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Anemia Caused by IFN/RBV Combination Therapy |
| Name: |
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WAZ |
| Date Posted: |
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Aug 21, 03 - 1:41 PM |
| IP Address: |
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68.173.159.27 |
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Anemia Caused by IFN/RBV Combination Therapy
The most notable adverse effect of RBV therapy is the development of a dose-dependent, extravascular hemolytic anemia, which is reversible with the discontinuation of the drug. The majority of patients receiving IFN/RBV experience a decrease in their Hb levels, which may be associated with fatigue, reduced exercise tolerance, and decreased quality of life.
Sulkowski and colleagues (2000) performed a retrospective analysis of pooled data from two combination therapy IFN/RBV clinical trials involving 655 treatment-naive and experienced patients receiving RBV with daily or thrice weekly IFN therapy as described below:
Study 1: IFN alfa-naive patients were randomized to receive RBV 1000-1200 mg/day based on body weight with IFN alfa 3 MIU daily or thrice weekly for 48 weeks
Study 2: IFN alfa-experienced patients were randomized to receive RBV 1000 mg/day with IFN alfa 3 MIU daily or thrice weekly for 4 weeks followed by thrice weekly dosing for 48 weeks.
Hemoglobin levels were determined at treatment weeks 0, 1, 2, and 4, and then monthly to week 48, and post-treatment weeks 4, 8, 12, 24, and 48. Ribavirin was reduced to 600 mg for a Hb less than 10 g/dL.
Study results demonstrated 10.3% of all patients had a Hb level of less than 10 g/dL. The incidence of Hb less than 10 g/dL was approximately 5-fold higher in women (20%, 95% CI: 13.7-27.5) than in men (4.8%, 95% CI: 2.9-7.5%); consequently, women required dose reduction of RBV more frequently than men.
Furthermore, the majority (56%) of patients experienced a significant reduction in Hb levels, defined as a decrease of greater than 3 g/dL from baseline levels, and more than 1/3 of patients experienced a greater than 25% reduction in Hb levels. Compared to women, men were significantly more likely to experience a decrease in Hb of greater than 3 g/dL during combination therapy (60% of men, 44% of women, RR 1.4, 95% CI: 1.2-1.6). Sulkowski and colleagues also observed that approximately 10% of men and 5% of women lost more than 5 g/dL of Hb during IFN/RBV therapy (Figure 13).
Figure 13. Magnitude of Hb Decline by Gender.
Sulkowski and colleagues evaluated the recovery of Hb following RBV dose reduction. One hundred and two patients required RBV dose reduction to 600 mg/day due to anemia, with a mean Hb level of 10.7 g/dL. The mean increase in Hb level at 4 to 8 weeks following dose reduction was 1.1 g/dL.
In a multivariate logistic regression analysis, the loss of greater than 27% of the baseline Hb level was associated independently with decreased creatinine clearance, higher baseline Hb levels, and increased age.
Thus, while only 10.3% of patients experienced a decline in Hb levels to less than 10 g/dL, the majority of men and women on IFN/RBV therapy experienced substantial reductions in their Hb levels of more than 25% from their pretreatment Hb levels. Researchers hypothesize that substantial relative declines in Hb may contribute significantly to the adverse effects on energy level and quality of life experienced by many patients receiving IFN/RBV therapy
Bone Marrow Suppression Due to IFN in Patients Receiving IFN Therapy With or Without RBV
In addition to the development of RBV-associated anemia, several studies suggest that patients receiving IFN or IFN/RBV therapy also experience IFN-associated suppression of hematopoesis, which may contribute to the decreases in Hb observed in patients receiving INF/RBV for the treatment of hepatitis C.
In the 3 large clinical trials comparing IFN alfa-2b alone to IFN alfa-2b plus RBV (Davis et al, 1998; McHutchison et al, 1998; Poynard et al, 199 , patients randomized to IFN and placebo experienced a small decrease in Hb levels (mean of approximately 1 g/dL), which was not associated with an increase in the reticulocyte count, suggesting that IFN monotherapy causes a decrease in Hb levels due to bone marrow suppression. In contrast, patients randomized to receive IFN and RBV experienced a substantial decrease in Hb levels (mean of >3 g/dL), which was associated with a brisk increase in reticulocyte count, indicative of a hemolytic anemia with an appropriate increase in RBC production
Anemia Associated With Combination IFN/RBV Therapy.
More recently, several studies indicated that the reticulocytosis observed in patients with RBV-related hemolysis is blunted by the concurrent IFN-related bone marrow suppression. In the above described study by De Franceschi and colleagues, the in vivo hematologic effects of RBV alone or in combination with IFN were evaluated in 11 patients. While the average Hb decrease was similar among the 6 patients receiving RBV 1000-1200 mg daily and the 5 patients receiving IFN 5 MIU thrice weekly and RBV 1000-1200 mg daily, the increases observed in the reticulocyte count at day 60 of treatment were significantly higher among those receiving only RBV (196 x 103 reticulocytes/µL, range 140 to 25 co |
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