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HBV Core Curriculum: Epidemiology, Prevention and Treatment of Hepatitis B

HBV Core Curriculum: Epidemiology, Prevention and Treatment of Hepatitis B. Norah Terrault, MD, MPH Adjunct Assistant Professor, Medicine/Gastroenterology University of California, San Francisco. About These Slides.

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HBV Core Curriculum: Epidemiology, Prevention and Treatment of Hepatitis B

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  1. HBV Core Curriculum:Epidemiology, Prevention and Treatment of Hepatitis B Norah Terrault, MD, MPH Adjunct Assistant Professor, Medicine/Gastroenterology University of California, San Francisco

  2. About These Slides • Users are encouraged to use 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 • These slides may not be published or posted online without permission from Clinical Care Options. • We are grateful to Norah Terrault, MD, MPH, University of California San Francisco, who aided in the content creation of these slides. • View more programs at the Clinical Care Options for Hepatitis web site: clinicaloptions.com/hep DisclaimerThe materials published on the Clinical Care Options Web site reflect the views of the authors, not those of Clinical Care Options, LLC, the CME providers, or the companies providing educational grants. The materials may discuss uses and dosages for therapeutic products that have not been approved by the United States Food and Drug Administration. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or using any therapies described in these materials.

  3. Global Burden of HBV • 2 billion current or past infections • 300-400 million with chronic HBV disease • 1.25 million in the US • 25%-40% of persons with chronic HBV disease die from cirrhosis or HCC • Over 300,000 cases/year of HBV-related HCC • HBV is second most important carcinogen behind tobacco World Health Organization. Fact sheet. Available at: http://www.who.int. Accessed January 31, 2006. Centers for Disease Control. Fact sheet. Available at: http://www.cdc.gov. Accessed January 31, 2006. Lai CL, et al.Lancet. 2003;362:2089-2094.

  4. Hepatitis B Disease Burden in the United States Centers for Disease Control. Hepatitis B fact sheet. Available at: http://www.cdc.gov/hepatitis. Accessed January 31, 2006. Mahoney FJ. Clin Microbiol Rev. 1999;12:351-366. Hepatitis B Foundation. Hepatitis B statistics. Available at: http://www.hepb.org/hepb/statistics.org. Accessed January 31, 2996.

  5. Prevalence of Chronic Hepatitis B ~ 2 million Asians ~ 930, 000 Europeans ~ 400,000 South Americans HBsAg Prevalence ~ 350,000 Africans > 8% - High 2-8% - Intermediate < 2% - Low Immigration numbers summed by continent from 1996-2002 Centers for Disease Control. Hepatitis B fact sheet. Available at: http://www.cdc.gov/hepatitis. Accessed January 31, 2006. Mahoney FJ. Clin Microbiol Rev. 1999;12:351-366. Hepatitis B Foundation. Hepatitis B statistics. Available at: http://www.hepb.org/hepb/statistics.org. Accessed January 31, 2006.

  6. HBV Seroprevalence Among Asian Americans • 5 large US cities (2001-2004) • Chinese • Korean • Vietnamese • Median age • 43 yrs (12-80) • HBsAg+, overall • 558/5341 (10.4%) Proportion of Individuals HBsAg+ 0% 4% 8% 12% 16% Philadelphia 11% San Francisco 14% Boston 10% Chicago 11% NY(1) 15% NY(2) 11% Overall 10.4% Guan R, et al. AASLD 2004. Abstract 1269.

  7. Clinical Consequences of HBV Acquisition • Acute Infection • Major risk of death related to development of fulminant liver failure (rare) • Chronic Infection • Progressive liver disease • Risk of cirrhosis, liver failure, hepatocellular carcinoma (HCC) • Rarely extrahepatic manifestations

  8. Reducing the Burden of Chronic HBV Disease • Prevention of infection • Vaccination! • Prevention of liver-related complications • Modify lifestyle: weight control, limit alcohol • Anti-HBV therapies: interferon, lamivudine, adefovir, entecavir • HCC surveillance

  9. Incidence of Acute Hepatitis B:United States, 1978-1995 Safer Injection and Sexual Practices 80 70 Infant immunization 60 50 Cases/100,000 40 Vaccine licensed HBsAg screening of pregnant women 30 20 Adolescent immunization 10 0 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 Year Available at: http://www.cdc.gov/ncidod/diseases/hepatitis/b/. Accessed February 5, 2006.

  10. Hepatitis B Vaccine • Vaccine licensed in 1982 • Plasma-derived  recombinant vaccine • 3-dose series, high efficacy, no boosters, safe • Since licensing, adolescents and adults at high risk recommended to receive vaccine • Comprehensive strategy to eliminate HBV transmission implemented in 1991 • 1991: universal infant vaccination recommended • 1995: expansion to include vaccination of all adolescents ages 11-12 yrs • 1998: vaccination of all persons age 0-18 yrs not previously vaccinated

  11. Achievements With HBV Vaccination • Decline in acute HBV in past decade by 67% • Reflects effects of routine infant and childhood vaccination • Vaccination rates high in this population but decline to ~ 60% in adolescents • Slowest rate of decline in adults • Some adult subgroups showing increase in incidence (men ≥ 19 yrs, women ≥ 40 yrs) • Decline in risk of serious complications of chronic HBV • Reduced rates of childhood HCC in countries of high endemnicity Centers for Disease Control and Prevention (CDC). MMWR Morb Mortal Wkly Rep. 2004;52:1252-1254.

  12. Annual Incidence of Liver Cancer in Children Aged 6-15 Years *P < .001 for comparison between birth cohort. Vaccination program in effect since July 1984 Chang MH, et al. N Engl J Med. 1997;336:1855-1859.

  13. Issues Related to HBV Vaccination • Poor or nonresponse to vaccination • Strategies to maximize likelihood of response • Durability of vaccine response • Need for booster vaccinations? • Missed opportunities for vaccination • Especially among adults at risk • During 1983-2000: ~ 110,000 adults acquired chronic HBV infection due to lack of adult hepatitis B immunization Centers for Disease Control and Prevention (CDC). MMWR Morb Mortal Wkly Rep. 2004;52:1252-1254.

  14. Factors Associated with Reduced Vaccine Responses Patient-Related • Older age (> 50 years) • Male gender • Smoking • Obesity • Immune deficiency • HIV • Transplant recipients • Dialysis • Compliance Vaccine-Related • Schedule (accelerated vs 0, 1, 2, 6 months) • Double vs single dose • Use of “adjuvants” • GCSF, levamisole • IM versus ID

  15. HBV Vaccination Durability of Response • Durable immunity 15-18 years • 84% of Alaskan natives at 15 years[1] • 85% of MSM (some HIV+) at 7 years[2] • > 50% of Chinese children at 15 years[3] • Immunity preserved in anti-HBs-negative persons • Amnestic response with booster dose • Preserved T cell responses in PBMCs in vitro 1. McMahon BJ, et al. Ann Intern Med. 2005;142:333-341. 2. Hadler SC, et al. N Engl J Med. 1986;315:209-214. 3. Ni YH, et al. Ann Intern Med. 2001;135:796-800.

  16. Predictors of decline in anti-HBs titers over 15 yrs Low initial antibody response Female gender Younger age (0-4 yrs greatest decline) HBV Vaccination: Durability of Response Vaccines With Specific Anti-HBs Titers 40 38 30 28 Percentage of Patients 20 18 16 10 0 < 2IU/L ≥ 2 IU/L ≥ 10 IU/L ≥ 100 IU/L McMahon B, et al. Ann Intern Med. 2005;143:333-341.

  17. Hepatitis B Vaccination in Adults:Missed Opportunities • Of all individuals with reported acute hepatitis B infection • 56% have been treated for an STD and/or were incarcerated prior to their illness • 89% are IDUs • 35% are MSM • 70% are persons with multiple sexual partners • Overlapping risks: IDU and sexual activities Goldstein ST, et.al. JID. 2002;185:713-719. Khan A, et al. Antiviral Therapy. 2000:5(suppl 1):21.

  18. Prevention of HBV InfectionSummary • Vaccine is highly effective – HBV incidence is declining • Infants and children vaccination rates high • In countries endemic for HBV, infant vaccination has reduced rates of liver complications • Missed opportunities among adults • If sexually active, IDU  at risk • HBV-related HCC is vaccine-preventable cancer

  19. Outcomes of Acute HBV Infection Recover Acute Hepatitis Subclinical Hepatitis Fulminant Hepatitis 5-20% ACUTE INFECTION < 1% 0.1-2.7% DEATH Chronic Infection Juszczyk J. Vaccine. 2000;18(suppl 1):S23-S25.

  20. Clinical-Epidemiologic Correlations Available at: http://www.who.int/mediacentre/factsheets/fs204/en/. Accessed February 6, 2006.

  21. HBsAg Anti-HBs Serology HBeAg Anti-HBe ALT level HBV DNA level (viremia) Cirrhosis/HCC Chronic activehepatitis Minimal inflammation Normal to cirrhosis/HCC Disease Immune tolerant (phase I) Immune Active (phase II) Non-Replicative (phase III) Chronicity Stage Resolved 0 10 20 30 40 50 60 70 Years Natural History of Chronic HBV Infection

  22. Possible Outcomes of HBeAg+ Chronic HBV Infection Spontaneous seroconversion (n = 283) 67% Sustained remission 33% ALT elevation (> 2 x ULN) 24% HBeAg-negative CHB with detectable HBV DNA 5% Undetermined causes 4% HBeAg reversion Hsu YS, et al. Hepatology. 2002;35:1522-1527.

  23. Possible Outcomes of HBeAg+ Chronic HBV Infection Lai CL, et al. Lancet. 2003:362:2089-2094. Lok AS, et al. Gastroenterology. 2001;120:1828-1853.

  24. Natural Clearance of HBsAg • Occurs in ~ 0.5% of HBsAg carriers/year • Duration of infection is primary determinant of HBsAg loss • ~ 50% of carriers who clear HBsAg have HBV DNA present in sera in low titer (1–2 logs) McMahon BJ, et al. Ann Intern Med. 2001;135:759-768.

  25. Annual Risk of HBV Progression HBeAg-Neg chronic hepatitis B All HBsAg + individuals HBeAg+ chronic hepatitis B 5.0% 1.0%-2.0% Cirrhosis 3.0% 2.0% 0.4% Decompensation HCC • Factors linked with progression • Duration of “active”disease • Heavy alcohol use • Immune suppression (HIV) Juszczyk J. Vaccine. 2000;18(suppl 1):S23-S25.

  26. History and PE Assess risk factors (coinfection) Alcohol use Family history of HBV and HCC Physical findings of cirrhosis Initial Evaluation of HBsAg+ Patient Investigations • Liver disease activity • Serologic and virologic markers • Screening for HCC (AFP and ultrasound) Lok AS, et al. Hepatology 2001;34:1225-1241. Tsai NC. Sem Liver Dis. 2004;24(suppl 1):71-76.

  27. Categorization of Disease • HBeAg positive or negative • Replication high or low (HBV DNA) • ALT elevated or normal • Liver histology

  28. Role of Baseline Liver Biopsy • Confirm diagnosis of chronic hepatitis B • Establish baseline severity • Grade: severity of necroinflammation • Stage: amount of fibrosis • Clarify diagnosis when ALT and HBV DNA levels are discordant • Exclude other coexistent causes of liver disease (eg, fatty liver or alcoholic liver disease) • Guide decision regarding initiation of treatment Ferrell L, et al. in McSween, et al, editors. Pathology of the liver, 4th ed. London:Churchill Livingstone; 2002:313-362. Buckley A ,et al. Can J Gastroenterol 2000;14:481-82. Park A , et al. Minerva Gastroenterol Dietol. 2004;50:289-303.

  29. Indications for Treatment ofChronic HBV • Patients with active liver disease: • Abnormal liver function tests (AST, ALT) • HBeAg positive and > 105 HBV DNA • HBeAg negative and > 104 HBV DNA • Biopsy if HBV DNA < 104 with  ALT • Treat if active hepatitis (biochemical or histologic) Lok AS, et al. Hepatology. 2001;34:1225-1241.

  30. 2 Distinct Patient Populations With Chronic HBV • HBeAg+ (wild-type), HBV DNA+ • HBeAg loss • Seroconversion to anti-HBe • Durability of response ~ 80% • HBeAg-/anti-HBe+/HBV DNA+ (precore mutant) • HBeAg seroconversion not an endpoint • Long-term therapy the rule

  31. Endpoints of Treatment • Sustained suppression of HBV DNA replication • HBeAg seroconversion • Improvement in liver histology • Reduced rates of liver complications

  32. Histologic Improvement in Cirrhosis: 3 Years of Lamivudine Therapy Pre-Rx Post-Rx Wild-Type HBV

  33. Long-Term Benefit of Lamivudine in Compensated Cirrhosis 30 All P values ≤ .05 Placebo (n = 215) Lamivudine (n = 436) 20 18% Patients, % 9% 10 8% 7% 4% 3% 0 Overall Disease Progression CPT Increase HCC Liaw et al. N Engl J Med. 2004;351:1521-1531.

  34. Screening for Liver Cancer:Lack of Consensus At what age should HCC screening be initiated? 1) Among HBV-infected individuals, HCC can occur at any age, including childhood 2) Optimal age for initiation of screening unknown1 3) Patients ≥ 35 yrs are at much higher risk for HCC than those < 35 years2 1. Lok AS, and McMahon BJ. Hepatology. 2001; 34:1225-1241. 2. Liaw YF, et al. Gastroenterology. 1986;90:263-267.

  35. Screening for Liver Cancer: Alpha-fetoprotein (AFP) • Up to 1/3 of patients with HCC have normal AFP • AFP may be elevated in 1/3 of patients with cirrhosis without HCC • Very high level of AFP (> 1000 ng/mL) diagnostic of HCC, with few exceptions • Persistently rising AFP levels highly suggestive of HCC but not often seen

  36. Screening for Liver Cancer:Patients With Chronic HBV • Cancer screening strategies: High Risk- AFP + U/S every 6 months • Cirrhosis • Family history HCC Medium Risk- AFP + U/S every year • Age ≥ 30-40 • Active disease (ALT) • If rising AFP or high AFP > 20 ng/mL, spiral CT or MRI at least once

  37. Chronic HBV Infection:Recent Advances • 4 antiviral drugs now available • Longer term benefits of treatment known • Resistance emerging as issue with oral antivirals • Combination therapy under study • Several new nucleos/tides in development

  38. Go Online to View More CCO Programs! Conference Coverage of all the key data presented at major hepatitis meetings News and Capsule Summaries covering the latest findings in the field of hepatitis Downloadable Slides, and much more! clinicaloptions.com/hep

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