Treatment of Chronic Hepatitis C

The therapy for chronic hepatitis C has evolved steadily since alpha interferon was first approved for use in this disease more than 10 years ago. At the present time, the optimal regimen appears to be a 24- or 48-week course of the combination of pegylated alpha interferon and ribavirin.

Alpha interferon is a host protein that is made in response to viral infections and has natural antiviral activity. Recombinant forms of alpha interferon have been produced, and several formulations (alfa-2a, alfa-2b, consensus interferon) are available as therapy for hepatitis C. These standard forms of interferon, however, are now being replaced by pegylated interferons (peginterferons). Peginterferon is alpha interferon that has been modified chemically by the addition of a large inert molecule of polyethylene glycol. Pegylation changes the uptake, distribution, and excretion of interferon, prolonging its half-life. Peginterferon can be given once weekly and provides a constant level of interferon in the blood, whereas standard interferon must be given several times weekly and provides intermittent and fluctuating levels. In addition, peginterferon is more active than standard interferon in inhibiting HCV and yields higher sustained response rates with similar side effects. Because of its ease of administration and better efficacy, peginterferon has been replacing standard interferon both as monotherapy and as combination therapy for hepatitis C.

Ribavirin is an oral antiviral agent that has activity against a broad range of viruses. By itself, ribavirin has little effect on HCV, but adding it to interferon increases the sustained response rate by two- to threefold. For these reasons, combination therapy is now recommended for hepatitis C, and interferon monotherapy is applied only when there are specific reasons not to use ribavirin.

Two forms of peginterferon have been developed and studied in large clinical trials: peginterferon alfa-2a (Pegasys: Hoffman La Roche: Nutley, NJ) and peginterferon alfa-2b (Pegintron: Schering-Plough Corporation, Kenilworth, NJ). These two products are roughly equivalent in efficacy and safety, but have different dosing regimens. Peginterferon alfa-2a is given subcutaneously in a fixed dose of 180 micrograms (mcg) per week. Peginterferon alfa-2b is given subcutaneously weekly in a weight-based dose of 1.5 mcg per kilogram per week (thus in the range of 75 to 150 mcg per week).

Ribavirin is an oral medication, given twice a day in 200-mg capsules for a total daily dose based upon body weight. The standard dose of ribavirin is 1,000 mg for patients who weigh less than 75 kilograms (165 pounds) and 1,200 mg for those who weigh more than 75 kilograms. In certain situations, an 800-mg dose (400 mg twice daily) is recommended (see below).

Combination therapy leads to rapid improvements in serum ALT levels and disappearance of detectable HCV RNA in up to 70 percent of patients. However, long-term improvement in hepatitis C occurs only if HCV RNA disappears during therapy and stays undetectable once therapy is stopped. Among patients who become HCV RNA negative during treatment, a proportion relapse when therapy is stopped. The relapse rate is lower in patients treated with combination therapy compared with monotherapy. Thus, a 48-week course of combination therapy using peginterferon and ribavirin yields a sustained response rate of approximately 55 percent. A similar course of peginterferon monotherapy yields a sustained response rate of only 35 percent. A response is considered "sustained" if HCV RNA remains undetectable for 6 months or more after stopping therapy.

The optimal duration of treatment varies depending on whether interferon monotherapy or combination therapy is used, as well as by HCV genotype. For patients treated with peginterferon monotherapy, a 48-week course is recommended, regardless of genotype. For patients treated with combination therapy, the optimal duration of treatment depends on viral genotype. Patients with genotypes 2 and 3 have a high rate of response to combination treatment (70 to 80 percent), and a 24-week course of combination therapy yields results equivalent to those of a 48-week course. In contrast, patients with genotype 1 have a lower rate of response to combination therapy (40 to 45 percent), and a 48-week course yields a significantly better sustained response rate. Again, because of the variable responses to treatment, testing for HCV genotype is clinically useful when using combination therapy.

In addition, the optimal dose of ribavirin appears to vary depending on genotype. For patients with genotypes 2 or 3, a dose of 800 mg daily appears adequate. For patients with genotype 1, the full dose of ribavirin (1,000 or 1,200 mg daily depending on body weight) appears to be needed for an optimal response.

Who Should Be Treated?

Patients with anti-HCV, HCV RNA, elevated serum aminotransferase levels, and evidence of chronic hepatitis on liver biopsy, and with no contraindications, should be offered therapy with the combination of alpha interferon and ribavirin. The National Institutes of Health Consensus Development Conference Panel recommended that therapy for hepatitis C be limited to those patients who have histological evidence of progressive disease. Thus, the panel recommended that all patients with fibrosis or moderate to severe degrees of inflammation and necrosis on liver biopsy should be treated and that patients with less severe histological disease be managed on an individual basis. Patient selection should not be based on the presence or absence of symptoms, the mode of acquisition, the genotype of HCV RNA, or serum HCV RNA levels.

Patients with cirrhosis found through liver biopsy can be offered therapy if they do not have signs of decompensation, such as ascites, persistent jaundice, wasting, variceal hemorrhage, or hepatic encephalopathy. However, interferon and combination therapy have not been shown to improve survival or the ultimate outcome in patients with preexisting cirrhosis.

Patients older than 60 years also should be managed on an individual basis, since the benefit of treatment in these patients has not been well documented and side effects appear to be worse in older patients. However, even patients in their late seventies have been successfully treated for hepatitis C.

The role of interferon therapy in children with hepatitis C remains uncertain. Ribavirin has yet to be evaluated adequately in children, and pediatric doses and safety have not been established. Thus, if children with hepatitis C are treated, monotherapy is recommended, and ribavirin should not be used outside of controlled clinical trials.

People with both HCV and HIV infection should be offered therapy for hepatitis C as long as there are no contraindications. Indeed, hepatitis C tends to be more rapidly progressive in patients with HIV co-infection, and end-stage liver disease has become an increasingly common cause of death in HIV-positive persons. For these reasons, therapy for hepatitis C should be recommended even in HIV-infected patients with early and mild disease. Once HIV infection becomes advanced, complications of therapy are more difficult and response rates are less. The decision to treat people co-infected with HIV must take into consideration the concurrent medications and medical conditions. The efficacy of peginterferon and ribavirin in HIV-infected people has been tested in only a small number of patients. Ribavirin may still have significant interactions with other antiretroviral drugs.

In many of these indefinite situations, the indications for therapy should be reassessed at regular intervals. In view of the rapid developments in hepatitis C today, better therapies may become available within the next few years, at which point expanded indications for therapy would be appropriate.

Patients with acute hepatitis C are a major challenge to management and therapy. Because such a high proportion of patients with acute infection develop chronic hepatitis C, prevention of chronicity has become a focus of attention. In small studies, 83 to 100 percent of persons treated within 1 to 4 months of onset have had resolution of the infection. What is unclear is what dose, duration, and regimen of treatment to use. A practical regimen is peginterferon monotherapy for 24 weeks. The possible role for ribavirin, for short courses of therapy, and for lower doses of peginterferon are under evaluation.

In patients with clinically significant extrahepatic manifestations, such as cryoglobulinemia and glomerulonephritis, therapy with alpha interferon can result in remission of the clinical symptoms and signs. However, relapse after stopping therapy is common. In some patients, long-term or maintenance alpha interferon therapy can be used despite persistence of HCV RNA in serum if clinical symptoms and signs resolve on therapy.

Who Should Not Be Treated?

Therapy is inadvisable outside of controlled trials for patients who have

• clinically decompensated cirrhosis because of hepatitis C
• normal aminotransferase levels
• a kidney, liver, heart, or other solid-organ transplant
• specific contraindications to either monotherapy or combination therapy

Contraindications to alpha interferon therapy include severe depression or other neuropsychiatric syndromes, active substance or alcohol abuse, autoimmune disease (such as rheumatoid arthritis, lupus erythematosus, or psoriasis) that is not well controlled, bone marrow compromise, and inability to practice birth control. Contraindications to ribavirin and thus combination therapy include marked anemia, renal dysfunction, and coronary artery or cerebrovascular disease, and, again, inability to practice birth control.

Alpha interferon has multiple neuropsychiatric effects. Prolonged therapy can cause marked irritability, anxiety, personality changes, depression, and even suicide or acute psychosis. Patients particularly susceptible to these side effects are those with preexisting serious psychiatric conditions and patients with neurological disease.

Strict abstinence from alcohol is recommended during therapy with interferon. Interferon therapy can be associated with relapse in people with a previous history of drug or alcohol abuse. Therefore, alpha interferon should be given with caution to a patient who has only recently stopped alcohol or substance abuse. Typically a 6-month abstinence is recommended before starting therapy, but this should be applied only to patients with a history of alcohol abuse, not to social drinkers. Patients with continuing alcohol or substance abuse problems should only be treated in collaboration with alcohol or substance abuse specialists or counselors. Patients can be successfully treated while on methadone or in an active substance abuse program. Indeed, the rigor and regular monitoring that accompany methadone treatment provide a structured format for combination therapy. The dose of methadone may need to be modified during interferon-based therapy for hepatitis.

Alpha interferon therapy can induce autoantibodies, and a 24- to 48-week course triggers an autoimmune condition in about 2 percent of patients, particularly if they have an underlying susceptibility to autoimmunity (high titers of antinuclear or antithyroid antibodies, for instance). Exacerbation of a known autoimmune disease (such as rheumatoid arthritis or psoriasis) occurs commonly during interferon therapy.

Alpha interferon has bone marrow suppressive effects. Therefore, patients with bone marrow compromise or cytopenias, such as low platelet count (<>3) or neutropenia (<>3) should be treated cautiously and with frequent monitoring of cell counts. These side effects appear to be more common with peginterferon than standard interferon.

Ribavirin causes red cell hemolysis to a variable degree in almost all patients. Therefore, patients with a preexisting hemolysis or anemia (hemoglobin <>

Growth factors such as erythropoietin to raise red blood cell counts or granulocyte stimulating factor to raise neutrophil counts have been used successfully to treat patients with cytopenias during combination therapy. The proper role, dose, and side effects of these adjunctive therapies have yet to be defined.

Ribavirin is excreted largely by the kidneys. Patients with renal disease can develop hemolysis that is severe and even life-threatening. Patients who have elevations in serum creatinine above 2.0 mg per deciliter (dL) should not be treated with ribavirin.

Finally, ribavirin causes birth defects in animal studies and should not be used in women or men who are not practicing adequate means of birth control. Alpha interferon also should not be used in pregnant women, as it has direct antigrowth and antiproliferative effects.

Combination therapy should therefore be used with caution. Patients should be fully informed of the potential side effects before starting therapy.

Side Effects of Treatment

Common side effects of alpha interferon and peginterferon (occurring in more than 10 percent of patients) include

• fatigue
• muscle aches
• headaches
• nausea and vomiting
• skin irritation at the injection site
• low-grade fever
• weight loss
• irritability
• depression
• mild bone marrow suppression
• hair loss (reversible)

Most of these side effects are mild to moderate in severity and can be managed. They are worse during the first few weeks of treatment, especially with the first injection. Thereafter, side effects diminish. Acetaminophen may be helpful for the muscle aches and low-grade fever. Fatigue and depression are occasionally so troublesome that the dose of interferon should be decreased or therapy stopped early. Depression and personality changes can occur on interferon therapy and be quite subtle and not readily admitted by the patient. These side effects need careful monitoring. Patients with depression may benefit from antidepressant therapy using selective serotonin reuptake inhibitors. Generally, the psychiatric side effects resolve within 2 to 4 weeks of stopping combination therapy.

Ribavirin also causes side effects, and the combination is generally less well tolerated than interferon monotherapy. The most common side effects of ribavirin are

• anemia
• fatigue and irritability
• itching
• skin rash
• nasal stuffiness, sinusitis, and cough

Ribavirin causes a dose-related hemolysis of red cells; with combination therapy, hemoglobin usually decreases by 2 to 3 g/dL and the hematocrit by 5 to 10 percent. The amount of decrease in hemoglobin is highly variable. The decrease starts between weeks 1 and 4 of therapy and can be precipitous. Some patients develop symptoms of anemia, including fatigue, shortness of breath, palpitations, and headache.

The sudden drop in hemoglobin can precipitate angina pectoris in susceptible people, and fatalities from acute myocardial infarction and stroke have been reported in patients receiving combination therapy for hepatitis C. For these important reasons, ribavirin should not be used in patients with preexisting anemia or with significant coronary or cerebral vascular disease. If such patients require therapy for hepatitis C, they should receive alpha interferon monotherapy.

Ribavirin has also been found to cause itching and nasal stuffiness. These are histamine-like side effects; they occur in 10 to 20 percent of patients and are usually mild to moderate in severity. In some patients, however, sinusitis, recurrent bronchitis, or asthma-like symptoms become prominent. It is important that these symptoms be recognized as attributable to ribavirin, because dose modification (by 200 mg per day) or early discontinuation of treatment may be necessary.

Uncommon side effects of alpha interferon, peginterferon, and combination therapy (occurring in less than 2 percent of patients) include

• autoimmune disease (especially thyroid disease)
• severe bacterial infections
• marked thrombocytopenia
• marked neutropenia
• seizures
• depression and suicidal ideation or attempts
• retinopathy (microhemorrhages)
• hearing loss and tinnitus

Rare side effects include acute congestive heart failure, renal failure, vision loss, pulmonary fibrosis or pneumonitis, and sepsis. Deaths have been reported from acute myocardial infarction, stroke, suicide, and sepsis.

A unique but rare side effect is paradoxical worsening of the disease. This is assumed to be caused by induction of autoimmune hepatitis, but its cause is really unknown. Because of this possibility, aminotransferases should be monitored. If ALT levels rise to greater than twice the baseline values, therapy should be stopped and the patient monitored. Some patients with this complication have required corticosteroid therapy to control the hepatitis.

Algorithm for Treatment Make the diagnosis based on aminotransferase elevations, anti-HCV and HCV RNA in serum, and chronic hepatitis shown by liver biopsy. Assess for suitability of therapy and contraindications. Discuss side effects and possible treatment outcomes. Test for HCV genotype. Genotype 1: Test for HCV RNA level immediately before starting therapy (baseline level). Genotype 1: Start therapy with peginterferon alfa-2a in a dose of 180 mg weekly or peginterferon alfa-2b in a dose of 1.5 mg/kg weekly in combination with oral ribavirin in two divided doses of 1,000 mg daily if body weight is <> 75 kilograms. Genotype 2 or 3: Start therapy with peginterferon alfa-2a in a dose of 180 mcg weekly or with alfa-2b in a dose of 1.5 mcg per kilogram weekly and oral ribavirin 800 mg daily in two divided doses. All patients: At weeks 1, 2, and 4 and then at intervals of every 4 to 8 weeks thereafter, assess side effects, symptoms, blood counts, and aminotransferases. Genotype 1: At week 12, retest for HCV RNA level. If HCV RNA is negative or has decreased by at least two log10 units (such as from 2 million IU to 20,000 IU or from 500,000 IU to 5,000 IU or less), continue therapy for a full 48 weeks, monitoring symptoms, blood counts, and ALT at 4- to 8-week intervals. If HCV RNA has not fallen by two log10 units, stop therapy. Genotype 2 or 3: At 24 weeks, assess aminotransferase levels and HCV RNA and stop therapy. All patients: After therapy, assess aminotransferases at 2- to 6-month intervals. In responders, repeat HCV RNA testing 6 months after stopping.

Before Starting Therapy Do a liver biopsy to confirm the diagnosis of HCV, assess the grade and stage of disease, and rule out other diagnoses. In situations where a liver biopsy is contraindicated, such as clotting disorders, combination therapy can be given without a pretreatment liver biopsy. Test for serum HCV RNA to document that viremia is present. Test for HCV genotype (or serotype) to help determine the duration of therapy and dose of ribavirin. Measure blood counts and aminotransferases to establish a baseline for these values. Counsel the patient about the relative risks and benefits of treatment. Side effects should be thoroughly discussed. During Therapy Measure blood counts and aminotransferases at weeks 1, 2, and 4 and at 4- to 8-week intervals thereafter. Adjust the dose of ribavirin downward (by 200 mg at a time) if significant anemia occurs (hemoglobin less than 10 g/dL or hematocrit <> Adjust the dose of peginterferon downward if there are intolerable side effects such as severe fatigue, depression, or irritability or marked decreases in white blood cell counts (absolute neutrophil count below 500 cells/mm3) or platelet counts (decrease below 30,000 cells/mm3). When using peginterferon alfa-2a, the dose can be reduced from 180 to 135 and then to 90 mcg per week. When using peginterferon alfa-2b, the dose can be reduced from 1.5 to 1.0 and then to 0.5 mcg per kilogram per week. In patients with genotype 1, measure HCV RNA level immediately before therapy and again (by the same method) at week 12. Therapy can be stopped early if HCV RNA levels have not decreased by at least two log10 units, as studies have shown that genotype 1 patients without this amount of decrease in HCV RNA are unlikely to have a sustained response (likelihood is <> Reinforce the need to practice strict birth control during therapy and for 6 months thereafter. Measure thyroid-stimulating hormone levels every 3 to 6 months during therapy. Patients with genotypes 2 or 3 can stop therapy at 24 weeks. Patients with genotype 1 and a drop in HCV RNA by 12 weeks should continue therapy for 48 weeks. At the end of therapy, test HCV RNA by PCR to assess whether there is an end-of-treatment response. After Therapy Measure aminotransferases every 2 months for 6 months. Six months after stopping therapy, test for HCV RNA by PCR. If HCV RNA is still negative, the chance for a long-term "cure" is excellent; relapses have rarely been reported after this point.

Options for Patients Who Do Not Respond to Treatment

Few options exist for patients who either do not respond to therapy or who respond and later relapse. Patients who relapse after a course of interferon monotherapy may respond to a course of combination therapy, particularly if they became and remained HCV RNA negative during the period of monotherapy. The response rates and optimal dose (800 vs. 1,000 mg to 1,200 mg of ribavirin) and duration (24 or 48 weeks) of peginterferon and ribavirin for relapse or previous nonresponder patients have not been defined. The algorithm for treatment given above is for treatment of naive patients.

An experimental approach to treatment of non-responders is the use of long-term or maintenance interferon, which is feasible only if the peginterferon is well tolerated and has a clear-cut effect on serum aminotransferases or liver histology, despite lack of clearance of HCV RNA. This approach is now under evaluation in long-term clinical trials in the United States. New medications and approaches to treatment are needed. Most promising for the future are the use of other cytokines and the development of newer antivirals, such as RNA polymerase, helicase, or protease inhibitors.

source: http://digestive.niddk.nih.gov/ddiseases/pubs/chronichepc/index.htm