December 30, 2013

Journal of Viral Hepatitis

Cost-effectiveness Analyses

L. M. Hagan, Z. Yang, M. Ehteshami, R. F. Schinazi

J Viral Hepat

Abstract and Introduction

Abstract

Interferon-based standard of care treatments (SOC) for chronic hepatitis C are unable to provide high cure rates in certain subgroups of the infected population and can cause debilitating side effects. Clinical trials evaluating all-oral, interferon-free treatments have demonstrated high rates of sustained virologic response with no resistance or major adverse events in most populations. As these drug regimens move towards FDA approval, it will be important to assess their cost-effectiveness in addition to their clinical efficacy. A decision-analytic Markov model with a lifetime, societal perspective was used to evaluate the cost-effectiveness of a generalized all-oral drug regimen compared to SOC by modelling the progression of a 50-year-old, HCV-positive cohort through disease natural history and treatment. In base case analysis, all-oral treatment dominated SOC across a range of willingness-to-pay (WTP) thresholds with an incremental cost-effectiveness ratio (ICER) of US$44 514/quality-adjusted life year (QALY). In sensitivity analyses, the model was sensitive to all-oral drug costs as well as rates of SVR and treatment uptake among noncirrhotic subjects, but robust to variations in all other parameters. All-oral treatment was most cost-effective among genotype 1 subjects but remained cost-effective for genotypes 2 and 3 at WTP thresholds ≥$80 000/QALY. Quality-adjusted life years gained per dollar spent were maximized in younger treatment cohorts. Using this model, the degree of cost-effectiveness depended on the WTP threshold and the final cost set for approved drug combinations.

Introduction

Approximately 150 million people globally and 3.3 million in the United States (US) are chronically infected with hepatitis C virus (HCV).[1] Because most cases are asymptomatic, up to 75% of HCV-positive individuals in the US are unaware of their infection, often resulting in untreated progression to advanced fibrosis, cirrhosis, hepatocellular carcinoma (HCC) and premature death.[2]

Chronic hepatitis C (CHC)-related mortality and healthcare costs are expected to rise as infected individuals in the high-prevalence 1945–1964 birth cohort, most of whom were infected 20–30 years ago, progress towards cirrhosis and liver cancer.[3–5] In response to this trend and to the demonstrated cost-effectiveness of birth cohort-based HCV screening,[6] the Centers for Disease Control and Prevention (CDC) recently recommended universal one-time screening for adults in this age group. This announcement coincided with the first National Hepatitis Testing Day in the US on 19 May 2012.[7]

As these screening initiatives yield increased CHC diagnoses, development of curative, cost-effective treatments will be paramount.[8] Treatment has evolved rapidly since the discovery of HCV in 1989, demonstrating progressive improvement in cure rates measured by sustained virologic response (SVR). The first treatment available, injected interferon monotherapy, resulted in SVR for 10% of those treated. Sustained virologic response increased to 25% with the addition of ribavirin and to 45% with the substitution of pegylated interferon.[8,9] Current standard of care (SOC) treatment for viral genotypes 2 and 3, pegylated interferon plus ribavirin (combination therapy), achieves SVR in up to 80% of noncirrhotic individuals, but in only 43% of those with cirrhosis,[10,11] Genotype 1 infections, which account for approximately 73% of CHC cases in the US, have historically been more difficult to treat and require triple therapy with the addition of a protease inhibitor (boceprevir or telaprevir),[12,13] SVR rates with triple therapy reach 72% among noncirrhotic genotype 1 individuals but are still much lower (42%) among those with cirrhosis,[14,15]

Despite rising SVR rates, current treatment with interferon and ribavirin often causes debilitating flu-like symptoms, depression, skin rashes and anaemia that can undermine treatment completion.[2] The next major advance in CHC treatment is expected to be the adoption of all-oral regimens that eliminate interferon, and possibly ribavirin, using direct-acting antiviral agents that increase SVR by preventing selection of drug resistant viruses and leveraging the lack of latent phase in HCV replication.[16]Numerous pharmaceutical companies are sprinting towards the finish line in advanced stage clinical trials testing novel all-oral, interferon-free drug combinations, some of which have achieved SVR in more than 90% of some subgroups, including null and partial responders to prior interferon-based treatment.[17]

The final cost of these drugs will be unknown until they reach the market and may ultimately exceed the cost of SOC for some genotypes. In addition, because clinical trial results are based on relatively small sample sizes of carefully chosen subjects, they may overestimate the SVR rates that will be attained among a more diverse and representative population. Therefore, while data on costs and anticipated SVR remain in flux, it will be important to consider the cost-effectiveness of emerging all-oral treatments across multiple possible scenarios.

This analysis investigated the cost-effectiveness of all-oral CHC treatment compared to SOC using a range of potential drug costs, treatment-associated quality of life estimates and rates of SVR for genotypes 1, 2 and 3-infected, treatment-naïve subjects with and without cirrhosis. Because it is not yet certain which specific drug combination(s) will receive FDA approval, our model used a generalized all-oral regimen to determine the cost threshold at which these drugs would be cost-effective compared to SOC.

Materials and Methods

Using TreeAge Pro 2012 software (TreeAge Software, Inc., Williamstown, MA, USA), we constructed a decision-analytic Markov model to simulate the progression of a 50-year-old cohort through CHC natural history and possible treatment with either SOC or an all-oral regimen. Cohort age was chosen based on CDC estimates of peak US HCV seroprevalence in the current 50–59 age group (4.3%),[18] coupled with the expected rise in CHC-related healthcare costs as infected individuals in this cohort progress to late-stage liver disease.[3–5]

Markov Model

A Markov model (Fig. 1) is a recursive decision tree that guides a cohort through a series of probabilities representing disease natural history, medical care, possible treatment and treatment outcomes. Based on the probability-driven pathways in our model (Fig. 2 and 3), subjects accrued costs and quality-adjusted life years (QALYs) at the end of each model year (stage), depending on their disease state and treatment profile. Cumulatively, these accruals were used to calculate the incremental cost-effectiveness ratio (ICER), which measures the cost per QALY gained by implementing all-oral treatment compared to SOC. Death was possible from any model stage. Subjects alive at the end of a given stage continued cycling through the model as determined by their health or treatment outcome in the preceding stage. Analysis terminated when the cohort reached its average life expectancy. Base case values for all model parameters, as well as ranges used in sensitivity analyses, can be found in Tables S1–S5.

817888-fig1

Figure 1. Simplified Markov model. As the HCV-positive cohort progresses through the model, subjects accrue medical costs and QALYs based on probabilities for disease progression and treatment outcome. Those who do not die from any cause during a given stage continue through the model for an additional year. Aggregate costs and QALYs are summed and used to calculate the ICER. HCV = hepatitis C virus; CHC = chronic hepatitis C; QALY = quality-adjusted life year; ICER = incremental cost-effectiveness ratio.

817888-fig2

Figure 2. Model schematic of CHC natural history and treatment. Model subjects progress through fibrosis stages F0–F4, decompensated cirrhosis and HCC based on annual probabilities (white circles, solid lines). Those who initiate SOC or all-oral treatment (light grey squares) either achieve SVR (black stars) or fail/discontinue and continue progressing through CHC natural history without retreatment (dark grey hexagons). Further fibrosis progression after SVR is possible for subjects in stages F3, F4 and decompensated cirrhosis (dotted lines). F3 subjects can progress directly to decompensated cirrhosis or HCC within one year, bypassing F4 (dotted lines). Subjects with decompensated cirrhosis can be treated in the all-oral treatment pathway, but not in the SOC pathway. Subjects with decompensated cirrhosis and HCC receive liver transplants according to published annual probabilities. Death is possible from any cause at any stage in the model. See Table S1 for specific progression probabilities. CHC = chronic hepatitis C; F0–F4 = Metavir fibrosis stages; Tx = treatment; SVR = sustained virologic response; HCC = hepatocellular carcinoma.

817888-fig3

Figure 3. Decision tree excerpt. A selection of the decision tree underlying the Markov model, where M represents the starting point for each annual model cycle, and individual probabilities are included under each branch. Subjects who reach terminal branches (boxes with thick borders) begin untreated progress through CHC natural history in the subsequent model year (solid black boxes). Chronic hepatitis C natural history progression probabilities are not depicted but are summarized in Table S1. Branches involved in treatment uptake and outcome are illustrated under F2 only, but this subtree was included in all fibrosis stages in the model. HCV = hepatitis C virus; SOC = standard of care treatment; CHC = chronic hepatitis C; F0–F4 = Metavir fibrosis stages; Tx = treatment.

Background Mortality Rates

Age-specific background morality rates were applied throughout the model, estimated at 2.37 times the rates for non-CHC-infected individuals,[19,20] After SVR, subjects were assigned lower mortality rates, estimated at 1.4 times non-CHC rates based on evidence that virus clearance improves overall health outcomes.[21] Subjects with advanced liver disease were assigned higher mortality rates based on published literature (Table S1).

Screening

This hypothetical cohort included only screened, laboratory confirmed HCV-positive subjects. It did not include HCV-positive individuals unaware of their infection because they would not have the opportunity to be treated with either drug regimen.

All-oral Parameter Estimates

Aside from SVR rates, which were estimated from clinical trial data, published values for parameters associated with all-oral CHC treatment were not available because these drugs are not yet approved. Estimates for specialist referral and attendance, contraindications to treatment, treatment uptake and discontinuation, and QALYs associated with all-oral treatment and SVR were derived from interviews with clinical hepatologists practicing at Emory University in Atlanta, Georgia, hereafter referenced as 'expert opinion' (Karpen S, Spivey J, Ford R, Parekh S. Personal communication). Due to the uncertainty of these estimates, most sensitivity analyses involving all-oral treatment parameters used ranges of at least ± 20%. To remain conservative, ranges often included the corresponding SOC parameter's base case (Tables S3–S5).

Fibrosis Progression

Probabilities of treatment uptake and SVR were dependent on CHC genotype and fibrosis stage, defined by METAVIR score (F0 = no fibrosis; F1 = portal fibrosis without septa; F2 = portal fibrosis with few septa; F3 = numerous septa without cirrhosis; F4 = compensated cirrhosis).[22] Initial distribution of subjects across fibrosis stages was based on a meta-analysis of 111 clinical studies including over 33 000 individuals with CHC in fibrosis stages F0–F4,[23] adjusted to include decompensated cirrhosis.[24]Subjects progressed to later fibrosis stages, HCC, liver transplant and death based on annual progression probabilities from the same meta-analysis and other published estimates (Tables S1–S2).[23,25–32] At the end of each model year in which a disease state transition occurred (e.g. progression from F0 to F1, or from F4 to decompensated cirrhosis), subjects accrued the costs and QALYs associated with the disease state in which they began the year; the following year, they accrued the costs and QALYs associated with the state to which they had transitioned.

Treatment Probabilities

Subjects had multiple opportunities to be treated. In the initial model year, a subject's probability of treatment was the product of individual probabilities for specialist referral, specialist attendance, likelihood of contraindications and acceptance of treatment that was offered, which varied by treatment pathway (Table S3; Fig. 3). Subjects eligible for treatment (i.e. with no immutable contraindications) but not treated in the initial model year transitioned to treatment in subsequent years at annual rates varying from 1–10% depending on genotype, fibrosis stage and treatment pathway. These probabilities were based on published literature for SOC and expert opinion for all-oral treatment,[28,33]

Due to lower SVR rates for genotype 1 compared to genotypes 2 and 3 with SOC treatment, combined with physicians' expectations for improved treatments in the near future, many genotype 1 individuals in clinical care with little or no fibrosis delay treatment.[28] To remain consistent with clinical practice, this model did not treat genotype 1 F0 subjects in the SOC pathway during the initial model year. However, these subjects transitioned to treatment at a higher rate in subsequent years compared to subjects in later fibrosis stages, as modelled in a recent cost-effectiveness analysis of CHC screening strategies by Coffin et al..[28] Because of high expectations for SVR with all-oral treatment, all genotype 1 subjects in the all-oral pathway were treated at the same rate in the initial model year, regardless of fibrosis stage. Subjects were assumed treatment-naïve. Those who failed or discontinued treatment were not retreated in the model.

Liver Biopsy

In the clinic, approximately 70% of genotype 1 subjects who attend a specialist visit undergo a liver biopsy to determine fibrosis stage, which helps determine whether to initiate treatment or to wait.[28] If SVR rates rise as expected with the adoption of all-oral treatment, most individuals diagnosed with CHC will likely be treated regardless of genotype or fibrosis stage, reducing the need for liver biopsy. Based on expert opinion, we assumed that only 40% of genotype 1 individuals would receive a liver biopsy once all-oral treatment becomes widespread.

Treatment of Subjects With Advanced Liver Disease

Because few individuals with decompensated cirrhosis can tolerate interferon, treatment with SOC is rare in this group,[34,35] One of the benefits of an eventual all-oral regimen is greater expected compatibility with late-stage disease, increasing treatment access for cirrhotic individuals. Therefore, this model allowed subjects with decompensated cirrhosis to be treated with all-oral therapy, but not with SOC. Estimates of treatment uptake and associated QALYs for decompensated subjects were derived from expert opinion. Treatment discontinuation rates were set at higher levels for these subjects compared to those in stages F0–F4 due to the possibility of more frequent adverse events.

Fibrosis Regression After SVR

To account for evidence of liver regeneration after viral eradication, this model allowed post-SVR fibrosis regression according to probabilities from clinical literature.[35–42] Regression rates for decompensated subjects after all-oral treatment were assumed equal to rates for those with compensated cirrhosis.

Costs and QALYs

Most costs and QALYs associated with SOC treatment and nontreatment-related CHC care were derived from two recent cost-effectiveness studies on CHC screening and treatment strategies, which provide comprehensive reviews of these parameters from a variety of published sources,[28,31]Treatment costs incorporate both the cost of the drugs themselves and the costs of medical care during treatment, including adverse events. Base case parameters were chosen as mid-range estimates (Tables S4-S5). Costs were adjusted to 2012 US dollars, and costs and QALYs were discounted 3% per year.

We used $70 000 as the base case cost for one course of all-oral treatment based on the anticipated market entry cost ($47 000) for sofosbuvir (GS-7977), one of the leading direct-acting antiviral candidates currently in advanced clinical trials,[43] combined with expectations that eventual FDA-approved all-oral regimens will include more than one drug. Due to the uncertainty of this estimate, we used a wide range of all-oral drug costs in sensitivity analyses (Figs 4,5).

817888-fig4

Figure 4. Top ten most influential parameters for cost-effectiveness. A series of one-way sensitivity analyses, generated by TreeAge Pro software, depicts the influence that individual model variables exert on the ICER. The length of a given bar indicates the magnitude of change effected by variations in a model parameter. Variables were tested over ranges listed in Tables S1–S5. ICER = incremental cost-effectiveness ratio; QALY = quality-adjusted life year; CHC = chronic hepatitis C; F0–F4 = Metavir fibrosis stages; SVR = sustained virologic response.

817888-fig5

Figure 5. Maximum all-oral drug costs at three WTP thresholds. Cost of all-oral drugs was plotted against the ICER to determine the maximum drug cost at which all-oral treatment (dashed line) can remain cost-effective compared to SOC treatment (solid line) at various WTP thresholds. Maximum costs of all-oral drugs at WTP thresholds of $50 000/QALY, $80 000/QALY and $100 000/QALY are shown in black boxes. WTP = willingness-to-pay; SOC = standard of care treatment; ICER = incremental cost-effectiveness ratio; QALY = quality-adjusted life year.

ICER and Sensitivity Analyses

To assess cost-effectiveness, we calculated the incremental cost-effectiveness ratio (ICER), which measured the average cost per QALY gained by using all-oral treatment instead of SOC. We conducted one-way sensitivity analyses to determine which model parameters had the greatest impact on the ICER and ran sub-analyses to explore differences in cost-effectiveness by viral genotype and age at treatment.

Results

Model Validation

Because no published models to date compare all-oral treatment to SOC, we validated our model indirectly by comparing a cohort sent through our SOC branch to a cohort that progressed untreated through CHC natural history. This strategy allowed us to validate our SOC pathway by comparing it to similar published models assessing cost-effectiveness of currently available therapies (SOC) vs no treatment. We then built the all-oral treatment pathway based on the validated SOC model.

Our SOC validation model yielded an average of $54 603 in medical costs and 13.4 QALYs for subjects in the treatment branch compared to $40 407 and 12.1 QALYs for untreated subjects. These numbers compare well with those reported by Salomon et al. ($22,000/19.4 QALYs treated vs $8,200/18.9 QALYs untreated).[44] The absolute numbers differ between the two models, partly due to differences in cohort age (40 year-olds in Salomon, published 10 years ago, vs. 50-year-olds in our model) and cost of treatment regimens (combination therapy for genotype 1 subjects in Salomon vs. more expensive triple therapy in our model). However, the cost and QALY differences between the treated and untreated branches in the two models are comparable. After validation, we added decompensated cirrhosis to the initial fibrosis distribution to account for the possibility of treatment for decompensated subjects in the all-oral pathway.

Base Case Results

In the base case model, all-oral treatment dominated SOC (ICER = $44 514/QALY), yielding higher costs but more QALYs for a cohort of 50-year-old subjects (SOC: $74 619/10.7 QALYs; all-oral: $93 315/11.1 QALYs).

Sensitivity Analysis

A series of one-way sensitivity analyses (Fig. 4) demonstrated that the ICER was driven primarily by all-oral drug costs and was also sensitive to rates of SVR and treatment uptake for noncirrhotic subjects. As rates of SVR and treatment uptake for all-oral therapy increased, the ICER decreased, demonstrating greater cost-effectiveness. The ICER was robust to changes in all other parameters including QALY estimates, extended treatment duration for cirrhotic subjects and nontreatment-related CHC costs.

All-oral Drug Cost and Willingness-to-Pay Threshold

Assessment of cost-effectiveness depended on the willingness-to-pay (WTP) threshold chosen, which indicates how much stakeholders are willing to pay for all-oral treatment per QALY gained compared to SOC. The maximum costs that all-oral drug regimens can reach while remaining cost-effective under different WTP scenarios are illustrated in Fig. 5. With a $50 000/QALY WTP threshold, the maximum cost-effective all-oral drug cost was $74 217 for one course of therapy; at WTP thresholds of $80 000/QALY and $100 000/QALY, all-oral treatment ceded cost-effectiveness to SOC at drug costs of $97 279 and $112 653, respectively.

Genotype

All-oral treatment dominated SOC in sub-analyses by viral genotype. It was most cost-effective for genotype 1 but remained cost-effective for genotypes 2 and 3 at WTP thresholds ~$80 000/QALY or higher (ICER = $30 881/QALY for genotype 1; $78 146/QALY for genotypes 2 and 3).

Age at Treatment

In parallel analyses comparing cohorts of 50-, 30- and 10-year-old subjects, all-oral treatment was most cost-effective among younger aged cohorts (cost/QALY = $8 384, $7 673, and $3 414, respectively).

Discussion

Using the base case parameters in this model, a generalized all-oral treatment regimen was cost-effective compared to SOC for a cohort of 50-year-old, monoinfected, cirrhotic and noncirrhotic subjects with genotype 1, 2 and 3 HCV infections. The model was robust to changes in treatment duration, nontreatment-related medical costs and QALY estimates, but sensitive to all-oral drug costs as well as rates of treatment uptake and SVR for noncirrhotic subjects. The cost ceiling for all-oral drugs was dependent on the WTP threshold and ranged from $74 217 at a $50 000/QALY WTP to $112 653 at a $100 000/QALY WTP. Depending on their budgets and priorities, diverse stakeholders may choose different WTP thresholds, which will affect the price at which these drugs can remain cost-effective compared to SOC.

The higher cost and lower SVR rates associated with SOC treatment for genotype 1 offer greater opportunity for cost reduction and QALY improvements compared to genotypes 2 and 3. As a result, all-oral treatment was most cost-effective for genotype 1 subjects. Cost per QALY gained was minimized in younger cohorts, possibly due to lower initial fibrosis levels among younger subjects and longer life expectancy after SVR.

This analysis has certain limitations. Because clinical trials investigating all-oral drugs are ongoing, most parameters involved in all-oral treatment are not yet known and were estimated from expert opinion. As additional data become available for a more generalizable population of CHC subjects, these parameters may need to be re-evaluated.

In addition, this model assumed that a 50-year-old CHC-infected cohort exhibited the same initial fibrosis distribution as the overall CHC-infected population. Because this age group falls into the high-risk 1945–1964 birth cohort likely to have been infected 20–30 years ago, this assumption may underestimate the true proportion of late-stage fibrosis and cirrhosis. A model including a higher percentage of late-stage disease may yield higher estimates of cost-effectiveness for all-oral drugs. Model costs associated with CHC treatment and care were based on direct medical costs only.

Due to the uncertainty of many parameters contributing to all-oral treatment and SVR, this model was designed to be conservative, and cost-effectiveness of all-oral treatment could be higher than we have reported for several reasons. Our model excluded certain groups that may ultimately be eligible for all-oral treatment. Specifically, although SOC treatment has demonstrated the potential to reduce reinfection following liver transplant, our model does not account for posttransplant treatment.[34]Similarly, it does not allow for treatment in those with HCC, which may be possible with all-oral drugs. Successful CHC treatment could allow some individuals with HCC to undergo cancer treatments for which they would otherwise be ineligible, potentially reducing HCC-related mortality and increasing cost-effectiveness of all-oral treatment. In addition, although clinical trial data demonstrate up to 90% SVR in some treatment-experienced subgroups, our model does not include treatment-experienced individuals, many of whom may be eligible for retreatment with all-oral drugs,[45,46] Once evidence-based estimates for treatment eligibility and outcomes are available for these groups, future models should account for late-stage treatment and retreatment with all-oral drugs to determine whether their inclusion impacts cost-effectiveness.

It is also possible that post-SVR fibrosis regression rates will be higher following treatment with all-oral drugs than our model has estimated. Even with SOC treatment, some subjects have demonstrated cirrhosis reversal after SVR, which we did not account for in our model.[47] The percentage of decompensated subjects treated with all-oral drugs may also be higher than we estimated due to tolerability of interferon-free regimens.

Finally, if advanced clinical trials confirm high expectations for SVR and tolerability of all-oral drugs, HCV screening efforts will likely intensify, and treatment uptake can be expected to increase from current low rates of 12–28%,[48,49] Uptake could increase more markedly than we have estimated, resulting in greater cost-effectiveness for all-oral regimens. Factors contributing to uptake include clinician confidence in treatment outcomes, the possibility of direct treatment by primary care physicians (possibly reducing loss to follow-up at the specialist referral stage), lower rates of discontinuation due to side effects and more widespread screening.

Universal clinical HCV screening in the general population has been demonstrated to be cost-effective under multiple scenarios,[28,50] and some researchers are investigating the feasibility and cost-effectiveness of targeted testing and treatment efforts in specific high prevalence populations such as prison inmates and high-risk birth cohorts, both to improve health and to curb further transmission.[6,17,51] Because of the increased SVR and tolerability of interferon-free regimens, all-oral treatments can be expected to reduce CHC-related morbidity and mortality beyond what is possible with current treatment options. Once these drugs become available in the clinic, it will be possible to determine whether broader treatment eligibility and greater opportunities for early treatment due to more aggressive screening efforts will have further implications for their cost-effectiveness.

References

  1. World Health Organization [Internet]. Hepatitis C Fact Sheet [cited 2012 Jul 1]. Available at: http://www.who.int/mediacentre/factsheets/fs164/en/index.html. (accessed 1 July 2012).

  2. United States Department of Health and Human Services. Combating the Silent Epidemic of Viral Hepatitis: Action Plan for the Prevention, Care & Treatment of Viral Hepatitis. Washington, DC: United States Department of Health and Human Services, 2011. Available at: http://www.hhs.gov/ash/initiatives/hepatitis/actionplan_viralhepatitis2011.pdf.

  3. Ly KN, Xing J, Klevens RM, Jiles RB, Ward JW, Holmberg SD. The increasing burden of mortality from viral hepatitis in the United States between 1999 and 2007. Ann Intern Med 2012; 156(4): 271–278.

  4. Rein DB, Wittenborn JS, Weinbaum CM, Sabin M, Smith BD, Lesesne SB. Forecasting the morbidity and mortality associated with prevalent cases of pre-cirrhotic chronic hepatitis C in the United States. Dig LiverDis2011; 43(1): 66–72.

  5. Wong JB, McQuillan GM, McHutchison JG, Poynard T. Estimating future hepatitis C morbidity, mortality, and costs in the United States. Am J Public Health 2000; 90(10): 1562–1569.

  6. Rein DB, Smith BD, Wittenborn JS, Lesesne SB, Wagner LD, Roblin DW, et al. The cost-effectiveness of birth cohort screening for hepatitis C antibody in U.S. primary care settings. Ann Intern Med 2012; 156(4): 263–270.

  7. Centers for Disease Control and Prevention [Internet]. CDC Announces First ever National Hepatitis Testing Day and Proposes that all Baby Boomers be Tested once for Hepatitis C [cited 2012 July 22]. Available at: http://www.cdc.gov/nchhstp/newsroom/HepTestingRecsPressRelease2012.html. (accessed 22 July 2012).

  8. Alter HJ, Liang TJ. Hepatitis C: the end of the beginning and possibly the beginning of the end. AnnIntern Med.2012; 156(4): 317–8.

  9. Hoofnagle JH, Seeff LB. Peginterferon and ribavirin for chronic hepatitis C. N Engl J Med 2006; 355(23): 2444–2451.

  10. Manns MP, McHutchison JG, Gordon SC, Rustgi VK, Shiffman M, Reindollar R, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial.Lancet 2001; 358(9286): 958–965.

  11. Veldt BJ, Heathcote EJ, Wedemeyer H, Reichen J, Hofmann WP, Zeuzem S, et al. Sustained virologic response and clinical outcomes in patients with chronic hepatitis C and advanced fibrosis. Ann Intern Med 2007; 147(10): 677–684.

  12. Ghany MG, Nelson DR, Strader DB, Thomas DL, Seeff LB. An update on treatment of genotype 1 chronic hepatitis C virus infection: 2011 practice guideline by the American Association for the Study of Liver Diseases.Hepatology 2011; 54(4): 1433–1444.

  13. National Institutes of Health. NIH consensus statement on management of hepatitis C. NIH ConsensState Sci Statements 2002; 19(3): 1–46.

  14. Inciveck/telaprevir (package insert). Cambridge, MA: Vertex Pharmaceuticals. October 2012.

  15. Victrelis/boceprevir (package insert). Whitehouse Station, NJ: Merck & Co, Inc. May 2011.

  16. Schinazi RF, Bassit L, Gavegnano C. HCV drug discovery aimed at viral eradication. J Viral Hepat 2010; 17 (2): 77–90.

  17. Hagan LM, Schinazi RF. Best strategies for global HCV eradication. LiverInt 2013; 33(Suppl 1): 68–79.

  18. Armstrong GL, Wasley A, Simard EP, McQuillan GM, Kuhnert WL, Alter MJ. The prevalence of hepatitis C virus infection in the United States, 1999 through 2002. AnnIntern Med 2006; 144(10): 705–714.

  19. El-Kamary SS, Jhaveri R, Shardell MD. All-cause, liver-related, and non-liver-related mortality among HCV-infected individuals in the general US population. Clin Infect Dis 2011; 53(2): 150–157.

  20. National Center for Health Statistics [Internet]. Compressed Mortality File 1999–2007 Series 20 No. 2M, 2010. CDC WONDER on-line database. Hyattsville, MD: Centers for Disease Control and Prevention, 2010. [cited 2012 Jul 22]. Available at: http://www.cdc.gov/nchs/data/nvsr/nvsr60/nvsr60_03.pdf.

  21. Veldt BJ, Saracco G, Boyer N, Camma C, Bellobuono A, Hopf U, et al. Long term clinical outcome of chronic hepatitis C patients with sustained virological response to interferon monotherapy. Gut 2004; 53 (10): 1504–1508.

  22. Bedossa P, Poynard T. An algorithm for the grading of activity in chronic hepatitis C. The METAVIR Cooperative Study Group. Hepatology 1996; 24(2): 289–293.

  23. 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; 48(2): 418–431.

  24. Davis GL, Albright JE, Cook SF, Rosenberg DM. Projecting future complications of chronic hepatitis C in the United States. Liver Transpl 2003; 9(4): 331–338.

  25. Ascher NL, Lake JR, Emond J, Roberts J. Liver transplantation for hepatitis C virus-related cirrhosis. Hepatology1994; 20(1 Pt 2): 24S–27S.

  26. Bennett WG, Inoue Y, Beck JR, Wong JB, Pauker SG, Davis GL. Estimates of the cost-effectiveness of a single course of interferon-alpha 2b in patients with histologically mild chronic hepatitis C. Ann Intern Med 1997; 127(10): 855–865.

  27. Bruno S, Zuin M, Crosignani A, Rossi S, Zadra F, Roffi L, et al. Predicting mortality risk in patients with compensated HCV-induced cirrhosis: a long-term prospective study. Am J Gastroenterol 2009; 104 (5): 1147–1158.

  28. Coffin PO, Scott JD, Golden MR, Sullivan SD. Cost-effectiveness and population outcomes of general population screening for hepatitis C. Clin Infect Dis 2012; 54(9): 1259–1271.

  29. Dienstag JL, Ghany MG, Morgan TR, Di Bisceglie AM, Bonkovsky HL, Kim HY, et al. A prospective study of the rate of progression in compensated, histologically advanced chronic hepatitis C. Hepatology 2011; 54(2): 396–405.

  30. Fattovich G, Giustina G, Degos F, Tremolada F, Diodati G, Almasio P, et al. Morbidity and mortality in compensated cirrhosis type C: a retrospective follow-up study of 384 patients. Gastroenterology 1997; 112(2): 463–472.

  31. Liu S, Cipriano LE, Holodniy M, Owens DK, Goldhaber-Fiebert JD. New protease inhibitors for the treatment of chronic hepatitis C: a cost-effectiveness analysis. AnnIntern Med 2012; 156(4): 279–290.

  32. Thuluvath PJ, Guidinger MK, Fung JJ, Johnson LB, Rayhill SC, Pelletier SJ. Liver transplantation in the United States, 1999–2008. Am JTransplant 2010; 10(4 Pt 2): 1003–1019.

  33. Center for Quality Management in Public Health. The State of Care for Veterans with Chronic Hepatitis C. Palo Alto, California: US Department of Veterans Affairs, Public Health Strategic Health Care Group, Center for Quality Management in Public Health., 2010. Available at: http://www.hepatitis.va.gov/pdf/HCVState-of-Care-2010.pdf.

  34. Fink SA, Jacobson IM. Managing patients with hepatitis-B-related or hepatitis-C-related decompensated cirrhosis.Nat Rev Gastroenterol Hepatol 2011; 8(5): 285–295.

  35. Pol S, Carnot F, Nalpas B, Lagneau JL, Fontaine H, Serpaggi J, et al. Reversibility of hepatitis C virusrelated cirrhosis. Hum Pathol 2004; 35(1): 107–112.

  36. Pearlman BL, Traub N. Sustained virologic response to antiviral therapy for chronic hepatitis C virus infection: a cure and so much more. Clin Infect Dis 2011; 52(7): 889–900.

  37. Maylin S, Martinot-Peignoux M, Moucari R, Boyer N, Ripault MP, Cazals-Hatem D, et al. Eradication of hepatitis C virus in patients successfully treated for chronic hepatitis C. Gastroenterology 2008; 135 (3): 821–829.

  38. Mallet V, Gilgenkrantz H, Serpaggi J, Verkarre V, Vallet-Pichard A, Fontaine H, et al. Brief communication: the relationship of regression of cirrhosis to outcome in chronic hepatitis C. Ann Intern Med 2008; 149(6): 399–403.

  39. George SL, Bacon BR, Brunt EM, Mihindukulasuriya KL, Hoffmann J, Di Bisceglie AM. Clinical, virologic, histologic, and biochemical outcomes after successful HCV therapy: a 5-year follow-up of 150 patients.Hepatology 2009; 49(3): 729–738.

  40. Balart LA, Lisker-Melman M, Hamzeh FM, Kwok A, Lentz E, Rodriguez-Torres M. Peginterferon alpha-2a plus ribavirin in Latino and non-Latino whites with HCV genotype 1: histologic outcomes and tolerability from the LATINO Study. Am J Gastroenterol 2010; 105(10): 2177–2185.

  41. Poynard T, McHutchison J, Manns M, Trepo C, Lindsay K, Goodman Z, et al. Impact of pegylated interferon alfa-2b and ribavirin on liver fibrosis in patients with chronic hepatitis C. Gastroenterology 2002; 122(5): 1303–1313.

  42. Iacobellis A, Perri F, Valvano MR, Caruso N, Niro GA, Andriulli A. Long-term outcome after antiviral therapy of patients with hepatitis C virus infection and decompensated cirrhosis. Clin Gastroenterol Hepatol 2011; 9(3): 249–253.

  43. UBS Securities, LLC. UBS Q-series: is the HCV market investable long term? A new analysis of diagnosis and treatment rates. New York, NY: UBS Investment Research, 2012.

  44. Salomon JA, Weinstein MC, Hammitt JK, Goldie SJ. Cost-effectiveness of treatment for chronic hepatitis C infection in an evolving patient population. JAMA 2003; 290(2): 228–237.

  45. Kowdley K, Lawitz E, Poordad F, Cohen D, Nelson D, Zeuzem S, et al. A 12-week interferon-free treatment regimen with ABT-450/r, ABT-267, ABT-333 and ribavirin achieves SVR12 rates (observed data) of 99% in treatment-naive patients and 93% in prior null responders with HCV genotype 1 infection. Proceedings of The Liver Meeting, 63rd Annual Meeting of the American Association for the Study of Liver Diseases; 2012 Nov 9–13; Boston, Massachusetts, USA.

  46. Suzuki Y, Ikeda K, Suzuki F, Toyota J, Karino Y, Chayama K, et al. Dual oral therapy with daclatasvir and asunaprevir for patients with HCV genotype 1b infection and limited treatment options. J Hepatol 2012; doi: 10.1016/j.jhep.2012.09.037.

  47. Cardoso A, Moucari R, Giuily N, Figueiredo-Mendes C, Boyer N, Ripault M, et al. Sustained virological response is associated with reversibility of cirrhosis in chronic hepatitis C patients. Proceedings of the International Liver Congress, 47th Annual Meeting of the European Association for the Study of the Liver; 2012 April 18–22; Barcelona, Spain.

  48. Bini EJ, Brau N, Currie S, Shen H, Anand BS, Hu KQ, et al. Prospective multicenter study of eligibility for antiviral therapy among 4,084 U.S. veterans with chronic hepatitis C virus infection. Am J Gastroenterol 2005; 100(8): 1772–1779.

  49. Butt AA, Justice AC, Skanderson M, Rigsby MO, Good CB, Kwoh CK. Rate and predictors of treatment prescription for hepatitis C. Gut 2007; 56(3): 385–389.

  50. Singer ME, Younossi ZM. Cost effectiveness of screening for hepatitis C virus in asymptomatic, average-risk adults. Am J Med 2001; 111(8): 614–621.

  51. Spaulding AC, Thomas DL. Screening for HCV infection in jails. JAMA 2012; 307(12): 1259–1260.

  52. Shiffman ML, Suter F, Bacon BR, Nelson D, Harley H, Sola R, et al. Peginterferon alfa-2a and ribavirin for 16 or 24 weeks in HCV genotype 2 or 3. N Engl J Med 2007; 357(2): 124–134.

  53. Groom H, Dieperink E, Nelson DB, Garrard J, Johnson JR, Ewing SL, et al. Outcomes of a hepatitis C screening program at a large urban VA medical center. J Clin Gastroenterol 2008; 42(1): 97–106.

  54. Putka B, Mullen K, Birdi S, Merheb M. The disposition of hepatitis C antibody-positive patients in an urban hospital. J Viral Hepat 2009; 16(11): 814–821.

  55. Castelnuovo E, Thompson-Coon J, Pitt M, Cramp M, Siebert U, Price A, et al. The cost-effectiveness of testing for hepatitis C in former injecting drug users. Health Technol Assess 2006; 10(32): iii–iv, ix-xii, 1–93.

  56. Ferenci P, Fried MW, Shiffman ML, Smith CI, Marinos G, Goncales FL Jr, et al. Predicting sustained virological responses in chronic hepatitis C patients treated with peginterferon alfa-2a (40 KD)/ribavirin. J Hepatol 2005; 43(3): 425–433.

  57. Gane EJ, Stedman CA, Hyland RH, Ding X, Svarovskaia E, Symonds WT, et al. Nucleotide polymerase inhibitor sofosbuvir plus ribavirin for hepatitis C. N Engl J Med. 2013; 368(1): 34–44.

  58. Lawitz E, Poordad F, Kowdley KV, Cohen DE, Podsadecki T, Siggelkow S, et al. A phase 2a trial of 12-week interferon-free therapy with two direct-activing antivirals (ABT-450/r, ABT-072) and ribavirin in IL28B C/C patients with chronic hepatitis C genotype 1. J Hepatol 2013; doi: 10.1016/j.jhep.2013.02.009.

  59. Poordad F, Lawitz E, Kowdley KV, Cohen DE, Podsadecki T, Siggelkow S, et al. Exploratory study of oral combination antiviral therapy for hepatitis C. N Engl J Med. 2013; 368(1): 45–53.

  60. Sulkowski M, Gardiner D, Lawitz E, Hinestrosa F, Nelson D, Thuluvath P, et al. Potent viral suppression with the all-oral combination of daclatasvir (NS5A inhibitor) and GS-7977 (nucleoside NS5B inhibitor), +/- ribavirin, in treatment-naive patients with chronic HCV GT1, 2, or 3 (100% SVR GT1, 91% GT2). Proceedings of the International Liver Congress, 47th Annual Meeting of the European Association for the Study of the Liver; 2012 April 18–22; Barcelona, Spain.

  61. Zeuzem S, Soriano V, Asselah T, Bronowicki J, Lohse A, Mu llhaupt B, et al. SOUND-C2 interim results: high efficacy, good safety profile of IFNfree BI 201335, BI 207127, and RBV combination therapy in treatment-naive patients with genotype 1 HCV. Proceedings of the International Liver Congress, 47th Annual Meeting of the European Association for the Study of the Liver; 2012 April 18–22; Barcelona, Spain.

  62. Foster GR, Goldin RD, Main J, Murray-Lyon I, Hargreaves S, Thomas HC. Management of chronic hepatitis C: clinical audit of biopsy based management algorithm. BMJ 1997; 315(7106): 453–458.

  63. Irving WL, Smith S, Cater R, Pugh S, Neal KR, Coupland CA, et al. Clinical pathways for patients with newly diagnosed hepatitis C - what actually happens. J Viral Hepat 2006; 13(4): 264–271.

  64. Pawlotsky J, Sarin S, Foster G, Peng C, Rasenack J, Flisiak R, et al. Alisporivir plus ribavirin achieves high rates of sustained HCV clearance (SVR24) as interferon (IFN)-free or IFN-add-on regimen in treatmentnaive patients with HCV GT2 or GT3: final results from VITAL-1 study. Proceedings of The Liver Meeting, 63rd Annual Meeting of the American Association for the Study of Liver Diseases; 2012 Nov 9–13; Boston, Massachusetts, USA.

  65. Sulkowski M, Gardiner D, Rodriguez-Torres M, Reddy R, Hassanein T, Jacobson I, et al. High rate of sustained virologic response with the all-oral combination of Daclatasvir (NS5A inhibitor) plus Sofosbuvir (nucleotide NS5B inhibitor), with or without ribavirin, in treatment- naive patients chronically infected with HCV genotype 1, 2, or 3. Proceedings of The Liver Meeting, 63rd Annual Meeting of the American Association for the Study of Liver Diseases; 2012 Nov 9–13; Boston, Massachusetts, USA.

  66. Thein HH, Krahn M, Kaldor JM, Dore GJ. Estimation of utilities for chronic hepatitis C from SF-36 scores. Am JGastroenterol 2005; 100(3): 643–651.

  67. Ratcliffe J, Longworth L, Young T, Bryan S, Burroughs A, Buxton M. Assessing health-related quality of life pre- and post-liver transplantation: a prospective multicenter study. Liver Transpl 2002; 8(3): 263–270.

  68. Thompson CJ, Rogers G, Hewson P, Wright D, Anderson R, Jackson S, et al. Surveillance of cirrhosis for hepatocellular carcinoma: a costutility analysis. Brit J Cancer 2008; 98(7): 1166–1175.

  69. Bownik H, Saab S. The effects of hepatitis C recurrence on health-related quality of life in liver transplant recipients. Liver Int 2010; 30(1): 19–30.

  70. McLernon DJ, Dillon J, Donnan PT. Health-state utilities in liver disease: a systematic review. MedDecis Making2008; 28(4): 582–592.

  71. Saab S, Hunt DR, Stone MA, McClune A, Tong MJ. Timing of hepatitis C antiviral therapy in patients with advanced liver disease: a decision analysis model. Liver Transpl 2010; 16(6): 748–759.

  72. Younossi ZM, Singer ME, McHutchison JG, Shermock KM. Cost effectiveness of interferon alpha2b combined with ribavirin for the treatment of chronic hepatitis C. Hepatology 1999; 30(5): 1318–1324.

  73. Brown DM, Everhart JE. Cost of digestive diseases in the United States. Bethesda, MD: Department of Health and Human Services, Public Health Service, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, 1994.

  74. Naugler WE, Sonnenberg A. Survival and cost-effectiveness analysis of competing strategies in the management of small hepatocellular carcinoma. Liver Transpl 2010; 16 (10): 1186–1194.

  75. Showstack J, Katz PP, Lake JR, Brown RS Jr, Dudley RA, Belle S, et al. Resource utilization in liver transplantation: effects of patient characteristics and clinical practice. NIDDK Liver Transplantation Database Group. JAMA 1999; 281(15): 1381–1386.

  76. Wong JB, Bennett WG, Koff RS, Pauker SG. Pretreatment evaluation of chronic hepatitis C: risks, benefits, and costs. JAMA 1998; 280 (24): 2088–2093.

Source

 

 

0 comments :

Post a Comment