Published online Sep 24, 2024. doi: 10.5306/wjco.v15.i9.1251
Revised: August 8, 2024
Accepted: August 19, 2024
Published online: September 24, 2024
Processing time: 127 Days and 16.8 Hours
Globally, hepatocellular carcinoma (HCC) is among the most prevalent and deadly cancers. Hepatitis B virus (HBV) infection is an important etiology and disease progression factor for HCC. Hepatectomy is a widely accepted curative treatment for HCC, but the long-term survival rate is still unsatisfactory due to the high recurrence rate after resection. Preoperative or postoperative antiviral therapy plays an important role in improving the prognosis for HBV-related HCC patients who underwent hepatectomy. However, many patients miss out on the chance to receive long-term preoperative antiviral medication because their HBV and HCC infections are discovered concurrently, necessitating the start of remedial antiviral therapy in the perioperative phase. Therefore, it is of great value to know when antiviral therapy is more appropriate and whether perioperative rescue antiviral therapy can achieve the effect of preoperative long-term antiviral therapy.
Core Tip: Hepatocellular carcinoma (HCC) is one of the most common and highly fatal malignancies worldwide and is usually associated with hepatitis B virus (HBV) infection. Hepatectomy is a widely accepted curative treatment for HCC, but the long-term survival rate is still unsatisfactory due to the high recurrence rate after resection. Preoperative or postoperative antiviral therapy plays an important role in improving the prognosis for HBV-related HCC patients who underwent hepatectomy. Therefore, we explored when antiviral therapy is more appropriate and whether perioperative rescue antiviral therapy can achieve the effect of preoperative long-term antiviral therapy in the paper.
- Citation: Wan DL, Sun LQ. Timing of antiviral therapy in patients with hepatitis B virus related hepatocellular carcinoma undergoing hepatectomy. World J Clin Oncol 2024; 15(9): 1251-1255
- URL: https://www.wjgnet.com/2218-4333/full/v15/i9/1251.htm
- DOI: https://dx.doi.org/10.5306/wjco.v15.i9.1251
Hepatocellular carcinoma (HCC) ranks fourth in terms of cancer-related mortality and is the sixth most frequent cancer globally[1]. One of the main causes of HCC is a persistent hepatitis B virus (HBV) infection[2]. Currently, the most effective curative treatments for HCC are liver transplantation and curative surgical resection[3]. Even with these therapies, there is a significant chance that HCC may return; over 70% of patients do so within five years following surgery[4]. Antiviral therapies administered both before and after surgery are acknowledged to be essential for improving the prognosis and length of life for patients with hepatectomy-related HBV-associated HCC. It's still unclear when antiviral medication is more advantageous for patients and if perioperative rescue antiviral therapy can match the impact of preoperative long-term antiviral therapy.
HBV is a class I carcinogen and chronic HBV infection carries a lifetime risk of developing HCC with a 10%-25% probability. HBV-related HCC is the result of a multi-gene, multi-step interaction mechanism. The synergistic action of various cancer-promoting mechanisms accelerates the evolution of the disease from inflammation to tumorigenesis[5]. The pathogenesis of HBV-related hepatocellular carcinoma (HBV-related HCC) includes HBV gene integration, genomic instability, and activation of cancer-promoting signaling pathways caused by mutations. After HBV enters the host cell, part of the double-stranded DNA is transformed into a stable covalently closed circular DNA (cccDNA) in the nucleus of the host cell and retained in the nucleus of the infected host cell, which is used as a template for transcription of the intermediates of the four virus mRNA[6]. With the progress of the research on the pathogenesis of HBV-HCC, many new mechanisms, such as epigenetics, exosomes, autophagy, metabolic regulation, and immunosuppression, are also being explored. HBV induces immune suppressive cells, such as MDSCs, NK-reg, and T-reg cells, through an immunosuppressive cascade. Excessive immunosuppression could contribute to an HBV persistent infection and the progression of liver fibrosis and HCC[7]. Moreover, it has been reported that HBV variants increase the risk of HCC[8]. Therefore, HBV plays a crucial role in the development and progression of HCC.
Long-term antiviral therapy to reduce the risk of HCC is one of the cornerstones for the management of chronic HBV[9]. Several studies have confirmed that antiviral therapy can significantly delay the progression of liver fibrosis and reduce the incidence of HCC in patients with HBV[10]. The overall survival and relapse-free survival of the antiviral group were significantly better than those of the non-antiviral group. Therefore, antiviral treatment is crucial for improving the prognosis of HCC patients.
The measure of successful treatment (functional cure) is the persistence of undetectable HBsAg and HBV DNA in serum with or without anti-HBs after a limited course of treatment[11]. However, in the absence of cccDNA eradication, even the functional cure is achieved with antiviral therapy, HBV-infected patients are still at risk of developing HCC, especially those who have already developed cirrhosis[12]. Pegylated interferon-α can enhance cccDNA degradation and anti-HBV immune response, and also has moderate antiviral activity. Nucleos(t)ide analogs are safe and effective in inhibiting HBV replication but have no direct effect on cccDNA. Nucleos(t)ide analogs rarely clear HBsAg and require long-term treatment to prevent recurrence[13,14]. Multiple steps need to be met to achieve the goal of functional cure of HBV: Complete inhibition of HBV DNA replication, suppression of HBsAg production, and restoration of innate and HBV-specific immune responses. Therefore, new antiviral agents and immunomodulatory therapies are being developed, while combinations of several drug classes will also be necessary[15].
Some studies have suggested that partial hepatectomy for HBV-related HCC can lead to reactivation of HBV re
Preoperative long-term antiviral therapy for at least 24 weeks reduces preoperative HBV-DNA levels in patients, and low preoperative HBV-DNA levels are associated with a reduced incidence of early tumor recurrence and vascular invasion after hepatectomy in patients with HBV-related HCC[17]. Perioperative antiviral therapy significantly reduced the risk of HBV reactivation and improved postoperative liver function, recurrence-free survival (RFS), and overall survival (OS) in both HBsAg-positive and HBV DNA-negative or positive patients before hepatectomy[18-20]. Postoperative adjuvant antiviral therapy can improve liver inflammation and fibrosis, reduce recurrence rate, and improve survival rate in patients with HBV-related HCC after hepatectomy[21-23]. Therefore, patients with HBV-related HCC who need hepatectomy can benefit from antiviral therapy, whether it is given before, after, or during the perioperative period. In a large, multinational study of participants with HBV-related HCC who underwent hepatic resection with curative intent, researchers determined that antiviral treatment was associated with substantial improvements in OS for HBV-related HCC, especially when initiated before or within 6 months from HCC diagnosis. HBV antiviral treatment is only suppressive, and its efficacy is dependent on long-term patient adherence[24]. It has also been demonstrated that RFS and OS of patients who received NAs (ETV or TDF) before and after surgery were significantly better than those who received NAs (ETV or TDF) after surgery[25].
First-line antiviral drugs ETV, TDF, TAF, or TMF are recommended for patients with HBV-related liver cancer. Antiviral therapy should be initiated for HBsAg-positive HCC patients before hepatectomy regardless of their viral load levels or antiHBs status. If HBsAg-positive HCC patients do not receive antiviral therapy, viral reactivation may occur during the process of cancer treatment[26]. In most patients, oral administration of nucleoside antiviral drugs can achieve virus-negative conversion (viral load < 500 copies/mL) in 3-6 months. Long-term (life-long) antiviral therapy with NAs is recommended for patients with HBV-related liver cancer[27]. Patients with preoperative liver decompensation can be given symptomatic and supportive treatment such as liver protection based on antiviral therapy, and elective surgery can be performed after liver function is improved[26]. Patients with HBV-related HCC treated with nucleos(t)ide analogs (tenofovir or entecavir) had significantly improved long-term survival compared with patients treated with other antiviral agents. The efficacies of entecavir and tenofovir in terms of enhancing prognosis after curative treatment of hepatitis B virus-related hepatocellular carcinoma[28]. Whether there is a difference between two highly active antiviral agents (ETV and TDF) in the prognosis of patients with HBV-related HCC after curative resection is still controversial. Some studies have shown that patients treated with TDF have significantly lower postoperative recurrence or mortality rates than those treated with ETV[29,30]. However, some studies have found that there is no statistically significant difference in recurrence rate and mortality rate between ETV and TDF patients with HBV-related HCC after curative treatment[31,32].
Surgical treatment should be performed immediately after the diagnosis of resectable HCC. Perioperative anti-hepatitis B therapy not only can rapidly reduce the level of HBV DNA in a short time but also can effectively prevent the rebound of HBV DNA after operation[33]. The goal of antiviral therapy for HBV-related HCC is to maximize the inhibition of HBV DNA replication, prevent the progression of the disease, reduce liver damage caused by viral replication, improve liver function, and provide a good liver function foundation for HCC treatment based on HCC comprehensive treatment. Thereby significantly improving the prognosis of patients with HBV-related HCC and prolonging the overall survival of patients with HBV-related HCC.
HBsAg-positive HCC patients, regardless of HBV DNA level, are recommended to initiate antiviral therapy immediately, and for viral suppression, it is recommended to achieve undetectable levels of the virus as quickly as possible. For patients with HBV-related HCC, ideal preoperative long-term antiviral therapy helps patients to tolerate more extensive hepatectomy and have a better prognosis, but rescue antiviral therapy (reducing preoperative HBV-DNA level to< 4 Log10 copies of DNA/mL) also improved outcomes.
1. | Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021;71:209-249. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 50630] [Cited by in F6Publishing: 50123] [Article Influence: 16707.7] [Reference Citation Analysis (122)] |
2. | Thomas London W, Petrick JL, McGlynn KA. Liver cancer. In: Thun M, Linet MS, Cerhan JR, Haiman CA, Schottenfeld D, eds. Cancer Epidemiology and Prevention. 4th ed. Oxford University Press; 2018: 635-660. Available from: https://academic.oup.com/book/25326. [Cited in This Article: ] |
3. | European Association for the Study of the Liver. EASL Clinical Practice Guidelines on haemochromatosis. J Hepatol. 2022;77:479-502. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 34] [Cited by in F6Publishing: 45] [Article Influence: 22.5] [Reference Citation Analysis (0)] |
4. | Lim KC, Chow PK, Allen JC, Siddiqui FJ, Chan ES, Tan SB. Systematic review of outcomes of liver resection for early hepatocellular carcinoma within the Milan criteria. Br J Surg. 2012;99:1622-1629. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 127] [Cited by in F6Publishing: 160] [Article Influence: 13.3] [Reference Citation Analysis (0)] |
5. | Jiang Y, Han Q, Zhao H, Zhang J. The Mechanisms of HBV-Induced Hepatocellular Carcinoma. J Hepatocell Carcinoma. 2021;8:435-450. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 23] [Cited by in F6Publishing: 79] [Article Influence: 26.3] [Reference Citation Analysis (0)] |
6. | Ganem D, Prince AM. Hepatitis B virus infection--natural history and clinical consequences. N Engl J Med. 2004;350:1118-1129. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 1700] [Cited by in F6Publishing: 1656] [Article Influence: 82.8] [Reference Citation Analysis (0)] |
7. | Li TY, Yang Y, Zhou G, Tu ZK. Immune suppression in chronic hepatitis B infection associated liver disease: A review. World J Gastroenterol. 2019;25:3527-3537. [PubMed] [DOI] [Cited in This Article: ] [Cited by in CrossRef: 60] [Cited by in F6Publishing: 76] [Article Influence: 15.2] [Reference Citation Analysis (1)] |
8. | Ligat G, Schuster C, Baumert TF. Hepatitis B Virus Core Variants, Liver Fibrosis, and Hepatocellular Carcinoma. Hepatology. 2019;69:5-8. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 13] [Cited by in F6Publishing: 23] [Article Influence: 4.6] [Reference Citation Analysis (0)] |
9. | European Association for the Study of the Liver. EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection. J Hepatol. 2017;67:370-398. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 2771] [Cited by in F6Publishing: 3295] [Article Influence: 470.7] [Reference Citation Analysis (0)] |
10. | Marcellin P, Gane E, Buti M, Afdhal N, Sievert W, Jacobson IM, Washington MK, Germanidis G, Flaherty JF, Aguilar Schall R, Bornstein JD, Kitrinos KM, Subramanian GM, McHutchison JG, Heathcote EJ. Regression of cirrhosis during treatment with tenofovir disoproxil fumarate for chronic hepatitis B: a 5-year open-label follow-up study. Lancet. 2013;381:468-475. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 1228] [Cited by in F6Publishing: 1271] [Article Influence: 115.5] [Reference Citation Analysis (0)] |
11. | Pondé RAA, Amorim GSP. Elimination of the hepatitis B virus: A goal, a challenge. Med Res Rev. 2024;44:2015-2034. [PubMed] [DOI] [Cited in This Article: ] [Reference Citation Analysis (0)] |
12. | Dargan A, Wong SY, Coben R, Conn M, Dimarino AJ, Hann HW. Persistent risk for hepatocellular carcinoma after more than a decade of successful hepatitis B virus suppression. Minerva Gastroenterol Dietol. 2017;63:74-76. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 1] [Cited by in F6Publishing: 7] [Article Influence: 1.0] [Reference Citation Analysis (0)] |
13. | Yoo J, Hann HW, Coben R, Conn M, DiMarino AJ. Update Treatment for HBV Infection and Persistent Risk for Hepatocellular Carcinoma: Prospect for an HBV Cure. Diseases. 2018;6. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 19] [Cited by in F6Publishing: 20] [Article Influence: 3.3] [Reference Citation Analysis (0)] |
14. | Hou JL, Zhao W, Lee C, Hann HW, Peng CY, Tanwandee T, Morozov V, Klinker H, Sollano JD, Streinu-Cercel A, Cheinquer H, Xie Q, Wang YM, Wei L, Jia JD, Gong G, Han KH, Cao W, Cheng M, Tang X, Tan D, Ren H, Duan Z, Tang H, Gao Z, Chen S, Lin S, Sheng J, Chen C, Shang J, Han T, Ji Y, Niu J, Sun J, Chen Y, Cooney EL, Lim SG. 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;18:457-467.e21. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 38] [Cited by in F6Publishing: 41] [Article Influence: 10.3] [Reference Citation Analysis (0)] |
15. | Jeng WJ, Papatheodoridis GV, Lok ASF. Hepatitis B. Lancet. 2023;401:1039-1052. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 1] [Cited by in F6Publishing: 114] [Article Influence: 114.0] [Reference Citation Analysis (0)] |
16. | Berzigotti A, Reig M, Abraldes JG, Bosch J, Bruix J. Portal hypertension and the outcome of surgery for hepatocellular carcinoma in compensated cirrhosis: a systematic review and meta-analysis. Hepatology. 2015;61:526-536. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 219] [Cited by in F6Publishing: 256] [Article Influence: 28.4] [Reference Citation Analysis (0)] |
17. | Li Z, Lei Z, Xia Y, Li J, Wang K, Zhang H, Wan X, Yang T, Zhou W, Wu M, Pawlik TM, Lau WY, Shen F. 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:e182721. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 40] [Cited by in F6Publishing: 67] [Article Influence: 11.2] [Reference Citation Analysis (0)] |
18. | Yang C, Zhang H, Zhang L, Zhu AX, Bernards R, Qin W, Wang C. Evolving therapeutic landscape of advanced hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol. 2023;20:203-222. [PubMed] [DOI] [Cited in This Article: ] [Cited by in F6Publishing: 169] [Reference Citation Analysis (0)] |
19. | Brown ZJ, Tsilimigras DI, Ruff SM, Mohseni A, Kamel IR, Cloyd JM, Pawlik TM. Management of Hepatocellular Carcinoma: A Review. JAMA Surg. 2023;158:410-420. [PubMed] [DOI] [Cited in This Article: ] [Cited by in F6Publishing: 118] [Reference Citation Analysis (1)] |
20. | Zhang B, Xu D, Wang R, Zhu P, Mei B, Wei G, Xiao H, Zhang B, Chen X. Perioperative antiviral therapy improves safety in patients with hepatitis B related HCC following hepatectomy. Int J Surg. 2015;15:1-5. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 9] [Cited by in F6Publishing: 7] [Article Influence: 0.8] [Reference Citation Analysis (0)] |
21. | Liu GM, Huang XY, Shen SL, Hu WJ, Peng BG. Adjuvant antiviral therapy for hepatitis B virus-related hepatocellular carcinoma after curative treatment: A systematic review and meta-analysis. Hepatol Res. 2016;46:100-110. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 30] [Cited by in F6Publishing: 34] [Article Influence: 4.3] [Reference Citation Analysis (0)] |
22. | Guan RY, Sun BY, Wang ZT, Zhou C, Yang ZF, Gan W, Huang JL, Liu G, Zhou J, Fan J, Yi Y, Qiu SJ. Antiviral therapy improves postoperative survival of patients with HBV-related hepatocellular carcinoma. Am J Surg. 2022;224:494-500. [PubMed] [DOI] [Cited in This Article: ] [Reference Citation Analysis (0)] |
23. | Rui S, Yan J, Zhang H, Wang Z, Zhou W. Intermediate-stage hepatocellular carcinoma patients with a high HBV-DNA load may benefit from postoperative anti-hepatitis B virus therapy. Medicine (Baltimore). 2017;96:e7608. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 2] [Cited by in F6Publishing: 2] [Article Influence: 0.3] [Reference Citation Analysis (0)] |
24. | Huang DQ, Hoang JK, Kamal R, Tsai PC, Toyoda H, Yeh ML, Yasuda S, Leong J, Maeda M, Huang CF, Won Jun D, Ishigami M, Tanaka Y, Uojima H, Ogawa E, Abe H, Hsu YC, Tseng CH, Alsudaney M, Yang JD, Yoshimaru Y, Suzuki T, Liu JK, Landis C, Dai CY, Huang JF, Chuang WL, Schwartz M, Dan YY, Esquivel C, Bonham A, Yu ML, Nguyen MH. Antiviral Therapy Utilization and 10-Year Outcomes in Resected Hepatitis B Virus- and Hepatitis C Virus-Related Hepatocellular Carcinoma. J Clin Oncol. 2024;42:790-799. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 1] [Reference Citation Analysis (0)] |
25. | Liang Y, Zhong D, Zhang Z, Su Y, Yan S, Lai C, Yao Y, Shi Y, Huang X, Shang J. Impact of preoperative antiviral therapy on the prognosis of hepatitis B virus-related hepatocellular carcinoma. BMC Cancer. 2024;24:291. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 1] [Reference Citation Analysis (0)] |
26. | The Chinese Chapter of International Hepato-Pancreato-Biliary Association; Chinese Society of Liver Cancer; Society for Hepato-pancreato-biliary Surgery of Chinese Research Hospital Association; Society for Virus and Tumor of Chinese Research Hospital Association; Chen XP, Fan J, Dong JH Li X, Chen CW, Zhou WP. [Chinese expert consensus on antiviral therapy for hepatitis B virus-related hepatocellular carcinoma] (2023 edition). Zhonghua Xiaohua Waike Zazhi. 2023;22:29-41. [DOI] [Cited in This Article: ] |
27. | Huang G, Lai EC, Lau WY, Zhou WP, Shen F, Pan ZY, Fu SY, Wu MC. Posthepatectomy HBV reactivation in hepatitis B-related hepatocellular carcinoma influences postoperative survival in patients with preoperative low HBV-DNA levels. Ann Surg. 2013;257:490-505. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 76] [Cited by in F6Publishing: 94] [Article Influence: 8.5] [Reference Citation Analysis (0)] |
28. | Lee JH, Kim BK, Park SY, Tak WY, Park JY, Kim DY, Ahn SH, Sinn DH, Kim SU. The efficacies of entecavir and tenofovir in terms of enhancing prognosis after curative treatment of hepatitis B virus-related hepatocellular carcinoma. Eur J Intern Med. 2021;89:48-55. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 18] [Cited by in F6Publishing: 24] [Article Influence: 8.0] [Reference Citation Analysis (0)] |
29. | Choi J, Jo C, Lim YS. Tenofovir Versus Entecavir on Recurrence of Hepatitis B Virus-Related Hepatocellular Carcinoma After Surgical Resection. Hepatology. 2021;73:661-673. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 46] [Cited by in F6Publishing: 70] [Article Influence: 23.3] [Reference Citation Analysis (0)] |
30. | Wang XH, Hu ZL, Fu YZ, Hou JY, Li WX, Zhang YJ, Xu L, Zhou QF, Chen MS, Zhou ZG. Tenofovir vs. entecavir on prognosis of hepatitis B virus-related hepatocellular carcinoma after curative resection. J Gastroenterol. 2022;57:185-198. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 6] [Cited by in F6Publishing: 13] [Article Influence: 6.5] [Reference Citation Analysis (0)] |
31. | Kim SU, Seo YS, Lee HA, Kim MN, Lee YR, Lee HW, Park JY, Kim DY, Ahn SH, Han KH, Hwang SG, Rim KS, Um SH, Tak WY, Kweon YO, Kim BK, Park SY. A multicenter study of entecavir vs. tenofovir on prognosis of treatment-naïve chronic hepatitis B in South Korea. J Hepatol. 2019;71:456-464. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 103] [Cited by in F6Publishing: 107] [Article Influence: 21.4] [Reference Citation Analysis (0)] |
32. | Lee SW, Kwon JH, Lee HL, Yoo SH, Nam HC, Sung PS, Nam SW, Bae SH, Choi JY, Yoon SK, Han NI, Jang JW. Comparison of tenofovir and entecavir on the risk of hepatocellular carcinoma and mortality in treatment-naïve patients with chronic hepatitis B in Korea: a large-scale, propensity score analysis. Gut. 2020;69:1301-1308. [PubMed] [DOI] [Cited in This Article: ] [Cited by in Crossref: 74] [Cited by in F6Publishing: 90] [Article Influence: 22.5] [Reference Citation Analysis (0)] |
33. | Li Z, Tan C, Liu X, Feng Z, Li K. Early and late recurrence after hepatectomy in patients with low-level HBV-DNA hepatocellular carcinoma under antiviral therapy. Infect Agent Cancer. 2022;17:56. [PubMed] [DOI] [Cited in This Article: ] [Reference Citation Analysis (0)] |