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By Diana Swift

NEW ORLEANS, LA--Side effects such as severe fatigue are dose-limiting in a significant proportion of patients receiving pegylated interferon and ribavirin for chronic hepatitis C. "During treatment, 20 to 40 per cent may require a dose modification of either drug, and data from earlier studies suggest that when you reduce the doses, the antiviral effect may be diminished, said Mitchell L. Shiffman, MD, Chief of Hepatology, Virginia Commonwealth University, Richmond, VA.

However, the data stem from retrospective re-analyses of clinical trials, in which investigators were unaware of the impact of dose reduction before the trials were designed. "Furthermore, the trials were not designed to evaluate the impact of dose reduction, and the reductions were rigidly mandated by the study protocols. Doses had to be reduced by fixed amounts and once you reduced a dose, you could not go back up-all of which place significant limitations on the data."

These early findings suggested that dose reduction or cessation caused sustained virological response (SVR) to drop by roughly half-from 65 per cent for patients treated with the maximal dose of peginterferon and ribavirin for 48 weeks to about 35 per cent. The first study to point out the impact of dose reduction (McHutchison et al, Gastroenterology 2002;123:1061) did not differentiate between which drugs were reduced-one or the other or both- and whether the medication was merely dose-reduced or stopped altogether. "As a result, it wasn't clear whether dose reduction or the cessation of treatment had the greater impact," Dr. Shiffman said.

More recent studies have tried to tease out the differences between dose reduction and dose discontinuation. Data presented at the 2001 annual meeting of the American Association for the Study of Liver Diseases by Dr Peter Ferenci, MD, a Professor in the Department of Internal Medicine, University of Vienna, Austria, show that dose reduction does not impact SVR to as great an extent as dose discontinuation. Patients with HCV genotype 1 who dose-reduced after they had achieved an early virologic response had a decline in SVR of only about 10 percentage points, from 67 to 56 per cent. In contrast, those patients who stopped treatment prematurely had an SVR of only seven per cent. A similar relationship was observed for patients with HCV genotypes 2 and 3.

Most recently, data from the lead-in phase of the National Institute of Health-sponsored HALT-C trial has evaluated the effects of discontinuing ribavirin and peginterferon by various amounts and the timing of when this dose reduction. The doses evaluated were more than 80 per cent of the starting dose, 80 to 60 per cent and less than 60 per cent of the starting dose. During the first 20 weeks of treatment, a stepwise reduction in peginterferon and ribavirin was associated with a stepwise decline in SVR from a maximal value of 21 per cent to a minimum of 11 per cent. In contrast, dose reduction after week 20, when patients were already HCV RNA-negative had no impact on SVR."These data suggest that the dose of peginterferon or ribavirin could be reduced in response to side effects that occur after week 20 without impacting SVR." Dr. Shiffman said. However, this study did not examine the effects of peginterferon and ribavirin independently. As a result, it remains unclear if it is peginterferon dose reduction or ribavirin dose reduction that is more important.

Some would argue that even with small reductions in dosage, SVR is adversely affected and the patient fails to get the maximum benefit of antiviral therapy. These individuals favour the use of hematologic growth factors to mitigate dose-limiting side effects. Recent data, however, suggest that the use of growth factors to prevent dose reduction may not be necessary after Week 20 in patients who have already achieved a virologic response. Supporting this observation is McHutchison's study in which dose reduction after Week 12 reduced SVR only slightly, from 62 per cent to 51 per cent.

The current obstacle in the U.S. to the use of a growth factor such as erythropoietin-alfa is that this medication is not FDA-approved for this indication, and requests to utilize this agent to correct ribavirin-induced anemia is frequently denied. In some cases, the physician may be allowed to utilize this agent on appeal, but by then the hemoglobin has declined to the point that the dose of ribavirin dose has already been reduced. At this point, the growth factor may correct anemia and improve quality of life, but may have little impact on SVR. No data have yet demonstrated that use of growth factors to correct ribavirin-induced anemia can improve SVR.

Two recently published studies demonstrated that growth factors can correct anemia, improve quality of life and symptoms of severe fatigue (Dietrich et al, Am J Gastro 2003; Afdahl Gastroenterology 2004). Unfortunately, neither of these studies addresses whether growth factors impact virologic response, and further investigation is needed (the manufacturers of two growth factors are currently planning new studies). "The current situation is a catch 22," Dr. Shiffman said. "By the time you do the end-runs necessary to get approval for a growth factor, it may be too late to impact what you want to impact."

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