HEPATITIS B VIRUS
July 14th, 2005
Amanda Pressman, M.D.
Background
discovered in 1966, Causes 1 million deaths worldwide annually, 350 million are HBV carriers
partially double-stranded DNA circular virus
part of the hepadnaviruses (e.g., duck hepatitis B virus, woodchuck hepatitis virus)
Most commonly transmitted blood-borne virus in the healthcare setting
Epidemiology
SE Asia/China – perinatal transmission mainly
USA – percutaneous and sexual transmission
70% with acute HBV develop “anicteric hepatitis” or subclinical hepatitis
30% with acute HBV develop “icteric hepatitis” (those with preexisting liver disease are at higher risk)
0.1-0.5% develop fulminant hepatitis secondary to massive immune mediated lysis of infected hepatocytes.
Mutant strains seem to be more apt to cause fulminant hepatitis.
Acute vs. Chronic HBV
Less than 1% of immunocompetent adults with acute HBV progress to chronic infection. Factors modifying
one’s risk of developing chronic infection include: Gender, alcohol consumption, h/o pre-existing liver
disease, if acquired perinatally, and age at infection.
SEROLOGY
Hepatitis B Surface Antigen (“envelope antigen”)/HBsAg
Immunity to this is protective
Recombinant HBsAg = basis for HBV vaccines
Ab to HBsAg indicates prior infection or immunization, though can be undetectable in those fully
recovered from infection. A “window” period may exist for months after Hbs Ag is gone before the
Ab circulates.
Hepatitis B Core Antigen/HBcAg
Nucleocapsid that encloses the viral DNA
Antibodies to this are not protective, though detected in all patient’s exposed to HBV
Ab to HBcAg are present in acute and chronic HBV and those recovered
IgM antibodies to HBcAg generally indicate acute infection and appear during the “window” period,
but disappear after 4-8 mo
*Can also reappear during flares of chronic disease
Hepatitis B e Antigen/ HBeAg
Circulating peptide derived from the core gene, modified and exported by hepatocytes
A marker for active viral replication
Antibodies to HBeAg appear once the antigen has been cleared and the virus is no longer
replicating.
In those with the pre-core mutation, may have active disease even with HBeAb circulating.
HBV DNA
Sensitivity varies, may persist in serum for years, even once recovered
Serum level of 105 is considered cutoff for chronic HBV by the NIH consensus conference
Pathophysiology of HBV-Mediated Liver Damage
HBcAg + other small epitopes of HBV proteins are presented on the surface of hepatocytes
HLA Class I-restricted CD8+ cells recognize them (note, only some of them are recognized and
polymorphism of this site + T-Cells + binding affinity  different outcomes of acute HBV infection)
Once recognized by CD8+ Cytotoxic T-lymphocytes  direct hepatocyte killing
The virus will be cleared if there is sufficient recognition and activation of the immune response. If
inadequate, the infection smolders.
4 Stages of HBV Infection
REPLICATIVE PHASE
1. Immune Tolerance
Lasts 2-4 weeks in adults (can be 10+ yrs in neonates/children)
HBV DNA and HBeAg are strongly positive. HbcAG is positive
LFTs are normal
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Ab-HBcAg develop and remain positive for life
2. Active Hepatitis
In acute form, lasts 3-4 weeks, can last decades in patients with chronic HBV
Less HBV DNA is found than in Stage 1
LFTs are elevated (AST/ALT in 1000-2000 range)
Also see positive HBsAg, Ab-HBcAg, HBeAg
INTEGRATIVE PHASE
3. Clearance of Virus-infected Cells
Replication ceases
HBeAg disappears
HBV DNA is detectable only by sensitive PCR assays
Ab-HBeAg forms
HBsAg still present
4. HBsAg disappears
Ab-HBsAg appears signaling full-immunity
LFTs remain normal
HBV DNA is undetectable
Chronic HBV
Most patients are asymptomatic, however, there is a wide range, including symptoms of hepatitis and those
who have frank liver failure.
*10-20% develop extra-hepatic symptoms thought to be mediated by circulating immune complexes.
Examples include Polyarteritis Nodosa and Glomerular disease (membranous nephropathy and
membranoproliferative glomerulonephritis). The latter can resolve spontaneously or cause ESRD.
10-20%  develop cirrhosis
20% of those with chronic HBV and compensated cirrhosis  develop hepatic decompensation
6-15% of those with chronic HBV and compensated cirrhosis  hepatocellular carcinoma (HCC)
Hepatocellular Carcinoma: difficult to screen for.
Ultrasound = sensitivity 79%, specificity 94%
AlfaFetoprotein = sensitivity 64%, specificity 91%
HBV and other Viruses
HBV + HCV: acute coinfection increases the risk of fulminant hepatic failure
Existing HCV + acute HBV  shorter duration of HBV antigenemia, lower peak transaminases.
M/a of this ? if HCV interferes with HBV replication leading to less liver damage.
HDV: A “passenger virus” (the only one in the animal kingdom)
Replicates independently
Requires HBV coinfection for complete virion assembly and secretion
if HDV + HBV  worse liver disease, accelerated progress to cirrhosis
HAV: If negative HAV antibody, vaccinate those with HBV as recommended by the ACIP (Advisory
Committee on Immunization Practices).
Treatment – Goal is to hasten progression from Stage 2 to Stage 3 of the disease and suppress HBV
replication before there is irreversible liver damage.
Interferon 2b (approved for use in 1992). Induces the display of HLA-1 molecules on hepatocytes and
promotes lysis. Also, directly inhibits viral protein synthesis. 35-45% remission rate after 4 mo of
treatment, however, fever, malaise, neutropenia and thrombocytopenia are common side effects.
Those most likely to respond have elevated transaminases (> 100 IU/mL), + HBV DNA titers (but <
200 pg/mL), + liver biopsy suggesting moderate or severe inflammatory activity, < 65 yrs old, HIV -,
adult acquired disease.
Nucleoside Analogs – First one = Zalcitabine, but too toxic and replaced by Lamivudine (Epivir). Treat 412 weeks  nearly 100% clearance of HBV DNA, but when stopped, recurrence inevitably occurs.
With prolonged treatment, escape mutants develop. Other antiviral agents such as Famciclovir are
being tested.
Also, combination therapies are currently being studied with possibly promising outcomes.
Reference: NEJM 337;24, UpToDate, Gut 50:443
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