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Original Research |

New Protease Inhibitors for the Treatment of Chronic Hepatitis C: A Cost-Effectiveness Analysis

Shan Liu, SM; Lauren E. Cipriano, BSc, BA; Mark Holodniy, MD; Douglas K. Owens, MD, MS; and Jeremy D. Goldhaber-Fiebert, PhD
[+] Article and Author Information

Acknowledgment: The authors thank Dr. Paul Barnett and Dr. Steven Asch for extensive and helpful comments on the manuscript.

Financial Support: Ms. Liu was supported by a Stanford Graduate Fellowship. Ms. Cipriano was supported by a doctoral scholarship from the Social Sciences and Humanities Research Council of Canada and by the Seth Bonder Scholarship for Applied Operations Research in Health Services from the Institute for Operations Research and the Management Sciences. Drs. Holodniy and Owens are supported by the Department of Veterans Affairs and supported in part by R01 DA15612-016. Dr. Goldhaber-Fiebert was supported in part by a National Institutes of Health National Institute on Aging Career Development Award (K01 AG037593-01A1; principal investigator, Dr. Goldhaber-Fiebert).

Potential Conflicts of Interest: None disclosed. Forms can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M11-1869.

Reproducible Research Statement:Study protocol: Not applicable. Statistical code and data set: Available from Ms. Liu (e-mail, mailto:shanliu@stanford.edu).

Requests for Single Reprints: Jeremy D. Goldhaber-Fiebert, PhD, CHP/PCOR, Stanford University, 117 Encina Commons, Stanford, CA 94305-6019.

Current Author Addresses: Ms. Liu and Ms. Cipriano: Management Science and Engineering, Huang Engineering Center 212H, 475 Via Ortega, Stanford, CA 94305-4121.

Dr. Holodniy: AIDS Research Center, VA Palo Alto Health Care System, 3801 Miranda Avenue (132), Palo Alto, CA 94304-5107.

Drs. Owens and Goldhaber-Fiebert: CHP/PCOR, Stanford University, 117 Encina Commons, Stanford, CA 94305-6019.

Author Contributions: Conception and design: S. Liu, L.E. Cipriano, M. Holodniy, D.K. Owens, J.D. Goldhaber-Fiebert.

Analysis and interpretation of the data: S. Liu, L.E. Cipriano, M. Holodniy, D.K. Owens, J.D. Goldhaber-Fiebert.

Drafting of the article: S. Liu, L.E. Cipriano, D.K. Owens, J.D. Goldhaber-Fiebert.

Critical revision of the article for important intellectual content: S. Liu, L.E. Cipriano, M. Holodniy, D.K. Owens, J.D. Goldhaber-Fiebert.

Final approval of the article: S. Liu, L.E. Cipriano, M. Holodniy, D.K. Owens, J.D. Goldhaber-Fiebert.

Statistical expertise: S. Liu, L.E. Cipriano, D.K. Owens, J.D. Goldhaber-Fiebert.

Obtaining of funding: D.K. Owens, J.D. Goldhaber-Fiebert.

Administrative, technical, or logistic support: L.E. Cipriano.

Collection and assembly of data: S. Liu, L.E. Cipriano, M. Holodniy, J.D. Goldhaber-Fiebert.


From the Center for Health Policy/Center for Primary Care and Outcomes Research, Stanford University, Stanford, and the Veterans Affairs Palo Alto Health Care System, Palo Alto, California.


Ann Intern Med. 2012;156(4):279-290. doi:10.7326/0003-4819-156-4-201202210-00005
Text Size: A A A

Background: Chronic hepatitis C virus is difficult to treat and affects approximately 3 million Americans. Protease inhibitors increase the effectiveness of standard therapy, but they are costly. A genetic assay may identify patients most likely to benefit from this treatment advance.

Objective: To assess the cost-effectiveness of new protease inhibitors and an interleukin (IL)–28B genotyping assay for treating chronic hepatitis C virus.

Design: Decision-analytic Markov model.

Data Sources: Published literature and expert opinion.

Target Population: Treatment-naive patients with chronic, genotype 1 hepatitis C virus monoinfection.

Time Horizon: Lifetime.

Perspective: Societal.

Intervention: Strategies are defined by the use of IL-28B genotyping and type of treatment (standard therapy [pegylated interferon with ribavirin]; triple therapy [standard therapy and a protease inhibitor]). Interleukin-28B–guided triple therapy stratifies patients with CC genotypes to standard therapy and those with non-CC types to triple therapy.

Outcome Measures: Discounted costs (in 2010 U.S. dollars) and quality-adjusted life-years (QALYs); incremental cost-effectiveness ratios.

Results of Base-Case Analysis: For patients with mild and advanced fibrosis, universal triple therapy reduced the lifetime risk for hepatocellular carcinoma by 38% and 28%, respectively, and increased quality-adjusted life expectancy by 3% and 8%, respectively, compared with standard therapy. Gains from IL-28B–guided triple therapy were smaller. If the protease inhibitor costs $1100 per week, universal triple therapy costs $102 600 per QALY (mild fibrosis) or $51 500 per QALY (advanced fibrosis) compared with IL-28B–guided triple therapy and $70 100 per QALY (mild fibrosis) and $36 300 per QALY (advanced fibrosis) compared with standard therapy.

Results of Sensitivity Analysis: Results were sensitive to the cost of protease inhibitors and treatment adherence rates.

Limitation: Data on the long-term comparative effectiveness of the new protease inhibitors are lacking.

Conclusion: Both universal triple therapy and IL-28B–guided triple therapy are cost-effective when the least-expensive protease inhibitor are used for patients with advanced fibrosis.

Primary Funding Source: Stanford University.

Figures

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Figure 1. Model schematics.

The small square represents the decision to implement a policy of standard therapy, universal triple therapy, or IL-28B–guided triple therapy. The small circle with inset “M” indicates the Markov model. During each 12-wk cycle of the model, all persons face a risk for death, depending on their age, sex, race, and health state. Persons begin the model receiving treatment, and if treatment is successful (the patient achieves sustained virologic response), the patient may transition along one of the dashed arrows to a fibrosis stage—stratified, recovered state. Treatment effectiveness is determined by type of treatment, race, fibrosis stage, and IL-28B genotype. If treatment is not successful, the person continues progressing through the natural history of HCV (solid arrows). Death can occur from any health state in the Markov model. HCC = hepatocellular carcinoma; HCV = hepatitis C virus; IL-28B = interleukin-28B; PEG-IFN = pegylated interferon; PI = protease inhibitor; Rb = ribavirin.

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Appendix Figure 1. Schematic of first-line response-guided therapy for standard 2-drug therapy.

Sustained virologic response is the goal of treatment, and it is measured 24 wk after treatment is stopped. Early virologic response is defined as a reduction of ≥2 log10/mL or complete absence of serum HCV RNA at week 12 of treatment compared with the baseline level. EVR = early virologic response; HCV = hepatitis C virus; PEG-IFN = pegylated interferon; Rb = ribavirin; SVR = sustained virologic response.

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Appendix Figure 2. Schematic of first-line response-guided therapy for triple therapy strategies.

EVR = early virologic response; HCV = hepatitis C virus; PEG-IFN = pegylated interferon; PI = protease inhibitor; Rb = ribavirin; SVR = sustained virologic response.

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Figure 2. Cost-effectiveness results: incremental costs incurred and QALYs for each intervention.

The graph plots the incremental discounted QALYs (y-axis) and incremental discounted total expected lifetime costs (x-axis) for each treatment strategy separately for cohorts of patients with mild and advanced fibrosis. The solid lines represent the cost-effectiveness frontier, those strategies that are potentially cost-effective depending on one's willingness to pay per unit of health benefit gained, expressed as an incremental cost-effectiveness ratio (defined as the ratio of the additional costs of an intervention and its additional effects compared with the next-best alternative). IL-28B = interleukin-28B; QALY = quality-adjusted life-year.

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Appendix Figure 3. Cost-effectiveness results, depending on the fibrosis stage of the cohort.

The ICER of strategies on the efficient frontier compared with the next best strategy on the frontier, assuming protease inhibitor costs $1100 per week. ICER = incremental cost-effectiveness ratio; IL-28B = interleukin-28B; QALY = quality-adjusted life-year.

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Appendix Figure 4. Protease inhibitor scenario analysis: ICERs between universal triple therapy using telaprevir to universal triple therapy using boceprevir (base case).

ADVANCE = A New Direction in HCV Care: A Study of Treatment-Naive Hepatitis C Patients with Telaprevir; ICER = incremental cost-effectiveness ratio; QALY = quality-adjusted life-year.

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Appendix Figure 5. Cost-effectiveness acceptability curve, assuming protease inhibitor costs $1100 per week.

The figure shows the probability of each strategy providing the maximum net monetary benefits at various willingness-to-pay thresholds. IL-28B = interleukin-28B; QALY = quality-adjusted life-year.

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Appendix Figure 6. Model schematics: 5 strategies.

The small square represents the decision to implement a policy of therapy. The small circle with inset “M” indicates the Markov model. IL-28B = interleukin-28B; PEG-IFN = pegylated interferon; PI = protease inhibitor; Rb = ribavirin.

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Appendix Figure 7. Overall probability of SVR; by race: 100 treatment effectiveness profiles.

SVR = sustained virologic response.

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Cart before the Horse
Posted on April 30, 2012
SammySaab, Head, Outcomes Research in Hepatology
UCLA
Conflict of Interest: None Declared

We read with great interest the manuscript by Liu et al (1). The study adds to an increasing body of literature assessing the cost- effective studies in viral hepatitis, with over 90% of cost effective studies in viral hepatitis have shown favorable results (2). Hepatitis C is indeed a medical and public health concern. Not only is does it appear that the prevalence of hepatitis C has been underestimated, but hepatitis C is now responsible for more deaths in this country than HIV (3,4). Indeed, results of a recent pharmacoeconomic study by the Centers of Disease and Control Prevention suggest that screening of members of the baby-boomer generation to be cost-effective (5). The current results of the study by Liu et al demonstrating that protease inhibitors are not cost-effective are refreshing (1). The study is timely as the hepatitis C protease inhibitors have been approved just within the past 12 months. However, this rapid publication may also highlight several deficiencies in basing cost effective studies on published effectiveness without clinical attribute. As it is understood, cost effective studies require reasonable data (published or assumed) on costs and efficacy. In their model, we did not find inference to the use of growth factors. Indeed, in the clinical trial using boceprevir, almost 50% of treated patients received erythropoietin (6,7). The use of these additional treatments will certainly add to the costs of treatment. The use of growth factors with boceprevir will likely become controversial with the recent data highlighting that growth factors do not necessarily result in improves sustained viral results (8). Additionally, transfusions and erythropoietin use in patients treated with telaprevir have been reported to be higher in a large observational study than that reported in the clinical trials (9). Moreover, we found the authors baseline comparison using the IL28b genotype to be out of touch with current standard of care. The updated American Association for the Study of Liver Diseases (AASLD) guidelines recommend the antiviral therapy for hepatitis C genotype 1 should consist of a pegylated interferon, ribavirin, and a protease inhibitor (Class 1, Level A) (10). However, the authors are incorrect that the guidelines state that the IL28b may be used in the decision whether or not to incorporate protease inhibitors with the use of pegylated interferon and ribavirin. Rather, the AASLD guidelines suggest that IL28b genotype may provide information on the likelihood of achieving a sustained viral response and the shorter treatment duration (Class 2a, Level B). Consideration of a only using pegylated interferon and ribavirin in na?ve patients without cirrhosis should be decided according to United Kingdom consensus guidelines only in the context of other parameters such as complete viral suppression after one month of dual therapy (10). The AASLD guidelines state that if this information affects a patient's decision of whether or not to be treated, careful consideration should be taken as there is insufficient data to determine whether IL28b testing can appropriately risk stratify treatment regimens with or without protease inhibitors (11). We urge caution on early introduction of pharmacoeconomic data before sufficient information is available on not only efficacy, but costs. It is important not to put the cart before the horse.

David Padua (1) and Sammy Saab (2)

Department of Medicine (1) and Surgery (2), David Geffen School of Medicine,

University of California at Los Angeles, Los Angeles, CA, US

Please address correspondence to: Sammy Saab, MD, MPH, AGAF Pfleger Liver Institute UCLA Medical Center 200 Medical Plaza, Suite 214 Los Angeles, CA 90095 310-206-6705 (V) 310-206-4197 (F) SSaab@mednet.ucla.edu

References

1. 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. Ann Intern Med. 2012; 156:271-90.

2. Saab S, Choi YM, Rahal H, Li K, Tong J. Trends in Reporting Viral Hepatitis Cost-Effectiveness Study Results. Am J Managed 2012 (in review).

3. Chak E, Talal AH, Sherman KE, Schiff ER, Saab S. Hepatitis C virus infection in USA: an estimate of true prevalence. Liver Int. 2011; 31:1090-101.

4. Ly KN, Xing J, Klevens M, Jiles RB, Ward JW, Holmberg SC. The increasing burden of mortality from viral hepatitis in the United States between 1999 and 2007. Ann Intern Med 2012;156:271-279.

5. 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. 156:263- 270.

6. Bacon BR, Gordon SC, Lawitz E, Marcellin P, Vierling JM, Zeuzem S, et al. Boceprevir for previously treated chronic HCV genotype 1 infection. N Engl J Med. 2011;364:1207-217.

7. Poordad F, McCone J, Bacon BR, Bruno S, Manns MP, Sulkoski MS, et al. Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med. 2011;364:1195-1206.

8. Poordad F, Lawitz EJ, Reddy KR, Afdhal NH, H?zode C, Zeuzem S, et al. Randomized trial comparing ribavirin dose reduction versus erythropoietin for anemia management in previously untreated patients with chronic hepatitis C receiving boceprevir plus peginterferon/ribavirin. 47th Annual Meeting of the European Association for the Study of Liver Diseases. 2012. Abstract 1419.

9. Hezode C, Dorival C, Zoulim F, de Ledinghen V, Poynard T, Mathurin P, et al. Safety of telaprevir or boceprevir in combination with peginterferon alfa/ribavirin, in cirrhotic non responders. First results of the French Early Access Program in real-time setting. Global Antiviral Journal. HEP DART 2011; 7;Suppl 1:54.

10. Ghany MG, Nelson DR, Strader DB, Thomas DL, Seeff LB; American Association for Study of Liver Diseases. 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;54:1433-44.

11. Ramachandran P, Fraser A, Agarwal K, Austin A, Brown A, Foster GR, et al. UK Consensus guidelines for the use of the protease inhibitors boceprevir and Telaprevir genotype 1 chronic hepatitis C infected patients. Aliment Pharmacol Ther 2012; 35:647-62.

Conflict of Interest:

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