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

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Presentation on theme: "HEPATITIS B Anna S. F. Lok, MD University of Michigan Ann Arbor, MI."— Presentation transcript:

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

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

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

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

5 Less than 0.5% (1 in 200) Americans have chronic hepatitis B 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 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 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 A much higher percent of Asian Americans compared to Americans of other races have hepatitis B Hepatitis B and Asian Americans

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

7 National Health and Nutrition Examination Survey (NHANES) Survey on prevalence of various diseases in the US Survey on prevalence of various diseases in the US Sampled cohorts representative of US population 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 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” 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” Hepatitis B and Asian Americans

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

9 Federal and state governments – public health Overall prevalence is low: not a very common problem here 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) 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 Not a common problem With an effective vaccine, hepatitis B will be eradicated in the next generation.. we predicted that in the 1980s With an effective vaccine, hepatitis B will be eradicated in the next generation.. we predicted that in the 1980s Competition for $$ and attention from other more trendy diseases: HIV, HCV, SARS, avian ‘flu, cancers…. Competition for $$ and attention from other more trendy diseases: HIV, HCV, SARS, avian ‘flu, cancers…. Why is it that hepatitis B gets so little attention in the US?

10 HBV is more easily spread than HIV (virus that causes AIDS) and HCV 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 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 log 10 copies/mL (100 billion) People with chronic hepatitis B can have very large amounts of virus in their blood – serum HBV DNA up to 11 log 10 copies/mL (100 billion) How is HBV spread?

11 Mainly through blood and bodily secretions Infected mother to babies at birth 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 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 Sexual contact with carriers How is HBV spread?

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

13 Outcome of Acute HBV Infection Acute Hepatitis Subclinical Hepatitis Fulminant Hepatitis Death Acute Infection Chronic Infection Recovery

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

15 Risk of Chronic HBV Infection Age at Infection Neonates Infants Children Adults % Risk % Risk

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

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

18 The only way to know is to have a blood test 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 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 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 Hepatitis B may be present even if liver enzymes were tested and were normal How can hepatitis B be diagnosed?

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 HBsAg Anti-HBs Anti- HBc Anti-HBc IgM Months Years HBeAg Anti-HBe HBV DNA Anti-HBe

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

22 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 Serum HBV DNA is the most reliable marker of HBV replication and infectivity

23 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 Hepatitis B Vaccines

24  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 Indications for HBV Vaccines

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 % % Vaccination of infants born to HBsAg+ mother HBsAg+ Anti-HBc+ 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 B Factors affecting disease activity and progression VIRUS Genotype Molecular Variants HOST Gender Age Immune Response Genetics ENVIRONMENT Alcohol HCV, HDV, HIV Carcinogens

29 < <> > HBeAg + (wild) HBeAg - / anti-HBe + (PC/CP variants) ALT HBV-DNA Normal / mild CH moderate/severe CH Normal/mild CH cirrhosis Inactive-carrier stateHBeAg – Chronic hepatitis HBeAg + Chronic hepatitis Immune tolerance Immune clearance Low replicative phase Reactivation phase cirrhosis cp/ml cp/ml <10 5 cp/ml >10 5 cp/ml Inactive cirrhosis Stages of chronic HBV infection

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

31 Immune Tolerant Phase First 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 < <> > HBeAg + (wild) HBeAg - / anti-HBe + (PC/CP variants) ALT HBV-DNA Normal / mild CH moderate/severe CH Normal/mild CH cirrhosis Inactive-carrier stateHBeAg – Chronic hepatitis HBeAg + Chronic hepatitis Immune tolerance Immune clearance Low replicative phase Reactivation phase cirrhosis cp/ml cp/ml <10 5 cp/ml >10 5 cp/ml Inactive cirrhosis Stages of chronic HBV infection

34 Inactive HBsAg Carrier State HBsAg+ > 6 months HBeAg-, anti-HBe+ Serum HBV DNA < 10 3 copies/ml Persistently normal ALT Outcome dependent on liver damage accrued prior to enteringinactive carrier state and any subsequent reactivation

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

36 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 Risk factors for progression to cirrhosis

37 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 Risk factors for progression to HCC

38 Do not drink alcohol Do not drink alcohol Do not take any herbal medicine that might hurt the liver Do not take any herbal medicine that might hurt the liver Eat a balanced diet, exercise regularly, avoid getting overweight 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 What can patients do to protect their liver?

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

40 Treatment of Chronic Hepatitis B Definition 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 Time to disease progression (months) Placebo (n=215)ITT population Lamivudine (n=436)p=0.001 Lamivudine Placebo P= % 9% Liaw YF, NEJM 2004; 351:1521

42 Licensed HBV therapies and those under development LicensedPhase IIIPhase IIPhase I Interferon  -2b Lamivudine Adefovir Entecavir Peg IFN  -2a Emtricitabine (FTC)* Tenofovir (TFV)* FTC+ TFV* Emtricitabine PegIFN  -2b Telbivudine (LdT) Clevudine Tenofovir Pradefovir Valtorcitabine (LdC) LB80380 Remofovir (MB06866) Elvucitabine (Fd4C) BAM 205 IL-12 MCC 478 FLG

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 Patient’s age Co-morbid illness Costs Likelihood of sustained response cirrhosis and HCC Side effects Drug resistance Likelihood of cirrhosis / HCC in the next yrs Likelihood of sustained viral suppression after a defined course of treatment

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

46 IFNLamivudineAdefovirEntecavir ParenteralOral Finite durationLong duration More durable response Primary nonresponse in 25% More potent than LAM Higher rate of HBsAg loss Effective vs. LAM- R mutants Activity vs. LAM-R mutants lower No resistant mutants Resistant mutants 15-30% yr 1 70% yr 5 Resistant mutants 0 yr 1, 29% yr 5 ~15-20% yr 2 (LAM-R pts switched to ADV only) Resistant mutants 0 yr 1, <1% yr 2 ~10% yr 2 (LAM-R pts) Frequent side effects (Nephrotoxic at high doses) (Limited track record)

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 disease BUT It can be prevented, and it can be treated GET TESTED


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