Division of Gastroenterology and Hepatology, E-Da Hospital, Kaohsiung, Taiwan; School of Medicine, College of Medicine, I-Shou University, Kaohsiung, Taiwan.
Division of Gastroenterology and Hepatology, E-Da Hospital, Kaohsiung, Taiwan; School of Medicine, College of Medicine, I-Shou University, Kaohsiung, Taiwan; Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan; Division of Gastroenterology, Fu Jen Catholic University Hospital, New Taipei, Taiwan.
Lancet Gastroenterol Hepatol. 2020 Dec;5(12):1039-1052. doi: 10.1016/S2468-1253(20)30249-1. Epub 2020 Sep 30.
It is unclear whether tenofovir disoproxil fumarate and entecavir differ in their association with risk of hepatocellular carcinoma in patients with chronic hepatitis B, and previous meta-analyses have shown conflicting conclusions with substantial heterogeneity. We aimed to analyse the updated data and elucidate the source of heterogeneity.
We searched PubMed, Embase, Web of Science, and the Cochrane library for relevant studies with time-to-event data for incident hepatocellular carcinoma occurring in patients with chronic hepatitis B who received tenofovir disoproxil fumarate or entecavir monotherapy with follow-up of at least 1 year. Studies published between Jan 1, 2006, and April 17, 2020, and abstracts from international conferences in 2018 and 2019 were included. We pooled covariate adjusted hazard ratios (HRs) for hepatocellular carcinoma using a random-effects model, assessed heterogeneity among included studies using the I statistic and Cochran's Q test, and identified the source of heterogeneity using prespecified subgroup analyses. This study is registered with PROSPERO, ID CRD42020176513.
31 studies involving 119 053 patients were analysed. The 5-year cumulative incidence of hepatocellular carcinoma was 5·97% (95% CI 5·81-6·13, 28 studies) for entecavir and 3·06% (2·86-3·26, 13 studies) for tenofovir disoproxil fumarate in studies with unmatched populations (p<0·0001). For all eight studies matched by propensity score, the 5-year cumulative incidence was 3·44% (95% CI 3·08-3·80) for entecavir and 3·39% (2·94-3·83) for tenofovir disoproxil fumarate (p=0·87). Analysis of 14 comparative studies with covariate adjustment found that tenofovir disoproxil fumarate and entecavir had similar risk of hepatocellular carcinoma (primary outcome); adjusted HR 0·88, 95% CI 0·73-1·07; p=0·20), although heterogeneity was significant (I=56·4%, p=0·0038). In a subgroup analysis for hospital-based clinical cohorts, there was no difference in hepatocellular carcinoma incidence between the two regimens (adjusted HR 1·03, 95% CI 0·88-1·21; I=0%). However, tenofovir disoproxil fumarate was associated with a lower risk of hepatocellular carcinoma compared with entecavir in administrative database research (adjusted HR 0·67, 0·59-0·76; I=0%).
Our study found no significant difference between tenofovir disoproxil fumarate and entecavir in their association with incident hepatocellular carcinoma. We suggest that treatment should be guided by patient tolerability and affordability rather than whether one drug is more effective than the other.
Supported in part by E-DA Hospital (EDAHP 106008; EDAHP 103046).
尚不清楚富马酸替诺福韦二吡呋酯和恩替卡韦在慢性乙型肝炎患者中发生肝细胞癌的风险方面是否存在差异，先前的荟萃分析显示存在具有显著异质性的相互矛盾的结论。我们旨在分析更新的数据并阐明异质性的来源。
我们检索了 PubMed、Embase、Web of Science 和 Cochrane 图书馆，以获取至少随访 1 年的接受富马酸替诺福韦二吡呋酯或恩替卡韦单药治疗的慢性乙型肝炎患者发生肝细胞癌的时间事件数据的相关研究。纳入了 2006 年 1 月 1 日至 2020 年 4 月 17 日发表的研究和 2018 年和 2019 年国际会议的摘要。我们使用随机效应模型汇总了调整协变量的肝癌风险比（HR），使用 I 统计量和 Cochran's Q 检验评估了纳入研究的异质性，并使用预先指定的亚组分析确定了异质性的来源。这项研究在 PROSPERO 注册，注册号为 CRD42020176513。
分析了 31 项涉及 119053 名患者的研究。在未匹配人群（p<0·0001）中，恩替卡韦的 5 年累积肝癌发生率为 5·97%（95%CI 5·81-6·13，28 项研究），替诺福韦二吡呋酯为 3·06%（2·86-3·26，13 项研究）。对于所有 8 项通过倾向评分匹配的研究，恩替卡韦的 5 年累积肝癌发生率为 3·44%（95%CI 3·08-3·80），替诺福韦二吡呋酯为 3·39%（2·94-3·83）（p=0·87）。对 14 项具有协变量调整的比较研究进行分析，发现替诺福韦二吡呋酯和恩替卡韦具有相似的肝癌风险（主要结局）；调整后的 HR 0·88，95%CI 0·73-1·07；p=0·20），尽管异质性显著（I=56·4%，p=0·0038）。在针对医院临床队列的亚组分析中，两种方案的肝癌发病率无差异（调整后的 HR 1·03，95%CI 0·88-1·21；I=0%）。然而，在行政数据库研究中，替诺福韦二吡呋酯与恩替卡韦相比，发生肝癌的风险较低（调整后的 HR 0·67，0·59-0·76；I=0%）。
我们的研究发现，富马酸替诺福韦二吡呋酯和恩替卡韦在与肝细胞癌发病风险的相关性方面没有显著差异。我们建议，治疗应根据患者的耐受性和可负担性来指导，而不是根据哪种药物更有效。
部分由长庚纪念医院（EDAHP 106008；EDAHP 103046）资助。
