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The Cost-effectiveness, Health Benefits, and Financial Costs of New Antiviral Treatments for Hepatitis C Virus- new study, commentary "virtually every patient with chronic HCV should be treated [2]. Now."
 
 
  Download the PDF here
 
Download the PDF here
 
"In this issue of CID, Rein and colleagues provide, for the first time, the cost-effectiveness data for the newer HCV drugs compared to use of the older, PEG-interferon containing therapy and to no therapy at all Our estimates indicate that the treatment alternatives for HCV of pegylated interferon combined with ribavirin and Sofosbuvir, and the all-oral combinations of Sofosbuvir and Simeprevir increase QALYs compared to their alternatives at a cost of $47 237 per QALY gained for PRS/SR and $72 169 per QALY gained for SS/SR. During review of this article, two interferon-free combination treatments were approved for the treatment of genotype 1 HCV patients (Harvoni and Viekira Pak) with lower list prices ($94 500 and $83 319) compared to SS/SR. Assuming an equal effectiveness for these combinations as for SS, the lower prices would result in cost-effectiveness of approximately $25 000 per QALY gained for new treatments compared to PRS/SR, and of approximately $32 000 to $35 000 per QALY gained compared to NT. Potentially lower prices would improve treatment cost-effectiveness further."
 
Incremental cost-effectiveness ratio.....https://en.wikipedia.org/wiki/Incremental_cost-effectiveness_ratio Interpretation of Cost-Effectiveness Analyses.....
 
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1497852/.......In summary, the choice of a cost-effectiveness threshold depends on who is making the decision; what the purpose of the analysis is; how the decision maker values health, money, and risk; and what the available resources are. Thus, the search for a single cost-effectiveness threshold is not likely to be fruitful. Given these considerations, it is not surprising that the authors studied by Azimi and Welch reached disparate conclusions.......As a practical matter, how can we interpret cost-effectiveness analyses? With recognition that different decision makers will not-and should not necessarily-agree with one another, I interpret the results of such analyses as providing general guidance on whether an intervention is reasonably efficient, of questionable efficiency, or inefficient. Most, but not all, decision makers in the United States will conclude that interventions that cost less than $50,000 to $60,000 per QALY gained are reasonably efficient. An example is screening for hypertension, which costs $27,519 per life-year gained in 40-year-old men.3, 8 For interventions that cost $60,000 to approximately $175,000 per QALY, certain decision makers may find the interventions sufficiently efficient; most others will not agree. For example, coronary artery bypass grafting for patients who have single-vessel disease and moderate angina costs $88,087 per life-year gained (in 1993 dollars).3, 9 Few decision makers will conclude that interventions that cost more than $175,000 per QALY are justifiable. Cost-effectiveness analysis alerts us to interventions for which lack of efficiency is an important consideration.......we should ask whether cost-effectiveness analyses prevent us from wasting money on interventions that provide minimal benefit relative to cost. That question warrants careful study; however, in evaluating the influence of cost-effectiveness analyses, we must realize that spending money wisely does not necessarily mean spending less money.
 
Cost-effectiveness analysis is a tool to help us understand what we get in return for the money we spend on health care. In a determination of whether to offer an intervention, economic efficiency is only one of many factors that deserve consideration. There may be good reasons to offer an inefficient intervention, and there may be good reasons not to offer an efficient intervention (such as concerns about equity or ethics). Used with an understanding of their limitations, cost-effectiveness analyses can inform decisions about the use of an intervention. We should not confuse the scalpel with the surgeon, however: cost-effectiveness analysis is a tool that cannot substitute for value judgments. We must still decide how much money we are willing to spend to improve our health.-Douglas K. Owens, MD, MSc, VA Palo Alto Health Care System and Departments of Medicine and Health Research and Policy, Stanford University, Palo Alto, Calif.
 
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The Cost-effectiveness, Health Benefits, and Financial Costs of New Antiviral Treatments for Hepatitis C Virus
 
(see this original article below following Editorial by Mike Saag)
 
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The Cost-effectiveness, Health Benefits, and Financial Costs of New Antiviral Editorial Commentary: Getting Smart in How We Pay for HCV Drugs: KAOS vs CONTROL
 
Clin Infect Dis July 15, 2015
 
Michael S. Saag
Center for AIDS Research, University of Alabama at Birmingham
 
(full text below following Editorial) - (See the Major Article by Rein et al on pages 157-68.)
 
Over the last 2 years a therapeutic revolution has been occurring for the treatment of hepatitis C virus (HCV) infections. Direct acting antiviral (DAA) agents that allow all-oral regimens have been released. These regimens replace the use of injectable peginterferon, which markedly reduce adverse effects, significantly reduce the duration of treatment (eg, from 48 weeks to 12 weeks), and increase cure rates from 60% to 70% to greater than 95% in most clinical scenarios [1]. Based on this set of facts alone, a clear message is that virtually every patient with chronic HCV should be treated [2]. Now. As the new HCV agents were released, however, the price-tag of the drugs created sticker shock, especially among the payers who were not fully prepared to treat so many patients at one time with such expensive medications. To keep expenditures under control, payers questioned the need to treat patients with less advanced disease (eg, those with F0- F2 fibrosis), owing to the uncertainty of who will progress (less than 50% of patients develop cirrhosis over 30 years) and the relatively slow progression of disease among those who do progress. The payer's reluctance to pay for drugs created barriers for patients and providers to gain access to therapy. All involved called out for data on the cost-effectiveness of the new all oral regimens, which heretofore did not exist.
 
In this issue of CID, Rein and colleagues provide, for the first time, the cost-effectiveness data for the newer HCV drugs compared to use of the older, PEG-interferon containing therapy and to no therapy at all [3]. Their results are informative, timely, and most welcomed. For their analysis, The Cost-effectiveness, Health Benefits, and Financial Costs of New Antiviral the investigators used a combination of simeprevir + sofosbuvir as the primary all oral DAA regimen, which has a wholesale acquisition cost (WAC) of $150 360. Using sophisticated models they determined that, compared to no treatment, the incremental cost-effectiveness ratio (ICER) of both PEG-based and DAA only treatments was sensitive to the fibrosis stage at the time of treatment, ranging from $173 800 per quality-adjusted life-year (QALY) gained for DAA use at stage F0 to $13 000 per QALY gained for PEG-based therapy in patients with cirrhosis. The investigators went on to determine what the cost of DAA treatment would need to be in order to achieve an ICER of $50 000/QALY gained, a value typically judged to be 'cost-effective.' This threshold was reached at a WAC of $139 000 or $136 000 when DAA treatment was compared to no treatment or PEG-based treatment regimens, respectively. In the treatment of patients with no fibrosis (F0), the cost of a treatment course with DAA therapy would need to be $47 000 per treatment course to achieve an ICER of $50 000 per QALY gained. With the release of the newer DAA agents, the team evaluated the cost-effectiveness for sofosbuvir-ledipasvir ($94 500/treatment course) and the new Abbvie drug combination ($83 000/treatment course) and determined that, compared to no treatment, the ICER was $35 100 and $31 828 per QALY, respectively.
 
The take home point of the analysis is obvious: Cost-effectiveness is dependent on the cost of treatment. With the release of several DAAs, and many more slated for release over the next 18-24 months, the hope is that market-based competition will drive the cost of regimens down, thereby improving the cost-effectiveness proportionately. This is how a free market works. But the question remains, does the pharmaceutical industry operate as a free market? [4].
 
Just in the last 6 months, evidence exists that free market forces are at play in the realm of HCV drugs, at least at the level of the pharmaceutical companies. With the release of Abbvie's '3D' combination therapy, reductions off of WAC were granted to gain 'exclusivity' within a certain pharmacy benefits manager (PBM) entity, whose job is to serve as an agent for a payer or care delivery system [5]. This was countered by Gilead creating special deals with other PBMs for the exclusive distribution of their combination regimen. On first glance, it seems that the market is working, and the payers (and their patient constituents) are paying less for HCV drugs. But are they? And if so, how much less?
 
Unfortunately, the chaos in the system prevents us from being able to answer these questions. Here's the way it works: Drug company A offers a rebate to PBM 'X' in exchange for exclusive distribution of company A's product. The amount of this rebated discount is not in the public domain and therefore unknowable to patients, providers, and, in some cases, payers. Therefore, it is unclear how much benefit is accrued to payers and how much reduction, if any, there is in copayments for patients. What's worse, the PBM makes its 'profit' based on a percentage of WAC, not on the net price after rebate. In this way, the PBMs are assured maximum profits regardless of the discounted rebate and, because the payers may not know the amount of the negotiated discount, extra profit may accrue to the PBM if the rebate benefit is not passed along to the payer or the patient.
 
Yet, the worst outcome of the occult dealings of the PBMs is that it impedes drug company B, who might be releasing their HCV drug at some point in the future, from pricing the WAC of their new regimen substantially below the WAC of other drugs in the market. If they were to price their new drug, for example, at 50% of the WAC of the competition, the PBM would make half as much. The PBM therefore might choose not to carry the newer drug as a 'preferred' drug (or perhaps not at all) even though the cost to the payer could be less. Rather, company B is encouraged to price the WAC at nearly the same level as the other drugs and attempt to gain market price advantage through provision of a more substantial rebate to the PBM. Not exactly a "free market."
 
In most every industrialized country outside of the United States, pharmaceutical companies negotiate pricing directly with the payers (usually a nationalized system), and the actual cost of drugs to the payer is in the public domain. Using cost-effectiveness data such as those provided in the article by Rein et al, these countries can make informed decisions about use of the drugs in all patient populations. In the United States, however, such direct decision making is impossible owing to the absence of information about the true expenditures made by payers for drugs.
 
In Mel Brooks' sitcom from the 1960s, Get Smart, CONTROL agent 86 (Maxwell Smart) and his colleagues fought against their nemesis KAOS. Working under the tagline, 'the international organization of evil,' KAOS was run by an amorphous cabal whose leadership was always referenced but never seen. As would be portrayed in Brook's Get Smart, HCV (and other expensive) drugs, as distributed through PBMs, are negotiated under a "cone of silence," thereby creating KAOS and corrupting the workings of true free-market forces. By exposing these business practices, we can gain CONTROL of the situation, lift the cone of silence, and eliminate some of the KAOS in our healthcare system. If we fail to do this, we will have "missed it by that much!"
 
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The Cost-effectiveness, Health Benefits, and Financial Costs of New Antiviral Treatments for Hepatitis C Virus
 
David B. Rein,1 John S. Wittenborn,1 Bryce D. Smith,2 Danielle K. Liffmann,1 and John W. Ward2 1Public Health Department, NORC at the University of Chicago, and 2Division of Viral Hepatitis, Centers for Disease Control and Prevention, Atlanta, Georgia
 
Abstract
 
Background. New hepatitis C virus (HCV) treatments deliver higher cure rates with fewer contraindications, increasing demand for treatment and healthcare costs. The cost-effectiveness of new treatments is unknown.
 
Methods.We conducted a microsimulation of guideline testing followed by alternative treatment regimens for HCV among the US population aged 20 and older to estimate cases identified, treated, sustained viral response, deaths, medical costs, quality-adjusted life-years (QALYs), and the incremental cost-effectiveness ratio (ICER) of different treatment options expressed as discounted lifetime costs and benefits from the healthcare perspective. Results. Compared to treatment with pegylated interferon and ribavirin (PR), and a protease inhibitor for HCV genotype (G) 1 and PR alone for G2/3, treatment with PR and Sofosbuvir (PRS) for G1/4 and treatment with Sofosbuvir and ribavirin (SR) for G2/3 increased QALYs by 555 226, reduced deaths by 80 682, and increased costs by $26.2 billion at an ICER of $47 304 per QALY gained. As compared to PRS/SR, treating with an all oral regimen of Sofosbuvir and Simeprevir (SS) for G1/4 and SR for G2/3, increased QALYs by 1 110 451 and reduced deaths by an additional 164 540 at an incremental cost of $80.1 billion and an ICER of $72 169. In sensitivity analysis, where treatment with SS effectiveness was set to the list price of Viekira Pak and then Harvoni, treatment cost $24 921 and $25 405 per QALY gained as compared to PRS/SR. Conclusions. New treatments are cost-effectiveness per person treated, but pent-up demand for treatment may create challenges for financing.
 
In 2012, the US Centers for Disease Control and Prevention (CDC) recommended that Americans born during 1945-1965 receive a 1-time antibody test to identify hepatitis C virus (HCV) infection (birth-cohort testing) [1-3]. In 2013, this recommendation was affirmed by the United States Preventive Services Task Force citing the large health benefits of birth-cohort testing predicted by modeling studies [2-6]. From 2011 to 2013, at least 6 published studies found HCV testing and treatment to be cost-effectiveness, using different parameters and assumption [2, 4, 6-9]. Adjusting the aggregate results from these studies into per person incremental costs and quality-adjusted life-years (QALYs) allows for the visual comparison of their results (Figure 1).
 
Since publication of the birth-cohort testing recommendations, new highly effective drugs have been released, and clinical treatment recommendations have been updated to incorporate their use [10]. In this article, we modified a previously published model of the cost-effectiveness of birth-cohort testing to assess the cost-effectiveness, financial impacts, and health benefits of birth-cohort testing using new treatments under the assumption of broad population-based implementation [2].
 
METHODS
 
Decision Analytic Model

 
We programmed (Microsoft Visual Studio 2010, Redmond, Washington) a Monte Carlo simulation model of the natural history of hepatitis C with antibody prevalence estimates stratified by age, gender, race/ethnicity, and history of injecting drugs. The model's natural history, validation, and economic parameters have been previously described, and revisions to the model's parameters are included in Tables 1 and 2 and technical documentation [2, 52]. Compared to previous versions, the model's structure now assumes that a sustained viral response (SVR) results in a reduced risk of hepatocellular carcinoma (HCC) instead of risk elimination. Additional information is included in the technical report, available as Supplementary materials.
 
Model Cohorts
 
We modeled the US population aged 20 or older, totaling 229 185 985 in 2012 [62]. We stratified the population based on age, sex, and lifetime risk of injecting drugs [63]. We further stratified these cohorts into those with and without antibody to HCV (based on year of birth), and those with antibodies into those with chronic (78%) and cleared (22%) infections [64]. We assumed 25% of chronically infected patients were not interested in treatment or were not reachable by the healthcare system and assumed the remainder would be offered testing [35, 36, 40, 65].
 
We estimated starting fibrosis rates using data from biopsy results of newly diagnosed patients observed in the retrospective component of the Birth-cohort Evaluation to Advance Screening and Testing for Hepatitis C (BEST-C) study [66]. We used census life tables to calculate the annual probability of mortality from nonhepatic causes and assigned a relative risk of mortality of 1.42 for individuals who reported ever injecting drugs [2, 67].
 
Screening and Treatment Scenarios
 
For the purpose of our simulation, we assumed that 18.5% of those outside the 1945 to 1965 birth-cohort would be offered testing and that 100% of those in the birth-cohort would be offered testing if they could be reached through the health system. Of those who accepted testing and tested positive for HCV RNA, we compared the cost-effectiveness and health impacts of 5 treatment alternatives: (1) No treatment (NT); (2) Pegylated interferon and ribavirin (PR) for 48 weeks for genotypes 1 and 4, and for 24 weeks for genotypes 2 and 3; (3) PR for 24 weeks plus an additional protease inhibitor (PRPI) for 12 weeks for genotypes 1 and 4 or PR for 24 weeks for genotypes 2 and 3; (4) PR plus Sofosbuvir (PRS) for 12 weeks for genotypes 1 and 4, Sofosbuvir plus ribavirin (SR) for 12 weeks for genotype 2, and SR for 24 weeks for genotype 3; or (5) Simeprevir and Sofosbuvir (SS) for 12 weeks for genotypes 1 and 4, SR for 12 weeks for genotype 2, and SR for 24 weeks for genotype 3. We assumed all treatments occurred in the first year of the simulation. These treatments are consistent with those evaluated by major medical societies in creating their HCV treatment guidelines [10].
 
Although guidelines discourage the use of older line treatments, we include them to facilitate comparisons with other studies. We also separately report preliminary incremental cost-effectiveness ratio (ICER) estimates for interferon-free combination of ledipasvir and sofosbuvir and the drugs in viekira pak, which were approved after initial submission of this article.
 
Screening, Contraindication, and Antiviral Initiation
 
We assumed that 91% of those offered testing would accept and 90% of those who tested positive would receive their result and be evaluated for treatment [37].
 
To estimate the proportion of patients who would receive treatment we conducted a meta-analysis of rates of treatment found across 12 published studies of community treatment of patients with HCV infection only [14-25]. We estimated the proportion who would be treated with pegylated interferon based treatments (0.242) and its credible interval (0.228-0.251) using Monte Carlo Markov Chain (MCMC) simulation methods programmed with Proc MCMC of the SAS 9.2 Software (SAS Institute, Cary, North Carolina) [68]. We also estimated the proportion of persons who would be treated (0.719) with nonpegylated interferon-based treatments and its credible interval (0.66-0.77).
 
Effectiveness, Cost, and Benefit of Antiviral Therapy
 
Older forms of treatment have exhibited lower rates of real world effectiveness and cost than in clinical trial data, but real-world data are not yet available for newer treatments. To enable equivalent comparisons we used clinical trial estimates of efficacy and published package estimates of cost for all treatments. The benefit of successful treatment was an SVR that varied with treatment type and virus genotype. For pegylated interferon based treatments, we also assumed a quality adjusted life year decrement that varied with the duration of treatment. We assumed an SVR eliminated fibrosis progression associated with chronic HCV infection. For patients with cirrhosis, we assumed an SVR was also associated with a relative risk of HCC of 0.24 [34].
 
Testing and Medical Treatment Costs
 
We set the cost of testing via routine risk-based assessments to $24.65 per person tested, equal to the incremental costs of testing using an electronic health record prompt system in an unpublished CDC study. Diagnosed patients who did not undergo antiviral therapy or achieve an SVR were assumed to receive HCV-related medical management, with costs per stage estimated as the average costs used across seven previously published cost-effectiveness studies [2, 4, 6-9, 53]. Patients who achieved an SVR accrued annual monitoring costs. Nontreatment clinical management increased costs without increasing benefits.
 
Utility Losses
 
Uninfected persons were assigned annual QALY values that decreased with age to account for other health conditions [69]. For persons with HCV, we collected utility losses from 5 studies across 7 HCV states: SVR, METAVIR 0-1, METAVIR 2-3, compensated cirrhosis, DCC, HCC, and post-liver transplant then summarized the scores as reported elsewhere [2, 69-74]. Annual QALYs for patients on pegylated interferon-based therapy were multiplied by 0.85 adjusting for treatment duration [13].
 
Simulation, Outcomes, and Sensitivity Analysis
 
We estimated medical outcomes, costs, and QALYs associated with each scenario accounting for uncertainty in each of the model's key parameters using probabilistic sensitivity analysis, reporting the mean and the empirical 95% credible interval for each outcome. We estimated the ICER for routine and birth-cohort testing combined followed by each treatment scenario as compared to the next most costly alternative. For PRS/SR and for SS/SR, we estimated the ICER of immediate treatment compared to no treatment (NT; scenario 1) for people in METAVIR stages F0, F1, F2, F3, and F4. For PRS/SR compared to PRPI and for SS/SR compared to PRS/SR we tested the univariate sensitivity of the ICER to uncertainty in the model's key parameters by evaluating results based on the upper and lower bounds of the 95% confidence interval of each parameter included in Tables 1 and 2.
 
We estimated the cost of treatment for SS/SR at which the ICER was equal to $50 000 per QALY gained compared to PRS/SR and compared to NT. Compared to NT, we estimated the treatment cost at which the ICER of PRS/SR and SS/SR was equal to $50 000 per QALY gained for patients treated at stages F0 and F1.
 
For all patients, we estimated the cost-effectiveness of SS/SR compared to PRS/SR and to NT when the cost of SS was set to the list price of Viekira Pak ($83 319) and the list price of Harvoni ($94 500). We provide only limited results for these scenarios, because these treatments were released during this manuscript's review process.
 
RESULTS
 
Of the 229.2 million Americans aged 20 years in 2012, we estimated 3.7 million were antibody positive for HCV, 2.9 million were chronically infected, and that 1.5 million would be identified through testing prior to the development of end-stage liver disease or death from other causes. With no testing or treatment (scenario 1), we estimated that 1.18 million of those chronically infected (41.1%) would develop DCC or HCC and die in those states prior to model termination at age 100 (Table3). For comparison to other studies, the model's 45-year mortality rate was 18.7% assuming age of infection of 25 years and a starting fibrosis state of F0. With no testing or treatment, currently infected patients were expected to generate $100.3 billion in discounted hepatitis C medical costs during their lifetimes.
 
The Health Benefits and Cost Impacts of Treatment Scenarios
 
With testing and PR treatment (scenario 2), 356 657 patients were treated of whom 156 880 achieved an SVR reducing the number of HCV-associated deaths from 1 181 554 to 1 131 638, a reduction of 49 916 deaths compared to NT. Compared to NT, testing followed by PR treatment increased QALYs by 306 537 and medical costs by $18.3 billion. With the same number of patients treated as compared to NT, PRPI (scenario 3) increased patients achieving an SVR by 237 618 and reduced the number of deaths from HCV to 1 106 130, a reduction of 75 424 deaths.
 
Compared to NT, PRPI increased QALYs by 477 066 and increased medical costs by $20.8 billion. With testing and PRS/SR treatment (scenario 4), 541 136 patients were treated of whom 489 573 achieved an SVR reducing the number of deaths from HCV by 156 106 compared to NT. Compared to NT, PRS/SR increased QALYs by 1 032 292 and increased and medical costs by $47.0 billion. Finally, with testing and SS/SR treatment (scenario 5), 1 057 148 patients were treated of whom 1 010 225 achieved an SVR reducing the number of deaths from HCV by 320 646 compared to NT. Compared to NT, SS/SR increased QALYs by 2 142 743 and medical costs by $127.1 billion.
 
Incremental Cost-effectiveness
 
The ICER of PR vs NT was $59 792 per QALY gained (Table 3). PR was extendedly dominated by PRPI. Compared to NT, the ICER of PRPI was $43 530 per QALY gained, PRS/SR cost $47 237 per QALY gained compared to PRPI, and SS/SR cost $72 169 per QALY gained compared to PRS/SR. Compared to NT, the incremental cost per QALY gained was $59 792 for PR, $43 530 for PRPI, $45 524 for PRS/SR, and $59 333 for SS/SR.
 
SENSITIVITY ANALYSES
 
Compared to NT, the ICER of both PRS/SR and SS/SR was sensitive to the fibrosis stage at the time of treatment, from $173 800 per QALY gained for SS/SR at stage F0 to $13 000 per QALY gained for PRS/SR for patients with cirrhosis (Figure 2).
 
The ICER of PRS/SR compared to PRPI was most sensitive to the cost of PRS/SR treatment, QALY improvements assumed to occur after an SVR, the speed of fibrosis progression, QALY losses associated with moderate fibrosis (F2, F3) and cirrhosis (F4), the medical cost of DCC, the probability of an SVR for PRS/SR, and the risk reduction of HCC among people with cirrhosis who had achieved an SVR (Figure 3A and 3B). No other parameter in the model changed the ICER by more than 5% when set to the bounds of its 95% confidence interval. The ICER of SS/SR compared to PRS/SR was sensitive to similar variables (cost of treatment, QALY losses associated with infection prior to end stage disease, the probability of an SVR, and the impact of an SVR on reducing HCC).
 
The ICER of SS/SR compared to PRS/SR fell to $50 000 per QALY gained at a treatment cost of $136 000. Compared to NT, the ICER of SS/SR was equal to $50 000 per QALY gained at a treatment cost of $139 000. Assuming the same level of effectiveness, SS/SR cost $24 921 per QALY gained compared to PRS/SR and $31 828 compared to NT at the price of Viekira Pak, and $25 405 per QALY gained compared to PRS/SR and $35 100 compared to NT at the list price of Harvoni.
 
Compared to NT, treating patients at stage F0 with PRS/SR would need to cost $37 600 to achieve an ICER of $50 000 per QALY; $47 000 for treatment with SS/SR. Also as compared to NT, treating patients at stage F1 with PRS/SR would need to cost $73 000 to achieve an ICER of $50 000 per QALY; $82 000 for treatment with SS/SR.
 
CONCLUSIONS
 
Our estimates indicate that the treatment alternatives for HCV of pegylated interferon combined with ribavirin and Sofosbuvir, and the all-oral combinations of Sofosbuvir and Simeprevir increase QALYs compared to their alternatives at a cost of $47 237 per QALY gained for PRS/SR and $72 169 per QALY gained for SS/SR. During review of this article, two interferon-free combination treatments were approved for the treatment of genotype 1 HCV patients (Harvoni and Viekira Pak) with lower list prices ($94 500 and $83 319) compared to SS/SR. Assuming an equal effectiveness for these combinations as for SS, the lower prices would result in cost-effectiveness of approximately $25 000 per QALY gained for new treatments compared to PRS/SR, and of approximately $32 000 to $35 000 per QALY gained compared to NT. Potentially lower prices would improve treatment cost-effectiveness further.
 
However, financing the treatment of all Americans who could benefit from antiviral therapy will be a continuing challenge given the number of individuals who are undiagnosed, untreated, or failed to respond to older treatment regimens. In addition, simply linking diagnosed patients to clinical settings in which they can be evaluated for treatment remains an ongoing challenge that is likely to reduce the potential benefits and costs of new treatments for the foreseeable future [75, 76].
 
Still our estimates indicate achieving modest identification and treatment benchmarks (1.06 million chronically infected individuals) could increase QALYs by over 2.1 million, decrease deaths from HCV by over 320 000, but also increase lifetime costs. Increased costs are a function of both the unit costs of new treatments that are declining as new drugs enter the market, and also the greater number of individuals that can tolerate all-oral regimens. Given the current difficulties of linking patients to care, the incremental costs of new treatments are likely to accrue over time and may be reduced as more treatments are approved for use and insurers negotiate discounts for their plan members. Our sensitivity analyses indicate that ICER of PRS/SR compared to PRPI and of SS/SR were highly sensitive to the costs of treatment. Lower costs (especially for all-oral regimens) would increase their cost-effectiveness and alleviate financing pressures.
 
Our sensitivity analyses also indicate that cost-effectiveness is sensitive to the stage at which a patient is treated. Treating with SS/SR costs $173 796 per QALY gained for people with a current fibrosis status of F0 compared to only $35 884 for patients in F3. However, this finding must be understood in context of our lack of knowledge of the health and cost impacts of chronic infection prior to the development of end-stage liver disease and the limited ability to identify patients' stage of liver fibrosis without the use of biopsy.
 
Limitations
 
Our study is limited by at least the following factors. First, we made a number of assumptions regarding the utilization of new treatments. Because the number of people who will seek care is unknown, we assumed that 25% of the population would be beyond the reach of the healthcare system. Given the current difficulties of linking identified individuals to clinical care, this number may be optimistic. To simplify estimation, we further assumed that all patients who received treatment would do so in the base year of the simulation. Compared to an alternative that treats all patients over time and assumes no missed opportunities to prevent disease, this limitation has the effect of making treatment appear more costly and less cost-effective as NT costs are discounted, and NT is averted due to death from non-HCV causes. Finally, we estimated the rates of interferon-based treatment uptake using data from studies prior to the inclusion of more effective agents, and made assumptions about how treatment rates would increase with interferon-free treatment. Sensitivity analyses indicate these assumptions do not have a large impact on cost-effectiveness; however, lower treatment uptake will lower the aggregate health benefits and costs reported for each scenario.
 
Second, our cost-effectiveness results are partially determined by the model's distribution of starting fibrosis rates which were derived from primary biopsy data from newly diagnosed patients. While, we believed these are superior to previously used simulated estimates, data on this parameter are sparse, and treatment will be less cost-effective if undiagnosed patients have milder progression. However, our sensitivity analyses estimate the cost-effectiveness of treatment at different stages of progression and indicate that treatment at earlier fibrosis stages is still moderately cost-effective compared to NT (at F1, $73 906 per QALY gained for PRS/SR, and $93 236 for SS/SR compared to NT). Updates to medical treatment guidelines call for prioritizing treatment in patients who are F1 or higher.
 
Our article reports an overall mortality rate of 41% among prevalent hepatitis C cases given NT, a rate higher than reported in earlier model publications [2, 21]. This higher rate of mortality results from the use of a longer time horizon in this paper (until age 100). Our model's 45-year mortality rate is identical to that from previous work [2].
 
Our model excludes the treatment benefits of averting secondary transmissions. Although such benefits remain hypothetical, modeling studies suggest that treatment reduces transmission especially among people who inject drugs [77]. The limitation results in a less favorable ICER than had these benefits been included.
 
Finally, ICER by fibrosis stage estimates assumes that fibrosis level can be reliably ascertained in clinical settings, although performing biopsies among all patients is likely unethical. Although nonbiopsy ascertainment methods like AST/Platelet Ratio Index (APRI), Fibrosis-4 scoring, and elastography are improving, they cannot yet reliably differentiate between pre-cirrhosis fibrosis stages.
 
Implications
 
New treatments for HCV infection have the potential to provide substantial public health benefits at a reasonable cost per patient treated. However, the high number of untreated hepatitis C patients creates financing challenges that need to be overcome.

 
 
 
 
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