2 Clinical need and practice
2.1 Chronic hepatitis B is defined as viraemia and hepatic inflammation that persists for more than 6 months after acute infection with hepatitis B virus. Hepatitis B virus is transmitted by sexual contact, through the use of infected blood and blood products, by reuse of contaminated needles and syringes, by vertical transmission from mother to child during, or soon after, birth, and by horizontal transmission among children. The risk of chronic infection with hepatitis B virus depends on the nature of the immune response to the initial infection. This varies according to the age at which the infection is acquired. Almost 100% of neonates, and about 50% of young children, develop chronic hepatitis B if infected with hepatitis B virus. In contrast, only about 2–10% of people who are infected as adults go on to develop chronic hepatitis B.
2.2 The Department of Health estimates that about 180,000 people in the UK have chronic hepatitis B. There are about 7700 new cases of chronic hepatitis B each year. Of these, around 300 people were infected within the UK; the remainder (mainly immigrants to the UK) were infected abroad, generally in areas of high prevalence where the virus is frequently transmitted from mother to child.
2.3 People with active chronic hepatitis B are at increased risk of liver cirrhosis (scarring of the liver tissue that may progress to liver failure) and primary liver cancer (hepatocellular carcinoma).
2.4 The diagnosis of chronic hepatitis B is based on the presence of well-characterised serological markers in the blood. Hepatitis B viral DNA (HBV DNA) is present in both acute and chronic hepatitis B. Hepatitis B surface antigen (HBsAg) is a viral protein detectable in the blood in both acute and chronic infection. Chronic hepatitis B is defined as persistence of HBsAg for 6 months or more after acute infection. Hepatitis B 'e' antigen (HBeAg) is an indicator of viral replication, although some variant forms of the virus do not express HBeAg (see section 2.5.5 below). Active infection can be described as HBeAg-positive or HBeAg-negative according to whether HBeAg is secreted.
2.5 The natural history of chronic hepatitis B can be divided into phases, each of which may last many years.
2.5.1 Immunotolerant phase.People who are affected at birth or in early childhood initially enter an 'immunotolerant' phase during which the immune system does not actively fight the virus. The virus replicates rapidly during this phase, but the person usually has no symptoms. The person is highly infectious, and may infect other members of the family and community. This phase can last for many years before progressing to active disease.
2.5.2 Incubation. The incubation period for hepatitis B infection ranges from 40–160 days, with an average of 60–90 days.
2.5.3 Active chronic hepatitis B.The first stage of active disease involves a period of increasing inflammatory hepatic necrosis as the immune system begins to fight the virus. This stage of the disease is characterised by elevated levels of viral DNA in the blood, persistently raised levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), and evidence of hepatic necrosis and inflammation on biopsy. The liver damage caused by infection and inflammation may eventually lead to cirrhosis of the liver. Progression to cirrhosis occurs at an annual rate of 2–5.5%, with a cumulative 5-year rate of progression of 8–20%.
2.5.4 HBeAg seroconversion . In people infected with an HBeAg-positive form of the virus, the next stage of the infection occurs when inflammation becomes sufficiently intense to cause lysis of infected hepatocytes. This produces a 'flare' of the disease with symptoms resembling acute hepatitis B, and leads to the development of antibodies against the 'e' antigen. This is referred to as 'HBeAg seroconversion'. The seroconverted disease state is associated with good quality of life and a relatively low risk of disease progression. It is referred to as the 'inactive HBsAg carrier state' because patients continue to express hepatitis B surface antigen (HBsAg). The spontaneous seroconversion rate is 5–10% per year, although this varies among populations. Once seroconversion has taken place, most people remain in the inactive HBsAg carrier state. However, increasing viraemia and recurrent hepatitis after seroconversion indicate the emergence of the HBeAg-negative strain of the virus.
2.5.5 HBeAg-negative chronic hepatitis B . In recent years a form of the virus that does not cause infected cells to secrete HBeAg has been discovered (sometimes called the 'precore mutant' strain). People can be infected with the so-called HBeAg-negative form of the virus from the beginning, or the viral mutation can emerge later in the course of infection in people initially infected with the HBeAg-positive form of the virus. The prevalence of HBeAg-negative hepatitis varies geographically; it is more common in Asia and the Mediterranean region than in Northern Europe. Infection with HBeAg-negative chronic hepatitis B is associated with a fluctuating course and a poor prognosis. Active disease is associated with either persistent elevation of ALT or an erratic pattern of ALT changes with flare-ups resembling acute hepatitis B that can be severe or even fatal. Few patients with HBeAg-negative chronic hepatitis B achieve a lasting remission. Progression to cirrhosis of the liver has been estimated to occur in 8-10% of people with HBeAg-negative chronic hepatitis B each year.
2.5.6 HBsAg seroconversion.The development of antibodies against HBsAg, with clearance of HBsAg, occurs spontaneously in about 0.5–2% of people with chronic hepatitis B each year in western countries. In countries where hepatitis B is endemic, the rate is much lower – between 0.05 and 0.08% per year. Clearance of HBsAg is most likely to occur in the year following HBeAg seroconversion. It signifies resolution of the chronic infection. Variants of hepatitis B (known as 'occult hepatitis B') that are not associated with detectable HBsAg by current immunoassays have been recognised.
2.5.7 The aim of treatment is to prevent progression to cirrhosis or hepatocellular carcinoma. Treatment may be given as a finite course (circumscribed therapy) – with the intention of allowing the immune system to respond and control the infection without the need for further drug treatment – or as long-term viral suppressive therapy. Long-term therapy is needed if short-term therapy is unsuccessful.
2.5.8 The first drugs to be licensed for the treatment of chronic hepatitis B were alfa interferons. Interferons are natural proteins that activate the immune system in response to viral infection. Three recombinant interferon products have UK marketing authorisation for the treatment of chronic hepatitis B: IntronA (interferon alfa-2b, Schering-Plough), Roferon-A (interferon alfa-2a, Roche) and Viraferon (interferon alfa-2b, Schering-Plough). Interferon alfa-2a is usually given at a dose of 2.5–5 million units per square metre of body surface area by subcutaneous injection three times a week for 4–6 months. Interferon alfa-2b is given at a dose of 5–10 million units three times a week for 4–6 months. The side effects of interferons can be severe and this means that they are not suitable for long-term treatment in chronic hepatitis B. Interferons are contraindicated in decompensated liver disease. There are no data on long-term maintenance therapy with an alfa interferon and the treatment is not licensed for this.
2.5.9 Lamivudine (Zeffix, GlaxoSmithKline) is a nucleoside reverse transcriptase inhibitor antiviral drug. The dose in adults is 100 mg per day. It can be given both as a circumscribed course of treatment or as long-term viral suppressive therapy. In HBeAg-positive chronic hepatitis B, treatment is usually given for a year with the aim of bringing about HBeAg seroconversion. In HBeAg-negative chronic hepatitis B, a circumscribed course of therapy is less likely to lead to long-term control of the infection, and long-term treatment is often needed. The main problem with long-term antiviral treatment is the emergence of resistance. Resistance to lamivudine occurs in more than 60% of cases after 3 years' treatment.