Long-term outcomes of direct acting antivirals in post-transplant advanced hepatitis C virus recurrence and fibrosing cholestatic hepatitis.

Long-term functional outcomes of sofosbuvir-based antiviral treatment were evaluated in a cohort study involving 16 Italian centres within the international compassionate use programme for post-transplant hepatitis C virus (HCV) recurrence. Seventy-three patients with cirrhosis (n=52) or fibrosing cholestatic hepatitis (FCH, n=21) received 24-week sofosbuvir with ribavirin±pegylated interferon or interferon-free sofosbuvir-based regimen with daclatasvir/simeprevir+ribavirin. The patients were observed for a median time of 103 (82-112) weeks. Twelve of 73 (16.4%) died (10 non-FCH, 2 FCH) and two underwent re-LT. Sustained virological response was achieved in 46 of 66 (69.7%): 31 of 47 (66%) non-FCH and 15 of 19 (79%) FCH patients. All relapsers were successfully retreated. Comparing the data of baseline with last follow-up, MELD and Child-Turcotte-Pugh scores improved both in non-FCH (15.3±6.5 vs 10.5±3.8, P<.0001 and 8.4±2.1 vs 5.7±1.3, P<.0001, respectively) and FCH (17.3±5.9 vs 10.1±2.8, P=.001 and 8.2±1.6 vs 5.5±1, P=.001, respectively). Short-treatment mortality was higher in patients with baseline MELD≥25 than in those with MELD<25 (42.9% vs 4.8%, P=.011). Long-term mortality was 53.3% among patients with baseline MELD≥20 and 7.5% among those with MELD<20 (P<.0001). Among deceased patients 75% were Child-Turcotte-Pugh class C at baseline, while among survivors 83.9% were class A or B (P<.0001). Direct acting antivirals-based treatments for severe post-transplant hepatitis C recurrence, comprising fibrosing cholestatic hepatitis, significantly improve liver function, even without viral clearance and permit an excellent long-term survival. The setting of severe HCV recurrence may require the identification of "too-sick-to-treat patients" to avoid futile treatments.

HCV NS3 sequencing as a reliable and clinically useful tool for the assessment of genotype and resistance mutations for clinical samples with different HCV-RNA levels.

OBJECTIVES: This study aims to evaluate the reliability and clinical utility of NS3 sequencing in hepatitis C virus (HCV) 1-infected patients who were candidates to start a PI-containing regimen. METHODS: NS3 protease sequencing was performed by in-house-developed HCV-1 subtype-specific protocols. Phylogenetic analysis was used to test sequencing reliability and concordance with previous genotype/subtype assignment by commercial genotyping assays. RESULTS: Five hundred and sixty-seven HCV plasma samples with quantifiable HCV-RNA from 326 HCV-infected patients were collected between 2011 and 2014. Overall, the success rate of NS3 sequencing was 88.9%. The success rate between the two subtype protocols (HCV-1a/HCV-1b) was similarly high for samples with HCV-RNA >3 log IU/mL (>92% success rate), while it was slightly lower for HCV-1a samples with HCV-RNA ≤3 log IU/mL compared with HCV-1b samples. Phylogenetic analysis confirmed the genotype/subtype given by commercial genotyping assays in 92.9% (303/326) of cases analysed. In the remaining 23 cases (7.1%), 1 was HCV-1g (previously defined as subtype 1a), 1 was HCV-4d (previously defined as genotype 1b) and 1 was HCV-1b (previously defined as genotype 2a/2c). In the other cases, NS3 sequencing precisely resolved the either previous undetermined/discordant subtype 1 or double genotype/subtype assignment by commercial genotyping assays. Resistance-associated variants (RAVs) to PI were detected in 31.0% of samples. This prevalence changed according to PI experience (17.1% in PI-naive patients versus 79.2% in boceprevir/telaprevir/simeprevir-failing patients). Among 96 patients with available virological outcome following boceprevir/telaprevir treatment, a trend of association between baseline NS3 RAVs and virological failure was observed (particularly for HCV-1a-infected patients: 3/21 failing patients versus 0/22 achieving sustained virological response; P = 0.11). CONCLUSIONS: HCV-NS3 sequencing provides reliable results and at the same time gives two clinically relevant pieces of information: a correct subtype/genotype assignment and the detection of variants that may interfere with the efficacy of PI.

Energetic α-particle sources produced through proton-boron reactions by high-energy high-intensity laser beams.

In an experiment performed with a high-intensity and high-energy laser system, α-particle production in proton-boron reaction by using a laser-driven proton beam was measured. α particles were observed from the front and also from the rear side, even after a 2-mm-thick boron target. The data obtained in this experiment have been analyzed using a sequence of numerical simulations. The simulations clarify the mechanisms of α-particle production and transport through the boron targets. α-particle energies observed in the experiment and in the simulation reach 10-20 MeV through energy transfer from 20-30 MeV energy incident protons. Despite the lower cross sections for protons with energy above the sub-MeV resonances in the proton-boron reactions, 10^{8}-10^{9}α particles per steradian have been detected.

Successful antiviral therapy determines a significant decrease in squamous cell carcinoma antigen-associated (SCCA) variants' serum levels in anti-HCV positive cirrhotic patients.

Aberrant squamous cell carcinoma antigen (SCCA) expression is an early event in hepatocarcinogenesis, and increasing serum levels of SCCA variants IgM immune complexes (SCCA-IgM IC) have been found in cirrhotic patients developing hepatocellular carcinoma (HCC). We longitudinally evaluated a cohort of cirrhotic patients with hepatitis C virus infection (HCV) who underwent pegylated interferon (PEG-IFN) and ribavirin treatment. SCCA-IgM IC levels were assessed in the sera of 33 cirrhotic patients with HCV (21 males, median age 57 years) before, at the end and at 6-month and 1-year follow-up after treatment with PEG-IFN and ribavirin. SCCA-IgM IC serum levels (arbitrary units/mL, AU/mL) were evaluated according to treatment outcome: sustained virological response (SVR) vs nonresponse (NR). Overall, 15 patients obtained a SVR to antiviral therapy (45%). There was no significant difference in baseline SCCA-IgM IC serum levels between SVR and NR patients. When compared to baseline (451.2 AU/mL), SVR patients showed a significant decrease in median SCCA-IgM IC serum levels at the end of treatment (186.8 AU/mL, P = 0.013) and at both 6-month (96.8 AU/mL, P < 0.001) and 1-year follow-up (52.4 AU/mL, P < 0.001), while no significant modification was observed in NR patients. In patients with HCV-related liver cirrhosis, successful antiviral therapy is associated with a dramatic and significant decrease in SCCA-IC serum levels. Because of the pathophysiological correlation between SCCA and liver carcinogenesis, it is hypothesized that in patients with liver cirrhosis, SVR may be accompanied by a decreased proliferative stimulation.

Predictive value of on-treatment response during full-dose antiviral therapy of patients with hepatitis C virus cirrhosis and portal hypertension.

OBJECTIVE: Therapy with full-dose pegylated interferon (PEG-IFN) and weight-based ribavirin has been evaluated in limited series of patients with hepatitis C virus (HCV) and advanced disease. In this study, we evaluated the efficacy and tolerability of full-dose antiviral therapy in patients with compensated, fully developed cirrhosis, and assessed the predictive value of on-treatment virological response. DESIGN AND SUBJECTS: We studied 85 HCV-positive cirrhotic patients (82 Child-Pugh class A; 41 treatment-naïve) who were treated with PEG-IFN alpha-2(a) (1.5 microg kg(-1)week(-1)) or alpha-2(b) (180 microg week(-1)) and weight-based ribavirin for 24 (genotype 2-3) or 48 (genotype 1-4) weeks. Forty-three patients were genotype 1 (51%), and HCV-RNA was >600,000 IU mL(-1) in 53 patients (62%). Prevalence of portal hypertension and diabetes was 81% and 18% respectively. RESULTS: Sustained virological response (SVR) was obtained in 22 patients (26%). Positive serum HCV-RNA at week 4 and week 12 of therapy predicted nonresponse (NR) in 85% (52/61) and 100% (38/38) of patients, respectively. Treatment was discontinued due to adverse events in 14 patients (16%). Genotype 1-4 (P = 0.02) and HCV-RNA >600,000 IU mL(-1) (P = 0.02) were the baseline parameters significantly associated with lack of SVR, whilst positive serum HCV-RNA at week 12 was the only parameter independently associated with NR (100% negative predictive value). CONCLUSION: Full-dose antiviral therapy with PEG-IFN and ribavirin can be safely carried out even in patients with compensated, fully established cirrhosis and portal hypertension. Selecting patients on the basis of HCV genotype and viral load, and application of on-treatment stopping rule may help rationalize treatment in patients who are unlikely to obtain SVR.

Hepatitis C infection in patients with chronic kidney disease.

The management of hepatitis C virus (HCV)-infected patients with chronic kidney disease (CKD) is complex and represents a particular concern since numerous issues, such as antiviral therapy in dialysis patients and post renal transplant, and prevention of HCV spread within dialysis units, remain unresolved. An enormous body of literature has been published on HCV in the CKD population; however, clinical evidence on important issues is mostly based on uncontrolled clinical trials or retrospective surveys. The aim of this paper is to provide a systematic review of the literature. Responses to the critical issues have been developed by a consensus of experts, endorsed by the Italian Association for the Study of the Liver (AISF) and some clinical recommendations have been added.

First experimental proof of Proton Boron Capture Therapy (PBCT) to enhance protontherapy effectiveness.

Protontherapy is hadrontherapy's fastest-growing modality and a pillar in the battle against cancer. Hadrontherapy's superiority lies in its inverted depth-dose profile, hence tumour-confined irradiation. Protons, however, lack distinct radiobiological advantages over photons or electrons. Higher LET (Linear Energy Transfer) 12C-ions can overcome cancer radioresistance: DNA lesion complexity increases with LET, resulting in efficient cell killing, i.e. higher Relative Biological Effectiveness (RBE). However, economic and radiobiological issues hamper 12C-ion clinical amenability. Thus, enhancing proton RBE is desirable. To this end, we exploited the p + 11B → 3α reaction to generate high-LET alpha particles with a clinical proton beam. To maximize the reaction rate, we used sodium borocaptate (BSH) with natural boron content. Boron-Neutron Capture Therapy (BNCT) uses 10B-enriched BSH for neutron irradiation-triggered alpha particles. We recorded significantly increased cellular lethality and chromosome aberration complexity. A strategy combining protontherapy's ballistic precision with the higher RBE promised by BNCT and 12C-ion therapy is thus demonstrated.

Pegylated interferon and ribavirin in re-treatment of responder-relapser HCV patients.

BACKGROUND: The re-treatment of patients who relapse after a course of standard interferon and ribavirin with pegylated interferon alfa-2b plus ribavirin is an open issue. AIMS: To evaluate efficacy and safety of treatment with pegylated interferon alfa-2b plus ribavirin and the role of early HCV-RNA assessment as a predictor of sustained response. PATIENTS: Between May 2001 and December 2002, 242 consecutive patients with chronic hepatitis C were enrolled in an open, regional, multicentre study. Seventy-eight of them were responder-relapsers to a previous course of combination therapy. METHODS: Patients were treated with pegylated interferon alfa-2b (1 microg/kg/week) plus ribavirin (800-1200 mg daily). Qualitative HCV-RNA was performed at week 2. Genotypes 1-4 were treated for 48 weeks, while genotypes 2 and 3 were treated for 24 weeks. RESULTS: We obtained an overall sustained virological response rate of 41.0% (78.6% for patients with genotypes 2-3). CONCLUSION: This treatment schedule prove to be safe and effective in relapsers with genotype non-1 while genotype 1-4 patients had a low rate of sustained virological response. Qualitative virological assessment after 2 weeks may identify patients who are more likely to reach sustained virological response, but it is not a valid tool for a stopping rule approach.

Medical report type in liver transplantation as a quality system document: new prospects for computerization.

The usage of a computerized system to organize data and ease the activity procedures of liver transplantation is useful in clinical transplantation. Preliminary cognitive research on systems of clinical transplantation database concerning medical reports was performed to verify their development level. The survey highlighted that, so far, there has been no experimentation that can be applied to a medical report type devoted to liver transplantation. Regulations in force substantially point out that the medical report ought to contain all items that have to be taken into account in handling the patient from pretransplantation to follow-up. The Department of Transplantation of Genoa chose its medical report model for liver transplantation. The medical report model included the following items: personal data; case history; diagnosis; initial examination for prelisting; fitness for transplantation; assistance context; clinical data including subjective, objective, and instrumental parameters; pharmacological therapies; informed consent, evaluation of fitness; nursing data; counseling and clinical evaluations according to protocols and guidelines of the national transplantation centers. If the computing is well trained, it is supposed to help maintain a whole data view provided it is supplied information in an adequate way. Immediate clinical procedural advantages and useful scientific observations may be obtained from a high-quality database. In fact, all functions have to be applied to specific clinical, administrative needs to be remotely shared and conveniently integrated with each other to make the liver transplantation medical report an easy and handy instrument for inputting and handling data. It must be a precise, complete instrument that may be accessible in real time from any site connected with the intranet network, be unchangeable, and be protected to ensure certification and forensic medicine value.

A randomized trial of pegylated-interferon-alpha2a plus ribavirin with or without amantadine in the re-treatment of patients with chronic hepatitis C not responding to standard interferon and ribavirin.

BACKGROUND: There is yet no established treatment for chronic hepatitis C patients non-responder to standard interferon and ribavirin. AIM: To evaluate efficacy and safety of pegylated-interferon-alpha2a plus ribavirin with or without amantadine in such patients. METHODS: 161 non-responders to standard interferon and ribavirin were randomized into two groups: 81 patients (Group 1) were given weekly Peg-IFN-alpha2a 180 microg plus ribavirin 1,000-1,200 mg/daily for 12 months, 80 patients (Group 2) received weekly Peg-IFN-alpha2a 180 microg plus ribavirin 1,000-1,200 mg/daily and amantadine 200 mg/daily for 12 months. RESULTS: At the end of follow-up, HCV-RNA was negative in 29.6% of Group 1 and in 21.2% of Group 2 patients (P = 0.22). Patients with genotypes 1 and 4 responded better to bi-therapy (21.7%) than to triple therapy (17.3%, P = 0.5) while among patients with genotypes 2 and 3 there was a trend towards a higher sustained virological response rate when retreated with triple treatment (80% vs. 75%, P = 0.82). On multivariate analysis, genotype 1 or 4, high body mass index and >20% reduction of Peg-interferon were associated with the treatment failure. CONCLUSIONS: The addition of amantadine does not improve the overall SVR rate in non-responder patients retreated with Peg-IFN and ribavirin; however, about 30% of non-responders may achieve a sustained response, in particular patients with genotypes 2 and 3 show a high SVR (75%).

Non-antigen-specific CD8(+) T suppressor lymphocytes in diseases characterized by chronic immune responses and inflammation.

Recent studies on regulatory lymphocytes demonstrate that CD8(+) T suppressor (Ts) cells may have great relevance in controlling immune system homeostasis and avoiding development of chronic inflammatory diseases. Among the three subpopulations of CD8(+) Ts cells so far recognized in humans, the type 2 (non-antigen-specific) cell is characterized by the capacity to inhibit both T cell proliferation and cytotoxic T lymphocyte activity through secretion of soluble factors. Previous work has shown the impairment of in vitro generation of type 2 CD8(+) Ts cells from the peripheral blood of relapsed patients with multiple sclerosis, systemic lupus erythematosus, or systemic sclerosis. Here, similar findings are demonstrated for patients with human immunodeficiency virus or chronic hepatitis C virus infection. Furthermore, the presence of type 2 CD8(+) Ts cells infiltrating diseased tissues in patients with autoimmune thyroiditis or cancer is shown. Collectively, these findings suggest that type 2 CD8(+) Ts cells may be involved in the control of pathologic chronic immune responses, contributing in some cases to the pathogenesis of the disease.

Serum intercellular adhesion molecule-1 and long-term response to IFN-alpha2b therapy in chronic hepatitis C.

We have attempted to correlate the outcome of interferon (IFN) therapy with circulating soluble intercellular adhesion molecule-1 (sICAM-1) and the level of viremia in a sample of patients with chronic hepatitis C virus (HCV) infection. Forty-two patients were studied. Eighteen patients were maintained in long-term remission following IFN therapy, whereas 24 did not respond or relapsed. Serum concentrations of sICAM-1 were measured by enzyme-linked immunoassay. Viremia was measured by branched DNA signal amplification assay. Basal sICAM-1 was significantly higher in long-term responders than in nonresponder/relapsing patients. It was found that very high levels (>1000 ng/ml) were closely associated with long-term clinical response. A quantitative evaluation of viremia in basal conditions, which was significantly lower in long-term responders, gave completely opposite results. During treatment, sICAM-1 concentrations significantly decreased in the group of long-term responders but not in the nonresponders. sICAM-1 reduction was apparent as early as 1 month after treatment started. Serum sICAM-1 may be a useful parameter in evaluating the outcome of patients with chronic hepatitis C infection treated with IFN.

Serum lipid levels during interferon therapy in patients with chronic hepatitis C.

Interferon-alpha (IFN-alpha) may affect lipid metabolism by stimulating hepatic fatty acid synthesis. The aim of this study was to evaluate serum lipid levels during IFN-alpha therapy in patients with biopsy-proven chronic active hepatitis C. A total of 22 patients (18 males and 4 females; age 25-55 years) received 3 MU of recombinant IFN-alpha 2b 3 times a week for 6 months. Serum lipids were determined at baseline and then every month until the end of therapy. All patients had normal serum lipid levels at baseline. No significant level of modification occurred in patients during the therapy. An increase in serum lipid levels during low-dose IFN-alpha therapy seems to be uncommon in hepatitis C virus-infected patients with baseline normal levels.

Single bedtime dose of famotidine: assessment of its antisecretory action by 24-hour intragastric pH monitoring.

The antisecretory efficacy of a single bedtime dose of famotidine, a new potent H2-receptor antagonist, was evaluated by means of continuous 24-hour intragastric pH monitoring. Of 20 patients with duodenal ulcers, ten randomly received famotidine 40 mg at 10 PM and ten were monitored without medication for control. Famotidine regimen led to a remarkable reduction of gastric acidity in patients who were treated for duodenal ulcer and the drug-induced pH levels were significantly different (P less than .0001) from those of untreated controls. The antisecretory action lasted for 12 hours, which comprised the nocturnal period, whereas no important difference was found between the two groups for the most part of the daytime. The drug was able to keep intragastric pH above 4 units during almost 50% of the whole 24-hour period. These results confirm that famotidine is a powerful and long-acting H2 blocker that relieves gastric acidity during the night and morning hours when administered as a single bedtime dose of 40 mg.

HCV-RNA levels play an important role independently of genotype in predicting response to interferon therapy.

OBJECTIVE: To evaluate the relationship between hepatitis C virus (HCV)-RNA levels and genotypes in order to establish their potentially predictive role in interferon (IFN) response. DESIGN: To detect HCV genotype at baseline and HCV viraemia levels before and during IFN treatment in three groups of patients with different IFN response. METHODS: Our study included 85 patients with biopsy-proven chronic hepatitis C who underwent IFN therapy at standard schedule (3 MU thrice weekly for 6 months). On the basis of IFN response they were subdivided into three groups as follows: non responders (NR: 27 cases) when alanine aminotransferase (ALT) values (normal value: 0-40 IU) at the end of treatment were abnormal (101.7 +/- 10.4); responders relapsing (RR: 29 cases) when normal ALT values at the end of therapy (28.14 +/- 1.7) increased during follow-up; sustained (long-term) responders (LTR: 29 cases) when ALT values remained normal for at least 12 months of follow-up (ALT values at the end of therapy: 21.8 +/- 1.4). ALT activity was monitored monthly during therapy and each month during 12 months of follow-up. HCV genotype was evaluated before starting treatment whereas HCV-RNA viraemia was checked at baseline and at the 1st and 6th months of therapy. RESULTS: The baseline viral load was higher in the NR group than in the RR and LTR groups independently of genotype; HCV-RNA levels progressively decreased during therapy independently of response but the levels remained significantly higher in the NR group. Genotype 1b was prevalent in the NR group. However, levels of viraemia in genotype 1b LTR patients are significantly lower than in genotype 1b NR patients. CONCLUSION: These results suggest that among viral-related parameters viraemia alone seems to play an important role in predicting response to IFN independently of genotype.

Detection of anti-HCV IgM antibodies in patients with chronic hepatitis C treated with interferon.

OBJECTIVE: To assess the role of IgM antibodies to hepatitis C virus core protein (anti-HCV IgM) as a marker of chronic HCV infection and as a predictor of successful interferon (IFN) treatment. DESIGN: Anti-HCV IgM levels were evaluated at baseline, during IFN therapy and during a follow-up period. METHODS: Anti-HCV IgM levels were evaluated in 62 patients (47 men and 15 women, aged 25-65 years) with biopsy-proven chronic active hepatitis C. Fifty-one of the patients received alpha-IFN 3 MU three times a week for 6 months and 11 received the same therapy for 12 months. Twenty patients showed a long-term response; fourteen responded but subsequently suffered a relapse; twenty-eight did not respond to the treatment. Follow-up in all patients lasted for at least 6 (mean +/- SD 9.8 +/- 5.4, range 6-29) months after the end of the therapy. RESULTS: Anti-HCV IgM were detected in 35 patients (56.4%) at baseline; no significant differences were observed between the three groups studied. Almost all members of the groups showing a relapse or no response remained positive at the end of therapy and follow-up. In contrast, we observed a progressive disappearance of anti-HCV IgM in patients responsive to interferon therapy over the long term. CONCLUSION: The loss of anti-HCV IgM positivity in patients positive at baseline can predict the long-term response to IFN therapy.

Interferon retreatment in chronic hepatitis C: which patients to choose, and what schedule to use.

UNLABELLED: OBJECTIVE; To evaluate the results of a large cohort of non-responder or relapsing responder patients with chronic hepatitis C retreated with various schedules of interferon (IFN). METHODS: Our study included 276 patients (158 non-responders and 118 relapsing responders) who underwent IFN retreatments. Among the non-responder group, 158 patients underwent further courses of IFN. In particular, 108 patients underwent one course of IFN retreatment, 40 patients underwent two courses, eight patients underwent three courses, and two patients underwent four courses. Regarding the relapsing responder group, the 118 patients were retreated with the same dosage for varying periods. In particular, 50 patients were treated for 6 months, 43 patients for 12 months, and 25 for 24 months. Patients in the subgroups of IFN retreatment were homogeneous as far as age and gender distribution, as well as virological and histological characteristics, are concerned. Qualitative and quantitative HCV-RNA was evaluated at baseline, at the end of treatment and at the last check-up of follow-up. HCV genotype was determined on baseline serum samples. Alanine transaminase (ALT) levels were tested monthly. RESULTS: Long-term biochemical (normal ALT levels) and virological (HCV-RNA negative) response was obtained in 2.6% of non-responder retreated patients, and in 33.9% of relapsing responder retreated patients. Evaluation of response on the basis of the duration of treatment showed that 48%, 19% and 16% of relapsing responder patients retreated for 24, 12 and 6 months, respectively, obtained long-term biochemical and virological response. CONCLUSION: Non-responder patient retreatment is inefficient especially in cirrhotic and/or genotype 1 b patients. IFN retreatment is warranted in relapsing responder patients. In particular, 24-month therapy induces significant long-term biochemical and virological response.

Outcome of liver disease in a large cohort of histologically proven chronic hepatitis C: influence of HCV genotype.

OBJECTIVE: To assess the influence of hepatitis C virus (HCV) genotypes on the clinical outcome of liver disease, we analysed 2,307 patients. RESULTS: The most frequently represented genotypes were 1b (40%) and 2 (28.1%). Patients with these genotypes had a median age higher than patients with other genotypes (P< 0.01). The overall survival of subjects with genotype 1b was poorer than the survival of patients with other genotypes (P< 0.01). Liver cirrhosis was found in 280 patients (12.1%), and type 1b was the most represented isolate among them (P< 0.01). Sixty-two patients (22%) developed hepatocellular carcinoma (HCC) during a follow-up of 1481.8 cumulative years (estimated crude incidence rate, 4.1 cases per 100 person-years for all cirrhotics; 5.9 cases for genotype 1a; 4.5 cases for genotype 1b; and 2.8 cases for genotypes non-1). Considering the whole population of 2,307 patients, only genotype 1b was associated significantly with both cirrhosis and the development of HCC. One hundred and nineteen cirrhotic patients underwent treatment with interferon in uncontrolled studies. Interferon therapy was associated with both better survival (P< 0.01) and a lower cumulative hazard for HCC (P< 0.01). CONCLUSIONS: Genotype 1b was associated with a poorer prognosis, probably because it leads to cirrhosis and consequently to HCC development. However, our data did not confirm genotype 1b as an independent risk factor for HCC in liver cirrhosis, which plays a major role in carcinogenesis. Interferon should be considered as a useful strategy in cirrhosis for improvement of survival and reduction of HCC risk.