Norio Hayashi

Hyogo Prefectural Amagasaki Hospital, Amagasaki, Hyōgo, Japan

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Publications (376)1758.09 Total impact

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    ABSTRACT: The number of hepatocellular carcinoma (HCC) patients with non-viral etiologies is increasing in Japan. We conducted a nation-wide survey to examine the characteristics of those patients.
    Journal of gastroenterology. 06/2014;
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    ABSTRACT: AimThe efficacy and safety of simeprevir in combination with peginterferon α-2b and ribavirin (PegIFNα-2b/RBV) were investigated in patients infected with hepatitis C virus (HCV) genotype-1 who were treatment-naïve or had previously received interferon (IFN)-based therapy.Combination therapy with peginterferon α-2b and ribavirin (PegIFNα-2b/RBV) has been widely used in treatment-naïve patients with hepatitis C virus (HCV) genotype-1. Options are limited for re-treatment of patients in whom previous interferon-based therapy failed.MethodsCONCERTO-4 (NCT01366638) was an open-label, non-comparative, multicenter study of once-daily simeprevir (TMC435) 100 mg in combination with PegIFNα-2b/RBV in treatment-naïve and -experienced patients (prior relapsers or non-responders to interferon-based therapy) with chronic HCV genotype-1 infection. Twelve-week combination treatment was followed by 24/48-week response-guided PegIFNα-2b/RBV therapy for treatment-naïve patients and prior relapsers, and 48-week PegIFNα-2b/RBV therapy for prior non-responders. Patients were followed for 72 weeks after treatment initiation. The proportions of patients with sustained viral response (SVR; undetectable HCV RNA) at treatment end and 12 weeks after the last treatment (SVR12) were among the major efficacy endpoints. Safety, including adverse events (AEs), was monitored.ResultsOf the 79 patients treated, the proportion achieving SVR12 was highest among treatment-naïve patients (91.7%) and prior relapsers (100%) vs 38.5% of prior non-responders. All treatment-naïve patients and prior non-responders who achieved SVR12 also achieved SVR at treatment end and 24 weeks after last dose; 96.6% of prior relapsers achieved both endpoints. Most AEs were of grade 1 or 2 severity. Grade 3 AEs occurred in 17 patients, most frequently neutropenia (6.3%).Conclusion Simeprevir combined with PegIFNα-2b/RBV was effective in patients infected with HCV genotype-1, both for initial treatment of naïve patients and for re-treatment of patients in whom previous interferon-based therapy had failed.
    Hepatology Research 06/2014; · 2.07 Impact Factor
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    ABSTRACT: Triple therapy with telaprevir (TVR), pegylated interferon and ribavirin has improved antiviral efficacy in patients with chronic hepatitis C (CH-C). However, the severe adverse effects caused by TVR are important to resolve. In this prospective, randomized, multicenter, open-label study, the antiviral efficacy and safety in the reduced administration of TVR were examined. A total of 81 CH-C Japanese patients with HCV genotype 1 were randomized into two regimens of TVR 2250 mg (TVR-2250) or 1500 mg (TVR-1500) and treated with triple therapy for 24 weeks. The mean HCV RNA at start, 2 and 4 weeks of treatment were 6.69 ± 0.70, 1.05 ± 0.74, 0.22 ± 0.48 log10 IU/ml in the TVR-2250 group and 6.70 ± 0.62, 1.02 ± 0.62, 0.13 ± 0.41 log10 IU/ml in the TVR-1500 group. The SVR rates were 85 % in both groups (35/41 and 34/40, respectively). There were no patients with viral breakthrough in either group. As for adverse effects, rash more than moderate and severe anemia with <8.5 g/dl of hemoglobin were higher in the TVR-2250 group than in the TVR-1500 group (p = 0.046, p < 0.001, respectively). The increase in serum creatinine levels and decrease in estimated glomerular filtration rates were higher in the TVR-2250 group than in the TVR-1500 group. The lower dose of TVR (1500 mg/day) can result in similar SVR rates and lower treatment-related adverse effects compared to the higher dose of TVR (2250 mg/day) in triple therapy (UMIN: 000007313, 000007330).
    Journal of Gastroenterology 05/2014; · 3.79 Impact Factor
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    ABSTRACT: Effective prophylactic therapies have not been established for hepatocellular carcinoma recurrence. Peretinoin represents one novel option for patients with hepatitis C virus-related hepatocellular carcinoma (HCV-HCC), and it was tested in a multicenter, randomized, double-blind, placebo-controlled study. Patients with curative therapy were assigned to one of the following regimens: peretinoin 600, 300 mg/day, or placebo for up to 96 weeks. The primary outcome was recurrence-free survival (RFS). Of the 401 patients initially enrolled, 377 patients were analyzed for efficacy. The RFS rates in the 600-mg group, the 300-mg group, and the placebo group were 71.9, 63.6, and 66.0 % at 1 year, and 43.7, 24.9, and 29.3 % at 3 years, respectively. The primary comparison of peretinoin (300 and 600-mg) with placebo was not significant (P = 0.434). The dose-response relationship based on the hypothesis that "efficacy begins to increase at 600 mg/day" was significant (P = 0.023, multiplicity-adjusted P = 0.048). The hazard ratios for RFS in the 600-mg group vs. the placebo group were 0.73 [95 % confidence interval (CI) 0.51-1.03] for the entire study period and 0.27 (95 % CI 0.07-0.96) after 2 years of the randomization. Common adverse events included ascites, increased blood pressure, headache, presence of urine albumin, and increased transaminases. Although the superiority of peretinoin to placebo could not be validated, 600 mg/day was shown to be the optimal dose, and treatment may possibly reduce the recurrence of HCV-HCC, particularly after 2 years. The efficacy and safety of peretinoin 600 mg/day should continue to be evaluated in further studies.
    Journal of Gastroenterology 04/2014; · 3.79 Impact Factor
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    ABSTRACT: In a Japanese Phase II study, the hepatitis C virus NS3/4A protease inhibitor simeprevir demonstrated potent antiviral activity and significantly improved sustained virologic response rates when added to peginterferon α-2a/ribavirin in treatment-naïve patients infected with hepatitis C virus genotype 1. CONCERTO-1 was a Phase III, randomized, double-blind, placebo-controlled trial. Treatment-naïve adults (⩽70 years) with chronic hepatitis C virus genotype 1 infection (hepatitis C virus RNA ⩾5log10IU/mL) were randomized (2:1) to simeprevir 100mg once-daily with peginterferon α-2a/ribavirin for 12 weeks then response-guided therapy with peginterferon α-2a/ribavirin for 12 or 36 weeks, or to placebo with peginterferon α-2a/ribavirin for 12 weeks then peginterferon α-2a/ribavirin for 36 weeks. Overall, 183 patients were treated. Sustained virologic response 12 weeks after treatment end (primary efficacy endpoint) was achieved in 88.6% of simeprevir- and 61.7% of placebo-treated patients (P<0.0001 for stratum-adjusted between-group difference). Overall, 91.9% of simeprevir-treated patients met response-guided therapy criteria and completed treatment at Week 24; sustained virologic response rate at 12 weeks in these patients was 92.0%. One simeprevir- (0.8%) and two placebo-treated patients (3.3%) experienced viral breakthrough; respective viral relapse rates were 7.6% and 30.6%. Overall adverse event profile in simeprevir-treated patients was comparable to that in patients who received peginterferon α-2a/ribavirin alone. Simeprevir once daily with peginterferon α-2a/ribavirin significantly improved sustained virologic response rate 12 weeks after treatment end in treatment-naïve patients with chronic hepatitis C virus genotype 1 infection, with a shorter 24-week treatment duration in most patients (ClinicalTrials.gov: NCT01292239).
    Journal of Hepatology 04/2014; · 9.86 Impact Factor
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    ABSTRACT: Efficacy of available therapies for patients with HCV who have previously failed treatment is limited. Two Phase III, open-label trials in Japan investigated efficacy and safety of simeprevir and peginterferon-α-2a/ribavirin (PR) combination therapy in treatment-experienced patients with genotype 1 HCV infection. In CONCERTO-2, prior non-responders to IFN-based therapy (N = 106) received simeprevir (TMC435) 100 mg QD with PR for 12 (SMV12, n = 53) or 24 weeks (SMV24, n = 53) followed by response-guided therapy (RGT) with PR for 12/36 (SMV12) or 0/24 (SMV24) weeks. In CONCERTO-3, relapsers after IFN-based therapy (N = 49) received simeprevir 100 mg QD with PR for 12 weeks followed by RGT with PR for 12/36 weeks. Primary endpoints were the rates of sustained virologic response 12 weeks after treatment end (SVR12). SVR12 rates were 52.8 % (SMV12) and 35.8 % (SMV24) for prior non-responders, and 95.9 % for prior relapsers (SMV12; p ≤ 0.0001 vs null hypothesis, respectively). Most prior non-responders (SMV12: 81.1 %; SMV24: 73.6 %) and prior relapsers (95.9 %) met RGT criteria and completed PR to Week 24. Of these, 60.5 %, 48.7 %, and 95.7 %, respectively, achieved SVR12. Viral breakthrough occurred in 13.2 % (SMV12) and 11.3 % (SMV24) of prior non-responders; no viral breakthrough occurred in prior relapsers. Viral relapse occurred in 38.6 % (SMV12) and 51.1 % (SMV24) of prior non-responders and 8.2 % of prior relapsers. Simeprevir with PR was generally well tolerated in both studies. Re-treatment with 12 weeks of simeprevir QD with PR provided high SVR in treatment-experienced patients with chronic HCV genotype 1 infection, and allowed most patients to complete treatment in 24 weeks.
    Journal of Gastroenterology 03/2014; · 3.79 Impact Factor
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    ABSTRACT: The degree of liver fibrosis is strongly associated with the antiviral effect of interferon on chronic hepatitis C patients. In this study, the accuracy of acoustic radiation force impulse (ARFI) in assessing liver fibrosis and the association between liver stiffness using ARFI and antiviral effects were investigated. The 124 patients with chronic hepatitis C enrolled in this study included 94 with HCV genotype 1 and 40 (30%) with moderate fibrosis (METAVIR fibrosis score ≥ F2). Sixty-one patients received pegylated interferon (peg-IFN) plus ribavirin combination therapy and the treatment responses were assessed. The shear wave velocity (Vs value) by ARFI had a strong correlation with the histological fibrosis stage (P < 0.001). The AUROC of the Vs value, aspartate aminotransferase platelet ratio index and FIB4 for the diagnoses of moderate fibrosis (≥F2) were 0.890, 0.779, and 0.737, respectively. HCV genotype 1 patients with the TT allele of IL28B and with a low Vs value (<1.40 m/sec) who were treated with peg-IFN plus ribavirin therapy achieved a sustained virologic response at a rate of 79% (15/19), while all patients with the TG/GG allele of IL28B and a high Vs value (≥1.40 m/sec) experienced a non-virologic response (6/6). The Vs value measured by ARFI could not predict the treatment response for patients with HCV genotype 2. It is concluded that the combination of ARFI at cut off of 1.4 m/sec and IL28B may be useful for patients with chronic hepatitis C with genotype 1 treated with peg-IFN/ribavirin combination therapy. J. Med. Virol. 86:241-247, 2014. © 2013 Wiley Periodicals, Inc.
    Journal of Medical Virology 02/2014; 86(2):241-7. · 2.37 Impact Factor
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    ABSTRACT: Daclatasvir-containing regimens have the potential to address limitations of current regimens combining peginterferon alfa and ribavirin with first-generation protease inhibitors for treatment of chronic hepatitis C virus (HCV) genotype 1 infection. In this randomized, double-blind study, 27 Japanese treatment-naive patients received once-daily daclatasvir 10 mg or 60 mg or placebo, each combined with peginterferon alfa-2b/ribavirin; 18 prior null (n=9) or partial (n=9) responders received the same daclatasvir-containing regimens without a placebo arm. Daclatasvir recipients with protocol-defined response (HCV RNA <15 IU/mL at week 4, undetectable at week 12) were treated for 24 weeks; those without protocol-defined response and placebo recipients continued treatment to week 48. Sustained virologic response 24 weeks posttreatment (SVR24) was achieved by 66.7%, 90.0%, and 62.5% of treatment-naive patients in the daclatasvir 10 mg, 60 mg, and placebo groups, respectively. Prior nonresponders had more frequent virologic failure; 22.2% and 33.3% of daclatasvir 10 mg and 60 mg recipients, respectively, achieved SVR24. Adverse events were similar across groups and were typical of peginterferon alfa-2b/ribavirin. Pyrexia, headache, alopecia, decreased appetite, and malaise were the most common adverse events; two daclatasvir recipients discontinued due to adverse events. Daclatasvir 60 mg combined with peginterferon alfa-2b and ribavirin achieved a high rate of SVR24 in treatment-naive patients with HCV genotype 1 infection, with tolerability similar to that of peginterferon alfa-2b/ribavirin alone. However, regimens with greater antiviral potency are needed for prior nonresponders.
    Antiviral therapy 01/2014; · 3.07 Impact Factor
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    ABSTRACT: Background & Aims In patients with chronic hepatitis C virus (HCV) infection, lack of sustained virologic response (SVR) 24 weeks after the end of interferon therapy is a significant risk factor for hepatocellular carcinoma (HCC). Although many pretreatment factors are known to affect HCC incidence, less is known about post-treatment factors—many change during the course of interferon therapy. Methods We performed a prospective study, collecting data from 2659 patients with chronic hepatitis C without a history of HCC who had been treated with pegylated interferon (Peg-IFN) plus ribavirin from 2002 through 2008 at hospitals in Japan. Biopsy specimens were collected before treatment; all patients received Peg-IFN plus ribavirin for 48 to 72 weeks (HCV genotype 1) or 24 weeks (HCV genotype 2). Hematologic, biochemical, and virologic data were collected every 4 weeks during treatment and every 6 months after treatment. HCC was diagnosed based on angiography, computed tomography, and/or magnetic resonance imaging findings. Results HCC developed in 104 patients during a mean observation period of 40 months. Older age, male sex, lower platelet counts and higher levels of α-fetoprotein at baseline, and lack of an SVR were significant risk factors for HCC. The cumulative incidence of HCC was significantly lower in patients without SVRs who relapsed than those with no response to treatment. Levels of α-fetoprotein 24 weeks after the end of treatment (AFP24) were significantly lower than levels of α-fetoprotein at baseline in patients with SVRs and those who relapsed, but not in nonresponders. Post-treatment risk factors for HCC among patients with SVRs included higher AFP24 level and older age; among those without SVRs, risk factors included higher AFP24 level, integrated level of alanine aminotransferase, older age, and male sex. AFP24 (≥10 ng/mL, 10–5 ng/mL, and then <5 ng/mL) was a better predictor of HCC incidence than pretreatment level of AFP among patients with and without SVRs. Conclusions In patients with chronic HCV infection, levels of α-fetoprotein decrease during interferon therapy. High post-treatment levels of α-fetoprotein predict HCC, regardless of whether patients achieve an SVR. University Hospital Medical Information Network Clinical Trials Registry: C000000196, C000000197.
    Clinical Gastroenterology and Hepatology. 01/2014; 12(7):1186–1195.
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    ABSTRACT: In patients with chronic hepatitis C virus (HCV) infection, lack of sustained virologic response (SVR) 24 weeks after the end of interferon therapy is a significant risk factor for hepatocellular carcinoma (HCC). Although many pre-treatment factors are known to affect HCC incidence, less is known about post-treatment factors- many change during the course of interferon therapy. We performed a prospective study, collecting data from 2659 patients with chronic hepatitis C without a history of HCC who had been treated with pegylated interferon (Peg-IFN) plus ribavirin from 2002 through 2008 at hospitals in Japan. Biopsies were collected before treatment; all patients received Peg-IFN plus ribavirin for 48-72 weeks (HCV genotype 1) or 24 weeks (HCV genotype 2). Hematologic, biochemical, and virologic data were collected every 4 weeks during treatment and every 6 months after treatment. HCC was diagnosed based on angiography, computed tomography, and/or magnetic resonance imaging findings. HCC developed in 104 patients during a mean observation period of 40 months. Older age, male sex, lower platelet counts and higher levels of α-fetoprotein at baseline, and lack of an SVR were significant risk factors for HCC. The cumulative incidence of HCC was significantly lower in patients without SVRs who relapsed than those with no response to treatment. Levels of α-fetoprotein 24 weeks after the end of treatment (AFP24) were significantly lower than levels of α-fetoprotein at baseline in patients with SVRs and those who relapsed, but not in non-responders. Post-treatment risk factors for HCC among patients with SVRs included higher AFP24 and older age; among those without SVRs, risk factors included higher AFP24, integrated level of alanine aminotransferase, older age, and male sex. AFP24 (>10 ng/ml, 10-5 ng/ml, and then <5 ng/ml) was a better predictor of HCC incidence than pre-treatment level of AFP among patients with and without SVRs. In patients with chronic HCV infection, levels of α-fetoprotein decrease during interferon therapy. High post-treatment levels of α-fetoprotein predict HCC, regardless of whether patients achieve an SVR. UMIN: C000000196, C000000197.
    Clinical gastroenterology and hepatology: the official clinical practice journal of the American Gastroenterological Association 12/2013; · 5.64 Impact Factor
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    ABSTRACT: Efficacy, safety and pharmacokinetics of simeprevir (TMC435), a once-daily, noncovalent, oral hepatitis C virus (HCV) NS3/4A protease inhibitor, was evaluated in combination with peginterferon α-2a/ribavirin (PegIFNα-2a/RBV) for treatment-naïve, HCV genotype 1-infected patients in Japan. In a multicenter, randomized clinical trial in Japan, ninety-two patients received either simeprevir (50 or 100 mg QD) for 12 or 24 weeks with PegIFNα-2a/RBV for 24 or 48 weeks (according to response-guided therapy [RGT] criteria), or PegIFNα-2a/RBV for 48 weeks (PR48 group). Compared with the PR48 group, plasma HCV RNA reductions in the simeprevir groups were rapid and more substantial (Week 4: -5.2, -5.2 and -2.9 log10IU/mL for simeprevir 50 mg combined, 100 mg combined, and PR48 groups, respectively). High rapid virologic response rates (83, 90, and 8 % for simeprevir 50 mg combined, 100 mg combined, and PR48 groups, respectively) led to high sustained virologic response rates (77-92 %, compared with 46 % for PR48). All but one of the simeprevir-treated patients were eligible to complete treatment after 24 weeks (RGT). Relapse rates in simeprevir-treated patients were low (8-17 %, compared with 36 % for the PR48 group). There were no notable differences in the safety profile between the simeprevir and PR48 groups. The addition of simeprevir QD to PegIFNα-2a/RBV, as compared with PegIFNα-2a/RBV alone, demonstrated potent antiviral activity and significantly improved the rates of sustained virologic response, with a shortened 24-week treatment duration, in treatment-naive patients infected with HCV genotype 1 in Japan. Simeprevir was generally safe and well tolerated. (ClinicalTrials.gov number, NCT00996476).
    Journal of Gastroenterology 09/2013; · 3.79 Impact Factor
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    ABSTRACT: Renal damage has been reported as an important complication during combination treatment of peginterferon (PEG-IFN), ribavirin (RBV), and telaprevir (TVR) for chronic hepatitis C. However, very little is known about this complication. We investigated the role TVR plays in renal damage during this triple therapy. Twenty-five chronic hepatitis C patients with genotype 1 and high vial load received TVR in combination with PEG-IFN and RBV for 12 weeks followed by treatment with PEG-IFN and RBV. Renal function of these patients was prospectively evaluated for 16 weeks. Creatinine clearance decreased significantly during PEG-IFN/RBV/TVR treatment (day7 69.9+17.6 vs. pretreatment 84.8+21.2 mL/min/1.73m(2) ,P<0.001). Consequently, serum creatinine and cystatin C significantly rose during PEG-IFN/RBV/TVR treatment (creatinene;day7 0.90+0.21 vs. pretreatment 0.78+0.19 mg/dL,P<0.001 and cystatin C;day7 1.21+0.25 vs. pretreatment 1.03+0.15 mg/dL,P<0.001). Serum creatinine returned to pretreatment levels after the termination of TVR. The increase of serum creatinine and cystatin C from baseline significantly correlated with serum TVR level at day7, which was determined by starting dose of TVR per body weight (TVR level at day7 vs. starting dose of TVR per body weight, r=0.775, P<0.001). When the patients were classified according to the starting dose of TVR per body weight, renal impairment was observed only in the high-dose (TVR>33mg/kg/day) group, not in the low-dose (TVR<33mg/kg/day) group. These results suggest that TVR dose per body weight is important for the occurrence of renal impairment in PEG-IFN/RBV/TVR treatment.
    Hepatology Research 09/2013; · 2.07 Impact Factor
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    ABSTRACT: In order to evaluate and judge a fibrotic stage of patients with chronic hepatitis C, multivariate regression analysis was performed using multiple fibrosis markers. A total of 581 patients from 8 Hepatology units and institutes were diagnosed by needle biopsy as having chronic liver disease caused by hepatitis C virus. Twenty-three variables and their natural logarithmic transformation were employed in the multivariate analysis. Multivariate regression analysis finally obtained the following function: z=2.89 x ln(type IV collagen 7S)(ng/ml) - 0.011 x (platelet count)(x10(3) /mm(3) ) + 0.79 x ln(total bilirubin)(mg/dl) + 0.39 x ln(hyaluronic acid)(microgram/L) - 1.87. Median values of the "fibrosis score" of F1 (N=172), F2 (N=80), F3 (N=37), and F4 (N=16) were calculated as 1.00, 1.45, 2.82, and 3.83, respectively. Multiple regression coefficient and coefficient of determination were 0.56 and 0.320, respectively. Validation with patient data from other institutions demonstrated good reproducibility of the "fibrosis score" for hepatitis C (FSC), showing 1.10 in F1 (N=156), 2.35 in F2 (N=73), 3.16 in F3 (N=36), and 3.58 in F4 (N=11), respectively. A concise multiple regression function using four laboratory parameters successfully predicted pathological fibrosis stage of patients with hepatitis C virus infection. (195 words).
    Hepatology Research 08/2013; · 2.07 Impact Factor
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    ABSTRACT: Concentrations of the branched-chain amino acid (BCAA) in the serum of patients with liver cirrhosis correlate with their liver function. Oral administration of BCAA can ameliorate hypoalbuminemia and hepatic encephalopathy. In this study, we aim to clarify the role of BCAA in regulating the replication of the hepatitis C virus (HCV). HCV sub-genomic replicon cells, genome-length replicon cells, and cells infected with cell culture-infectious HCV (HCVcc) were cultured in media supplemented with various concentrations of BCAA, followed by evaluation of the replicon or HCV abundance. BCAA was capable of suppressing the HCV replicon in a dose-dependent manner and the effect was independent of the mTOR pathway. Of the three BCAAs, valine was identified as being responsible for suppressing the HCV replicon. Surprisingly, an abundance of HJ3-5(YH/QL), an HCVcc, in Huh7 cells was augmented by BCAA supplementation. In contrast, BCAA suppressed an abundance of HJ3-5(wild), an HCVcc that cannot assemble virus particle in Huh7 cells. Internal ribosome entry site of HCV was shown to be a target of BCAA. Single-cycle virus production assays using Huh7-25 cells, which lacked CD81 expression, revealed that BCAA, especially valine, promoted infectious virus particle formation with minimal effect on virus secretion. Thus, BCAA was found to have two opposing effects on HCV production: suppression of the HCV genome RNA replication and promotion of infectious virus formation. BCAA accelerates HCV production through promotion of infectious virus formation in infected cells despite its suppressive effect on HCV genome replication.
    Biochemical and Biophysical Research Communications 06/2013; · 2.41 Impact Factor
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    ABSTRACT: BACKGROUND: HCV kinetics during treatment demonstrated strong association with the antiviral outcome of patients treated with pegylated interferon (Peg-IFN) plus ribavirin. However, the relationship between HCV kinetics and pre-treatment factors remains unclear. METHODS: Of 547 patients with HCV genotype 1 treated with Peg-IFN alfa-2b plus ribavirin, 401 completed the response-guided therapy and were assessed for per protocol analysis. RESULTS: The sustained virologic response (SVR) rate was 53 % for all patients, 60 % for those with genotype TT, and 19 % for those with genotype TG/GG according to IL28B (rs8099917) single nucleotide polymorphisms. The SVR rates increased with HCV decrease at week 4; 4 % (2/56) with <1 log10 decrease, 13 % (7/56) with 1-2 log10 decrease, 51 % (44/87) with 2-3 log10 decrease, 64 % (56/87) with 3-4 log10 decrease, 88 % (72/82) with more than 4 log10 decrease but with detectable HCV RNA and 100 % (33/33) with undetectable HCV RNA (p < 0.001). Similarly, SVR rates increased step-by-step in proportion to HCV decrease in both IL28B TT and TG/GG groups, showing almost the same SVR rates for the same conditions. In multivariate analysis, age (p = 0.005) and the magnitude of HCV decrease at week 4 (p < 0.001) but not IL28B were associated with SVR. Advanced liver fibrosis (p = 0.004) and the magnitude of HCV decrease at week 4 (p < 0.001) but not IL28B were associated with non-response. CONCLUSIONS: The magnitude of the HCV decrease at week 4 seems to be the most reliable marker for predicting antiviral outcome after starting Peg-IFN plus ribavirin therapy.
    Journal of Gastroenterology 05/2013; · 3.79 Impact Factor
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    ABSTRACT: The polymorphisms in the interleukin (IL)-28B (interferon-lambda [IFN]-λ3) gene are strongly associated with the efficacy of hepatitis C virus (HCV) clearance. Dendritic cells (DCs) sense HCV and produce IFNs, thereby playing some cooperative roles with HCV-infected hepatocytes in the induction of interferon-stimulated genes (ISGs). Blood dendritic cell antigen 3 (BDCA3)+ DCs were discovered as a producer of IFN-λ upon Toll-like receptor 3 (TLR3) stimulation. We thus aimed to clarify the roles of BDCA3+ DCs in anti-HCV innate immunity. Seventy healthy subjects and 20 patients with liver tumors were enrolled. BDCA3+ DCs, in comparison with plasmacytoid DCs and myeloid DCs, were stimulated with TLR agonists, cell-cultured HCV (HCVcc), or Huh7.5.1 cells transfected with HCV/JFH-1. BDCA3+ DCs were treated with anti-CD81 antibody, inhibitors of endosome acidification, TIR-domain-containing adapter-inducing interferon-β (TRIF)-specific inhibitor, or ultraviolet-irradiated HCVcc. The amounts of IL-29/IFN-λ1, IL-28A/IFN-λ2, and IL-28B were quantified by subtype-specific enzyme-linked immunosorbent assay (ELISA). The frequency of BDCA3+ DCs in peripheral blood mononuclear cell (PBMC) was extremely low but higher in the liver. BDCA3+ DCs recovered from PBMC or the liver released large amounts of IFN-λs, when stimulated with HCVcc or HCV-transfected Huh7.5.1. BDCA3+ DCs were able to induce ISGs in the coexisting JFH-1-positive Huh7.5.1 cells. The treatments of BDCA3+ DCs with anti-CD81 antibody, cloroquine, or bafilomycin A1 reduced HCVcc-induced IL-28B release, whereas BDCA3+ DCs comparably produced IL-28B upon replication-defective HCVcc. The TRIF-specific inhibitor reduced IL-28B release from HCVcc-stimulated BDCA3+ DCs. In response to HCVcc or JFH-1-Huh7.5.1, BDCA3+ DCs in healthy subjects with IL-28B major (rs8099917, TT) released more IL-28B than those with IL-28B minor genotype (TG). Conclusion: Human BDCA3+ DCs, having a tendency to accumulate in the liver, recognize HCV in a CD81-, endosome-, and TRIF-dependent manner and produce substantial amounts of IL-28B/IFN-λ3, the ability of which is superior in subjects with IL-28B major genotype. (HEPATOLOGY 2013)
    Hepatology 05/2013; 57(5). · 12.00 Impact Factor
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    ABSTRACT: α-Galactosylceramide (α-GalCer) has been reported to be therapeutic against metastatic liver tumors in mice. However, little is known regarding the efficacy of combined chemo-immunotherapy using α-GalCer and anti-cancer drugs. In this study, we evaluated the antitumor effect of the combination therapy of α-GalCer and 5-fluorouracil (5-FU) against liver tumors of MC38 colon cancer cells. The liver weights of tumor-bearing mice treated with the combination were significantly lower than those of non-treated mice and of mice treated with 5-FU or α-GalCer alone. No toxic effects on the liver and renal functions were observed in any of the treatment groups. α-GalCer treatment induced significant activation of liver NK cells in vivo, but 5-FU treatment did not. 5-FU treatment resulted in a significant up-regulation of NKG2D activating molecules (Rae-1 and H60) and DNAM-1 ligands (CD112 and CD155) on MC38 cells, but α-GalCer did not. The cytolytic activity of α-GalCer-activated liver mononuclear cells against 5-FU-treated MC38 cells was significantly higher than that against non-treated cells. The increase of the cytolytic activity induced by 5-FU partially depended on NKG2D-Rae-1 or H60 signals. Depletion of NK cells significantly inhibited the antitumor efficacy of 5-FU against MC38 liver tumors, which suggested that the antitumor effect of 5-FU partially depended on the cytolytic activity of NK cells. These results demonstrated that the combination therapy of α-GalCer and 5-FU produced synergistic antitumor effects against liver tumors by increasing the expression of NK activating molecules on cancer cells. The present study suggests a promising new chemo-immunotherapy against metastatic liver cancer. © 2013 Wiley Periodicals, Inc.
    International Journal of Cancer 02/2013; · 6.20 Impact Factor
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    ABSTRACT: Aim:  This study aimed to clarify the factors associated the efficacy of re-treatment with pegylated interferon (PEG IFN) plus ribavirin combination therapy for patients with chronic hepatitis C who had failed to respond to previous treatment. Methods:  One hundred and forty-three patients who had previously shown relapse (n = 79), non-response (n = 34) or intolerance (n = 30) to PEG IFN plus ribavirin were re-treated with PEG IFN plus ribavirin. Results:  Twenty-five patients with intolerance to previous treatment completed re-treatment and the sustained virological response (SVR) rates were 55% and 80% for hepatitis C virus (HCV) genotype 1 and 2, respectively. On re-treatment of the 113 patients who completed the previous treatment, the SVR rates were 48% and 63% for genotype 1 and 2, respectively. Relapse after previous treatment and a low baseline HCV RNA level on re-treatment were associated with SVR in genotype 1 (P < 0.001). Patients with the interleukin-28B major genotype responded significantly better and earlier to re-treatment, but the difference in the SVR rate did not reach a significant level between the major and minor genotypes (P = 0.09). Extended treatment of 72 weeks raised the SVR rate among the patients who attained complete early virological response but not rapid virological response with re-treatment (72 weeks, 73%, 16/22, vs 48 weeks, 38%, 5/13, P < 0.05). Conclusion:  Relapse after previous treatment and a low baseline HCV RNA level have predictive values for a favorable response of PEG IFN plus ribavirin re-treatment for HCV genotype 1 patients. Re-treatment for 72 weeks may lead to clinical improvement for genotype 1 patients with complete early virological response and without rapid virological response on re-treatment.
    Hepatology Research 01/2013; 43(1):35-43. · 2.07 Impact Factor
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    ABSTRACT: It has been established that the long-term infection of chronic hepatitis C leads to the increased risk of hepatic fibrosis and hepatocellular carcinoma. Currently, histological diagnosis by invasive and painful liver biopsy is the gold standard for evaluating the hepatic fibrosis stage. Because of a side effect or patient inability to cope with the pain, it is difficult to assess the fibrosis stage frequently using liver biopsy. Recently, instead of liver biopsy, many articles have been published showing the usefulness of ultrasound elastography to evaluate the stage of hepatic fibrosis. We also reported the usefulness of real-time tissue elastography (RTE) for liver fibrosis staging in 2007. However, in our previous report, fibrosis classification was performed manually and the number of patients involved was also small. In the current study, the fibrosis staging is performed automatically using software by characterizing the elastography images. We have also increased the number of patients from 64 to 310. Thus, the aim of this study is to increase objectivity by using a newly developed automatic analysis method. We obtain the Liver Fibrosis Index (LFI), which is calculated from image features of RTE images, using multiple regression analysis performed on clinical data of 310 cases as the training data set. The correlation coefficient obtained between the LFI and the stage of hepatic fibrosis was r = 0.68, and significant differences exist between all stages of fibrosis (p < 0.001). Our new method seems promising since it has the ability to diagnose fibrosis even in the presence of inflammation.
    Oncology 01/2013; 84 Suppl 1:3-12. · 2.17 Impact Factor
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    ABSTRACT: AIM: In order to evaluate and judge a fibrotic stage of patients with chronic hepatitis B, multivariate regression analysis was performed using multiple fibrosis markers. METHOD: A total of 227 patients from seven hepatology units and institutes were diagnosed by needle biopsy as having chronic liver disease caused by hepatitis B virus. Twenty-three variables and their natural logarithmic transformation were employed in the multivariate analysis. Multiple regression function was generated from data of 158 patients in one hospital, and validation was performed using the other data of 69 patients from six other hospitals. RESULTS: After stepwise variable selection, multivariate regression analysis finally obtained the following function: z = 1.40 × ln (type IV collagen 7S) (ng/mL) - 0.017 × (platelet count) (×1000(3) /mm(3) ) + 1.24 × ln (tissue inhibitor of matrix metalloproteinase-2) (ng/mL) + 1.19 × ln (α-2-macroglobulin) (mg/dL) - 9.15. Median values of fibrosis scores of F1 (n = 73), F2 (n = 42), F3 (n = 31) and F4 stages (n = 12) were calculated as 0.95, 2.07, 2.98 and 3.63, respectively. Multiple regression coefficient and coefficient of determination were 0.646 and 0.418, respectively. Validation with patient data from other institutions demonstrated good reproducibility of fibrosis score for hepatitis B (FSB), showing 1.33 in F1 (n = 27), 2.20 in F2 (n = 20), 3.11 in F3 (n = 20) and 5.30 in F4 (n = 2), respectively. CONCLUSION: A concise multiple regression function using four laboratory parameters successfully predicted pathological fibrosis stage of patients with hepatitis B virus infection.
    Hepatology Research 11/2012; · 2.07 Impact Factor

Publication Stats

5k Citations
1,758.09 Total Impact Points

Institutions

  • 2012–2014
    • Hyogo Prefectural Amagasaki Hospital
      Amagasaki, Hyōgo, Japan
  • 2010–2014
    • Kansai Rosai Hospital
      Itan, Hyōgo, Japan
    • Chiba University
      • Department of Medicine and Clinical Oncology
      Chiba-shi, Chiba-ken, Japan
    • Kurume University
      • Division of Gastroenterology
      Куруме, Fukuoka, Japan
    • Nippon Telegraph and Telephone
      Edo, Tōkyō, Japan
  • 2011–2013
    • Toranomon Hospital
      Edo, Tōkyō, Japan
  • 1997–2013
    • Osaka City University
      • • Graduate School of Medicine
      • • Department of Biochemistry
      Ōsaka, Ōsaka, Japan
  • 1993–2012
    • Osaka University
      • • Department of Integrated Medicine
      • • Division of Gastroenterology and Hepatology
      • • Department of Internal Medicine
      • • School of Medicine
      Ōsaka-shi, Osaka-fu, Japan
  • 2009
    • Okayama University
      • Department of Gastroenterology and Hepatology
      Okayama, Okayama, Japan
  • 2008
    • Rhode Island Hospital
      Providence, Rhode Island, United States
    • The University of Tokyo
      • Department of Internal Medicine
      Tokyo, Tokyo-to, Japan
  • 1985–2005
    • Osaka National Hospital
      Ōsaka, Ōsaka, Japan
  • 1996–2004
    • Osaka Kosei Nenkin Hospital
      Ōsaka, Ōsaka, Japan
  • 1996–2002
    • Osaka Rosai Hospital
      Ōsaka, Ōsaka, Japan
  • 1991–1992
    • Gunma University
      Maebashi, Gunma Prefecture, Japan
  • 1987
    • University of London
      Londinium, England, United Kingdom