chronic hepatitis c virus (hcv) disease burden and cost in the

CHRONIC HEPATITIS C VIRUS (HCV) DISEASE BURDEN AND COST IN THE UNITED STATES

H. Razavi1, A. El Khoury2, E. Elbasha2, C. Estes1, K. Pasini1, T. Poynard3, R. Kumar2

1. Center for Disease Analysis, Louisville, Colorado, USA 2. Merck, Sharp, & Dohme Corp., Whitehouse Station, NJ 3. Université Pierre et Marie Curie Liver Center, Paris, France

Disclosure

1. Received funding for this project from Merck & Co. Inc. 2. Employee of Merck & Co. Inc. 3. Consulted with Merck, Roche, Vertex, and Gilead

Correspondence and Request for Reprints: Homie Razavi, Center for Disease Analysis, 901

Front Street, Suite 291, Louisville, CO 80027, USA. Tel: +1 720 890 4848, Fax: +1 720 890

3817, E-mail: [email protected].

Abbreviations

CDC, Centers for Disease Control and Prevention; CI, confidence interval; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; IDU, injection drug use; NHANES, National Health and Nutrition Examination Survey; PPPY, per patient per year; SVR, sustained viral response

Hepatology

This article has been accepted for publication and undergone full peer review but has not beenthrough the copyediting, typesetting, pagination and proofreading process which may lead todifferences between this version and the Version of Record. Please cite this article as an ‘Accepted Article’, doi: 10.1002/hep.26218

2

ABSTRACT

Background: Hepatitis C virus (HCV) infection is a leading cause of cirrhosis, hepatocellular

carcinoma, and liver transplantation. A better understanding of HCV disease progression and

the associate cost can help the medical community manage HCV and develop treatment

strategies in light of the emergence of several potent anti-HCV therapies. Methods: A system

dynamic model with 36 cohorts was used to provide maximum flexibility and improved

forecasting. Results: New infections incidence of 16,020 (95% confidence interval of 13,510-

19,510) was estimated in 2010. HCV viremic prevalence peaked in 1994 at 3.3 (2.8-4.0) million,

but it is expected to decline by two thirds by 2030. The prevalence of more advanced liver

disease, however, is expected to increase, as well as the total cost associated with chronic HCV

infection. Today, the total cost is estimated at $6.5 ($4.3-$8.4) billion and it will peak in 2024 at

$9.1 ($6.4-$13.3) billion. The lifetime cost of an individual infected with HCV in 2011 was

estimated at $64,490. However, this cost is significantly higher among individuals with a longer

life expectancy. Conclusions: This analysis demonstrated that US HCV prevalence is in

decline due to lower incidence of infections. However, the prevalence of advanced liver disease

will continue to increase as well as the corresponding healthcare costs. Lifetime healthcare

costs for an HCV infected person are significantly higher than for non-infected persons. In

addition, it is possible to substantially reduce HCV infection through active management.

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BACKGROUND

In a recent study, over 15,000 deaths were attributed to chronic HCV infection in 2007 (1),

already exceeding earlier estimates (2). HCV infection is associated with chronic, progressive

liver disease. Chronic hepatitis C is a leading cause of cirrhosis and hepatocellular carcinoma

(HCC) (3;4), which are major indications for liver transplantation (5). A better understanding of

HCV disease progression and the associate baseline cost, which excludes the cost of antiviral

treatment, can help the medical community manage HCV and develop treatment strategies in

light of the emergence of several potent anti-HCV therapies.

Historically, researchers have studied HCV disease progression and cost using Markov models

(2;6-13). In these models, a homogenous cohort of HCV infected individuals are introduced, and

the model is used to track their progression and cost over time. A recent study (14) varied the

age at infection, gender, and disease duration over time using six cohorts to estimate future

disease burden. However, in a previous analysis (15), it was found that the predictability of the

HCV epidemiology model is very sensitive to the number of age and gender cohorts used, due

to the large difference in new infections’ incidence and mortality across cohorts. Thus, we set

out to create a disease progression and cost model that was more refined than those used in

previous studies.

The present study represents an improvement over previous work. A total of 36 cohorts

composed of 17 five-year age cohorts and one age cohort for 85+ was used for each gender. A

system dynamic model was developed to provide maximum flexibility in changing inputs

(incidence rate, age at infection, background mortality, transplantation rate, treatment rate, and

cost) over time. Finally, more recent healthcare cost data (16) were used to estimate the HCV

cost burden as compared to previous studies which relied on older data (17).

The goal of this study is to describe the future disease and cost burden of HCV infection in the

United States using a systems approach, assuming there is no incremental increase in

treatment as the result of the new therapies.

METHODOLOGY

A system dynamic modeling framework was used to construct the model in Microsoft Excel®

(Microsoft Corp., Redmond, WA) to quantify the hepatitis C virus (HCV) infected population, the

disease progression, and the associated cost from 1950-2030. Uncertainty and sensitivity

analyses were completed using Crystal Ball®, an Excel® add-in by Oracle®. Beta-PERT

distributions were used to model uncertainty associated with all inputs. Sensitivity analysis was

used to identify the uncertainties that had the largest impact on the peak cost in 2025. Monte-

Carlo simulation was used to determine the 95% confidence interval for cost and prevalence.

When historical data were available, nonlinear polynomial extrapolation of historical data was

used for future assumptions in 2012-2030. The Excel® optimization add-in, Solver, was used to

calibrate the model using reported NHANES prevalence data (18) as described below.

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Populations in a given health state (incident HCV, cured, F1, F2, etc.) were handled as stocks,

while annual transitions from one health state to another were treated as flows with an

associated rate/probability (see Appendix A, Figure 1). Historical data reporting the number and

indications for liver transplantations from 1988 to 2010 were used to estimate the number of

transplantations attributable to chronic HCV infection (5). Trended transplantation rates from

1988-2011 were used for 1971-1987 and 2011-2030.

The populations were tracked by age cohorts and gender. Five-year age cohorts were used

through age 84, and those aged 85 and older were treated as one cohort. Each year, one fifth of

the population in each age group, except for 85 and older, was moved to the next age cohort to

simulate aging, after accounting for mortality.

The model started in 1950 to track the prevalent population from the time of infection and

forecasted the sequelae populations to 2030. The impact of individuals infected with HCV prior

to 1950 was expected to be small and within the margin of error of our analysis. Prevalence of

chronic HCV in any given year was calculated by the sum of viremic incidence of new infections

(incidence) minus mortality and cured cases, up to that year, as shown below:

�� Mortality� � Cured�$�

�%&'()

Annual background mortality rates by age and gender (19) were adjusted for incremental

increase in mortality due to injection drug use (IDU) and transfusion (15). These rates were

applied to all populations. For individuals with decompensated cirrhosis (diuretic sensitive and

refractory ascites, variceal hemorrhage, and hepatic encephalopathy), hepatocellular carcinoma

(HCC), and those who required a liver transplantation, a separate mortality rate was also

applied for liver related deaths (7;9;20), as shown in Appendix A, Tables 1 & 2.

The number of cured patients in 2002-2007 was estimated using published data for the number

of treated patients (21) and an average sustained viral response (SVR) of 34%, as shown in

Appendix B, Table 1. The number of cured patients prior to 2002 was ignored. The number of

patients cured in 2008-2030 was extrapolated using 2002-2007 data. The objective of this

analysis was to estimate the HCV disease progression and the associated cost in the US when

there was no incremental increase in treatment as the result of the new therapies. The launch of

direct acting antivirals in 2011, the increased number of treated patients, and the higher SVR of

new therapies were not incorporated in this model. The impact and cost of new therapies were

specifically excluded in order to establish a baseline for future comparisons. This, however, will

lead to higher projections of advanced liver diseases and poor outcomes as compared to the

real world.

With known annual mortality and cured population, annual incidence was calculated using a

constant multiplied by the relative incidence. Relative incidence was calculated from the

literature data (14) by dividing each year’s incidence by the 1950 incidence to result in a relative

incidence of 1 in 1950, as shown in Appendix C, Table 1. Incidence in the US peaked in 1989

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when it was 11.5 times higher than incidence in 1950. Solver was used to find the constant that

resulted in a prevalence of 3.2 (95% confidence interval, 2.7-3.9) million in 2000 (18).

The annual incidence was distributed among different age and gender cohorts using

distributions reported by the CDC (22-25) from 1992-2007. Incidence distribution from 2007 was

used for 2008-2030 based on the assumption that the future risk factors will remain the same. In

1967-1991, the incidence distribution by age and gender was changed every five years and the

rates within each five-year period (e.g., 1967-1971) were extrapolated linearly by age cohort

and gender. The distribution was kept constant prior to 1966 based on the assumption that the

risk factors remained the same. Solver was used to calculate the annual age and gender

distributions, which minimized the difference between the forecasted prevalence age and

gender distribution in 2000 and those reported by NHANES (18).

Since the objective of this study was to determine healthcare costs associated with HCV

infection, incremental costs derived from a matched cohort study were utilized. The cost by

sequelae data came from previously published work by McAdam-Marx, et al. (16). The

healthcare costs among chronic HCV individuals in F0-F3 stages were adjusted for the

proportion not under care (see Appendix D). The 1950-2010 costs were inflation adjusted using

the Medical Care Services component of the Consumer Price Index (26). The 2011 annual

medical inflation rate of 3.06% (2.88%-5.33%) was used to estimate future costs in 2012-2030.

The lifetime cost of an HCV infected individual by age and gender was calculated by introducing

1,000 viremic incident cases in 2011 and using the model to track the progression of these

cases and the annual cost over time. The annual healthcare costs for all sequelae and all years

were summed and divided by 1,000 to calculate the individual cost. The average cost was

calculated by distributing 1,000 new viremic incident cases using 2010 incidence age and

gender distribution (27).

RESULTS

The annual background and liver related mortality are shown in Appendix E. Background

mortality is forecasted to peak at 39,935 in 2022 as the HCV population ages, while liver related

deaths peak at 29,695 in 2019 as the number of deaths from decompensated cirrhosis reach

their maximum.

Relative incidence and estimated incidence are shown in Appendix C, Table 1. The constant

multiplier for incidence was estimated at 23,790 (20,070-28,990), resulting in a prevalence of

3.2 (2.7-3.9) million in the year 2000 (18). Incidence values represent acute cases, and 82%

(55%-85%) (28) of these cases progressed to chronic HCV with a METAVIR score of F0, as

shown in Appendix A, Table 1. Incidence for all sequelae is shown in Figure 1.

Peak viremic prevalence of chronic HCV infection was reached in 1994 with 3.3 (2.8-4.0) million

infected individuals (Figure 2). While the overall prevalence has been declining since, the

prevalence of more advanced liver diseases has been increasing. The prevalent population with

compensated cirrhosis is projected to peak in 2015 at 626,500 cases, while the population with

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decompensated cirrhosis will peak in 2019 with 107,400 cases. The number of individuals with

HCC, caused by HCV infection, will increase to 23,800 cases in 2018 before starting to decline.

In 2011, the total healthcare cost associated with HCV infection was $6.5 ($4.3-$8.2) billion.

Total cost is expected to peak in 2024 at $9.1 billion ($6.4-$13.3 billion), as shown in Figure 3.

The majority of peak cost will be attributable to more advanced liver diseases—decompensated

cirrhosis (46%), compensated cirrhosis (20%), and hepatocellular carcinoma (16%). The

maximum cost associated with mild to moderate fibrosis (F0-F3) occurred in 2007 at nearly

$780 million. The cost associated with compensated cirrhosis is expected to peak in 2022 at

$1.9 billion, while the peak cost for decompensated cirrhosis and HCC is predicted to occur in

2025, with annual costs in excess of $4.2 billion and $1.4 billion respectively.

The lifetime cost of an individual infected in 2011 was estimated at $64,490 ($46,780-$73,190)

in 2011 dollars. When medical inflation was applied, the lifetime cost increased to $205,760

($154,890-$486,890). The lifetime cost estimate varies widely by age and gender due to life

expectancy. As shown in Table 1, costs for HCV infections among younger individuals and

females will be higher than among the elderly and males.

DISCUSSION

The predictive value of a model can be confirmed by comparing its forecasts with real world

observations. The model was calibrated using HCV prevalence by age and gender in the year

2000, as reported by NHANES (18). The incidence was back calculated and the model was

used to fit reported prevalence in 2000. Total prevalence in other years, prevalence and

incidence by sequelae, and mortality were calculated. A 2010 incidence of 16,020 (13,510-

19,510) was forecasted versus the reported incidence of 17,000 (29). The wide confidence

interval for incidence was driven by the large uncertainty in reported prevalence (18). According

to the study by Davis, et al. (14), HCV incidence peaked in 1989 when it was 11.5 times higher

than the incidence in 1950. This corresponded to a peak incidence of 274,000 in a single year.

A 2010 prevalence of 2.5 (2.1-3.2) million cases was estimated, matching the most recent

NHANES data that showed 2.5 million cases in the 2009-2010 (30). In comparison, Davis, et al.

reported an HCV prevalence of about 3.3 million in the same period (14).

Our analysis predicted that HCV prevalence in the US peaked in 1994 at 3.3 million viremic

cases. The overall prevalence is declining, and the 2030 prevalence is expected to be one third

of the peak prevalence. Incidence has dropped significantly since its peak in 1989 due to the

implementation of HCV antibody screening of the blood supply in 1992, with full implementation

of universal donation screening for viral RNA through nucleic acid testing (NAT) in 1999 (31;32),

and to a decline in IDU (33). However, disease burden continues to grow. The dichotomy of

HCV is that, while the overall number of infections is projected to decline, the number of

individuals experiencing advanced liver diseases, liver related deaths, and healthcare costs are

expected to increase. This was a key insight provided by this analysis.

A recent study by the CDC (1) reported increased recorded mortality rate in the US HCV

infected population in 1999-2007. Consistent with this study, we forecast that mortality will

continue to increase and peak in 2020 (Appendix E). After 2020, the decline in the number of

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HCV infections will outweigh the increase in background mortality, and liver related deaths and

the number of deaths will decrease. Mortality is projected to peak at approximately 69,440

deaths, with 29,650 deaths attributable to liver disease, including over 9,000 attributed to HCC

in 2020.

As shown in Figure 1, the incidence of more advanced liver diseases will continue to increase,

with incidence of decompensated cirrhosis and HCC peaking in 2016-2017. However, not all

infected individuals progress to the next stage, and the peak incidence is lower at each

consecutive sequelae. The total prevalent population of each sequela is shown in Figure 2.

Over 50% of the HCV prevalent population resides in F0-F3 stage of the disease at any point in

time. However, by 2030, compensated cirrhosis cases will account for 37% of all prevalent

cases. The HCV compensated cirrhotic population is projected to peak in 2015, while the

decompensated cirrhotic population will peak in 2019. A smaller portion of the HCV infected

population will go on to have HCC, but the size of this population does not grow substantially

beyond 24,000 due to the very high mortality rate in this population.

A key observation was that peak healthcare costs lag peak prevalence by almost three

decades. This is due to the time required for infected cases to progress to more advanced forms

of liver disease, which are more expensive to treat.

Sensitivity analysis identified the key drivers of variance in peak healthcare cost. The incidence

uncertainty (20,070-28,990), calculated from the uncertainty in NHANES 2000 prevalence,

accounted for 52% of the variance in peak cost. Higher incidence led to more prevalent cases

and higher cost. Uncertainty in the annual cost of diuretic sensitive ascites ($2,525-$29,860)

(16;17) accounted for 15% of the total variance. Finally, uncertainty in persistence (32%-80%)

(34;35) accounted for 13% of the variance. Higher persistence resulted in higher SVR and a

greater number of cured patients, which in turn resulted in lower healthcare costs. This

highlights the importance of SVR on future costs. In this study, the treatment cost was

specifically excluded, and yet the SVR of historically treated cases still turned out to be

important. The treated population had to be included in the disease progression portion of the

model since it affected the size of prevalent populations. In 2002-2011, we estimated that

322,700 individuals were cured. If persistence in the real world were the same as observed in

clinical trials (80%) (35), the average SVR would be 46%, resulting in 430,000 cured cases in

2002-2011. This would result in a decrease of $1 billion dollars in peak healthcare costs.

Patients experiencing decompensated cirrhosis accounted for the majority of future costs. In

2011, it accounted for 40% of total costs, and by 2030 it accounted for 47%. This was followed

by compensated cirrhosis (22% of 2011 and 19% of 2030 total cost) and HCC (15% of 2011

and 16% of 2030 total cost). The prevalence of decompensated cirrhosis was 20% of

compensated cirrhosis, but the annual cost was twelve times higher (16).

The average lifetime cost of a patient was estimated at $64,490 as compared to a recent study

that reported an average cost of $19,660 per patient in 2002-2010 alone (16). The analysis of

cost by age at infection demonstrates a link between life expectancy and healthcare cost.

Individuals infected in the 1950s were expected to have lower lifetime costs due to lower life

expectancy (and lower medical costs), while newly HCV infected individuals are expected to

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cost the healthcare systems more due to the longer life expectancy. This highlights the

continued importance of prevention as a means of managing future healthcare expenditure.

The effects of new therapies were excluded from our model. However, if the number of treated

patients is doubled and kept constant at 126,000 per year in 2012-2030 and the average SVR is

increased to 70%, the 2030 prevalent population is projected to be less than 100,000 cases.

This illustrates that it is possible to substantially reduce HCV infection in the US through active

management.

There were a number of limitations in this study that impact the accuracy of our base

projections. There is strong evidence that progression transition rates change with age and

gender. A single transition rate was used for all ages and genders. This led to a higher

incidence/prevalence in early years and among females, as well as higher liver related mortality

among the younger age groups. However, the confidence intervals in our study did capture

uncertainty in the above assumptions.

The model does not explicitly account for alcohol consumption and metabolic syndrome.

Frequent heavy intake of alcohol significantly increases fibrosis progression (36;37), and

accelerated disease progression has been associated with metabolic syndrome (38;39). The

model implicitly takes these factors into account, as the transition probabilities and sequelae

cost incorporate some level of alcohol consumption and metabolic syndrome. If an increasing

proportion of the prevalent population experiences heavy alcohol intake or metabolic syndrome,

progression to advanced liver disease, and the associated costs, will likely increase.

The model does not take into account the persistent risk of fibrosis progression and liver cancer

in virologically cured patients. Observational studies have demonstrated that most patients who

achieve SVR experience stabilization or regression of fibrosis. After SVR, episodes of cirrhotic

decompensation are extremely rare, and instances of HCC are likely to be small in number and

not greatly impact overall disease burden or costs (40).

A limitation of prevalence measures used in this analysis is that high prevalence populations

may be under-sampled through the NHANES (41). In particular, under-sampling of veterans,

prisoners, and the homeless would result in underestimation of the current prevalence, future

disease, and cost burden. In addition, while IDU has declined from a peak in the 1970s, there is

some evidence of a recent increase in IDU among middle-aged adults, potentially leading to a

higher incidence of HCV (33). In all cases, the sequelae prevalence and the healthcare costs

will be higher than the estimated base value.

A further limitation is that the model does not consider recent recommendations (42) to

implement birth cohort screening for HCV. Such screening could reduce the future incidence of

advanced liver disease and associated costs, when infected individuals identified through

screening receive appropriate treatment and achieve SVR (43).

Treatment of HCV prior to 2002 was also ignored. The first pegylated Interferon launched in

August of 2001, and the number of patients treated with pegylated Interferons was small in that

year. Prior to that launch, patients were treated with non-pegylated Interferon. The number of

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individuals cured prior to 2001 was small, and their exclusion did not have a material impact on

the outcome of the model.

The rate of SVR utilized in the model was derived from studies of treatment naïve patients;

however, average SVR is lower in treatment experienced patients. Because the majority of

treated patients are naïve, it is unlikely that the use of a single rate for SVR substantially

impacted estimates of treated and cured patients beyond our confidence intervals.

A final limitation is that the future cost of liver transplants is based on the assumption that

transplantation will remain at the same rate as today. All other sequelae costs were determined

as the result of the disease progression. The number of liver transplants, however, is

determined by the clinical guidelines and availability of donors. Thus, the future costs

associated with liver transplants could be higher if transplantation rates increase.

In conclusion, our analysis demonstrated that overall HCV prevalence in the US is in decline

due to lower incidence. However, the prevalence of advanced liver disease will continue to

increase, as will the corresponding healthcare costs. Lifetime healthcare costs for an HCV

infected person are significantly higher than for non-infected persons, and the expected cost is

higher among populations with a higher life expectancy. Finally, it is possible to substantially

reduce HCV infection in the US through active management.

ACKNOWLEDGEMENTS

We would like to thank Steven Wiersma of the World Health Organization (WHO) and Charles

Gore of the World Hepatitis Alliance, who challenged us to develop a robust cost burden model

for HCV. The authors would also like to acknowledge the contributions of Scott Holmberg of the

Centers for Disease Control and Prevention (CDC). His explanations of how to interpret the data

published by CDC and feedback on our forecasts were critical in calibrating this model. In

addition, we want to give credit to Greg Armstrong of CDC for proposing the methodology used

to estimate incidence when prevalence, mortality, and cured populations are known. He

developed this methodology and shared it with us as a way of estimating incidence. We would

like to thank Regina Klein of the Center for Disease Analysis (CDA) for the background research

and Kim Murphy of CDA for developing the custom Excel codes to run the model. Finally, we

thank Carrie McAdam-Marx of the University of Utah for explaining the methodology used by

her group to calculate the incremental cost of HCV sequelae.

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36. Bellentani S, Pozzato G, Saccoccio G, Crovatto M, Croce LS, Mazzoran L, Masutti F, Cristianini G, Tiribelli C. Clinical course and risk factors of hepatitis C virus related liver disease in the general population: report from the Dionysos study. Gut 1999 Jun;44(6):874-80.

37. 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 Mar 22;349(9055):825-32.

38. Marcellin P, Asselah T, Boyer N. Fibrosis and disease progression in hepatitis C. Hepatology 2002 Nov;36(5 Suppl 1):S47-S56.

39. Hourigan LF, Macdonald GA, Purdie D, Whitehall VH, Shorthouse C, Clouston A, Powell EE. Fibrosis in chronic hepatitis C correlates significantly with body mass index and steatosis. Hepatology 1999 Apr;29(4):1215-9.

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40. Alberti A. Impact of a sustained virological response on the long-term outcome of hepatitis C. Liver Int. 2011 Jan;31 Suppl 1:18-22.

41. Chak E, Talal A, Sherman KE, Schiff E, Saab S. Hepatitis C virus infection in the United States: an estimate of true prevalence. Liver Int. 2011;31(8):1090-101.

42. Recommendations for the identification of chronic hepatitis C virus infection among persons born during 1945-1965. MMWR Recomm.Rep. 2012 Aug 17;61(RR-4):1-32.

43. McGarry LJ, Pawar VS, Panchmatia HR, Rubin JL, Davis GL, Younossi ZM, Capretta JC, O'Grady MJ, Weinstein MC. Economic model of a birth cohort screening program for hepatitis C virus. Hepatology 2012 May;55(5):1344-55.

44. Alter MJ, Margolis HS, Krawczynski K, Judson FN, Mares A, Alexander WJ, Hu PY, Miller JK, Gerber MA, Sampliner RE. The natural history of community-acquired hepatitis C in the United States. The Sentinel Counties Chronic non-A, non-B Hepatitis Study Team. N.Engl.J.Med. 1992 Dec 31;327(27):1899-905.

45. Villano SA, Vlahov D, Nelson KE, Cohn S, Thomas DL. Persistence of viremia and the importance of long-term follow-up after acute hepatitis C infection. Hepatology 1999 Mar;29(3):908-14.

46. Thein HH, Yi Q, Dore GJ, Krahn MD. Estimation of stage-specific fibrosis progression rates in chronic hepatitis C virus infection: a meta-analysis and meta-regression. Hepatology 2008 Aug;48(2):418-31.

47. Ries LAG, Young GL, Keel GE, Eisner MP, Lin YD, Horner M-J. SEER survival monograph: cancer survival among adults: U.S. SEER program, 1988-2001,patient and tumor characteristics. [NIH Pub.No.07-6215]. 2007. Bethesda, MD, National Cancer Institute,SEER Program.

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Figures

Figure 1. HCV sequelae incidence - US 1950-2030

Figure 2. HCV sequelae and total prevalence (millions) - US 1950-2030

Figure 3. Projected HCV sequelae cost - US 1950-2030

Figure 4. Total prevalence and healthcare costs with 95% confidence intervals

Tables

Table 1. Lifetime cost by age, HCV infection, and gender (in 2011 dollars)

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Age Male Female

0-4 $116,600 $147,130

5-9 $105,960 $138,360

10-14 $94,810 $128,440

15-19 $83,430 $117,590

20-24 $76,550 $108,260

25-29 $70,000 $98,040

30-34 $62,950 $87,680

35-39 $57,030 $77,550

40-44 $51,610 $67,880

45-49 $47,180 $59,030

50-54 $35,940 $46,560

55-59 $26,310 $35,510

60-64 $18,540 $26,200

65-69 $12,660 $18,750

70-74 $8,530 $13,170

75-79 $5,630 $9,010

80-84 $3,770 $6,150

85+ $2,680 $4,330

Average - all ages & genders* $64,490 ($46,780 - $73,190)

* Using 2011 incidence age and gender distribution. All values in 2011 dollars with no inflation adjustment.

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Figure 1. HCV sequelae incidence - US 1950-2030

133x69mm (300 x 300 DPI)

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Figure 2. HCV sequelae and total prevalence (millions) - US 1950-2030

142x81mm (300 x 300 DPI)

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Figure 3. Projected HCV sequelae cost - US 1950-2030

136x73mm (300 x 300 DPI)

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Figure 4. Total prevalence and healthcare costs with 95% confidence intervals 144x82mm (300 x 300 DPI)

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Appendix A

Figure 1. Modeled HCV Disease Progression Diagram

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Table 1. Annual Transition Probabilities

Base Range Source

from Acute (Incidence)

% Progress to Chronic HCV 82.00% (0.85 - 0.55) (28;44;45)

from Chronic HCV (F0)

…F1 11.70% (0.104 - 0.13) (46)

from F1

…F2 8.50% (0.075 - 0.096) (46)

from F2

…F3 12.00% (0.109 - 0.133) (46)

from F3

…F4 (= Cirrhosis) 11.60% (0.104 - 0.129) (46)

…HCC 0.10% ( 0.0 - 0.002 ) (7;9)

from Cirrhosis

….Diuretic Sensitive Ascites 2.50% (0.018 - 0.032) (7;9)

.…Variceal Hemorrhage 1.10% (0.006 - 0.016) (7;9)

…Hepatic Encephalopathy 0.40% (0.001 - 0.007) (7;9)

…HCC 1.50% (0.01 - 0.02) (7;9)

from Diuretic Sensitive Ascites

….Diuretic Refractory Ascites 6.70% (0.04 - 0.094 ) (7;9)

….Liver Transplant See below

….Liver Related Death 11.00% (0.077 - 0.143) (7;9)

from Variceal Hemorrhage

….Liver Transplant (1st Year) See below

….Liver Related Death (1st Year) 40.00% (0.334 - 0.466) (7;9)

….Liver Related Death (Sub Yrs) 13.00% (0.085 - 0.175) (7;9)

from Hepatic Encephalopathy

….Liver Transplant (1st Year) See below

….Liver Related Death (1st Year) 68.00% (0.659 - 0.701) (7;9)

….Liver Related Death (Sub Yrs) 40.00% (0.378 - 0.422) (7;9)

from Diuretic Refractory Ascites

….Liver Transplant See below

….Liver Related Death 33.00% (0.28 - 0.38) (7;9)

from HCC

….Liver Related Death (1st Year) 70.70% (0.43 - 0.77) (7;9;47)

….Liver Related Death (Sub Yrs) 16.20% (0.11 - 0.23) (7;9;47)

Liver Transplant (1950-1970) 0% Transplant rates were negligible

Liver Transplant (1971-1987) 5.3% (0.031 - 0.0542) (7), Trended Data

Liver Transplant (1988-2010) Actual Data 33% attributed to HCV (5)

Liver Transplant (2011-2030) 1.7% (0.0169 - 0.045) Trended Data

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Table 2. Liver Transplantation – Liver Related Mortality Rates by Year

First Year Std Error

Subsequent Years Std Error

1971-1986 33.10% 2.80% 3.87% 7.64%

1987 33.10% 2.80% 3.87% 7.64%

1988 24.20% 1.10% 3.64% 2.80%

1989 24.20% 1.00% 3.94% 2.63%

1990 21.30% 0.90% 3.84% 2.29%

1991 20.80% 0.80% 4.11% 2.10%

1992 19.50% 0.80% 4.28% 2.09%

1993 17.80% 0.70% 4.16% 1.82%

1994 15.60% 0.70% 3.85% 1.73%

1995 15.80% 0.60% 3.93% 1.54%

1996 15.90% 0.60% 4.06% 1.56%

1997 14.10% 0.60% 4.02% 1.52%

1998 14.10% 0.60% 4.02% 1.52%

1999 14.70% 0.60% 4.22% 1.20%

2000 13.30% 0.50% 3.91% 1.11%

2001 14.10% 0.50% 4.05% 1.12%

2002 13.00% 0.50% 3.97% 1.11%

2003 13.60% 0.50% 4.03% 1.12%

2004 12.90% 0.50% 5.19% 0.96%

2005 13.40% 0.50% 4.85% 0.96%

2006 12.50% 0.50% 4.85% 0.96%

2007 10.70% 0.40% 4.85% 0.96%

2008-2030 10.70% 0.40% 4.85% 0.96%

Data from Organ Procurement and Transplantation Network was used for 1987-2007. It was assumed that mortality

rates in 2008-2030 were the same as 2007. In addition, the mortality rates for 1987 were applied to 1971-1986.

(Source: 2009 OPTN/SRTR Annual Report 1999-2008: Table 9.15a. Unadjusted Patient Survival by Year of

Transplant at 3 Months, 1 Year, 3 Years, 5 Years and 10 Years, Deceased Donor Liver Transplants Organ

Procurement and Transplantation Network (OPTN). Rockville, MD: U.S. Department of Health and Human Services,

Health Resources and Services Administration, Healthcare Systems Bureau, Division of Transplantation; 2009.)

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Appendix B

Table 1. Estimated number of treated and cured HCV patients in the US*

Year Treated HCV

Patients Cured HCV

Patients

2002 126,040 43,293

2003 107,131 36,798

2004 144,276 49,557

2005 114,197 39,225

2006 88,083 30,255

2007 82,270 28,259

2008 79,301 27,239

2009 71,907 24,699

2010 63,115 21,679

2011-2030 63,115 21,679

* The annual number of treated patients came from previous studies (21). Treated patients in 2008-2010 were

extrapolated from the reported numbers in 2002-2007. The number of treated patients in 2011-2030 was kept

constant at 63,115, same as 2010. Previous studies suggest that the genotype distribution of the treated population is

the same as the prevalent population (34). Thus, it was assumed that 22% of the treated population were genotypes

2/3 (Alter, et al., 1999) with a sustained viral response (SVR) of 66% (Manns, et al., 2011) and the rest, who are

composed mostly of genotype 1, had an SVR of 40% (35), resulting in a weighted average SVR of 46%. In clinical

trials, 80% of patients completed treatment (35). Among veterans, only 32% of patients completed treatment (34).

However, veterans represent a mostly male population with a higher percentage of drug and alcohol abuse and

depression as compared to the US population. A persistence of 60% was assumed for the HCV treated population in

the real world, resulting in an average SVR of 34%.

Sources:

Alter MJ, Kruszon-Moran D, Nainan OV, McQuillan GM, Gao F, Moyer LA, Kaslow RA, Margolis HS. The prevalence

of hepatitis C virus infection in the United States, 1988 through 1994. N.Engl.J.Med. 1999 Aug 19;341(8):556-62.

Manns M, Zeuzem S, Sood A, Lurie Y, Cornberg M, Klinker H, Buggisch P, Rossle M, Hinrichsen H, Merican I, et al.

Reduced dose and duration of peginterferon alfa-2b and weight-based ribavirin in patients with genotype 2 and 3

chronic hepatitis C. J.Hepatol. 2011 Sep;55(3):554-63.

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Appendix C

Figure 1. Relative incidence 1950-2030*

* Calculated from incidence estimates by Davis, et al. (14). Each year’s incidence was divided by

incidence in 1950 to calculate the relative incidence over time.

-

2.00

4.00

6.00

8.00

10.00

12.00

1950 1960 1970 1980 1990 2000 2010 2020 2030

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Table 1. Annual Relative Incidence and Incidence

Year Relative

Incidence Annual

Incidence Year Relative

Incidence Annual

Incidence

1950 1.0 23,790 1991 4.4 105,520

1951 1.0 23,790 1992 2.9 68,780

1952 1.0 23,790 1993 2.3 53,700

1953 1.0 23,790 1994 2.1 50,880

1954 1.0 23,790 1995 1.4 33,920

1955 1.0 23,790 1996 1.4 33,920

1956 1.0 23,790 1997 1.5 35,800

1957 1.0 23,790 1998 1.6 38,630

1958 1.0 23,790 1999 1.5 36,740

1959 1.0 23,790 2000 1.5 35,800

1960 1.0 23,790 2001 1.0 22,610

1961 1.2 27,650 2002 1.1 27,320

1962 1.3 31,520 2003 1.1 26,380

1963 1.5 35,380 2004 1.0 24,500

1964 1.6 39,250 2005 0.8 19,790

1965 1.8 43,110 2006 0.8 17,900

1966 2.2 52,290 2007 0.7 16,020

1967 2.6 61,470 2008 0.7 16,960

1968 3.0 70,650 2009 0.6 15,070

1969 3.4 79,830 2010 0.7 16,020

1970 3.7 89,010 2011 0.7 16,020

1971 4.2 100,190 2012 0.7 16,020

1972 4.7 111,380 2013 0.7 16,020

1973 5.2 122,570 2014 0.7 16,020

1974 5.6 133,760 2015 0.7 16,020

1975 6.1 144,940 2016 0.7 16,020

1976 6.4 152,310 2017 0.7 16,020

1977 6.7 159,690 2018 0.7 16,020

1978 7.0 167,060 2019 0.7 16,020

1979 7.3 174,430 2020 0.7 16,020

1980 7.6 181,800 2021 0.7 16,020

1981 7.4 175,690 2022 0.7 16,020

1982 7.1 169,590 2023 0.7 16,020

1983 7.4 177,120 2024 0.7 16,020

1984 8.7 206,330 2025 0.7 16,020

1985 10.3 245,900 2026 0.7 16,020

1986 10.4 246,840 2027 0.7 16,020

1987 8.6 203,500 2028 0.7 16,020

1988 9.5 226,110 2029 0.7 16,020

1989 11.5 274,160 2030 0.7 16,020

1990 7.1 168,640

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Appendix D

Table 1. The Incremental Cost of HCV Patients by Sequelae (16)*

PPPY*** Cost (2011 $) - Base Range

HCV (F0-F3) **** $426 ($240 - $610)

Compensated Cirrhosis $2,375 ($1,600 - $3,140)

Diuretic Sensitive Ascites $28,130 ($2,525** - $29,860)

Refractory Ascites $28,130 ($26,400 - $29,860)

Variceal Hemorrhage - 1st Yr $28,130 ($26,400 - $29,860)

Variceal Hemorrhage - Subseq Yrs $28,130 ($5,165** - $29,860)

Hepatic Encephalopathy - 1st Year $28,130 ($26,400 - $29,860)

Hepatic Encephalopathy - Subseq Yrs $28,130 ($3,930** - $29,860)

Decompensated Cirrhosis $28,130 ($26,400 - $29,860)

Hepatocellular Carcinoma $44,870 ($40,270 - $49,465)

Liver Transplant $178,130 ($164,265 - $191,990)

Liver Transplant - Subseq Yrs $38,795 ($31,700 - $45,890)

* These costs reflect the incremental cost of HCV patients. The medical cost of patient cohort without HCV has been

subtracted from the above numbers. For example, total healthcare cost for the first year of liver transplant was

estimated at $203,740 in 2011 dollars. However, the cost among HCV infected individuals was $178,127 higher than

for the matched comparison persons in 2011 dollars. In addition, the cost of antiviral therapy, as reported by the

McAdam-Marx, et al. study (16), was subtracted to reflect the incremental medical costs net of HCV treatment.

** Only cost for all decompensated cirrhosis was reported in the McAdam-Marx, et al. study (16). A lower range was

used for select indications when significantly lower estimates were reported in the literature (17)

*** PPPY – per patient per year

**** The cost of individuals with chronic HCV infections was adjusted for percentage of patients not under medical

care. According to McAdam-Marx, et al. study (16), the cost of HCV patients without liver disease is $3,654 per

patient in 2011 dollars (net cost of antiviral therapies). However, this cost applies only to patients who were under

medical care. According to the same study, 30.4% of these HCV patients had antiviral utilization. According to our

model, 3.5% of individuals in F0-F3 stage were treated in 2002-2010. Thus, we estimated that 11.6% (3.5%/30.4%)

of all HCV infected (F0-F3) individuals were under medical care in this period. The average medical cost for all HCV

infected without liver disease was estimated at $426 ($3,654 times 11.6%) per patient per year (PPPY).

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Appendix E

Table 1. Annual Mortality

Liver Related Deaths by Sequela

Year Background Mortality

Diuretic Sensitive Ascites

Variceal Hemorrhage

Hepatic Encephalopathy

Diuretic Refractory Ascites

HCC Liver

Transplant

Total Liver-related Deaths

Total Deaths

1950 0 0 0 0 0 0 0 0 0

1951 210 0 0 0 0 0 0 0 210

1952 418 0 0 0 0 0 0 0 418

1953 619 0 0 0 0 0 0 0 619

1954 813 0 0 0 0 0 0 0 813

1955 966 0 0 0 0 0 0 0 966

1956 1,167 0 0 0 0 0 0 0 1,167

1957 1,371 0 0 0 0 0 0 1 1,372

1958 1,617 0 0 0 0 1 0 1 1,618

1959 1,803 0 1 0 0 2 0 3 1,807

1960 2,005 1 1 1 0 4 0 7 2,012

1961 2,263 2 2 1 0 7 0 13 2,276

1962 2,475 4 4 2 1 11 0 21 2,496

1963 2,827 6 6 4 1 17 0 33 2,860

1964 3,234 9 9 5 2 24 0 50 3,283

1965 3,587 14 13 8 3 34 0 72 3,658

1966 4,034 20 19 11 5 46 0 100 4,134

1967 4,589 28 25 14 7 60 0 134 4,723

1968 5,081 37 33 18 10 77 0 176 5,257

1969 5,824 49 43 23 14 97 0 226 6,049

1970 6,339 63 54 29 19 119 0 284 6,623

1971 6,852 79 67 36 25 145 0 351 7,204

1972 7,358 94 81 43 31 174 17 439 7,798

1973 8,006 111 97 51 37 206 38 540 8,546

1974 8,640 131 113 58 45 242 56 644 9,284

1975 9,034 153 131 67 53 281 73 759 9,793

1976 9,590 179 152 77 63 325 90 885 10,475

1977 10,184 208 174 88 74 374 108 1,025 11,209

1978 10,966 239 200 101 86 427 127 1,180 12,146

1979 11,849 275 228 115 99 487 149 1,353 13,202

1980 12,673 314 260 130 115 553 172 1,544 14,217

1981 13,875 358 295 148 132 627 198 1,756 15,632

1982 14,502 406 334 167 151 709 226 1,993 16,495

1983 14,901 460 377 188 172 800 258 2,255 17,156

1984 15,719 521 426 212 195 902 293 2,548 18,267

1985 16,874 588 480 239 221 1,015 332 2,874 19,748

1986 18,356 662 540 268 250 1,140 376 3,236 21,592

1987 20,245 745 606 301 282 1,279 424 3,638 23,883

1988 21,411 837 680 338 318 1,433 358 3,963 25,374

1989 23,180 939 762 378 358 1,602 434 4,473 27,653

1990 24,701 1,054 852 422 403 1,788 454 4,972 29,672

1991 25,749 1,174 951 470 450 1,990 535 5,571 31,319

1992 26,599 1,310 1,059 523 504 2,212 599 6,207 32,806

1993 27,644 1,465 1,175 579 566 2,452 635 6,872 34,515

1994 29,381 1,630 1,304 642 633 2,713 648 7,570 36,951

1995 30,327 1,814 1,445 710 709 2,993 742 8,413 38,740

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1996 30,995 2,014 1,596 783 793 3,292 840 9,319 40,314

1997 29,971 2,236 1,761 862 886 3,612 839 10,197 40,168

1998 31,207 2,479 1,938 946 992 3,953 919 11,227 42,435

1999 31,683 2,737 2,130 1,038 1,106 4,313 1,036 12,361 44,044

2000 32,148 3,015 2,335 1,134 1,230 4,690 1,036 13,440 45,588

2001 32,590 3,310 2,550 1,234 1,365 5,082 1,160 14,700 47,290

2002 32,915 3,623 2,776 1,337 1,511 5,486 1,165 15,898 48,813

2003 32,967 3,903 3,010 1,443 1,647 5,900 1,285 17,189 50,156

2004 33,155 4,190 3,207 1,525 1,790 6,255 1,308 18,275 51,430

2005 33,197 4,453 3,410 1,610 1,926 6,608 1,524 19,531 52,728

2006 33,348 4,728 3,590 1,682 2,069 6,925 1,497 20,491 53,840

2007 33,671 5,013 3,774 1,757 2,220 7,240 1,412 21,415 55,086

2008 34,049 5,304 3,963 1,836 2,376 7,550 1,501 22,530 56,579

2009 34,489 5,592 4,149 1,912 2,537 7,842 1,565 23,596 58,086

2010 34,973 5,872 4,330 1,985 2,698 8,111 1,615 24,610 59,584

2011 35,529 6,145 4,505 2,053 2,860 8,357 1,654 25,574 61,103

2012 36,104 6,394 4,671 2,115 3,015 8,581 1,691 26,467 62,572

2013 36,694 6,622 4,822 2,166 3,162 8,773 1,727 27,272 63,966

2014 37,275 6,824 4,952 2,207 3,299 8,931 1,759 27,972 65,248

2015 37,835 6,999 5,062 2,239 3,424 9,052 1,786 28,562 66,397

2016 38,347 7,143 5,151 2,260 3,536 9,137 1,808 29,034 67,382

2017 38,821 7,256 5,218 2,271 3,632 9,182 1,825 29,383 68,204

2018 39,227 7,334 5,261 2,271 3,712 9,189 1,837 29,604 68,831

2019 39,552 7,378 5,279 2,261 3,773 9,157 1,846 29,694 69,246

2020 39,787 7,386 5,274 2,241 3,816 9,087 1,849 29,652 69,439

2021 39,917 7,359 5,244 2,210 3,839 8,979 1,847 29,479 69,396

2022 39,933 7,296 5,190 2,171 3,843 8,835 1,841 29,176 69,109

2023 39,830 7,200 5,113 2,122 3,826 8,656 1,828 28,747 68,577

2024 39,599 7,071 5,014 2,066 3,790 8,446 1,811 28,198 67,797

2025 39,241 6,911 4,894 2,002 3,735 8,206 1,787 27,535 66,776

2026 38,752 6,723 4,754 1,931 3,662 7,939 1,758 26,766 65,518

2027 38,133 6,507 4,597 1,854 3,571 7,648 1,723 25,900 64,033

2028 37,391 6,268 4,423 1,772 3,465 7,336 1,683 24,947 62,338

2029 36,529 6,009 4,236 1,686 3,344 7,007 1,637 23,918 60,447

2030 35,553 5,731 4,037 1,597 3,210 6,664 1,586 22,824 58,378

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Figure 1. Relative incidence 1950-2030*

143x81mm (300 x 300 DPI)

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chronic hepatitis c virus (hcv) disease burden and cost in the

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