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A. Viral Characteristics [3] navigator

  1. Major worldwide health problem
    1. Infects >400 million persons worldwide
    2. Accounts for ~10% of chronic liver disease / cirrhosis in USA
    3. Cause of ~80% of hepatocellular carcinoma (HCC) worldwide
    4. ~5% of acutely infected people develop chronic HBV infection
    5. Completely preventable disease using currently available vaccines
  2. Incomplete double stranded DNA virus (~3200 bases)
    1. Replication through an RNA intermediate
    2. Virus encodes a reverse transcriptase
    3. Other major proteins include surface, core, and envelope genes
    4. Virus particles are 42nm (complete, formerly called "Dane Particle")
    5. Small non-infectious particles of HBV env protein ~22nm
    6. Eight major HBV genotypes (A to H); F and G found in USA
    7. Oncogenic potential with strong linkage to HCC
  3. Liver Damage
    1. Only occurs in patients with active HBV DNA replication
    2. Minimal or no liver damage in HBV DNA negative persons, even with HBsAg present
    3. Cytolytic T lymphocytes no longer believed to play major role in virus elimination
    4. Interferon gamma and TNFa released from CD8+ T lymphocytes appears to halt virus
    5. Functionally active CD8+ T cells need not cause damage to infected hepatocytes
  4. HBV required for hepatitis delta virus (HDV) superinfection
    1. HDV is a replication defective, RNA virus
    2. HDV only exists with HBV infection
    3. Presence of HDV increases risk of chronic severe hepatitis and complications

B. Symptoms of Acute HBV Infection navigator

  1. Flu-like Illness: malaise, arthralgias, fever
  2. Jaundice
  3. Nausea (vomiting uncommon)
  4. ~94% of patients have self limiting illness
  5. ~5% of patients have chronic active or persistent hepatitis
  6. 1% of patients will progress to fulminant hepatic failure

C. Diagnostic Testingnavigator

  1. Surface antigen (HBsAg)
    1. Indicates chronic active or persistent infection (uncleared HBV)
    2. Persistence of HBsAg for >6 months indicates chronic infection
  2. Surface antibody (anti-HBs Ab) - indicates clearance of infection
  3. Core Antibody (anti-HBc Ab) - indicates previous infection
  4. Envelope Antigen (HBeAg)
    1. Carriers are highly contagious
    2. Increased risk of HCC in HBeAg+ versus HBeAg- patients [4]
  5. Delta Antigen - indicates superinfection with HDV (see below)
  6. HBV DNA Detection
    1. Branched DNA test - detects 700,000 copies/mL
    2. Hybrid capture test - detects 140,000 copies/mL
    3. Polymerase chain reaction (PCR) - detects 200 copies/mL
    4. Unlcear what cutoff level is associated with stable liver function
  7. Liver biopsy generally recommended to assess severity of disease prior to therapy

[Figure] "Hepatitis B Virus Protein Expression and Serology"
Stage of InfectionHBsAgAnti-HBsIgManti-HBc IgGHBeAgAnti-HBeAg
Latent Incubation+±±±±±
Acute Hepatitis B++±+++++±
HBsAg Carrier++±±++++/-+
Chronic Hepatitis B+±±++++/-±
Resolved Infection
within 6 months±+++++±+
>6 months±+±++±±
Vaccination±++±±±±

D. Hepatic Complications of HBV Infectionnavigator

  1. Infectivity
    1. In adults, ~90% of infected persons clear virus and are HBsAb positive
    2. Persons infected at birth progress to chronic infection at higher rate (~50%)
  2. Chronic Hepatitis [3,5]
    1. Occurs in 5-8% of adult patients with acute infection
    2. Occurs in >90% of infected children with acute infection
    3. Three phases of chronic HBV infection described
    4. Long immune tolerance phase in children and adolescents with normal histology, high levels of HBV DNA, HBeAg+
    5. Adolescents have short and adults no immune tolerance phase
    6. Immune clearance phase with seroconversion from HBeAg to HBeAb accompanied by acute inflammation, fibrosis, fluctuating elevated serum aminotransferase levels
    7. Residual phase with low concentrations of HBV DNA and normal transaminase levels
  3. Cirrhosis [5,6]
    1. Progression to cirrhosis occurs in some of these patients, usually over 5-10 years
    2. >30% of patients with untreated chronic HBV+ hepatitis develop cirrhosis [5]
    3. Cirrhosis is a major risk factor for death, HCC, liver failure
    4. Lamivudine + interferon alpha prevent progression in most patients
    5. Monitor therapy with monthly evaluations of serum HBV DNA, HBeAg, anti-HBe, and ALT
    6. About 10% of untreated patients will develop polyarteritis nodosa (see below)
  4. Fulminant Hepatitis
    1. Massive liver cell necrosis with progression to failure in days
    2. Related to mutations with prevent HBV e Antigen expression
    3. Occurs in about 1% of persons infected with HBV
  5. Superinfection with Hepatitis Delta Virus (HDV)
    1. HDV superinfection predicts poorer prognosis
    2. Progressive hepatic dysfunction
    3. Increased risk of cirrhosis and hepatocellular carcinoma
  6. Coinfection with hepatitis C virus (HCV) increases risk of death, cirrhosis, HCC [6]
  7. Hepatocellular Carcinoma (HCC) [27]
    1. Major risk factor for liver cancer is chronic HBV with cirrhosis
    2. Risk is as high as 15% over ~10 years, highly dependent on HBV DNA levels [27]
    3. Overall risk in HBV+ cirrhosis is 5-10% per year [5]
    4. Serum levels of HBV DNA independently correlate strongly with risk of HCC [27]
    5. HBV levels >10,000 copies/mL is a strong predictor of HCC [27]
    6. Highest risk in patients with HBeAg [4]
    7. Presence of HDV and/or Hepatitis C virus increases risk
    8. HBV integration is usually found in HBV-associated tumors
    9. HBV integration into host genome causes deregulation of certain host genes
    10. Vaccination against HBV reduces incidence HCC
  8. Occult HBV (seropositive OR negative) in HCV infected persons may worsen the course of HCV related disease and reduce responses to interferon [7]
  9. HIV-1 coinfection with HBV increases risk of liver-related mortality, particularly in patients with reduced CD4 counts [8]
  10. In HBsAg+ patients receiving cancer chemotherapy, LAM prophylaxis prevents reactivation by >80% and may eliminate HBV-related hepatic failure [41]

E. Renal Diseasenavigator

  1. Membranous Nephropathy most often seen
    1. Adults may have membranoproliferative nephritis
    2. Mesangial proliferative also seen
  2. Usually develops in HBeAg+ patients with chronic infection
  3. Role of cryoglobulin in HBV renal dysfunction is unclear
  4. Renal insufficiency often responds to treatment with interferon alpha (5MU qd sc)
  5. Polyarteritis Nodosa (PAN) [9]
    1. May develop ~10% of patients with untreated chronic HBV
    2. PAN is a p-ANCA positive vasculitis syndrome
    3. PAN includes medium-sized arterial vessel destruction, renal disease, other
    4. Treatment includes immunosuppression along with antiviral therapy (lamivudine)

F. Treatment [10,11]navigator

  1. Supportive therapy
    1. Majority of patient have self-limited disease
    2. Rare acute infections show increase in prothrombin time
    3. Patients may require rehydration if nausea and vomiting are severe
  2. Severe acute infection may also be treated with Interferon alpha (IFNa)
  3. Indications for Treating Chronic HBV [3,11]
    1. Chronic HBV infection may be treated due to risk of cirrhosis and carcinoma
    2. Decision to treat or not determined by patient and physician
    3. In HBeAg+ patients, viral suppression without HBeAg clearance leads to relapse
    4. Clearance of HBeAg associated with ~70% cures
    5. In HBeAg- patients, treatment (with IFNa) associated with ~25% complete remission
    6. Treatment is generally indicated if aminotransfferases levels are elevated or if liver biopsy shows marked inflammation or fibrosis
    7. Various oral nucleoside analogs are also effective, but interferons are superior [35]
    8. Combined lamuvidine with (peg)-IFNa provides little additional benefit to IFNa alone [29,35]
    9. Monitor therapy with monthly evaluations of serum HBV DNA, HBeAg, anti-HBe, and ALT
    10. Yearly ultrasound and serum alpha-fetoprotein for progression to Hepatocellular CA
  4. Agents for HBV (HIV+ or HIV-) [38]
    1. Telbivudine
    2. Lamivudine
    3. Entecavir
    4. Adefovir
    5. Tenofovir
    6. Tenofovir + emtricitabine
    7. Pegylated IFNa
  5. Telbivudine (Tyzeka®) [9]
    1. Nucleoside analog reverse transcriptase inhibitor, anti-HBV
    2. Dose 600mg qd x 1 year superior for HBV DNA negativity against lamivudine 100mg qd
    3. HBV DNA negative at 52 weeks: 60% of HBeAg+, 88% of HBeAg- patients
    4. In HBeAg+ persons, superior viral and histologic response at one year versus LAM [12]
    5. In HBeAg+ persons, superior viral suppression at 24 and 52 weeks versus adefovir [40]
    6. No activity against HIV or HCV
    7. Fatigue, malaise, fever, joint pain, GI upset, elevated muscle enzyme levels
  6. Lamivudine (3TC, Epivir HBV®, LAM) [3,33]
    1. Oral (-) enantiomer of 2'-deoxy-3'thiacytidine, blocks HBV DNA synthesis
    2. Dose of 100mg/d is as effective as higher doses and should be first line
    3. 100mg qd po reduces HBV DNA 98%, normalizes ALT in ~70% persons
    4. About 15% of HBeAg+ patients seroconverted to HBeAb after 1 year therapy
    5. LAM should be used in ALL patients with chronic active HBV infection
    6. Monotherapy is initially effective but resistance develops frequently
    7. Resistance develops through mutations in YMDD motif of the viral reverse transcriptase
    8. Improves inflammation, reduces fibrosis progression in chronic HBV infection
    9. Continuous treatment (to 42 months) with LAM 100mg qd reduces hepatic decompensation and hepatocellular carcinoma in chronic HBV with advanced liver disease [13]
    10. May be used pre-transplant in patients with cirrhosis and active HBV infection
    11. Also effective in acute HBV infection and may permit clearance of virus [14]
    12. Combining IFNa with LAM in LAM resistant patients is of no benefit
    13. Well tolerated with some response in children with chronic HBV [15]
    14. Safe and effective in patients with decompensated liver disease
    15. In most patients, viral DNA reappears after drug is stopped
    16. Appears less effective, at least in HBeAg+ persons, than telbivudine [12]
  7. LAM Resistant HBV
    1. Significant prevalance in HBV+ patients with or without HIV
    2. YMDD mutants arise 15-30% in first year, up to 70% within 5 years
    3. Adefovir approved for LAM resistant HBV indication
    4. Entecavir is quite active against LAM resistant HBV
  8. Entecavir (Baraclude®) [32]
    1. 2'-deoxyguanosine analog with anti-HBV activity with reported anti-HIV activity
    2. Extremely potent, effective aginst YMDD mutants with 3-4 log10 reductions in HBV DNA
    3. Slightly superior to LAM in LAM naive patients (~9% overall superior ALT normalization)
    4. Good activity in LAM resistant patients (61% normalize ALT)
    5. In HBeAg+ patients for 52 weeks, entecavir produced superior anti-HBV activity, serum ALT normalization, and similar seroconversion to HBeAg- as LAM [23]
    6. In HBeAg- patients for 48 weeks, entecavir produced suprior anti-HBV activity and serum ALT normalization compared with LAM [36]
    7. Viral resistance to entecavir was not reported in two large studies [23,36]
    8. Can reduce HIV levels in coinfected patients but induces high levels of M184V mutation in HIV reverse transcriptase, causing resistance to Lam and entecavir [39]
    9. Generally well tolerated; some lactic acidosis and hepatomegaly steatosis reported
    10. Dose is 0.5mg po qd
  9. Adefovir (Hepsera®) [16]
    1. Nucleotide analog (prodrug) with broad antiviral activity (mainly anti-HIV and HBV)
    2. Activated by phosphorylation to adefovir diphosphate which is a DNA chain terminator
    3. Dose is 10-30mg po qd (begin 10mg po qd)
    4. Serum concentrations of HBV DNA reduced ~3.5 logs over 48 weeks theapy
    5. In HIV- HBeAg- patients, reduces HBV DNA levels to <400 copies/mL in 50% [17]
    6. In HIV- HBeAg- patients, improves liver histology in 64% (versus 33% with placebo) [17]
    7. In HIV- HBeAg- patients, suppresses serum HBV DNA levels 3.47 log after 96 weeks,
  10. 63 log after 144 weeks; 144 weeks strongly recommended to maintain suppression [34]
    1. In HIV- HBeAg+ patients, causes seroconversion to HBeAb+ in 12-14% [18]
    2. In HIV- HBeAg+ patients, histologic improvement occurred in ~55% (25% with placebo) [18]
    3. In HIV+ HBV patients, 48 weeks of adefovir reduced LAM resistant HBV levels [19]
    4. Severe hepatitis exacerbations can occur after cessation of therapy in ~25% patients
    5. Causes creatinine elevation and may be nephrotoxic
    6. Caution in patients with pre-existing renal dysfunction
    7. Variant HBV with primary adefovir resistance reported, sensitive to tenofovir [28]
    8. Appears less effective, at least in HBeAg+ persons, than telbivudine [40]
  11. Tenofovir (Viread®) [2,28]
    1. Nucleotide reverse transcriptase inhibitor with good anti-HBV activity
    2. Approved for combination therapy in resistant HIV
    3. Has good activity in LAM resistant strains of HBV
    4. Once daily 300mg dosing taken with food
    5. Nausea, vomiting, diarrhea are most common adverse events
    6. May be effective against LAM resistant strains
  12. IFNa and Pegylated-IFNa [33,35]
    1. May be used for chronic infection with transaminase elevation
    2. Not used if transaminases are normal or if liver biopsy shows little inflammation
    3. IFNa or PEG-IFNa can convert ~30% of HBeAg+ patients to HBeAg- status
    4. PEG-IFNa2a can induce HBsAg seroconversion (true cure) in a minority of patients
    5. Treatment duration is 3-6 months, 10 MU 3X/week or 5 MU daily sc or im
    6. Efficacy is seen at >6-12 months, with conversion of patients to HBeAb+ (~37%) and HBsAb+ (~8%)
    7. Only ~25% of treated patients maintain lasting responses with IFNa
    8. Peginterferon alpha2a (PEG-IFNa2a) 180µg weekly induces sustained complete responses viral levels <400/mL) in ~20% versus 7% with LAM in chronic HBV (HBeAg-) [22]
    9. Reponse rate (viral load <20,000/mL) ~60% with PEG-IFNa2a versus 44% with LAM [22]
    10. No benefit to combining IFNa or PEG-INFa2a or PEG-IFNa2b with LAM in chronic HBV [22,29,35]
    11. Staggard combination PEG-IFNa2b with LAM in HBeAg+ patients lead to 36% virologic response rate versus 14% for LAM alone [30]
    12. PEG-IFNa2b 100µg weekly for 52 weeks cleared HBeAg in 35% of HBeAg+ patients [29]
    13. IFNa is relatively contraindicated in patients with HIV or decompensated liver disease
    14. IFNa is poorly or not effective in patients on immunosuppressive agents
    15. Significant rates of adverse events include serious adverse events ~5%
    16. Most effective but poorly tolerated therapy for chronic HBV
  13. Famciclovir (Famvir®) [2]
    1. Approved for herpes simplex varicella zoster virus infections
    2. Active against HBV; most tests in transplant setting
    3. Combination therapy is being investigated
  14. Liver Transplantation [2]
    1. For patients with cirrhosis or other severe manifestation of liver failure
    2. Recurrent HBV infection in new liver occurs in 80% of cases without prophylaxis
    3. HBV immune globulin and LAM both reduce incidence of post-transplant HBV infection
    4. Combination of LAM and HBV immune globulin reduces HBV reinfection to 10% at 5 years
    5. Likely that only 6-12 months of HBV immune globulin is required post-transplant

G. Prevention navigator

  1. Blood product screening - standard
  2. Vaccination [21]
    1. Original product used isolated Surface (HBV-S Ag) Protein (such as Hepatovax®)
    2. Yeast recombinant surface (and pre-S) protein vaccine now used
    3. Two versions are available: Recombivax HB® and Engerix-B®
    4. These vaccines are extremely effective and represent major healthcare advances
    5. Normal dose (0.5mL) regimen is given im at 0, 1 and 6 months
    6. Double dose given at 0, 1, 2 and 6 months for hemodialysis and alcoholic patients
  3. All infants and adults should be vaccinated against HBV
  4. Global, universal use of HBV vaccine is being investigated for possible HBV eradication
  5. Vaccination against HBV reduces incidence of HCC
  6. Booster Vaccinations [24]
    1. Generally unnecessary in immunocompetent persons
    2. However, in immunocompromised persons, test anti-HBS titer
    3. Booster vaccinations should be given when titer is below 10 mIU/mL
  7. HBV vaccination does not increase the risk for multiple sclerosis (MS) or MS relapses [25,26]
  8. HBV vaccine induces protective antibody levels for at least 15 years in most people [31]

H. Hepatitis D (Delta) Virus (HDV) [1,2] navigator

  1. RNA virus requires helper function from HBV
    1. HBSAb positive patients (vaccinated or cleared HBV infection) are not at risk
    2. HBV uninfected persons not at risk
  2. Causes acute or chronic hepatitis in setting of HBV
    1. May cause severe exacerbation of chronic hepatitis
    2. When coinfects with HBV, more likely to cause a fulminant course
    3. ~80% of patients with D infection will go on to cirrhosis
    4. Therefore, this is the hepatitis virus most commonly associated with cirrhosis
  3. High dose IFNa therapy (9MU 3X/week) has also been used but newer antivirals preferred

References navigator

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  24. European Consensus Group on Hepatitis B Immunoity. 2000. Lancet. 355(9203):561 abstract
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  27. Chen CJ, Yang HI, Su J, et al. 2006. JAMA. 295(1):65 abstract
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  31. McMahon BJ, Bruden DL, Petersen KM, et al. 2005. Ann Intern Med. 142(5):333 abstract
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