We assessed the cost-effectiveness of sofosbuvir (SOF)-based triple therapy (TT) compared with boceprevir (BOC)- and telaprevir (TVR)-based TT in untreated genotype 1 (G1) chronic hepatitis C (CHC) patients discriminated according to IL28B genotype, severity of liver fibrosis, and G1 subtype. The available published literature provided the data source. The target population was made up of untreated Caucasian patients, aged 50 years, with G1CHC and these were evaluated over a lifetime horizon by Markov model. The study was carried out from the perspective of the Italian National Health Service. Outcomes included discounted costs (in euros at 2013 value), life-years gained (LYG), quality-adjusted life year (QALY), and incremental cost-effectiveness ratio (ICER). Cost of SOF was assumed to be €3,500 per week, i.e., the price generating a willingness-to-pay threshold of €25,000 per LYG compared with TVR in the entire population of untreated G1 patients. The robustness of the results was evaluated by one-way deterministic and multivariate probabilistic sensitivity analyses. SOF was cost-effective compared with BOC in all strategies with the exception of cirrhosis and IL28B CC patients. In comparison with TVR-based strategies, SOF was cost-effective in IL28B CT/TT (ICER per LYG €22,229) and G1a (€19,359) patients, not cost-effective in IL28B CC (€45,330), fibrosis F0-F3 (€26,444), and in cirrhosis (€34,906) patients, and dominated in G1b patients. The models were sensitive to SOF prices and to likelihood of sustained virological response. Conclusion: In untreated G1 CHC patients, SOF-based TT may be a cost-effective alternative to first-generation protease inhibitors depending on pricing. The cost-effectiveness of SOF improved in IL28B CT/TT and G1a patients. SOF was dominated by TVR in G1b patients even if, in clinical practice, this issue could be counterbalanced by the good tolerability profile of SOF and by the shorter treatment duration. (Hepatology 2014;59:1692–1705)
The estimated global prevalence of hepatitis C virus (HCV) infection is 2.2%, corresponding to about 130 million HCV-positive persons worldwide, most of whom are chronically infected. In Europe, a recent revision reported that the estimated prevalence of HCV infection ranges from 0.6% to 5.6%. This is of growing interest because HCV is one of the main causes of both cirrhosis and hepatocellular carcinoma (HCC) in Western countries.
Considering the burden of HCV-related cirrhosis and its complications, the achievement of a sustained virological response (SVR) is a very important surrogate outcome in the management of chronic hepatitis C (CHC) patients. In fact, viral eradication prevents not only the development of cirrhosis in CHC but also, in subjects with cirrhosis, the occurrence of its complications, such as esophageal varices, and liver-related death, also reducing HCC occurrence.[6, 7]
In the last few years the standard of care for untreated genotype 1 (G1) CHC patients changed from dual therapy (DT) with peginterferon α (PEG-IFN) and weight-based ribavirin (RBV), to triple therapy (TT) with PEG-IFN, RBV, and first-generation NS3-NS4 HCV protease inhibitors (PI) boceprevir (BOC) or telaprevir (TVR). Registered randomized controlled trials (RCTs), namely SPRINT2 and ADVANCE,[9, 10] showed that a course of 12 to 44 weeks of a first-generation PI combined with 24 to 48 weeks of PEG-IFN plus RBV, with the duration of therapy guided by the on-treatment response and the presence of cirrhosis, provided a gain in SVR rate of about 25% compared with DT. Although we demonstrated that TT with first-generation PI is a highly cost-effective treatment in untreated G1 CHC patients, particularly when allocation systems based on rapid virological response or IL28B genotype-guided strategies are applied, the use of these new drugs in clinical practice needs to be carefully evaluated because of such factors as the low genetic barrier to the development of resistance, the poor tolerability profile especially in cirrhosis patients, the issue of drug interactions, and the long-term complicated regimens with high pill burdens.
A nucleotide analog HCV NS5B polymerase inhibitor, sofosbuvir (SOF), has recently been developed and is waiting for approval by regulatory authorities. The NEUTRINO RCT showed that SOF, in combination with DT for 12 weeks, achieves SVR in 89% of untreated G1 CHC patients with a very good tolerability profile. This RCT identified IL28B CC and the absence of cirrhosis as the only independent predictors of SVR, also showing a higher SVR rate in G1a compared with G1b-infected patients.
The aim of this analysis was to determine the cost-effectiveness of SOF-based TT compared with TVR- and BOC-based TT in different subsets of untreated G1 CHC patients differentiated according to IL28B genotype, severity of liver fibrosis, and G1 subtype.
We demonstrated that SOF-based TT improves survival compared with first-generation PI-based TT in untreated G1 CHC patients, and that it is cost-effective by assuming a drug price of €3,500 per week. SOF was always, but not in patients with cirrhosis and in IL28B CC patients, cost-effective compared with BOC. SOF was cost-effective compared with TVR in IL28B CT/TT and G1a patients, not cost-effective in IL28B CC, fibrosis F0-F3, and in cirrhosis patients, and dominated in G1b patients. The robustness of these results was confirmed in the probabilistic sensitivity analyses. The cost-effectiveness of SOF was sensitive to SOF price, SVR rate variations of both SOF and first-generation PI, and annual discount rate.
To our knowledge, this is the first cost-effectiveness analysis evaluating SOF-based TT in untreated G1 CHC patients. SOF is waiting for FDA and EMA authorization, and therefore our results were obtained by assuming that the SOF price is €3,500 per week, i.e., the price generating a willingness-to-pay threshold of €25,000 per LYG compared with TVR in the entire population of untreated G1 patients. According to this assumption and considering different subsets of patients, we found that, on the one hand, SOF-based therapy was almost always cost-effective compared with BOC while, on the other hand, it was cost-effective compared with TVR in some clinical subgroups only, i.e., IL28B CT/TT and G1a, lacking its cost-effectiveness in easy to treat (IL28B CC), F0-F3, and in difficult to treat (cirrhosis) patients. Following from this, sensitivity analyses showed that the cost-effectiveness of SOF was sensitive to SOF price variation, lacking its cost-effectiveness in some assumptions, and that, by considering the value of €25,000 per LYG as the threshold for willingness-to-pay, the cost-effectiveness of SOF compared with TVR was maintained at the minimum cost of €3,106 per week in IL28B CC, and at the maximum cost of €3,763 per week in G1a patients.
We observed that in the subset of the G1b population, SOF was slightly less effective and more expensive than TVR and, consequently, it was dominated. This issue is of particular interest, since G1b is the most prevalent G1 subtype in Europe.
From a clinical point of view, considering that SOF approval is expected in the first quarter of 2014 and that relevant efforts should be performed to give SOF cost-effectiveness in all clinical scenarios, all the above-quoted data suggest that a deferral strategy for IL28B CT/TT, F0-F3, and G1a patients should be adopted, where SOF is clearly more effective than first-generation PI.
In G1b patients, if the lower SVR rates of SOF compared with TVR will be further confirmed in future studies, its slightly lower efficacy could be counterbalanced by the good tolerability profile of SOF. In fact, the major advantages of SOF-based therapies compared with first-generation PI strategies are the short treatment duration, i.e., 12 weeks, the good tolerability profile, and the simplicity of the therapeutic schedule, one pill per day.
Finally, in patients with cirrhosis, even if SOF is more effective than both TVR and BOC, deferral should be carefully evaluated due to the risk of liver disease decompensation potentially associated with a delay of treatment. However, deferring treatment may be counterbalanced by the good tolerability of SOF in patients with cirrhosis and by the risk of life-threatening adverse events during TVR and BOC treatment, as observed in the CUPIC cohort.
All these issues, together with the high likelihood of SVR achievement, give SOF highly promising and preferable perspectives compared with BOC and TVR, if sold at an acceptable cost. In any case, especially in patients with mild liver damage, and/or with a contraindication to PEG-IFN and/or RBV, the indication to SOF-based TT should be carefully evaluated considering the promising results arising from IFN-free protocols including SOF or not.
Congruent with the above data, although the proposed algorithms are useful tools for decision-making, the treatment strategy must be carefully agreed upon with the individual patient. In particular, according to the editorial of Aronsohn and Jensen reporting that deferring treatment is justifiable and appropriate for many patients, an informed deferral is needed considering risks related to inaccurate staging of liver disease, inability to predict progression of fibrosis, and comorbidity changes over time. Obviously, the clinical value and ethical impact of treatment or deferral should not be compromised by any economic analysis.
This study has several limitations. 1) The efficacy data are derived from registered trials of HCV PI. In fact, data from RCTs are not directly transferable to clinical practice, since trial patients are healthier, show greater adherence to trial protocol, and are more closely monitored. 2) The current model uses aggregate rather than individual patient data. Consequently, our results reflect group averages rather than individual data. More detailed treatment comparisons could be achieved by an analysis of individual patient data, or by combining the different variables affecting the achievement of SVR using multivariate risk modeling. In addition, the hypo-representation of G1b patients in the NEUTRINO RCT further limits our analyses in this setting of patients, where the real effectiveness and cost-effectiveness of SOF-based TT needs to be further evaluated in larger studies. 3) The lack of data on the economic impact of drug-drug interaction and on management of all side effects, of the induction of viral mutations, and especially of the tolerability profile of TT in real life and in patients with cirrhosis could also have affected our analyses. 4) We used the utilities considered acceptable for an Italian population. However, it is well known that utilities may vary widely across different patient subgroups and that they critically depend on Quality of Life assumptions. Accordingly, we assessed LYG, but not QALY, as the primary measure of effectiveness. 5) Another important limitation regards the transition probabilities from CHC to cirrhosis that were assumed to stay constant over time, sometimes slightly differing from those reported in other models.[27-30, 46, 47] However, our results were robust under a broad range of parameters used in the model as assessed by both deterministic and probabilistic sensitivity analyses, and produced similar outcomes compared to other models. In addition, the possible variation of BOC and TVR prices after SOF registration could also affect our results. 6) This was not a societal study. Therefore, our analysis was limited to direct medical costs; indirect costs, such as lost productivity and salaries of caregivers, were not included.
In conclusion, we found that treatment with SOF-based TT could be a cost-effective alternative to first-generation PI in untreated G1 CHC patients aged 50 years. These results were robust over a wide range of model assumptions but were sensitive to SOF costs. For IL28B CT/TT and G1a patients, the ICER of SOF compared with first-generation PI improved. SOF was dominated by TVR in G1b patients. However, this last issue could be counterbalanced by the good tolerability profile of SOF and by the shorter treatment duration.
S. Petta, M. Enea, F.S. Macaluso, G. Cabibbo, R. Bruno, A. Gasbarrini, A. Plaia, A. Craxì, C. Cammà take full responsibility for the study design, data analysis and interpretation, and preparation of the article. All authors were involved in planning the analysis and drafting the article. All authors approved the final draft of the article.