Jona T. Stahmeyer , Siegbert Rossol, Sebastian Liersch, Ines Guerra, Christian Krauth
Published: January 3, 2017
http://dx.doi.org/10.1371/journal.pone.0169401
Abstract
Background
Infections with the hepatitis C virus (HCV) are a global public health problem. Long-term consequences are the development of liver cirrhosis and hepatocellular carcinoma. Newly introduced direct acting antivirals, especially interferon-free regimens, have improved rates of sustained viral response above 90% in most patient groups and allow treating patients who were ineligible for treatment in the past. These new regimens have replaced former treatment and are recommended by current guidelines. However, there is an ongoing discussion on high pharmaceutical prices. Our aim was to assess the long-term cost-effectiveness of treating hepatitis C genotype 1 patients with sofosbuvir/ledipasvir (SOF/LDV) treatment in Germany.
Material and Methods
We used a Markov cohort model to simulate disease progression and assess cost-effectiveness. The model calculates lifetime costs and outcomes (quality-adjusted life years, QALYs) of SOF/LDV and other strategies. Patients were stratified by treatment status (treatment-naive and treatment-experienced) and absence/presence of cirrhosis. Different treatment strategies were compared to prior standard of care. Sensitivity analyses were performed to evaluate model robustness.
Results
Base-case analyses results show that in treatment-naive non-cirrhotic patients treatment with SOF/LDV dominates the prior standard of care (is more effective and less costly). In cirrhotic patients an incremental cost-effectiveness ratio (ICER) of 3,383 €/QALY was estimated. In treatment-experienced patients ICERs were 26,426 €/QALY and 1,397 €/QALY for treatment-naive and treatment-experienced patients, respectively. Robustness of results was confirmed in sensitivity analyses.
Conclusions
Our analysis shows that treatment with SOF/LDV is cost-effective compared to prior standard of care in all patient groups considering international costs per QALY thresholds.
Discussion Only
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The introduction of direct acting antivirals was the milestone in the treatment of chronic hepatitis C. Newly introduced treatment regimens have substantially increased SVR-rates, shortened treatment duration and show a favorable toxicity profile. Furthermore, these regimens allow curing patients who could not be treated previously (e.g. due to interferon intolerance, advanced cirrhosis, comorbidities).
We analyzed cost-effectiveness of SOF/LDV±RBV for the treatment of HCV genotype 1 patients. Analyses were conducted for treatment-naive and treatment-experienced patients considering presence/absence of liver cirrhosis. This regimen is recommended by the current German guideline as well as the regimen containing PTV/r/OMV/DSV±RBV and was also included our analyses [57].
Results show that treatment with SOF/LDV±RBV is cost-effective compared to prior standard of care considering a willingness-to-pay threshold of €30,000. The regimen of SOF/LDV even is cost saving (showed better outcomes and lower costs) in treatment-naive non-cirrhotic patients as a large part only require treatment for 8 weeks; treatment in cirrhotic patients resulted in 3,383 €/QALY. Incremental cost-effectiveness ratios were 26,426 €/QALY in non-cirrhotic and 1,397 €/QALY in cirrhotic treatment-experienced patients. Results were robust in multiple sensitivity analyses.
Several international studies have analyzed cost-effectiveness of newly introduced direct acting antivirals, especially for the US, but have not been performed for the German setting yet.
Najafzadeh et al (2015) analyzed cost-effectiveness of novel treatment regimens in treatment-naive hepatitis C patients. In genotype 1 patients, different strategies were compared to the previous standard of care (BOC+PegIFN+RBV). Treatment with SOF/LDV for 12 weeks resulted in an incremental cost-effectiveness ratio of 12,825 $/QALY. Other interferon-free regimens showed less favorable results (12 weeks SMV/SOF: 71,445 $/QALY; 12 weeks DCV/SOF: 63,355 $/QALY). The authors conclude that new treatment regimens represent good long-term economic value in genotype 1 patients [9].
Results from another US study by Chhatwal et al. (2015) evaluated cost-effectiveness of SOF/LDV (8 or 12 weeks) compared to the old standard of care (TVR+ PegIFN+RBV and BOC+PegIFN+RBV). The analyses showed incremental cost-effectiveness ratios of 31,452 $/QALY for non-cirrhotic and 9,703 $/QALY for cirrhotic treatment-naive patients. In treatment-experienced patients 35,853 $/QALY and 79,238 $/QALY were estimated for non-cirrhotic and cirrhotic patients, respectively. Assuming a willingness-to-pay threshold of 50,000 €/QALY treatment of genotype 1 patients with SOF/LDV is cost-effective in most patient groups [8].
A study by Younossi et al. (2015) comes to the conclusion that SOF/ treatment LDV (8,12 or 24 weeks depending on patient characteristics) dominates other treatment strategies except for SOF+SMV (12 or 24 weeks), which provides slightly better results but is considerably more expensive. Sensitivity analyses show that costs of alternative treatment strategies have the greatest impact on study results [7].
Zhang et al. (2015) analyzed cost-effectiveness of recently introduced regimens, primarily considering treatment-naive patients [10]. In non-cirrhotic genotype 1 patients both, SOF/LDV (12 weeks) and OMV/PTV/RTV + DSV + RBV (12 weeks), dominate triple-therapy with TVR + PegIFN/RBV the prior standard of care (higher effectiveness and lower lifetime costs). In patients with cirrhosis SOF/LDV (12 weeks) dominates TVR+PegIFN+RBV, whereas treatment with OMV/PTV/RTV+DSV+RBV (12 weeks) shows an incremental cost-effectiveness ratio of 25,227 $/QALY [10].
In comparing different studies, it has to be taken into account that transferability of economic evaluations is limited since healthcare systems, structures of care provision and remuneration schemes differ considerably between countries [58]. The comparability is made even more difficult considering differences in study design like modeling approaches, patient characteristics and treatment strategies. Therefore, there is a high need for the defining of up-to-date national data. Nevertheless, there are comparable results such as the dominant factor of treatment costs on study results. Most studies prove that treatment with SOF/LDV is cost-effective.
There are some limitations that have to be taken into account when interpreting the results of our study. Efficacy data is based on the results from different clinical trials and data for certain treatment regimens are based on a relatively small patient samples. Usually SVR-rates from clinical trials are not easily transferable into clinical practice [59]. Nevertheless, recent data from real-world SVR-rates show comparable SVR-rates in clinical practice. In the TRIO study SVR-rates in treatment-naive non-cirrhotic patients of 95% for an 8-week treatment with SOF/LDV and 96% for a 12-week treatment with SOF/LDV±RBV were observed [60]. Data on treatment-experienced patients show SVR-rates of 84% for 12 weeks of SOF/LDV, 96% for 12 weeks of SOF/LDV+RBV and 92% for 24 weeks of SOF/LDV [61]. German data confirm high SVR-rates for newly introduced interferon-free regimens [62]. A general problem is the reliability and availability of data. Extensive literature analyses were performed to determine the best available data. Furthermore, the impact of special patient types (e.g. with certain comorbidities, alcohol or drug abuse) was insufficiently taken into account as data refers to average patients. To determine cost-effectiveness in special HCV populations separate analyses and modeling approaches are necessary.
Although several studies have shown that HCV treatment with new DAA is cost-effective or even cost-saving in certain patient groups, affordability for healthcare systems and payers is doubtful. In addition to high costs of newly introduced agents, new treatment options allow to treat and cure patients who were not eligible for treatment in the past (e.g. patients with certain comorbidities or advanced liver disease, interferon-intolerant). Therefore, the number of patients available for treatment increased significantly, which stresses healthcare budgets further. Even western countries have limited or delayed access to new treatment options and restricted the use for patients with advanced liver disease [63;64]. Prioritization of severely ill might be a short-term solution for reducing expenditure. However, it should be taken into account that a major goal of treating hepatitis C is to prevent the development of liver cirrhosis and its complications. Even if patients with liver cirrhosis are successfully treated, they are still at risk of decompensation or developing HCC [43].
Treatment with SOF/LDV is recommended by national and international guidelines. Our analyses showed that this treatment is cost-effective compared to the prior standard of care in genotype 1 patients (triple-therapy with TVR). Besides individual treatment costs, impact of new treatments on healthcare budgets should not be forgotten.
The introduction of direct acting antivirals was the milestone in the treatment of chronic hepatitis C. Newly introduced treatment regimens have substantially increased SVR-rates, shortened treatment duration and show a favorable toxicity profile. Furthermore, these regimens allow curing patients who could not be treated previously (e.g. due to interferon intolerance, advanced cirrhosis, comorbidities).
We analyzed cost-effectiveness of SOF/LDV±RBV for the treatment of HCV genotype 1 patients. Analyses were conducted for treatment-naive and treatment-experienced patients considering presence/absence of liver cirrhosis. This regimen is recommended by the current German guideline as well as the regimen containing PTV/r/OMV/DSV±RBV and was also included our analyses [57].
Results show that treatment with SOF/LDV±RBV is cost-effective compared to prior standard of care considering a willingness-to-pay threshold of €30,000. The regimen of SOF/LDV even is cost saving (showed better outcomes and lower costs) in treatment-naive non-cirrhotic patients as a large part only require treatment for 8 weeks; treatment in cirrhotic patients resulted in 3,383 €/QALY. Incremental cost-effectiveness ratios were 26,426 €/QALY in non-cirrhotic and 1,397 €/QALY in cirrhotic treatment-experienced patients. Results were robust in multiple sensitivity analyses.
Several international studies have analyzed cost-effectiveness of newly introduced direct acting antivirals, especially for the US, but have not been performed for the German setting yet.
Najafzadeh et al (2015) analyzed cost-effectiveness of novel treatment regimens in treatment-naive hepatitis C patients. In genotype 1 patients, different strategies were compared to the previous standard of care (BOC+PegIFN+RBV). Treatment with SOF/LDV for 12 weeks resulted in an incremental cost-effectiveness ratio of 12,825 $/QALY. Other interferon-free regimens showed less favorable results (12 weeks SMV/SOF: 71,445 $/QALY; 12 weeks DCV/SOF: 63,355 $/QALY). The authors conclude that new treatment regimens represent good long-term economic value in genotype 1 patients [9].
Results from another US study by Chhatwal et al. (2015) evaluated cost-effectiveness of SOF/LDV (8 or 12 weeks) compared to the old standard of care (TVR+ PegIFN+RBV and BOC+PegIFN+RBV). The analyses showed incremental cost-effectiveness ratios of 31,452 $/QALY for non-cirrhotic and 9,703 $/QALY for cirrhotic treatment-naive patients. In treatment-experienced patients 35,853 $/QALY and 79,238 $/QALY were estimated for non-cirrhotic and cirrhotic patients, respectively. Assuming a willingness-to-pay threshold of 50,000 €/QALY treatment of genotype 1 patients with SOF/LDV is cost-effective in most patient groups [8].
A study by Younossi et al. (2015) comes to the conclusion that SOF/ treatment LDV (8,12 or 24 weeks depending on patient characteristics) dominates other treatment strategies except for SOF+SMV (12 or 24 weeks), which provides slightly better results but is considerably more expensive. Sensitivity analyses show that costs of alternative treatment strategies have the greatest impact on study results [7].
Zhang et al. (2015) analyzed cost-effectiveness of recently introduced regimens, primarily considering treatment-naive patients [10]. In non-cirrhotic genotype 1 patients both, SOF/LDV (12 weeks) and OMV/PTV/RTV + DSV + RBV (12 weeks), dominate triple-therapy with TVR + PegIFN/RBV the prior standard of care (higher effectiveness and lower lifetime costs). In patients with cirrhosis SOF/LDV (12 weeks) dominates TVR+PegIFN+RBV, whereas treatment with OMV/PTV/RTV+DSV+RBV (12 weeks) shows an incremental cost-effectiveness ratio of 25,227 $/QALY [10].
In comparing different studies, it has to be taken into account that transferability of economic evaluations is limited since healthcare systems, structures of care provision and remuneration schemes differ considerably between countries [58]. The comparability is made even more difficult considering differences in study design like modeling approaches, patient characteristics and treatment strategies. Therefore, there is a high need for the defining of up-to-date national data. Nevertheless, there are comparable results such as the dominant factor of treatment costs on study results. Most studies prove that treatment with SOF/LDV is cost-effective.
There are some limitations that have to be taken into account when interpreting the results of our study. Efficacy data is based on the results from different clinical trials and data for certain treatment regimens are based on a relatively small patient samples. Usually SVR-rates from clinical trials are not easily transferable into clinical practice [59]. Nevertheless, recent data from real-world SVR-rates show comparable SVR-rates in clinical practice. In the TRIO study SVR-rates in treatment-naive non-cirrhotic patients of 95% for an 8-week treatment with SOF/LDV and 96% for a 12-week treatment with SOF/LDV±RBV were observed [60]. Data on treatment-experienced patients show SVR-rates of 84% for 12 weeks of SOF/LDV, 96% for 12 weeks of SOF/LDV+RBV and 92% for 24 weeks of SOF/LDV [61]. German data confirm high SVR-rates for newly introduced interferon-free regimens [62]. A general problem is the reliability and availability of data. Extensive literature analyses were performed to determine the best available data. Furthermore, the impact of special patient types (e.g. with certain comorbidities, alcohol or drug abuse) was insufficiently taken into account as data refers to average patients. To determine cost-effectiveness in special HCV populations separate analyses and modeling approaches are necessary.
Although several studies have shown that HCV treatment with new DAA is cost-effective or even cost-saving in certain patient groups, affordability for healthcare systems and payers is doubtful. In addition to high costs of newly introduced agents, new treatment options allow to treat and cure patients who were not eligible for treatment in the past (e.g. patients with certain comorbidities or advanced liver disease, interferon-intolerant). Therefore, the number of patients available for treatment increased significantly, which stresses healthcare budgets further. Even western countries have limited or delayed access to new treatment options and restricted the use for patients with advanced liver disease [63;64]. Prioritization of severely ill might be a short-term solution for reducing expenditure. However, it should be taken into account that a major goal of treating hepatitis C is to prevent the development of liver cirrhosis and its complications. Even if patients with liver cirrhosis are successfully treated, they are still at risk of decompensation or developing HCC [43].
Treatment with SOF/LDV is recommended by national and international guidelines. Our analyses showed that this treatment is cost-effective compared to the prior standard of care in genotype 1 patients (triple-therapy with TVR). Besides individual treatment costs, impact of new treatments on healthcare budgets should not be forgotten.
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