Hepatitis - What is viral hepatitis?

Hepatitis

What is viral hepatitis

Hepatitis means inflammation of the liver. Many illnesses and conditions can cause inflammation of the liver, for example, drugs, alcohol, chemicals, and autoimmune diseases. Many viruses, for example, the virus of mononucleosis and the cytomegalovirus can inflame the liver. Most viruses, however, do not primarily attack the liver; the liver is just one of several organs that the viruses affect. When doctors speak of viral hepatitis, they usually are referring to hepatitis caused by a few specific viruses that primarily attack the liver. There are several hepatitis viruses; they have been named types A, B, C, D, E, F (not confirmed), and G. As our knowledge of hepatitis viruses grows, it is likely that this alphabetical list will become longer. The most common hepatitis viruses are types A, B, and C. The liver is located in the upper right hand side of the abdomen, mostly behind the rib cage. The liver of an adult normally weighs close to three pounds. The liver performs the following vital functions:

The liver helps purify the blood by changing harmful chemicals into harmless ones. The source of these chemicals can be external, such as medications or alcohol, or internal, such as ammonia or bilirubin. Typically, these harmful chemicals are broken down into smaller chemicals or attached to other chemicals that then are eliminated from the body in the urine or stool.

2. The liver produces many important substances, especially proteins that are necessary for good health. For example, it produces albumin, the protein building block of the body, as well as the proteins that cause blood to clot properly.

3. The liver stores many sugars, fats and vitamins until they are needed elsewhere in the body.

4. The liver builds smaller chemicals into larger, more complicated chemicals that are needed elsewhere in the body. An example of this type of function is the manufacture of cholesterol.

When the liver is inflamed, it does not perform these functions well, which brings about many of the symptoms, signs, and problems associated with hepatitis

What are the common types of viral hepatitis?

Hepatitis A

Viral hepatitis A (HAV) accounts for about 150,000 of the 500,000-600,000 new cases of viral hepatitis that occur each year in the United States. The hepatitis caused by HAV is an acute illness (acute viral hepatitis) that never becomes chronic. At one time, hepatitis A was referred to as 'infectious hepatitis' because it could be spread from person to person like other viral infections. Infection with hepatitis A virus can be spread through the ingestion of food or water, especially where unsanitary conditions allow water or food to become contaminated by human waste containing hepatitis A (the fecal-oral mode of transmission). Hepatitis A typically is spread among household members and close contacts through the passage of oral secretions (intimate kissing) or stool (poor hand washing). It also is common to have infection spread to customers in restaurants and among children and workers in day care centers if hand washing and sanitary precautions are not observed

Hepatitis B

There are 200,000-300,000 new cases of viral hepatitis B (HBV) infection each year in the United States. Type B hepatitis was at one time referred to as 'serum hepatitis,' because it was thought that the only way hepatitis B virus (HBV) could spread was through blood or serum (the liquid portion of blood) containing the virus. It is now known that hepatitis B can spread by sexual contact, the transfer of blood or serum through shared needles in drug abusers, accidental needle sticks with needles contaminated with infected blood, blood transfusions, hemodialysis, and by infected mothers to their newborns. The infection also can be spread by tattooing, body piercing, and sharing razors and toothbrushes (if there is contamination with infected blood). About 6-10% of patients with hepatitis B develop chronic HBV infection (infection lasting at least six months and often years to decades) and can infect others as long as they remain infected. Patients with chronic hepatitis B infection also are at risk of developing cirrhosis, liver failure and liver cancer. It is estimated that there are 1.2 million people in the United States and 200-300 million people world-wide who suffer with chronic hepatitis B infection.

Hepatitis C

There are about 150,000 new cases of hepatitis C each year. Type C hepatitis was previously referred to as 'non-A, non-B hepatitis,' because the causative virus had not been identified, but it was known to be neither hepatitis A nor hepatitis B. The hepatitis C virus (HCV) usually is spread by shared needles among drug abusers, blood transfusion, hemodialysis, and needle sticks. Approximately 90% of transfusion-associated hepatitis is caused by hepatitis C. Transmission of the virus by sexual contact has been reported, but is considered rare. An estimated 50-70% of patients with acute hepatitis C infection develop chronic HCV infection. Patients with chronic hepatitis C infection can continue to infect others. Patients with chronic hepatitis C infection are at risk for developing cirrhosis, liver failure, and liver cancer. It is estimated that there are about 3.5 million people with chronic hepatitis C infection in the United States.

What is the scope of the hepatitis C problem?

The hepatitis C virus (HCV) is one of the most significant health problems affecting the liver. More than 4 million Americans (1.3% of the U.S. population) and 170 million individuals in the world (3% worldwide) are infected with hepatitis C virus. The prevalence (number of cases in a population at a specific time) of hepatitis C virus infections varies in different parts of the world. For example, the prevalence of hepatitis C virus in Scandinavia is less than 0.5% of the population, whereas the prevalence in Egypt is over 20%. In the U.S. and Western Europe, the complications of hepatitis C virus chronic hepatitis and cirrhosis are the most common reasons for liver transplantation.

One of the major problems with hepatitis C virus infections is that 85% of individuals initially infected with this virus will become chronically infected, usually for decades. The other 15% of hepatitis C virus infected individuals simply have an acute infection; that is, one that resolves spontaneously in a few weeks or months. The propensity of hepatitis C virus to cause chronic infection is explained by the extraordinary ability of this virus (in contrast to most other viruses, including hepatitis A) to avoid destruction by the body's immune defense system. (The immune system includes antibodies and specialized white blood cells, called lymphocytes).

Once established, chronic hepatitis C virus infection causes an inflammation of the liver called chronic hepatitis. This condition can progress to scarring of the liver, called fibrosis, or more advanced scarring, called cirrhosis. Some patients with cirrhosis will go on to develop liver failure or the complications of cirrhosis, including liver cancer.

In the U.S., the number of new cases of hepatitis C has declined over the last 10 years from a peak of some 200,000 annually to about 28,000 in 1999. This striking reduction is the result of a drop in the number of cases of acute hepatitis C among intravenous drug users. Perhaps this decrease among the drug users is due to changes in their practices brought on by their awareness of HIV infection. Furthermore, sensitive blood tests for the detection of hepatitis C virus became available to screen the blood supply and individuals at high risk for hepatitis C virus. Indeed, with blood being routinely screened for hepatitis C virus, the risk of a single unit of blood transmitting hepatitis C today is less than 1 in 100,000. Still, because of the many individuals who became infected 10 to 20 years ago, the number of deaths (or the need for liver transplantation) due to the complications of chronic hepatitis C virus liver disease is expected to triple within the next decade or two. On the other hand, in recent years, our understanding of the hepatitis C virus and its management

What is the nature (biology) of the hepatitis C virus (HCV)?

Hepatitis C virus is one of several viruses that can cause hepatitis, which is inflammation of the liver. It is unrelated to the other common hepatitis viruses (A, B, D, and E). Hepatitis C virus is a member of the Flaviviridae family of viruses. Other members of this family of viruses include those that cause yellow fever and dengue.

Viruses belonging to this family all have ribonucleic acid (RNA) as their genetic material. They are, therefore, referred to as RNA viruses. The RNA of hepatitis C virus is made up of almost 10,000 units called nucleotides that are organized to serve as the virus's genetic blue print for the manufacture of proteins. Thus, the virus contains structural proteins to build its structure, including its coat (envelope), and non-structural proteins (e.g., the enzyme polymerase) to carry out its functions. Understanding the nature (biology) of hepatitis C virus allows scientists to develop therapy that specifically targets the virus's structure or functions.

There are considerable differences in the genetic structure of hepatitis C virus. Accordingly, hepatitis C virus is categorized into six major genetic types (genotypes) and many more subtypes, based on the sequence (order) of nucleotides in the virus. Although the different genotypes are found throughout the world, there is a distinct distribution of genotypes in certain geographic regions. For instance, the most common genotype in the U.S. is genotype 1 (1a and 1b), which accounts for 80% of hepatitis C virus cases in the U.S.

The influence of genotype on the long-term prognosis of hepatitis C virus disease is still unclear. However, what is clear is that patients infected with genotypes 2 or 3 are much more likely to respond to interferon therapy. In contrast, patients infected with genotype 1 (particularly 1b) or genotype 4 do not respond very well to interferon therapy.

In addition, within a single host, there are minor genetic differences in the hepatitis C virus. These minor differences give rise to what are called quasispecies (quasi means resembling each other). Where do the quasispecies come from? Well, one of the non-structural hepatitis C virus proteins mentioned above is the enzyme polymerase. This enzyme is the machine that allows the virus to reproduce its genetic material (RNA) in order to multiply. Now, this RNA polymerase is very prone to making mistakes, resulting in changes (mutations) in the genetic material. The majority of these mutations result in a non-viable (not living) new quasispecies of hepatitis C virus, but sometimes the mutation results in viable quasispecies. With time, the accumulation of these viable mutations results in multiple quasispecies of the virus within the same host.

Why are there so many different varieties of hepatitis C virus anyway? Perhaps the different varieties confer an advantage to the survival of this virus over the years. For example, some of the new species may become more efficient in reproducing themselves (replication). By the same token, however, the genetic variability of hepatitis C virus has made the development of a protective vaccine against all of these genotypes and quasispecies a near impossible task with our present technology. Moreover, this variability probably also explains how this virus results in such a high rate of chronic infection. Thus, the genetic variability may enable the hepatitis C virus to avoid destruction by the host's cellular immune cells or antibodies, and so maintain (perpetuate) the chronic infection.

How does liver damage occur in hepatitis C infection? The basis (mechanism) of liver damage in chronic hepatitis C virus infection is not very well understood. The virus itself probably does not cause liver cell damage directly. Indeed, the level of the virus in the blood does not correlate with the actual liver damage seen on the liver biopsy. Liver damage in chronic hepatitis C virus is probably caused by the interplay between the virus and the body's immune system, which includes cytotoxic (injurious to cells) lymphocytes and specific inflammatory messengers (cytokines).

How is hepatitis C virus spread and how can transmission be prevented? Hepatitis C is spread (transmitted) most efficiently through the blood. Therefore, hepatitis C virus is transmitted by infected blood or blood products, transplantation of infected solid organs (e.g., liver, kidney, heart), and the sharing of contaminated needles among intravenous drug users. In retrospect, hepatitis C virus was the most common cause of hepatitis that resulted from blood transfusions in the 1980's. At that time, hepatitis C virus had not yet been identified and post-transfusion cases of hepatitis were called non-A non-B hepatitis.

In the early 1980's, the risk of contracting hepatitis C virus from a blood transfusion was as high as 15%. In the mid 1980's, when the practice of using commercial (paid) donors was stopped and blood was screened for the human immunodeficiency virus (HIV), the risk of post-transfusion hepatitis fell to about 5%. This risk was then cut in half when blood was screened with the substitute (surrogate) markers, elevated alanine aminotransferase (ALT, the liver enzyme), and hepatitis B core antibodies. Finally, the isolation of the hepatitis C virus and the development of a screening test for hepatitis C virus dramatically lowered the risk of acquiring hepatitis C virus infection through blood transfusions.

All blood donors are currently screened with the following panel; hepatitis C antibodies, hepatitis B surface antigen, hepatitis B core antibodies, elevated alanine aminotransferase, HIV antibodies, and syphilis. As a result, the risk of contracting hepatitis C virus from a single unit of blood is less than 1:100,000. This risk will be even lower one day when tests that measure minute quantities of hepatitis C viral nucleic acids are universally adopted for blood screening.

Today, hepatitis C virus is most commonly transmitted by intravenous drug abuse, which accounts for about 60% of new cases. Moreover, 50 to 60% of new intravenous drug users are infected within the first 6 months of use, and nearly 90% are infected by one year. Other types of illegal drug usage, such as snorting cocaine, have also been associated with an increased risk of acquiring an hepatitis C virus infection.

Hepatitis C virus can be sexually transmitted, but not very efficiently. Hepatitis C virus has been isolated in the semen, vaginal fluid, and saliva. Nevertheless, the risk of transmission of hepatitis C virus from an infected individual to a non-infected spouse or partner without the use of condoms over a lifetime is only about 1 to 4%. The Centers for Disease Control (CDC) and Prevention has not recommended using a barrier technique (for example, condoms) for hepatitis C virus infected individuals in a long-term monogamous relationship. On the other hand, individuals with multiple sexual partners should definitely use condoms. Furthermore, the practice of safe sex is key in preventing the transmission of other sexually transmitted diseases, such as HIV and hepatitis B.

Food, water, breast-feeding, sneezing, coughing, hugging, casual contact, or sharing eating utensils or drinking glasses have not been shown to spread hepatitis C. What's more, hepatitis C is not transmissible by kissing, unless an open wound is involved. However, to further recognize that hepatitis C is transmitted through blood, the sharing of razors and toothbrushes should be avoided.

Interestingly, the CDC has not found a definite association between tattoos and the transmission of hepatitis C virus. It is critical, nevertheless, that appropriate precautions be taken in applying tattoos, including the artist wearing gloves and using disposable equipment. In contrast to hepatitis B, the transmission of hepatitis C from the mother to the newborn around the time of delivery is unusual.

Hepatitis C virus infection can also be acquired through occupational exposures. Thus, health care workers in contact with contaminated bloods, fluids, and needles are at an increased risk for hepatitis C virus. The risk of acquiring hepatitis C virus from a needle stick involving an individual who has detectable virus in the blood is as high as 5% and about 2% on the average. The risk is higher if a hollow bore needle makes the needle stick since the potential for a greater amount of blood is higher with this type of needle. In the medical setting, patients receiving hemodialysis and medical providers in renal dialysis units have a higher frequency of hepatitis C virus infection than people in the general population.

What else can be done to prevent hepatitis C? Immune serum globulin, given after an exposure to hepatitis C virus, would not be expected to protect a susceptible individual from acquiring an hepatitis C virus infection. Moreover, no vaccine is currently available for hepatitis C virus. It should be noted, however, that hepatitis A and B vaccinations are recommended for patients who have hepatitis C virus liver disease. As already mentioned, intravenous drug abuse remains the most common mode of transmission of hepatitis C. Ideally, users should stop using drugs and enter a rehabilitation program. However, active users of drugs should not reuse or share needles, syringes, water, and other materials.

What are the symptoms of hepatitis C infection? At the beginning of an hepatitis C virus infection, only about 25% of patients exhibit the characteristic symptoms of acute (rapid onset) hepatitis. These symptoms include fatigue, muscular aches, poor appetite, and low-grade fever. Rarely, yellowing of the skin and/or eyes (jaundice) also occurs. However, most patients (about 75%) experience minimal or no symptoms at the onset of hepatitis C virus.

As the hepatitis becomes chronic, most individuals remain asymptomatic (without symptoms). Indeed, many persons with chronic hepatitis C are diagnosed while undergoing routine blood work for unrelated purposes. Infected individuals may exhibit no symptoms despite progressive liver inflammation, necrosis (death of liver cells), and fibrosis (scarring). Other patients may experience chronic or intermittent fatigue and a diminished sense of well-being as a result of advancing disease. On the other hand, fatigue has been described in some individuals with relatively mild disease.

With the subsequent development of cirrhosis of the liver (more advanced scarring), hepatitis C virus patients can have muscle wasting, generalized weakness, and easy bruising. Later symptoms, which are due to the complications of cirrhosis, include fluid retention, which leads to edema (swelling of the lower extremities) or ascites (fluid in the abdominal cavity), internal bleeding (usually from dilated esophageal veins called varices), and mental confusion or sleepiness (due to hepatic encephalopathy). Another complication of hepatitis C virus cirrhosis is cancer of the liver (hepatocellular carcinoma or hepatoma), which can cause abdominal pain, weight loss, and fever

What conditions outside the liver are associated with hepatitis C?
Several extra-hepatic (outside of the liver) conditions are associated with chronic hepatitis C. These conditions are not very common and their occurrence does not correlate with the severity of the underlying liver disease. The most widely described associated condition is cryoglobulinemia. This condition is due to the presence of abnormal antibodies (called cryoglobulins) that come from hepatitis C virus stimulation of lymphocytes (white blood cells). These antibodies can deposit in small blood vessels, thereby causing inflammation of the vessels (vasculitis) in tissues throughout the body. For example, the skin, joints, and kidneys (glomerulonephritis) may be involved.

Patients with cryoglobulinemia can have quite a variety of symptoms. These symptoms may include weakness, joint pain or swelling (arthralgia or arthritis), a raised, purple skin rash (palpable purpura) usually in the lower portion of the legs, swelling of the legs and feet due to loss of protein in the urine from the kidney involvement, and nerve pain (neuropathy). In addition, these patients may develop Raynaud's phenomenon, in which the fingers and toes turn color (white, then purple, then red) and become painful in cold temperatures.

The diagnosis of cryoglobulinemia is made by doing a special test in the laboratory to detect the cryoglobulins in the blood. In this test, the cryoglobulins are identified when the blood sample is exposed to the cold (cryo means cold). In addition, a finding of typical inflammation of small blood vessels in certain tissue biopsies (e.g., the skin or kidney) supports the diagnosis of cryoglobulinemia. All of the symptoms of cryoglobulinemia often resolve with successful treatment of the hepatitis C virus infection.

B-cell non-Hodgkin's lymphoma, a cancer of the lymph tissue, has also been associated with chronic hepatitis C virus. The cause is thought to be the excessive stimulation by the hepatitis C virus of B-lymphocytes, which results in the abnormal reproduction of the lymphocytes. Interestingly, the disappearance (remission) of an hepatitis C virus-associated low-grade (not very active) non-Hodgkin's lymphoma has been reported with interferon therapy. Most individuals with hepatitis C virus-associated high-grade non-Hodgkin's lymphoma, however, will require the usual anti-cancer therapies.

Two skin conditions, lichen planus and porphyria cutanea tarda, have been associated with chronic hepatitis C virus. It is important to know that both of these skin conditions can resolve with successful interferon therapy for the hepatitis C virus. In addition, up to 25% of hepatitis C virus patients have autoimmune antibodies (against one's own proteins), such as anti-nuclear antibody, anti-smooth muscle antibodies, and rheumatoid factor.

What is the usual progression of chronic infection with hepatitis C virus?
Our understanding of the natural progression (history) of hepatitis C infection is still evolving. About 15% of patients with acute hepatitis C virus infection spontaneously recover (clear the virus). Eighty five percent, however, develop chronic liver disease. How many of these patients progress to cirrhosis of the liver? Is there a way to predict who will develop cirrhosis? And then, how many will develop liver failure, including the complications of cirrhosis, or liver cancer? Once a person has cirrhosis, how long is he/she expected to live? These are very pertinent questions for which there are no clear-cut answers, only reasonable estimates.

There are several ways to examine the natural history of chronic hepatitis C infection; retrospective (looking back in time), prospective (looking forward), or combined retrospective/prospective studies. A retrospective study involves identifying patients with established chronic hepatitis C infection and correlating their current stage of liver disease to the duration of their infection. Several such investigations have suggested that after acquiring hepatitis C virus, it takes about 10 to14 years for biopsy evidence of chronic hepatitis to appear, about 20 years to develop cirrhosis, and about 28 years to develop liver cancer.

There are problems with retrospective studies, however. For example, retrospective studies are inclined (biased) to select chronic hepatitis C patients who have symptoms, which is the reason the patients sought medical attention. Accordingly, information about the actual duration of infection in these patients may be inaccurate, that is, underestimated. Furthermore, retrospective studies do not tell what proportion of patients with chronic hepatitis C virus will develop cirrhosis, liver failure, or HCC.

In a prospective study, an entire group of hepatitis C patients are followed from the time they first become infected. These studies have necessarily involved patients who received contaminated blood, since in these individuals, the time of acquisition of hepatitis C virus can be accurately determined. However, the follow-up in most of these studies is relatively short. Furthermore, since some of these patients are being treated with antiviral therapy, the natural progression of the disease may be modified by the treatment. Anyway, these prospective studies suggest that about 10 to 25% of patients develop cirrhosis within a 10 to 15 year follow-up. Moreover, only about 10% of patients develop symptoms related to their liver disease.

Retrospective/prospective studies involve identifying a group of patients who were exposed to hepatitis C virus many years ago, accounting for almost all of these patients, and then following them prospectively. The advantage of these studies is that there is a head start to the follow-up as compared to a prospective study. These retrospective studies confirm that the natural progression of chronic hepatitis C virus is quite slow and in general, complications develop over decades, not years.

Again, these retrospective/prospective studies have involved patients who were exposed to contaminated blood or blood products (such as immunoglobulin). On average, these studies have looked at patients who were exposed over twenty years ago. In two studies involving women who acquired chronic hepatitis C virus after receiving contaminated immunoglobulin over 20 years ago, less than 3% of the patients developed cirrhosis. The vast majority of patients had only mild inflammation and no fibrosis (scarring) of the liver. About one third of patients had aminotransferase (liver enzyme) levels over 100 U/L (2 to 3 times normal) and one third had normal liver tests. However, one quarter of the patients reported fatigue.

According to these retrospective/prospective studies, once cirrhosis is established, the risk of developing liver failure, that is, the complications of cirrhosis, is about 10% per year. These complications include bleeding from varices (dilated veins, usually in the esophagus), ascites (fluid in the abdomen), encephalopathy (confusion), and jaundice. The risk of developing liver cancer in a cirrhotic patient with hepatitis C virus is 1.4% per year. However, patients who have cirrhosis without complications (compensated cirrhosis) have an 80% likelihood of surviving 10 years. On the other hand, patients who have cirrhosis with complications (referred to either as decompensated cirrhosis or liver failure) have a much lower likelihood of survival, less than 50% at 5 years.

It is unclear which factors promote the progression of chronic liver disease in hepatitis C virus infection. Earlier studies suggested that individuals infected with genotype 1b may develop more serious disease, but these findings could not be substantiated. Moreover, as previously mentioned, the level of virus in the blood does not correlate with disease severity. What is clear, however, is that the regular use of alcohol, even in moderation, is detrimental in hepatitis C virus chronic liver disease.

Who is at high risk and should be tested for hepatitis C infection? The Centers for Disease Control and Prevention recommend that certain people who are at high risk for hepatitis C infection should undergo testing for hepatitis C virus. These include individuals who:

       Have been notified that they received a blood transfusion from a donor who later tested positive for hepatitis C

       Injected illegal drugs, even if they experimented only a few times many years ago

       Received a blood transfusion or solid organ transplant before July, 1992

       Received a blood product for clotting problems that was produced before 1987

       Have ever been on long term kidney dialysis (filtering blood to treat kidney failure)

       Have evidence of liver disease (e.g., persistently abnormal ALT levels)

Guidelines for hepatitis C virus testing are less clear in certain other people who may also be at increased risk of acquiring hepatitis C virus. These include individuals who:

       Are recipients of transplanted tissue (e.g., cornea, skin, heart, kidney)

       Used intranasal cocaine and other non-injecting illegal drugs

       Have had tattoos and/or body piercing

       Have had multiple sex partners or a history of sexually transmitted disease*

       Are long term steady sex partners of an hepatitis C virus positive person*

*The National Institutes of Health Consensus Development Conference recommends that these persons be tested.

What are the diagnostic tests for hepatitis C virus and how are they used to diagnose hepatitis C virus infection? A number of diagnostic tests are currently available for hepatitis C virus. They are categorized below according to the function of the specific tests.What about screening tests?

Screening tests are done to determine the presence of antibodies to hepatitis C virus in the blood. The enzyme immunosorbent assay (EIA) is the conventional, initial screening test to diagnose hepatitis C infection. The EIA measures specific antibodies to small pieces of the hepatitis C virus proteins (antigens). This test, therefore, is referred to as the anti-hepatitis C virus antibody test. Patients who have elevated liver enzymes (ALT/AST) and/or any of the risk factors for hepatitis C virus can be diagnosed to have hepatitis C virus with a greater than 95% certainty when the EIA is positive.

On the other hand, certain patients whose immune systems are impaired (suppressed) may not have detectable anti-hepatitis C virus antibodies even if they are actually infected with hepatitis C virus. Such immunosuppressed patients include those who are on renal dialysis, suffer from cancer and are receiving chemotherapy (drugs to kill cancer cells), or have active HIV infection. These patients cannot produce enough anti-hepatitis C virus antibodies necessary to generate a positive EIA test.

When there is a low likelihood (risk) of hepatitis C infection, individuals who test positive for hepatitis C by EIA should undergo confirmatory testing using a specialized assay that likewise tests for antibodies against the hepatitis C virus proteins. This assay is called the Recombinant Immunoblot Assay (RIBA).

Both the EIA and RIBA tests, however, do not distinguish among acute, chronic, and resolved hepatitis C virus infections because the anti-hepatitis C virus antibodies are in the blood in all three of these situations. Although EIA and RIBA are tests that measure antibodies against hepatitis C virus, these antibodies do not confer protection to the patient against acquiring hepatitis C virus. Rather, they only indicate exposure of the patient to the virus.

What are molecular tests for hepatitis C virus?
As previously described, hepatitis C virus is an RNA virus. The code of the genetic material, hepatitis C virus RNA, is unique to this virus. Several types of tests (assays) are available to measure the hepatitis C virus RNA in a person's blood. These tests are referred to as molecular tests because they examine the virus at the molecular level. The two most common systems for measuring hepatitis C virus RNA are the reverse transcription polymerase chain reaction (RT-PCR) assay and the branched chain DNA (bDNA) assay. Recently, a third type of assay, called transcription-mediated amplification (TMA), has been released.

First of all, it is important to put in perspective the relative amount of virus in an individual infected with hepatitis C virus as compared to some other types of chronic viral infection. The average number of virus particles/milliliter of blood in an individual with chronic hepatitis C virus is hundreds of thousands to several million. In contrast, someone with active hepatitis B infection has several hundred million to billions of copies (virus particles) per milliliter of blood. The relatively low concentration of the hepatitis C virus in the blood is one of the reasons it took so long for scientists to characterize the hepatitis C virus.

RT-PCR is a very powerful tool for detecting relatively low amounts of genetic material (RNA or DNA). The basis of this technique is the amplification of a target piece of nucleic acid several million times so that this target becomes measurable. Due to the extreme sensitivity of this technique, however, the slightest contamination can lead to a false positive result. On the other hand, RNA is relatively unstable (degrades easily), so that blood and tissue samples need to be handled with special precautions. If not, this instability would lead to a false negative result, that is, a negative result in someone who has hepatitis C virus.

In the early 1990's, each laboratory had its own in-house technique for the RT-PCR assay and the reliability of these assays was quite variable. Even as of now, the FDA has not approved any of the RT-PCR assays. However, most laboratories currently use one of the several available diagnostic kits that are automated and designed to reduce the likelihood of contamination. There are two types of RT-PCR, qualitative and quantitative. Qualitative hepatitis C virus RT-PCR provides the greatest sensitivity, meaning that it can measure as few as 100 copies (viral particles) of hepatitis C virus/ml of serum. As the name implies, however, qualitative RT-PCR provides only a positive (presence of hepatitis C virus) or negative (absence of hepatitis C virus) result.

By contrast, quantitative RT-PCR measures the amount of virus. These tests, however, are only accurate within a certain range of viremia (circulating virus in the blood). This means that quantitative assays are not as sensitive as qualitative assays and can only detect as few as 500 copies/ml. Moreover, these assays are less accurate at extremely high viral levels (over 2 million copies/ml). In the past year, there has been an attempt to standardize these various quantitative assays so that the levels of virus that are measured by different assays can be compared. As a matter of fact, results of quantitative RT-PCR are now reported in standard International Units/ml (IU/ml).

Branched chain DNA (bDNA) is the other quantitative technique. It is based on the amplification of the detection signal rather than of the nucleic acid itself. As a result, this test is less prone to contamination and is more accurate when measuring higher levels of the virus as compared to RT-PCR. However, the bDNA assay is not as sensitive as the RT-PCR and is unable to measure levels of virus below 200,000 copies/ml.

Finally, transcription mediated amplification (TMA) is a qualitative technique that is distinct from PCR. This test can measure as few as 2 to 5 copies of virus/ml.

What is the role of the qualitative molecular tests?

Qualitative RT-PCR is a useful test in determining whether or not a patient has circulating virus in the blood (viremia). Hence, it can be used to confirm that a reactive (positive) anti-hepatitis C virus result reflects active hepatitis C virus infection. However, confirmatory testing is usually not necessary in someone who tested reactive (positive) for anti-hepatitis C virus and also has risk factors and abnormal liver tests. In this situation, the RT-PCR most certainly would be positive. On the other hand, an individual who is anti-hepatitis C virus reactive and has risk factors but normal liver tests should undergo confirmatory testing with RT-PCR. This person may have cleared the viral infection some time ago, leaving the anti-hepatitis C virus as a marker of past exposure.

Qualitative hepatitis C virus RNA testing should also be done in individuals who may have been recently exposed to hepatitis C. Hepatitis C virus RNA is more sensitive (that is, will detect more cases) than the conventional anti-hepatitis C virus (EIA) testing in this setting. The reason for this greater sensitivity is that it may take a person as many as six to eight weeks after exposure to hepatitis C virus to develop the antibodies, whereas hepatitis C virus RNA becomes detectable five to ten days after exposure. Finally, qualitative hepatitis C virus RNA testing may be helpful to assess the patient's virologic response at certain time points during antiviral therapy (see treatment of hepatitis C virus below).

How are the results of the hepatitis C virus tests interpreted?

The table provides guidelines for interpreting the results of testing for anti-hepatitis C virus by EIA and RIBA and for hepatitis C virus RNA by qualitative RT-PCR or TMA.

What is the role of quantitative hepatitis C virus RNA testing?

It should be noted that a single quantitative measurement of the level of hepatitis C virus in the blood (viral load) does not correlate with the severity of hepatitis C virus liver disease. Moreover, the viral load fluctuates in a given infected individual, although the variation is usually insignificant, that is, less than a log-fold (ten times) difference. So, there is no practical value in quantitatively measuring viral loads in patients who are not undergoing treatment.

Quantitative hepatitis C virus RNA measurements are pertinent, however, in patients who are being considered for antiviral therapy or who are being monitored during therapy. For example, patients with hepatitis C virus RNA initial levels of greater than 2 millioncopies/ml(>800,000IU/ml) are less likely to have a sustained response to conventional interferon alone or to combined interferon and ribavirin therapy. What is more, patients who experience less than a 100-fold (2-log) drop in the viral load after 12 weeks of pegylated interferon therapy are also unlikely to have a sustained response.

What tests identify the virus genotypes?

PCR assays of nucleic acids are available to determine the hepatitis C virus genotype. In some instances, the purpose of obtaining genotype information is to tailor the duration of antiviral therapy. Thus, patients with genotype 2 or 3 can be treated with a six-month course of Rebetron combination therapy (see treatment of hepatitis C virus below) instead of the conventional twelve-month course for patients infected with genotype 1. Furthermore, patients infected with genotype 2 or 3 are more likely to respond to interferon therapy than those with genotype 1. Thus, knowledge of the genotype may be useful in predicting the likelihood of a favorable response to interferon therapy.

What is the role of a liver biopsy in the management of chronic hepatitis C? A considerable amount of discussion has focused on the role of a liver biopsy in the management of patients with chronic hepatitis C. Many liver specialists feel that a biopsy should be part of the work-up of any individual with chronic hepatitis C infection. For one thing, patients may have significant underlying liver disease without having any symptoms or abnormal physical or laboratory findings. For another, the biopsy provides important information about the severity and, therefore, the outcome (prognosis) of the liver disease.

Some pathologists use the Knodell Histological Activity Index (HAI), which is a composite score that incorporates evaluations of four different features of the liver biopsy. With the HAI, a normal liver biopsy has a score of 0, whereas a biopsy showing cirrhosis with highly active inflammation receives a top score of 22. Most pathologists (specialists who study tissues), however, now use a newer system. This system reports the cause (etiology) of the hepatitis, the extent of scarring (fibrosis) on a scale from 0 (no fibrosis) to 4 (cirrhosis), and the amount of inflammation (lymphocytes causing liver cell damage) on a scale from 0 to 4.

A frequently cited study suggests that the initial biopsy can predict the likelihood of the patient progressing to cirrhosis within ten years. Not surprisingly, patients with moderate fibrosis and inflammation are much more likely to progress to cirrhosis than persons with no fibrosis and only minimal inflammation. Moreover, with respect to therapy, patients with cirrhosis are much less likely to respond to conventional interferon alone (monotherapy) than patients without cirrhosis. The information gained from the liver biopsy, therefore, can help the patient and doctor weigh the potential risks versus benefits of antiviral therapy.

On the other hand, there are other liver specialists who do not advocate the need for a liver biopsy, citing, among other reasons, the cost of the biopsy in relation to its benefit. A liver biopsy costs anywhere between $1500 and $2000. In view of this, many individuals who are otherwise suitable candidates for antiviral therapy may consider this treatment without having a liver biopsy.

Who should receive antiviral therapy for hepatitis C virus? Any individual with chronic hepatitis C infection is a potential candidate for antiviral therapy. However, given our understanding of the natural history of chronic hepatitis C virus infection and the effectiveness and side effects of current antiviral therapy, the NIH Consensus Development Conference recommends treatment for those patients who are at the greatest risk of developing cirrhosis. Such individuals have all of the following characteristics:

       Persistent ALT elevation

       Detectable hepatitis C virus RNA

       Evidence of fibrosis (scarring) on liver biopsy

       Evidence of at least moderate inflammation and liver cell injury (necrosis) on liver biopsy

It is less clear whether patients who meet some but not all of these criteria should be treated. Accordingly, the NIH consensus advocates that patients who do not fit into all of the recommended criteria be treated in the setting of research protocols. The consensus called for participation in the research protocols so that knowledge can be gained from the experience of treating these patients. Such patients include those:

       With persistently normal liver tests and mild inflammation on liver biopsy

       With compensated cirrhosis (no signs of liver failure, such as jaundice, ascites, encephalopathy, or bleeding)

       Below the age of 18 or over 65 years

       Who are co-infected with HIV

Patients with decompensated cirrhosis (signs of chronic liver failure) should be treated only in research settings. Moreover, they should be closely monitored, preferably at a facility with a liver transplant program.

Individuals who should not be treated with antiviral therapy include those who are actively using illicit drugs or alcohol, have major psychiatric depression, low blood counts, untreated thyroid gland disease, autoimmune disease, have other serious medical conditions (e.g., symptomatic heart disease, uncontrolled hypertension, or diabetes), are pregnant, or are recipients of solid organ (e.g., kidney) transplant.

Fundamentally, the decision regarding antiviral therapy in chronic hepatitis C patients should be tailored to the individual with careful consideration of the risks and benefits.

What are the different patterns of response to antiviral treatment?
In medical reports, patients who have never received antiviral therapy are called nave patients. Three patterns of response to antiviral treatment have been described, each based on the effect of the treatment on the virus: sustained response, relapse, and non-response.

The optimal response to antiviral therapy is called a sustained response. A sustained response is defined as the absence of detectable hepatitis C virus RNA using the RT-PCR or TMA assay 6 months after treatment is stopped. Most of these individuals will remain in remission (no signs of the disease) indefinitely, with no detectable hepatitis C virus RNA in the blood or liver. Moreover, follow-up biopsies will show a marked reduction in inflammation and regression of scarring (fibrosis). A longer follow-up of these patients is necessary, however, to evaluate whether sustained responders will avoid the complications of cirrhosis and live longer.

Relapsers are patients who seem to respond initially to treatment, that is, whose hepatitis C virus RNA becomes undetectable during therapy, but then becomes detectable shortly after discontinuing therapy. The virus becomes detectable again within six months and usually within the first three months of stopping treatment. This type of response to antiviral treatment is known as a relapse.

Finally, patients who have detectable hepatitis C virus RNA during therapy are known as non-responders. This type of response to antiviral treatment actually is called a non-response. In addition, other patients in whom the hepatitis C virus RNA becomes undetectable during the early period of treatment but reappears before the end of therapy, should probably likewise be considered non-responders. This reappearance of hepatitis C virus RNA during therapy is referred to as a break through because the hepatitis C virus RNA breaks through what initially appears to be successful (loss of hepatitis C virus RNA) treatment.

What are the goals of therapy for hepatitis C virus? The ultimate goals of antiviral therapy are to eliminate the viral infection, improve or normalize the liver tests and histology (microscopic appearance), prevent progression to cirrhosis and liver cancer, prolong survival, and improve the quality of life.

Currently, the only relevant measurement to assess the benefit of treatment is the virologic response to therapy as measured by RT-PCR or TMA. Moreover, as already indicated, only a sustained response provides the possibility of achieving the ultimate goals. As previously mentioned, a sustained response is defined as undetectable hepatitis C virus RNA 6 months after completing a course of antiviral therapy. Most patients who have an SR will remain in remission indefinitely.

Many non-responders (in terms of the virus) may have a biochemical response (for example, normalization of ALT), with or without relief of symptoms. But such a biochemical (and symptomatic) response is not sufficient to indicate or predict a favorable outcome as long as the hepatitis C virus RNA remains detectable. Yet, even in relapsers or non-responders, an improvement in liver injury and scarring can sometimes be seen after interferon treatment. Naturally, however, the improvement in these patients is not as substantial as that seen in the sustained responders. Indeed, only when the virus is eradicated can one really anticipate a favorable outcome.

What are the therapy options for previously untreated patients with chronic hepatitis C?
The treatment options for previously untreated patients with hepatitis C include conventional interferon (now outdated), combined conventional interferon and ribavirin, pegylated interferon, and combined pegylated interferon and ribavirin.

Conventional interferon alone (monotherapy)

In the past, the mainstay for treatment of chronic hepatitis C had been interferon-alpha. Interferons are a family of naturally occurring proteins that are produced by the body to fight viral infections. Interferon is administered as an injection under the skin, similar to the way insulin is given. As treatment with interferon has evolved, the sustained response rate has increased dramatically.

In fact, it is useful to review the evolution of interferon therapy. Until recently, three types of interferon-alpha had been approved by the FDA; interferon alpha-2b (Intron-A), interferon alpha -2a (Roferon), and consensus interferon alpha (Infergen). All of these forms appear to be equally effective and have similar side effects. The sustained response rate (SR) with 6 months of interferon-alpha was in the vicinity of only 8%. Extending the duration of treatment to 48 weeks improved the SR to 15%. Then, with the arrival of the molecular assays, several factors, such as the genotype of the virus, the amount of virus in the blood, the microscopic appearance of the liver tissue, and certain patient characteristics were identified as favorable predictors for a SR. These favorable characteristics were:

       Genotype 2 or 3

       Viral load of less than 2 million copies/ml

       Absence of cirrhosis

       Female gender

       Age less than 40 years

For example, individuals infected with genotype 2 were twice as likely to respond to conventional interferon therapy as patients infected with genotype 1. Accordingly, selecting patients with these characteristics for treatment with interferon further increased the SR.

Combined conventional interferon and ribavirin

The antiviral agent, ribavirin (Rebetol), is a nucleoside analogue that is taken by mouth. Nucleoside analogues are man-made molecules that closely resemble the biochemical units that make up genetic material (RNA and DNA). Ribavirin works, therefore, as an imposter to trick the viral genetic material and thereby slow down viral reproduction.

It turns out that ribavirin is not effective in treating hepatitis C when used alone, but is beneficial when combined with conventional interferon. The overall SR with combined interferon-alpha 2b and ribavirin (Rebetron) for 48 weeks was about 40%. However, the SR for patients infected with genotype 2 or 3 patients was about 60% as compared to an SR of about 30% for patients infected with genotype 1.

Patients infected with genotype 1, probably even those with low viral loads, benefited by being treated for 48 weeks rather than 24 weeks. On the other hand, patients infected with genotype 2 or 3, regardless of their viral loads, responded similarly whether they received 24 or 48 weeks of Rebetron therapy. Therefore, regardless of the viral load, patients with genotype 1 should receive 48 weeks and patients with genotype 2 or 3 should receive 24 weeks of Rebetron therapy.

The Rebetron combination is associated with significantly more side effects than conventional interferon alone. As a matter of fact, up 20% of patients receiving Rebetron required a reduction of dose or discontinuation of therapy because of the side effects. Nevertheless, this combination therapy represented significant progress in the treatment of chronic hepatitis C and became the standard of care against which future therapy was to be measured.

In previous trials using interferon alone, a detectable level of the virus after twelve weeks of treatment indicated that a patient would not respond even if the treatment was continued for a year. However, some patients, when treated with Rebetron combination, had detectable virus at 12 weeks of treatment but still went on to have a sustained response. Therefore, patients on combination therapy should have a qualitative hepatitis C virus RNA PCR measured at 24 weeks of therapy. Those who are positive for the virus at that time should stop treatment, since they have little chance of achieving an eventual sustained response.

Pegylated interferon monotherapy

Conventional interferon alpha is absorbed and cleared rapidly from the body by the kidneys. During the first 12 hours of interferon treatment, the drug causes the viral levels to decrease significantly because the virus is being destroyed by the interferon. After that, however, the viral levels begin to increase again due to the rapid clearance of the interferon. One way to keep the viral levels down is to slow down the clearance of interferon from the body.

A chemical process called pegylation of interferon (forming pegylated interferon) was found to slow the clearance of interferon. Pegylation is the attachment of polyethylene glycol (PEG) molecules to the interferon. When bound to interferon, PEG substantially increases the time over which the interferon can work in the body to destroy the virus.

There are currently two types of pegylated interferon; pegylated interferon alpha 2b (Peg-Intron A) and pegylated interferon alpha 2a (Pegasys). Both pegylated interferons are administered once per week and result in constant blood levels of interferon for 7 days. Thus, the availability of pegylated interferon will eliminate the need for daily dosing with conventional interferon. Moreover, despite differences in structure and dosing between the two pegylated interferons, there probably are no substantial differences between them in effectiveness and safety.

Data regarding pegylated interferons are still emerging from clinical trials. It is very important to understand, however, that as yet, there are no head to head comparisons between the two pegylated interferons. In other words, the two pegylated interferons have not yet been compared directly with each other in the same clinical trial. Therefore, the sustained response rate (SR) obtained with one pegylated interferon in one study cannot confidently be compared to the SR obtained in a different study. The overall SR in previously untreated patients who received Pegasys for 48 weeks was 39%, which is comparable to the previously reported SR with combined conventional interferon and ribavirin (Rebetron combination).

In a separate study, a lower SR was found for Peg-Intron A. This difference from the SR reported for Pegasys may not be significant, however, because of the different proportions of genotype 1 in the two different studies. Accordingly, it is probably safe to say that the two pegylated interferons result in about an equal SR, which is equivalent to that of the Rebetron combination. Beyond that, the pegylated interferons are better tolerated than the Rebetron combination. (See the section on side effects below.)

Combined pegylated interferon and ribavirin

In studies comparing combined pegylated interferon (either Peg-Intron A or Pegasys) and ribavirin to the Rebetron combination, the pegylated interferon and ribavirin combinations appeared to be more effective, especially in patients infected with genotype 1. With genotype 1, the sustained response rate (SR) was 45% for the pegylated interferon and ribavirin combinations versus 35% for the Rebetron combination. As expected, the overall results in genotype 2 or 3 patients for each of these treatment groups were even better (SR 60% to 80%). However, the differences among the treatment groups for the patients with genotype 2 or 3 are a bit more difficult to interpret than for the patients with genotype 1 for at least two reasons.

First, all patients in these studies received 48 weeks of treatment. (Remember that only 24 weeks of the Rebetron combination is required for genotype 2 or 3.) Second, the different patient populations in which these results were obtained may well differ in their responses to treatment. Therefore, the verdict is still out on which treatment is the best for patients with genotype 2 or 3 hepatitis C virus infections: the two pegylated interferon and ribavirin combinations versus each other and each of them versus the Rebetron combination. Clinical trials are needed of head to head comparisons (in a single study) among these treatment regimens for genotype 2 or 3 patients.

Types D, E, F, and G Hepatitis

There also are viral hepatitis types D, E, F (not confirmed yet), and G. The most important of these at present is the hepatitis D virus (HDV), also known as the delta virus or agent. It is a small virus that requires concomitant infection with hepatitis B to survive. HDV cannot survive on its own because it requires a protein that the hepatitis B virus makes (the envelope protein, also called surface antigen) to enable it to infect liver cells. The ways in which hepatitis D is spread are by shared needles among drug abusers, contaminated blood, and by sexual contact, essentially the same ways as for hepatitis B.

Patients who already have chronic hepatitis B infection can acquire delta virus infection at the same time as they acquire the hepatitis B infection or, alternatively, on top of a chronic hepatitis B infection. Patients with chronic hepatitis due to hepatitis B and hepatitis D viruses develop cirrhosis (severe liver scarring) rapidly. Moreover, the combination of delta and B virus infection is very difficult to treat

Who is at risk for viral hepatitis?

People who are most at risk for developing viral hepatitis are workers in the health care professions, people with multiple sexual partners, intravenous drug users, and hemophiliacs who receive blood clotting factors. Blood transfusion, once a common means of spreading viral hepatitis, now is a rare cause of hepatitis. Viral hepatitis is generally thought to be as much as ten times more common among lower socioeconomic and poorly educated individuals. About one third of all cases of hepatitis come from an unknown or unidentifiable source. This means that you don't have to be in a high risk group in order to be infected with a hepatitis virus.

What are the symptoms and signs of viral hepatitis

The period of time between exposure to hepatitis and the onset of the illness is called the incubation period. The incubation period varies depending on the specific hepatitis virus. Hepatitis A has an incubation period of about 15-45 days; hepatitis B from 45-160 days, and hepatitis C from 2 weeks to 6 months.

Many patients infected with hepatitis A, B, and C have few or no symptoms of illness. For those who do develop symptoms of viral hepatitis, the most common are flu- like symptoms including:

       loss of appetite

       nausea

       vomiting

       fever

       weakness

       tiredness

       aching in the abdomen

Less common symptoms include:

       dark urine

       light-colored stools

       fever

       jaundice (a yellow appearance to the skin and white portion of the eyes)

What is the prognosis of viral hepatitis?

The prognosis of viral hepatitis for most patients is good. Symptoms of viral hepatitis such as fatigue, poor appetite, nausea, and jaundice usually subside in several weeks to months, without any specific treatment. In fact, virtually all patients with acute infection with hepatitis A and most adults (greater than 95%) with acute hepatitis B recover completely. Complete recovery from viral hepatitis means

1. the hepatitis virus has been completely eliminated from the liver by the body's immune system,
2. the inflammation in the liver subsides,
3. the patient develops immunity to future infection with the same virus, and
4. the patient cannot transmit the infection to others.

Unfortunately, not all patients with viral hepatitis infections recover completely. Five percent of patients with acute hepatitis B infection and 80% of patients with acute hepatitis C infection develop chronic hepatitis.

Acute viral hepatitis needs no specific treatment. Patients who develop chronic infection have chronic viral hepatitis and often need treatment to prevent further liver damage.

What is acute fulminant hepatitis?

Rarely, individuals with acute infections with hepatitis A and hepatitis B develop severe inflammation, and the liver fails (acute fulminant hepatitis). These patients are extremely ill with the symptoms of acute hepatitis already described and the additional problems of confusion or coma (due to the liver's failure to detoxify chemicals) and bruising or bleeding (due to a lack of blood clotting factors). In fact, up to 80% of people with acute fulminant hepatitis can die within days to weeks; therefore, it is fortunate that acute fulminant hepatitis is rare. For example, less than 0.5% of adults with acute infection with hepatitis B will develop acute fulminant hepatitis.

How is viral hepatitis prevented?

Prevention of hepatitis involves measures to avoid exposure to the viruses, using immunoglobulin in the event of exposure, and vaccines. Administration of immunoglobulin is called passive protection because antibodies from patients who have had viral hepatitis are given to the patient. Vaccination is called active protection because killed viruses or noninfective components of viruses are given to stimulate the body to produce its own antibodies.

Avoidance if exposure to viruses

Prevention of viral hepatitis, like any other illness, is preferable to reliance upon treatment. Taking precautions to prevent exposure to another individual's blood (exposure to dirty needles), semen (unprotected sex), and other bodily waste (stool) will help prevent the spread of these viruses.

Use of immunoglobulins

Immune serum globulin (ISG) is human serum that contains antibodies to hepatitis A. ISG can be administered to prevent infection in individuals who have been exposed to hepatitis A. ISG works immediately upon administration, and the duration of protection is several months. ISG usually is given to travelers to regions of the world where there are high rates of hepatitis A infection and to close or household contacts of patients with hepatitis A. ISG is safe with few side effects.

Hepatitis B immune globulin or HBIG (BayHep B), is human serum that contains antibodies to hepatitis B. HBIG is made from plasma (a blood product) that is known to contain a high concentration of antibodies to the hepatitis B surface antigen. If given within 10 days of exposure to the virus, HBIG almost always is successful in preventing infection. Even if given a bit later, however, HBIG may lessen the severity of HBV infection. The protection against hepatitis B lasts for about three weeks after the HBIG is given. HBIG also is given at birth to infants born to mothers known to have hepatitis B infection. In addition, HBIG is given to individuals exposed to HBV because of sexual contact or to healthcare workers accidentally stuck by a needle known to be contaminated with blood from an infected person.

There is no effective immunoglobulin that can be given to protect against hepatitis B.

Vaccination

Hepatitis A. Two hepatitis A vaccines are available in the US, Havrix and Vaqta. Both contain inactive (killed) hepatitis A virus. For adults, two doses of the vaccine are recommended. After the first dose, protective antibodies develop in 70% of vaccine recipients in 2 weeks and more than 95% of recipients in 4 weeks. After two doses of the hepatitis A vaccine, immunity against hepatitis A infection is believed to last for many years.

Individuals at increased risk for acquiring hepatitis A and individuals with chronic liver disease (e.g., cirrhosis or chronic hepatitis C) should be vaccinated. Although individuals with chronic liver disease are not at increased risk for acquiring hepatitis A, they can develop serious (sometimes fatal) liver failure if infected with hepatitis A and, thus, they should be vaccinated.

Individuals at increased risk of acquiring hepatitis A are:

       Travelers to countries where hepatitis A is common

       Men who have sex with men

       Illegal drug users (either injection or non-injection drug use)

       Researchers working with hepatitis A or primates that are susceptible to infection with hepatitis A

       Patients with clotting factor disorders who are receiving clotting factor concentrates that can transmit hepatitis A

Some local health authorities or private companies may require hepatitis A vaccination for food handlers.

Because protective antibodies take weeks to develop, travelers to countries where hepatitis A is common should be vaccinated at least 4 weeks before departure. The Centers for Disease Control (CDC) recommends immunoglobulin be given in addition to vaccination if departure is prior to 4 weeks. Immunoglobulin provides quicker protection than the vaccines, but the protection is short-lived.

Hepatitis B

For active vaccination, a harmless hepatitis B antigen is given to stimulate the body's immune system to produce protective antibodies against the surface antigen of hepatitis B. Vaccines that are currently available in the United States are made (synthesized) using recombinant DNA technology (joining DNA segments). These recombinant hepatitis B vaccines (Energix-B and Recombivax-HB) are constructed to contain only that part of the surface antigen that is very potent in stimulating the immune system to produce antibodies. The vaccine contains no viral component other than the surface antigen and is not infectious. Hepatitis B vaccines should be given in three doses with the second dose 1-2 months after the first dose, and the third dose 4-6 months after the first dose. For the best results, the vaccinations should be given in the deltoid (shoulder) muscles and not in the buttocks.

Hepatitis B vaccines are 95% effective. Five percent of vaccinated individuals will fail to develop the necessary antibodies for immunity after the three doses. Patients with weakened immunity (such as HIV infection), elderly patients, and patients undergoing kidney hemodialysis are more likely to fail to respond to the vaccines.

Hepatitis B vaccine is recommended for:

       All infants

       Adolescents under 18 years of age who did not receive hepatitis B vaccine as infants

       People occupationally exposed to blood or body fluids

       Residents and staff of institutions for the developmentally disabled

       Patients receiving kidney hemodialysis

       Hemophiliacs and other patients receiving clotting factor concentrates

       Household contacts and sexual partners of patients infected with hepatitis B chronically

       Travelers who will spend more than 6 months in regions with high rates of hepatitis B infection

       Injection drug users and their sexual partners

       Men who have sex with men, men or women with multiple sex partners, or recent infection with a sexually transmitted infection

       Inmates of long-term correctional facilities

All pregnant women should have a blood test for the antibody to hepatitis B surface antigen. Women who test positive for hepatitis B risk transmitting the virus to their infants during labor, and, therefore, infants born to mothers with hepatitis B infection should receive HBIG in addition to hepatitis B vaccine at birth. The reason for giving both immunoglobulin and vaccine is that even though hepatitis B vaccine can offer long lasting, active immunity, immunity takes weeks or months to develop. Until active immunity develops, the short-lived, passive antibodies from the HBIG protect the infant.

Unvaccinated individuals exposed to materials infected with hepatitis B (such as healthcare workers stuck by a contaminated needle) will need HBIG in addition to hepatitis B vaccine for the same reason as infants born to mothers with hepatitis B infection.

Hepatitis C

There is currently no vaccine for hepatitis C.

Viral Hepatitis At A Glance

       Many illnesses and conditions can cause inflammation of the liver (hepatitis).

       Viruses that primarily attack the liver are called hepatitis viruses. There are several types of hepatitis viruses including types A, B, C, D, E, F (not yet confirmed), and G. Types A, B, and C are the most common.

       Those at risk for viral hepatitis include workers in the health care profession, people with multiple sexual partners, intravenous drug abusers, and hemophiliacs. Blood transfusion is a rare cause of viral hepatitis.

       All hepatitis viruses can cause acute hepatitis.

       Viral hepatitis types B and C can cause chronic hepatitis.

       Symptoms of acute viral hepatitis include fatigue, flu-like symptoms, dark urine, light-colored stools, fever, and jaundice. Rarely, acute viral hepatitis causes fulminant hepatic failure.

       The symptoms of chronic viral hepatitis often are mild and nonspecific, and the diagnosis of chronic hepatitis often is delayed.

       Chronic viral hepatitis often requires treatment in order to prevent progressive liver damage, cirrhosis, liver failure, and liver cancer

       Hepatitis infections can be prevented by avoiding exposure to viruses, injectable immunoglobulins or vaccines