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Direct-Acting Antiviral Agents for Patients With Hepatitis C Virus Genotype 1 Infection Are Cost-Saving

  • Jagpreet Chhatwal
    Correspondence
    Reprint requests Address requests for reprints to: Jagpreet Chhatwal, PhD, MGH Institute for Technology Assessment, 101 Merrimac Street, Floor 10th, Boston, Massachusetts 02114. fax: 1-617-726-9414.
    Affiliations
    Institute for Technology Assessment, Massachusetts General Hospital, Boston, Massachusetts

    Harvard Medical School, Boston, Massachusetts

    Liver Center and Gastrointestinal Division, Massachusetts General Hospital, Boston, Massachusetts
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  • Tianhua He
    Affiliations
    Tsinghua University School of Medicine, Beijing, China
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  • Chin Hur
    Affiliations
    Institute for Technology Assessment, Massachusetts General Hospital, Boston, Massachusetts

    Harvard Medical School, Boston, Massachusetts

    Liver Center and Gastrointestinal Division, Massachusetts General Hospital, Boston, Massachusetts
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  • Maria A. Lopez-Olivo
    Affiliations
    Department of General Internal Medicine, The University of Texas, MD Anderson Cancer Center, Houston, Texas
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Open AccessPublished:September 17, 2016DOI:https://doi.org/10.1016/j.cgh.2016.09.015

      Background & Aims

      Direct-acting antivirals (DAAs) are effective in treatment of hepatitis C virus (HCV) genotype 1 infection, but their cost and value have been debated. We performed a systematic review of published cost-effectiveness analyses of DAAs, synthesized their results with updated drug prices, and calculated the maximum price at which DAA therapy for HCV genotype 1 infection is cost-effective (increased quality-adjusted life-years [QALYs] and increased cost that the society is willing to pay) and cost-saving (increased QALYs and decreased costs).

      Methods

      We conducted a systematic review of the PubMed, Medline, EMBASE, Cochrane library, EconLit, Database of Abstracts of Reviews of Effects, National Health Service Economic Evaluation Database, Health Technology Assessment, and Tufts University databases for cost-effectiveness analyses published from 2011 through 2015. Our analysis included cost effectiveness of DAAs versus previous standard-of-care regimens (peginterferon and ribavirin, boceprevir and telaprevir), or no treatment, performed for patients with HCV genotype 1 infection. We excluded studies that were not written in English or those that did not report QALYs. Reported incremental cost-effectiveness ratios (ICERs) and treatment costs for each comparison were extracted; the threshold price was estimated for each analysis in which regimens were found to be cost-effective (ICER ≤$100,000/QALY) or cost-saving (ICER <$0), those that decreased costs and increased QALYs.

      Results

      We identified 24 cost-effectiveness studies that reported 170 ICERs for combinations of 11 drugs, from 11 countries. Of those, 81 ICERs were determined for first-generation DAAs (boceprevir and telaprevir) and 89 ICERs were determined for second-generation DAAs (drugs approved after the first-generation DAAs) as a primary intervention. The median threshold prices at which first-generation and second-generation DAAs became cost-effective were estimated as $120,100 (interquartile range, $90,700–$176,800) and $227,200 (interquartile range, $142,800–$355,800), respectively. At the discounted price of $60,000, a total of 71% of the analyses found second-generation DAAs to be cost-saving and 22% to be cost-effective.

      Conclusions

      In a systematic review, we found treatment of HCV genotype 1 infection with second-generation DAAs to be cost-effective when they cost less than and $227,200; these drugs produced cost savings at current discounts.

      Keywords

      Abbreviations used in this paper:

      CEA (cost-effectiveness analysis), CHEERS (The Consolidated Health Economic Evaluation Reporting Standards), DAA (direct-acting antiviral), HCV (hepatitis C virus), ICER (incremental cost-effectiveness ratio), IQR (interquartile range), QALY (quality-adjusted life-year), WTP (willingness to pay)
      See editorial on page 838.
      Worldwide, more than 170 million people are chronically infected with hepatitis C virus (HCV).

      Hepatitis C fact sheet. Geneva: World Health Organization. Available at: http://www.who.int/mediacentre/factsheets/fs164/en. Accessed June 8, 2015.

      HCV infection is the leading cause of hepatocellular carcinoma and is the most common indication for liver transplantation in the United States and Europe.
      • Rosen H.R.
      Chronic Hepatitis C infection.
      Of the 6 HCV genotypes, genotype 1 is the most prevalent in the Western world and accounts for at least 70% of all chronic infections.
      • Manos M.M.
      • Shvachko V.A.
      • Murphy R.C.
      • et al.
      Distribution of hepatitis C virus genotypes in a diverse US integrated health care population.
      HCV treatment has rapidly evolved over the past few years beginning with the launch of 2 direct-acting antivirals (DAAs), boceprevir and telaprevir, in 2011 for genotype 1, followed by the availability of several new oral DAAs from 2013 onward, including sofosbuvir, simeprevir, ledipasvir, daclatasvir, and Viekira Pak. New oral therapies are superior, with efficacy greater than 95% in most patients, and require shorter duration of treatment and have fewer adverse effects than the older therapies.
      However, the high price coupled with the high demand for oral DAAs has created concerns about their impact on health care budgets, delaying timely treatment to several HCV patients. The high price of these drugs has led to a national debate about the value and affordability of HCV treatment in the United States and elsewhere. Citing these concerns, several payers, including state Medicaid programs, have restricted these treatments to patients with advanced stages of hepatic fibrosis.
      • Canary L.A.
      • Klevens R.M.
      • Holmberg S.D.
      Limited access to new hepatitis C virus treatment under state Medicaid programs.
      Cost-effectiveness analysis (CEA) can inform stakeholders regarding the value of HCV treatment and allow them to compare its value with other medical interventions. Using a decision-analytic modeling approach, such analysis can project the long-term health benefits of HCV treatment, predict long-term costs of HCV sequelae, and weigh them against the cost of up-front treatment.
      Several CEAs using models of HCV were recently published that assessed the value of treatment by estimating the incremental cost-effectiveness ratios (ICERs), which provide the cost of gaining 1 additional quality-adjusted life-year (QALY). However, different modeling assumptions, including those regarding the costs of DAAs, may have influenced their results. Furthermore, drug prices have come down considerably after the publication of these cost-effectiveness studies, so their results are outdated and may not accurately depict the current real-world value. Our objective was 2-fold: to systematically review the published CEAs of DAAs and synthesize published results after updating their cost assumptions, and to estimate the threshold drug prices below which HCV treatment is cost-effective and/or cost-saving.

      Methods

      We synthetized the cost-effectiveness results by controlling for the drug price, HCV genotype, treatment history, and geographic region. We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement to report our results.

       Information Sources and Search

      We conducted a literature search in general (ie, PubMed, Medline, EMBASE, The Cochrane library) and content-specific electronic databases (ie, EconLit, Database of Abstracts of Reviews of Effects, National Health Service Economic Evaluation Database and Health Technology Assessment database, Tufts CEA registry). The search covered peer-reviewed original articles published from January 1, 2011, until September 8, 2015. The list of references from potentially relevant articles was also searched. All results were imported into a reference manager software and merged, and then duplicates were removed. Supplementary Table 1 shows the search strategy used for the Medline database.

       Inclusion and Exclusion Criteria

      We included any article that reported an economic model to estimate the cost-effectiveness of treating HCV patients with DAAs in comparison with old standard of care, which was dependent on the primary intervention and the target population. We included all approved DAAs categorized as first-generation and second-generation DAAs. The first-generation DAAs included boceprevir and telaprevir; and second-generation DAAs included simeprevir, paritaprevir, asunaprevir, ledipasvir, ombitasvir, sofosbuvir, daclatasvir, and dasabuvir. The comparators for first-generation DAAs were peginterferon-ribavirin or no treatment, and the comparators for second-generation DAAs were first-generation DAAs, peginterferon-ribavirin, or no treatment.
      We excluded articles that were not published in English, not original studies (ie, reviews, opinion articles), did not provide modeling techniques used, did not report QALYs, reported only budget impact or cost-of-illness analysis, did not report any results for genotype 1 patients, reported a drug regimen that has not been approved by the Food and Drug Administration or recommended by a professional organization, did not report cost-effectiveness results compared with the old standard of care, did not report sensitivity analysis on the cost of HCV treatment, or only included patients coinfected with other viral infections (eg, human immunodeficiency virus, hepatitis B virus).

       Study Selection

      Two reviewers screened the titles and abstracts of the unique citations independently. The first step was to assess whether inclusion criteria were met. Any disagreements regarding whether or not a particular analysis fulfilled the initial inclusion criteria were resolved by discussion leading to consensus. We then retrieved the full text of those relevant citations and excluded unsuitable analyses according to our exclusion criteria, resulting in the final group of studies analyzed.

       Data Collection Process and Data Items

      We used a standardized extraction form to collect information. One reviewer abstracted data from the included studies and another reviewer crosschecked the abstracted information. We collected basic information regarding the study including study year; country for which the analysis was performed; drug regimen as primary intervention, which was further categorized as first-generation DAAs (boceprevir- and telaprevir-based therapies) and second-generation DAAs; and the comparator regimen. Additional information, such as characteristics of the modeled population including presence of cirrhosis, HCV genotype, and treatment experience, was extracted. Model features relevant to the cost-effectiveness of HCV treatment, such as perspective, discount rate, treatment-as-prevention benefits, extrahepatic benefits, and reinfection after sustained virologic response (SVR), were also noted.

       Quality Appraisal

      One investigator (T.H.) assessed the quality of reporting using the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) statement,
      • Husereau D.
      • Drummond M.
      • Petrou S.
      • et al.
      Consolidated health economic evaluation reporting standards (CHEERS) statement.
      and another investigator (M.L.-O.) cross-checked the entries. The CHEERS statement is a 24-item checklist evaluating 6 sections of an economic evaluation. Each of the items was explicitly judged as follows: Yes = “information reported” or No = “information not reported.” The quality of the included studies was reported as the number of missing information across studies per item and converted to percentages.

       Synthesis of Results: Reanalysis of Incremental Cost-Effectiveness Ratios and Threshold Drug Price

      To account for differences in treatment costs used by published studies, we recalculated each ICER at the wholesale acquisition cost of DAAs and over a range of $20,000–$100,000. We converted all costs to 2014 US dollar value using the Consumer Price Index for each country and the average currency conversion rate in 2014.

      Inflation: current and historic inflation by country. Available at: http://www.inflation.eu. Accessed May 18, 2016.

      XE Currency Exchange Rates. Available at: http://www.xe.com/. Accessed May 18, 2016.

      Because treatment costs and ICERs have a linear relationship, we used the linear interpolation approach to find the ICER at any treatment cost. For that purpose, we first extracted all reported costs, QALYs, and ICERs from all studies. For each analysis, we also extracted an ICER at a different price either using the published 1-way sensitivity analysis or price-threshold analysis. If the sensitivity analysis on the cost of HCV treatment was not reported, we removed that ICER from our analysis. The following equation provides the ICER (denoted by ICERX) when the price of DAAs is X:
      ICERX=(ICERBICERAPriceBPriceA)×(XPriceA)+ICERA


      where PriceA and PriceB along with their corresponding ICERs (ICERA and ICERB) were extracted from the published studies.
      For each study, we further estimated the threshold price below which treatment with DAAs would become cost-effective using the willingness-to-pay (WTP) threshold of $100,000-per-QALY and cost-saving (ie, WTP threshold of $0-per-QALY). The following equation provides the relationship between the threshold drug price and WTP:
      Pricethreshold=PriceA+(WTPICERA)×(PriceBPriceAICERBICERA)


      Results

      Our search yielded 304 records. After exclusion of duplicates and 2-step screening, 24 unique studies were included in our analysis (Figure 1).
      Figure thumbnail gr1
      Figure 1Flow chart of study selection process. FDA, Food and Drug Administration; HIV, human immunodeficiency virus; SOC, standard of care; TEL, telaprevir.

       Overview of Studies and Patient Characteristics

      Twenty-four studies were included in the systematic review. Supplementary Table 2 provides an overview of the study characteristics. These studies evaluated 170 ICERs of 11 different drug combinations from 11 different countries (Supplementary Table 3). Among them, 81 ICERs evaluated first-generation DAAs as the primary intervention; 67 were compared with peginterferon-ribavirin and 14 with no treatment. Furthermore, 89 ICERs evaluated second-generation DAAs as the primary intervention; 67 were compared with the old standard-of-care (peginterferon-ribavirin or first-generation DAAs) and 22 with no treatment. Table 1 summarizes key modeling features of the included studies.
      Table 1Summary of Modeling Features of Included Studies
      Author, year, countryPrior treatmentDrug regimens evaluatedTime horizonPerspectiveDiscount rate (cost, QALY), %TasP benefitExtrahepatic benefitsIndirect economic benefitsReinfection after SVRSponsor type
      Camma et al, 2012
      • Camma C.
      • Petta S.
      • Enea M.
      • et al.
      Cost-effectiveness of boceprevir or telaprevir for untreated patients with genotype 1 chronic hepatitis C.
      , Italy
      NaiveBOC- and TEL-based therapies compared with PEG-RBV20 yPayer3, 3NoNoNoNoNonprofit center
      Liu et al, 2012
      • Liu S.
      • Cipriano L.E.
      • Holodniy M.
      • et al.
      New protease inhibitors for the treatment of chronic hepatitis C: a cost-effectiveness analysis.
      , United States
      NaiveBOC- and TEL-based therapies compared with PEG-RBVLife-longPayer3, 3NoNoNoNoNonprofit center
      Camma et al, 2013
      • Camma C.
      • Petta S.
      • Cabibbo G.
      • et al.
      Cost-effectiveness of boceprevir or telaprevir for previously treated patients with genotype 1 chronic hepatitis C.
      , Italy
      ExperiencedBOC- and TEL-based therapies compared with PEG-RBVLife-longPayer3, 3NoNoNoNoNonprofit center
      Chhatwal et al, 2013
      • Chhatwal J.
      • Ferrante S.A.
      • Brass C.
      • et al.
      Cost-effectiveness of boceprevir in patients previously treated for chronic hepatitis C genotype 1 infection in the United States.
      , United States
      ExperiencedBOC-based therapies compared with PEG-RBVLife-longPayer3, 3NoNoNoNoPharma
      Elbasha et al, 2013
      • Elbasha E.H.
      • Chhatwal J.
      • Ferrante S.A.
      • et al.
      Cost-effectiveness analysis of boceprevir for the treatment of chronic hepatitis C virus genotype 1 infection in Portugal.
      , Portugal
      Naive, experiencedBOC-based therapies compared with PEG-RBVLife-longPayer3, 3NoNoNoNoPharma
      Ferrante et al, 2013
      • Ferrante S.A.
      • Chhatwal J.
      • Brass C.A.
      • et al.
      Boceprevir for previously untreated patients with chronic hepatitis C genotype 1 infection: a US-based cost-effectiveness modeling study.
      , United States
      NaiveBOC-based therapies compared with PEG-RBVLife-longPayer3, 3NoNoNoNoPharma
      Brogan et al, 2014
      • Brogan A.J.
      • Talbird S.E.
      • Thompson J.R.
      • et al.
      Cost-effectiveness of telaprevir combination therapy for chronic hepatitis C.
      , United States
      Naive, experiencedTEL-based therapies compared with PEG-RBVLife-longPayer3, 3NoNoNoNoPharma
      Cure et al, 2014
      • Cure S.
      • Bianic F.
      • Gavart S.
      • et al.
      Cost-effectiveness of telaprevir in combination with pegylated interferon alpha and ribavirin in treatment-experienced chronic hepatitis C genotype 1 patients.
      , United Kingdom
      ExperiencedBOC- and TEL-based therapies compared with PEG-RBVLife-longPayer3.5, 3.5NoNoNoNoPharma
      Cure et al, 2014
      • Cure S.
      • Bianic F.
      • Gavart S.
      • et al.
      Cost-effectiveness of telaprevir in combination with pegylated interferon alpha and ribavirin in previously untreated chronic hepatitis C genotype 1 patients.
      , United Kingdom
      NaiveBOC- and TEL-based therapies compared with PEG-RBVLife-longPayer3.5, 3.5NoNoNoNoPharma
      Dan et al, 2014
      • Dan Y.Y.
      • Ferrante S.A.
      • Elbasha E.H.
      • et al.
      Cost-effectiveness of boceprevir co-administration versus peginterferon alpha-2b and ribavirin only for patients with hepatitis C genotype 1 in Singapore.
      , Singapore
      Naive, experiencedBOC-based therapies compared with PEG-RBVLife-longPayer3, 3NoNoNoNoPharma
      Liu et al, 2014
      • Liu S.
      • Watcha D.
      • Holodniy M.
      • et al.
      Sofosbuvir-based treatment regimens for chronic, genotype 1 hepatitis C virus infection in U.S. incarcerated populations: a cost-effectiveness analysis.
      , United States
      NaiveSOF-based therapies, BOC-based therapies, PEG-RBV, and no treatmentLife-longPayer3, 3NoNoNoYesGovernment
      Petta et al, 2014
      • Petta S.
      • Cabibbo G.
      • Enea M.
      • et al.
      Cost-effectiveness of sofosbuvir-based triple therapy for untreated patients with genotype 1 chronic hepatitis C.
      , Italy
      NaiveSOF-based therapies compared with BOC- and TEL-based therapiesLife-longPayer3, 3NoNoNoNoNonprofit center
      Saab et al, 2014
      • Saab S.
      • Gordon S.C.
      • Park H.
      • et al.
      Cost-effectiveness analysis of sofosbuvir plus peginterferon/ribavirin in the treatment of chronic hepatitis C virus genotype 1 infection.
      , United States
      Naive, experiencedSOF-based therapies compared with SMV-, BOC-, and TEL-based therapies, and PEG-RBVLife-longPayer3, 3NoNoNoNoPharma
      Vellopoulou et al, 2014
      • Vellopoulou A.
      • van Agthoven M.
      • van der Kolk A.
      • et al.
      Cost utility of telaprevir–PR (peginterferon–ribavirin) versus boceprevir–PR and versus PR alone in chronic hepatitis C in the Netherlands.
      , The Netherlands
      Naive, experiencedBOC- and TEL-based therapies compared with PEG-RBVLife-longSocietal4, 1.5NoNoYesYesPharma
      Warren et al, 2014
      • Warren E.
      • Wright A.
      • Jones B.
      Cost-effectiveness of telaprevir in patients with genotype 1 hepatitis C in australia.
      , Australia
      Naive, experiencedTEL-based therapies compared with PEG-RBV60 y (life-long)Payer5, 5NoNoNoNoPharma
      Chhatwal et al, 2015
      • Chhatwal J.
      • Kanwal F.
      • Roberts M.S.
      • et al.
      Cost-effectiveness and budget impact of hepatitis C virus treatment with sofosbuvir and ledipasvir in the United States.
      , United States
      Naive, experiencedSOF-based therapies compared with BOC- and TEL-based therapies, and PEG-RBVLife-longPayer3, 3NoNoNoNoGovernment
      Najafzadeh et al, 2015
      • Najafzadeh M.
      • Andersson K.
      • Shrank W.H.
      • et al.
      Cost-effectiveness of novel regimens for the treatment of hepatitis C virus.
      , United States
      NaiveSOF/LDV, SOF/DCV, and SOF/RBV compared with PEG/RBVLife-longPayer3, 3NoNoNoNoInsurance
      Younossi et al, 2015
      • Younossi Z.M.
      • Park H.
      • Saab S.
      • et al.
      Cost-effectiveness of all-oral ledipasvir/sofosbuvir regimens in patients with chronic hepatitis C virus genotype 1 infection.
      , United States
      Naive, experiencedSOF/LDV compared with other available therapiesLife-longPayer3, 3NoNoNoNoPharma
      Athanasakis et al, 2015
      • Athanasakis K.
      • Ferrante S.A.
      • Kyriopoulos I.I.
      • et al.
      Boceprevir for chronic genotype 1 hepatitis C virus in the current health care setting in Greece: a cost-effectiveness analysis.
      , Greece
      Naive, experiencedBOC-based therapies compared with PEG-RBVLife-longPayer3, 3NoNoNoNoPharma
      Pfeil et al, 2015
      • Pfeil A.M.
      • Reich O.
      • Guerra I.M.
      • et al.
      Cost-effectiveness analysis of sofosbuvir compared to current standard treatment in Swiss patients with chronic hepatitis C.
      , Switzerland
      Naive, experiencedSOF-based therapies compared with BOC- and TEL-based therapies, PEG-RBV, and no treatmentLife-longPayer3, 3NoNoNoYesPharma
      Zhang et al, 2015
      • Zhang S.
      • Bastian N.D.
      • Griffin P.M.
      Cost-effectiveness of sofosbuvir-based treatments for chronic hepatitis C in the US.
      , United States
      NaiveSOF-based therapies compared with PEG-RBV on G2 patients; CEA of SOF/LDV, SOF/SMV, SOF/PEG-RBV, Viekira Pak, and TEL-based therapiesLife-longPayer3, 3NoNoNoYesNone
      Westerhout et al, 2015
      • Westerhout K.
      • Treur M.
      • Mehnert A.
      • et al.
      A cost utility analysis of simeprevir used with peginterferon + ribavirin in the management of genotype 1 hepatitis C virus infection, from the perspective of the UK National Health Service.
      , United Kingdom
      Naive, experiencedSMV-based therapies compared with PEG-RBVLife-longPayer3.5, 3.5NoNoNoNoPharma
      Odhiambo et al, 2013
      • Odhiambo R.
      • Chhatwal J.
      • Ferrante S.
      • et al.
      Economic evaluation of boceprevir for the treatment of patients with genotype 1 chronic hepatitis C virus infection in Hungary.
      , Hungary
      Naive, experiencedBOC-based therapies compared with PEG-RBVLife-longPayer5, 5NoNoNoNoNone
      Gimeno-Ballester et al, 2015
      • Gimeno-Ballester V.
      • Mar J.
      • San Miguel R.
      Cost-effectiveness analysis of simeprevir with daclatasvir for non-cirrhotic genotype-1b-naive patients plus chronic hepatitis C.
      , Spain
      NaiveSOF/DCV therapies compared with BOC- and TEL-based therapiesLife-longPayer3, 3NoNoNoNoNone
      BOC, boceprevir; DCV, daclatasvir; LDV, ledipasvir; PEG, peginterferon; RBV, ribavirin; SMV, simeprevir; SOF, sofosbuvir; SVR; TasP, treatment-as-prevention; TEL, telaprevir; Viekira Pak, a combination of ombitasvir, paritaprevir, ritonavir, and dasabuvir.

       Region

      Among the selected studies, 110 ICERs (65%) were reported by 10 (42%) studies conducted in the United States, 51 (26%) ICERs by 12 (44%) studies in Europe, 7 (4%) ICERs by 1 (4%) study in Asia, and 2 (1%) ICERs by 1 (4%) study in Australia (Supplementary Table 4).

       Treatment Strategies

      The cost-effectiveness models evaluated the following DAAs as primary interventions: first-generation DAAs boceprevir or telaprevir, in combination with peginterferon and ribavirin; and second-generation DAAs consisting of sofosbuvir and/or simeprevir with peginterferon and ribavirin, and oral DAAs consisting of different combinations of sofosbuvir, ledipasvir, daclatasvir with or without ribavirin, and ombitasvir/paritaprevir/ritonavir with dasabuvir and/or ribavirin (Figure 2).
      Figure thumbnail gr2
      Figure 2Counts of drug regimens evaluated as primary intervention. BOC, boceprevir; DCV, daclatasvir; LDV, ledipasvir; PEG, peginterferon; RBV, ribavirin; SMV, simeprevir; SOF, sofosbuvir; TEL, telaprevir. Other category evaluated: SMV-DCV and Viekira Pak + RBV.

       Modeling Assumptions

      We noted structural assumptions made by published studies that are important in the context of HCV modeling and could impact the cost-effectiveness results. With the exception of 1 study,
      • Vellopoulou A.
      • van Agthoven M.
      • van der Kolk A.
      • et al.
      Cost utility of telaprevir–PR (peginterferon–ribavirin) versus boceprevir–PR and versus PR alone in chronic hepatitis C in the Netherlands.
      which used a societal perspective, all other studies used the payer’s perspective. We found that none of the studies captured the benefits of HCV treatment in reducing HCV transmission (ie, treatment as prevention); no study considered extrahepatic benefits associated with HCV treatment; only 1 study considered indirect economic benefits resulting from HCV cure
      • Vellopoulou A.
      • van Agthoven M.
      • van der Kolk A.
      • et al.
      Cost utility of telaprevir–PR (peginterferon–ribavirin) versus boceprevir–PR and versus PR alone in chronic hepatitis C in the Netherlands.
      ; and only 4 out of 24 studies
      • Vellopoulou A.
      • van Agthoven M.
      • van der Kolk A.
      • et al.
      Cost utility of telaprevir–PR (peginterferon–ribavirin) versus boceprevir–PR and versus PR alone in chronic hepatitis C in the Netherlands.
      • Liu S.
      • Watcha D.
      • Holodniy M.
      • et al.
      Sofosbuvir-based treatment regimens for chronic, genotype 1 hepatitis C virus infection in U.S. incarcerated populations: a cost-effectiveness analysis.
      • Pfeil A.M.
      • Reich O.
      • Guerra I.M.
      • et al.
      Cost-effectiveness analysis of sofosbuvir compared to current standard treatment in Swiss patients with chronic hepatitis C.
      • Zhang S.
      • Bastian N.D.
      • Griffin P.M.
      Cost-effectiveness of sofosbuvir-based treatments for chronic hepatitis C in the US.
      modeled the possibility of reinfection after achieving SVR.

       Quality of Reporting

      Supplementary Figure 1 summarizes the percentage of studies adequately reporting (and not reporting) each CHEERS methodologic item evaluated. In 29% of the studies an adequate structured abstract according to CHEERS standards was not provided, 20% did not adequately describe target population and subgroups, and 54% did not adequately describe the population and methods used to elicit preferences for outcomes. In addition, 17% did not provide the methodologic approach used to estimate resource use, and 29% did not explore all characteristics of uncertainty associated with patient-level data or model parameters.

       Incremental Cost-Effectiveness Ratios

      We estimated the ICER of each reported analysis by varying the price of DAAs from $20,000 to $100,000 and summarized the results by plotting the percentage of analyses that would be cost-saving, cost-effective, and not cost-effective for a given drug price. Figure 3A shows the results of 81 ICERs reported for first-generation DAAs. For instance, at a $60,000 price for DAAs, 2% analyses found first-generation DAAs to be cost-saving, 91% were found to be cost-effective, and 7% were found to be not cost-effective. Similarly, Figure 3B summarizes the results of 89 ICERs reported for second-generation DAAs. At a $60,000 price for these DAAs, 71% of the analyses found them to be cost-saving, 22% found them cost-effective, and 7% of the analyses found them not cost-effective.
      Figure thumbnail gr3
      Figure 3(A) Summary of 81 ICERs reported for first-generation DAAs when compared with the old standard of care (peginterferon-ribavirin or no treatment). (B) Summary of 89 ICERs reported for second-generation DAAs when compared with the old standard of care (first-generation DAAs, peginterferon-ribavirin, or no treatment).
      We further conducted a subgroup analysis of second-generation DAAs. The cost-effectiveness of DAAs was similar in treatment-naive versus -experienced patients (Figure 4A and B) and patients with cirrhosis versus patients without cirrhosis (Figure 4C and D). However, results differed substantially in US versus non-US-based analyses (Figure 4E and F). All of the analyses that found HCV treatment not cost-effective evaluated a combination of simeprevir-sofosbuvir-ribavirin.
      Figure thumbnail gr4
      Figure 4Summary of ICERs of second-generation DAAs compared with the old standard of care (first-generation DAAs, peginterferon-ribavirin, or no treatment) in (A) treatment-naive patients (TN), (B) treatment-experienced patients (TE), (C) patients with cirrhosis, (D) patients without cirrhosis, (E) U.S. studies, and (F) non-U.S. studies.

       Threshold Drug Price

      The price thresholds at which DAA regimens become cost-effective and cost-saving were substantially lower for first-generation therapies compared with second-generation therapies (Figure 5). The median threshold price of the treatment at which first-generation and second-generation DAAs become cost-effective compared with the old standard-of-care was $120,100 (interquartile range [IQR], $90,700–$176,800) and $227,200 (IQR, $142,800–$335,900), respectively. The corresponding threshold price for DAAs to become cost-saving were $11,700 (IQR, $2,200–$19,300) and $70,900 (IQR, $43,300–$103,700), respectively.
      Figure thumbnail gr5
      Figure 5Box plots showing the median, 25th percentile, and 75th percentile price threshold analyses below which treatment with DAAs is cost-effective (using $100,000-per-QALY willingness-to-pay threshold) and cost-saving.
      We further conducted a subgroup analysis on second-generation DAAs (Supplementary Figure 2AC). The media drug price of DAAs used in US and non-US studies was $84,000 and $55,800, respectively. The median threshold price of the treatment at which these DAAs become cost-effective was above $200,000 irrespective of patients’ prior treatment history or presence of cirrhosis. Similarly, the threshold price of treatment at which DAAs become cost-saving was around $70,000 irrespective of patients’ prior treatment history or presence of cirrhosis. However, the price thresholds were substantially different for US versus non-US studies. The median threshold price for DAA regimens to become cost-effective was $260,300 (IQR, $183,800–$369,600) in US studies and $161,000 (IQR, $0–$219,600) in non-US studies. The corresponding price at which they become cost-saving was $79,000 (IQR, $60,300–$110,000) in US studies in contrast to $15,000 (IQR, $0–$31,200) in non-US studies.

       Sensitivity Analysis Using $50,000 Willingness-to-Pay Threshold

      We also conducted a sensitivity analysis using a conservative WTP threshold of $50,000-per-QALY. We found that the median threshold price of DAA regimens to become cost-effective in first-generation and second-generation drugs decreased to $66,800 (IQR, $44,900–$100,500) and $156,600 (IQR, $98,700–$228,100), respectively. The corresponding threshold prices in US and non-US analyses were $167,200 (IQR, $114,300–$232,000) and $94,800 (IQR, $0–$114,900), respectively, which still remained substantially below the listed wholesale acquisition cost of the DAAs.

      Discussion

      The recent availability of DAAs is expected to dramatically impact the landscape of HCV burden.
      • Kabiri M.
      • Jazwinski A.B.
      • Roberts M.S.
      • et al.
      The changing burden of hepatitis C in the United States: model-based predictions.
      • Chhatwal J.
      • Wang X.
      • Ayer T.
      • et al.
      Hepatitis C disease burden in the United States in the era of oral direct-acting antivirals.
      However, the cost of DAAs and the large number of patients with HCV infection have become a barrier to provision of timely treatment. Although the effective prices of oral DAAs have fallen substantially since their launch in late 2013, the results of published cost-effectiveness models have not been updated to accurately estimate the current value of HCV treatment. To address this crucial but missing gap in evidence, we systematically analyzed the results of 24 studies of HCV genotype 1 presenting 170 ICERs of combinations of 11 drugs from 11 countries. We found that most of the modeling studies concluded that oral DAAs provide good value for money, and can also result in substantial economic savings at current discounts.
      To our knowledge, our study is the first to synthesize the results of the published cost-effectiveness studies of HCV treatment in the era of DAAs. Previous studies limited their scope to the systematic review of modeling approaches of HCV models and did not evaluate or reanalyze the cost-effectiveness results.
      • Chhatwal J.
      • He T.
      • Lopez-Olivo M.A.
      Systematic review of modelling approaches for the cost effectiveness of hepatitis C treatment with direct-acting antivirals.
      • Geue C.
      • Wu O.
      • Xin Y.
      • et al.
      Cost-effectiveness of HBV and HCV screening strategies: a systematic review of existing modelling techniques.
      Moreover, we used a novel approach to present the cost-effectiveness results by providing the percent of studies per ICER and controlling for the drug price, patient’s HCV genotype, prior treatment history, disease severity, and the region of the analysis. The evidence from our study that included 24 modeling studies is stronger than the evidence from any individual CEA study.
      Our study has some limitations, therefore our results should be interpreted with caution. First, our synthesis is limited by the reported information in the included studies. For this reason, we evaluated their quality of reporting using the CHEERS statement and found that most items were adequately reported with only 1 poorly reported area (methods used to derive preferences for outcomes) in half of the studies. Second, our results could not control for several other model inputs including quality of life weights, discount rate, and cost of health states, which could lead to heterogeneity in results. Third, the focus of our study was on the cost-effectiveness of HCV treatment using DAAs, so our analysis did not include modeling studies that evaluated the cost-effectiveness of HCV screening plus treatment.
      We observed that US-based studies found HCV treatments to be more cost-effective than non-US-based studies despite the fact that the price of DAAs was higher in the United States than outside the United States. The reason for such trend could be that the cost of managing HCV-associated sequelae is higher in the United States; therefore, the economic benefits of preventing advanced sequelae were higher in the United States.
      We believe that the published modeling studies could have underestimated the value of HCV treatment because most studies did not consider the benefits of HCV treatment in preventing transmission, extrahepatic benefits resulting from HCV treatment, such as in reduction in the incidence of non-Hodgkin lymphoma.
      • Takahashi K.
      • Nishida N.
      • Kawabata H.
      • et al.
      Regression of Hodgkin lymphoma in response to antiviral therapy for hepatitis C virus infection.
      Therefore, future modeling studies should consider the previously mentioned factors to evaluate a more precise value of HCV treatment with DAAs.
      Our study reinforces the message that the widespread and unrestricted treatment of HCV is the optimal strategy from a public health and economic perspective. There is an unprecedented situation with the availability of DAAs, which are potentially cost-saving interventions but the upfront (or initial) budget impact to implement these interventions is large. Our study provides evidence suggesting that HCV treatment can result in cost-savings. To our knowledge, not many treatments have been shown to be cost-saving in the history of medicine. Hence, we would support additional resources allocated to increased access to HCV treatment, as has been the case with human immunodeficiency virus.
      In conclusion, our systematic reanalysis of cost-effectiveness studies found that HCV treatment with second-generation DAAs is highly cost-effective and could likely result in cost-savings at currently available discounts. Therefore, timely treatment with DAAs without restrictions for HCV should be a priority to improve public health.

      Acknowledgments

      The authors thank Greg Pratt, DDS, MLS, for his help in creating the search strategy.

      Supplementary Material

      Figure thumbnail fx1
      Supplementary Figure 1Summary of the reported items according to CHEERS checklist.
      Figure thumbnail fx2
      Supplementary Figure 2Box plots showing the median threshold price, 25th quartile, and 75th quartile at which treatment with second-generation DAAs is cost-effective (using $100,000-per-QALY willingness-to-pay threshold) and cost-saving in (A) treatment-naive versus treatment-experienced patients, (B) patients with versus without cirrhosis, and (C) and US versus non-US studies.
      Supplementary Table 1Medline Search Strategy
      #Searches
      1exp HEPATITIS C/
      2exp HEPACIVIRUS/
      3((hepatitis adj3 “C”) or hepacivir* or HCV).ti,ab.
      4or/1-3
      5(telaprevir* or Incivek*).mp.
      6(boceprevir* or Victrelis*).mp.
      7(simeprevir* or Olysio* or TMC-435* or TMC435* or TMC-435350* or TMC435350*).mp.
      8(paritaprevir* or Veruprevir*).mp.
      9(asunaprevir* or BMS-650032* or BMS650032*).mp.
      10(ledipasvir* or GS-5885* or GS5885*).mp.
      11(ombitasvir* or ABT-267* or ABT267*).mp.
      12(sofosbuvir* or Sovaldi* or GS-7977* or GS7977* or PSI-7977* or PSI7977*).mp.
      13(dasabuvir* or ABT-333* or ABT333*).mp.
      14(daclatasvir* or Daklinza*).mp.
      15exp PROTEASE INHIBITORS/
      16(protease* adj3 inhibit*).mp.
      17(direct* adj3 (anti-viral* or antiviral*)).mp.
      18exp ANTIVIRAL AGENTS/ and (direct* adj3 (act or acting)).ti,ab.
      19or/5-18
      204 and 19
      21limit 20 to English language
      22limit 21 to yr=“2011 -Current”
      23limit 22 to “review”
      2422 not 23
      25exp HEPATITIS C/ec
      26exp ANTIVIRAL AGENTS/ec
      27exp PROTEASE INHIBITORS/ec
      28exp MODELS, ECONOMIC/
      29exp ECONOMICS/
      30(cost or costs or costing or economi* or budget* or financ* or pharmacoeconom* or pharmacoeconom* or price* or pricing or expenditure* or affordab* or fee or fees or charg* or monetar*).ti,hw,kw.
      31(economic* adj2 (burden* or barrier* or restriction* or resources)).ab.
      32((cost or costs) adj3 (utilit* or effectiv* or benefit* or minimiz* or minimis* or model*)).ab.
      33((decision* or cost*) adj3 (model* or analy*)).ti,ab,sh.
      34or/25-33
      3524 and 34
      NOTE. Databases include Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations and Ovid MEDLINE(R). Searched on September 9, 2015.
      Supplementary Table 2Summary of Study and Patient Characteristics
      StudiesFirst-generation DAAsSecond-generation DAAs
      Number of ICERsNumber of studiesNumber of ICERsNumber of studies
      All studies81188910
      By treatment history
       Treatment naive40156610
       Treatment experienced4112234
      By cirrhosis
       Noncirrhosis only126276
       Cirrhosis only84255
       Mixed
      Mixed implies that results included patients with and without cirrhosis.
      6117378
      By region
       United States366746
       Non-United States4512154
      a Mixed implies that results included patients with and without cirrhosis.
      Supplementary Table 3Cost-Effectiveness Results Extracted From Each Study and Analysis of the Results
      NumberStudyCountryTreatment historyFibrosis stageIFN tolerancePrimary interventionComparatorReported ICERICER at $60,000Threshold drug price ($100,000 ICER)Threshold drug price ($0 ICER)
      1Camma et al, 2012
      • Camma C.
      • Petta S.
      • Enea M.
      • et al.
      Cost-effectiveness of boceprevir or telaprevir for untreated patients with genotype 1 chronic hepatitis C.
      ItalyTNNoncirrhosisYesBOC-PEG-RBVPEG-RBV$9835$23,204$222,808$10,808
      2ItalyTNNoncirrhosisYesTEL-PEG-RBVPEG-RBV$14,194$17,762$296,845$8845
      3Liu et al, 2012
      • Liu S.
      • Cipriano L.E.
      • Holodniy M.
      • et al.
      New protease inhibitors for the treatment of chronic hepatitis C: a cost-effectiveness analysis.
      United StatesTNNoncirrhosisYesBOC-PEG-RBVPEG-RBV$67,891$170,642$36,688$3688
      4United StatesTNMixYesBOC-PEG-RBVPEG-RBV$35,670$86,279$69,193$2193
      5United StatesTNNoncirrhosisYesTEL-PEG-RBVPEG-RBV$89,490$112,469$54,140$7140
      6United StatesTNMixYesTEL-PEG-RBVPEG-RBV$46,973$58,463$99,045$5045
      7Camma et al, 2013
      • Camma C.
      • Petta S.
      • Cabibbo G.
      • et al.
      Cost-effectiveness of boceprevir or telaprevir for previously treated patients with genotype 1 chronic hepatitis C.
      ItalyTEMixYesBOC-PEG-RBVNo treatment$7140$13,824$442,623< $0
      8ItalyTEMixYesTEL-PEG-RBVNo treatment$5964$13,385$501,737< $0
      9ItalyTEMixYesBOC-PEG-RBVNo treatment$8793$18,067$322,184$2184
      10ItalyTEMixYesTEL-PEG-RBVNo treatment$11,049$18,505$352,566< $0
      11ItalyTEMixYesTEL-PEG-RBVNo treatment$19,281$32,027$202,743< $0
      12Chhatwal et al, 2013
      • Chhatwal J.
      • Ferrante S.A.
      • Brass C.
      • et al.
      Cost-effectiveness of boceprevir in patients previously treated for chronic hepatitis C genotype 1 infection in the United States.
      United StatesTEMixYesBOC-PEG-RBVPEG-RBV$28,939$66,098$90,173$1173
      13United StatesTEMixYesBOC-PEG-RBVPEG-RBV$33,489$75,788$78,643$1643
      14United StatesTEMixYesBOC-PEG-RBVPEG-RBV$33,436$72,072$84,576< $0
      15United StatesTENoncirrhosisYesBOC-PEG-RBVPEG-RBV$35,173$73,728$80,755$1755
      16United StatesTECirrhosisYesBOC-PEG-RBVPEG-RBV$10,055$15,566$329,346$10,346
      17United StatesTEMixYesTEL-PEG-RBVPEG-RBV$14,087$19,712$214,154$22,154
      18United StatesTEMixYesTEL-PEG-RBVPEG-RBV$30,274$37,774$149,606$5606
      19United StatesTEMixYesTEL-PEG-RBVPEG-RBV$66,822$80,492$75,411< $0
      20Elbasha et al, 2013
      • Elbasha E.H.
      • Chhatwal J.
      • Ferrante S.A.
      • et al.
      Cost-effectiveness analysis of boceprevir for the treatment of chronic hepatitis C virus genotype 1 infection in Portugal.
      PortugalTNMixYesBOC-PEG-RBVPEG-RBV$14,854$76,662$75,870$7870
      21PortugalTEMixYesBOC-PEG-RBVPEG-RBV$11,240$41,204$131,731$9731
      22Ferrante et al, 2013
      • Ferrante S.A.
      • Chhatwal J.
      • Brass C.A.
      • et al.
      Boceprevir for previously untreated patients with chronic hepatitis C genotype 1 infection: a US-based cost-effectiveness modeling study.
      United StatesTNMixYesBOC-PEG-RBVPEG-RBV$14,072$71,761$77,508$15,508
      23United StatesTNMixYesBOC-PEG-RBVPEG-RBV$54,891$90,981$65,863$863
      24Brogan et al, 2014
      • Brogan A.J.
      • Talbird S.E.
      • Thompson J.R.
      • et al.
      Cost-effectiveness of telaprevir combination therapy for chronic hepatitis C.
      United StatesTNMixYesTEL-PEG-RBVPEG-RBV$16,311$15,919$160,898$40,898
      25United StatesTEMixYesTEL-PEG-RBVPEG-RBV-$4099-$4273$341,538$71,538
      26United StatesTEMixYesTEL-PEG-RBVPEG-RBV$23,565$23,251$175,123$25,123
      27United StatesTEMixYesTEL-PEG-RBVPEG-RBV$32,204$31,812$141,826$21,826
      28Cure et al, 2014
      • Cure S.
      • Bianic F.
      • Gavart S.
      • et al.
      Cost-effectiveness of telaprevir in combination with pegylated interferon alpha and ribavirin in treatment-experienced chronic hepatitis C genotype 1 patients.
      United KingdomTEMixYesTEL-PEG-RBVPEG-RBV$3170$19,964$178,453$30,453
      29United KingdomTEMixYesTEL-PEG-RBVPEG-RBV$10,962$36,083$127,752$21,752
      30United KingdomTEMixYesTEL-PEG-RBVPEG-RBV$32,049$77,181$73,463$14,463
      31United KingdomTEMixYesBOC-PEG-RBVPEG-RBV$28,412$46,306$112,083$15,083
      32United KingdomTEMixYesBOC-PEG-RBVPEG-RBV$20,460$35,295$135,705$18,705
      33Cure et al, 2014
      • Cure S.
      • Bianic F.
      • Gavart S.
      • et al.
      Cost-effectiveness of telaprevir in combination with pegylated interferon alpha and ribavirin in previously untreated chronic hepatitis C genotype 1 patients.
      United KingdomTNNoncirrhosisYesTEL-PEG-RBVPEG-RBV$21,955$55,764$97,159$13,159
      34United KingdomTNCirrhosisYesTEL-PEG-RBVPEG-RBV$13,944$46,966$105,609$19,609
      35United KingdomTNMixYesTEL-PEG-RBVPEG-RBV$19,215$52,238$101,075$15,075
      36United KingdomTNMixYesBOC-PEG-RBVPEG-RBV$32,626$78,755$73,809$8809
      37Dan et al, 2014
      • Dan Y.Y.
      • Ferrante S.A.
      • Elbasha E.H.
      • et al.
      Cost-effectiveness of boceprevir co-administration versus peginterferon alpha-2b and ribavirin only for patients with hepatitis C genotype 1 in Singapore.
      SingaporeTNMixYesBOC-PEG-RBVPEG-RBV$135$35,874$108,237$20,237
      38SingaporeTEMixYesBOC-PEG-RBVPEG-RBV-$1493$14,512$174,054$31,054
      39SingaporeTNNoncirrhosisYesBOC-PEG-RBVPEG-RBV-$988$33,572$112,255$21,255
      40SingaporeTNCirrhosisYesBOC-PEG-RBVPEG-RBV$114,559$299,558$17,881$881
      41SingaporeTENoncirrhosisYesBOC-PEG-RBVPEG-RBV$961$22,350$134,891$27,891
      42SingaporeTECirrhosisYesBOC-PEG-RBVPEG-RBV-$6009-$110$440,234$52,234
      43SingaporeTEMixYesBOC-PEG-RBVPEG-RBV$4098$34,338$120,094$16,094
      44Liu et al, 2014
      • Liu S.
      • Watcha D.
      • Holodniy M.
      • et al.
      Sofosbuvir-based treatment regimens for chronic, genotype 1 hepatitis C virus infection in U.S. incarcerated populations: a cost-effectiveness analysis.
      United StatesTNMixYesSOF-PEG-RBVNo treatment$28,877$31,906$200,274< $0
      45United StatesTNMixYesSOF-PEG-RBVPEG-RBV$8179$12,055$201,591$40,591
      46United StatesTNMixYesBOC-PEG-RBVNo treatment$40,627$67,582$102,467< $0
      47United StatesTNMixYesBOC-PEG-RBVPEG-RBV$8028$49,088$103,784$17,784
      48United StatesTNMixYesSOF-PEG-RBVBOC-PEG-RBV$8353$16,673$180,866$42,175
      49Petta et al, 2014
      • Petta S.
      • Cabibbo G.
      • Enea M.
      • et al.
      Cost-effectiveness of sofosbuvir-based triple therapy for untreated patients with genotype 1 chronic hepatitis C.
      ItalyTNMixYesSOF-PEG-RBVBOC-PEG-RBV$15,772$19,454$232,059$22,842
      50ItalyTNMixYesSOF-PEG-RBVTEL-PEG-RBV$19,482$25,182$181,078$25,537
      51ItalyTNNoncirrhosisYesSOF-PEG-RBVBOC-PEG-RBV$16,409$19,491$264,777$14,826
      52ItalyTNNoncirrhosisYesSOF-PEG-RBVTEL-PEG-RBV$25,407$31,617$162,326$19,569
      53ItalyTNCirrhosisYesSOF-PEG-RBVBOC-PEG-RBV$4132$6142$423,260$40,003
      54ItalyTNCirrhosisYesSOF-PEG-RBVTEL-PEG-RBV$27,488$37,395$120,729$31,240
      55Saab et al, 2014
      • Saab S.
      • Gordon S.C.
      • Park H.
      • et al.
      Cost-effectiveness analysis of sofosbuvir plus peginterferon/ribavirin in the treatment of chronic hepatitis C virus genotype 1 infection.
      United StatesTNNoncirrhosisYesBOC-PEG-RBVNo treatment$7757$27,751$169,096$18,096
      56United StatesTNCirrhosisYesBOC-PEG-RBVNo treatment$21,623$32,561$246,131< $0
      57United StatesTNCirrhosisYesBOC-PEG-RBVPEG-RBV$25,168$52,366$112,873$1873
      58United StatesTNCirrhosisYesTEL-PEG-RBVNo treatment$23,297$28,483$282,417< $0
      59United StatesTNCirrhosisYesTEL-PEG-RBVPEG-RBV$27,884$38,932$149,159$3159
      60United StatesTNCirrhosisYesSOF-PEG-RBVBOC-PEG-RBV$7632-$11,266$265,838$68,976
      61United StatesTNCirrhosisYesSMV-PEG-RBVBOC-PEG-RBV$60,815$14,661$75,290$51,582
      62United StatesTNCirrhosisYesSOF-PEG-RBVTEL-PEG-RBV-$3349-$29,436$283,024$90,450
      63United StatesTNCirrhosisYesSMV-PEG-RBVTEL-PEG-RBV$22,127$1,000,000
      QALYs of primary intervention scenario were less than that of comparator scenario, and no drug price could make the primary intervention cost-effective or cost-saving. Therefore, our calculations and plotting, we assigned ICER of $1,000,000 and threshold DAA prices to $0.
      $0
      QALYs of primary intervention scenario were less than that of comparator scenario, and no drug price could make the primary intervention cost-effective or cost-saving. Therefore, our calculations and plotting, we assigned ICER of $1,000,000 and threshold DAA prices to $0.
      $0
      QALYs of primary intervention scenario were less than that of comparator scenario, and no drug price could make the primary intervention cost-effective or cost-saving. Therefore, our calculations and plotting, we assigned ICER of $1,000,000 and threshold DAA prices to $0.
      64United StatesTNMixYesBOC-PEG-RBVNo treatment$11,552$29,104$181,941$9941
      65United StatesTNNoncirrhosisYesBOC-PEG-RBVPEG-RBV$254,296$505,879$11,295< $0
      66United StatesTNMixYesBOC-PEG-RBVPEG-RBV$107,421$215,242$27,732< $0
      67United StatesTNMixYesTEL-PEG-RBVNo treatment$12,793$20,818$219,157$18,157
      68United StatesTNMixYesTEL-PEG-RBVPEG-RBV$63,021$91,319$64,948$7948
      69United StatesTNMixYesSOF-PEG-RBVBOC-PEG-RBV-$7089-$36,358$220,119$93,011
      70United StatesTNMixYesSMV-PEG-RBVBOC-PEG-RBV-$8430-$27,180$129,278$70,919
      71United StatesTNMixYesSOF-PEG-RBVTEL-PEG-RBV-$21,995-$67,278$219,341$108,402
      72United StatesTNMixYesSMV-PEG-RBVTEL-PEG-RBV-$284,726-$484,726$100,422$91,475
      73United StatesTEMixYesBOC-PEG-RBVNo treatment$49,271$66,575$94,093< $0
      74United StatesTEMixYesBOC-PEG-RBVPEG-RBV$31,168$56,027$91,221$20,221
      75United StatesTNNoncirrhosisYesTEL-PEG-RBVNo treatment$9067$18,129$205,731$27,731
      76United StatesTEMixYesTEL-PEG-RBVNo treatment$39,675$50,611$121,737< $0
      77United StatesTEMixYesTEL-PEG-RBVPEG-RBV$22,836$37,378$118,864$24,864
      78United StatesTEMixYesSOF-PEG-RBVBOC-PEG-RBV-$19,350-$44,350$315,079$121,465
      79United StatesTEMixYesSMV-PEG-RBVBOC-PEG-RBV$3586-$8659$197,841$61,096
      80United StatesTEMixYesSOF-PEG-RBVTEL-PEG-RBV-$24,539-$57,415$286,726$123,944
      81United StatesTEMixYesSMV-PEG-RBVTEL-PEG-RBV$9309-$13,767$145,118$57,878
      82United StatesTNNoncirrhosisYesTEL-PEG-RBVPEG-RBV$89,591$130,950$47,929$8929
      83United StatesTNNoncirrhosisYesSOF-PEG-RBVBOC-PEG-RBV-$12,484-$45,817$209,540$97,933
      84United StatesTNNoncirrhosisYesSMV-PEG-RBVBOC-PEG-RBV-$13,525-$30,192$140,533$74,880
      85United StatesTNNoncirrhosisYesSOF-PEG-RBVTEL-PEG-RBV-$29,808-$83,141$206,271$112,077
      86United StatesTNNoncirrhosisYesSMV-PEG-RBVTEL-PEG-RBV-$103,270-$169,937$120,561$93,719
      87Vellopoulou et al, 2014
      • Vellopoulou A.
      • van Agthoven M.
      • van der Kolk A.
      • et al.
      Cost utility of telaprevir–PR (peginterferon–ribavirin) versus boceprevir–PR and versus PR alone in chronic hepatitis C in the Netherlands.
      The NetherlandsTNMixYesBOC-PEG-RBVPEG-RBV$9390$51,674$101,077$16,077
      88The NetherlandsTNMixYesTEL-PEG-RBVPEG-RBV-$445$24,495$144,566$32,566
      89The NetherlandsTEMixYesBOC-PEG-RBVPEG-RBV$15,519$54,586$101,781$9,781
      90The NetherlandsTEMixYesTEL-PEG-RBVPEG-RBV-$6532$10,604$205,715$42,715
      91The NetherlandsTEMixYesBOC-PEG-RBVPEG-RBV$3729$30,352$154,025$19,025
      92The NetherlandsTEMixYesTEL-PEG-RBVPEG-RBV-$9131$5570$239,416$49,416
      93The NetherlandsTEMixYesBOC-PEG-RBVPEG-RBV$3729$30,352$154,025$19,025
      94The NetherlandsTEMixYesTEL-PEG-RBVPEG-RBV-$9131$5570$239,416$49,416
      95Warren et al, 2014
      • Warren E.
      • Wright A.
      • Jones B.
      Cost-effectiveness of telaprevir in patients with genotype 1 hepatitis C in australia.
      AustraliaTNMixYesTEL-PEG-RBVPEG-RBV$26,499$52,640$98,835$16,835
      96AustraliaTEMixYesTEL-PEG-RBVPEG-RBV$20,704$38,120$138,588$11,588
      97Chhatwal et al, 2015
      • Chhatwal J.
      • Kanwal F.
      • Roberts M.S.
      • et al.
      Cost-effectiveness and budget impact of hepatitis C virus treatment with sofosbuvir and ledipasvir in the United States.
      United StatesTNNoncirrhosisYesSOF-LDVBOC-PEG-RBV$25,069-$1571$108,760$54,530
      98United StatesTECirrhosisYesSOF-LDVTEL-PEG-RBV$79,205-$28,146$197,139$58,022
      99United StatesTNNoncirrhosisYesSOF-LDVTEL-PEG-RBV$25,069-$1571$132,315$46,650
      100United StatesTNNoncirrhosisNoSOF-LDVNo treatment$39,636$32,644$138,268$22,068
      101United StatesTNCirrhosisYesSOF-LDVBOC-PEG-RBV$5344-$20,800$259,895$74,181
      102United StatesTNCirrhosisYesSOF-LDVTEL-PEG-RBV$5344-$20,800$278,416$73,135
      103United StatesTNCirrhosisNoSOF-LDVNo treatment$17,974$7799$278,424$41,524
      104United StatesTENoncirrhosisYesSOF-LDVBOC-PEG-RBV$35,801-$29,880$120,602$63,752
      105United StatesTENoncirrhosisYesSOF-LDVBOC-PEG-RBV$35,801-$29,880$133,356$56,640
      106United StatesTECirrhosisYesSOF-LDVBOC-PEG-RBV$79,205-$28,146$196,224$61,506
      107Najafzadeh et al, 2015
      • Najafzadeh M.
      • Andersson K.
      • Shrank W.H.
      • et al.
      Cost-effectiveness of novel regimens for the treatment of hepatitis C virus.
      United StatesTNMixYesSOF-PEG-RBVBOC-PEG-RBV$21,673-$4701$194,488$53,429
      108United StatesTNMixYesSOF-SMVBOC-PEG-RBV$71,528-$20,309$184,824$62,517
      109United StatesTNMixYesSOF-DCVBOC-PEG-RBV$63,723-$19,610$198,896$64,110
      110United StatesTNMixYesSOF-LDVBOC-PEG-RBV$11,927-$16,585$250,176$73,418
      111Younossi et al, 2015
      • Younossi Z.M.
      • Park H.
      • Saab S.
      • et al.
      Cost-effectiveness of all-oral ledipasvir/sofosbuvir regimens in patients with chronic hepatitis C virus genotype 1 infection.
      United StatesTNNoncirrhosisNoSOF-PEG-RBVNo treatment-$8022-$17,148$368,098$105,098
      112United StatesTNNoncirrhosisYesSOF-LDVBOC-PEG-RBV-$28,897-$31,259$337,115$124,453
      113United StatesTNCirrhosisNoSOF-PEG-RBVNo treatment-$6535-$12,461$515,467$110,467
      114United StatesTNCirrhosisNoSMV-PEG-RBVNo treatment-$1248-$3215$374,805$69,805
      115United StatesTNCirrhosisNoSOF-RBVNo treatment$38,334-$5215$320,932$72,932
      116United StatesTNCirrhosisNoSOF-SMVNo treatment$25,382-$18,333$700,181$159,181
      117United StatesTNCirrhosisNoSOF-LDVNo treatment-$11,582-$18,048$679,752$154,752
      118United StatesTNCirrhosisYesSOF-PEG-RBVBOC-PEG-RBV-$6283-$25,483$274,364$95,254
      119United StatesTNCirrhosisYesSMV-PEG-RBVBOC-PEG-RBV$59,232$35,232$82,559$41,942
      120United StatesTNCirrhosisYesSOF-RBVBOC-PEG-RBV-$355,253$1,000,000
      QALYs of primary intervention scenario were less than that of comparator scenario, and no drug price could make the primary intervention cost-effective or cost-saving. Therefore, our calculations and plotting, we assigned ICER of $1,000,000 and threshold DAA prices to $0.
      $0
      QALYs of primary intervention scenario were less than that of comparator scenario, and no drug price could make the primary intervention cost-effective or cost-saving. Therefore, our calculations and plotting, we assigned ICER of $1,000,000 and threshold DAA prices to $0.
      $0
      QALYs of primary intervention scenario were less than that of comparator scenario, and no drug price could make the primary intervention cost-effective or cost-saving. Therefore, our calculations and plotting, we assigned ICER of $1,000,000 and threshold DAA prices to $0.
      121United StatesTNCirrhosisYesSOF-SMVBOC-PEG-RBV$59,744-$30,869$411,402$125,973
      122United StatesTNNoncirrhosisNoSMV-PEG-RBVNo treatment-$6561-$9193$308,960$80,960
      123United StatesTNCirrhosisYesSOF-LDVBOC-PEG-RBV-$17,220-$31,077$487,422$151,752
      124United StatesTEMixNoSOF-PEG-RBVNo treatment-$4284-$13,586$353,052$95,052
      125United StatesTEMixNoSMV-PEG-RBVNo treatment$9318$6348$249,177$47,177
      126United StatesTEMixNoSOF-RBVNo treatment$25,234-$17,119$358,653$103,653
      127United StatesTEMixNoSOF-SMVNo treatment$13,003-$20,663$466,634$129,634
      128United StatesTEMixNoSOF-LDVNo treatment-$5907-$16,206$449,290$114,290
      129United StatesTEMixYesSOF-PEG-RBVBOC-PEG-RBV-$17,169-$41,411$260,722$109,895
      130United StatesTEMixYesSMV-PEG-RBVBOC-PEG-RBV$29,949$15,995$119,534$43,113
      131United StatesTEMixYesSOF-RBVBOC-PEG-RBV$60,835-$51,665$213,398$97,482
      132United StatesTEMixYesSOF-SMVBOC-PEG-RBV$21,278-$42,460$341,552$128,018
      133United StatesTNNoncirrhosisNoSOF-RBVNo treatment$46,864-$12,152$265,239$82,239
      134United StatesTEMixYesSOF-LDVBOC-PEG-RBV-$14,622-$34,224$384,950$131,552
      135United StatesTEMixYesSOF-RBVNo treatment$25,234-$17,119$358,653$103,653
      136United StatesTEMixYesSOF-PEG-RBVNo treatment-$4284-$13,586$353,052$95,052
      137United StatesTEMixYesSOF-LDVNo treatment-$6449-$21,365$471,428$132,428
      138United StatesTNNoncirrhosisNoSOF-SMVNo treatment$10,758-$19,648$414,157$118,157
      139United StatesTNNoncirrhosisNoSOF-LDVNo treatment-$16,736-$17,742$410,872$112,872
      140United StatesTNNoncirrhosisYesSOF-PEG-RBVBOC-PEG-RBV-$8614-$34,701$227,181$95,356
      141United StatesTNNoncirrhosisYesSMV-PEG-RBVBOC-PEG-RBV-$3135-$13,661$161,511$68,903
      142United StatesTNNoncirrhosisYesSOF-RBVBOC-PEG-RBV$824,450-$75,550$65,598$51,463
      143United StatesTNNoncirrhosisYesSOF-SMVBOC-PEG-RBV$36,013-$35,987$246,271$95,817
      144Athanasakis et al, 2015
      • Athanasakis K.
      • Ferrante S.A.
      • Kyriopoulos I.I.
      • et al.
      Boceprevir for chronic genotype 1 hepatitis C virus in the current health care setting in Greece: a cost-effectiveness analysis.
      GreeceTNMixYesBOC-PEG-RBVPEG-RBV$13,691$55,509$98,707$11,707
      145GreeceTEMixYesBOC-PEG-RBVPEG-RBV$14,803$35,959$140,051$15,051
      146Pfeil et al, 2015
      • Pfeil A.M.
      • Reich O.
      • Guerra I.M.
      • et al.
      Cost-effectiveness analysis of sofosbuvir compared to current standard treatment in Swiss patients with chronic hepatitis C.
      SwitzerlandTNMixYesBOC-PEG-RBVPEG-RBV$25,748$76,382$74,171$14,171
      147SwitzerlandTNMixYesTEL-PEG-RBVPEG-RBV$24,598$58,187$93,451$13,451
      148SwitzerlandTNMixYesSOF-PEG-RBVBOC-PEG-RBV$14,543$13,700$160,953$43,412
      149SwitzerlandTNMixYesSOF-PEG-RBVTEL-PEG-RBV$11,240$9,977$138,973$50,568
      150SwitzerlandTNMixNoSOF-RBVNo treatment$92,190$41,348$130,382$10,382
      151Zhang et al, 2015
      • Zhang S.
      • Bastian N.D.
      • Griffin P.M.
      Cost-effectiveness of sofosbuvir-based treatments for chronic hepatitis C in the US.
      United StatesTNNoncirrhosisYesSOF-LDVTEL-PEG-RBV-$1224-$22,450$437,725$98,651
      152United StatesTNCirrhosisYesSOF-PEG-RBVTEL-PEG-RBV$13,016-$24,484$218,376$63,893
      153United StatesTNNoncirrhosisYesSOF-SMVTEL-PEG-RBV$35,268-$21,011$304,048$66,071
      154United StatesTNNoncirrhosisYesViekira PakTEL-PEG-RBV-$7021-$19,908$525,201$110,140
      155United StatesTNNoncirrhosisYesSOF-PEG-RBVTEL-PEG-RBV$2411-$17,075$374,114$76,831
      156United StatesTNCirrhosisYesSOF-LDVTEL-PEG-RBV-$5204-$17,653$702,679$124,581
      157United StatesTNCirrhosisYesSOF-SMVTEL-PEG-RBV$65,184-$16,770$421,962$71,663
      158United StatesTNCirrhosisYesViekira PakTEL-PEG-RBV$25,227-$14,729$436,136$69,511
      159Westerhout et al, 201534United KingdomTNMixYesBOC-PEG-RBVPEG-RBV$26,919$54,143$102,142$10,242
      160United KingdomTNMixYesTEL-PEG-RBVPEG-RBV$24,148$49,546$108,789$12,089
      161United KingdomTNMixYesSMV-PEG-RBVBOC-PEG-RBV$11,713$1,000,000
      QALYs of primary intervention scenario were less than that of comparator scenario, and no drug price could make the primary intervention cost-effective or cost-saving. Therefore, our calculations and plotting, we assigned ICER of $1,000,000 and threshold DAA prices to $0.
      $0
      QALYs of primary intervention scenario were less than that of comparator scenario, and no drug price could make the primary intervention cost-effective or cost-saving. Therefore, our calculations and plotting, we assigned ICER of $1,000,000 and threshold DAA prices to $0.
      $0
      QALYs of primary intervention scenario were less than that of comparator scenario, and no drug price could make the primary intervention cost-effective or cost-saving. Therefore, our calculations and plotting, we assigned ICER of $1,000,000 and threshold DAA prices to $0.
      162United KingdomTNMixYesSMV-PEG-RBVTEL-PEG-RBV$8959$1,000,000
      QALYs of primary intervention scenario were less than that of comparator scenario, and no drug price could make the primary intervention cost-effective or cost-saving. Therefore, our calculations and plotting, we assigned ICER of $1,000,000 and threshold DAA prices to $0.
      $0
      QALYs of primary intervention scenario were less than that of comparator scenario, and no drug price could make the primary intervention cost-effective or cost-saving. Therefore, our calculations and plotting, we assigned ICER of $1,000,000 and threshold DAA prices to $0.
      $0
      QALYs of primary intervention scenario were less than that of comparator scenario, and no drug price could make the primary intervention cost-effective or cost-saving. Therefore, our calculations and plotting, we assigned ICER of $1,000,000 and threshold DAA prices to $0.
      163United KingdomTEMixYesBOC-PEG-RBVPEG-RBV$22,514$36,137$145,385$11,685
      164United KingdomTEMixYesTEL-PEG-RBVPEG-RBV$14,382$31,227$160,271$14,471
      165United KingdomTEMixYesSMV-PEG-RBVBOC-PEG-RBV-$72,693$1,000,000
      QALYs of primary intervention scenario were less than that of comparator scenario, and no drug price could make the primary intervention cost-effective or cost-saving. Therefore, our calculations and plotting, we assigned ICER of $1,000,000 and threshold DAA prices to $0.
      $0
      QALYs of primary intervention scenario were less than that of comparator scenario, and no drug price could make the primary intervention cost-effective or cost-saving. Therefore, our calculations and plotting, we assigned ICER of $1,000,000 and threshold DAA prices to $0.
      $0
      QALYs of primary intervention scenario were less than that of comparator scenario, and no drug price could make the primary intervention cost-effective or cost-saving. Therefore, our calculations and plotting, we assigned ICER of $1,000,000 and threshold DAA prices to $0.
      166United KingdomTEMixYesSMV-PEG-RBVTEL-PEG-RBV-$64,056$1,000,000
      QALYs of primary intervention scenario were less than that of comparator scenario, and no drug price could make the primary intervention cost-effective or cost-saving. Therefore, our calculations and plotting, we assigned ICER of $1,000,000 and threshold DAA prices to $0.
      $0
      QALYs of primary intervention scenario were less than that of comparator scenario, and no drug price could make the primary intervention cost-effective or cost-saving. Therefore, our calculations and plotting, we assigned ICER of $1,000,000 and threshold DAA prices to $0.
      $0
      QALYs of primary intervention scenario were less than that of comparator scenario, and no drug price could make the primary intervention cost-effective or cost-saving. Therefore, our calculations and plotting, we assigned ICER of $1,000,000 and threshold DAA prices to $0.
      167Odhiambo et al, 201335HungaryTNMixYesBOC-PEG-RBVPEG-RBV$28,621$90,835$65,407$6407
      168HungaryTEMixYesBOC-PEG-RBVPEG-RBV$21,850$45,662$121,402$8402
      169Gimeno-Ballester et al, 201536SpainTNNoncirrhosisYesSMV-DCVBOC-PEG-RBV$37,923$20,460$183,082$11,252
      170SpainTNNoncirrhosisYesSMV-DCVTEL-PEG-RBV$31,615$12,746$219,639$10,203
      NOTE. The threshold drug price of < $0 implies that the DAA will not be cost-saving at any price.
      BOC, boceprevir; DCV, daclatasvir; LDV, ledipasvir; PEG, peginterferon; RBV, ribavirin; SMV, simeprevir; SOF, sofosbuvir; TE, treatment-experienced patients; TEL, telaprevir; TN, treatment-naive patients; Viekira Pak is a combination of four medications: ombitasvir, paritaprevir, ritonavir and dasabuvir,
      a QALYs of primary intervention scenario were less than that of comparator scenario, and no drug price could make the primary intervention cost-effective or cost-saving. Therefore, our calculations and plotting, we assigned ICER of $1,000,000 and threshold DAA prices to $0.
      Supplementary Table 4Summary of Studies and ICERs by Country
      CountryNumber of ICERsNumber of studies
      United States11010
      United Kingdom173
      The Netherlands81
      Switzerland51
      Spain21
      Singapore71
      Portugal21
      Italy133
      Hungary21
      Greece21
      Australia21
      Total17024

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