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Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Acknowledgements
  9. References

Background  Although the current standard of care for controlling anaemia and neutropenia during anti-viral therapy for hepatitis C is to use dose reduction of ribavirin and pegylated interferon, respectively, erythropoietin and granulocyte colony-stimulating factor are now being advocated as alternatives to dose reduction.

Aim  To determine the cost-effectiveness of erythropoietin and granulocyte colony-stimulating factor as an alternative to anti-viral dose reduction during antihepatitis C therapy.

Methods  Decision analysis was used to assess cost-effectiveness by estimating the cost of using a growth factor per quality-adjusted life-year gained.

Results  Under baseline assumptions, the cost per quality-adjusted life-year of using growth factors ranged from $16 247 for genotype 1 with neutropenia to $145 468 for genotype 2/3 patients with anaemia. These findings are sensitive to the relationship between dose reduction and sustained virological response.

Conclusions  Based upon our findings and the varying strength of the evidence for a relationship between dose reduction and sustained virological response: granulocyte colony-stimulating factor may be cost-effective for genotype 1 patients; erythropoietin is probably not cost-effective for genotype 2/3 patients; no conclusion can be reached regarding the cost-effectiveness of erythropoietin for genotype 1 patients or granulocyte colony-stimulating factor for genotype 2/3 patients. Randomized trials are needed to firmly establish the relationship between dose reduction and sustained virological response.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Acknowledgements
  9. References

Hepatitis C virus (HCV) is estimated to affect 2.7 million individuals in the United States1 and 170 million worldwide with 3–4 million new infections worldwide each year.2 With current therapy consisting of pegylated interferon (Peg-IFN) and ribavirin (RBV), sustained virological responses (SVR; no virus detected in the blood 6 months after the end of treatment) of 54–61% have been achieved.3,4 Unfortunately, side-effects of both RBV and interferon, including anaemia and neutropenia, have resulted in the need to dose reduce or discontinue therapy in up to 30% of patients.4–11

Although anaemia and neutropenia typically resolve when anti-viral therapy is stopped,12 treatment efficacy may be diminished as a result of dose modification or cessation of therapy. In order to help maintain full-dose therapy and, hence, improve the overall SVR, some have suggested the ‘off-label’ use of growth factors,5,13–17 including erythropoietin (EPO) for anaemia and granulocyte colony-stimulating factor (G-CSF) for neutropenia. Even recent treatment recommendations by national organizations suggest their use under limited circumstances.18–20 While studies have shown that EPO13,21–23 and G-CSF24 are effective in limiting dose reduction and that EPO improves quality of life,15,25 it has not yet been shown that maintaining higher doses with expensive growth factors have improved SVR rates. In addition, studies of the relationship between Peg-IFN or RBV dose reduction and SVR have methodological shortcomings and are at times inconsistent.3,4,11,26–35 As Schrag36 argues, we need to better understand the relationship between the high cost of new therapies and their impact on patients.

Decision analysis provides a tool to estimate the cost-effectiveness of these supportive therapies.37 In this context, decision analysis can be used to calculate SVR and total cost of therapy by integrating information on the cost of anti-viral medications and growth factors, future healthcare costs, duration of therapy, probability of growth factor effectiveness, effect of dose reduction on SVR and other parameters. Thus, we constructed a decision analytic model reflecting the treatment of hepatitis C viral infection, and evaluated the cost-effectiveness of EPO and G-CSF vs. standard-dose reduction strategies in the setting of anaemia and neutropenia, respectively.

Given the high cost of growth factors, cost-effectiveness analyses can have an important impact on the total cost of treatment given the large number of individuals with hepatitis C worldwide and the substantial proportion of individuals experiencing anaemia or neutropenia during anti-viral therapy.

Materials and methods

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Acknowledgements
  9. References

Two decision analysis models were used to predict cost and rate of SVR from the use of growth factors as an alternative to Peg-IFN or RBV dose reduction to manage patients who have developed either neutropenia or anaemia. We assumed that patients develop either neutropenia or anaemia after 4 weeks of therapy and that treatment duration is 48 weeks for patients with genotype 1 HCV, and 24 weeks for patients with genotype 2/3 HCV. Figure 1 presents the decision tree used to conduct this analysis for patients with anaemia. The anaemia tree starts with branches that divide the individuals into those being treated for anaemia with initiation of EPO and those being treated with RBV dose reduction. Within each treatment group, the anaemia can either be controlled or can persist, as represented by the next two branches of the tree. If the anaemia is controlled, the treatment continues (i.e. no change in RBV dose or use of EPO). If the anaemia persists, then all treatment is discontinued to allow for spontaneous resolution of anaemia. Patients who continue treatment can either have an early virological response (EVR; at least a 2 log decrease in viral load at the end of the first 12 weeks of treatment) or not as represented by the next two branches of the tree. Anti-viral and anaemia treatment are discontinued for patients who do not experience an EVR.4,20,28 For patients with an EVR, the final pair of branches indicates whether the individual has experienced an SVR or not. A comparable tree was used for neutropenia.

image

Figure 1.  Decision tree for anaemia (a comparable decision tree was used for neutropenia).

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Parameters

Parameters in the tree include anti-viral dosing, time to various events, length of anti-viral treatment, the probability of an EVR, the probability of the neutropenia or anaemia resolving, the probability of an SVR, and pharmacy costs as well as future hepatitis C-related treatment costs if anti-viral treatment fails. A review of the literature was conducted to estimate the relevant parameters in the model. Baseline values of these parameters are presented in Table 1, and are stratified by complication and genotype.

Table 1.   Baseline parameter values
 AnaemiaNeutropeniaReferences
Genotype 1Genotype 2/3Genotype 1Genotype 2/3
  1. * As the costs for Peg-IFNα-2b were very similar to Peg-IFNα-2a at both http://www.Drugstore.com and in the VA, we arbitrarily elected to use the former costs in all analyses.

  2. † Data from Hadziyannis et al.9 suggested that RBV dose reduction may not affect SVR for genotype 2/3 patients when reduced from 1000 or 1200 mg/day to 800 mg/day. However, the cost per SVR and the cost per QALY cannot be calculated when the effect on SVR is zero. For this reason we used a value of 0.01.

  3. EPO, erythropoietin; EVR, early virological response; G-CSF, granulocyte colony-stimulating factor; Peg-IFN, pegylated Interferon; RBV, ribavirin; SVR, sustained virological response.

Duration of anti-viral therapy (weeks)48244824(19, 20)
Start of treatment for anaemia or neutropenia (weeks)44444, 5, 13, 14, 21, 49)
Time to stop ineffective dose reduction (weeks)8888(8)
Time to stop ineffective growth factor (weeks)8888(13, 16, 23, 53)
Time to assess EVR (weeks)12121212(18, 20, 28)
Peg-IFNα-2a (full-dose –μg/week)*180180180180(19, 20)
RBV (full-dose – mg/day)12008001200800(19, 20)
EPO (units/week)40 00040 000  (16, 19)
G-CSF (Monday and Thursday)  300300(17, 19)
Peg-IFNα-2a dose reduction (proportion of full)1.001.000.750.75(16, 19)
RBV dose reduction (proportion of full)0.500.501.001.00(16, 19)
Cost/week of full-dose Peg-IFNα-2a (180 μg/week)*$328.99$328.99$328.99$328.99http://www.Drugstore.com
Cost/week of full-dose RBV (1200 or 800 mg/day)$181.99$121.33$181.99$121.33http://www.Drugstore.com
Cost/week of EPO (40 000 units/week)$489.89$489.89  http://www.Drugstore.com
Cost/week of G-CSF (300 μg 2 days/week)  $372.33$372.33http://www.Drugstore.com
Future cost of hepatitis C care if patient not cured$9853$9853$9853$9853(39)
Anaemia/neutropenia controlled by growth factor (proportion)0.960.960.960.96(5, 13, 15–17, 22, 24)
Anaemia/neutropenia controlled by dose reduction (proportion)0.960.960.960.96(11, 12)
EVR with growth factor (proportion)0.810.970.810.97(40)
EVR with dose reduction (proportion)0.810.970.810.97(40)
Absolute reduction in SVR resulting from dose reduction (proportion)0.120.01†0.130.06(9, 11)
Costs

The baseline costs for medications presented in Table 1 were obtained in December 2004 from http://www.Drugstore.com, a national retailer of pharmaceutical products in the United States. These represent a reasonable estimate for the costs faced by patients in the United States who must pay out of pocket or insurance plans that do not aggressively negotiate for lower drug prices. We also obtained the cost of medications from the 2004 Red Book,38 but in all cases the Red Book average wholesale price was slightly higher than the http://www.Drugstore.com prices. The United States Department of Veterans Affairs (VA) is able to purchase medications in large quantities at negotiated discount prices. As these costs may better reflect the costs to large healthcare organizations or insurers, we also determined the cost-effectiveness of growth factors using these values. The November 2004 VA cost per week are as follows: full-dose Peg-IFNα-2a (180 μg/week) –$120.15; full-dose RBV for genotype 1 patients (1200 mg/day) –$39.90; full-dose RBV for genotype 2/3 patients (800 mg/day) –$26.60; EPO (40 000 units/week) –$208.05; cost/week of G-CSF (300 μg 2 days/week) –$227.68. As the costs for Peg-IFNα-2b were very similar to Peg-IFNα-2a at both http://www.Drugstore.com and in the VA, we arbitrarily elected to use the former costs in all analyses.

The future cost of treatment for the consequences of hepatitis C, if anti-viral therapy fails, was estimated by Salomon et al.39 to be $8200 in 2001 dollars for a 40 year olds with elevated levels of alanine aminotransferase, positive results on quantitative HCV-RNA and no histological evidence of fibrosis on liver biopsy. Using the medical care component of the United States Bureau of Labor Statistics’ Consumer Price Index, this cost was projected to be $9431 in November 2004 dollars. These costs are relatively low because only a minority of patients with hepatitis C progress to decompensated cirrhosis, hepatocellular carcinoma, or require liver transplantation.

Impact of dose reduction or growth factors on anaemia and neutropenia

The probability of managing treatment-related anaemia or neutropenia with either dose reduction or growth factors is not well documented in the literature. The reported percentage of patients for which anaemia is not controlled by EPO ranges from 0% to 17%.13,15,21–23,40 The percentage of patients for which anaemia is not adequately controlled by RBV dose reduction is not reported precisely, but two papers indicate that outright discontinuation of anti-viral therapy is a relatively rare event.11,12 Sood et al.24 found that only one of 12 patients receiving G-CSF for neutropenia also required IFN dose reduction and none required discontinuation of anti-viral therapy. Manns et al.11 reported that when Peg-IFN dose reduction was used to control neutropenia, discontinuation of Peg-IFN was rare. Therefore, the baseline probability of anaemia or neutropenia being controlled after treatment with either dose reduction or growth factor is set at 0.96,21 as indicated in Table 1.

Relationship between pegylated interferon or ribavirin dose and SVR

Several papers present analyses of the relationship between Peg-IFN or RBV dose and SVR.3,4,11,26–35 However, the reported findings typically suffer from two or more of the following shortcoming: non-randomized assignment to Peg-IFN or RBV dose; the findings were not reported by genotype; the analysis was not limited to patients with anaemia or neutropenia; dosing in the low-dose group was not as low as the recommended dose reduction for anaemia or neutropenia; discontinuation of treatment was grouped with dose reduction; the exact dose received within the high- and low-dose group was not reported; dosing varied considerably within the high- and low-dose groups; Peg-IFN and RBV dose reductions were not analysed separately; the observed differences were not statistically significant; and the number of patients was small. In sum, it is not possible to reach any definitive conclusions about the absolute impact of Peg-IFN or RBV dose reduction upon SVR based upon the existing literature. Our baseline estimates of the relationship between dose reduction and SVR are based upon the two best designed studies that address this issue.9,11 However, because of the ambiguity in the relationship between dose reduction and SVR, we will report cost-effectiveness of growth factors as a function of the relationship between dose reduction and SVR.

Outcomes

The decision analysis calculates three primary outcomes.

Total prescription (Rx) drug cost per patient treated

This is the average pharmacy cost per patient for Peg-IFN and RBV over the 24 or 48 weeks of treatment when anaemia or neutropenia is managed with dose reduction or with growth factors.

Cost of growth factor per added SVR

This is the additional cost per added SVR of using growth factors instead of dose reduction to treat anaemia or neutropenia. It is equal to the difference in Total Rx Cost Per Patient Treated between patients receiving growth factor and patients receiving dose reduction divided by the difference in the SVR rates between patients receiving growth factors and patients receiving dose reduction:

  • image
Cost of growth factor per additional quality-adjusted life-year

This is the cost per added SVR using growth factors, divided by the quality-adjusted life-years (QALYs) gained once SVR is achieved. Prior work by Younossi et al.41 estimated the likelihood of various consequences of hepatitis C (e.g. cirrhosis, liver cancer, liver transplant) for a 45-year-old man with chronic hepatitis C, elevated aminotransferase, but currently without cirrhosis or liver cancer. Each consequence was assigned a QALY decrement. Based upon this model, the patient in question would experience 7.13 higher QALYs if their anti-viral treatment resulted in an SVR than if it did not.

Sensitivity analysis

The baseline analysis used the parameters presented in Table 1. As the impacts of Peg-IFN and RBV dose reduction on SVR are not consistent between studies and the studies have methodological shortcomings, results are presented in graphical form as a function of absolute percentage reduction in SVR resulting from dose reduction compared with growth factor use (e.g. if dose reduction causes SVR to fall from 50% to 40%, then this represents a 10% reduction in SVR). The impact of the following changes from baseline parameters were also investigated: (i) using VA pharmacy costs as an alternative to the http://www.Drugstore.com costs; (ii) using higher or lower estimates of the future cost of hepatitis C care if anti-viral therapy is not effective in achieving SVR (50% lower and 400% higher than baseline); (iii) change in the QALY gained from eliminating the virus (20% lower and 20% higher than baseline) and (iv) probability (0.85–1.00) that growth factor use or dose reduction would control anaemia or neutropenia.

Results

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Acknowledgements
  9. References

Figure 2a presents growth factor costs per added SVR as a function of the absolute percentage decline in SVR resulting from dose reduction. Under baseline assumptions, the cost per added SVR of using G-CSF instead of interferon dose reduction is $115 870 for genotype 1 patients with neutropenia and $134 628 for genotype 2/3 patients with neutropenia. The cost per added SVR of using EPO instead of RBV dose reduction is $164 029 for genotype 1 patients with anaemia and $1 037 471 for genotype 2/3 patients with anaemia. The figure also indicates that the cost per added SVR increases dramatically when dose reduction has a smaller effect on SVR. For example, the cost per added SVR of using G-CSF for genotype 2/3 patients with neutropenia increases from $48 192 if dose reduction results in a 15% reduction in SVR; to $163 439 if dose reduction results in a 5% reduction in SVR; to $854 921 if dose reduction results in a 1% reduction in SVR. Figure 2b presents analogous relationships based upon Department of Veterans Affairs pharmacy costs. The cost of growth factors per added SVR is considerably lower for VA compared with http://www.Drugstore.com pharmacy costs.

image

Figure 2.  (a) Cost of growth factor per added sustained virological response (SVR) when http://www.Drugstore.com pharmacy costs are used (2004 dollars). (b) Cost of growth factor per added SVR when Department of Veterans Affairs pharmacy costs are used (2004 dollars).

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Figure 3a presents the cost of the growth factor per added QALY as a function of the percentage reduction in SVR resulting from dose reduction. Under baseline assumptions, the cost per QALY of using G-CSF instead of interferon dose reduction is $16 247 for genotype 1 patients with neutropenia and $18 877 for genotype 2/3 patients with neutropenia. The cost per QALY of using EPO instead of RBV dose reduction is $22 999 for genotype 1 patients with anaemia and $145 468 for genotype 2/3 patients with anaemia. The figure also indicates that cost per QALY increases dramatically when dose reduction has a smaller effect on SVR. For example, the cost per QALY of using G-CSF instead of dose reduction for genotype 2/3 patients with neutropenia increases from $6757 if dose reduction results in a 15% reduction in SVR; to $22 916 if dose reduction results in a 5% reduction in SVR; to $119 872 if dose reduction results in a 1% reduction in SVR. Figure 3b presents analogous relationships based upon Department of Veterans Affairs pharmacy costs. Again, the cost of growth factors per QALY is considerably lower for VA compared with http://www.Drugstore.com pharmacy costs.

image

Figure 3.  (a) Cost of growth factor per QALY when http://www.Drugstore.com pharmacy costs are used (2004 dollars). (b) Cost of growth factor per QALY when Department of Veterans Affairs pharmacy costs are used (2004 dollars).

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A sensitivity analysis to determine the influence of varying the future cost of medical care over a range of 0.5–4 times baseline for patients who do not achieve SVR after anti-viral therapy found only a minimal influence on the cost of growth factor use per QALY (data not shown). Likewise, the cost of growth factor use per QALY was minimally influenced by varying the probability that growth factor use or dose reduction would control anaemia or neutropenia (data not shown). The cost per QALY was fairly sensitive to and inversely related to the QALYs gained from eliminating the virus. For example, a 20% reduction in QALY's gained results in a 25% increase in the cost per QALY. A 20% increase in the QALY's gained results in a 17% decrease in the cost per QALY.

Discussion

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Acknowledgements
  9. References

We used the cost of growth factors per gain in QALY as our primary measure of cost-effectiveness when assessing the use of EPO and G-CSF to control anaemia and neutropenia, respectively, in patients receiving anti-viral therapy for hepatitis C. Our findings, as illustrated in Figure 3a,b, indicate that cost-effectiveness is sensitive to the effect of Peg-IFN or RBV dose reduction on SVR; to HCV genotype and to the cost of these medications. Given this wide variation in cost-effectiveness, there may be some circumstances under which the use of growth factors is warranted and other circumstances under which their utility is less clear or unwarranted, as discussed below. Table 2 presents the minimum effect of dose reduction on SVR needed for EPO and G-CSF to be considered cost-effective, according to three criteria.32,42–45

Table 2.   Minimum effect of dose reduction on SVR needed for growth factor to be considered cost-effective based upon http://www.Drugstore.com costs
Cost-effectiveness criterionEPO (minimum absolute effect of RBV dose reduction on SVR; %)G-CSF (minimum absolute effect of Peg-IFN dose reduction on SVR; %)
Cost per QALY of growth factor compared to:Cost per QALY ($)Genotype 1Genotype 2/3Genotype 1Genotype 2/3
  1. Peg-IFN, pegylated Interferon; RBV, ribavirin; SVR, sustained virological response; QALY, quality-adjusted life-year; EPO, erythropoietin; G-CSF, granulocyte colony-stimulating factor.

Well-established medical interventions4360 0004.82.43.52.0
Proposed standard32, 44100 0002.81.42.31.2
Alternate proposed standard45200 0001.4<1.01.2<1.0

Several studies provide data regarding the relationship between RBV dose reduction and SVR.9,11,29,34 Our baseline assumption for the relationship of RBV dose reduction and SVR is based upon a study by Hadziyannis et al.9 because it has the fewest shortcomings. Hadziyannis et al.9 randomized all anti-viral treatment patients to receive Peg-IFNα-2a with either ‘standard weight-based dose’ (1000–1200 mg/day) or ‘low dose’ (800 mg/day) of RBV. For genotype 1 patients, the SVR was 11.9% (CI: 4.7–18.9) lower for low- compared with standard-dose RBV. For genotype 2/3 patients, the SVR was 0.7% (CI: −7.8 to 6.3) higher for low-dose compared with standard-dose RBV. Using Table 2, the Hadziyannis et al.9 findings suggest that EPO would be cost-effective for genotype 1 patients. However, a recent randomized trial found that the prophylactic use of EPO in genotype 1 patients decreased from 40% to 10% the necessity for RBV dose reduction but also decreased SVR.35 The apparently contradictory findings from these two studies highlight the tentative nature of any statement regarding the cost-effectiveness of EPO for genotype 1 patients. The Hadziyannis et al.9 findings indicate that EPO would not be cost-effective for genotype 2/3 patients.

Spiegel et al.46 conducted an analysis of EPO and conclude that its use to treat anaemia during HCV treatment is cost-effective. Our conclusions differ from and expand upon their analysis for several reasons. First, their study does not report cost-effectiveness as a function of the relationship between dose reduction and SVR. Secondly, they do not consider the lack of a positive effect of EPO on SVR as reported by Shiffman et al.35 Thirdly, their analysis does not distinguish HCV genotype 1 vs. genotype 2/3 patients.

Several studies provide data regarding the relationship between Peg-IFN dose reduction and SVR.11,26,34 Of these studies, we feel that the study by Manns et al.11 had the fewest shortcomings, though the study was not limited to patients with neutropenia. Controlling for RBV dose, they found that lower dose Peg-IFN resulted in a 13% decrease in SVR for genotype 1 patients and a 6–7% decrease in SVR for genotype 2/3 patients. However, observed differences were only statistically significant for genotype 1 patients receiving higher dose RBV. These findings, in conjunction with Table 2, suggest that G-CSF may be cost-effective for genotype 1 patients. Cost-effectiveness for genotype 2/3 patients is less clear.

It should also be noted that the cost-effectiveness of growth factors is a function of the absolute reduction in SVR resulting from dose reduction and is independent of the level of SVR without dose reduction. For this reason, we did not present a value for the baseline assumptions regarding SVR without dose reduction. As absolute levels of SVR in clinical practice may well be lower than in clinical trials, the absolute reduction in SVR resulting from dose reduction may also be lower, resulting in lower cost-effectiveness.

Limitations

Our study has several limitations that merit discussion. First, we did not consider alternate strategies of growth factor use, such as short-term use during the initiation of anti-viral therapy. A study by Davis et al.29 suggests that dose reductions during the first 12 weeks of HCV anti-viral therapy may have the largest impact on SVR. If this is the case, then the use of growth factors through the 12th week, followed by dose reduction may be more cost-effective than using a growth factor throughout the course of anti-viral therapy. Some clinicians may increase the growth factor dose if anaemia or neutropenia persist rather than discontinue anti-viral therapy. We did not consider such a strategy because it would affect only a small minority of patients and therefore have minimal effect on cost-effectiveness. The use of growth factors will be more cost-effective if: (i) the anaemia or neutropenia resolves and the growth factor can be discontinued early without a need for dose reduction or (ii) the use of growth factors is started later than in week 4, as assumed in our baseline analysis. In contrast, many patients may not need or receive the magnitude of dose reduction assumed in the model and would therefore be more likely to experience an SVR. In addition, growth factors may not avoid the need for dose reduction in all cases. Both of these events would lessen the cost-effectiveness of using growth factors. Secondly, it is critical to bear in mind that these long-term cost-effectiveness models assume that there will not be new, more effective, or less expensive therapies for the consequences of hepatitis C in the future. In addition, future anti-viral therapies, such as viramidine, may have a better side-effect profile and reduce the need for growth factors or dose reduction.47 Thirdly, in our analysis, the future impact of an SVR on QALYs is based on Younossi et al.’s41 estimates for a 45-year-old man with chronic hepatitis C, elevated aminotransferase, but currently without cirrhosis or liver cancer. In their analysis, they assumed a 7.3% per year risk of cirrhosis. For older patients or in the setting of a lower risk of progression to cirrhosis, the impact of SVR on QALY will be diminished. In contrast, eliminating HCV for patients with more advanced disease or a greater risk of disease progression may have a larger benefit in terms of QALYs. For this reason, it may be more cost-effective to use growth factors for younger patients with advanced fibrosis, HIV/HCV co-infected patients, and preliver or postliver transplant patients. We should also note that the estimate of future cost of treatment for patients who do not experience an SVR was obtained from Salomon et al.39 who made there estimates for a 40 year olds. This age differs somewhat from the 45 year olds who Younossi et al.41 used to estimate the impact of SVR on QALYs. However, this age difference will probably not have a great impact on our conclusions because our findings where not very sensitive to the future cost of treatment. Furthermore, our model does not consider patient level characteristics, such as race and ethnicity, which have been shown to predict response to anti-viral therapy.48 It is conceivable that cost-effectiveness of growth factors could vary by this and other patient level factors. Nor does our model account for costs associated with increased clinical and laboratory monitoring that may be associated with either dose reduction or growth factor use, or the use of co-therapies, such as blood transfusions. Also, EPO does improve quality of life during anti-viral treatment15,25 and, therefore, may improve compliance. This effect of EPO on SVR is currently unknown, but is likely to be small, and was not considered in the analysis.

Finally, there are other issues to consider with regard to the cost-effective use of growth factors during hepatitis C anti-viral therapy. Fried14 points out that the current recommendations to initiate Peg-IFN dose reduction when neutrophil counts fall below 750 cells/mm may be too conservative. Both Fried14 and Soza et al.49 argue that patients undergoing hepatitis C anti-viral therapy will probably tolerate considerably lower neutrophil counts than the oncology patients for whom this threshold was developed, as oncology patients appear to be at a higher risk for infection than HCV patients. Research is needed to determine the most appropriate neutrophil count threshold for initiating Peg-IFN dose reduction or the use of G-CSF.

Fried14 also argues that the most appropriate haemoglobin levels for initiating RBV dose reduction or using EPO to avoid dose reduction are not clear. Afdhal et al.15 randomized patients with anaemia (Hb: ≤12 g/dL) to either EPO or placebo and found that 88% of the EPO group vs. 60% of the placebo were able to avoid RBV dose reduction. Dieterich et al.22 report similar differences in the avoidance of dose reduction. While these findings indicate that EPO is effective in avoiding dose reduction in most cases, data from the placebo group suggests that dose reduction may be unnecessary for many patients with anaemia. Moreover, the use of EPO does carry a small risk of complications, including thrombotic events and pure red cell aplasia.50–52 Research is needed to determine the most appropriate haemoglobin threshold for initiating RBV dose reduction or the use of EPO. Despite these limitations, our study does provide an objective analysis of the potential cost-effectiveness of growth factors across a reasonable range of assumptions about the effectiveness of these medications. Furthermore, this study makes explicit the importance of randomized-controlled trials of the impact of growth factors on SVR.

Conclusions

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Acknowledgements
  9. References

In conclusion, the cost-effectiveness of using EPO or G-CSF is dependent upon the strength of the empirical evidence for a relationship between dose reduction and SVR. Based upon this evidence and our analysis we conclude that: (i) no conclusion can be reached regarding the cost-effectiveness of using EPO for genotype 1 patients with anaemia because of inconsistent findings regarding the relationship between RBV dose and SVR;9, 35 (ii) EPO is probably not cost-effective for genotype 2/3 patients with anaemia; (iii) G-CSF may be cost-effective for genotype 1 patients with neutropenia and (iv) it is not clear if G-CSF is cost-effective for genotype 2/3 patients with neutropenia because the reported positive relationship between Peg-IFN dose and SVR was not statistically significant.11 Therefore, growth factors should not be used or only used judiciously as an adjunct to hepatitis C anti-viral therapy. We feel strongly that randomized trials need to be conducted that explicitly examine the magnitude of the effect on SVR of RBV and Peg-IFN dose reduction, specifically in patients with anaemia or neutropenia. Given the relatively small effect of dose reduction needed for growth factor to be considered cost-effective (see Table 2) the sample size needed to detect such small differences would be very large. However, such trials would allow for more definitive conclusions regarding the cost-effectiveness of EPO and G-CSF.

Acknowledgements

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Acknowledgements
  9. References

We gratefully acknowledge helpful comments from Drs Helen Yee, George Ioannou and Elizabeth Morrison. The work reported in this paper was supported by the Department of Veterans Affairs National Hepatitis C Program. The views expressed in this article are those of the authors and do not necessarily represent the views of the Department of Veterans Affairs.

References

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Acknowledgements
  9. References
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