Background A new scenario of therapy for chronic hepatitis C (CHC) is being established with the approval of sofosbuvir (SOF).
Objective To estimate the cost-effectiveness of SOF-based regimens approved in the Summary of Product Characteristics (SmPC) versus the standard of care for different genotypes and patient populations (naive or pretreated).
Methods A Markov model simulating CHC progression was used to estimate disease treatment costs and effects over patients’ lifetimes, from the Spanish National Public Healthcare System perspective. Different therapeutic options were analysed for genotypes 1, 2 and 3 in naive population and for genotype 2 and 3 pretreated patients, according to data obtained from clinical trials. A one-way sensitivity analysis was performed to evaluate the uncertainty of certain parameters: treatment starting age, transition probabilities, drug costs and discount rate. A probabilistic sensitivity analysis was also carried out.
Results For the naive population, the option SOF+pegylated-interferon-α (pIFN)+ribavirin (RBV) for 12 weeks recorded in SmPC for genotype 1 and 3 versus pIFN+RBV for 24 weeks estimated an incremental cost-effectiveness ratio (ICER) below the €40 000/quality-adjusted life-year (QALY) benchmark. For the pretreated population, SOF triple therapy reached an ICER on the threshold limit for genotype 3. Other options included in SmPC for different genotypes exceeded the accepted efficiency limit in our setting.
Conclusions The options that included SOF+RBV+pIFN in a 12-week course regimen fell below the efficiency threshold considered in our setting. IFN-free regimens administered for 24 weeks reached figures over the benchmark of €40 000/QALY.
- CHRONIC HEPATITIS
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Significance of this study
What is already known on this subject?
The introduction of sofosbuvir (SOF) in hepatitis C therapeutic regimens improves virological suppression.
The approval of SOF introduces the possibility of treating patients with interferon (IFN)-free regimens.
The acquisition cost of this new drug is high and needs to be weighed against the potential benefits.
What are the new findings?
Triple therapy including SOF for 12 weeks may be cost-effective for the scenarios evaluated.
Some IFN-free regimens present an incremental cost-effectiveness ratio (ICER) over the threshold limit considered in our setting.
ICER estimates for genotype 1 pretreated patients were not possible to be evaluated due to the lack of efficacy data on pivotal clinical trials for this population.
How might it impact on clinical practice in the foreseeable future?
Patients’ selection could improve efficiency in decision making so as not all therapeutic options approved in the Summary of Product Characteristics could be considered cost-effective, which would be especially relevant in case of budgetary restrictions.
Chronic hepatitis C (CHC) is the leading cause of chronic liver disease and liver transplantation in Western Europe and the USA. The prevalence ranged from 0.4% to 3.5% by country in Europe, making CHC an important public health issue.1–5
Pegylated-interferon-α (pIFN) plus ribavirin (RBV) has been the standard of care (SoC) for the last decade, until the approval of the protease inhibitors (PIs) boceprevir and telaprevir in 2011. These new drugs added to pIFN and RBV have led to an increase in sustained viral response (SVR) but also to a profile of unfavourable side effects and high acquisition costs. This new therapeutic scenario has been established for both naive and pretreated patients, but only for HCV genotype 1 infection.6–9
Sofosbuvir (SOF), an oral bioavailable direct-acting antiviral (DAA) recently approved by the US Food and Drug Administration and European Medicines Agency, is a nucleotide analogue inhibitor of the NS5B polymerase protein. Its efficacy in combination with pIFN plus RBV has been analysed in several studies and it has meant the emergent possibility of IFN-free regimens for certain patients’ population.10 ,11 Shorter treatment courses, easy-to-administer regimens, an acceptable side effect profile, no resistance-associated mutations evidenced in virological failure and pan-genotypic activity make it a suitable option from the clinical point of view.12 As generally occurs with therapeutic innovation, its high acquisition cost deserves an efficiency analysis before generalised use is stabilised.13–15
The aim of this study is to estimate the cost-effectiveness of SOF-based regimens for different genotypes and patients' populations according to data obtained from clinical trials (CTs) and summary of product characteristics (SmPC).16
Design and analysis perspective
A Markov model was developed to estimate costs and clinical outcomes, from the beginning of the therapy with a lifelong time horizon, using different SOF-based therapeutic strategies. We simulated the progression between the different health states presented in hepatitis C monoinfection, including death by disease or by other causes.
A discount rate was applied to reflect the time preference, transforming future costs and outcomes (from first year) to current values, and thus, compare them with the initial cost of therapy. The annual discount rate considered was 3%, as recommended in the literature.14 This study was conducted from the perspective of the Spanish National Healthcare System and considered a threshold limit of €40 000/quality-adjusted life-years (QALY) for cost-effectiveness.17
Treatment strategies and effectiveness
We evaluated SOF-based regimens for naive and pretreated patients, separately for each genotype on the basis of different CTs, according to SmPC. Efficacy estimations were based on the sustained viral eradication 12 weeks after completion of treatment. If discrepancies between SmPC and CTs publications existed, data from SmPC were recorded.10 ,11 ,16 ,18–25
The SmPC covers two therapeutic regimens.16 On the one hand, the triple therapy based on NEUTRINO CT with an SVR of 90%.11 On the other hand, SmPC recorded dual therapy with SOF+RBV for 24 weeks based on the phase II CTs QUANTUM and 11-I-0258, where SVR was 65%.18 ,19 Given the lack of control group in the cited CTs, the SVR rate for pIFN+RBV group was obtained from an alternative source.20 A comparison versus PI triple therapy was also performed as could be considered in most cases the SoC for genotype 1 patients.6 ,7
The label information recorded treatment option with SOF+RBV for 12 weeks. Efficacy parameters were based on the FISSION CT, which evidenced an SVR of 95% for SOF+RBV and 77.6% for pIFN+RBV.11
The label information included two options. First, SOF triple therapy based on phase II ELECTRON and PROTON CTs that included 39 patients with an estimated SVR of 97%.21 ,22 Second, dualtherapy with SOF+RBV for 24 weeks based on VALENCE CT with an SVR of 93%.23
The main methodological limitation of the CTs VALENCE, ELECTRON and PROTON21–23 was the absence of control group with the SoC, so it was necessary to obtain the pIFN+RBV option SVR from the FISSION CT.11
The label information included treatment with SOF plus RBV for 12 weeks with an 82% of SVR based on FUSION CT.10 Control group efficacy estimations with pIFN+RBV were obtained from the genotype 2 subgroup included in the EPIC CT.24
The SmPC included two treatment options. First, SOF triple therapy based on the LONESTAR-2 phase II CT, which reached an 83% SVR. Second, dual therapy with SOF+RBV for 24 weeks based on the VALENCE CT, which achieved a 77% SVR.23
The absence of a control group for the LONESTAR-2 and VALENCE CTs required another source of information for SoC SVR, obtained from the EPIC study genotype 3 subpopulation.23–25
Drugs costs were estimated on the basis of the dosing and therapeutic schemes included in the CTs and SmPC. The absence of stopping rules, in contrast to the boceprevir and telaprevir CT,16 simplified the average cost estimates of therapeutic options. A perfect adherence was considered on estimations.
Due to its recent approval, SOF does not yet have a registered price so the one for the ‘expanded access’ programme was applied. The acquisitions of pIFN and RBV in our setting are subjected to considerable discounts with regards to the official price due to the competition among therapeutic alternatives. As this is widely practised, actual prices were used instead of the official prices.26 ,27
Cost estimations were performed considering a regimen of 400 mg/day SOF, 1000 mg/day of RBV and a weekly dose of 180 µg peginterferon α-2a with a variable duration (12–24 weeks) according to the SmPC (table 1).28–31
Drug adverse reactions are associated with an additional cost due to drug consumption, medical visits, hospital admissions and other resources generated from their treatment. The association of SOF+RBV seems to be better tolerated than the pIFN+RBV association according to FISSION CT.11 No additional cost was considered for pIFN+RBV derived from its dose reduction managing. The impact of drug toxicity on health-related quality of life (HRQL) was taken into account as mentioned in the next section.
Healthcare resource costs associated to disease progression were obtained from hospitals in the Basque Health Service in 2013. The estimated cost for each disease state is summarised in table 1. We differentiated transition costs from state costs. The former correspond to the in-hospital care of patients due to different complications related to chronic liver disease. The latter include the cost of resources used in the follow-up.32–35 The model included costs associated for SVR states, which derived from the consumption of healthcare resources associated with patients' monitoring.
Additional information about costs estimations is detailed in the Technical Annex.
Quality of life
Quality of life was assessed by applying a specific value of utility to each health state. Because values for Spanish patients were not available, we used the figures elicited by applying EQ-5D and Time Trade-Off tariffs to a sample of UK patients with hepatitis C that have been widely used in literature.35–38 Different utility figures were used for SVR states according to the health state they came from.37 ,38 The HRQL weights are recorded in table 2, and more detailed information is given in the Technical Annex. Estimations were also performed with utility values from a different source in sensitivity analysis.39
A Markov-based decision model was built to transform SVR figures on QALY establishing the impact of long-term therapeutic alternatives and analysing the efficiency of the SOF-based regimens. The Markov diagram outlined in figure 1 represents the natural history of hepatitis C and was carried out using TreeAge Pro 2014 software (Tree-Age Software, Inc, Boston, Massachusetts, USA). We used a lifelong time horizon to estimate QALYs expectancy and lifetime direct costs. The initial cohort population candidate for treatment was defined according to the patient's average characteristics of CTs,10 ,11 with 50 years of age, and assuming a distribution of 50% of patients in ‘mild hepatitis’ estate (F0–F1) and other 50% in ‘moderate hepatitis’ (F2–F3). The cycle duration was 3 months, and based on the recommendations, a mid-cycle correction was carried out.40 Transition rates were obtained from the literature and had been widely used in previous models.28–31 ,41–48
Estimations of life expectancy in different states of hepatitis C were made to validate the model. We calculated the life expectancies from different states and the percentage of patients who progress to cirrhosis (21% at 20 years and 37.4% at 30 years). These data are similar to those of other models.42 Detailed information about Markov model framework and validation is shown in the Technical Annex.
A one-way sensitivity analysis was carried out for each therapeutic option analysed in the base case to show the influence of different variables on incremental cost-effectiveness ratio (ICER).
We analysed the consequences of starting treatment at different ages by establishing a framework from 30 to 70 years. Furthermore, several scenarios were developed using an interval of transition probability values between states of moderate hepatitis to cirrhosis; these were the maximum and minimum values offered by Townsend et al28 in their review. A different acquisition cost for SOF was also considered including a hypothetical 20% and 40% cost reduction. Different discount rates were also applied. Conducting a sensibility analysis for every susceptible parameter was avoided, as introducing a large number of variables into the estimates would complicate its interpretation. Changes from base-case scenario were evaluated assuming a different distribution of the initial cohort for 100% of patients in mild hepatitis state first, and 100% of patients in moderate hepatitis state later, as well as for a cohort of cirrhotic patients (‘supplementary digital content’). The impact of other included variables was also considered in supplementary digital content.
A probabilistic sensitivity analysis was developed to offset the limitations of a traditional sensitivity analysis.49–53 All the distribution parameters applied in this analysis are shown in the Technical Annex.
The manuscript content was structured on the basis of the established recommendations by the ‘Health Economic Evaluation Publication Guidelines Good Reporting Practices Task Force’ (Consolidated Health Economic Evaluation Reporting Standards checklist).54
Our analysis results for different SOF strategies applied to the base-case patients cohort are shown in table 3, showing the ICER versus dual therapy.
Two therapeutic options were approved in SmPC for genotype 1. The SOF+RBV+pIFN for 12 weeks option estimated an ICER of €26 281/QALY, while the IFN-free regimen (SOF+RBV for 24 weeks) reached an ICER of €138 070/QALY, being considered a dominated option (more expensive and less effective than SOF+RBV+pIFN for 12 weeks). Comparison versus PIs triple therapy maintained the ICER in similar figures for SOF+RBV+pIFN and became SOF IFN-free regimens as a dominated option.
An IFN-free therapeutic option was approved for genotype 2 patients consisting of SOF+RBV for 12 weeks, estimating an ICER of €71 865/QALY compared with pIFN+RBV for 24 weeks.
Regarding genotype 3, two therapeutic options were stated in the SmPC. The SOF+RBV+pIFN for 12-week option estimated an ICER of €35 341/QALY, while the IFN-free regimen (SOF+RBV for 24 weeks) reached an ICER of €83 679/QALY, being considered again a dominated option under triple therapy for 12 weeks.
No clinical data evaluated efficacy of SOF-based regimens for genotype 1 pretreated patients, so ICER estimates were precluded.
Genotype 2 pretreated population receiving SOF+RBV for 12 weeks reached an ICER of €46 636/QALY.
Genotype 3 patients recorded two therapeutic options in SmPC. The SOF+RBV+pIFN for 12 weeks estimated an ICER of €39 387/QALY, in the limit of efficiency in our setting, while the IFN-free regimen (SOF+RBV for 24 weeks) reached an ICER of €108 258/QALY, being considered a dominated option compared with SOF+RBV+pIFN for 12 weeks.
One-way sensitivity analysis
Sensitivity analyses showed the influence of different variables on ICER. Results versus SoC are shown in table 4.
Increasing the age at the start of treatment significantly increased the ICER that reached by the efficiency threshold for genotype 1 at around 60 years of age. In case of genotype 3, the efficiency limit of €40 000/QALY was reached when almost past the fifties.
Annual transition rates from CHC to cirrhosis were also modified for an interval from the revised literature.28 A reduction of ICER for the higher annual transition rate figure of 7.3% was observed, but none of the options considered non-cost-effective for base-case scenario changed to cost-effective.
ICER was estimated for two alternative scenarios to analyse potential future SOF cost reductions (20% and 40%) derived from drug competition, manufacturer discounts, shared risk agreements or other programmes that meant a price reduction. A relevant ICER reduction was observed for all therapeutic options; however, 24-week SOF alternatives remained over the chosen efficiency threshold.
Significant ICER reductions were observed applying a 0% discount rate.
Changes from base-case scenario are shown in supplementary digital content (see online supplementary tables) for an initial cohort of patients in mild hepatitis state and an initial cohort of patients in moderate hepatitis state. Estimations for a cohort of cirrhotic genotype 1-naive patients were also performed. The impact of other analysed variables is shown in the same annex.
Probabilistic sensitivity analysis
A probabilistic sensitivity analysis was carried out for the options considered cost-effective in the base-case scenario via the cost-effectiveness plane and the cost-effectiveness acceptability curves (figures 2⇓⇓–5). An ICER below €40 000/QALY was presented for 98% of the simulations for the scenario of SOF+RBV+pIFN versus RBV+pIFN in genotype 1 patients. For the genotype 3-naive patients’ scenario, 82% of the simulations presented an ICER under the efficiency threshold compared with only 63% for genotype 3 pretreated patients.
The efficiency analysis of introducing SOF into CHC therapeutic strategies shows different results based on the target population analysed. These differences are explained by patients’ clinical heterogeneity, according to their different genotypes, and whether treatment-naive or treatment-experienced. The variability of results is also conditioned by the length of treatment with SOF, differing from 12 to 24 weeks, as this has a decisive impact on the efficiency of the regimens considered. In general, the 12-week treatment course that contributes significant increases of SVR situates the ICER versus the SoC slightly below the efficiency thresholds of our healthcare environment. However, the options to extend its duration to 24 weeks, although bringing a slight increase in the SVR, brought the ICER well above the commonly accepted threshold.
For naive patients, the scenario for genotypes 1, 2 and 3 was analysed, and no other genotypes were considered due to their underrepresentation in CTs. For genotype 1, the 12-week treatment course was compared with dual therapy. The ICER was estimated at €26 000/QALY, making it an acceptable option from the cost-effectiveness point of view. Furthermore, the probabilistic sensitivity analysis obtained an ICER below €40 000/QALY in 98% of the simulations made. The main limitation of this result was the need to estimate the efficacy of pIFN+RBV treatment from another source due to the design of the CT as it did not include an SoC comparator arm. An alternative comparator to the SOF strategy could be a therapeutic option that includes a PI, as currently this could be considered as the SoC for the majority of genotype 1 infection cases. This option results in a smaller difference with SOF, both in terms of costs and SVR. The estimates converted the option of IFN-free SOF for 24 weeks into a dominated option. In the case of the 12-week SOF+pIFN+RBV option, the estimated ICER (vs PI-based regimen) remains similar to the one obtained versus pIFN+RBV, with a figure of €24 135/QALY. Estimations carried out in a different setting go in the same direction, considering in general SOF triple-therapy regimens cost-effective and SOF IFN-free regimens over the threshold limit.55
The therapeutic option stated in SmPC for genotype 2 significantly increases the SVR16 and the cost of the dual therapy with SOF+RBV, establishing an ICER of €71 865/QALY. This places the intervention above the efficiency threshold limit. For genotype 3, the SmPC offers two treatment options. On the one hand, dual therapy with SOF+RBV for 24 weeks, which increments the SVR, increasing the drug acquisition cost to figures exceeding €90 000 per patient, thereby showing an ICER well above the threshold of acceptability. This extension to 24 weeks in genotype 3 is based on the VALENCE CT, as well as on the unfavourable results of SOF+RBV for 12 weeks, which was inferior to the SoC and were highlighted in the FUSION CT. On the other hand, triple therapy with SOF+RBV+pIFN for 12 weeks where the cost of treatment is reduced by half, but increasing the SVR. This improved the ICER to figures close to the established efficiency threshold limit. Both these options registered in the SmPC are based on CTs that did not include an SoC comparator arm, so the SVR of the pIFN+RBV treatment group was obtained from the results of the FISSION CT. A further limitation in the case of the SOF+RBV+pIFN option was the estimate of efficacy from a group that included only 39 patients and that may reflect a greater interest in investigating interferon-free therapies rather than other alternative therapies.21–23
In the case of treatment-experienced patients, the lack of efficacy data on SOF-based regimens for genotype 1 patients is noteworthy, as opposed to that of the first-generation DAA agents.8 ,9 This limitation, even assuming that the significant increase in SVR in the treatment-naive patient can be moved to the treatment-experienced patient, is a major shortcoming since this subpopulation could represent the patient group of treatment candidates who are most often under consultation. Added to this fact is the SmPC recommendation to prolong the treatment duration to 24 weeks, bringing a significant cost increase. In the case of the PIs, the efficacy spanned a very wide range depending on the subpopulation of patients analysed. It reached an SVR of 61% among the ‘partial responders’ and 84% among the ‘relapsers’,8 ,9 with a cost of around €40 000 per patient treated. In the case of the ‘null-responders’, the estimated SVR was 31%.9 The SVR reached by the SOF+pIFN+RBV treatment for 24 weeks in these three subpopulations of patients is unknown, but the treatment cost rose to €105 000, which is about 2.5 times greater than PI treatment. However, it would have been desirable to include treatment-experienced patients in the pivotal CTs of SOF as those results would limit the uncertainty and facilitate decision making from both a clinical and a pharmacoeconomic point of view. In the case of genotypes 2 and 3, only the triple-therapy option with SOF+pIFN+RBV in genotype 3 estimated an ICER just on the threshold of acceptability, where the probabilistic sensitivity analysis reduced the percentage of simulations within the range to 63%. The rest of the analysed options placed the ICER well above the threshold.
As in all the cost-effectiveness studies of CHC treatment, among the variables that have a decisive influence on the results are the subject's age at the start of treatment and the cost of drugs. Age is an important determinant in the efficiency analysis, as the main cost is fixed and it is generated at the beginning, while the health benefits are obtained in the distant future and decrease with age. The more advanced the age at the onset of treatment, the fewer potential health outcomes are obtained, while using the same amount of resources, carrying an increase of the ICER. Two scenarios were analysed to evaluate the impact of potential SOF cost reduction (20% and 40%). This was analysed because the high acquisition cost at the beginning of the drug life often undergoes a progressive reduction with the subsequent appearance of new therapies that compete for the same area, which results in an important factor for cost-effectiveness. Fibrosis stage at the start of treatment had a clear impact on ICER, increasing figures for mild hepatitis, where only SOF triple-therapy options for genotype 1-naive patients remained just under the threshold limit. Starting treatment in the moderate hepatitis state reduced ICER figures. However, none of the options over the limit of €40 000/QALY changed its condition except for genotype 2 pretreated patients, close to this limit. Estimations for genotype 1 cirrhotic cohort patients left the ICER also behind the mentioned limit.
The approval of SOF introduces the novelty of potential establishing of IFN-free therapeutic strategies. However, herein two clarifications should be stated. First, the removal of IFN, according to the studies analysed, results in a reduction of the SVR even extending therapy from 12 to 24 weeks. Second, the only CT to analyse IFN intolerance included 50% of patients who simply ‘refused’ to receive IFN, and in the remaining 50%, the contraindication was ‘relative’ in a significant number of patients.10 Both the results that imply a reduction in SVR and the costs associated with IFN-free therapy that increases the duration from 12 to 24 weeks require the candidates to be properly selected for these IFN-free options. Arising from the inclusion of patients in the POSITRON CT who refused to receive IFN without an established contraindication,10 it would be interesting to determine the social benefit provided by this option. Establishing the ‘willingness to pay’ in these cases would determine whether the social benefit of eliminating IFN treatment is greater than the amount of €45 000 resulting from prolonging the treatment with SOF from 12 to 24 weeks, or whether it falls far short of this figure.
The CTs currently on the drawing board associate DAA agents free of IFN and RBV that allow the SVR to increase with an optimal tolerance. A progressive acquisition cost increase of upcoming drugs as seen to date would have a significant therapy cost increment. This aspect might cause financing problems to healthcare systems, where, regardless of the ICER, its introduction would carry with them a budgetary impact difficult to handle. This concern has been evaluated by expert panels, although the disputes have also reached mainstream media.56–58
The main limitations of the study are due to the design and results of the CTs used to obtain the efficacy data. Three of the four ‘pivotal’ CTs analysed therapeutic options without an SoC comparator, limiting the design to a single arm, or comparing different SOF options. This fact makes it difficult to establish the marginal benefit provided by SOF-based strategies. At the same time, some therapeutic options recorded in the SmPC are based on phase II CTs. Accordingly, the small number of patients included in CTs prevented us from analysing the impact of clinical heterogeneity variables such as the degree of fibrosis or the IL28B polymorphism. The absence of this information complicates the therapeutic positioning of the new drug that could help to establish a prioritisation of its use. Other limitation related to this issue was the CTs patient's classification as ‘cirrhotic’ or ‘non-cirrhotic’, giving no information of degree of fibrosis for non-cirrhotics. That made us to assume a ‘base-case cohort’ equally distributed between mild and moderate hepatitis.
Tolerance differences between the treatment regimens depending on the pIFN inclusion have only been reflected by the estimated ‘disutility’ values for each treatment. This has proved to be another limiting force to our analysis. Although the SOF+RBV treatment in the FISSION CT shows a lower proportion of adverse effects such as anaemia, neutropenia or flu-like syndrome, an economic estimate of the same was not carried out. Management based on dose reductions as may be the case with anaemia due to RBV, and which may be more acute at the start of treatment while producing a progressive tolerance, would justify their non-inclusion. In turn, this increased incidence of adverse events in the pIFN+RBV group can be compensated by a higher incidence of ‘severe’ adverse events in the case of the SOF+RBV group.11
The study of the HIV coinfected population was not included in our analysis as not enough CTs with a large coinfected patient population were available to estimate their specific SVR. Moreover, the progression of the disease is determined by the coinfection, and therefore the model should introduce its influence on the progression of this chronic liver disease. However, this aspect of the natural history of patients is poorly documented.
The approval of SOF means a significant advance in the treatment of CHC, providing an increase in SVR, good tolerance and presenting activity for any viral genotype.
The ICER estimates provide figures that vary depending on the analysed population and the therapeutic option considered; while treatment with triple therapy for 12 weeks in genotype 1 patients could be considered a cost-effective option, the strategies free of IFN in genotype 1, 2 and 3 position the ICER above the efficiency threshold.
The high cost of treatment, the existence of strategies analysed in a small number of patients without an SoC comparator, as well as the lack of results in treatment-experienced genotype 1 patients, hinders its therapeutic positioning.
Contributors RS, VG, AB and JM conceived the study and wrote the manuscript. RS, VG and AB reviewed the literature and analysed clinical trials data. RS and JM reviewed and updated CHC Markov model. RS, VG and JM designed and estimated cost-effectiveness results where JM performed probabilistic sensitivity analysis. All authors have approved the final version to be published.
Competing interests None.
Provenance and peer review Not commissioned; externally peer reviewed.