Resident Editors: Sharmin Shekarchian, MD, Allison Kwong, MD

Faculty Editor: Don Ng, MD

• Approximately 257 million people are chronically infected with hepatitis B virus (HBV) internationally.
•  In the United States, it is estimated that 1.25 million people are Hepatitis B carriers (HBsAg+ for more than 6 mos)
• Although most HBV carriers do not develop complications from chronic HBV, 15-40% will develop hepatic complications
•  HBV carriers are at increased risk of cirrhosis, end stage liver disease, and hepatocellular carcinoma (HCC) (even in the absence of cirrhosis)
• Transmission:
  • High prevalence areas (>8% carriers): vertical transmission, early childhood infection via close contacts
  • Low prevalence areas (< 2% carriers, i.e. United States): sexual contact, IVDU, occupational exposure (i.e. needlesticks), close household contacts
  • Blood transfusion risk approximately 1/63,000.  Donated blood is screened via HBsAg and anti-HBc, however risk exists if donor is in the window period.
  • Risk of developing chronic HBV is inversely correlated to age at exposure (up to 90% in newborns of HBeAg + mothers, <5% in older children and adults). 
  • Immunocompromised persons are more likely to develop chronic HBV after acute infection

Evaluation

• A. Diagnosis and interpretation of serologies (acute, chronic, or immune) requires HBsAg, anti-HBc, and anti-HBs 
  • + HBV surface antigen (HBsAg): INFECTED (acute OR chronic if present > 6 mos)
  • + HBV surface antibody (anti-HBs): Past infection or immunized (via viral infection, vaccination, or immune globulin)
  • + HBV core antibody (anti-HBc): EXPOSED (IgM < 6 months after exposure; IgG > 6 months after exposure)
• Only send anti-HBc IgM if suspecting an acute HBV infection during “window period,” during which HBsAg is negative and anti-HBs is not yet positive

  	HBsAg	Anti-HBs	Anti-HBc
  Acute or chronic HBV	+	-	+
  Immunity from vaccine	-	+	-
  Past infection	-	+	+

Common initial lab patterns:

If patients are HBc positive but HBsAg negative and HBsAb negative, there are 4 possibilities:

1. Distant past infection with low or undetectable levels of anti-HBs
2. Window period of acute HBV, as anti-HBc is IgM-predominant
3. Susceptible with a false-positive anti-HBc: needs vaccination
4. Chronic HBV infection with an undetectable level of HBsAg (send HBV DNA to rule out chronic viral replication – occurs < 5%, usually in high-prevalence populations or HCV or HIV infection)
   • If suspected active HBV infection, i.e. HBsAg positive, check:
     • + HBV “e” antigen (HBeAg): pre-core protein, marker of viral replication, risk factor for the development of HCC
     • + HBV “e” antibody (anti-HBe): lower risk of infectivity/transmission if present
       • HBV DNA:  directly reflects viral replication; also independent risk factor for HCC

• B. High-risk groups: screen for HBV 
  • People born in areas of high and intermediate prevalence (>2%) including immigrants and internationally adopted children, regardless of vaccination status in their country of origin. See references for relevant countries.
  • U.S. born persons not vaccinated as infants whose parents were born in regions with high HBV endemicity (>8%)
  • Household or sexual contacts of HBs Ag positive persons
  • Men who have sex with men
  • Anyone who has ever used injection drugs
  • Hemodialysis patients
  • HIV and/or HCV infected people
  • All pregnant women should be screened as those who screen positive are at high risk of transmitting HBV to their infants
  • DM patients <50 years of age
  • Inmates of correctional institutions
  • Patients with persistently elevated AST/ALT of unknown etiology
  • Patients needing chemotherapy or immunosuppression related to organ transplant, rheumatologic or GI disorders

•  C. Known chronic HBV infection
  • History and physical: assess for additional risk factors, including EtOH use, family history of liver disease and/or HCC. Examine liver edge, look for signs/symptoms of cirrhosis/ESLD (i.e. ascites, caput medusa, jaundice, icterus, gynecomastia, telangiectasias)
  • Labs/tests: assess liver function (CBC, INR, LFTs, Albumin; tests for HBV replication (HBV DNA, HBeAg, anti-HBe); check for Hep A immunity (anti-HAV IgG); evaluate for co-infections (anti-HCV, anti-HDV, HIV) if at risk; baseline alpha fetoprotein (AFP)
  • Liver biopsy: may be required to assess degree of inflammation/fibrosis and rule out other causes of liver disease. Mostuseful in patients on the border for treatment by current guidelines. Discuss indication with GI/hepatologist.
    • Follow up: depends on HBeAg status, follow HBV DNA and ALT level q3-12 months (refer to AASLD Algorithm for management of chronic HBV); work in conjunction with specialist. Note that ALT/HBV DNA levels may fluctuate, so regular lab evaluation is warranted. If HBeAg positive, check HBeAg q6-12 months for seroconversion (8-10% per year).
  • Risk factors for progression of HBV-related liver disease:
    • Cirrhosis:Older age, genotype C, higher HBV DNA levels, EtOH use, co-infection with HCV, HDV or HIV.
      • Hepatocellular carcinoma: Male gender, family history, older age, history of anti-HBe  HBeAg reversions, HBV genotype C, HCV co-infection, vertically acquired infection, cirrhosis (though 20-50% of HBV-associated HCC occurs in absence of cirrhosis)
  • HCC screening
    • HBV carriers at high risk for HCC should be screened with ultrasound every 6-12 months
    • AFP currently not recommended when ultrasound is available (per AASLD; APASL and EASL still recommend). AFP lower sensitivity, specificity, diagnostic accuracy compared to ultrasound.
    • Periodic screening with AFP can be used when ultrasound is not available, or cost is an issue
    • High risk groups requiring q6- month HCC screening: Asian men > 40, Asian women > 50, patients with cirrhosis, family history of HCC, Africans > 20, any patient > 40 with persistent or intermittent ALT elevation or HBV DNA > 2000 IU/mL

Treatment

• All patients with chronic HBV infection should be considered for treatment.
• Because therapy is rapidly changing, treatment should be considered and initiated only under the management of a specialist. Treatment decision is based on HBeAg status, HBV DNA viral load, ALT, liver disease stage, and patient age.
  • (1) HBeAg positive: treat if ALT persistently ≥2x ULN 
  • (2) HBeAg negative: treat if ALT persistently ≥2x ULN and HBV ≥ 20,000 IU/mL
  • (3) If ALT 1-2x ULN or HBV VL 2,000-20,000 IU/mL, then consider biopsy and discuss treatment with specialist.
• Goals of treatment: prevent cirrhosis and HCC, and improve survival by suppression of HBV DNA. Although complete eradication of virus or loss of HBsAg is rarely achieved (current literature suggests 1-3%), viral suppression is possible.
• FDA-approved antiviral medications: standard IFN-a, pegIFN-a 2a, lamivudine, adefovir, entecavir, telbivudine, and tenofovir (two formulations). Current first-line therapy includes entecavir or tenofovir based on existing safety, efficacy, and resistance data. 
• Counseling/ongoing care of the chronic HBV patient:
  • All chronic HBV patients should receive HAV vaccine if not already immune: 
  • 2 doses of HAV vaccine 6-18 months apart (see “Adult Immunization” for more information)
  • Counsel about transmission prevention: sexual contacts should be vaccinated; if partner not naturally immune or vaccinated, use barrier contraception; do not share toothbrushes or razors; cover open cuts/sores; clean blood spills with detergent or bleach; do not donate blood, sperm, or organs. Children who are chronic HBV carriers CAN engage in contact sports, all daycare and school activities, no isolation from school activities needed.
  • HCC screening: AASLD guidelines recommend screening HBV carriers at high risk for HCC with ultrasound q 6-12 mos. (see above section on HCC Screening)
  • Alcohol use: >20g/d women and >30 g/d men are likely associated with progression of chronic HBV. Patients should also avoid hepatotoxic medications.
  • Pregnant women who are HBsAg positive should be counseled that their neonates should receive Hepatitis B immune globulin (HBIG) and HBV vaccine immediately after birth (studies show >95% efficacy in preventing perinatal transmission).  No antiviral agents are FDA-approved for HBV in pregnancy, but tenofovir (category B) is preferred (discuss with hepatologist). Telbuvidine (B) and lamivudine (C) are also options, but have lower barrier for drug resistance.

When to refer

• Refer to GI/Hepatology clinic for consideration of antiviral therapy, atypical ALT/HBV DNA patterns or if abnormalities found on HCC screening (AFP or ultrasound).

Immunization

• High-risk individuals who test negative for HBsAg and anti-HBs should be vaccinated against HBV (see “Adult Immunization” chapter for more information).
• Hepatitis B vaccination has been recommended for all infants born in the US since 1991, and is at least 95% effective.
• People who are at increased risk for HBV infection (i.e. infants of HBV carriers, healthcare workers, hemodialysis patients, sexual contacts of HBV carriers) should be tested for HBV vaccination response. Infants should be tested at 9-15 months of age, and at 1-2 months following the last vaccination in other persons. Chronic hemodialysis patients should be tested annually for continued immunity.

HBV reactivation

Patients receiving cytotoxic or immunosuppressive therapy are at risk for HBV reactivation and should receive prophylactic antiviral therapy if HBsAg or anti-HBc are positive. Patients with HBV and HCV coinfection are at risk of HBV reactivation if undergoing treatment with direct-acting antiviral therapy and not receiving treatment for HBV

References

Lin K, and Kirchner J. Hepatitis B. American Family Physician. 2004;69:75-82.

Lok AS and McMahon BJ. Chronic hepatitis B Practice Guidelines. AASLD Practice Guidelines. 2009.

MMWR. Recommendations for identification and public health management of persons with chronic hepatitis B virus infection. Center for Disease Control and Prevention. 2008 vol. 57

Pungpapong S, Kim R, Poterucha J. Natural history of hepatitis B virus infection: An update for clinicians. Mayo Clinic Proceedings 2007;82(8):967-975.