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HEPATITIS B Anna S. F. Lok, MD University of Michigan Ann Arbor, MI What is Hepatitis B? • Hepatitis B is an infection of the liver caused by the hepatitis B virus 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 liverrelated illness Geographic Distribution of Chronic HBV Infection HBsAg Prevalence 8% - High 2-7% - Intermediate <2% - Low 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 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 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” 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 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…. 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) 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 How is HBV spread? HBV is not spread by: • Hugging or kissing • Coughing or sneezing • Sharing eating utensils Outcome of Acute HBV Infection Recovery Subclinical Hepatitis Acute Hepatitis Acute Infection Chronic Infection Fulminant Hepatitis Death 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 Risk of Chronic HBV Infection 100 80 % 60 Risk 40 20 0 Neonates Infants Children Age at Infection Adults Outcome of Chronic HBV Infection Chronic HBV Infection Inactive Carrier State Chronic Hepatitis Cirrhosis HCC 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 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 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 Acute HBV Infection HBV DNA HBeAg Anti-HBe Anti-HBe Anti-HBs AntiHBc HBsAg 0 Anti-HBc IgM 2 Months 4 6 Years Chronic HBV Infection HBV DNA HBeAg Anti-HBe HBsAg Anti-HBc Anti-HBc IgM Months Years 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 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 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 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% Impact of HBV vaccination on HBV infection rates in Taiwanese children 30 HBsAg+ Anti-HBc+ 20 % 10 0 1984 Vaccination of infants born to HBsAg+ mother Universal vaccination 1994 of infant/preschool children Ni YH, Ann Intern Med 2001;135:796 1999 Impact of HBV Vaccination on Incidence of HCC in Taiwanese Children Avg Annual Incidence of HCC (per 100,000) 0.80 0.70 0.60 0.50 0.40 0.30 0.20 0.10 0.00 1981-1986 1986-1990 Universal Vaccination of Newborns Chang MH, NEJM 1997;336:1855 1990-1994 Hepatitis B Factors affecting disease activity and progression VIRUS Genotype Molecular Variants HOST Gender Age Immune Response Genetics ENVIRONMENT Alcohol HCV, HDV, HIV Carcinogens Stages of chronic HBV infection Immune tolerance < Immune clearance HBeAg + (wild) Low replicative phase >< Reactivation phase HBeAg - / anti-HBe + (PC/CP variants) >105 cp/ml <105 cp/ml HBV-DNA 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 Inactive-carrier state HBeAg – Chronic hepatitis HBeAg + Chronic hepatitis Unique Aspects of Hepatitis B among Asians Clinical Manifestations/Natural history • Immune tolerant phase • Frequent exacerbations and reactivations • Increased risks of HCC 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/treatmentinduced HBeAg seroconversion 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 Stages of chronic HBV infection Immune tolerance < Immune clearance HBeAg + (wild) Low replicative phase >< Reactivation phase HBeAg - / anti-HBe + (PC/CP variants) >105 cp/ml <105 cp/ml HBV-DNA 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 Inactive-carrier state HBeAg – Chronic hepatitis HBeAg + Chronic hepatitis 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 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 Risk factors for progression to cirrhosis Viral factors ● Persistently high HBV DNA levels Host Factors External Factors ● Older age ● Male gender ● HBV precore/CP variant? ● Advanced fibrosis ● HBV genotype (C > B) ● Persistent ALT elevation ● Recurrent hepatitis flares ● HDV, HCV coinfections ● HIV coinfection ● Alcohol Risk factors for progression to HCC Viral factors ● Persistently high HBV Host Factors External Factors ● Older age ● Alcohol ● Male gender ● Aflatoxin ● HBV CP variant ● Asians?? ● Smoking ● HBV genotype (C > B) ● Advanced fibrosis DNA levels ● Persistent ALT elevation ● Recurrent hepatitis flares ● HDV, HCV coinfections ● HIV coinfection ● Family history of HCC 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 Treatment of Chronic Hepatitis B Goals • Suppression of HBV replication • Decrease hepatic necroinflammation and fibrosis • Prevent progression to cirrhosis, liver failure and HCC 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 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) Lamivudine (n=436) ITT population p=0.001 Liaw YF, NEJM 2004; 351:1521 Licensed HBV therapies and those under development Licensed Phase III Interferon -2b Emtricitabine Lamivudine PegIFN -2b Phase II Pradefovir Entecavir Valtorcitabine Telbivudine (LdT) (LdC) LB80380 Clevudine Peg IFN -2a Tenofovir Adefovir Emtricitabine (FTC)* Tenofovir (TFV)* FTC+ TFV* Remofovir (MB06866) Elvucitabine (Fd4C) BAM 205 IL-12 Phase I MCC 478 FLG 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 When to start treatment? Benefits Likelihood of sustained response cirrhosis and HCC Risks Side effects Patient’s age Co-morbid illness Costs Drug resistance Likelihood of cirrhosis / HCC in the next 10-20 yrs Likelihood of sustained viral suppression after a defined course of treatment What should be the primary treatment? Long-term Benefits Antiviral potency Durability of response Long-term Risks Side effects Contraindications Drug resistance Ease of administration Duration of Rx Costs of Rx & monitoring Patient and provider preference IFN Lamivudine Adefovir Entecavir Parenteral Oral Oral Oral Finite duration Long duration Long duration Long duration More durable response Primary nonresponse in 25% More potent than LAM Higher rate of HBsAg loss Effective vs. LAMR mutants Activity vs. LAM-R mutants lower Resistant mutants Resistant mutants Resistant mutants No resistant mutants Frequent side effects 15-30% yr 1 0 yr 1, 29% yr 5 0 yr 1, <1% yr 2 70% yr 5 ~15-20% yr 2 (LAM-R pts switched to ADV only) ~10% yr 2 (LAM-R pts) (Nephrotoxic at high doses) (Limited track record) 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 Hepatitis B can be a deadly disease BUT It can be prevented, and it can be treated GET TESTED