HEPATITIS B

The hepatitis B virus consists of a core containing DNA and a DNA polymerase enzyme needed for virus replication. The core of the virus is surrounded by surface protein . The virus, also called a Dane particle, and an excess of its surface protein (known as hepatitis B surface antigen) circulate in the blood. Humans are the only source of infection. . Hepatitis B surface antigen (HBsAg) is a protein which makes up part of the viral envelope. Hepatitis B core antigen (HBcAg) is a protein which makes up the capsid or core part of the virus (found in the liver but not in blood). Hepatitis B e antigen (HBeAg) is part of the HBcAg which can be found in the blood and indicates infectivity. Hepatitis B infection affects 300 million people and is one of the most common causes of chronic liver disease and hepatocellular carcinoma world-wide. Hepatitis B may cause an acute viral hepatitis; however, the acute infection is often asymptomatic, particularly when acquired at birth. Many individuals with chronic hepatitis B are also asymptomatic. Chronic hepatitis, associated with elevated serum transaminases, may occur and can lead to cirrhosis, usually after decades of infection  The risk of progression to chronic liver disease depends on the source of infection  Vertical transmission, from mother to child in the perinatal period, is the most common cause of infection world-wide and carries the highest risk.  SOURCE OF HEPATITIS B INFECTION AND RISK OF CHRONIC INFECTION Route of transmission Risk of chronic infection Horizontal transmission 10% Injection drug use   Infected unscreened blood products   Tattoos/acupuncture needles   Sexual (homosexual and heterosexual)   Vertical transmission 90% HbsAg-positive mother   There is an initial immunotolerant phase with high levels of virus and normal liver biochemistry. An immunological response to the virus then occurs, with elevation in serum transaminases which causes liver damage: chronic hepatitis. If this response is sustained over many years and viral clearance does not occur promptly, chronic hepatitis may result in cirrhosis. In individuals where the immunological response is successful, viral load falls, HBe antibody develops and there is no further liver damage. Some individuals may subsequently develop HBV-DNA mutants, which escape from immune regulation, and viral load again rises with further chronic hepatitis. Mutations in the core protein result in the virus's inability to secrete HBe antigen despite high levels of viral replication; such individuals have HBeAg-negative chronic hepatitis. (ALT = alanine aminotransferase; AST = aspartate aminotransferase)  (HBsAg = hepatitis B surface antigen; anti-HBs = antibody to HBsAg; HBeAg = hepatitis B e antigen; anti-HBe = antibody to HBeAg; anti-HBc = antibody to hepatitis B core antigen)  INTERPRETATION OF MAIN INVESTIGATIONS USED IN THE SEROLOGICAL DIAGNOSIS OF HEPATITIS B VIRUS INFECTION     Anti-HBc   Interpretation HBsAg IgM IgG Anti-HBs Incubation period + + - - Acute hepatitis Early + + - - Established + + + - Established (occasional) - + + - Convalescence   (3-6 months) - ± + ±   (6-9 months) - - + + Post-infection > 1 year - - + + Uncertain - - + - Chronic infection Usual + - + - Occasional - - + - Immunisation without infection - - - + + positive; - negative; ± present at low titre or absent. Investigations Serology HBV contains several antigens to which infected persons can make immune responses  these antigens and their antibodies are important in identifying HBV infection  In acute infection the hepatitis B surface antigen (HBsAg) is a reliable marker of HBV infection, and a negative test for HBsAg makes HBV infection very unlikely but not impossible . HBsAg appears in the blood late in the incubation period and before the prodromal phase of acute type B hepatitis; it may be present for only a few days, disappearing even before jaundice has developed, but usually lasts for 3-4 weeks and can persist for up to 5 months. Antibody to HBsAg (anti-HBs) usually appears after about 3-6 months and persists for many years or perhaps permanently. Anti-HBs implies either a previous infection, in which case anti-HBc (see below) is usually also present, or previous vaccination when anti-HBc is not present. The hepatitis B core antigen (HBcAg) is not found in the blood, but antibody to it (anti-HBc) appears early in the illness and rapidly reaches a high titre which then subsides gradually but persists. Anti-HBc is initially of IgM type with IgG antibody appearing later. Anti-HBc (IgM) can sometimes reveal an acute HBV infection when the HBsAg has disappeared and before anti-HBs has developed (and  The hepatitis B e antigen (HBeAg) appears only transiently at the outset of the illness and is followed by the production of antibody (anti-HBe). The HBeAg reflects active replication of the virus in the liver. The persistence of HBsAg for longer than 6 months indicates chronic infection. Chronic HBV infection (see below) is marked by the presence of HBsAg and anti-HBc (IgG) in the blood. Usually, HBeAg or anti-HBe is also present; HBeAg indicates continued active replication of the virus in the liver while anti-HBe implies that replication is occurring at a much lower level or that HBV-DNA has become integrated into host hepatocyte DNA. Viral load  HBV-DNA encodes four proteins: a DNA polymerase needed for viral replication (P), a surface protein (S), a core protein (C) and an X protein. The pre-C and C regions encode a core protein and an e antigen. Although mutations in the hepatitis B virus are frequent occurrences, certain mutations have important clinical effects. Pre-C encodes a signal sequence needed for the C protein to be secreted from the liver cell into serum as e antigen. A mutation in the pre-core region leads to a failure of secretion of e antigen into serum and so individuals have high levels of viral production but no detectable e antigen in the serum. Mutations can also occur in the surface protein and may lead to the failure of vaccination (surface antibodies produced against native S protein) to prevent infection. Mutations also occur in the DNA polymerase during antiviral treatment with lamivudine. HBV-DNA can be measured by polymerase chain reaction (PCR) in the blood. Viral loads are usually in excess of 105 copies/ml in the presence of active viral replication, as indicated by the presence of e antigen. In contrast, in those with low viral replication, HBsAg- and anti-HBe-positive, viral loads are less than 105 copies/ml. The exception is in patients who have a mutation in the pre-core protein, which means they cannot secrete e antigen into serum . Such individuals will be anti-HBe-positive but have a high viral load and often evidence of chronic hepatitis. These mutations are common in the Far East and those affected are classified as having e antigen-negative chronic hepatitis. They respond differently to antiviral drugs from those with classical e antigen-positive chronic hepatitis. Measurement of viral load is important in monitoring antiviral therapy and identifying patients with pre-core mutants. Specific HBV genotypes can also be identified using PCR. Genotypes B and C appear to have more aggressive disease that responds less well to antiviral therapy. Management Acute hepatitis B Treatment is supportive with monitoring for acute liver failure, which occurs in less than 1% of cases. Chronic hepatitis B Treatments are still limited, with no drug able to eradicate hepatitis B infection completely. The indication for treatment is a high viral load in the presence of active hepatitis, as demonstrated by elevated serum transaminases and/or histological evidence of inflammation. Alfa-interferon This is most effective in selected patients with a low viral load and serum transaminases greater than twice the upper limit of normal in whom it acts by augmenting a native immune response. In HBeAg-positive chronic hepatitis 33% lose e antigen after 4-6 months of treatment compared to 12% of controls. Response rates are lower in HBeAg-negative chronic hepatitis, even when patients are given longer courses of treatment. Interferon is contraindicated in the presence of cirrhosis as it may cause a flare in serum transaminases and precipitate liver failure. Longer-acting pegylated interferons which can be given once weekly have been evaluated in both HBeAg-positive and HBeAg-negative chronic hepatitis . Other antiviral therapies are required because many patients with chronic hepatitis B have high levels of viraemia and/or low transaminase levels and are not therefore candidates for interferon. Lamivudine PEGYLATED INTERFERONS IN CHRONIC HEPATITIS B INFECTION 'In HBeAg-positive chronic hepatitis treatment with pegylated interferon for 6 months eliminates HBeAg in 35%, and normalises liver biochemistry in 25% of patients. In HBeAg-negative chronic hepatitis treatment with pegylated interferon for 12 months leads to normal liver biochemistry in 60%, and sustained suppression of hepatitis B virus load below 400 copies/ml in 20% of patients.'

LAMIVUDINE IN CHRONIC HEPATITIS B INFECTION

'48 weeks of treatment with lamivudine induces anti-HBe seroconversion in 27% of patients with HBeAg-positive chronic hepatitis, despite 38% developing HBV-DNA polymerase mutations. Treatment also improves histology and liver biochemistry.'

ADEFOVIR IN CHRONIC HEPATITIS B INFECTION

'In HBeAg-positive chronic hepatitis treatment with 10 mg of adefovir for 48 weeks produces normal liver biochemistry in 48% (NNTB 3), suppresses serum HBV-DNA in 39% (NNTB 5) and leads to e antigen seroconversion in 14% (NNTB 16) of patients. In HBeAg-negative chronic hepatitis treatment with adefovir for 48 weeks reduces ALT to normal in 72% (NNTB 2.3) and renders serum HBV-DNA undetectable in 55% (NNTB 2) of patients.'

This is a nucleoside analogue which inhibits DNA polymerase and suppresses HBV-DNA levels. It is effective in improving liver function in patients with decompensated cirrhosis and may prevent the need for transplantation. Long-term therapy is complicated by the development of HBV-DNA polymerase mutants which may occur after 9 months of treatment and is characterised by a rise in viral load during treatment. These viral mutants are less hepatotoxic than native virus so the drug can often be continued (Box 23.40). Flares in transaminases occur when lamivudine is stopped if mutant virus is present, as native virus replaces mutant virus.

Adefovir

This is a nucleotide analogue that is phosphorylated to yield active drug which inhibits HBV-DNA polymerase. It reduces HBV-DNA levels by 3-4 logs, enhances the frequency of HBeAg seroconversion and leads to histological improvement, but is contraindicated in renal failure. The HBV-DNA mutants develop at a lower rate than with lamivudine, 2% being identified after 2 years of treatment (Box 23.41). Relapse occurs on stopping treatment and the optimum length of treatment remains unknown. Adefovir is effective in suppressing most of the lamivudine-induced DNA polymerase mutant viruses.

Other drugs

Other drugs which are currently been studied in chronic hepatitis B include tenofovir, which has anti-HIV efficacy, and L-deoxythymidine. The role of combination antiviral therapy, as used in HIV infection, is still unclear.

Liver transplantation

Historically, liver transplantation was contraindicated in the presence of hepatitis B because infection often recurred in the graft. However, the use of post-liver transplant prophylaxis with lamivudine and hepatitis B immunoglobulins has reduced the reinfection rate to 10% and increased 5-year survival to 80%, making transplantation an acceptable treatment option in selected cases.

Prevention

AT-RISK GROUPS MERITING HEPATITIS B VACCINATION IN LOW ENDEMIC AREAS

Parenteral drug users Men who have sex with Close contacts of infected individuals Newborn of infected mothers Regular sexual partners Patients on chronic haemodialysis Patients with chronic liver disease men Medical/nursing personnel

Individuals are most infectious when markers of continuing viral replication, such as HBeAg, and high levels of HBV-DNA are present in the blood; they are least infectious when only anti-HBe is present with low levels of virus. HBV-DNA can be found in saliva, urine, semen and vaginal secretions. The virus is about ten times more infectious than hepatitis C, which in turn is about ten times more infectious than HIV.

A recombinant hepatitis B vaccine containing HBsAg is available (Engerix) and is capable of producing active immunisation in 95% of normal individuals. The vaccine gives a high degree of protection and should be offered to those at special risk of infection who are not already immune, as evidenced by anti-HBs in the blood . The vaccine is ineffective in those already infected by HBV. Infection can also be prevented or minimised by the intramuscular injection of hyperimmune serum globulin prepared from blood containing anti-HBs. This should be given within 24 hours, or at most a week, of exposure to infected blood in circumstances likely to cause infection (e.g. needlestick injury, contamination of cuts or mucous membranes). Vaccine can be given together with hyperimmune globulin (active-passive immunisation).

Neonates born to hepatitis B-infected mothers should be immunised at birth and given immunoglobulin. Hepatitis B serology should then be checked at 12 months of age.

Prognosis

Acute hepatitis

Full recovery occurs in 90-95% of adults following acute HBV infection. The remaining 5-10% develop a chronic infection which usually continues for life, although later recovery occasionally occurs. Infection passing from mother to child at birth leads to chronic infection in the child in 90% of cases and recovery is rare. Chronic infection is also common in immunodeficient individuals such as those with Down's syndrome or HIV infection.

Recovery from acute HBV infection occurs within 6 months and is characterised by the appearance of antibody to viral antigens. Persistence of HBeAg beyond this time indicates chronic infection. Combined HBV and HDV infection causes more aggressive disease.

Chronic infection

Most patients with chronic hepatitis B are asymptomatic and develop complications such as cirrhosis and hepatocellular carcinoma only after many years . Cirrhosis develops in 15-20% of patients with chronic HBV over 5-20 years. This proportion is higher in those who are e antigen-positive.