Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
Division of Gastroenterology and Hepatology, Department of Medicine, National University Hospital, Singapore.
JAMA Netw Open. 2022 Jun 1;5(6):e2219407. doi: 10.1001/jamanetworkopen.2022.19407.
Conventional meta-analyses with aggregated study-level data have yielded conflicting results for the comparative effectiveness of tenofovir disoproxil fumarate vs entecavir in reducing hepatocellular carcinoma (HCC) risk among patients with chronic hepatitis B virus. Within-study heterogeneity, between-study heterogeneity, and the inability of conventional meta-analyses to capture time-to-event data were associated with these results.
To perform a reconstructed individual patient data meta-analysis of high-quality propensity score-matched studies to provide robust estimates for comparative HCC risk between groups receiving tenofovir or entecavir.
Medline and Embase databases were searched from inception to October 6, 2021.
The initial search yielded 3435 articles. Fourteen studies that used propensity score matching to balance baseline characteristics were included in the final analysis.
The Preferred Reporting Items for Systematic Reviews and Meta-analyses guideline was followed. Individual patient data were reconstructed from Kaplan-Meier curves. Risk of HCC was evaluated using random-effects hazard ratios (HRs) via a shared-frailty model and a Cox proportional hazards model stratified by study group. Restricted mean survival time (RMST) analysis was conducted to account for varying estimated treatment effect across time.
The comparative risk of HCC with tenofovir vs entecavir treatment.
From analysis of 14 studes with 24 269 patients (10 534 receiving tenofovir and 13 735 receiving entecavir; mean age, 49.86 [95% CI, 48.35-51.36] years; 65.05% [95% CI, 58.60%-71.00%] men), tenofovir was associated with decreased HCC incidence compared with entecavir (stratified Cox HR, 0.85 [95% CI, 0.76-0.94] at 5 years; P = .002). However, there was no significant difference in subanalysis of clinical cohort studies (stratified Cox HR, 0.92 [95% CI, 0.80-1.06] at 5 years; P = .24). Among administrative database studies, proportionality was violated, and HRs could not be obtained via Cox proporational hazards-based models. The mean time to HCC development in RMST analysis was 2.8 (95% CI, 1.8-3.7) weeks longer (P < .001) for tenofovir vs entecavir at 5 years. The RMST analyses for other subgroups revealed either insignificant or minimal differences (<3 weeks) in the mean time to HCC at 5 years.
In this meta-analysis, there was no clinically meaningful difference in the risk of HCC between patients who received entecavir and patients who received tenofovir. There was no difference between tenofovir and entecavir among clinical cohort studies, whereas the mean time to HCC development was less than 3 weeks longer for patients who received tenofovir vs those who received entecavir at year 5 among administrative database studies. The choice between tenofovir or entecavir should be decided based on patient convenience and tolerability.
常规的汇总研究水平数据的荟萃分析对于替诺福韦酯富马酸二甲酯与恩替卡韦在降低慢性乙型肝炎病毒患者肝细胞癌 (HCC) 风险方面的比较疗效产生了相互矛盾的结果。 这些结果与研究内异质性、研究间异质性以及常规荟萃分析无法捕捉到时间事件数据有关。
对高质量倾向评分匹配研究进行个体化患者数据的再分析，为接受替诺福韦或恩替卡韦治疗的患者之间 HCC 风险的比较提供可靠的估计。
从建立到 2021 年 10 月 6 日，对 Medline 和 Embase 数据库进行了检索。
最初的搜索产生了 3435 篇文章。最终分析纳入了 14 项使用倾向评分匹配来平衡基线特征的研究。
遵循系统评价和荟萃分析的首选报告项目指南。从 Kaplan-Meier 曲线重建个体患者数据。使用共享脆弱性模型和按研究组分层的 Cox 比例风险模型通过随机效应风险比 (HR) 评估 HCC 风险。进行限制平均生存时间 (RMST) 分析以考虑随时间变化的估计治疗效果。
替诺福韦与恩替卡韦治疗相比 HCC 的相对风险。
从对 14 项研究的分析中，纳入了 24269 名患者（10534 名接受替诺福韦和 13735 名接受恩替卡韦；平均年龄 49.86 [95%CI，48.35-51.36] 岁；65.05% [95%CI，58.60%-71.00%] 为男性），与恩替卡韦相比，替诺福韦降低了 HCC 发生率（分层 Cox HR，5 年时为 0.85 [95%CI，0.76-0.94]；P = .002）。然而，在临床队列研究的亚组分析中没有显著差异（分层 Cox HR，5 年时为 0.92 [95%CI，0.80-1.06]；P = .24）。在行政数据库研究中，比例性受到侵犯，并且无法通过基于 Cox 比例风险的模型获得 HR。RMST 分析表明，替诺福韦与恩替卡韦相比，5 年内 HCC 发展的平均时间延长了 2.8（95%CI，1.8-3.7）周（P < .001）。其他亚组的 RMST 分析显示，5 年内 HCC 发病的平均时间差异不明显或最小（<3 周）。
在这项荟萃分析中，接受恩替卡韦和接受替诺福韦的患者 HCC 风险没有临床意义上的差异。在临床队列研究中，替诺福韦与恩替卡韦之间没有差异，而在行政数据库研究中，替诺福韦组与恩替卡韦组相比，患者在第 5 年时 HCC 发病的平均时间提前了不到 3 周。替诺福韦或恩替卡韦的选择应根据患者的便利性和耐受性来决定。
