Epidemiology

The World Health Organization (WHO) has estimated that over 350 million people worldwide are chronically infected with hepatitis B virus (HBV).^[2]

• Worldwide, hepatitis B is the most common cause of hepatitis.
• 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.
• In the UK around 1 person in 350 is thought to have chronic (persistent) hepatitis B infection.
• The greatest decline has happened among children and adolescents, due to routine hepatitis B vaccination.

Note: most reports of acute infection in the UK occur as a result of injecting drug use or sexual exposure.

Presentation^[3]

• Many new infections with hepatitis B are subclinical or may have a flu-like illness.
• The incubation period ranges from 40 to 160 days, with an average of 60 to 90 days.
• Jaundice only occurs in about 10% of younger children and in 30-50% 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.

Chronic hepatitis B

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

• Although many patients with chronic hepatitis B are healthy carriers, some patients do have symptoms. These include fatigue, anorexia and nausea and right upper quadrant pain.
• The risk of developing chronic hepatitis B infection depends on the age at which infection is acquired; the risk is lowest in adults and >90% in neonates whose mothers are hepatitis B e antigen positive.^[4]
• Chronic infection is less frequent in those infected as children.
• The risk of becoming chronically infected with hepatitis B is increased in those whose immunity is impaired.
• Approximately 25% of adults who become chronically infected during childhood later die from hepatitis B virus (HBV)-related liver cancer or cirrhosis.
• 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.
• Chronic hepatitis B infection usually has a benign course in healthy non-drinkers with normal liver function.

Route of transmission

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 (eg 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.

Investigations^[5]

The following investigations are usually performed under specialist care:

• Investigations related to hepatitis B:
  • Hepatitis B surface antigen (HBsAg), hepatitis B e antigen (HBeAg), anti-HBe, anti-HBs, anti-HBcore.
  • Quantitative hepatitis B virus DNA.
  • Hepatitis B virus genotype (for those considered for interferon).
  • Hepatitis delta virus (HDV) serology.

• General liver investigations:
  • FBC.
  • Bilirubin.
  • Liver enzymes.
  • Clotting.
  • Ferritin.
  • Lipid profile.
  • Autoantibody screen.
  • Caeruloplasmin.

• Tests for hepatitis C virus and HIV:
  • Screening for liver cancer.
  • Ultrasonography.
  • Alpha-fetoprotein.

• Staging of disease:
  • Fibro-elastography
  • Liver biopsy

Serological markers

• Hepatitis B surface antigen (HBsAg) is the only serological marker detected during the first 3-5 weeks after being infected.
• The mean time from exposure to detection of HBsAg is 30 days.
• 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 implies high infectivity. HBeAg is usually present for 1½-3 months after the acute illness.
• Antibodies to hepatitis B core antigen (HBcAg) - ie anti-HBc - imply past infection.
• Antibodies to HBsAg - ie anti-HBs - alone imply vaccination.
• Dane particles are hepatitis B virus (HBV) virions. Anti-Dane particles are antibodies formed against them.
• DNAP is DNA polymerase, which is present during viral replication.
• HBV/HDV infection has a different natural history and different treatment to HBV mono-infection.
• Patients with acute infection have raised levels of IgM to HBcAg (anti-HBc).
• Patients with chronic hepatitis B are positive HBsAg for at least six months or positive HBsAg and negative IgM to HBcAg.

Management^[6][7]

General advice

• Patients should be advised to avoid unprotected sexual intercourse, including oro-anal and orogenital 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, and routes of transmission of infection, and should be advised not to donate blood.

Treatment of acute infection

Manage supportively as for hepatitis A.

Treatment of chronic infection

• The management of hepatitis B virus (HBV) has improved during recent years with the use of interferon and with the development of safe and potent oral antiviral nucleoside/nucleotide analogues.
• The goal of treatment is to prevent the progression to cirrhosis and to reduce the risk of hepatocellular carcinoma.
• HBV treatment is recommended for those patients who have moderate hepatic necro-inflammation or fibrosis and high serum HBV DNA.
• Patients with established cirrhosis should receive oral antiviral therapy regardless of HBV DNA titre.
• HBV DNA quantification is a key determinant for selection of patients for treatment.
• Antiviral efficacy is measured by the degree of HBV DNA suppression and rates of hepatitis B e antigen (HBeAg) and hepatitis B surface antigen (HBsAg) loss, and is reflected by improvement in liver histology.
• In patients positive for HBeAg, seroconversion to become negative for HBeAg or positive for anti-HBe is associated with sustained suppression of HBV DNA after treatment withdrawal and can be considered an end point of therapy.
• Pegylated interferon (as a weekly injection) gives a lasting response in around 30% of patients positive for HBeAg after one year.
• However, side-effects of pegylated interferon mean that it is not often used in clinical practice.
• There are now numerous antiviral treatments available, including lamivudine, entecavir, adefovir, tenofovir. These suppress HBV replication.
• The best choice of antiviral treatment is still contentious.^[5]
• Viral resistance does occur with these drugs. Combinations of drugs are sometimes given.
• Treatment responders have long-term benefits in terms of reduced liver damage and decreased risk of liver cancer.

Hepatitis B infection and HIV infection^[8]

• Approximately 10% of those with HIV infection worldwide are also infected with hepatitis B.
• Both viruses can be treated with a simplified combination of drugs.
• Liver disease may progress more rapidly in those patients co-infected with HBV/HIV and could lead to serious liver disease complications such as cirrhosis and liver cancer at younger ages.
• There is a higher risk of developing hepatotoxicity following the initiation of antiretroviral therapy in HIV patients co-infected with hepatitis B than there is in patients infected with HIV alone.
• In patients infected with hepatitis B, HIV can lead to higher rates of chronicity, decreased rates of anti-HBe and anti-HBs seroconversion, and increased viral replication, probably due to the impairment of the body's immune responses.
• There is no evidence that hepatitis B affects HIV disease progression.
• The choice of treatment of hepatitis B in patients with HIV infection depends on several factors, including the severity of liver disease and the patient's CD4 count.

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 (HBIG) should be administered to a non-immune contact after a single unprotected sexual exposure or parenteral exposure, eg 'needlestick' 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.^[3]
  • An accelerated course of vaccine (at 0, 1 and 2 months) should be given to those who receive HBIG, plus a booster dose at 12 months for those at continued risk.

Pregnancy

• Vertical transmission (mother to infant) of infection occurs in 90% of pregnancies where the mother is HBeAg-positive and in about 10% of HBsAg-positive, HBeAg-negative mothers.
• All babies born to infected mothers should receive a complete course of vaccine on time.
• Babies born to highly infectious mothers should receive HBIG (preferably given within 24 hours of delivery) as well as active immunisation
• HBIG may be given simultaneously with vaccine but at a different site.
• This reduces vertical transmission by 90%.

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.
• 'Needlestick' victims.
• Sexual partners of positive or high-risk patients.
• Workers with occupational risk, eg healthcare workers.

If non-immune, consider vaccination. If found to be chronic carriers, consider referral for therapy.

Complications

• Fulminant hepatic failure (rare).
• Relapse.
• Prolonged cholestasis.
• Chronic hepatitis.
• Cirrhosis.
• Hepatocellular carcinoma (HCC) - there is high risk of this in some non-cirrhotic patients, including African patients over the age of 20, Asian males over the age of 40, Asian females over the age of 50, and patients with a family history of HCC.
• Glomerulonephritis.
• Cryoglobulinaemia.
• Concurrent hepatitis C infection can lead to fulminant hepatitis, more aggressive chronic hepatitis and increased risk of liver cancer.
• Concurrent HIV infection increases the risk of progression to cirrhosis.

Prevention

See related separate article Hepatitis B Vaccination and Prevention.

• 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 immunisation with specific hepatitis B immunoglobulin may be given to non-immune contacts after high-risk exposure.