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Effectiveness of tenofovir alafenamide for chronic hepatitis B patients with a poor response to the previously used nucleos(t)ide analogs

Abstract

Background

Few studies have demonstrated the potency of tenofovir alafenamide (TAF) in patients with poor response to other nucleos(t)ide analogs (NAs).

Methods

We conducted a retrospective study comprising consecutive 40 patients exhibiting a poor response to other NAs, who subsequently received TAF-containing regimens. The primary outcome was the prevalence of virological response (VR) at each time and maintained virological response (MVR) under TAF-containing regimens until week 96.

Results

In the entire cohort, the prevalence of MVR was 71.1% (27/38). Further, poor tenofovir disoproxil fumarate (TDF) response was significantly associated with a lower prevalence of MVR (p = 0.014). In TDF-naïve patients, the prevalence of MVR was 92.3% (12/13) and 62.5% (5/8) in patients with lamivudine resistance (LAM-r) and entecavir resistance (ETV-r), respectively. Further, viral load and HBeAg status at baseline were associated with a lower prevalence of MVR (p = 0.013). Among the seven patients with prior TDF exposure, 2 patients achieved MVR. Among them, one patient with development of viral breakthrough during TDF/LAM achieved MVR after switching to TAF/ETV. In contrast, one of the five patients with non-MVR had three substitutions (rtS106C, rtD134N/S, and rtL269I) of quadruple mutations in addition to ETV-r. Other patients with rtA181T + rtN236T also could not achieve MVR.

Conclusion

TAF exhibited high antiviral potency in patients with LAM-r and ETV-r. However, TAF potency was associated with previous TDF response, viral load, and HBeAg status at baseline. Additionally, a quadruple mutation may impact tenofovir resistance; however, further studies are needed to verify this.

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References

  1. 1.

    Trépo C, Chan HLY, Lok A. Hepatitis B virus infection. Lancet. 2014;384(9959):2053–63.

    Article  Google Scholar 

  2. 2.

    Liaw YF, Sung JJY, Chow WC, et al. Lamivudine for patients with chronic hepatitis B and advanced liver disease. N Engl J Med. 2004;351:1521–31.

    CAS  Article  Google Scholar 

  3. 3.

    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.

    CAS  Article  Google Scholar 

  4. 4.

    Wu CY, Lin JT, Ho HJ, et al. Association of nucleos(t)ide analogue therapy with reduced risk of hepatocellular carcinoma in patients with chronic hepatitis B—a nationwide cohort study. Gastroenterology. 2014;147:143–151.e5.

    CAS  Article  Google Scholar 

  5. 5.

    Zoulim F, Locarnini S. Hepatitis B virus resistance to nucleos(t)ide analogues. Gastroenterology. 2009;137:1593–608.e1.

    CAS  Article  Google Scholar 

  6. 6.

    Papatheodoridis GV, Dimou E, Dimakopoulos K, et al. Outcome of hepatitis B e antigen-negative chronic hepatitis B on long-term nucleos(t)ide analog therapy starting with lamivudine. Hepatology. 2005;42:121–9.

    CAS  Article  Google Scholar 

  7. 7.

    Tenney DJ, Rose RE, Baldick CJ, et al. Two-year assessment of entecavir resistance in lamivudine-refractory hepatitis B virus patients reveals different clinical outcomes depending on the resistance substitutions present. Antimicrob Agents Chemother. 2007;51:902–11.

    CAS  Article  Google Scholar 

  8. 8.

    Baldick CJ, Tenney DJ, Mazzucco CE, et al. Comprehensive evaluation of hepatitis B virus reverse transcriptase substitutions associated with entecavir resistance. Hepatology. 2008;47:1473–82.

    CAS  Article  Google Scholar 

  9. 9.

    Lim YS, Byun KS, Yoo BC, et al. Tenofovir monotherapy versus tenofovir and entecavir combination therapy in patients with entecavir-resistant chronic hepatitis B with multiple drug failure: results of a randomised trial. Gut. 2016;65:852–60.

    CAS  Article  Google Scholar 

  10. 10.

    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.

    CAS  Article  Google Scholar 

  11. 11.

    Fung S, Kwan P, Fabri M, et al. Randomized comparison of tenofovir disoproxil fumarate vs emtricitabine and tenofovir disoproxil fumarate in patients with lamivudine-resistant chronic hepatitis B. Gastroenterology. 2014;146:980–8.

    CAS  Article  Google Scholar 

  12. 12.

    Patterson SJ, George J, Strasser SI, et al. Tenofovir disoproxil fumarate rescue therapy following failure of both lamivudine and adefovir dipivoxil in chronic hepatitis B. Gut. 2011;60:247–54.

    CAS  Article  Google Scholar 

  13. 13.

    Chung GE, Cho EJ, Lee JH, et al. Tenofovir has inferior efficacy in adefovir-experienced chronic hepatitis B patients compared to nucleos(t)ide-naïve patients. Clin Mol Hepatol. 2017;23:66–73.

    Article  Google Scholar 

  14. 14.

    Park ES, Lee AR, Kim DH, et al. Identification of a quadruple mutation that confers tenofovir resistance in chronic hepatitis B patients. J Hepatol. 2019;70:1093–102.

    CAS  Article  Google Scholar 

  15. 15.

    Liu Y, Chang S, Martin R, et al. Characterization of hepatitis B virus polymerase mutations A194T and CYEI and tenofovir disoproxil fumarate or tenofovir alafenamide resistance. J Viral Hepat. 2021;28:30–9.

    CAS  Article  Google Scholar 

  16. 16.

    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.

    Article  Google Scholar 

  17. 17.

    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.

    Article  Google Scholar 

  18. 18.

    Suzuki F, Kumada H, Nakamura H. Changes in viral loads of lamivudine-resistant mutants and evolution of HBV sequences during adefovir dipivoxil therapy. J Med Virol. 2006;78:1025–34.

    CAS  Article  Google Scholar 

  19. 19.

    Suzuki F, Sezaki H, Hosaka T, et al. Virologic analysis of tenofovir resistance in a patient with chronic hepatitis B experiencing viral breakthrough during combination treatment with tenofovir disoproxil fumarate and entecavir. Hepatol Res. 2021;51:503–8.

    CAS  Article  Google Scholar 

  20. 20.

    Lampertico P, Buti M, Fung S, et al. Switching from tenofovir disoproxil fumarate to tenofovir alafenamide in virologically suppressed patients with chronic hepatitis B: a randomised, double-blind, phase 3, multicentre non-inferiority study. Lancet Gastroenterol Hepatol. 2020;5:441–53.

    Article  Google Scholar 

  21. 21.

    Agarwal K, Brunetto M, Seto WK, et al. 96 Weeks treatment of tenofovir alafenamide vs. tenofovir disoproxil fumarate for hepatitis B virus infection. J Hepatol. 2018;68:672–81.

    CAS  Article  Google Scholar 

  22. 22.

    Ogawa E, Nomura H, Nakamuta M, et al. Tenofovir alafenamide after switching from entecavir or nucleos(t)ide combination therapy for patients with chronic hepatitis B. Liver Int. 2020;40:1578–89.

    CAS  Article  Google Scholar 

  23. 23.

    Qi X, Xiong S, Yang H, et al. In vitro susceptibility of adefovir-associated hepatitis B virus polymerase mutations to other antiviral agents. Antivir Ther. 2007;12:355–62.

    CAS  PubMed  Google Scholar 

  24. 24.

    Lim YS, Yoo BC, Byun KS, et al. Tenofovir monotherapy versus tenofovir and entecavir combination therapy in adefovir-resistant chronic hepatitis B patients with multiple drug failure: results of a randomised trial. Gut. 2016;65:1042–51.

    CAS  Article  Google Scholar 

  25. 25.

    van Bömmel F, de Man RA, Wedemeyer H, et al. Long-term efficacy of tenofovir monotherapy for hepatitis B virus-monoinfected patients after failure of nucleoside/nucleotide analogues. Hepatology. 2010;51:73–80.

    Article  Google Scholar 

  26. 26.

    Lee S, Ahn SH, Jung KS, et al. Tenofovir versus tenofovir plus entecavir for chronic hepatitis B with lamivudine resistance and entecavir resistance. J Viral Hepat. 2017;24:141–7.

    CAS  Article  Google Scholar 

  27. 27.

    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.

    Article  Google Scholar 

  28. 28.

    Lim YS, Lee YS, Gwak GY, et al. Monotherapy with tenofovir disoproxil fumarate for multiple drug-resistant chronic hepatitis B: 3-year trial. Hepatology. 2017;66:772–83.

    CAS  Article  Google Scholar 

  29. 29.

    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.

    Article  Google Scholar 

  30. 30.

    European Association for the Study of the Liver. Electronic address: easloffice@easloffice.eu, European Association for the Study of the Liver. EASL. Clinical Practice Guidelines on the management of hepatitis B virus infection. J Hepatol. 2017;2017(67):370–98.

    Google Scholar 

  31. 31.

    Drafting Committee for Hepatitis Management. Japan Society of Hepatology Guidelines for the management of hepatitis B virus infection: 2019 update. Hepatol Res. 2020;50:892–923.

    Article  Google Scholar 

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Acknowledgements

Hiromitsu Kumada has served as a speaker for Gilead Sciences, AbbVie Inc., MSD K.K., Eisai Co., Ltd, and Dainippon Sumitomo Pharma. Masahiro Kobayashi served as a speaker for Eisai Co., Ltd. Norio Akuta served as a speaker for the Gilead Sciences, AbbVie Inc. This study was supported in part by the Program for Basic and Clinical Research on Hepatitis, Japan Agency for Medical Research and Development (AMED) (Grant number: JP21fk0210084), Okinaka Memorial Institute for Medical Research, and Taiju Life Social Welfare Foundation.

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Authors

Contributions

DY: Study concept and design, data collection, data analysis and interpretation, and drafting of the manuscript. TH: Study concept and design, data collection, data analysis and interpretation, and critical review of the manuscript. FS: Data collection, data analysis and interpretation, and review of the manuscript. SF: Data collection and review of the manuscript. YK: Data collection and review of the manuscript. HS: Data collection and review of the manuscript. NA: Data collection and review of the manuscript. MK: Data collection and review of the manuscript. YS: Data collection and review of the manuscript. SS: Data collection and review of the manuscript. YA: Data collection and review of the manuscript. KI: Data collection and review of the manuscript. MK: Assistance with data collection, sequencing drug resistances, and review of the manuscript. HK: Study concept and design, data collection, data analysis and interpretation, and critical review of the manuscript. All authors had access to the data and participated in the writing of this manuscript.

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Correspondence to Tetsuya Hosaka.

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Yamashige, D., Hosaka, T., Suzuki, F. et al. Effectiveness of tenofovir alafenamide for chronic hepatitis B patients with a poor response to the previously used nucleos(t)ide analogs. J Gastroenterol 56, 1008–1021 (2021). https://doi.org/10.1007/s00535-021-01826-8

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Keywords

  • Tenofovir alafenamide
  • Tenofovir disoproxil fumarate
  • Entecavir
  • Drug resistance