Effectiveness of entecavir vs tenofovir disoproxil fumarate for functional cure of chronic hepatitis B in an international cohort (original) (raw)

Abstract

Introduction

Both entecavir (ETV) and tenofovir disoproxil fumarate (TDF) are first-line therapies for chronic hepatitis B (CHB), but their comparative effectiveness with regards to hepatitis B surface antigen (HBsAg) seroclearance remains unclear.

Methods

This international multicenter cohort study enrolled 7697 treatment-naïve CHB patients (median age 50 years; male 66.75%) initiated on either ETV (n = 5430) or TDF (n = 2267) without baseline malignancy or immunosuppression from 23 centers across 10 countries or regions. Patients were observed for HBsAg seroclearance until death, loss to follow-up, or treatment discontinuation or switching. The incidences of HBsAg seroclearance were adjusted for competing mortality and compared between ETV and TDF cohorts with inverse probability of treatment weighting (IPTW) and also by multivariable regression analysis.

Results

The study population was followed up for a median duration of 56.1 months with 36,929 11 person-years of observation. HBsAg seroclearance occurred in 70 ETV-treated and 21 TDF-treated patients, yielding 8-year cumulative incidence of 1.69% (95% confidence interval [CI] 1.32–2.17) for ETV and 1.34% (95% CI 0.85–2.10%), for TDF (p = 0.58). In the IPTW analysis with the two study cohorts more balanced in background covariates, the age-adjusted hazard ratio (HR) of TDF versus ETV for HBsAg seroclearance was 0.91 (95% CI 0.50–1.64; p = 0.75). Furthermore, there was no significant difference between the two medications in the multivariable competing risk regression model (adjusted sub-distributional HR 0.92 for TDF vs. ETV; 95% CI 0.56–1.53; p = 0.76).

Conclusions

ETV and TDF did not differ significantly in the incidence of HBsAg seroclearance, which rarely occurred with either regimen.

Access this article

Log in via an institution

Subscribe and save

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

Abbreviations

ALT:

Alanine transaminase

AST:

Aspartate transaminase

CHB:

Chronic hepatitis B

CI:

Confidence interval

FIB-4:

Fibrosis-4 index

HBeAg:

Hepatitis B e antigen

HBsAg:

Hepatitis B surface antigen

HBV:

Hepatitis B virus

HCC:

Hepatocellular carcinoma

SHR:

Sub-distribution hazard ratio

NA:

Nucleos(t)ide analog

References

  1. Schweitzer A, Horn J, Mikolajczyk RT, et al. Estimations of worldwide prevalence of chronic hepatitis B virus infection: a systematic review of data published between 1965 and 2013. Lancet. 2015;386:1546–1555
    Article PubMed Google Scholar
  2. Polaris OC. Global prevalence, treatment, and prevention of hepatitis B virus infection in 2016: a modelling study. Lancet Gastroenterol Hepatol. 2018;3:383–403
    Article Google Scholar
  3. Huang YT, Jen CL, Yang HI, et al. Lifetime risk and sex difference of hepatocellular carcinoma among patients with chronic hepatitis B and C. J Clin Oncol. 2011;29:3643–3650
    Article PubMed PubMed Central Google Scholar
  4. Lok AS, McMahon BJ, Brown RS Jr, et al. Antiviral therapy for chronic hepatitis B viral infection in adults: a systematic review and meta-analysis. Hepatology. 2016;63:284–306
    Article CAS PubMed Google Scholar
  5. Zoulim F, Poynard T, Degos F, et al. A prospective study of the evolution of lamivudine resistance mutations in patients with chronic hepatitis B treated with lamivudine. J Viral Hepat. 2006;13:278–288
    Article CAS PubMed PubMed Central Google Scholar
  6. 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;67:1560–1599
    Article PubMed Google Scholar
  7. European Association for the Study of the Liver. European Association for the Study of the L. EASL. Clinical practice guidelines on the management of hepatitis B virus infection. J Hepatol. 2017;2017(67):370–398
    Google Scholar
  8. Sarin SK, Kumar M, Lau GK, et al. Asian-pacific clinical practice guidelines on the management of hepatitis B: a 2015 update. Hepatol Int. 2016;10:1–98
    Article CAS PubMed Google Scholar
  9. Lai CL, Wong D, Ip P, et al. Reduction of covalently closed circular DNA with long-term nucleos(t)ide analogue treatment in chronic hepatitis B. J Hepatol. 2017;66:275–281
    Article CAS PubMed Google Scholar
  10. Nguyen MH, Wong G, Gane E, et al. Hepatitis B virus: advances in prevention, diagnosis, and therapy. Clin Microbiol Rev. 2020;33(2):e00046
    Article PubMed PubMed Central Google Scholar
  11. Seto WK, Hui AJ, Wong VW, et al. Treatment cessation of entecavir in Asian patients with hepatitis B e antigen negative chronic hepatitis B: a multicentre prospective study. Gut. 2015;64:667–672
    Article CAS PubMed Google Scholar
  12. Yip TC, Wong GL, Wong VW, et al. Durability of hepatitis B surface antigen seroclearance in untreated and nucleos(t)ide analogue-treated patients. J Hepatol. 2017. https://doi.org/10.1016/j.jhep.2017.09.018
    Article PubMed Google Scholar
  13. Yip TC, Wong GL, Chan HL, et al. HBsAg seroclearance further reduces hepatocellular carcinoma risk after complete viral suppression with nucleos(t)ide analogues. J Hepatol. 2019;70:361–370
    Article CAS PubMed Google Scholar
  14. Lok AS, Zoulim F, Dusheiko G, et al. Hepatitis B cure: from discovery to regulatory approval. Hepatology. 2017;66:1296–1313
    Article PubMed Google Scholar
  15. Raimondo G, Locarnini S, Pollicino T, et al. Update of the statements on biology and clinical impact of occult hepatitis B virus infection. J Hepatol. 2019;71:397–408
    Article PubMed Google Scholar
  16. Kim GA, Lim YS, An J, et al. HBsAg seroclearance after nucleoside analogue therapy in patients with chronic hepatitis B: clinical outcomes and durability. Gut. 2014;63:1325–1332
    Article CAS PubMed Google Scholar
  17. Hsu YC, Yeh ML, Wong GL, et al. Incidences and determinants of functional cure during entecavir or tenofovir disoproxil fumarate for chronic hepatitis B. J Infect Dis. 2021;224(11):1890–1899
    Article CAS PubMed Google Scholar
  18. Choi J, Kim HJ, Lee J, et al. Risk of hepatocellular carcinoma in patients treated with entecavir vs tenofovir for chronic hepatitis b: a Korean nationwide cohort study. JAMA Oncol. 2019;5:30–36
    Article PubMed Google Scholar
  19. Yip TC, Wong VW, Chan HL, et al. Tenofovir is associated with lower risk of hepatocellular carcinoma than entecavir in patients with chronic HBV infection in China. Gastroenterology. 2020;158(215–225): e6
    Google Scholar
  20. Kim SU, Seo YS, Lee HA, et al. A multicenter study of entecavir vs. tenofovir on prognosis of treatment-naive chronic hepatitis B in South Korea. J Hepatol. 2019;71:456–464
    Article CAS PubMed Google Scholar
  21. Papatheodoridis GV, Dalekos GN, Idilman R, et al. Similar risk of hepatocellular carcinoma during long-term entecavir or tenofovir therapy in Caucasian patients with chronic hepatitis B. J Hepatol. 2020;73:1037–1045
    Article CAS PubMed Google Scholar
  22. Tseng CH, Hsu YC, Chen TH, et al. Hepatocellular carcinoma incidence with tenofovir versus entecavir in chronic hepatitis B: a systematic review and meta-analysis. Lancet Gastroenterol Hepatol. 2020;5:1039–1052
    Article PubMed Google Scholar
  23. Dave S, Park S, Murad MH, 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;73:68–78
    Article CAS PubMed Google Scholar
  24. Gray RJ. A class of K-sample tests for comparing the cumulative incidence of a competing risk. Ann Stat. 1988;16:1141–1154
    Article Google Scholar
  25. Van Buuren S, Groothuis-Oudshoorn K. Mice: multivariate imputation by chained equations in R. J Stat Soft. 2011;45:1–67
    Article Google Scholar
  26. Tibshirani R. Regression Shrinkage and Selection via the Lasso. J R Statistical Soc. 1996;58:267–288
    Google Scholar
  27. Austin PC. Balance diagnostics for comparing the distribution of baseline covariates between treatment groups in propensity-score matched samples. Stat Med. 2009;28:3083–3107
    Article PubMed PubMed Central Google Scholar
  28. Fine JP, Gray RJ. A proportional hazards model for the subdistribution of a competing risk. J Am Stat Assoc. 1999;94:496–509
    Article Google Scholar
  29. Yeo YH, Ho HJ, Yang HI, et al. Factors associated with rates of HBsAg seroclearance in adults with chronic HBV infection: a systematic review and meta-analysis. Gastroenterology. 2019;156(635–646): e9
    Google Scholar
  30. Woo G, Tomlinson G, Nishikawa Y, et al. Tenofovir and entecavir are the most effective antiviral agents for chronic hepatitis B: a systematic review and Bayesian meta-analyses. Gastroenterology. 2010;139:1218–1229
    Article CAS PubMed Google Scholar
  31. Liu Y, Corsa AC, Buti M, et al. No detectable resistance to tenofovir disoproxil fumarate in HBeAg+ and HBeAg- patients with chronic hepatitis B after 8 years of treatment. J Viral Hepat. 2017;24:68–74
    Article CAS PubMed Google Scholar
  32. Suzuki F, Hosaka T, Suzuki Y, et al. Long-term outcome of entecavir treatment of nucleos(t)ide analogue-naive chronic hepatitis B patients in Japan. J Gastroenterol. 2019;54:182–193
    Article CAS PubMed Google Scholar
  33. Honda M, Shirasaki T, Terashima T, et al. Hepatitis B virus (HBV) core-related antigen during nucleos(t)ide analog therapy is related to intra-hepatic HBV replication and development of hepatocellular carcinoma. J Infect Dis. 2016;213:1096–1106
    Article CAS PubMed Google Scholar
  34. Chuaypen N, Posuwan N, Chittmittraprap S, et al. Predictive role of serum HBsAg and HBcrAg kinetics in patients with HBeAg-negative chronic hepatitis B receiving pegylated interferon-based therapy. Clin Microbiol Infect. 2018;24(306):e7-306 e13
    Google Scholar

Download references

Acknowledgements

There is no external funding to disclose for this study but authors from Kaohsiung Medical University would like to acknowledge research funding (KMU-TC108B06, KMU-TC108B07, KMU-DK109002 and KMU-TC109B05) from the Kaohsiung Medical University.

Funding

The authors have not disclosed any funding.

Author information

Authors and Affiliations

  1. Center for Liver Diseases and School of Medicine, E-Da Hospital/I-Shou University, Kaohsiung, Taiwan
    Yao-Chun Hsu
  2. Division of Gastroenterology, Fu-Jen Catholic University Hospital, New Taipei, Taiwan
    Yao-Chun Hsu
  3. Institute of Biomedical Informatics, National Yang-Ming University, New Taipei, Taiwan
    Yao-Chun Hsu
  4. Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan
    Yao-Chun Hsu
  5. Department of Internal Medicine, Hanyang University Hospital, Hanyang University College of Medicine, Seoul, South Korea
    Dae Won Jun, Hyunwoo Oh & Eilleen Yoon
  6. Center for Digestive Medicine, China Medical University Hospital, Taichung, Taiwan
    Cheng-Yuan Peng & Chia-Hsin Lin
  7. Hepatobiliary Division, Department of Internal Medicine and Hepatitis Center, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
    Ming-Lun Yeh, Pei-Chien Tsai, Chung-Feng Huang, Jee Fu Huang, Chia-Yen Dai, Wan-Long Chuang & Ming-Lung Yu
  8. San Jose Gastroenterology, San Jose, CA, USA
    Huy Trinh & Lindsey Trinh
  9. Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China
    Grace Lai-Hung Wong & Vincent Wai-Sun Wong
  10. Department of Internal Medicine, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, Anyang, South Korea
    Sung Eun Kim
  11. Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
    Chien-Hung Chen
  12. Department of Internal Medicine, Sanggye Paik Hospital, Inje University College of Medicine, Seoul, South Korea
    Eilleen Yoon
  13. Department of Internal Medicine, Nowon Eulji Medical Center, Eulji University College of Medicine, Seoul, South Korea
    Sang Bong Ahn
  14. Division of Gastroenterology and Hepatology, National University Hospital, Singapore, Singapore
    Daniel Huang & Seng Gee Lim
  15. Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
    Daniel Huang & Seng Gee Lim
  16. Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, South Korea
    Yong Kyun Cho
  17. Department of Internal Medicine, Hanyang University Guri Hospital, Hanyang University College of Medicine, Guri, South Korea
    Jae Yoon Jeong
  18. Department of Internal Medicine, Soonchunhyang University Hospital, Soonchunhyang University College of Medicine, Seoul, South Korea
    Soung Won Jeong
  19. Department of Internal Medicine, Hallym University Kangdong Sacred Heart Hospital, Hallym University College of Medicine, Seoul, South Korea
    Hyoung Su Kim
  20. Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
    Qing Xie
  21. Department of Infection Disease, The Third Hospital of Kumming City, Kumming, China
    Li Liu
  22. Liver Unit, Department of Internal Medicine, Hospital Universitari Valle d’Hebron, Vall d’Hebron Barcelona Hospital Campus, Universitat Autònoma de Barcelona, Barcelona, Spain
    Mar Riveiro-Barciela, Elena Vargas Accarino & Maria Buti
  23. Department of Gastroenterology, Ogaki Municipal Hospital, Ogaki, Japan
    Hidenori Toyoda & Satoshi Yasuda
  24. Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka, Japan
    Masaru Enomoto & Ritsuzo Kozuka
  25. Institutul Clinic Fundeni‐Gastroenterologie si Hepatologie, Bucharest, Romania
    Carmen Preda & Doina Istratescu
  26. Hepatology and Department of Research, Hospital Italiano De Buenos Aires, Buenos Aires, Argentina
    Sebastián Marciano & Adrian Gadano
  27. Department of Medicine, Stanford University Medical Center, Palo Alto, CA, USA
    Joseph Hoang, Ramsey Cheung & Mindie H. Nguyen
  28. Department of Gastroenterology, Good Gang-An Hospital, Busan, South Korea
    Dong-Hyun Lee
  29. Institute of Statistical Science, Academia Sinica, Taipei, Taiwan
    Jia-Ying Su & Yen-Tsung Huang
  30. Department of Medicine, The University of Hong Kong, Hong Kong SAR, China
    Man-Fung Yuen
  31. Department of Epidemiology and Population Health, Stanford University Medical Center, Palo Alto, CA, USA
    Mindie H. Nguyen
  32. Division of Gastroenterology and Hepatology, Stanford University Medical Center, Palo Alto, CA, USA
    Mindie H. Nguyen
  33. CIBERehd, Instituto Carlos III, Madrid, Spain
    Mar Riveiro-Barciela
  34. School of Medicine and Hepatitis Research Center, College of Medicine, and Center for Liquid Biopsy and Cohort Research, Kaohsiung Medical University, Kaohsiung, Taiwan
    Ming-Lun Yeh

Authors

  1. Yao-Chun Hsu
  2. Dae Won Jun
  3. Cheng-Yuan Peng
  4. Ming-Lun Yeh
  5. Huy Trinh
  6. Grace Lai-Hung Wong
  7. Sung Eun Kim
  8. Chien-Hung Chen
  9. Hyunwoo Oh
  10. Chia-Hsin Lin
  11. Lindsey Trinh
  12. Vincent Wai-Sun Wong
  13. Eilleen Yoon
  14. Sang Bong Ahn
  15. Daniel Huang
  16. Yong Kyun Cho
  17. Jae Yoon Jeong
  18. Soung Won Jeong
  19. Hyoung Su Kim
  20. Qing Xie
  21. Li Liu
  22. Mar Riveiro-Barciela
  23. Pei-Chien Tsai
  24. Elena Vargas Accarino
  25. Hidenori Toyoda
  26. Masaru Enomoto
  27. Carmen Preda
  28. Sebastián Marciano
  29. Joseph Hoang
  30. Chung-Feng Huang
  31. Ritsuzo Kozuka
  32. Satoshi Yasuda
  33. Doina Istratescu
  34. Dong-Hyun Lee
  35. Jia-Ying Su
  36. Yen-Tsung Huang
  37. Jee Fu Huang
  38. Chia-Yen Dai
  39. Wan-Long Chuang
  40. Man-Fung Yuen
  41. Adrian Gadano
  42. Ramsey Cheung
  43. Seng Gee Lim
  44. Maria Buti
  45. Ming-Lung Yu
  46. Mindie H. Nguyen

Contributions

Concept: MHN. Design: Y-CH, MHN. Administrative support and study supervision: MN. Data collection and/or data interpretation: all authors. Data analysis: Y-CH, J-YS, Y-TH, MHN. Manuscript drafting: Y-CH, MHN. Manuscript edition and final approval: all authors.

Corresponding author

Correspondence toMindie H. Nguyen.

Ethics declarations

Conflict of interest

Yao-Chun Hsu has received research support from Gilead Sciences and has served as an advisory board member or consultant for Gilead Sciences, and has served as a speaker for Abbvie, Bristol-Myers Squibb, Gilead Sciences, Merck Sharp & Dohme, and Novartis. Grace Lai-Hung Wong has received research funding from Gilead Sciences and has served as an advisory board member or consultant for Gilead Sciences and Janssen, and has served as a speaker for Abbott, Abbvie, Bristol-Myers Squibb, Echosens, Furui, Gilead Sciences, Janssen and Roche. Cheng-Yuan Peng has served as an advisory board member or consultant for Abbvie, Bristol-Myers Squibb, Gilead Sciences, and Roche. Sebastian Marciano has received research or educational support from, Gilead Sciences, Bristol-Myers and Abbvie. Adrián Gadano has received research or educational support from, Gilead Sciences, Bristol-Myers and Abbvie. Hidenori Toyoda has served as a speaker for Gilead, AbbVie, Bayer, Eisai, Terumo, and Otsuka Pharmaceuticals. Seng Gee Lim has received educational or research funding from Abbott, Merck Sharpe and Dohme, Gilead Sciences, has served as an advisory board member for Gilead Sciences, Merck Sharpe and Dohme, Abbvie, and Abbott, and has served as a speaker for Gilead Sciences, Abbott, Merck Sharpe and Dohme, Roche. Mar Riveiro-Barciela has received research support from Gilead and has served as a speaker for Grifols. Dong Hyun Lee has received research support from Gilead Sciences Korea, Korea Pharma, and Jassen Korea. Jee Fu Huang has served as an advisory board member or consultant for Gilead Sciences and Abbvie, and has served as a speaker for Gilead Sciences, Abbvie, Bristol-Myers-Squibb, Merck Sharp & Dohme, Roche, and Sysmex. Chia-Yen Dai has served as an advisory board member or consultant for Abbvie and Gilead Sciences, and has served as a speaker for Abbvie, Bristol-Myers Squibb, Gilead Sciences, and Merck Sharp & Dohme. Wan-Long Chuang has served as a consultant for Abbvie, Bristol-Myers Squibb, Gilead Sciences, and Merck Sharp & Dohme, PharmaEssentia, and has served as a speaker for Abbvie, Bristol-Myers Squibb, Gilead Sciences, and Merck Sharp & Dohme, PharmaEssentia. Man-Fung Yuen has served as a consultant for AbbVie, Arbutus Biopharma, Assembly Biosciences, Bristol Myer Squibb, Dicerna Pharmaceuticals, GlaxoSmithKline, Gilead Sciences, Janssen, Merck Sharp and Dohme, Clear B Therapeutics, Springbank Pharmaceutical. Vincent Wai-Sun Wong has received research support from Gilead Sciences and has served as an advisory board member or consultant for 3 V-BIO, AbbVie, Allergan, Boehringer Ingelheim, Echosens, Gilead Sciences, Hanmi Pharmaceutical, Intercept, Merck, Novartis, Novo Nordisk, Perspectum Diagnostics, Pfizer, ProSciento, Sagimet Biosciences, TARGET PharmaSolutions, and Terns, and has served as a speaker for AbbVie, Bristol-Myers Squibb, Echosens, and Gilead Sciences. Maria Buti has received research support from Abbvie and Gilead Sciences, and has served as an advisory board member or consultant for Abbvie, Arbutus, Gilead, Janssen and Spring Bank. Ming-Lung Yu has received research grant from Abbott, BMS, Gilead and Merck and has served as a consultant for Abbvie, Abbott, Ascletis, BMS, Gilead, Merck and Roche, and a speaker of Abbvie, Abbott, BMS, Gilead, Merck, and IPSEN. Mindie H. Nguyen has received research support from Pfizer, Gilead Sciences, Enanta, Vir Biotech, Glycotests, B. K. Kee Foundation and the National Cancer Institute and has served as an advisory board member or consultant for Gilead, Intercept, Novartis, Eisai, Bayer, Exact Science, Laboratory of Advanced Medicine, Sprin Bank, and Janssen. Conduction of this study conformed to the ethics principles of the Declaration of Helsinki in 1975, as revised in 2008, and was approved by the Institutional Review Board of Stanford University (protocol number 13927) as well as at each site.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Rights and permissions

Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Cite this article

Hsu, YC., Jun, D.W., Peng, CY. et al. Effectiveness of entecavir vs tenofovir disoproxil fumarate for functional cure of chronic hepatitis B in an international cohort.Hepatol Int 16, 1297–1307 (2022). https://doi.org/10.1007/s12072-022-10411-x

Download citation

Keywords