Aliment Pharmacol Ther. ;40(6):657-675.
Discussion Only
Full Text Available At Medscape
This study comprises a health economic analysis of sofosbuvir + pegIFN/RBV for the treatment of patients with HCV genotype 1. Outcomes from the cost-effectiveness model show that sofosbuvir + pegIFN/RBV yields the most favourable future health economic outcomes compared with other currently available regimens across a broad spectrum of patients, including those with different treatment experiences and severity of fibrosis as well as individuals with and without HIV co-infection.
Compared with other current treatment regimens, sofosbuvir + pegIFN/RBV was associated with the lowest incidence of liver-disease complications such as decompensated cirrhosis, HCC, liver transplant and HCV-related deaths. In all patient subgroups, the estimated percentage reduction in these sequelae was greater than 43% for sofosbuvir vs. the comparator regimens, except for simeprevir + pegIFN/RBV in the treatment-experienced patient subgroup (a reduction of 33%). The lower 1-year cost per SVR associated with sofosbuvir + pegIFN/RBV indicated that more patients can be successfully treated under a fixed budget with this regimen than with boceprevir + pegIFN/RBV, telaprevir + pegIFN/RBV and simeprevir + pegIFN/RBV. The greater increase in SVR rate and the shorter treatment duration with sofosbuvir than with other regimens resulted in significant risk reductions in morbidity (i.e. liver-disease complications), death and costs. The 1-year SVR costs associated with sofosbuvir + pegIFN/RBV were higher than those associated with pegIFN/RBV alone in treatment-naïve patients and those without cirrhosis. However, it should be noted that pegIFN/RBV alone or with boceprevir or telaprevir is not recommended for treatment of HCV genotype 1 in either of these patient populations.[31]
Previous cost analyses have revealed that HCV treatment regimens including protease inhibitors (boceprevir and telaprevir) are cost-effective.[32,33,79] The findings from the present analysis, relating to the lifetime incremental cost per QALY gained for patients infected with HCV genotype 1, indicate that sofosbuvir + pegIFN/RBV is currently the most cost-effective option available, even including treatment-experienced patients and those with cirrhosis. Sofosbuvir + pegIFN/RBV was both less costly and more effective than boceprevir + pegIFN/RBV, telaprevir + pegIFN/RBV and simeprevir + pegIFN/RBV regimens. Results from the sensitivity analysis indicated that sofosbuvir + pegIFN/RBV continued to be a cost-effective strategy (compared with both simeprevir + pegIFN/RBV and no treatment) even when key clinical and cost parameters (such as SVR rates, adverse event incidence, costs for treatment monitoring and management of adverse events and transition probability estimates) were adjusted across wide, yet plausible, ranges. The outcomes from this model were also robust when sensitivity analyses were performed to account for lower cirrhosis prevalence and fibrosis rates, various transition probabilities to recurrence in patients who achieve SVR (with and without cirrhosis), and the rate of HCC and decompensation in patients with cirrhosis. These findings support those from other recently published cost-effectiveness models, which indicated that oral anti- viral regimens are cost-effective compared with the current standard of care for HCV genotype 1.[34,35]
The outcomes from the model revealed that, for all treatment regimens analysed, the 1-year costs per SVR were lower for treatment-naïve patients than for treatment-experienced patients; similarly, they were also lower for patients without cirrhosis than cirrhotic patients. These findings are comparable to those reported in a recent cost analysis of protease inhibitor-based therapy.[80] Cases of liver-disease complications are lower when therapy is initiated early, because of higher SVR rates among patients without cirrhosis than among patients with cirrhosis, and the resulting costs avoided via averted cases of liver-disease complications.
Another important finding from this study is that the benefits of treating HCV are considerable, with over a 69% reduction in advanced liver disease cases when treating with an efficacious regimen such as sofosbuvir + pegIFN/RBV compared with no treatment. Gordon et al. demonstrated that the annual costs of end-stage liver disease in patients with untreated HCV were five times higher than the annual costs of noncirrhotic disease in treated patients.[4] Hagan et al. found that the ICER for receiving HCV treatment vs. no treatment was $10 920/QALY.[34] Our cost-effectiveness model found similar ICERs. The ICER for the treatment of HCV genotype 1 treatment-naïve patients with sofosbuvir was around $6000/QALY compared with no treatment. This ICER is well below the commonly accepted willingness-to-pay threshold of $50 000/QALY and less than the ICERs for Papanicolaou test and biennial mammography screening ($17 000/QALY and $27 000/QALY, respectively, in 2013 US dollars).[81,82]
There are a few potential limitations of this model. First, it is predominantly populated with clinical trial data, which represents a controlled rather than a real-world environment. Numerous studies have suggested that real-world therapy completion rates and SVR rates associated with existing treatment regimens are substantially lower, and adverse event incidence is higher, than previously reported in clinical trial settings.[21,42,52,83,84] The cost per SVR achieved may be substantially higher than those reported in this analysis when real-world adverse event incidence, discontinuation and virological failures are considered. Sufficient real-world data to populate the model fully are not available; therefore, issues related to differences between clinical trial and real-world efficacy and safety could not be accounted for in this analysis. In addition, the SVR rates for each comparator were obtained from separate clinical trial arms, as no head-to-head clinical trials or meta-analyses including sofosbuvir and its comparators were available at the time of this analysis. Furthermore, some of the SVR rates for the treatment options in the cirrhosis patient subgroup were based on clinical trials with small sample sizes; as a result, F3 and F4 data were combined in some instances. Patient demographical and clinical characteristics may be different across clinical trials, which can affect patients' SVR rates. However, we took stage of cirrhosis at baseline into consideration, which is the most significant predictor of SVR rate in patients with HCV. In addition, the deterministic sensitivity analysis demonstrates that the findings from this study are robust over a range of SVR rates. Overall, adverse event management accounted for less than 3% of costs for all comparators. When the relevant data become available, additional analyses will be necessary to determine the potential impact of the greater expected real-world differences between the sofosbuvir-based regimens and the other available therapies.
Another potential limitation to consider is that in order to estimate the long-term impact of health and economic outcomes in a clinical trial setting, the model predicted the course of liver disease for each individual over their remaining lifetime and mortality based on literature estimates of natural disease progression data. It is possible that disease progression may vary depending on a patient's gender, race, other comorbidities (e.g. co-infection with hepatitis B virus) or alcohol consumption, which were not accounted for in this model. However, to estimate transition probabilities, we used nationally representative, recent data that controlled for covariates or previously used data for HCV models. The model is also limited with regard to the fact that it does not account for the potential risk of HCC to develop in patients who achieve SVR (specifically if treated at F4 cirrhosis stage).[85] An additional limitation is that this study only included US data; costs of HCV treatments may vary considerably across other countries which may influence cost-effectiveness analysis outcomes. In the future, it would therefore be beneficial for this analysis to be repeated for other countries. Furthermore, other benefits of efficacious and tolerable regimens, such as lower indirect costs, reduction in the incidence of extrahepatic manifestations, impact on viral transmission and improved work productivity were not considered in this model. The model does, however, reflect the best available evidence consistent with the opinions of a panel of experts in hepatology and serves as a valuable tool for evaluating the health economic outcomes associated with HCV infection therapies.
Clinical trials have demonstrated that sofosbuvir-based regimens for patients infected with HCV genotypes 1–6 resulted in high SVR rates and a favourable safety profile and tolerability as substantiated by the recommended status on the AASLD/IDSA guidelines.[27,29,31] In combination with the outcomes from this evaluation, the clinical attributes of sofosbuvir and its broad utility across patient populations can be projected to result in advantageous real-world economic outcomes. Further analyses need to incorporate real-world data, additional genotypes and future comparators.
In summary, these findings demonstrate that long- term sofosbuvir + pegIFN/RBV is the most cost-effective treatment option for patients infected with HCV genotype 1 because of averted liver-disease costs. Earlier initiation of the more effective sofosbuvir-based regimen yields improved health economic outcomes than later initiation, reducing advanced liver-disease complications and the downstream costs associated with advancing disease.
This study comprises a health economic analysis of sofosbuvir + pegIFN/RBV for the treatment of patients with HCV genotype 1. Outcomes from the cost-effectiveness model show that sofosbuvir + pegIFN/RBV yields the most favourable future health economic outcomes compared with other currently available regimens across a broad spectrum of patients, including those with different treatment experiences and severity of fibrosis as well as individuals with and without HIV co-infection.
Compared with other current treatment regimens, sofosbuvir + pegIFN/RBV was associated with the lowest incidence of liver-disease complications such as decompensated cirrhosis, HCC, liver transplant and HCV-related deaths. In all patient subgroups, the estimated percentage reduction in these sequelae was greater than 43% for sofosbuvir vs. the comparator regimens, except for simeprevir + pegIFN/RBV in the treatment-experienced patient subgroup (a reduction of 33%). The lower 1-year cost per SVR associated with sofosbuvir + pegIFN/RBV indicated that more patients can be successfully treated under a fixed budget with this regimen than with boceprevir + pegIFN/RBV, telaprevir + pegIFN/RBV and simeprevir + pegIFN/RBV. The greater increase in SVR rate and the shorter treatment duration with sofosbuvir than with other regimens resulted in significant risk reductions in morbidity (i.e. liver-disease complications), death and costs. The 1-year SVR costs associated with sofosbuvir + pegIFN/RBV were higher than those associated with pegIFN/RBV alone in treatment-naïve patients and those without cirrhosis. However, it should be noted that pegIFN/RBV alone or with boceprevir or telaprevir is not recommended for treatment of HCV genotype 1 in either of these patient populations.[31]
Previous cost analyses have revealed that HCV treatment regimens including protease inhibitors (boceprevir and telaprevir) are cost-effective.[32,33,79] The findings from the present analysis, relating to the lifetime incremental cost per QALY gained for patients infected with HCV genotype 1, indicate that sofosbuvir + pegIFN/RBV is currently the most cost-effective option available, even including treatment-experienced patients and those with cirrhosis. Sofosbuvir + pegIFN/RBV was both less costly and more effective than boceprevir + pegIFN/RBV, telaprevir + pegIFN/RBV and simeprevir + pegIFN/RBV regimens. Results from the sensitivity analysis indicated that sofosbuvir + pegIFN/RBV continued to be a cost-effective strategy (compared with both simeprevir + pegIFN/RBV and no treatment) even when key clinical and cost parameters (such as SVR rates, adverse event incidence, costs for treatment monitoring and management of adverse events and transition probability estimates) were adjusted across wide, yet plausible, ranges. The outcomes from this model were also robust when sensitivity analyses were performed to account for lower cirrhosis prevalence and fibrosis rates, various transition probabilities to recurrence in patients who achieve SVR (with and without cirrhosis), and the rate of HCC and decompensation in patients with cirrhosis. These findings support those from other recently published cost-effectiveness models, which indicated that oral anti- viral regimens are cost-effective compared with the current standard of care for HCV genotype 1.[34,35]
The outcomes from the model revealed that, for all treatment regimens analysed, the 1-year costs per SVR were lower for treatment-naïve patients than for treatment-experienced patients; similarly, they were also lower for patients without cirrhosis than cirrhotic patients. These findings are comparable to those reported in a recent cost analysis of protease inhibitor-based therapy.[80] Cases of liver-disease complications are lower when therapy is initiated early, because of higher SVR rates among patients without cirrhosis than among patients with cirrhosis, and the resulting costs avoided via averted cases of liver-disease complications.
Another important finding from this study is that the benefits of treating HCV are considerable, with over a 69% reduction in advanced liver disease cases when treating with an efficacious regimen such as sofosbuvir + pegIFN/RBV compared with no treatment. Gordon et al. demonstrated that the annual costs of end-stage liver disease in patients with untreated HCV were five times higher than the annual costs of noncirrhotic disease in treated patients.[4] Hagan et al. found that the ICER for receiving HCV treatment vs. no treatment was $10 920/QALY.[34] Our cost-effectiveness model found similar ICERs. The ICER for the treatment of HCV genotype 1 treatment-naïve patients with sofosbuvir was around $6000/QALY compared with no treatment. This ICER is well below the commonly accepted willingness-to-pay threshold of $50 000/QALY and less than the ICERs for Papanicolaou test and biennial mammography screening ($17 000/QALY and $27 000/QALY, respectively, in 2013 US dollars).[81,82]
There are a few potential limitations of this model. First, it is predominantly populated with clinical trial data, which represents a controlled rather than a real-world environment. Numerous studies have suggested that real-world therapy completion rates and SVR rates associated with existing treatment regimens are substantially lower, and adverse event incidence is higher, than previously reported in clinical trial settings.[21,42,52,83,84] The cost per SVR achieved may be substantially higher than those reported in this analysis when real-world adverse event incidence, discontinuation and virological failures are considered. Sufficient real-world data to populate the model fully are not available; therefore, issues related to differences between clinical trial and real-world efficacy and safety could not be accounted for in this analysis. In addition, the SVR rates for each comparator were obtained from separate clinical trial arms, as no head-to-head clinical trials or meta-analyses including sofosbuvir and its comparators were available at the time of this analysis. Furthermore, some of the SVR rates for the treatment options in the cirrhosis patient subgroup were based on clinical trials with small sample sizes; as a result, F3 and F4 data were combined in some instances. Patient demographical and clinical characteristics may be different across clinical trials, which can affect patients' SVR rates. However, we took stage of cirrhosis at baseline into consideration, which is the most significant predictor of SVR rate in patients with HCV. In addition, the deterministic sensitivity analysis demonstrates that the findings from this study are robust over a range of SVR rates. Overall, adverse event management accounted for less than 3% of costs for all comparators. When the relevant data become available, additional analyses will be necessary to determine the potential impact of the greater expected real-world differences between the sofosbuvir-based regimens and the other available therapies.
Another potential limitation to consider is that in order to estimate the long-term impact of health and economic outcomes in a clinical trial setting, the model predicted the course of liver disease for each individual over their remaining lifetime and mortality based on literature estimates of natural disease progression data. It is possible that disease progression may vary depending on a patient's gender, race, other comorbidities (e.g. co-infection with hepatitis B virus) or alcohol consumption, which were not accounted for in this model. However, to estimate transition probabilities, we used nationally representative, recent data that controlled for covariates or previously used data for HCV models. The model is also limited with regard to the fact that it does not account for the potential risk of HCC to develop in patients who achieve SVR (specifically if treated at F4 cirrhosis stage).[85] An additional limitation is that this study only included US data; costs of HCV treatments may vary considerably across other countries which may influence cost-effectiveness analysis outcomes. In the future, it would therefore be beneficial for this analysis to be repeated for other countries. Furthermore, other benefits of efficacious and tolerable regimens, such as lower indirect costs, reduction in the incidence of extrahepatic manifestations, impact on viral transmission and improved work productivity were not considered in this model. The model does, however, reflect the best available evidence consistent with the opinions of a panel of experts in hepatology and serves as a valuable tool for evaluating the health economic outcomes associated with HCV infection therapies.
Clinical trials have demonstrated that sofosbuvir-based regimens for patients infected with HCV genotypes 1–6 resulted in high SVR rates and a favourable safety profile and tolerability as substantiated by the recommended status on the AASLD/IDSA guidelines.[27,29,31] In combination with the outcomes from this evaluation, the clinical attributes of sofosbuvir and its broad utility across patient populations can be projected to result in advantageous real-world economic outcomes. Further analyses need to incorporate real-world data, additional genotypes and future comparators.
In summary, these findings demonstrate that long- term sofosbuvir + pegIFN/RBV is the most cost-effective treatment option for patients infected with HCV genotype 1 because of averted liver-disease costs. Earlier initiation of the more effective sofosbuvir-based regimen yields improved health economic outcomes than later initiation, reducing advanced liver-disease complications and the downstream costs associated with advancing disease.
