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The Hepatic Barracuda Hepatitis B

The Hepatic Barracuda Hepatitis B. By William E. Stevens. History of Hepatitis B. 1883 15% receiving small pox vaccination in Germany develop jaundice 1941 > 50,000 U.S. soldiers develop jaundice after yellow fever vaccination

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The Hepatic Barracuda Hepatitis B

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  1. The Hepatic BarracudaHepatitis B By William E. Stevens

  2. History of Hepatitis B • 1883 15% receiving small pox vaccination in Germany develop jaundice • 1941 > 50,000 U.S. soldiers develop jaundice after yellow fever vaccination • 1947 “serum hepatitis” is designated Hepatitis B • 1963 Hepatitis B Surface Antigen identified • 1988 Pregnant mothers screened for HBV S Ag • 1991 Universal vaccination for children

  3. The Hepatitis B Virus • Family: Hepadnaviridae • 60% shared homology with human, duck, squirrel, and woodchuck hepatitis viruses • Genome: 3.2 Kb partially double stranded, circular DNA • Structure: • Envelope: Surface Ag, L and M proteins • Nucleocapsid core: Core Ag, DNA, and DNA polymerase

  4. The Hepatitis B Genome • Four partially overlapping open reading frames: • Envelope (Pre S/S) • Large, Middle, and Surface antigens • Core (Precore/core) • Core and E antigens • Polymerase • DNA polymerase with reverse transcriptase activity • X protein • Transactivation protein; ?hepatocarcinogenesis

  5. HBV Replication • L protein binds to hepatocyte membrane • Virus enters by direct fusion of envelope with cell membrane • Viral uncoating in cytoplasm • Nucleocapsid transported to nucleus • Host RNA polymerase transcribes viral DNA into mRNA and genomic RNA • RNA’s transported to cytoplasm for translation • Viral DNA polymerase / reverse transcriptase activity: genomic RNA  Neg DNA  Pos DNA • Virus assembly in Golgi apparatus • Exits hepatocyte by vesicular transport

  6. Hepatitis B Epidemiology • Worldwide • 2 billion have HBV markers (25%) • 400 million have chronic infection (5%) • Tenth leading cause of death in the world (1 million deaths annually) • U.S. • 1.25 million have chronic hepatitis • 50% are first generation Asian immigrants • 200,000 acute infections per year • Number declining since 1985 • 250 deaths / year from fulminant HBV • 4000 deaths / year from chronic HBV • 800 deaths / year from HBV related hepatoma

  7. Hepatitis B EpidemiologyPopulations at Risk Group % HBV S Ag+ • Asian immigrants 10-15% • Native Alaskans 6.4% • Homosexuals 6% • HIV+ 10% • IVDA 7% • Black > White • Men > Women • Peak incidence 20-29 years old

  8. Hepatitis B Transmission • HBV is found in blood and all body fluids except stool • Perinatal transmission • Primary route of infection outside of U.S. • Occurs at or after delivery • 70-90% transmission rate from HBV E Ag + mother to baby • Additional 60% children not infected at birth acquire infection by age 5 • Percutaneous / Sexual transmission • Primary route of transmission in U.S. (80%) • Sexual contact accounts for 50% cases • Percutaneous route accounts for 20% cases • IVDA, health care workers, tattoos, acupuncture, transfusions, hemodialysis, residence in institutions • Unknown causes 30%..... • HBV remains viable in environment for ~7 days

  9. Hepatitis BPathogenesis • Liver injury occurs from host immunologic response • Many chronic carriers with active viral replication have normal ALT • Fulminant HBV occurs due to hyper-vigorous immune response • Cytotoxic T-lymphocytes destroy infected hepatocytes • TNF and gamma-interferon activate non-antigenic clearance pathways

  10. Hepatitis B Variant Viruses • Precore / Core mutants • Point mutation in core promoter region • HBV E Ag negative • Increased likelihood for fulminant hepatitis • E Ag functions as “immune deflector” • More common in Mediterranean region (30%) than U.S. (10%) • Surface gene mutants • Occurs in neonates and transplant patients given HBIG • S Ag pos and S Ab pos • Polymerase gene mutants • Selected for by exposure to nucleoside analogues • HBV Surface Ag negative HBV infection • Rare transmission HBV from S Ag neg Core Ab pos individuals • HBV DNA rarely found in persons lacking all markers • HBV DNA often found in Hepatoma patients that lack S Ag • ? Mutation impairing expression of S Ag

  11. Natural History of Acute Hepatitis B • 3-5% in U.S. have HBV markers • >50% anicteric (subclinical) illness • <1% fulminant hepatitis • 90% have spontaneous resolution < 6 months • Incubation is 60-180 days • S Ag occurs 1-12 weeks after exposure • Core IgM and clinical hepatitis occurs 4 weeks after appearance of S Ag • E Ag indicates period of infectivity • S Ab indicates resolving infection • Rare “window period” between loss of S Ag and before S Ab appears; Core IgM will be positive

  12. Natural History of Chronic Hepatitis B • Persistent S Ag, E Ag, DNA > 6 months • Risk of chronicity is dependent on host age and immune status • Perinatal infection 90% • Childhood infection < age 6 30% • Acute adult infection 5% • HIV coinfection 30%

  13. Phases of Chronic Hepatitis B • Immune Tolerant Phase • S Ag +, E Ag +, DNA +, ALT normal • E Ag rarely clears with ALT fluctuations • Low risk for cirrhosis • Nonreplicative (low replicative) Phase (Integrated Phase) • S Ag+, E Ag--, DNA--, ALT usually normal • Prognosis is good: cirrhotic complications occur in 0.5/1000 patient years • ALT fluctuates in 20%; 50% have low detectable DNA levels • Some will progress to cirrhosis; 97% 5 year survival • Immune Clearance Phase • S Ag +, E Ag+, DNA +, ALT > 2 x normal • Chronic Active Hepatitis • 20% cirrhosis in 5 years (2-4% per year); 72% 5 year survival • 400 times risk of hepatoma • 10% per year spontaneously convert E Ag pos to neg • 1% per year spontaneously loose S Ag

  14. Hepatitis BExtrahepatic Manifestations • Arthralgias and rash 25% • Serum sickness-like syndrome, angioneurotic edema • Polyarteritis nodosa, systemic vasculitis • Mononeuritis, polyneuropathy • Membranoproliferative glomerulonephritis • Arthritis • Raynauds phenomena • Type II mixed essential cryroglobulinemia • Guillian Barre Syndrome • Pancreatitis • Pericarditis

  15. Hepatitis BCoinfection • HIV • 10% with HIV are S Ag+; 80% have HBV markers • Higher viral replication, lower ALT, less inflammation but more fibrosis on biopsy • Progression to cirrhosis is more rapid • Hepatitis C • Lower HBV replication • Increased rate of loss of S Ag • HCV predominates; more progressive liver disease • Hepatitis D • More common in Mediterranean region; uncommon in U.S. • Coinfection or superinfection • 34% fulminant hepatitis; 90% chronic hepatitis • 15% cirrhosis in 1 year

  16. Hepatitis B Prevention • Behavior modification • Eliminate high risk behavior; use condoms • Acute infection has declined for 20 years • Screen pregnant mothers • HBIG and HBV vaccination at birth prevents 95% of perinatal infections • HBV Vaccination • Perinatal exposure • Persons with sexual, mucosal, percutaneous exposures • Persons with HCV or IV drug abuse • Homosexuals • Health care workers • Hemodialysis patients • Universal vaccination for children • Hepatitis B Immune Globulin • Perinatal exposure • Needle stick exposure • Persons with recent sexual, mucosal, percutaneous exposures

  17. Hepatitis BTreatment • Who to treat • Chronic active hepatitis > 6 months duration • S Ag+, E Ag +/-, DNA+, ALT > 2 x normal • Active hepatitis, advanced fibrosis on biopsy • Goal of treatment • Stop viral replication: HBV DNA becomes Neg • Convert E Ag+ to E Ag--; E Ab becomes pos • Improve histology, prevent progression to cirrhosis • Prevent hepatoma • With successful treatment 1-2% per year will loose S Ag

  18. Hepatitis B TreatmentAlpha-interferon 2b • 5 mu sq qd for 4-6 months • 35% response rate: E Ag seroconversion; 10% loose S Ag • Hepatitis flare is common during treatment • Favorable pretreatment variables: • Low HBV DNA levels < 200 pg/ml • High ALT > 100 • Active hepatitis on biopsy • Shorter duration of infection • Others: female, HIV neg

  19. Hepatitis B TreatmentAlpha-Interferon 2b • Pros • Short, finite period of treatment • Effective viral response persists in 90% • After 8 year f/u: hepatoma risk reduced from 12% to 1.5%; survival improved to 98% vs. 57% • No resistant mutants • Cons • Expensive: $ 2000 per month • Side effects; 35% require dose reduction • May cause cirrhosis to decompensate: CONTRAINDICATED • Less effective with E Ag mutants • Lower sustained response rate: 25% • Higher relapse rate: 50% • Requires 12 month treatment

  20. Hepatitis B TreatmentPEG Interferon Alpha 2a • 180 ug sq q week for 48 weeks • 35% became E Ag negative (c/w 25% with standard interferon) • 32% DNA negative • 41% normal ALT • No benefit with addition of lamivudine • Except lower incidence YMDD mutants • Effective with E Ag neg mutants • One year PEG compared to lamivudine treatment: • 20% receiving PEG were DNA Neg 6 months after treatment • 4% became S Ag neg; 59% normal ALT; 81% improved histology • 7 % given lamivudine were DNA Neg after 6 month f/u • 0% were S Ag neg

  21. Hepatitis B TreatmentNucleoside Analogues • Inhibit HBV DNA polymerase / reverse transcriptase • Lamivudine (Epivir) 100 mg po qd • Adefovir (Hepsera) 10 mg po qd • Entecavir (Baraclude) 0.5 mg - 1 mg po qd • Others • Famciclovir ?benefit in combination with lamivudine • Emtricitabine efficacy similar to lamivudine • Tenofovir similar to adefovir, less nephrotoxicity, ideal if HIV+ • Clevudine pyrimadine analogue in phase 1-2 trials

  22. Lamivudine • Competes with dCTP • Normalizes LFT’s, inhibits viral replication, and improves histology • Prolonged use leads to viral resistance • 15-30% per year; 70% at 4 years • YMDD mutants replicate less efficiently • Safe in pregnancy • 0/38 babies developed perinatal HBV • Cost: $230 per month • E Ag seroconvervison occurs in 17% at one year; 50% at 5 years • More effective if ALT higher: 2% response if ALT normal vs. 42% if ALT 5x • Stop treatment 3-6 months after loss of E Ag • 20-40% will relapse • Effective in E Ag negative mutants • 70% are DNA neg at one year; 40% at 3 years • 90% relapse if stopped < 1 year • Delays progression of cirrhosis and reduces risk of Hepatoma • After 3 years: risk of cirrhosis progression reduced from 20% to 10% • Hepatoma risk reduced from 7.4% to 3.9% • No benefit when combined with interferon

  23. Adefovir • Prodrug for AMP analogue • Efficacy seems similar to lamivudine after 1 year • 12% E Ag serosonversion; 43% at 3 years • DNA neg 51%, ALT normal 72%, improved histology 64% • Viral resistance is uncommon: 0% at 1 year, 2.5% at 2 years • Effective in Lamivudine resistance • Effective in E Ag mutants • Cost $500-600 per month • Nephrotoxicity occurs in 2.5% after 1 year • No benefit when combined with lamivudine

  24. Entecavir • Deoxyguanosine analog • In vitro seems more potent than lamivudine, adefovir • O.5 mg/d for nucleoside naïve patients; 1 mg/d for lamivudine resistance • 6% with lamivudine resistance develop resistance to entecavir • Cost: more • Compared to one year treatment with lamivudine: E L • More improved histology: 72% vs 62% • DNA negative: 69% vs 38% • ALT normal: 78% vs 70% • E Ag seroconversion: 21% vs. 18%

  25. Hepatitis B TreatmentAlgorithm

  26. Hepatitis BFollow Up • S Ag +, E Ag -, DNA – • Follow LFT’s every 6-12 months • S Ag +, E Ag +, DNA + • Liver biopsy, stage hepatitis • Treat • Follow LFT’s every 3-6 months • Hepatoma Surveillance • High risk group • Men, age >45, cirrhosis, E Ag +, DNA +, high ALT, ETOH+, HCV +, tobacco+, aflatoxin exposure, family history HCC • AFP every 6 months + US every 6 -12 months • Low risk group: check AFP annually • Surveillance findings • Hepatomas are smaller and more resectable • One study shows improved 1 year survival • Cost of surveillance is $10-15,000 per year of life saved

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