Topic Highlight
Copyright ©2013 Baishideng Publishing Group Co., Limited. All rights reserved.
World J Gastroenterol. Dec 21, 2013; 19(47): 8861-8866
Published online Dec 21, 2013. doi: 10.3748/wjg.v19.i47.8861
Anti-viral therapy to reduce recurrence and improve survival in hepatitis B virus-related hepatocellular carcinoma
Toru Ishikawa
Toru Ishikawa, Department of Gastroenterology and Hepatology, Saiseikai Niigata Daini Hospital, Niigata 950-1104, Japan
Author contributions: Ishikawa T collected the materials and wrote the manuscript.
Correspondence to: Toru Ishikawa, MD, PhD, Department of Gastroenterology and Hepatology, Saiseikai Niigata Daini Hospital, 280-7 Teraji, Niigata 950-1104, Japan.
Telephone: +81-25-2336161 Fax: +81-25-2338880
Received: August 29, 2013
Revised: October 29, 2013
Accepted: November 28, 2013
Published online: December 21, 2013


Hepatocellular carcinoma (HCC) is the most common malignancy and the third leading cause of cancer death worldwide. Chronic infection with hepatitis B virus (HBV) and hepatitis C virus accounts for approximately 75%-80% of HCC cases worldwide. In particular, chronic HBV infection is a predominant risk factor for HCC in Asia and Africa. Hepatic resection and radiofrequency ablation are increasingly used for the curative treatment of HCC, and good local control can be achieved. However, the high rate of recurrence is a major obstacle to improving prognosis. A high viral load of HBV DNA is the most important correctable risk factor for recurrence. Furthermore, interferon and/or nucleotide analogues may decrease HBV DNA. Therefore, these drugs may decrease recurrence. In this article, treatment strategies for HBV-related HCC are described in order to reduce recurrence and improve survival.

Key Words: Hepatocellular carcinoma, Hepatitis B virus, Recurrence, Nucleotide analogues, Interferon

Core tip: Recent advances in treatment modalities have improved the survival rate of patients with hepatocellular carcinoma (HCC). However, hepatitis B virus (HBV)-related HCC has a much higher recurrence rate. In this article, we describe strategies for reducing recurrent HCC using anti-viral therapy for HBV infection.


Hepatic resection or liver transplantation provide a complete curative treatment for hepatocellular carcinoma (HCC)[1,2]. In addition, regional ablation therapy including radiofrequency ablation (RFA) is now increasingly used for the curative treatment of HCC, and good local control can be achieved[3-5]. However, these techniques are unsatisfactory due to a high post-treatment recurrence rate[6]. It was reported that up to 70% of patients relapse within 5 years after curative treatment[7].

This high rate of recurrence is a major obstacle to improving prognosis. Therefore, antiviral and anti-inflammatory therapies both before and after curative treatment may be crucial in preventing HCC recurrence and improving survival. Current approved medications for chronic hepatitis B treatment are interferon-α (IFNα) and nucleotide analogues (NAs), including lamivudine (LVD), entecavir (ETV), tenofovir disoproxil fumarate, adefovir-dipivoxil (ADV), and telbivudine[8]. However, despite curative treatment of HCC, the 5-year recurrence rate remains high, at 70%-80%[9]. The mechanisms of HCC recurrence differ greatly from those of other carcinomas in terms of the high rate of intrahepatic metastases and multicentric carcinogenesis against a background of viral liver disease. Whether antiviral therapy after treatment of HCC can prevent recurrences is thus an important issue. Interferon (IFN) therapy in hepatitis C virus (HCV)-related HCC has been reported to reduce recurrence rates and contribute to survival, and its significance in preventing secondary carcinogenesis[10-14] including improvement of hepatic functional reserve[15] has been established.

The treatment of hepatitis B virus (HBV)-related HCC has centered on nucleic acid analogues to reduce viral load and inactivate hepatitis, however, treatment with IFN, similar to that in type C hepatitis, has recently attracted attention. Nucleic acid analogues and IFN may act together, but therapeutic strategies for preventing secondary carcinogenesis after treatment of HBV-related HCC remain unclear. This paper reviews the clinical evidence regarding treatment from the perspective of preventing secondary carcinogenesis, including reducing recurrence rates and improving prognosis after curative treatment of HBV-related HCC.


The mechanism of hepatocarcinogenesis by HBV includes direct malignant transformation and other indirect effects. With regard to direct malignant transformation, HBV gene integration into the host hepatocyte genome causes changes in host gene expression and properties, facilitating hepatocarcinogenesis[16,17].

Hence, as an indirect effect, persistent infection by HBV leads to hepatocyte destruction and regeneration, increasing genetic instability[18]. Epidemiological studies have examined differences in carcinogenesis due to HBV DNA load[19], however, the mechanisms by which HBV DNA load causes differences in malignant transformation remain unclear.

HBV DNA load has been shown to play a role in carcinogenesis in patients with type B chronic liver disease, and more recently, HBV DNA load has also been reported to be involved in recurrence after curative treatment of HCC.

In a retrospective study of 72 patients with hepatic resection for HBV-related HCC, Hung et al[20] reported that patients with a high serum HBV DNA load at the time of tumor resection showed a significantly higher recurrence rate, compared to patients with a low viral load. Multivariate analysis showed that a high HBV DNA load, alpha-fetoprotein level, tumor size, and age were factors contributing to recurrence. Xia et al[21] reported that high serum hyaluronic acid and HBV viral load are the main prognostic factors of local recurrence after complete radiofrequency ablation of hepatitis B-related small HCC.

Because HBV DNA load changes with the administration of antiviral drugs, patients with a high viral load at the time of HCC treatment who receive antiviral drugs subsequently show differences in HBV DNA load compared to those who do not receive such treatment. Kim et al[22] analyzed the patients excluded from antiviral drug therapy. After the patients treated with antiviral drugs were excluded, recurrence-free survival rates in a total of 157 patients with HBV-related HCC who underwent hepatic resection were compared between 89 patients with a persistently low HBV DNA load and 68 patients with a persistently high viral load. Recurrence-free survival rates were better in the persistently low HBV DNA load group compared to the high level group.

NAs preparations

The direct antitumor activity of nucleotide analogues has not been reported. Lamivudine has no inhibitory effects on integrated HBV DNA, thus there is no suppressive effect on de novo carcinogenesis due to HBV gene integration into the host genome[23,24].

Considering that HBV DNA load is related to HCC recurrence, the prevention of recurrence by antiviral drugs, rather than direct antitumor effects, is due to a reduction in HBV DNA load which improves hepatocyte destruction and regeneration and reduces genetic instability, thus decreasing HCC recurrence rates. Hosaka et al[25] reported that HBV core-related antigen levels were independent risk factors for HCC recurrence. In addition, Chuma et al[26] reported that recurrence was significantly lower in patients who received lamivudine before the development of HCC.

In a retrospective study by Kubo et al[27] of 24 patients with HBV-related HCC who underwent liver resection, a difference in recurrence-free survival rates was seen between 14 patients who received lamivudine and 10 patients who did not. Multivariate analysis also showed that lack of antiviral therapy and multiple tumors were factors related to recurrence-free survival rates.

In another retrospective study of 49 patients who underwent curative treatment for HBV-related HCC (liver resection, 31 patients; RFA, 18 patients), Kuzuya et al[28] examined cumulative recurrence rates of HCC in 16 patients who received lamivudine and 33 patients who did not. There was no significant difference between the two groups. Although there was no significant difference in HCC recurrence rates, hepatic functional reserve was improved and survival was better in the lamivudine group. In the lamivudine group, hepatic functional reserve was significantly better at the time of HCC recurrence, a higher percentage of patients were able to undergo curative treatment, and prognosis tended to be better (Table 1).

Table 1 Studies in which Nucleoside analogues were administered after treatment for hepatitis B virus-related hepatocellular carcinoma.
AuthorsTreated vs UntreatedTreatmentObservation timeHCC TxRecurrenceSurvival
Kubo et al[27]14 vs 10LVD1117 dOpeNATumor-free survival
(median)(P = 0.0086)
Kuzuya et al[28]16 vs 33LVD38.0 mo vs 32.6 moOpe/RFANSNS
(median)(P = 0.622)(P = 0.623)
Li et al[29]43 vs 36LVD with/without ADV12 moOpeNSOverall survival
(P = 0.077)(P = 0.0094)
Piao et al[30]30 vs 40LVD24 moOpe/RFANSNS
(P = 0.12)
Wu et al[31]518 vs 4051LVD/ETV/Telbivudine2.64 yrOpeP < 0.001P < 0.001

Other studies[29,30] have reported significantly larger remnant liver volume and better prognosis after liver resection in lamivudine-treated groups, and that lamivudine improves liver function and reduces deaths due to liver failure. Lamivudine after treatment of HCC may not prevent cancer recurrence, but may contribute to an improved prognosis by maintaining hepatic functional reserve[28]. Wu et al[31] recently reported that NAs were important in preventing recurrences after liver resection (Table 1).

At present, opinion is divided regarding whether administration of NAs after HCC treatment prevents HCC recurrence[32]. However, NAs may improve prognosis by improving hepatic functional reserve. NAs treatment was able to improve survival post-HCC treatment compared with no NAs therapy[33]. Recently, ETV therapy was found to be more effective with a rapid reduction in viral load compared with LVD. ETV is safe and well-tolerated during long-term treatment[34]. Furthermore, ETV has a higher genetic barrier to resistance[35]. ETV treatment might have potent protective effects against recurrence of HCC.


Basic research has shown that IFN has antiviral effects, antitumor effects against HCC[36,37], and inhibits the proliferation of cancer cells. In a retrospective study by Someya et al[38] evaluating IFN therapy in patients after curative treatment for HCC who also had HBV-related cirrhosis, uni- and multivariate analysis showed that IFN prevented recurrences, especially in the group with high aspartate transaminase. In addition, in a randomized controlled trial (RCT) of high-dose IFN in patients with HCC who could not undergo surgery, the IFN-treated group showed a significantly higher rate of ≥ 50% tumor size reduction compared to the control group[39] (Table 2).

Table 2 Studies on the effects of interferon on hepatitis B virus-related hepatocellular carcinoma after treatment.
AuthorsTreated vs UntreatedTreatmentObservation timeHCC TxRecurrenceSurvival
Someya et al[38]11 vs 69IFNα16 yrOpe/RFAP = 0.013 (High AST group)NA
Lai et al[39]35 vs 36IFNα30 moInoperableP = 0.001 (Tumor regression)P = 0.047
Lo et al[40]40 vs 40IFNα60 moOpe (Stage III/IVA)P = 0.031NS (P = 0.311)
Sun et al[41]118 vs 118IFNα36.5 mo (median)OpeP = 0.048P = 0.0003
Chen et al[42]106 vs 109IFNα63.8 mo (median)OpeNS (P = 0.766)NS (P = 0.826)

Furthermore, RCTs have been conducted to investigate the effects of IFN in preventing recurrences in patients after treatment for HCC. Lo et al[40] conducted a RCT in 40 patients with HBV-related HCC after curative hepatic resection. They compared a group treated with IFN-α2b 10 MU/m2, three times weekly, for 12 wk and a non-treated control group. The 1- and 5-year survival rates in the IFN group were 97% and 79%, respectively, compared to 85% and 61% in the control group (P = 0.137). Multivariate analysis showed that IFN therapy may lower the risk of death. In a subgroup analysis, the 5-year survival rate in stage I/II patients did not differ between the IFN and control groups, but with IFN therapy in stage III/IVA patients, early recurrence of HCC was prevented, and the 5-year survival rate improved from 24% to 68% (P = 0.038). Sun et al[41] also compared an IFN group and control group after HCC surgery in a randomized study. IFN therapy was reported to be useful, with significant increases both in median overall survival and median disease-free survival times. However, the results of a recent phase III randomized study of IFN-α2b after curative resection for HBV- and HCV-related HCC conducted in Taiwan showed no prevention of HBV or HCV recurrence[42] (Table 2).

Therefore, the effects of IFN therapy after curative treatment of HCC remain unclear. Pegylated (PEG)-IFN has superseded conventional IFN due to a higher response rate and once weekly administration instead of daily or three times a week. Recently, it was reported that high levels of hepatitis B surface antigen (HBsAg) increase HCC development among hepatitis B envelope antigen (HBeAg)-negative patients with a low viral load[43]. A recent study clearly showed that the rates of HBsAg clearance after PEG-IFN treatment are substantial and durable in HBeAg-negative patients. Rates of HBsAg clearance were shown to increase further during long-term follow-up, with 12% of patients achieving HBsAg clearance at 5 years post-treatment[44]. Better results are anticipated in the future using PEG-IFN.


Patients with high HBV DNA levels at HCC onset show significantly higher HCC recurrence rates compared to patients with low HBV DNA levels. In patients with high HBV DNA levels, the administration of antiviral drugs relatively early during treatment is recommended to prevent HCC recurrences. However, to more accurately evaluate the effects of antiviral therapy in preventing HCC recurrence, large-scale studies in more patients should be conducted.

Persistent viral suppression by antiviral therapy can inhibit carcinogenesis. Treatment with PEG-IFN results in a higher virological therapeutic response compared with conventional IFN. In addition, ETV, which has become a drug of first choice instead of LVD, has a very low resistance mutation rate, thus long-term viral suppression is possible. The long-term therapeutic effects of PEG-IFN and ETV are currently uncertain, but equal or better efficacy than conventional IFN or lamivudine for the prevention of carcinogenesis is expected. Future research should be aimed at clarifying the effects of anti-viral therapy in HBV-related HCC.


P- Reviewers: Colagrande S, Peng, T, Takahashi T, Tanaka Y S- Editor: Cui XM L- Editor: Webster JR E- Editor: Ma S

1.  Song TJ, Ip EW, Fong Y. Hepatocellular carcinoma: current surgical management. Gastroenterology. 2004;127:S248-S260.  [PubMed]  [DOI]
2.  Ioannou GN, Perkins JD, Carithers RL. Liver transplantation for hepatocellular carcinoma: impact of the MELD allocation system and predictors of survival. Gastroenterology. 2008;134:1342-1351.  [PubMed]  [DOI]
3.  Rossi S, Garbagnati F, Lencioni R, Allgaier HP, Marchianò A, Fornari F, Quaretti P, Tolla GD, Ambrosi C, Mazzaferro V. Percutaneous radio-frequency thermal ablation of nonresectable hepatocellular carcinoma after occlusion of tumor blood supply. Radiology. 2000;217:119-126.  [PubMed]  [DOI]
4.  Rossi S, Buscarini E, Garbagnati F, Di Stasi M, Quaretti P, Rago M, Zangrandi A, Andreola S, Silverman D, Buscarini L. Percutaneous treatment of small hepatic tumors by an expandable RF needle electrode. AJR Am J Roentgenol. 1998;170:1015-1022.  [PubMed]  [DOI]
5.  Rossi S, Di Stasi M, Buscarini E, Quaretti P, Garbagnati F, Squassante L, Paties CT, Silverman DE, Buscarini L. Percutaneous RF interstitial thermal ablation in the treatment of hepatic cancer. AJR Am J Roentgenol. 1996;167:759-768.  [PubMed]  [DOI]
6.  Toyama T, Hiramatsu N, Yakushijin T, Oze T, Nakanishi F, Yasumaru M, Mochizuki K, Kanto T, Takehara T, Kasahara A. A new prognostic system for hepatocellular carcinoma including recurrent cases: a study of 861 patients in a single institution. J Clin Gastroenterol. 2008;42:317-322.  [PubMed]  [DOI]
7.  Llovet JM, Schwartz M, Mazzaferro V. Resection and liver transplantation for hepatocellular carcinoma. Semin Liver Dis. 2005;25:181-200.  [PubMed]  [DOI]
8.  Kim SR, Yang J, Kudo M, Hino O. Recent advances in the management of chronic hepatitis B. Hepat Mon. 2011;11:601-611.  [PubMed]  [DOI]
9.  Poon RT, Fan ST, Lo CM, Liu CL, Ng IO, Wong J. Long-term prognosis after resection of hepatocellular carcinoma associated with hepatitis B-related cirrhosis. J Clin Oncol. 2000;18:1094-1101.  [PubMed]  [DOI]
10.  Ikeda K, Arase Y, Saitoh S, Kobayashi M, Suzuki Y, Suzuki F, Tsubota A, Chayama K, Murashima N, Kumada H. Interferon beta prevents recurrence of hepatocellular carcinoma after complete resection or ablation of the primary tumor-A prospective randomized study of hepatitis C virus-related liver cancer. Hepatology. 2000;32:228-232.  [PubMed]  [DOI]
11.  Kubo S, Nishiguchi S, Hirohashi K, Tanaka H, Shuto T, Yamazaki O, Shiomi S, Tamori A, Oka H, Igawa S. Effects of long-term postoperative interferon-alpha therapy on intrahepatic recurrence after resection of hepatitis C virus-related hepatocellular carcinoma. A randomized, controlled trial. Ann Intern Med. 2001;134:963-967.  [PubMed]  [DOI]
12.  Suou T, Mitsuda A, Koda M, Matsuda H, Maruyama S, Tanaka H, Kishimoto Y, Kohno M, Hirooka Y, Kawasaki H. Interferon alpha inhibits intrahepatic recurrence in hepatocellular carcinoma with chronic hepatitis C: a pilot study. Hepatol Res. 2001;20:301-311.  [PubMed]  [DOI]
13.  Shiratori Y, Shiina S, Teratani T, Imamura M, Obi S, Sato S, Koike Y, Yoshida H, Omata M. Interferon therapy after tumor ablation improves prognosis in patients with hepatocellular carcinoma associated with hepatitis C virus. Ann Intern Med. 2003;138:299-306.  [PubMed]  [DOI]
14.  Sakaguchi Y, Kudo M, Fukunaga T, Minami Y, C H, Kawasaki T. Low-dose, long-term, intermittent interferon-alpha-2b therapy after radical treatment by radiofrequency ablation delays clinical recurrence in patients with hepatitis C virus-related hepatocellular carcinoma. Intervirology. 2005;48:64-70.  [PubMed]  [DOI]
15.  Ishikawa T. Secondary prevention of recurrence by interferon therapy after ablation therapy for hepatocellular carcinoma in chronic hepatitis C patients. World J Gastroenterol. 2008;14:6140-6144.  [PubMed]  [DOI]
16.  Kim CM, Koike K, Saito I, Miyamura T, Jay G. HBx gene of hepatitis B virus induces liver cancer in transgenic mice. Nature. 1991;351:317-320.  [PubMed]  [DOI]
17.  Paterlini P, Poussin K, Kew M, Franco D, Brechot C. Selective accumulation of the X transcript of hepatitis B virus in patients negative for hepatitis B surface antigen with hepatocellular carcinoma. Hepatology. 1995;21:313-321.  [PubMed]  [DOI]
18.  Colombo M, Sangiovanni A. Etiology, natural history and treatment of hepatocellular carcinoma. Antiviral Res. 2003;60:145-150.  [PubMed]  [DOI]
19.  Ishikawa T, Ichida T, Yamagiwa S, Sugahara S, Uehara K, Okoshi S, Asakura H. High viral loads, serum alanine aminotransferase and gender are predictive factors for the development of hepatocellular carcinoma from viral compensated liver cirrhosis. J Gastroenterol Hepatol. 2001;16:1274-1281.  [PubMed]  [DOI]
20.  Hung IF, Poon RT, Lai CL, Fung J, Fan ST, Yuen MF. Recurrence of hepatitis B-related hepatocellular carcinoma is associated with high viral load at the time of resection. Am J Gastroenterol. 2008;103:1663-1673.  [PubMed]  [DOI]
21.  Xia F, Lai EC, Lau WY, Ma K, Li X, Bie P, Qian C. High serum hyaluronic acid and HBV viral load are main prognostic factors of local recurrence after complete radiofrequency ablation of hepatitis B-related small hepatocellular carcinoma. Ann Surg Oncol. 2012;19:1284-1291.  [PubMed]  [DOI]
22.  Kim BK, Park JY, Kim do Y, Kim JK, Kim KS, Choi JS, Moon BS, Han KH, Chon CY, Moon YM. Persistent hepatitis B viral replication affects recurrence of hepatocellular carcinoma after curative resection. Liver Int. 2008;28:393-401.  [PubMed]  [DOI]
23.  Doong SL, Tsai CH, Schinazi RF, Liotta DC, Cheng YC. Inhibition of the replication of hepatitis B virus in vitro by 2’,3’-dideoxy-3’-thiacytidine and related analogues. Proc Natl Acad Sci USA. 1991;88:8495-8499.  [PubMed]  [DOI]
24.  Matsumoto A, Tanaka E, Rokuhara A, Kiyosawa K, Kumada H, Omata M, Okita K, Hayashi N, Okanoue T, Iino S. Efficacy of lamivudine for preventing hepatocellular carcinoma in chronic hepatitis B: A multicenter retrospective study of 2795 patients. Hepatol Res. 2005;32:173-184.  [PubMed]  [DOI]
25.  Hosaka T, Suzuki F, Kobayashi M, Hirakawa M, Kawamura Y, Yatsuji H, Sezaki H, Akuta N, Suzuki Y, Saitoh S. HBcrAg is a predictor of post-treatment recurrence of hepatocellular carcinoma during antiviral therapy. Liver Int. 2010;30:1461-1470.  [PubMed]  [DOI]
26.  Chuma M, Hige S, Kamiyama T, Meguro T, Nagasaka A, Nakanishi K, Yamamoto Y, Nakanishi M, Kohara T, Sho T. The influence of hepatitis B DNA level and antiviral therapy on recurrence after initial curative treatment in patients with hepatocellular carcinoma. J Gastroenterol. 2009;44:991-999.  [PubMed]  [DOI]
27.  Kubo S, Tanaka H, Takemura S, Yamamoto S, Hai S, Ichikawa T, Kodai S, Shinkawa H, Sakaguchi H, Tamori A. Effects of lamivudine on outcome after liver resection for hepatocellular carcinoma in patients with active replication of hepatitis B virus. Hepatol Res. 2007;37:94-100.  [PubMed]  [DOI]
28.  Kuzuya T, Katano Y, Kumada T, Toyoda H, Nakano I, Hirooka Y, Itoh A, Ishigami M, Hayashi K, Honda T. Efficacy of antiviral therapy with lamivudine after initial treatment for hepatitis B virus-related hepatocellular carcinoma. J Gastroenterol Hepatol. 2007;22:1929-1935.  [PubMed]  [DOI]
29.  Li N, Lai EC, Shi J, Guo WX, Xue J, Huang B, Lau WY, Wu MC, Cheng SQ. A comparative study of antiviral therapy after resection of hepatocellular carcinoma in the immune-active phase of hepatitis B virus infection. Ann Surg Oncol. 2010;17:179-185.  [PubMed]  [DOI]
30.  Piao CY, Fujioka S, Iwasaki Y, Fujio K, Kaneyoshi T, Araki Y, Hashimoto K, Senoh T, Terada R, Nishida T. Lamivudine treatment in patients with HBV-related hepatocellular carcinoma--using an untreated, matched control cohort. Acta Med Okayama. 2005;59:217-224.  [PubMed]  [DOI]
31.  Wu CY, Chen YJ, Ho HJ, Hsu YC, Kuo KN, Wu MS, Lin JT. Association between nucleoside analogues and risk of hepatitis B virus–related hepatocellular carcinoma recurrence following liver resection. JAMA. 2012;308:1906-1914.  [PubMed]  [DOI]
32.  Yin J, Li N, Han Y, Xue J, Deng Y, Shi J, Guo W, Zhang H, Wang H, Cheng S. 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;31:3647-3655.  [PubMed]  [DOI]
33.  Toyoda H, Kumada T, Tada T, Sone Y, Fujimori M. Transarterial chemoembolization for hepatitis B virus-associated hepatocellular carcinoma: improved survival after concomitant treatment with nucleoside analogues. J Vasc Interv Radiol. 2012;23:317-22.e1.  [PubMed]  [DOI]
34.  Chang TT, Gish RG, de Man R, Gadano A, Sollano J, Chao YC, Lok AS, Han KH, Goodman Z, Zhu J. A comparison of entecavir and lamivudine for HBeAg-positive chronic hepatitis B. N Engl J Med. 2006;354:1001-1010.  [PubMed]  [DOI]
35.  Colonno RJ, Rose R, Baldick CJ, Levine S, Pokornowski K, Yu CF, Walsh A, Fang J, Hsu M, Mazzucco C. Entecavir resistance is rare in nucleoside naïve patients with hepatitis B. Hepatology. 2006;44:1656-1665.  [PubMed]  [DOI]
36.  Wang L, Tang ZY, Qin LX, Wu XF, Sun HC, Xue Q, Ye SL. High-dose and long-term therapy with interferon-alfa inhibits tumor growth and recurrence in nude mice bearing human hepatocellular carcinoma xenografts with high metastatic potential. Hepatology. 2000;32:43-48.  [PubMed]  [DOI]
37.  Yano H, Ogasawara S, Momosaki S, Akiba J, Kojiro S, Fukahori S, Ishizaki H, Kuratomi K, Basaki Y, Oie S. Growth inhibitory effects of pegylated IFN alpha-2b on human liver cancer cells in vitro and in vivo. Liver Int. 2006;26:964-975.  [PubMed]  [DOI]
38.  Someya T, Ikeda K, Saitoh S, Kobayashi M, Hosaka T, Sezaki H, Akuta N, Suzuki F, Suzuki Y, Arase Y. Interferon lowers tumor recurrence rate after surgical resection or ablation of hepatocellular carcinoma: a pilot study of patients with hepatitis B virus-related cirrhosis. J Gastroenterol. 2006;41:1206-1213.  [PubMed]  [DOI]
39.  Lai CL, Lau JY, Wu PC, Ngan H, Chung HT, Mitchell SJ, Corbett TJ, Chow AW, Lin HJ. Recombinant interferon-alpha in inoperable hepatocellular carcinoma: a randomized controlled trial. Hepatology. 1993;17:389-394.  [PubMed]  [DOI]
40.  Lo CM, Liu CL, Chan SC, Lam CM, Poon RT, Ng IO, Fan ST, Wong J. A randomized, controlled trial of postoperative adjuvant interferon therapy after resection of hepatocellular carcinoma. Ann Surg. 2007;245:831-842.  [PubMed]  [DOI]
41.  Sun HC, Tang ZY, Wang L, Qin LX, Ma ZC, Ye QH, Zhang BH, Qian YB, Wu ZQ, Fan J. Postoperative interferon alpha treatment postponed recurrence and improved overall survival in patients after curative resection of HBV-related hepatocellular carcinoma: a randomized clinical trial. J Cancer Res Clin Oncol. 2006;132:458-465.  [PubMed]  [DOI]
42.  Chen LT, Chen MF, Li LA, Lee PH, Jeng LB, Lin DY, Wu CC, Mok KT, Chen CL, Lee WC. Long-term results of a randomized, observation-controlled, phase III trial of adjuvant interferon Alfa-2b in hepatocellular carcinoma after curative resection. Ann Surg. 2012;255:8-17.  [PubMed]  [DOI]
43.  Tseng TC, Liu CJ, Yang HC, Su TH, Wang CC, Chen CL, Kuo SF, Liu CH, Chen PJ, Chen DS. High levels of hepatitis B surface antigen increase risk of hepatocellular carcinoma in patients with low HBV load. Gastroenterology. 2012;142:1140-1149.e3; quiz e13-4.  [PubMed]  [DOI]
44.  Marcellin P, Bonino F, Yurdaydin C, Hadziyannis S, Moucari R, Kapprell HP, Rothe V, Popescu M, Brunetto MR. Hepatitis B surface antigen levels: association with 5-year response to peginterferon alfa-2a in hepatitis B e-antigen-negative patients. Hepatol Int. 2013;7:88-97.  [PubMed]  [DOI]