The Wider Public Health Value of HCV Treatment Accrued by Liver Transplant Recipients

May 3, 2016
Anupam B. Jena, MD, PhD
Anupam B. Jena, MD, PhD

,
Warren Stevens, PhD
Warren Stevens, PhD

,
Yuri Sanchez Gonzalez, PhD
Yuri Sanchez Gonzalez, PhD

,
Steven E. Marx, PharmD
Steven E. Marx, PharmD

,
Timothy Juday, PhD
Timothy Juday, PhD

,
Darius N. Lakdawalla, PhD
Darius N. Lakdawalla, PhD

,
Tomas J. Philipson, PhD
Tomas J. Philipson, PhD

Volume 22, Issue SP 6

Advances in treatment for hepatitis C virus (HCV) have the potential to generate considerable spillover benefits to patients awaiting transplants, especially among those with non—HCV-mediated liver failure.

ABSTRACT

Objectives: Organs for transplantation are scarce, but new medical therapies can prevent organ failure and the need for transplants. We sought to describe the unique value created by treatments that spare organs from failure and thus conserve donated organs for transplant into others, using hepatitis C virus (HCV) as a case study.

Study Design: Epidemiologic-economic model.

Methods: Using data on trends in chronic liver disease, liver disease progression, and liver transplant allocation models, as well as the effectiveness of new HCV treatments, we estimate the potential effects of systematic HCV screening and treatment on the demand for liver transplants in the United States. We estimate the spillover benefits to patients with all-cause liver disease in terms of increased availability of transplants and life-years gained.

Results: We estimated that systematic HCV screening and treatment could spare 10,490 liver transplants to HCV-infected patients from 2015 to 2035. An estimated 7321 transplants would accrue to patients with end-stage liver disease without HCV and 3169 transplants to those with uncured HCV, providing approximately 52,700 and 22,800 additional life-years, respectively.

Conclusions: Treatment advances for HCV have the potential to generate considerable spillover benefits to patients awaiting transplants for non—HCV-mediated liver failure. For other diseases in which organ transplants are in short supply, our study provides a novel pathway by which positive spillovers may accrue from treatments that prevent end-stage organ disease.

Am J Manag Care. 2016;22(5 Spec Issue No. 6):SP212-SP219

Take-Away Points

  • Organs for transplantation are scarce, but innovative hepatitis C virus (HCV) therapies can prevent liver failure and the need for transplants.
  • Systematic HCV screening and treatment would spare 10,490 livers for transplant over 20 years, with almost 70% of these livers benefitting patients with non—HCV-mediated liver failure.
  • The increased availability of donor livers will lead to 52,700 additional life-years for patients without HCV infection and 22,800 life-years for patients with HCV, providing economic values of $7.9 billion and $3.5 billion, respectively.
  • Such spillover benefits to untreated populations underscore the value of innovative therapies in preventing organ failure.

Medical treatments can offer value to society that extends beyond the patients who are directly treated. For example, vaccinations not only reduce the likelihood of infection in those who are vaccinated, they also reduce the spread of infection. Such positive spillovers generate considerable value.1,2 These spillovers may also result from the treatment of diseases that would otherwise lead to organ damage and transplantation. For example, improvements in nephropathy treatment within diabetes reduce the incidence of end-stage renal disease, thus sparing kidneys for use in patients with end-stage renal disease who do not have diabetes.

eAppendix

The availability of organs for transplantation is scarce. In the United States alone, more than 7000 individuals die awaiting organ transplantation each year.3 In this study, we explored this idea by applying it to recently introduced therapies for hepatitis C virus (HCV) infection. An estimated 3 million individuals in the United States are affected by chronic HCV, a condition associated with long-term injury to the liver and with complications including cirrhosis, hepatocellular carcinoma, and, ultimately, liver failure (see , available at www.ajmc.com, for further details).4,5 The most common reason for liver transplantation in the United States is end-stage liver disease (ESLD), and currently, nearly 50% (14,000/29,000) of ESLD cases among transplant recipients are due to HCV.3

Until recently, treatments for HCV were neither particularly effective nor well tolerated.6 However, newer HCV therapies suppress the virus in more than 90% of patients, making an effective cure of HCV highly likely for the majority of those affected.7-9 Curing patients of HCV obviates their need for future liver transplantation due to HCV, thus creating opportunities for transplantation into patients with other forms of ESLD.

Currently, only one-third of Americans who need liver transplants receive them,10 and shortages are expected to rise as the transplant waiting list continues to grow while the supply of organs remains flat.11 Obesity and the aging of the population are reducing the quality of deceased donor livers, while obesity-related liver disease is also increasing the demand for them.12

We simulated the effect of a systematic HCV screening and treatment program in the United States on the number of livers spared from transplantation into patients with HCV-mediated ESLD. We estimated the number of these spared livers that could be transplanted into patients with other forms of ESLD, as well as the resulting benefits to both groups. Our analysis takes a broader perspective than do existing models of HCV burden5,13-17 because it recognizes that treatment of patients with HCV creates positive spillovers for non-HCV patients with ESLD.

METHODS

Overview of Data Sources

Our study relied on 2 main data sources: first, the National Health and Nutrition Examination Survey (NHANES), a biennial survey administered to a nationally representative sample of the US population. Along with a survey of health and healthcare utilization, participants also give blood samples and undergo other diagnostic tests. This data set was used to generate trends over time in liver disease and in key risk factors. Our second data source was the United Network for Organ Sharing (UNOS) database, which holds information on every patient on the waiting list for organ transplantation in the United States since 1987, including patient characteristics, primary disease, source of organ, and time spent on waiting list.

Overview of Approach

We developed an epidemiologic-economic model to estimate how a systematic HCV screening and treatment program would: a) reduce the number of livers transplanted into patients with HCV with ESLD and b) increase the number of spared livers that could be transplanted into patients with other forms of ESLD. We converted livers spared into life-years by using prior literature on life expectancy gained from transplants. Finally, we transformed these longevity benefits into economic values using conventional estimates of the value of a statistical life-year.18,19

We compared the effects of 2 types of HCV screening and treatment interventions (“real-world” and “comprehensive”) with a baseline in which screening and treatment did not change from the status quo. First, we simulated the baseline annual demands for liver transplants from 2015 to 2035, for patients with ESLD, according to underlying disease (ie, HCV, alcohol-related, and nonalcoholic fatty liver disease [NAFLD]). Second, using historical data on national liver transplantation rates, we projected the supply of livers available for transplantation from 2015 to 2035. Third, we performed a simulation of how 2 different interventions in HCV screening and treatment would reduce the demand for liver transplantation among patients with HCV-mediated ESLD during 2015 to 2035. Together, these steps estimated, year-by-year, the impact of systematic HCV screening and treatment on the number of livers newly spared for transplantation.

Projected Annual Baseline Demand for HCV-Mediated Liver Transplants

We obtained HCV prevalence data from 2001 to 2012 from NHANES and annual HCV incidence data from 2001 to 2010 from the CDC.20 The incidence of HCV was estimated to be 17,000 cases in 2010 (see eAppendix).20 In our baseline scenario, we assumed constant incidence of 18,000 cases per year from 2011 onward.

Figure 1

To estimate the baseline demand for transplants among patients with HCV-mediated ESLD, we adapted previous HCV modeling studies21 to develop a Monte Carlo Markov simulation model that transitioned patients through each stage of liver disease, from chronic infection without liver fibrosis to decompensated cirrhosis or hepatocellular carcinoma. The latter 2 states comprise candidacy for liver transplantation ( describes the Markov model). The conceptual flow diagram highlights the inputs to the model, steps taken to validate key model assumptions, and the model outputs: a) livers spared from transplantation into patients with HCV as a result of a systematic HCV screening and treatment intervention, and b) the allocation of these spared livers to patients without HCV and patients with uncured HCV on the transplant list.

Projected Annual Baseline Demand for Non—HCV-Mediated Liver Transplants

Figure 2

To project the baseline demand for liver transplants among individuals with non—HCV-mediated ESLD, we used data from UNOS. We counted the number of individuals on the liver transplant waiting list with a primary diagnosis of NAFLD or liver disease due to alcohol, iron deposition, or copper deposition. As illustrated in , the incidence of NAFLD on the transplant waitlist increased significantly in the last decade. From historical data, we linearly extrapolated the annual incidence of NAFLD from 2015 to 2035, and we assumed that rates of liver disease due to alcohol or iron/copper deposition increased linearly until 2025. Based on prior studies,22 we allowed for a “leveling off” between 2025 and 2035 by reducing the linearly extrapolated rates by 1.5% per year.

Projected Annual Number of Patients Receiving Transplant

Using our incidence forecasts, we projected the annual number of patients with HCV-mediated and non—HCV-mediated ESLD receiving liver transplants. Not all patients on the waiting list receive transplants; the likelihood of transplant varies by etiology of liver disease and clinical severity. UNOS data record whether and when a patient receives a liver transplant, as well as time spent on the waitlist. Using individual-level data from UNOS, we estimated the likelihood of liver transplantation as a function of time spent on the waitlist, adjusting for patient age, sex, and body mass index (BMI). Empirically, the probability of transplantation varied by sex and BMI among patients with HCV-mediated liver disease, but not among those without it. We applied sex- and BMI-specific transplant probabilities to HCV-mediated ESLD incidence estimates to project transplants for patients with HCV from 2015 to 2035. For non–HCV-mediated patients with ESLD, we used unadjusted Kaplan-Meier estimates of the probability of transplantation at a given year (45.7%, 52.3%, 54.8%, 56.4%, and 57.3%, after 1, 2, 3, 4, and 5 years, respectively).

Projected Supply of Livers Available for Transplantation

The supply of livers available for transplantation, at approximately 6700 per year (2.25 per 100,000 population), remained the same from 2005 to 2013. We conservatively assumed the liver supply would grow proportionately with the population from 2015 to 2035. We conducted several sensitivity analyses around this assumption, as described below.

Effect of HCV Screening and Treatment on Rates of HCV-Mediated ESLD and Liver Transplants

We simulated the annual impact of implementing two 5-year policies to screen for and treat HCV. We assumed that treatment with novel HCV therapies leads to sustained virologic response (SVR) rates of 90% among patients with liver disease fibrosis in stages F0 to F4 where severity of diseases increases with fibrosis stage.21,23 Subjects achieving SVR at stage F4 were assumed to either remain in SVR or to transition to either decompensated liver disease (at an annual probability of 0.008) or hepatocellular carcinoma (at an annual probability of 0.005).24

In reality, some patients may not accept screening, others may not receive their results, and still others who are aware of their HCV infection may not initiate treatment. Our real-world screening and treatment intervention rate relies on prior studies to assume that the percent of patients accepting HCV screening is 91%25 and the percent of those screened positive who initiate treatment is 80% (regardless of liver fibrosis stage).21,22,26,27

We calculated the difference in the transplant waitlist size between the real-world scenario and a baseline scenario in which HCV screening and treatment remained at current rates from 2015 to 2035. In the real-world scenario, screening would take place over 5 years during 2015 to 2019, with 100% of patients with HCV aware of their disease status by 2019. In the baseline scenario, we assumed that 25% of subjects between F0 and F3 would be aware of their HCV status, and 75% of subjects would be aware of it at F4.21 In both scenarios, we used Markov models to project the annual number of patients with and without HCV on the liver transplantation waitlist from 2015 to 2035. Finally, we calculated the number of livers spared and the number of additional patients receiving transplants in the real-world scenario. (Additional details are in the eAppendix.)

Measuring Spillovers in Terms of Number and Value of Life-Years Gained

To estimate the economic value of these gains, we applied a value of $150,000 per life-year.18,19 We computed life-years gained from newly available liver transplants using prior research, estimating that each new transplant adds 7.2 years of life.28 To calculate social value as life-years gained multiplied by $150,000, we utilized prior research estimating the value of a quality-adjusted life-year.29-31

Sensitivity Analyses

We conducted 3 additional sensitivity analyses. First, we simulated the impact of a comprehensive HCV screening and treatment scenario, with 100% take-up of screening and treatment and 90% effectiveness for those treated. This exercise assessed the potential maximum impact of a systematic screening and treatment program. Second, we assumed a rising, rather than constant, incidence of liver disease due to alcohol, iron deposition, or copper deposition. Third, we simulated the impact of an opt-out organ donation policy, which allows organs from deceased donors to be used unless the deceased has officially requested otherwise.32-34 Under current law, individuals must opt in and officially request to make their organs available for potential transplants in the event of death. Based on recent meta-analyses, we estimated that an opt-out policy in the United States would increase the supply of livers by 45%.34

RESULTS

Table 1

The impact of a systematic HCV screening and treatment program on the total number of livers spared from 2015 to 2035 is shown in . The projected numbers of patients with HCV with each stage of liver fibrosis were lower under a systematic HCV screening and treatment program (our real-world scenario) relative to baseline. For example, the projected number of patients with HCV and decompensated liver failure was 30% lower under a systematic HCV screening and treatment program, and deaths from liver disease fell by 22%. The projected total number of new patients with HCV to be added to the liver transplant list between 2015 and 2035 was 28% lower under a systematic HCV screening and treatment program.

Table 2

Our model predicted that 45,541 livers would be transplanted into patients with HCV during the 2015-to-2035 period under the baseline scenario compared with 35,052 under the real-world HCV screening and treatment program. The 10,490 spared livers were projected to be primarily allocated to individuals on the waitlist with non—HCV-mediated ESLD (7321 liver transplants), with a lower proportion allocated to those with uncured HCV-mediated ESLD (3169 transplants). shows these spared livers broken down by subsets of patient characteristics.

×

×

The total life-years gained from additional transplants in each group were projected to be 52,711 years (7321 7.2 years) and 22,817 years (3169 7.2 years), respectively. This amounts to $7.9 billion in economic value accrued to patients with non—HCV-mediated liver disease over this time period, with an additional $3.5 billion accruing to patients with HCV. Of note, the total number of transplants and life-years gained from newly allocated transplants to patients with non–HCV-mediated ESLD were approximately twice as large as those gained by patients with uncured HCV ESLD requiring transplantation. This is due to the larger projected prevalence of patients who do not have HCV on the transplant waiting list after implementation of the HCV screening and treatment program.

Figure 3

shows the projected year-by-year cumulative number of liver transplants to patients without HCV and those with uncured HCV on the liver transplant list. At each year, the cumulative number of spared livers transplanted into patients with non—HCV-mediated ESLD is roughly twice that among those with uncured HCV on the transplant list. From 2015 to 2035, our model projected 80,451 liver transplantations to patients without HCV, of which the 7321 newly allocated spared livers would account for approximately 9% of the total.

Additional Analyses

Table 3

shows how our projections were affected by not only various sensitivity analyses regarding future trends in NAFLD and other liver disease, but by a comprehensive HCV screening and treatment scenario, in which both screening uptake and treatment rates were 100%, and by an opt-out organ donation policy in the United States that was estimated to increase the supply of transplantable livers by 45%.

We found that increasing trends in NAFLD and liver disease due to alcohol or iron/copper deposition would increase the total number of spared livers allocated to these patients from 7321 to 7653 between 2015 and 2035. The use of an opt-out policy for organ donation would further increase the number of livers spared from 7653 to 10,953, and a comprehensive HCV screening and treatment intervention would further raise the number of spared livers from 10,953 to 16,557.

DISCUSSION

Our findings highlight a novel mechanism by which positive disease spillovers occur when the same scarce resource—in this case transplantable organs—is used for treatment. We estimated that the treatment of HCV by novel direct-acting antiviral therapies may have large, positive spillovers by reducing the future number of liver transplants to patients with HCV, thus sparing livers for transplants into other patients with ESLD. We projected that 10,490 liver transplants to patients infected with HCV could be prevented over a 20-year period, with 7321 of these spared livers going to patients without HCV. Over this period, HCV screening or treatment would make nearly 1 in 10 liver transplants possible. Additionally, this intervention would provide approximately 52,000 additional life-years for patients with ESLD without HCV (valued at $7.9 billion).28 Because not all patients with HCV will be screened and successfully treated under the real-world scenario, the remaining 3169 spared livers would be allocated to patients with uncured HCV, generating an additional 22,817 life-years (valued at $3.5 billion).

Although our analysis focused on HCV, the disease spillover that we identified applies to other medical advances that reduce the demand for organ transplantation. This has important implications for how society values new treatments that may reduce the demand for future organ transplantation in the disease that is treated. For example, current policy debates around new HCV therapies and HCV screening policies revolve around the question of costs and benefits for patients given an HCV diagnosis and patients with undiagnosed HCV. Although that question is of utmost importance, this study demonstrates that these and other therapies may have an impact that extends beyond the population of patients who are directly treated. In countries with scarce liver supplies, for example, our analysis suggests that patients with ESLD who do not have HCV may still benefit from widespread HCV screening and treatment. To our knowledge, this point has not found its way into the broader public policy debate over HCV or other therapies that reduce the future demand for organ transplantation.

More generally, our research highlights an important mechanism through which organ shortages may be alleviated. This mechanism may be particularly significant, given the limited success of prior efforts to improve transplant supply rates (eg, improving the effectiveness of liver donor transplants,35 or expanding the supply of deceased donor livers by increasing the number of individuals signing up as organ donors10,12,36).

Our study also highlights the negative impact that the growing burden of a single disease can have on outcomes in other diseases. For example, it is widely recognized that increasing rates of obesity lead to higher population rates of hypertension, diabetes, hyperlipidemia, obstructive sleep apnea, and other diseases. Less well-appreciated is the resulting increase in the demand for liver and kidney transplants stemming from obesity-related complications.

Limitations

Our study had several limitations. First, our analyses were based on predictive modelling. Although model parameters were based on published evidence, there is uncertainty in every parameter. To limit the uncertainty, a number of sensitivity analyses were performed around key parameters. Second, HCV screening and treatment were modelled according to existing evidence on rates of screening and treatment uptake (ie, a real-world scenario). Increases in providers offering HCV treatment would likely raise screening and treatment rates, which is why the upper-bound comprehensive scenario, with 100% screening and treatment uptake, was modelled. Third, our model did not account for infectious disease dynamics, namely that the treatment of patients with HCV reduces overall transmission rates. Fourth, our analysis did not account for the impact of HCV treatment on potential organ donation by individuals cured of HCV.

CONCLUSIONS

We identified a novel mechanism by which positive disease spillovers can occur when the same scarce treatment—in this case transplantable organs—applies to multiple diseases. Illustrating this mechanism in ESLD, our analyses suggest that because the outcomes of patients with various forms of ESLD are linked by the scarcity of liver transplants, a systematic HCV screening and treatment program in the United States could substantially improve transplant opportunities and outcomes for patients with ESLD from causes other than HCV.

Author Affiliations: Harvard Medical School (ABJ), Boston, MA; Precision Health Economics (WS), Los Angeles, CA; AbbVie, Inc. (YSG, SEM, TJ), North Chicago, IL; Leonard D. Schaeffer Center for Health Policy & Economics, University of Southern California (DNL), Los Angeles, CA; Irving B. Harris Graduate School of Public Policy and the Becker Friedman Institute, University of Chicago (TJP), Chicago, IL.

Source of Funding: Support for this research was provided by AbbVie, Inc.

Author Disclosures: Drs Juday, Marx, and Sanchez Gonzalez are employees and stockholders of AbbVie, Inc, which develops and markets treatments for hepatitis C virus. Dr Stevens is an employee of Precision Health Economics (PHE), a healthcare consultancy to life science firms. Dr Lakdawalla is the chief strategy officer and owns equity in PHE, and Drs Jena and Philipson are consultants for PHE.

Authorship Information: Concept and design (YSG, ABJ, TJ, DNL, SEM, TP, WS); acquisition of data (WS); analysis and interpretation of data (YSG, ABJ, TJ, DNL, SEM, TP, WS); drafting of the manuscript (YSG, ABJ, TJ, SEM, WS); critical revision of the manuscript for important intellectual content (YSG, ABJ, TJ, DNL, SEM, TP, WS); statistical analysis (ABJ, TJ); obtaining funding (YSG, TJ); and supervision (YSG, ABJ, TJ, DNL, WS).

Address correspondence to: Anupam Jena, MD, PhD, Harvard Medical School, Department of Health Care Policy, 180 Longwood Ave, Boston, MA 02115. E-mail: jena@hcp.med.harvard.edu.

REFERENCES

1. Darkow T, Maclean R, Joyce GF, Goldman D, Lakdawalla DN. Coverage and use of cancer therapies in the treatment of chronic myeloid leukemia. Am J Manag Care. 2012;18(suppl 11):S272-S278.

2. Boulier BL, Datta TS, Goldfarb RS. Vaccination externalities. The B.E. Journal of Economic Analysis & Policy. 2007;7(1):article 23.

3. Organ Procurement and Transplantation Network. Health Resources and Services Administration website. http://optn.transplant.hrsa.gov. Accessed April 5, 2016.

4. 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(5):293-300. doi: 10.7326/M13-1133.

5. Biggins SW, Bambha KM, Terrault NA, et al. Projected future increase in aging hepatitis C virus-infected liver transplant candidates: a potential effect of hepatocellular carcinoma. Liver Transpl. 2012;18(12):1471-1478. doi: 10.1002/lt.23551.

6. McHutchison JG, Lawitz EJ, Shiffman ML, et al; IDEAL Study Team. Peginterferon alfa-2b or alfa-2a with ribavirin for treatment of hepatitis C infection. N Engl J Med. 2009;361(6):580-593. doi: 10.1056/NEJMoa0808010.

7. Afdhal N, Reddy KR, Nelson DR, et al; ION-2 Investigators. Ledipasvir and sofosbuvir for previously treated HCV genotype 1 infection. N Engl J Med. 2014;370(16):1483-1493. doi: 10.1056/NEJMoa1316366.

8. Afdhal N, Zeuzem S, Kwo P, et al; ION-1 Investigators. Ledipasvir and sofosbuvir for untreated HCV genotype 1 infection. N Engl J Med. 2014;370(20):1889-1898. doi: 10.1056/NEJMoa1402454.

9. Kowdley KV, Gordon SC, Reddy KR, et al; ION-3 Investigators. Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis. N Engl J Med. 2014;370(20):1879-1888.

doi: 10.1056/NEJMoa1402355.

10. Wertheim JA, Petrowsky H, Saab S, Kupiec-Weglinski JW, Busuttil RW. Major challenges limiting liver transplantation in the United States. Am J Transplant. 2011;11(9):1773-1784. doi: 10.1111/j.1600-6143.2011.03587.x.

11. Abouna G. Organ shortage crisis: problems and possible solutions. Transplant Proc. 2008;40(1):34-38. doi: http://dx.doi.org/10.1016/j.transproceed.2007.11.067.

12. Orman ES, Barritt AS 4th, Wheeler SB, Hayashi PH. Declining liver utilization for transplantation in the United States and the impact of donation after cardiac death. Liver Transpl. 2013;19(1):59-68. doi: 10.1002/lt.23547.

13. Rein DB, Wittenborn JS, Weinbaum CM, Sabin M, Smith BD, Lesesne SB. Forecasting the morbidity and mortality associated with prevalent cases of pre-cirrhotic chronic hepatitis C in the United States. Dig Liver Dis. 2011;43(1):66-72. doi: 10.1016/j.dld.2010.05.006.

14. McCombs JS, Yuan Y, Shin J, Saab S. Economic burden associated with patients diagnosed with hepatitis C. Clin Ther. 2011;33(9):1268-1280. doi: 10.1016/j.clinthera.2011.07.008.

15. Davis KL, Mitra D, Medjedovic J, Beam C, Rustgi V. Direct economic burden of chronic hepatitis C virus in a United States managed care population. J Clin Gastroenterol. 2011;45(2):e17-e24. doi: 10.1097/MCG.0b013e3181e12c09.

16. El Khoury AC, Klimack WK, Wallace C, Razavi H. Economic burden of hepatitis C-associated diseases in the United States. J Viral Hepat. 2012;19(3):153-160. doi: 10.1111/j.1365-2893.2011.01563.x.

17. Davis GL, Alter MJ, El-Serag H, Poynard T, Jennings LW. Aging of hepatitis C virus (HCV)-infected persons in the United States: a multiple cohort model of HCV prevalence and disease progression. Gastroenterology. 2010;138(2):513-521, 521.e1-e6. doi: 10.1053/j.gastro.2009.09.067.

18. Hirth RA, Chernew ME, Miller E, Fendrick AM, Weissert WG. Willingness to pay for a quality-adjusted life year: in search of a standard. Med Decis Making. 2000;20(3):332-342.

19. Viscusi WK, Aldy JE. The value of a statistical life: a critical review of market estimates throughout the world. J Risk Uncertain. 2003;27(1):5-76.

20. Disease burden from viral hepatitis A, B, and C in the United States. CDC website. http://www.cdc.gov/hepatitis/pdfs/disease_burden.pdf. Accessed April 5, 2016.

21. Kabiri M, Jazwinski AB, Roberts MS, Schaefer AJ, Chhatwal J. The changing burden of hepatitis C virus infection in the United States: model-based predictions. Ann Intern Med. 2014;161(3):170-180. doi: 10.7326/M14-0095.

22. Falck-Ytter Y, Kale H, Mullen KD, Sarbah SA, Sorescu L, McCullough AJ. Surprisingly small effect of antiviral treatment in patients with hepatitis C. Ann Intern Med. 2002;136(4):288-292.

23. Kanwal F, El-Serag HB. Hepatitis C virus treatment: the unyielding chasm between efficacy and effectiveness. Clin Gastroenterol Hepatol. 2014;12(8):1381-1383. doi: 10.1016/j.cgh.2014.02.031.

24. Cardoso AC, Moucari R, Figueiredo-Mendes C, et al. Impact of peginterferon and ribavirin therapy on hepatocellular carcinoma: incidence and survival in hepatitis C patients with advanced fibrosis. J Hepatol. 2010;52(5):652-657. doi: 10.1016/j.jhep.2009.12.028.

25. Ghany MG, Strader DB, Thomas DL, Seeff LB; American Association for the Study of Liver Diseases. Diagnosis, management, and treatment of hepatitis C: an update. Hepatology. 2009;49(4):1335-1374. doi: 10.1002/hep.22759.

26. 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(4):263-270.

doi: 10.7326/0003-4819-156-4-201202210-00378.

27. Honeycutt AA, Harris JL, Khavjou O, Buffington J, Jones TS, Rein DB. The costs and impacts of testing for hepatitis C virus antibody in public STD clinics. Public Health Rep. 2007;122(suppl 2):55-62.

28. Rana A, Gruessner A, Agopian VG, et al. Survival benefit of solid-organ transplant in the United States. JAMA Surg. 2015;150(3):252-259. doi: 10.1001/jamasurg.2014.2038.

29. Weinstein MC. How much are Americans willing to pay for a quality-adjusted life year? Med Care. 2008;46(4):343-345. doi: 10.1097/MLR.0b013e31816a7144.

30. Neumann PJ, Cohen JT, Weinstein MC. Updating cost-effectiveness—the curious resilience of the $50,000-per-QALY threshold. N Engl J Med. 2014;371(9):796-797.doi: 10.1056/NEJMp1405158.

31. Braithwaite RS, Meltzer DO, King JT Jr, Leslie D, Roberts MS. What does the value of modern medicine say about the $50,000 per quality-adjusted life-year decision rule? Med Care. 2008;46(4):349-356. doi: 10.1097/MLR.0b013e31815c31a7.

32. Horvat LD, Cuerden MS, Kim SJ, Koval JJ, Young A, Garg AX. Informing the debate: rates of kidney transplantation in nations with presumed consent. Ann Intern Med. 2010;153(10):641-649. doi: 10.7326/0003-4819-153-10-201011160-00006.

33. Rithalia A, McDaid C, Suekarran S, Norman G, Myers L, Sowden A. A systematic review of presumed consent systems for deceased organ donation. Health Technol Assess. 2009;13(26):iii, ix-xi, 1-95. doi: 10.3310/hta13260.

34. Shepherd L, O’Carroll RE, Ferguson E. An international comparison of deceased and living organ donation/transplant rates in opt-in and opt-out systems: a panel study. BMC Med. 2014;12:131. doi: 10.1186/s12916-014-0131-4.

35. Goldaracena N, Marquez M, Selzner N, et al. Living vs. deceased donor liver transplantation provides comparable recovery of renal function in patients with hepatorenal syndrome: a matched case-control study. Am J Transplant. 2014;14(12):2788-2795. doi: 10.1111/ajt.12975.

36. Coppen R, Friele RD, van der Zee J, Gevers SK. The potential of legislation on organ donation to increase the supply of donor organs. Health Policy. 2010;98(2-3):164-170. doi: 10.1016/j.healthpol.2010.05.019.