IDEAL Study Shows that Greater Hemoglobin Decline during Treatment with Pegylated Interferon plus Ribavirin Is Associated with Better Response

By Liz Highleyman

Chronic hepatitis C patients who experience larger decreases in hemoglobin during treatment with pegylated interferon plus ribavirin are more likely to achieve sustained virological response (SVR), according to study findings presented at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL 2009) last month in Copenhagen.

Ribavirin may cause hemolytic anemia, a condition in which red blood cells are destroyed and levels of hemoglobin -- the protein that carries oxygen -- are reduced. This side effect leads to ribavirin dose reduction in approximately 30% of hepatitis C patients, and decreasing the ribavirin dose raises the risk of HCV relapse after completion of treatment. Erythropoietin (EPO), a hormone that stimulates red blood cell production, may be used to help patients stay on therapy.

In the IDEAL Study (sponsored by Schering-Plough), 3070 HCV genotype 1 patients were randomly assigned to receive 1.0 or 1.5 mcg/kg/week pegylated interferon alfa-2b (Schering-Plough's PegIntron) plus 800-1400 mg/day weight-adjusted ribavirin, or else 180 mcg/week pegylated interferon afa-2a (Roche's Pegasys) plus 1000-1200mg/day weight-adjusted ribavirin, all for 48 weeks.

As previously reported, patients who received Pegasys had a higher end-of-treatment (EOT) response rate, but those taking PegIntron had a lower relapse rate, so SVR rates ended up about the same.

In the analysis presented at this year's EASL meeting, investigators looked at the relationship between anemia and sustained response. Anemia was defined as a hemoglobin level < 10 g/dL; 3023 patients had hemoglobin measurements at baseline and at least once during therapy. EPO use was permitted for anemic patients after protocol-defined ribavirin reductions.

Results

Overall, anemia occurred in 865 (28%) patients, 449 (52%) of whom used EPO.

Among all patients, the mean maximum hemoglobin decline was 4 g/dL.

The end-of-treatment response rate was significantly associated with the magnitude of hemoglobin decline (P< 0.0001):

Hemoglobin decline > 3 g/dL: EOT rate 61.6% (1386 out of 2250);

Hemoglobin decline < 3 g/dL: EOT rate 41.8% (323 out of 773). \

The likelihood of sustained response was also significantly associated with the magnitude of hemoglobin decline (P< 0.0001):

Hemoglobin decline > 3 g/dL: SVR rate 43.7% (984 out of 2250);

Hemoglobin decline < 3 g/dL: SVR rate 29.9% (231 out of 773).

Use of EPO was significantly associated with higher SVR rate among patients with an early onset of anemia, but not those with a later onset:

Anemia onset < 4 weeks:

EPO use: SVR rate 43.0% (58 out of 135);

No EPO: SVR rate 23.5% (19 out of 81)(P = 0.004).

Anemia onset > 4-8 weeks:

EPO use: SVR rate 47.6% (49 out of 103);

No EPO: SVR rate 29.0% (18 out of 62)(P = 0.019).

Anemia onset > 8-12 weeks:

EPO use: SVR rate 47.4% (27 out of 57);

No EPO: SVR rate 51.6% (32 out of 62)(P = 0.644).

Anemia onset > 12 weeks:

EPO use: SVR rate 57.8% (89 out of 154);

No EPO: SVR rate 61.6% (130 out of 211)(P = 0.462).

Patients with early-onset anemia treated with EPO also had a lower rate of treatment discontinuation than those with later-onset anemia.

Based on these findings, the investigators concluded, "Among HCV genotype 1-infected patients treated with [pegylated interferon/ribavirin], the magnitude of hemoglobin decline is strongly associated with the likelihood of SVR."

"The effect of EPO varied by time to anemia; no benefit was observed for patients who became anemic after treatment week 8," they continued. "These data suggest that hemoglobin decline may be a pharmacodynamic marker of treatment effectiveness and that the primary effect of EPO was to prevent treatment discontinuation in patients with early anemia."

Johns Hopkins University School of Medicine, Baltimore, MD; Virginia Commonwealth University Medical Centeru, Richmond, VA; Beth Israel Deaconess Liver Center, Boston, MA; University of Pennsylvania Health System, Philadelphia, PA; McCone Endoscopy Center, Alexandria, VA; Clinical Center for Liver Diseases, Dallas, TX; Thomas Jefferson University, Philadelphia, PA; Brooke Army Medical Center, Fort Sam Houston, TX; Schering-Plough Research Institute, Kenilworth, NJ; Duke Clinical Research Institute, Durham, NC.

5/22/09

Reference
M Sulkowski, M Shiffman, N Afdhal, and others. Hemoglobin Decline Is Associated With SVR among HCV Genotype 1-Infected Persons Treated with Peginterferon (Peg)/Ribavirin (RBV): Analysis from the IDEAL Study. 44th Annual Meeting of the European Association for the Study of the Liver (EASL 2009). Copenhagen, Denmark. April 22-26, 2009.

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