Hepatitis B

This disease is notifiable in the UK under the Public Health (Infectious Diseases) Regulations 1988.

Hepatitis B is an infection of the liver caused by the hepatitis B virus (HBV), a double-stranded DNA virus which replicates by reverse transcription (hepadnaviridae family).
Mutations of the surface coat protein, core and other proteins have been identified.¹

The World Health Organization (WHO) has estimated that over 350 million people worldwide are chronically infected with HBV.²

• In many high-prevalence countries, 10% or more of the population have chronic hepatitis B infection.
• High-prevalence regions include sub-Saharan Africa, most of Asia and the Pacific islands.

The UK is a very low-prevalence country, but prevalence of HBsAg varies across the country. This is reflected in the prevalence rates found in antenatal women; during 2002 amongst 115,230 women booked for antenatal care in London, 998 were HBsAg positive (approx. 1 in 1000).³

• Number of new infections per year has declined from an average of 260,000 in the 1980s to about 60,000 in 2004.⁴
• Highest rate of disease occurs in 20-49 year-olds.
• Greatest decline has happened among children and adolescents due to routine hepatitis B vaccination.

Many new infections with hepatitis B are sub-clinical or may have a flu-like illness.

• Jaundice only occurs in about 10% of younger children and in 30 to 50% of adults.
• Acute infection may occasionally lead to fulminant hepatic necrosis, which is often fatal.
• The illness usually starts insidiously – with anorexia and nausea and an ache in the right upper abdomen.
• Fever, when present, is usually mild. Malaise may be profound, with disinclination to smoke or to drink alcohol.
• As jaundice develops, there is progressive darkening of the urine and lightening of the faeces.

In patients who do not develop symptoms suggestive of hepatitis, the illness will only be detected by abnormal liver function tests and/or the presence of serological markers of hepatitis B infection (e.g. hepatitis B surface antigen (HBsAg), antiHBc IgM).

• The incubation period ranges from 40 to 160 days, with an average of 60 to 90 days.
• Current infection can be detected by the presence of HBsAg in the serum.
• Blood and body fluids from these individuals should be considered to be infectious.
• In most individuals, infection will resolve and HBsAg disappears from the serum, but the virus persists in some patients who become chronically infected with hepatitis B.

This is defined as persistence of HBsAg in the serum for six months or longer. Individuals with chronic infection are sometimes referred to as chronic carriers.

• The risk of developing chronic hepatitis B infection depends on the age at which infection is acquired.
• Chronic infection occurs in 90% of those infected perinatally but is less frequent in those infected as children (e.g. 20 to 50% in children between one and five years of age).²
• About 5% or less of previously healthy people, infected as adults, become chronically infected.⁵
• The risk is increased in those whose immunity is impaired.

Around 20 to 25% of individuals with chronic HBV infection worldwide have progressive liver disease, leading to cirrhosis in some patients. The risk of progression is related to the level of active viral replication in the liver.
Individuals with chronic hepatitis B infection (particularly those with an active inflammation and/or cirrhosis, where there is rapid cell turnover) are at increased risk of developing hepatocellular carcinoma.

The virus is transmitted by parenteral route via infected blood or body fluids.
Transmission mostly occurs:

• Through vaginal or anal intercourse
• As a result of blood-to-blood contact (e.g. sharing of needles and other equipment by injecting drug users or ‘needlestick’ injuries
• Through perinatal transmission from mother to child

Transmission has also followed bites from infected persons, although this is rare.
Transfusion-associated infection is now rare in the UK as blood donations are screened. Viral inactivation of blood products has eliminated these as a source of infection in this country.

• In areas of high prevalence, infection is acquired predominantly in childhood – by perinatal transmission or by horizontal transmission among young children.
• In low-endemicity countries most infections are acquired in adulthood, where sexual transmission or sharing of blood-contaminated needles and equipment by injecting drug users accounts for a significant proportion of new infections.

• Liver function tests may show the following:
  • AST and ALT values up to 100x upper limit of normal
  • Alkaline phosphatase is raised
  • Albumin is low
• Prothrombin time may be prolonged in severe disease.
• Serology, which should be interpreted as below.
• Screen for other sexually transmitted diseases in cases thought to have been sexually acquired, or if behaviour places them at risk.
• Liver biopsy (for assessment of chronic disease) should be performed by a specialist.⁶

• HBsAg (surface antigen) is present from 1–6 months after exposure. The persistence of HBsAg for >6 months defines carrier status. This follows 5–10% of infections.
  • Among those who are HBsAg positive, those in whom hepatitis B e-antigen (HBeAg) is also detected in the serum are the most infectious.
  • Those who are HBsAg positive and HBeAg negative (usually anti-HBe positive) are infectious but generally of lower infectivity.
• The presence of HBeAg (e-antigen) implies high infectivity.
  • It is usually present for 1½–3 months after the acute illness.
  • Recent evidence suggests that a proportion of chronically infected people who are HBeAg negative will have high HBV DNA levels, and may be more infectious.
• Antibodies to HBcAg (core antigen, ie anti-HBc) imply past infection.
• Antibodies to HBsAg (ie anti-HBs) alone implies vaccination.

General advice

• Patients should be advised to avoid unprotected sexual intercourse, including oro-anal and oro-genital contact until they have become non-infectious or their partners have received a full course of vaccination.
• Patients should be given a detailed explanation of their condition with particular emphasis on the long-term implications for the health of themselves and their partner, routes of transmission of infection and advised not to donate blood.

Acute icteric hepatitis

Manage supportively, as for hepatitis A.

Treatment of chronic infection

• Treatment should normally be given in partnership with a liver specialist or physician experienced in the management of liver disease.
• Patients should be considered for therapy with lamivudine, adefovir or alpha interferon.⁸
  • Treatment responders have long-term benefits in terms of reduced liver damage and decreased risk of liver cancer.
  • Lamivudine, adefovir and tenofovir will suppress hepatitis B viral replication during therapy of immunocompromised patients, including those with HIV (see also the British HIV association guidelines on the treatment of HIV/HBV co-infection⁹), and may delay liver damage.
  • Few patients are cured; anti-viral resistance may develop after prolonged monotherapy and rebound hepatitis can occur if treatment is stopped or resistance develops.
• There are some emerging treatments which show promise, including pegylated interferons, entecavir and emtricitabine (FTC).¹⁰
• Specific therapy is not indicated unless de-compensated liver disease follows.

Intimate contacts

• Partners should be notified, and this documented at subsequent follow-up.
  • Contact tracing should include any sexual contact (penetrative vaginal or anal sex or oro/anal sex) or needle sharing partners during the period in which the index case is thought to have been infectious.
  • The infectious period is from two weeks before the onset of jaundice until the patient becomes surface antigen negative.
  • In cases of chronic infection contacts should be traced as far back as any episode of jaundice, or to the time when infection is thought to have been acquired. This may be very difficult when looking back longer than two or three years.
• Children who have been born to infectious women should be screened for hepatitis B, if the child was not vaccinated at birth.
• Specific hepatitis B immunoglobulin 500 iu intramuscularly (HBIG) may be administered to a non-immune contact after a single unprotected sexual exposure or parenteral exposure e.g. needle-stick injury, if the contact is known to be infectious.
  • This is optimally given within 48 hours and is of no use after more than seven days.¹¹
  • An accelerated course of recombinant vaccine should be offered to those given HBIG, plus all sexual and household contacts.
  • This is given at 0, 7 and 21 days, or 0, 1, 2 months. A booster dose is given at 12 months in either scenario.^12,13
  • Vaccination theoretically provides some protection from disease if started up to six weeks after exposure.
  • Sexual contact should be avoided until vaccination has been successful i.e. anti-HBs titres >10 iu/l.
  • The ultra-rapid vaccination schedule (0, 7, 21 days) leads to an anti-HBs antibody response in only 80% of recipients 4-12 weeks after the third dose.¹³
  • This may rise to 95% by 12 months.
  • Booster vaccinations of up to three further doses should be offered to sexual or household contacts without detectable antibodies 4-12 weeks after the primary course.

Pregnancy and breastfeeding

• Vertical transmission (mother to infant) of infection occurs in 90% of pregnancies where the mother is hepatitis B e antigen positive and in about 10% of surface antigen positive, e antigen negative mothers.
  • Most (>90%) of infected infants become chronic carriers.¹⁴
  • Infants born to infectious mothers are vaccinated at birth, usually in combination with Hepatitis B specific Immunoglobulin 200 iu IM.
  • This reduces vertical transmission by 90%.
• There is some evidence that treating the mother in the last month of pregnancy with lamivudine may further reduce the transmission rate if she is highly infectious. Further work is required to support this.¹²
• Infected mothers should continue to breast feed as there is no additional risk.

Screening and primary prevention

Hepatitis B testing in asymptomatic patients should be considered in:

• Men who have sex with men
• Sex workers (of either sex)
• Intravenous drug users
• HIV-positive patients
• Sexual assault victims
• People from countries where hepatitis B is common
• Needle-stick victims
• Sexual partners of positive or high-risk patients

If non-immune, consider vaccination.
If found to be chronic carriers consider referral for therapy.
The simplest initial screening test in someone who is unvaccinated or is of unknown infection status is anti-HBc; some also screen for HBsAg initially.

• Fulminant hepatic failure (rare)
• Relapse
• Prolonged cholestasis
• Chronic hepatitis
• Cirrhosis
• Hepatocellular carcinoma (HCC)
• Glomerulonephritis
• Cryoglobulinaemia

Concurrent hepatitis C infection can lead to fulminant hepatitis, more aggressive chronic hepatitis and increased risk of liver cancer.^15,16 Concurrent HIV infection increases the risk of progression to cirrhosis and death.¹⁷

• Vaccination may be universal or just for high-risk groups.
• The current recombinant vaccine is one of the safest available, but being grown in yeast cells should not be given to those allergic to yeast.
• Passive immunization with specific antihepatitis B immunoglobulin may be given to non-immune contacts after high-risk exposure.

• Acute infection: as for hepatitis A. In view of the possibility of chronic infection, serology should be repeated after six months even if the LFT is normal.⁶
• Chronic infection (HBeAg+ve or HBV-DNA >105 iu /ml): If untreated, patients should be regularly reviewed at intervals of one year or less, ideally by a physician with expertise in this disease
• Immunity after recovery from infection (surface antigen negative) is lifelong in over 90%.