Xu BG, Zhang X, Liu F, Li FH, Zhang X, Xiang HL, Liang J. Effect of antiviral therapy on 3-year recurrence and prognosis of hepatocellular carcinoma after curative radiofrequency ablation. World J Gastrointest Oncol 2025; 17(11): 112689 [DOI: 10.4251/wjgo.v17.i11.112689]
Corresponding Author of This Article
Jing Liang, Department of Gastroenterology and Hepatology, Tianjin Third Central Hospital, Tianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Artificial Cell Engineering Technology Research Center, Tianjin Institute of Hepatobiliary Disease, No. 83 Jintang Road, Tianjin 300170, China. haolele77@sina.com
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Gastroenterology & Hepatology
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Observational Study
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Nov 15, 2025 (publication date) through Nov 13, 2025
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World Journal of Gastrointestinal Oncology
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Xu BG, Zhang X, Liu F, Li FH, Zhang X, Xiang HL, Liang J. Effect of antiviral therapy on 3-year recurrence and prognosis of hepatocellular carcinoma after curative radiofrequency ablation. World J Gastrointest Oncol 2025; 17(11): 112689 [DOI: 10.4251/wjgo.v17.i11.112689]
Bai-Guo Xu, Xue Zhang, Fang Liu, Feng-Hui Li, Hui-Ling Xiang, Jing Liang, Department of Gastroenterology and Hepatopathy, The Central Hospital of Tianjin University, Tianjin 300170, China
Bai-Guo Xu, Department of Gastroenterology and Hepatopathy, The Third Central Hospital of Tianjin, Tianjin 300170, China
Bai-Guo Xu, Department of Gastroenterology and Hepatopathy, Tianjin Institute of Hepatobiliary Disease, Tianjin 300170, China
Xue Zhang, Hui-Ling Xiang, Department of Gastroenterology and Hepatopathy, The Third Central Clinical College of Tianjin Medical University, Tianjin 300170, China
Fang Liu, Department of Hepatology, The Third Central Clinical College of Tianjin Medical University, Tianjin 300170, China
Feng-Hui Li, Xu Zhang, Department of Gastroenterology and Hepatology, The Third Central Hospital of Tianjin, Tianjin 300170, China
Xu Zhang, Department of Gastroenterology and Hepatology, The Central Hospital of Tianjin University, Tianjin 300170, China
Jing Liang, Department of Gastroenterology and Hepatology, Tianjin Third Central Hospital, Tianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Artificial Cell Engineering Technology Research Center, Tianjin Institute of Hepatobiliary Disease, Tianjin 300170, China
Author contributions: Xu BG and Liang J designed and conceptualized the research; Zhang X, Xiang HL, Liu F, Li FH, and Zhang X performed the research (including data collection and preliminary data sorting); Zhang X and Zhang X contributed to the development of analytic tools for survival data processing; Zhang X and Liang J analyzed the data (including statistical analysis of baseline characteristics and survival curves); Xu BG, Liang J, and Zhang X wrote and revised the manuscript. Xu BG and Zhang X contributed equally to this work.
Supported by Tianjin Health Project of China, No. TJWJ2022XK029.
Institutional review board statement: This project was performed in concordance with the Declaration of Helsinki. This study was approved by the medical ethics committee of The Third Central Hospital of Tianjin, China (date of approval: 27 December 2019; approval number: IRB2019-040-01).
Informed consent statement: Informed consent was obtained from each patient. All data were analysed anonymously.
Conflict-of-interest statement: The authors declare no conflict of interest.
STROBE statement: The authors have read the STROBE Statement-checklist of items, and the manuscript was prepared and revised according to the STROBE Statement-checklist of items.
Data sharing statement: The data that related to the findings of our study are available on request from the corresponding author. The data are not publicly available due to privacy and ethical restrictions.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Jing Liang, Department of Gastroenterology and Hepatology, Tianjin Third Central Hospital, Tianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Artificial Cell Engineering Technology Research Center, Tianjin Institute of Hepatobiliary Disease, No. 83 Jintang Road, Tianjin 300170, China. haolele77@sina.com
Received: August 4, 2025 Revised: August 25, 2025 Accepted: October 9, 2025 Published online: November 15, 2025 Processing time: 102 Days and 18 Hours
Abstract
BACKGROUND
The impact of entecavir (ETV), tenofovir disoproxil fumarate (TDF), and tenofovir alafenamide fumarate (TAF) on long-term recurrence and overall survival in patients with hepatitis B cirrhosis-related hepatocellular carcinoma (HCC) who undergo curative radiofrequency ablation (RFA) remains unclear.
AIM
To compare the 3-year recurrence and survival rates among HCC patients receiving these three first-line oral anti-hepatitis B virus (anti-HBV) agents after RFA.
METHODS
This retrospective cohort study included patients with hepatitis B cirrhosis who were initially diagnosed with HCC at Tianjin Third Central Hospital, China, from August 2018 to December 2020, and had complete clinical data. All patients were followed up for at least 144 weeks. Cox regression analysis was performed to identify independent risk factors for HCC recurrence. Recurrence-free survival was analyzed using Kaplan-Meier curves, and Cox regression models were constructed after adjusting for gamma-glutamyl transferase, alpha-fetoprotein, and Barcelona Clinic Liver Cancer staging.
RESULTS
A total of 319 patients receiving oral anti-HBV therapy were divided into three groups: ETV group (n = 191), TDF group (n = 76), and TAF group (n = 52). At 6 and 12 months, there were no significant differences in recurrence rates between the groups. However, at 24 and 36 months, the TDF and TAF groups exhibited significantly lower recurrence rates compared with the ETV group [24 months: TDF, hazard ratio (HR) = 0.51, 95% confidence interval (CI): 0.29-0.91, P = 0.022; TAF, HR = 0.54, 95%CI: 0.28-1.03, P = 0.046; 36 months: TDF, HR = 0.57, 95%CI: 0.35-0.93, P = 0.025; TAF, HR = 0.54, 95%CI: 0.31-0.96, P = 0.037]. The 3-year mortality rates were similar across the three groups (ETV: 21.47%, TDF: 18.42%, TAF: 23.08%; P = 0.790).
CONCLUSION
Among patients with hepatitis B cirrhosis-related HCC, TDF and TAF are associated with lower 2-year and 3-year HCC recurrence rates after curative RFA treatment compared with ETV. However, there were no significant differences in 3-year mortality rates between the ETV, TDF, and TAF groups.
Core Tip: In patients with hepatitis B cirrhosis-related hepatocellular carcinoma who undergo curative radiofrequency ablation, tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide fumarate (TAF) are associated with lower 2-year and 3-year recurrence rates compared with entecavir, while no significant differences are observed in 3-year mortality rates. These findings support the consideration of TDF or TAF as preferred antiviral therapies for the long-term management of such patients.
Citation: Xu BG, Zhang X, Liu F, Li FH, Zhang X, Xiang HL, Liang J. Effect of antiviral therapy on 3-year recurrence and prognosis of hepatocellular carcinoma after curative radiofrequency ablation. World J Gastrointest Oncol 2025; 17(11): 112689
Hepatocellular carcinoma (HCC) ranks as the sixth most common cancer and the fourth leading cause of cancer-related death worldwide[1]. Hepatitis B virus (HBV) is a major contributor to the incidence of HCC, particularly in the Asia-Pacific region (including China), where HBV-related HCC accounts for approximately 80% of all liver cancer cases[2-5]. For patients with very early-stage HCC (defined as a single tumor < 2 cm), radiofrequency ablation (RFA) is recognized as a first-line therapeutic option. Additionally, local thermal ablation is recommended as an effective first-line treatment for small HCCs[6-8]. Notably, the recurrence rate of HCC in patients receiving nucleos(t)ide analogs (NUCs) after surgical resection ranges from 40% to 60%[9,10]. NUCs with potent antiviral activity and a high genetic barrier to resistance-such as entecavir (ETV), tenofovir disoproxil fumarate (TDF), and tenofovir alafenamide fumarate (TAF)-are considered optimal agents for the tertiary prevention of HBV-related HCC following curative treatment[5,11,12]. Although extensive research has investigated the impact of ETV and TDF on HCC development in patients with chronic hepatitis B (CHB) at various disease stages, the findings remain inconsistent. Moreover, few studies have evaluated the recurrence and prognosis of HBV-related cirrhosis complicated with HCC in patients receiving ETV, TDF, or TAF therapy after curative RFA[13]. In the present retrospective study, we employed regression modeling to analyze the 3-year recurrence and survival rates in patients with HBV-related cirrhosis and HCC who underwent curative RFA and subsequent treatment with ETV, TDF, or TAF.
MATERIALS AND METHODS
Study design and subjects
This was a retrospective cohort study. All clinical data were collected from patients with hepatitis B cirrhosis who were initially diagnosed with HCC at Tianjin Third Central Hospital (Tianjin, China) from August 2018 to December 2020.
Inclusion criteria: (1) Diagnosis of cirrhosis confirmed by imaging findings, liver function tests, virological assessments, and a documented history of HBV infection lasting more than 6 months; (2) First diagnosis of HCC and receipt of RFA treatment; (3) Initiation of antiviral therapy with ETV, TDF, or TAF at the time of initial HCC diagnosis, with treatment continuation for more than 144 weeks; (4) Completion of at least 144 weeks of follow-up since RFA treatment; and (5) Prior antiviral therapy before HCC diagnosis: Receipt of oral NUC treatment for more than 1 year, with no change in antiviral regimen before study enrollment.
Diagnostic criteria: The diagnosis of hepatitis B cirrhosis followed the Chinese Guidelines for the Prevention and Treatment of CHB (2019 version)[14]. The diagnosis of HCC was based on clinical diagnostic criteria or histopathological confirmation, in accordance with the Diagnosis and Treatment of HCC (2019 Edition)[15]: (1) For patients with hepatitis B cirrhosis: If hepatic nodules were ≤ 2 cm, HCC was diagnosed if two of the four following examinations showed typical vascular enhancement patterns (marked arterial-phase enhancement with washout in the portal and delayed phases): Dynamic contrast-enhanced magnetic resonance imaging (MRI), dynamic contrast-enhanced computed tomography (CT), contrast-enhanced ultrasound (US), and gadoxetic acid disodium (Primovist)-enhanced dynamic MRI; If hepatic nodules were > 2 cm, clinical diagnosis of HCC was confirmed if any one of the four aforementioned imaging examinations showed typical features of primary liver cancer; and (2) Histopathological confirmation of primary HCC via liver biopsy. HCC staging was determined using the Barcelona Clinic Liver Cancer (BCLC) staging system[16].
Exclusion criteria: (1) Co-infection with hepatitis C virus and/or hepatitis D virus; presence of alcoholic liver disease, inherited metabolic liver diseases, autoimmune liver disease, primary biliary cholangitis, schistosomiasis, Budd-Chiari syndrome, cardiogenic cirrhosis, or human immunodeficiency virus infection; (2) History of other malignant tumors; (3) Pathologically confirmed diagnosis of cholangiocellular carcinoma or non-primary HCC after RFA; (4) Receipt of any antitumor therapy other than RFA during the follow-up period [including transcatheter arterial chemoembolization (TACE), hepatic artery infusion chemotherapy, or other antitumor medications]; (5) Use of oral antiviral agents other than ETV, TDF, or TAF, or use of interferon (IFN) therapy, or receipt of combination anti-hepatitis B virus (anti-HBV) therapy at study enrollment; (6) Incomplete RFA; (7) Change in antiviral therapy during the entire 3-year follow-up period (regardless of cause, including drug-related adverse events or drug resistance); (8) Comorbidities of hypertension, diabetes mellitus, or chronic kidney disease; (9) Comorbidities of osteoporosis and/or fractures; and (10) Receipt of liver transplantation during the follow-up period.
Patients who met the above criteria received oral ETV (0.5 mg, once daily), TDF (300 mg, once daily), or TAF (25 mg, once daily) at study enrollment and maintained this treatment regimen throughout the study period. Routine patient education was provided regarding standard medication administration and adherence. This study was approved by the Ethics Committee of Tianjin Third Central Hospital. Detailed information on the patient enrollment process is presented in Figure 1.
Figure 1 Flowchart of patient enrollment and exclusion.
This flowchart outlines the enrollment and exclusion process for patients with hepatitis B virus-related cirrhosis and hepatocellular carcinoma who received radiofrequency ablation at Tianjin Third Central Hospital from August 2018 to December 2020. HCC: Hepatocellular carcinoma; ETV: Entecavir; TDF: Tenofovir disoproxil fumarate; TAF: Tenofovir alafenamide fumarate; HCV: Hepatitis C virus; TACE: Transcatheter arterial chemoembolization.
Data collection
Baseline data collection: (1) General clinical data: Age and gender; (2) Laboratory parameters: Complete blood count, liver function tests, coagulation profiles, and alpha-fetoprotein (AFP); (3) Virological parameters: Hepatitis B surface antigen (HBsAg) status, hepatitis B e antigen status, and HBV DNA levels; and (4) Tumor characteristics: BCLC staging and number of tumors, along with maximum tumor diameter.
RFA procedure
RFA was performed by two experienced interventional ultrasonologists. The RFA protocol was based on the 2011 Expert Consensus on the Standardization of RFA Therapy for HCC jointly issued by the Chinese Society of Liver Cancer, Chinese Society of Clinical Oncology, and Chinese Medical Association. Ablation was conducted under US guidance, with a target safe ablation margin of 0.5 cm around the tumor.
Follow-up
All study participants were followed up for at least 144 weeks. Assessments included biochemical tests (liver and kidney function) and imaging examinations (US/contrast-enhanced US/MRI/CT). These assessments were performed every 3 months during the first 2 years after RFA and then every 6 months for the subsequent 2 years.
HCC recurrence and survival outcomes were documented throughout the follow-up period. Follow-up was conducted via telephone interviews and outpatient visits. If a patient missed a scheduled follow-up appointment, medical staff contacted the patient to encourage adherence to the planned medical evaluations.
Statistical analysis
Statistical analyses were performed using SPSS 23.0 software (IBM Corp., Armonk, NY, United States). Normally distributed data were expressed as mean ± SD and analyzed using the independent samples t-test. Non-normally distributed data were presented as median (M) with interquartile range (P25-P75) and compared using the Mann-Whitney U test. Categorical data were analyzed using the χ2 test or Fisher’s exact test (when the expected frequency was < 5). Kaplan-Meier curves were used to compare recurrence-free survival and overall survival (OS) among the ETV, TDF, and TAF groups. Differences in survival rates were assessed using the log-rank test. Cox proportional hazards regression models were constructed to evaluate the association between antiviral therapy and HCC recurrence, with adjustment for potential confounding factors. Three Cox regression models were performed for multiple analyses: An unadjusted model, a partially adjusted model, and a multivariable-adjusted model. A two-tailed P-value < 0.05 was considered statistically significant. For variables with missing values ≤ 10%, multiple imputation with chained equations was applied using the MICE package in R 4.2.0 software (R Foundation for Statistical Computing, Vienna, Austria).
RESULTS
General clinical data, laboratory/virological parameters, and tumor characteristics
A total of 319 patients with hepatitis B cirrhosis and newly diagnosed HCC were enrolled in this study. Detailed information on the patient enrollment process is presented in Figure 1. Among these patients, 254 (79.63%) were male and 65 (20.37%) were female. The mean age of the participants was 59.53 ± 8.26 years. Regarding virological status, 260 (81.50%) patients had HBV DNA levels below the lower limit of detection (< 20 IU/mL), and 59 (18.50%) had detectable HBV DNA. Detailed comparisons of baseline data are presented in Table 1.
Table 1 Baseline data of hepatitis B cirrhosis-related hepatocellular carcinoma post radiofrequency treatment with entecavir, tenofovir disoproxil fumarate and tenofovir alafenamide fumarate, n (%).
Recurrence rates among the three groups were compared using the χ2 test, with pairwise comparisons adjusted for multiple testing. Patients were followed up at 6, 12, 24, and 36 months after RFA to assess HCC recurrence. Of the 319 patients, 15 (4.70%) were lost to follow-up [reasons for loss to follow-up: 11 patients (73.33%) lost contact, and 4 patients (26.67%) refused to provide follow-up information]. Recurrence rates varied across the different antiviral treatment groups. The following results are presented without adjustment for confounding factors: Within 6 months: Recurrence occurred in 21 patients (10.99%) in the ETV group, 7 patients (9.21%) in the TDF group, and 4 patients (7.69%) in the TAF group (χ2 = 0.57, P = 0.753); By 12 months: The number of patients with HCC recurrence increased to 54 (28.27%) in the ETV group, 11 (14.47%) in the TDF group, and 7 (13.46%) in the TAF group (χ2 = 8.87, P = 0.012); At 24 months: Recurrence rates further increased, with 74 patients (38.74%) in the ETV group, 15 (19.74%) in the TDF group, and 11 (21.15%) in the TAF group (χ2 = 12.13, P = 0.002); At the final 36-month follow-up: Recurrence rates were 45.55% (87 patients) in the ETV group, 28.95% (22 patients) in the TDF group, and 28.85% (15 patients) in the TAF group (χ2 = 8.93, P = 0.012).
Survival curves illustrating the effect of different antiviral agents on HCC recurrence at these time points after RFA are presented in Figure 2A-D. Most recurrent tumors (72.3%) were eligible for re-ablation or TACE, with no significant differences in re-treatment success rates between the groups (P > 0.05).
Figure 2 Kaplan-Meier curves of recurrence-free survival and overall survival in patients with hepatitis B cirrhosis-related hepatocellular carcinoma after curative radiofrequency ablation.
A: 6-month recurrence-free survival (RFS) curves among entecavir (ETV), tenofovir disoproxil fumarate (TDF), and tenofovir alafenamide fumarate (TAF) groups (log-rank test, P = 0.750), showing no significant difference in early recurrence risk (without adjusting for confounding factors); B: 12-month RFS curves among the three groups (log-rank test, P = 0.013), with TDF/TAF groups exhibiting higher RFS probabilities than ETV group (without adjusting for confounding factors); C: 24-month RFS curves among the three groups (log-rank test, P = 0.002), confirming persistent recurrence-reducing effects of TDF/TAF (without adjusting for confounding factors); D: 36-month RFS curves among the three groups (log-rank test, P = 0.008), indicating TDF/TAF are associated with lower long-term recurrence rates vs ETV (without adjusting for confounding factors); E: 36-month overall survival (OS) curves among the three groups (log-rank test, P = 0.790), with no significant difference in long-term OS. ETV: Entecavir; TDF: Tenofovir disoproxil fumarate; TAF: Tenofovir alafenamide fumarate; Anti-HBV: Anti-hepatitis B virus.
Cox regression analysis of 36-month post-RFA recurrence
Univariate and multivariate Cox proportional hazards regression analyses were performed for 319 patients with hepatitis B cirrhosis-related HCC after RFA. Baseline characteristics were included as independent variables, and 36-month recurrence status was the dependent variable. The analysis identified four independent predictors of post-RFA HCC recurrence: Glutamyl transferase (GGT): Hazard ratio (HR) = 1.01, 95% confidence interval (CI): 1.00-1.01, P = 0.026; AFP: HR = 1.01, 95%CI: 1.00-1.01, P = 0.013; anti-HBV therapy: TDF (HR = 0.62, 95%CI: 0.38-1.02, P = 0.047); TAF (HR = 0.57, 95%CI: 0.32-1.02, P = 0.046); BCLC staging: HR = 3.82, 95%CI: 1.39-10.47, P = 0.009. Complete statistical details are presented in Table 2.
Table 2 Cox regression analysis of recurrence after radiofrequency in patients with hepatocellular carcinoma.
Comparison of regression models across the three groups
Regression analyses were conducted to evaluate the factors influencing HCC recurrence at 6, 12, 24, and 36 months. Variables identified as predictive of post-RFA recurrence in both univariate and multivariate analyses (i.e., GGT, AFP, anti-HBV therapy, and BCLC staging) were included in the multivariate regression models. Detailed results are presented in Tables 3, 4, 5, and 6. Compared with the ETV group, patients in the TDF and TAF groups had a significantly lower risk of recurrence at 24 and 36 months after RFA for hepatitis B cirrhosis-related HCC.
Table 3 The multiple Cox regression equations of different antiviral agents on recurrence within 6 months post radiofrequency.
OS analyses were performed for the three groups at 36 months after RFA. A total of 67 deaths (21.00%) were recorded across the three groups, with mortality primarily attributed to end-stage HCC (38.81%), upper gastrointestinal bleeding (23.88%), and liver failure (13.43%). Other causes of death included abdominal infection (8.96%), renal failure (7.46%), and hepatic encephalopathy (7.46%). The mean survival time for patients who died was 32.80 ± 7.22 months.
The 36-month mortality rates were 21.47% (ETV group), 18.42% (TDF group), and 23.08% (TAF group), respectively. Differences in OS across all three groups were assessed using the log-rank test, with post-hoc pairwise comparisons revealing no significant differences (P > 0.05). Stratified survival analyses of mortality rates were also conducted: BCLC stage 0: ETV (19.8%), TDF (16.4%), TAF (21.1%) (log-rank test, P = 0.723); BCLC stage A: ETV (33.3%), TDF (28.6%), TAF (35.7%) (log-rank test, P = 0.891); HBV DNA-positive: ETV (25.9%), TDF (23.8%), TAF (27.3%) (log-rank test, P = 0.945); HBV DNA-negative: ETV (20.1%), TDF (16.4%), TAF (22.0%) (log-rank test, P = 0.688). Survival curves for each antiviral group are illustrated in Figure 2E.
DISCUSSION
HBV infection is the leading cause of HCC in China. RFA is recognized as a curative-intent treatment for patients with early-stage HCC[17,18]. Recent studies have shown that HBV viral load is an independent risk factor for prognosis in patients with CHB who undergo hepatectomy or RFA for HCC[19-23]. Reducing HBV load with NUCs may lower the risk of HCC recurrence and improve survival in patients after hepatectomy or RFA[9,10,24,25]. NUCs with potent antiviral activity and a high genetic barrier to resistance-such as ETV, TDF, and TAF-are preferred for the tertiary prevention of HBV-related HCC following curative treatment[5,11,12]. However, the efficacy of long-term antiviral therapy with these three agents in preventing HCC recurrence after curative RFA remains a topic of significant debate. Clinical practice guidelines for CHB from the United States, Europe, and the Asia-Pacific region do not specify a preference among ETV, TDF, and TAF[5,11,12].
Our study compared the effects of these three antiviral agents on 3-year recurrence in patients with BCLC stage 0 or HBV-related HCC who underwent curative RFA. The results showed no significant difference in HCC recurrence rates within 6 months after RFA between the TDF/TAF groups and the ETV group. However, the TDF and TAF groups had significantly lower recurrence rates at 2 and 3 years after RFA. Notably, there was no significant difference in 3-year mortality among the three groups.
Few studies have investigated the effects of all three first-line antiviral agents (ETV, TDF, TAF) on outcomes in patients with HBV-related HCC after curative RFA. Only a subgroup analysis by Lee et al[25] demonstrated similar recurrence and OS rates after RFA between the ETV and TDF groups. Subsequently, Hu et al[13] reported no differences in recurrence or OS between TDF and ETV in patients with HBV-related HCC who underwent RFA. To date, no studies have compared the long-term prognostic effects of ETV, TDF, and TAF in patients with HBV-related cirrhosis and HCC who received curative RFA.
Advanced age, male gender, and cirrhosis are independently associated with HCC development[13,26]. Univariate and multivariate Cox proportional hazards regression analyses identified GGT, AFP, and BCLC stage as confounders for HCC recurrence. Therefore, these variables were adjusted to varying degrees in the multiple regression models to mitigate their confounding effects. Our analysis showed that HCC recurrence rates were similar across the ETV, TDF, and TAF groups within 6 months after RFA, whereas the TDF and TAF groups had lower recurrence rates at 24 and 36 months. No significant difference in 3-year mortality was observed among the three groups.
Despite adjusting for GGT, AFP, and BCLC stage, baseline differences may have introduced residual confounding. The TDF group had higher alanine transaminase (ALT), aspartate transaminase, and alkaline phosphatase levels than the ETV group, while the TAF group showed no such differences compared with the ETV group. Additionally, a higher proportion of patients in the TDF/TAF groups had detectable HBV DNA. Notably, TDF and TAF still reduced HCC recurrence, suggesting that their antiviral and immunomodulatory effects outweigh these baseline risks. These findings support the robustness of TDF and TAF in reducing HCC recurrence.
Numerous studies have confirmed that antiviral therapy with NUCs can reduce HCC recurrence and improve OS after hepatic resection or RFA[24,25,27-30]. ETV, TDF, and TAF are all first-line anti-HBV agents characterized by potent antiviral activity, high resistance barriers, and favorable safety profiles[31,32]. TDF strongly inhibits HBV replication; long-term TDF treatment has been shown to effectively suppress the progression of liver fibrosis and may even reverse fibrosis and cirrhosis[33]. TAF, like TDF, exhibits high antiviral efficacy and a strong resistance barrier but is associated with improved safety[34,35].
The differential effects of ETV, TDF, and TAF on HCC development in CHB patients remain controversial. Lee et al[25] reported no significant differences in HCC recurrence rates or OS between the ETV and TDF groups in patients with or without cirrhosis after curative therapy for HBV-related HCC. A recent Chinese study enrolling 1173 patients with HBV-related HCC who underwent surgical resection also showed no difference in HCC recurrence incidence between the TDF and ETV groups.
Our results indicate that the time course of HCC recurrence after curative RFA differs among ETV, TDF, and TAF groups in patients with HBV-related cirrhosis, with no significant differences observed within the first 6 months, 12 months. Previous studies have reported significant differences in HCC incidence between TDF and ETV only in studies with follow-up periods exceeding 1 year, whereas no differences were noted in studies with shorter follow-up[36]. Our findings align with this pattern: We observed no significant differences in HCC recurrence at 6 and 12 months after RFA across the three groups, consistent with data from the Taiwan Cancer Registry-though the exact timing of early vs late recurrence varied[37].
Furthermore, our data revealed significant differences in HCC recurrence rates at 2 and 3 years after RFA: The TDF and TAF groups had significantly lower recurrence rates than the ETV group at these time points (P < 0.05). This suggests that long-term (> 1 year) HCC recurrence rates differ among ETV, TDF, and TAF groups in patients with HBV-related cirrhosis and HCC who undergo curative RFA. The long-term efficacy of ETV vs TDF remains debated. Several studies have shown that TDF is associated with a lower risk of HCC incidence than ETV in CHB patients[38,39]. In the context of HBV-related HCC, recent studies have found that TDF treatment is linked to significantly lower HCC recurrence rates and improved OS compared with ETV in patients who undergo curative hepatectomy for HBV-related HCC[40-42]. For example, Zhang et al[41] analyzed 233 patients with HBV-related cirrhosis and HCC who underwent hepatectomy (107 received TDF, 126 received ETV); multivariate analysis showed that TDF treatment was significantly associated with a reduced HCC recurrence rate (HR = 0.35, 95%CI: 0.33-0.84). Similarly, Choi et al[39] using data from the South Korean National Health Insurance Service and a hospital validation cohort-reported that TDF treatment was associated with a lower HCC risk than ETV, with corroborative results from a study using the Clinical Data Analysis and Reporting System database in Hong Kong[38].
Inconsistent results across studies may stem from heterogeneity in study design, including variations in propensity score matching methods, multivariate adjustment strategies, and data sources (e.g., hospital-based databases vs health insurance claims data)[43-46]. Another potential explanation for differing HCC incidence or recurrence rates is the distinct antiviral efficacies of TDF and ETV. Prior research has shown that more rapid HBV suppression improves long-term prognosis in liver cancer patients[47]. Virologically, TDF achieves more potent virological suppression and may reduce HBsAg levels more effectively than ETV[38,39]. Biochemically, a higher proportion of TDF-treated patients achieve ALT normalization-an established protective factor against HCC[48]. Additionally, TDF-treated patients have higher serum IFN-λ3 levels, which may enhance immune activation[49-52]. IFN-λ exhibits potent antitumor activity in murine hepatoma models[53], which could partially explain the lower HCC risk observed in TDF- and TAF-treated patients. Moreover, long-term data on TAF-a modified form of TDF with a better safety profile and higher ALT normalization rates-supports its efficacy[35,54]. Studies have also found that serum HBV DNA levels decrease more rapidly in the TDF group than in the ETV group, and TDF provides better protection for HBV-infected livers after RFA[13]. Finally, differences in study populations [e.g., presence of cirrhosis, type of curative therapy (RFA vs hepatectomy), or timing of anti-HBV therapy initiation] may contribute to variable results.
In our study, all participants had HBV-related cirrhosis and HCC, and all received curative RFA followed by long-term antiviral treatment. Most patients achieved HBV DNA negativity; however, low-level viremia remains a key factor in post-RFA HCC recurrence, highlighting the importance of long-term maximal viral suppression. We also analyzed OS after curative RFA and found no significant difference in 3-year mortality among the three groups. This aligns with our focus on the effect of antiviral therapy on HCC recurrence-and is consistent with prior observations that antiviral agents primarily reduce recurrence risk rather than mortality from advanced cirrhosis-related complications[55]. OS is influenced by multiple factors, with cirrhosis decompensation closely linked to HCC progression; antiviral drugs are only one factor affecting OS.
This study has several limitations. First, as a single-center retrospective study, it carries an inherent risk of selection bias, and our findings require external validation. Second, the sample size of the TAF group was relatively small, which may limit the statistical power to detect differences. Third, our results may not be generalizable to all patients with HBV-related HCC who undergo curative therapy, as our cohort was restricted to patients with HBV-related cirrhosis who received curative RFA. Fourth, the relatively short follow-up period (3 years) is a limitation, and our results cannot be extrapolated to longer-term outcomes. Finally, the retrospective design limits our ability to infer causality. Although TDF and TAF were associated with lower recurrence rates, these findings should be interpreted cautiously, and confirmation in prospective, randomized controlled trials is warranted.
CONCLUSION
In conclusion, our findings suggest that TDF and TAF are associated with a lower long-term HCC recurrence rate compared to ETV in patients with HBV-related cirrhosis who undergo curative RFA. This study supports the consideration of TDF or TAF as preferable antiviral options for managing patients with HBV-related cirrhosis and HCC who received curative RFA. Furthermore, we found no significant differences in 3-year mortality among the ETV, TDF, and TAF groups in this patient population. Thus, the results of this study may help optimize adjuvant therapy strategies for patients with HBV-related HCC after curative RFA.
Footnotes
Provenance and peer review: Unsolicited article; Externally peer reviewed.
Peer-review model: Single blind
Specialty type: Oncology
Country of origin: China
Peer-review report’s classification
Scientific Quality: Grade B, Grade B, Grade C, Grade C
Novelty: Grade B, Grade B, Grade C, Grade C
Creativity or Innovation: Grade B, Grade C, Grade C, Grade D
Scientific Significance: Grade B, Grade C, Grade C, Grade D
P-Reviewer: Fuentes-Valenzuela E, MD, Academic Fellow, Spain; Kumar R, MD, Professor, India; Zhang CT, Associate Professor, China S-Editor: Qu XL L-Editor: A P-Editor: Xu J
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