Cost-Effectiveness of Tenofovir Alafenamide for Treatment of Chronic Hepatitis B in Canada

  • Feng Tian
  • Sherilyn K. D. Houle
  • Mhd. Wasem Alsabbagh
  • William W. L. WongEmail author
Original Research Article



Tenofovir alafenamide (TAF) has been approved for treating chronic hepatitis B (CHB) due to a proposed better safety profile in comparison with current therapies. We evaluated the cost effectiveness of TAF and other available treatment options for hepatitis B envelope antigen (HBeAg)-positive and HBeAg-negative CHB patients from a Canadian provincial Ministry of Health perspective.


A state-transition model based on the published literature was developed to compare treatment strategies involving entecavir (ETV), tenofovir disoproxil fumarate (TDF), and TAF. It adopted a lifetime time horizon. Outcomes measured were predicted number of liver-related deaths, costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs).


For HBeAg-positive patients, TAF followed by ETV generated an additional 0.16 QALYs/person at an additional cost of Can$14,836.18 with an ICER of Can$94,142.71/QALY compared with TDF followed by ETV. Of the iterations, 28.7% showed that it is the optimal strategy with a Can$50,000 willingness-to-pay threshold. For HBeAg-negative patients, ETV followed by TAF would prevent an additional 13 liver-related deaths per 1000 CHB patients compared with TDF, followed by ETV. It generated an additional 0.13 QALYs/person at an additional cost of Can$59,776.53 with an ICER of Can$461,162.21/QALY compared with TDF, followed by ETV. TAF-containing strategies are unlikely to be a rational choice in either case. The results were sensitive to the HBeAg seroconversion rates and viral suppression rates of the treatments.


Our analysis suggests that TAF is not cost effective at its current cost. A 33.4% reduction in price would be required to make it cost effective for HBeAg-positive patients with a Can$50,000 willingness-to-pay threshold.



Dr Wong’s research program was supported by Canadian Institutes of Health Research (CIHR), Natural Sciences and Engineering Research Council (NSERC), and Ontario Ministry of Research, Innovation, and Science Early Researcher Award.

Author Contributions

FT implemented the model, collected and analyzed the data, and drafted the manuscript. SKH and WA contributed to analysis of the data and interpretation of the results. WW contributed to the design of the study, analysis, and interpretation of the data. All authors contributed in the revision of the manuscript and gave final approval for the version to be published.

Compliance with Ethical Standards

Funding/Grant Support

This work was supported by an Ontario Ministry of Research, Innovation, and Science Early Researcher Award that was awarded to WW.

Conflict of interest

WW received a research grant from the Canadian Liver Foundation. FT, SAK, and WA declared no conflicts of interest.

Supplementary material

40273_2019_852_MOESM1_ESM.docx (1 mb)
Supplementary material 1 (DOCX 1037 kb)


  1. 1.
    World Health Organization. Hepatitis B; 2017. Accessed 5 Apr 2018.
  2. 2.
    Pan CQ, Zhang JX. Natural history and clinical consequences of hepatitis B virus infection. Int J Med Sci. 2005;2:36–40.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Wu J-F, Chang M-H. Natural history of chronic hepatitis B virus infection from infancy to adult life—the mechanism of inflammation triggering and long-term impacts. J Biomed Sci. 2015;22:92.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Lok ASF, McMahon BJ. Chronic hepatitis B. Hepatology. 2007;45:507–39.CrossRefGoogle Scholar
  5. 5.
    McMahon BJ. The natural history of chronic hepatitis B virus infection. Hepatology. 2009;49:45–55.CrossRefGoogle Scholar
  6. 6.
    Gish R, Jia JD, Locarnini S, et al. Selection of chronic hepatitis B therapy with high barrier to resistance. Lancet Infect Dis. 2012;12:341–53.CrossRefGoogle Scholar
  7. 7.
    Sherman M, Shafran S, Burak K, et al. Management of chronic hepatitis B: consensus guidelines. Can J Gastroenterol. 2007;21(Suppl C):5C–24C.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Marcellin P, Gane EJ, Flisiak R, et al. Long-term treatment with tenofovir disoproxil fumarate for chronic hepatitis B infection is safe and well tolerated and associated with durable virologic response with no detectable resistance: 8 year results from two phase 3 trials. Hepatology. 2014;60(Suppl):313A–4A.Google Scholar
  9. 9.
    Chan HLY, Fung S, Seto WK, et al. Tenofovir alafenamide versus tenofovir disoproxil fumarate for the treatment of HBeAg-positive chronic hepatitis B virus infection: a randomised, double-blind, phase 3, non-inferiority trial. Lancet Gastroenterol Hepatol. 2016;1:185–95.CrossRefGoogle Scholar
  10. 10.
    Buti M, Gane E, Seto WK, et al. Tenofovir alafenamide versus tenofovir disoproxil fumarate for the treatment of patients with HBeAg-negative chronic hepatitis B virus infection: a randomised, double-blind, phase 3, non-inferiority trial. Lancet Gastroenterol Hepatol. 2016;1:196–206.CrossRefGoogle Scholar
  11. 11.
    Ontario Drug Benefit. eFormulary. Prices are effective as of May 31, 2019. Accessed 16 June 2019.
  12. 12.
    Terrault NA, Lok ASF, McMahon BJ, et al. Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance. Hepatology. 2018;67:1560–99.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Ontario Drug Policy Research Network. Hepatitis B environmental scan report; 2015. Accessed 12 June 2019.
  14. 14.
    He J, Bowen JM, Xie F, et al. Cost-effectiveness analysis of antiviral treatments for HBeAg-positive chronic hepatitis B in Canada. Value Health. 2012;15:894–906.CrossRefGoogle Scholar
  15. 15.
    Dakin H, Sherman M, Fung S, et al. Cost effectiveness of tenofovir disoproxil fumarate for the treatment of chronic hepatitis B from a Canadian public payer perspective. Pharmacoeconomics. 2011;29:1075–91.CrossRefGoogle Scholar
  16. 16.
    Ontario Drug Policy Research Network. Hepatitis B Pharmacoeconomics report; 2015. Accessed 6 June 2019.
  17. 17.
    Chan HLY, Fung S, Cathcart AL, et al. No resistance to tenofovir alafenamide detected through 48 weeks of treatment in patients with chronic hepatitis B. Hepatology. 2016;64(1 Suppl):909A.Google Scholar
  18. 18.
    European Association for the Study of the Liver. EASL 2017 clinical practice guidelines on the management of hepatitis B virus infection. J Hepatol. 2017;67:370–98.CrossRefGoogle Scholar
  19. 19.
    Siebert U, Alagoz O, Bayoumi AM, et al. State-transition modeling: a report of the ISPOR-SMDM modeling good research practices task force-3. Value Health. 2012;15:812–20.CrossRefGoogle Scholar
  20. 20.
    Canadian Agency for Drugs and Technologies in Health. Guidelines for the economic evaluation of health technologies: Canada. 4th ed.; 2017. Accessed 7 Aug 2018.
  21. 21.
    Mcmahon BJ, Holck P, Bulkow L, et al. Serologic and clinical outcomes of 1536 Alaska Natives chronically infected with hepatitis B virus. Ann Intern Med. 2001;135:759–68.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Veenstra DL, Sullivan SD, Clarke L, et al. Cost effectiveness of entecavir versus lamivudine with adefovir salvage in HBeAg-positive chronic hepatitis B. Pharmacoeconomics. 2007;25:963–77.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Wong WWL, Woo G, Jenny Heathcote E, et al. Cost effectiveness of screening immigrants for hepatitis B. Liver Int. 2011;31:1179–90.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Hutton DW, Tan D, So SK, et al. Cost-effectiveness of screening and vaccinating Asian and Pacific Islander adults for hepatitis B. Ann Intern Med. 2007;147:460–9.CrossRefGoogle Scholar
  25. 25.
    Kanwal F, Gralnek IM, Martin P, et al. Treatment alternatives for chronic hepatitis B virus infection: a cost-effectiveness analysis. Ann Intern Med. 2005;142:821–31.CrossRefGoogle Scholar
  26. 26.
    Papatheodoridis GV, Manolakopoulos S, Touloumi G, et al. Risk of hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) patients with or without cirrhosis treated with oral antivirals: results of the nationwide HEPNET. Greece cohort study. Boston: AASLD; 2009.Google Scholar
  27. 27.
    Benvegnù L, Gios M, Boccato S, et al. Natural history of compensated viral cirrhosis: a prospective study on the incidence and hierarchy of major complications. Gut. 2004;53:744–9.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Fattovich G, Giustina G, Schalm SW, et al. Occurrence of hepatocellular carcinoma and decompensation in Western European patients with cirrhosis type B. Hepatology. 1995;21:77–82.PubMedGoogle Scholar
  29. 29.
    Kanwal F, Farid M, Martin P, et al. Treatment alternatives for hepatitis B cirrhosis: a cost-effectiveness analysis. Am J Gastroenterol. 2006;101:2076–89.CrossRefGoogle Scholar
  30. 30.
    Craxi A, Colombo P, D’Amico G, et al. Hepatitis B infection and liver cirrhosis: a reappraisal from the Mediterranean area. Ann Ist Super Sanita. 1987;24:257–65.PubMedGoogle Scholar
  31. 31.
    D’Amico G, Morabito A, Pagliaro L, et al. Survival and prognostic indicators in compensated and decompensated cirrhosis. Dig Dis Sci. 1986;31:468–75.CrossRefGoogle Scholar
  32. 32.
    Fattovich G, Pantalena M, Zagni I, et al. Effect of hepatitis B and C virus infections on the natural history of compensated cirrhosis: a cohort study of 297 patients. Am J Gastroenterol. 2002;97:2886–95.CrossRefGoogle Scholar
  33. 33.
    Liaw YF, Tai DI, Chu CM, et al. The development of cirrhosis in patients with chronic type B hepatitis: a prospective study. Hepatology. 1988;8:493–6.CrossRefGoogle Scholar
  34. 34.
    Lin S-M, Sheen I-S, Chien R-N, et al. Long-term beneficial effect of interferon therapy in patients with chronic hepatitis B virus infection. Hepatology. 1999;29:971–5.CrossRefGoogle Scholar
  35. 35.
    Iloeje UH, Yang HI, Su J, et al. Predicting cirrhosis risk based on the level of circulating hepatitis B viral load. Gastroenterology. 2006;130:678–86.CrossRefGoogle Scholar
  36. 36.
    Veenstra DL, Spackman DE, Bisceglie A, et al. Evaluating anti-viral drug selection and treatment duration in HBeAg-negative chronic hepatitis B: a cost-effectiveness analysis. Aliment Pharmacol Ther. 2008;27:1240–52.CrossRefGoogle Scholar
  37. 37.
    Hsu YS, Chien RN, Yeh CT, et al. Long-term outcome after spontaneous HBeAg seroconversion in patients with chronic hepatitis B. Hepatology. 2002;35:1522–7.CrossRefGoogle Scholar
  38. 38.
    Gigi E, Lalla T, Orphanou E, et al. Long term follow-up of a large cohort of inactive HBsAg (+)/ HBeAg (−)/anti-HBe (+) carriers in Greece. J Gastrointest Liver Dis. 2007;16:19–22.Google Scholar
  39. 39.
    Wong WWL, Lee KM, Singh S, et al. Drug therapies for chronic hepatitis C infection: a cost-effectiveness analysis. CMAJ Open. 2017;5:E97–108.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Wong WWL, Pechivanoglou P, Wong J, et al. Antiviral treatment for treatment-naïve chronic hepatitis B: systematic review and network meta-analysis of randomized controlled trials. Syst Rev. 2019;8:207.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Statistics Canada. Life tables, Canada, provinces and territories 1980/1982 to 2014/2016; 2018. Accessed 23 July 2018.
  42. 42.
    Dakin H, Bentley A, Dusheiko G. Cost-utility analysis of tenofovir disoproxil fumarate in the treatment of chronic hepatitis B. Value Health. 2010;13:922–33.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Hosaka T, Suzuki F, Kobayashi M, et al. Long-term entecavir treatment reduces hepatocellular carcinoma incidence in patients with hepatitis B virus infection. Hepatology. 2013;58:98–107.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Wong GL-H, Chan HL-Y, Mak CW-H, et al. Entecavir treatment reduces hepatic events and deaths in chronic hepatitis B patients with liver cirrhosis. Hepatology. 2013;58:1537–47.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Canadian Institute for Health Information. Health care in Canada 2010; 2010. Accessed 7 Aug 2018.
  46. 46.
    Gagnon YM, Levy AR, Iloeje UH, et al. Treatment costs in Canada of health conditions resulting from chronic hepatitis B infection. J Clin Gastroenterol. 2004;38:S179–86.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Canadian Agency for Drugs and Technologies in Health. Pharmacoeconomic review report for Vemlidy; 2018. Accessed 16 June 2019.
  48. 48.
    Ontario Ministry of Health and Long-Term Care. Physician Services Under the Health Insurance Act; 2015. Accessed 26 Sep 2018.
  49. 49.
    Statistics Canada. Consumer price index, annual average, not seasonally adjusted; 2019. Accessed 16 June 2018.
  50. 50.
    Woo G, Tomlinson G, Yim C, et al. Health state utilities and quality of life in patients with hepatitis B. Can J Gastroenterol. 2012;26:445–51.CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Lin C-L, Kao J-H. Risk stratification for hepatitis B virus related hepatocellular carcinoma. J Gastroenterol Hepatol. 2013;28:10–7.CrossRefGoogle Scholar
  52. 52.
    Blachier M, Leleu H, Peck-Radosavljevic M, et al. The burden of liver disease in Europe: a review of available epidemiological data. J Hepatol. 2013;58:593–608.CrossRefGoogle Scholar
  53. 53.
    Laupacis A, Feeny D, Detsky AS, et al. How attractive does a new technology have to be to warrant adoption and utilization? Tentative guidelines for using clinical and economic evaluations. CMAJ. 1992;146:473–81.PubMedPubMedCentralGoogle Scholar
  54. 54.
    McCabe C, Claxton K, Culyer AJ. The NICE cost effectiveness threshold: what it is and what it means. Pharmacoeconomics. 2008;26:733–44.CrossRefGoogle Scholar
  55. 55.
    Colombo GL, Gaeta GB, Viganò M, et al. A cost-effectiveness analysis of different therapies in patients with chronic hepatitis B in Italy. Clinicoecon Outcomes Res. 2011;3:37–46.CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Kockaya G, Kose A, Yenilmez FB, et al. Cost-effectiveness analysis of oral anti-viral drugs used for treatment of chronic hepatitis B in Turkey. Cost Effect Resour Alloc. 2015;13:21.CrossRefGoogle Scholar
  57. 57.
    Wiens A, Lenzi L, Venson R, et al. Economic evaluation of treatments for chronic hepatitis B. Braz J Infect Dis. 2013;17:418–26.CrossRefGoogle Scholar
  58. 58.
    Bermingham SL, Hughes R, Fenu E, et al. Cost-effectiveness analysis of alternative antiviral strategies for the treatment of HBeAg-positive and HBeAg-negative chronic hepatitis B in the United Kingdom. Value Health. 2015;18:800–9.CrossRefGoogle Scholar
  59. 59.
    Buti M, Oyagüez I, Lozano V, et al. Cost effectiveness of first-line oral antiviral therapies for chronic hepatitis B : a systematic review. Pharmacoeconomics. 2013;31(1):63–75.CrossRefGoogle Scholar
  60. 60.
    World Health Organization. World hepatitis summit harnesses global momentum to eliminate viral hepatitis; 2015. Accessed 28 May 2018.
  61. 61.
    Government of Canada. Message from the Minister of Health World Hepatitis Day—July 28, 2018; 2018.–july-28-2018.html. Accessed 11 Apr 2019.

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.School of Pharmacy, Faculty of ScienceUniversity of WaterlooKitchenerCanada

Personalised recommendations