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Another Step Toward Hepatitis C Elimination: An Economic Evaluation of an Irish National Birth Cohort Testing Program

Open AccessPublished:June 28, 2022DOI:https://doi.org/10.1016/j.jval.2022.05.010

      Highlights

      • Birth cohort testing for hepatitis C virus (HCV) has been recommended by the World Health Organization and implemented in the United States with the aim of enhancing the prospects of achieving HCV elimination. Nevertheless, the cost-effectiveness of birth cohort testing will vary according to population- and health system–specific characteristics given the significant investment required for its implementation.
      • We conducted an economic evaluation of birth cohort testing to identify people in Ireland born between 1965 and 1985 with undiagnosed chronic HCV infection. It is the first Irish-specific study and the first internationally to compare the cost-effectiveness of introducing national systematic and opportunistic birth cohort testing programs.
      • We found that, despite the substantial upfront costs, systematic birth cohort testing would be the optimal strategy in Ireland. Further consideration of the feasibility and budget impact of implementing a national program will be central to decision making. These factors should be carefully examined by policy makers considering the introduction of birth cohort testing in Ireland and elsewhere.

      Abstract

      Objectives

      We aimed to evaluate the cost-effectiveness of offering once-off birth cohort testing for hepatitis C virus (HCV) to people in Ireland born between 1965 and 1985, the cohort with the highest reported prevalence of undiagnosed chronic HCV infection.

      Methods

      Systematic and opportunistic HCV birth cohort testing programs, implemented over a 4-year timeframe, were compared with the current practice of population risk-based testing only in a closed-cohort decision tree and Markov model hybrid over a lifetime time horizon. Outcomes were expressed in quality-adjusted life-years (QALYs). Costs were presented from the health system’s perspective in 2020 euro (€). Uncertainty was assessed via deterministic, probabilistic, scenario, and threshold analyses.

      Results

      In the base case, systematic testing yielded the largest cost and health benefits, followed by opportunistic testing and risk-based testing. Compared with risk-based testing, the incremental cost-effectiveness ratio for opportunistic testing was €14 586 (95% confidence interval €4185-€33 527) per QALY gained. Compared with opportunistic testing, the incremental cost-effectiveness ratio for systematic testing was €16 827 (95% confidence interval €5106-€38 843) per QALY gained. These findings were robust across a range of sensitivity analyses.

      Conclusions

      Both systematic and opportunistic birth cohort testing would be considered an efficient use of resources, but systematic testing was the optimal strategy at willingness-to-pay threshold values typically used in Ireland. Although cost-effective, any decision to introduce birth cohort testing for HCV (in Ireland or elsewhere) must be balanced with considerations regarding the feasibility and budget impact of implementing a national testing program given high initial costs and resource use.

      Keywords

      Introduction

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      In 2016, the World Health Assembly endorsed the Global Health Sector Strategy that established the goal of viral hepatitis elimination by 2030.
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      As per international guidelines, risk-based criteria (presented in Appendix 1 in Supplemental Materials found at https://doi.org/10.1016/j.jval.2022.05.010) are primarily used to identify populations in Ireland with known risk factors (such as recipients of contaminated blood products, people who inject drugs, people who are incarcerated).
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      The World Health Organization has also recommended birth cohort testing—to screen subpopulations with a disproportionately high prevalence of HCV and HCV-related morbidity—in countries with a lower overall prevalence.
      World Health Organization
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      Crucially, this approach can augment existing risk-based strategies given that it does not require previous risk ascertainment.
      In 2017, an Irish National Clinical Guideline conditionally recommended birth cohort testing for people born between 1965 and 1985, subject to the outcome of a full health technology assessment (ie, an economic assessment of the costs and benefits of introducing birth cohort testing).
      Hepatitis C screening (NCEC National Clinical Guideline No. 15). Department of Health.
      This cohort, now aged 36 to 56 years and representing approximately 40% of the adult population, was identified on the basis of a disproportionately high prevalence of HCV relative to the rest of the Irish general population.
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      Although current evidence is insufficient to identify the precise reasons as to why prevalence is highest in this cohort, it is likely a combination of factors such as history of injection drug use, other risk behaviors, receipt of contaminated blood products before the introduction of routine screening, and other contributing factors.
      From the budget holder’s perspective, the costs of screening up to 40% of the total adult population in Ireland would be substantial, but early intervention could also result in healthcare savings from prevention of the long-term consequences of chronic HCV infection. Therefore, an economic evaluation is necessary to assess whether such an investment would represent value for money. We recently conducted a systematic review of cost-effectiveness of published economic evaluations that examined the cost-effectiveness of introducing birth cohort testing in a number of countries including Canada, Korea, the United Kingdom, the United States, and other European countries.
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      Nonetheless, jurisdiction-specific economic evaluations are needed to account for population- and health system–specific characteristics (such as the prevalence of undiagnosed HCV infection, the incidence of risk factors, access to and costs of treatment) given the significant investment required for its implementation.
      We aimed to examine the cost-effectiveness of birth cohort testing for HCV compared with the current risk-based screening approach, with a view to informing national decision making in Ireland regarding its potential introduction.
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      An economic evaluation of birth cohort testing was not conducted as part of the development process for the Irish National Clinical Guideline. If implemented, it is anticipated that all people in Ireland born between 1965 and 1985 would be eligible to undergo HCV screening and treatment in the public healthcare system free at the point of delivery.

      Methods

      Overview

      A cost-utility analysis (CUA) was undertaken, the primary outcomes of which were the incremental cost-effectiveness ratio (ICER), expressed as the cost per quality-adjusted life-year (QALY) gained, and the incremental net monetary benefit (INMB). Willingness-to-pay (WTP) thresholds of €20 000 and €45 000 were adopted as reference points for interpreting cost-effectiveness.
      Guidelines for the economic evaluation of health technologies in Ireland. Health Information and Quality Authority.
      The perspective of the publicly funded health and social care system, the Health Service Executive (HSE), was adopted. Costs and outcomes were estimated over a lifetime time horizon and discounted at a rate of 4% in accordance with Irish national health technology assessment guidelines.
      Guidelines for the economic evaluation of health technologies in Ireland. Health Information and Quality Authority.
      The CUA was undertaken in Microsoft Office Excel 2013 (Microsoft, Redmond, WA) and R Studio version 4.0.2 (RStudio, PBC, Boston, MA). All data and analyses were reviewed by an experienced economic modeler. Model parameters and structural assumptions were reviewed by an expert advisory group comprising clinical, methodological, and patient representatives (Health technology assessment of birth cohort testing for hepatitis C Expert Advisory Group, Personal Communication, 2021). Uncertainty was assessed via deterministic, probabilistic, scenario, and threshold analysis.

      Modeled Alternatives

      The CUA considered 2 alternative birth cohort testing strategies relative to the current practice of risk-based testing. The first was a systematic, population-based testing program whereby members of the 1965 to 1985 birth cohort would be systematically invited to attend general practice (primary) care to undergo HCV testing.
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      The second was an opportunistic birth cohort testing program that would be offered to people attending general practice care for another purpose. A staggered implementation was assumed, whereby testing would be sequentially offered to the birth cohort over a 4-year period (see Appendix 2 in Supplemental Materials found at https://doi.org/10.1016/j.jval.2022.05.010 for details), to manage the impact on general practice and laboratory services.

      Model Structure and Disease Progression

      A closed-cohort decision tree and Markov model hybrid was used to track the 1965 to 1985 birth cohort from the outset of the simulation until death. The decision tree (Appendix 3 in Supplemental Materials found at https://doi.org/10.1016/j.jval.2022.05.010) estimated the number and costs of patients tested and identified for treatment. The Markov model (Fig. 1) simulated the natural progression of disease for patients with chronic HCV infection and estimated the costs and consequences of patient outcomes. External validation was performed by replicating the inputs and outputs from published studies.
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      Figure 1Model schematic. ∗Patients can die at any stage in the model.
      CC indicates compensated cirrhosis; DCC, decompensated cirrhosis; F, fibrosis level; HCC, hepatocellular carcinoma; LT, liver transplant; SVR, sustained virological response.
      At the outset of each simulation, patients with chronic HCV infection were distributed across the liver fibrosis health states (F0-F4), informed by the fibrosis status of people born in 1965 to 1985 and registered with the national treatment registry during 2018 to 2019 before receiving treatment.
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      Disease progression between the fibrosis health states F0 and F4 was estimated by meta-analysis of studies in community settings.
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      There is also an elevated risk of liver-related mortality after the development of DCC and HCC (National Cancer Registry Ireland. Personal Communication. 2019),
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      Patients could experience all-cause mortality at any time during the model.
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      A 6-month cycle length was used to facilitate the staggered implementation, with annual transition probabilities converted to 6-month probabilities.
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      A full list of model parameters is presented in Appendix 5 in Supplemental Materials found at https://doi.org/10.1016/j.jval.2022.05.010.

      Testing, Linkage to Care, and Treatment

      It was assumed that a general practitioner (GP) or GP practice nurse would draw a blood sample from screening program participants. Samples would be sent to a central laboratory for screening for antibodies to HCV (anti-HCV). If anti-HCV is detected, thereby indicating previous exposure to HCV, evidence for active HCV infection would be sought by reflex antigen testing. The accuracy of these tests was based on published literature reviews.
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      Given that historical exposure to HCV is suspected among the 1965 to 1985 birth cohort (rather than known recent or ongoing risky behaviors), it was assumed that no false negatives would result from a lack of production of detectable antibodies due to recent exposure and that the detection of antigen would reflect chronic rather than acute infection that may subsequently resolve.
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      It was recognized that a small proportion of the birth cohort could overlap with other risk groups, but it was assumed that those at risk would be detected by current practice.
      The uptake of systematic testing was based on that observed for the national colorectal screening program.
      Publications. National Screening Service.
      The uptake of opportunistic testing was based on GP utilization rates in Ireland.
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      In each modeled strategy, patients could be identified through risk-based testing (ie, background testing) or their HCV-related disease could progress to symptomatic presentation (ie, post-F4), at which point their diagnosis is known and they become ineligible for birth cohort testing. The rates of background testing from a UK study were used for the reported age bands,
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      coupled with assumptions that there is reduced testing in older age groups. These rates were applied to Irish population data by age band and then adjusted to reflect the total annual number of HCV tests performed in Ireland, based on available data.
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      ,
      Central Statistics Office.
      Patients are offered a first-line direct-acting antiviral (DAA) regimen and if they do not achieve an SVR can be retreated with a second-line DAA regimen. If retreatment is not successful, the model assumes that the patient follows the natural course of disease. Treatment effectiveness was estimated by meta-analysis of the SVR rates for DAA therapies recommended in Ireland, as reported by a previously published systematic review.
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      , The pooled SVR rates were then weighted by the estimated HCV genotype distribution in the undiagnosed population (C. De Gascun. Personal communication; National Virus Reference Laboratory; 2019).

      HCV Prevalence

      The prevalence of HCV in Ireland was previously estimated using 2015 data.
      • Garvey P.
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      • Franzoni G.
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      Hepatitis C virus seroprevalence and prevalence of chronic infection in the adult population in Ireland: a study of residual sera, April 2014 to February 2016.
      For this analysis, the current prevalence of HCV in the birth cohort was estimated by updating the study’s estimates and adjusting for diagnoses, incidence, and mortality in the years from 2016 to 2021.
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      Utilities and QALYs

      QALYs were generated by weighting the projected life-years by relevant utility scores over the modeled time horizon. Baseline utilities of the general Irish population were derived from a representative sample of EQ-5D-5L survey data.
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      Disease-specific utilities were derived from EQ-5D-3L survey data collected in an observational study of HCV patients (N = 270) treated in Ireland.
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      EQ-5D instruments 2019. EuroQol.
      A short-term disutility multiplier was used to reflect the anxiety and stress associated with a false-positive diagnosis of chronic HCV infection.
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      Economic model of a birth cohort screening program for hepatitis C virus.
      It was assumed that these patients would be identified by baseline ribonucleic acid testing at clinical follow-up thus incurring no further utility decrements.

      Costs

      The costs of setting up and running a systematic testing program were estimated based on the resource requirements of the business case of the national diabetic retinopathy program (Health technology assessment of birth cohort testing for hepatitis C Expert Advisory Group, Personal Communication, 2021). Salary costs, adjusted for pay-related costs as per national economic guidelines,
      Guidelines for the economic evaluation of health technologies in Ireland. Health Information and Quality Authority.
      were estimated from HSE salary scales.
      Payscales for HSE staff
      Health Service Executive.
      The cost of a public awareness campaign to support implementation included the costs of qualitative research, creative development, focus testing, and media dissemination (Health technology assessment of birth cohort testing for hepatitis C Expert Advisory Group, Personal Communication, 2021).
      For systematic birth cohort testing, it was assumed that patients explicitly visit their GP to receive HCV testing and the GP visit is reimbursed by the HSE. For opportunistic birth cohort testing, it was assumed that people already attending their GP for another purpose are invited to return on a future date to have blood drawn for HCV testing, with the subsequent appointment reimbursed. The cost of a GP consultation was based on the opportunity cost of the GP’s time, estimated as a function of the annual number of GP visits in Ireland and the total income used to fund GP and other health services.
      Health Technology Assessment (HTA)
      of smoking cessation interventions. Health Information and Quality Authority.
      The costs of the diagnostic tests needed to provide a diagnosis of chronic HCV infection were based on published estimates (Health technology assessment of birth cohort testing for hepatitis C Expert Advisory Group, Personal Communication, 2021).
      Hepatitis C screening (NCEC National Clinical Guideline No. 15). Department of Health.
      It was assumed that patients who receive an erroneous screening result would incur the cost of an outpatient department visit and baseline ribonucleic acid test, but would not incur subsequent health state or treatment costs (Health technology assessment of birth cohort testing for hepatitis C Expert Advisory Group, Personal Communication, 2021).
      Hepatitis C screening (NCEC National Clinical Guideline No. 15). Department of Health.
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      Regarding model-based events, it was assumed that patients with undiagnosed chronic HCV infection would not accrue health state costs until they were identified by testing or became symptomatic, at which point their HCV diagnosis becomes known. Accordingly, people became ineligible for testing upon symptomatic presentation and followed the natural course of disease incurring costs for clinical workup, treatment, and management. Health state costs were based on an Irish microcosting study of ambulatory healthcare utilization for chronic HCV infection.
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      • et al.
      Hepatitis C in the era of direct-acting antivirals: real-world costs of untreated chronic hepatitis C; a cross-sectional study.
      The reimbursement of first- and second-line DAA therapies in Ireland is subject to an annual national procurement process. These prices were provided by the respective manufacturers. Nevertheless, the unit costs are not presented given their commercial sensitivity. All costs are reported in 2020 Irish euro (€).

      Sensitivity Analysis

      Monte Carlo simulation using 10 000 iterations was undertaken to assess parameter uncertainty. Subgroup analysis was conducted according to the age bands of the birth cohort. Deterministic sensitivity and scenario analyses were undertaken to assess structural uncertainty. The range of scenario analyses undertaken is presented in Appendix 6 in Supplemental Materials found at https://doi.org/10.1016/j.jval.2022.05.010. The base case, scenario, and subgroup analyses each comprised fully probabilistic analyses. We also conducted univariate and bivariate threshold analyses, with prevalence and testing uptake rates arbitrarily varied to investigate their potential influence on the estimated ICERs.

      Results

      Base Case Analysis

      The estimated number of cases of undiagnosed chronic HCV infection in the 1965 to 1985 birth cohort was 11 799 (95% confidence interval [CI] 7772-16 649). The introduction of birth cohort testing (whether systematic or opportunistic) would lead to increased costs and benefits compared with current practice. Systematic testing yielded the largest benefit of the modeled strategies (see Table 1).
      Table 1Base case results over lifetime time horizon.
      Age groupStrategyTotal (per patient)Incremental (per patient)ICER (95% CI)INMB (95% CI) at €20 000 per QALY
      Costs (95% CI)QALYs (95% CI)Costs (95% CI)QALYs (95% CI)
      1981-1985 (36-40 years)No BC testing€13 256 (€8974-€19 075)6.07 (5.55-6.55)----
      Opportunistic BC testing€19 672 (€13 571-€29 769)6.25 (5.78-6.70)€6417 (€2174-€15 475)0.18 (0.09-0.31)€38 348 (€10 356-€105 002)−€2720 (−€12 037 to €2345)
      Systematic BC testing€23 680 (€15 635-€39 125)6.36 (5.90-6.79)€4008 (€1363-€9665)0.10 (0.05-0.17)€41 702 (€11 653-€112 377)−€1920 (−€7724 to €1142)
      1976-1980 (41-45 years)No BC testing€13 756 (€9087-€19 964)5.57 (5.08-6.01)----
      Opportunistic BC testing€15 758 (€11 160-€22 017)5.77 (5.33-6.17)€2002 (−€24-€5852)0.20 (0.10-0.32)€11 179 (−€131 to €36 310)€1984 (−€2204 to €5488)
      Systematic BC testing€16 952 (€12 038-€24 287)5.88 (5.45-6.27)€1194 (−€31 to €3570)0.11 (0.06-0.18)€11 767 (−€245 to €38 592)€1042 (−€1495 to €2981)
      1971-1975 (46-50 years)No BC testing€13 886 (€9005-€20 538)5.14 (4.66-5.58)----
      Opportunistic BC testing€14 992 (€10 730-€20 771)5.36 (4.94-5.75)€1106 (−€484 to €3185)0.22 (0.10-0.36)€5807 (−€2016 to €19 311)€3241 (€102-€6775)
      Systematic BC testing€15 485 (€11 339-€21 225)5.45 (5.04-5.83)€493 (−€230 to €1527)0.09 (0.05-0.15)€6127 (−€2307 to €21 089)€1324 (−€69 to €2788)
      1965-1970 (51-56 years)No BC testing€14 534 (€9295-€21 903)4.67 (4.16-5.11)----
      Opportunistic BC testing€15 828 (€11 166-€22 122)4.88 (4.44-5.27)€1295 (−€506 to €3557)0.21 (0.10-0.35)€7084 (−€2044 to €22 559)€2913 (−€321 to €6572)
      Systematic BC testing€16 452 (€11 875-€22 536)4.98 (4.56-5.36)€623 (−€273 to €1830)0.10 (0.05-0.16)€7077 (−€2390 to €23 792)€1388 (−€235 to €3108)
      Overall (36-56 years)No BC testing€55 432 (€37 349-€79 366)21.45 (19.67-23.10)----
      Opportunistic BC testing€66 250 (€49 243-€88 193)22.26 (20.65-23.75)€10 819 (€3948-€21 378)0.81 (0.40-1.31)€14 586 (€4185-€33 527)€5417 (−€7375 to €18 107)
      Systematic BC testing€72 569 (€54 784-€95 924)22.67 (21.09-24.14)€6318 (€2355-€12 553)0.41 (0.21-0.64)€16 827 (€5106-€38 843)€1833 (−€5406 to €8257)
      BC indicates birth cohort; CI, confidence interval; ICER, incremental cost-effectiveness ratio; INMB, incremental net monetary benefit; QALY, quality-adjusted life-year.
      Compared with risk-based testing, opportunistic testing would lead to an overall incremental benefit of 0.81 QALYs (95% CI 0.40-1.31) at an incremental cost of €10 819 (95% CI €3948-€21 378). The ICER and INMB (at the €20 000 WTP threshold) were €14 586 (95% CI €4185-€33 527) per QALY and €5417 (95% CI −€7375 to €18 107), respectively. Compared with opportunistic testing, the incremental benefits and costs of systematic testing were 0.41 QALYs (95% CI 0.21-0.64) and €6318 (95% CI €2355-€12 553), respectively. The ICER was €16 827 (95% CI €5106-€38 843) per QALY, with an INMB of €1833 (95% CI −€5406 to €8257) at the €20 000 WTP threshold. Average cost-effectiveness ratios comparing systematic birth cohort testing with risk-based testing are presented in Appendix 7 in Supplemental Materials found at https://doi.org/10.1016/j.jval.2022.05.010. From Figures 2 and 3, it can be seen that systematic birth cohort testing was most likely to be the optimal strategy at WTP thresholds of €20 000 (P = .73) and €45 000 (P = .99).
      Figure thumbnail gr2
      Figure 2Cost-effectiveness plane.
      HCV indicates hepatitis C virus; QALY, quality-adjusted life-year; WTP, willingness to pay.
      Figure thumbnail gr3
      Figure 3Cost-effectiveness acceptability curve.
      QALY indicates quality-adjusted life-year; WTP, willingness to pay.

      Subgroup Analysis

      Imprecision in the ICERs was widest for the 1981 to 1985 subgroup (36-40 years old). Compared with risk-based testing, the ICER for opportunistic testing was €38 348 (95% CI €10 356-€105 002) in the 1981 to 1985 subgroup. Compared with opportunistic testing, the ICER for systematic testing was €41 702 (95% CI €11 653-€112 377). In this age group, risk-based testing was the most likely option to be cost-effective (P = .79) at a €20 000 WTP threshold, whereas systematic testing was most likely to be optimal (P = .68) at a €45 000 WTP threshold. The ICERs for the remaining subgroups were below the €20 000 WTP threshold, with probabilities of 0.85, 0.97, and 0.95 estimated for systematic testing in the 1976 to 1980, 1971 to 1975, and 1965 to 1970 subgroups, respectively (see Appendices 8 and 9 in Supplemental Materials found at https://doi.org/10.1016/j.jval.2022.05.010). In these age groups, the ICERs for systematic testing were estimated at €11 767 (95% CI −€245 to €38 592), €6127 (95% CI −€2307 to €21 089), and €7077 (95% CI −€2390 to €23 792) compared with opportunistic testing, respectively.

      Deterministic Sensitivity Analysis

      The ICERs were most sensitive to variation in the F4-to-DCC transition probability. The ICERs were also sensitive to changes in the utility derived from SVR, the prevalence of undiagnosed chronic HCV infection, and the costs of DCC. The 20 parameters that, when set at their upper and lower bounds, resulted in the largest change in the ICER are presented in Figure 4A,B . The variation in the ICERs was <11% for all other parameters.
      Figure thumbnail gr4a
      Figure 4Results of deterministic sensitivity analysis. (A) Opportunistic birth cohort testing versus no birth cohort testing. (B) Systematic birth cohort testing versus opportunistic birth cohort testing.
      CC indicates compensated cirrhosis; CI, confidence interval; DAA, direct-acting antiviral; DCC, decompensated cirrhosis; F, fibrosis stage; HCC, hepatocellular carcinoma; SVR, sustained virological response.
      Figure thumbnail gr4b
      Figure 4Results of deterministic sensitivity analysis. (A) Opportunistic birth cohort testing versus no birth cohort testing. (B) Systematic birth cohort testing versus opportunistic birth cohort testing.
      CC indicates compensated cirrhosis; CI, confidence interval; DAA, direct-acting antiviral; DCC, decompensated cirrhosis; F, fibrosis stage; HCC, hepatocellular carcinoma; SVR, sustained virological response.

      Scenario Analysis

      See Appendix 6 in Supplemental Materials found at https://doi.org/10.1016/j.jval.2022.05.010 for detailed results and interpretation of the scenario analyses. Briefly, reversing the sequence of the staggered implementation, using reduced fibrosis progression rates and unit costs of the DCC, HCC, and LT health states all led to inflated overall ICERs, but birth cohort testing remained cost-effective in each of these scenarios. Testing was more likely to be cost-effective if fibrosis progression was more advanced in the undiagnosed birth cohort. This finding reflects that undiagnosed cases will soon become symptomatic and incur the substantial healthcare costs associated with DCC, HCC, and LT. Therefore, immediate intervention would generate substantial cost savings through prevention of long-term HCV-related sequelae. Each of the estimated ICERs reduced when differential discounting rates were applied to costs and benefits. Finally, the ICERs increased marginally when costs of twice-yearly HCC surveillance were included, but birth cohort testing remained cost-effective.

      Threshold Analysis

      The univariate analyses indicated that birth cohort testing would be cost-effective at a testing uptake rate above 10% or prevalence rate above 0.5%, ceteris paribus. When a positive correlation was assumed between these parameters in the bivariate analysis, there was a clear trend in favor of a higher prevalence and testing uptake (see Appendix 10 in Supplemental Materials found at https://doi.org/10.1016/j.jval.2022.05.010).

      Discussion

      We conducted a CUA to inform decision making in Ireland regarding the potential introduction of a national screening program in which all people born between 1965 and 1985 would be offered once-off screening for HCV.
      HTA of birth cohort testing for hepatitis C. Health Information and Quality Authority.
      We modeled systematic and opportunistic testing programs as competing alternatives relative to the current practice of risk-based testing. Our analysis found that implementation of systematic birth cohort testing over a 4-year period would be cost-effective at a WTP threshold of €20 000 (0.73 probability of being cost-effective). Notably nevertheless, the subgroup analysis revealed that testing the youngest group within this cohort (ie, people born 1981-1985) would only be cost-effective at a WTP threshold of €45 000 (the upper bound of the WTP range used in Ireland; 0.67 probability of being cost-effective). This finding was expected given that the prevalence of chronic HCV was lowest in this subgroup (0.27% vs 0.95% in the others) and the current rate of background screening in this age group is higher than in the other subgroups. Overall, these findings were robust across a range of sensitivity and scenario analyses and are in line with the results of previous studies.
      • Carty P.G.
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      A 2018 study found that 7 of 51 high-income countries had recommended general population (eg, birth cohort) testing independent of HCV risk factor status.
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      Nevertheless, other than in Japan and the United States,
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      ,
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      U.S. Preventive Services Task Force
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      Hepatitis C virus infection in adolescents and adults: screening. US Preventive Services Task Force.
      the extent to which these recommendations have been implemented is unclear.
      • Goel A.
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      ,
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      Treating hepatitis C.
      Our analysis identified several factors that should be carefully examined by policy makers considering the introduction of birth cohort testing in Ireland and elsewhere. First, the potential structure adopted by a birth cohort testing program should be central to decision making given its direct impact on program participation and costs. A systematic population-based structure, formally organized by the health service, could be adopted to ensure that all members of the target cohort are invited to attend a healthcare appointment specifically for the purpose of undergoing HCV testing. Although there is only limited direct evidence of the comparative effectiveness of systematic and opportunistic testing programs, a systematic structure is likely to maximize equity of access, acceptability, and testing uptake in addition to establishing in-built mechanisms for quality assurance and evaluation of program performance.
      WHO Regional Office for Europe
      Screening Programmes: a Short Guide. Increase Effectiveness, Maximize Benefits and Minimize Harm.
      ,
      Cancer. World Health Organization
      ,
      Hepatitis C screening in Alberta: a health technology assessment. University of Calgary.
      The implementation of a systematic program via general practice in Ireland would require a substantial upfront investment, but our CUA found that this would be a cost-effective use of resources. In other countries, a systematic program implemented via dedicated community clinics or mobile testing units could also be considered, but in Ireland this would be associated with additional setup costs given a lack of existing infrastructure.
      The costs of a testing program may be limited where HCV testing can be offered to the target population through an existing healthcare appointment. In the United Kingdom, adding HCV testing to the National Health Service health check, offered once every 5 years to people aged 40 to 74 years to assess their risk of heart disease, diabetes, kidney disease, and stroke, was found to be cost-effective by a 2019 economic evaluation.
      • Williams J.
      • Miners A.
      • Harris R.
      • et al.
      Cost-effectiveness of one-time birth cohort screening for hepatitis C as part of the National Health Service Health Check Program in England.
      , Similar general health screening programs also exist in Korea and Japan,
      • Nakamura J.
      • Terajima K.
      • Aoyagi Y.
      • Akazawa K.
      Cost-effectiveness of the national screening program for hepatitis C virus in the general population and the high-risk groups.
      ,
      • Kim J.
      • Haacker M.
      • Keshavjee S.
      • Atun R.
      Cost-effectiveness of scaling up of hepatitis C screening and treatment: a modelling study in South Korea.
      but there is no comparable health screen in many other countries, including Ireland. As such, an opportunistic testing program would likely comprise offering HCV testing to people already attending their GP for another reason. Patients who opt in to the testing program would then be required to return for a subsequent appointment to undergo HCV testing. Such an approach would be challenging from the GP’s perspective and would run the risk of missing a proportion of the target cohort (particularly in countries where GP care is not universally free at the point of access), could potentially increase the risk of patient drop-off between healthcare attendances, and could prove problematic for evaluation of program performance.
      WHO Regional Office for Europe
      Screening Programmes: a Short Guide. Increase Effectiveness, Maximize Benefits and Minimize Harm.
      ,
      • Feld J.J.
      Hepatitis C virus diagnostics: the road to simplification.
      We identified 3 further sources of decision uncertainty arising from our analysis. First, given the slow and latent progression of HCV-related disease, it is inevitably challenging to derive accurate estimates of the prevalence of undiagnosed HCV infection. Many European countries currently lack robust epidemiological data to support monitoring progress toward HCV elimination.
      European Centre for Disease Prevention and Control
      Hepatitis B and C Epidemiology in Selected Population Groups in the EU/EEA.
      In Ireland, the best source of prevalence data is a 2017 cross-sectional study.
      • Garvey P.
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      Hepatitis C virus seroprevalence and prevalence of chronic infection in the adult population in Ireland: a study of residual sera, April 2014 to February 2016.
      Although representative of the general population, the study’s estimates are imprecise due to the small number of observed chronic HCV infections (n = 33 of 3795 samples). The study also provided evidence of regional variation in prevalence, with most HCV cases emanating from the east of Ireland, which includes Dublin, the largest population center. As has been the case in France and Spain,
      • Brouard C.
      • Saboni L.
      • Gautier A.
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      HCV and HBV prevalence based on home blood self-sampling and screening history in the general population in 2016: contribution to the new French screening strategy.
      ,
      • Viejo L.G.E.
      • Herola A.G.
      • Lloret I.S.
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      Screening of hepatitis C virus infection in adult general population in Spain.
      further research could be considered to provide nationally representative prevalence information, but such a study would need to be of a suitable scale to allow identification of sufficient HCV cases and adequately account for potential geographical bias. Such challenges have also recently been highlighted in the context of severe acute respiratory syndrome coronavirus 2.
      • McConnell D.
      • Hickey C.
      • Bargary N.
      • et al.
      Understanding the challenges and uncertainties of seroprevalence studies for SARS-CoV-2.
      Our CUA showed that although prevalence is important, the finding that birth cohort testing was cost-effective withstood low prevalence rates. Given that HCV prevalence in Europe and the United States ranges between 0.5% and 1.5%,
      • Han R.
      • Zhou J.
      • François C.
      • Toumi M.
      Prevalence of hepatitis C infection among the general population and high-risk groups in the EU/EEA: a systematic review update.
      ,
      • Bradley H.
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      Hepatitis C virus prevalence in 50 U.S. States and D.C. by sex, birth cohort, and race: 2013-2016.
      this suggests that our findings could be applicable to other high-income countries.
      Second, the introduction of birth cohort testing could have substantial capacity implications across the clinical pathway, particularly in terms of primary care and laboratory testing, where there is potential for the health service utilization generated by birth cohort testing to displace other care.
      HTA of birth cohort testing for hepatitis C. Health Information and Quality Authority.
      The health system’s capacity to implement birth cohort testing, in addition to both the cost and cost-effectiveness of testing, will be directly influenced by the uptake rate of testing. Although the uptake rate was derived from data observed during the implementation of an existing national screening program and is in line with that of previous studies,
      Publications. National Screening Service.
      ,
      • Goel A.
      • Sanchez J.
      • Paulino L.
      • et al.
      A systematic model improves hepatitis C virus birth cohort screening in hospital-based primary care.
      ,
      • Viejo L.G.E.
      • Herola A.G.
      • Lloret I.S.
      • et al.
      Screening of hepatitis C virus infection in adult general population in Spain.
      these data are of limited applicability due to differences in population demographics, diagnostic samples and tests, disease outcomes, and the once-off nature of birth cohort testing. The threshold analysis demonstrated that low levels of testing uptake would affect the cost-effectiveness of birth cohort testing, but we believe that the uptake rate modeled in the base case represents a conservative estimate given that modeled by previous studies.
      • Carty P.G.
      • Fawsitt C.G.
      • Gillespie P.
      • et al.
      Population-based testing for undiagnosed hepatitis C: a systematic review of economic evaluations.
      From the decision maker’s perspective, the main concern regarding the uptake rate of testing will be in relation to the potential budget impact of birth cohort testing. This uncertainty could be further addressed by surveying a representative sample of the 1965 to 1985 birth cohort.
      Third, there are clear logistical issues associated with the use of reflex testing (ie, if a sample tests anti-HCV antibody positive, the same sample is then used to verify chronic HCV infection) that should be considered. To enable reflex testing, venous blood samples must undergo centrifugation, freezing, and cold-chain storage within 6 to 24 hours after phlebotomy to ensure that sample degradation is prevented.
      World Health Organization
      Guidelines on Hepatitis B and C Testing.
      ,
      Hepatitis C diagnostics technology landscape. World Health Organization.
      This is logistically complex to organize and may not always be feasible. Dried blood spots, widely used in the context of national newborn bloodspot screening programs, could be used to overcome these issues,
      World Health Organization
      Guidelines on Hepatitis B and C Testing.
      ,
      • Feld J.J.
      Hepatitis C virus diagnostics: the road to simplification.
      ,
      • Fourati S.
      • Feld J.J.
      • Chevaliez S.
      • Luhmann N.
      Approaches for simplified HCV diagnostic algorithms.
      but further research is needed to evaluate their use as part of a national screening program.
      HTA of birth cohort testing for hepatitis C. Health Information and Quality Authority.
      Consideration could be given to an initial pilot program that addresses concerns regarding the feasibility of reflex testing, including the potential use of dried blood spots. Reflex testing reduces the potential drop-off from repeated healthcare attendance
      • Feld J.J.
      Hepatitis C virus diagnostics: the road to simplification.
      and mitigates the stress and anxiety caused by a positive anti-HCV diagnosis in those whose infection has resolved and who are therefore not at risk of HCV-related disease sequelae.
      • Chapko M.K.
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      Our analysis had a number of limitations. First, the CUA was based on a closed-cohort model. Nevertheless, we believe that the additional complexity and data requirements for a dynamic transmission model were unwarranted given the low incidence of HCV and conflicting evidence regarding the incidence of reinfection,
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      with the most at-risk populations captured by existing screening pathways.
      Hepatitis C screening (NCEC National Clinical Guideline No. 15). Department of Health.
      Second, it was assumed that people accepting the invitation to attend their GP practice for HCV testing will in fact attend and complete the blood draw. In reality, some people may decline the offer of testing after consultation with their GP. In those cases, the cost of the GP visit accrues without the potential benefit of HCV detection, thereby reducing the cost-effectiveness of the systematic program. Nevertheless, it is anticipated that, of those who consult with their GP, the vast majority will consent to testing
      • Goel A.
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      • Paulino L.
      • et al.
      A systematic model improves hepatitis C virus birth cohort screening in hospital-based primary care.
      ,
      • O’Kelly M.
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      and that participation will be positively influenced by the use of a comprehensive public awareness campaign. Third, our analysis did not account for the potential benefits that may occur from a reduction in the incidence of extrahepatic manifestations associated with chronic HCV infection (eg, non-Hodgkin’s lymphoma and renal dysfunction).
      World Health Organization
      Guidelines for the Care and Treatment of Persons Diagnosed With Chronic Hepatitis C Virus Infection.
      ,
      • Modi A.A.
      • Liang T.J.
      Hepatitis C: a clinical review.
      ,
      • Cacoub P.
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      Extrahepatic manifestations of chronic hepatitis C virus infection.
      • Westbrook R.H.
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      Modifiable risk factors and cancer in Ireland. National Cancer Registry Ireland.
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      • Sherman K.E.
      Extrahepatic manifestations of hepatitis C infection: navigating CHASM.
      Recent studies have also indicated that, owing to the regenerative potential of the liver, early provision of DAA therapy to patients with chronic HCV infection before they accumulate irreversible liver damage can reduce the demand for LT and expand the pool of potential organ donors.
      • Bethea E.D.
      • Samur S.
      • Kanwal F.
      • et al.
      Cost effectiveness of transplanting HCV-infected livers into uninfected recipients with preemptive antiviral therapy.
      ,
      • Jena A.B.
      • Snider J.T.
      • Diaz Espinosa O.
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      • Lakdawalla D.
      How does treating chronic hepatitis C affect individuals in need of organ transplants in the United Kingdom?.
      We believe that these exclusions are consistent with a conservative approach and reinforce the strength of the CUA’s finding that birth cohort testing would be cost-effective. Finally, in instances where Irish-specific parameter data were not readily available, efforts were made to ensure that the data adopted were appropriate and generalizable to the Irish population.

      Conclusions

      Our study found that once-off birth cohort testing of people born between 1965 and 1985 would be cost-effective and significantly improve Ireland’s chances of achieving its HCV elimination targets. Nevertheless, any decision to introduce birth cohort testing for HCV in Ireland must be balanced with considerations regarding the feasibility, opportunity cost, and budget impact of implementing a national testing program. These challenges will be applicable to other countries considering the adoption of birth cohort testing.

      Article and Author Information

      Author Contributions: Concept and design: Carty, Teljeur, De Gascun, Harrington, McCormick, Smith, Ryan
      Acquisition of data: Carty, Teljeur, De Gascun, McCormick
      Analysis and interpretation of data: Carty, Teljeur
      Drafting of the manuscript: Carty, Teljeur, Gillespie, Smith
      Critical revision of the paper for important intellectual content: Carty, Teljeur, De Gascun, Gillespie, Harrington, McCormick, O’Neill, Smith, Ryan
      Statistical analysis: Carty, Teljeur
      Obtaining funding: Ryan
      Administrative, technical or logistical support: O’Neill
      Supervision: Teljeur, Gillespie, Harrington, O’Neill, Smith, Ryan
      Conflict of Interest Disclosures: The authors reported no conflicts of interest. The views expressed in this publication are those of the authors and not necessarily those of the Expert Advisory Group.
      Funding/Support: This work was conducted as part of the SPHeRE Programme under grant number SPHeRE/2013/1. Nevertheless, no funding was received for this work.
      Role of the Funder/Sponsor: The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication.

      Acknowledgment

      The authors thank the Health Information and Quality Authority’s Expert Advisory Group who contributed their time and support.

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