Long- term efficacy and safety of tenofovir alafenamide, tenofovir disoproxil fumarate, and entecavir in treating hepatitis B virus-related acute-on-chronic liver failure: A 144-week data analysis

Abstract

Background and aims: Antiviral therapy is essential for hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF). No data are available on the long-term prognosis or safety of tenofovir alafenamide (TAF), tenofovir disoproxil fumarate (TDF), or entecavir (ETV) in treating HBV-ACLF globally. This study was conducted to investigate the long-term efficacy and safety of the three nucleos(t)ide analogs in the treatment of HBV-ACLF.

Methods: In this prospective, real-world cohort study, patients with HBV-ACLF were assigned to the TAF, TDF, and ETV groups. A total of 199 patients completed the 144-week follow-up. After propensity score matching (PSM), 44 patients remained in each group for further analysis of survival status, incidence of hepatocellular carcinoma (HCC), virological response, and liver and renal function indicators.

Results: In the original cohort, HCC developed in one patient in each group. No serious drug-related adverse events were observed. In the PSM cohort, the 144-week survival rates were 56.82%, 75.00%, and 59.09% in the TAF, TDF, and ETV groups, respectively (P = 0.118). When stratified into noncirrhosis and cirrhosis subgroups at baseline, the survival rate of the ETV group was slightly lower than that of the TAF and TDF group in noncirrhosis patients (P = 0.338), and the survival rate of the TAF group was slightly lower than that of the TDF and ETV group in cirrhosis patients (P = 0.052), but the differences were not statistically significant. The long-term overall survival rates in the TAF, TDF, and ETV groups were comparable. After 144 weeks, no significant difference in the virological response rate or liver or renal function indicators was found among the three groups, except for the level of aspartate aminotransferase, which was significantly higher in the TDF group than in the ETV group at week 144 (P = 0.001).

Conclusions: There were no significant differences in the survival rate, incidence of HCC, efficacy or safety associated with the use of these three nucleos(t)ide analogs in treating HBV-ACLF.

Keywords

Tenofovir alafenamide (TAF) / Tenofovir disoproxil fumarate (TDF) / Entecavir (ETV) / Hepatitis B virus (HBV) / Acute-on-chronic liver failure (ACLF)

Authors’ contributions

Yeqiong Zhang, Wenxiong Xu, and Zhexuan Deng: contributed equally to this work. Yeqiong Zhang: Writing e review & editing, Writing e original draft, Formal analysis, Data curation. Wenxiong Xu: Writing e review & editing, Writing e original draft, Formal analysis, Data curation, Conceptualization. Zhexuan Deng: Writing e review & editing, Writing e original draft, Formal analysis, Data curation. Lu Wang: Writing e review & editing, Data curation. Xingrong Zheng: Writing e review & editing, Data curation. Xiang Zhu: Writing e review & editing, Data curation. Xuejun Li: Writing e review & editing, Data curation. Jianguo Li: Writing e review & editing, Data curation. Xin Shu: Writing e review & editing, Data curation. Jing Lai: Writing e review & editing, Data curation. Liang Peng: Writing e review & editing, Supervision, Project adminis-tration, Funding acquisition, Data curation, Conceptualization. Chan Xie: Writing e review & editing, Supervision, Funding acquisition, Conceptualization. All authors reviewed the manu-script and provided comments, and they have all read and approved the final version.

Data availability statement

Data are contained within the article or supplementary mate-rial. The data in the current study are available from the corre-sponding author upon request. The study protocol, standard operating procedures, and patient information are also available upon request.

Declaration of competing interest

The authors declare that there is no conflicts of interest.

Acknowledgements

This study was supported by grants from Key-Area Research and Development Program of Guangdong Province (No. 2020B0101130015), Guangdong Medical Science and Technology Research Fund (No. A2021304), the Natural Science Foundation of China (No. 82070611), Guangzhou Science and Technology Plan Projects (No.2023B03J1287), Guangzhou Science and Technology Program Key Projects (No.2023B01J1007), Sun Yat-Sen University Clinical Research 5010 Program (No.2020007), and the Five-Year Plan of Third Affiliated Hospital of Sun Yat-sen University (No.2023W106). Clinical trial number: ClinicalTrials.gov ID: NCT03920618.

Appendix A. Supplementary data

Supplementary data to this article can be found online at https://doi.org/10.1016/j.livres.2024.10.001.

References

[1] Bajaj JS, O’Leary JG, Lai JC, et al. Acute-on-chronic liver failure clinical guide-lines. Am J Gastroenterol. 2022;117:225-252. https://doi.org/10.14309/ajg.0000000000001595.

[2] World Health Organization.Global progress report on HIV, viral hepatitis and sexually transmitted infections, 2021. Accountability for the global health sector strategies 2016-2021: actions for impact. https://www.who.int/publications/i/item/9789240027077. Accessed February 24,2024.

[3] Mezzano G, Juanola A, Cardenas A, et al. Global burden of disease: acute-on-chronic liver failure, a systematic review and meta-analysis. Gut. 2022;71: 148-155. https://doi.org/10.1136/gutjnl-2020-322161.

[4] Cao Z, Liu Y, Cai M, et al. The use of NACSELD and EASL-CLIF classification systems of ACLF in the prediction of prognosis in hospitalized patients with cirrhosis. Am J Gastroenterol. 2020;115:2026-2035. https://doi.org/10.14309/ajg.0000000000000771.

[5] Xiao LL, Wu XX, Chen JJ, et al. Progress in hepatitis B virus-related acute-on-chronic liver failure treatment in China: a large, multicenter, retrospective cohort study using a propensity score matching analysis. Hepatobiliary Pancreat Dis Int. 2021;20:535-541. https://doi.org/10.1016/j.hbpd.2021.05.010.

[6] Abdelhamed W, El-Kassas M. Hepatitis B virus as a risk factor for hepatocellular carcinoma: there is still much work to do. Liver Res. 2024;8:83-90. https://doi.org/10.1016/j.livres.2024.05.004.

[7] 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 acute-on-chronic liver failure. J Hepatol. 2023;79: 461-491. https://doi.org/10.1016/j.jhep.2023.04.021.

[8] Lv H, Zheng H, Liu J, et al. Expert consensus on liver transplantation periop-erative evaluation and rehabilitation for acute-on-chronic liver failure. Liver Res. 2022;6:121-129. https://doi.org/10.1016/j.livres.2022.08.002.

[9] Sarin SK, Choudhury A, Sharma MK, et al. Acute-on-chronic liver failure: consensus recommendations of the Asian Pacific association for the study of the liver (APASL): an update. Hepatol Int. 2019;13:353-390. https://doi.org/10.1007/s12072-019-09946-3.

[10] Ma K, Guo W, Han M, et al. Entecavir treatment prevents disease progression in hepatitis B virus-related acute-on-chronic liver failure: establishment of a novel logistical regression model. Hepatol Int. 2012;6:735-743. https://doi.org/10.1007/s12072-012-9344-9.

[11] Lin B, Pan CQ, Xie D, et al. Entecavir improves the outcome of acute-on-chronic liver failure due to the acute exacerbation of chronic hepatitis B. Hepatol Int. 2013;7:460-467. https://doi.org/10.1007/s12072-012-9415-y.

[12] Wan YM, Li YH, Xu ZY, et al. Tenofovir versus entecavir for the treatment of acute-on-chronic liver failure due to reactivation of chronic hepatitis B with genotypes B and C. J Clin Gastroenterol. 2019;53:e171ee177. https://doi.org/10.1097/MCG.0000000000001038.

[13] Hung CH, Hu TH, Lu SN, et al. Tenofovir versus entecavir in treatment of chronic hepatitis B virus with severe acute exacerbation. Antimicrob Agents Chemother. 2015;59:3168-3173. https://doi.org/10.1128/AAC.00261-15.

[14] Choi J, Kim HJ, Lee J, Cho S, Ko MJ, Lim YS. 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. https://doi.org/10.1001/jamaoncol.2018.4070.

[15] Yip TC, Wong VW, Chan HL, Tse YK, Lui GC, Wong GL. Tenofovir is associated with lower risk of hepatocellular carcinoma than entecavir in patients with chronic HBV infection in China. Gastroenterology. 2020;158:215e 225 (e6). https://doi.org/10.1053/j.gastro.2019.09.025.

[16] Zhang Y, Xu W, Zhu X, et al. The 48-week safety and therapeutic effects of tenofovir alafenamide in HBV-related acute-on-chronic liver failure: apro-spective cohort study. J Viral Hepat. 2021;28:592-600. https://doi.org/10.1111/jvh.13468.

[17] Cai X, Chong Y, Gan W, Li X. Progress on clinical prognosis assessment in liver failure. Liver Res. 2023;7:101-107. https://doi.org/10.1016/j.livres.2023.05.004.

[18] Li J, Liang X, You S, et al. Development and validation of a new prognostic score for hepatitis B virus-related acute-on-chronic liver failure. J Hepatol. 2021;75: 1104-1115. https://doi.org/10.1016/j.jhep.2021.05.026.

[19] Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med. 1999;130:461-470. https://doi.org/10.7326/0003-4819-130-6-199903160-00002.

[20] Li J, Hu C, Chen Y, et al. Short-term and long-term safety and efficacy of tenofovir alafenamide, tenofovir disoproxil fumarate and entecavir treatment of acute-on-chronic liver failure associated with hepatitis B. BMC Infect Dis. 2021;21:567. https://doi.org/10.1186/s12879-021-06237-x.

[21] Peng W, Gu H, Cheng D, et al. Tenofovir alafenamide versus entecavir for treating hepatitis B virus-related acute-on-chronic liver failure: real-world study. Front Microbiol. 2023;14:1185492. https://doi.org/10.3389/fmicb.2023.1185492.

[22] Lee SW, Kwon JH, Lee HL, et al. Comparison of tenofovir and entecavir on the risk of hepatocellular carcinoma and mortality in treatment-naïve patients with chronic hepatitis B in Korea: a large-scale, propensity score analysis. Gut. 2020;69:1301-1308. https://doi.org/10.1136/gutjnl-2019-318947.

[23] Simonetto DA, Gines P, Kamath PS. Hepatorenal syndrome: pathophysiology, diagnosis, and management. BMJ. 2020;370:m2687. https://doi.org/10.1136/bmj.m2687.

[24] Liu A, Le A, Zhang J, et al. Increasing co-morbidities in chronic hepatitis B pa-tients: experience in primary care and referral practices during 2000-2015. Clin Transl Gastroenterol. 2018;9:141. https://doi.org/10.1038/s41424-018-0007-6.

[25] Nguyen MH, Lim JK, Burak Ozbay A, et al. Advancing age and comorbidity in a US insured population-based cohort of patients with chronic hepatitis B. Hepatology. 2019;69:959-973. https://doi.org/10.1002/hep.30246.

[26] Wong GL, Seto WK, Wong VW, Yuen MF, Chan HL. Review article: long-term safety of oral anti-viral treatment for chronic hepatitis B. Aliment Pharmacol Ther. 2018;47:730-737. https://doi.org/10.1111/apt.14497.

[27] Jung CY, Kim HW, Ahn SH, Kim SU, Kim BS. Tenofovir is associated with higher risk of kidney function decline than entecavir in patients with chronic hepatitis B. Clin Gastroenterol Hepatol. 2022; 20:956e958(e2). https://doi.org/10.1016/j.cgh.2021.05.032.

[28] Buti M, Gane E, Seto WK, et al. Tenofovir alafenamide versus tenofovir dis-oproxil 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. https://doi.org/10.1016/S2468-1253(16)30107-8.

[29] Chan HL, Fung S, Seto WK, et al. Tenofovir alafenamide versus tenofovir dis-oproxil 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;1:185-195. https://doi.org/10.1016/S2468-1253(16)30024-3.

[30] Agarwal K, Brunetto M, Seto WK, et al. 96 weeks treatment of tenofovir ala-fenamide vs. tenofovir disoproxil fumarate for hepatitis B virus infection. J Hepatol. 2018;68:672-681. https://doi.org/10.1016/j.jhep.2017.11.039.

[31] Jung CY, Kim HW, Ahn SH, Kim SU, Kim BS. Higher. risk of kidney function decline with entecavir than tenofovir alafenamide in patients with chronic hepatitis B. Liver Int. 2022;42:1017-1026. https://doi.org/10.1111/liv.15208.