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The main goal of treatment of chronic hepatitis C is to eliminate detectable viral RNA from the blood. Lack of detectable hepatitis C virus RNA from blood six months after completing therapy is known as a sustained response. Studies suggest that a sustained response is equated with a very favorable prognosis and that it may be equivalent to a cure. There may be other more subtle benefits of treatment, such as slowing the progression of liver scarring (fibrosis) in patients who do not achieve a sustained response.
All current treatment protocols for hepatitis C are based on the use of various preparations of interferon alpha, which are administered by intramuscular or subcutaneous injection. Interferon alpha is a naturally occurring glycoprotein that is secreted by cells in response to viral infections. It exerts its effects by binding to a membrane receptor. Receptor binding initiates a series of intracellular signaling events that ultimately leads to enhanced expression of certain genes. This leads to the enhancement and induction of certain cellular activities including augmentation of target cell killing by lymphocytes and inhibition of virus replication in infected cells.
Interferon alfa-2a (Roferon-A; Hoffmann-La Roche), inteferon alpha-2b (Intron-A; Schering-Plough) and interferon alfacon-1 (Infergen; Intermune) are all approved in the United States for the treatment of adults with chronic hepatitis C as single agents. The recommended dose of interferons alfa-2b and alpha-2a for the treatment of chronic hepatitis C is 3,000,000 units three times a week, administered by subcutaneous or intramuscular injection. Treatment is administered for six months to two years. For interferon alfacon-1, the recommended dose is 9 mcg three times a week for first time treatment and 15 mcg three times a week for another six months for patients who do not respond or relapse. During the treatment periods with any of these recombinant interferons, the patient must be monitored carefully for side effects including flu-like symptoms, depression, rashes, other unusual reactions and abnormal blood counts. Treatment with interferon alone leads to a sustained response in less than 15% of subjects. Because of this low response rate, these interferons alone are rarely used for the treatment of patients with chronic hepatitis C.
More recently peginterferon alpha, sometimes called pegylated interferon, has been available for the treatment of chronic hepatitis C. There are two preparations of peginterferon alpha that have been studied in patients with hepatitis C: peginterferon alpha-2b (Peg-Intron; Schering-Plough) and peginterferon alpha-2a (Pegasys; Hoffmann-La Roche). The differences between these two preparations are subtle and most data suggest that they are equivalent with regards to efficacy and side effect profile. Peginterferon alphas differ from the older, unmodified interferon alphas in that a polyethylene glycol molecule is attached to the interferon molecule. As a result its elimination from the body is slowed and higher, more constant blood levels of interferon alpha are achieved with less frequent dosing. In contrast to unmodified interferon alpha, which must be injected three times a week to treat chronic hepatitis C, peginterferon alpha needs to be injected only once a week. With peginterferon alpha-2a alone, approximately 30% to 40% of patients achieve a sustained response to treatment for 24 to 48 weeks (Zeuzem et al. New England Journal of Medicine. 2000; 343:1666-1172; Heathcote et al. New England Journal of Medicine. 2000; 343: 673-1680).
The addition of ribavirin to interferon alpha is superior to interferon alpha alone in the treatment of chronic hepatitis C. Ribavirin is a synthetic nucleoside that has activity against a broad spectrum of viruses. In the United States, it was first approved in aerosol form for the treatment of a certain type of respiratory virus infection in children. In several studies, oral ribavirin was examined as a single agent for the treatment of adults with chronic hepatitis C. Although decreases in serum ALT activities were seen with treatment, the overall results of these studies were discouraging as sustained-responses were rarely achieved. The FDA did not approve ribavirin alone for hepatitis C. Because of its partial effectiveness, ribavirin was studied in subsequent trials in combination with interferon alpha. FDA approval of interferon alpha-2b plus ribavirin for the treatment of individuals with chronic hepatitis C who "relapsed" after previous interferon alpha therapy was based on the results of two controlled, double-blind clinical trials involving 345 subjects. "Relapsers" were defined as patients who had normal serum ALT activities at the end of up to 18 months of alpha interferon therapy with abnormal ALT activities within one year following the end of the most recent course of therapy. Subjects in these trials received either injections of interferon alpha-2b at a dose of 3 million units three times a week and either oral ribavirin at a dose of 1.0 g to 1.2 g daily or a matched placebo for 24 weeks of treatment. Six months after treatment was discontinued, 45.7% of subjects who received interferon alpha-2b plus ribavirin had undetectable serum viral RNA as compared to 4.7% who received only interferon alpha-2b.
Subsequent studies showed that the combination of interferon alpha-2b plus ribavirin is more effective in achieving a sustained response than interferon alpha-2b alone in the treatment of patients with chronic hepatitis C not previously treated with interferon. This led to FDA approval for this indication in December 1998. Results from three double-blind, placebo-controlled trials supporting this were published in 1998 (Reichard et al. Lancet. 1998; 351:83-87; Poynard et al. Lancet. 1998; 352:1426-1432; McHutchison et al. New England Journal of Medicine. 1998; 339:1485-1492). The controlled trial by Reichard et al. studied 100 previously untreated patients with chronic hepatitis C and compared 24 weeks of interferon alpha-2b (3,000,000 units three times a week) alone to the same regimen in combination with ribavirin (1.0 g or 1.2 g daily). In the interferon alpha-2b plus ribavirin group, 36% of 50 subjects had undetectable serum virus RNA 24 weeks after stopping treatment as compared to 18% of 50 in the interferon alpha-2b alone group (P = 0.047). Sustained responses were also significantly greater in the combination group one year after stopping treatment. Seven subjects were withdrawn from the combination group because of non-compliance or side effects compared to 3 subjects receiving interferon alpha-2b alone. The difference in response rates was greater in the subjects with higher (>3,000,000 equivalents per ml) pre-treatment concentrations of viral RNA in serum than in those with lower concentrations. In the trial by Poynard et al., 832 patients were enrolled and randomly assigned to receive either interferon alpha-2b plus placebo for 48 weeks, interferon alpha-2b plus ribavirin for 48 weeks or interferon alpha-2b plus ribavirin for 24 weeks. Sustained responses were achieved in 43% of patients who received combination therapy for 48 weeks, 35% of patients who received combination therapy for 24 weeks and 19% of the patients who received interferon alpha-2b alone. Both combination groups had statistically significant better responses than the group who received interferon alpha-2b alone. McHutchison et al. randomized 912 patients with chronic hepatitis C to receive either interferon alpha-2b alone or in combination with ribavirin for 24 or 48 weeks. The sustained response rates were 31% and 38% for those receiving combination therapy for 24 or 48 weeks, respectively, compared to 6% and 13% for those receiving interferon alpha-2b alone for 24 or 48 weeks respectively. The differences were significant between the combination and mono therapy groups. More patients in the combination group also had improvements in liver biopsy after treatment.
Most recently, the FDA has approved the combination of peginterferon alpha plus ribavirin for for the treatment of chronic hepatitis C. For eligible patients with chronic hepatitis C, a peginterferon alpha plus ribavirin is likely to be the best treatment option for the near future. Clinical trials have show that the sustained response rate is around 50% of patients given this combination for 24 to 48 weeks.
Interferon alpha, with or without ribavirin, is associated with may side effects. During treatment, patients must be monitored carefully for side effects including flu-like symptoms, depression, rashes, other unusual reactions and abnormal blood counts. Ribavirin is associated with a significant risk of abnormal fetal development and women of childbearing potential should not begin therapy until a report of a negative pregnancy test has been obtained and not become pregnant during treatment. In general, the patient probably needs to have blood tests approximately once a month, and somewhat more frequently at the beginning of treatment. Patients considered for treatment with interferon alpha-2b plus ribavirin should not have the complications of serious liver dysfunction and such subjects should only be considered for treatment of hepatitis C in specialized studies. Certain groups of patients who cannot take ribavirin, for example those with anemia, heart disease or kidney disease, may be treated with peginterferon alpha alone.
The question of viral genotype often comes up in discussing treatment of chronic hepatitis C. Most studies indicate that genotypes 1a and 1b are more resistant to treatment with any interferon alpha-based therapy than non-type 1 genotypes. For this reason, some doctors may prescribe longer durations of treatment for patients infected with viral genotypes 1a or 1b.
In summary, the best available current treatment for chronic hepatitis C of peginterferon alpha plus ribavirin leads to an overall sustained response rate in over 50% of all patients. The sustained response rates are even better for individuals infected with non-type 1 genotypes of the hepatitis C virus. As the currently available interferon alpha-based treatments for chronic hepatitis C are associated with many side effects and effective in only about half of patients, more research is definitely needed to develop safer, more effective and cheaper drugs (see Evolving Treatments for Chronic Viral Hepatitis C).