Tenofovir vs. Entecavir on Recurrence of Hepatitis B Virus-Related Hepatocellular Carcinoma Beyond Milan Criteria After Hepatectomy
Hepatocellular carcinoma (HCC) is the fifth most common cancer and the third leading cause of cancer-related deaths globally, with over 50% of cases attributed to chronic hepatitis B virus (HBV) infection. In China, HBV-related HCC accounts for 42.5% of global cases. While curative hepatectomy is recommended for early-stage HCC, a significant proportion of patients in China are diagnosed at intermediate or advanced stages, where tumors extend beyond the Milan criteria (single tumor ≤5 cm or up to three tumors, all <3 cm, without major vascular invasion). Despite expanding surgical indications for these patients, post-operative HCC recurrence remains a major obstacle to long-term survival, with rates exceeding 60%. This study investigates the comparative efficacy of tenofovir (TDF) and entecavir (ETV), two first-line antiviral therapies for HBV, in reducing recurrence after hepatectomy for HCC beyond Milan criteria.
Study Design and Patient Selection
A multicenter retrospective analysis was conducted across five Chinese hospitals, involving 1,532 patients who underwent hepatectomy and received antiviral therapy between January 2014 and January 2019. After applying exclusion criteria—such as prior antitumor therapy, extrahepatic metastasis, or incomplete follow-up—595 HBV-related HCC patients with tumors beyond Milan criteria were included. The cohort comprised 533 patients treated with ETV (0.5 mg/day) and 62 with TDF (300 mg/day). Baseline characteristics, including age, gender, liver function, tumor pathology, and virological markers, were balanced between groups, though the TDF group had higher albumin levels (82.3% vs. 66.8%, P = 0.020).
Key Findings on Recurrence and Survival
Over a median follow-up of 28.5 months, 418 patients (70.2%) experienced HCC recurrence, and 289 (48.6%) died. The overall 5-year recurrence-free survival (RFS) and overall survival (OS) rates were 21.3% and 44.7%, respectively. Early recurrence (within 2 years post-surgery) occurred in 88.1% of cases and correlated with significantly worse 5-year OS (21.6% vs. 73.1% in non-early recurrence, P < 0.001).
Notably, TDF demonstrated superior efficacy in reducing recurrence. The 1-, 3-, and 5-year RFS rates for TDF were 65.1%, 41.8%, and 37.2%, compared to 46.3%, 27.4%, and 19.6% for ETV (P < 0.001). After adjusting for confounders using inverse probability treatment weighting (IPTW), TDF maintained a significant advantage (5-year RFS: 37.4% vs. 19.6%, P = 0.006).
Prognostic Factors for HCC Recurrence
Multivariate Cox regression identified several independent predictors of recurrence:
- TDF treatment: Reduced recurrence risk by 40% (HR: 0.604, 95% CI: 0.427–0.856, P = 0.005).
- Liver cirrhosis: Increased risk by 56% (HR: 1.557, P = 0.004).
- Tumor size: Each 1 cm increase raised risk by 3.7% (HR: 1.037, P = 0.008).
- Microvascular invasion (MVI): Increased risk by 40% (HR: 1.403, P = 0.002).
- Portal vein tumor thrombus (PVTT): Increased risk by 36% (HR: 1.358, P = 0.012).
- Capsular invasion: Increased risk by 23% (HR: 1.228, P = 0.040).
- Creatinine levels: Higher levels marginally reduced risk (HR: 0.993, P = 0.031).
Mechanistic Insights and Clinical Implications
The superior performance of TDF over ETV may stem from differences in drug class and antiviral potency. TDF, a nucleotide analog, induces higher serum interferon-λ3 (IFN-λ3) levels, which exhibit antitumor effects, whereas ETV, a nucleoside analog, lacks this immunomodulatory property. Additionally, TDF’s higher genetic barrier to resistance ensures sustained viral suppression, potentially mitigating HBV-driven oncogenesis. These findings align with prior studies suggesting TDF’s association with lower HCC incidence in chronic HBV patients.
Limitations and Future Directions
The retrospective design introduces potential selection bias, particularly in antiviral therapy allocation. The smaller TDF cohort (n = 62) reflects its later approval in China (2014 vs. ETV in 2006), though baseline characteristics were largely comparable. Viral load (HBV-DNA) and HBeAg status did not independently predict recurrence, possibly due to effective viral suppression by both drugs. Future randomized controlled trials (RCTs) are needed to validate these findings and explore the interplay between antiviral efficacy, immune modulation, and tumor biology.
Conclusion
For HBV-related HCC patients beyond Milan criteria undergoing hepatectomy, TDF significantly reduces post-operative recurrence compared to ETV, offering a 5-year RFS advantage of 17.6%. This study underscores the importance of selecting optimal antiviral therapy as part of a multidisciplinary strategy to improve outcomes in advanced HCC.
doi.org/10.1097/CM9.0000000000001864
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