HEPATITIS C MANAGEMENT: EFFICACY OF PEGINTERFERON AND STANDARD INTERFERON COMBINATION VERSUS MONOTHERAPY

Background

Hepatitis C virus (HCV) infection is the most common blood-borne infection worldwide and an important health care problem (National Center for Health Statistics, 1996; National Institutes of Health, 1997), as it represents the leading indication for liver transplantation. Nearly 4 million Americans are estimated to have hepatitis C, and deaths from HCV-associated chronic liver disease are estimated to range from 8,000-10,000 each year (National Center for Health Statistics, 1996; Alter, 1997). Approximately 20-30% of patients with chronic hepatitis C develop cirrhosis (Hoofnagle, 1997). The course of hepatitis C is variable among individuals, but it eventually can lead to chronic hepatitis, decompensated cirrhosis, and hepatocellular carcinoma.

Several advances in the management of chronic HCV infection have occurred in the last decade. More recent research has propelled a shift from interferon alfa monotherapy to combination therapy with pegylated interferon (peginterferon) and ribavirin as the standard treatment for chronic hepatitis C. Numerous clinical studies and review articles have been published in the recent literature, the aim of which is to investigate the efficacy of peginterferon versus standard interferon as monotherapy and combination therapy with ribavirin. Clearly defining the terminology of the treatment endpoints to better understand the clinical findings in these studies is important. An earlier review article used the following definitions:

• End-of-treatment response occurs on the basis of having no detectable HCV RNA (virologic response) at the end of the treatment.
  
  
• Sustained response occurs based on reference range ALT levels and no detectable HCV RNA at the end of the treatment and throughout the observation period after stopping the therapy. Sustained virologic response (SVR) is defined as the absence of detectable HCV RNA 24 weeks after cessation of therapy.
  
  
• Nonresponse to treatment is when ALT levels remain abnormal at all time points evaluated during the study period or ALT levels become elevated (or HCV RNA appears) after having been in the reference range (or having no detectable HCV RNA) on treatment.
  
  
• A histologic response is defined as a reduction in the Knodell score of 2 or more points compared to the baseline (Lindsay, 1997).

Peginterferon alfa-2a and ribavirin versus interferon alfa-2b and ribavirin combination therapy

A multicenter, randomized, controlled clinical trial was conducted involving 1121 interferon-naïve patients that compared the efficacy of peginterferon (180 µg SC each week) plus ribavirin (1000-1200 mg) with standard interferon alfa-2b plus ribavirin (Rebetron) and peginterferon alfa-2a monotherapy (Fried, 2002). Patients were treated for 48 weeks. All patients had abnormal ALT levels within 6 months of the initiation of the study and liver biopsies demonstrating chronic hepatitis, while 12-15% had cirrhosis. Approximately 65% of patients had genotype 1.

A greater proportion of patients who received peginterferon alfa-2a plus ribavirin were observed to have an SVR compared to patients who received interferon alfa-2b plus ribavirin (56% vs 44%) or peginterferon alfa-2a monotherapy (56% vs 29%). Patients with all HCV genotypes were more likely to have an SVR when treated with peginterferon alfa-2a plus ribavirin than with the other 2 regimens. The response rate was significantly higher for patients with genotype 2 or 3 compared to genotype 1 (76% vs 46%) with the peginterferon alfa-2a regimen. The overall safety profiles of the 3 treatment regimens were similar. In addition, patients with a 2-log decline in their HCV RNA titer or those who became HCV RNA negative within 12 weeks of initiation of the therapy had a 65% chance of achieving an SVR, which was subsequently termed as having an early virologic response. In contrast, of the patients who did not have a 2-log decline or undetectable levels of HCV RNA at week 12, 97% did not achieve an SVR. Other studies since have substantiated these findings (Ferenci, 2001; Ferenci, 2005). Thus, stopping therapy after 3 months in those patients who do not achieve an early virologic response should be considered. Therapy is generally discontinued in patients who have persistent detectable HCV RNA at the 24 week mark after initiation of therapy, even if those patients are considered responders.

Another study investigated the optimal duration of treatment with peginterferon alfa-2a and dosage of ribavirin (Hadziyannis, 2004). In this study, 1311 interferon-naïve patients were randomly assigned to peginterferon alfa-2a (180 µg SC/wk) plus ribavirin (either 800 or 1200 mg/d) for 24 or 48 weeks. Among patients with genotype 1, the highest SVR rate (52%) occurred after 48 weeks of treatment using the higher dose of ribavirin. In contrast, in patients with genotype 2 or 3 (80%), a shorter duration of treatment (24 weeks) and low-dose ribavirin (800 mg/d) was sufficient to achieve an SVR. Therefore, the National Institutes of Health Consensus conference recommends that patients with genotypes 2 and 3 should be treated with the lower dose of ribavirin for only 24 weeks.

Peginterferon alfa-2a versus interferon alfa-2a in monotherapy trials

In a study comparing peginterferon alfa-2a (180 µg/wk) and standard interferon alfa-2a (6 mU 3 times per week for 12 weeks followed by 3 mU 3 times per week for 36 weeks), the mean SVR rates were 39% and 19%, respectively (Zeuzem, 2000). In addition, histologic scores improved in both groups but were not significantly different, and genotype 1 was less likely to be associated with an SVR. In a more recent study, peginterferon alfa-2a 135 µg/wk and 180 µg/wk produced similar SVR rates, both of which were significantly higher than that achieved with interferon alfa-2a 3 times per week (Pockros, 2004). Furthermore, a significantly higher proportion of patients treated with the 180-µg dose of peginterferon alfa-2a had clinically significant histologic improvement. The results of this study are similar to those reported in the pivotal peginterferon alfa-2a trials, which have consistently demonstrated significantly greater SVR rates compared with the rates from treatment with interferon alfa-2a (Zeuzem, 2000; Heathcote, 2000; Reddy, 2001).

An earlier study found that an SVR to interferon therapy is associated with regression of fibrosis (Shiratori, 2000). In addition, it has been demonstrated that histologic improvement is more common in patients treated with interferon and ribavirin than in patients treated with interferon alone (McHutchison, 1998). Both observations support the findings that a greater proportion of patients treated with peginterferon alfa-2a combination therapy would have a histologic response, as stated earlier.

Future targets of therapy

Combining peginterferons with ribavirin considerably improves efficacy but at the expense of poor tolerability attributable to ribavirin, and a significant proportion of patients in these trials did not respond to treatment. Given the significant adverse effects attributed to interferon-ribavirin therapy, patients need to be screened carefully to assess their candidacy for this therapy. Future therapeutic developments may include 1 or more of the following approaches: understanding the HCV genomic organization, elucidating the viral life cycle and HCV replication strategy, and understanding the immune mechanisms required for viral propagation or infectivity (Sookoian, 2003). Therapies under development and evaluation for patients with hepatitis C include adjunctive use of the antiviral agent amantadine and the immunomodulatory agent thymalfasin as well as novel small molecules, which include the ribavirin analogs, viramidine and levovirin, and BILN 2061, an inhibitor of HCV serine protease (Foster, 2004).

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