HEPATITIS B VIRUS


A DNA virus (Hepadnavirus)

I. Transmission

  1. Parenteral (e.g. transfusion, sharing needles for drug abuse, etc.)
  2. Vertical transmission (transplacental)
  3. Sexual

II. Prevention

  1. Hepatitis B Vaccine (recommended for universal use in U.S.--Click on link for details)
  2. Prevention of vertical transmission
    1. In a meta-analysis of 26 randomized trial in infants born to HBSAg-positive women for prevention of neonatal infection with HBV:
      1. Hepatitis B Immunoglobulin (HBIG) significantly reduced incidence of HBV infection (RR 0.50 c/w no treatment)
      2. Hepatitis B vaccine significantly reduced incidence of HBV infection (RR 0.28 c/w no treatment)
      3. Combination of HBIG and Hepatitis B vaccine was sig. better than vaccine alone (RR 0.54) (BMJ 332:328, 2006--JW)

III. Clinical features  and natural history

  1. Transient infection
    1. 95% of those infected experience transient infection and no persistent viremia
  2. Chronic infection
    1. 4% experience chronic infection (persistent viremia) with or without liver damage
    2. Sequelae of chronic infection
      1. Hepatitis (10-30% of pts)
      2. Hepatic cirrhosis
        1. In a prospective study of 3,582 pts with chronic Hepatitis B but no hepatocellular Ca, hepatitis C infection, or cirrhosis at baseline, over mean 11y f/u, independent predictors for development of cirrhosis included HBV DNA level (RR 2.5 for levels 10E4-10E5 copies/mL, 5.6 for 10E5-10E6, and 6.5 for 10E6 and higher), male sex, older age, HBeAg-positive status, and ALT > 44.  (Gastroent. 130:678, 2006--JW)
      3. Hepatocellular Carcinoma
        1. Incidence about 10% of those with cirrhosis)
      4. Risk factors for progression to Hepatocellular Carcinoma
        1. HBSAg positivity
        2. HBeAg positivity
        3. HBV DNA level
          1. In a prospective study in 3,653 pts with hepatitis B 30-65yo, over mean 11.4y f/u, after adjustment for potential confounders, HBV DNA levels > 10,000 copies/mL was associated with sig. increase in incidence of hepatocellular carcinoma, compared with those with HBV DNA levels < 300 copies/mL.  There was a dose-response relationship identified with higher categories of HBV DNA level assocaited with higher risk.  > 1 million copies/mL was associated with RR of 6.1 c/w < 300 copies/mL (JAMA 295:65, 2006--JW)
    3. Natural history in chronic HBV with normal transaminases
      1. In a study in 296 asymptomatic HBsAg-positive pts w/normal or near-normal serum ALT levels, all of whom were e antigen-negative, over mean 29y f/u, had no sig. diff. in overall mortality c/w sex-, age-, and alcohol use-matched controls (Gastroent. 127:756, 2004-JW)
    4. Natural history in chronic HBV with very low viral DNA levels
      1. In a cohort study in 1,932 pts with positive HBSAg but HBV DNA < 10,000 copies/mL and normal ALT and negative Hep B e Ag, compared with 18,137 HBSAg-negative controls, over mean 13y f/u, the chronic HBV patients had sig. annual higher incidence of hepatocellular carcinoma (0.6% vs. 0.2%) and liver-related death (0.04% vs. 0.02%) (Gastroent. 138:1747, 2010-JW)
    5. Extrahepatic manifestations
      1. Rash
      2. Glomerulonephritis
      3. Transient arthritis
      4. Angioneurotic edema
    6. Chronic infection occurs in 90% of neonates infected with HBV
      1. Therefore, if mom has acute HBV, some recommend giving HBV hyperimmune globulin <12h post-partum, then HBV vaccine
  1. 1% experience a fulminant course with severe rapid liver damage.

IV. Diagnostic tests for hepatitis B infection

  1. Hepatitis B Surface Antigen (HBSAg): Represents ongoing infection (viremia), either recent or chronic
  2. IgM antibody to Hepatitis B Core Antigen (anti-HBc): Represents recent infection; should be checked if HBSAg is positive
    1. If positive, can recheck HBSAg after 6mos to determine whether the acute infection has evolved into a chronic infection
    2. If negative with positive HBSAg, indicates that infection is chronic
  3. Hepatitis B E Antigen (HBeAg)
    1. Represents active viral replication
    2. Ass'd with RR 6.3 (sig.) of hepatocellular Ca in a prospective trial of 2260 HBSAg-positive men (NEJM 347:168, 2002--AFP)
    3. Should be checked if HBSAg is positive and anti-HBc is negative
    4. If positive, some consider an indication for antiviral therapy

V. Treatment

  1. Interferon alfa-2b 5MU/d or 10MU 3x/wk SC/IM x 4mos
  2. Lamivudine (a nucleoside reverse transcriptase inhibitor; a.k.a. "3TC")
    1. Lamivudine monotherapy vs. placebo
      1. 358 pts with chronic Hep B randomized to lamivudine 25mg or 100mg/d vs. placebo. At 1y; both lamivudine groups were sig. more likely than placebo group to have improved liver by (49% and 56% vs. 25%), lose HBeAg, develop HBeAb, have sustained reduction in serum ALT levels, and have reductions in HBV DNA quantitative PCR; and less likely to have worsened liver bx (10% and 7% vs. 32%) (NEJM 339:61, 1998--JW)
      2. 137 pts > 18yo with chronic hep B (HBSAg+, HBeAg+, elevated ALT), chronic hepatitis on Bx, and positive serum HBV PCR and HBeAg randomized to lamivudine 100mg/d PO vs. placebo. After 1y, lamivudine had sig. greater in likelihood of reduction in inflammatory activity (64% vs. 34%), sig. greater likelihood of HBeAg seroconversion (17% vs. 6%), and lesser likelihood of progressive fibrosis on liver bx (5% vs. 20%) (NEJM 341:1256, 1999--JW)
      3. 651 pts with chronic hepatitis B and advanced fibrosis or cirrhosis on liver bx randomized to lamivudine vs. placebo; after median 32mo f/u, incidence of disease progression was sig. lower in lamivudine group (8% vs. 18%) (NEJM 351:1521, 2004--JW)
      4. In a randomized trial of 288 children with chronic hepatitis B randomized to lamivudine 3mg/kg/d PO vs. placebo x 1y, virologic remission was sig. higher among lamivudine recipients (23% vs. 13%) (NEJM 346:1706, 2002--abst)
    2. Lamivudine monotherapy may induce resistance
      1. 5 pts with chronic active hep B failing Alpha-IFN tx were tx'd with lamivudine monotherapy; all had immediate decreases in viral DNA levels followed by rebounds after 11-22mos of tx. At that time famcicylovir was added but at 3mos none had responded to the 2-drug regimen (J. Inf. Dis. 181:713, 2000--JW)
    3. Lamivudine + Interferon vs. Lamivudine alone or Interferon alone
      1. Lamivudine + alfa-interferon not superior to IFN monotherapy in one study (Lancet Inf. Dis. 1:232, 2001--Med. Lett.)
      2. 537 pts with chronic hepatitis B, elevated ALT, necroinflammatory changes on liver bx and negative HBeAg randomized to lamivudine monotherapy, PEG-Interferon alfa-2a monotherapy, or both  x 48wks; at 72wks, incidence of suppression of HBV PCR to < 20,000 copies/mL was sig. higher in both IFN-containing regimens than lamivudine monotherapy (43% and 44% vs. 29%) (NEJM 351:1206, 2004--JW)
      3. In a study of 266 pts with HBeAg-positive chronic hepatitis B undergoing PEG-IFN-alfa-2b ts Qwk randomized to lamivudine vs. placebo x 52wks, the combination-therapy group, at conclusion of treatment, had sig. greater likelihood of having no detectable HBeAg (44% vs. 29%), no detectable HBV DNA (33% vs. 10%), and normalization of ALT levels (51% vs. 34%); at 26wks post-conclusion of treatment, there were no sig. diffs. in any of these parameters (Lancet 365:123, 2005--JW)
      4. In a randomized study in 814 pts with positive chronic hepatitis B and Hep B E antigenemia randomized to pegylated interferon alfa (180ug Qwk), lamivudine (100mg/d), or both x 48wks, at f/u 24wks after treatment completion, incidence of Hep B E Ag seroconversion and decline of Hep B DNA levels to < 100k copies/mL were both sig. greater with the IFN-containing regimens than lamivudine monotherapy.  There were no sig. diffs noted in the main outcomes between the IFN + lamividine and the plain IFN recipients (NEJM 352:2682, 2005--abst)
  3. Adefovir dipivoxil (Hepsera) 10mg PO QD--a nucleoside analog, a prodrug of adefovir
    1. In E Ag-negative patients
      1. 185 pts with E Ag-negative chronic HBV infection w/abnormal liver Bx, elevated ALT, & HBV DNA > 100k copies/mL randomized to Adefovir dipivoxil 10mg PO QD vs. placebo x 48wks.  64% of adefovir recipients, vs. 33% of placebo recipients, had improvement of histologic findings on post-tx liver bx (sig.).  No excess adverse events seen in active tx group (NEJM 348:800, 2003--JW)
        1. In a follow-up report from this study, pts on adefovir were randomized to continue adefovir or switch to placebo x 48wks more; the adefovir group had sig. higher likelihood of undetectable HBV DNA at 96wks (71% vs. 8%) (NEJM 352:2673, 2005--JW)
    2. In E Ag-positive patients
      1. 515 pts with E Ag-positive chronic HBV infection w/abnormal liver bx, elevated ALT, & HBV DNA > 1 million copies/mL randomized to Adefovir dipivoxil 30mg PO QD, 10mg PO QD, vs. placebo x 48wks.  Post-tx histologic improvement seen in 59% of 30mg recipients, 53% in 10mg recipients, and 25% of placebo recipients (sig. for either active tx group vs. placebo).  8% of 30mg recipients had reversible increases in serum creatinine levels  (NEJM 348:808, 2003--JW)
  4. Entecavir (Baraclude)
    1. A nucleoside analogue which inhibits HBV DNA polymerase
    2. In an unpublished study in 709 pts with chronic HBV and detectable HBeAg randomized to entecavir 0.5mg/d vs. lamivudine 100mg/d x 52wks, entecavir pts had sig. greater histologic improvement (PDR Monthly Prescribing Guide May 2005).
    3. Entecavir vs. Lamivudine
      1. In a study of 715 pts with chronic hepatitis B and positive Hepatitis B e-antigen assays randomized to entecavir 0.5mg/d vs. lamivudine 100mg/d x 52wks, the entecavir group had sig. higher incidence at 48wks of histologic improvements (72% vs. 62%) and virologic response (67% vs. 36%); no sig. diff. in incidence of HBeAg loss or HBeAg seroconversion.  No sig. diff. in incidence of adverse effects (NEJM 354:1001, 2006--JW)
      2. In a study of 648 pts with chronic hepatitis B and negative Hepatitis B e-antigen assays randomized to entecavir 0.5mg/d vs. lamivudine 100mg/d x 52wks, the entecavir group had sig. higher incidence at 48wks of histologic improvements (70% vs. 61%) and virologic response (90% vs. 72%).  No sig. diff. in incidence of adverse effects (NEJM 354:1011, 2006--JW)
  5. Emtricitabine (Emtriva)
    1. In a study in 248 pts with chronic Hepatitis B randomized to emtricitabine vs. placebo, at 48wks, emtricitabine group was sig. more likely to have improved liver histology (62% vs. 25%), HBV DNA < 400 copies/mL (54% vs. 2%), and normalization of ALT (65% vs. 25%) (Arch. Int. Med. 166:49, 2006--JW)
  6. Telbivudine (Tyzeka)
    1. A nucleoside analogue, active against HBV DNA polymerase
    2. Myopathy has been reported in pts on this medication