The Hepatitis B virus, first identified in the late 1960's, infects nearly 300 million people worldwide. Knowledge of the life cycle and immunology of this virus has led, in a relatively brief period of time, to the development of a vaccine to protect against hepatitis B viral infection, and to treatment which can eradicate this virus. The purpose of this short review is to provide a summary, in laymen's terms, of our understanding of this complex virus. This is only to serve as a reference for you and should not take the place of a full discussion of the disease with your doctor.
What is Viral Hepatitis?
A virus is a particle which is smaller than bacteria, and contains complex genetic information called DNA or RNA. This genetic material allows the virus to infect bacteria or living cells, set up the machinery to reproduce itself, leading to destruction of the cell in which it resides. To date, five viruses, labelled A through E, have been identified which appear to cause viral hepatitis. Viruses A and E can be contracted from contaminated water or food (by mouth), while viruses B, C and D are transmitted by direct injection into the bloodstream (through any method of injection under the skin). The term viral hepatitis describes any one of the illnesses caused by the five viruses mentioned, and consists of an infection of liver cells which leads to damage of the liver over days in some cases, but over many years in others. Thirty years ago, none of the hepatitis viruses had been identified. In the 1960's, transfusion-related viral hepatitis was extremely common, with 30% of patients receiving blood products becoming infected. By 1970, a blood test called the Australia antigen, was developed which appeared to identify those infected with one hepatitis virus which we now call hepatitis B. The investigator who discovered the Australia antigen, the protein which makes up the coat of the virus and which is now called the hepatitis B surface antigen (HBsAg), was awarded the Nobel prize. Our understanding of viral hepatitis has grown tremendously since the discovery of the Australia antigen. For example, not all transfusion-related hepatitis was found to be associated with the hepatitis B virus. For many years, these 'other' cases were called 'non-A, non-B' hepatitis, because no evidence of either hepatitis A or hepatitis B was found in blood samples from these patients. Recently, the main non-A, non-B virus has been identified, and is now termed hepatitis C. This is covered in a separate information sheet.
What is the Hepatitis B Virus?
The hepatitis B virus (HBV) is a DNA-containing virus which is capable of infecting human liver cells and other cells in the body, once it gains access to the blood stream. One of the most interesting features of the hepatitis B virus is that the virus itself does not damage the liver, the damage being caused by the individual's own immune system attacking the virus-infected cells. Since liver damage from the virus may be very little, many patients are called healthy carriers. This means that although they may transmit the disease to others, they have normal-appearing livers and normal liver function tests. While many individuals remain healthy for many years or a lifetime, others develop chronic hepatitis, cirrhosis, and occasionally liver cell cancer. These outcomes are linked to the virus and its effects, although it is unlikely that the virus directly causes cancer. Those patients who develop hepatitis (damage to liver cells with inflammation), do so on account of the body's normal inclination to attack the foreign proteins contained in viruses, and in the cells in which the viruses are found. This process, called the immune response, determines the pace and the severity of the liver cell injury in this condition, and will be described in more detail below.
Since the identification of the hepatitis B virus, several other viruses which are nearly identical, have been identified in Eastern woodchucks, ground squirrels and Peking ducks. The members of this virus family, termed the 'Hepadna' viruses, have similar life cycles to that observed in man and can serve as animal models, allowing further study of these unique disease-causing agents.
What is Hepatitis B Infection Like?
When most individuals become infected with the hepatitis B virus, they are not aware of the infection for several weeks, until they develop symptoms of acute hepatitis, such as nausea, fatigue and jaundice (yellowing of the eyes). The acute hepatitis phase may last for several weeks and occasionally leads to hospitalization, but acute hepatitis B resolves completely in 95% of those infected. Others who do not develop significant symptoms following exposure may not be aware of the infection. These individuals may also overcome the infection completely and develop immunity, but frequently become chronic carriers. The outcome of hepatitis B infection depends to a great extent on the status of the person's immune system at the time of exposure. Most chronic carriers or those with chronic hepatitis B are not aware of their on-going infection, although some have persistent fatigue.
Some terms you will need to know:
HBV the hepatitis B virus. An important DNA-containing disease-causing agent capable of infecting humans and chimpanzees. This virus is spread by needle-stick exposure and intimate contact, and infects as many as 20% of the population in certain areas of the world.
HBsAg hepatitis B surface antigen. A common test for the presence of the hepatitis B virus, which actually identifies a protein on the surface or coat of the virus. The hepatitis B virus characteristically programs the liver cells to produce many times more coat particles than whole viruses. Each milliliter (ml) of blood (1/5 of a teaspoon) contains as many as 100,000,000 viruses and 10,000,000,000 HBsAg particles.
Anti-HBs antibody to the hepatitis B surface antigen. This protein is produced in response to exposure to HBsAg and confers protective immunity on the host. It is found in patients who have recovered from acute hepatitis B, and in those immunized with the hepatitis B vaccine.
Anti-HBc antibody to the hepatitis B core antigen. This antibody is detected in all patients who have ever been exposed to the hepatitis B virus, but unlike anti-HBs, is not protective. Those who carry the hepatitis B virus are anti-HBc positive, as are those who have recovered from hepatitis B.
HBeAg hepatitis B e antigen. This protein is exported from liver cells when whole viruses are being made within the liver. It serves as a marker of active viral production, termed replication.
Anti-HBe antibody to the hepatitis B e antigen. This antibody appears as part of the immune response to the virus once replication of virus is no longer occurring in liver cells.
HBV DNA hepatitis B virus deoxyribonucleic acid. DNA represents the genetic code for production of the virus and its proteins. When active viral replication (production by liver cells), is occurring, HBV DNA can be measured in the blood. Blood samples containing HBV DNA are highly infectious.
AST, ALT Transaminases, aminotransferases, SGOT,SGPT. These two similar liver enzymes are called by a confusing array of names. They are basically two proteins which can be measured in the blood samples of all individuals regardless of the condition of their liver, which are contained within liver cells normally, but which are released into the blood stream in increased amounts with liver cell injury or death. Elevated transaminases signal the presence of hepatitis, and the quantity measured in the blood is a rough guide to the severity of infection or liver damage.
This is a confusing array of terms! The importance of each is that those which apply to hepatitis B specifically reflect the stage in the life cycle of the virus within its host. Each antibody is made by the immune system in the process of ridding the virus from the body, and protecting against future infection, but they also serve as markers or signposts for the physician and patient to understand what stage of the illness one is in.
How Does the Body Deal with the Virus?
The life cycle of virus infection in humans comprises four stages. As has already been emphasized, how one passes through these stages depends on the immune system and its response to the virus at the time of infection. For example, a newborn has an immature immune system and is more likely to mount an poor immune response to the virus. If this occurs, he or she becomes a carrier, the virus infection persists, the liver continues over a long period of time to serve as the virus factory, and the bloodstream contains large quantities of infectious virus. The following stages serve as a rough approximation of how the virus cycle take place. By knowing the results of blood tests related to the virus, such as the HBeAg test, one can predict which stage the virus (and therefore the disease) is in, and whether treatment will be helpful or appropriate.
Stage 1: Shortly after infection, the virus enters the liver and spreads to many liver cells, and viral replication begins. During this stage, there is no active immune response, either because it is too early (most immune reactions take at least a week or two to develop), or because the immune system is inadequate to the task (example, the newborn baby). Active viral replication occurs, but there is no acute hepatitis, since the virus does not hurt liver cells. The signature in the blood tests is that the HBsAg and HBeAg will both be detected, HBV DNA and anti-HBc will usually be present, but there will be no elevation in the liver enzymes (AST or ALT).
Stage 2: At some point, the body's immune system becomes capable of recognizing the virus proteins appearing on the liver cell surface as foreign and an immune attack begins against the infected cells bearing the evidence of their infection. At this point, the immune cells attack the virus-infected liver cells, the transaminases become elevated and hepatitis symptoms begin. Typical blood results would include all of those in stage 1, plus elevated transaminases.
Stage 3: When the immune attack successfully rids the liver of all infected cells, viral replication (production) ceases and the hepatitis is over. At this point, the transaminases return to normal, HBeAg and HBV DNA are no longer detectable, and anti-HBe first appears. Once the disease becomes quiescent, there is little risk of infection, since little, if any, remaining whole virus is present in the blood. The peculiar feature is that the liver cells maintain the capacity to produce HBsAg, often for many months or even years. As a result, the HBsAg test will continue to be positive since this excess coat material continues to be produced by the liver, even in the absence of the virus itself. Most patients during this period will feel fine, since the hepatitis has resolved.
Stage 4: At a later time, HBsAg is finally cleared from the blood and anti-HBs appears for the first time. This antibody is protective and confers immunity from subsequent exposure to the virus (the infection cannot get started).
The complete life cycle of HBV may take only a few weeks, or it may take a lifetime to evolve. This depends on the competency of the immune system to deal promptly and completely with the virus. Patients often remain in a given stage for years. Nevertheless, particularly for those with active liver disease, gradual evolution to the later stages continues.
How Infectious is the Hepatitis B Virus?
Very. Hepatitis B virus is easily spread by any method in which bodily fluids (which all contain some quantity of virus), come into contact with the blood stream of another individual. As mentioned the quantity of virus in the bloodstream is very high, much higher than that observed for hepatitis C or the human immunodeficiency virus (HIV). At present, blood transfusions are a very rare method of HBV transmission, since all blood products are screened by very good tests for HBsAg and for anti-HBc. However, those who share needles for the purpose of intravenous drug use, tattoos or even ear piercing, those who are inadvertently stuck by contaminated needles such as hospital personnel, or those who have sexual contact with a hepatitis B virus-infected individual (an HBV carrier), may become infected. Casual contact such as shaking hands, hugging, sitting at the same table or even drinking from the same cup are rarely a problem. Nevertheless, family members such as children of carriers often show evidence of exposure after many years, presumably because of inapparent exposures such as sharing toothbrushes or razors of the infected individual. Needless to say, one cannot become infected from donating blood, getting blood drawn for testing or by receiving the hepatitis vaccine or immune globulin.
What Can I Do to Protect Myself?
The hepatitis B vaccine is safe and effective in protecting those who have not been exposed to the virus previously. Hepatitis B vaccine is now part of the routine childhood immunizations recommended by the Center for Communicable Diseases and the American Academy of Pediatrics. If you are exposed in any situation to others' bodily fluids, blood or blood products in any form, you are 'at risk' and should be vaccinated. The list of 'at risk' professions is long but includes health care workers, mortuary workers, intravenous drug users, prostitutes, and EMS technicians, to name a few. Spouses or sexual contacts of hepatitis B carriers or those with acute or chronic hepatitis B need urgent evaluation and consideration of vaccination and/or passive immunization with antibody to hepatitis B called hepatitis B immune globulin (HBIG).
If you become aware of contact with a hepatitis B carrier, consult your doctor. In general, there is plenty of time to be tested for the presence of the virus and to check your immune status before committing to a course of vaccination. If a bona fide exposure is documented and you are not immune, then hepatitis B immune globulin (HBIG) may also be recommended. This product is safe and provides immediate protection, whereas the protection afforded by vaccination is slower to develop. However, HBIG is costly and should not be used following a casual contact with a carrier, or a needle stick from an individual who is not a carrier. This topic is quite complex and requires a doctor's consultation. You should not make important decisions or take risks concerning your health without this consultation.
What Treatment is Available if I Suffer From Hepatitis B?
Until recently, no treatment was available for patients with viral hepatitis. Over the last seven years, interferons, which are naturally occurring proteins produced by white blood cells, have been used because of their anti-viral and immune system-stimulating properties. In addition, drugs called nucleoside analogues are also being tested and one has been approved by the US Food and Drug Administration.
Interferon Treatment
The effects of interferons in hepatitis B are different from those observed in hepatitis C, presumably because the viruses are entirely different in their life cycles and genetic content. Our understanding of the role of interferon in helping to resolve hepatitis B has been developed, in part, from the experience with interferon treatment. The most commonly used interferon is called interferon alfa 2b, a genetically engineered product which closely resembles naturally occurring alpha interferons. This product, manufactured by Schering Laboratories as Intron-A, has recently been approved for the treatment of chronic hepatitis B. Only certain categories of patients will benefit from this treatment, and many carriers will not have any appreciable effect or do not need to be treated. Therefore, it is important to understand which patients might benefit, and why. Interferon alfa appears to decrease viral production within the liver, and to increase the immune response against affected liver cells. It is necessary, however, for there to be active viral replication and a partially active immune system before treatment can be effective. For example, most patients in stage 1 will have no response to interferon, since the immune system appears to be inactive, and those in stage 2 who have nearly normal liver enzyme values indicating only a minimal immune response, will similarly have little benefit.
The 'purpose' of the interferon is to rid the liver of the remaining infected cells. Treatment with interferon usually is by self-injection either three times a week or daily, and continues for 16 weeks. During the course of interferon treatment, if the treatment is to be effective, the liver enzyme levels will increase as evidence that more liver cells are being damaged in the process of wiping out the infection. Accordingly, many patients who did not have symptoms of hepatitis may develop them, and may even become jaundiced. If no increase in liver enzyme levels occur, then the disease seldom resolves. In selected patients, the rate of clearance of HBV following a course of interferon therapy is at least 40%. When resolution takes place, the levels of AST and ALT return rapidly to normal, and HBV DNA and HBeAg disappear, as evidence that viral replication no longer occurs. In the process, the hepatitis has evolved from stage 2 to stage 3, in which HBsAg may still be detected, but the hepatitis has become inactive. Thereafter, HBsAg may also disappear at a later date. The patient who is already in stage 3 or 4 does not need treatment since the virus is already eradicated. The continued production of virus has been halted and the liver injury stopped as well. Once this improved situation appears, it is usually well-maintained, with only a small percentage of patients ever sliding back to an earlier stage. With clearance of the virus from the liver, anti-HBe, the antibody to the 'e' antigen appears, and later, when the HBsAg disappears from serum, antibody to the surface antigen appears, and the patient is immune from further attack from the virus.
Nucleoside Analogue Treatments
The only other accepted form of treatment for hepatitis B is the use of nucleoside analogues. These are drugs which can be taken orally to interfere with the virus' ability to multiply in the liver cell. Two new agents, lamivudine and famciclovir, have been used in large U.S. trials for treatment of hepatitis B as single agents, or in combination with interferon. Although famciclovir is effective for treatment of herpes infections, it has not proven useful for hepatitis B and is not approved for that use. Lamivudine (brand name Epivir-HBV) was FDA approved in December 1998. It slows viral division and thereby decreases the quantity of virus in the blood stream by 1000 times in most individuals. It appears to be safe and well-tolerated. It does seem to decrease the amount of inflammation and liver damage over time in those who continue to take it. However, when the drug is discontinued, more than 80% of patients will return to their previous state, although a small number will appear to have gone on the next stage, as with interferon treatment. For the time that the patient continues to take the medication, it remains effective in reducing the HBV DNA quantity in the blood stream. However, it also may lose its effect in some patients due to the development of drug resistance. The new slightly changed virus, sometimes called the YMDD mutant, can resist the effect of the drug and begin to multiply more quickly again, but it typically never comes back as much as it had originally, so the drug remains at least partially effective. Patients who are taking lamivudine and develop the mutation should continue the drug and seek consultation regarding possibly adding on a second agent. One example of a second drug, adefovir, has been used in combination with lamivudine for those individuals who have developed the drug resistant mutant virus. It is now FDA approved and has shown very good results with little side effects. Other nucleoside analogues, including emtricitabine and entecavir, are also being tested for previously untreated patients and compared to lamivudine. We now are also looking at the value of entecavir for lamivudine resistant patients and for those with the HBeAg negative mutation. The virtue of the oral nucleoside analogues is their ease of administration and lack of side effects. The down side is the development of mutations and the likelihood that treatment needs to be continued indefinitely, since the drugs are mainly suppressive and do not directly eradicate the virus.
Summary
Hepatitis B virus is a unique virus which currently can be found in nearly three hundred million people worldwide. Although there are many things about this virus that remain a mystery, the life cycle of the virus in humans is quite well understood. HBV appears in many forms and causes a variable amount of disease from individual to individual. Many patients after years of infection develop cirrhosis with all its complications, but this is not the case for everyone. Interferon therapy offers the opportunity to arrest the disease if it is still in the active phase of infection. Lamivudine is effective in decreasing but seldom eradicating hepatitis B virus. New treatment are on the horizon and the Liver Center is involved in the conduct of many of these research studies. If you are infected with this virus, it is wise to understand your disease, since treatment options ultimately depend on your consent. Vaccination for hepatitis B is available and is recommended for all children and any adults who have any concern about hepatitis risk. Once again, this brief overview is to help you understand a complex virus and the unique way it interacts with the liver and the rest of your body. Your best bet is still consultation with your own doctor.
