Hepatitis B

Hepatitis B

Hepatitis B is a disease of the liver caused by the Hepatitis B virus (HBV), a member of the Hepadnavirus family and one of several unrelated viral species which cause viral hepatitis. It was originally known as “serum hepatitis” and has caused current epidemics in parts of Asia and Africa. Hepatitis B is recognized as endemic in China and various other parts of Asia. The proportion of the world’s population currently infected with the virus is 3 to 6%, but up to a third have been exposed. Symptoms of the acute illness caused by the virus include liver inflammation, vomiting, jaundice, and rarely, death. Chronic hepatitis B may cause liver cirrhosis which may then lead to liver cancer. The hepatitis B virus is the second most prevalent cause of cancer in humans after Tobacco smoke.

Structure

Virions consist of an outer lipid envelope and an icosahedra nucleocapsid core, the latter being composed of both protein and DNA. The outer envelope contains embedded proteins which are involved in viral binding of, and release into, susceptible cells. Virion shape is generally spherical with a diameter of 40 – 48 nanometers (nm) but pleomorphic forms exist, including filamentous and spherical bodies lacking a core. These “sub-viral” particles are not infectious.

The DNA genome is not segmented but rather partially double-stranded, containing a long and short segment which overlap approximately 240 nucleotides to form an open circle. The longer strand is 3020-3320 nucleotides long, and the shorter is 1700-2800 nucleotides long. The virus can be divided into four major serotypes (adr, adw, ayr, ayw) based on antigenic epitopes present on its envelope proteins, and into eight genotypes (A-H) according to overall nucleotide sequence variation of the genome. Different genotypes have distinct geographic distributions. For example, genotypes B and C are prevalent in China and neighboring countries.

Replication

Hepatitis B is one of a few known non-retroviral viruses which employ reverse transcription as a part of its replication process. (HIV, a completely unrelated virus, also uses reverse transcription.) Hepatitis B’s genome is DNA, and reverse transcription is one of the later steps in making new viral particles. (Because HIV has an RNA genome, reverse transcription is one of the first steps in replication).

Upon entry into a host cell, the virus’ double-stranded DNA genome is relocated to the cell’s nucleus and converted to covalently closed circular DNA form, from which viral mRNAs are transcribed. These transcripts are exported to cytoplasm for translation of the envelope proteins (also known as hepatitis B surface antigen, or HBsAg), hepatitis B e antigen (HBeAg), and the X protein, whose function is still under debate. A fourth pre-genomic RNA is transcribed, which translates the viral polymerase and core proteins. Polymerase and pre-genomic RNA are encapsidated in the assembling core particles, where reverse transcription of the pre-genomic RNA to genomic DNA occurs by the Reverse Transcriptase (RT) protein. The mature core particle then exits the cell via normal secretory pathway, acquiring an envelope along the way.

Transmission

Hepatitis B is largely transmitted through exposure to bodily fluids containing the virus. This includes unprotected sexual contact, blood transfusions, re-use of contaminated needles and syringes, vertical transmission from mother to child during childbirth, and so on. The primary method of transmission depends on the prevalence of the disease in a given area. In low prevalence areas, such as the continental United States, injection drug abuse and unprotected sex are the primary methods. In moderate prevalence areas, the disease is predominantly spread among children. In high prevalence areas, such as South East Asia, vertical transmission is most common. Without intervention, a mother who is positive for the hepatitis B surface antigen confers a 20% risk of passing the infection to her offspring at the time of birth. This risk is as high as 90% if the mother is also positive for the hepatitis B e antigen.

Roughly 16-40% of unimmunized sexual partners of individuals with hepatitis B will be infected through sexual contact. The risk of transmission is closely related to the rate of viral replication in the infected individual at the time of exposure.

Immunopathogenesis

During HBV infection the host immune response is responsible for both hepatocellular damage and viral clearance. While the innate immune response does not play a significant role in these processes, the adaptive immune response, particularly virus-specific cytotoxic T lymphocytes (CTLs), contributes to nearly all of the liver injury associated with HBV infection. By killing infected cells and by producing antiviral cytokines capable of purging HBV from viable hepatocytes, CTLs also eliminate the virus. Although liver damage is initiated and mediated by the CTLs, antigen-nonspecific inflammatory cells can worsen CTL-induced immunopathology and platelets may facilitate the accumulation of CTLs into the liver.

Symptoms and Complications

Hepatitis B virus infection may either be acute (self-limited) or chronic (long-standing). Persons with self-limited infection clear the infection spontaneously within weeks to months.

The greater a person’s age at the time of infection, the greater the chance their body will clear the infection. More than 95% of people who become infected as adults or older children will stage a full recovery and develop protective immunity to the virus. However, only 5% of new-borns that acquire the infection from their mother at birth will clear the infection. Of those infected between the age of one to six, 70% will clear the infection. When the infection is not cleared, one becomes a chronic carrier of the virus.

Acute infection with hepatitis B virus is associated with acute viral hepatitis – an illness that begins with general ill-health, loss of appetite, nausea, vomiting, body aches, mild fever, dark urine, and then progresses to development of jaundice. It has also been noted that itchy skin all over the body, has been an indication as a possible symptom of all hepatitis virus types. The illness lasts for a few weeks and then gradually improves in most of the affected people. A few patients may have more severe liver disease (fulminant hepatic failure), and may die as a result of it. The infection may also be entirely asymptomatic and may go unrecognized.

Chronic infection with hepatitis B virus may be either asymptomatic or may be associated with a chronic inflammation of the liver (chronic hepatitis), leading to cirrhosis over a period of several years. This type of infection dramatically increases the incidence of liver cancer. Hepatitis D infection requires a concomitant infection with hepatitis B. Co-infection with hepatitis D increases the risk of liver cirrhosis and subsequently, liver cancer.

Polyarteritis nodosa is more common in people with hepatitis B infection.

Diagnosis

The original assays for detection of hepatitis B virus infection involve serum or blood tests that detect either viral antigens (proteins produced by the virus) or antibodies produced by the host. Interpretation of these assays is complex. The hepatitis B surface antigen (HBsAg) is most frequently used to screen for the presence of this infection. It is the first detectable viral antigen to appear during infection with this virus; however, early in an infection, this antigen may not be present and it may be undetectable later in the infection as it is being cleared by the host. During this ‘window’ in which the host remains infected but is successfully clearing the virus, IgM antibodies to the hepatitis B core antigen (anti-HBc IGM) may be the only serologic evidence of disease.

Shortly after the appearance of the HBsAg, another antigen named as the hepatitis B e antigen (HBeAg) will appear. Traditionally, the presence of HBeAg in a host’s serum is associated with much higher rates of viral replication; however, some variants of the hepatitis B virus do not produce the ‘e’ antigen at all, so this rule does not always hold true. During the natural course of an infection, the HBeAg may be cleared, and antibodies to the ‘e’ antigen (anti-HBe) will arise immediately afterward. This conversion is usually associated with a dramatic decline in viral replication. If the host is able to clear the infection, eventually the HBsAg will become undetectable and will be followed by antibodies to the hepatitis B surface antigen (anti-HBs). A person negative for HBsAg but positive for anti-HBs has either cleared an infection or has been vaccinated previously. A number of persons who are positive for HBsAg may have very little viral multiplication, and hence may be at little risk of long-term complications or of transmitting infection to others.

More recently, PCR tests have been developed to detect and measure the amount of viral nucleic acid in clinical specimens. These tests are useful to assess a person’s infection status and to monitor treatment.

Treatment

There are currently several treatments for chronic hepatitis B that can increase a person’s chance of clearing the infection. Treatments are available in the form of antiviral such as lamivudine and adefovir and immune system modulators such as interferon alpha (Uniferon). There are several other antiviral under investigation. Roughly, all of the currently available treatments, when used alone, are about equally efficacious. However, some individuals are much more likely to respond than others. It does not appear that combination therapy offers any advantages. In general, each works by reducing the viral load by several orders of magnitude thus helping a body’s immune system clear the infection. Treatment strategies should be individualized by a doctor and patient. Considerations include the risks associated with each treatment, a person’s likelihood of clearing the virus with treatment, a person’s risk for developing complications of persistent infection, and development of viral resistance with some of the treatments.

On March 29, 2005, the US Food and Drug Administration (FDA) approved Entecavir for the treatment of hepatitis B.

On February 25, 2005, the EU Commission approved PEGASYS for the treatment of hepatitis B making it the first pegylated interferon to be approved for hepatitis B.

On October 27, 2006 telbivudine gained FDA approval for chronic treatment of chronic hepatitis B. Its side effects profile is generally less than that of other anti-virals in comparison, especially lamivudine. It is marketed under the brand name Tyzeka in the US and Sebivo outside the US. It is already approved in Switzerland.

Chronic carriers should be strongly encouraged to avoid consuming alcohol as it increases their risk for cirrhosis and hepatocellular carcinoma (liver cancer).

Infants born to mothers known to carry hepatitis B can be treated with antibodies to the hepatitis B virus (hepatitis B immune globulin or HBIg). When given with the vaccine within twelve hours of birth, the risk of acquiring hepatitis B is reduced 95%. This treatment also allows a mother to safely breastfeed her child.

An individual exposed to the virus who has never been vaccinated may be treated with HBIg immediately following the exposure. For instance, a health care worker accidentally stuck by a needle used in a hepatitis B carrier would qualify. Treatment must be soon after exposure, however.

Prevention

Several vaccines have been developed for the prevention of hepatitis B virus infection. These rely on the use of one of the viral proteins (hepatitis B surface antigen or HBsAg). The vaccine was originally prepared from plasma obtained from patients who had long-standing hepatitis B virus infection. However, currently, these are more often made using recombinant technology, though plasma-derived vaccines continue to be used; the two types of vaccines are equally effective and safe.

Many countries now routinely vaccinate infants against hepatitis B. Babies born to HBeAg positive mothers are strongly recommended to be vaccinated and injected with immune globulin immediately after birth, so as to prevent transmission of infection. In many areas, vaccination against hepatitis B is also required for all health-care workers. Some college campus housing units now require proof of vaccination as a prerequisite. Booster doses are not needed for low-risk general population. Some recommend such doses every five to ten years for health-care workers, though the evidence supporting such doses is quite limited.

The vaccine is highly effective. In endemic countries with high rates of hepatitis B infection, vaccination of newborns has not only reduced the risk of infection, but has also led to marked reduction in liver cancer. This was reported in Taiwan where the implementation of a nationwide hepatitis B vaccination program in 1984 was associated with a decline in the incidence of childhood hepatocellular carcinoma. In that sense, this vaccine can be thought of as an anti-cancer vaccine.

Patients with HIV appear to have inferior antibody responses to hepatitis B vaccination.