December 30, 2013

All-oral, Interferon-free Treatment for Chronic Hepatitis C -- Cost-effectiveness Analyses

Journal of Viral Hepatitis

Cost-effectiveness Analyses

L. M. Hagan, Z. Yang, M. Ehteshami, R. F. Schinazi

J Viral Hepat

Abstract and Introduction


Interferon-based standard of care treatments (SOC) for chronic hepatitis C are unable to provide high cure rates in certain subgroups of the infected population and can cause debilitating side effects. Clinical trials evaluating all-oral, interferon-free treatments have demonstrated high rates of sustained virologic response with no resistance or major adverse events in most populations. As these drug regimens move towards FDA approval, it will be important to assess their cost-effectiveness in addition to their clinical efficacy. A decision-analytic Markov model with a lifetime, societal perspective was used to evaluate the cost-effectiveness of a generalized all-oral drug regimen compared to SOC by modelling the progression of a 50-year-old, HCV-positive cohort through disease natural history and treatment. In base case analysis, all-oral treatment dominated SOC across a range of willingness-to-pay (WTP) thresholds with an incremental cost-effectiveness ratio (ICER) of US$44 514/quality-adjusted life year (QALY). In sensitivity analyses, the model was sensitive to all-oral drug costs as well as rates of SVR and treatment uptake among noncirrhotic subjects, but robust to variations in all other parameters. All-oral treatment was most cost-effective among genotype 1 subjects but remained cost-effective for genotypes 2 and 3 at WTP thresholds ≥$80 000/QALY. Quality-adjusted life years gained per dollar spent were maximized in younger treatment cohorts. Using this model, the degree of cost-effectiveness depended on the WTP threshold and the final cost set for approved drug combinations.


Approximately 150 million people globally and 3.3 million in the United States (US) are chronically infected with hepatitis C virus (HCV).[1] Because most cases are asymptomatic, up to 75% of HCV-positive individuals in the US are unaware of their infection, often resulting in untreated progression to advanced fibrosis, cirrhosis, hepatocellular carcinoma (HCC) and premature death.[2]

Chronic hepatitis C (CHC)-related mortality and healthcare costs are expected to rise as infected individuals in the high-prevalence 1945–1964 birth cohort, most of whom were infected 20–30 years ago, progress towards cirrhosis and liver cancer.[3–5] In response to this trend and to the demonstrated cost-effectiveness of birth cohort-based HCV screening,[6] the Centers for Disease Control and Prevention (CDC) recently recommended universal one-time screening for adults in this age group. This announcement coincided with the first National Hepatitis Testing Day in the US on 19 May 2012.[7]

As these screening initiatives yield increased CHC diagnoses, development of curative, cost-effective treatments will be paramount.[8] Treatment has evolved rapidly since the discovery of HCV in 1989, demonstrating progressive improvement in cure rates measured by sustained virologic response (SVR). The first treatment available, injected interferon monotherapy, resulted in SVR for 10% of those treated. Sustained virologic response increased to 25% with the addition of ribavirin and to 45% with the substitution of pegylated interferon.[8,9] Current standard of care (SOC) treatment for viral genotypes 2 and 3, pegylated interferon plus ribavirin (combination therapy), achieves SVR in up to 80% of noncirrhotic individuals, but in only 43% of those with cirrhosis,[10,11] Genotype 1 infections, which account for approximately 73% of CHC cases in the US, have historically been more difficult to treat and require triple therapy with the addition of a protease inhibitor (boceprevir or telaprevir),[12,13] SVR rates with triple therapy reach 72% among noncirrhotic genotype 1 individuals but are still much lower (42%) among those with cirrhosis,[14,15]

Despite rising SVR rates, current treatment with interferon and ribavirin often causes debilitating flu-like symptoms, depression, skin rashes and anaemia that can undermine treatment completion.[2] The next major advance in CHC treatment is expected to be the adoption of all-oral regimens that eliminate interferon, and possibly ribavirin, using direct-acting antiviral agents that increase SVR by preventing selection of drug resistant viruses and leveraging the lack of latent phase in HCV replication.[16]Numerous pharmaceutical companies are sprinting towards the finish line in advanced stage clinical trials testing novel all-oral, interferon-free drug combinations, some of which have achieved SVR in more than 90% of some subgroups, including null and partial responders to prior interferon-based treatment.[17]

The final cost of these drugs will be unknown until they reach the market and may ultimately exceed the cost of SOC for some genotypes. In addition, because clinical trial results are based on relatively small sample sizes of carefully chosen subjects, they may overestimate the SVR rates that will be attained among a more diverse and representative population. Therefore, while data on costs and anticipated SVR remain in flux, it will be important to consider the cost-effectiveness of emerging all-oral treatments across multiple possible scenarios.

This analysis investigated the cost-effectiveness of all-oral CHC treatment compared to SOC using a range of potential drug costs, treatment-associated quality of life estimates and rates of SVR for genotypes 1, 2 and 3-infected, treatment-naïve subjects with and without cirrhosis. Because it is not yet certain which specific drug combination(s) will receive FDA approval, our model used a generalized all-oral regimen to determine the cost threshold at which these drugs would be cost-effective compared to SOC.

Materials and Methods

Using TreeAge Pro 2012 software (TreeAge Software, Inc., Williamstown, MA, USA), we constructed a decision-analytic Markov model to simulate the progression of a 50-year-old cohort through CHC natural history and possible treatment with either SOC or an all-oral regimen. Cohort age was chosen based on CDC estimates of peak US HCV seroprevalence in the current 50–59 age group (4.3%),[18] coupled with the expected rise in CHC-related healthcare costs as infected individuals in this cohort progress to late-stage liver disease.[3–5]

Markov Model

A Markov model (Fig. 1) is a recursive decision tree that guides a cohort through a series of probabilities representing disease natural history, medical care, possible treatment and treatment outcomes. Based on the probability-driven pathways in our model (Fig. 2 and 3), subjects accrued costs and quality-adjusted life years (QALYs) at the end of each model year (stage), depending on their disease state and treatment profile. Cumulatively, these accruals were used to calculate the incremental cost-effectiveness ratio (ICER), which measures the cost per QALY gained by implementing all-oral treatment compared to SOC. Death was possible from any model stage. Subjects alive at the end of a given stage continued cycling through the model as determined by their health or treatment outcome in the preceding stage. Analysis terminated when the cohort reached its average life expectancy. Base case values for all model parameters, as well as ranges used in sensitivity analyses, can be found in Tables S1–S5.


Figure 1. Simplified Markov model. As the HCV-positive cohort progresses through the model, subjects accrue medical costs and QALYs based on probabilities for disease progression and treatment outcome. Those who do not die from any cause during a given stage continue through the model for an additional year. Aggregate costs and QALYs are summed and used to calculate the ICER. HCV = hepatitis C virus; CHC = chronic hepatitis C; QALY = quality-adjusted life year; ICER = incremental cost-effectiveness ratio.


Figure 2. Model schematic of CHC natural history and treatment. Model subjects progress through fibrosis stages F0–F4, decompensated cirrhosis and HCC based on annual probabilities (white circles, solid lines). Those who initiate SOC or all-oral treatment (light grey squares) either achieve SVR (black stars) or fail/discontinue and continue progressing through CHC natural history without retreatment (dark grey hexagons). Further fibrosis progression after SVR is possible for subjects in stages F3, F4 and decompensated cirrhosis (dotted lines). F3 subjects can progress directly to decompensated cirrhosis or HCC within one year, bypassing F4 (dotted lines). Subjects with decompensated cirrhosis can be treated in the all-oral treatment pathway, but not in the SOC pathway. Subjects with decompensated cirrhosis and HCC receive liver transplants according to published annual probabilities. Death is possible from any cause at any stage in the model. See Table S1 for specific progression probabilities. CHC = chronic hepatitis C; F0–F4 = Metavir fibrosis stages; Tx = treatment; SVR = sustained virologic response; HCC = hepatocellular carcinoma.


Figure 3. Decision tree excerpt. A selection of the decision tree underlying the Markov model, where M represents the starting point for each annual model cycle, and individual probabilities are included under each branch. Subjects who reach terminal branches (boxes with thick borders) begin untreated progress through CHC natural history in the subsequent model year (solid black boxes). Chronic hepatitis C natural history progression probabilities are not depicted but are summarized in Table S1. Branches involved in treatment uptake and outcome are illustrated under F2 only, but this subtree was included in all fibrosis stages in the model. HCV = hepatitis C virus; SOC = standard of care treatment; CHC = chronic hepatitis C; F0–F4 = Metavir fibrosis stages; Tx = treatment.

Background Mortality Rates

Age-specific background morality rates were applied throughout the model, estimated at 2.37 times the rates for non-CHC-infected individuals,[19,20] After SVR, subjects were assigned lower mortality rates, estimated at 1.4 times non-CHC rates based on evidence that virus clearance improves overall health outcomes.[21] Subjects with advanced liver disease were assigned higher mortality rates based on published literature (Table S1).


This hypothetical cohort included only screened, laboratory confirmed HCV-positive subjects. It did not include HCV-positive individuals unaware of their infection because they would not have the opportunity to be treated with either drug regimen.

All-oral Parameter Estimates

Aside from SVR rates, which were estimated from clinical trial data, published values for parameters associated with all-oral CHC treatment were not available because these drugs are not yet approved. Estimates for specialist referral and attendance, contraindications to treatment, treatment uptake and discontinuation, and QALYs associated with all-oral treatment and SVR were derived from interviews with clinical hepatologists practicing at Emory University in Atlanta, Georgia, hereafter referenced as 'expert opinion' (Karpen S, Spivey J, Ford R, Parekh S. Personal communication). Due to the uncertainty of these estimates, most sensitivity analyses involving all-oral treatment parameters used ranges of at least ± 20%. To remain conservative, ranges often included the corresponding SOC parameter's base case (Tables S3–S5).

Fibrosis Progression

Probabilities of treatment uptake and SVR were dependent on CHC genotype and fibrosis stage, defined by METAVIR score (F0 = no fibrosis; F1 = portal fibrosis without septa; F2 = portal fibrosis with few septa; F3 = numerous septa without cirrhosis; F4 = compensated cirrhosis).[22] Initial distribution of subjects across fibrosis stages was based on a meta-analysis of 111 clinical studies including over 33 000 individuals with CHC in fibrosis stages F0–F4,[23] adjusted to include decompensated cirrhosis.[24]Subjects progressed to later fibrosis stages, HCC, liver transplant and death based on annual progression probabilities from the same meta-analysis and other published estimates (Tables S1–S2).[23,25–32] At the end of each model year in which a disease state transition occurred (e.g. progression from F0 to F1, or from F4 to decompensated cirrhosis), subjects accrued the costs and QALYs associated with the disease state in which they began the year; the following year, they accrued the costs and QALYs associated with the state to which they had transitioned.

Treatment Probabilities

Subjects had multiple opportunities to be treated. In the initial model year, a subject's probability of treatment was the product of individual probabilities for specialist referral, specialist attendance, likelihood of contraindications and acceptance of treatment that was offered, which varied by treatment pathway (Table S3; Fig. 3). Subjects eligible for treatment (i.e. with no immutable contraindications) but not treated in the initial model year transitioned to treatment in subsequent years at annual rates varying from 1–10% depending on genotype, fibrosis stage and treatment pathway. These probabilities were based on published literature for SOC and expert opinion for all-oral treatment,[28,33]

Due to lower SVR rates for genotype 1 compared to genotypes 2 and 3 with SOC treatment, combined with physicians' expectations for improved treatments in the near future, many genotype 1 individuals in clinical care with little or no fibrosis delay treatment.[28] To remain consistent with clinical practice, this model did not treat genotype 1 F0 subjects in the SOC pathway during the initial model year. However, these subjects transitioned to treatment at a higher rate in subsequent years compared to subjects in later fibrosis stages, as modelled in a recent cost-effectiveness analysis of CHC screening strategies by Coffin et al..[28] Because of high expectations for SVR with all-oral treatment, all genotype 1 subjects in the all-oral pathway were treated at the same rate in the initial model year, regardless of fibrosis stage. Subjects were assumed treatment-naïve. Those who failed or discontinued treatment were not retreated in the model.

Liver Biopsy

In the clinic, approximately 70% of genotype 1 subjects who attend a specialist visit undergo a liver biopsy to determine fibrosis stage, which helps determine whether to initiate treatment or to wait.[28] If SVR rates rise as expected with the adoption of all-oral treatment, most individuals diagnosed with CHC will likely be treated regardless of genotype or fibrosis stage, reducing the need for liver biopsy. Based on expert opinion, we assumed that only 40% of genotype 1 individuals would receive a liver biopsy once all-oral treatment becomes widespread.

Treatment of Subjects With Advanced Liver Disease

Because few individuals with decompensated cirrhosis can tolerate interferon, treatment with SOC is rare in this group,[34,35] One of the benefits of an eventual all-oral regimen is greater expected compatibility with late-stage disease, increasing treatment access for cirrhotic individuals. Therefore, this model allowed subjects with decompensated cirrhosis to be treated with all-oral therapy, but not with SOC. Estimates of treatment uptake and associated QALYs for decompensated subjects were derived from expert opinion. Treatment discontinuation rates were set at higher levels for these subjects compared to those in stages F0–F4 due to the possibility of more frequent adverse events.

Fibrosis Regression After SVR

To account for evidence of liver regeneration after viral eradication, this model allowed post-SVR fibrosis regression according to probabilities from clinical literature.[35–42] Regression rates for decompensated subjects after all-oral treatment were assumed equal to rates for those with compensated cirrhosis.

Costs and QALYs

Most costs and QALYs associated with SOC treatment and nontreatment-related CHC care were derived from two recent cost-effectiveness studies on CHC screening and treatment strategies, which provide comprehensive reviews of these parameters from a variety of published sources,[28,31]Treatment costs incorporate both the cost of the drugs themselves and the costs of medical care during treatment, including adverse events. Base case parameters were chosen as mid-range estimates (Tables S4-S5). Costs were adjusted to 2012 US dollars, and costs and QALYs were discounted 3% per year.

We used $70 000 as the base case cost for one course of all-oral treatment based on the anticipated market entry cost ($47 000) for sofosbuvir (GS-7977), one of the leading direct-acting antiviral candidates currently in advanced clinical trials,[43] combined with expectations that eventual FDA-approved all-oral regimens will include more than one drug. Due to the uncertainty of this estimate, we used a wide range of all-oral drug costs in sensitivity analyses (Figs 4,5).


Figure 4. Top ten most influential parameters for cost-effectiveness. A series of one-way sensitivity analyses, generated by TreeAge Pro software, depicts the influence that individual model variables exert on the ICER. The length of a given bar indicates the magnitude of change effected by variations in a model parameter. Variables were tested over ranges listed in Tables S1–S5. ICER = incremental cost-effectiveness ratio; QALY = quality-adjusted life year; CHC = chronic hepatitis C; F0–F4 = Metavir fibrosis stages; SVR = sustained virologic response.


Figure 5. Maximum all-oral drug costs at three WTP thresholds. Cost of all-oral drugs was plotted against the ICER to determine the maximum drug cost at which all-oral treatment (dashed line) can remain cost-effective compared to SOC treatment (solid line) at various WTP thresholds. Maximum costs of all-oral drugs at WTP thresholds of $50 000/QALY, $80 000/QALY and $100 000/QALY are shown in black boxes. WTP = willingness-to-pay; SOC = standard of care treatment; ICER = incremental cost-effectiveness ratio; QALY = quality-adjusted life year.

ICER and Sensitivity Analyses

To assess cost-effectiveness, we calculated the incremental cost-effectiveness ratio (ICER), which measured the average cost per QALY gained by using all-oral treatment instead of SOC. We conducted one-way sensitivity analyses to determine which model parameters had the greatest impact on the ICER and ran sub-analyses to explore differences in cost-effectiveness by viral genotype and age at treatment.


Model Validation

Because no published models to date compare all-oral treatment to SOC, we validated our model indirectly by comparing a cohort sent through our SOC branch to a cohort that progressed untreated through CHC natural history. This strategy allowed us to validate our SOC pathway by comparing it to similar published models assessing cost-effectiveness of currently available therapies (SOC) vs no treatment. We then built the all-oral treatment pathway based on the validated SOC model.

Our SOC validation model yielded an average of $54 603 in medical costs and 13.4 QALYs for subjects in the treatment branch compared to $40 407 and 12.1 QALYs for untreated subjects. These numbers compare well with those reported by Salomon et al. ($22,000/19.4 QALYs treated vs $8,200/18.9 QALYs untreated).[44] The absolute numbers differ between the two models, partly due to differences in cohort age (40 year-olds in Salomon, published 10 years ago, vs. 50-year-olds in our model) and cost of treatment regimens (combination therapy for genotype 1 subjects in Salomon vs. more expensive triple therapy in our model). However, the cost and QALY differences between the treated and untreated branches in the two models are comparable. After validation, we added decompensated cirrhosis to the initial fibrosis distribution to account for the possibility of treatment for decompensated subjects in the all-oral pathway.

Base Case Results

In the base case model, all-oral treatment dominated SOC (ICER = $44 514/QALY), yielding higher costs but more QALYs for a cohort of 50-year-old subjects (SOC: $74 619/10.7 QALYs; all-oral: $93 315/11.1 QALYs).

Sensitivity Analysis

A series of one-way sensitivity analyses (Fig. 4) demonstrated that the ICER was driven primarily by all-oral drug costs and was also sensitive to rates of SVR and treatment uptake for noncirrhotic subjects. As rates of SVR and treatment uptake for all-oral therapy increased, the ICER decreased, demonstrating greater cost-effectiveness. The ICER was robust to changes in all other parameters including QALY estimates, extended treatment duration for cirrhotic subjects and nontreatment-related CHC costs.

All-oral Drug Cost and Willingness-to-Pay Threshold

Assessment of cost-effectiveness depended on the willingness-to-pay (WTP) threshold chosen, which indicates how much stakeholders are willing to pay for all-oral treatment per QALY gained compared to SOC. The maximum costs that all-oral drug regimens can reach while remaining cost-effective under different WTP scenarios are illustrated in Fig. 5. With a $50 000/QALY WTP threshold, the maximum cost-effective all-oral drug cost was $74 217 for one course of therapy; at WTP thresholds of $80 000/QALY and $100 000/QALY, all-oral treatment ceded cost-effectiveness to SOC at drug costs of $97 279 and $112 653, respectively.


All-oral treatment dominated SOC in sub-analyses by viral genotype. It was most cost-effective for genotype 1 but remained cost-effective for genotypes 2 and 3 at WTP thresholds ~$80 000/QALY or higher (ICER = $30 881/QALY for genotype 1; $78 146/QALY for genotypes 2 and 3).

Age at Treatment

In parallel analyses comparing cohorts of 50-, 30- and 10-year-old subjects, all-oral treatment was most cost-effective among younger aged cohorts (cost/QALY = $8 384, $7 673, and $3 414, respectively).


Using the base case parameters in this model, a generalized all-oral treatment regimen was cost-effective compared to SOC for a cohort of 50-year-old, monoinfected, cirrhotic and noncirrhotic subjects with genotype 1, 2 and 3 HCV infections. The model was robust to changes in treatment duration, nontreatment-related medical costs and QALY estimates, but sensitive to all-oral drug costs as well as rates of treatment uptake and SVR for noncirrhotic subjects. The cost ceiling for all-oral drugs was dependent on the WTP threshold and ranged from $74 217 at a $50 000/QALY WTP to $112 653 at a $100 000/QALY WTP. Depending on their budgets and priorities, diverse stakeholders may choose different WTP thresholds, which will affect the price at which these drugs can remain cost-effective compared to SOC.

The higher cost and lower SVR rates associated with SOC treatment for genotype 1 offer greater opportunity for cost reduction and QALY improvements compared to genotypes 2 and 3. As a result, all-oral treatment was most cost-effective for genotype 1 subjects. Cost per QALY gained was minimized in younger cohorts, possibly due to lower initial fibrosis levels among younger subjects and longer life expectancy after SVR.

This analysis has certain limitations. Because clinical trials investigating all-oral drugs are ongoing, most parameters involved in all-oral treatment are not yet known and were estimated from expert opinion. As additional data become available for a more generalizable population of CHC subjects, these parameters may need to be re-evaluated.

In addition, this model assumed that a 50-year-old CHC-infected cohort exhibited the same initial fibrosis distribution as the overall CHC-infected population. Because this age group falls into the high-risk 1945–1964 birth cohort likely to have been infected 20–30 years ago, this assumption may underestimate the true proportion of late-stage fibrosis and cirrhosis. A model including a higher percentage of late-stage disease may yield higher estimates of cost-effectiveness for all-oral drugs. Model costs associated with CHC treatment and care were based on direct medical costs only.

Due to the uncertainty of many parameters contributing to all-oral treatment and SVR, this model was designed to be conservative, and cost-effectiveness of all-oral treatment could be higher than we have reported for several reasons. Our model excluded certain groups that may ultimately be eligible for all-oral treatment. Specifically, although SOC treatment has demonstrated the potential to reduce reinfection following liver transplant, our model does not account for posttransplant treatment.[34]Similarly, it does not allow for treatment in those with HCC, which may be possible with all-oral drugs. Successful CHC treatment could allow some individuals with HCC to undergo cancer treatments for which they would otherwise be ineligible, potentially reducing HCC-related mortality and increasing cost-effectiveness of all-oral treatment. In addition, although clinical trial data demonstrate up to 90% SVR in some treatment-experienced subgroups, our model does not include treatment-experienced individuals, many of whom may be eligible for retreatment with all-oral drugs,[45,46] Once evidence-based estimates for treatment eligibility and outcomes are available for these groups, future models should account for late-stage treatment and retreatment with all-oral drugs to determine whether their inclusion impacts cost-effectiveness.

It is also possible that post-SVR fibrosis regression rates will be higher following treatment with all-oral drugs than our model has estimated. Even with SOC treatment, some subjects have demonstrated cirrhosis reversal after SVR, which we did not account for in our model.[47] The percentage of decompensated subjects treated with all-oral drugs may also be higher than we estimated due to tolerability of interferon-free regimens.

Finally, if advanced clinical trials confirm high expectations for SVR and tolerability of all-oral drugs, HCV screening efforts will likely intensify, and treatment uptake can be expected to increase from current low rates of 12–28%,[48,49] Uptake could increase more markedly than we have estimated, resulting in greater cost-effectiveness for all-oral regimens. Factors contributing to uptake include clinician confidence in treatment outcomes, the possibility of direct treatment by primary care physicians (possibly reducing loss to follow-up at the specialist referral stage), lower rates of discontinuation due to side effects and more widespread screening.

Universal clinical HCV screening in the general population has been demonstrated to be cost-effective under multiple scenarios,[28,50] and some researchers are investigating the feasibility and cost-effectiveness of targeted testing and treatment efforts in specific high prevalence populations such as prison inmates and high-risk birth cohorts, both to improve health and to curb further transmission.[6,17,51] Because of the increased SVR and tolerability of interferon-free regimens, all-oral treatments can be expected to reduce CHC-related morbidity and mortality beyond what is possible with current treatment options. Once these drugs become available in the clinic, it will be possible to determine whether broader treatment eligibility and greater opportunities for early treatment due to more aggressive screening efforts will have further implications for their cost-effectiveness.


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