Impact of tenofovir vs. entecavir treatment on progression of chronic hepatitis B: A nationwide cohort study

Background & Aims: Conflicting evidence exists on hepatocellular carcinoma (HCC) risk in patients with chronic hepatitis B (CHB) receiving tenofovir vs. entecavir. We assessed the impacts of the two drugs on the clinical trajectory of CHB at a population level. Methods: We conducted a retrospective nationwide cohort study using data from Taiwan's National Health Insurance Research Database, including 55,885 patients with CHB who were treatment-naïve aged 30–75 years receiving tenofovir (n = 17,137) or entecavir (n = 38,748) monotherapy for ≥3 months between November 2009 and December 2020, and followed until December 2022. Multi-state modeling was applied to evaluate treatment impacts on disease progression trajectory, comprising CHB (with/without compensated cirrhosis), hepatic decompensation, HCC, death, and a switching treatment state. Propensity score matching/weighting and subgroup analyses were used to confirm the robustness of findings. Results: During a median 6.3 years of follow-up, 1,524 patients developed hepatic decompensation, 3,591 developed HCC, and 3,436 died. Tenofovir compared with entecavir was associated with lower risk of CHB progression, with adjusted-hazard ratios (95% CIs) of 0.84 (0.75–0.95) and 0.76 (0.70–0.83), respectively, for transitions to hepatic decompensation and HCC from baseline, and 0.65 (0.48–0.89) for HCC risk from decompensation. Propensity score matching/weighting analyses yielded similar results. Among patients without experiencing decompensation, a significantly lower HCC risk with tenofovir was observed across multiple subgroups, including age, sex, diabetes, and cirrhosis, and by sensitivity analyses. The 5-year risk of major adverse liver-related outcomes (decompensation, HCC, and liver-related deaths) was 5.5% and 7.5% for tenofovir and entecavir, respectively (adjusted-hazard ratio 0.80; 95% CI 0.74–0.85). Conclusions: Using multi-state modeling on the temporal evolution of CHB severity, long-term tenofovir treatment compared with entecavir was associated with a lower risk of severe liver outcomes. Impact and implications: The comparative effectiveness of tenofovir vs. entecavir treatment in preventing hepatocellular carcinoma (HCC) for patients with chronic hepatitis B (CHB) remains controversial. Using a nationwide cohort study involving 55,885 patients to investigate CHB as a multi-state disease over 13 years, we show that tenofovir (vs. entecavir) treatment is associated with lower risks of HCC, hepatic decompensation, and a composite endpoint of adverse liver-related outcomes (hepatic decompensation, HCC, and liver-related deaths), regardless of age, sex, diabetes, alcohol-related disorders, and cirrhosis state. Our results provide new evidence justifying the use of tenofovir or entecavir to prevent the evolution of CHB severity.