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Hepatitis B
Jason Chao, MD, MS
image BASICS
DESCRIPTION
Systemic viral infection associated with acute and chronic liver disease and hepatocellular carcinoma (HCC)
EPIDEMIOLOGY
Incidence
  • Predominant age: can infect patients of all ages
  • Predominant sex: fulminant hepatitis B virus (HBV): male > female (2:1)
  • In the United States, estimated 38,000 new infections in 2009, 70% due to IV drug use
  • African Americans have the highest rate of acute HBV infection in the United States.
  • Overall rate of new infections is down 82% since 1991 (due to national immunization strategy).
  • U.S. vaccine coverage for the birth dose of HBV increased from 68.6% in 2011 to 71.6% in 2012.
Prevalence
  • In the United States, 800,000 to 1.4 million people have chronic HBV.
  • Asia and the Pacific Islands have the largest populations at risk for HBV.
  • Chronic HBV worldwide: 350 to 400 million persons
    • 1 million deaths annually
      • Second most important carcinogen (behind tobacco)
      • Of chronic carriers with active disease, 25% die due to complications of cirrhosis or HCC.
      • Of chronic carriers, 75% are Asian.
ETIOLOGY AND PATHOPHYSIOLOGY
HBV is a DNA virus of the Hepadnaviridae family. Highly infectious via blood and secretions for at least a week outside the body.
Genetics
Family history of HBV and/or HCC
RISK FACTORS
  • Screen the following high-risk groups for HBV with HBsAg/sAb. Vaccinate if seronegative (1)[A]:
    • Persons born in endemic areas (45% of world)
    • Hemodialysis patients
    • IV drug users (IVDUs), past or present
    • Men who have sex with men (MSM)
    • HIV- and HCV-positive patients
    • Household members of HBsAg carriers
    • Sexual contacts of HBsAg carriers
    • Inmates of correctional facilities
    • Patients with chronically elevated aspartate aminotransferase/alanine aminotransferase (AST/ALT)
  • Additional risk factors:
    • Needle stick/occupational exposure
    • Recipients of blood/products; transplanted organ recipients
    • Intranasal drug users
    • Body piercing/tattoos
    • Survivors of sexual assault
Pediatric Considerations
  • Shorter acute course; fewer complications
  • 90% of vertical/perinatal infections become chronic.
Pregnancy Considerations
  • Screen all prenatal patients for HBsAg (1)[A].
  • Consider treating patients with high viral load at 28 weeks with oral nucleos(t)ide medicines beginning at 32 weeks to reduce perinatal transmission (2)[C].

    Marker

    Acute Infection

    Chronic Infection

    Inactive Carrier

    Resolved Infection

    Susceptible to Infection

    Vaccinated

    HBsAg

    +

    +

    +

    -

    -

    -

    HBsAb

    -

    -

    -

    +

    -

    +

    HBcAb

    +IgM

    -IgM;+total/IgG

    +

    +

    -

    -

    HBeAg

    +

    ±

    -

    -

    -

    -

    HBeAb

    -

    ±

    +

    ±

    -

    -

    HBV DNA

    Present

    Present

    Low-negative

    -

    -

    -

    ALT

    Marked elevation

    Normal to mildly elevated

    Normal

    Normal

    Normal

    Normal

  • Infants born to HBV-infected mothers require HB immune globulin (HBIg) (0.5 mL) and HBV vaccine within 12 hours of birth.
  • Breastfeeding is safe if HBIg and HBV vaccine are administered and the areolar complex is without fissures or open sores. Oral nucleos(t)ide medications are not recommended during lactation.
  • HIV coinfection significantly increases risk of vertical transmission.
  • Continue medications if pregnancy occurs while on an oral antiviral therapy to prevent acute flare.
GENERAL PREVENTION
Most effective: HBV vaccination series (three doses)
  • Vaccinate
    • All infants at birth and during well-child care visits
    • All at-risk patients (see “Risk Factors”)
    • Health care and public safety workers
    • Sexual contacts of HBsAg carriers
    • Household contacts of HBsAg carriers
  • Proper hygiene/sanitation by health care workers, IVDU, and tattoo/piercing artists
    • Barrier precautions, needle disposal, sterilize equipment, cover open cuts
  • Do not share personal items exposed to blood (e.g., nail clipper, razor, toothbrush).
  • Safe sexual practices (condoms)
  • HBsAg carriers cannot donate blood or tissue.
  • Postexposure (e.g., needle stick): HBIg 0.06 mL/kg in <24 hours in addition to vaccination
COMMONLY ASSOCIATED CONDITIONS
HIV coinfection, hepatitis C coinfection
image DIAGNOSIS
PHYSICAL EXAM
Acute: ill; jaundice/scleral icterus; RUQ tenderness; hepatomegaly
DIFFERENTIAL DIAGNOSIS
  • Epstein-Barr virus (EBV); cytomegalovirus (CMV); hepatitis A, C, or E
  • Drug-induced, alcoholic, or autoimmune hepatitis
  • Wilson disease or rheumatologic/immunologic disorders
DIAGNOSTIC TESTS & INTERPRETATION
Initial Tests (lab, imaging)
  • AST/ALT: markedly elevated in acute HBV (particularly ALT), with levels in the hundreds to several thousand IU/mL. Transaminases may be normal or mildly elevated in chronic HBV:
    • Transaminases elevate before bilirubin
  • Bilirubin (conjugated/unconjugated): normal to markedly elevated in acute HBV
    • Last test to normalize as acute infection resolves
  • Alkaline phosphatase: mild elevation
  • HBcAb IgM may be the only early finding (“window period,” before HBsAg turns positive)
  • For acute hepatitis:
    • Monitor PT, albumin, electrolytes, glucose, and CBC.
    • If severe acute HBV, check for superinfection with hepatitis D (HDV Ag and HDV Ab)
    • Hepatitis B serologic markers
  • Hepatitis B e-antigen (HBeAg+) indicates high replication/infectivity; confirmed with high HBV DNA (≥105 copies/mL); these patients benefit from medical therapy.
  • HBV precore mutants have undetectable HBeAg despite active viral replication (confirm with HBV DNA level) as well as antibody to e-antigen (HBeAb+).
  • Screen for HDV, HIV, HCV, and immunity to hepatitis A virus (HAV Ab total/IgG).
  • Ultrasound to document ascites, organomegaly, signs of portal hypertension, hepatic or portal obstruction, and to screen for HCC
  • Contrast CT or MRI if ultrasound is abnormal or if &agr;-fetoprotein (AFP) is elevated.
Follow-Up Tests & Special Considerations
HBsAg+ persistence >6 months defines chronic HBV:
  • Measure HBV DNA level and ALT every 3 to 6 months.
  • If age >40 years and ALT borderline or mildly elevated, consider liver biopsy.
  • Measure baseline AFP.
  • Follow HBeAg for elimination (every 6 to 12 months)
  • Lifetime monitoring for progression, need for treatment, and screening for HCC
Diagnostic Procedures/Other
  • Liver biopsy
  • Noninvasive tests (Hepascore, Fibrotest) or measurement of elastography (Fibroscan) to assess for hepatic fibrosis.
Test Interpretation
Liver biopsy in chronic HBV may show interface hepatitis and inflammation, necrosis, cholestasis, fibrosis, cirrhosis, or chronic active hepatitis.
P.469

image TREATMENT
GENERAL MEASURES
  • Vaccinate for HAV if seronegative
  • Monitor CBC, coagulation, electrolytes, glucose, renal function, and phosphate.
  • Monitor ALT and HBV DNA; increased ALT and reduced DNA implies response to therapy.
  • Screen for HCC if HBsAg+.
MEDICATION
First Line
  • Acute HBV
    • Supportive care; spontaneously resolves in 95% of immunocompetent adults
    • Antiviral therapy not indicated except for fulminant liver failure or immunosuppressed.

    Chronic Hepatitis B Therapy

    HBeAg

    HBV DNA viral load

    ALT*

    Recommend

    (+)

    ≥20,000 IU/mL

    Elevated

    Treat with antiviral or interferon.

    (-)

    ≥2,000 IU/mL

    Elevated

    Consider biopsy or serum fibrosis marker and treatment.

    (+)

    ≤20,000 IU/mL

    Any

    Monitor q6-12mo

    (-)

    ≥2,000 IU/mL

    Normal

    Biopsy; treat if disease

    (+)

    ≥20,000 IU/mL

    Normal

    Observe, consider treatment if ALT elevated. Biopsy if age >40 years or ALT is high normal to mild elevation.

    (-)

    ≤2,000 IU/mL

    Any

    Monitor q6-12mo

    Cirrhosis

    Any

    Any

    Treat with mono or combination treatment.

    Liver failure

    Any

    Any

    Treat + refer for transplant

    * ALT elevated if >2 × ULN; ULN for male = 30 IU/mL and for female = 19 IU/mL.

  • Chronic HBV: Treatment is based on HBeAg status:
    • FDA-approved drugs: lamivudine 100 mg, adefovir 10 mg, entecavir 0.5 to 1 mg, telbivudine 600 mg, or tenofovir 300 mg, all given PO every day (dose based on renal function); pegylated interferon (peg-IFN) &agr;2a, &agr;2b SC weekly (3)[A]
  • Entecavir, tenofovir, and peg-IFN are preferred first-line agents (3)[A].
  • Extended oral agents regimens indicated (3)[A]:
    • If HBeAg+, treat 6 to 12 months post loss of HBeAg and gain of HBeAb, and monitor after cessation.
    • If HBeAg-, treat indefinitely or until HBsAg clearance and HBsAb development.
  • Change/add drug based on resistance:
    • Confirm patient adherence with medications before assuming resistance.
    • Adherence to therapy lowers rate of resistance.
  • Adjust dosing for renal function
  • Peg-IFN preferred to standard interferon:
    • Weekly peg-IFN (Pegasys) injections for 48 weeks
    • Most efficacious for genotype A
    • Contraindicated if decompensated cirrhosis
  • Goals of therapy: undetectable HBV DNA, normal ALT, loss of HBeAg, gain of HBeAb; loss of HBsAg and gain of HBsAb
  • Precautions:
    • Oral drugs: renal insufficiency
    • Peg-IFN: coagulopathy, myelosuppression, depression/suicidal ideation
Second Line
Emtricitabine suppresses viral load; not FDA approved.
ISSUES FOR REFERRAL
  • Refer all persistent HBsAg+ patients to have them evaluated for antiviral therapy.
  • Refer immediately to liver transplant program if fulminant acute hepatitis, end-stage liver disease, or HCC
SURGERY/OTHER PROCEDURES
Liver transplantation, operative resection, radiofrequency ablation for HCC
INPATIENT CONSIDERATIONS
Admission Criteria/Initial Stabilization
  • Worsening course (marked increase in bilirubin, transaminases, or symptoms)
  • Hepatic failure (high PT, encephalopathy)
image ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
Patient Monitoring
  • Monitor serial ALT and HBV DNA:
    • High ALT + low HBV DNA associated with favorable response to therapy
  • Serologic markers: See table.
  • CBC to monitor WBC and platelets for patients on interferon therapy
  • Monitor HBV DNA q3-6mo during therapy:
    • Undetectable DNA at week 24 of oral drug therapy associated with low resistance at year 2
  • Monitor for complications (ascites, encephalopathy, variceal bleed) in cirrhosis.
  • Recommend vaccination for all household contacts and sexual partners.
  • Ultrasound q6-12mo to screen for HCC starting at age 40 years in men and age 50 in women (3)[B].
DIET
Avoid alcohol.
PATIENT EDUCATION
  • Acute HBV
    • Review transmission precautions.
  • Chronic HBV
    • Alcohol and tobacco use accelerate progression
    • Strict medication compliance to prevent flare
  • Patient education materials in English and others, including many Asian languages, available at http://www.cdc.gov/hepatitis/Resources/PatientEdMaterials.htm
PROGNOSIS
  • Acute infection: 95% of adults recover
  • Severity of encephalopathy predicts survival in fulminant hepatic failure
  • Acute HBV: mortality 1%
  • Acute HBV + HDV: mortality 2-20%
  • Chronic HBV
    • Spontaneous resolution: 0.5% per year
    • Premature death from cirrhosis or HCC: 25%
    • Risk of HCC rises with rate of viral replication, even if no cirrhosis
REFERENCES
1. Weinbaum CM, Williams I, Mast EE, et al. Recommendations for identification and public health management of persons with chronic hepatitis B virus infection. MMWR Recomm Rep. 2008;57(RR-8):1-20.
2. Borgia G, Carleo MA, Gaeta GB, et al. Hepatitis B in pregnancy. World J Gastroenterol. 2012;18(34):4677-4683.
3. McMahon BJ. Chronic hepatitis B virus infection. Med Clin North Am. 2014;98(1):39-54.
Additional Reading
&NA;
Centers for Disease Control and Prevention. Updated CDC recommendations for the management of hepatitis B virus-infected health-care providers and students. MMWR Recomm Rep. 2012;61(RR-3):1-12.
See Also
&NA;
  • Cirrhosis of the Liver; Hepatitis A; Hepatitis C
  • Algorithm: Hyperbilirubinemia, Cirrhosis, and Jaundice
Codes
&NA;
ICD10
  • B19.10 Unspecified viral hepatitis B without hepatic coma
  • B16.9 Acute hepatitis B w/o delta-agent and without hepatic coma
  • B18.1 Chronic viral hepatitis B without delta-agent
Clinical Pearls
&NA;
  • All patients born in endemic countries should be screened for HBV infection with HBsAg.
  • Patients with chronic HBV need lifetime monitoring for disease progression and HCC.
  • HBV is the second most common worldwide carcinogen (behind tobacco).