Chronic Hepatitis C: Current Disease Management

Alpha interferon is currently the only approved treatment for hepatitis C. It improves serum aminotransferase levels in 50 percent of patients during treatment, and a majority of these patients also become negative for HCV RNA by PCR. However, many of these patients relapse once interferon is discontinued. In patients who relapse, the reappearance of HCV RNA and rise of serum ALT levels usually occurs within 1 to 3 months after treatment; only rarely does it occur later. A sustained, long-term response (defined as no relapse at least 6 months after stopping interferon) occurs in 10 to 15 percent of patients who are treated for 6 months and 20 to 25 percent of those treated for 1 year.

Characteristics that predict a good response to interferon are absence of cirrhosis, a short duration of infection, low levels of HCV RNA in serum, and viral genotypes 2 and 3. None of these features are perfect predictors, but they can help in evaluating the chances of success.

Who Should Be Treated?

Patients with anti-HCV, HCV RNA, elevated aminotransferase levels, and evidence of chronic hepatitis on liver biopsy should be offered therapy with alpha interferon. A recent NIH Consensus Development Conference recommended that all patients with fibrosis on liver biopsy or at least moderate degrees of inflammation and necrosis should be treated, and that patients with milder histological disease be managed on an individual basis. Patient selection should not be based on symptoms, mode of acquisition, genotype of HCV, or serum HCV RNA levels.

Patients found to have cirrhosis 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 therapy is less likely to be successful in patients with cirrhosis than those without, and therapy has not been proven to improve survival or ultimate outcome.

Children and patients older than 60 years also should be managed on an individual basis, as the benefit in these patients has not been well documented. In 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 soon be available, at which point expanded indications for therapy would be appropriate.

In patients with clinically significant extra-hepatic manifestations, such as cryoglobulinemia and glomerulonephritis, long-term maintenance therapy with alpha interferon aimed at suppression of the disease may be needed rather than a 12-month course aimed at eradication of HCV RNA. In these patients, continuous therapy can be given 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 prospective controlled trials in patients who have

• Clinically decompensated cirrhosis due to hepatitis C.
• Normal aminotransferase levels.
• Severe depression or other neuropsychiatric syndromes.
• Autoimmune disease that is not well controlled (rheumatoid arthritis, psoriasis).
• Active substance or alcohol abuse.
• Immunosuppression, particularly those who have had a solid-organ transplant.

Patients with bone marrow compromise or cytopenias, such as low platelet counts (<75,000 cells/mm³) or neutropenia (<1,000 cells/mm³), should be treated with caution and frequent monitoring of cell counts.

Finally, the effects of interferon on the fetus are not well known. Female patients should agree to avoid becoming pregnant during therapy, and male patients should practice adequate forms of birth control until therapy is completed.

Current Optimal Treatment Regimens

In the United States, the approved regimen for alpha interferon is 3 million units (mu) by subcutaneous injection three times a week for 6 to 12 months. A recent NIH Consensus Development Conference recommended that therapy be given for 12 months. Treatment should be stopped early if aminotransferase levels do not improve and HCV RNA does not become undetectable within 12 weeks. Late responses are extremely rare, and continuing therapy provides no further benefit. Furthermore, therapy should be stopped if side effects are too troublesome. In some patients, lowering the dose to 2 mu may be necessary because of side effects; however, breakthrough with reappearance of HCV RNA and rises in ALT levels often occurs when the dose is reduced.

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 6-month course of interferon may respond to a second, longer course of therapy (lasting 12 to 18 months), particularly if they became and remained HCV RNA negative during therapy. New treatments are needed for those who do not respond to interferon at all. The most promising is ribavirin, an oral nucleoside analog, which is now being evaluated in combination with alpha interferon in large clinical trials. This combination may improve the long-term response rate above that achieved with interferon alone. Thus, the results of these trials may change recommendations regarding therapy.

Brief Recommendations for Evaluating and Monitoring Interferon Therapy

Before Beginning Interferon Treatment

• Do a liver biopsy to confirm the diagnosis, assess the grade and stage of disease, and rule out other diagnoses. In situations where a liver biopsy is contraindicated, such as clotting disorders, interferon can be given without a pretreatment liver biopsy.

• Measure serum HCV RNA by PCR to document that viremia is present.

• Measure blood counts and aminotransferases to establish the baseline for these values.

• Measure levels of serum thyroid-stimulating hormone (TSH) to rule out subclinical thyroid disease, which is common in patients with liver disease.

• Counsel the patient about the relative risks and benefits of treatment. Side effects should be thoroughly discussed.

During Treatment

• Measure blood counts (including platelets) and aminotransferases at 2- to 8-week intervals.

• Measure aminotransferase levels and HCV RNA by PCR at 3 months. If ALT is still elevated and HCV RNA is present, stop interferon treatment. If either ALT is normal or HCV RNA is undetectable or both (they usually improve together), continue therapy for 9 more months.

• Assess side effects, particularly psychological problems, regularly.

• Measure TSH levels every 6 months during therapy.

• At the end of therapy, test aminotransferases and HCV RNA to assess whether there is an end-of-treatment response.

After Treatment

• Measure aminotransferases every 8 weeks for 6 months.

• If aminotransferases are still normal 6 months after stopping treatment, measure serum HCV RNA by PCR to assess whether a "sustained" virological and biochemical response has occurred. If aminotransferases are normal and HCV RNA is negative at 6 months, the chance for a long-term "cure" is excellent; relapses have rarely been reported after this point.

Side Effects of Treatment

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

• Fatigue.
• Muscle aches.
• Nausea and vomiting.
• Skin irritation at the injection site.
• Low grade fever.
• Weight loss.
• Headache.
• 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 alleviate the muscle aches and low grade fever, and side effects may be less troublesome if interferon is taken in the evening. 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.

Uncommon side effects (occurring in less than 2 percent of patients) include

• Autoimmune disease (especially thyroid disease).
• Severe bacterial infections.
• Marked thrombocytopenia.
• Marked neutrophilia.
• Seizures.
• Depression with suicidal ideation or attempts.
• Retinopathy (microhemorrhages and cotton wool spots).
• Hearing loss.

Rare side effects include acute congestive heart failure, renal failure, visual loss, pulmonary fibrosis, and sepsis. Deaths have been reported from suicide and sepsis.

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

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