Address correspondence to: E. Beth Devine, PharmD, MBA, Research Assistant Professor, Department of Pharmacy, University of Washington, Box 357630, Seattle, WA 98195–7630. E-mail: email@example.com.
Objectives: Recently published studies have demonstrated increased efficacy and cost-effectiveness of combination therapy with interferon and α-2b/ribavirin compared with interferon-alpha monotherapy in the treatment of chronic hepatitis C (CHC). Combination therapy is associated with a clinically important adverse effect: ribavirin-induced hemolytic anemia (RIHA). The objective of this study was to evaluate the direct health-care costs and management of RIHA during treatment of CHC in a clinical trial setting.
Methods: A systematic literature review was conducted to synthesize information on the incidence and management of RIHA. Decision-analytic techniques were used to estimate the cost of treating RIHA. Uncertainty was evaluated using sensitivity analyses.
Results: RIHA, defined as a reduction in hemoglobin to less than 100 g/L, occurs in approximately 7% to 9% of patients treated with combination therapy. The standard of care for management of RIHA is reduction or discontinuation of the ribavirin dosage. We estimated the direct cost of treating clinically significant RIHA to be $170 per patient receiving combination therapy per 48-week treatment course (range $68–$692). The results of the one-way sensitivity analyses ranged from $57 to $317. In comparison, the cost of 48 weeks of combination therapy is $16,459.
Conclusions: The direct cost of treating clinically significant RIHA is 1% ($170/$16,459) of drug treatment costs. Questions remain about the optimal dose of ribavirin and the incidence of RIHA in a real-world population. Despite these uncertainties, this initial evaluation of the direct cost of treating RIHA provides an estimate of the cost and management implications of this clinically important adverse effect.
It is estimated that up to 80% of individuals exposed to hepatitis C virus develop chronic infection . Worldwide prevalence rates of chronic hepatitis C (CHC) range from 0.3% in Australia to 14.5% in Egypt, and the hepatitis C virus infects over 170 million people worldwide . The prevalence rate in the US population is 1.8%, corresponding to a caseload of almost 4 million individuals . Progression to cirrhosis and end-stage liver disease occurs in many patients, resulting in significant morbidity from the complications of decompensated disease, including variceal bleeding, hepatic encephalopathy, and ascites . Furthermore, CHC is the leading indication for liver transplantation in the United States .
Until recently, interferon-alpha has been the mainstay of therapy . However, sustained biochemical and virologic responses are uncommon with interferon-alpha monotherapy [7,8]. Combination therapy with interferon α-2b and ribavirin has increased the rate of sustained biochemical, virologic, and histologic responses to initial therapy and after relapse following interferon-alpha monotherapy. Only 15% to 20% of treatment-naïve patients with CHC have a sustained virologic response to interferon-alpha monotherapy when measured 24 weeks after treatment. Combination therapy has increased the sustained virologic response to 35% to 43% 24 weeks after discontinuation of a 24-week course of therapy . This combination has recently been approved in the United States for treatment of both initial infection and relapse [9–11]. The major dose-limiting toxicity of ribavirin is reversible hemolytic anemia. A mean maximum decrease in hemoglobin of 29 to 31 g/L was observed in clinical trials , with hemoglobin values of less than 100 g/L in approximately 7% to 9% of patients [9–11].
Ribavirin-induced hemolytic anemia (RIHA) is typically managed with reduction or discontinuation of the ribavirin dosage, but transfusion of packed red blood cells is occasionally necessary in cases of severe or symptomatic anemia . Some clinicians are exploring the use of the erythroid blood progenitor precursor epoetin for the treatment of RIHA, primarily in patients undergoing liver transplants [14–17].
The purpose of this study is to analyze the direct health-care costs associated with the treatment of clinically significant RIHA in the context of overall drug-therapy costs. Management strategies for minimizing this adverse effect are also discussed, including treating RIHA with epoetin. Uncertainty in the incidence of RIHA in a real-world setting underscores the importance of RIHA as an adverse effect of clinical concern.
We performed a systematic literature review to assess the incidence and treatment of RIHA. We searched the MEDLINE database from 1991 through August 1999 using the key words hepatitis C, interferon, and ribavirin. In an effort to capture more recent information on RIHA, we conducted a focused search of MEDLINE, the Drugs and Pharmacology Database (EMBASE), and International Pharmaceutical Abstracts (IPA) for 1996 through August 1999, using the search term ribavirin-induced hemolytic anemia. Thirty English-language studies, abstracts, and review articles were found. References cited in relevant articles from this initial bibliography were reviewed for additional studies. All studies were reviewed for inclusion in the analysis. Studies involving treatment with ribavirin monotherapy, or interferon α-2b and ribavirin combination therapy that included incidence and treatment of adverse effects, were included in the study. Case reports, abstracts with insufficient data on the incidence of RIHA, and early versions of subsequently published reports were excluded. The selected studies were grouped according to the number of patients included in the studies, patient characteristics, and treatment regimens, resulting in seven distinct groupings of trials [9–11,14–36](Table 1).
Using decision-analytic techniques, a model (Fig. 1) was constructed to estimate the incidence and costs of RIHA. The model represents a cohort of patients with CHC receiving interferon α-2b/ribavirin therapy for a 48-week treatment course. Patients with decompensated cirrhosis and underlying hemolysis were excluded from the model.
Because RIHA usually appears within 2 to 4 weeks of initiation of therapy , the branches of the model where the dose of ribavirin was reduced or the drug discontinued included only 4 weeks of combination therapy. Patients in whom ribavirin was discontinued completed the remainder of the treatment course with interferon-alpha therapy only. The current clinical standard of care for dosage reduction, a 50% reduction in the ribavirin dosage, was assumed .
Likelihood of Events
Data from three large, randomized trials were used to estimate the probability in the base case [9–11]. The percentage of patients requiring dosage reduction, or in whom ribavirin was discontinued, or who required transfusions or administration of epoetin, were obtained from these trials and verified with a review of the data prepared by Maddrey . Because definitions of clinically significant hemolytic anemia and mild, moderate, and severe anemia were not available in the literature, these categories were extrapolated using the absolute hemoglobin reductions published by Maddrey . The mean reduction in hemoglobin from baseline in the trials was 29 to 31 g/L. Based on Maddrey's work, we designated an absolute decrease in hemoglobin of greater than 20 g/L as clinically significant. Accordingly, we defined mild hemolytic anemia as an absolute decrease of 20 to 30 g/L, a moderate decrease between 30 and 40 g/L, and a severe decrease as greater than 40 g/L. Transfusions were used in only 0.1% of the patients in these trials, and only in the patients in whom the drug was discontinued. This percentage was divided equally between patients experiencing moderate or severe anemia and those who subsequently discontinued ribavirin as represented in the decision-tree model of RIHA in Figure 1. Epoetin was not used in the phase III trials and thus was not included in the base case [9–11]. The probabilities for the base case are listed in Table 2.
Developing not clinically significant hemolytic anemia
Developing mild hemolytic anemia, given development of clinically significant anemia
Developing moderate hemolytic anemia, given development of clinically significant anemia
Developing severe hemolytic anemia, given development of clinically significant anemia
No change in dose will be required, given moderate anemia
Dosage reduction will be required, given moderate anemia
Ribavirin discontinuation will be required, given moderate anemia
Dosage reduction will be required, given severe anemia
Ribavirin discontinuation will be required, given severe anemia
No epoetin and no transfusions
Receiving epoetin and transfusion
Unit Costs and Frequency Parameters
The average wholesale prices obtained from the 1999 Drug Topics Red Book were used to establish medication costs for the base case . Costs from an online retailer of pharmaceuticals were utilized to obtain a range for the sensitivity analyses . Laboratory costs, clinic visit costs, and infusion center administration costs for 1995 were obtained from a large, private, health insurer database for the state of Washington. These were updated to 1999 figures using the US consumer price index for medical care. The average cost of the transfusion of one unit of packed red blood cells, including laboratory, processing, and administrative costs, was obtained from the Puget Sound Blood Center and University of Washington Medical Center. The unit costs for the base case are listed in Table 3. Frequency of laboratory draws and clinic visits was taken from the clinical trials, whereas frequency of transfusions and of visits to the blood center were clinical estimates [9–11]. The duration of epoetin therapy was taken from a standard drug therapy . These parameters are all listed in Table 3.
Table 3. Costs and frequencies used in the model
Base case value (range $)
Reference for range
AHFS, AHFS '99 Drug Information, American Society of Health-System Pharmacists, Bethesda, MD, 1999; CJ, clinical judgment; PSBC, Puget Sound Blood Center; TIW, three times weekly; UWMC, University of Washington Medical Center.
Frequency/Count Parameter in Combination Therapy Arm
Frequency of laboratory draw—bilirubin/ Uric acid
Frequency of laboratory draw—complete blood count
3 (1– 6)
Frequency of laboratory draw—hemogram
Frequency of laboratory draw—reticulocytes
3–12 (no change)
Frequency of clinic visit, moderately complex
Frequency of clinic visit, simple
Frequency of transfusion
Count, Blood Center, first hour
1 (no change)
Count, Blood Center, additional hours
Duration of epoetin therapy (weeks)
Number of hours, Blood Center
Outcome Assessment–Base Case
The primary outcome was the direct medical cost of treating clinically significant RIHA. The cost was determined by subtracting the direct costs of monitoring for RIHA in the population in whom it was not clinically significant from the costs of treating RIHA in the population in whom it was determined to be clinically significant.
We performed a one-way sensitivity analysis on each probability and cost parameter, the frequency of laboratory draws and clinic visits, and the epoetin dose and duration of therapy. Each parameter was varied individually while the others were held constant. We relied on the inclusion of additional studies in the data set to determine the range used for the probabilities [24–36]. When literature estimates were not available for probabilities, and when estimating the ranges for frequencies and costs, we assumed a decrease of 50% and an increase of 50% to 100%. These assumptions were based on clinical judgment and the desire to provide a conservative estimate that would yield a robust model. The probability ranges are provided in Table 2.
We also conducted analyses of best- and worst-case scenarios. The probabilities used in these analyses are also given in Table 2. Probabilities from additional studies in the data set were incorporated into these models. For example, in the best-case scenario, the percentage of patients in the combination arm who experienced moderate RIHA requiring dose reduction was taken from the combination of all trials enrolling more than 50 patients, or 5.0% (Table 1, Group 5). Other parameters were varied as outlined above.
In the worst-case scenario, we pooled the data from 763 ribavirin patients (Groups 2 through 6 in Table 1), and used the weighted averages of 8.5% and 3.1% as the probabilities of developing moderate RIHA requiring dosage reduction or discontinuation, respectively. Probabilities for the development of clinically significant hemolytic anemia, of moderate or severe anemia, of severe anemia requiring ribavirin discontinuation, and costs made use of assumptions previously outlined. Probabilities in the branches outlining the use of epoetin and transfusions were based on a study population of recurrent hepatitis C patients following orthotopic liver transplant (OLT) (Table 1, Group 3). Use of epoetin and transfusions was more frequent in this group of patients than in any other.
We also explored two additional, clinically plausible scenarios. In the first scenario, we modeled a ribavirin dose of 800 mg/day to reflect the possibility that if a lower dose of ribavirin were used (800 mg/day vs. 1000–1200 mg/day) the incidence of RIHA may be reduced. We adjusted the cost of ribavirin to 800 mg/day and varied the incidence of mild hemolytic anemia from 41% to 72% (an increase of 75%), moderate from 37% to 19% (a decrease of 50%), and severe from 22% to 11% (a decrease of 50%). Importantly, the clinical and economic impacts of a potential reduction in efficacy due to discontinuation of combination therapy is not easily estimated and thus were not included in the scenario.
To assess the impact of greater use of epoetin therapy, we modeled a scenario that included data from the studies in which patients had received an OLT and transfusions or epoetin. This scenario used the percentage of transfusions (6.7%) and epoetin (11%) found in the OLT trials [14–16], but used the probabilities of clinical significance and severity found in the base case.
Twenty-six articles met the inclusion criteria and were categorized into seven distinct groupings of trials [9–11,14–36]. These provided the incidence and treatment data used in the analysis (Table 1). The first six articles comprise a group of early studies that explored the use of ribavirin as single-agent therapy in the treatment of CHC [18–23]. They are a mix of pilot studies and randomized, placebo-controlled trials that used a dose of ribavirin of at least 1000 mg/day during the treatment course. Seven additional studies, enrolling fewer than 50 patients each and using combination therapy with interferon α-2b and ribavirin, comprise the second group [24–30]. A third group of studies consists of patients who had undergone OLT [14–16]. Recurrent hepatitis C after OLT can be more aggressive, leading to graft loss, recurrent cirrhosis, and subsequent liver failure . A fourth group is comprised of a single abstract in which the authors used epoetin to reduce morbidity associated with RIHA . The fifth group consists of larger (greater than 50 patients each) randomized, controlled trials evaluating combination therapy [31–35]. A sixth group consists of one meta-analysis of individual patient data from four European centers . Finally, the phase III approval trials comprise the seventh group [9–11].
The base case analysis reflects the difference between the direct cost of treating clinically significant RIHA ($303) and the direct cost of routine monitoring for nonclinically significant RIHA ($133) for one patient over a 48-week course of treatment. The attributable difference was $170 per patient per treatment course. These results are listed in Table 4.
Table 4. Results: direct costs of treating ribavirin-induced hemolytic anemia
Cost of treating clinically significant RIHA ($)
Cost of monitoring for not clinically significant RIHA ($)
Incremental cost difference (attributable to clinically significant) RIHA ($)
Sensitivity analyses, one way
Probability of developing clinically significant hemolytic anemia
We conducted a series of one-way sensitivity analyses on all parameters and grouped the results according to the type of parameter varied: probability, cost, or frequency. In the cost category, the lowest and highest costs, $77 and $177, respectively, occurred in the analysis where the cost of a simple clinic visit was varied between the lower and upper boundaries of the $10 to $37 range (baseline $24). Similarly, the frequency of simple clinic visits revealed the greatest cost variation in the frequency category: $77 to $317. This occurred when the frequency of simple clinic visits was varied from 2 to 12 visits (baseline 3 to 6 visits). Finally, in the category in which probabilities were varied, the possibility of developing clinically significant hemolytic anemia while receiving combination therapy was the parameter that resulted in the lowest cost, $57. This parameter was varied from the lower boundary of 0.37 to the upper boundary of 1.0 (base case = 0.74). The highest cost in the probability category was $197, and occurred when the probability of receiving epoetin therapy was varied from 0% to 11%.
The best- and worst-case scenarios showed an attributable cost difference of $68 and $692 per treatment course, respectively.
The results of the case wherein a reduced dose of 800 mg/day of ribavirin was used resulted in a cost of treating hemolytic anemia of $149, a $21 (12%) reduction from the base case. This is the result of changes in two factors: the lower cost of 800 mg/day when compared with 1000 to 1200 mg/day of ribavirin, and the decreased incidence of RIHA when this lower dose is used.
Last, we modeled the scenario based on the percentage of epoetin used in the OLT trials. Because transfusions were used 6.7% of the time and epoetin was used 11% of the time in this scenario, the cost of treating RIHA increased from $170 to $284 per patient, or 67%[14–16].
The use of combination interferon α-2b/ribavirin therapy for the treatment of CHC results in an incidence of RIHA, defined as a reduction in hemoglobin to less than 100 g/L, of approximately 7% to 9%[9–11]. The mean maximum drop in hemoglobin is between 29 and 31 g/L in phase III trials [9–12]. In the base case, the cost of managing clinically significant RIHA was $170 per patient per 48-week treatment course. In comparison, the direct drug cost of a 48-week treatment course of combination therapy with interferon α-2b/ribavirin is approximately $16,459, while for a 48-week treatment course of interferon α-2b monotherapy, the direct drug cost is $5,460 . Thus, the direct cost of managing RIHA comprises 1% or 3% of the cost of combination therapy or monotherapy, respectively. It does not increase costs significantly. To the best of our knowledge, no one else has systematically estimated the direct cost of managing RIHA in this patient population.
It is important to remember that this number reflects only the direct cost of medical management. Because management of RIHA can include ribavirin dosage reduction early in the treatment course, there is a potential for reduction in efficacy for patients who complete the course of therapy with a reduced dose of ribavirin. Whether this decrease in dose decreases efficacy is controversial. In a population previously resistant to interferon α-2b monotherapy, Salmeron et al.  recently compared the effectiveness of interferon α-2b/ribavirin 600 mg/day with interferon α-2b monotherapy. They found the combination no more effective than interferon α-2b alone. In contrast, Bonkovsky et al.  studied a similar population and found a 600-mg daily dose of ribavirin to be at least as effective as a 1000- to 1200-mg daily dose of ribavirin when given in combination with interferon α-2b for CHC.
Similarly, early discontinuation of ribavirin potentially causes a reduction in efficacy, resulting in a rate similar to that observed in patients receiving interferon α-2b monotherapy. Wong et al. [42,43] have found that combination therapy with interferon α-2b/ribavirin is cost-effective when compared with interferon α-2b monotherapy, in both initial treatment and relapse. Equally as pertinent however, is the work of Younossi et al. , which demonstrated the cost-effectiveness of interferon α-2b monotherapy over no therapy. In our work, if we assume that patients in whom ribavirin is discontinued complete their course of therapy with interferon α-2b, cost-effectiveness is maintained.
We addressed the uncertainty in our model by conducting one-way sensitivity analyses on all parameters, including the cost and frequency of simple clinic visits and the probability of developing clinically significant RIHA. Variations in the cost and frequency of simple clinic visits resulted in a cost difference ranging from $77 to $317 per treatment course. Because the progress of patients receiving combination therapy for CHC is frequently monitored through follow-up simple clinic visits, a reduction or increase in the cost or frequency of these visits would impact significantly on the model. Decreasing the probability of developing clinically significant RIHA resulted in the lowest cost when this factor was analyzed independently ($57). Because the percentage of patients experiencing clinically significant RIHA drives all other costs, reducing this probability by 50% (from 74% to 37%) logically results in the lowest cost of treatment of this adverse effect. However, when these specific parameters are varied in combination, the outcome is a range of costs between $57 and $317. Although the baseline cost was not high, the uncertainty was relatively high. This reflects the variability in the frequency and cost of resources used in the management of RIHA.
Our analysis also has implications for using the reduced dose (800 mg/day) of ribavirin. The 800-mg/day dose is important because dose-finding studies were not published prior to initiation of the phase III trials, and the dose of ribavirin that minimizes the risk-benefit ratio has not yet been firmly established. It is possible that the 800-mg dose may have the same efficacy as higher doses. Studies are currently under way to address this issue [41,45]. Should future data demonstrate that 800 mg/day is the optimal dose of ribavirin, the direct cost of treating RIHA will be reduced in our model from $170 to $149 per patient.
Some authors, especially those working with the OLT population, have evaluated the use of epoetin to manage and overcome RIHA. The OLT population is distinct from the population in the phase III approval trials in that it has recurrent, and possibly more refractory, CHC. In this population, the use of epoetin may be more important in overcoming RIHA. We included the OLT population only in the sensitivity analysis. Using the data to model this strategy, we found this increased the direct cost to $284 per patient per treatment course. This large variation occurs because epoetin therapy is relatively expensive ($199 per week for a 6-week treatment course). Still, when compared with the direct drug cost of a 48-week treatment course of combination therapy, $284 does not add significantly to drug costs.
We recognize that our analysis is limited in some respects. There were uncertainties in some of the probability estimates, even though the majority of these were derived from the literature. The clinical data set was limited by the lack of a uniform trial design, lack of a consistent definition for hemolysis, and missing data on both the percentage of patients experiencing hemolysis and the mean reduction in hemoglobin concentration. Despite this, we were able to catalog the percentage of patients in whom the ribavirin dose was reduced, the percentage of patients in whom ribavirin was discontinued, and the percentage of patients in whom hemolytic anemia was treated with packed red blood cell transfusions or epoetin. This information was sufficient to provide us with reference points to establish a parametric model. Because of these limitations in the data set, we used only the data from the Phase III pivotal trials, on which the US approval of the drug regimen was based, to populate the base case [9–11]. Parameters from the additional studies were used in the best- and worst-case sensitivity analyses, as well as in the analyses modeling the 800-mg dose of ribavirin and the OLT model [14–36].
In the OLT scenario, we included a 6- to 12-week treatment course for epoetin. This yields a conservative cost estimate, because there is the potential to continue the use of epoetin beyond this time frame in an effort to overcome the RIHA and continue ribavirin concomitantly with epoetin for the duration of the treatment course.
Generalizations that can be made from our work are limited. The cost of treating potential morbidity caused by hemolytic anemia, including deterioration of cardiac function or exacerbation of the symptoms of coronary artery disease, was also considered in the model. In his summary of the phase III trials, Maddrey described a mean decrease in hemoglobin and an exacerbation of cardiac events in only nine patients receiving combination therapy with interferon α-2b and ribavirin . This constitutes less than 1% of the patients in the combination therapy arm. It was not possible to definitively determine whether combination therapy was associated with the exacerbation of cardiac symptoms more than was monotherapy with interferon-alpha . However, the incidence of underlying comorbidities in a community-based population may be different from that in a controlled clinical trial. In their study of community-based patients, Lyons et al.  found that 50% of the patients required a dose reduction of ribavirin due to thrombocytopenia, leukopenia, and/or anemia. An adverse-effect profile this significant, especially in those with underlying comorbidities, would incur a significantly greater toll on both morbidity and medical costs.
Combination therapy with interferon α-2b/ribavirin has become the standard of care in the treatment of CHC, and the importance of managing the dose-limiting adverse effect of RIHA is now a clinical concern. We estimated the direct medical cost of treating RIHA in a controlled clinical trial population to be low—$170 per patient per 48-week treatment course, or about 1% of annual drug treatment costs of combination therapy. Cost-effectiveness is maintained even if discontinuation of ribavirin is required due to RIHA, requiring completion of a treatment course with interferon α-2b monotherapy. Questions remain about the optimal dose of ribavirin and the incidence of RIHA in a real-world population with underlying comorbidities. Despite these uncertainties, this initial evaluation of the direct cost of treating RIHA in a controlled population sheds light on the clinical and economic implications and offers useful strategies for managing this clinically important adverse effect.