Hepatitis C
Medical Author: Tse-Ling Fong, M.D.
Medical Editor: Leslie J. Schoenfield, M.D., Ph.D.
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 HCV. The prevalence (number of cases in a population at a specific time) of HCV infections varies in different parts of the world. For example, the prevalence of HCV 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 HCV chronic hepatitis and cirrhosis are the most common reasons for liver transplantation.
One of the major problems with HCV infections is that 85% of individuals initially infected with this virus will become chronically infected, usually for decades. The other 15% of HCV infected individuals simply have an acute infection; that is, one that resolves spontaneously in a few weeks or months. The propensity of HCV 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 HCV 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 HCV became available to screen the blood supply and individuals at high risk for HCV.
Indeed, with blood being routinely screened for HCV, 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 HCV 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 has increased substantially.
What is the nature (biology) of the hepatitis C virus (HCV)?
HCV 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). HCV 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 HCV 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 HCV allows scientists to develop therapy that specifically targets the virus's structure or functions.
There are considerable differences in the genetic structure of HCV. Accordingly, HCV 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 HCV cases in the U.S.
The influence of genotype on the long-term prognosis of HCV 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 HCV. 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 HCV 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 HCV, 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 HCV 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 HCV 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 HCV 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 HCV 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 HCV 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 HCV spread and how can transmission be prevented?
Hepatitis C is spread (transmitted) most efficiently through the blood. Therefore, HCV 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, HCV was the most common cause of hepatitis that resulted from blood transfusions in the 1980's. At that time, HCV 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 HCV 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 HCV dramatically lowered the risk of acquiring HCV 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 HCV 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, HCV 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 HCV infection.
HCV can be sexually transmitted, but not very efficiently. HCV has been isolated in the semen, vaginal fluid, and saliva. Nevertheless, the risk of transmission of HCV 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 HCV 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 HCV. 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.
HCV 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 HCV. The risk of acquiring HCV 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 HCV infection than people in the general population.
What else can be done to prevent hepatitis C? Immune serum globulin, given after an exposure to HCV, would not be expected to protect a susceptible individual from acquiring an HCV infection. Moreover, no vaccine is currently available for HCV. It should be noted, however, that hepatitis A and B vaccinations are recommended for patients who have HCV 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 HCV 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 HCV.
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), HCV 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 HCV 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 HCV 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 HCV infection.
B-cell non-Hodgkin's lymphoma, a cancer of the lymph tissue, has also been associated with chronic HCV. The cause is thought to be the excessive stimulation by the HCV of B-lymphocytes, which results in the abnormal reproduction of the lymphocytes. Interestingly, the disappearance (remission) of an HCV-associated low-grade (not very active) non-Hodgkin's lymphoma has been reported with interferon therapy. Most individuals with HCV-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 HCV. It is important to know that both of these skin conditions can resolve with successful interferon therapy for the HCV. In addition, up to 25% of HCV 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 HCV?
Our understanding of the natural progression (history) of hepatitis C infection is still evolving. About 15% of patients with acute HCV 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 HCV, 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 HCV 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 HCV 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 HCV 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 HCV 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 HCV 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 HCV 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 HCV 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 HCV 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 HCV. 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 HCV testing are less clear in certain other people who may also be at increased risk of acquiring HCV. 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 HCV positive person*
*The National Institutes of Health Consensus Development Conference recommends that these persons be tested.
What are the diagnostic tests for HCV and how are they used to diagnose HCV infection?
A number of diagnostic tests are currently available for HCV. 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 HCV 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 HCV proteins (antigens). This test, therefore, is referred to as the anti-HCV antibody test. Patients who have elevated liver enzymes (ALT/AST) and/or any of the risk factors for HCV can be diagnosed to have HCV 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-HCV antibodies even if they are actually infected with HCV. 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-HCV 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 HCV 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 HCV infections because the anti-HCV antibodies are in the blood in all three of these situations. Although EIA and RIBA are tests that measure antibodies against HCV, these antibodies do not confer protection to the patient against acquiring HCV. Rather, they only indicate exposure of the patient to the virus.
What are molecular tests for HCV?
As previously described, HCV is an RNA virus. The code of the genetic material, HCV RNA, is unique to this virus. Several types of tests (assays) are available to measure the HCV 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 HCV 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 HCV as compared to some other types of chronic viral infection. The average number of virus particles/milliliter of blood in an individual with chronic HCV 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 HCV.
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 HCV RT-PCR provides the greatest sensitivity, meaning that it can measure as few as 100 copies (viral particles) of HCV/ml of serum. As the name implies, however, qualitative RT-PCR provides only a positive (presence of HCV) or negative (absence of HCV) 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-HCV result reflects active HCV infection. However, confirmatory testing is usually not necessary in someone who tested reactive (positive) for anti-HCV 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-HCV 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-HCV as a marker of past exposure.
Qualitative HCV RNA testing should also be done in individuals who may have been recently exposed to hepatitis C. HCV RNA is more sensitive (that is, will detect more cases) than the conventional anti-HCV (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 HCV to develop the antibodies, whereas HCV RNA becomes detectable five to ten days after exposure. Finally, qualitative HCV RNA testing may be helpful to assess the patient's virologic response at certain time points during antiviral therapy (see treatment of HCV below).
How are the results of the HCV tests interpreted?
The table provides guidelines for interpreting the results of testing for anti-HCV by EIA and RIBA and for HCV RNA by qualitative RT-PCR or TMA.
| Anti-HCV (EIA) | Anti-HCV (RIBA) | HCV RNA
(Qualitative RT-
PCR or TMA) | Interpretation | | Non-reactive | Non-reactive | Undetectable | No present or past infection | | Reactive | Non-reactive | Undetectable | False positive EIA; no present or past infection | | Reactive | Undeterminate | Undetectable | In the absence of risk factors, probable false positive EIA | | Reactive | Positive | Undetectable | Probable past exposure with clearance of infection. Qualitative RNA testing should be repeated to exclude fluctuating low levels of viremia | | Reactive | Positive | Detectable | Ongoing infection | | Non-reactive | Non-reactive | Detectable | Acute HCV infection or chronic HCV infection in an immunocompromised person unable to make adequate antibodies |
What is the role of quantitative HCV RNA testing?
It should be noted that a single quantitative measurement of the level of HCV virus in the blood (viral load) does not correlate with the severity of HCV 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 HCV 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 HCV RNA initial levels of greater than 2 million copies/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 HCV 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 HCV 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 HCV?
Any individual with chronic hepatitis C infection is a potential candidate for antiviral therapy. However, given our understanding of the natural history of chronic HCV 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 HCV 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 naïve 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 HCV 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 HCV 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 HCV 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 HCV 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 HCV 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 HCV RNA during therapy is referred to as a break through because the HCV RNA breaks through what initially appears to be successful (loss of HCV RNA) treatment.
What are the goals of therapy for HCV?
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 HCV 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 HCV 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 HCV 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). Peg-Intron A already has received FDA approval whereas Pegasys is still undergoing FDA review. 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 HCV 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.
How are relapsers and nonresponders treated?
Patients who were treated with conventional interferon monotherapy and then relapsed may be retreated with one of two regimens. These regimens are either a 24 week course of Rebetron combination (SR 48%) or a 48 week course of Infergen (15 mg three times weekly) (SR 58%). Both forms of therapy are approved for the treatment of relapsers. Furthermore, for patients who relapsed after a course of Rebetron combination and then received Infergen (15mg) administered daily may result in an SR as high as 50%. Of course, there will be tremendous interest in learning (from the results of new studies) about the effectiveness of combined pegylated interferon and ribavirin in the treatment of people who relapsed after Rebetron treatment.
Nonresponders to interferon treatment present an even more difficult clinical challenge than relapsers. To date, no sufficiently effective regimen has been found for these patients. Re-treatment with standard doses of interferon alone has shown essentially no benefit. Higher doses of interferon have produced only varied results and increased side effects. Re-treating non-responders with Rebetron or high doses of Infergen achieved only a 15% SR. Data using combined pegylated interferon and ribavirin for re-treatment will soon be available from clinical trials. Moreover, an NIH sponsored trial called HALT C is currently investigating the potential benefit of long term maintenance antiviral therapy in non-responders.
Should individuals with acute hepatitis C be treated?
The short answer is yes. About 85% of patients with acute hepatitis C will progress to chronic liver disease. Accordingly, the goal of antiviral therapy in acute hepatitis C is to prevent the infection from becoming chronic. Otherwise, there has been no standard, effective treatment for acute hepatitis C.
Most studies of treatment for acute hepatitis C were conducted over ten years ago using conventional interferon given three times per week. From the data, it appears that at least six months of interferon therapy should be offered. Sustained responses were seen in about 60 to 80% of treated patients with acute hepatitis C. Therefore, at this time, it makes sense to treat patients who have acute hepatitis C with at least a six month course of pegylated interferon, with or without ribavirin.
What are the side effects of treatment for HCV?
Flu-like symptoms (which are alleviated by acetaminophen/Tylenol), hair loss , and depression are common side effects of interferon. These symptoms generally lessen after the first few weeks of therapy and are not worsened by the addition of ribavirin. Less common side effects of interferon include anemia , low white blood cell count (leukopenia), low platelet count (thrombocytopenia), and decreased thyroid function. Death rarely occurs and when it does, it is principally due to progressive liver failure in patients with advanced cirrhosis.
Certain side effects are attributed to the addition of ribavirin to interferon, including nausea, cough, shortness of breath, rash, itching, insomnia, and loss of appetite. Ribavirin also causes anemia due to the destruction of red blood cells (hemolysis). This anemia is usually mild but can become clinically significant. This condition improves with dose reduction and rarely warrants stopping the ribavirin. Ribavirin also accumulates in the testicles and ovaries and causes birth defects in animals. Although no birth defects have been reported in humans as yet, both men and women should use contraceptive measures to avoid pregnancy during and for at least six months after ribavirin treatment.
In head to head comparisons (that is, in the same study) between pegylated interferon and conventional interferon, the side-effects were similar. It stands to reason, therefore, that the side effects of the Rebetron combination versus combined pegylated interferon and ribavirin would also be comparable.
What about liver transplantation for hepatitis C?
End stage (advanced, with complications) liver disease that is associated with chronic hepatitis C infection is the leading reason for liver transplantation in the U.S. today. The recurrence of the HCV virus in the blood, however, is almost universal after liver transplantation for HCV liver disease. In fact, about 25 % of patients will develop significant recurrence of hepatitis (seen on liver biopsy) in the new grafted liver. Moreover, these patients with recurrent hepatitis will develop cirrhosis within five years of their transplant.
Some patients will actually develop severe HCV disease with deep jaundice shortly after transplantation. Two situations can lead to this type of severe, recurrent liver disease. One is a high level of the virus in the blood at the time of transplantation. The other is the occurrence of episodes of acute immunological rejection of the graft after the transplant. These rejection episodes require steroid treatment, which enhances viral reproduction. Some centers found that patients infected with genotype 1b are more likely to have severe, recurrent HCV after transplant, but others have disputed this observation.
Despite these findings of recurrence, the five-year survival rate for hepatitis C patients is comparable to that of patients who are transplanted for other types of liver disease. Still, the failure of the transplanted liver that is caused by recurrent HCV infection is the number one reason to consider re-transplantation.
Studies looking at the prevention and/or treatment of recurrent HCV with Rebetron or pegylated interferon alone or combined with ribavirin are underway. There are concerns, however, that because interferon is an immune modulator (modifier), it might actually cause or promote rejection of (immunological resistance to) the liver graft. Furthermore, interferon may not be well tolerated by patients who just underwent transplantation and are taking many different kinds of medications.
What is the current research and what is in the future for hepatitis C?
As our awareness of hepatitis C infection increases, more and more patients are being diagnosed with this condition. The main areas of current research concerning hepatitis C include diagnosis, natural history, treatment, and vaccine development.
Diagnosis: More accurate tests are being developed to ensure that the blood supply for transfusions is safe. In the next few years, highly sensitive nucleic acid type tests, like the transcription mediated assay (TMA), will be routinely used for the screening and diagnosis of HCV.
Natural history: The challenge here is to distinguish between those individuals with chronic hepatitis C who will remain asymptomatic without progression from those who will develop cirrhosis and its complications. To make this distinction will require long term epidemiological (population) studies as well as a better understanding of HCV's nature (biology) and the body's immune response to this virus.
Treatment: Successful treatment can be achieved in up to 80% of patients infected with genotype 2 or 3. Genotype 1 patients and those who have previously failed interferon (relapsers and particularly non-responders), however, remain a challenge. In reality, these patients make up the majority of patients who currently need treatment. In the foreseeable future, interferon will remain the mainstay of therapy for HCV. As a matter of fact, combined pegylated interferon and ribavirin represents an enormous improvement in the treatment of HCV infection.
Trials are underway that are examining other combinations of medications. These combinations include pegylated interferon+ribavirin+amantadine (Symmetrel, an antiviral agent approved for influenza ), pegylated interferon+ribavirin+mycophenylate mofetil (CellCept, an anti-rejection medication), and pegylated interferon+thysmosin (thymus gland proteins that enhance the immune system).
Compounds that specifically interfere with the reproduction of the HCV virus are now being studied as well. (See the section on the biology of HCV.) These compounds include agents that inhibit the HCV related proteins (e.g., the enzyme polymerase), which are required to normally process the virus. Another class of agents being studied is called ribozymes, which are made of genetic material, in this case ribonucleic acid (RNA). The ribozymes interfere with the life cycle of the HCV by cutting or splicing the genetic material of the virus. Studies of ribozymes are just underway in humans.
Vaccine development: Development of a successful vaccine to protect against HCV infection has been elusive. As previously explained, the reason for this difficulty is the ability of the HCV to change (mutate) itself to evade the body's immune responses. Remember that the genetic makeup of the different HCV can vary substantially. The challenge for the researchers is to find a portion of the virus that is conserved (does not change among the different HCV). This piece of conserved virus could make the entire virus vulnerable to the body's immune cells. - In the U.S., hepatitis C virus (HCV) infection is the most common cause of chronic hepatitis, and the complications of HCV cirrhosis are the most common reasons for liver transplantation.
- HCV is one of several viruses (A, B, C, D, and E) that can cause hepatitis (inflammation of the liver). HCV is distinct from these other viruses.
- One of the major problems with HCV is that 85% of individuals who are initially (acutely) infected with HCV will become chronically (long duration) infected. About one third of individuals chronically infected with HCV will progress to cirrhosis.
- HCV is spread (transmitted) through the blood. Intravenous drug abuse is the most common mode of transmission, while the risk of acquiring HCV through sexual contact is quite low.
- Generally, patients do not develop symptoms until they have progressed to advanced cirrhosis. Some individuals, however, may have fatigue and other non-specific symptoms in the absence of cirrhosis. A minority of HCV patients may have symptoms coming from involved organs outside of the liver.
- Hepatitis C is diagnosed by anti-HCV antibody tests, which diagnosis is then confirmed by nucleic acid based tests for the virus itself. The amount of the virus in the blood (viral load) does not correlate with the severity of the disease.
- A liver biopsy is used to assess the amount of liver damage (liver cell injury and scarring), which may be important in determining the outcome (prognosis) and in planning treatment.
- Considerable progress has been made in the treatment of HCV. For patients infected with genotype 2 or 3, successful treatment with combined interferon (conventional or pegylated) and ribavirin can be achieved in up to 80% of patients.
- Treatment for patients infected with genotype 1 HCV, for whom the success rate with combined pegylated interferon and ribavirin is just under 50%, remains a challenge.
- Treatment is recommended for patients with detectable HCV RNA who have persistently elevated liver tests and evidence of scarring and at least moderate inflammation on their liver biopsy, but without outward signs of liver failure.
- Treatment results in improvement in the inflammation and scarring of the liver in most sustained responders and also occasionally (and to a much lesser extent) in relapsers and non-responders.
- Clinical trials are underway to evaluate combinations of various antiviral agents and pegylated interferon in the treatment of hepatitis C.
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