Cost-effectiveness of antiviral therapy in untreated compensated cirrhosis patient with serum HBV–DNA level < 2000 IU/mL (original) (raw)

Abstract

Background

Due to stringent reimbursement criteria, significant numbers of patients with compensated cirrhosis (CC) and low-level viremia [LLV; serum hepatitis B virus (HBV)–DNA levels of 20–2000 IU/mL] remain untreated especially in the East Asian countries, despite potential risk of disease progression. We analyzed cost-effectiveness to assess rationales for antiviral therapy (AVT) for this population.

Methods

We compared cost and effectiveness (quality-adjusted life years, QALYs) in a virtual cohort including 10,000 54-year-old CC-LLV patients receiving AVT (Scenario I) versus no treatment (Scenario II). A Markov model, including seven HBV-related conditions, was used. Values for transition probabilities and costs were mostly obtained from recent real-world South Korean data.

Results

As per a simulation of a base-case analysis, AVT reduced costs by $639 USD and yielded 0.108 QALYs per patient for 5 years among CC-LLV patients compared to no treatment. Thus, AVT is a cost-saving option with lower costs and better effectiveness than no treatment. If 10,000 patients received AVT, 815 incident cases of hepatocellular carcinoma (HCC) and 630 HBV-related deaths could be averted in 5 years compared to no treatment. In case of 10-year observation, AVT was consistently dominant. Even when the transition probabilities from CC-LLV vs. maintained virological response to HCC were same, fluctuation of results also lied within willingness-to-pay in South Korea. In the probabilistic sensitivity analysis with the willingness-to-pay threshold, the probability of AVT cost-effectiveness was 100%.

Conclusion

The extended application of AVT in CC-LLV patients may contribute positively to individual clinical benefits and national healthcare budgets.

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Abbreviations

AVT:

Antiviral therapy

NUCs:

Nucleos(t)ide analogs

ETV:

Entecavir

TDF:

Tenofovir disoproxil fumarate

HBV:

Hepatitis B virus

HCC:

Hepatocellular carcinoma

DCC:

Decompensated cirrhosis

AASLD:

American Association for the Study of the Liver

EASL:

European Association for the Study of the Liver

LLV:

Low-level viremia

RWE:

Real-world evidence

NHIS:

National Health Insurance Service

MVR:

Maintained virological response

OLT:

Orthotopic liver transplantation

RWD:

Real-world data

SA:

Sensitivity analysis

NPS:

National Patients Sample

CKD:

Chronic kidney disease

ICER:

Incremental cost-effectiveness ratio

QALY:

Quality-adjusted life years

CI:

Confidence interval

CEAC:

Cost-effectiveness acceptability curve

References

  1. 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(2):370–98. https://doi.org/10.1016/j.jhep.2017.03.021.
    Article Google Scholar
  2. Terrault NA, Lok ASF, McMahon BJ, Chang KM, Hwang JP, Jonas MM, et al. Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance. Hepatology 2018;67(4):1560–1599. https://doi.org/10.1002/hep.29800
    Article PubMed Google Scholar
  3. Yim HJ, Kim JH, Park JY, Yoon EL, Park H, Kwon JH, et al. Comparison of clinical practice guidelines for the management of chronic hepatitis B: when to start, when to change, and when to stop. Clin Mol Hepatol 2020;26(4):411–429. https://doi.org/10.3350/cmh.2020.0049
    Article PubMed PubMed Central Google Scholar
  4. Sarin SK, Kumar M, Lau GK, Abbas Z, Chan HL, Chen CJ, et al. Asian-Pacific clinical practice guidelines on the management of hepatitis B: a 2015 update. Hepatol Int 2016;10(1):1–98. https://doi.org/10.1007/s12072-015-9675-4
    Article CAS PubMed Google Scholar
  5. Hsu YC, Yip TC, Ho HJ, Wong VW, Huang YT, El-Serag HB, et al. Development of a scoring system to predict hepatocellular carcinoma in Asians on antivirals for chronic hepatitis B. J Hepatol 2018;69(2):278–285. https://doi.org/10.1016/j.jhep.2018.02.032
    Article PubMed Google Scholar
  6. Berzigotti A. Advances and challenges in cirrhosis and portal hypertension. BMC Med 2017;15(1):200. https://doi.org/10.1186/s12916-017-0966-6
    Article CAS PubMed PubMed Central Google Scholar
  7. Kim J, Kang W, Sinn DH, Gwak GY, Paik YH, Choi MS, et al. Substantial risk of recurrence even after 5 recurrence-free years in early-stage hepatocellular carcinoma patients. Clin Mol Hepatol 2020;26(4):516–528. https://doi.org/10.3350/cmh.2020.0016
    Article PubMed PubMed Central Google Scholar
  8. Lesmana CRA, Raharjo M, Gani RA. Managing liver cirrhotic complications: overview of esophageal and gastric varices. Clin Mol Hepatol 2020;26(4):444–460. https://doi.org/10.3350/cmh.2020.0022
    Article PubMed PubMed Central Google Scholar
  9. Korean Association for the Study of the Liver (KASL). KASL clinical practice guidelines for liver cirrhosis: varices, hepatic encephalopathy, and related complications. Clin Mol Hepatol 2020;26(2):83–127. https://doi.org/10.3350/cmh.2019.0010n.
    Article Google Scholar
  10. D’Amico G, Pasta L, Morabito A, D’Amico M, Caltagirone M, Malizia G, et al. Competing risks and prognostic stages of cirrhosis: a 25-year inception cohort study of 494 patients. Aliment Pharmacol Ther 2014;39(10):1180–1193. https://doi.org/10.1111/apt.12721
    Article CAS PubMed Google Scholar
  11. Lee HW, Park SY, Lee YR, Lee H, Lee JS, Kim SU, et al. Episodic detectable viremia does not affect prognosis in untreated compensated cirrhosis with serum hepatitis B virus-DNA< 2,000 IU/mL. Am J Gastroenterol. 2022;117:288–294.
    Article PubMed Google Scholar
  12. Sinn DH, Lee J, Goo J, Kim K, Gwak GY, Paik YH, et al. Hepatocellular carcinoma risk in chronic hepatitis B virus-infected compensated cirrhosis patients with low viral load. Hepatology 2015;62(3):694–701. https://doi.org/10.1002/hep.27889
    Article CAS PubMed Google Scholar
  13. http://opendata.hira.or.kr/op/opc/olap3thDsInfo.do#none. Accessed 22 Dec 2021
  14. Vemer P, Corro Ramos I, van Voorn GA, Al MJ, Feenstra TL. AdViSHE: a validation-assessment tool of health-economic models for decision makers and model users. Pharmacoeconomics 2016;34(4):349–361. https://doi.org/10.1007/s40273-015-0327-2
    Article CAS PubMed Google Scholar
  15. Cho JY, Sohn W, Sinn DH, Gwak GY, Paik YH, Choi MS, et al. Long-term real-world entecavir therapy in treatment-naïve hepatitis B patients: base-line hepatitis B virus DNA and hepatitis B surface antigen levels predict virologic response. Korean J Intern Med 2017;32(4):636–646. https://doi.org/10.3904/kjim.2016.096
    Article CAS PubMed Google Scholar
  16. Kwon JH, Song MJ, Jang JW, Bae SH, Choi JY, Yoon SK, et al. Efficacy and safety of tenofovir disoproxil fumarate in treatment-naïve patients with chronic hepatitis B in Korea. Dig Dis Sci 2019;64(7):2039–2048. https://doi.org/10.1007/s10620-019-05489-7
    Article CAS PubMed Google Scholar
  17. Ahn DG, Lee JI, Lee KS, Kim S, Kim SU, Kim BK, et al. Two-year treatment with tenofovir alafenamide versus tenofovir disoproxil fumarate in patients with chronic hepatitis B. Proc Liver Week 2020;190
  18. https://opendata.hira.or.kr/op/opc/selectPatDataAplInfoView.do. Accessed 10 July 2019
  19. Kim SU, Seo YS, Lee HA, Kim MN, Lee YR, Lee HW, et al. A multicenter study of entecavir vs. tenofovir on prognosis of treatment-naïve chronic hepatitis B in South Korea. J Hepatol 2019;71(3):456–464. https://doi.org/10.1016/j.jhep.2019.03.028
    Article CAS PubMed Google Scholar
  20. Kim BG, Park NH, Lee SB, Lee H, Lee BU, Park JH, et al. Mortality, liver transplantation and hepatic complications in patients with treatment-naïve chronic hepatitis B treated with entecavir vs tenofovir. J Viral Hepat 2018;25(12):1565–1575. https://doi.org/10.1111/jvh.12971
    Article CAS PubMed Google Scholar
  21. Jang JW, Choi JY, Kim YS, Yoo JJ, Woo HY, Choi SK, et al. Effects of virologic response to treatment on short- and long-term outcomes of patients with chronic hepatitis B virus infection and decompensated cirrhosis. Clin Gastroenterol Hepatol 2018;16(12):1954-1963.e1953. https://doi.org/10.1016/j.cgh.2018.04.063
    Article PubMed Google Scholar
  22. Kim BK, Kim DY, Han KH, Seong J. Changes in real-life practice for hepatocellular carcinoma patients in the Republic of Korea over a 12-year period: A nationwide random sample study. PLoS ONE 2019;14(10): e0223678. https://doi.org/10.1371/journal.pone.0223678
    Article CAS PubMed PubMed Central Google Scholar
  23. https://www.ubcare.co.kr/Contents/26/. Accessed 20 Dec 2021
  24. Dave S, Park S, Murad MH, Barnard A, Prokop L, Adams LA, et al. Comparative effectiveness of entecavir versus tenofovir for preventing hepatocellular carcinoma in patients with chronic hepatitis B: a systematic review and meta-analysis. Hepatology 2021;73(1):68–78. https://doi.org/10.1002/hep.31267
    Article CAS PubMed Google Scholar
  25. Choi WM, Choi J, Lim YS. Effects of tenofovir vs entecavir on risk of hepatocellular carcinoma in patients with chronic HBV infection: a systematic review and meta-analysis. Clin Gastroenterol Hepatol 2021;19(2):246-258.e249. https://doi.org/10.1016/j.cgh.2020.05.008
    Article CAS PubMed Google Scholar
  26. Lee H, Kim BK, Jang S, Ahn SH. Cost-effectiveness analysis of antiviral therapy for untreated minimally active chronic hepatitis B to prevent liver disease progression. Clin Transl Gastroenterol 2021;12(2):e00299. https://doi.org/10.14309/ctg.0000000000000299
    Article PubMed PubMed Central Google Scholar
  27. Center for Korean Network for Organ Sharing. Annual Report of the Transplant 2019. https://www.konos.go.kr/konosis/common/bizlogic.jsp. Accessed 20 May 2021
  28. Health Insurance Review and Assessment Service, Guidelines for economic evaluation of pharmaceuticals in Korea, March 2021. http://www.hira.or.kr/sViewer/index.do?ebookSn=630. Accessed 6 June 2021
  29. Health Insurance Review and Assessment Service, drug reimbursement list in Korea, March 2021. https://www.hira.or.kr/bbsDummy.do?pgmid=HIRAA030014050000&brdScnBltNo=4&brdBltNo=1640. Accessed 6 June 2021
  30. Kim L, Kim JA, Kim S. A guide for the utilization of Health Insurance Review and Assessment Service National Patient Samples. Epidemiol Health 2014;36: e2014008. https://doi.org/10.4178/epih/e2014008
    Article PubMed PubMed Central Google Scholar
  31. Kim HL, An J, Park JA, Park SH, Lim YS, Lee EK. Magnetic resonance imaging is cost-effective for hepatocellular carcinoma surveillance in high-risk patients with cirrhosis. Hepatology 2019;69(4):1599–1613. https://doi.org/10.1002/hep.30330
    Article PubMed Google Scholar
  32. Park JY, Heo J, Lee TJ, Yim HJ, Yeon JE, Lim YS, et al. A novel estimation of the relative economic value in terms of different chronic hepatitis B treatment options. PLoS ONE 2013;8(3): e57900. https://doi.org/10.1371/journal.pone.0057900
    Article CAS PubMed PubMed Central Google Scholar
  33. Kwon JW, Park HY, Kim YJ, Moon SH, Kang HY. Cost-effectiveness of pharmaceutical interventions to prevent osteoporotic fractures in postmenopausal women with osteopenia. J Bone Metab 2016;23(2):63–77. https://doi.org/10.11005/jbm.2016.23.2.63
    Article PubMed PubMed Central Google Scholar
  34. Go DS, Kim SH, Park J, Ryu DR, Lee HJ, Jo MW. Cost-utility analysis of the National Health Screening Program for chronic kidney disease in Korea. Nephrology (Carlton) 2019;24(1):56–64. https://doi.org/10.1111/nep.13203
    Article Google Scholar
  35. Levy AR, Kowdley KV, Iloeje U, Tafesse E, Mukherjee J, Gish R, et al. The impact of chronic hepatitis B on quality of life: a multinational study of utilities from infected and uninfected persons. Value Health 2008;11(3):527–538
    Article PubMed Google Scholar
  36. Åberg F, Mäklin S, Räsänen P, Roine RP, Sintonen H, Koivusalo AM, et al. Cost of a quality-adjusted life year in liver transplantation: the influence of the indication and the model for end-stage liver disease score. Liver Transpl 2011;17(11):1333–1343
    Article PubMed Google Scholar
  37. Korea National Health and Nutrition Examination Survey, 2019. https://knhanes.kdca.go.kr/knhanes/eng/index.do. Accessed 9 May 2021
  38. Briggs AH, Weinstein MC, Fenwick EA, Karnon J, Sculpher MJ, Paltiel AD. Model parameter estimation and uncertainty: a report of the ISPOR-SMDM Modeling Good Research Practices Task Force-6. Value Health 2012;15(6):835–842. https://doi.org/10.1016/j.jval.2012.04.014
    Article PubMed Google Scholar
  39. https://www.imf.org/external/pubs/ft/weo/2019/02/weodata/weorept.aspx?pr.x=45&pr.y=21&sy=2016&ey=2021&scsm=1&ssd=1&sort=country&ds=.&br=1&c=542&s=NGDP_RPCH%2CNGDPD%2CPPPGDP%2CNGDPDPC%2CPPPPC%2CPCPIPCH&grp=0&a=. Accessed 6 June 2021
  40. Hsu YC, Ho HJ, Lee TY, Huang YT, Wu MS, Lin JT, et al. Temporal trend and risk determinants of hepatocellular carcinoma in chronic hepatitis B patients on entecavir or tenofovir. J Viral Hepat 2018;25(5):543–551. https://doi.org/10.1111/jvh.12832
    Article CAS PubMed Google Scholar
  41. Chun CB, Kim SY, Lee JY, Lee SY. Republic of Korea: health system review. Health Syst Transit 2009;11(7):1–184
    Google Scholar
  42. https://repository.hira.or.kr/handle/2019.oak/2541. Accessed 11 Dec 2021
  43. Cho JY, Sohn W, Paik YH, Gwak GY, Choi MS, Lee JH, et al. Long-term hepatitis B surface antigen (HBsAg) kinetics during entecavir treatment in Korean patients-Functional cure unlikely. J Viral Hepat 2020;27(9):951–954. https://doi.org/10.1111/jvh.13306
    Article CAS PubMed Google Scholar
  44. Seto WK, Liu K, Wong DK, Fung J, Huang FY, Hung IF, et al. Patterns of hepatitis B surface antigen decline and HBV DNA suppression in Asian treatment-experienced chronic hepatitis B patients after three years of tenofovir treatment. J Hepatol 2013;59(4):709–716. https://doi.org/10.1016/j.jhep.2013.06.007
    Article CAS PubMed Google Scholar

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Funding

This study was supported by the Research Supporting Program of the Korean Association for the Study of the Liver (KASL2020-01).

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Authors and Affiliations

  1. College of Pharmacy, Ajou University, Suwon, Gyeonggi-do, Republic of Korea
    Hankil Lee
  2. Institute of Health Services Research, Yonsei University, Seoul, Republic of Korea
    Sungin Jang
  3. Department of Preventive Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
    Sungin Jang
  4. Department of Internal Medicine, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea
    Sang Hoon Ahn & Beom Kyung Kim
  5. Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea
    Sang Hoon Ahn & Beom Kyung Kim
  6. Yonsei Liver Center, Severance Hospital, Yonsei University Health System, Seoul, Republic of Korea
    Sang Hoon Ahn & Beom Kyung Kim

Authors

  1. Hankil Lee
  2. Sungin Jang
  3. Sang Hoon Ahn
  4. Beom Kyung Kim

Contributions

Conception and design: HL and BKK; development of methodology: HL, SJ and BKK; acquisition, analysis and interpretation of data: HL and BKK; writing, review, and/or revision of the manuscript: HL, SJ, SHA, and BKK; administrative, technical, or material support: HL, SJ, SHA, and BKK; study supervision: BKK.

Corresponding author

Correspondence toBeom Kyung Kim.

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Conflict of interest

Nothing to declare for Hankil Lee, Sungin Jang, Sang Hoon Ahn, Beom Kyung Kim.

Ethical approval

The study protocol was consistent with the ethical guidelines of the 1975 Declaration of Helsinki and was approved by the Institutional Review Board. The need for patient consent was waived due to the use of untraceable and de-identified secondary claims data.

Animal research (ethics)

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Lee, H., Jang, S., Ahn, S.H. et al. Cost-effectiveness of antiviral therapy in untreated compensated cirrhosis patient with serum HBV–DNA level < 2000 IU/mL.Hepatol Int 16, 294–305 (2022). https://doi.org/10.1007/s12072-022-10310-1

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