Hepatitis B

• Background

  Hepatitis B is a double stranded DNA virus that causes liver inflammation (acute and/or chronic hepatitis). In people with chronic infection around 25% will develop cirrhosis that progresses to end stage liver disease [1] and there is a 200-fold increase in risk of hepatocellular carcinoma (HCC) [2] . Adults with chronic Hepatitis B infection acquired in childhood develop HCC at a rate of 5% per decade [3].

  • Hepatitis B may be transmitted vertically (from mother to child) or horizontally by exposure to infected body fluids (blood or semen). Horizontal transmission is important in children < 5 years and household or sexual contacts of people with Hepatitis B infection [4].
  • The incubation period is 45 -160 days (mean of 90 days) [5, 6].
  • Clinical manifestations depend on the age at acquisition, viral load and host immune status. The virus itself is probably not cytopathogenic; most complications are the result of the  host immune response attempting to destroy viral infected cells.
    • Infants infected perinatally usually have no symptoms or signs. Infection produces a clinical illness in approximately 5-15% of children aged 1-5 years and 33-50% of older children and adults [7, 8]. Between 0.1-1% of acute infections will progress to fulminant hepatitis [8].
    • Age at infection is the most important determinant of chronic infection. The rate of progression from acute infection to chronic infection is around 90% in Hepatitis B acquired perinatally or in infancy, 25-50% in children aged 1-5 years and 6-10% in older children and adults [3].
  • Chronic hepatitis B infection is described in four stages
    • Immune tolerance - characterized by high levels of Hepatitis B virus and presence of HB eAg. There is minimal immune response to presence of virus, and therefore low risk of liver damage in this stage.
    • Immune clearance - (immune active)where the immune system attempts to clear virus, resulting in liver damage.  This phase is characterized by fluctuating ALT, and variable levels of Hepatitis B DNA.
    • Immune control - where the immune system successfully controls virus, resulting in low levels of Hepatitis B DNA.  In this stage patients are usually HB eAb positive, with normal liver function tests.  If complete eradication is achieved (in children ~ 0.5 - 1%/year), the patient will eliminate HBsAg and develop HBsAb, indicating resolution of infection.
    • Immune escape - (immune reactivation) where the hepatitis B virus ‘escapes’ immune control and begins to replicate again, despite the presence of HBeAb.  This may result in high levels of HB DNA.  Liver damage may again occur in this phase.
  • The risk of vertical transmission is dependent upon the maternal viral load. Women who are Hep BeAg positive have a 90% risk of transmission in the absence of immunoprophylaxis [9].  Even in the presence of appropriate immunoprophylaxis, mothers with a high viral load (HBV DNA >200,000 IU (10⁶ copies)/mL)) have a transmission risk of 8-30% [10].
  • In Australia, pregnant women are screened for Hepatitis B infection at their first antenatal visit.  
    • Infants of mothers with Hepatitis B infection (sAg +) receive immunoprophylaxis with Hepatitis B immunoglobulin and vaccine on the day of birth (preferably, or within 7 days), which reduces the risk of vertical transmission by more than 95%[10]. In the absence of neonatal vaccination, transmission rates (from mother to neonate) are 5-20% where mothers are HBsAg + and HBeAg -, and 70-90% where mothers are HBsAg + and HBeAg +[3].
    • All infants of women with Hepatitis B infection should receive then receive Hepatitis B vaccine according to the National Immunisation Program Schedule and be screened for Hepatitis B infection (sAg, cAb, sAb) after 12 months of age [11].
  • Hepatitis B vaccination is part of the routine immunisation schedule in Australia (given at birth, 2,4 and 6 months) and in many countries of origin for Humanitarian entrants.Worldwide vaccination schedules are available.

  Prevalence

  The prevalence rate of hepatitis B infection is highest in South-East Asia and Sub-Saharan Africa [12]. Recent studies in refugee cohorts in Australia suggest the prevalence of CHB is:

  • 3 – 16% in people from Africa% [13-18]
  • 3.5% – 9.7% in people from South & South East Asia[14, 19, 20]
  • 0 - 2.5% for those from the Afghanistan and Iraq.[14, 21]

  Summary of Hepatitis B serology

  Antibody	Abbreviation	Significance
  Hepatitis B surface antigen	HBsAg	Infection (acute or chronic)
  Hepatitis B surface antibody	HBsAb	Immunity (either after resolutionof infection or due to immunisation)
  Hepatitis B core IgM	HBcIgM	Acute infection
  Hepatitis B core IgG	HBcIgG	Previous or current infection
  Hepatitis B core antibody	HBcAb or anti HBc	Total core antibody (both HBcIgM and HBcIgG)
  Hepatitis B e antigen	HBeAg	Immune tolerant phase, high infectivity
  Hepatitis B e antibody	HBeAb	Immune control, or immune escape phase, variable infectivity
  Hepatitis B virus DNA	HBV DNA	Measure of infectivity, may be the only positive marker in occult Hepatitis B
  Liver function tests	LFT	ALT is the most useful marker of liver damage
  Alpha fetoprotein	αFP	Marker of hepatocellular carcinoma (HCC)

   

  Acute infection HBsAg +, HBcIgM +, +/- HBeAg, +/- clinical illness

  Chronic infection HBsAg present >6m, HBcIgM -, HBcIgG + or anti HBc total +, +/- HBeAg

  Past infection HBsAb +, HBcIgG +,

  Past vaccination HBsAb +, HBcAb -

  Screening

  • All children attending Immigrant health clinic are screened for:
    • HBsAg (infection)
    • HBsAb (immunity- either due to past infection or immunisation)
    • HBcAb (clarifies if immunity due to infection or vaccination)
  • A titre of HBsAb >10 IU/L indicates adequate immunity. If HBsAb is <10 IU/L, exclude infection, then give Hepatitis B catch-up vaccination; see Immunisation Handbook
  • If children are HBsAg + they should have further tests to determine acute vs chronic infection and presence/absence eAg to give information about infectivity:
    • LFT, HBcAb IgM and IgG, HBeAg, HBeAb
    • HBV DNA for viral load
  • Children with Hepatitis B infection should be screened for Hepatitis A immunity (HAV), hepatitis C (HCV Ab) and Hepatitis delta. 
  • Sexually transmitted infection screening may be needed, depending on age and history
  • Screen (and treat if positive) for Schistosoma infection if from an endemic area
  • Consider risk factors and screening for HIV in children with hepatitis B.

  Further management of children with chronic hepatitis B infection

  • All children with acute hepatitis B and clinical illness need immediate referral to Gastroenterology (note that acute hepatitis B is rare in childhood)
  • Explanation/education/counselling. Translated information sheets are available
  • Advice re: blood spills and infection risk- suggest gloves to clean blood spills and disinfection with diluted (1:10) household bleach[4].
  • Advice to notify their treating doctors when starting medications.
  • Advice for adolescents re: alcohol consumption and using barrier contraception.
  • Immunise against Hepatitis A if serology negative (see Immunisation handbook).
  • Screen and vaccinate household contacts against hepatitis B (adult vaccinations are funded for household contacts). Check for seroconversion after immunisation.
  • Remember hepatitis if starting hepatotoxic drugs- particularly anti-tuberculous therapy.
  • Hepatitis B (sAg positive) is a notifiable disease (Group B - within 5 days)
  • The clearance rate of HBsAg is 0.5 -1 % per year and the clearance of HBeAg is 2 - 5% per year in children.

  Other management depends on serology and clinical status. The primary goal of management in the individual is to eliminate or suppress hepatitis B[1, 8].

  HBeAg negative and normal LFT

  • Review at primary care level. This is the profile in the immune control stage
  • Annual LFT and αFP
  • Refer to gastroenterology if elevated ALT

  HBeAg negative and abnormal LFT

  • Review by gastroenterology, ongoing management in specialist setting. The concern is immune escape/reactivation
  • HBV DNA - if viral load high, gastroenterology review for consideration of liver biopsy
  • LFT monitoring
  • αFP 12 monthly
  • HBsAg/sAb and eAg/eAb 12 monthly - may revert back to HBeAg +

  HBeAg positive and normal LFT

  • Review by gastroenterology, this is the profile in the immune tolerant stage
  • LFT 6 monthly
  • αFP 12 monthly
  • HBsAg/sAb and eAg/eAb 12 monthly
  • HBV DNA if seroconversion from eAg+ to eAb +

  HBeAg positive and abnormal LFT

  • Review by gastroenterology, ongoing management in specialist setting, this is the profile in the immune active stage
  • Ultrasound
  • LFT monitoring
  • αFP 12 monthly
  • HBsAg/sAb and eAg/eAb 12 monthly
  • HBV DNA if seroconversion from eAg+ to eAb +

  Treatment has been less well studied in children than adults, although it may be indicated in a few circumstances, such as the immune clearance phase, where there is evidence of liver damage on biopsy [22].

  Other serology results

  • Isolated HBcAb positive (HBsAg negative and HBsAb negative) may represent:
    • Test error
    • The window stage of acute hepatitis B infection (antiHBcAb is the first antibody to develop)
    • Resolved hepatitis B with waning levels of HBsAb
    • Remote hepatitis B infection with persisting HBV DNA (without detectable HBsAg)
    • Management - there is no consensus on the approach to manage this situation. A reasonable approach is to clarify LFT at the time of testing, repeat the HBcAb test in 3 - 6 months to exclude test error and window stage, and check HBV DNA at this point. 
      • If HBV-DNA is positive - annual LFT and αFP, refer to gastroenterology if elevated ALT. Patient education about possible reactivation if immunosuppressed, transmission prevention (although risk not clear) and advice against blood donation
      • If HBV-DNA is negative - consider giving either a booster dose of vaccine or a repeat primary course to see if patient has a "booster" anamnestic response (HBsAb >= 10 IU/L on serology at least one month later)
  • Isolated HBsAg positive (HBcAb negative and HBsAb negative) may represent:
    • Test error
    • Post immunisation (within 4 weeks) - suggest retest serology in 1 - 2 months
    • Early infection - if repeat test the same, and no recent immunisation, suggest HBV DNA to confirm.

  Other resources

  • The HepBHelp website provides advice and support for health providers diagnosing hepatitis B infections.
  • B positive - ASHM resource

  References

  • References

  Immigrant health clinic protocols
  Author: Georgie Paxton and Vanessa Clifford, revised June 2013
  Royal Children‘s Hospital