Cost analysis of sofosbuvir/ribavirin versus sofosbuvir/simeprevir for genotype 1 hepatitis C virus in interferon-ineligible/intolerant individuals

Authors

  • Liesl M. Hagan,

    Corresponding author
    1. Center for AIDS Research, Emory University School of Medicine and Veterans Affairs Medical Center, Atlanta, GA
    • Address reprint requests to: Liesl M. Hagan, cMPH, Emory University School of Medicine, 1760 Haygood Drive NE, Room E420, Atlanta, GA 30322. E-mail: lhagan2@emory.edu; fax: +1-404-727-1330.

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  • Mark S. Sulkowski,

    1. Johns Hopkins University School of Medicine, Baltimore, MD
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  • Raymond F. Schinazi

    1. Center for AIDS Research, Emory University School of Medicine and Veterans Affairs Medical Center, Atlanta, GA
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  • Potential conflict of interest: Dr. Sulkowski consults and received grants from AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, Janssen, Merck, and Gilead.

  • This work was supported, in part, by the National Institutes of Health (grant nos.: P30-AI-050409 [to R.F.S.] and K24-DA-034621 [to M.S.S.]) and the Department of Veterans Affairs (to R.F.S.).

  • See Editorial on Page 12

Abstract

Treatment guidance for chronic hepatitis C (CHC) released by the American Association for the Study of Liver Diseases (AASLD) and the Infectious Diseases Society of America (IDSA) offers two options for interferon (IFN)-ineligible/intolerant individuals with genotype 1 infection: sofosbuvir/ribavirin (SOF/RBV) for 24 weeks or sofosbuvir/simeprevir (SOF/SMV) for 12 weeks. A 24-week course of SOF/RBV costs approximately US$169,000, with sustained virologic response (SVR) rates ranging from 52% to 84%; 12 weeks of SOF/SMV costs approximately $150,000, with SVR between 89% and 100%. Because SOF/SMV is currently used off-label, debate exists among physicians and payers about whether it should be prescribed and covered. This article presents a cost-effectiveness analysis of these two treatment regimens accounting for costs of drugs, treatment-related medical care, retreatment for individuals who do not achieve SVR, and natural history of continued HCV infection after failed retreatment. Analysis uses a Markov model with a lifetime horizon and a societal perspective. In the base-case scenario, SOF/SMV dominated SOF/RBV in a modeled 50-year-old cohort of treatment-naïve and -experienced subjects, excluding those who failed earlier therapy with telaprevir or boceprevir. SOF/SMV yielded lower costs and more quality-adjusted life years (QALYs) for the average subject, compared to SOF/RBV ($165,336 and 14.69 QALYs vs. $243,586 and 14.45 QALYs, respectively). In base-case cost analysis, the SOF/SMV treatment strategy saved $91,590 per SVR, compared to SOF/RBV. Under all one-way sensitivity scenarios, SOF/SMV remained dominant and resulted in cost savings. Conclusions: These results suggest that a 12-week course of SOF/SMV is a more cost-effective treatment for genotype 1 CHC than 24 weeks of SOF/RBV among IFN-ineligible/intolerant individuals, supporting the AASLD/IDSA guidance and offering implications for both clinical and regulatory decision making as well as pharmaceutical pricing. (Hepatology 2014;60:37–45)

Abbreviations
AASLD

the American Association for the Study of Liver Diseases

AEs

adverse events

CBC

complete blood count

CHC

chronic hepatitis C

DAAs

direct-acting antivirals

FDA

U.S. Food and Drug Administration

HCV

hepatitis C virus

ICER

incremental cost-effectiveness ratio

IDSA

the Infectious Diseases Society of America

IFN

interferon

NS

nonstructural protein

Peg-IFN

pegylated interferon

QALY

quality-adjusted life year

qPCR

quantitative polymerase chain reaction

SMV

simeprevir

SOF

sofosbuvir

SOF/LDV

sofosbuvir plus ledipasvir for 24 weeks

SOF/RBV

sofosbuvir plus ribavirin for 24 weeks

SOF/SMV

sofosbuvir plus simeprevir for 12 weeks

SVR

sustained virologic response

Newly approved direct-acting antiviral (DAA) agents for chronic hepatitis C (CHC) have increased rates of sustained virologic response (SVR) to unprecedented levels, curing more than 90% of infections in many subgroups without the need for interferon (IFN).[1] However, individuals with genotype 1 infection remain more difficult to treat, and both clinical guidelines and U.S. Food and Drug Administration (FDA) approvals call for continued use of IFN alongside DAAs sofosbuvir (SOF) or simeprevir (SMV) for this group.[2-4] In some populations, up to 56% of those with CHC are ineligible to receive IFN-based treatment as a result of medical or psychological comorbidities, substance abuse, or earlier treatment failure.[5, 6] For these people, there are currently two IFN-free treatment options available in some regions: SOF plus ribavirin (SOF/RBV) for 24 weeks, which yields SVR rates between 52% and 84% at a cost of approximately US$169,000,[7-12] and SOF plus SMV (SOF/SMV) for 12 weeks, with SVR rates ranging from 89% to 100% at a cost of $150,000.[13, 14] Although treatment with SOF/SMV is more effective, less costly, and of shorter duration compared to SOF/RBV, it has not yet been specifically approved for clinical use by the FDA, resulting in debate among both physicians and payers about whether it should be prescribed and reimbursed. This analysis compares the long-term cost-effectiveness of these two treatment strategies.

Materials and Methods

Markov Model

Using TreeAge Pro 2013 software (TreeAge Software, Inc., Williamstown, MA), we constructed a decision-analytic Markov model to simulate the progression of a 50-year-old genotype 1 cohort through CHC natural history and treatment with either SOF/RBV or SOF/SMV, using a societal perspective over a lifetime horizon (Fig. 1). Cohort age was chosen based on estimates that U.S. hepatitis C virus (HCV) seroprevalence peaks in the 50- to 59-year age group.[15] The model cohort reflects both treatment-naïve and -experienced subjects, with the exception of those who have failed earlier telaprevir/boceprevir-based treatment and may harbor HCV variants resistant to HCV protease inhibitors, including SMV.

Figure 1.

Simplified Markov model. HCV+ model subjects progress through fibrosis stages F0-F4, DC, and HCC based on annual probabilities. Those who fail treatment can be retreated with rescue therapy; those who fail retreatment continue progressing through CHC natural history. Further fibrosis progression after SVR is possible for subjects in stages F3 and F4, and F3 subjects can progress directly to DC or HCC, bypassing F4 (dotted lines). DC, decompensated cirrhosis; F0-F4, Metavir fibrosis stages; HCC, hepatocellular carcinoma; Re-tx, retreatment; Tx, treatment.

The decision tree that underlies the Markov model is presented in Fig. 2. Parameters representing CHC natural history, treatment, treatment outcomes, and retreatment determined subjects' pathways through the decision tree. Base-case values for all model parameters and ranges used in sensitivity analyses are listed in Tables 1-5.

Figure 2.

Decision tree excerpt. A selection from the decision tree underlying the Markov model, where M represents the starting point for each annual model cycle in the two treatment arms. Subjects who fail treatment and retreatment continue progressing through CHC natural history in the subsequent model year. *SVR rates vary by fibrosis stage (not depicted).

At the end of each model year (stage), subjects accrued the costs and quality-adjusted life years (QALYs) associated with their disease state and treatment status during that year. Death was possible from any model stage. Subjects alive at the end of a given stage continued progressing through the model as determined by their disease state or treatment outcome in the preceding year, and they continued accumulating costs and QALYs each year until death. Analysis terminated when the cohort reached its average life expectancy. Cumulatively, the costs and QALYs accrued by the subjects in each treatment branch were used to calculate the incremental cost-effectiveness ratio (ICER). Cumulative costs were used to calculate the cost per SVR under each treatment strategy. Costs considered in this analysis include the direct costs of treatment-related drugs, medical care, and adverse events (AEs), as well as continued CHC-related medical care for subjects who failed treatment.

Measures

To assess cost-effectiveness, we calculated the ICER, which measures the incremental cost of the more effective treatment strategy per QALY it adds to the average subject's lifespan, compared to the less costly treatment strategy. We also calculated cost savings per SVR under the dominant treatment strategy. We conducted one-way sensitivity analyses to determine whether variation in key model parameters affected the ICER or the cost per SVR, including subanalyses exploring differences by viral genotype (1a vs. 1b) and Q80K status.

Background Mortality Rates

Age-specific background mortality rates were applied throughout the model. Before SVR, they were set at 2.37 times the mortality rates for individuals without CHC.[16, 17] After SVR, subjects were assigned lower mortality rates, set at 1.4 times non-CHC rates, based on evidence that viral clearance improves overall health outcomes (Table 1).[18] Subjects with end-stage liver disease were assigned higher mortality rates based on published literature (Table 2).

Genotype 1a Versus 1b and Q80K Polymorphism

Q80K is a naturally occurring polymorphism found in up to 47% of those infected with HCV genotype 1/subtype A, and its presence has been associated with lower SVR rates among individuals treated with SMV in combination with other drugs.[19, 20] In the SOF/SMV treatment arm of this model, genotype 1a outcomes were stratified by Q80K status to reflect lower SVR rates among Q80K+ subjects (Fig. 2), and Q80K screening was included in treatment costs associated with SOF/SMV treatment. Variation in the proportion of Q80K+ individuals was explored in sensitivity analyses. In the SOF/RBV arm, genotypes 1a and 1b were collapsed, Q80K status was not incorporated into the model structure, and Q80K testing was not included in treatment-associated costs.

Fibrosis Stages

Probability of SVR was dependent on 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).[21] Cost of noninvasive fibrosis staging was included in the analysis for both treatment arms. Initial distribution of subjects across fibrosis stages and annual progression probabilities to later stages are listed in Tables 1 and 2. The model did not include subjects with decompensated cirrhosis because of uncertainty regarding treatment tolerance. To reflect the possibility that individuals with early-stage fibrosis may elect to postpone treatment, sensitivity analyses include a scenario under which only subjects with advanced fibrosis (stages F3-F4) are treated.

To account for evidence of liver regeneration after viral eradication, the model allowed post-SVR fibrosis regression according to probabilities from published literature (Table 3).[22-26] When a disease state transition occurred (e.g., progression from F0 to F1 before SVR or from F3 to F2 after SVR), subjects accrued the costs and QALYs associated with the disease state in which they began the year; they accrued the costs and QALYs associated with their new health state in the following year.

Retreatment

To reflect clinical expectations, most subjects not cured with initial treatment (SOF/SMV or SOF/RBV) were retreated with rescue therapy. The percentage retreated was assumed to be 90% for base-case analysis and was varied in sensitivity analyses (Table 3). SOF plus ledipasvir for 24 weeks (SOF/LDV) was chosen as the rescue therapy drug regimen for this model, based on its estimated availability in 2014 and its very high SVR rates in clinical trials (95%-100%).[27] Furthermore, because LDV is an inhibitor of HCV nonstructural protein (NS)5A, this agent is expected to be effective in individuals who failed earlier treatment that included HCV NS3/4A protease inhibitors, such as SMV. The base-case cost of SOF/LDV was set at 1.5 times the cost of SOF alone for 24 weeks, with a range extending from $0 to 2 times the cost of SOF (Table 5). QALYs associated with SOF/LDV rescue therapy were set equal to QALY estimates for SOF/SMV treatment because of the absence of RBV in both regimens. The rate of possible reinfection after viral clearance was assumed equal for both treatment arms and was not included in the model structure.

Treatment-Related Medical Care

Both SOF/RBV and SOF/SMV treatment strategies included the costs of initial HCV screening, a new patient visit, genotype assay, and noninvasive fibrosis staging (estimated based on the mean of FibroScan and FibroSURE prices through the U.S. Department of Veterans Affairs National Acquisition Center).[12] The SOF/SMV arm included the cost of a Q80K test, also based on Department of Veterans Affairs pricing.

Medical monitoring was included in the costs associated with all treatment regimens. In the SOF/RBV treatment arm (24 weeks), monitoring included office visits at weeks 0, 4, 8, 12, 16, 20, 24, and post-treatment week 12 (eight total visits). Metabolic panels and complete blood counts (CBCs) were included in all eight visits, and quantitative polymerase chain reaction (qPCR) checks to monitor viral load were included in four visits (weeks 0, 12, 24, and post-treatment week 12).

In the SOF/SMV treatment arm (12 weeks), monitoring included office visits at weeks 0, 4, 8, 12, and post-treatment week 12 (five total visits). Metabolic panels were included in all five visits, and qPCR checks were included in four visits (weeks 0, 4, 12, and post-treatment week 12). Treatment with SOF/SMV has not been shown to induce anemia (because of the absence of RBV); therefore, a CBC test was only included in the week 0 baseline visit.

Medical monitoring was also included in the cost of retreatment with SOF/LDV (24 weeks). Monitoring included office visits at weeks 0, 4, 8, 12, 16, 20, 24, and post-treatment week 12 (eight total visits). Metabolic panels were included in all eight visits, and qPCR checks were included in four visits (weeks 0,12, 24, and post-treatment week 12). A CBC test was included in the week 0 baseline visit.

The model also includes the cost of treatment-related AEs, identified from published prescribing information and clinical trial data for the relevant drug regimens. Costs of AEs were weighted based on estimated incidence of each event.[3, 4, 27]

Costs and QALYs

Most medical costs and QALYs were derived from two recent cost-effectiveness studies that provide comprehensive reviews of these parameters from a variety of published sources (Tables 4 and 5).[28, 29] Costs to manage treatment-related AEs were obtained from the Department of Veterans Affairs National Acquisition Center database.[12] Costs were adjusted to 2013 U.S. dollars, and both costs and QALYs were discounted 3% per year.

QALY values associated with IFN-free treatments have not yet been published because of the short amount of time since FDA approval. For these parameters, we used treatment-related QALY values generated in a previous cost-effectiveness study based on expert opinion.[30] Because of the uncertainty of these values, sensitivity analyses involving QALY parameters incorporated ranges of ±10%.

Because these QALY estimates refer to an all-oral regimen that included RBV, we increased them slightly in the SOF/SMV and SOF/LDV regimens in the present analysis to reflect a reduction in AEs without RBV (Table 4). This decision is supported by placebo-controlled trials of SOF/RBV, in which subjects in the active treatment group experienced greater incidence of hemolytic anemia, insomnia, fatigue, and cough, compared to the placebo group.[4] Documented photosensitivity and increased bilirubin associated with SMV were not deemed severe enough to counteract the absence of RBV in terms of quality-of-life measures during treatment with SOF/SMV. Likelihood of AEs was doubled in sensitivity analyses.

Drug interactions between SOF and SMV are not expected because of differing modes of metabolism (renal vs. hepatic), and published prescribing information for these drugs indicates minimal interactions with other medications.[3, 4] Therefore, drug-drug interactions were not included in related quality-of-life measures or treatment costs, though we expect that, on an individual level, clinicians will consider concurrent medications in decisions regarding eligibility for treatment with SOF/SMV or SOF/RBV.

Results

Base-Case Analysis

In the base-case scenario, SOF/SMV dominated SOF/RBV. Over the duration of the model, the SOF/SMV regimen yielded lower costs and more QALYs for the average subject, compared to the SOF/RBV regimen ($165,336 and 14.69 QALYs vs. $243,586 and 14.45 QALYs, respectively), resulting in a negative ICER. Because of the clear dominance of SOF/SMV in cost-effectiveness analysis, we also conducted a cost-analysis to calculate cost savings per SVR. The SOF/SMV strategy resulted in cost savings of $91,590 per SVR, compared to SOF/RBV in base-case analysis (Table 6).

Table 1. Model Cohort Characteristics
Model ParameterBase-Case Value (Range)References
  1. Values in tables have been rounded. For full decimal places, consult cited sources.

  2. Abbreviation: F0-F4, Metavir fibrosis stages.

Average life expectancy, years
50-year-old cohort81[17]
Viral genotype and Q80K distribution
Genotype 1a0.60[31]
Q80K+0.40 (0.23-0.48)[19, 20, 32, 33]
Genotype 1b0.40[31]
Initial fibrosis distribution
F00.17 (0.15-0.19)[28, 34]
F10.35 (0.32-.39)[28, 34]
F20.22 (0.20-0.24)[28, 34]
F30.14 (0.13-0.15)[28, 34]
F40.12 (0.11-0.13)[28, 34]
Mortality rates (compared to non-CHC population)
All-cause mortality before SVR2.37[16]
All-cause mortality after SVR1.4[18]
Table 2. CHC Natural History Parameters
Model ParameterBase-Case Value (Range)References
  1. Values in tables have been rounded. For full decimal places, consult cited sources.

  2. Abbreviations: F0-F4, Metavir fibrosis stages; HCC, hepatocellular carcinoma.

CHC natural history and fibrosis progression (annual rates)
F0 to F10.12 (0.09-0.14)[28, 34]
F1 to F20.09 (0.07-0.10)[28, 34]
F2 to F30.12 (0.10-0.14)[28, 34]
F3 to F40.12 (0.09-0.14)[28, 34]
F3 to decompensated cirrhosis0.012 (0.010-0.014)[28, 35]
F3 to HCC0.011 (0.009-0.013)[28, 36]
F4 to decompensated cirrhosis0.04 (0.03-0.05)[28, 29, 35, 37]
F4 to HCC0.03 (0.02-0.04)[28, 36]
Decompensated cirrhosis to HCC0.014 (0.011-0.017)[28, 37]
Decompensated cirrhosis to liver transplant0.031 (0.025-0.037)[28, 38]
Decompensated cirrhosis to death0.13 (0.10-0.16)[28, 37]
HCC to liver transplant0.031 (0.025-0.037)[28, 38]
HCC to death0.43 (0.34-0.51)[28, 37]
Liver transplant to death (year 1)0.14 (0.11-0.16)[28, 39]
Liver transplant to death (years 2+)0.030 (0.027-0.057)[28, 39, 40]
Table 3. CHC Treatment Parameters
Model ParameterBase-Case Value (Range)References
  1. Values in tables have been rounded. For full decimal places, consult cited sources.

  2. Abbreviations: F0-F4, Metavir fibrosis stages; HCC, hepatocellular carcinoma.

SVR rates
SOF/RBV  
F0-F40.70 (0.52-0.84)[7-10]
SOF/SMV  
Q80K+  
F0-F20.89 (0.80-0.98)[13]
F3-F40.91 (0.82-0.98)[13]
Q80K  
F0-F40.98 (0.88-0.98)[13]
SOF/LDV  
F0-F40.96 (0.90-0.98)[27]
Retreatment
Proportion re-treated after initial treatment failure0.90 (0.80-1.0)Estimation
Disease progression after SVR (annual rates)
F3 SVR to decompensated cirrhosis0.0010 (0.0008-0.0012)[28, 36]
F3 SVR to HCC0.007 (0.006-0.008)[28, 36]
F4 SVR to decompensated cirrhosis0.003 (0.002-0.004)[28, 36]
F4 SVR to HCC0.019 (0.015-0.023)[28, 36]
Fibrosis regression after SVR (proportions)
F3 to F20.50 (0.25-0.82)[22-24, 26]
F4 to F20.08 (0.06-0.10)[25]
F4 to F30.34 (0.19-0.49)[22, 24, 26]
Table 4. QALY Estimates
Model ParameterBase-Case Value (Range)References
  1. Values in tables have been rounded. For full decimal places, consult cited sources.

  2. Abbreviations: F0-F4, Metavir fibrosis stages; HCC, hepatocellular carcinoma.

QALYs associated with disease stages
CHC F0-F20.85 (0.83-0.87)[28, 41]
CHC F30.79 (0.77-0.81)[28, 41]
CHC F40.76 (0.70-0.79)[28, 41]
Decompensated cirrhosis0.69 (0.44-0.69)[28, 41]
HCC0.67 (0.60-0.72)[28, 41]
Liver transplant (year 1)0.50 (0.40-0.69)[28, 38, 42, 43]
Liver transplant (years 2+)0.77 (0.57-0.77)[28, 41, 44-46]
QALYs after SVR
SVR after F0-F20.92 (0.90-0.94)[28]
SVR after F30.86 (0.84-0.88)[28, 41]
SVR after F40.83 (0.81-0.85)[28]
QALYs during treatment
SOF/RBV  
F0-F20.80 (0.72-0.88)[30]
F30.74 (0.67-0.81)[30]
F40.71 (0.64-0.78)[30]
SOF/SMV  
F0-F20.85 (0.77-0.93)Calculated value
F30.79 (0.72-0.86)Calculated value
F40.76 (0.69-0.83)Calculated value
SOF/LDV  
F0-F20.85 (0.77-0.93)Calculated value
F30.79 (0.72-0.86)Calculated value
F40.76 (0.69-0.83)Calculated value
Table 5. Costs of CHC Treatment and Medical Care
Model ParameterBase-Case Value (Range)References
  1. Values in tables have been rounded. For full decimal places, consult cited sources.

  2. Abbreviations: F0-F4, Metavir fibrosis stages; HCC, hepatocellular carcinoma.

Annual costs of non-treatment-related CHC care (in 2013 U.S. dollars)
CHC F0-F3187 (89-547)[28, 38, 47]
CHC F41,245 (728-1,761)[28, 38, 47]
Decompensated cirrhosis15,958 (12,767- 39,444)[28, 38, 48]
HCC49,954 (24,977-74,930)[28, 38]
Liver transplant (year 1)305,136 (244,109-366,163)[28, 49]
Liver transplant (years 2+)46,245 (36,996- 55,493)[28, 50]
Costs of treatment (in 2013 U.S. Dollars)
SOF/RBV regimen  
SOF (24 weeks)168,000[11]
RBV (24 weeks)1,038[12]
Treatment-associated medical care2,100 (1,890-2,310)Calculated value
SOF/SMV regimen  
SOF (12 weeks)84,000[11]
SMV (12 weeks)66,000[14]
Treatment-associated medical care2,096 (1,886-2,306)Calculated value
SOF/LDV regimen  
Drugs only (combination)252,000 (0-336,000)Calculated value
Treatment-associated medical care1,160 (1,044-1,276)Calculated value
Table 6. Results: Base Case and Sensitivity Analyses
Base case costs and QALYs for SOF + RBV and SOF + SMV
Treatment ScenarioCostQALYsCost/QALY
SOF + SMV (base case)$165,33614.69$11,255
SOF + RBV (base case)$243,58614.45$16,857
Cost savings per SVR with SOF/SMV: Base case and sensitivity analyses
Treatment ScenarioCost per SVR (SOF/RBV)Cost per SVR (SOF/SMV)Cost savings per SVR with SOF/SMV
  1. a

    See Table 3 for low and high SVR thresholds for each drug regimen and for low threshold for proportion retreated after initial failure. Q80K refers to a naturally occurring polymorphism found in up to 47% of HCV genotype 1/subtype A–infected individuals and less commonly in those with HCV genotype 1/subtype B; the presence of this polymorphism has been associated with lower SVR rates in subjects treated with SMV in combination with other drugs.

  2. Abbreviation: F3/F4, Metavir fibrosis stages 3 and 4.

Base case$262,046$170,456$91,590
Sensitivity Analyses   
Disease characteristics   
Advanced fibrosis (Metavir stage F3/F4) only$284,407$186,968$97,439
Genotype 1/subtype A with Q80K polymorphism only (all fibrosis stages)$262,046$188,856$73,190
SVR rates*   
Low SOF/SMV; high SOF/RBV$221,156$175,450$45,706
High SOF/SMV; low SOF/RBV$312,160$162,404$149,756
High SOF/SMV; base case SOF/RBV$262,046$162,404$99,642
Low SOF/LDV$265,425$170,494$94,931
Tolerability   
Doubled likelihood of adverse events during treatment$262,171$170,463$91,708
Retreatment   
Cost of SOF/LDV rescue therapy set at $0 per treatment$194,347$165,432$28,915
Decreased proportion retreated after initial failure*$261,081$169,965$91,116

Sensitivity Analyses

We conducted sensitivity analyses among subgroups who have experienced lower SVR rates with SOF/SMV treatment in clinical trials (genotype 1a, Q80K+ subjects only), as well as those who have shown greater incidence of AEs with both regimens (F3 and F4 subjects only). Additional parameters that were varied in sensitivity analyses included the proportion of subjects in all fibrosis stages experiencing treatment-related AEs, cost of SOF/LDV rescue therapy for those who fail to achieve SVR with initial treatment with SOF/RBV or SOF/SMV, SVR rates for SOF/SMV, SOF/RBV, and SOF/LDV regimens, and proportion of subjects retreated with SOF/LDV rescue therapy after initial treatment failure. Under all scenarios tested, the SOF/SMV treatment strategy remained dominant and resulted in cost savings per SVR, compared to SOF/RBV (Table 6).

Discussion

The initial approval of SOF was limited to its use with RBV, with or without pegylated interferon (Peg-IFN), and the approval of SMV was limited to a combination with both RBV and Peg-IFN. As a result, some clinicians face reimbursement barriers when prescribing SOF/SMV together because it is not a specifically approved combination of antiviral agents. However, clinical guidance recently released by the American Association for the Study of Liver Diseases and the Infectious Diseases Society of America recommends SOF/SMV as the preferred treatment modality for genotype 1, IFN-ineligible or -intolerant individuals as well as those who are nonresponders to treatment with Peg-IFN and RBV.[2] The present analysis provides economic support for this guidance, demonstrating that a 12-week course of SOF/SMV is not only more effective against genotype 1 CHC, but also results in cost savings, compared to 24 weeks of SOF/RBV, both in base-case analysis as well as multiple sensitivity analyses in which clinically relevant individual and treatment-related characteristics were varied.

This study has some limitations. Primary efficacy measurements for these drug regimens are based on data from clinical trials, some of which have not yet been completed. Specifically, SVR12 data for cohort 2 in the COSMOS trial are not yet available, necessitating the use of SVR4 data for F3-F4 individuals treated with SOF/SMV.[13] Furthermore, the sample sizes in some cited trials are relatively small, contributing to parameter uncertainty with respect to the expected SVR rates with these regimens (e.g., n = 167 in the COSMOS study for SOF/SMV and n = 114 and n = 60 in the PHOTON-1 and SPARE studies for SOF/RBV, respectively).[9, 10, 13] CHC natural history after treatment with these specific drug regimens is also uncertain, as is the specific distribution of fibrosis stages among genotype 1 IFN-ineligible/intolerant individuals (assumed in this analysis to mirror the fibrosis distribution in the general population with CHC). Sensitivity analyses were included to model these uncertainties in SVR and natural history parameters; in each of these models, treatment with SOF/SMV remained dominant.

The cost of a SOF/LDV regimen is not yet known and is modeled under a wide range in sensitivity analyses. QALY estimates for treatment with IFN-free regimens are not available in published literature, thus quality-of-life studies specific to these treatment regimens are warranted. In addition, this model does not account for the possibility of reinfection after SVR nor for the population benefit of preventing incident HCV infections through reductions in the pool of infected individuals. This analysis considers direct medical costs only and does not reflect indirect costs, such as productivity losses attributable to CHC. Some of these limitations could result in overestimation of cost savings (i.e., high SVR rates and absence of reinfection probabilities), whereas others could contribute to estimates that are more conservative (i.e., absence of indirect costs and the prevention benefit of infections cured).

Whereas these potential limitations warrant careful consideration, this analysis offers evidence that the ability of SOF/SMV to cure a greater number of individuals and reduce the need for retreatment can be expected to result in lower immediate and long-term costs to payers as well as better outcomes for individuals, compared to SOF/RBV. Combined with its potential for improved tolerability in the absence of RBV, shorter treatment duration, and higher resulting adherence to treatment, the economic dominance of SOF/SMV can contribute to the debate regarding its reimbursement.

In this analysis, SOF/SMV continued to yield cost savings per SVR when the cost of SOF/LDV rescue therapy was set to zero. Thus, even if the cost of retreatment for those who fail to achieve SVR with SOF/RBV were to be covered at no additional cost to the payer, SOF/SMV remains a less costly option overall for payers, patients, and providers. In addition to the direct costs considered here, individuals failing SOF/RBV and retreated with SOF/LDV would require a total of 48 weeks of therapy instead of 12 with SOF/SMV, resulting in higher exposure to drugs, greater risk of complications, and added pressure on providers amidst high treatment demand. Prospective payers should consider this larger context when determining whether to include SOF/SMV in their drug formularies.

Ancillary