Interferon decreases hepatocellular carcinogenesis in patients with cirrhosis caused by the hepatitis B virus

Ikeda, Kenji; Saitoh, Satoshi; Suzuki, Yoshiyuki; Kobayashi, Masahiro; Tsubota, Akihito; Fukuda, Mitsutoshi; Koida, Isao; Arase, Yasuji; Chayama, Kazuaki; Matsumoto, Naoya; Kumada, Hiromitsu

doi:10.1002/(sici)1097-0142(19980301)82:5<827::aid-cncr5>3.0.co;2-g

Cited by 173 publications

(121 citation statements)

References 29 publications

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“…7 Perhaps the most important finding of the present study is that the incidence of HCC development was significantly reduced in the IFN-treated patients. Similar to the observation in patients with hepatitis C virus and cirrhosis, 12,14-17 a beneficial effect of IFN therapy on the prevention of HCC in HBV patients with cirrhosis was observed in a few nonrandomized controlled studies, [11][12][13] which could be biased because the untreated patients might have more advanced disease and thus not be suitable or contraindicated for IFN therapy. 14 To the best of our knowledge, this could be the first randomized controlled study that shows that IFN therapy reduces HCC development in HBV patients with or without cirrhosis.…”

Section: Discussionmentioning

confidence: 57%

Long–Term Beneficial Effect of Interferon Therapy in Patients With Chronic Hepatitis B Virus Infection

et al. 1999

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To examine the long-term effect of interferon (IFN) therapy in patients with chronic hepatitis B virus (HBV) infection, particularly on survival and hepatocellular carcinoma (HCC) prevention, 101 male patients with chronic hepatitis B in a randomized controlled trial were followed up for 1.1 to 11.5 years after the end of therapy. Of the 101 patients, 34 patients received a placebo (control), and 67 patients were treated with IFN (31 patients were treated with IFN alone and 36 patients were treated with IFN after prednisolone priming). Follow-up studies included clinical, biochemical, and virological aspects and HCC screening every 3 to 6 months. Twenty-eight (42%) of the 67 IFNtreated patients and 8 (24%) of the 34 untreated patients seroconverted by the end of the trial. During follow-up, 22 (56%) of the 39 patients who did not seroconvert in the treated group and 5 (19%) of the 26 patients who did not seroconvert in the control group showed a delayed sustained response (P F .005). The cumulative incidence of sustained response was highest in the steroid priming group (P ‫؍‬ .049 vs. the IFN-alone group; P ‫؍‬ .028 vs. the control group). HCC was detected in 1 (1.5%) of the 67 treated patients and 4 (12%) of the 34 untreated patients (P ‫؍‬ .043). The interval between entry and HCC detection was 3.5 to 8.2 years. The cumulative incidence of HCC development was significantly higher in the control group than in the treated group (P ‫؍‬ .013). In contrast, the cumulative survival rate was higher in the treated group than the control group (P ‫؍‬ .018). Multivariate analysis showed that IFN therapy, preexisting cirrhosis, and the patient's age at entry are significant independent factors for both survival and HCC development. The results suggest that IFN has long-term beneficial effects in terms of HBV clearance, reduction of HCC, and prolonging survival. (HEPATOLOGY 1999;29:971-975.)Interferon (IFN) has antiviral, immunomodulatory, antitumoral, and antiproliferative effects. 1-3 The aims of IFN therapy for chronic hepatitis B virus (HBV) infection are to eradicate HBV, to halt hepatic necroinflammation, and to prevent or reduce the risk of cirrhosis and hepatocellular carcinoma (HCC) development. 4 It is generally agreed that IFN therapy is effective in 30% to 40% of the patients with chronic HBV infection in terms of virological and histological remission. 5,6 However, long-term follow-up data are limited. 7-10 Although several studies have suggested that IFN therapy may reduce the risk of HCC in patients with HBV or hepatitis C virus-related cirrhosis, 11-17 evidence derived from randomized controlled studies is still lacking. Therefore, the effect of IFN on the prevention of HCC in patients with chronic HBV infection still remains to be clarified or confirmed.A randomized controlled trial comparing the effect of IFN, prednisolone priming followed by IFN, and placebo in patients with chronic hepatitis B was conducted in our unit starting in December 1986. 18 The last patient was enrolled in the study in March 1...

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Section: Discussionmentioning

confidence: 57%

Long–Term Beneficial Effect of Interferon Therapy in Patients With Chronic Hepatitis B Virus Infection

et al. 1999

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“…The poor prognosis of HCC highlights the Interferon-a and hepatocarcinogenes P Merle et al urgent need for the setting of preventive approaches, and IFN-a is the only known molecule suggesting a possible preventive effect on HCC development in clinical studies (Ikeda et al, 1998;Nishiguchi et al, 2001). However, data from clinical trials are still controversial and no mechanisms have been clarified in these studies.…”

Section: Discussionmentioning

confidence: 99%

“…IFN-a was the first cytokine to be used clinically in human cancers. It is of note that although the benefit derived from IFN-a on established HCCs remains rather disappointing (Llovet et al, 2000), several clinical studies have suggested that IFN-a might prevent HCC development in HBV-or HCV-related cirrhosis, although the data remain controversial and no clear mechanism has been described in these studies (Ikeda et al, 1998;Nishiguchi et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

Long-term high-dose interferon-α therapy delays Hepadnavirus-related hepatocarcinogenesis in X/myc transgenic mice

et al. 2003

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The role of interferon-a (IFN-a) remains unclear in prevention of virus-induced hepatocellular carcinoma in humans. We have investigated it herewith in the X/myc transgenic mouse model of Hepadnavirus-related hepatocarcinogenesis because of upregulation of c-myc oncogene in the liver. We have demonstrated that IFN-a can downregulate dose-dependently hepatocyte proliferation and c-myc overexpression at early premalignant stages, while it does not affect either hepatocyte apoptosis or telomerase activity at these steps. However, continuous and long-term administration of IFN-a dose-dependently delays tumor onset in dysplastic livers and increases overall survival of animals, more efficiently whether started before the onset of dysplasia. The present study therefore highlights that early preventive administration of IFN-a can slow down evolution towards hepatocellular carcinoma via repression of c-myc and hepatocyte proliferation at premalignant steps in experimental cmyc-induced hepatocarcinogenesis. However, the transient effect observed in this study emphasizes a need to clarify the possible mechanisms of acquired resistance and subsequent therapeutic escape. Our experimental model may be a pertinent tool to explore antioncogenic properties of IFN-a in human cirrhotic livers showing c-myc upregulation.

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“…Although the virologic features of the two viruses are entirely different, both viruses infect the human liver and initiate a series of processes leading to chronic hepatitis, cirrhosis, and HCC (Watson, 1999). Some epidemiological findings suggest different modes of disease progression and HCC promotion between HBV and HCV infection (Shiratori et al, 1995;Ikeda et al, 1998;Marotta et al, 2004). The mechanisms underlying such differences are unknown.…”

Section: Introductionmentioning

confidence: 99%

Association of common promoter polymorphisms of MCP1 with hepatitis B virus clearance

Park

Kim²,

Cheong³

et al. 2006

Exp Mol Med

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Hepatocellular carcinoma (HCC) is one of the most common malignant cancers closely associated with chronic infection by the hepatitis B virus (HBV) or the hepatitis C virus (HCV) throughout the world. In this study, the genetic associations of 20 known polymorphisms in eight candidate genes, including angiotensinogen (AGT), cadherin 1 (CDH1), cyclooxygenase 2 (COX2), monocyte chemotactic protein-1 (MCP1), multidrug resistance 1 (MDR1), chemokine ligand 5 (RANTES), thrombospondin 2 (THBS2), and thrombospondin 4 (THBS4), were analyzed in a large chronic hepatitis B cohort (n = 1,095) recruited from the Korean population. In addition, three polymorphisms in chemokine receptor 4 (CXCR4) and vimentin (VIM) identified in this study were also genotyped. Using logistic regression analysis controlling possible confounding factors, one common (freq.=0.367) promoter polymorphism of MCP1 (MCP1-2518G>A) among analyzed polymorphisms was significantly associated with clearance of HBV infection. The frequency of homozygotes for the MCP1-2518A allele (MCP1-2518A/A) among chronic hepatitis B virus (HBV) carrier patients was significantly higher than that among spontaneously recovered (SR) subjects (17.7% vs. 10.4%)(OR=1.78, P = 0.004). Our findings imply a plausible explanation for the contribution of host genetic determinants to the variable outcome of HBV infection, which might provide valuable information for future genetic study in this area.

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Interferon decreases hepatocellular carcinogenesis in patients with cirrhosis caused by the hepatitis B virus

Cited by 173 publications

References 29 publications

Long–Term Beneficial Effect of Interferon Therapy in Patients With Chronic Hepatitis B Virus Infection

Long–Term Beneficial Effect of Interferon Therapy in Patients With Chronic Hepatitis B Virus Infection

Long-term high-dose interferon-α therapy delays Hepadnavirus-related hepatocarcinogenesis in X/myc transgenic mice

Association of common promoter polymorphisms of MCP1 with hepatitis B virus clearance

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