Mu-Gen Dai,1,2 Si-Yu Liu,2 Lin Zhu,3 Wen-Feng Lu,4 Gui-Lin Xie,5 Lei Liang,6 Jun-Wei Liu,6 Bin Ye1

1Department of Gastroenterology, The Fifth Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, People’s Republic of China; 2Department of Laboratory Medicine, The Key Laboratory of Imaging Diagnosis and Minimally Invasive Interventional Research of Zhejiang Province, Zhejiang University Lishui Hospital, Lishui, Zhejiang, People’s Republic of China; 3Department of Gastroenterology, Wenzhou Medical University, Wenzhou, Zhejiang Province, People’s Republic of China; 4Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Navy Medical University), Shanghai, People’s Republic of China; 5Department of Hepatobiliary Surgery, Affiliated Hospital of Shaoxing University, Shaoxing, Zhejiang Province, 312000, People’s Republic of China; 6General Surgery, Cancer Center, Department of Hepatobiliary & Pancreatic Surgery and Minimally Invasive Surgery, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, People’s Republic of China

Correspondence: Jun-Wei Liu, General Surgery, Cancer Center, Department of Hepatobiliary & Pancreatic Surgery and Minimally Invasive Surgery, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, People’s Republic of China, Email [email protected] Bin Ye, Department of Gastroenterology, The Fifth Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, People’s Republic of China, Email [email protected]

Background & Aims: To examine the association of the history of preoperative antiviral therapy (AVT) with the tumor recurrence and overall survival in HBV-related HCC patients undergoing curative-intent hepatectomy.
Methods: Patients who underwent curative-intent hepatectomy for HBV-related HCC between 2014 and 2019 at 4 Chinese hospitals were analyzed. Patients were categorized as having undergone preoperative antiviral therapy (AVT) > 1 year or without antiviral therapy (non-AVT). Patient clinical features, short-term outcomes, overall survival (OS), and time-to-recurrence (TTR) were also compared. Multivariate Cox regression analysis was performed to identify the impact of preoperative AVT on the OS and TTR.
Results: Among the 565 patients, 190 (33.6%) underwent continuous AVT > 1 year before surgery. Patients in the non-AVT group were more likely to have worse liver function and more advanced tumor pathological characteristics than those in the AVT group. Postoperative morbidity and mortality rates were comparable between the two groups. Multivariate analyses revealed that a preoperative HBV viral level ≥ 2000 IU/mL was independently associated with poorer TTR (hazard ratio, 1.328; 95% CI, 1.049– 1.682) and preoperative AVT was a protective factor for OS (hazard ratio, 0.691; 95% CI, 0.484– 0.986).
Conclusion: A high preoperative HBV DNA level was an independent risk factor for tumor recurrence. Preoperative AVT > 1 year was associated with better OS and a reduced incidence of tumor recurrence by inhibiting the preoperative level of HBV DNA.

Keywords: hepatectomy, hepatitis B virus, antiviral therapy, survival, recurrence

Introduction

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and ranks as the fifth most prevalent tumor and second leading cause of cancer-related deaths worldwide.1 Partial liver resection remains as the mainstay of curative modality used to treat HCC in appropriately selected patients.2,3 Owing to the high recurrence and mortality rates of HCC, long-term prognosis outcomes remain unsatisfactory, despite patients undergoing radical treatment. Hepatitis B virus (HBV) infection is a significant risk factor for HCC, and China has the highest prevalence of HCC cases associated with HBV.4,5

However, a host of HCC patients commonly only become aware of their HBV infection when they seek medical attention because of symptoms caused by advanced tumors.6,7 Previous studies have shown that long-term antiviral therapy (AVT) with nucleoside analogs (NAs) can reduce the incidence of HCC and prolong the survival of patients with chronic HBV infection.8–11 A high preoperative HBV load is associated with postoperative recurrence.12–14 Antiviral treatment after surgery for HBV-related HCC can reduce tumor recurrence and is widely used in clinical practice.15–17 Preoperative short-term AVT has been reported to reduce early recurrence18 and prolong OS.19,20 Although many patients with chronic HBV infection receive long-term antiviral treatment, they still progress to HCC. Understanding the clinicopathological characteristics of patients receiving AVT compared with those who did not benefit from our clinical practice. However, studies on the correlation between preoperative long-term AVT and prognosis following surgery for HBV-related HCC are currently limited.

As such, the aim of current study was to investigate the clinicopathological features, perioperative outcomes and long-term oncologic prognosis of preoperative AVT versus non-AVT with HBV-related HCC.

Patients and Methods Patients and Study Design

With the approval of the institutional review boards of all participating centers, a retrospective study was performed on a primary cohort of newly diagnosed patients who underwent curative hepatectomy between January 2015 and December 2019 at Zhejiang University Lishui Hospital, Zhejiang Provincial People’s Hospital, Eastern Hepatobiliary Surgery Hospital, and ShaoXing Municipal Hospital in China. HCC was confirmed via postoperative pathological examination. Curative liver resection was defined as removal of HCC with a microscopically negative margin (R0 resection). All patients with HBV-related HCC, except for those with HBsAg seroclearance, were routinely treated with antiviral drugs after hepatectomy.

The inclusion criteria were as follows: 1) curative-intent resection, 2) no history of previous anti-cancer therapy, 3) no history of other malignancies, 4) HBV-related HCC, and 5) an Eastern Cooperative Oncology Group (ECOG) status score less than 2. The exclusion criteria were as follows: 1) gross vascular invasion, 2) recurrent HCC, 3) incomplete preoperative or postoperative follow-up medical records, and 4) palliative resection and presence of tumor rupture. Informed consent was obtained from all patients to be used for the research. This study was performed in accordance with the Declaration of Helsinki and Ethical Guidelines for Clinical Studies in all participating hospitals.

Clinicopathological Characteristics and Operative Variables

Risk factors for survival and recurrence were evaluated as categories related to the patient, tumor, and treatment. Patient-related variables included age, sex, American Society of Anesthesiologists (ASA) score, serum Hepatitis B Surface Antigen (HBsAg) seroclearance, presence of cirrhosis or portal hypertension, albumin-bilirubin score (ALBI),21 Child-Pugh grade, preoperative serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, and preoperative HBV DNA level. Portal hypertension was defined as the presence of esophageal varices or splenomegaly with a decreased platelet count (≤ 100×109/L). Tumor-related variables included preoperative serum alpha-fetoprotein (AFP) level, largest tumor diameter, tumor number (solitary or multiple), microvascular invasion (MVI) (negative or positive), satellite (negative or positive), tumor differentiation, tumor encapsulation, and tumor stage identified by the Barcelona Clinic Liver Cancer (BCLC) staging system.22 Operative variables included intraoperative blood loss (≤ 400 mL or > 400 mL), intraoperative blood transfusion (negative or positive), extent of liver resection (minor or major), type of hepatectomy (anatomical or non-anatomical), and resection margin status. Cirrhosis and tumor-related variables were diagnosed using imaging studies, including ultrasonography, contrast-enhanced computed tomography (CT), and magnetic resonance imaging (MRI) of the abdomen. Major hepatectomy was defined as the removal of three or more Couinaud’s segments through partial hepatectomy, whereas minor hepatectomy involved the removal of fewer than three segments. Anatomical resections were determined according to the Brisbane 2000 nomenclature of liver anatomy.23 Non-anatomical resections include limited or wedge resection.

Follow-Up and Primary Outcomes

Patients included in this study were closely monitored by both participating hospitals using a comprehensive surveillance strategy. Following discharge from the hospital, the patients underwent regular follow-up examinations at intervals of 2–3 months for the first 6 months, 3–4 months for the subsequent one and year, and every 3–6 months thereafter. These examinations included measurements of serum alpha-fetoprotein (AFP) and prothrombin induced by Vitamin K Absence-II (PIVKA II) levels as well as abdominal ultrasound, CT, or MRI. When HCC recurrence was suspected, contrast-enhanced CT or MRI, bone scan, or positron emission tomography was performed as clinically indicated.24,25 Tumor recurrence was defined as the new appearance of an intra- or extra-hepatic nodule(s), with or without an increase in serum AFP or PIVKA II levels, which had typical imaging features consistent with the characteristics of HCC on enhanced CT or MRI examinations. Patients with tumor recurrence were actively treated with re-resection, TACE, percutaneous local ablation, radiotherapy, oral sorafenib, lenvatinib, or conservative treatment either alone or in combination. The primary endpoints of this study were survival and recurrence rates. At the time of initial recurrence, detailed information regarding the recurrence patterns and primary treatment received was documented.

Study Endpoints

The main goal of this study was to examine the long-term outcomes of patients. These outcomes included two primary endpoints, overall survival (OS) and time-to-recurrence (TTR). OS was defined as the period from the date of liver resection to either the date of death or the date of the last follow-up, which was crucial in determining the effectiveness of the treatment and assessing its impact on patients’ life expectancy. TTR was defined as the time from surgery to tumor recurrence or the occurrence of new HCC, which aimed to evaluate the effectiveness of surgical intervention in preventing tumor recurrence. For TTR, patients who died without tumor recurrence were censored at the last documented assessment.

Statistical Analysis

Clinical characteristics, operative variables, perioperative outcomes, and long-term outcomes were compared between the two groups. Statistical analyses were performed using SPSS software (version 25.0; SPSS, Chicago, IL, USA). Categorical variables are expressed as numbers or proportions, while continuous variables are expressed as mean ± standard deviation or median (range). Fisher’s exact test and Wilcoxon rank-sum test were used for categorical and continuous variables, respectively. The OS and TTR rates were calculated using the Kaplan-Meier method and compared using the Log rank test. Univariate and multivariate Cox proportional hazards regression analyses were performed using forward stepwise variable selection. Variables with a P < 0.1 on univariable analysis, were subjected to multivariable Cox regression analysis. Statistical significance was set at P < 0.05.

Results Comparisons Clinicopathologic Characteristics

During the study period, 565 consecutive patients who underwent curative-intent liver resection for HBV-related HCC met the inclusion criteria (Figure 1). A total of 34 (6.0%) HBV-related HCC patients achieved HBsAg seroclearance before surgery. Clinicopathological characteristics of patients in the non-AVT and AVT groups were compared. Regarding clinicopathological variables, patients in the AVT group patients less often had lower preoperative ALT (11.1% vs 31.2%), AST (7.9% vs 24.8%), and HBV DNA levels (7.4% vs 52.5%). The proportion of patients with the largest tumor size of > 5 cm (25.3 vs 45.9%) and satellites (4.2% vs 12.8%) was higher among patients without AVT (all P < 0.05). Therefore, there was a statistically significant difference in the BCLC stage between the two groups (P = 0.003). As for operative variables, the operation time was longer, and the proportion of major hepatectomy and non-anatomical hepatectomy was higher in the non-AVT group (all P < 0.05).

Figure 1 Selection of the study population.

Comparisons of Perioperative and Long-Term Outcomes

With respect to perioperative outcomes, there were no differences between AVT and non-AVT patients, including the incidence of postoperative 30-day morbidity (overall, minor, or major), mortality, 90-day mortality, and duration of postoperative hospital stay (all P > 0.05), as shown in Table 1. After excluding postoperative early deaths, a comparison of long-term outcomes between the two groups is shown in Table 2. The overall incidence of recurrence in patients receiving AVT was lower than those not receiving AVT (P = 0.004), but there were no differences in the patterns (intrahepatic, extrahepatic, or both) and BCLC stage of the initial recurrence. 22.6% patients in the AVT groups, 22.6% and 39.4% of the patients in the non-AVT group died during follow-up, but the proportions of cancer-specific and non-cancer-specific mortality between the two groups were similar (P = 0.371). The OS and TTR among patients receiving AVT versus those not receiving AVT are shown in Figure 2A and B, respectively. The 1-, 3-, and 5-year OS rates in the AVT and non-AVT group patients were 95.3%, 89.5%, and 79.0% vs 96.0%, 77.8%, and 63.4%, respectively, and the difference in OS between the two groups was significant (P < 0.01). Meanwhile, the1-, 3-, and 5-year TTR rates for patients in the AVT and non-AVT groups were 17.9%, 32.8%, and 41.9% versus 27.3%, 45.9%, and 54.3%, respectively, and the difference in TTR between the groups was significant (P = 0.002).

Table 1 Baseline Characteristics of the Patients in the Two Cohorts

Table 2 Long-Term Outcomes After Excluding Postoperative Early Deaths (Postoperative 90-Day Mortality)

Figure 2 Curves comparisons of survival (A) and recurrence (B) between two groups in the whole cohort (calculated by Log rank test).

Prognostic Analyses of OS and TTR in the Whole Cohort

Tables 3 and 4 describe the risk factors associated with OS and TTR after hepatectomy for HBV-related HCC, which were examined using univariate and multivariate Cox regression analyses, respectively. After adjusting for other confounding factors, preoperative AVT was independently associated with better OS (hazard ratio, 0.691; 95% confidence interval: 0.484–0.986, P = 0.042) but not poorer TTR (P = 0.371).

Table 3 Univariable and Multivariable Cox Regression Analyses of Preoperative Predictive Factors for Survival

Table 4 Univariable and Multivariable Cox Regression Analyses of Preoperative Predictive Factors for Recurrence

Prognostic analyses of OS and TTR in the non-AVT cohort.

In the sub-analysis of the non-AVT cohort, the OS and TTR of patients with low HBV DNA levels versus those with high HBV DNA levels are shown in Figure 3A and B. Similarly, independent risk factors were identified in patients who did not undergo AVT using a multivariate Cox regression analysis as shown in Table 5. We found that high HBV DNA levels remained independent of an increased TTR (hazard ratio, 1.362; 95% confidence interval: 1.026–1.810, P = 0.032).

Table 5 Independent Risk Factors Associated with Overall Survival (OS) and Time-to-Recurrence (TTR) in Patients Not Receiving AVT After Liver Resection for HBV-Related Hepatocellular Carcinoma

Figure 3 Curves comparisons of survival (A) and recurrence (B) between two groups in the non-AVT cohort (calculated by Log rank test).

Discussion

The present multicenter study from China analyzed the clinicopathological characteristics and short- and long-term outcomes of curative hepatectomy for HBV-related HCC. In this study, only 190 (33.6%) HCC patients received regular antiviral therapy before surgery, indicating the neglect of HBV infection and ignorance of disease progression by the patients. Patients who did not receive any AVT preoperatively were more likely to have high preoperative HBV DNA levels and advanced tumor pathological features (proportion of tumor size > 5 cm, satellites, and BCLC stage B/C) than those who received AVT for more than 1 year. Short-term outcomes, including postoperative mortality and morbidity, were comparable between the AVT and non-AVT groups. Patients who underwent continuous preoperative AVT had better OS than those who did not. In addition, a viral level of > 2000 IU/mL was significantly associated with increased HCC recurrence after partial liver resection. Eliminating social discrimination against HBV, strengthening communication between doctors and patients, and enhancing the awareness of HBV patients about the disease may increase the antiviral treatment rate.

Numerous previous studies have shown that HBeAg-positive status in patients with chronic HBV infection is a significant risk factor for HCC.26–28 Interestingly, the proportion of HBeAg-positive in AVT group was significantly higher in the AVT group than that in the non-AVT group. If patients with chronic HBV who have received AVT remain HBeAg-positive, more attention should be paid to HBV control and regular screening for HCC development. The preoperative AVT group exhibited a relatively lower tumor burden, potentially owing to the heightened awareness of liver cancer prevention among these patients. In this study, HCC patients who received preoperative AVT demonstrated superior liver function reserve, which may contribute to better OS.29

In this cohort, all patients with HBV-related HCC except those with HBsAg seroclearance were routinely treated with antiviral drugs after hepatectomy.30 Tenofovir disoproxil might be associated with better long-term OS and RFS rates compared with entecavir for HBV-related HCC patients undergoing curative liver resection.31 Portal vein tumor thrombosis (PVTT) is an independent factor of 90-day mortality and long-term outcomes.32 We excluded the HCC patients with PVTT due to the effect of preoperative antiviral therapy was easily overshadowed by the extremely high-risk factor. To explore the association between preoperative AVT and HBV DNA and long-term prognosis in patients with HCC who underwent liver resection, it may be more intuitive to further divide preoperative AVT and non-AVT patients into four groups based on the level of HBV DNA to demonstrate their potential relationship. However, because only 14 (7.4%) patients in the preoperative AVT group had viral levels of > 2000 IU/mL, further analysis was not possible. Therefore, subgroup analysis was performed in the non-AVT cohort, and the results showed that a high preoperative viral level was still an independent risk factor for recurrence but not for overall survival. Several previous studies have suggested that preoperative antiviral therapy may reduce the incidence of MVI for HBV-related HCC.18,33 Concerning 2362 HBV-related HCC patients who underwent liver resection, Li et al demonstrated that antiviral treatment administered more than 90 days before surgery was associated with early tumor recurrence by reducing the incidence of MVI.18 Huang et al further reported that preoperative antiviral therapy can prolong survival and decrease the recurrence rate of patients with recurrent HCC.34 However, it was not an independent risk factor for recurrence, although the survival curves indicated that the preoperative AVT group performed significantly better than the non-AVT group did. In our opinion, this result may be due to the fact that preoperative antiviral drugs indirectly affect the recurrence by controlling the level of viral DNA. The effect of antiviral drugs on improving OS in our study is consistent with the results of previous studies.20,34,35

Our study has some limitations. First, the study was retrospective in nature, which could have led to inherent bias. In addition, chronic HBV infection is the leading etiology of HCC in China and many Asian countries, and is distinct from the pattern of disease seen in the United States and other Western countries. Furthermore, owing to the retrospective nature of the study, the specific antiviral duration of each patient could not be determined; therefore, the optimal preoperative antiviral duration could not be further analyzed.

Ethics Approval and Consent to Participate

The study was performed in accordance with the Declaration of Helsinki and was approved by the Institutional Review Boards of all the participating hospitals.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Funding

This study was supported by the Public Welfare Technology Application Research Projects from the Science and Technology Bureau of Lishui (No. 2022GYX50), the Natural Science Foundation of Zhejiang Province (No. LQ23H160049), and Health Science and Technology Plan of Zhejiang Province (No. 2022KY453).

Disclosure

The authors report no conflicts of interest in this work.

References

1. Llovet JM, Kelley RK, Villanueva A. et al. Hepatocellular carcinoma. Nat Rev Dis Primers. 2021;7(1):6. doi:10.1038/s41572-020-00240-3

2. Kulik L, El-Serag HB. Epidemiology and management of hepatocellular carcinoma. Gastroenterology. 2019;156(2):477–491.e1.

3. Zaydfudim VM, Vachharajani N, Klintmalm GB, et al. Liver resection and transplantation for patients with hepatocellular carcinoma beyond Milan criteria. Ann Surg. 2016;264(4):650–658. doi:10.1097/SLA.0000000000001866

4. Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209–249. doi:10.3322/caac.21660

5. Chen S, Li J, Wang D, Fung H, Wong LY, Zhao L. The hepatitis B epidemic in China should receive more attention. Lancet. 2018;391(10130):1572. doi:10.1016/S0140-6736(18)30499-9

6. Galle PR, Tovoli F, Foerster F, Wörns MA, Cucchetti A, Bolondi L. The treatment of intermediate stage tumours beyond TACE: from surgery to systemic therapy. J Hepatol. 2017;67(1):173–183.

7. Forner A, Gilabert M, Bruix J, Raoul JL. Treatment of intermediate-stage hepatocellular carcinoma. Nat Rev Clin Oncol. 2014;11(9):525–535. doi:10.1038/nrclinonc.2014.122

8. Hosaka T, Suzuki F, Kobayashi M, et al. Long-term entecavir treatment reduces hepatocellular carcinoma incidence in patients with hepatitis B virus infection. Hepatology. 2013;58(1):98–107. doi:10.1002/hep.26180

9. Tang L, Covert E, Wilson E, Kottilil S. Chronic hepatitis B infection: a review. JAMA. 2018;319(17):1802–1813. doi:10.1001/jama.2018.3795

10. Hou JL, Zhao W, Lee C, et al. Outcomes of long-term treatment of chronic HBV infection with entecavir or other agents from a randomized trial in 24 countries. Clin Gastroenterol Hepatol. 2020;18(2):457–467.e21. doi:10.1016/j.cgh.2019.07.010

11. Liaw YF, Sung JJ, Chow WC, et al. Lamivudine for patients with chronic hepatitis B and advanced liver disease. N Engl J Med. 2004;351(15):1521–1531. doi:10.1056/NEJMoa033364

12. Ohkubo K, Kato Y, Ichikawa T, et al. Viral load is a significant prognostic factor for hepatitis B virus-associated hepatocellular carcinoma. Cancer. 2002;94(10):2663–2668. doi:10.1002/cncr.10557

13. Zhang D, Feng D, Ren M, Bai Y, Liu Z, Wang H. Preoperative serum hepatitis B virus DNA was a risk factor for hepatocellular carcinoma recurrence after liver transplantation. Ann Med. 2022;54(1):2213–2221. doi:10.1080/07853890.2022.2107233

14. Kubo S, Hirohashi K, Tanaka H, et al. Effect of viral status on recurrence after liver resection for patients with hepatitis B virus-related hepatocellular carcinoma. Cancer. 2000;88(5):1016–1024. doi:10.1002/(SICI)1097-0142(20000301)88:5<1016::AID-CNCR10>3.0.CO;2-V

15. Huang G, Li PP, Lau WY, et al. Antiviral therapy reduces hepatocellular carcinoma recurrence in patients with low HBV-DNA levels: a randomized controlled trial. Ann Surg. 2018;268(6):943–954. doi:10.1097/SLA.0000000000002727

16. Huang G, Lau WY, Wang ZG, et al. Antiviral therapy improves postoperative survival in patients with hepatocellular carcinoma: a randomized controlled trial. Ann Surg. 2015;261(1):56–66. doi:10.1097/SLA.0000000000000858

17. Yin J, Li N, Han Y, et al. Effect of antiviral treatment with nucleotide/nucleoside analogs on postoperative prognosis of hepatitis B virus-related hepatocellular carcinoma: a two-stage longitudinal clinical study. J Clin Oncol. 2013;31(29):3647–3655. doi:10.1200/JCO.2012.48.5896

18. Li Z, Lei Z, Xia Y, et al. Association of preoperative antiviral treatment with incidences of microvascular invasion and early tumor recurrence in hepatitis B virus-related hepatocellular carcinoma. JAMA Surg. 2018;153(10):e182721. doi:10.1001/jamasurg.2018.2721

19. Li C, Li ZC, Ma L, et al. Perioperative antiviral therapy improves the prognosis of HBV DNA-negative patients with HBV-related hepatocellular carcinoma. Expert Rev Gastroenterol Hepatol. 2020;14(8):749–756. doi:10.1080/17474124.2020.1784727

20. Liu XF, Zhang T, Tang K, Sui LL, Xu G, Liu Q. Study of Preoperative Antiviral Treatment of Patients with HCC Negative for HBV-DNA. Anticancer Res. 2017;37(8):4701–4706. doi:10.21873/anticanres.11875

21. Johnson PJ, Berhane S, Kagebayashi C, et al. Assessment of liver function in patients with hepatocellular carcinoma: a new evidence-based approach-The ALBI grade. J Clin Oncol. 2015;33(6):550–558. doi:10.1200/JCO.2014.57.9151

22. Reig M, Forner A, Rimola J, et al. BCLC strategy for prognosis prediction and treatment recommendation: the 2022 update. J Hepatol. 2022;76(3):681–693. doi:10.1016/j.jhep.2021.11.018

23. Pang YY, Belghiti J, Clavien P-A. The Brisbane 2000 terminology of liver anatomy and resections. HPB. 2000;2(3):333–339. doi:10.1016/S1365-182X(17)30755-4

24. Yamamoto K, Imamura H, Matsuyama Y, et al. AFP, AFP-L3, DCP, and GP73 as markers for monitoring treatment response and recurrence and as surrogate markers of clinicopathological variables of HCC. J Gastroenterol. 2010;45(12):1272–1282. doi:10.1007/s00535-010-0278-5

25. Feng H, Li B, Li Z, Wei Q, Ren L. PIVKA-II serves as a potential biomarker that complements AFP for the diagnosis of hepatocellular carcinoma. BMC Cancer. 2021;21(1):401. doi:10.1186/s12885-021-08138-3

26. Yang HI, Lu SN, Liaw YF, et al. Hepatitis B e antigen and the risk of hepatocellular carcinoma. N Engl J Med. 2002;347(3):168–174. doi:10.1056/NEJMoa013215

27. Yang HI, Yuen MF, Chan HL, et al. Risk estimation for hepatocellular carcinoma in chronic hepatitis B (REACH-B): development and validation of a predictive score. Lancet Oncol. 2011;12(6):568–574. doi:10.1016/S1470-2045(11)70077-8

28. Yang HI, Sherman M, Su J, et al. Nomograms for risk of hepatocellular carcinoma in patients with chronic hepatitis B virus infection. J Clin Oncol. 2010;28(14):2437–2444. doi:10.1200/JCO.2009.27.4456

29. Wang X, Liu X, Wang P, et al. Antiviral therapy reduces mortality in hepatocellular carcinoma patients with low-level hepatitis B viremia. J Hepatocell Carcinoma. 2021;8:1253–1267. doi:10.2147/JHC.S330301

30. He Z, Tang D. Perioperative predictors of outcome of hepatectomy for HBV-related hepatocellular carcinoma. Front Oncol. 2023;13:1230164. doi:10.3389/fonc.2023.1230164

31. Li P, Wang Y, Yu J, et al. Tenofovir vs Entecavir among patients with HBV-related HCC after resection. JAMA Network Open. 2023;6(10):e2340353. doi:10.1001/jamanetworkopen.2023.40353

32. Yin Y, Cheng JW, Chen FY, et al. A novel preoperative predictive model of 90-day mortality after liver resection for huge hepatocellular carcinoma. Ann Transl Med. 2021;9(9):774. doi:10.21037/atm-20-7842

33. Wang Z, Duan Y, Zhang J, et al. Preoperative antiviral therapy and microvascular invasion in hepatitis B virus-related hepatocellular carcinoma: a meta-analysis. Eur J Pharmacol. 2020;883:173382. doi:10.1016/j.ejphar.2020.173382

34. Huang S, Xia Y, Lei Z, et al. antiviral therapy inhibits viral reactivation and improves survival after repeat hepatectomy for hepatitis B virus-related recurrent hepatocellular carcinoma. J Am Coll Surg. 2017;224(3):283–293.e4. doi:10.1016/j.jamcollsurg.2016.11.009

35. Fu J, Ding Z, Chen Q, et al. Distinct impacts of pre-operative antiviral treatment on post-operative outcomes of HBV-related hepatocellular carcinoma: a landmark analysis. J Cancer. 2021;12(1):170–180. doi:10.7150/jca.47125