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.