Hepatocellular carcinoma risk in patients with chronic hepatitis B receiving tenofovir- vs. entecavir-based regimens: Individual patient data meta-analysis

Won Mook Choi, Terry Cheuk Fung Yip, Grace Lai Hung Wong*, W. Ray Kim, Leland J. Yee, Craig Brooks-Rooney, Tristan Curteis, Harriet Cant, Chien Hung Chen, Chi Yi Chen, Yi Hsiang Huang, Young Joo Jin, Dae Won Jun, Jin Wook Kim, Neung Hwa Park, Cheng Yuan Peng, Hyun Phil Shin, Jung Woo Shin, Yao Hsu Yang, Young Suk Lim*

*Corresponding author for this work

Research output: Contribution to journalJournal Article peer-review

18 Scopus citations


BACKGROUND & AIMS: The comparative risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB) receiving tenofovir disoproxil fumarate (TDF) vs. entecavir (ETV) remains controversial. In this individual patient data (IPD) meta-analysis, we aimed to compare HCC risk between the two drugs and identify subgroups who may benefit more from one treatment than the other.

METHODS: Published meta-analyses, electronic databases and congress proceedings were searched to identify eligible studies through January 2021. We compared HCC risk between the two drugs using a multivariable Cox proportional hazards model with anonymised IPD from treatment-naïve patients with CHB receiving TDF or ETV for ≥1 year. Treatment effect consistency was explored in propensity score matching (PSM), weighting (PSW) and subgroup analyses for age, sex, hepatitis B e-antigen (HBeAg) positivity, cirrhosis and diabetes status.

RESULTS: We included 11 studies from Korea, Taiwan and Hong Kong involving 42,939 patients receiving TDF (n = 6,979) or ETV (n = 35,960) monotherapy. Patients receiving TDF had significantly lower HCC risk (adjusted hazard ratio [HR] 0.77; 95% CI 0.61-0.98; p = 0.03). Lower HCC risk with TDF was consistently observed in PSM (HR 0.73; 95% CI 0.59-0.88; p <0.01) and PSW (HR 0.83; 95% CI 0.67-1.03; p = 0.10) analyses and in all subgroups, with statistical significance in the ≥50 years of age (HR 0.76; 95% CI 0.58-1.00; p <0.05), male (HR 0.74; 95% CI 0.58-0.96; p = 0.02), HBeAg-positive (HR 0.69; 95% CI 0.49-0.97; p = 0.03) and non-diabetic (HR 0.79; 95% CI 0.63-1.00; p <0.05) subgroups.

CONCLUSION: TDF was associated with significantly lower HCC risk than ETV in patients with CHB, particularly those with HBeAg positivity. Longer follow-up may be needed to better define incidence differences between the treatments in various subgroups.

IMPACT AND IMPLICATIONS: Previous aggregate data meta-analyses have reported inconsistent conclusions on the relative effectiveness of tenofovir disoproxil fumarate and entecavir in reducing hepatocellular carcinoma risk in patients with chronic hepatitis B (CHB). This individual patient data meta-analysis on 11 studies involving 42,939 patients from Korea, Taiwan and Hong Kong suggested that tenofovir disoproxil fumarate-treated patients have a significantly lower hepatocellular carcinoma risk than entecavir-treated patients, which was observed in all subgroups of clinical interest and by different analytical methodologies. These findings should be taken into account by healthcare providers when determining the optimal course of treatment for patients with CHB and may be considered in ensuring that treatment guidelines for CHB remain pertinent.

Original languageEnglish
Pages (from-to)534-542
Number of pages9
JournalJournal of Hepatology
Issue number3
StatePublished - 03 2023
Externally publishedYes

Bibliographical note

Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.


  • Chronic hepatitis B
  • entecavir
  • hepatocellular carcinoma
  • individual patient data
  • meta-analysis
  • tenofovir disoproxil fumarate
  • Carcinoma, Hepatocellular/etiology
  • Hepatitis B e Antigens
  • Humans
  • Middle Aged
  • Male
  • Treatment Outcome
  • Hepatitis B, Chronic/drug therapy
  • Liver Neoplasms/etiology
  • Antiviral Agents/therapeutic use
  • Female
  • Retrospective Studies
  • Tenofovir/therapeutic use


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