This study demonstrates that considerable and potentially clinically significant decreases in hemoglobin from baseline can be predicted by a decrease in hemoglobin of ≥1.5 g/dL after only 2 weeks of therapy (RHR). This may provide clinicians with an early opportunity to evaluate the pros and cons of reducing the dose of ribavirin in patients at a high risk of developing anemia, or to consider the later use of hematological growth factors to treat ribavirin-associated anemia thereby enabling patients to maintain their ribavirin exposure. Early indicators of subsequent considerable anemia should prompt the physician to primarily consider early and small reductions in ribavirin dose (200 mg decrements) to reduce the risk of considerable anemia while maintaining adequate exposure to ribavirin. In addition, recent trials have demonstrated that higher starting doses of ribavirin can improve SVR rates in difficult-to-treat populations,9–11
making the early identification of patients at risk of significant hemoglobin reductions increasingly important. Growth factors may be considered as an adjunct to dose reduction but should be used at the lowest dose to gradually increase hemoglobin concentrations to the lowest level sufficient to maintain ribavirin dosing – they should not be used to target hemoglobin levels >12 g/dL and should not result in increases of >1 g/dL over a 2-week period.12
In our analysis we identified several independent baseline factors, including race, cirrhosis, hemoglobin count, and creatinine clearance, that were predictive of subsequent development of considerable hemoglobin decreases at week 4, allowing physicians the opportunity to identify patients at heightened risk of developing anemia even before starting therapy.
Our findings confirm other recent reports of predictors of anemia. Although Spangler and colleagues found no baseline predictors of ribavirin-associated anemia in a small study of 58 patients infected with HCV-1, they did show that 81% of patients with a ≥1.5 g/dL drop in hemoglobin at week 2 had considerable anemia at week 4 compared with only 18% of patients with a <1.5 g/dL hemoglobin drop at week 2 (p<0.001).7
These finding are remarkably similar to those of our own.
In a different analysis based upon a generalized additive logistic model, the probability of anemia has been calculated to increase from 6% to 16% as a function of ribavirin dose (from 12 mg/kg/day to 16 mg/kg/day).13
A number of baseline characteristics were prognostic factors for anemia, including gender, baseline hemoglobin, age, baseline ALT, and cirrhosis. Interestingly, in our analysis, gender and age were not shown to be independent predictors of considerable hemoglobin decrease at week 4 in the multiple logistic regression analysis (both p>0.05).
Our results and those of others clearly show that anemia is a common and significant problem during treatment with interferon and ribavirin. A decline in hemoglobin begins shortly after initiation of treatment and generally reaches the lowest level after 4 to 6 weeks of therapy.6,14
Indeed, treatment-induced anemia has been shown to be one of the most frequently reported adverse events in pivotal trials and contributes to dose reductions and treatment discontinuations.1,2,6,8,15–18
Although anemia is reversible when therapy is discontinued, it has a considerable impact on treatment outcome in relation to adequate ribavirin dosing. Compared with interferon or peginterferon monotherapy, the combination of interferon and ribavirin greatly increased the rate of SVR and decreased the risk of relapse after discontinuation of therapy.1,2
In our analysis, while the rate of SVR among those patients with hemoglobin decreases ≥2.5 g/dL was similar to that among patients without such decreases, it was shown that across the whole range of hemoglobin drops, either at week 2 or week 4, greater decreases in hemoglobin were associated with a lower probability of achieving an SVR. Consequently the failure to show a significant reduction in SVR in our analysis may be explained by dichotomizing the population at hemoglobin decreases of ≥2.5 g/dL and those with smaller decreases in hemoglobin.
It has been suggested that higher exposure to ribavirin (15 mg/kg) may greatly improve treatment efficacy, especially by decreasing the risk of relapse. However, this approach is anticipated to have a significantly higher association with anemia.13,19
Certainly, ribavirin is not the only cause of treatment-related anemia, as interferon has been shown to suppress bone marrow hematopoiesis,20
and erythropoietin production is blunted in patients with anemia receiving peginterferon and ribavirin.21
In conclusion, although associated with anemia, ribavirin is a critical component to the successful treatment of HCV. To maintain the highest likelihood of achieving an SVR the dose of ribavirin should be initiated at the highest appropriate dose and maintained for as long as possible. In our analysis, achieving an RHR (decline in hemoglobin of ≥1.5 g/dL at week 2) was a reliable predictor of greater and potentially clinically relevant decreases in hemoglobin later in the course of peginterferon and ribavirin therapy and provides an early indication that the dose of ribavirin may need to be modified. However, when warranted, the dose of ribavirin should be reduced by the smallest decrement possible (200 mg), avoiding reduction to ≤60% of the target dose since this is known to be associated with a significant reduction in the rate of SVR.
What is current knowledge?
- Anemia is common following interferon and ribavirin therapy
- Dose modifications of ribavirin for anemia may result in a diminished therapeutic response
What is new?
- Determination of >1.5 gm/dL decline in hemoglobin at week 2 strongly predicts >2.5 gm/dL decline at week 4.
- Independent variables associated with a decrease in hemoglobin: baseline creatinine clearance and a rapid decline in hemoglobin at week 2.