Factors Contributing to Ribavirin-Induced Anemia

Hideyuki Nomura; Hironori Tanimoto; Eiji Kajiwara; Junya Shimono; Toshihiro Maruyama; Nobuyuki Yamashita; Masanori Nagano; Masashi Higashi; Tamotsu Mukai; Yutaka Matsui; Jun Hayashi; Seizaburo Kashiwagi; Hiromi Ishibashi

J Gastroenterol Hepatol. 2004;19(11) 

In This Article

Discussion

The therapeutic effect of IFN monotherapy in patients with chronic hepatitis C with high viral loads is extremely low. It has been confirmed that the addition of ribavirin to IFN in these patients results in a higher therapeutic effect than with IFN alone.[8,9,10] The efficacy of pegylated IFN and ribavirin combination therapy has also been reported.[5,6] Several significant adverse reactions are, however, associated with ribavirin. One is hemolytic anemia.[8,9] There are patients who must discontinue combination therapy because of anemia, and it is therefore important to determine the factor(s) associated with anemia caused by ribavirin. It is also important to reduce the dose of ribavirin at as early a stage as possible to allow the safe continuation of treatment in patients who experience a marked fall in hemoglobin concentrations and to reduce the number of patients who must discontinue treatment. To do this, it is important to identify patients who will develop anemia in the early phase of treatment. For use as a predictive factor and for application to every patient who receives ribavirin, the test items must be simple, inexpensive, and quick. In this study we examined the factors of baseline age, sex, complete blood count, viral load and serotype.

Hemoglobin concentrations decreased during week 2 to week 8 and thereafter remained unchanged until the completion of treatment in this study. The reduction of hemoglobin concentrations as a result of ribavirin-induced anemia was the same as reported by van Vlierbergh et al.[13] All patients with anemia were observed by week 12. A 2 g/dL decrease of hemoglobin concentrations was observed at week 2 in patients with anemia. A significant relationship was also observed between the amount of reduction of hemoglobin concentrations at week 2 and the incidence of anemia. Hemoglobin concentrations of patients with ≥2 g/dL decrease from baseline at week 2 was significantly lower after 2 weeks. Therefore, the incidence of anemia was significantly higher in patients with ≥2 g/dL decrease from baseline at week 2. A decrease in hemoglobin concentrations by ≥2 g/dL at week 2 is predictive of further, more severe reduction in hemoglobin concentrations. It is therefore necessary to consider an earlier reduction in the ribavirin dose in such patients to prevent discontinuation of treatment because of anemia.

The mechanism of ribavirin-induced hemolytic anemia has not been clearly established. Lau et al. explain that ribavirin, following uptake into cells, is phosphorylated and converts to ribavirin triphosphates, which then must be dephosphorylated for elimination from cells.[14] However, because red blood cells lack dephosphorylation enzymes, ribavirin accumulates in cells and destroys the cells, causing hemolytic anemia.

The pretreatment hemoglobin concentration could be a significant factor in ribavirin-induced anemia. However, in this study, hemoglobin concentrations in patients with anemia decreased rapidly in the early stage after the start of administration of ribavirin. Hemoglobin concentrations in these patients thereafter decreased and became <10 g/dL. If the pretreatment hemoglobin concentration was >16 g/dL, anemia was not observed in any patient during administration of ribavirin, while if it was <16 g/dL, the incidence of anemia was similar in all grades.

Van Vlierbergh et al. have reported that many anemia patients, as high as 67%, were observed in their study.[13] However, they defined anemia as hemoglobin concentrations of <13.3 g/dL for men and <11.7 g/dL for women at week 8 after the start of treatment. We examined the factors of ribavirin-induced anemia for the purpose of more safe administration of ribavirin and to reduce treatment discontinuations. We defined ribavirin-induced anemia as hemoglobin concentrations of <10 g/dL. In the present study, anemia was observed in 18 patients (20%). In their study, seriously ill anemia patients who need to stop treatment cannot be distinguished. The relationship between the ribavirin dose by body weight and the incidence of anemia was not supposed to be observed in their study. Moreover, because the criteria for anemia was different for men and women, no relationship between sex and anemia was observed. In the present study, the first predictive factor of anemia was sex (women). The significant factors of anemia were also sex (women) and the ribavirin dose by body weight (≥12 mg/kg) by stepwise selection.

The package insert for ribavirin in Japan calls for the administration of 600 mg to patients weighing <60 kg and 800 mg to patients weighing ≥60 kg. The ribavirin dose may therefore exceed 12 mg/kg in patients weighing <50 kg and in patients weighing between 60 and 66 kg. More female patients tend to weigh <50 kg than men in Japan.

No relationship was observed between HCV-RNA negativity and anemia. In other words, preventing a reduction in hemoglobin concentrations as much as possible and minimizing treatment discontinuation, thereby raising therapeutic efficacy, appear to be important. Instead of changing the ribavirin dose at the level of 60 kg, per kilogram body weight dosing of ribavirin should be considered. The dose of ribavirin should not exceed 12 mg/kg and a more reduced dose should be considered for elderly female patients.

Tsubota et al. reported that plasma ribavirin concentration is elevated during week 4 to week 24 and then gradually decreases after discontinuation of treatment.[15] The sustained response rate was higher in patients with high plasma ribavirin concentrations, but the relationship between ribavirin concentrations and anemia was not clarified. Because the cost of assay of plasma ribavirin concentrations is high, it is not feasible to conduct measurement for all patients. Assay results are also not immediately obtainable. In contrast, the measurement of hemoglobin concentration is simple, quick and inexpensive. It is therefore extremely important to predict the patients who may develop anemia by determining hemoglobin concentrations at week 2.

In conclusion, careful administration is necessary in patients ≥60 years old, in female patients, as well as in patients receiving a ribavirin dose of ≥12 mg/kg. Patients who experience a fall in hemoglobin concentrations of 2 g/dL or more at week 2 after the start of treatment should be monitored with particular care.


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