract 36. 0 20 40 60 80 100
  • 60. Changes in HBV DNA Levels During 48 Weeks of Treatment Nucleos(t)ide-Naive Compensated HBV* 1. Lai CL, et al. N Engl J Med. 2006;354:1011. 2. Chang et al. N Engl J Med. 2006;354:1001. 3. Hadziyannis S, et al. N Engl J Med. 2003;348:800. 4. Marcellin P, et al. N Engl J Med. 2003;348:808. *Only lamivudine and entecavir compared head-to-head 90% HBeAg- 1 67% HBeAg+ 2 -5.0 HBeAg- 1 -6.9 HBeAg+ 2 Entecavir 51% HBeAg- 3 21% HBeAg+ 4 -3.91 HBeAg- 3 -3.52 HBeAg+ 4 Adefovir 72% HBeAg- 1 36% HBeAg+ 2 % with undetectable HBV DNA -4.5 HBeAg- 1 -5.4 HBeAg+ 2 Change HBV DNA baseline to wk 48 Lamivudine
  • 61. Methods to Prevent Resistance <ul><li>Maximize antiviral activity </li></ul><ul><ul><li>Select most effective regimen </li></ul></ul><ul><ul><li>Change if poor response </li></ul></ul><ul><li>Maximize genetic barriers to resistance </li></ul><ul><ul><li>Avoid sequential therapy </li></ul></ul><ul><ul><li>Choose drugs requiring multiple resistance mutations </li></ul></ul><ul><li>Increase pharmacologic barriers </li></ul><ul><ul><li>Patient compliance </li></ul></ul><ul><ul><li>Drug doses appropriate for renal function </li></ul></ul>Locarnini S, et al. Antiviral Therapy. 2004;9:679.
  • 62. Summary of Strategies to Minimize Drug Resistance in Treatment-Naive HBV Infected Patients <ul><li>First-line therapy = adefovir, entecavir, peginterferon </li></ul><ul><li>Avoid lamivudine </li></ul><ul><ul><li>Limit to those with low-level virus and expected short-duration therapy </li></ul></ul><ul><li>Monitor response and be prepared to modify (ie, add or change) if indicated </li></ul><ul><ul><li>Fail to see progressive viral load decline </li></ul></ul><ul><ul><li>Persistence of HBV DNA (≥ 10 3 log IU/mL) at 6 months; certainly at 12 months </li></ul></ul>
  • 63. Monitoring During Treatment <ul><li>Assessment of initial response </li></ul><ul><ul><li>Progressive decline in HBV DNA levels is the goal </li></ul></ul><ul><ul><li>Suboptimal response warrants change in antiviral strategy </li></ul></ul><ul><ul><li>Recommend following HBV DNA levels every 3 months </li></ul></ul><ul><li>Detection of virologic breakthrough (resistance) </li></ul><ul><ul><li>Recommend following HBV DNA levels every 3 months once suppressed </li></ul></ul><ul><ul><li>Confirm HBV DNA results (decisions should not be based on single viral load result) </li></ul></ul><ul><ul><li>Make treatment change before clinical breakthrough </li></ul></ul>
  • 64. Response to Second-Line Therapy by Type of Resistance Adapted from Lampertico P, et al. Hepatology. 2005;42:1414. Virologic breakthrough (<6 log HBV DNA) Virologic breakthrough (6–8 log HBV DNA) Clinical breakthrough (> 8 log HBV DNA) P < .0001 Patients with Undetectable HBV DNA Patients still at risk 28 3 1 0 0 0 0 0 0 32 22 14 10 9 6 5 4 2 14 13 12 11 10 9 5 4 3 Months 0 3 6 9 12 15 18 21 24 0 20 40 60 80 100
  • 65. Management of Drug-Resistant HBV Disease <ul><li>Add or change antivirals </li></ul><ul><ul><li>If resistant to lamivudine </li></ul></ul><ul><ul><ul><li>Change to adefovir or entecavir </li></ul></ul></ul><ul><ul><ul><li>Add adefovir </li></ul></ul></ul><ul><ul><li>If resistant to adefovir </li></ul></ul><ul><ul><ul><li>Change to entecavir </li></ul></ul></ul><ul><ul><ul><li>Add lamivudine </li></ul></ul></ul><ul><ul><li>If resistant to entecavir </li></ul></ul><ul><ul><ul><li>Change to adefovir </li></ul></ul></ul>
  • 66. Conclusions <ul><li>Resistance is a risk with all oral nucleos(t)ide antiviral agents </li></ul><ul><ul><li>Highest with lamivudine </li></ul></ul><ul><ul><li>Known risk factors = baseline HBV DNA level and HBV DNA level at 24 and 48 weeks of treatment </li></ul></ul><ul><li>Monitor for lack of HBV DNA suppression (≥10 3 IU/mL) and virological breakthrough </li></ul><ul><ul><li>Both scenarios require change of therapy </li></ul></ul><ul><li>Treat when virologic breakthrough apparent; do not wait until clinical breakthrough occurs (ALT increase) </li></ul><ul><li>If using oral antivirals, combination therapy is better long-term strategy than sequential therapy </li></ul>
  • 67. Duration of Therapy — How Long Do You Treat? Ching-Lung Lai, MD Professor of Medicine and Hepatology Department of Medicine University of Hong Kong Queen Mary Hospital Hong Kong, China
  • 68. Effect of Timing of Infection <ul><li>Asians, Africans, some Mediterraneans </li></ul><ul><li>Prolonged immune tolerance and immune clearance phases </li></ul><ul><li>Respond less well to immunomodulatory therapy </li></ul><ul><li>Disease continues to progress in a proportion of anti-HBe patients </li></ul><ul><li>Majority of Caucasian patients </li></ul><ul><li>No immune tolerance phase </li></ul><ul><li>Disease of relatively short duration </li></ul><ul><li>Respond better to immunomodulatory therapy </li></ul><ul><li>Disease nonprogressive after HBeAg seroconversion, with HBV DNA levels undetectable by hybridization assays—“healthy carriers” 2 </li></ul>1. Lai CL, et al. Lancet. 2003;362:2089. 2. Hoofnagle JH, et al. Hepatology. 1987;7:758. Patients Infected During Early Childhood 1 Patients Infected During Adolescence/Adulthood
  • 69. “ Healthy” Hepatitis B Carrier <ul><li>1987 1-2 </li></ul><ul><ul><li>HBeAg seroconversion to anti-HBe </li></ul></ul><ul><ul><li>HBV DNA not detectable by (relatively insensitive) hybridization assays </li></ul></ul><ul><li>2001 3 </li></ul><ul><ul><li>HBeAg seroconversion </li></ul></ul><ul><ul><ul><li>Preceded by decrease in HBV DNA levels to 10 5 copies/mL (20,000 IU/mL) </li></ul></ul></ul><ul><ul><ul><li>Followed by ALT normalization </li></ul></ul></ul><ul><ul><ul><li>“ Inactive” HBsAg carrier state </li></ul></ul></ul>1. Hoofnagle JH, et al. Hepatology. 1987;7:758. 2. Di Bisceglie AM, et al. Gastroenterology. 1987;93:1236. 3. Lok AS, et al. Gastroenterology. 2001;120:1828.
  • 70. Current Endpoints of Treatment <ul><li>HBeAg+ </li></ul><ul><ul><li>HBeAg seroconversion 1 </li></ul></ul><ul><ul><li>HBeAg seroconversion, HBV DNA ≤10 5 copies/mL (20,000 IU/mL) and ALT normalization 2 </li></ul></ul><ul><ul><li>HBeAg seroconversion +/- HBV DNA undetectable by PCR 3 </li></ul></ul><ul><li>HBeAg– </li></ul><ul><ul><li>HBV DNA undetectable by PCR plus ALT normalization 1,3 </li></ul></ul>1. Lok ASF, et al. Hepatol 2004;39:857. 2. de Franchis R, et al. J Hepatol. 2003:39:S3. 3. Liaw YF, et al. Liver Int. 2005;25:422.
  • 71. Ultimate Aim of Treatment for Chronic Hepatitis B <ul><li>To prevent/delay the development of complications of cirrhosis and hepatocellular carcinoma </li></ul><ul><li>HBeAg seroconversion, HBV DNA reduction, and ALT normalization are only means to achieve the ultimate aim </li></ul>
  • 72. HBeAg Seroconversion to Anti-HBe
  • 73. “ Healthy” Hepatitis B Carrier <ul><li>Probably true for some patients who acquire the HBV infection at adolescence/adulthood, ie, Caucasian patients </li></ul>
  • 74. Risk of C irrhosis/HCC for Northern Italian HBV C arriers <ul><li>296 HBsAg carriers detected at blood donation </li></ul><ul><ul><li>Mean follow-up 30 years </li></ul></ul><ul><ul><li>No increase in liver-related morbidity or mortality compared with controls </li></ul></ul><ul><ul><li>32.2% cleared HBsAg (1% per year) </li></ul></ul><ul><li>Possible explanation for lack of increase in liver-related mortality </li></ul><ul><ul><li>“ Healthy” subjects with no co-morbidity </li></ul></ul><ul><ul><li>Normal ALT </li></ul></ul><ul><ul><li>Instruction to abstain from alcohol </li></ul></ul><ul><ul><li>Age of acquiring the HBV infection </li></ul></ul>Manno M, et al. Gastroenterology . 2004;127:756.
  • 75. Survival After HBeAg Seroconversion <ul><li>103 IFN-treated vs 53 untreated patients followed for a mean of 50 months </li></ul><ul><li>Predominantly adult-acquired infection </li></ul><ul><li>53/103 patients receiving IFN achieved HBeAg seroconversion </li></ul><ul><li>7/53 control patients achieved HBeAg seroconversion </li></ul>Reprinted with permission, from Niederau C, et al. N Engl J Med . 1996;334:1422. Copyright © 1996 Massachusetts Medical Society. All rights reserved. Proportion of Patients Surviving Clearance of HBeAg No clearance of HBeAg 1.0 0.8 0.6 0.4 0.2 0.0 96 84 72 60 48 36 24 12 0 Month IFN Control
  • 76. HBeAg Seroconversion and Precore/Core Promoter Mutations <ul><li>HBeAg+ </li></ul><ul><ul><li>Disease progresses both histologically and clinically after HBeAg seroconversion in patients who acquire the HBV infection at birth/early childhood, ie, Asians and some Mediterraneans 1 </li></ul></ul><ul><li>HBeAg– </li></ul><ul><ul><li>Mediterraneans >90% precore mutations 2 </li></ul></ul><ul><ul><li>Asian 45% 3 –56.5% 4 precore mutations 41% 3 –69.5% 4 core promoter mutations </li></ul></ul>1. Lai CL, et al. Lancet. 2003;362:2089. 2. Laras A, et al. J Viral Hepat. 1998;5:241. 3. Chan HL, et al. Hepatology. 2000;31:763. 4. Yuen MF, et al. J Infect Dis. 2002;186:1335.
  • 77. Development of Cirrhosis HBeAg Seroconversion to Anti-HBe <ul><li>684 Taiwanese patients </li></ul><ul><ul><li>HBV infection acquired in early childhood </li></ul></ul><ul><li>Mean follow-up 35.3 months </li></ul><ul><li>Development of cirrhosis </li></ul><ul><ul><li>HBeAg+ 6.9%; annual incidences 2.4% </li></ul></ul><ul><ul><li>Anti-HBe 4.0%; annual incidences 1.3% </li></ul></ul><ul><ul><li>( P = NS) </li></ul></ul>Liaw YF, et al. Hepatology. 1988;8:493.
  • 78. Cumulative Risk of Complications Among Asian Patients with Chronic HBV <ul><li>N = 3233 </li></ul>Median Age of Study Population = 38 y Yuen MF, et al. Gut. 2005;54:1610. Reprinted with permission from the BMJ Publishing Group. Risk of Complications (%) Follow-up (Months) 180 150 120 90 60 30 0 15 12 9 6 3 0
  • 79. Age and Anti-HBe Status at Time of Complications <ul><li>3233 Chinese patients </li></ul><ul><li>Infection acquired in early childhood </li></ul><ul><li>Mean follow-up 46.9 months </li></ul>Yuen MF, et al. Gut. 2005;54:1610. SBP = spontaneous bacterial peritonitis; HCC = hepatocellular carcinoma. Median Age (y) anti-HBe (%) HBeAg seroconversion 35 - All complications 57.2 73.5 Ascites 57.7 68.8 SBP 60.0 76.7 Varices 54.3 76.3 Encephalopathy 58.5 65.0 HCC 59.0 81.1
  • 80. Progression of Disease HBeAg Seroconversion to Anti-HBe <ul><li>In patients acquiring the disease at birth/early childhood, disease progresses after HBeAg seroconversion </li></ul><ul><li>Majority of complications occurs after HBeAg seroconversion </li></ul>
  • 81. HBV DNA <10 5 copies/mL (20,000 IU/mL)
  • 82. HBV DNA Levels Associated with HBeAg Clearance <ul><li>165 Chinese patients </li></ul><ul><ul><li>51% patients HBV DNA >10 5 copies/mL (20,000 IU/mL) at HBeAg seroconversion </li></ul></ul><ul><ul><li>45% HBeAg– patients with active disease (ie, high ALT levels) and HBV DNA <10 5 copies/mL (20,000 IU/mL) </li></ul></ul><ul><li>Conclusion: not possible to define cut-off HBV DNA value for HBeAg– patients with active and inactive disease </li></ul>Chu CJ, et al. Hepatology . 2002;36:1408.
  • 83. <ul><li>79 Chinese with cirrhosis-related complications (158 controls) </li></ul><ul><ul><li>32.9% HBeAg+, 67.1% anti-HBe+ </li></ul></ul><ul><ul><li>In anti-HBe+ patients with complications </li></ul></ul><ul><ul><ul><li>37.7% HBV DNA <10 5 copies/mL (20,000 IU/mL) </li></ul></ul></ul><ul><ul><ul><li>24.5% HBV DNA <10 4 copies/mL (2000 IU/mL) </li></ul></ul></ul><ul><li>The most important factor associated with development of cirrhosis complications and HCC is HBV DNA level (which can become <10 4 copies/mL [2000 IU/mL] at the time of complications) </li></ul>HBV DNA Levels and Cirrhosis-Related Complications Yuan HJ, et al. J Viral Hepatitis. 2005;12:373.
  • 84. The Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer (REVEAL)–HBV Study, Taiwan <ul><li>Prospective, multicenter, observational cohort study </li></ul><ul><li>3851 HBsAg+ subjects with baseline HBV DNA levels for HCC and cirrhosis analysis </li></ul><ul><ul><li>3653 seronegative for anti-HCV and included in study </li></ul></ul>Chen CJ, et al. JAMA. 2006;295:65.
  • 85. Persistent HBV Viral Load Elevation Is Associated with Greatest Risk of HCC REVEAL Study 289 study participants, last follow-up serum samples not available Cohort Entry Examination <10 4 10 4 –10 5 10 4 –10 5 10 4 –10 5  10 5  10 5  10 5 Serum level of HBV DNA (copies/mL) Multivariate-Adjusted RR** (95% CI) 1.0 (referent) 1.6 (0.7–3.9) 0.5 (0.1–3.6) 3.5 (1.4–9.2) 3.8 (1.7–8.4) 7.3 (3.5–15.3) 10.1 (6.3–16.2) Follow-Up Examination Not tested <10 4 10 4 –10 5  10 5 <10 4 10 4 –10 5  10 5 *Adjustment for gender, age, cigarette smoking, and alcohol consumption Chen CJ, et al. JAMA. 2006;295:65.
  • 86. Disease Progression in Early Childhood-Acquired Infection <ul><li>For patients acquiring the hepatitis B infection in early childhood, disease progression can occur when HBV DNA levels are <10 4 copies/mL (2000 IU/mL) </li></ul>
  • 87. ALT Normalization
  • 88. ALT Levels and Liver-Related Mortality <ul><li>Korea Medical Insurance Corporation </li></ul><ul><li>94,533 men; 47,522 women </li></ul><ul><li>35–59 years of age </li></ul>Kim HC, et al. BMJ. 2004;328:983. <ul><ul><li>Relative Risk for Liver-Related Mortality compared with Serum Aminotransferase Levels at Baseline <20 IU/L </li></ul></ul>Men Women AST (IU/L) 20–29 2.5 3.3 30–39 8.0 18.2 ALT (IU/L) 20–29 2.9 3.8 30–39 9.5 6.6 Conclusion: People with AST and ALT levels in the upper ranges of “normal” are at risk of liver disease/mortality
  • 89. <ul><li>3233 Chinese CHB patients </li></ul><ul><li>Stratified: ALT < 0.5 x ULN ALT > 0.5–1 x ULN, ALT > 1–2 x ULN ALT > 2–6 x ULN, ALT > 6 x ULN </li></ul>ALT and Hepatic Complications Yuen MF, et al. Gut. 2005;54:1610. Reprinted with permission from the BMJ Publishing Group. Months of Follow-Up Risk of Complications (%) 0 10 20 30 0 30 60 90 120 150 180 ALT <0.5 X ULN ALT 0.5–1 X ULN ALT >2–6 X ULN ALT >1–2 X ULN ALT >6 X ULN
  • 90. <ul><li>Risk for cirrhosis (including HCC) complications lowest when ALT < 0.5 x ULN </li></ul><ul><li>Risk significantly higher when ALT 0.5–1 x ULN </li></ul><ul><li>Risk highest when ALT >1–2 x ULN </li></ul>ALT and Hepatic Complications Yuen MF, et al. Gut. 2005;54:1610.
  • 91. Treatment Endpoints and Infection Acquired at Birth/Early Childhood <ul><li>In patients who acquire the HBV infection at birth/early childhood, disease progression continues </li></ul><ul><ul><li>After HBeAg seroconversion (and HBsAg seroclearance) </li></ul></ul><ul><ul><li>At HBV DNA levels <10 5 copies/mL (20,000 IU/mL) </li></ul></ul><ul><ul><li>At ALT levels >0.5–2 x ULN </li></ul></ul><ul><li>Current treatment endpoints stop treatment with patients still at risk </li></ul>
  • 92. Summary <ul><li>For patients acquiring the disease in adolescence/adulthood </li></ul><ul><ul><li>HBeAg seroconversion with HBV DNA levels at <10 5 copies/mL (20,000 IU/mL) and ALT normalization may be adequate endpoints </li></ul></ul><ul><li>For patients acquiring the disease in early childhood </li></ul><ul><ul><li>HBeAg seroconversion is not an adequate endpoint, more a “way station” in the natural history of HBV infection </li></ul></ul><ul><ul><li>Ideal endpoints of treatment </li></ul></ul><ul><ul><ul><li>HBV DNA permanently low (<10 4 copies/mL [2000 IU/mL] preferably undetectable by PCR) </li></ul></ul></ul><ul><ul><ul><li>ALT < 0.5 x ULN </li></ul></ul></ul><ul><ul><ul><li>Clearance of cccDNA from the liver—not currently feasible </li></ul></ul></ul>
  • 93. Conclusion Eugene R. Schiff, MD Leonard Miller Professor of Medicine Chief, Division of Hepatology Director, Center for Liver Disease University of Miami School of Medicine Miami, Florida
  • 94. When Do You Initiate HBV Therapy? <ul><li>Parameters </li></ul><ul><ul><li>HBV DNA levels >10 4-5 copies/mL </li></ul></ul><ul><ul><li>ALT levels >1–2 x ULN </li></ul></ul><ul><li>Factors </li></ul><ul><ul><li>HBeAg+ vs HBeAg– </li></ul></ul><ul><ul><li>Cirrhosis vs no cirrhosis </li></ul></ul><ul><ul><li>Compensated vs decompensated disease </li></ul></ul>
  • 95. Initial Therapy: What Are the Therapeutic Options and Considerations? <ul><li>First-line therapy </li></ul><ul><ul><li>Adefovir </li></ul></ul><ul><ul><li>Entecavir </li></ul></ul><ul><ul><li>Peginterferon alfa-2a </li></ul></ul><ul><li>Lamivudine no longer considered first-line therapy due to high rate of resistance, except in specific settings </li></ul>
  • 96. How Do You Manage Resistance, Breakthrough, and Suboptimal Response? <ul><li>Choose antivirals with a low likelihood of resistance </li></ul><ul><li>Monitor the response every 3 months to ensure viral suppression is achieved </li></ul><ul><li>If viral suppression is not achieved, change/add antiviral agent(s) </li></ul><ul><li>Reinforce the importance of adherence </li></ul>
  • 97. How Long Do You Treat? <ul><li>Traditional endpoints </li></ul><ul><ul><li>HBeAg seroconversion </li></ul></ul><ul><ul><li>HBV DNA <10 5 copies/mL (20,000 IU/mL) </li></ul></ul><ul><ul><li>Normalization of ALT </li></ul></ul><ul><li>These endpoints may be insufficient for patients with infection acquired at birth or early childhood </li></ul><ul><li>Potential ideal endpoints </li></ul><ul><ul><li>HBV DNA undetectable </li></ul></ul><ul><ul><li>ALT within normal limits </li></ul></ul>

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