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Aging of Hepatitis C Virus (HCV)-Infected Persons in the United States: A Multiple Cohort Model of HCV Prevalence and Disease Progression

Published:October 26, 2009DOI:https://doi.org/10.1053/j.gastro.2009.09.067

      Background & Aims

      The prevalence of chronic hepatitis C (CH-C) remains high and the complications of infection are common. Our goal was to project the future prevalence of CH-C and its complications.

      Methods

      We developed a multicohort natural history model to overcome limitations of previous models for predicting disease outcomes and benefits of therapy.

      Results

      Prevalence of CH-C peaked in 2001 at 3.6 million. Fibrosis progression was inversely related to age at infection, so cirrhosis and its complications were most common after the age of 60 years, regardless of when infection occurred. The proportion of CH-C with cirrhosis is projected to reach 25% in 2010 and 45% in 2030, although the total number with cirrhosis will peak at 1.0 million (30.5% higher than the current level) in 2020 and then decline. Hepatic decompensation and liver cancer will continue to increase for another 10 to 13 years. Treatment of all infected patients in 2010 could reduce risk of cirrhosis, decompensation, cancer, and liver-related deaths by 16%, 42%, 31%, and 36% by 2020, given current response rates to antiviral therapy.

      Conclusions

      Prevalence of hepatitis C cirrhosis and its complications will continue to increase through the next decade and will mostly affect those older than 60 years of age. Current treatment patterns will have little effect on these complications, but wider application of antiviral treatment and better responses with new agents could significantly reduce the impact of this disease in coming years.

      Abbreviations used in this paper:

      CH-C (chronic hepatitis C), HCV (hepatitis C virus), HCC (hepatocellular carcinoma), NHANES III (Third National Health and Nutrition Examination Survey)
      It is estimated that up to 4 million persons in the United States have chronic hepatitis C virus (HCV) infection (CH-C).
      • Alter M.J.
      • Kruszon-Moran D.
      • Nainan O.V.
      • et al.
      The prevalence of hepatitis C virus infection in the United States, 1988 through 1994.
      • Armstrong G.L.
      • Wasley A.
      • Simard E.P.
      • et al.
      The prevalence of hepatitis C virus infection in the United States, 1999 through 2002.
      Despite the marked decrease in newly acquired infections in recent years, overall prevalence of CH-C has not fallen.
      • Armstrong G.L.
      • Wasley A.
      • Simard E.P.
      • et al.
      The prevalence of hepatitis C virus infection in the United States, 1999 through 2002.
      Most individuals with CH-C acquired their infection 20−40 years ago, before identification of the virus and availability of screening tests.
      • Alter M.J.
      • Hadler S.C.
      • Judson F.N.
      • et al.
      Risk factors for acute non-A, non-B hepatitis in the United States and association with hepatitis C virus infection.
      Because CH-C typically progresses slowly and does not result in morbidity for many years, most remain undiagnosed. We are only now beginning to recognize the magnitude of the consequences of infection that has persisted for decades.
      • Seeff L.B.
      • Buskell-Bales Z.
      • Wright E.C.
      • et al.
      Long-term mortality after transfusion-associated non-A, non-B hepatitis.
      • El-Serag H.B.
      • Mason A.C.
      Rising incidence of hepatocellular carcinoma in the United States.
      Outpatient and hospital visits for CH-C have doubled in recent years and show no sign of leveling off.
      • Everhart J.E.
      • Ruhl C.E.
      Burden of digestive disease in the United States Part III: liver, biliary tract and pancreas.
      National Ambulatory Medical Care Survey (NAMCS), National Hospital Medical Care Survey (NHMCS), National Hospital Discharge Survey), National Center for Health Statistics
      • Kim W.R.
      • Gross Jr, J.B.
      • Poterucha J.J.
      • et al.
      Outcome of hospital care of liver disease associated with hepatitis C in the United States.
      In the United States, complications of CH-C are the leading indication for liver transplantation and the disease is reported to contribute to 4600−12,000 deaths per year based on death certificate documentation,
      • Armstrong G.L.
      • Wasley A.
      • Simard E.P.
      • et al.
      The prevalence of hepatitis C virus infection in the United States, 1999 through 2002.
      • Everhart J.E.
      • Ruhl C.E.
      Burden of digestive disease in the United States Part III: liver, biliary tract and pancreas.
      • Vong S.
      • Bell B.P.
      Chronic liver disease mortality in the United States, 1990−1998.
      • Wise M.
      • Bialek S.
      • Finelli L.
      • et al.
      Changing trends in hepatitis C-related mortality in the United States, 1995–2004.
      despite the limitations of this method in estimating true death rates.
      • Manos M.M.
      • Leyden W.A.
      • Murphy R.C.
      • et al.
      Limitations of conventionally derived chronic liver disease mortality rates: Results of a comprehensive assessment.
      • Neal R.K.
      Trent Hepatitis C Study Group
      Excess mortality in a cohort of persons infected with the hepatitis C virus: a prospective study.
      Although some have suggested that the health care burden resulting from complications of CH-C has reached a plateau,
      • Wise M.
      • Bialek S.
      • Finelli L.
      • et al.
      Changing trends in hepatitis C-related mortality in the United States, 1995–2004.
      others have projected a further increase in cirrhosis and its complications for another 2 to 3 decades.
      • Davis G.L.
      • Albright J.E.
      • Cook S.F.
      • Rosenberg D.M.
      Projecting the future healthcare burden from hepatitis C in the United States.
      • Armstrong G.L.
      • Alter M.J.
      • McQuillan G.M.
      • Margolis H.S.
      The past incidence of hepatitis C virus infection: Implications for the future burden of chronic liver disease in the United States.
      Several models have been developed during the last decade to predict the future course of CH-C.
      • Davis G.L.
      • Albright J.E.
      • Cook S.F.
      • Rosenberg D.M.
      Projecting the future healthcare burden from hepatitis C in the United States.
      • Armstrong G.L.
      • Alter M.J.
      • McQuillan G.M.
      • Margolis H.S.
      The past incidence of hepatitis C virus infection: Implications for the future burden of chronic liver disease in the United States.
      • Deuffic S.
      • Buffat L.
      • Poynard T.
      • Valleron A.J.
      Modeling the hepatitis C epidemic in France.
      • Wong J.B.
      • McQuillan G.M.
      • McHutchison J.G.
      • Poynard T.
      Estimating future hepatitis C morbidity, mortality and costs in the United States.
      However, simple transition-state (Markov) models have significant limitations in that the studied cohort is considered homogeneous and traverses through their disease at a fixed and predictable rate over time. In reality, however, the population is quite heterogeneous due to factors such as age at infection, gender, and disease duration; therefore, the course of disease is variable and nonlinear over time.
      • Yi Q.
      • Yi Q.
      • Wang P.P.
      • Krahn M.
      Improving the accuracy of long-term prognostic estimates in hepatitis C virus infection.
      • Datz C.
      • Cramp M.
      • Haas T.
      • et al.
      The natural course of hepatitis C virus infection 18 years after an epidemic outbreak of non-A, non-B hepatitis in a plasmapheresis centre.
      • Poynard T.
      • Ratziu V.
      • Charlotte F.
      • et al.
      Rates and risk factors of liver fibrosis progression in persons with chronic hepatitis C.
      Also, previous models used standard population mortality, which recent studies suggest might underestimate true mortality in a chronic disease population.
      • Manos M.M.
      • Leyden W.A.
      • Murphy R.C.
      • et al.
      Limitations of conventionally derived chronic liver disease mortality rates: Results of a comprehensive assessment.
      • Guiltinan A.M.
      • Kaidarova Z.
      • Custer B.
      • et al.
      Increased all-cause, liver, and cardiac mortality among hepatitis C virus-seropositive blood donors.
      • Cruts G.
      • Buster M.
      • Vincente J.
      • et al.
      Estimating the total mortality among problem drug users.
      Advances in computer software now permit construction of complex models that allow parallel cohorts with different disease states and probabilities to run over time in order to provide a more realistic estimation of end-point events. The purpose of this project was to utilize state-of-the-art statistical modeling techniques and the latest epidemiologic, demographic, and natural history data to more accurately model the evolution of CH-C during the last 60 years and project its course in the coming decades.

      Materials and Methods

       Model Construction

      Construction and computer simulations of our model utilized TreeAge Pro 2009 Suite (TreeAge Software, Williamstown, MA) linked with Microsoft Excel 2007 (Microsoft Corporation, Redmond, WA). TreeAge allows construction of complex Markov models with progression rates that can be varied with time according to calendar year, patient age, year of disease, or dwell time within a specific state, eg, years of cirrhosis. It also allows the dynamic import of information such as disease incidence, population demographic change, and other factors from Excel spreadsheets.
      The model was developed in stages starting with a traditional bubble diagram of disease states that served as the basis for developing a more detailed mathematical model that followed infected persons from the time of acute infection until death. Both the bubble diagram and the more detailed TreeAge model are provided in Supplementary Figure 1, Supplementary Figure 2 available in the online version of this article. Acute infection could resolve, evolve to fulminant hepatitis, progress to chronic hepatitis, or end with death due to background (nonhepatic) mortality. CH-C was modeled through fibrosis stages (Metavir F0 to F4), disease complications, and death. The model cycled at yearly intervals allowing individuals to move to another state; however, all states except acute infection and fulminant hepatitis could resolve back into themselves indefinitely.
      It has become apparent in recent years that age at infection and gender greatly influence the risk of developing chronic infection and progressing to fibrosis.
      • Datz C.
      • Cramp M.
      • Haas T.
      • et al.
      The natural course of hepatitis C virus infection 18 years after an epidemic outbreak of non-A, non-B hepatitis in a plasmapheresis centre.
      • Poynard T.
      • Ratziu V.
      • Charlotte F.
      • et al.
      Rates and risk factors of liver fibrosis progression in persons with chronic hepatitis C.
      • Guiltinan A.M.
      • Kaidarova Z.
      • Custer B.
      • et al.
      Increased all-cause, liver, and cardiac mortality among hepatitis C virus-seropositive blood donors.
      • Cruts G.
      • Buster M.
      • Vincente J.
      • et al.
      Estimating the total mortality among problem drug users.
      • Zarski J.P.
      • McHutchison J.G.
      • Bronowicki J.P.
      • et al.
      Rate of natural disease progression in persons with chronic hepatitis C.
      • Thein H.H.
      • Yi Q.
      • Dore G.J.
      • Krahn M.D.
      Estimation of stage-specific fibrosis progression rates in chronic hepatitis C virus infection: a meta-analysis and meta-regression.
      • Pradat P.
      • Voirin N.
      • Tillmann H.L.
      • et al.
      Progression to cirrhosis in hepatitis C persons: an age-dependent process.
      • Wright M.
      • Goldin R.
      • Fabre A.
      • et al.
      Measurement and determinants of the natural history of liver fibrosis in hepatitis C virus infection: a cross sectional and longitudinal study.
      • Ryder S.D.
      Trent Hepatitis C Study Group
      Progression of hepatic fibrosis in persons with hepatitis C: a prospective repeat liver biopsy study.
      To accommodate this heterogeneity, we divided acutely infected individuals into 6 cohorts, each with their own cohort-specific transition states for chronicity, fibrosis progression, and complications (Table 1). The output of the 6 models was then collated and exported as an Excel spreadsheet defining cohort-specific and overall projections by year. Cohort and population projections included numbers with resolved infection, chronic infection, stage of fibrosis (F0 to cirrhosis), liver failure, hepatocellular carcinoma (HCC), liver-related deaths, and age- and gender-specific (nonliver) deaths.
      Table 1Model Variables by Cohort
      Cohort F0 30F31−50F>50M0 30M31−50M>50Variable
      123456Cohort
      195019501950195019501950Start year
      0.450.20.10.250.150.1p SpontaneousRecover from acute infection
      0.0050.0050.0050.0050.0050.005p FulmHepatitis
      0.850.850.850.850.850.85p FulmToDeath
      0.150.150.10.150.150.1p RecoveryFulm
      0.010.0050.0010.010.0050.001p ChronicRecover
      0.04200.05500.07700.09300.15500.1938p F0 to 1
      0.05250.06880.07700.11630.19380.1938p F0 to 1 after age 50
      0.04500.05100.07140.06350.10580.1323p F1 to 2
      0.05630.07140.07140.07940.13230.1323p F1 to 2 after age 50
      0.09200.07000.09800.09040.15060.1883p F2 to 3
      0.11500.08750.09800.11300.18830.1883p F2 to 3 after age 50
      0.07000.04800.06720.09460.15770.1971p F3 to 4
      0.08750.06000.06720.11830.19710.1971p F3 to 4 after age 50
      0.030.030.030.030.030.03p F4toDecomp
      0.50.50.50.50.50.5p DecompProgressive
      0.30.30.30.30.30.3p DecompProgToStable
      0.10.10.10.10.10.1p DecompToDeath
      0.00040.00040.00160.0010.0010.004p ChronicF2_3toHCC
      0.0040.0040.0120.010.010.03p F4toHCC
      0.0060.0060.0180.020.020.045P F4toHCC after 10 years of cirrhosis
      0.80.80.850.80.80.85p NewHCCtoDeath first year
      0.350.350.350.350.350.35p HCC to death after 1 year
      NOTE. In the column under the heading variable, p represents the transitional rate for moving from one state to another. For example, p ChronicRecover is the proportion moving from chronic hepatitis to resolved infection within an annual cycle of the model.
      HCC, hepatocellular carcinoma.
      Antiviral treatment, ablation of tumors, and liver transplantation could not be modeled because the indications for these practices and procedures are not standardized, their use varies considerably by geography, none is widely applied, and the outcomes are not well-defined in subgroups. Of these, only antiviral treatment has the possibility of significantly altering disease end points from a population perspective. Therefore, we subsequently modified the model to estimate the potential impact of antiviral treatment on cirrhosis and its complications. To do so, we considered treatment penetrance ranging from 0% to 100% in the infected population and sustained viral response rates of 40% to 80%. All cases were treated in 2010 and outcomes were calculated for the year 2020. It was assumed that patients with sustained viral response had no chance of progressing to cirrhosis or, if already cirrhotic, had no chance of subsequent hepatic failure.
      • Bruno S.
      • Stroffolini T.
      • Colombo M.
      • et al.
      Sustained virological response to interferon-alpha is associated with improved outcome in HCV-related cirrhosis: a retrospective study.
      The risk of progressing from cirrhosis to HCC after sustained viral response was assumed to be 0.66% per annum.
      • Bruno S.
      • Stroffolini T.
      • Colombo M.
      • et al.
      Sustained virological response to interferon-alpha is associated with improved outcome in HCV-related cirrhosis: a retrospective study.
      Other assumptions of the model were unchanged.

       Data Sources

      Medical literature was reviewed by the authors to provide best estimates of the range of probabilities for moving between disease states. Because reported progression rates vary between studies, a consensus rate was chosen (Table 1). We used conservative estimates when a particular transition was in doubt. Transition rates varied for some states according to the age and gender of the cohorts.
      • Thein H.H.
      • Yi Q.
      • Dore G.J.
      • Krahn M.D.
      Estimation of stage-specific fibrosis progression rates in chronic hepatitis C virus infection: a meta-analysis and meta-regression.
      • Pradat P.
      • Voirin N.
      • Tillmann H.L.
      • et al.
      Progression to cirrhosis in hepatitis C persons: an age-dependent process.
      • Wright M.
      • Goldin R.
      • Fabre A.
      • et al.
      Measurement and determinants of the natural history of liver fibrosis in hepatitis C virus infection: a cross sectional and longitudinal study.
      • Ryder S.D.
      Trent Hepatitis C Study Group
      Progression of hepatic fibrosis in persons with hepatitis C: a prospective repeat liver biopsy study.
      • Bruno S.
      • Stroffolini T.
      • Colombo M.
      • et al.
      Sustained virological response to interferon-alpha is associated with improved outcome in HCV-related cirrhosis: a retrospective study.
      • Freeman A.J.
      • Law M.G.
      • Kaldor J.M.
      • Dore G.J.
      Predicting progression to cirrhosis in chronic hepatitis C virus infection.
      For example, in the young female cohort, progression from acute to chronic infection was lower (55%) and the rate of fibrosis progression was slower than the oldest male cohort.
      Transition rates for moving from one fibrosis stage to another largely utilized the pooled rates from a meta-analysis reported by Thein and colleagues.
      • Yi Q.
      • Yi Q.
      • Wang P.P.
      • Krahn M.
      Improving the accuracy of long-term prognostic estimates in hepatitis C virus infection.
      • Thein H.H.
      • Yi Q.
      • Dore G.J.
      • Krahn M.D.
      Estimation of stage-specific fibrosis progression rates in chronic hepatitis C virus infection: a meta-analysis and meta-regression.
      However, our model also included tunnel states that kept a portion of the cohort with minimal fibrosis (F0 and F1) from progressing to the next state for variable periods of time in order to simulate slower rates of progression or no progression in some persons. To accommodate the tunnel states, fibrosis transitions were adjusted accordingly such that overall rates remained consistent with those of Thein and colleagues
      • Thein H.H.
      • Yi Q.
      • Dore G.J.
      • Krahn M.D.
      Estimation of stage-specific fibrosis progression rates in chronic hepatitis C virus infection: a meta-analysis and meta-regression.
      (Table 1). Alcohol intake was not modeled separately because its influence in the different cohorts is unknown; rather our transition rates are based on observational studies in which excessive alcohol use was present in 19% of the cohorts.
      • Thein H.H.
      • Yi Q.
      • Dore G.J.
      • Krahn M.D.
      Estimation of stage-specific fibrosis progression rates in chronic hepatitis C virus infection: a meta-analysis and meta-regression.
      Risks of developing HCC in persons with bridging fibrosis or cirrhosis were taken from longitudinal studies in North America and Europe.
      • Poynard T.
      • Ratziu V.
      • Charlotte F.
      • et al.
      Rates and risk factors of liver fibrosis progression in persons with chronic hepatitis C.
      • Guiltinan A.M.
      • Kaidarova Z.
      • Custer B.
      • et al.
      Increased all-cause, liver, and cardiac mortality among hepatitis C virus-seropositive blood donors.
      • Cruts G.
      • Buster M.
      • Vincente J.
      • et al.
      Estimating the total mortality among problem drug users.
      • Zarski J.P.
      • McHutchison J.G.
      • Bronowicki J.P.
      • et al.
      Rate of natural disease progression in persons with chronic hepatitis C.
      • Thein H.H.
      • Yi Q.
      • Dore G.J.
      • Krahn M.D.
      Estimation of stage-specific fibrosis progression rates in chronic hepatitis C virus infection: a meta-analysis and meta-regression.
      • Pradat P.
      • Voirin N.
      • Tillmann H.L.
      • et al.
      Progression to cirrhosis in hepatitis C persons: an age-dependent process.
      • Wright M.
      • Goldin R.
      • Fabre A.
      • et al.
      Measurement and determinants of the natural history of liver fibrosis in hepatitis C virus infection: a cross sectional and longitudinal study.
      • Ryder S.D.
      Trent Hepatitis C Study Group
      Progression of hepatic fibrosis in persons with hepatitis C: a prospective repeat liver biopsy study.
      • Bruno S.
      • Stroffolini T.
      • Colombo M.
      • et al.
      Sustained virological response to interferon-alpha is associated with improved outcome in HCV-related cirrhosis: a retrospective study.
      • Freeman A.J.
      • Law M.G.
      • Kaldor J.M.
      • Dore G.J.
      Predicting progression to cirrhosis in chronic hepatitis C virus infection.
      • Fattovich G.
      • Giustina G.
      • Degos F.
      • et al.
      Morbidity and mortality in compensated cirrhosis type C: a retrospective follow-up study of 384 persons.
      • Sangiovanni A.
      • Prati G.M.
      • Fasani P.
      • et al.
      The natural history of compensated cirrhosis due to hepatitis C virus: A 17-year cohort study of 214 persons.
      • Chiaramonte M.
      • Stroffolini T.
      • Vian A.
      • et al.
      Rate of incidence of hepatocellular carcinoma in persons with compensated viral cirrhosis.
      • Degos F.
      • Christidis C.
      • Ganne-Carrie N.
      • et al.
      Hepatitis C virus related cirrhosis: time to occurrence of hepatocellular carcinoma and death.
      HCC risk in those with bridging fibrosis was estimated to be 10% of that in cirrhosis. HCC risk in females was estimated to be 40% of that in males.
      • Yoshida H.
      • Tateishi R.
      • Arakawa Y.
      • et al.
      Benefit of interferon therapy in hepatocellular carcinoma prevention for individual persons with chronic hepatitis C.
      Finally, transition rates for fibrosis progression and HCC risk were allowed to increase after age 50 or 10 years of cirrhosis, respectively, consistent with previous observations that these risks are not linear.
      • Yi Q.
      • Yi Q.
      • Wang P.P.
      • Krahn M.
      Improving the accuracy of long-term prognostic estimates in hepatitis C virus infection.
      • Datz C.
      • Cramp M.
      • Haas T.
      • et al.
      The natural course of hepatitis C virus infection 18 years after an epidemic outbreak of non-A, non-B hepatitis in a plasmapheresis centre.
      • Poynard T.
      • Ratziu V.
      • Charlotte F.
      • et al.
      Rates and risk factors of liver fibrosis progression in persons with chronic hepatitis C.
      • Yoshida H.
      • Tateishi R.
      • Arakawa Y.
      • et al.
      Benefit of interferon therapy in hepatocellular carcinoma prevention for individual persons with chronic hepatitis C.
      • El-Serag H.B.
      Epidemiology of hepatocellular carcinoma in USA.
      Confirmation of the accuracy of the estimated transition rates was done by comparing the projected chronic infection prevalence in 1994 to results from the Third National Health and Nutrition Examination survey (NHANES III) and the projected cirrhosis and HCC prevalence in the different cohorts to published observations in similar groups.
      Annual numbers with newly acquired HCV infections between 1960 and 2006 were generated from a previously published model that estimated the past incidence of acute HCV infection given the actual prevalence measured at the time (1988−1994) of the NHANES III.
      • Alter M.J.
      • Kruszon-Moran D.
      • Nainan O.V.
      • et al.
      The prevalence of hepatitis C virus infection in the United States, 1988 through 1994.
      • Armstrong G.L.
      • Alter M.J.
      • McQuillan G.M.
      • Margolis H.S.
      The past incidence of hepatitis C virus infection: Implications for the future burden of chronic liver disease in the United States.
      Disease burden from hepatitis A, B and C in the United States
      Annual infections were stratified by age and gender based on actual distributions of these variables for cases of acute hepatitis reported to the Centers for Disease Control and Prevention's Sentinel Counties Study for each year from 1979 to 2006
      • Armstrong G.L.
      • Wasley A.
      • Simard E.P.
      • et al.
      The prevalence of hepatitis C virus infection in the United States, 1999 through 2002.
      • Alter M.J.
      • Margolis H.S.
      • Krawczynski K.
      • et al.
      The natural history of community-acquired hepatitis C in the United States The Sentinel Counties Chronic non-A, non-B Hepatitis Study Team.
      (personal communication, MJ Alter, November 25, 2008). For years when data from the Sentinel Counties Study were not available, number and distribution were assumed to be the same as the closest year with data. We sequentially entered these incident infections in annual cycles into the cohort models and projected disease outcomes through the year 2030. Annual incidence data and cohort distribution utilized in the model are shown in Supplementary Table 1 available online.
      Age- and gender-specific all-cause mortality was derived from standard US mortality tables.
      Centers for Disease Control and Prevention
      Mortality tables.
      The ages within each cohort were tracked through the annual cycles of the model such that background mortality would be appropriate as the cohorts aged.

       Sensitivity Analysis and Validation

      Sensitivity analysis was performed to assess the extent to which the model's calculations were affected by uncertainty in our assumptions. The ranges utilized in the sensitivity analysis were derived from the medical literature.
      • Chiaramonte M.
      • Stroffolini T.
      • Vian A.
      • et al.
      Rate of incidence of hepatocellular carcinoma in persons with compensated viral cirrhosis.
      • Franchini M.
      • Rossetti G.
      • Tagliaferri A.
      • et al.
      The natural history of chronic hepatitis C in a cohort of HIV-negative Italian persons with hereditary bleeding disorders.
      • Kenny-Walsh E.
      Irish Hepatology Research Group
      Clinical outcomes after hepatitis C infection from contaminated anti-D immune globulin.
      • Levine R.A.
      • Sanderson S.O.
      • Ploutz-Snyder R.
      • et al.
      Assessment of fibrosis progression in untreated Irish women with chronic hepatitis C contracted from immunoglobulin anti-D.

      Seeff LB, Miller RN, Rabkin CS, et al. 45-Year follow-up of hepatitis C virus infection in healthy young adults. Ann Intern Med 132:105−111.

      • Seeff L.B.
      Natural history of chronic hepatitis C.
      • Di Bisceglie A.M.
      • Goodman Z.D.
      • Ishak K.G.
      • et al.
      Long-term clinical and histopathological follow-up of chronic posttransfusion hepatitis.
      • Farci P.
      • Alter H.J.
      • Shimoda A.
      • et al.
      Hepatitis C virus associated fulminant hepatitic failure.
      • Yousuf M.
      • Nakano Y.
      • Sodeyama T.
      • Kiyosawa K.
      Persistence of viremia in persons with type-C chronic hepatitis during long term follow-up.
      • El-Serag H.B.
      Hepatocellular carcinoma and hepatitis C in the United States.
      • El-Serag H.B.
      Hepatocellular carcinoma: recent trends in the United States.
      and are reported in Supplementary Table 2 available online. Sensitivity analyses were confined to the young female and oldest male cohorts because these were the most disparate in transition probabilities and, therefore, most likely to identify potential sources of weakness within the model assumptions. First, one-way sensitivity analysis with tornado diagrams were utilized to identify dominant variables and to rank the impact of different variables on disease outcome (cirrhosis). If no dominant variable was identified, a second one-way sensitivity analysis was done. Finally, we examined the impact of increasing background mortality, consistent with some reports that suggest higher all-cause mortality in persons with CH-C.
      • El-Serag H.B.
      • Mason A.C.
      Rising incidence of hepatocellular carcinoma in the United States.
      • Deuffic S.
      • Buffat L.
      • Poynard T.
      • Valleron A.J.
      Modeling the hepatitis C epidemic in France.

      Results

       Population-Based Model Outcomes

      There was a rapid increase in the prevalence of CH-C between 1970 and 1990, when the incidence of acute HCV infection was greatest (Figure 1). We estimated 3.49 million infected persons in 1994, which is similar to previous predictions based on NHANES III.
      • Davis G.L.
      • Albright J.E.
      • Cook S.F.
      • Rosenberg D.M.
      Projecting the future healthcare burden from hepatitis C in the United States.
      • Armstrong G.L.
      • Alter M.J.
      • McQuillan G.M.
      • Margolis H.S.
      The past incidence of hepatitis C virus infection: Implications for the future burden of chronic liver disease in the United States.
      Estimated prevalence peaked at 3.57 million in 2001 and began to decline slowly thereafter, reaching about half its peak level by the year 2030 (Figure 1). Similarly, the model estimated that the number of persons who had ever been infected (resolved or chronic) peaked in 2001 at 5.04 million.
      Figure thumbnail gr1
      Figure 1Estimates by year of prevalent cases ever infected (top line), with chronic hepatitis C (open circles), and cirrhosis (solid squares). Acute infections (solid gray line) peaked between 1970 and 1990. The peak of chronic hepatitis prevalence was 2001, while the highest prevalence of cirrhosis is projected to be between 2010 and 2030, about 40 years after the peak of acute infections.
      Predicted distribution of histologic stages of fibrosis over time is shown in Figure 2. In 1970 and throughout the period during which HCV prevalence grew, the majority of cases were stage F0 or F1 (1970: 86.5%, 1980: 84.2%, 1990: 77.6%). Indeed, F0 and F1 fibrosis accounted for the majority of cases of CH-C until just recently. Currently, 41.8% of infected persons have minimal-to-mild fibrosis (F0 or F1), and 39.5% have F3 or F4 fibrosis.
      Figure thumbnail gr2
      Figure 2Distribution of histologic stages of fibrosis by year in persons with chronic hepatitis C (F0 = closed black squares, F1 = closed gray diamonds, F2 = open triangles, F3 = solid gray, and cirrhosis (including decompensated and hepatocellular carcinoma) = fine line with closed circles).
      Cirrhosis accounted for just 5% of all cases (diagnosed and undiagnosed) of CH-C in 1989, 10% in 1998, and 20% in 2006 (Figures 1 and 2). This proportion began to rise sharply after 1990, as the age and duration of infection of those infected began to increase. Indeed, the proportion with cirrhosis is projected to reach 24.8% in 2010, 37.2% in 2020, and 44.9% in 2030, although the total number of persons with cirrhosis is expected to peak at 1.04 million (30.5% higher than its current level) in 2020 and slowly decline thereafter. Men, particularly those infected before age 50, account for the majority of cases of cirrhosis today (73.6%) because of their more rapid rate of progression (Figure 3). Although men who acquired their infection after age 50 have the most rapid disease progression, they account for a small proportion of all cirrhosis (7.7%) because they often died of other causes before their fibrosis had a chance to progress. Although females who acquired infection before age 50 accounted for almost the same proportion of acute HCV infections as similarly aged men during the peak incidence years (43.0% vs 50.3%), they represent a much smaller proportion of those who have progressed to cirrhosis as of 2009 (16.1%) because chronicity was less likely and CH-C had a slower rate of progression than men.
      Figure thumbnail gr3
      Figure 3Stacked prevalence curves showing number of cases by year with cirrhosis according to gender and age at time of initial hepatitis C virus infection.
      Hepatic decompensation and HCC are late complications of CH-C occurring in persons with advanced fibrosis. The model suggests that decompensation became more common after 1995 and is currently estimated to be present in 11.7% of persons with cirrhosis (Figure 4). The proportion of cirrhotics with decompensation is expected to continue to rise at least through 2030, although the total number of persons with liver failure will start to decline after 2022. The number with HCC began to rise steeply after 1990 (Figure 4). The model estimated 37,697 cases between 1990 and 1999 compared to 86,765 (+130%), 130,366 (+50%), and 124,298 (−5%), respectively in each of the subsequent decades. The incidence of HCV-related HCC is projected to peak in 2019 at almost 14,000 cases per year if the risk in HCV-infected persons with fibrosis remains stable. Assuming that 55% of HCC cases are due to hepatitis C, the HCC projections in males and females in 2005 approximate estimates from a recent report based on the Surveillance, Epidemiology and End Results database (predicted vs estimated cases: male, 7700 vs 8053; female, 1608 vs 922).
      • Altekruse S.F.
      • McGlynn K.A.
      • Reichman M.E.
      Hepatocellular carcinoma incidence, mortality, and survival trends in the United States from 1975 to 2005.
      • Snowberger N.
      • Chinnakotla S.
      • Lepe R.M.
      • et al.
      Alpha fetoprotein, ultrasound, computerized tomography and magnetic resonance imaging for detection of hepatocellular carcinoma in persons with advanced cirrhosis.
      Figure thumbnail gr4
      Figure 4Projected number of cases by year of decompensated cirrhosis (black) and hepatocellular carcinoma (gray). The model assumes a first year mortality of 80% to 85%, so in contrast to the decompensated cirrhosis projection, the number of cases of hepatocellular carcinoma the prevalence demonstrated here closely resembles annual incidence of liver cancer.
      We projected that hepatic deaths due to HCV would continue to increase through 2022, although the rate of year-to-year change began to slowly decline after 1991. Consistent with the increasing average duration of infection in persons with CH-C and the severity of liver disease described here, we estimated 29,090 liver-related deaths from 1980 to 1989, 56,377 (93%) in 1990−1999, 145,667 (+158%) in 2000−2009, 254,550 (+74%) in 2010−2019, and 283,378 from 2020 to 2029.

       Cohort Analysis

      The proportions with cirrhosis, decompensation, HCC, liver-related death, and non-liver−related death after 10, 20, and 30 years in each of the 6 cohorts are shown in Table 2. These proportions apply to the entire cohort that was ever infected, including those who resolved infection early. For example, although 1.33% of women in the youngest cohort were expected to have cirrhosis after 20 years, these cases occurred only among the 55% who had not resolved acute infection spontaneously; this represented 2.59% of persons with CH-C. Fibrosis and cirrhosis increased over time in all cohorts, but never exceeded 40% within the 30-year observation period. However, if only those who developed CH-C are considered, cirrhosis was predicted in more than half of the 2 older male cohorts after 30 years because progression rates were more rapid in these persons. The majority of these remained compensated.
      Table 2Projections for Cirrhosis, Decompensation, Hepatocellular Carcinoma, and Death by Cohort
      Of all infected, %Of chronic hepatitis survivors, %
      GenderAge at Infection, yYears since infectionNot resolved, %All cirrhosisDecompensation cirrhosisHCCLiver deathNon-liver DeathAll cirrhosisDecompensation cirrhosisHCC
      Female0−3010550.100.000.000.430.740.190.000.00
      201.330.100.010.492.012.590.200.01
      304.240.440.020.924.958.590.900.05
      31−5010800.120.000.000.431.920.150.000.00
      202.380.170.010.526.723.270.230.02
      307.750.790.041.2817.0012.131.230.07
      >5010900.430.010.010.447.580.520.020.01
      204.120.320.070.8222.636.010.470.10
      307.360.800.122.2950.4617.431.230.28
      Male0−3010650.500.020.010.431.180.710.030.01
      205.390.430.070.832.827.760.620.16
      3013.921.550.192.916.4121.472.390.29
      31−5010803.240.130.030.482.564.010.160.04
      2027.762.440.342.758.2436.863.300.45
      3038.115.130.5011.1421.1169.319.340.92
      >5010906.390.260.190.709.567.950.320.24
      2024.272.410.866.0829.7542.624.231.50
      3015.242.210.5615.0659.8770.6810.242.57
      HCC, hepatocellular carcinoma.
      Duration of infection before the peak prevalence of cirrhosis and its complications always varied inversely with the age at acute infection. Therefore, the estimated average ages at the peaks for disease complications were surprisingly consistent in the 6 cohorts (Supplementary Table 3). In the female cohorts, the peak for cirrhosis appeared at ages 71.5−87.0 years, decompensation at 74.5−82.5 years, and HCC at 72.5−87.0 years. In males, cirrhosis appeared at ages 64.5−79.0 years, decompensation at 68.0−82, and HCC at 65.5−80.0 years.

       Effect of Treatment

      Our original model was not designed to examine treatment effects so a second model was designed to test the effects of treating various proportions of persons with CH-C and no preexisting complications of liver disease. All treatment was administered in the year 2010. Assuming current estimates that 30% of cases of HCV are diagnosed and up to 25% of those are treated, we would anticipate just a 1.0% reduction in cirrhosis by 2020 compared to 7.8% or 15.6% reductions if half or all of individuals were treated, respectively (Figure 5A). However, if viral clearance increased to 80%, as appears possible with evolving treatments, treatment of half or all of infected persons would reduce cirrhosis by 15.2% or 30.4%, respectively, after just 10 years. The effects are more pronounced when looking at complications of liver disease. Indeed, treatment of half or all of infected persons in 2010 would result decrease cases of liver failure of 39.4% or 78.9%, HCC by 30.2% or 60.4%, and liver-related deaths by 34.0% or 68.0% over the next decade (Figure 5B).
      Figure thumbnail gr5
      Figure 5Estimated reductions in cirrhosis (5A) and liver-related death (5B) by 2020 assuming incremental treatment of zero to 100 percent of infected persons and sustained viral response (SVR) rates of 40%, 60% and 80%.

       Sensitivity Analyses

      One-way sensitivity analysis in the youngest female and male cohorts found the rate of chronicity after acute infection was dominant over all other variables in determining the risk of cirrhosis. No other transition rates significantly impacted the risk of cirrhosis after 20 years. The group's predicted estimates of cirrhosis after 17 and 24 years were 0.8% and 2.3%, respectively. These proportions are similar to the 2.0% and 3.1% reported in young Irish women by Kenny-Walsh and Levine
      • Kenny-Walsh E.
      Irish Hepatology Research Group
      Clinical outcomes after hepatitis C infection from contaminated anti-D immune globulin.
      • Levine R.A.
      • Sanderson S.O.
      • Ploutz-Snyder R.
      • et al.
      Assessment of fibrosis progression in untreated Irish women with chronic hepatitis C contracted from immunoglobulin anti-D.
      (Table 3). Similarly, we predicted that a 1.8% hepatic death rate in men infected before age 30, which is similar to the 5.9% observed in the small study of military recruits reported by Seeff and colleagues

      Seeff LB, Miller RN, Rabkin CS, et al. 45-Year follow-up of hepatitis C virus infection in healthy young adults. Ann Intern Med 132:105−111.

      (Table 3). These projections appear to confirm the accuracy of the assumptions in the younger cohorts. In the oldest males, the initial transition from F0 to F1 had the greatest impact on the risk of cirrhosis. However, when the sensitivity analysis in this group was confined to stage-to-stage fibrosis transition rates, no single transition dominated, and risk of cirrhosis after 20 years varied from just 3.75−6.08% less to 2.39−5.69% more than our model projection. In addition, the projected prevalence of cirrhosis after 20 years in the older male group was 24%, consistent with the high rate of fibrosis progression reported by others in this group.
      • Poynard T.
      • Ratziu V.
      • Charlotte F.
      • et al.
      Rates and risk factors of liver fibrosis progression in persons with chronic hepatitis C.
      • Sersté T.
      • Bourgeois N.
      Aging and the liver.
      • Ferenci P.
      • Ferenci S.
      • Datz C.
      • et al.
      Morbidity and mortality in paid Austrian plasma donors infected with hepatitis C at plasma donation in the 1970s.
      (Table 3).
      Table 3Comparison of Model Projections to Published Observations
      MeasureObservedModel projectionReference
      Chronic hepatitis C prevalence, millions2.7−3.93.49
      • Davis G.L.
      • Albright J.E.
      • Cook S.F.
      • Rosenberg D.M.
      Projecting the future healthcare burden from hepatitis C in the United States.
      ,
      • Armstrong G.L.
      • Alter M.J.
      • McQuillan G.M.
      • Margolis H.S.
      The past incidence of hepatitis C virus infection: Implications for the future burden of chronic liver disease in the United States.
      Cirrhosis in females infected at young age, %
       17 years2.00.8
      • Kenny-Walsh E.
      Irish Hepatology Research Group
      Clinical outcomes after hepatitis C infection from contaminated anti-D immune globulin.
       25 years3.12.3
      • Levine R.A.
      • Sanderson S.O.
      • Ploutz-Snyder R.
      • et al.
      Assessment of fibrosis progression in untreated Irish women with chronic hepatitis C contracted from immunoglobulin anti-D.
      Cirrhosis in men infected at young age, %5.91.8

      Seeff LB, Miller RN, Rabkin CS, et al. 45-Year follow-up of hepatitis C virus infection in healthy young adults. Ann Intern Med 132:105−111.

      Incremental change in mortality, %
       1995−1999 to 2000−2004+123+94
      • Wise M.
      • Bialek S.
      • Finelli L.
      • et al.
      Changing trends in hepatitis C-related mortality in the United States, 1995–2004.
      Liver-related death (HCV on death certificate), n
       20047426
      • Wise M.
      • Bialek S.
      • Finelli L.
      • et al.
      Changing trends in hepatitis C-related mortality in the United States, 1995–2004.
       200411,29213,797
      • Everhart J.E.
      • Ruhl C.E.
      Burden of digestive disease in the United States Part III: liver, biliary tract and pancreas.
      HCV, hepatitis C virus.
      Another potential source of uncertainty stems from our use of tunnel states to slow progression during early fibrosis stages and acceleration of progression rates when younger cohorts reached age 50. We felt that these age- and duration-adjusted fibrosis progression rates best reflected the observations from previous reports.
      • Yi Q.
      • Yi Q.
      • Wang P.P.
      • Krahn M.
      Improving the accuracy of long-term prognostic estimates in hepatitis C virus infection.
      • Datz C.
      • Cramp M.
      • Haas T.
      • et al.
      The natural course of hepatitis C virus infection 18 years after an epidemic outbreak of non-A, non-B hepatitis in a plasmapheresis centre.
      • Poynard T.
      • Ratziu V.
      • Charlotte F.
      • et al.
      Rates and risk factors of liver fibrosis progression in persons with chronic hepatitis C.
      • Yoshida H.
      • Tateishi R.
      • Arakawa Y.
      • et al.
      Benefit of interferon therapy in hepatocellular carcinoma prevention for individual persons with chronic hepatitis C.
      • El-Serag H.B.
      Epidemiology of hepatocellular carcinoma in USA.
      • Kenny-Walsh E.
      Irish Hepatology Research Group
      Clinical outcomes after hepatitis C infection from contaminated anti-D immune globulin.
      • Levine R.A.
      • Sanderson S.O.
      • Ploutz-Snyder R.
      • et al.
      Assessment of fibrosis progression in untreated Irish women with chronic hepatitis C contracted from immunoglobulin anti-D.

      Seeff LB, Miller RN, Rabkin CS, et al. 45-Year follow-up of hepatitis C virus infection in healthy young adults. Ann Intern Med 132:105−111.

      However, we also tested a fixed stage-to-stage progression rate as reported in the meta-analysis by Thein and colleagues.
      • Thein H.H.
      • Yi Q.
      • Dore G.J.
      • Krahn M.D.
      Estimation of stage-specific fibrosis progression rates in chronic hepatitis C virus infection: a meta-analysis and meta-regression.
      As expected, this led to front-loading of morbidity and hepatic mortality, particularly in the younger cohorts, during the years when standard age-related mortality was low. As a result, the fixed rate model overestimated cases of cirrhosis, decompensation or HCC, and liver-related death by 41%, 86%, and 41%, respectively, compared to the more conservative base case model, and these estimates were much higher than those reported in previous prospective studies.
      • Kenny-Walsh E.
      Irish Hepatology Research Group
      Clinical outcomes after hepatitis C infection from contaminated anti-D immune globulin.
      • Levine R.A.
      • Sanderson S.O.
      • Ploutz-Snyder R.
      • et al.
      Assessment of fibrosis progression in untreated Irish women with chronic hepatitis C contracted from immunoglobulin anti-D.

      Seeff LB, Miller RN, Rabkin CS, et al. 45-Year follow-up of hepatitis C virus infection in healthy young adults. Ann Intern Med 132:105−111.

      Therefore, we maintained our more conservative assumptions for the base case model.
      Finally, we looked at the impact of utilizing higher background (nonhepatic) age- and gender-related mortality rates on our projections of chronic hepatitis and cirrhosis in coming decades. Recent studies have suggested that comorbid medical conditions might increase background mortality in HCV-infected persons by as much as 3 times the reported actuarial rates.
      • Manos M.M.
      • Leyden W.A.
      • Murphy R.C.
      • et al.
      Limitations of conventionally derived chronic liver disease mortality rates: Results of a comprehensive assessment.
      • Neal R.K.
      Trent Hepatitis C Study Group
      Excess mortality in a cohort of persons infected with the hepatitis C virus: a prospective study.
      • Guiltinan A.M.
      • Kaidarova Z.
      • Custer B.
      • et al.
      Increased all-cause, liver, and cardiac mortality among hepatitis C virus-seropositive blood donors.
      Increasing background mortality rates in the model by 50% or 100% had no impact on the proportion of infected persons with cirrhosis, but it significantly reduced the total number with cirrhosis. A 50% increase in background mortality decreased the number of persons with chronic hepatitis or cirrhosis in 2020 by 35% and 31%, respectively, compared to the base case model projections. A 100% increase decreased the number with chronic hepatitis or cirrhosis in 2020 by 46% and 43%, respectively, compared to base case projections.
      Our sensitivity analysis did not include incidence data because no other estimates exist and these data have previously been shown to be consistent with prevalence data as estimated by NHANES III.
      • Alter M.J.
      • Kruszon-Moran D.
      • Nainan O.V.
      • et al.
      The prevalence of hepatitis C virus infection in the United States, 1988 through 1994.
      • Armstrong G.L.
      • Alter M.J.
      • McQuillan G.M.
      • Margolis H.S.
      The past incidence of hepatitis C virus infection: Implications for the future burden of chronic liver disease in the United States.

      Discussion

      Our model estimated that the prevalence of CH-C in the United States peaked at 3.6 million in 2001 and will decline to about half this number by 2030. Although the decline in overall infections is encouraging, other trends in the data are of concern. First, similar to reports by others,
      • Davis G.L.
      • Albright J.E.
      • Cook S.F.
      • Rosenberg D.M.
      Projecting the future healthcare burden from hepatitis C in the United States.
      • Armstrong G.L.
      • Alter M.J.
      • McQuillan G.M.
      • Margolis H.S.
      The past incidence of hepatitis C virus infection: Implications for the future burden of chronic liver disease in the United States.
      • Wong J.B.
      • McQuillan G.M.
      • McHutchison J.G.
      • Poynard T.
      Estimating future hepatitis C morbidity, mortality and costs in the United States.
      the proportion of cases with advanced fibrosis will continue to rise during the next 2 decades, with the number of cases of cirrhosis and hepatic decompensation peaking after the year 2020. Second, the age of those with cirrhosis and its complications will continue to rise. Because about 40 years elapses from the peak incidence years of HCV infection until the peak prevalence of cirrhosis and other complications (Figure 1), it is not surprising that we found the group of persons aged 60 to 80 years to be those most affected. This phenomenon is already beginning to occur.
      • Snowberger N.
      • Chinnakotla S.
      • Lepe R.M.
      • et al.
      Alpha fetoprotein, ultrasound, computerized tomography and magnetic resonance imaging for detection of hepatocellular carcinoma in persons with advanced cirrhosis.
      • Thabut D.
      • Le Calvez S.
      • Thibault V.
      • et al.
      Hepatitis C in 6,865 persons 65 yr or older: a severe and neglected curable disease?.
      • Mindikoglu A.L.
      • Miller R.R.
      Hepatitis C in the elderly: epidemiology, natural history, and treatment.
      • D'Souza R.D.
      • Glynn M.J.
      • Ushiro-Lumb I.
      • et al.
      Prevalence of hepatitis C cirrhosis in elderly Asian patients infected during childhood.
      Indeed, Ferenci and colleagues found that 34% of infected paid plasma donors identified in the 1970s had bridging fibrosis, cirrhosis, or HCC 30 years later.
      • Ferenci P.
      • Ferenci S.
      • Datz C.
      • et al.
      Morbidity and mortality in paid Austrian plasma donors infected with hepatitis C at plasma donation in the 1970s.
      In addition, Thabut and colleagues reported that cirrhosis was more prevalent in the elderly and 14% of them presented with decompensation compared to just 4% in persons younger than 65 years.
      • Thabut D.
      • Le Calvez S.
      • Thibault V.
      • et al.
      Hepatitis C in 6,865 persons 65 yr or older: a severe and neglected curable disease?.
      Indeed, D'Souza and others have even suggested that patients who live long enough will almost invariably develop advanced hepatic fibrosis.
      • D'Souza R.D.
      • Glynn M.J.
      • Ushiro-Lumb I.
      • et al.
      Prevalence of hepatitis C cirrhosis in elderly Asian patients infected during childhood.
      • Seeff L.B.
      • Everhart J.E.
      Is cirrhosis an inevitable consequence of chronic hepatitis C virus infection?.
      We also predicted a modest increase in HCV-related HCC in coming years, despite using a very conservative estimate of the annual risk in our model. HCV infection currently accounts for most of the HCC in the United States.
      • Snowberger N.
      • Chinnakotla S.
      • Lepe R.M.
      • et al.
      Alpha fetoprotein, ultrasound, computerized tomography and magnetic resonance imaging for detection of hepatocellular carcinoma in persons with advanced cirrhosis.
      HCC in persons older than the age of 65 years with HCV infection has doubled during the last several years,
      • Altekruse S.F.
      • McGlynn K.A.
      • Reichman M.E.
      Hepatocellular carcinoma incidence, mortality, and survival trends in the United States from 1975 to 2005.
      • Davila J.A.
      • Morgan R.O.
      • Shaib Y.
      • et al.
      Hepatitis C infection and the increasing incidence of hepatocellular carcinoma: a population-based study.
      consistent with our predictions. Taken together, our findings suggest that the CH-C that we have become familiar with during the last 30 years is much different than the hepatitis C we will come to know during the next decade or 2.
      Although we purposefully chose conservative estimates of disease progression and complications, it is still possible that we and others might have overestimated the number of cases that will progress to liver failure from CH-C due to the influence of competing risks.
      • Manos M.M.
      • Leyden W.A.
      • Murphy R.C.
      • et al.
      Limitations of conventionally derived chronic liver disease mortality rates: Results of a comprehensive assessment.
      • Neal R.K.
      Trent Hepatitis C Study Group
      Excess mortality in a cohort of persons infected with the hepatitis C virus: a prospective study.
      • Guiltinan A.M.
      • Kaidarova Z.
      • Custer B.
      • et al.
      Increased all-cause, liver, and cardiac mortality among hepatitis C virus-seropositive blood donors.
      • Kim W.R.
      • Poterucha J.J.
      • Benson J.T.
      • Therneau T.M.
      The impact of competing risks on the observed rate of chronic hepatitis C progression.
      Indeed, when we increased the background (nonhepatic) mortality by just 50%, there was a striking reduction in the number of cases of cirrhosis, liver failure, and cancer. However, we believe that such high background mortality is unlikely in HCV-infected patients. If it occurs it is probably limited to a short period around the time of acute infection and would be unlikely to influence long-term outcomes. Furthermore, common comorbid conditions, such as diabetes, obesity, and alcohol, lead to more rapid progression of fibrosis, which can offset any potential impact of a change in background mortality.
      • Ryder S.D.
      Trent Hepatitis C Study Group
      Progression of hepatic fibrosis in persons with hepatitis C: a prospective repeat liver biopsy study.
      • Missiha S.B.
      • Ostrowski M.
      • Heathcote E.J.
      Disease progression in chronic hepatitis C: modifiable and nonmodifiable factors.
      • Hui J.M.
      • Sud A.
      • Farrell G.C.
      • et al.
      Insulin resistance is associated with chronic hepatitis C virus infection and fibrosis progression.
      • El Serag H.B.
      • Hampel H.
      • Javadi F.
      The association between diabetes and hepatocellular carcinoma: a systemic review of epidemiologic evidence.
      Competing risks could certainly influence resource utilization and might explain why, for example, the number of liver transplantations related to hepatitis C has started to plateau, despite our prediction of more disease complications.
      These projections emphasize how critical it is to identify infected persons and treat their disease before advanced fibrosis or liver failure ensues. Currently, only a small proportion of those with CH-C are aware of their infection and, of these, just 10% to 27% are offered treatment.
      • Russmann S.
      • Dowlatshahi E.A.
      • Printzen G.
      • et al.
      Prevalence and associated factors of viral hepatitis and transferrin elevations in 5036 persons admitted to the emergency room of a Swiss university hospital: cross-sectional study.
      • Irving W.L.
      • Smith S.
      • Cater R.
      • et al.
      Clinical pathways for persons with newly diagnosed hepatitis C - what actually happens.
      • Morrill J.A.
      • Shrestha M.
      • Grant R.W.
      Barriers to the treatment of hepatitis C Patient, provider, and system factors.
      Many physicians still do not ask their patients about risk factors for HCV infection and some remain confused about treatment options and efficacy.
      • Shehab R.M.
      • Sonnad S.S.
      • Lok A.S.
      Management of hepatitis C persons by primary care physicians in the USA: results of a national survey.
      And yet, antiviral therapy is becoming increasingly effective
      • Fried M.W.
      • Shiffman M.L.
      • Reddy R.
      • et al.
      Peg-interferon alfa-2a plus ribavirin for chronic hepatitis C virus infection.
      • Pawlotsky J.M.
      • Chevaliez S.
      • McHutchison J.G.
      The hepatitis C virus life cycle as a target for new antiviral therapies.
      and eradication of virus clearly reduces risk of liver failure or cancer.
      • Bruno S.
      • Stroffolini T.
      • Colombo M.
      • et al.
      Sustained virological response to interferon-alpha is associated with improved outcome in HCV-related cirrhosis: a retrospective study.
      • Veldt B.J.
      • Heathcote E.J.
      • Wedemeyer H.
      • et al.
      Sustained virologic response and clinical outcomes in persons with chronic hepatitis C and advanced fibrosis.
      Certainly, as we have shown, a far higher proportion of cases will need to be identified and treated to impact the dire projections described here. It is in the immediate best interest of patients, providers, insurers, and governments to promote guidelines and encourage better screening for infection and early antiviral treatment.
      • Alter M.J.
      • Seeff L.B.
      • Bacon B.R.
      • et al.
      Testing for hepatitis C infection should be routine for persons at increased risk of infection.
      Without such a proactive policy, it is likely that we will spend a considerable amount of resources during the next 2 or 3 decades dealing with liver failure in our elderly population.

      Acknowledgments

      The authors wish to acknowledge Andrew Munzer, TreeAge Software Support, Neil Warnock, MD, MBA, Medical Affairs, Vertex Pharmaceuticals, Cambridge, MA, and Steven Kymes, PhD, Department of Ophthalmology, St Louis University, St Louis, Missouri for technical assistance in the model development.

      Supplementary data

      Figure thumbnail gre1
      Supplementary Figure 1Bubble diagram showing the transition states incorporated into our Markov model. Subjects moved from left-to-right in 1-year cycles. Each state with the exceptions of acute infection and fulminant hepatitis could resolve to itself (no progression) for periods ranging from 1 year to indefinitely. Each state is subject to normal age- and gender-related mortality based on the age of acute infection plus the number of cycles that had occurred (accrued age). Interventions such as antiviral therapy, tumor ablation, or liver transplantation were not allowed in the model (see text).
      Figure thumbnail gre2
      Supplementary Figure 2Schematic of the Markov model developed for each of 6 cohorts. Transitions states are listed in the first order branches along the left. All subjects started as acute infection. Subjects move right and downward over time. Possible transitions states for subsequent years after a particular state are listed in the branches to the right of a given state.
      Supplementary Table 1Incident Cases for Each of 6 Age and Gender Cohorts by Year from 1950 to 2030
      FemaleMale
      Model cycleYearAge <30 yAge 31−50 yAge >50 yAge <30 yAge 31−50 yAge >50 y
      019507463428483887485029984
      119517463428483887485029984
      219527463428483887485029984
      319537463428483887485029984
      419547463428483887485029984
      519557463428483887485029984
      619567463428483887485029984
      719577463428483887485029984
      819587463428483887485029984
      919597463428483887485029984
      1019607463428483887485029984
      111961867649809741016958461144
      1219629888567611101159066631304
      13196311101637212471301274801464
      14196412313706813831443382981624
      15196513526776415191585491151783
      161966164059417184319230110552163
      1719671928511070216622605129962543
      1819682216412723249025980149362923
      1919692504414376281329356168773303
      2019702792416029313732731188173682
      2119713143318044353136845211824145
      2219723494320059392540958235474608
      2319733845222073432045072259125071
      2419744196224088471449186282775534
      2519754547126103510853299306425997
      2619764778427430536856010322016302
      2719775009628758562858721337596607
      2819785240930085588861431353176912
      2919795472131413614764142368767217
      3019805703432740640766853384347522
      3119815511831640619264607371437269
      3219825320230541597762362358527016
      3319835128729441576260116345616764
      3419845985234358672470156403337893
      3519857115040843799383399479479383
      3619867092838165642490209485748176
      3719875833731390528474196399526725
      3819886492734936588082577444647484
      39198978761423817133100172539399079
      4019903485928239517356605460758440
      4119912175917627322935333287605268
      4219921417911486210423024187413433
      431993111259012165118065147042693
      441994105078512155917062138882544
      451995602638529851389789882299
      461996602438509851389189842298
      4719976431411010511482995902453
      48199869074414112915926103002635
      4919996671426410901538399492545
      5020003807856514456732152282570
      51200123505287892415593991586
      5220022879647710935091115151943
      5320032780625310554915111181876
      542004258158079804564103231742
      55200520854690791368683381407
      56200618864243716333575441273
      57200718864243716333575441273
      58200818864243716333575441273
      59200918864243716333575441273
      60201018864243716333575441273
      61201118864243716333575441273
      62201218864243716333575441273
      63201318864243716333575441273
      64201418864243716333575441273
      65201518864243716333575441273
      66201618864243716333575441273
      67201718864243716333575441273
      68201818864243716333575441273
      69201918864243716333575441273
      70202018864243716333575441273
      71202118864243716333575441273
      72202218864243716333575441273
      73202318864243716333575441273
      74202418864243716333575441273
      75202518864243716333575441273
      76202618864243716333575441273
      77202718864243716333575441273
      78202818864243716333575441273
      79202918864243716333575441273
      80203018864243716333575441273
      Supplementary Table 2Probabilities for Sensitivity Analyses
      Cohort
      ProbabilityFemale 0−30Male >50VariableReferences
      Best estimate0.4500.100p Spontaneous Recover from acute HCV
      • Alter M.J.
      • Margolis H.S.
      • Krawczynski K.
      • et al.
      The natural history of community-acquired hepatitis C in the United States The Sentinel Counties Chronic non-A, non-B Hepatitis Study Team.
      ,
      • Franchini M.
      • Rossetti G.
      • Tagliaferri A.
      • et al.
      The natural history of chronic hepatitis C in a cohort of HIV-negative Italian persons with hereditary bleeding disorders.
      ,
      • Kenny-Walsh E.
      Irish Hepatology Research Group
      Clinical outcomes after hepatitis C infection from contaminated anti-D immune globulin.
      ,
      • Levine R.A.
      • Sanderson S.O.
      • Ploutz-Snyder R.
      • et al.
      Assessment of fibrosis progression in untreated Irish women with chronic hepatitis C contracted from immunoglobulin anti-D.
      ,

      Seeff LB, Miller RN, Rabkin CS, et al. 45-Year follow-up of hepatitis C virus infection in healthy young adults. Ann Intern Med 132:105−111.

      ,
      • Di Bisceglie A.M.
      • Goodman Z.D.
      • Ishak K.G.
      • et al.
      Long-term clinical and histopathological follow-up of chronic posttransfusion hepatitis.
      ,
      • Di Bisceglie A.M.
      • Goodman Z.D.
      • Ishak K.G.
      • et al.
      Long-term clinical and histopathological follow-up of chronic posttransfusion hepatitis.
       Low0.3000.050
       High0.5000.250
      Best estimate0.0050.005p Fulm Hepatitis
      • Farci P.
      • Alter H.J.
      • Shimoda A.
      • et al.
      Hepatitis C virus associated fulminant hepatitic failure.
       Low0.0010.000
       High0.0100.010
      Best estimate0.8500.850p Fulm To Death
      • Farci P.
      • Alter H.J.
      • Shimoda A.
      • et al.
      Hepatitis C virus associated fulminant hepatitic failure.
       Low0.7500.750
       High0.9000.900
      Best estimate0.1500.100p Fulminant Recover
      • Farci P.
      • Alter H.J.
      • Shimoda A.
      • et al.
      Hepatitis C virus associated fulminant hepatitic failure.
       Low0.1000.100
       High0.2500.250
      Best estimate0.0100.001p Chronic (F0-1) Recover
      • Yousuf M.
      • Nakano Y.
      • Sodeyama T.
      • Kiyosawa K.
      Persistence of viremia in persons with type-C chronic hepatitis during long term follow-up.
       Low0.0010.000
       High0.0150.005
      Best estimate0.0420.194p F0 to 1
      • Yi Q.
      • Yi Q.
      • Wang P.P.
      • Krahn M.
      Improving the accuracy of long-term prognostic estimates in hepatitis C virus infection.
      ,
      • Poynard T.
      • Ratziu V.
      • Charlotte F.
      • et al.
      Rates and risk factors of liver fibrosis progression in persons with chronic hepatitis C.
      ,
      • Thein H.H.
      • Yi Q.
      • Dore G.J.
      • Krahn M.D.
      Estimation of stage-specific fibrosis progression rates in chronic hepatitis C virus infection: a meta-analysis and meta-regression.
      ,
      • Pradat P.
      • Voirin N.
      • Tillmann H.L.
      • et al.
      Progression to cirrhosis in hepatitis C persons: an age-dependent process.
      ,
      • Wright M.
      • Goldin R.
      • Fabre A.
      • et al.
      Measurement and determinants of the natural history of liver fibrosis in hepatitis C virus infection: a cross sectional and longitudinal study.
      ,
      • Ryder S.D.
      Trent Hepatitis C Study Group
      Progression of hepatic fibrosis in persons with hepatitis C: a prospective repeat liver biopsy study.
       Low0.0370.172
       High0.0470.215
      Best estimate0.0450.132p F1 to 2
      • Yi Q.
      • Yi Q.
      • Wang P.P.
      • Krahn M.
      Improving the accuracy of long-term prognostic estimates in hepatitis C virus infection.
      ,
      • Poynard T.
      • Ratziu V.
      • Charlotte F.
      • et al.
      Rates and risk factors of liver fibrosis progression in persons with chronic hepatitis C.
      ,
      • Thein H.H.
      • Yi Q.
      • Dore G.J.
      • Krahn M.D.
      Estimation of stage-specific fibrosis progression rates in chronic hepatitis C virus infection: a meta-analysis and meta-regression.
      ,
      • Pradat P.
      • Voirin N.
      • Tillmann H.L.
      • et al.
      Progression to cirrhosis in hepatitis C persons: an age-dependent process.
      ,
      • Wright M.
      • Goldin R.
      • Fabre A.
      • et al.
      Measurement and determinants of the natural history of liver fibrosis in hepatitis C virus infection: a cross sectional and longitudinal study.
      ,
      • Ryder S.D.
      Trent Hepatitis C Study Group
      Progression of hepatic fibrosis in persons with hepatitis C: a prospective repeat liver biopsy study.
       Low0.0400.117
       High0.0510.149
      Best estimate0.0920.188p F2 to 3
      • Yi Q.
      • Yi Q.
      • Wang P.P.
      • Krahn M.
      Improving the accuracy of long-term prognostic estimates in hepatitis C virus infection.
      ,
      • Poynard T.
      • Ratziu V.
      • Charlotte F.
      • et al.
      Rates and risk factors of liver fibrosis progression in persons with chronic hepatitis C.
      ,
      • Thein H.H.
      • Yi Q.
      • Dore G.J.
      • Krahn M.D.
      Estimation of stage-specific fibrosis progression rates in chronic hepatitis C virus infection: a meta-analysis and meta-regression.
      ,
      • Pradat P.
      • Voirin N.
      • Tillmann H.L.
      • et al.
      Progression to cirrhosis in hepatitis C persons: an age-dependent process.
      ,
      • Wright M.
      • Goldin R.
      • Fabre A.
      • et al.
      Measurement and determinants of the natural history of liver fibrosis in hepatitis C virus infection: a cross sectional and longitudinal study.
      ,
      • Ryder S.D.
      Trent Hepatitis C Study Group
      Progression of hepatic fibrosis in persons with hepatitis C: a prospective repeat liver biopsy study.
       Low0.0840.171
       High0.0870.177
      Best estimate0.0700.197p F3 to 4
      • Yi Q.
      • Yi Q.
      • Wang P.P.
      • Krahn M.
      Improving the accuracy of long-term prognostic estimates in hepatitis C virus infection.
      ,
      • Poynard T.
      • Ratziu V.
      • Charlotte F.
      • et al.
      Rates and risk factors of liver fibrosis progression in persons with chronic hepatitis C.
      ,
      • Thein H.H.
      • Yi Q.
      • Dore G.J.
      • Krahn M.D.
      Estimation of stage-specific fibrosis progression rates in chronic hepatitis C virus infection: a meta-analysis and meta-regression.
      ,
      • Pradat P.
      • Voirin N.
      • Tillmann H.L.
      • et al.
      Progression to cirrhosis in hepatitis C persons: an age-dependent process.
      ,
      • Wright M.
      • Goldin R.
      • Fabre A.
      • et al.
      Measurement and determinants of the natural history of liver fibrosis in hepatitis C virus infection: a cross sectional and longitudinal study.
      ,
      • Ryder S.D.
      Trent Hepatitis C Study Group
      Progression of hepatic fibrosis in persons with hepatitis C: a prospective repeat liver biopsy study.
       Low0.0630.177
       High0.0780.219
      Best estimate0.0300.030p F4 to Decomp
      • Fattovich G.
      • Giustina G.
      • Degos F.
      • et al.
      Morbidity and mortality in compensated cirrhosis type C: a retrospective follow-up study of 384 persons.
      ,
      • Sangiovanni A.
      • Prati G.M.
      • Fasani P.
      • et al.
      The natural history of compensated cirrhosis due to hepatitis C virus: A 17-year cohort study of 214 persons.
       Low0.0100.010
       High0.0500.050
      Best estimate0.5000.500p Decomp Progressive
      • Fattovich G.
      • Giustina G.
      • Degos F.
      • et al.
      Morbidity and mortality in compensated cirrhosis type C: a retrospective follow-up study of 384 persons.
      ,
      • Sangiovanni A.
      • Prati G.M.
      • Fasani P.
      • et al.
      The natural history of compensated cirrhosis due to hepatitis C virus: A 17-year cohort study of 214 persons.
       Low0.3000.300
       High0.6000.600
      Best estimate0.3000.300p Decomp Prog To Stable
      • Fattovich G.
      • Giustina G.
      • Degos F.
      • et al.
      Morbidity and mortality in compensated cirrhosis type C: a retrospective follow-up study of 384 persons.
      ,
      • Sangiovanni A.
      • Prati G.M.
      • Fasani P.
      • et al.
      The natural history of compensated cirrhosis due to hepatitis C virus: A 17-year cohort study of 214 persons.
       Low0.2500.250
       High0.4000.400
      Best estimate0.1000.100p Decomp To Death
      • Fattovich G.
      • Giustina G.
      • Degos F.
      • et al.
      Morbidity and mortality in compensated cirrhosis type C: a retrospective follow-up study of 384 persons.
      ,
      • Sangiovanni A.
      • Prati G.M.
      • Fasani P.
      • et al.
      The natural history of compensated cirrhosis due to hepatitis C virus: A 17-year cohort study of 214 persons.
       Low0.1000.100
       High0.2000.200
      Best estimate0.0000.004p Chronic F2_3 to HCC
      • El-Serag H.B.
      • Mason A.C.
      Rising incidence of hepatocellular carcinoma in the United States.
      ,
      • Fattovich G.
      • Giustina G.
      • Degos F.
      • et al.
      Morbidity and mortality in compensated cirrhosis type C: a retrospective follow-up study of 384 persons.
      ,
      • Sangiovanni A.
      • Prati G.M.
      • Fasani P.
      • et al.
      The natural history of compensated cirrhosis due to hepatitis C virus: A 17-year cohort study of 214 persons.
      ,
      • Chiaramonte M.
      • Stroffolini T.
      • Vian A.
      • et al.
      Rate of incidence of hepatocellular carcinoma in persons with compensated viral cirrhosis.
      ,
      • Degos F.
      • Christidis C.
      • Ganne-Carrie N.
      • et al.
      Hepatitis C virus related cirrhosis: time to occurrence of hepatocellular carcinoma and death.
      ,
      • Yoshida H.
      • Tateishi R.
      • Arakawa Y.
      • et al.
      Benefit of interferon therapy in hepatocellular carcinoma prevention for individual persons with chronic hepatitis C.
      ,
      • El-Serag H.B.
      Epidemiology of hepatocellular carcinoma in USA.
      ,
      • El-Serag H.B.
      Hepatocellular carcinoma and hepatitis C in the United States.
      ,
      • El-Serag H.B.
      Hepatocellular carcinoma: recent trends in the United States.
       Low0.0000.001
       High0.0100.035
      Best estimate0.0040.030p F4 to HCC
      • El-Serag H.B.
      • Mason A.C.
      Rising incidence of hepatocellular carcinoma in the United States.
      ,
      • Fattovich G.
      • Giustina G.
      • Degos F.
      • et al.
      Morbidity and mortality in compensated cirrhosis type C: a retrospective follow-up study of 384 persons.
      ,
      • Sangiovanni A.
      • Prati G.M.
      • Fasani P.
      • et al.
      The natural history of compensated cirrhosis due to hepatitis C virus: A 17-year cohort study of 214 persons.
      ,
      • Chiaramonte M.
      • Stroffolini T.
      • Vian A.
      • et al.
      Rate of incidence of hepatocellular carcinoma in persons with compensated viral cirrhosis.
      ,
      • Degos F.
      • Christidis C.
      • Ganne-Carrie N.
      • et al.
      Hepatitis C virus related cirrhosis: time to occurrence of hepatocellular carcinoma and death.
      ,
      • Yoshida H.
      • Tateishi R.
      • Arakawa Y.
      • et al.
      Benefit of interferon therapy in hepatocellular carcinoma prevention for individual persons with chronic hepatitis C.
      ,
      • El-Serag H.B.
      Epidemiology of hepatocellular carcinoma in USA.
      ,
      • El-Serag H.B.
      Hepatocellular carcinoma and hepatitis C in the United States.
      ,
      • El-Serag H.B.
      Hepatocellular carcinoma: recent trends in the United States.
       Low0.0010.015
       High0.0200.070
      Best estimate0.8000.850p New HCC to Death first year
      • El-Serag H.B.
      • Mason A.C.
      Rising incidence of hepatocellular carcinoma in the United States.
      ,
      • Fattovich G.
      • Giustina G.
      • Degos F.
      • et al.
      Morbidity and mortality in compensated cirrhosis type C: a retrospective follow-up study of 384 persons.
      ,
      • Sangiovanni A.
      • Prati G.M.
      • Fasani P.
      • et al.
      The natural history of compensated cirrhosis due to hepatitis C virus: A 17-year cohort study of 214 persons.
      ,
      • Chiaramonte M.
      • Stroffolini T.
      • Vian A.
      • et al.
      Rate of incidence of hepatocellular carcinoma in persons with compensated viral cirrhosis.
      ,
      • Degos F.
      • Christidis C.
      • Ganne-Carrie N.
      • et al.
      Hepatitis C virus related cirrhosis: time to occurrence of hepatocellular carcinoma and death.
      ,
      • Yoshida H.
      • Tateishi R.
      • Arakawa Y.
      • et al.
      Benefit of interferon therapy in hepatocellular carcinoma prevention for individual persons with chronic hepatitis C.
      ,
      • El-Serag H.B.
      Epidemiology of hepatocellular carcinoma in USA.
      ,
      • El-Serag H.B.
      Hepatocellular carcinoma and hepatitis C in the United States.
      ,
      • El-Serag H.B.
      Hepatocellular carcinoma: recent trends in the United States.
       Low0.6000.600
       High0.9000.900
      Best estimate0.3500.350p HCC to Death after 1 year
      • El-Serag H.B.
      • Mason A.C.
      Rising incidence of hepatocellular carcinoma in the United States.
      ,
      • Fattovich G.
      • Giustina G.
      • Degos F.
      • et al.
      Morbidity and mortality in compensated cirrhosis type C: a retrospective follow-up study of 384 persons.
      ,
      • Sangiovanni A.
      • Prati G.M.
      • Fasani P.
      • et al.
      The natural history of compensated cirrhosis due to hepatitis C virus: A 17-year cohort study of 214 persons.
      ,
      • Chiaramonte M.
      • Stroffolini T.
      • Vian A.
      • et al.
      Rate of incidence of hepatocellular carcinoma in persons with compensated viral cirrhosis.
      ,
      • Degos F.
      • Christidis C.
      • Ganne-Carrie N.
      • et al.
      Hepatitis C virus related cirrhosis: time to occurrence of hepatocellular carcinoma and death.
      ,
      • Yoshida H.
      • Tateishi R.
      • Arakawa Y.
      • et al.
      Benefit of interferon therapy in hepatocellular carcinoma prevention for individual persons with chronic hepatitis C.
      ,
      • El-Serag H.B.
      Epidemiology of hepatocellular carcinoma in USA.
      ,
      • El-Serag H.B.
      Hepatocellular carcinoma and hepatitis C in the United States.
      ,
      • El-Serag H.B.
      Hepatocellular carcinoma: recent trends in the United States.
       Low0.2500.250
       High0.5000.500
      NOTE. In the column under the heading variable, p represents the transitional rate for moving from one state to another. For example, p ChronicRecover is the proportion moving from chronic hepatitis to resolved infection within an annual cycle of the model.
      HCC, hepatocellular carcinoma.
      Supplementary Table 3Median Duration of Infection Until Peak Prevalence of Complication and Estimated Age Then in the 6 Cohorts
      CohortMedian age at infection, yDuration to peak prevalence cirrhosisAge at peak prevalence cirrhosis, yDuration to peak decompensationAge at peak decompensation, yDuration to peak HCCAge at peak HCC, y
      Female
       <30 years21.050.571.553.574.551.572.5
       31−50 years40.041.081.042.582.541.081.0
       >50 years57.030.087.032.079.030.087.0
      Male
       <30 years21.043.564.547.068.044.565.5
       31−50 years40.029.079.032.072.030.070.0
       >50 years57.022.079.025.082.023.080.0
      HCC, hepatocellular carcinoma.

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