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    Hepatitis C: Treatment

    Your doctor has told you that you have hepatitis C. Now what? Prompt evaluation and treatment, that's what. And given certain restrictions, the sooner the better. For people who have not yet developed symptoms and have moderate progressive liver disease as well as moderate viral loads and liver enzyme levels, treatment options include interferon or a combination of interferon and ribavirin. This provides the best chance of improving the quality of life, clearing the virus from the bloodstream and halting the progression of the disease.

    What are treatments for hepatitis C?

    Current treatment options for hepatitis C include:

    Interferon, a protein produced and secreted by special immune cells, which acts as an antiviral, immune-regulating chemical. When it enters the bloodstream, interferon interferes with the hepatitis C virus's ability to replicate. Additionally, interferon appears to "shore up" the immune system's disease-fighting T helper-1 cells sop that they are strong enough to kill off the hepatitis C viruses.

    Alpha interferon therapy is the standard treatment for management of acute and chronic hepatitis C. It is given 3 times a week for 12 to 18 months. If after 3 months of treatment enzyme levels remain elevated and viral load is not falling dramatically, treatment should be discontinued and the person should enroll in a clinical trial for an alternative treatment.

    Pegylated Interferon A new, long-acting, time-release form of interferon (called PEG interferon) keeps interferon blood levels high for three to five days, delivering a more sustained punch. Injections are needed only once or twice a week. The Food & Drug Administration approved PEG-Intron in January 2001.

    Ribavirin is a an antiviral medication called a nucleoside analogue that appears to block the virus's ability to replicate and may alter the immune system cells that fight viruses, making them more effective. It is the drug treatment of choice these days, and it is used in conjunction with alpha interferon. About 80 to 90 percent of those receiving treatment now start out on the combination therapy.

    Approved treatments for chronic active hepatitis C include the following:

    Approved treatments for chronic active hepatitis C include the following:

    • Alfa- interferon-2b (Intron-A, Schering) without or with ribavirin (Rebetol) [Rebetron].

    • PEG-Alfa-interferon-2b (PEG-Intron-A, Schering) without or with ribavirin (Rebetol)[Rebetron].

    • Alfa-interferon-2a (Roferon, Roche) with and without ribavirin

    • PEG Alfa-interferon-2a (PEGASYS, Roche)

    • Alfa-con1 interferon (Infergen, Amgen)

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    Who should be treated?

    Anyone with antibodies to HCV, HCV RNA, elevated serum AST and ALT (liver enzyme) levels and evidence of chronic hepatitis on a liver biopsy, and with no contraindications, should be offered therapy with the combination of alpha interferon and ribavirin. If a person is not a good candidate for combination therapy, monotherapy should be discussed.

    The National Institutes of Health Consensus Development Conference Panel suggests that treatment is appropriate for people whose lab tests indicate moderate to severe inflammation, fibrosis and liver cell necrosis (detected by biopsy). People who reveal less severe inflammation and minor or no fibrosis or cell necrosis should receive treatment based on individual evaluation.

    In all cases, treatment should not depend on whether the person has overt symptoms, how they contracted the disease, the genotype of HCV infection or viral load levels.

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    Who should not be treated?

    Monotherapy and combination therapy are not options outside of controlled scientific studies for anyone who has:

    • Clinically decompensated cirrhosis because of hepatitis C;

    • Abnormal aminotransferase levels;

    • A kidney, liver, heart or other solid-organ transplant;

    • Clinical depression that is not controlled by taking antidepressants or has a history of suicide attempts or chronic mental disease.
    Alpha interferon should not be given to a patient who has recently stopped alcohol or substance abuse because it has been associated with relapse. Typically, a two-year abstinence is recommended before starting therapy. For other contraindications to alpha-interferon, please check with your hepatologist.

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    If I develop acute hepatitis C after a known or unknown exposure, how should I be treated?

    Although no standard of care exists for hepatitis C, the recommended regimen following the development of acute hepatitis C is immediate treatment with interferon and ribavirin for at least six months. Early administration of these drugs for patients with acute hepatitis C is critical, as it may improve the chance of response.

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    What is alfa-interferon?

    Alfa-interferon, or interferon, is a genetically engineered protein that increases lymphocyte (white blood cell) activity to help clear HCV from the blood and liver. Interferon fights the formation of scar tissue in the liver and has been shown to prolong an individual's life, thus preventing or delaying the need for liver transplantation. This medication can reduce the amount of liver inflammation and decrease scar tissue levels or its formation (the precursor of cirrhosis).

    By using higher doses of interferon for long periods and slowly tapering off the medicine, some published studies suggest a higher long-term remission rate (possibly 30-35%). Twenty percent of patients in remission long-term (one to three years following treatment) have normal liver enzymes and clearance of hepatitis C from the blood and liver.

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    Are all brands of interferon exactly the same?

    No. There are five commercially available forms of interferon in the United States (see list above). Because each interferon is slightly different, you should use the same one throughout your course of treatment.

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    How is alfa-interferon given?

    Treatment with alfa-interferon is a self-administered injection beneath the skin (similar to an insulin shot for diabetes) three times a week. Your protocol may vary, however, so your physician will review the treatment regimen. Patients taking alfa-interferon are taught to administer their own shots after instruction from their doctor or a nurse.

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    Are there any alfa-interferon pills that can be taken orally?

    No, there are presently no oral forms or alfa-interferon. However, a new medicine that stimulates the immune system is currently being studied for hepatitis B (tucaresol) and may enter studies for hepatitis C.

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    What is the initial response rate to alfa-interferon monotherapy?

    Approximately 35% to 60% of patients taking only alfa-interferon (monotherapy) will show viral clearance normalization of the liver enzymes, improvement of inflammation and decreased scar tissue on their liver biopsy after six to twelve months of treatment. This response rate diminishes long term and only 12% of patients will show viral clearance improvement in their liver biopsy and normal liver enzymes between one to three years following treatment.

    It is highly probable that alfa-interferon will prevent cirrhosis or liver cancer in patients who clear the virus, however some studies have shown decreased scar tissue after treatment, meaning interferon may be able to slow the development of cirrhosis.

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    Is there any difference between alfa-interferons as monotherapy in terms of response?

    The interferons are very similar in terms of both initial and long-term response.

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    Are there newer forms of interferon available or in development?

    Two forms of interferon--called pegylated or PEG interferon--are now approved and can be used once a week. The information about initial and long-term response of PEG interferon has been analyzed for both monotherapy and combination with ribavirin showing an overall 54-56% response rate for all patients, with 37%-42% in Genotype 1 and >80% in Genotype 2 and 3.

    It is very clear that patients need to be on at least 1.5 mcg/kg/week of PEG-Intron and 12 mg/kg/day of ribavirin. The Roche Pegasys PEG-interferon product has a 37% sustained response rate as a single medication. Combination data with ribavirin is preliminary but it appears that a 56% sustained response rate can be expected. PEGASYS is given on a fixed dose: 180 mcg SQ QW.

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    What will happen if I do not receive interferon treatment for my chronic active hepatitis C?

    Interferon helps slow the hepatitis C disease by reducing the amount of virus in one's body and slowing liver damage. The suppression of liver disease is important because patients with hepatitis C have a 20% chance of developing cirrhosis (scarring of liver tissue) and those with cirrhosis eventually require a liver transplant to survive.

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    Should I have a liver biopsy?

    A liver biopsy is the best way to determine the amount of hepatitis and liver damage (including cirrhosis and fibrosis) and a patient's prognosis. The biopsy process is not perfect, however.

    There is less than a 3% chance of underestimating the level of disease in the liver and a 1% chance of overestimating the disease. Ask your doctor for more information on the liver biopsy process.

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    What is an example of an alpha-interferon ribavirin protocol being used at California Pacific Medical

    The following is an example of an alpha-interferon protocol being used at California Pacific Medical Center:

    1. Patient has history of elevated liver tests for at least six months or a clear risk factor for hepatitis C virus

    2. A liver biopsy is performed (or may have already been performed by your doctor).

    3. Alfa-interferon and ribavirin is prescribed and patient is taught how to give the injection by a physician or nurse.

    4. Patients who are Genotype 1 take weekly injections of a PEG Interferon product with ribavirin daily.

      • During the first month, patients have their blood tested and are seen by a doctor every two weeks.

      • During the remainder of the protocol, patients have their blood tested and are seen by a doctor monthly or more frequently if necessary.
    5. At one to three months of treatment, hepatitis C RNA will be measured by bDNA, PCR or TMA test and if the level is not zero (unmeasurable) or decreased by 1,000-fold, a patient will be considered a treatment failure. At that time, an alternate protocol will be discussed.

    6. Patients should follow their liver tests monthly during treatment and every six months if no treatment is applied.

    7. Consider a second liver biopsy.

    8. If a patient's liver tests should worsen when not on medication, the alfa-interferon may need to be restarted.

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    What are the side effects of taking alfa-interferon?

    Almost any patient taking alfa-interferon notices some side effects which are usually the worst during the first few weeks of treatment. These side effects may include:

    • Reduction in white blood count, red blood cell count and/or platelet count;

    • Increase in blood sugar

    • Flu-like symptoms

    • Nausea or loss of appetite

    • Drowsiness

    • Fatigue

    • Hair loss (not permanent)

    • Skin rash

    • Eye and retina changes or disease (if you have vision problems, immediately consult an eye doctor)

    • Muscle aches and pains

    • Depression (if a patient has a psychiatric history, suicide attempts have been reported)

    • Thyroid disease

    • Worsening of autoimmune disease such as psoriasis

    • Headaches

    • Arthritis

    • Weight loss

    • Mood swings and emotional liability (a few patients worldwide have had an exacerbation of depression so severe that there was a suicide risk)

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    Do the side effects improve or do they stay the same throughout treatment?

    The side effects from alfa-interferon improve and almost disappear as your body adapts to the medicine. Some patients have found that taking the medicine at night before bedtime seems to help. Additionally, Tylenol or ibuprofen can be taken from four hours before the injection to four hours following to decrease symptoms. If necessary, the alfa-interferon dose can be reduced or stopped if side effects are unbearable.

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    Are there any long-term side effects to alfa-interferon?

    The only long-term or permanent side effect reported from alfa-interferon is the worsening of thyroid disease.

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    What lab tests should be monitored and how should my dose of interferon be changed if lab tests are abnormal?

    The dose of interferon should be decreased if:

    • Platelet count is less than 70,000

    • Neutrophil count is less than 1,000
    Interferon should be stopped if:
    • Platelet count is less than 40,000

    • Neutrophil count is less than 750

    • Blood sugar > 500mg/dL

    • Triglycerides > 1,000

    • ALT >1,000 IU/L

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    How much does alfa-interferon cost and will my insurance pay for it?

    The average cost of interferon is approximately $40 per five-million unit injection. Most insurance companies cover the cost of medication up to their policy limits as well as lab tests, liver biopsies and doctor's visits.

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    Are there any newer medications for the treatment of hepatitis C?

    Yes. Among the new medications for hepatitis C include Ribavirin, Thymosin-alpha and PEG interferon. A description of each follows:

    • Ribavirin (Virazole): This oral medication is approved for the treatment or relapse after an initial course of interferon treatment and for patients who are untreated. Ribavirin must be used in combination with interferon and results in a "cure" or sustained response (virus negative six months after stopping treatment in at least 40% of patients treated according to recent studies).

      Couples must not conceive children until six months after the man or woman stops medication. Because the major side effect of ribavirin is anemia, the medication should not be given to individuals with active coronary artery disease (angina).

    • Thymosin-alfa -1 is similar to protein made in the human thymus gland (a large lymph node-like organ in the chest). This medication may be tested in the U.S. for the treatment of hepatitis C, but at this time, the data is inconclusive.

    • PEG interferon is a form of interferon developed for use once a week, versus three times a week with alfa-interferon. Information about initial and long-term response with PEG monotherapy appears to result in a sustained response or cure rate of 30-35%. Side effects are similar and data on combination therapy with ribavirin is encouraging.

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    What does it mean when my liver enzymes rise or fall?

    Liver enzymes are a very poor signal of what is occurring in a patient's liver. Patients who have hepatitis C may have both severe liver disease and cirrhosis, yet have normal liver enzymes. The presence of the hepatitis C virus should lead to a liver biopsy regardless of the level of liver enzymes. If a patient has abnormal liver enzymes before treatment and the level goes to normal during therapy, there is usually an accompanying decrease in liver inflammation.

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