Cost-effectiveness of Universal and Targeted Hepatitis C Virus Screening in the United States

IMPORTANCE Between 2 and 3.5 million people live with chronic hepatitis C virus (HCV) infection in the US, most of whom (approximately 75%) are not aware of their disease. Despite the availability of effective HCV treatment in the early stages of infection, HCV will result in thousands of deaths in the next decade in the US. OBJECTIVE To investigate the cost-effectiveness of universal screening for all US adults aged 18 years or older for HCV in the US and of targeted screening of people who inject drugs. DESIGN, SETTING, AND PARTICIPANTS This simulated economic evaluation used cohort analyses in a Markov model to perform a 10 000-participant Monte Carlo microsimulation trail to evaluate the cost-effectiveness of HCV screening programs, and compared screening programs targeting people who inject drugs with universal screening of US adults age 18 years or older. Data were analyzed in December 2019. EXPOSURES Cost per quality-adjusted life-year (QALY). MAIN OUTCOMES AND MEASURES Cost per QALY gained. RESULTS In a 10 000 Monte Carlo microsimulation trail that compared a baseline of individuals aged 40 years (men and women) and people who inject drugs in the US, screening and treatment for HCV were estimated to increase total costs by $10 457 per person and increase QALYs by 0.23 (approximately 3 months), providing an incremental cost-effectiveness ratio of $45 465 per QALY. Also, universal screening and treatment for HCV are estimated to increase total costs by $2845 per person and increase QALYs by 0.01, providing an incremental cost-effectiveness ratio of $291 277 per QALY. CONCLUSIONS AND RELEVANCE The findings of this study suggest that HCV screening for people who inject drugs may be a cost-effective intervention to combat HCV infection in the US, which could potentially decrease the risk of untreated HCV infection and liver-related mortality. JAMA Network Open. 2020;3(9):e2015756. doi:10.1001/jamanetworkopen.2020.15756


Introduction
The exact number of individuals in the US who are currently infected with hepatitis C virus (HCV) (presence of HCV RNA) is unknown, but it is estimated to be more than 2 million people and as many as 3.5 million people. 1,2 Most individuals with HCV infection (approximately 75%) are not aware of their infection because few symptoms are evident in the early stages of the disease. 3,4 However, 70% to 85% of acute HCV infections become a chronic disease. 5  HCV causes nearly 40% of all chronic liver disease and is among the most common indications for liver transplantation in the US. 7,8 From 2003 to 2014, 20 782 adults with chronic HCV underwent liver transplantation. 8 HCV infection accounted for approximately 18 000 deaths in the US in 2016, 9,10 and HCV infection-related mortality exceeds all other deaths from infectious diseases combined. 11 Most people with HCV in the United States are individuals born between 1946 and 1964 (ie, the Baby Boomers). 12 However, due to the slow progression of hepatitis C disease, the disease may remain undiagnosed for decades. 12 Infection rates among persons who inject drugs (PWID) range from 30% to 90%, depending on frequency and duration of use, and account for approximately 60% of all HCV cases in the US. [13][14][15][16][17] In 2011, the number of adults and adolescents (US population aged 13 years or older) who had injected drugs in their lifetime was reported to be approximately 6.6 million people. 18 Therefore, while rates of HCV are higher among an older population, the US opioid epidemic has led to an evolving epidemiology of HCV. 4 Sharing needles among PWID is a key risk factor for HCV transmission in US prisons and jails. 19 Inmates in correctional institutions account for up to one-third of all US hepatitis C cases. 20,21 Compared with a 1% infection rate for the general US population, HCV infection rates are particularly high in correctional institutions and range from 17.4% to 23.1%. 20,21 One in 10 million people who pass through correctional settings each year have an undiagnosed HCV infection; more than 90% of these individuals are released to the general population. [22][23][24] Throughout, these individuals may have little contact with the health care system, and as a result play a prominent role in the spread of HCV in US communities. [23][24][25][26] HCV treatment can be very effective, especially if HCV is diagnosed in the early stages of the infection. 27 Existing research shows that universal HCV screening in developed countries is effective. [28][29][30] Prior studies on the cost-effectiveness of HCV screening in the US examined voluntary screening, specific population groups (eg, individuals born in the Baby Boomer generation, women experiencing pregnancy, volunteers for blood donations, and screening performed in US primary care settings), or older forms of treatment. [31][32][33][34][35] However, few studies that have assessed the costeffectiveness of HCV screening in the US account for recent and highly effective treatment regimens for HCV. Furthermore, the cost of new drugs is relatively lower than older drugs; prices for HCV treatments have decreased by approximately half. In the absence of such knowledge, the costeffectiveness of universal and targeted screening for HCV remains uncertain.
The primary aim of this study was to assess and compare the cost-effectiveness of targeted screening for people who inject drugs with a universal HCV screening program for US adults aged 18 years or older, considering the most effective and recent medical treatments for HCV.

Methods
This study was conducted based on structured reporting of economic evaluations of health interventions according to Consolidated Health Economic Evaluation Reporting Standards (CHEERS) guideline. 36 CHEERS was followed in study assumptions and for reporting the cost-effectiveness analysis of universal HCV screening and targeted screening for PWID. The Common Rule exempts this study from institutional board review because no human participants were involved.

Natural History of HCV
This study was conducted using a decision-analytic Markov model of the natural history and progression of HCV to evaluate the cost-effectiveness of screening for HCV in the US population. The Markov model used in this study, based on the natural history of HCV according to empirically calibrated models, clinical characteristics, and published literature, [37][38][39] shows disease progression for a person with HCV infection using a 10-year horizon (Figure 1). The base case at the time of screening and diagnosis was considered 40 years, which is approximately the median age in the US.
Disease progression was described in terms of METAVIR score, a liver biopsy staging system that assesses the severity of liver fibrosis. 40 METAVIR scores assess the degree of scarring or fibrosis

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Cost-effectiveness of Universal and Targeted Hepatitis C Virus Screening in the United States of the liver, ranging from F0 (no fibrosis) to F4 (cirrhosis). Health states were categorized in 2 main phases of disease progression: fibrosis progression stages F0 to F4, and nonfibrosis progression after stage F4. Health states included healthy (no HCV), no fibrosis (F0), portal fibrosis with no septa (F1), portal fibrosis with few septa (F2), numerous septa without cirrhosis (F3), compensated cirrhosis (F4), decompensated cirrhosis, hepatocellular carcinoma, post-hepatocellular carcinoma, liver transplantation, and post-liver transplantation. [40][41][42] Without treatment, patients in the F0 state might experience spontaneous clearance of the HCV and return to a no HCV state in state F0.
Otherwise, patients may progress to the next severity state of the disease (Figure 1). Patients who receive treatment and achieve sustained virologic response will transition to recovered states based on fibrosis severity. Patients with compensated cirrhosis who do not receive treatment will transition to hepatocellular carcinoma or decompensated cirrhosis and may receive liver transplantations.
Because natural death could occur while a patient is in any state, likelihood of natural death in the Markov model is based on US life tables. 43 Death from the disease can occur in the final nonfibrosis progression states. People may be reinfected at the same rate (1%) as the general population during and after successful treatment and, if reinfected, 44 will begin fibrosis progression from the F0 state.
The initial fibrosis state distribution was based on existing literature. 45 The fibrosis transition rates (

Treatment
The treatment regimen included in this analysis was a combination of glecaprevir and pibrentasvir, used to treat chronic HCV genotypes 1, 2, 3, 4, 5, or 6 without cirrhosis or with compensated cirrhosis.
The treatment protocol is 3 tablets (100 mg glecaprevir and 40 mg pibrentasvir) taken daily for 8 weeks. The treatment is highly effective, with a success rate of 98%. 46 The regimen is not effective for people with advanced cirrhosis (ie, decompensated cirrhosis).

Cost
Direct medical costs related to HCV included in the study are listed in Table 1. Drug costs in this study were based on wholesale acquisition cost, which is an estimate of the manufacturer's list price and does not include discounts or rebates, and covered the duration of the treatment. 47 Health state medical costs, which are the cost of treatment based on the severity and progress of the disease, were obtained from the published literature on an annual timeframe. 37,48,50 Costs considered included visits (inpatient and outpatient), diagnostic and laboratory testing, physician services, emergency department place of service, and pharmacy. 44,48 The total cost for liver transplantation was obtained from US organ and tissue transplantation cost estimates provided by a prior study. 49 The cost of an HCV screening test was assumed to be $140 based on the existing literature. 50 Finally, the cost of no HCV was assumed to be $0. Costs were inflation-adjusted to 2019 US dollars using the US Consumer Price Index, when necessary. 51

Statistical Analysis
The primary outcome of this study was quality-adjusted life-years (QALYs) gained, and incremental   Results from a 10 000 trial Monte Carlo microsimulation analysis showed that PWID screening vs status quo is estimated to reduce liver-related mortality by 88 deaths and new infections by 8754.

Results
In addition, the model estimated that the number of liver transplantations decrease by 18 during a 10-year horizon. Results from a 10 000 trial Monte Carlo microsimulation analysis showed that universal screening vs the status quo is estimated to reduce liver-related mortality by 1 death and new infections by 3053 during a 10-year horizon.
Results from the 2-way sensitivity analysis for PWID showed that, based on the assumption that 60% of PWID have HCV infection and the reinfection rate is 1%, the cost of the HCV drug treatment could increase from $26 400 to $29 054 per PWID and ICER would still be less than $50 000 per QALY, meaning HCV screening would still be cost-effective (Figure 2). Additionally, HCV screening for PWID is estimated to be cost-effective over a broad range of HCV infection rates. Given the HCV drug treatment cost of $26 400 per patient, the HCV infection rate could decrease to 40% and ICER  would still be less than $50 000 per QALY; HCV screening would still be cost-effective. Moreover, based on the assumption that 60% of the PWID have HCV infection and that HCV drug treatment costs $26 400 per patient, the reinfection rate could increase to 3.5% and the ICER would still be less than $50 000 per QALY and HCV screening would still be cost-effective.
Universal HCV screening could be cost-effective across a range of HCV infection rates and costs of HCV drug treatment. For example, if the cost of the HCV drug treatment decreased from $26 400 to $13 200 per patient and the infection rate increased to 10%, the ICER would be less than $50 000 per QALY and HCV screening would still be cost-effective. Also, if the infection rate increased to 4% and the cost of the HCV drug treatment decreased to $2640 per patient, the ICER would be less than $50 000 per QALY and HCV screening would still be cost-effective. However, universal screening for the total adult US population was not cost-effective in our analysis.
Our study findings for PWID-targeted HCV screening were consistent with results of screening of high-risk populations reported in other countries, including the Netherlands, Canada, Japan, and the United Kingdom. [28][29][30]56 Previous studies of HCV screening in the US are mixed. HCV screening is reported to be cost-effective when the prevalence of HCV is high in the total population or in The dark blue portion of each bar represents the low range of the parameter listed on the y-axis, and the light blue portion of the bar represents the high range of the parameter. When dark blue is on the left and light blue on the right, the ICER increases as the parameter value increases; when light blue is on the left of the baseline, ICER decreases as parameter value increases. EV indicates expected value; HCV, hepatitis C virus; ICER, incremental cost-effectiveness ratio. In our study, a combination of glecaprevir and pibrentasvir was examined as the drug treatment of early stage HCV. It is a highly effective regimen that is low cost relative to older drug protocols, costing $26 400 for an 8-week treatment period. However, despite the lower cost, screening of all US adults was not found to be cost-effective in our analysis, resulting in an ICER of nearly $300 000 per QALY.
Our study also analyzed the cost-effectiveness of targeted HCV screening for the PWID population. The prevalence of HCV infection among PWID is very high, having been estimated to be between 30% to 90%. 13-17 Addressing HCV infection among PWID by diagnosing and treating infection in its early stages can prevent many HCV-related complications and deaths in the US and substantially decrease health care expenditures. Our study did not examine how PWID screening may be best accomplished. For example, routine screening of incarcerated populations may be effective. 22 However, ineffective or costly screening programs of PWID will limit the potential costeffectiveness that we report in our analysis.

Limitations
Our study has limitations. In the Markov model, potential HCV reinfection was assumed to be 1%, which is the probability of infection for the general population. However, HCV reinfection rates are higher among PWID (11%). 60 Furthermore, our model included only direct medical costs. Indirect costs related to HCV treatment may be significant, such as patient mental health status and caregiver costs. We used wholesale acquisition costs, which are frequently used in economic analysis because they are reasonably transparent and consistent. 61 Direct cost estimates were obtained from published sources and may not fully reflect the actual costs of treatment for a particular region or medical system within the US. Finally, our modeling assumes individuals complete the 8-week drug treatment regimen if diagnosed. To the extent that individuals fail to complete the regimen, our analysis may overstate the cost-effectiveness of screening.

Conclusions
Drug injection is a key risk behavior for HCV infection, resulting in an infection rate among PWID of 30% to 90%. If untreated, HCV infection may progress to liver cirrhosis and, ultimately, death. New drug protocols have been developed to successfully treat HCV, and this study examines the costeffectiveness of targeted screening of PWID and universal screening for the US adult population.
Results from our analysis, using an ICER of $50 000 per QALY as a cutoff, suggest that HCV screening that is tailored to PWID is cost-effective in averting premature deaths and liver transplantations associated with HCV disease progression.

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Cost-effectiveness of Universal and Targeted Hepatitis C Virus Screening in the United States