Wu Wan-Jung, Liu Wen-Jie, Lin Chih-Lin, Liu Chun-Jen, Huang Yi-Wen, Hu Jui-Ting, Yu Ming-Whei
Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan.
Department of Gastroenterology, Ren-Ai Branch, Taipei City Hospital, Taipei, Taiwan.
JHEP Rep. 2025 Jul 5;7(10):101511. doi: 10.1016/j.jhepr.2025.101511. eCollection 2025 Oct.
BACKGROUND & AIMS: Conflicting evidence exists on hepatocellular carcinoma (HCC) risk in patients with chronic hepatitis B (CHB) receiving tenofovir entecavir. We assessed the impacts of the two drugs on the clinical trajectory of CHB at a population level.
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.
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).
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.
The comparative effectiveness of tenofovir 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 ( 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.
关于接受替诺福韦或恩替卡韦治疗的慢性乙型肝炎（CHB）患者患肝细胞癌（HCC）的风险，存在相互矛盾的证据。我们在人群层面评估了这两种药物对CHB临床病程的影响。
我们利用台湾国民健康保险研究数据库的数据进行了一项全国性回顾性队列研究，纳入55885例初治的30 - 75岁CHB患者，这些患者在2009年11月至2020年12月期间接受替诺福韦（n = 17137）或恩替卡韦（n = 38748）单药治疗≥3个月，并随访至2022年12月。采用多状态建模来评估治疗对疾病进展轨迹的影响，疾病进展轨迹包括CHB（有/无代偿期肝硬化）、肝失代偿、HCC、死亡以及换药治疗状态。采用倾向评分匹配/加权和亚组分析来确认研究结果的稳健性。
在中位6.3年的随访期间，1524例患者发生肝失代偿，3591例发生HCC，3436例死亡。与恩替卡韦相比，替诺福韦与CHB进展风险较低相关，从基线状态转变为肝失代偿和HCC的调整后风险比（95%置信区间）分别为0.84（0.75 - 0.95）和0.76（0.70 - 0.83），从失代偿状态发生HCC的风险比为0.65（0.48 - 0.89）。倾向评分匹配/加权分析得出了类似结果。在未发生失代偿的患者中，在包括年龄、性别、糖尿病和肝硬化等多个亚组以及敏感性分析中，均观察到替诺福韦组HCC风险显著较低。替诺福韦和恩替卡韦的5年主要肝脏相关不良结局（失代偿、HCC和肝脏相关死亡）风险分别为5.5%和7.5%（调整后风险比0.80；95%置信区间0.74 - 0.85）。
通过对CHB严重程度的时间演变进行多状态建模，与恩替卡韦相比，长期替诺福韦治疗与严重肝脏结局风险较低相关。
替诺福韦和恩替卡韦治疗在预防慢性乙型肝炎（CHB）患者肝细胞癌（HCC）方面的相对疗效仍存在争议。通过一项涉及55885例患者的全国性队列研究，对CHB作为一种多状态疾病进行了13年的研究，我们发现替诺福韦（与恩替卡韦相比）治疗与较低的HCC、肝失代偿以及肝脏相关不良结局（肝失代偿、HCC和肝脏相关死亡）复合终点风险相关，无论年龄、性别、糖尿病、酒精相关疾病和肝硬化状态如何。我们的结果为使用替诺福韦或恩替卡韦预防CHB严重程度的进展提供了新的证据。
