Systematic Review with Meta-Analysis: Comparison of the Risk of Hepatocellular Carcinoma in Antiviral-Naive Chronic Hepatitis B Patients Treated with Entecavir versus Tenofovir: The Devil in the Detail

Abstract

Tenofovir disoproxil fumarate (TDF) and entecavir (ETV) are the preferred anti-viral agents used as first-line treatments for chronic hepatitis B (CHB). However, the efficacy of these agents in reducing the incidence of hepatocellular carcinoma (HCC) remains unclear. We conducted this meta-analysis to assess the efficacy of anti-viral agent on preventing HCC in CHB. Two investigators independently searched all relevant studies that examined the efficacy of anti-viral agent for preventing HCC using MEDLINE, Embase, and Cochrane Library databases through August 2021. The extracted data were analysed using a random-effects meta-analysis model based on the inverse-variance method (DerSimonian–Laird) and expressed as hazard ratio (HR) and 95% confidence interval (95% CI). We included 19 retrospective studies in the analysis. Although there was substantial heterogeneity between the studies, the overall pooled HR indicated that TDF significantly lowered the risk of HCC (HR: 0.72, 95% CI: 0.58–0.90, I2 = 66.29%). However, the pooled analysis of propensity score (PS)-matched subpopulations showed no significant differences (HR, 0.83; 95% CI, 0.65–1.06; I2 = 52.30%) between TDF and ETV. In a subgroup analysis, an interval of over three years in the start point of patient enrolment and excluding alcoholic liver disease patients significantly lowered the HCC risk associated with TDF. In conclusion, TDF may be more effective than ETV at reducing HCC incidence in treatment-naive CHB patients, but this effect was not consistent in the PS-matched subpopulation that reduced heterogeneity. As a result of subgroup analysis, the conflicting findings of previous studies may result from heterogeneous inclusion criteria. Further studies with standardised protocols are needed to reduce the residual heterogeneity.

The power of prevention: how tenofovir and entecavir are changing the game in hepatocellular carcinoma

“…Two recent meta-analyses did not include most of the recent high-quality studies ( 3 , 6 ). Among studies showing no differences in the HCC risk among the two NAs, the cohort study by Kim et al [2019] ( 18 ) and the retrospective study by Lee et al [2020] ( 19 ) were not included in the meta-analyses by Zhang et al [2019] ( 3 ), Wang et al [2020] ( 6 ), and Oh et al [2022] ( 15 ); the same studies were not included in the meta-analysis by Choi et al [2023] ( 1 ). Besides, data from the Spanish prospective, multicenter database CIBERHEP study of Riveiro-Barciela et al [2017] ( 20 ) were only included in the meta-analyses of Wang et al [2020] ( 6 ), Yuan et al [2021] ( 13 ), and Dave et al [2021] ( 7 ).…”

“…In terms of publication bias, Zhang et al ( 3 ) and Choi et al [2021] ( 8 ) used the funnel plot to test the publication bias, but did not specify the test used; Huang et al ( 17 ) and Choi et al [2023] ( 1 ) did not mention the bias analysis. Oh et al ( 15 ), on the other hand, used an unusual test (the AS-Thomson test). Finally, all authors except Dave et al ( 7 ) and Choi et al ( 8 ) used the Newcastel-Ottawa scale or the Jadad scale as primary tools for assessing the quality of observational studies.…”

Overview of the immunological mechanisms in hepatitis B virus reactivation: Implications for disease progression and management strategies

“…Moreover, the anti-viral effectiveness of Entecavir has a significant role in reducing the advancement of liver fibrosis and decreasing the likelihood of consequences, including Cirrhosis and hepatocellular cancer. Nevertheless, although Entecavir has exhibited significant anti-viral efficacy, its effectiveness can vary depending on specific patient attributes, HBV genotypes, and previous treatment experiences[ 122 , 123 ]. Like any therapeutic intervention, it is essential to conduct a thorough patient assessment and develop individualized treatment plans to optimize the efficacy of Entecavir in managing HBV reactivation.…”

Cost–Utility Analysis of Tenofovir Alafenamide and Entecavir in Chronic Hepatitis B Patients: A Markov Decision Model

“…We used the cost-utility analysis to conduct the decision analysis and to investigate whether the first-line drug TAF is more cost effective than ETV for CHB patients. The Markov model utilized in this study was developed by integrating insights from local clinical practices and referencing pertinent studies, as illustrated in Figure 2 [3][4][5][6]. This model categorizes post-treatment conditions of patients receiving the first-line drug into four distinct states: CHB, hepatocellular carcinoma (HCC), cirrhosis, and mortality.…”

“…The current pharmacological approaches for treating CHB involve long-acting interferon and oral antiviral drugs [3,4]. Interferon, administered through injections, presents challenges due to suboptimal rates of e antigen (HBeAg) seroconversion and surface antigen (HBsAg) seroclearance, coupled with notable adverse effects [5]. Oral antiviral drugs, such as tenofovir disoproxil (TDF), tenofovir alafenamide (TAF), and entecavir (ETV), offer more sustained options.…”