Transcript The Hepatic Barracuda Hepatitis B By William E. Stevens History of Hepatitis B • 1883 • 1941 • 1947 • 1963 • 1988 • 1991 15% receiving small pox vaccination in.

The Hepatic Barracuda
Hepatitis B
By
William E. Stevens
History of Hepatitis B
• 1883
• 1941
• 1947
• 1963
• 1988
• 1991
15% receiving small pox
vaccination in Germany develop
jaundice
> 50,000 U.S. soldiers develop
jaundice after yellow fever
vaccination
“serum hepatitis” is designated
Hepatitis B
Hepatitis B Surface Antigen identified
Pregnant mothers screened for HBV S Ag
Universal vaccination for children
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
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
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
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
Hepatitis B Epidemiology
Populations at Risk
Group
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Asian immigrants
Native Alaskans
Homosexuals
HIV+
IVDA
Black > White
Men > Women
Peak incidence 20-29 years old
% HBV S Ag+
10-15%
6.4%
6%
10%
7%
Hepatitis B Transmission
• HBV is found in blood and all body fluids except stool
• Perinatal transmission
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–
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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
Hepatitis B
Pathogenesis
• 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 nonantigenic clearance pathways
Hepatitis B Variant Viruses
• Precore / Core mutants
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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
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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
Natural History of Acute Hepatitis B
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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
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
– Childhood infection < age 6
– Acute adult infection
– HIV coinfection
90%
30%
5%
30%
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)
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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
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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
Hepatitis B
Extrahepatic Manifestations
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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
Hepatitis B
Coinfection
• 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
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More common in Mediterranean region; uncommon in U.S.
Coinfection or superinfection
34% fulminant hepatitis; 90% chronic hepatitis
15% cirrhosis in 1 year
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
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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
Hepatitis B
Treatment
• 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
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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
Hepatitis B Treatment
Alpha-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:
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Low HBV DNA levels < 200 pg/ml
High ALT > 100
Active hepatitis on biopsy
Shorter duration of infection
Others: female, HIV neg
Hepatitis B Treatment
Alpha-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
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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
Hepatitis B Treatment
PEG 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
Hepatitis B Treatment
Nucleoside 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
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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
Lamivudine
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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
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Safe in pregnancy
– 0/38 babies developed perinatal HBV
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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
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Stop treatment 3-6 months after loss of E Ag
– 20-40% will relapse
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Effective in E Ag negative mutants
– 70% are DNA neg at one year; 40% at 3 years
– 90% relapse if stopped < 1 year
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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%
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No benefit when combined with interferon
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
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
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More improved histology:
DNA negative:
ALT normal:
E Ag seroconversion:
72% vs 62%
69% vs 38%
78% vs 70%
21% vs. 18%
Hepatitis B Treatment
Algorithm
E Ag
DNA
ALT
Treatment
Positive
>105
>2x
PEG if DNA low,
or nucleoside if
DNA high
normal
Follow LFT’s
Consider biopsy.
Nucleoside if
biopsy advanced
<105
normal
Follow LFT’s. No
treatment unless
biopsy advanced
>104
>2x
PEG or
nucleoside
<104
normal
Follow LFT’s.
Consider biopsy.
Nucleoside if
biopsy advanced.
Negative
Hepatitis B
Follow 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