In Asia, hepatocellular carcinoma (HCC) is most frequently caused by hepatitis B virus (HBV) infection. Treatments such as radical resection, transarterial chemoembolization (TACE), and radiofrequency ablation (RFA) can effectively improve the prognosis of patients with hepatitis B virus-associated hepatocellular carcinoma (HBV-HCC). Nevertheless, despite treatment, the 5-year survival rate remains at only 50%, with a recurrence rate surpassing 70% (Shen et al., 2018). Research has demonstrated that postoperative antiviral therapy using nucleos(t)ide analogs such as lamivudine (LAM), entecavir (ENT), adefovir (ADV), telbivudine (Ldt), and tenofovir disoproxil fumarate (TDF) can suppress the replication of hepatitis B virus deoxyribonucleic acid (HBV-DNA), reduce the HBV-DNA level in the body, improve overall survival (OS) and recurrence-free survival (RFS) in HBV-HCC patients (Choi et al., 2021; He et al., 2019; Huang et al., 2013; Kao et al., 2023; Li et al., 2023; Linye et al., 2023; Qi et al., 2021; Qi et al., 2020; Ren et al., 2018; Rui et al., 2017; Shen et al., 2022; Wang et al., 2022; Xiao et al., 2021; Xu et al., 2019; Zhong et al., 2016; Chen, 2015; Cheng et al., 2011; Ding et al., 2014; Fang et al., 2012; Lin et al., 2016; Zhang, 2015; Huang et al., 2015; Ke et al., 2013; Zhang et al., 2014; Chen et al., 2017), and thereby improve patient prognosis. However, no consensus has been reached on which specific antiviral drug offers the optimal effect for improving the prognosis. Some studies comparing tenofovir and ENT have suggested that TDF is superior to ENT in improving the survival rate and reducing the recurrence rate of HBV-HCC patients (Hu et al., 2022). However, research has reported no significant differences in OS or recurrence rate between the two drugs (Li et al., 2023). Similarly, studies comparing the efficacy of ENT and LAM have reported conflicting results. Research has found similar effects of ENT and LAM on OS in HBV-HCC patients (Shin et al., 2012), while ENT has been reported in other research to provide superior effects for improving OS compared to LAM (Kim et al., 2016). Therefore, we utilized a systematic review and network meta-analysis to integrate existing evidence, aiming to identify the optimal antiviral treatment for affected patients.

The results of this study indicated that nucleos(t)ide analogs, such as LAM, ENT, ADV, Ldt, and TDF, significantly improved OS and RFS in HBV-HCC patients after radical resection, compared to those who did not receive nucleos(t)ide analog antiviral therapy. A key mechanism of HBV-induced carcinogenesis is the extensive replication of HBV in the body following infection. This process leads to the integration of HBV DNA into the host hepatocyte genome, triggering the activation of proto-oncogenes and impairing the function of tumor suppressor genes, thereby driving the development and progression of liver cancer (Jiang et al., 2021). In HBV-HCC patients, after taking nucleos(t)ide analog antiviral drugs, these analogs are converted into triphosphate compounds through catalysis by cellular kinases. Due to the absence of a 3′-hydroxyl group in their ribose molecules, the triphosphate compounds, once integrated into viral DNA, cause the termination of DNA chain elongation. This process inhibits HBV-DNA replication and effectively reduces the HBV viral load (Levrero and Zucman-Rossi, 2016). Studies have found that high HBV viral load in the serum can promote the growth and metastasis of HCC (Su et al., 2013; Huang et al., 2011). Radical resection alters the immune status of HBV-HCC patients, making them prone to HBV reactivation and high HBV viral load replication postoperatively (Li et al., 2020; Wang et al., 2023). Nucleos(t)ide analogs, which can inhibit HBV-DNA replication, effectively reduce the HBV-DNA level, thereby improving OS and RFS in these patients. Additionally, treatment with nucleos(t)ide analogs has been shown to reduce the levels of regulatory T cells (Tregs) in the peripheral blood of patients with chronic hepatitis B (He and Zhao, 2019; Xu, 2021). Research has indicated that CD4⁺CD25^high regulatory T cells suppress Th cell responses and HBV-specific cytotoxic T lymphocyte-mediated immune responses, which are considered key contributors to HBV immune tolerance (Cheng et al., 2023; Yu, 2018). Nucleos(t)ide analogs can decrease the levels of peripheral Tregs, thereby reducing immune tolerance, modulating the patient’s immune status (He and Zhao, 2019), and facilitating viral clearance in HBV-HCC patients. This mechanism contributes to the improvement of OS and RFS in these patients.

Furthermore, our study findings suggested that different types of nucleos(t)ide analogs exhibited varying effects on improving OS and RFS in HBV-HCC patients. LAM, ENT, and ADV were less effective than Ldt in improving OS, while ENT was less effective than TDF. In terms of improving RFS, LAM was less effective than ENT, and both LAM and ADV were less effective than Ldt. Moreover, LAM, ENT, and ADV were all less effective than TDF. These differences may be attributed to variations in the specific mechanisms by which different nucleos(t)ide analogs inhibit HBV-DNA replication. LAM is a cytosine analog that inhibits DNA replication by competitively binding to the active site of HBV reverse transcriptase, thereby blocking its activity. ADV is an adenosine monophosphate analog that competes with natural nucleoside triphosphates (NTPs) to inhibit HBV DNA polymerase. ENT is a guanosine analog that competes with dGTP for HBV DNA polymerase. Ldt is a thymidine deoxynucleotide analog that competes with HBV’s natural substrate, thymidine 5′-adenosine. TDF is a diphosphate of fovir, which competes for incorporation into the viral DNA chain. Due to the absence of a 3′-OH group, tenofovir blocks DNA chain elongation and inhibits viral replication (Hruba et al., 2023; Zhang et al., 2019). Since HBV is a retrovirus, its reverse transcriptase lacks proofreading capability and cannot correct mismatched nucleotides (Yasutake et al., 2020). This characteristic leads to the presence of viral strains with diverse genetic sequences in HBV-HCC patients. During long-term postoperative use of nucleos(t)ide analogs, drug-resistant strains with greater survival ability and replication potential are gradually selected. Consequently, drug resistance frequently develops, leading to reduced sensitivity of the virus to antiviral therapy (Song et al., 2012; Liu et al., 2021). Clinical trial evidence has indicated that the rates of drug resistance vary depending on the type of nucleos(t)ide analog used in treatment. During LAM treatment, the drug resistance rate was approximately 20% after 1 year and increased to as high as 70% after 5 years. Furthermore, about 50% of patients who develop LAM resistance would also develop resistance to ENT within 5 years of treatment (Amini-Bavil-Olyaee et al., 2010). For ADV, the resistance rate was around 2% after 2 years and approximately 29% after 5 years (Roediger et al., 2022). During Ldt, the resistance rate was 11% after 2 years (Tacke and Kroy, 2016). For ENT, the resistance rate was 1.2% after 5 years of treatment (Takayama et al., 2021), while TDF showed a similarly low resistance rate during treatment (Li et al., 2021). This may be related to the poorer effectiveness of LAM in improving OS and RFS, compared to the better outcomes observed with Ldt, TDF, and ENT. The differences in resistance rates among various nucleos(t)ide analogs may be attributed to their specific resistance mechanisms and mutation sites. For LAM, resistance is primarily associated with mutations at rtM204I/V in the POL/RT region. ADV resistance is linked to mutations at rtN236T in the D domain. ENT resistance develops after the emergence of the rtM204V + rtL180M mutations. Ldt resistance is associated with mutations at rtL80I and rtL80V, while TDF resistance is related to mutations at rtP177G and rtF249A (Li et al., 2021).

This study has certain limitations. First, most of the included studies are cohort studies, with relatively few RCTs addressing the topic. Second, some of the included studies had small sample sizes. The study did not ascertain the effects of other non-nucleoside antiviral drugs, such as interferons, or combination therapy regimens due to the limited number of studies. All participants were from East Asian populations, limiting the generalizability of the conclusions. Caution is needed when applying these findings to populations in other regions. Future research should consider including multinational data to enhance global applicability. Third, many of the included RCTs were open-label designed, with no mention of allocation concealment or blinding methods, raising the possibility of implementation and measurement biases, which could affect the reliability of the results. Fourth, the outcome measures did not account for the incidence of adverse events, as only a few studies provided relevant data. Fifth, owing to the small number of included studies, publication bias was not examined. Sixth, excluding preoperative antiviral therapy may affect the external validity of the findings, as preoperative treatment is clinically significant in preventing viral reactivation and improving prognosis. Future research could consider evaluating the impact of preoperative treatment.

Different types of nucleos(t)ide analogs can improve both OS and RFS in HBV-HCC patients after radical resection. Although the findings of this study suggest that Ldt and TDF exhibit the most notable effects on OS and RFS in HBV-HCC patients, it may cause drug resistance. As the Ldt therapy is used continuously, drug resistance may occur, which may limit its long-term effectiveness. Due to the limitations of this study, the results of this study should be interpreted with caution. Clinicians should be cautious when applying these findings to long-term treatment plans. Further research is needed to explore strategies to prevent and manage drug resistance in these patients.