Isolated in 1965, hepatitis B, (HBV), is classified as a hepadnavirus.

Hepatitis B is generally an immunopathic virus. This means that the damage that occurs in the bodies of infected patients is primarily caused by their immune response to the presence of the virus, rather than the pathogen itself. In the case of HBV the damage mainly happens in the liver. This can be called auto-immune hepatitis. However when HBV is highly active and replicating large numbers of virus it may cause damage to cells on its own and so work cytopathically as well. Knowledge of HBV has changed significantly in the past decade and people who were told they had 'natural immunity' to hepatitis B in the past may not be. Anyone in this situation should be retested in case they have are infectious or have undetected chronic HBV.

Disease progression

In the period immediately following exposure to hepatitis B most adults develop an acute illness with symptoms ranging from influenza to severe jaundice (yellow skin and eyes). This illness is debilitating in just under half of those infected. A tiny minority develop fulminant infection which means that the patient's liver is overwhelmed and this can be fatal. Most adults, estimated at over 90%, infected with HBV recover spontaneously. There is a high level of circulating virus in the acute phase and so people are often highly infectious to others during this time.

7-10% of people infected with HBV suffer chronic detectable infection. Some of these people eventually get rid of HBV, usually within the first two years of infection. The longer HBV is present, the more difficult it is to clear.

Persons in this group suffer from varying degrees of illness associated with chronic hepatitis B.

There are three broad categories, although individuals may not necessarily fit comfortably in any one category;

• Healthy carriers do not manifest symptoms. HBV persists, but is not accompanied by liver inflammation. The immune system appears not to react too violently to HBV despite the presence of high levels of virus a state known as immunotolerance. They remain infectious to other people.
• Periodically symptomatic persons experience episodes of active liver inflammation caused by a process called immunoelimination. The immune system appears to stop tolerating the presence of HBV and symptomatic liver disease follows, as the immune system attacks infected liver cells. It is not known exactly why this occurs. Sometimes the active episodes end and the person returns to an immunotolerant state like healthy carriers, whilst other times it becomes progressive liver disease. Levels of the virus increase when people have active immunoelimination episodes and so they become more infectious.
• About 25% of chronic persons go on to develop progressive liver disease, which is characterised by ongoing liver inflammation. It seems that the persons who are most at risk of progression to this phase have immune systems that continue to try to eliminate HBV, despite failure to do so. The immune system attacks infected liver cells in a vain attempt to clear the virus, causing serious injury in the process. This can develop into cirrhosis and for a small minority liver cancer.

As with all forms of chronic hepatitis there is a risk of cirrhosis developing.

Chronic hepatitis B significantly increases a person’s risk of hepatocellular carcinoma (HCC) or liver cancer. Currently it is thought that about 5-15% of chronic HBV patients will progress to HCC. The majority of people with HCC already have cirrhosis but over a third do not and the liver should be routinely monitored for tumours in people with chronic HBV. It remains uncertain if HBV impacts on the effect of HIV.

Transmission routes

The virus can enter the body through mucous membranes. This is usually when semen, vaginal fluid or the blood of an infected individual gets into the mouth, eyes, penis (inside the urethra), rectum or the vagina of an uninfected person. The virus can also enter the bloodstream through needles or through cuts or wounds in the skin. Hepatitis B cannot be contracted through intact skin. No research to date has proven transmission from the saliva of an infected individual.

Intravenous drug use

Hepatitis B is easily passed on in situations of intravenous drug use. HBV can also be spread via the sharing of spoons, filters and other paraphernalia as well as hypodermic needles and syringes.

Sexual transmission

Hepatitis B is a well known for being a sexually transmissible disease and a frequent one for gay men. Hepatitis B can be found in infectious quantities in blood, semen and vaginal fluid. It is therefore transmissible by any unprotected sexual contact which involves the combination of body fluids between partners. Oral sex with ejaculation is a risk factor for HBV transmission. Practices which involve blood-to-blood contact or breaking of the skin also constitutes a risk. No research to date has established direct evidence of HBV transmission from wet or sloppy kisses.

Occupational

The risk of exposure in healthcare settings from needle stick injuries is higher for hepatitis B than either HIV or hepatitis C. All health workers providing patient care in the UK should be vaccinated against HBV and some employers insist upon it. The transmission rate has been found to vary between 6 and 30% (from 1 in 17 to 1 in 3). The rate for HIV is between 0.2 and 0.4% (from 1 in 500 to 1 in 250) (University of Virginia 2001)

Vertical

This is a common route in Asia. Children born with hepatitis B appear to be more likely to develop chronic HBV than people contracting the virus by other routes.

Household contact: sharing razors or toothbrushes

Sharing any piece of equipment that is likely to break the skin and have blood, semen or vaginal fluid on it on it is a risk for transmission of hepatitis B.

Blood transfusions and blood products

Hepatitis B was a major concern for people with haemophilia prior to the heat-treating of blood products in the mid-1980s. (UKHCDO 2004). It is still possible that people could be infected with hepatitis B from blood transfusions if the blood is not screened for the virus. All blood collected now in Britain is screened for hepatitis B.

Cosmetics and tattoos

A small percentage of people with hepatitis B may have been infected by cosmetic contact. Practices that can lead to the drawing of blood including tattooing, piercing and shaving are assumed to be responsible.

Tests for HBV

There are a number of tests for hepatitis B that try to ascertain if someone is immune, a chronic carrier or has never had the disease. The results for some of these tests can be confusing to experienced liver doctors never mind patients. The history of testing for HBV has been a series of certainties that have been gradually eroded by the continual finding of new exceptions to received wisdom. People who were believed to have recovered from acute HBV have later been shown to have a chronic infection. Some who were thought to be immune and no longer infectious have been shown to have passed on the virus. Others who had been believed to have cleared the virus have been found to have low levels of it circulating in the blood. Classifying someone as either recovered, immune or no longer infectious has become a hazardous task that may be right in the majority of cases but is inevitably wrong in others. Coinfection with HIV only makes the picture more difficult.

Antibody and antigen tests

The tests done initially are usually antigen and antibody tests. These tests are for different proteins of the viral particle and the antibodies to those proteins. There are three antigens that can be tested for, the Surface or 's' antigen, the Core or 'c' antigen and the 'e' antigen which is another protein in the core of the viral particle. These are abbreviated to HBsAg, HBcAg and HBeAg with 'HB' standing for Hepatitis B and 'Ag' for Antigen. These three antigens may provoke the immune system to make an antibody which can also be tested for and these tests are labelled anti-HBs, anti-HBc and anti-HBe tests (or confusingly HBsAb, HBcAb and HbeAb). The immune system produces anti-bodies to the antigens at different stages of the disease.

Antibodies can also be lost from the body after a period of time and with HBV it seems quite possible to have some of the HBV antibodies without others in what seem to be quite illogical ways. They can also be present or lacking in ways that are confusing to liver doctors so do not be surprised if results are difficult to interpret.

Not previously had HBV

If all the antigen tests and all the anti-body tests are negative the person is presumed not to have ever been infected with hepatitis B. Often only the HbsAg, anti-HBs and anti-HBc tests are done initially. If these three are negative the person should receive the vaccine. The anti-HBs test is also used after inoculation to check the effectiveness of the vaccine.

Immune to HBV?

If the result to the HBsAg test is negative and the anti-HBs positive the person was previously assumed to have recovered from the infection and be immune to Hepatitis B. However some people in this situation have been shown to have low levels still circulating in the blood. This is sometimes called 'occult HBV infection'. What this means for a person is unclear.

Infected with HBV

If a person is positive to the surface antigen test (HbsAg+) they have hepatitis B.

Uncertainty

All other combinations require expert interpretation and often repetition of these tests alongside others to try and understand the situation. This may be immediately after the first set of tests to act as a means of confirming the results or they may become part of a yearly monitoring routine.

Presence of the virus

When there is uncertainty over the result of antigen and antibody tests the HBV-DNA test is used to directly detect and quantify the presence of HBV virus in the blood. This test could be a good idea in people with HIV anyway because HIV may impact on the presence of anti-bodies, either affecting the immune systems production of them or causing the antibodies to be lost more quickly.

A positive HBV-DNA result indicates that the virus is present and active and the person is definitely infected. The sensitivity of the HBV-DNA test varies with newer ones much more sensitive and older ones much less so. It is worth asking how low a level of the virus can be detected by the test being used. The HBV-PCR test is a sensitive indicator of the presence of the virus in the blood but less accurate in determining the level of circulating virus and so less useful at staging the disease. This test can show low levels of the virus circulating that are not detected by older HBV-DNA tests. The newer HBV-DNA tests are almost as sensitive as the PCR test with limits of detection as low as 100-200 copies.

The 'e' antigen test was previously used as a marker for infectivity with the belief that when the immune system had produced antibodies to this antigen and the antigen had disappeared the person had achieved immunity. This is true for many people and can be a way of assessing if treatment has worked and made someone immune.

However there is a mutation of the hepatitis B virus that means it does not produce the e antigen at all in which case tests for it are inevitably negative despite on-going infection. In people with this mutant form no 'e' antibody will be produced either. As anti-bodies may later be lost by a person anyway, someone who tests negative on both 'e' antigen and antibody has either recovered and developed natural immunity from the usual HBV infection or has the mutant form and is suffering chronic HBV.

This means that anti-HBV testing does not work in all cases but is still useful for many in staging the infection and determining resolution of infection.

Signs of active liver disease

The standard liver function tests mentioned at the start of the chapter are also used to help define whether the person has liver damage.

Genotypes of HBV

Different types of the same virus are known as genotypes. Six different genotypes have been identified for HBV and are labelled alphabetically A-G. The test to define an individual's genotype is rarely done for hepatitis B and usually only for research purposes because the results currently have no impact on treatment recommendations. The different genotypes probably affect how likely the disease is to become chronic, how aggressive it is and how it responds to treatment but more research is needed before specific recommendations can be made.

Genotypes A and D are prevalent in Europe and the USA while genotype E seems to be restricted to Africa and F is prevalent in Central and South America.Genotypes B and C are common in East Asia. Genotype G was found in both France and the US. The mutant form of HBV that causes the virus not to produce the e antigen (HBeAg) may occur with each genotypes but is more thought to be more frequent in genotypes B and D than genotype A.

Treatment

The purpose of treatment will vary depending on a person's situation. It may be to improve the state of a person liver, reduce the level of circulating virus, production of antibodies to the e antigen or all three of these.

Acute HBV

Treatment in acute hepatitis B has not been shown to be effective.

The only qualification to this is the case of newborn babies to mothers with HIV and HBV. Although this may not be classically defined as 'acute infections' they run an increased risk of developing chronic infection. They should receive Hepatitis B Immunoglobulin at birth and have a course of the vaccine to try and avoid chronic infection (BHIVA 2004a).

Chronic HBV

There are a number of treatments for chronic HBV including interferon, lamivudine, emtricitabine, adefovir and tenofovir.

Some of these treatments are active against HIV as well. This complicates matters in HIV co-infection because if the person is not on anti-HIV therapy it is very important not to expose them to an anti-HIV drug on its own and provoke HIV to develop resistance to that drug as this will make treating HIV much harder. Hepatitis B can also develop resistance to some drugs and so a management strategy for both conditions together is vital. If a drug is active against one virus but resisted by the second virus removing the drug is probably a bad idea and the rest of the treatment should be changed to take account of this.

An individual's circumstances will impact on the choice of therapy but generally people not taking any HIV medication should avoid the drugs that have an effect on HIV. People already on HIV combination therapy should try and ensure this combination includes drugs that are active against HBV as well or add them to a successful anti-HIV combination.

Interferon is a sub-cutanaeous injection and the classical form of it is called alpha-interferon and taken for 4-6 months. There is no recommended dose for the UK but the US propose five million units daily or ten million three times per week for at least 16 weeks (Lok 2001) while European guidelines merely note that treatment is more effective at higher doses (EASL 2003). Its use is likely to be superseded by the use of pegylated interferon which is a longer lasting form of interferon and only needs to be injected once a week. Results from the use of alpha-interferon are poor, successful in less than a third of the people who take it, regardless of which marker of treatment success is used and it produces many uncomfortable side-effects. It also tends to reduce the level of a persons CD4 cells which may make it a less attractive option for someone who is not taking HIV treatment. HBV does not seem to develop resistance against interferon.

Lamivudine comes in tablet form. The dose for HBV is less than that required for HIV and so it should not be used at the lower dose in people not on HIV treatment as it is likely to lead to HIV resistance to lamivudine. If a person's HIV has already become resistant to lamivudine it may still be used against hepatitis B. Hepatitis B can develop it's own resistance to lamivudine. It should not be used alone in people not already on HIV therapy.

Emtricitabine is a new improved relative of lamivudine that also comes as a tablet. It seems to work for longer but is cross-resistant with lamivudine. This means that once HBV has become resistant to lamivudine it will also be resistant to emtricitabine and vice versa. They should not be used together. Emtricitabine is also effective against HIV and for this reason should not be used alone in people not already on HIV therapy.

Adefovir is a tablet that was tried as an anti-HIV drug but was not very successful. It does however work well against hepatitis B. At the level prescribed for HBV it has no effect on HIV and so can be given to people not on HIV combination therapy. It works against HBV that is resistant to lamivudine and, presumably, emtricitabine as well.

Tenofovir is a tablet taken once a day. It is also active against HIV and so should not be used alone in people who are not on anti-HIV therapy. It seems to be effective against HBV that is resistant to lamivudine.

Combination therapy

For HIV combining drugs to prevent viral resistance and ensure effective suppression of the virus has been very successful. It is very possible this approach will be used with HBV to overcome issues of resistance in the future.

Is there a vaccine?

Yes. Hepatitis B vaccination is safe and recommended in people with HIV, though appears most effective if administered when the CD4 count is above 500 (BHIVA 2004a). It is administered as 4 injections over a twelve month period. The course is four injections with three in the first two months and another after a year. The rapid course which has three injections in a month and another after a year has not been evaluated in people with HIV. The vaccine appears to be somewhat less effective in people with HIV with a higher proportion needing a booster dose or a repeat of the whole vaccination cycle in order to achieve full immunisation (Smith 2002). Protective antibodies produced after vaccination disappear over time and this seems to happen more quickly in people coinfected with HIV (Rey 2000). Annual checks to ensure the immune system maintains an effective level of protective anti-bodies are recommended (BHIVA 2004a).

HBV vaccination can be obtained through GPs, or if you do not wish to discuss aspects of your lifestyle which may put you at risk of HBV infection, you may obtain the vaccination through a GUM clinic or through a local drugs project. Nurses and health care workers should be offered the vaccination as part of routine occupational health procedures.

Epidemiology

The World Health Organization estimates that two billion people have been infected with HBV worldwide. More than 350 million are chronic carriers (WHO Global Health Situation Projection and Estimates, 2000).

In industrialised countries rates of infection are generally low, at less than 1%. In Western Europe prevalence rates are generally greater in the South than the North of the continent.

Multiple coinfections

Having HIV and HBV is bad enough but to contract hepatitis A as well will inevitably add more strain to the liver. Vaccination is the best option whenever possible to prevent this.