Clinical Management

Establishing the diagnosis of chronic hepatitis C can be difficult. Many patients with chronic hepatitis C have fluctuating ALT activity, and it is easy to miss the periodic elevations that occur. Therefore, anti-HCV positive patients with normal ALT values on initial determination should be periodically tested to be certain that intermittent elevations are not occurring. Anti-HCV-positive patients with elevated ALT values should be referred to a specialist for further evaluation that may include liver biopsy, and for possible treatment.

Indications for Treatment

Treatment with alpha interferon is generally recommended for patients with chronic hepatitis C who are at the greatest risk for progression to cirrhosis. These patients generally have persistently elevated ALT levels, detectable HCV RNA, and a liver biopsy with either portal or bridging fibrosis and at least moderate degrees of inflammation and necrosis.

Indications for treatment in patients with persistent ALT elevations, but with less severe histologic changes (i.e., no fibrosis and minimal necroinflammatory changes) are less clear. In these patients, observation -- including serial ALT measurements and liver biopsy every 3 to 5 years -- may be an acceptable alternative to treatment with interferon because progression to cirrhosis is likely to be slow, if at all.

Patients with persistently normal ALT values should not be treated with interferon, and patients with compensated cirrhosis (without jaundice, ascites, variceal hemorrhage, or encephalopathy) may not benefit from interferon treatment. In addition, patients with advanced cirrhosis who may be at risk for decompensation with therapy should not be treated. Interferon treatment is not licensed for patients below 18 years of age.

Treatment of patients who are drinking significant amounts of alcohol or who are injecting illicit drugs should be delayed until these habits have been discontinued for at least 6 months. Contraindications to treatment with interferon include major depressive illness, cytopenias, hyperthyroidism, renal transplant, and evidence of autoimune disease.

Treatment Guidelines

Most of the clinical trials of patients with chronic hepatitis C have evaluated interferon alpha-2b. The recommended regimen is 3 million units administered subcutaneously 3 times per week for 12 months. Using this regimen, approximately 50% of treated patients have a complete response, with normalization of serum ALT activity and a loss or decrease of HCV RNA in serum at the end of therapy. Up to 25% have a sustained response one or more years after therapy is stopped. For patients who do not respond at the end of therapy, retreatment with a standard dose of interferon is rarely effective. Patients who have persistently increased ALT levels and detectible HCV RNA in serum after 3 months of interferon are unlikely to respond to treatment. For these patients, interferon treatment should be discontinued, and they should be encouraged to participate in clinical trials of alternative treatments.

Many patients with biochemical and virologic response to interferon also have had histological improvement found on liver biopsy. However, it should be recognized that the effects of interferon treatment on important clinical outcomes, including quality of life and disease progression, have not been determined.

Decreased interferon response rates have been found in patients with higher serum HCV RNA titers and HCV genotype 1; however, treatment should not be withheld on the basis of these parameters.

A majority of patients receiving interferon experience flu-like symptoms early in treatment, but these symptoms diminish with continued treatment. Later side effects include fatigue, bone marrow suppression, and neuropsychiatric effects such as apathy, cognitive changes, irritability, and depression. The frequency of side effects can be reduced by giving interferon at night, and the severity of the flu-like symptoms can be reduced by pretreatment with acetaminophen. Even so, the interferon dosage must be reduced in 10% to 40% of patients because of the severity of side effects, and treatment must be discontinued in 5% to 15%.

Preliminary data from experimental studies suggest that combination therapy with ribavirin and interferon will increase the proportion of patients who have a sustained response. Other treatments that have been tried, including corticosteroids, ursodiol, and thymosin, have not been effective. Because high iron levels in the liver may reduce the efficacy of interferon, the use of iron reduction therapy (phlebotomy or chelation) in combination with interferon has been studied, but the results have thus far been inconclusive.