Cost Effectiveness of Universal Screening for Hepatitis C Virus Infection in the Era of Direct-Acting, Pangenotypic Treatment Regimens

Clinical Gastroenterology and Hepatology 2019;17:930–939

PANCREAS, BILIARY TRACT, AND LIVER Cost Effectiveness of Universal Screening for Hepatitis C Virus Infection in the Era of Direct-Acting, Pangenotypic Treatment Regimens Mark H. Eckman,* John W. Ward,‡ and Kenneth E. Sherman§ *Division of General Internal Medicine and the Center for Clinical Effectiveness, University of Cincinnati, Cincinnati, Ohio; ‡Task Force for Global Health and Centers for Disease Control and Prevention, Atlanta, Georgia; and §Division of Digestive Diseases, University of Cincinnati, Cincinnati, Ohio BACKGROUND & AIMS:

Most persons infected with hepatitis C virus (HCV) in the United States were born from 1945 through 1965; testing is recommended for this cohort. However, HCV incidence is increasing among younger persons in many parts of the country and treatment is recommended for all adults with HCV infection. We aimed to estimate the cost effectiveness of universal 1-time screening for HCV infection in all adults living in the United States and to determine the prevalence of HCV antibody above which HCV testing is cost effective.

METHODS:

We developed a Markov state transition model to estimate the effects of universal 1-time screening of adults 18 years or older in the United States, compared with the current guideline-based strategy of screening adults born from 1945 through 1965. We compared potential outcomes of 1-time universal screening of adults or birth cohort screening followed by antiviral treatment of those with HCV infection vs no screening. We measured effectiveness with quality-adjusted life-years (QALY), and costs with 2017 US dollars.

RESULTS:

Based on our model, universal 1-time screening of US residents with a general population prevalence of HCV antibody greater than 0.07% cost less than $50,000/QALY compared with a strategy of no screening. Compared with 1-time birth cohort screening, universal 1-time screening and treatment cost $11,378/QALY gained. Universal screening was cost effective compared with birth cohort screening when the prevalence of HCV antibody positivity was greater than 0.07% among adults not in the cohort born from 1945 through 1965.

CONCLUSIONS:

Using a Markov state transition model, we found a strategy of universal 1-time screening for chronic HCV infection to be cost effective compared with either no screening or birth cohort– based screening alone.

Keywords: Screening; Decision Analysis; Cost-Effectiveness Analysis; Hepatitis C.

See related editorial on page 835. epatitis C virus (HCV) is a major cause of morbidity and mortality in the United States. Based on National Health and Nutrition Examination Surveys for 2003 to 2010, the Centers for Disease Control (CDC) estimates 2.7 million persons have chronic HCV infection in the United States.1 Of HCV-infected persons, 81% were born during 1945 to 1965. Most were infected decades earlier, before implementation of HCV screening of the blood supply. Thus, more than a quarter of this birth cohort has severe fibrosis or cirrhosis and is at risk for HCV-associated mortality.2 In 2011, in addition to testing people who inject drugs and other people with possible exposure to HCV, the CDC recommended 1-time

H

testing for all persons born during 1945 to 1965.3 In 2012, the United States Preventive Services Task Force (USPSTF) joined the CDC in this recommendation.4 The incidence of acute infection with HCV has increased more than 2.9-fold between 2010 and 2015. This increase is associated with increases in injection

Abbreviations used in this paper: AASLD, American Association for the Study of Liver Diseases; CDC, Centers for Disease Control; DAA, directacting antiviral; HCV, hepatitis C virus; ICER, incremental costeffectiveness ratio; IDSA, Infectious Disease Society of America; PSA, probabilistic sensitivity analysis; QALY, quality-adjusted life-year; RAS, resistance-associated substitution; SVR, sustained virologic response; USPSTF, United States Preventive Services Task Force. Most current article © 2019 by the AGA Institute 1542-3565/$36.00 https://doi.org/10.1016/j.cgh.2018.08.080

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drug use.5 The largest increases in HCV are among persons younger than 40 years of age. Since 2013, several drugs have been approved by the Food and Drug Administration, providing highly effective, interferon-free regimens with sustained viral responses (SVRs) greater than 95%, shorter treatment durations, and fewer adverse effects.6–9 The American Association for the Study of Liver Diseases (AASLD) and the Infectious Disease Society of America (IDSA) now recommend treating virtually all patients with chronic HCV infection.10 Our goal was to analyze the cost effectiveness of universal 1-time screening (hereafter denoted as universal screening) for chronic HCV infection in the United States in the era of pangenotypic direct-acting antiviral (DAA) therapy, compared with the current standard, so-called birth cohort screening or no screening. In particular, we wished to assess the threshold prevalence above which screening is cost effective in the United States.

Methods Review of Data Patient Characteristics. The estimated prevalence of chronic HCV antibody positivity among adults born between 1945 and 1965 is 2.6% (Table 1).1 Based on the prevalence of HCV antibody positivity in the overall US population of 1.0%,1 and US Census data,11 the calculated prevalence of HCV antibody positivity in adults older than age 18 who are not part of the birth cohort is 0.29%. This is a lower-bound estimate because it does not account for new cases in younger patients resulting from the opioid epidemic, which may exceed 40,000 new infections per year. Because we are screening patients, we assume they are treatment naive, never having been diagnosed with chronic HCV infection, and are clinically asymptomatic; thus, we assume no patients have progressed to decompensated cirrhosis. Treatment of Chronic Hepatitis C Virus. Treatment for chronic HCV infection is evolving with the availability of new DAA and interferon-free regimens. The 2017 update of the AASLD/IDSA guidelines recommends several all-oral regimens as first-line treatment.10 Sofosbuvir–velpatasvir and glecaprevir–pibrentasvir are pangenotypic agents for treatment-naive patients. AASLD/IDSA guidelines also suggest testing for NS5A resistance-associated substitutions (RAS) for cirrhotic patients with genotype 3 receiving treatment with sofosbuvir–velpatasvir.10 If the Y93H RAS is present, weight-based ribavirin is added to the DAA regimen. Sofosbuvir–velpatasvir is a relatively new pangenotypic NS5A–NS5B inhibitor that was approved in 2016. The treatment course is 12 weeks in patients with or without compensated cirrhosis. SVR at 12 weeks ranges between 88% and 99%, depending on

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What You Need to Know Background Testing for hepatitis C virus (HCV) is recommended for people born between 1945 and 1965. However, HCV incidence is increasing among young people as a result of the opioid epidemic. Our objective was to examine the cost effectiveness of universal HCV testing of all adults. Findings Compared with birth cohort–based screening, universal screening followed by antiviral treatment of those with chronic HCV infection costs $11,378 per quality-adjusted life-year gained. Universal screening continues to cost less than $50,000 per qualityadjusted life-year (highly cost effective), as long as the prevalence of HCV antibody positivity is greater than 0.07% in members outside of the birth cohort born between 1945 and 1965. The current estimate of the prevalence of antibody positivity in this group is 0.29%. Implications for patient care Universal screening for chronic HCV infection in the United States is highly cost effective compared with birth cohort–based screening alone.

genotype and the presence of RAS variants (Table 1).7 Glecaprevir–pibrentasvir is an NS3/4A–NS5A inhibitor that was approved in 2017. The treatment course is 8 weeks in patients without cirrhosis and 12 weeks for patients with compensated cirrhosis. SVR at 12 weeks ranges between 95% and 100%.12–14 Patients who fail to achieve SVR are re-treated with a 12-week, triple-DAA regimen consisting of sofosbuvir–velpatasvir–voxilaprevir. SVRs were 93% and 99% among patients with and without cirrhosis, respectively.6 In contrast to the era of interferon-based regimens, when a significant proportion of patients did not qualify for treatment owing to comorbidities, pre-existing psychiatric conditions, alcohol or intravenous drug use, we assumed that all patients without decompensated cirrhosis or a life expectancy less than 1 year will be eligible for treatment and explored this assumption in sensitivity analyses.15

Description of Simulation Model We used a computer program (Decision Maker, Boston, MA), to develop a Markov state transition model, analyze decision trees, and perform sensitivity analyses, using a lifelong time horizon.16 We considered 3 strategies (Supplementary Figure 1): (1) no screening; (2) universal screening of adults 18 years of age or older,

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Table 1. Data Required in the Analysis: Probabilities, Rates, Costs, and Quality of Life Variable Patient characteristics at time of screening Prevalence of HCV, % Birth cohort (birth year 1945–1965) Non–birth cohort US general population Proportion of HCV-antibody positive with chronic infection Gender distribution in US population, % males34 Birth cohort, birth year 1945–1965 Non–birth cohort Racial distribution in US population34 Birth cohort, birth year 1945–1965 Caucasian African American Non–birth cohort Caucasian African American Average age, y11 Birth cohort, birth year 1945–1965 Non–birth cohort adults
18 y Test characteristics Third-generation EIA Sensitivity Specificity Natural history parameters Annual rate of METAVIR fibrosis stage progression, % F0–F1 F1–F2 F2–F3 F3–F4 Annual rate of decompensated cirrhosis From compensated cirrhosis, METAVIR fibrosis stage F4 Annual rate of hepatocellular carcinoma From compensated or uncompensated cirrhosis Probability of being eligible for transplantation Annual rate of liver transplantation Decompensated cirrhosis Hepatocellular carcinoma 30-day mortality after transplant Annual excess mortality rate after transplant Without hepatocellular carcinoma At 3 months At 1 year At 5 years At 10 years With hepatocellular carcinoma At 3 months At 1 year At 5 years At 10 years Annual excess mortality rate Compensated cirrhosis Decompensated cirrhosis Hepatocellular carcinoma HCV-antibody positive/viral RNA negative Treatment-related parameters Proportion eligible for (and accepting) treatment Sofosbuvir–velpatasvir: treatment naive (12-wk course) SVR Genotype 1a Genotype 1b Genotype 2 Genotype 3

Base-case value [95% CI or clinically plausible range]

Distribution type

1,27,31–34

2.6 [2.1–3.2] 0.29 1.0 [0.8–1.2] 0.78 [0.66–0.95]30

Logit Logit Logit

47.84 [47.83–47.86] 49.06 [49.06–49.07]

b b

73.32 [73.33–73.33] 10.59 [10.58–10.60]

b b

61.04 [61.04–61.05] 12.56 [12.56–12.57]

b b

61.85 40.85

0.94 [0.89–0.98]35 0.97 [0.96–0.98]35

b b

13.2 [12.2–14.5]17 9.0 [8.2–9.9]17 13.2 [12.2–14.3]17 12.7 [11.8–13.6]17

Logit Logit Logit Logit

0.066 [0.045–0.087]36

Logit

0.021 [0.011–0.033]36 0.10

Logit

0.51 [0.39–0.63]37 4.36 [3.78–5.06]37 0.019 [0.018–0.020]38

Logit Lognormal Logit

0.115 0.094 0.049 0.049

[0.109–0.122]38 [0.092–0.095]38 [0.049–0.049]38 [0.049–0.049]38

Logit Logit Logit Logit

0.090 0.101 0.069 0.054

[0.065–0.115]38 [0.097–0.104]38 [0.067–0.072]38 [0.050–0.059]38

Logit Logit Logit Logit

0.013 [0.00–0.029]36 0.129 [0.097–0.168]36 0.872 [0.649–1.907]39 0.012 [0.008–0.014]40

Logit Logit Lognormal Logit

1.0

Logit

0.98 [0.96–1.0]7 0.99 [0.98–1.0]7 0.99 [0.98–1.0]41

b b b b

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Table 1. Continued Variable NS5A-RAS positive NS5A-RAS negative Genotype 4 Glecaprevir–pibrentasvir: treatment-naive without cirrhosis (8-wk course) Genotype 1a Genotype 1b Genotype 2 Genotype 3 Genotype 4 Glecaprevir–pibrentasvir: treatment-naive with cirrhosis (12-wk course) Genotype 1a Genotype 1b Genotype 2 Genotype 3 Genotype 4 Sofosbuvir–velpatasvir–voxilaprevir: treatment experienced, after initial treatment failure (12-wk course) Without cirrhosis With compensated cirrhosis

Base-case value [95% CI or clinically plausible range]

Distribution type

0.88 [0.79–0.98]41 0.97 [0.95–0.99]41 1.07

b b b

0.99 [0.98–1.0]9 0.99 [0.98–1.0]9 0.98 [0.96–1.0]42 0.95 [0.92–0.98]14 0.99 [0.96–1.0]9

0.98 [0.94–1.0]9 0.99 [0.98–1.0]9 0.99 [0.98–1]42 1.014 1.09

0.93 [0.87–0.97]6 0.99 [0.95–1.0]6

b b

Cost, (SD) Disease states Chronic hepatitis C (annual)a,b 43,44 Metavir F0, F1 Metavir F2 Metavir F3 Compensated cirrhosis Decompensated cirrhosis Hepatocellular carcinoma Liver transplantc (annual) First year Subsequent years Drug costs, $/mo (clinically plausible range) Ribavirin for genotype 1a, NS5A–RAS positive (weight-based dosing; 1200 mg for wt > 75 kg) Sofosbuvir 400 mg, velpatasvir 100 mg (once daily)d Glecaprevir 100 mg, pibrentasvir 40 mg (3 times/d)d Sofosbuvir 400 mg, velpatasvir 100 mg, voxilaprevir 100 mg (once daily) Laboratory testing and office visit costs (item description, Current Procedural Terminology code) Hepatitis C antibody EIA (86803) Hepatitis C RNA amplification probe (87521) Hepatitis C RNA quantitative (87522) Genotype hepatitis C (87902) NS5A-resistance–associated variant testing Uric acid (84550) Triglycerides (84478) Hepatic function panel (80076) Complete blood count (85025) Renal panel (80069) Thyroid-stimulating hormone (84443) Urine pregnancy test (81025) Office outpatient visit established patient Level 1 visit (99211) Level 2 visit (99212) Level 3 visit (99213) Level 4 visit (99214)

$799 ($599–$4402) $808 ($606–$4402) $1641 ($1231–$4402) $1914 ($1436–$4402) $21,268 ($15,951–$33,893) $39,110 ($29,333–$54,073)

Lognormal Lognormal Lognormal Lognormal Lognormal Lognormal

$113,093 ($84,820–$214,622) $29,679 ($22,259–$48,858)

Lognormal Lognormal

$18823 ($99–$277)

Lognormal

$809023 ($8090–$24,920) $983023 ($7260–$12,400) $19,28523 ($18,541–$24,920)

Lognormal Lognormal Lognormal

$19.5745 $48.1445 $58.7645 $353.1545 $563.0046 $6.2045 $7.8845 $11.2145 $10.6645 $11.9145 $23.0545 $8.6747 $20.4647 $44.1447 $73.9347 $108.7447

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Table 1. Continued Cost, (SD) Costs related to screening Cost of screeninge Cost of liver elastography Quality of lifef Well without HCV infection, male/female48 Ages 20–29 Ages 30–39 Ages 40–49 Ages 50–59 Ages 60–69 Ages 70–79 Ages
80 Chronic HCV infection Without cirrhosis With compensated cirrhosis With decompensated cirrhosis After liver transplantation With hepatocellular carcinoma Treatment Ribavirin DAA

$40.0347 $166.6447

0.928/0.913 0.918/0.893 0.887/0.863 0.861/0.837 0.84/0.811 0.802/0.771 0.782/0.724 0.7919 0.7919 0.7219 0.7519 0.7218 0.9920 0.9649

HCV, hepatitis C virus; RAS, resistance-associated substitution; SVR, sustained virologic response. a Year 2009 US dollars, inflated to 2017 US dollars using the Medical Care component of the Consumer Price Index (see Supplementary Methods section). b Costs of chronic HCV infection excluding costs of antiviral therapy. c Assumes antiviral therapy only given in first year after liver transplant. d Cost of full treatment course for sofosbuvir/velpatasvir (12 wk), $24,270; glecaprevir/pibrentasvir (8 wk in patients without cirrhosis), $19,660; and glecaprevir/ pibrentasvir (12 wk in patients with compensated cirrhosis), $29,490. e HCV antibody ELISA test and level 1 office visit (99211). f We used a multiplicative model for quality-of-life weights when multiple health states were combined (eg, age adjustment and chronic HCV infection status).

followed by treatment of infected patients with guideline-recommended therapy10; and (3) 1-time birth-cohort screening of adults born between 1945 and 1965. We developed a 2-stage simulation model. The first stage modeled the progression of fibrosis from the time and age of initial infection (Supplementary Figure 2). The simulation starts with infection at an age of 25.5 years, based on the average for community-dwelling patients in the meta-regression.17 The simulation stops after 36 years of follow-up evaluation for individuals in the birth cohort, who are on average 61.85 years old, and after 15 years for those not in the birth cohort, who have an average age of 40.85 years. We then used 2 separate distributions to seed the starting distribution of fibrosis categories for the second stage of the model (Supplementary Figure 3). The second stage involves a more complex Markov model containing 48 states of health (Supplementary Figure 1). Before entering the Markov, the model divides the population into members of the birth cohort born between 1945 and 1965 (current age, 53–73 y) or adults 18 years of age or older who are not members of the birth cohort. We then divided patients into major clinical subgroups depending on the following: (1) sex, (2) race, (3) presence of antibodies to HCV, (4) chronic HCV infection as documented by viral RNA, and (5) resolved HCV infection (antibodies to HCV, but undetectable viral RNA). Patients

enter the Markov simulation distributed across the 5 fibrosis stages as described earlier. With each 1-month of follow-up evaluation, patients move from one health state to another, depending on chance events that may occur. Details of events modeled among those receiving treatment are presented in Supplementary Figures 4 and 5 and Supplementary Tables 1 and 2. Costs. We performed the analysis from the health care system perspective using 2017 US dollars. Details of the microcosting models are described in Table 1 and the Supplementary Methods section. Future costs and effectiveness were discounted at 3% per year. Quality of Life. Numerous studies have examined the impact of HCV infection on health-related quality of life.18–20 We used standard gamble utility assessments calculated by McLernon et al19 in a meta-regression based on a systematic literature review for HCV with moderate disease, compensated cirrhosis, decompensated cirrhosis, and after liver transplant. Because the meta-regression did not include utilities for patients with hepatocellular carcinoma, we used standard gamble assessments from a utility study by Chong et al18 on 193 outpatients with chronic HCV for this outcome. Utilities for HCV health states were consistent across the studies by McLernon et al,19 Chong et al,18 and Sherman et al.21 Calculation of incremental cost-effectiveness ratios. Strategies were rank ordered by increasing cost,

and incremental cost-effectiveness ratios (ICERs) were

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calculated between each progressively more expensive but effective strategy. Sensitivity analyses. We performed both deterministic and probabilistic sensitivity analyses (PSAs) to examine the impact of uncertainty in parameter estimates and population-level variation in parameters. We conducted PSAs using second-order Monte Carlo simulation.22 We used b and logit distributions for probabilities and lognormal distributions for relative risks, hazard ratios, rates, and costs. Deterministic sensitivity analyses were performed by systematically varying 1 or more parameter values over clinically relevant ranges (Table 1).

Results Universal screening followed by guideline-based treatment of all patients with chronic HCV infection had an ICER of $11,378 dollars per QALY gained compared with birth cohort screening alone. Not screening was more expensive and less effective than both of the screening strategies (Table 2).

Deterministic Sensitivity Analyses We performed sensitivity analyses on the sofosbuvir–velpatasvir model. We first explored the threshold prevalence above which universal screening is cost effective compared with no screening. HCV prevalence in the United States is between 0.8% and 1.2%.1 However, prevalence varies markedly in different subpopulations and test settings depending on the numbers and types of risk factors in a target population. As shown in Figure 1, below a prevalence of 0.07%, the ICER is greater than the generally accepted societal willingnessto-pay threshold of $50,000 per QALY for highly costeffective interventions. Above an HCV prevalence of 1.0%, screening dominates by being less expensive and more effective. Although we have good estimates for HCV prevalence among adults born between 1945 and 1965, we do not have good contemporary estimates for adults who are not members of the birth cohort. We next

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explored the impact of changes in the prevalence of HCV antibody positivity in adults who are not members of the birth cohort on the cost effectiveness of universal screening compared with birth cohort screening. Because prevalence in the non–birth cohort population increased above the base-case value of 0.29%, the ICER for universal screening decreased. At a prevalence greater than 0.07%, universal screening costs less than $50,000 per QALY compared with birth cohort screening (Figure 2). The cost of antiviral treatment for patients with chronic HCV infection is a major consideration in policy decisions about screening. Although there have been several treatments suggested by the AASLD/IDSA, our base-case analysis uses sofosbuvir–velpatasvir. Although the wholesale acquisition cost is $24,920 per month, the monthly cost in the Federal Supply Schedule is $8090.23 Depending on the genotype, other recommended firstline treatments include glecaprevir–pibrentasvir, elbasvir–grazoprevir, or ledipasvir–sofosbuvir. Figure 3 shows the ICER for screening as a function of DAA cost. The average monthly acquisition and Federal Supply Schedule costs for these DAAs are $13,200 and $9830 for glecaprevir–pibrentasvir (only requires an 8-wk course), $31,500 and $28,493 for ledipasvir–sofosbuvir (VA pricing, $21,907), and $17,742 and $17,377 for elbasvir–grazoprevir. Although the ICER increases with increasing monthly drug costs, it does not exceed $50,000 per QALY until average monthly DAA costs are greater than $28,000. Figure 4 uses a tornado plot to summarize the results of multiple 1-way sensitivity analyses. Cost effectiveness was most sensitive to parameters at the top of the figure.

Probabilistic Sensitivity Analysis In more than 10,000 iterations, universal screening was preferred over birth cohort screening alone 89% of the time, yielding an average gain of 0.002 QALYs (SD, 0.001 QALY) at an average incremental cost of $34.16 (SD, $33.77). The ICER was $29,357 (SD, $43,191). As shown in the cost-effectiveness acceptability curve

Table 2. Results of Base-Case Analysis of Sofosbuvir/Velpatasvir

Strategy

Cost, $

Effectiveness, QALYs

Discount, 3%/y Birth cohort screening 363.15 17.7441 Universal screening 388.19 17.7463 Do not screen 426.81 17.7362 Results of base-case analysis: glecaprevir/pibrentasvir Birth cohort screening 405.65 17.7441 Do not screen 426.81 17.7362 Universal screening 433.23 17.7463

QALY, quality-adjusted life-year.

Incremental cost, $

Incremental effectiveness, QALYs

Incremental cost effectiveness, $/QALY

25.04 38.62

0.0022 -0.0101

11,378.00 Dominated

21.16 27.58

-0.0079 0.0022

Dominated 12,515.87

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Figure 1. One-way sensitivity analysis examining the ICER of universal screening compared with no screening, as a function of the prevalence of HCVantibody positivity in the general population. K$/ QALY, signifies thousands of dollars/quality-adjusted life year.

(Supplementary Figure 6), screening was cost saving 8.1% of the time and was cost saving or had an ICER less than $50,000 per QALY 78.3% of the time. Table 1 shows the CIs and types of distributions used in the PSA.

Discussion In the United States, the CDC,4 USPSTF,4 and AASLD/ IDSA provide screening guidelines for HCV.10 In 2012, the CDC first recommended birth cohort–based screening of residents born between 1945 and 1965. Of note, the USPSTF and CDC are in the midst of updating their guidelines, and exploring the possibility of broaderbased recommendations.24 HCV testing is recommended for persons born between 1945 and 1965 because almost 50% of persons with chronic HCV in this cohort do not report risk factors for HCV infection on national surveys, showing the limitations of eliciting information about HCV exposures in the

Figure 2. One-way sensitivity analysis examining the ICER of universal screening compared with birth cohort screening, as a function of the prevalence of HCV-antibody positivity in adults who are not members of the birth cohort born between 1945 and 1955. Above a prevalence of 0.07%, universal screening costs less than $50,000 per QALY compared with birth cohort screening.

distant past.25 Furthermore, risk-based screening alone has significant limitations. In 1 survey of more than 4000 patients with chronic HCV infection, only 22.3% reported being tested as a result of risk-based indications.26 Because of the poor demonstrated efficacy of risk-based screening, we did not include this as part of cohortbased screening in our analysis. Analyses performed during the era of first-generation DAAs and interferonbased treatment regimens found birth cohort screening to be cost-effective.27,28 However, the availability of a new generation of highly effective, non– interferon-based oral regimens, with fewer side effects and shorter treatment courses, has altered the dynamic around the question of screening. Results of our analyses suggest that universal screening for chronic HCV infection is cost effective compared with birth cohort screening. Results of another recently published analysis also found an expanded age-based testing strategy (1-time testing of all adults
18 y) to be cost effective ($28,000/QALY) compared with birth cohort–based screening.29

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Figure 3. One-way sensitivity analysis examining monthly cost of DAA agent. The base-case value for this parameter is $8090. Below a monthly cost of roughly $2500, universal screening dominates, being less costly and more effective than birth cohort screening.

Our estimate for the prevalence of HCV-antibody positivity in adults who are not part of the cohort of adults born between 1945 and 1965 likely is low because it is based on estimates made before the steep increase in new cases of HCV infection associated with the opioid epidemic. The majority of new cases are in younger patients born after 1965 who are not members of the birth cohort. There is value in examining the threshold of HCV prevalence above which universal testing is cost effective or cost saving. HCV prevalence among younger adults varies from state to state. In states with a high prevalence, there is even marked variation by county and community level. Prevalence also can vary

widely by test location, including primary care, obstetrics/gynecology, emergency care, and drug treatment settings. With the adoption of a policy of universal adult testing, all clinical care settings should initiate HCV testing programs. However, realizing that resources are scarce, data regarding the cost-effectiveness threshold can guide local policy decisions by directing testing services to settings in which they generate sufficient benefit for the cost. Finally, HCV testing is cost effective even at a very low prevalence of HCV, reflecting the great benefit at a system and community level of finding and curing persons of their HCV infection. Universal screening costs less than $50,000 per QALY as long as

Figure 4. Tornado diagram of 1-way sensitivity analyses for the strategy of universal screening compared with birth cohort screening. The ICER, in dollars per QALY (horizontal axis) ranges between minus $10,000 and $100,000/QALY. For each parameter, the upper and lower limits of the sensitivity analysis are based on either the 95% CIs, or a clinically reasonable range. A negative ICER indicates that the strategy is less expensive and more effective than its competitor. The base-case result is marked by the dotted line at the center of the tornado plot. Parameters at the top of the figure (wide mouth of the tornado) have a larger impact on the ICER within their 95% CIs or clinically plausible range. EIA, ELISA.

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the prevalence of HCV antibody positivity in non–birth cohort adults is greater than 0.07%. We also explored the prevalence threshold for the general population, above which universal screening is cost effective compared with no screening. Universal screening is cost effective as long as the probability of HCV antibody positivity is greater than 0.07% in the population being tested. Populations for whom screening is not cost effective are only the very lowest risk subgroups, such as 20- to 59-year-old Caucasian women with 0 to 1 lifetime sexual partners and no history of drug use or other HCV risk factors, or Caucasians older than the age of 60 years with no history of blood transfusions before 1992 and no other HCV risk factors.30 In summary, our analysis found universal screening in the United States to be highly cost effective ($11,378/QALY gained) compared with birth cohort screening. A recommendation for HCV testing of all adults will support the national response to the epidemic of HCV infection among young persons in the United States.

Supplementary Material Note: To access the supplementary material accompanying this article, visit the online version of Clinical Gastroenterology and Hepatology at www.cghjournal.org, and at https://doi.org/10.1016/j.cgh.2018.08.080.

References 1. Denniston MM, Jiles RB, Drobeniuc J, et al. Chronic hepatitis C virus infection in the United States, National Health and Nutrition Examination Survey 2003 to 2010. Ann Intern Med 2014; 160:293–300. 2. Klevens RM, Canary L, Huang X, et al. The burden of hepatitis C infection-related liver fibrosis in the United States. Clin Infect Dis 2016;63:1049–1055. 3. Centers for Disease Control and Prevention. Surveillance for viral hepatitis - United States, 2016. 2016. Available at: https:// www.cdc.gov/hepatitis/statistics/2016surveillance/pdfs/2016Hep SurveillanceRpt.pdf. Accessed May 21, 2018. 4. U.S. Preventive Services Task Force. Human immunodeficiency virus (HIV) infection: screening. 2013. Available at: https://www. uspreventiveservicestaskforce.org/Page/Document/UpdateSummary Final/hepatitis-c-screening. Accessed March 13, 2018. 5. Zibbell JE, Asher AK, Patel RC, et al. Increases in acute hepatitis C virus infection related to a growing opioid epidemic and associated injection drug use, United States, 2004 to 2014. Am J Public Health 2018;108:175–181. 6. Bourliere M, Gordon SC, Flamm SL, et al. Sofosbuvir, velpatasvir, and voxilaprevir for previously treated HCV infection. N Engl J Med 2017;376:2134–2146.

Clinical Gastroenterology and Hepatology Vol. 17, No. 5 infection and prior direct-acting antiviral treatment. Hepatology 2017;66:389–397. 9. Zeuzem S, Ghalib R, Reddy KR, et al. Grazoprevir-elbasvir combination therapy for treatment-naive cirrhotic and noncirrhotic patients with chronic hepatitis C virus genotype 1, 4, or 6 infection: a randomized trial. Ann Intern Med 2015;163:1–13. 10. HCV guidance: recommendations for testing, managing, and treating hepatitis C: American Association for the Study of Liver Diseases, and the Infectious Diseases Society of America, 2017. Available at: http://www.hcvguidelines.org. Accessed September 29, 2017. 11. United States Census Bureau PD. Annual estimates of the resident population by single year of age and sex for the United States: April 1, 2010 to July 1, 2016. 2016. Available at: https:// factfinder.census.gov/faces/tableservices/jsf/pages/product view.xhtml?pid=PEP_2016_PEPASR6H&prodType=table. Accessed May 21, 2018. 12. Forns X, Lee SS, Valdes J, et al. Glecaprevir plus pibrentasvir for chronic hepatitis C virus genotype 1, 2, 4, 5, or 6 infection in adults with compensated cirrhosis (EXPEDITION-1): a singlearm, open-label, multicentre phase 3 trial. Lancet Infect Dis 2017;17:1062–1068. 13. Kwo PY, Poordad F, Asatryan A, et al. Glecaprevir and pibrentasvir yield high response rates in patients with HCV genotype 1-6 without cirrhosis. J Hepatol 2017;67:263–271. 14. Zeuzem S, Foster GR, Wang S, et al. Glecaprevir-pibrentasvir for 8 or 12 weeks in HCV genotype 1 or 3 infection. N Engl J Med 2018;378:354–369. 15. Muir AJ, Provenzale D. A descriptive evaluation of eligibility for therapy among veterans with chronic hepatitis C virus infection. J Clin Gastroenterol 2002;34:268–271. 16. Lau J, Kassirer JP, Pauker SG. Decision maker 3.0. Improved decision analysis by personal computer. Med Decis Making 1983;3:39–43. 17. Thein HH, Yi Q, Dore GJ, et al. Estimation of stage-specific fibrosis progression rates in chronic hepatitis C virus infection: a meta-analysis and meta-regression. Hepatology 2008; 48:418–431. 18. Chong CA, Gulamhussein A, Heathcote EJ, et al. Health-state utilities and quality of life in hepatitis C patients. Am J Gastroenterol 2003;98:630–638. 19. McLernon DJ, Dillon J, Donnan PT. Health-state utilities in liver disease: a systematic review. Med Decis Making 2008; 28:582–592. 20. Thein HH, Krahn M, Kaldor JM, et al. Estimation of utilities for chronic hepatitis C from SF-36 scores. Am J Gastroenterol 2005;100:643–651. 21. Sherman KE, Sherman SN, Chenier T, et al. Health values of patients with chronic hepatitis C infection. Arch Intern Med 2004;164:2377–2382. 22. Doubilet P, Begg CB, Weinstein MC, et al. Probabilistic sensitivity analysis using Monte Carlo simulation. A practical approach. Med Decis Making 1985;5:157–177.

7. Feld JJ, Jacobson IM, Hezode C, et al. Sofosbuvir and velpatasvir for HCV genotype 1, 2, 4, 5, and 6 infection. N Engl J Med 2015;373:2599–2607.

23. United States Department of Veterans Affairs. Federal supply schedule - pharmaceutical prices. Vol 2018. United States Department of Veterans Affairs, Office of Acquisition and Logistics (OAL), 2018. Hines, IL. Available at: https://www.va.gov/ oal/business/fss/pharmprices.asp. Accessed February 6, 2018.

8. Poordad F, Felizarta F, Asatryan A, et al. Glecaprevir and pibrentasvir for 12 weeks for hepatitis C virus genotype 1

24. U.S. Preventive Services Task Force. Draft research plan for hepatitis C virus infection in adolescents and adults: screening,

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2018. Available at: https://www.uspreventiveservicestaskforce. org/Page/Document/draft-research-plan/hepatitis-c-screening1. Accessed March 13, 2018.

41. Foster GR, Afdhal N, Roberts SK, et al. Sofosbuvir and velpatasvir for HCV genotype 2 and 3 infection. N Engl J Med 2015; 373:2608–2617.

25. Smith BD, Morgan RL, Beckett GA, et al. Recommendations for the identification of chronic hepatitis C virus infection among persons born during 1945–1965. MMWR Recomm Rep 2012; 61:1–32.

42. Hassanein T, Wyles D, Wang S, et al. SURVEYOR-II, part 4: glecaprevir/pibrentasvir demonstrates high SVR rates in patients with HCV genotype 2, 4, 5, or 6 infection without cirrhosis following an 8-week treatment duration (abstract LB15). 66th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD). 2016. Available at: http:// www.natap.org/2016/AASLD/AASLD_40.htm. Accessed March 18, 2018.

26. Centers for Disease Control and Prevention. Locations and reasons for initial testing for hepatitis C infection - chronic hepatitis cohort study, United States, 2006-2010. MMWR Morb Mortal Wkly Rep 2013;62:645–648. 27. Rein DB, Smith BD, Wittenborn JS, et al. The cost effectiveness of birth-cohort screening for hepatitis C antibody in U.S. primary care settings. Ann Intern Med 2012;156:263–270. 28. McGarry LJ, Pawar VS, Panchmatia HR, et al. Economic model of a birth cohort screening program for hepatitis C virus. Hepatology 2012;55:1344–1355. 29. Barocas JA, Tasillo A, Eftekhari Yazdi G, et al. Population level outcomes and cost effectiveness of expanding the recommendation for age-based hepatitis C testing in the United States. Clin Infect Dis 2018;67:549–556. 30. Armstrong GL, Wasley A, Simard EP, et al. The prevalence of hepatitis C virus infection in the United States, 1999 through 2002. Ann Intern Med 2006;144:705–714. 31. Alter MJ, Kruszon-Moran D, Nainan OV, et al. The prevalence of hepatitis C virus infection in the United States, 1988 through 1994. N Engl J Med 1999;341:556–562. 32. Wasley A, Miller JT, Finelli L, et al. Surveillance for acute viral hepatitis–United States, 2005. MMWR Surveill Summ 2007; 56:1–24. 33. Chak E, Talal AH, Sherman KE, et al. Hepatitis C virus infection in USA: an estimate of true prevalence. Liver Int 2011;31:1090–1101. 34. United States Census Bureau PD. Annual estimates of the resident population by sex, age, race, and Hispanic origin for the United States: April 1, 2010 to July 1, 2016. 2016. Available at: https://factfinder.census.gov/faces/tableservices/jsf/pages/ productview.xhtml?pid¼PEP_2016_PEPASR6H&prodType¼ table. Accessed May 21, 2018. 35. Chou R, Clark E, Helfand M. Screening for hepatitis C virus infection. Systematic evidence review, 24. Bethesda, MD: Agency for Healthcare Research and Quality, 2004. 36. Fattovich G, Pantalena M, Zagni I, et al. Effect of hepatitis B and C virus infections on the natural history of compensated cirrhosis: a cohort study of 297 patients. Am J Gastroenterol 2002;97:2886–2895. 37. Scientific Registry of Transplant Recipients. Time to transplant, 2000 to 2009, new liver waiting list registrations, Table 15.2. Vol 2012. Organ Procurement and Transplantation Network, Minneapolis, MN, 2009. 38. Unadjusted patient survival, deceased donor liver transplants survival at 3 months, 1 year, 3 years, and 5 years, Table 9.14a. Vol 2012. Organ Procurement and Transplantation Network, Minneapolis, MN, 2009. 39. Degos F, Christidis C, Ganne-Carrie N, et al. Hepatitis C virus related cirrhosis: time to occurrence of hepatocellular carcinoma and death. Gut 2000;47:131–136. 40. Omland LH, Jepsen P, Krarup H, et al. Increased mortality among persons infected with hepatitis C virus. Clin Gastroenterol Hepatol 2011;9:71–78.

43. McAdam-Marx C, McGarry LJ, Hane CA, et al. All-cause and incremental per patient per year cost associated with chronic hepatitis C virus and associated liver complications in the United States: a managed care perspective. J Manag Care Pharm 2011;17:531–546. 44. Chhatwal J, Kanwal F, Roberts MS, et al. Cost effectiveness and budget impact of hepatitis C virus treatment with sofosbuvir and ledipasvir in the United States. Ann Intern Med 2015; 162:397–406. 45. Centers for Medicare and Medicaid Services. Clinical laboratory fee schedule, 2017. Hyattsville, MD: US Department of Health and Human Services, 2017. 46. Elbasha EH, Robertson MN, Nwankwo C. The cost effectiveness of testing for NS5a resistance-associated polymorphisms at baseline in genotype 1a-infected (treatment-naive and treatment-experienced) subjects treated with all-oral elbasvir/ grazoprevir regimens in the United States. Aliment Pharmacol Ther 2017;45:455–467. 47. Centers for Medicare and Medicaid Services. Physician fee schedule. 2017 National physician fee schedule relative value file, 2017. Hyattsville, MD: US Department of Health and Human Services, 2017. 48. Hanmer J, Lawrence WF, Anderson JP, et al. Report of nationally representative values for the noninstitutionalized US adult population for 7 health-related quality-of-life scores. Med Decis Making 2006;26:391–400. 49. Younossi ZM, Stepanova M, Esteban R, et al. Superiority of interferon-free regimens for chronic hepatitis C: the effect on health-related quality of life and work productivity. Medicine (Baltimore) 2017;96:e5914.

Reprint requests Address requests for reprints to: Mark H. Eckman, MD, Division of General Internal Medicine and the Center for Clinical Effectiveness, University of Cincinnati Medical Center, PO Box 670535, Cincinnati, Ohio 45267-0535. e-mail: [email protected]; fax: (513) 558-4399. Conflicts of interest These authors disclose the following: Kenneth Sherman has received grants/ contracts (institutional funding) from AbbVie, Bristol-Myer-Squibb, Gilead, Inovio, Intercept, MedImmune, and Merck, serves on the advisory boards for Abbott Laboratories, Gilead, MedImmune, Merck, and Inovio, and also serves on the safety monitoring boards for Watermark and MedPace; and Mark Eckman has received grant support from Merck through the Merck Investigator Studies Program. The remaining author discloses no conflicts. Funding Supported in part by the National Foundation for the Centers for Disease Control and Prevention (Centers for Disease Control and Prevention Foundation), with funding provided through multiple donors to the Centers for Disease Control and Prevention Foundation’s Viral Hepatitis Action Coalition. The funding source had no role in the design, data collection and analysis, or manuscript preparation.

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Supplementary Methods Decision Analytic Model Supplementary Figure 1 describes the details of the decision analytic model. The decision node is shown in Supplementary Figure 1A along with chance events before entry in the Markov portion of the model describing the characteristics of the patient population in terms of membership in the birth cohort born between 1945 and 1965, sex, ethnicity, antibody status, results of polymerase chain reaction and Recombinant ImmunoBlot Assay testing as appropriate, and eligibility for and acceptance of treatment. The Markov simulation portion of the model is shown in Supplementary Figure 1B. Although the current recommendations from the CDC and the USPSTF include screening of high-risk individuals along with birth-cohort screening, we did not include risk-based screening as part of the birth-cohort screening strategy. Although theoretically appealing, risk-based screening has significant limitations. These limitations were highlighted in a survey of 4689 individuals infected with hepatitis C who were asked about the reason for their HCV testing. Only 22.3% of patients had HCV testing performed for risk-based indications such as injection drug use or hemodialysis.1 The poor efficacy of risk-based screening was a major factor in the CDC’s decision to recommend birth cohort (birth years 1945–1965) screening in 2012.

Natural History of Chronic Hepatitis C The computer simulation of the natural history of chronic hepatitis C was based on a previously published model of disease progression and outcomes with chronic HCV infection.2 The progression of fibrosis is based on a series of meta-regressions using the METAVIR scoring system3 and data from 111 studies of more than 33,000 individuals with chronic HCV infection.4 Fibrosis proceeds until cirrhosis develops (METAVIR stage F4). Once patients have developed compensated cirrhosis they may progress further to decompensated cirrhosis and/or hepatocellular carcinoma. Patients may receive liver transplants for either decompensated cirrhosis or hepatocellular carcinoma.5 As such, we developed a 2-stage simulation model. The first stage of the model (Supplementary Figure 2) is used to calculate the progression of fibrosis from the time of infection. All patients begin this simulation in METAVIR stage F0 at the time of infection. During each monthly cycle patients may remain in their current stage, progress to the next stage of fibrosis, or die. In the base-case analysis, we ran this simulation for 36 or for 15 years, for members of the birth cohort and those who were not members of the birth cohort, and then used the stage distributions at this point (Supplementary Figure 3) as the starting distributions for the second stage.

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The second stage of the simulation model began with a mixed population of HCV-infected men and women who were either members of the birth cohort, or were adults 18 years of age or older who were not born between 1945 and 1965. Patients who were uninfected or who had antibodies to HCV but undetectable viral RNA may either die or survive. Patients who did not receive treatment, with fibrosis stages F0 through F3, may either die, remain in their current fibrosis stage, or progress to the next stage of fibrosis. Once cirrhosis developed (fibrosis stage F4), patients may die from nonexplicitly modeled causes (life-table–based), die from compensated cirrhosis, develop hepatocellular carcinoma, progress to decompensated cirrhosis, or remain in their current stage. Patients who either developed hepatocellular carcinoma or progressed to decompensated cirrhosis may be considered for liver transplantation.6,7 Those undergoing transplantation may die within the first 30 days. Patients who developed decompensated cirrhosis or hepatocellular carcinoma and had not undergone transplantation faced the same events as patients with compensated cirrhosis, although with different probabilities of outcomes. After liver transplantation we only modeled death or survival. As shown in Supplementary Figure 4, disease progressed over time from the initial seed distribution of fibrosis stages. The proportion of patients living with earlier stages of fibrosis (F0–F2) decreased over time, whereas patients with stage F3 and F4 (cirrhosis) fibrosis increased, peaking at roughly 5 and 10 years, respectively. A small proportion of patients progressed to either decompensated cirrhosis or hepatocellular carcinoma, the latter group being very small given the high mortality rate associated with hepatocellular carcinoma. Similarly, a small proportion of the cohort underwent liver transplantation either for decompensated cirrhosis or hepatocellular carcinoma. Over time, patients died from either liver-related or nonexplicitly modeled causes (natural death), with roughly 27% of HCV-infected patients dying from cirrhosis, 10% dying from hepatocellular carcinoma, and 63% dying from nonexplicitly modeled causes. Supplementary Figure 5 shows the cumulative probability of the major outcomes over time. Over the lifetime of the cohort, 66%, 31%, 12%, 6%, and 4% of individuals will develop compensated cirrhosis, decompensated cirrhosis, hepatocellular carcinoma, and liver transplant for decompensated cirrhosis or hepatocellular carcinoma, respectively. Life expectancies projected by the natural history model for various patient subgroups are listed in Supplementary Table 1. Among patients with antibodies to hepatocellular carcinoma, those with active infection have the shortest life expectancies, whereas those who cleared the virus do better. However, the patients who were antibody positive but had no detectable viral load still did not survive as long as uninfected patients because of the excess mortality risk associated with the psychosocial and behavioral patterns that lead to HCV exposure in the first place.

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Efficacy of Treatment Regimens for Chronic Hepatitis C Virus Sofosbuvir–velpatasvir. In the ASTRAL-1 trial of HCVinfected patients with genotypes 1a,1b, 2, 4, 5, and 6, SVR was 98% and 99% in patients with genotypes 1a and 1b, respectively, and 100% in patients with genotype 4.8 ASTRAL-2 focused specifically on patients with genotype 2 and reported an SVR of 99%.9 ASTRAL-3 studied patients with genotype 3. SVR at 12 weeks in patients with and without NS5A–RAS variants were 88% and 97%, respectively.9 Glecaprevir–pibrentasvir. In the ENDURANCE-1 trial of noncirrhotic HCV-infected patients with genotypes 1a and 1b, SVR was 99% at 12 weeks.10 SURVEYOR-II reported an SVR of 99% at 12 weeks for treatment-naive patients with genotype 2.11 A larger pooled analysis of 9 phase 2 and 3 trials of noncirrhotic patients across multiple genotypes reported an SVR of 98% for patients with genotype 2.12 In the 8-week treatment arm of ENDURANCE-3, treatment-naive patients with genotype 3 had an SVR of 95% at 12 weeks.13 Similar results were noted in the pooled analysis.12 ENDURANCE-4 reported an SVR of 99% at 12 weeks in noncirrhotic patients with genotype 4.14 Similar efficacy was noted in studies of patients with compensated cirrhosis. EXPEDITION-1 reported SVRs of 98%, 99%, 99%, and 100% at 12 weeks in patients with genotypes 1a, 1b, 2, and 4, respectively.15 SURVEYOR-II reported an SVR of 100% at 12 weeks for patients with genotype 3.16

Treatment Failures Patients who failed to achieve SVR were re-treated with a 12-week triple DAA regimen consisting of sofosbuvir–velpatasvir–voxilaprevir (400 mg/100 mg/100 mg once daily). POLARIS-1 studied patients who had prior treatment experience with NS5A-containing regimens. A high proportion of treated patients had compensated cirrhosis (46%), so subgroup analyses were reported with SVRs of 93% and 99% among patients with and without cirrhosis, respectively.17

Model Calibration We compared predicted survival in our natural history model of HCV-infected patients with observations from a large Danish cohort study of patients diagnosed with HCV infection (DANVIR) between 1996 and 2006.18,19 Sixty-four percent of the 10,991 HCVinfected patients in the DANVIR cohort were male. Five- and 10-year survival rates were 81.7% (95% CI, 80.2–83.2) and 67.8% (95% CI, 64.9–70.8), respectively. In our initial model, outcomes for a population of 45-year-old HCV-infected individuals, 64% of whom were men, were 87.7% and 73.0% survival at 5 and 10

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years, respectively. Our initial assumption was that the risk of non–liver-related natural death would be the same among HCV-infected patients and antibodynegative uninfected patients (ie, age- and sex-matched general population). However, a careful review of causes of death among HCV-infected patients in the DANVIR cohort showed an excess risk of non–liver-related natural death of approximately 1% per year compared with the general population. We tuned our model by adding this additional excess mortality risk to patients with HCV infection and once more compared our results with the DANVIR experience. Five- and 10-year survival in our updated models were 83.6% and 66.3%, respectively (Supplementary Table 2). Although 5-year survival was just outside of the 95% CI of the DANVIR cohort, 10-year survival was well within the 95% CI. We next looked at specific causes of death to ensure that the natural history model also was calibrated on a more granular level. As shown in Supplementary Table 2, the cumulative probability of death projected by the natural history model at 5 and 10 years, resulting from liver-related causes and non–liverrelated causes, decreased within the 95% CIs of the DANVIR cohort. As a last measure of calibration, we also compared the natural history model’s projection for the time by which 50% of HCV-infected individuals would develop compensated cirrhosis with one of the larger observational studies. Poynard et al20 recruited patients from 3 large populations: the Observatoire de l’Hépatatite C population, the Cohorte Hépatite C Pitié-Salpêtrière population, and the original population from the METAVIR scoring system validation study to assess the natural history of liver fibrosis progression in patients with HCV infection. Among the 2235 patients in this study, 404 were between 21 and 30 years of age at the time of infection, similar to the average age of infection of 21 years in our natural history model. Fifty percent of these patients developed cirrhosis by 38 years (95% CI, 32–40), compared with a 32.5-year median duration of HCV infection before the development of cirrhosis in our natural history model.

Probabilistic Sensitivity Analysis Supplementary Figure 6 shows a cost-effectiveness acceptability curve. We calculated the ICER of universal screening of adults for chronic HCV infection compared with birth cohort screening of adults born between 1945 and 1965, followed by guideline-guided treatment. Results are based on 10,000 second-order Monte Carlo simulations. Values were varied simultaneously based on picks from their respective distributions (Table 1). ICERs less than zero correspond to situations in which screening is both cost saving and results in superior outcomes. This occurred in 8.1% of the simulations.

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Screening was either cost saving or cost effective (ICER, < $50,000/QALY) in 78.3% of the simulations.

Costs The initial cost of screening was $40.03 and consisted of a level 1 office visit (Current Procedural Terminology code 99211) and a blood test for antibody to hepatitis C. Patients with positive antibody screens then had hepatitis C polymerase chain reaction testing, with an additional cost of $48.14. Patients with a positive polymerase chain reaction had additional testing consisting of complete blood count, liver function tests, renal panel, and pregnancy testing (for women), at an incremental cost of $42.45. Patients with antibodies to hepatitis C but a negative polymerase chain reaction underwent Recombinant ImmunoBlot Assay testing at an additional cost of $21.25. Additional screening costs for those who were eligible for and accepted treatment included quantitative polymerase chain reaction ($58.76), genotyping ($353.15), triglycerides ($7.88), uric acid ($6.20), and thyroid-stimulating hormone ($23.05). Liver elastography was performed on all patients to evaluate the degree of liver fibrosis at a total cost of $166.64 (technical component cost, $127.52; professional cost, $39.12). Treatment costs included costs of the drug and associated physician visits and laboratory testing. The number of physician visits and particulars of laboratory testing depended on the specific treatment being used. In addition to the incremental costs of screening, testing, and treatment, costs also were associated with disease states. The higher costs were for end-stage liver disease, the more universal screening saves, resulting in improved cost effectiveness. A variety of costs for HCV-related disease stages are published in the literature.21–24 To bias our results against universal screening, we used as our base-case the cost estimates for disease stage from a recent analysis by Chhatwal et al21 that were somewhat lower than other published costs. Costs in this analysis were in 2014 US dollars, so we inflated these to 2017 US dollars, using the medical care component of the Consumer Price Index for 2014 to 2015, 2015 to 2016, and so on, through 2016 to 2017. The respective rates were 2.6%, 4.1%, and 2.7%.25 Converting these into 2017 US dollars, the annual health care costs of patients with HCV and Metavir fibrosis stages of F0, F1, F2, F3, compensated cirrhosis (F4), decompensated cirrhosis, hepatocellular carcinoma, and liver transplant during the first year and following years, were as follows: $799, $799, $808, $1641, $1914, $21,268, $39,110, $113,093, and $29,679, respectively. We used data from another source to set upper limits on sensitivity analyses for the costs associated with each disease stage. McAdam-Marx et al23 used data from a large insurance claims database between 2001 and 2010 on 34,597 patients with chronic HCV (Optum Insight, Eden

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Prairie, MN) to calculate costs for a variety of disease stages (no clinically evident liver disease, compensated cirrhosis, decompensated cirrhosis, hepatocellular carcinoma, and liver transplantation – first year and subsequent years). Cost components included overall pharmacy, anti-HCV treatment in particular, and medical care. We subtracted treatment costs for antiviral therapy from their calculations so we could substitute up-to-date costs for current antiviral treatment. They reported costs in 2009 US dollars. We converted these to 2017 US dollars, once again, using the medical care component of the Consumer Price Index for the appropriate time periods. In this analysis, fibrosis stages F0, F1, F2, and F3 were grouped together as asymptomatic liver disease. The annual health care costs of patients with HCV and asymptomatic liver disease, compensated cirrhosis (Metavir fibrosis stage F4), decompensated cirrhosis, hepatocellular carcinoma, and liver transplant during the first year and the following years, were as follows: $4402, $33,893, $54,073, $214,622, and $48,858, respectively. Cost estimates for medications were obtained from the Federal Supply Schedule26 for base-case estimates, and from Red Book 2017 for sensitivity analyses.27 The monthly cost of sofosbuvir–velpatasvir in the Federal Supply Schedule was $8090. Thus, a 12-week course cost $24,270. The wholesale acquisition cost was $24,920 per month. We used this as an upper bound in our probabilistic sensitivity analyses. The monthly cost of glecaprevir–pibrentasvir in the Federal Supply Schedule was $9830. Thus, an 8-week course for patients with noncirrhotic liver disease cost $19,660 and a 12-week course for patients with compensated cirrhosis cost 29,490. The Veterans Administration’s acquisition cost was $7260, whereas the wholesale acquisition cost was $12,400. We used these as the lower and upper bounds for sensitivity analyses. The monthly cost of sofosbuvir–velpatasvir– voxilaprevir in the Federal Supply Schedule was $19,285. Patients who failed to achieve SVR with sofosbuvir– velpatasvir received a 12-week course of this regimen at a total cost of $57,855. As upper and lower bounds for probabilistic sensitivity analyses, we used the wholesale acquisition cost of $24,920 per month, and the Veterans Administration’s acquisition cost of $18,541. Monthly costs for ribavirin were $188 (1200 mg orally qd for weight-based dosing of patients >75 kg). As described earlier, we used wholesale acquisition costs and Veterans Administration acquisition costs as upper and lower bounds for sensitivity analyses. These were $277 and $99 per month, respectively. For procedures, laboratory tests, and office visits, the average Medicare reimbursement in 2017 for the corresponding Current Procedural Terminology28,29 codes were used as a proxy for cost. Reimbursement for professional services was calculated from the nonfacility total relative value units using the 2017 global conversion factor.

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References 1. Centers for Disease Control and Prevention. Locations and reasons for initial testing for hepatitis C infection - chronic hepatitis cohort study, United States, 2006-2010. Morbid Mortal Wk Rep 2013;62:645–648. 2. Eckman MH, Talal AH, Gordon SC, et al. Cost-effectiveness of screening for chronic hepatitis C infection in the United States. Clin Infect Dis 2013;56:1382–1393. 3. Bedossa P, Poynard T. An algorithm for the grading of activity in chronic hepatitis C. The METAVIR Cooperative Study Group. Hepatology 1996;24:289–293. 4. Thein HH, Yi Q, Dore GJ, et al. Estimation of stage-specific fibrosis progression rates in chronic hepatitis C virus infection: a meta-analysis and meta-regression. Hepatology 2008; 48:418–431. 5. Willems M, Metselaar HJ, Tilanus HW, et al. Liver transplantation and hepatitis C. Transpl Int 2002;15:61–72. 6. Aranda-Michel J, Dickson RC, Bonatti H, et al. Patient selection for liver transplant: 1-year experience with 555 patients at a single center. Mayo Clin Proc 2008; 83:165–168. 7. Kemmer N, Alsina A, Neff GW. Social determinants of orthotopic liver transplantation candidacy: role of patient-related factors. Transplant Proc 2011;43:3769–3772. 8. Feld JJ, Jacobson IM, Hezode C, et al. Sofosbuvir and velpatasvir for HCV genotype 1, 2, 4, 5, and 6 infection. N Engl J Med 2015;373:2599–2607. 9. Foster GR, Afdhal N, Roberts SK, et al. Sofosbuvir and velpatasvir for HCV genotype 2 and 3 infection. N Engl J Med 2015; 373:2608–2617. 10. Zeuzem S, Feld J, Wang S. ENDURANCE-1: efficacy and safety of 8- versus 12-week treatment with ABT-493/ABT-530 in patients with chronic HCV genotype 1 infection [abstract 253]. 67th Annual Meeting of the American Association for the Study of Liver diseases, 2016. Available at: http://www.hcvguidelines. org. Accessed September 29, 2017. 11. Hassanein T, Wyles D, Wang S, et al. SURVEYOR-II, part 4: glecaprevir/pibrentasvir demonstrates high SVR rates in patients with HCV genotype 2, 4, 5, or 6 infection without cirrhosis following an 8-week treatment duration [abstract LB-15]. 66th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD). 2016. 12. Puoti M, Foster GR, Wang S, et al. High SVR12 with 8-week and 12-week glecaprevir/pibrentasvir: integrated analysis of HCV genotype 1-6 patients without cirrhosis. J Hepatol 2018; 69:293–300. 13. Zeuzem S, Foster GR, Wang S, et al. Glecaprevir-pibrentasvir for 8 or 12 weeks in HCV genotype 1 or 3 infection. N Engl J Med 2018;378:354–369. 14. Asselah T, Hezode C, Zadeikis N, et al. ENDURANCE-4: efficacy and safety of ABT-493/ABT-530 treatment in patients with chronic HCV genotype 4, 5, or 6 infection [abstract 114]. 67th Annual Meeting of the American Association for the Study of Liver Diseases, Boston, MA, 2016.

Cost Effectiveness of Universal HCV Screening 939.e4 15. Forns X, Lee SS, Valdes J, et al. Glecaprevir plus pibrentasvir for chronic hepatitis C virus genotype 1, 2, 4, 5, or 6 infection in adults with compensated cirrhosis (EXPEDITION-1): a singlearm, open-label, multicentre phase 3 trial. Lancet Infect Dis 2017;17:1062–1068. 16. Kwo PY, Wyles D, Wang S, et al. 100% SVR4 with ABT-493 and ABT-530 with or without ribavirin in treatment-naïve HCV genotype 3-infected patients with cirrhosis. J Hepatol 2016;64:S208. 17. Bourliere M, Gordon SC, Flamm SL, et al. Sofosbuvir, velpatasvir, and voxilaprevir for previously treated HCV infection. N Engl J Med 2017;376:2134–2146. 18. Omland LH, Jepsen P, Krarup H, et al. Increased mortality among persons infected with hepatitis C virus. Clin Gastroenterol Hepatol 2011;9:71–78. 19. Omland LH, Krarup H, Jepsen P, et al. Mortality in patients with chronic and cleared hepatitis C viral infection: a nationwide cohort study. J Hepatol 2010;53:36–42. 20. Poynard T, Bedossa P, Opolon P. Natural history of liver fibrosis progression in patients with chronic hepatitis C. The OBSVIRC, METAVIR, CLINIVIR, and DOSVIRC groups. Lancet 1997; 349:825–832. 21. Chhatwal J, Kanwal F, Roberts MS, et al. Cost-effectiveness and budget impact of hepatitis C virus treatment with sofosbuvir and ledipasvir in the United States. Ann Intern Med 2015; 162:397–406. 22. Davis KL, Mitra D, Medjedovic J, et al. Direct economic burden of chronic hepatitis C virus in a United States managed care population. J Clin Gastroenterol 2011;45:e17–e24. 23. McAdam-Marx C, McGarry LJ, Hane CA, et al. All-cause and incremental per patient per year cost associated with chronic hepatitis C virus and associated liver complications in the United States: a managed care perspective. J Manag Care Pharm 2011;17:531–546. 24. Rein DB, Smith BD, Wittenborn JS, et al. The cost-effectiveness of birth-cohort screening for hepatitis C antibody in U.S. primary care settings. Ann Intern Med 2012;156:263–270. 25. US Department of Labor Bureau of Labor Statistics. Consumer price index. In: Archived consumer price index detailed report information, 2017. 2017. Available at: https://www.bls.gov/cpi/ tables/detailed-reports/home.htm. Accessed September 20, 2017. 26. United States Department of Veterans Affairs. Federal supply schedule - pharmaceutical prices. Vol 2018. United States Department of Veterans Affairs, Office of Acquisition and Logistics (OAL), 2018. 27. Red Book Online. Montvale, NJ: Thomson Medical Economics, 2017. 28. Centers for Medicare and Medicaid Services. Clinical laboratory fee schedule. 2017 clinical laboratory fee schedule file, 2017. Hyattsville, MD: US Department of Health and Human Services, 2017. 29. Centers for Medicare and Medicaid Services. Physician fee schedule. 2017 national physician fee schedule relative value file, 2017. Hyattsville, MD: US Department of Health and Human Services, 2017.

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A

RIBA positive | HCV AB positive RNA negative PCR negative

RIBA negative | No Infection Genotype 1a

EIA positive

UNIVERSAL SCREENING

Eligible & Accepts Treatment Member Birth Cohort

BIRTH COHORT SCREENING

Genotype 2

PCR positive

Caucasian

Male

Genotype 1b

Ineligible or Declines Treatment

Genotype 4

Chronic HCV Infection

Genotype 3

NS5A RAS +

African American Not Member Birth Cohort

Female Hispanic

MARKOV

HCV AB positive

NO SCREENING

NS5A RAS HCV AB positive RNA negative

EIA negative

No Infection

B

Die

Uninfected

Dead

HCV Antibody positive | RNA negative

Survive F0

Die

Dead

F1

Treat F2

?Treat F3

F0 F1 F2 F3 | Genotype 1,2,3,4

Treatment – Genotypes 1,2,3,4; F0=>F3

Compensated Cirrhosis | Genotypes 1,2,3 - RAS negative, 4

Treatment – Genotypes I,2,3 RAS - negative, 4; Compensated Cirrhosis

Compensated Cirrhosis | Genotype 3 - RAS positive

Treatment – Genotype 3 RAS positive; Compensated Cirrhosis

Progression

Next Stage

Don’t Treat No Progression

Current Stage

F4

Liver Transplant

Carcinoma Decompensated Cirrhosis

Hepatocellular Carcinoma

s/p Liver Transplant

Decompensated Cirrhosis Die

Dead

Survive

Dead No Progression

s/p Liver Transplant

Die

s/p Liver Transplant for Carcinoma

Survive

?Treat

No Transplant

Dead

No – Continue Rx Treatment – Genotypes I,2,3,4 - F0 => F3

Die

F0 HCV RX

F0

?Rx Completed F1 SVR

Treatment – Genotypes I,2,3 RAS – negative, 4 – Compensated Cirrhosis Treatment – Genotype 3 RAS – positive - Compensated Cirrhosis

?SVR Die

Post-Treatment – Compensated Cirrhosis

F2

Dead

F2

No SVR

Post-Treatment – F0 => F3

Die

F1 Post RX

F3 F3

Dead

Survive Dead

F4 F4

Dead

Supplementary Figure 1. (A) Decision tree model. (B) Markov model. AB, antibody; EIA, ELISA; PCR, polymerase chain reaction; RAS, resistance associated substitution; Rx, treatment; s/p, status post.

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F0

F1

∞

Markov Model

DEAD

F2

F3

F4 Supplementary Figure 2. State transitions for Metavir fibrosis stages.

Members of Birth Cohort 0.5504

0.1503

0.1491

0.1409

F1

F2

F3

0.0093 F0

F4

Not Members of the Birth Cohort 0.4475

0.2231 0.1377

F0

0.1097

F1

F2

F3

0.0820

F4

METAVIR Fibrosis Stage Supplementary Figure 3. Seed distributions of Metavir fibrosis stages at beginning of Markov simulation.

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Supplementary Figure 4. Natural history of chronic hepatitis C infection - health state transitions across lifetime. HCC, hepatocellular carcinoma; s/p, status post.

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0.6

Cumulave Probability

0.5

compensated cirrhosis

0.4

0.3

decompensated cirrhosis

0.2

Supplementary Figure 5. Cumulative probability of complications of end-stage liver disease. HCC, hepatocellular carcinoma.

0.1

HCC Liver Transplant for Decompensated Cirrhosis Liver Transplant for HCC

0 0

5

10

Supplementary Figure 6. Cost-effectiveness acceptability curve.

15

20

25

Years from Start of Simulaon

30

35

40

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Supplementary Table 1. Life Expectancy of Subgroups Life expectancy, y Men Not infected All HCV-antibody positive HCV-antibody positive, RNA negative HCV-infected Women Not infected All HCV-antibody positive HCV-antibody positive, RNA negative HCV-infected

32.58 16.44 27.25 13.40 36.40 17.39 28.92 14.15

Supplementary Table 2. Natural History Model Calibration: Comparison of Outcomes for HCV-Infected Individuals Outcome Overall survival 5-year 10-year Liver-related death 5-year 10-year Non–liver-related death, natural and unnatural 5-year 10-year

Natural history model

DANVIR cohort

% survival 83.6 66.3 Cumulative probability of death, %%

% survival (95% CI) 81.7 (80.2–83.2) 67.8 (64.9–70.8) Cumulative probability of death, % (95% CI)

4.6 11.7

5.3 (4.5–6.2) 9.9 (8.1–11.8)

11.8 22.0

13.0 (11.2–15.0) 22.3 (18.8–26.1)