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New Cost Effectiveness Study Published: HCV Protease Inhibitor Triple Therapy Cost Effective, Saves Lives..... Universal treatment led to greater benefit but at higher cost
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Download the PDF here
"Both universal triple therapy and IL-28B-guided triple therapy are cost-effective when the least-expensive protease inhibitor are used for patients with advanced fibrosis".....'adherence rates matter' ....preventing HCC[liver cancer] in advanced disease patients matter'.....
[separate previous adherence studies report modeled 100% adherence to telaprevir increased SVR rates from 75% to 86% Quantification of the Effect of Adherence to Clinical Outcomes in Telaprevir-based Regimens (12/06/11)...
>80% adherence to boceprevir increased SVR from 68% to 90%
...Adherence To Assigned Dosing Regimen and Sustained Virologic Response Among Hepatitis C-Genotype 1 Previously Untreated and Peginterferon/Ribavirin Treatment-Failure Patients Treated With Boceprevir Plus Peginterferon Alfa-2b/Ribavirin (patients with >80% adherence to all dosing achieved 90% cure rates. My guess is if adherence is 100% SVR rates will be higher) - (04/05/11)
"For patients with advanced fibrosis, universal triple therapy increases the proportion achieving SVR to 51% compared with 32% SVR for standard therapy"......"Using new protease inhibitors as part of triple therapy for all patients chronically infected with genotype 1 HCV or targeted to those who are most likely to benefit from IL-28B, genotyping improves health outcomes compared with current standard 2-drug therapy (Table 3). For patients with advanced fibrosis, universal triple therapy increases the proportion achieving SVR to 51% compared with 32% SVR for standard therapy. This increase in SVR results in reductions in the lifetime risk for decompensated cirrhosis (from 23.0% to 16.5%), HCC (from 13.2% to 9.5%), and liver transplant (from 4.6% to 3.3%). For patients with mild fibrosis, universal triple therapy increases SVR from 38% to 61% and reduces the lifetime risk for decompensated cirrhosis (from 8.4% to 5.1%), HCC (from 4.7% to 2.9%), and liver transplant (from 1.5% to 0.9%) compared with standard therapy. Interleukin-28B-guided triple therapy achieved SVR in 48% of patients with advanced fibrosis and 57% of patients with mild fibrosis. Reductions in lifetime decompensated cirrhosis and HCC obtained with IL-28B-guided triple therapy were approximately 83% of those achieved with universal triple therapy."
"Because of the high cost and risk for adverse effects with protease inhibitors, some health systems (Europe) may consider reserving them for second-line rather than first-line treatment, especially for patients with less severe fibrosis. However, for patients with advanced fibrosis, in our main analyses we found that universal, first-line triple therapy reaches conventional levels of cost-effectiveness."......"Despite the highly anticipated benefits of the new protease inhibitors, tailoring HCV treatment to specific patient characteristics has garnered interest in the medical community. We find that IL-28B genotype may be useful for such stratification, and our findings are consistent with the recommendations on IL-28B genotyping in the 2011 American Association for the Study of Liver Diseases treatment guidelines (17)."
"Interleukin (IL)-28B genotype (CC, CT, or TT type) predicts response to HCV therapy and may prove valuable in targeting protease inhibitors to persons who are least likely to benefit from standard therapy and may also shorten treatment duration (8-11). Patients with non-CC types have a 30% sustained virologic response (SVR) rate with standard therapy and up to a 70% SVR rate when treated with triple therapy (12-14). In contrast, CC types are more responsive to treatment: 70% achieve SVR with standard therapy and up to 90% achieve SVR with triple therapy."
"For treatment-naive patients with chronic genotype 1 HCV monoinfection, universal triple therapy yields greater health benefits than both standard therapy and IL-28B-guided triple therapy. Although it also increases total costs, universal triple therapy provides reasonable value for money, costing approximately $50 000 per QALY compared with IL-28B-guided triple therapy for patients with advanced fibrosis, if the protease inhibitor added to standard therapy is available for $1100 per week. Universal triple therapy becomes less cost-effective when the cost of the protease inhibitors is higher, or when adherence rates are substantially lower for triple therapy than for standard therapy. For patients with mild fibrosis, universal triple therapy at a cost of $1100 per week is not cost-effective, even at $100 000 per QALY, but IL-28B-guided triple therapy costs $62 900 per QALY compared with standard therapy."
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New Protease Inhibitors for the Treatment of Chronic Hepatitis C
A Cost-Effectiveness Analysis
Annals of Internal Medicine
Shan Liu, SM; Lauren E. Cipriano, BSc, BA; Mark Holodniy, MD; Douglas K. Owens, MD, MS; and Jeremy D. Goldhaber-Fiebert, PhD
Abstract
Background: Chronic hepatitis C virus is difficult to treat and affects approximately 3 million Americans. Protease inhibitors increase the effectiveness of standard therapy, but they are costly. A genetic assay may identify patients most likely to benefit from this treatment advance.
Objective: To assess the cost-effectiveness of new protease inhibitors and an interleukin (IL)-28B genotyping assay for treating chronic hepatitis C virus.
Design: Decision-analytic Markov model.
Data Sources: Published literature and expert opinion.
Target Population: Treatment-naive patients with chronic, genotype 1 hepatitis C virus monoinfection.
Time Horizon: Lifetime.
Perspective: Societal.
Intervention: Strategies are defined by the use of IL-28B genotyping and type of treatment (standard therapy [pegylated interferon with ribavirin]; triple therapy [standard therapy and a protease inhibitor]). Interleukin-28B-guided triple therapy stratifies patients with CC genotypes to standard therapy and those with non-CC types to triple therapy.
Outcome Measures: Discounted costs (in 2010 U.S. dollars) and quality-adjusted life-years (QALYs); incremental cost-effectiveness ratios.
Results of Base-Case Analysis: For patients with mild and advanced fibrosis, universal triple therapy reduced the lifetime risk for hepatocellular carcinoma by 38% and 28%, respectively, and increased quality-adjusted life expectancy by 3% and 8%, respectively, compared with standard therapy. Gains from IL-28B-guided triple therapy were smaller. If the protease inhibitor costs $1100 per week, universal triple therapy costs $102 600 per QALY (mild fibrosis) or $51 500 per QALY (advanced fibrosis) compared with IL-28B-guided triple therapy and $70 100 per QALY (mild fibrosis) and $36 300 per QALY (advanced fibrosis) compared with standard therapy.
Results of Sensitivity Analysis: Results were sensitive to the cost of protease inhibitors and treatment adherence rates.
Limitation: Data on the long-term comparative effectiveness of the new protease inhibitors are lacking.
Conclusion: Both universal triple therapy and IL-28B-guided triple therapy are cost-effective when the least-expensive protease inhibitor are used for patients with advanced fibrosis.
Primary Funding Source: Stanford University.
Editors' Notes
Context
· Addition of protease inhibitors to standard therapy for hepatitis C improves virologic suppression, but the drugs are expensive. Genetic testing can identify a subgroup of patients who are likely to derive greater relative benefit from the addition of protease inhibitors.
Contribution
· In a decision-analytic model, a strategy of adding protease inhibitors to standard therapy for all patients or a targeted treatment strategy based on genetic testing both improved quality-adjusted life expectancy compared with standard therapy alone. Universal treatment led to greater benefit but at higher cost.
Caution
· Drugs may not be as effective in real-world practice as in clinical trials.
Implication
· Addition of protease inhibitors to standard therapy in hepatitis C is cost-effective.
-The Editors
Hepatitis C virus (HCV) infection is a serious liver disease affecting 180 million persons worldwide (1). In the United States, 2.7 to 3.9 million persons live with chronic HCV infection, approximately 75% of whom are infected with HCV genotype 1 (2, 3). Chronic HCV causes liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC) and is the most common cause of liver transplantation (1). Standard therapy for chronic HCV infection is pegylated interferon and ribavirin, which is effective in 40% to 60% of patients with HCV genotype 1 (2, 4).
New viral protease inhibitors, boceprevir (Victrelis, Merck & Co., Whitehouse Station, New Jersey) and telaprevir (Incivek, Vertex Pharmaceuticals, Cambridge, Massachusetts), used in conjunction with standard therapy, significantly increase treatment success in persons infected with genotype 1 and shorten treatment duration (5, 6). These new treatment regimens are more expensive (boceprevir, $1100 per week; telaprevir, $4100 per week) and can cause more severe adverse effects than standard therapy (7). Whether they are best used as first-line therapy for all patients infected with genotype 1 or for the subset of patients with the poorest expected outcomes with standard therapy is unclear.
Interleukin (IL)-28B genotype (CC, CT, or TT type) predicts response to HCV therapy and may prove valuable in targeting protease inhibitors to persons who are least likely to benefit from standard therapy and may also shorten treatment duration (8-11). Patients with non-CC types have a 30% sustained virologic response (SVR) rate with standard therapy and up to a 70% SVR rate when treated with triple therapy (12-14). In contrast, CC types are more responsive to treatment: 70% achieve SVR with standard therapy and up to 90% achieve SVR with triple therapy.
We performed a model-based cost-effectiveness analysis of treatment strategies for eligible patients infected with chronic HCV genotype 1. We evaluated adding new protease inhibitors to standard therapy in the context of response-guided therapy and the use of IL-28B genotyping to target triple therapy.
Results
Using new protease inhibitors as part of triple therapy for all patients chronically infected with genotype 1 HCV or targeted to those who are most likely to benefit from IL-28B, genotyping improves health outcomes compared with current standard 2-drug therapy (Table 3). For patients with advanced fibrosis, universal triple therapy increases the proportion achieving SVR to 51% compared with 32% SVR for standard therapy. This increase in SVR results in reductions in the lifetime risk for decompensated cirrhosis (from 23.0% to 16.5%), HCC (from 13.2% to 9.5%), and liver transplant (from 4.6% to 3.3%). For patients with mild fibrosis, universal triple therapy increases SVR from 38% to 61% and reduces the lifetime risk for decompensated cirrhosis (from 8.4% to 5.1%), HCC (from 4.7% to 2.9%), and liver transplant (from 1.5% to 0.9%) compared with standard therapy. Interleukin-28B-guided triple therapy achieved SVR in 48% of patients with advanced fibrosis and 57% of patients with mild fibrosis. Reductions in lifetime decompensated cirrhosis and HCC obtained with IL-28B-guided triple therapy were approximately 83% of those achieved with universal triple therapy.
For patients with advanced fibrosis, IL-28B-guided triple therapy and universal triple therapy increased discounted quality-adjusted life expectancy by 0.54 and 0.67 years, respectively, compared with standard therapy; and for patients with mild fibrosis, the increases were 0.27 and 0.33 years, respectively.
If the protease inhibitor costs $1100 per week, universal triple therapy improves outcomes but also substantially increases total costs ($24 135 for advanced fibrosis and $22 801 for mild fibrosis compared with standard therapy). Compared with IL-28B-guided triple therapy, universal triple therapy costs $51 500 per QALY for patients with advanced fibrosis and $102 600 per QALY for patients with mild fibrosis (Figure 2, A and B). The more favorable cost-effectiveness results for patients with advanced fibrosis are due largely to the greater health gains achieved by universal triple therapy for patients at roughly equal increases in costs.
In situations where IL-28B-guided therapy is unavailable, universal triple therapy costs $36 300 per QALY for patients with advanced fibrosis and $70 100 per QALY for patients with mild fibrosis compared with standard therapy (Table 3).
Chronic HCV is a slowly progressing disease that can take 30 years to cause end-stage liver disease. Meanwhile, patients may die of non-liver-related causes. Therefore, initial fibrosis stage affects the cost-effectiveness of treatment strategies. We considered clinical treatment scenarios in which a patient's specific fibrosis stage had been determined via biopsy (Appendix Figure 3). In general, universal triple therapy provides relatively more benefit per dollar spent for patients with more advanced liver fibrosis than those with less advanced fibrosis (ICERs below $50 000 per QALY for patients with F4 fibrosis increasing to >$150 000 per QALY for those with no fibrosis).
Treatment Costs
The treatment cost of the 2 protease inhibitors differs, and the cost considered in our base-case analysis was that of boceprevir ($1100 per week for 24 to 32 weeks). If the price of the protease inhibitor were higher-equal to telaprevir ($4100 per week for 12 weeks)-and the effectiveness was that of telaprevir reported in the ADVANCE trial, the ICERs of universal triple therapy versus IL-28B-guided triple therapy are $54 100 per QALY for patients with advanced fibrosis and $102 400 per QALY for patients with mild fibrosis- similar to the results for a protease inhibitor, such as boceprevir (Figure 2, C and D). In situations where IL-28B-guided therapy is unavailable, universal triple therapy costs $47 400 per QALY for patients with advanced fibrosis and $91 000 per QALY for patients with mild fibrosis compared with standard therapy (Table 3).
Comparing the 2 drugs, the effectiveness of universal triple therapy using telaprevir needs to be substantially greater than that observed in the ADVANCE trial to yield an ICER below $50 000 per QALY compared with universal triple therapy using boceprevir (Appendix Figure 4), although differences, including patterns of adverse effects, and uncertainties about adherence and effectiveness make a definitive comparison difficult.
Prices for brand-name drugs vary substantially between purchasing institutions. For example, the Veterans Health Administration may purchase drugs at the Federal Supply Schedule price. In that case, the ICERs for universal triple therapy compared with IL-28B-guided triple therapy are $41 100 per QALY gained for advanced fibrosis and $81 300 per QALY gained for mild fibrosis, although specific estimates depend on the price levels and relative prices of standard therapy and new protease inhibitors (Appendix Table 3).
Adverse Events From Therapy
Adverse effects from triple therapy are more frequent and potentially more severe than those from standard therapy, which include anemia, depression, rash, and flu-like symptoms. Higher rates and severity of adverse effects may undermine the cost-effectiveness of universal triple therapy. We performed a threshold analysis to determine how severe the adverse effect profile would need to be for the ICER to exceed $100 000 per QALY for patients with advanced fibrosis (Appendix Table 4). We found that it did not exceed this threshold, even when the costs of adverse effects were tripled ($7500) and the disutility of adverse effects were doubled (equal to a disutility of -0.36 QALYs per year with triple therapy).
Adherence
In our base-case analysis, we assumed equal adherence for standard therapy and triple therapy (70% of patients taking ³80% of their HCV medications). In a threshold analysis, we found that if adherence to standard therapy remained at 70% but was as low as 50% for triple therapy, then universal triple therapy is more costly but achieves no additional benefit compared with IL-28B-guided triple therapy and was consequently not cost-effective for patients with either mild or advanced fibrosis (Appendix Table 5). However, when compared with standard therapy with 70% adherence for those with advanced fibrosis, universal triple therapy, even with 50% adherence, cost $73 200 per QALY. For mild fibrosis, universal triple therapy for this scenario cost more than $150 000 per QALY compared with standard therapy.
Risk for HCC
Limited evidence suggests a risk for HCC from more advanced fibrosis stages, even after achieving SVR. To explore this, we conducted a sensitivity analysis in which we assumed that patients with F4 fibrosis who were successfully treated had an annual rate of developing HCC that was 20% of that for F4 before treatment. The results did not alter the main conclusions (Appendix Table 6).
Other Sensitivity Analyses
Appendix Tables 7, 8, 9, and 10 show additional sensitivity analyses considering non-liver-related mortality and retreatment and subgroup analyses by race, sex, age, IL-28B genotype, and fibrosis stage.
Probabilistic Sensitivity Analyses
In probabilistic sensitivity analyses, we used the boceprevir cost (Appendix Figure 5). For patients with advanced fibrosis, using either universal triple therapy or IL-28B-guided triple therapy was optimal 98% of the time at a willingness-to-pay threshold of $50 000 per QALY or 100% at a threshold of $100 000 per QALY, respectively. For patients with mild fibrosis, the corresponding values were 18% and 95%. Conversely, at a threshold of $50 000 per QALY, standard therapy was optimal 82% of the time for mild fibrosis but only 2% of the time for advanced fibrosis.
Discussion
For treatment-naive patients with chronic genotype 1 HCV monoinfection, universal triple therapy yields greater health benefits than both standard therapy and IL-28B-guided triple therapy. Although it also increases total costs, universal triple therapy provides reasonable value for money, costing approximately $50 000 per QALY compared with IL-28B-guided triple therapy for patients with advanced fibrosis, if the protease inhibitor added to standard therapy is available for $1100 per week. Universal triple therapy becomes less cost-effective when the cost of the protease inhibitors is higher, or when adherence rates are substantially lower for triple therapy than for standard therapy. For patients with mild fibrosis, universal triple therapy at a cost of $1100 per week is not cost-effective, even at $100 000 per QALY, but IL-28B-guided triple therapy costs $62 900 per QALY compared with standard therapy.
Because of the high cost and risk for adverse effects with protease inhibitors, some health systems may consider reserving them for second-line rather than first-line treatment, especially for patients with less severe fibrosis. However, for patients with advanced fibrosis, in our main analyses we found that universal, first-line triple therapy reaches conventional levels of cost-effectiveness. We explored the cost-effectiveness of treating all patients with standard therapy and reserving protease inhibitors for second-line treatment and found that this strategy is less effective and more costly than other strategies that use triple therapy as a first-line treatment for at least some patients (Appendix 2).
Despite the highly anticipated benefits of the new protease inhibitors, tailoring HCV treatment to specific patient characteristics has garnered interest in the medical community. We find that IL-28B genotype may be useful for such stratification, and our findings are consistent with the recommendations on IL-28B genotyping in the 2011 American Association for the Study of Liver Diseases treatment guidelines (17).
Our main analysis did not directly compare boceprevir with telaprevir. We considered a general protease inhibitor in comparison with standard 2-drug therapy and IL-28B-guided triple therapy. We varied the costs of the general protease inhibitor, treatment algorithms, and effectiveness to be similar to either boceprevir or telaprevir. It is important to note that key differences, especially the difference in cost, are relevant for health systems that are considering whether to include 1 or both new drugs in their formularies. The weekly cost of telaprevir is 4 times greater than that of boceprevir, and depending on treatment duration, the total drug cost for a complete course of telaprevir can be 140% to 190% of the cost of boceprevir. The effectiveness of telaprevir seems higher than boceprevir in separate clinical trials (SVR of 75% vs. 68%), although the populations represented in the studies may not be comparable, because the observed effectiveness also differed in the respective control groups. The difference between the 2 drugs has not been evaluated in a head-to-head comparison. The types and rates of adverse effects differ between the 2 drugs, but the overall costs from adverse effects seem to be similar. Modeled as a general protease inhibitor, universal triple therapy was found to be cost-effective compared with standard therapy for patients with advanced fibrosis (costing approximately $50 000 per QALY or less). However, when the 2 drugs are directly compared, the increase in the effectiveness of telaprevir relative to that of boceprevir needed to achieve conventional levels of cost-effectiveness may well be substantially higher than that observed in the ADVANCE trial (6). Clinical trials directly comparing the 2 drugs are needed to address comparative effectiveness. A head-to-head evaluation of the cost-effectiveness of these drugs would need to include more detailed modeling of adverse events, which would, in turn, require substantially more information about treatment patterns in real-world clinical practice.
Because the protease inhibitors we evaluated were only recently approved by the U.S. Food and Drug Administration, the feasibility of implementation of response-guided therapy recommendations in routine practice, the treatment effectiveness, and adherence to treatment are unknown. Adherence is especially important to treatment effectiveness and cost-effectiveness. If adherence to triple therapy is lower than that of standard therapy, IL-28B-guided therapy may be the optimal strategy.
Although the main analysis focuses on initial treatment of chronic HCV infections, important questions remain about retreating patients whose initial treatment fails. Our analysis does not primarily address this topic, but data and studies of effectiveness in this setting are forthcoming. We explored this issue and found that IL-28B-guided triple therapy with retreatment of patients in whom initial treatment with standard therapy failed is cost-effective in the advanced fibrosis group (Appendix 2). However, given the lack of evidence, we did not consider strategies involving retreatment with triple therapy after initial failure with triple therapy. Clinicians will require a strategy for managing patients whose triple therapy fails, especially if failure results from poor adherence or toxicities. Of note, HCV viral resistance to protease inhibitors can also alter the effectiveness in retreatment, although data on this are still emerging.
Our analysis has several limitations. Interleukin-28B genotyping is a relatively new approach to predicting patients' response to standard HCV therapy. Additional studies will provide further confidence of the predictive value of IL-28B. We did not include reductions in HCV transmission due to successful treatment and, thus, may have underestimated the benefits associated with improving SVR rates, such as those from triple therapy. A substantial minority of patients infected with chronic HCV is also coinfected with hepatitis B virus, HIV, or both. Our results are limited to persons who are monoinfected and should be interpreted only in the context of this population because studies evaluating the effectiveness of new protease inhibitors in persons coinfected with HIV are ongoing. In addition, challenges with standard HCV-HIV drug interactions are already known, and HCV protease inhibitor interactions are emerging (52, 53). Future analyses should address the complex management issues surrounding treatment decisions for patients with coinfections.
New HCV protease inhibitors show promise in increasing treatment effectiveness for patients infected with HCV genotype 1, even though their additional benefits come with increased adverse effects and treatment costs. Our study supports the important role of protease inhibitors in treating chronic HCV for patients with advanced fibrosis as part of a first-line regimen. Management of chronic HCV in the United States could be improved by a shift toward response-guided triple-drug strategies, provided that the price of protease inhibitors and adherence to taking them are maintained at reasonable levels.
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