HEPATITIS B

1. HEPATITIS B Anna S. F. Lok, MD University of Michigan Ann Arbor, MI

2. What is Hepatitis B? • Hepatitis B is an infection of the liver caused by the hepatitis B virus

3. How common is hepatitis B? Worldwide • 400 million people are chronic carriers • About 75% of HBV carriers live in Asia • 0.5-1 million deaths per year due to HBV Asia • Liver cancer is the 2nd cancer killer among Asian men and the 5th cancer killer among Asian women • Roughly 40% of Asian men and 15% of Asian women with chronic hepatitis B die of a liver-related illness

4. Geographic Distribution of Chronic HBV Infection HBsAg Prevalence 8% - High 2-7% - Intermediate <2% - Low

5. Hepatitis B and Asian Americans • Less than 0.5% (1 in 200) Americans have chronic hepatitis B • About 10-15% (1 in 8 to 10) Asian Americans have chronic hepatitis B • About 50% (1 in 2) of the people in the US with chronic hepatitis B are Asian Americans • A much higher percent of Asian Americans compared to Americans of other races have hepatitis B

6. Why is Hepatitis B so common among Asian Americans? • Hepatitis B is very common in Asia • Many Asian Americans were infected with hepatitis B before they came to the US • Asian Americans born in the US may be infected through their mother or other family members, who are HBV carriers

7. Hepatitis B and Asian Americans National Health and Nutrition Examination Survey (NHANES) • Survey on prevalence of various diseases in the US • Sampled cohorts representative of US population • African Americans and Hispanics over sampled to ensure sufficient number studied to permit conclusions on prevalence of diseases among those racial/ethnic groups • Reliable data not available for Asian Americans because Asians not over sampled, number studied too small to be conclusive, and Asians lumped as “other racial/ethnic groups”

8. Hepatitis B and Asian Americans • NHANES III – 1988-1994 • Current and past HBV infection: 4.9% • Chronic HBV infection: 0.4% • Highest prevalence among blacks • 5%-15% among immigrants from Central and Southeast Asia, Middle East and Africa • Prevalence data for Asians not available

9. Why is it that hepatitis B gets so little attention in the US? Federal and state governments – public health • Overall prevalence is low: not a very common problem here • Most of those affected by HBV are Asians – who are politically silent (squeaky wheel gets the oil) NIH, CDC, Scientific organizations – research and education • Not a common problem • With an effective vaccine, hepatitis B will be eradicated in the next generation.. we predicted that in the 1980s • Competition for $$ and attention from other more trendy diseases: HIV, HCV, SARS, avian ‘flu, cancers….

10. How is HBV spread? • HBV is more easily spread than HIV (virus that causes AIDS) and HCV • HBV can live outside the human body for up to 7 days • People with chronic hepatitis B can have very large amounts of virus in their blood – serum HBV DNA up to 11 log10 copies/mL (100 billion)

11. How is HBV spread? Mainly through blood and bodily secretions • Infected mother to babies at birth • Contact with blood from carriers through wounds, contaminated household articles such as razors, toothbrushes, or contaminated needles used for tattoos and injecting drugs • Sexual contact with carriers

12. How is HBV spread? HBV is not spread by: • Hugging or kissing • Coughing or sneezing • Sharing eating utensils

13. Outcome of Acute HBV Infection Recovery Acute Hepatitis SubclinicalHepatitis FulminantHepatitis Death Acute Infection Chronic Infection

14. What is Hepatitis B? Hepatitis B may be ACUTE • Recent infection • May have no symptoms, especially in children • Common symptoms: easily tired, poor appetite, nausea, abdominal discomfort, jaundice • Roughly 95% recover, usually in 2-3 months • About 1% severe hepatitis with acute liver failure • About 5% go on to chronic infection, lasts longer than 6 months

15. 100 80 60 % Risk 40 20 0 Neonates Infants Children Adults Age at Infection Risk of Chronic HBV Infection

16. Outcome of Chronic HBV Infection Chronic HBV Infection Inactive Carrier State Chronic Hepatitis Cirrhosis HCC

17. What is Hepatitis B? Hepatitis B may be CHRONIC • Long-lasting infection, persists for more than 6 months • Most people have no symptoms • Common symptoms: easily tired, poor appetite, nausea, abdominal discomfort • Can go on to cirrhosis, liver failure, liver cancer, and death

18. How can hepatitis B be diagnosed? • The only way to know is to have a blood test • Most people with hepatitis B have no symptoms until late stages of liver disease • Tests for hepatitis B or liver enzymes are not included in most routine check-ups • Hepatitis B may be present even if liver enzymes were tested and were normal

19. Serological Markers of HBV Infection HBsAg Acute/Chronic infection Anti-HBc IgM Recent infection HBeAg High infectivity Anti-HBe Low infectivity Anti-HBs Immunity Anti-HBc IgG + HBsAg Chronic infection Anti-HBc IgG + anti-HBs Resolved infection

20. Acute HBV Infection HBV DNA HBeAg Anti-HBe Anti-HBe Anti-HBs Anti-HBc HBsAg Anti-HBc IgM 0 2 4 6 Months Years

21. HBV DNA HBeAg Anti-HBe HBsAg Anti-HBc Anti-HBc IgM Months Years Chronic HBV Infection

22. Serum HBV DNA is the most reliable marker of HBV replication and infectivity • Fluctuating levels, serial tests important for clinical assessment • Virus persists at low levels even after recovery • Reactivation can occur spontaneously and more often when immune system is suppressed • HBV DNA levels do not always correlate with ALT levels or histologic activity of liver disease • Persistently high serum HBV DNA levels are associated with increased risk of cirrhosis and HCC

23. Hepatitis B Vaccines • Genetically engineered hepatitis B surface antigen only • 3 doses: month 0, 1, 6 • Immune response: 50% after 1 dose 95% after 3 doses • Duration of protection: >15 years, dependent on initial antibody response • Factors associated with poor response: older age, chronic medical illness (cirrhosis, kidney failure, diabetes), decreased immune response, smoking, obesity, genetics

24. Indications for HBV Vaccines • Hepatitis B immune globulin and HB vaccine to infants of HBsAg+ mothers • All infants • All children and adolescents who were not vaccinated at birth • Vaccination of adults at risk of infection • Occupational • Sexual / household contacts • Injection drug users • Long-term residence in high prevalence areas

25. HBV Vaccine: Safety Worldwide, more than 500 million individuals have received HB vaccine over the past 20 years Most common adverse event – soreness and erythema at the injection site Systemic symptoms – transient low-grade fever, headache, malaise and myalgia in ~10%

26. Impact of HBV vaccination on HBV infection rates in Taiwanese children 30 HBsAg+ Anti-HBc+ 20 % 10 0  1984 1994 1999 Vaccination of infants born to HBsAg+ mother Universal vaccination of infant/preschool children Ni YH, Ann Intern Med 2001;135:796

27. Impact of HBV Vaccination on Incidence of HCC in Taiwanese Children  Universal Vaccination of Newborns Chang MH, NEJM 1997;336:1855

28. Hepatitis BFactors affecting disease activity and progression VIRUS Genotype Molecular Variants HOST Gender Age Immune Response Genetics ENVIRONMENT Alcohol HCV, HDV, HIV Carcinogens

29. Stages of chronic HBV infection Immune Immune Low replicative Reactivation tolerance clearance phase phase HBeAg - / anti-HBe + (PC/CP variants) HBeAg + (wild) > < < > >105 cp/ml HBV-DNA <105 cp/ml 109-1010 cp/ml 107-108 cp/ml ALT Normal / mild CH moderate/severe CH Normal/mild CH moderate/severe CH cirrhosis Inactive cirrhosis cirrhosis HBeAg + Chronic hepatitis Inactive-carrier state HBeAg – Chronic hepatitis

30. Unique Aspects of Hepatitis B among Asians Clinical Manifestations/Natural history • Immune tolerant phase • Frequent exacerbations and reactivations • Increased risks of HCC

31. Immune Tolerant Phase • First 10-30 years of perinatally acquired HBV infection • Asymptomatic • High HBV DNA levels but normal ALT • Very low rates of spontaneous/treatment-induced HBeAg seroconversion

32. Immune Clearance Phase HBeAg → anti-HBe seroconversion Predictors : ALT, age, gender, HBV genotype Annual rate = 5-15% Hepatitis Flares ⅔ HBeAg seroconversion preceded by flares ¼ flares followed by HBeAg seroconversion More common in men Increased risk of cirrhosis

33. Stages of chronic HBV infection Immune Immune Low replicative Reactivation tolerance clearance phase phase HBeAg - / anti-HBe + (PC/CP variants) HBeAg + (wild) > < < > >105 cp/ml HBV-DNA <105 cp/ml 109-1010 cp/ml 107-108 cp/ml ALT Normal / mild CH moderate/severe CH Normal/mild CH moderate/severe CH cirrhosis Inactive cirrhosis cirrhosis HBeAg + Chronic hepatitis Inactive-carrier state HBeAg – Chronic hepatitis

34. Inactive HBsAg Carrier State HBsAg+ > 6 months HBeAg- , anti-HBe+ Serum HBV DNA < 103 copies/ml Persistently normal ALT Outcome dependent on liver damage accrued prior to entering inactive carrier state and any subsequent reactivation

35. HBeAg – Chronic Hepatitis B • HBsAg + • HBeAg – • Serum HBV DNA > 104-5 copies/ml • Elevated ALT / moderate-severe inflammation on biopsy • Frequently associated with precore or core promoter mutations that prevent or decrease HBeAg production

36. Risk factors for progression to cirrhosis Viral factors Host Factors External Factors • Persistently high HBV DNA levels • HBV precore/CP variant? • HBV genotype (C > B) • Older age • Male gender • Advanced fibrosis • Persistent ALT elevation • Recurrent hepatitis flares • HDV, HCV coinfections • HIV coinfection • Alcohol

37. Risk factors for progression to HCC Viral factors Host Factors External Factors • Persistently high HBV DNA levels • HBV CP variant • HBV genotype (C > B) • Older age • Male gender • Asians?? • Advanced fibrosis • Persistent ALT elevation • Recurrent hepatitis flares • HDV, HCV coinfections • HIV coinfection • Family history of HCC • Alcohol • Aflatoxin • Smoking

38. What can patients do to protect their liver? • Do not drink alcohol • Do not take any herbal medicine that might hurt the liver • Eat a balanced diet, exercise regularly, avoid getting overweight Hepatitis B is a chronic health problem, HBV levels and severity of liver damage can change with time, see their doctor and get tested at least once a year even if they have no symptoms

39. Treatment of Chronic Hepatitis B Goals • Suppression of HBV replication • Decrease hepatic necroinflammation and fibrosis • Prevent progression to cirrhosis, liver failure and HCC

40. Treatment of Chronic Hepatitis BDefinition of Response HBeAg+ patients • Serum HBV DNA decrease to <100,000 copies/ml • Loss of HBeAg ± anti-HBe seroconversion • Normalization of ALT level HBeAg- patients • Serum HBV DNA decrease to undetectable by PCR • Normalization of ALT level On-treatment response – initial / maintained Off-treatment sustained response – FU mo 6 or 12 Lok A et al., Gastro 2001;120:1828

41. Randomized controlled trial of lamivudine in patients with advanced liver disease HBeAg+ and/or serum HBV DNA >700,000 gEq/mL % with disease progression 21% Placebo P=0.001 9% Lamivudine Time to disease progression (months) Placebo (n=215) ITT population Lamivudine (n=436) p=0.001 Liaw YF, NEJM 2004; 351:1521

42. Licensed HBV therapies and those under development

43. Who Should be Treated? • Not a question of who to treat but when – treat now or monitor and treat when indicated • All HBV carriers are potential treatment candidates • A patient who is not a treatment candidate now can be a treatment candidate in the future • Changes in HBV replication status and/or activity/stage of liver disease • Availability of new and better treatments

44. When to start treatment? Benefits Risks Likelihood of sustained response cirrhosis and HCC Side effects Drug resistance Patient’s age Co-morbid illness Costs Likelihood of cirrhosis / HCC in the next 10-20 yrs Likelihood of sustained viral suppression after a defined course of treatment

45. What should be the primary treatment? Long-term Benefits Long-term Risks Antiviral potency Durability of response Side effects Drug resistance Contraindications Ease of administration Duration of Rx Costs of Rx & monitoring Patient and provider preference

47. When can treatment be stopped? • IFN treatment: finite duration, 12 mos • Nucleoside/tide analogues • HBeAg+ patients: 6-12 mos after HBeAg seroconversion (~50% after 5 yr Rx) • HBeAg- patients: endpoint not defined, ?until HBsAg loss (~5% after 5 yr) • Cirrhosis patients: endpoint not defined, ?life-long

48. Hepatitis B can be a deadly diseaseBUTIt can be prevented, and it can be treated GET TESTED