 Hepatitis C is a chronic viral infection of the liver which has been called Non A Non B hepatitis and transfusion hepatitis in the past. Hepatitis C is an epidemic in the United States. The Center for Disease Control (CDC) estimates that during the past years a maximum of 180,000 new cases of HCV were identified. Fortunately, with screening and the development of antibody screening tests, the number of newly acquired acute hepatitis C infection has decreased. In the 1980's, 180,000 cases were identified. At present, this rate has dropped to approximately 28,000 new cases. This represents a significant decrease in the development of new cases of hepatitis C. The decrease is associated with improvement in identification of those at risk and increase physician awareness of the problem. Hepatitis C currently infects approximately 4 million United States patients. It is responsible for 8,000 to 10,000 deaths per year. These deaths are usually secondary to hepatocellular carcinoma and other complications of HCV associated cirrhosis. Over the next 10 to 20 years, it is expected that the number of HCV associated deaths will triple. At present, hepatitis C is the most common cause for orthotopic liver transplant. Based upon the above figures, the need for liver transplantation will increase exponentially over the next two decades. This will place an increased number of patients on waiting lists for a limited number of orthotopic liver transplants. It is the goal of physicians and investigators to identify and treat patients before the development of cirrhosis. Unfortunately, only a small number of HCV cases have been confirmed despite the estimated 4 million cases present in the United States. Initial steps to prevent this dilemma are identification of patients at risk by knowing the risk factors associated with the transmission of HCV. In general, the acute infection with HCV results in essentially no symptoms or jaundice (turning yellow). Some patients can clear the virus and develop antibodies that may be protective for the rest of their lives. Most patients develop a chronic infection that results in chronic inflammation of the liver. After 20 years, some patients will develop cirrhosis. This appears to be about 20 to 30 percent. One of the major problems with HCV is determining how fast the damage occurs. Some patients will have rapid progression of their disease while others may harbor the disease for decades and have little or no damage to their liver. Risk factors for Acquisition of HCV The HCV virus is acquired through direct innoculation into the blood stream. This is the common mechanism amongst many different routes of transmission. Some patients have no identifiable risk factors. The manner in which they became infected is unclear. Some physicians have estimated this may account for up to 40% of patients. Patients who have an increased risk for hepatitis C have a history that includes:
Identification of patients who are risk for hepatitis C is based upon these historical factors. However, any patient who has elevated liver function tests, particularly ALT, should undergo screening test for hepatitis C. Sexual transmission of the HCV virus is quite low when compared to Hepatitis B and HIV. Studies have shown that long-term monogamous relationships where one partner has HCV and the other does not remain this way for long periods of time. The rate of transmission is thought to be about 3-4% in these groups. However, higher risk activities such as anal sex, multiple sexual partners or frequenting prostitutes may increase the rate of transmission. The best possible protection is the use of the condom until the HCV positive partner can be treated and the infection eradicated. Transmission during pregnancy is again limited. The risk of passing the virus from mother to fetus is approximately 5% It is always important to inform your gynecologist that you have HCV. Prevention of HCV is based upon limiting the exposures described above. Family members should follow the same precautions for HCV as they would for HBV. This includes not sharing razor blades, toothbrushes etc. There is no vaccine available at present although work is underway to develop one. If you have a history of one of the above, please contact your physician to see if you need a screening test for HCV performed. Natural History of HCV Hepatitis C is often asymptomatic. Most symptoms begin only when irreversible liver damage (cirrhosis) is established. The best outcomes for HCV patients depend upon early recognition of the infection. Any person with risk factors should be screened for HCV. Multiple studies have shown that earlier treatment of patients who have chronic liver disease associated with hepatitis C results in improved outcomes. Chronic infection with HCV is an epidemic within the United States. A majority of patients who acquire hepatitis C will progress to some form of chronic liver disease. Recent evidence published in the New England Journal of Medicine indicates some patients may have a long course in which the disease does not causes significant damage to the liver. However, it is difficult to identify those patients since their clinical characteristics are unknown. There are no blood or radiologic tests which identify this group of HCV patients. Most patients who acquire HCV infection are not aware that they have become infected. Acute infection with HCV is usually associated with flu like symptoms and not jaundice (turning yellow). As a result, patients may have the infection for years before being identified. Most patients are identified during routine physical exam or blood donations. Abnormal liver function tests are identified during these evaluations. When abnormal liver function tests or a history of risk factors are identified, further testing is recommended. Once the infection has been established, the liver experiences inflammation which over 20 years may result in cirrhosis. It is thought that 85 % patients infected with HCV will develop some form of chronic inflammation of the liver. Of these patients, about 20 % will develop cirrhosis of the liver after about 20 years of infection. Some patient populations seem to tolerate the infection better than others. These patients are under investigation to identify the means by which this is accomplished. The primary goal for patients with HCV is early institution of therapy to prevent the development of cirrhosis. Once cirrhosis is present, the response rates for treatment decrease significantly. In addition, the possibilities of developing complications from cirrhosis (such as hepatocellular carcinoma and portal hypertension) increase rapidly. Patients with Hepatitis C infection may have normal, fluctuating or persistently elevated ALT levels. It is important that these liver function test abnormalities be present for at least 6 months. However, if an individual has recently had been identified as having elevated liver function test, and has one or more of the above risk factors, an immediate test for the Hepatitis C antibody test (EIA) is appropriate. Hepatitis C is a heterogeneous infection. Its interrelationship with the human immune system is variable and difficult to correlate. However, some trends have been identified. In some patients serious liver disease may occur within the first several years. However, in most patients chronic liver disease requires infection for 20 to 30 years. When acquired in older age, the disease may progress more rapidly. Ingestion of alcohol has been clearly associated with an increased rate of hepatic inflammation. HCV patients who drink often have an acceleration of their disease. Associated Diseases Hepatitis C is thought to be associate with multiple other diseases:
Clinical Presentation The most common presentation of hepatitis C is a patient with no complaints. Many patients, especially when questioned closely, report a history of fatigue and malaise. Intermittent right upper quadrant abdominal pain may also be present. However, the typical patient with hepatitis C will be asymptomatic and have normal, intermittently elevated, or persistently elevated liver function test. The primary problem for patients with HCV and their physicians is communication regarding possible risk factors for acquisition of the HCV virus. If you have a history of any of the risk factors, please contact your physician. Diagnosis of Hepatitis C The initial test for hepatitis C is the enzyme-linked immunoassay. This is also known as the enzyme immunoassay (EIA). This test looks for the antibody to HCV in the blood. Over the past 10 years three generations of EIA antibody tests for hepatitis C has been developed. The most commonly used today, EIA 3, is 95 percent specific and sensitive for hepatitis C. However, this test, even when positive, needs to be confirmed with a polymerase chain reaction (PCR) to evaluate the presence of HCV virus. If the PCR is positive, further blood testing for the viral load (amount of virus in one milliliter of serum) and the genotype (type of HCV present) can be performed. Hepatitis C Genotype There are 6 subtypes of hepatitis C. These are labeled types 1 through 6. In United States, type 1 is the most common. It is also the most difficult to treat. Types 2,3,4,5,6 are less common. Many patients have difficulty with the concept of a genotype. To help explain, it is useful to think of a family. In families, there are parents and children. The children are all genetically related but behave somewhat differently. Indeed, this is the case with respect to Hepatitis C genotype. The family is HCV and the children are types 1 through 6. The separate genotypes are all genetically related but respond to therapy differently. Hepatitis C Viral Load Multiple studies have indicated that when a higher viral load is present, eradication of the virus is more difficult. Currently, a high viral load is defined as greater than 2.0 million copies per milliliter (ml) as determined by the PCR test. If the viral load is lower than 2.0 million copies per ml, Hepatitis C viral eradication is more likely. Evaluation of the Patient with Hepatitis C The goal of evaluation for patients with newly diagnosed hepatitis C is to assess the degree of hepatic damage present in that individual. Since the initial infection with hepatitis C is usually not associated with the development of jaundice, the time of the initial infection is unknown. Thus, physicians inquire regarding risk factors. They're particularly interested in knowing the onset and cessation of a particular risk factor. This allows the physician to begin to estimate the possible duration of infection in an individual. If a patient can report specific information regarding change in their liver function tests etc., this may be extremely important in assessing the duration of the disease. The extent of liver disease is determined by a number of different tests. These include ultrasound of the liver, evaluation of co-morbid diseases, Hepatitis C viral load, Hepatitis C genotype, CBC, PT/PTT and alpha-fetoprotein. A liver biopsy is often used for further evaluation. Although the above information is quite useful liver biopsy is the gold standard by which the degree of liver damage is assessed. It has been clearly shown in studies that the degree of elevation of liver function tests (especially the ALT) does not correlate with the degree of liver disease. For these reasons, a liver biopsy is often advocated. Once the extent of disease has been determined, the physician and patient review the data and determine which treat regimen is best. Sometimes this includes a research protocol or referral to a University for further advanced treatment options. Treatment of Hepatitis C
Therapy for chronic hepatitis C is indicated for patients who are between the ages of 18 and 60. Additional factors include persistently elevated liver function tests, confirmed virus within the serum, and evidence of chronic hepatitis on liver biopsy. Those patients who have cirrhosis, or have a history of complications associated with cirrhosis, may not be generally treated with currently available regimens. These patients may treated but this is usually in a clinical trial.
The treatment of Hepatitis C is based upon subclasses of patients. In general, patients are divided into groups. These are:
The primary factors affecting response to therapy include the following:
The two major aspects of Knodell's criteria are the degree of inflammation (Grades 1 through 4, with 4 being the more severe) and the degree of fibrosis (Stages 1 through 4). The more advanced the stage of fibrosis reflects the closer the patient is to developing cirrhosis. Cirrhosis itself is classified differently and will not be discussed further here. To illustrate the influence of the above factors on outcomes of treatment, one can look at patients who have non-type 1 genotype (genotype 2 or 3). This patient population may achieve rates of sustained response (SR) twice as high as those patients with genotype 1. (It is thought that genotypes 4, 5 and 6 may have similar response rates. However, firm conclusions regarding these last three genotypes are difficult to establish because the relative smaller distribution in the population.) For genotypes 2 and 3, a six-month treatment course is as effective as a twelve-month treatment course. Conversely, genotype 1 has a significant increase in sustain viral response at twelve-month versus six months (30 percent vs. 17 percent respectively). Viral load also affects Hepatitis C outcomes. In general, if the viral load is greater than 2 million copies per milliliter (copies/ml) the response rates decreases in all patients irrespective of their genotype. However, if a patient has less than 2 million copies per milliliter, and a genotype 1, a six-month course of therapy is as effective as a twelve-month course of therapy (32 percent vs. 33 percent respectively). Thus, patients with HCV are different based upon many different characteristics. Consultation with a trained hepatologist or gastroenterologist experienced with HCV is strongly recommended.
In the 1980's, a group of investigators published results of a study involving six months treatment with interferon (alpha 2b 3 MU SQ TIW for six months). Previously, no adequate therapy for HCV had been identified. These results showed this treatment which resulted in a beneficial outcome. Thus, a treatment for HCV had finally been identified. Unfortunately, only 10 % of patients had a sustained response to this medical regimen. This plan of therapy is now generally referred to as monotherapy. Since only one agent had been identified which was effective against HCV, multiple trials throughout the world searched for the optimum regimen. These investigations assessed variable methods of using the interferons by assessing the response rates to higher doses of interferon, longer treatment regimens, escalating and de-escalating doses. After massive research, the most appropriate treatment regimen derived from these studies of monotherapy is to increase the period of time in which monotherapy was administered. In the 1990's, the standard of care was changed from 6 months of treatment to 12 months of treatment using the same dose (3 million units) and frequency (3 times a week). By doubling the duration of treatment, a doubling of the sustained response was accomplished. In addition, most interferons work equally as well when used in equivalent dose, frequency and duration. Multiple other medications were tried for the treatment of HCV. Many failed, but ribavirin was noted to have some efficacy. In addition, it had the advantage of being an oral medication. Ribavirin acts against the RNA of the Hepatitis C virus. It should be noted that ribavirin, as a single agent, does not effectively treat patients with hepatitis C. It will improve or normalize their liver function tests and improve the histology in 30 % to 50 % of patients. It does not increase or decrease the HCV viral load. Ribavirin as a single agent was not approved by the FDA because of its lack of improvement in the viral load. During this period of time, some investigators had tried ribavirin in combination with interferon. This resulted in an improvement in the sustained viral response in HCV patients. The FDA did allow the combination trials to be performed. As a result, combination therapy has become the standard of therapy. Two major research trials performed in the United States and Europe confirmed the improved efficacy of combination therapy. These were published in the New England Journal of Medicine in November 1998. Selection of patients for combination therapy is based upon viral load, genotype, and liver histology. These three primary characteristics determine the response rates for combination therapy. Patients with non-type 1 (i.e. genotypes 2 and 3) Hepatitis C generally require only 6 months worth of treatment with combination therapy. Patients with type 1 hepatitis C usually require 12 months worth of treatment.
Acute Hepatitis C: Acute hepatitis C, when identified, is usually treated with 12 weeks of interferon (3 million units alpha 2b subcutaneously TIW). This appears to result in similar long-term response rates as long term therapy for chronic Hepatitis C. The optimal regimen for acute HCV patients is under investigation. Chronic Hepatitis C Treatment: Naive patient treatment: Naive patients are currently treated with 12 months of combination therapy. The dose of ribavirin is based upon the weight of the patient. If the patient is 75 kg in weight or higher, ribavirin is usually dose at 1200 mg per day. If the patient is less than 75 kg, the dose is 1000 mg. Ribavirin tablets are 200 mg in size. The standard interferon dose is 3 million units injected subcutaneously three times a week. The duration of this treatment is 12 months for patients who have type1 Hepatitis C. Many patients with non-type 1 (genotypes 2,3) Hepatitis C may be treated for six months. The role of combination therapy for patients who have previously been treated with interferon (monotherapy) has not yet been resolved. The current data indicates support for treatment of relapsing patients with combination therapy. However, it is still unclear as to whether a 48-week treatment regimen should be used or a 24-week regimen. Further information regarding the genotype, viral load and liver biopsy findings will be useful in determining this information. In this patient population, many physicians recommend a repeat liver biopsy to assess the current state of the liver. Patients who are non-responders to monotherapy do not respond well to combination therapy. However, some patient have been reported to respond to combination therapy. The current volume of data regarding these groups of patients is limited making exact recommendations difficult. This group of patients is often times included in clinical trials. New Treatment Regimens: At present, the treatment regimens for hepatitis C have improved significantly over the past 15 years. Current research protocols are designed to maximize the response rates associated with currently available effective medical therapy. These approaches include use of different types of interferon, induction therapy and long acting interferon (pegylated interferon). Induction therapy is a technique of introducing a higher dose of interferon to the patient during initiation of treatment. Usually, interferon is administered to the patient on a daily basis. The duration of this daily administration is variable and is usually governed by the research protocol in which a patient is enrolled. Duration of these studies is usually 48 weeks (twelve-month). The studies may or may not include use of ribavirin. Pegylated interferon is a long acting preparation that requires subcutaneous injection on a weekly basis. Studies are currently being performed as both monotherapy and combination therapy (with ribavirin) for relapsing and non-responders. Naive patients are not currently being treated due to limited availability of pegylated interferon. Currently, research protocols are available through Colorado Center for Digestive Disorders. Please go to the research button for further information regarding protocols that are currently available. Side Effects and Treatment Labs During treatment, a CBC and liver function tests are obtained at 2 weeks and 4 weeks. Subsequently, CBC and liver panels are drawn on a monthly basis. Usually, patients are seen once a month during the first two months of treatment. A follow up appointment every 2 to 3 months thereafter is scheduled if the patient is doing well. Certainly, if further problems arise the patient is seen earlier. Some controversy exists about the timing of viral load determinations during treatment of Hepatitis C. Some authors advocate using a viral load at 3 months to determine whether continued medication should be administered to the patient. This approach allows the physician to determine whether the patient is responding to the medication by comparing pretreatment and treatment viral load values. If a significant decrease in viral load has been accomplished, the medication is continued. A viral load may be repeated at 6, 9 and 12 months depending upon the specific situation. During the treatment, a thyroid function test (TSH) is obtained usually approximate six months. If there is evidence of hypothyroidism, institution of Synthroid is usually carried out. Common side effects associated with interferon include:
Common side effects associated with ribavirin:
Uncommon but serious side effects associated with either ribavirin or interferon:
Although the above complications are rare they are severe and should be reported to your physician as soon as possible. A primary concern is depression. You should tell your physician if you feel you have problems with depression or suicidal thoughts. Interferon based regimens can exacerbate depression particularly in the second three month period of treatment. A simple depression score can be obtained to your physician's office that will help you and your physician assess your degree of depression more objectively. Oftentimes abdominal pain occurs with treatment of hepatitis C with interferon base to regimens. This is usually mild and can be treated with small amount of acetaminophen (Tylenol). This is safe medication when used in small doses (about 2 to 3 grams per day) for patients without cirrhosis. However, you should always inform your physician to ensure that this is an appropriate drug for your particular case. Alternatives, which are available in over-the-counter preparations, include ibuprofen. This is a mild nonsteroidal anti-inflammatory drug that can be used in small amounts to ameliorate side effects of interferon. Since these drugs can cause other gastrointestinal problems, such as ulcers, is important for you to discuss this with your physician. Nausea and fatigue are very commonly associated with both Hepatitis C and interferon regimens. It is important to understand that other causes of nausea and fatigue are present as well. Nausea and decreased appetite can be partially ameliorated by eating small frequent meals, avoiding acidic foods, adequate hydration, and use of higher protein based products such as yogurt and soy-based supplements. In some cases, and evaluation by nutritionist can be of significant help. Overall, hepatitis C and its treatment should not preclude patients from pursuing their normal daily activities. Certainly companies may need to be restricted or limited during interferon based treatment regimens. Summary of Terminology
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