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Abstract:

Pegylated interferons have been shown to be significantly more effective than non-pegylated (unmodified) versions in the treatment of hepatitis C. The clinical advantage of pegylated interferons is a sustained viral suppression that allows doses to be administered on a weekly basis. This randomized, placebo-controlled study was conducted in patients with chronic hepatitis C virus (HCV) infection to compare the effectiveness of two combination therapies (peginterferon alfa-2a with ribavirin and interferon alfa-2b with ribavirin) with peginterferon alfa-2a monotherapy as initial treatment strategies for chronic hepatitis C infection. The treatments were provided for 48 weeks with 24 weeks of follow-up data collection beyond treatment cessation. The primary endpoint of end-of-treatment virologic response was achieved by more patients in the peginterferon alfa-2a plus ribavirin group compared to the other two groups. In addition the virologic response was sustained significantly better through the post-treatment observation period in the peginterferon alfa-2a plus ribavirin compared to the other two groups. Side effect and safety profiles were similar among the three groups. 

interferon, peginterferon, ribavirin, hepatitis C, virologic response

Discussion:

Pegylated interferon plus daily ribavirin and peginterferon monotherapy are tested in this study, along with unmodified interferon plus ribavirin. The researchers note that peginterferon alfa has been shown to be clinically superior to their unmodified interferon counterparts in several trials. This study was designed to determine the most effective treatment for chronic hepatitis C, be that peginterferon alfa plus ribavirin, interferon alfa-2b plus ribavirin, or peginterferon alone.

Participants were only enrolled in the study after several measures were taken, including a liver biopsy result consistent with hepatitis C, and no participants were enrolled if they had received interferon before the start of the study, or had particular blood-derived diseases one year prior to trial inclusion. All participants were required to have at least 200 copies of HCV RNA per ml of serum and serum alanine aminotransferase levels above the upper limit of normal within a six month timeframe prior to the start of the study.

This randomized, multicenter study included 1121 participants and included 81 centers worldwide. Participants were randomized in a 2:2:1 ratio according to the groups shown below and received their enrollment regimen as was consistent with the group they were randomly assigned to between February 1999 and April 2001. The regimens included:

• Group 1 (n=453): Weekly subcutaneous injections of 180μg pegylated interferon alfa-2a with once daily 1000 mg or 1200 mg oral ribavirin*

• Group 2 (n=444): Three times weekly subcutaneous injections of 3 million units interferon alfa-2b with once daily 1000 mg or 1200 mg oral ribavirin*

• Group 3 (n=224): Weekly subcutaneous injections of 180μg pegylated interferon alfa-2a with once daily placebo

*Ribavirin dose was 1000 mg for patients who weighed ≤75 kg and 1200 mg for patients who weighed >75 kg

Participant’s end points were determined by when they achieved a sustained virologic response (defined by the researchers as the absence of detectable HCV RNA levels). Participants that had at least 20 weeks of therapy, the most recent HCV RNA level was used to determine effectiveness. For those with less than 20 weeks of therapy, they were grouped into the non-responder category. All patients that received any medication at all during the study period were considered in the results, and patients that had at least one safety analysis were included in the collection of safety data.

Peginterferon alfa-2a plus ribavirin proved to be much more effective at achieving a sustained virologic response than did the other treatment modalities.

Participants with Sustained Virologic Response

Success was determined by the achievement of sustained virologic response, one of the objectives for this trial was to determine if there was an early detection mechanism that could be used to assess the probability of later virologic response, if none was seen by week 12. In the peginterferon alfa-2a plus ribavirin group, 86% demonstrated a virologic response. It was noted that those that had an early virologic response were more likely to have a sustained virologic response, especially as compared to those that only showed a mild decrease in HCV RNA levels. Among those participants that did not show an early virologic response, 97 percent never did achieve a sustained virologic response. The researchers concluded that there was a correlation between the early presence of a virologic response (by week 12) and the probability of a sustained virologic response by week 48.

Some participants needed to be dropped from the study for various reasons including laboratory abnormalities and other adverse events. The incidence of these were similar among the three groups.

Adverse events usually seen in interferon treatment accounted for most of the adverse events seen in this study. Differences that were seen in adverse events between the treatment regimens included lower rates of flu-like symptoms and depression in the peginterferon alfa-2a arms compared with the interferon alfa-2b arm. Three deaths that were unrelated to treatment were reported during the study.

Results:

Peginterferon alfa-2a plus ribavirin was significantly more effective than interferon alfa-2b plus ribavirin in treating chronic hepatitis C in participants. The peginterferon alfa alone was not as effective nor did it achieve as sustained a response when compared with the combination therapies (peginterferon plus ribavirin or interferon plus ribavirin). Patients with high baseline viral load and resistant HCV genotype 1 showed better sustained response with peginterferon alfa-2a.

If clinicians can learn to use early predictors with confidence, note the authors, proper therapy can save patients the costs and side-effects associated with ineffective therapy. They found that if a virologic response had not been achieved by week 12, one was not likely to be ever seen. However, the researchers noted that incremental benefits of continuing therapy after a non-response indicated at week 12 must be evaluated for patients on an individual basis.

Adverse events are another reason to discontinue treatment in patients receiving interferon and peginterferon. However, the researchers found that those receiving peginterferon alfa-2a experienced less side-effects than those on unmodified interferon. Those receiving peginterferon alone fared best, having the fewest number of complications associated with their therapy. In those patients receiving peginterferon alfa-2a plus ribavirin where an early virologic response was seen and that required a reduction of their dosing, completion of their therapy with the dose reduction did not cause a substantial decrease in overall efficacy.

The researchers saw a significant improvement in sustained virologic response in the peginterferon alfa-2a plus ribavirin group, as compared to the other two groups in this study. They also felt that a useful clinical tool can be developed from their experience of analyzing HCV RNA levels at week 12 to predict the absence of a virologic response, and by doing so thereby saving the patient money and possible side-effects associated with a therapy regimen of this type. The trial demonstrated that peginterferon alfa-2a plus ribavirin offers a considerable clinical advantage over unmodified interferon.

Summary of Study 3