Intervirology 2013;56:37–45
(DOI:10.1159/000342746)

Efficacy and Anticarcinogenic Activity of Ribavirin Combination Therapy for Hepatitis C Virus-Related Compensated Cirrhosis

Akuta N.a · Suzuki F.a · Seko Y.a · Kawamura Y.a · Sezaki H.a · Suzuki Y.a · Hosaka T.a · Kobayashi M.a · Kobayashi M.b · Saitoh S.a · Arase Y.a · Ikeda K.a · Kumada H.a
aDepartment of Hepatology, Toranomon Hospital, and Okinaka Memorial Institute for Medical Research, and bLiver Research Laboratory, Toranomon Hospital, Tokyo, Japan
email Corresponding Author


 Outline


 goto top of outline Key Words

  • Hepatitis C virus
  • Interferon
  • Ribavirin
  • Hepatocellular carcinoma
  • Cirrhosis
  • Biochemical response

 goto top of outline Abstract

Objective: Anticarcinogenic activity of ribavirin combination therapy for hepatitis C virus (HCV)-related compensated cirrhosis is still unclear. Methods: In study 1, in 157 consecutive patients with HCV-related compensated cirrhosis, treatment efficacy with interferon plus ribavirin therapy was evaluated for 48 weeks of HCV genotype 1b (HCV-1b) or 24 weeks of HCV-2a/2b. In study 2, in 185 consecutive patients with HCV-related compensated cirrhosis, who showed no sustained virological response following the first course of interferon monotherapy, hepatocarcinogenesis rates were evaluated according to the additional treatment, and they were classified into three groups: no treatment, interferon monotherapy, and ribavirin combination therapy. Results: In study 1, in HCV-1b, rates of sustained virological response and sustained biochemical response were 21 and 56%, respectively. In HCV-2a/2b, rates of sustained virological response and sustained biochemical response were 70 and 78%, respectively. In HCV-1b, sustained biochemical response rates were significantly higher than those of sustained virological response. In study 2, the hepatocarcinogenesis rates in ribavirin combination therapy were significantly lower than those in interferon monotherapy and no treatment, respectively. Conclusion: Ribavirin combination therapy for HCV-related compensated cirrhosis reduces the risk of hepatocarcinogenesis in comparison with interferon monotherapy, and higher rates of sustained biochemical response might be associated with lower hepatocarcinogenesis rates.

Copyright © 2012 S. Karger AG, Basel


goto top of outline Introduction

Hepatitis C virus (HCV) usually causes chronic infection, which can result in chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma [1,2,3,4,5]. The life expectancy of patients with HCV-related cirrhosis is largely influenced by the development of hepatocellular carcinoma during the clinical course [3]. Because an effective and curative therapy for hepatocellular carcinoma remains limited at best, primary prevention of hepatocellular carcinoma in patients with chronic liver disease is of great importance at present.

Treatment of HCV-chronic hepatitis with interferon can induce viral clearance and marked biochemical and histological improvement [6,7]. Furthermore, previous studies showed that interferon monotherapy reduced the risk of hepatocellular carcinoma [8,9,10]. However, an extended analysis of the Hepatitis C Antiviral Long-Term Treatment against Cirrhosis (HALT-C) cohort recently showed that long-term peginterferon (PEG-IFN) monotherapy could not reduce the incidence of hepatocellular carcinoma among patients with advanced hepatitis C who did not achieve sustained virological response, and patients with cirrhosis who received PEG-IFN monotherapy had a lower risk of hepatocellular carcinoma than controls [11]. Thus, it is controversial whether interferon monotherapy for patients with liver cirrhosis might reduce hepatocarcinogensis. Furthermore, it is still unclear whether ribavirin combination therapy for patients with liver cirrhosis might reduce the risk of hepatocellular carcinoma, and there are also no reports on whether ribavirin combination therapy could reduce the risk in comparison with interferon monotherapy.

The present study investigated the efficacy and anticarcinogenic activity of ribavirin combination therapy for HCV-related compensated cirrhosis, especially in comparison with interferon monotherapy.

 

goto top of outline Materials and Methods

goto top of outline Study Population

Two retrospective cohort studies were performed to investigate treatment efficacy and anticarcinogenic activity of ribavirin combination therapy for HCV-related compensated cirrhosis.

In the study 1 cohort, 157 consecutive patients of HCV-related compensated cirrhosis were recruited into the study protocol of interferon (PEG-IFNα-2b or IFNα-2b) plus ribavirin combination therapy for 48 weeks of HCV genotype 1b (HCV-1b) or 24 weeks of HCV-2a/2b, from 2001 to 2010 at Toranomon Hospital. In this retrospective study the rates of sustained virological response [HCV-RNA negativity at 24 weeks after the completion of therapy based on the COBAS TaqMan HCV test (Roche Diagnostics)] were evaluated as well as sustained biochemical response [normal level of serum alanine aminotransferase at 24 weeks after the completion of therapy (6–50 IU/l)]. Treatment efficacy was evaluated by intention-to-treat (ITT) analysis classified as treatment failure in patients who could not complete the treatment regimen and per protocol (PP) analysis. Table 1 summarizes the profiles and data of the 157 patients at the commencement of combination therapy with interferon plus ribavirin in study 1. They included 105 men and 52 women aged 34–74 years (median 58 years). 110 (70.1%) patients received PEG-IFNα-2b plus ribavirin, and the remaining 47 (29.9%) patients received IFNα-2b plus ribavirin. They received PEG-IFNα-2b at a median dose of 1.3 µg/kg (range 0.5–1.9 µg/kg) subcutaneously each week or IFNα-2b at a median dose of 6 million units (range 3–6 million units) intramuscularly each day (7 times per week for the initial 2 weeks followed by 3 times per week). They also received oral ribavirin at a median dose of 10.7 mg/kg (range 2.7–15.1 mg/kg) daily. In 56 of the 157 (35.7%) patients, the dose of ribavirin was reduced during treatment due to a fall in hemoglobin concentration. The median total duration of treatment in 120 patients of HCV-1b was 48 weeks (range 1–48 weeks), and that in 37 patients of genotype 2a or 2b was 24 weeks (range 5–24 weeks).

TAB01
Table 1. Profile and laboratory data at the start of ribavirin combination therapy in 157 patients with HCV-related compensated cirrhosis (study 1)

In the study 2 cohort (fig. 1), 185 consecutive patients of HCV-related compensated cirrhosis, who showed no sustained virological response following at the first course of interferon monotherapy (≥24 weeks) from 1987 to 2010 at Toranomon Hospital, were recruited. Hepatocarcinogenesis rates were evaluated according to the additional treatment (second course of treatment), and were classified into three groups: no treatment (106 patients), interferon monotherapy (≥24 weeks; 55 patients), and ribavirin combination therapy (≥24 weeks; 24 patients). 106 patients without treatment did not receive the additional treatment because of concerns about adverse effects, lack of time for treatment, physician recommendation based on the appearance of depression and cardiopulmonary disease during and after the first course of interferon monotherapy or the lower levels of serum alanine aminotransferase. The median follow-up time, from the end of the first course of interferon monotherapy until the last visit, was 6.4 years (range 0.0–21.0 years). 24 of the 157 patients in study 1 were also included in study 2; they showed no sustained virological response following the first course of interferon monotherapy (≥24 weeks) and were treated additionally with ribavirin combination therapy (≥24 weeks).

FIG01
Fig. 1. For study 2, 185 patients with HCV-related compensated cirrhosis, who showed no sustained virological response following the first course of interferon monotherapy (≥24 weeks), were recruited. Hepatocarcinogenesis rates were evaluated according to the additional treatment (second course of treatment), and patients were classified into three groups: no treatment, interferon monotherapy (≥24 weeks), and ribavirin combination therapy (≥24 weeks). * 24 of 157 patients with HCV-related compensated cirrhosis in study 1 were also included in study 2.

At the additional treatment of interferon monotherapy, 43 patients (78.2%) received IFNα alone, and the remaining 12 patients (21.8%) received IFNβ alone. They received interferon monotherapy including initial aggressive induction therapy (every day for 8 weeks followed by 3 times per week), with a median treatment duration of 44 weeks (range 24–382 weeks) at a median dose of 3 million units (range 3–10 million units) intramuscularly each day.

At the additional treatment of ribavirin combination therapy, 11 patients (45.8%) received PEG-IFNα-2b plus ribavirin, and the remaining 13 patients (54.2%) received IFNα-2b plus ribavirin. They received PEG-IFNα-2b at a median dose of 1.5 µg/kg (range 0.8–1.7 µg/kg) subcutaneously each week or IFNα-2b at a median dose of 6 million units (range 3–6 million units) intramuscularly each day (7 times per week for the initial 2 weeks followed by 3 times per week), with a median treatment duration of 26 weeks (range 24–48 weeks). They also received oral ribavirin at a median dose of 11.0 mg/kg (range 3.0–12.5 mg/kg) daily.

In the present studies, the patients were selected based on the following criteria. (1) Patients had compensated cirrhosis, but no decompensated cirrhosis or hepatocellular carcinoma. The diagnosis of compensated cirrhosis was based on clinical features (absence of signs for decompensation of ascites, encephalopathy, or gastrointestinal bleeding), laboratory tests, and peritoneoscopy or liver biopsy. (2) Patients were negative for hepatitis B surface antigen (radioimmunoassay, Dainabot, Tokyo, Japan), positive for anti-HCV (third-generation enzyme immunoassay, Chiron Corp., Emerville, Calif., USA), and positive for HCV-RNA by qualitative or quantitative analysis. (3) Patients were free of coinfection with human immunodeficiency virus. (4) Lifetime cumulative alcohol intake was <500 kg (mild to moderate alcohol intake). (5) Patients were free of other types of hepatitis, including hemochromatosis, Wilson disease, primary biliary cirrhosis, alcoholic liver disease, and autoimmune liver disease. (6) Each patient signed a consent form of the study protocol that had been approved by the human ethics review committee.

goto top of outline Laboratory Investigations

Blood samples were frozen at –80° within 4 h of collection and were not thawed until used for testing. HCV genotype was determined by PCR using a mixed primer set derived from nucleotide sequences of the NS5 region [12]. HCV-RNA quantitative analysis was measured by branched DNA assay version 2.0 (Chiron Corp., Emeryville, Calif., USA), AMPLICOR GT HCV Monitor version 2.0 using the 10-fold dilution method (Roche Molecular Systems Inc., Pleasanton, Calif., USA), or COBAS TaqMan HCV test (Roche Diagnostics, Tokyo, Japan). High viral load of viremia levels was defined as branched DNA assay ≥1.0 MEq/ml, AMPLICOR GT HCV Monitor ≥100 × 103 IU/ml, or COBAS TaqMan HCV test ≥5.0 log IU/ml. Low viral load was defined as branched DNA assay <1.0 MEq/ml, AMPLICOR GT HCV Monitor <100 × 103 IU/ml, or COBAS TaqMan HCV test <5.0 log IU/ml. The lower limit of HCV-RNA qualitative analysis (Amplicor, Roche Diagnostics, Mannheim, Germany) was 100 copies/ml, and that of COBAS TaqMan HCV test was 1.2 log IU/ml. The undetectable samples by HCV-RNA qualitative analysis or COBAS TaqMan HCV test were defined as negative HCV-RNA.

goto top of outline Follow-Up and Diagnosis of Hepatocellular Carcinoma

Clinical and laboratory assessments were performed at least once every month before, during, and after treatment. Adverse effects were monitored clinically by careful interviews and medical examination at least once every month. Patient compliance with treatment was evaluated with a questionnaire. Blood samples were also obtained at least once every month before, during, and after treatment, and were also analyzed for levels of serum alanine aminotransferase and HCV-RNA at various time points.

Patients were examined for hepatocellular carcinoma by abdominal ultrasonography every 3–6 months. If hepatocellular carcinoma was suspected based on ultrasonographic results, additional procedures, such as computed tomography, magnetic resonance imaging, abdominal angiography, and ultrasonography-guided tumor biopsy if necessary, were used to confirm the diagnosis.

goto top of outline Statistical Analysis

χ2 test, Fisher’s exact probability test, and Mann-Whitney’s U test were used to compare the background characteristics between groups. Multiple comparisons were examined by the Bonferroni test. The cumulative hepatocarcinogenesis rates were calculated using the Kaplan-Meier technique, and differences between the curves were tested using the log-rank test. Statistical analysis of the hepatocarcinogenesis rates according to groups was calculated using the period from the end of the first course of interferon monotherapy until the appearance of hepatocellular carcinoma or until the last visit or until the start of the third course of interferon-based treatment. Stepwise Cox regression analysis was used to determine independent predictive factors that were associated with hepatocarcinogenesis. The hazard ratio (HR) and 95% confidence interval were also calculated. Potential predictive factors associated with hepatocarcinogenesis included the following 13 variables: age, sex, serum aspartate aminotransferase, serum alanine aminotransferase, platelet count, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, HCV genotype, levels of viremia, total duration of additional treatment, and group of additional treatment. Each variable was transformed into categorical data consisting of two simple ordinal numbers for univariate and multivariate analyses. All p values <0.05 and <0.1 by the two-tailed test were considered significant (p < 0.05) and marginally significant (p < 0.1), respectively. Variables that achieved statistical significance (p < 0.05) on univariate analysis were tested by multivariate Cox proportional hazard model to identify significant independent factors. Statistical comparisons were performed using the SPSS software (SPSS Inc., Chicago, Ill., USA).

 

goto top of outline Results

goto top of outline Efficacy of Ribavirin Combination Therapy (Study 1)

Treatment efficacy of a 48-week regimen of interferon plus ribavirin combination therapy in 120 patients infected with HCV-1b was evaluated. In ITT analysis, rates of sustained virological response and sustained biochemical response were 21% (25 of 120 patients) and 56% (67 of 120 patients), respectively. In the PP analysis, rates of sustained virological response and sustained biochemical response were 34% (18 of 53 patients) and 57% (28 of 49 patients), respectively (fig. 2). In both analyses, rates of sustained biochemical response were significantly higher than those of sustained virological response (ITT analysis, p < 0.001, and PP analysis, p = 0.028).

FIG02
Fig. 2. In 157 patients with HCV-related compensated cirrhosis treatment efficacy with interferon plus ribavirin therapy was evaluated for 48 weeks of HCV genotype 1b or 24 weeks of genotype 2a/2b. In HCV genotype 1b, rates of sustained biochemical response (SBR) were significantly higher than those of sustained virological response (SVR; ITT analysis, p < 0.001, and PP analysis, p = 0.028).

Treatment efficacy of a 24-week regimen of interferon plus ribavirin combination therapy in 37 patients infected with HCV-2a or 2b was evaluated. In the ITT analysis, rates of sustained virological response and sustained biochemical response were 70% (26 of 37 patients) and 78% (29 of 37 patients), respectively. In the PP analysis, rates of sustained virological response and sustained biochemical response were 81% (26 of 32 patients) and 90% (27 of 30 patients), respectively (fig. 2). In both analyses, rates of the sustained biochemical response were not significantly higher than those of the sustained virological response.

goto top of outline Profile, Laboratory Data, and Efficacy according to Additional Treatment Groups (Study 2)

Profile and laboratory data, at the start of the first course of interferon monotherapy of 185 patients with HCV-related compensated cirrhosis, are summarized in table 2. The age of patients with ribavirin combination therapy was significantly lower than that of patients with no treatment (p = 0.013; Bonferroni test) and interferon monotherapy (p = 0.030; Bonferroni test). The platelet count of patients of ribavirin combination therapy was significantly higher than that of patients without treatment (p = 0.002; Bonferroni test) and interferon monotherapy (p = 0.015; Bonferroni test). The total cholesterol level of patients with interferon monotherapy was significantly lower than that of patients without treatment (p = 0.039; Bonferroni test). Low viral load rates of patients with interferon monotherapy were significantly higher than those of patients with ribavirin combination therapy (p = 0.006; Bonferroni test). There were no other significant differences in clinical features at the start of the first course of interferon monotherapy among the three groups.

TAB02
Table 2. Profile and laboratory data of 185 patients with HCV-related compensated cirrhosis according to additional treatment groups (study 2)

Additional treatment duration of only 1 patient, who was diagnosed with hepatocellular carcinoma during additional treatment, was evaluated using the period from the start of the second course of interferon monotherapy until the appearance of hepatocellular carcinoma. During additional treatment, the total duration of interferon monotherapy was significantly longer than that of ribavirin combination therapy (p = 0.044; Mann-Whitney U test). In ITT analysis, sustained virological response rates of ribavirin combination therapy (29%) were not different from those of interferon monotherapy (20%), but sustained biochemical response rates of ribavirin combination therapy (67%) tended to be higher than those of interferon monotherapy (45%; p = 0.083; χ2 test) (table 2).

goto top of outline Predictive Factors Associated with Hepatocarcinogenesis by Multivariate Analysis

The data for the whole population sample were analyzed to determine those factors that could predict hepatocarcinogenesis. Hepatocarcinogenesis rates in older patients (≥55 years), in patients with higher levels of aspartate aminotransferase (≥58 IU/l), and lower levels of platelet count (<15.0 × 104/mm3) were significantly higher than those in younger patients (<55 years), in patients with lower levels of aspartate aminotransferase (<58 IU/l), and higher levels of platelet count (≥15.0 × 104/mm3), respectively (p < 0.001, p = 0.006, and p = 0.017; log-rank test). Furthermore, the rates in no treatment were significantly higher than those in interferon monotherapy (p = 0.047; log-rank test) and ribavirin combination therapy (p < 0.001; log-rank test), and the rates in interferon monotherapy were significantly higher than those in ribavirin combination therapy (p < 0.001; log-rank test) (fig. 3). Thus, univariate analysis identified four parameters that significantly correlated with hepatocarcinogenesis. These factors were entered into multivariate analysis, which then identified three parameters that significantly influenced hepatocarcinogenesis independently: additional treatment (no treatment; HR 9.14, p = 0.002), age (≥55 years; HR 2.87, p < 0.001), and levels of aspartate aminotransferase (≥58 IU/l; HR 2.11, p = 0.010) (table 3).

TAB03
Table 3. Factors associated with hepatocarcinogenesis in 185 patients of HCV-related compensated cirrhosis identified by multivariate analysis (study 2): Cox proportional hazard model

FIG03
Fig. 3. Cumulative hepatocarcinogenesis rates in the three groups of additional treatment. The rates in no treatment were significantly higher than those in interferon monotherapy (p = 0.047; log-rank test) and ribavirin combination therapy (p < 0.001; log-rank test), and the rates in interferon monotherapy were significantly higher than those in ribavirin combination therapy (p < 0.001; log-rank test).

The data for 167 patients, except for 18 patients who showed a sustained virological response following additional treatment, were also analyzed to determine those factors that could predict hepatocarcinogenesis. Hepatocarcinogenesis rates in older age (≥55 years) and higher levels of aspartate aminotransferase (≥58 IU/l) were significantly higher than those in younger age (<55 years) and lower levels of aspartate aminotransferase (<58 IU/l), respectively (p < 0.001 and p = 0.007; log-rank test). Furthermore, the rates in ribavirin combination therapy were significantly lower than those in interferon monotherapy (p < 0.001; log-rank test) and no treatment (p < 0.001; log-rank test) (fig. 4). Thus, univariate analysis identified three parameters that significantly correlated with hepatocarcinogenesis. These factors were entered into multivariate analysis, which then identified three parameters that significantly influenced hepatocarcinogenesis independently: additional treatment (no treatment; HR 7.87, p = 0.005), age (≥55 years; HR 2.52, p < 0.001), and levels of aspartate aminotransferase (≥58 IU/l; HR 2.13, p = 0.010) (table 4).

TAB04
Table 4. Factors associated with hepatocarcinogenesis in 167 patients of HCV-related compensated cirrhosis, except for 18 patients who showed sustained virological response following additional treatment identified by multivariate analysis (study 2): Cox proportional hazard model

FIG04
Fig. 4. Cumulative hepatocarcinogenesis rates in the three groups of additional treatment, except for patients who showed sustained virological response following additional treatment. The rates in ribavirin combination therapy were significantly lower than those in interferon monotherapy (p < 0.001; log-rank test) and no treatment (p < 0.001; log-rank test).

 

goto top of outline Discussion

One of our previous studies indicated that the cancer-suppressive activity of interferon monotherapy in patients with HCV-RNA eradication was similar to that in patients with alanine aminotransferase normalization without HCV-RNA elimination [9]. Other studies also indicated a higher incidence and more rapid development of hepatocellular carcinoma in HCV patients with high levels of alanine aminotransferase [13,14]. Collectively, these results suggest that the carcinogenic process in patients with chronic HCV infection is enhanced by high levels and fluctuations of alanine aminotransferase, and indicate a close relationship between suppression of inflammatory necrosis of hepatocytes and a lower incidence of hepatocellular carcinoma in patients with HCV-associated chronic liver disease. Recent studies based on interferon plus ribavirin combination therapy also showed that the attainment of sustained virological response or lower levels of alanine aminotransferase after ribavirin combination therapy could reduce the rates of hepatocellular carcinoma [15,16], but the small numbers of patients with compensated cirrhosis (5% or less of all patients) were recruited. The present study 1 based on the patients with compensated cirrhosis showed that rates of sustained virological response and sustained biochemical response in HCV-2a/2b were high rates of 70 and 78%, and that rates of sustained biochemical response (57%) were significantly higher than those of sustained virological response (34%) in HCV-1b. Furthermore, the present study 2 based on the patients with compensated cirrhosis, who showed no sustained virological response following the first course of interferon monotherapy, also showed that sustained biochemical response rates of ribavirin combination therapy (67%) tended to be higher than those of interferon monotherapy (45%). Thus, in ribavirin combination therapy for compensated cirrhosis, higher rates of sustained biochemical response might be associated with lower rates of hepatocarcinogenesis. One limitation is that the present study was performed based on the small numbers of patients who showed no sustained virological response with interferon monotherapy. In further prospective studies a larger number of patients need to be investigated to confirm this finding.

Previous studies have shown that gender, age, fibrosis stage, alanine aminotransferase, and interferon regimen are important pretreatment predictors of hepatocarcinogenesis [9,10,17]. In the present study 2 based on the patients with compensated cirrhosis, higher age and aspartate aminotransferase were associated with higher hepatocarcinogenesis rates in the whole population sample and in the sample which excluded patients who showed sustained virological response following additional treatment. Furthermore, as treatment-related factors, the hepatocarcinogenesis rates in ribavirin combination therapy were significantly lower than those in interferon monotherapy. Thus, in patients with compensated cirrhosis representing a high-risk group of hepatocarcinogenesis, ribavirin combination therapy might reduce the risk of hepatocellular carcinoma in comparison with interferon monotherapy. One reason for the higher anticarcinogenic activity by ribavirin combination therapy might be due to higher rates of sustained biochemical response. The other reason might be due to the difference in the background (lower age and higher levels of platelet count as an indicator of fibrosis stage) of patients with ribavirin combination therapy. Further studies of a larger number of patients matched for background, including age, sex, genotype, and platelet count, are required to investigate the rates of hepatocarcinogenesis and the mechanism of anticarcinogenic activity by ribavirin combination therapy for HCV-related compensated cirrhosis.

Two previous studies (PROVE1 and PROVE2) showed that the 12- and 24-week regimen of telaprevir/PEG-IFN/ribavirin could achieve sustained virological response rates of 35–60 and 61–69% in patients infected with HCV-1, respectively [18,19]. However, a recent study (PROVE3) also showed that the sustained virological response rates were the lower rates of 39 and 38% with the 24- and 48-week regimen of triple therapy in previously nonresponding patients infected with HCV-1, who do not become HCV-RNA negative during or at the end of the initial PEG-IFN/ribavirin treatment, respectively [20]. Furthermore, the telaprevir-based regimen induces resistant variants [21,22,23] and has side effects including anemia and rash [18,19,20,24]. Hence, patients, who do not achieve sustained virological response by triple therapy, need to be identified, in order to avoid unnecessary side effects and telaprevir-resistant variants. Recent studies identified amino acid substitutions at position 70 and/or 91 in the HCV-1b core region, advanced fibrosis stage, and higher levels of α-fetoprotein as pretreatment predictors of poor virological response to PEG-IFN/ribavirin combination therapy or triple therapy of telaprevir/PEG-IFN/ribavirin [23,25,26,27,28], and these factors are also risk factors and surrogate markers of hepatocarcinogenesis [29,30,31,32,33,34]. Hence, ribavirin combination therapy for these patients might be an efficacious therapeutic regimen for sustained biochemical response and thus a reduction of the risk of hepatocarcinogenesis. Large-scale prospective studies should be conducted in the future to confirm this finding.

In conclusion, the present retrospective study indicated that ribavirin combination therapy for HCV-related compensated cirrhosis could reduce the risk of hepatocarcinogenesis in comparison with interferon monotherapy. Large-scale prospective studies need to be conducted in the future to confirm these findings.

 

goto top of outline Acknowledgments

This study was supported in part by a Grant-in-Aid from the Ministry of Health, Labor and Welfare, Japan.


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  34. Akuta N, Suzuki F, Seko Y, Kawamura Y, Sezaki H, Suzuki Y, Hosaka T, Kobayashi M, Hara T, Kobayashi M, Saitoh S, Arase Y, Ikeda K, Kumada H: Complicated relationships of amino acid substitution in HCV core region and IL28B genotype influencing hepatocarcinogenesis. Hepatology 2012, E-pub ahead of print.

 goto top of outline Author Contacts

Norio Akuta, MD
Department of Hepatology, Toranomon Hospital
2-2-2 Toranomon, Minato-ku
Tokyo 105-0001 (Japan)
E-Mail akuta-gi@umin.ac.jp


 goto top of outline Article Information

Received: June 19, 2012
Accepted after revision: August 14, 2012
Published online: October 4, 2012
Number of Print Pages : 9
Number of Figures : 4, Number of Tables : 4, Number of References : 34


 goto top of outline Publication Details

Intervirology (International Journal of Basic and Medical Virology)

Vol. 56, No. 1, Year 2013 (Cover Date: November 2012)

Journal Editor: Manuguerra J.-C. (Paris)
ISSN: 0300-5526 (Print), eISSN: 1423-0100 (Online)

For additional information: http://www.karger.com/INT


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