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Aim: The aim of this study was to evaluate the use of a new classification for safer transradial access hepatic interventional radiology, based on preoperative evaluation of the location of the left subclavian artery bifurcation in the aortic arch., Methods: A total of 38 consecutive patients with hepatocellular carcinoma and 74 sessions of radial access for visceral intervention (R.A.V.I.) were reviewed. We classified the location of the left subclavian artery bifurcation in the aortic arch in three areas using an oblique view computed tomography image matched with the curve of the aortic arches according to a new criteria Three Areas Criteria For R.A.V.I. (named "TAC-F-R"), and measured the required time from initial left radial artery arteriography to celiac artery or superior mesenteric artery arteriography., Results: The median time required for left radial artery arteriography to the celiac artery or superior mesenteric artery arteriography in each of the three areas were: area A, 0:11:10 (h, min, s); area B, 0:14:44; and area C, 0:31:51. There were significant differences between each area after Bonferroni correction (p < 0.01; A vs. B, p = 0.086; A vs. C, p = 0.001; and B vs. C, p = 0.045), with areas A and B requiring a significantly shorter time. Finally, no patients showed neurogenic disfunction within 1 week after the R.A.V.I., Conclusions: The new classification, "TAC-F-R," for safer transradial access hepatic interventional radiology is effective for avoiding difficult cases, and selects more suitable patients with hepatocellular carcinoma for the R.A.V.I., (© 2023 Japan Society of Hepatology.)

Aims: The effects of genetic polymorphism on a personalized diet and exercise program for steatotic liver disease (SLD) are still unclear., Methods: Participants of this retrospective cohort study were 203 Japanese patients with SLD diagnosed by abdominal ultrasonography. All of them were introduced the personalized diet and exercise treatment. A diet of 25-30 kcal/kg multiplied by ideal body weight (BW) daily and aerobic and resistance exercise (exercise intensity of 4-5 metabolic equivalents daily, respectively) were performed for 6 days. Treatment efficacy was evaluated in terms of the rate of decrease of liver function tests, glycolipid metabolism markers, physical findings, image findings, and cardiovascular disease (CVD) risk score at 6 months compared with baseline. Furthermore, the impact of genetic polymorphism was also investigated., Results: At 6 months compared with baseline, liver function tests (AST, ALT, γGTP), glycolipid metabolism markers (hemoglobin A1c, triglycerides [TG], low-density lipoprotein cholesterol), physical findings (BW, body mass index), image finding (liver stiffness measurement), and CVD risk score (Suita score) improved significantly. There was no significant difference in treatment efficacy, except for the rates of decrease of TG, according to genotype PNPLA3 rs738409, TM6SF2 rs58542926, and HSD17B13 rs6834314. The rates of decrease of TG with TM6SF2 CT were significantly higher than those with CC or TT, and the rates of TG with HSD17B13 AA were significantly higher than those with AG by multiple comparisons., Conclusion: Personalized diet and exercise program for SLD improved liver function tests, physical findings, glycolipid metabolism markers, and CVD risk score. Genetic polymorphism might partially affect treatment efficacy. Further studies should be performed to develop an individualized program for SLD, considering genetic polymorphism., (© 2023 Japan Society of Hepatology.)

Aim: There are few reports on the prognosis of liver-related events in Japanese patients with nonalcoholic fatty liver disease (NAFLD). We undertook an observational study to compare the prognosis between fibrotic and nonfibrotic groups in Japanese NAFLD patients., Methods: Prognosis in 393 NAFLD patients who underwent liver biopsy between April 2013 and April 2015 at multiple centers were investigated. The time to onset of liver-related events, cardiovascular events, development of extrahepatic cancers, and death were compared between the pathologically fibrotic nonalcoholic steatohepatitis (NASH) group and nonalcoholic fatty liver (NAFL) + nonfibrotic NASH group. A similar analysis was carried out based on the fibrotic classification diagnosed using four noninvasive fibrosis prediction models., Results: The mean age and body mass index at the time of liver biopsy was 55.7 years old and 28.04 kg/m 2 , respectively The cumulative incidence of liver-related events at 1080 days after liver biopsy was 5.79% in the pathologically fibrotic NASH group and 0% in the NAFL + nonfibrotic NASH group, with a significant difference (p = 0.0334). The cumulative incidence of liver-related events was significantly higher in the positive group for the prediction model than in the negative group in all four models (all p values were <0.0001). There was no significant difference between the pathologically fibrotic NASH group and NAFL + nonfibrotic NASH group in terms of cumulative incidence of cardiovascular events, development of extrahepatic cancers, and death., Conclusions: The incidence of liver-related events was significantly higher in the fibrotic NASH group than that of the NAFL + nonfibrotic NASH group in Japanese NAFLD patients., (© 2023 Japan Society of Hepatology.)

Aims: Both diet and exercise counseling are recommended for patients with fatty liver, including nonalcoholic fatty liver disease (NAFLD), to achieve weight loss goals. However, data evaluating treatment efficacy are limited., Methods: The subjects of this retrospective cohort study were 186 consecutive Japanese cases with fatty liver diagnosed by abdominal ultrasonography. Treatment efficacy and predictive factors of "Hospitalization Program for Improvement Purpose for Fatty Liver" as a combined diet and aerobic and resistance exercise program were evaluated according to the hospitalization group (153 cases) or the no hospitalization group (33 cases). To balance the confounding biases, treatment efficacy was evaluated using propensity score-matched analysis. In the hospitalization group, a diet of 25-30 kcal/kg multiplied by ideal body weight (BW) daily and aerobic and resistance exercise (exercise intensity of 4-5 metabolic equivalents daily, respectively) were performed for 6 days., Results: In liver function tests and BW at 6 months compared with baseline, the rates of decrease of the hospitalization group (24 cases) were significantly higher than those of the no hospitalization group (24 cases), using propensity score-matched analysis. In markers of glycolipid metabolism and ferritin levels, the rates of the hospitalization group were not different from those of the no hospitalization group. In the hospitalization group (153 cases), multivariate regression analysis identified the etiology of non-NAFLD, the presence of diabetes mellitus, and large waist circumference as independent predictors of decreased rates of hemoglobin A1c levels., Conclusion: The diet and exercise program for fatty liver improved liver function tests and BW. Further study should be performed to develop a feasible and suitable program., (© 2023 Japan Society of Hepatology.)

Background & Purpose: Protease-free regimens for chronic hepatitis C virus (HCV) infection are safe and effective for persons with either compensated or decompensated cirrhosis. We examined the efficacy and safety of sofosbuvir-velpatasvir in participants with HCV and compensated cirrhosis in Japan., Methods: This was a Phase 3, multi-center, open-label study. At 20 sites, 37 individuals with chronic HCV infection of any genotype and compensated cirrhosis received sofosbuvir-velpatasvir (400 mg/100 mg) daily for 12 weeks. Participants were treatment-naïve or treatment-experienced with interferon-based treatments with or without HCV NS3/4A protease inhibitors. Prior exposure with HCV NS5A or NS5B inhibitors was prohibited. The primary study endpoint was sustained virologic response 12 weeks after treatment (SVR12)., Results: Among participants, 62% had HCV genotype 1 infection, and 38% had HCV genotype 2. More than three quarters (29/37, 78%) were HCV treatment naïve. All participants (37/37, 100%) achieved SVR12. Seventeen participants (46%) and three participants (8%) had pretreatment resistance-associated substitutions to HCV NS5A and NS5B nucleoside inhibitors respectively, yet no on-treatment breakthrough or relapse occurred. Sofosbuvir-velpatasvir for 12 weeks treatment was safe and well tolerated. The most commonly reported adverse events were headache (8%, 3/37) and diarrhea (5%, 2/37). One serious adverse event, patella fracture, occurred and was considered not treatment related. No participants discontinued study treatment due to an adverse event. Three participants (8%) had a Grade 3 laboratory abnormality; all were hyperglycemia., Conclusion: Sofosbuvir-velpatasvir resulted in high SVR rates and was well tolerated among Japanese patients with HCV and compensated cirrhosis. This single-tablet regimen offers a highly effective, protease-inhibitor free regimen for treating HCV., Clinicaltrials: gov Identifier: NCT04112303., (© 2022 Gilead Sciences and The Authors. Hepatology Research published by John Wiley & Sons Australia, Ltd on behalf of Japan Society of Hepatology.)

Aim: The phase III REFLECT study utilized bodyweight-based lenvatinib dosing in patients with unresectable hepatocellular carcinoma, based on results of the phase II Study 202. This post hoc analysis compared efficacy and safety in patients with lower and higher bodyweights., Methods: This comparison included patients from Study 202 (Japanese, n = 43; Korean, n = 3) and Japanese patients from REFLECT (n = 81) who received lenvatinib. In Study 202, all patients received a starting dose of lenvatinib 12 mg/day; in REFLECT, patients received starting doses based on bodyweight (patients <60 kg, 8 mg/day; ≥60 kg, 12 mg/day). Safety and efficacy were assessed in both studies according to bodyweight., Results: In Study 202, treatment-related, treatment-emergent adverse events (TEAEs) led to dose reductions in 80.8% and 55.0% of patients in the lower and higher bodyweight groups, respectively. In REFLECT, treatment-related TEAEs led to dose reductions in 52.5% and 70.7% of patients in the 8 and 12 mg groups, respectively. In Study 202, median overall survival (OS) was 16.2 months (95% confidence interval [CI], 9.8-25.1) and 21.3 months (95% CI, 10.1-not estimable) in the lower and higher bodyweight groups, respectively. In REFLECT, median OS was 15.8 months (95% CI, 10.4-27.6) and 18.2 months (95% CI, 11.3-26.9) in the 8 and 12 mg groups, respectively., Conclusions: Comparison between patients in Study 202 and REFLECT demonstrates efficacy was maintained with improved safety in patients with lower bodyweights who received lenvatinib 8 mg/day in REFLECT versus patients who received lenvatinib 12 mg/day in Study 202., (© 2022 The Authors. Hepatology Research published by John Wiley & Sons Australia, Ltd on behalf of Japan Society of Hepatology.)

Background: Long-term use of nucleotide analogs such as adefovir (ADV) or tenofovir disoproxil fumarate (TDF) may cause renal impairment. Tenofovir alafenamide (TAF) has less systemic exposure than TDF did. The aims were to examine longitudinal changes in renal function and biochemical parameters for 2 years after switching from long-term ADV and TDF to TAF, and to explore factors associated with improved renal function after TAF in patients with chronic hepatitis B., Methods: The prospective observational cohort study included 306 patients with chronic hepatitis B who underwent switching from long-term TDF or ADV to TAF. The primary outcome was the changes in estimated glomerular filtration rate (eGFR) after TAF., Results: Among 306 patients, 190 (65.3%) and 106 (34.7%) had chronic kidney disease (CKD) stages 1-2 and 3a-4 at baseline. In patients with CKD stages 3a-4, the mean eGFR significantly increased until week 12 and plateaued from week 12 to year 2 (adjusted slope using linear mixed effect models: +9.01 ml/min/1.73 m 2 /year until week 12; p < 0.001). In contrast, the mean eGFR plateaued from baseline to year 2 in the CKD stages 1-2 subgroup. Multivariate logistic regression showed that baseline CKD stage ≥3a, steeper decline in eGFR 1 year before TAF, and shorter duration of any nucleotide analog use was significantly associated with ≥10% improvement in eGFR in year 1., Conclusions: Switching from TDF or ADV to TAF resulted in favorable renal safety for 2 years. In CKD stage 3a-4 subgroup, eGFR after TAF was recovered in the first 12 weeks and subsequently stabilized., (© 2021 Japan Society of Hepatology.)

Aim: To evaluate the efficacy, safety, and tolerability of apararenone 10 mg/day in patients with nonalcoholic steatohepatitis (NASH)., Methods: In this multicenter, randomized, double-blind, placebo-controlled phase II study, patients received apararenone 10 mg or placebo once daily for 72 weeks. The primary efficacy end-point was percent change in serum alanine aminotransferase (ALT) from baseline to 24 weeks after randomization. Secondary efficacy end-points included changes in liver fibrosis markers. Adverse drug reactions (ADRs) and serum potassium levels were evaluated., Results: Forty-eight patients were randomly assigned to treatment (placebo, 23; apararenone, 25). The percent change in ALT at 24 weeks was -3.0% and -13.7% with placebo and apararenone, respectively (p = 0.308). The apararenone group showed greater reductions from baseline in fibrosis markers (type IV collagen 7S and procollagen-3 N-terminal peptide) and noninvasive tests of fibrosis (enhanced liver fibrosis score and Fibrosis-4 index) at all time points versus placebo. The percentage of patients with improvement of 1 point or more in fibrosis stage/without nonalcoholic fatty liver disease activity score worsening was 41.7% with apararenone and 26.1% with placebo (p = 0.203). Adverse drug reactions were reported in three (13.0%) and three (12.5%) patients in the placebo and apararenone groups, respectively. Serum potassium levels increased in the apararenone group during the study and decreased to near baseline after the end of treatment., Conclusions: In patients with NASH, apararenone 10 mg/day for 72 weeks was effective in decreasing ALT levels, improved multiple potential fibrosis markers, and was safe and well tolerated. Pathological findings showed anti-inflammatory and antifibrotic effects of apararenone., (© 2021 The Authors. Hepatology Research published by John Wiley & Sons Australia, Ltd on behalf of Japan Society of Hepatology.)

Aims: Hepatitis B surface antigen (HBsAg) seroclearance indicates a "functional cure" in chronic hepatitis B (CHB) virus infection. However, several cases of hepatocellular carcinoma (HCC) development have been reported after HBsAg seroclearance. We evaluated the potential of HBsAg and hepatitis B core-related antigen (HBcrAg), measured by the ultra-highly sensitive assays, in cases with HCC development after HBsAg seroclearance., Methods: We enrolled 17 patients with CHB who achieved HBsAg seroclearance, defined by the conventional assay using Architect HBsAg QT kit (five HCC patients and 12 non-HCC patients). HBsAg and HBcrAg were measured in their stored serum samples using ultra-highly sensitive assays featuring "immunoassay for total antigen including complex via pretreatment (iTACT)" technology., Results: All five patients who developed HCC were positive for HBsAg or HBcrAg by iTACT-HBsAg or iTACT-HBcrAg at all follow-up points. HBcrAg levels in the HCC group, using iTACT-HBcrAg, were significantly higher than those in the non-HCC group at HBsAg seroclearance (3.6 LogU/ml (2.8-4.2) versus 2.6 (<2.1-3.8), p = 0.020). The best cutoff value of iTACT-HBcrAg for predicting HCC development was 2.7 LogU/ml by receiver operating characteristic curve analysis. The prevalence of HBcrAg ≥2.7 in the HCC group was significantly higher than that in non-HCC group (100% [5/5] versus 33% [4/12], p = 0.029)., Conclusions: Residual low viral antigen might predict HCC development even if HBsAg seroclearance was achieved according to a conventional assay. The results suggest that iTACT assays of HBsAg and HBcrAg would be useful for monitoring CHB patients., (© 2020 The Japan Society of Hepatology.)

Aim: The number of patients with fatty liver disease (FLD) is increasing globally. Ethanol consumption in FLD is known to be associated with an increased risk of hepatocellular carcinoma (HCC), but the effects of alcohol consumption on the occurrence of multiple HCCs remain unclear. We explored the relationship between the daily ethanol intake and the HCC number., Methods: This single-center retrospective study enrolled 114 patients without viral or immune hepatitis undergoing first-line HCC treatment who had been diagnosed with FLD by abdominal ultrasonography or a liver biopsy at the same time as or before HCC detection. We categorized patients into four groups according to the daily alcohol consumption (<20 g: non-alcoholic fatty liver disease, n = 45; 20-39 g: low-intermediate ethanol intake with FLD, n = 13; 40-69 g: high-intermediate ethanol intake with FLD, n = 31; ≥70 g: alcoholic fatty liver disease, n = 25). The relationship between the daily ethanol consumption and the number of HCCs (single or multiple) was examined., Results: The risk of multiple HCCs was significantly higher in the high-intermediate ethanol intake with FLD (HR 2.89, 95% CI 1.04-8.02, P = 0.042) and alcoholic fatty liver disease (HR 3.14, 95% CI 1.07-9.22, P = 0.037) groups than in the others. A multivariate analysis showed that a daily ethanol intake ≥40 g was associated with a significantly increased risk of multiple HCCs (HR 2.82, 95% CI 1.16-6.88, P = 0.023)., Conclusions: Our findings suggest that a high daily ethanol intake might lead to multiple hepatocarcinogenesis in patients with FLD., (© 2020 The Japan Society of Hepatology.)

Aim: The risk of development of hepatocellular carcinoma (HCC) persisted in patients with advanced fibrosis, even after achieving sustained virologic response (SVR). This study aimed to show the advantage of liver stiffness measurement (LSM) at baseline and after SVR to predict HCC occurrence and esophageal varices (EV) exacerbation., Methods: These risks were evaluated in 398 chronic hepatitis C patients without a history of HCC who achieved SVR after direct-acting antiviral agent and evaluated LSM at least twice during follow up. We defined liver cirrhosis and chronic hepatitis as LSM of ≥12 kPa and <12 kPa, respectively., Results: LSM was significantly correlated with serum fibrosis markers, such as Fib-4 index and Wisteria floribunda agglutinin-positive Mac-2 binding protein, at baseline and SVR at 24 weeks after treatment (SVR24). Five patients received preventive treatment of EV, but no EV bleeding occurred after SVR, and their LSM at baseline and SVR24 was significantly higher than that of other cirrhosis patients. The annual rate of HCC during the first 4 years was 1.5%. LSM in HCC patients tended to decrease after direct-acting antiviral agent therapies, but significantly higher than that of cirrhosis patients without HCC before and after treatment. Multivariate analysis identified LSM and alpha-fetoprotein at baseline and LSM at SVR24 as significant independent predictors of HCC., Conclusions: Evaluating LSM not only at baseline, but also SVR24, was found to be useful for the detection of advanced fibrosis patients at high risk of HCC occurrence and EV exacerbation. We recommend focused surveillance of HCC and EV for these patients., (© 2019 The Japan Society of Hepatology.)

Aim: The long-term effects of sustained virologic response (SVR) to antiviral therapy on the risk of liver complications, such as exacerbation of esophageal varices (EV), hepatocellular carcinoma (HCC), malignant lymphoma, and liver-related and overall death in hepatitis C virus (HCV)-infected patients with liver cirrhosis are not fully known., Methods: These risks were evaluated during long-term follow up of 457 patients with HCV-related Child-Pugh Class A liver cirrhosis without history of HCC., Results: The respective cumulative 5- and 10-year rates of EV exacerbation were 2.0% and 3.1%. Multivariate analysis identified the presence of EVs, thrombocytopenia at baseline. and alcohol intake as significant independent predictors of EV exacerbation before and after SVR. The cumulative 5- and 10-year rates of HCC were 6.8% and 10.2%, respectively. Male sex and the presence of EV were significant independent determinants of HCC before and after SVR. Although the cumulative 5-year HCC recurrence rate was 49.4%, the overall survival rate since HCC was 73.6% at 5 years. The overall survival rates since SVR were 98.7% and 93.6% at 5 and 10 years, respectively. Progression of HCC was the most frequent all-cause mortality, but none of the patients died of liver decompensation. Male sex and Fibrosis-4 index of ≥3.0 after SVR were significant and independent predictors of mortality., Conclusion: Patients with HCV remain at risk of HCC for >10 years after achieving SVR, and HCC is the most common cause of mortality. We recommend long-term surveillance of cirrhotic patients with HCV, even after achieving SVR., (© 2019 The Japan Society of Hepatology.)

Aim: Rifaximin (RFX) improves hepatic encephalopathy (HE). However, information on long-term treatment with RFX is limited. In this study, we aimed to investigate the effect of long-term treatment with RFX on HE and liver function. Moreover, we investigated factors associated with the recurrence of HE under RFX treatment., Methods: In this retrospective cohort study, we consecutively enrolled 65 patients with HE who initiated RFX treatment (1200 mg/day) in our hospital from January 2017 to June 2018. We evaluated liver function test results, including blood ammonia levels, and the recurrence rate of HE after RFX treatment., Results: The median follow-up duration was 41.6 weeks (range, 1.4-96.7 weeks). The blood ammonia level significantly declined from 157 to 86 μg/dL at 4 weeks after RFX treatment (P < 0.01), and the effect was prolonged. Furthermore, Child-Pugh score decreased in 51% (26/51) of the patients at 12 weeks during RFX treatment. The recurrence rate of HE after RFX treatment was 26.2% (17/65), and presence of ascites at baseline was identified as the only independent risk factor for HE recurrence (hazard ratio 4.71; 95% confidence interval, 1.27-17.5; P = 0.02). The cumulative recurrence rate of HE was significantly lower in patients without ascites than in patients with ascites at baseline (13.8% vs. 50.8%, P = 0.001)., Conclusions: Long-term treatment with RFX was beneficial for HE and liver function in patients with HE. Furthermore, the recurrence rate of HE was low in RFX-treated patients without ascites. Thus, long-term treatment with RFX could be effective for the management of Japanese patients with HE., (© 2019 The Japan Society of Hepatology.)

Aim: The aim of this study was to investigate the therapeutic potential of sodium glucose cotransporter 2 inhibitor (SGLT2I) as an effective therapeutic option for non-alcoholic fatty liver disease (NAFLD)., Methods: In this prospective study, nine patients with NAFLD complicated by type 2 diabetes mellitus (DM), were introduced to the regimen of canagliflozin 100 mg once daily for 24 weeks and were evaluated by liver histology at pretreatment and at 24 weeks after the start of treatment. The primary outcome was histological improvement, defined as a decrease in NAFLD activity score of one point or more without worsening in fibrosis stage. Glucose metabolism was evaluated based on the meal tolerance test. The usefulness of extracellular and exosome microRNA-122 (miR-122) as early predictors of histological improvement was investigated., Results: All of the nine patients achieved histological improvement. Scores of steatosis, lobular inflammation, ballooning, and fibrosis stage decreased by 78%, 33%, 22%, and 33% at 24 weeks compared to the pretreatment, respectively. Six patients showed improvement in insulin resistance, and the other three patients showed partial improvement of insulin secretion function. Six patients, who showed a decrease in both extracellular and exosome miR-122 ratios (the ratio of miR-122 levels at 1 day after treatment to that at baseline), showed histological improvement. Furthermore, one patient, who showed a decrease in exosome miR-122 ratios regardless of the increase in extracellular miR-122 ratios, also showed decreases in NAFLD activity score and fibrosis stage., Conclusion: A prospective study showed that SGLT2I for NAFLD complicated by DM improved histological features in connection with glucose metabolism. This trial was registered as clinical trial UMIN000018166., (© 2018 The Japan Society of Hepatology.)

Aim: Treatment with all-oral direct-acting antiviral agents (DAAs) elbasvir/grazoprevir (EBR/GZR) is associated with high sustained virologic response (SVR). The aim of this study was to evaluate the safety and treatment efficacy of EBR/GZR in hepatitis C virus (HCV)-infected patients., Methods: This retrospective cohort study included 147 consecutive patients with chronic HCV genotype 1b infection who were treated with EBR (50 mg) plus GZR (100 mg) once daily for 12 weeks. The rates of SVR at 12 weeks after the end of treatment (SVR12) were evaluated based on patient baseline characteristics. Treatment efficacy was analyzed according to background chronic kidney disease (CKD), and retreatment efficacy in patients who failed to respond to previous DAAs., Results: The SVR12 was 94% (138 of 147 patients), based on intention-to-treat analysis. Rates of SVR12 were 97% (131 of 135) and 58% (7 of 12) in cases naïve to DAA treatment and failure to respond to prior DAAs, respectively. The SVR12 rates in patients with CKD stage 4-5 was 100% (8 of 8). All patients (4 of 4 patients) with stage 4-5 and advanced fibrosis (Fibrosis-4 index ≥3.25) also achieved SVR12. Multivariate analysis that included the above variables identified pretreatment with other DAAs as an independent factor that was significantly and independently associated with non-SVR12 (odds ratio, 97.5; P < 0.001). Relapsers of first DAAs, excluding the combination of ledipasvir and sofosbuvir, achieved SVR12. Characteristic novel non-structural protein 5A substitutions were not detected after failure of retreatment with EBR/GZR., Conclusion: Treatment with EBR/GZR was highly efficacious with acceptable safety, even in patients with CKD stage 4-5. Retreatment of relapsers to prior DAAs, excluding ledipasvir and sofosbuvir, achieved SVR12., (© 2018 The Japan Society of Hepatology.)

Aim: The aim of this study was to clarify the utility of a no-touch pincer ablation procedure that uses bipolar electrodes to prevent intrasubsegmental tumor recurrence after radiofrequency ablation (RFA) for patients with hepatocellular carcinoma (HCC) compared to surgical resection., Methods: We evaluated 175 consecutive patients with HCC (single nodule, tumor diameter ≤ 30 mm) who underwent surgical resection (146 received partial resection) and 313 patients who received RFA; 277 patients received touch ablation using a monopolar or bipolar RFA device, and 36 received no-touch ablation using a bipolar RFA device. Pretreatment arterial and portal phase dynamic computed tomography (CT) or magnetic resonance imaging (MRI) images were classified into four enhancement patterns: Type 1 and Type 2 are homogeneous enhancement patterns without or with increased arterial blood flow, respectively; Type 3 is a heterogeneous enhancement pattern with a septum-like structure; and Type 4 is an irregularly shaped ring structure enhancement pattern., Results: Cumulative recurrence rates significantly differed between procedures (surgical resection, 7.5%; no-touch ablation, 2.9%; and touch ablation, 17.7% at the third year; P = 0.005). Multivariate Cox proportional hazards analysis revealed that enhancement pattern type (Type 3: hazard ratio [HR], 2.95; P = 0.002; and Type 4: HR, 3.88, P = 0.002), treatment procedure (touch ablation: HR, 3.36; P < 0.001), and serum α-fetoprotein level (≥30 μg/L: HR, 1.87; P = 0.009) were significant predictors of intrasubsegmental recurrence. No significant differences between no-touch ablation and surgical resection were observed., Conclusion: The no-touch pincer ablation procedure has the potential to prevent intrasubsegmental recurrence after RFA for patients with HCC to the same degree as partial resection., (© 2018 The Japan Society of Hepatology.)

Aim: Hepatic fibrosis is the most important factor for estimating the prognosis of patients with non-alcoholic fatty liver disease (NAFLD). A novel non-invasive scoring system, the FM-fibro index, showed high accuracy in a pilot study. The purpose of this study was to validate the efficacy of the FM-fibro index in a multicenter cohort., Methods: Among 18 institutions, we analyzed 400 Japanese patients with biopsy-proven NAFLD. We evaluated the accuracies of the FM-fibro index, CA-fibro index, and European Liver Fibrosis (ELF) panel by area under the receiver operator characteristics curves (AUROC). The FM-fibro index includes three formulas for type IV collagen 7S, hyaluronic acid, and vascular cell adhesion molecule-1., Results: Among 400 patients, 205 were women, and the median age was 56 years. The histological distribution of Matteoni types 1, 2, 3, and 4 was 11, 40, 15, and 334, and the distribution of hepatic fibrosis stages 0 to 4 was 67, 183, 55, 63, and 32, respectively. The AUROCs of the FM-fibro index, CA-fibro index, and ELF panel for non-alcoholic steatohepatitis (NASH)-related fibrosis were 0.7178/0.7095/0.7065, 0.7093, and 0.7245, respectively. The sensitivity and specificity of the FM-fibro index for predicting NASH-related fibrosis was 0.5359/0.5210/0.4641 and 0.8333/0.8182/0.8788, respectively. The accuracy of the FM-fibro index was not significantly different from that of the CA-fibro index or the ELF panel., Conclusions: The FM-fibro index can predict NASH-related fibrosis with sufficient accuracy compared with previous scoring systems. Further analyses that verify the accuracy of the FM-fibro index to distinguish significant or advanced fibrosis in patients with NAFLD are awaited. (UMIN-CTR: UMIN000018158)., (© 2018 The Japan Society of Hepatology.)

Aim: A novel jelly lactulose preparation (SK-1202) has been developed to improve compliance and reduce the elevation of blood glucose levels in diabetic patients. To compare the equivalence in the efficacy and safety of SK-1202 and an approved commercially available syrup preparation, we undertook a randomized multicenter cross-over study in hyperammonemia patients with liver cirrhosis who were taking lactulose., Methods: Forty-four patients were enrolled and took each preparation for 2 weeks. Efficacy was evaluated using the Number Connection Test, blood ammonia concentration, coma grade, and the flapping tremor grade. Safety was evaluated by the number of adverse events observed, vital signs, and laboratory tests. We also examined the acceptability of each preparation using questionnaires evaluating sweetness, aftertaste, ease of use, and preference of the preparations., Results: There were no differences in efficacy or safety between SK-1202 and the approved syrup preparation. With regard to the acceptability evaluation, given over 80% of the participants chose the SK-1202 preparation, it appears to be preferred by patients., Conclusions: It is expected that SK-1202 could represent a useful agent for patients with hepatic encephalopathy., (© 2018 The Authors. Hepatology Research published by John Wiley & Sons Australia, Ltd on behalf of Japan Society of Hepatology.)

Aim: The recurrence rates of pruritus after stopping nalfurafine hydrochloride are unknown in chronic liver disease., Methods: A prospective confirmatory trial was carried out to determine the recurrence rates of pruritus after cessation of nalfurafine hydrochloride in chronic liver disease. After pretreatment with nalfurafine hydrochloride for 4 weeks or more, 15 consecutive Japanese patients, who confirmed the improvement of pruritus (decrease in the visual analogue scale (VAS) of ≥50 mm), were enrolled in the present study. Patients were classified to the continuous group (continuation of nalfurafine hydrochloride for 4 weeks) or the discontinuous group (cessation of nalfurafine hydrochloride) at the time of consent to study protocol, by self-determination., Results: The recurrence rates (increase in VAS of ≥25 mm after stopping nalfurafine hydrochloride) were 100% (5 of 5 patients) and 0% (0 of 10) in the discontinuous and continuous groups, respectively. In the discontinuous group, 3 patients selected retreatment with nalfurafine hydrochloride as salvage therapy, and they generally recovered to the levels of VAS at the discontinuation of treatment., Conclusion: The present prospective trial showed the high recurrence rates of pruritus after the stop of nalfurafine hydrochloride in chronic liver disease., (© 2018 The Japan Society of Hepatology.)

Aim: To assess the efficacy and safety of telaprevir (TVR) when used in combination with natural human interferon-β (IFN-β) and ribavirin (RBV) for genotype 1 patients with depression compared to IFN-β/RBV therapy in Japan. We also examined the efficacy of the TVR/IFN-β/RBV therapy in treatment failure genotype 2 patients with depression., Methods: For the genotype 1 patients, 30 patients received TVR (750 mg every 8 h) for 12 weeks combined with IFN-β and RBV for 24 weeks (Group A), and 30 received IFN-β and RBV for 48 weeks (Group B). For the genotype 2 patients, 14 patients were dosed only with the TVR-based regimen., Results: The sustained virologic response (SVR) rates for Group A and Group B were 63.3% and 20.0%, respectively (P = 0.001, likelihood ratio test). The SVR rate for genotype 2 patients previously treated with pegylated IFN and/or RBV was 71.4%. No patient dropped out due to exacerbation of depression. The trend of platelet counts after the drugs were given was similar in the TVR/IFN-β/RBV therapy group and the IFN-β/RBV therapy group. Common resistance-associated variants of TVR were identified in 4 of the 13 patients who did not achieve SVR., Conclusion: This study showed that an addition of TVR to IFN-β/RBV therapy raised SVR in previously treated and untreated genotype 1 patients and previously treated genotype 2 patients with chronic hepatitis C and depression., (© 2017 The Japan Society of Hepatology.)

Aim: Pruritus is one of the complications of chronic liver disease, and it is important to investigate the predictors., Methods: Six hundred and seventy-three consecutive Japanese patients with chronic liver disease were retrospectively investigated for itch severity. Furthermore, 138 of all 673 patients were introduced to nalfurafine hydrochloride, and the improvement of itch severity was evaluated. The itch severity was self-assessed using the pruritus scores by Kawashima's criteria and visual analog scale., Results: Two hundred and twenty-nine of the 673 patients (34.0%) were evaluated as 1 point or more of pruritus severity of Kawashima's criteria, and 46 patients (6.8 %) as 3 points or more. Multivariate analysis established that being negative for hepatitis B surface antigen (HBsAg) and presence of hepatocellular carcinoma (HCC) were significant determinants of pruritus (≥1 point of Kawashima's criteria), and being negative for HBsAg and having lower levels of platelet count were significant determinants of severe pruritus (≥3 points). Ninety-three of the 138 patients (67.4%) with nalfurafine hydrochloride indicated improvement of itch, defined as a decrease in VAS of 50 mm or more. There were no significant differences in treatment efficacy of nalfurafine hydrochloride, regardless of the three predictors of pruritus (HBsAg, HCC and platelet count)., Conclusion: The present retrospective study indicated the predictors for pruritus, based on the large number of patients with chronic liver disease. Furthermore, this study demonstrated that nalfurafine hydrochloride may be useful for pruritus, regardless of the predictors., (© 2017 The Japan Society of Hepatology.)

Objective: The aim of this study was to clarify the usefulness of a no-touch pincer ablation procedure that uses bipolar electrodes to prevent intrasubsegmental tumor recurrence after radiofrequency ablation (RFA) for patients with hepatocellular carcinoma (HCC)., Methods: We studied 303 consecutive patients with HCC (single nodule and tumor diameter ≤30 mm) who received RFA between January 2005 and April 2015; 268 patients received touch ablation using a monopolar or bipolar RFA device, and 35 received no-touch ablation using a bipolar RFA device. The pretreatment arterial and portal phase dynamic computed tomography or magnetic resonance images were classified into four enhancement patterns. Type 1 and Type 2 are homogeneous enhancement patterns without or with increased arterial blood flow, respectively. Type 3 is a heterogeneous enhancement pattern with a septum-like structure, and Type 4 is an irregularly shaped ring structure enhancement pattern., Results: With regard to intrasubsegmental tumor recurrence, among the 268 patients who underwent the touch ablation procedure, tumors recurred in 52 (19.4%) patients, and among the 35 patients who underwent the no-touch ablation procedure, tumors recurred in one (2.9%) patient. Cumulative intrasubsegmental tumor recurrence rates tended to be higher with touch ablation (P = 0.083). Multivariate Cox proportional hazards analysis revealed that ablation procedure (touch ablation, hazard ratio [HR] 10.32, P = 0.032), type of enhancement pattern (Type 3, HR 3.05, P = 0.006; and Type 4, HR 8.87, P < 0.001) and serum des-γ-carboxyprothrombin level (≥100 AU/L; HR 2.73, P = 0.035) were significant predictors for intrasubsegmental recurrence., Conclusion: The no-touch pincer ablation procedure has the potential to prevent intrasubsegmental recurrence after RFA for patients with HCC., (© 2016 The Japan Society of Hepatology.)

Aims: Patients with chronic liver disease sometimes develop cholestasis, which induces severe whole-body pruritus that may disrupt daily activities and sleep. To determine the efficacy of nalfurafine hydrochloride (5 μg), which is a selective κ-opioid receptor agonist, in improving pruritus, we undertook a double-blind placebo-controlled study in patients with chronic liver disease with refractory pruritus. Nalfurafine hydrochloride at 2.5 μg was also used to evaluate the dose-response relationship., Methods: In total, 318 subjects were randomly assigned to receive the placebo or nalfurafine hydrochloride (2.5 or 5 μg) given orally once daily for 84 consecutive days. Pruritus was assessed based on the visual analog scale and pruritus scores., Results: Changes in the visual analog scale at week 4 (last observation carried forward) were significantly greater in the nalfurafine hydrochloride groups at 28.56 and 27.46 mm in the 2.5 μg and 5 μg groups, respectively, compared to 19.25 mm in the placebo group (P = 0.0022 and 0.0056, respectively). The major adverse drug reactions (ADRs) included pollakiuria (including nocturia), somnolence, insomnia (including middle insomnia), and constipation. Most ADRs were mild., Conclusions: Nalfurafine hydrochloride (2.5 or 5 μg daily) was effective in the treatment of refractory pruritus in patients with chronic liver disease. Furthermore, no clinically significant ADRs were observed at either dose., (© 2016 The Authors. Hepatology Research published by John Wiley & Sons Australia, Ltd on behalf of Japan Society of Hepatology.)

Aim: Acquisition of nucleos(t)ide analog (NA) inhibitor resistance is critical in successful chronic hepatitis B treatment. As the pattern of tenofovir disoproxil fumarate (TDF) resistance mutations differs from that of other antiviral drugs, we sought to clarify the salvaging potential of TDF in patients with hepatitis B virus (HBV) infection who are poor responders or resistant to other NAs., Methods: A prospective, multicenter, single-arm, open-label study was carried out from December 2011 to October 2014. Poor responders defined as subjects with serum HBV-DNA levels >4 log 10  copies/mL were enrolled. Subjects receiving lamivudine (LAM) + adefovir pivoxil (ADV) before the initiation of the study were switched to LAM + TDF. Subjects on entecavir hydrate (ETV) with or without ADV were switched to ETV + TDF. The primary efficacy end-point was the proportion of subjects achieving HBV-DNA <2.1 log 10  copies/mL (LLQ) at week 24. The secondary efficacy end-points were the proportion of subjects with LLQ at weeks 48 and 96, serum alanine aminotransferase normalization, hepatitis B envelope antigen/antibody and hepatitis B surface antigen/antibody seroconversion., Results: Thirty-four subjects were enrolled, 21 subjects were switched to ETV + TDF, and 13 subjects were switched to LAM + TDF. Drug resistance mutations were determined in 85% of the subjects at the time of the enrolment. The proportion of subjects who achieved LLQ was 59%, 62%, and 71% at weeks 24, 48, and 96, respectively. No serious adverse event related to TDF was reported., Conclusion: Our study clearly showed that TDF containing regimens were effective in salvaging poor responders and/or those who are drug-resistant to other NAs. This study is registered with ClinicalTrials.gov (NCT01475851) and the GSK Clinical Study Register (GSK LOC115912)., (© 2016 The Authors. Hepatology Research published by John Wiley & Sons Australia, Ltd on behalf of The Japan Society of Hepatology.)

Aim: The effect of transcatheter arterial chemoembolization (TACE) is not necessarily sufficient in patients with multiple hepatocellular carcinoma (HCC). We evaluated the antitumor activity and adverse events of TACE using warmed miriplatin suspension for multiple HCC., Methods: Seventy patients with multiple HCC received TACE using warmed miriplatin/lipiodol suspension, including patients who were TACE-naïve (group A, n = 5), those undergoing initial TACE after radical therapies (group B, n = 31), and those with a history of repeated TACE (group C, n = 34). Median tumor size was 19.5 mm and a median of four nodules., Results: Complete necrosis (TE 4) and partial necrosis (TE 3) of 50% or more were attained in 24 and 19 patients at 3 months after TACE, respectively. Response rates (TE 4 + TE 3) were 60.0% in group A, 83.9% in group B, and 41.2% in group C (P = 0.038). Survival rates of all patients after TACE were 82.6% after 1 year, 65.6% after 2 years, and 47.7% after 3 years. Three-year survival rates of patients in groups A, B, and C were 53.3%, 78.8%, and 29.7%, respectively (P = 0.0029)., Conclusion: Transcatheter arterial chemoembolization using warmed miriplatin induced high response rate in multiple HCC, and the rate was significantly high in those patients with recurrent multiple HCCs after curative therapies., (© 2016 The Japan Society of Hepatology.)

Aim: To assess the efficacy and safety of telaprevir (TVR) in combination with pegylated interferon α-2a (PEG-IFNα-2a) and ribavirin (RBV) for treatment-naïve patients and relapsed patients compared to previous TVR-based triple therapy in Japan., Methods: The study group included 35 treatment-naïve (median age, 55 years) and 19 relapsed (median age, 55 years) patients with genotype 1 hepatitis C virus infection. Patients received TVR (750 mg every 8 h) for 12 weeks, in combination with PEG-IFNα-2a and RBV., Results: The sustained virological response (SVR 24 ) rates for naïve and relapsed patients were 85.7% (30/35) and 94.7% (18/19), respectively. The discontinuation rate of all study drugs due to adverse events was 5.6% (3/54). Among the 54 patients, grade 3 skin disorders and grade 3 anemia (<8.0 g/dL) were reported in 2 (3.7%) and 6 patients (11.1%), respectively. Although the overall safety profiles were similar for the TVR/PEG-IFNα-2a/RBV and TVR/PEG-IFNα-2b/RBV regimens (previous study), the proportion of patients discontinuing all study drugs due to adverse events was lower in the patients treated with the TVR/PEG-IFNα-2a/RBV regimen (3/54, 5.6%) than TVR/PEG-IFNα-2b/RBV regimen (44/267, 16.5%)., Conclusion: Telaprevir in combination with PEG-IFNα-2a/RBV provided a high sustained virological response rate for the treatment of genotype 1 hepatitis C virus in both treatment-naïve and relapsed patients in Japan. Telaprevir-based therapy may provide a useful treatment option for patients who are difficult to treat due to NS5A (Y93, L31) and NS3/4A (D168) variants., (© 2016 The Japan Society of Hepatology.)

Aim: The two-point Dixon method for magnetic resonance imaging (MRI) is commonly used to non-invasively measure fat deposition in the liver. The aim of the present study was to assess the usefulness of MRI-fat fraction (MRI-FF) using the two-point Dixon method based on the non-alcoholic fatty liver disease activity score., Methods: This retrospective study included 106 patients who underwent liver MRI and MR spectroscopy, and 201 patients who underwent liver MRI and histological assessment. The relationship between MRI-FF and MR spectroscopy-fat fraction was used to estimate the corrected MRI-FF for hepatic multi-peaks of fat. Then, a color FF map was generated with the corrected MRI-FF based on the non-alcoholic fatty liver disease activity score. We defined FF variability as the standard deviation of FF in regions of interest. Uniformity of hepatic fat was visually graded on a three-point scale using both gray-scale and color FF maps. Confounding effects of histology (iron, inflammation and fibrosis) on corrected MRI-FF were assessed by multiple linear regression., Results: The linear correlations between MRI-FF and MR spectroscopy-fat fraction, and between corrected MRI-FF and histological steatosis were strong (R 2  = 0.90 and R 2  = 0.88, respectively). Liver fat variability significantly increased with visual fat uniformity grade using both of the maps (ρ = 0.67-0.69, both P < 0.001). Hepatic iron, inflammation and fibrosis had no significant confounding effects on the corrected MRI-FF (all P > 0.05)., Conclusions: The two-point Dixon method and the gray-scale or color FF maps based on the non-alcoholic fatty liver disease activity score were useful for fat quantification in the liver of patients without severe iron deposition., (© 2016 The Japan Society of Hepatology.)

Aim: The aim of this study is to clarify the usefulness and limitations of balloon-occluded transcatheter arterial chemoembolization (B-TACE) using miriplatin for patients with four or fewer hepatocellular carcinoma (HCC) nodules., Methods: We studied 47 nodules in 30 consecutive patients who received miriplatin by B-TACE to treat HCC with four or fewer nodules per patient. The treatment effect was evaluated using the Response Evaluation Criteria in Cancer of the Liver., Results: Nodules were divided according to the presence or absence of portal vein visualization during B-TACE. In the presence group, dynamic computed tomography at 3 months post-therapy showed Response Evaluation Criteria in Cancer of the Liver treatment effect (TE) 4 in 88% (14/16), TE3 in 0% (0/16), TE2 in 0% (0/16), TE1 in 12% (2/16), and objective response in 88% of nodules. In the absence group, the results were TE4 in 35% (11/31), TE3 in 13% (4/31), TE2 in 26% (8/31), TE1 in 26% (8/31), and objective response decreased to 48% of nodules. In addition to typical hypervascular nodules, we treated three nodules with irregular ring enhancement that predicted poorly differentiated HCC and four nodules that included a hypoenhancement area that predicted well to moderately differentiated HCC. All irregular ring enhancement nodules achieved TE4. Other nodules that were predicted to be well to moderately differentiated HCC did not have portal vein visualization during B-TACE and could not achieve TE4., Conclusion: Balloon-occluded transcatheter arterial chemoembolization is a useful technique for treatment of classical hypervascular HCC, and portal vein visualization during the B-TACE procedure may provide more favorable local control., (© 2016 The Japan Society of Hepatology.)

Aim: We analyzed the 5-year post-treatment response to peginterferon α-2a (PEG IFN-α-2a) in hepatitis B e-antigen (HBeAg) positive and negative chronic hepatitis B patients., Methods: One hundred and thirty-seven chronic hepatitis B (CHB) patients receiving 90 μg or 180 μg of PEG IFN-α-2a for 24 or 48 weeks in phase II or III studies were enrolled in the study, including 100 HBeAg positive patients and 37 HBeAg negative patients; 121 patients (88.4%) had genotype C., Results: Of the 137 patients, 94 received additional antiviral therapy because of viral reactivation and 43 did not receive any additional antiviral treatment during follow up. Five years upon PEG IFN-α-2a treatment, 32 patients (23.4%) who did not receive any additional antiviral agent after PEG IFN-α-2a therapy achieved a good response (normal serum alanine aminotransferase, low-level hepatitis B virus [HBV] DNA, and HBeAg negativity). Female sex and low HBV DNA levels by the end of treatment were independently associated with favorable 5-year post-treatment responses. Forty-eight-week administration of PEG IFN-α-2a showed a better response (26.4%) than 24-week administration (18.0%). Six patients (4.3%), four males and two females, cleared hepatitis B surface antigen (HBsAg) during the 5-year follow-up period., Conclusion: The 48-week administration of PEG IFN-α-2a achieved better biochemical and virological responses than the 24-week administration, particularly in younger females. The 5-year post-treatment response rate was 23.4%; however, more than two-thirds of the patients received additional antiviral therapy because of viral reactivation after PEG IFN-α-2a treatment. HBsAg clearance was noted in six patients (4.3%). PEG IFN-α-2a is effective in young female patients., (© 2016 The Japan Society of Hepatology.)

Aim: Standard of care for chronic hepatitis C in Japan is currently a pegylated interferon (IFN)-α + ribavirin (PR)-based regimen, notably associated with efficacy and tolerability issues. The advent of novel direct-acting antivirals (DAA) has provided more efficacious and better tolerated treatments. This study investigated the cost-effectiveness of the daclatasvir + asunaprevir (DCV + ASV) DAA regimen in patients infected with hepatitis C virus (HCV) genotype 1b who had previously not responded to or were ineligible for IFN-containing regimens., Methods: A cost-utility analysis using an established Markov model compared DCV + ASV with simeprevir + PR (SMV + PR), telaprevir + PR (TVR + PR) and no treatment using Japanese-specific model inputs, with costs and utility values discounted at 2%. A cohort of patients was simulated until death and predicted quality-adjusted life-years (QALY) and costs were estimated. A subgroup analysis of patients with no DCV resistance was conducted., Results: In all scenarios, DCV + ASV was predicted to be dominant over the comparator; namely, DCV + ASV was associated with increased QALY gains and decreased cost. In patients treated during the chronic hepatitis C stage, cost reductions were ¥1 057 288-2 619 206, and in patients treated during the compensated cirrhosis (CC) stage, reductions were ¥1 032 224-2 531 930. QALY gains were 0.749-2.609 and 0.874-3.043, respectively. Results improved when considering the subgroup of patients without DCV resistance., Conclusion: Cost-effectiveness conclusions are similar for patients treated in the chronic hepatitis C and CC disease stages, with DCV + ASV expected to be cost-saving versus standard of care in Japan for patients with HCV genotype 1b patients who have failed prior therapy or are IFN-ineligible/intolerant., (© 2015 The Japan Society of Hepatology.)

Aim: Tolvaptan, an oral arginine vasopressin V2 receptor antagonist, became available for hepatic ascites. We evaluated the therapeutic efficacy and safety of tolvaptan administration to treat refractory ascites., Methods: Data were collected from 15 hospitalized patients with cirrhosis (hepatitis C, 10; alcoholism, five) after adding tolvaptan (3.75-11.25 mg/day) to conventional diuretics. Bodyweights and serum sodium and creatinine concentrations were measured. Tolvaptan was continued for 4 weeks or longer for a median follow-up period of 42 days (range, 28-56)., Results: In the first week (introduction phase), tolvaptan significantly reduced median weight (66.6, 65.9 and 63.1 kg on days 0, 1 and 7, respectively; P < 0.004). The numbers of good responders (≥3 kg reduction in 4 days), responders (<3 kg weight reduction) and non-responders (no weight reduction) were seven (46.7%), six (40.0%) and two of the 15 (13.3%), respectively. The two non-responders had concomitant chylous pleural effusion or spontaneous bacterial peritonitis. All patients continued tolvaptan for 2 weeks or longer and six (40%, three good responders and three responders) were treated for a median of 42 days without additional intervention. During this intermediate-term administration of tolvaptan, the median weight reduction was statistically significant (65.4, 61.9 and 56.9 kg on days 0, 7 and 42, respectively; P < 0.030) and there was no serum sodium imbalance or renal dysfunction; but two of these six developed hepatic coma., Conclusion: Tolvaptan safely alleviated fluid retention caused by hepatic cirrhosis. Intermediate-term administration of tolvaptan apparently helped maintain weight reduction achieved during the introduction phase., (© 2014 The Japan Society of Hepatology.)

Aim: This study assessed the efficacy and safety of telaprevir in combination with peginterferon-α-2b (PEG IFN) and ribavirin (RBV), for Japanese difficult-to-treat patients with hepatitis C virus (HCV) genotype 2 who had not achieved sustained virological response (SVR) during prior treatment., Methods: In total, 108 relapsed (median age, 59.0 years) and 10 non-responding (median age, 59.0 years) patients with genotype 2 HCV participated. Patients received telaprevir (750 mg, every 8 h) for 12 weeks and PEG IFN/RBV for 24 weeks., Results: The SVR rates for relapsers and non-responders were 88.0% (95/108) and 50.0% (5/10), respectively. The SVR rates did not differ significantly between patients with rs8099917 TT and non-TT. The SVR rates for relapsers and non-responders with extended rapid viral response (eRVR) were 97.6% (82/84) and 100% (5/5), respectively. On the other hand, the SVR rates for relapsers and non-responders completing the treatment protocol were 98.4% (61/62) and 100% (5/5), respectively. The overall safety profiles of telaprevir-based regimens were similar for Japanese patients with genotype 1 and 2 HCV infection who experienced treatment failure., Conclusion: Telaprevir, in combination with PEG IFN/RBV, provided a high SVR rate for genotype 2 HCV, difficult-to-treat patients who had not achieved SVR during prior IFN-based treatment. The eRVR had a strong influence on the cure rate of telaprevir-based therapy. In addition, the continuation of telaprevir-based treatment for up to 24 weeks was a significant predictor of SVR., (© 2014 The Japan Society of Hepatology.)

Aim: The efficacy and safety of simeprevir in combination with peginterferon-α-2b and ribavirin (PEG IFN-α-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., Methods: CONCERTO-4 (NCT01366638) was an open-label, non-comparative, multicenter study of once-daily simeprevir (TMC435) 100 mg in combination with PEG IFN-α-2b/RBV in treatment-naïve and -experienced patients (prior relapsers or non-responders to IFN-based therapy) with chronic HCV genotype 1 infection. Twelve-week combination treatment was followed by 24/48-week response-guided PEG IFN-α-2b/RBV therapy for treatment-naïve patients and prior relapsers, and 48-week PEG IFN-α-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 end-points. Safety, including adverse events (AE), was monitored., Results: Of the 79 patients treated, the proportion achieving SVR12 was highest among treatment-naïve patients (91.7%) and prior relapsers (100%) versus 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 end-points. Most AE were of grade 1 or 2 severity. Grade 3 AE occurred in 17 patients, most frequently neutropenia (6.3%)., Conclusion: Simeprevir combined with PEG IFN-α-2b/RBV was effective in patients infected with HCV genotype 1, both for initial treatment of naïve patients and for retreatment of patients in whom previous IFN-based therapy had failed., (© 2014 The Japan Society of Hepatology.)

Aim: To investigate the potential impact of joint association of alanine aminotransferase (ALT) and γ-glutamyltransferase (GGT) on insulin resistance and β-cell dysfunction in healthy Japanese individuals with a normal range of liver enzymes., Methods: This study included 1010 individuals (545 men and 465 women) aged 20-89 years who underwent an oral glucose tolerance test for health screening. Participants were divided into four groups on the basis of median values for ALT and GGT: (i) both ALT and GGT low (both-low); (ii) ALT high and GGT low (ALT-high); (iii) ALT low and GGT high (GGT-high); and (iv) both ALT and GGT high (both-high). Logistic regression analysis was used to investigate the relationship between liver enzyme and insulin dynamics, such as Homeostasis Model of Assessment - Insulin Resistance (HOMA-IR) and insulinogenic index (IGI). The insulin resistance was defined when HOMA-IR was 2.5 or more. IGI of less than 0.4 was considered to be decreased early-phase insulin secretion., Results: Mean values of HOMA-IR in men was 1.5 in the both-low group, 1.8 in ALT-high, 1.8 in GGT-high and 2.8 in both-high. The mean HOMA-IR in women was 1.3 in the both-low group, 1.3 in ALT-high, 1.6 in GGT-high and 2.0 in both-high. HOMA-IR in the both-high group was significantly higher than that in the both-low group regardless of the difference of sex. Multivariate analysis showed that insulin resistance occurred when the patient had high liver enzymes., Conclusion: Combining the two liver function markers would be effective for identifying individuals with insulin resistance., (© 2014 The Japan Society of Hepatology.)

Aim: Treatment of hepatocellular carcinoma located on the liver surface is frequently difficult because direct puncture of the tumor must be avoided during needle insertion. The aim of this study was to investigate the utility of a no-touch pincer ablation procedure that uses a multipolar radiofrequency ablation (RFA) system for a tumor located on the liver surface., Methods: The experimental animals were three pigs, and RFA was performed with two internally cooled bipolar electrodes. Three ablative procedures were compared: linear insertion at regular 13-mm intervals (pattern 1; virtual target tumor size, <10 mm); fan-shape insertion, maximum interval 20 mm (pattern 2; virtual target tumor size, <15 mm); and 25 mm (pattern 3; virtual target tumor size, <20 mm). All electrodes were inserted at a 30-mm depth. For patterns 1 and 2, ablation was performed on three other parts of the liver, and for pattern 3, ablation was performed on two other parts., Results: For the median transverse and longitudinal diameter to the shaft, with the pattern 1 procedure, the ablative areas were 32 mm × 30 mm, and with the pattern 2 procedure, the ablative areas were 27 mm × 30 mm with carbonization of the liver surface. In contrast, with the pattern 3 procedure, the ablative areas were 45 mm × 26 mm; however, the ablative margin did not reach the surface, and carbonization was not apparent., Conclusion: The no-touch pincer ablation procedure (with an electrode interval of ≤20 mm) may be useful when performed with two internally cooled bipolar electrodes for small nodules that protrude from the liver surface., (© 2013 The Japan Society of Hepatology.)

Aim: In order to evaluate and judge a fibrotic stage of patients with chronic hepatitis C, multivariate regression analysis was performed using multiple fibrotic markers., Methods: A total of 581 patients from eight 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., Results: Multivariate regression analysis finally obtained the following function: z = 2.89 × ln (type IV collagen 7S) (ng/mL) - 0.011 × (platelet count) (×10(3) /mm(3) ) + 0.79 × ln (total bilirubin) (mg/dL) + 0.39 × ln (hyaluronic acid) (μg/L) - 1.87. Median values of the fibrotic 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 fibrotic 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)., Conclusion: A concise multiple regression function using four laboratory parameters successfully predicted pathological fibrotic stage of patients with hepatitis C virus infection., (© 2013 The Japan Society of Hepatology.)

Aim: To compare the early virological effectiveness, sustained virological response and safety of telaprevir 1500 mg/day with telaprevir 2250 mg/day, when combined in triple therapy with pegylated interferon and ribavirin in Japanese patients with high viral loads of genotype 1 hepatitis C virus., Methods: The telaprevir 2250 mg/day and 1500 mg/day groups each contained 60 patients matched by age, sex and history of previous interferon-based treatment. Serum levels of genotype 1 hepatitis C virus RNA, hemoglobin levels, drug adherence and drug discontinuation rates were monitored during and after triple therapy., Results: Patients receiving telaprevir 1500 mg/day had significantly lower telaprevir adherence and lower initial ribavirin dose but similar or superior pegylated interferon and ribavirin adherence and a lower rate of telaprevir discontinuation than did those receiving telaprevir 2250 mg/day. The early virological responses and sustained virological response rates were similar in both groups. Hemoglobin levels decreased to a greater extent in patients treated with telaprevir 2250 mg/day., Conclusion: Compared to triple therapy including telaprevir 2250 mg/day, that including telaprevir at a reduced dose of 1500 mg/day was associated with lower rates of anemia and similar antiviral efficacy. Such a regimen may meaningfully improve sustained virological response rates, especially among female and elderly Japanese patients., (© 2013 The Japan Society of Hepatology.)

Aim: This study evaluated the efficacy of interferon plus ribavirin and examined whether interleukin 28B (IL28B) polymorphism influenced treatment outcome in Japanese patients with hepatitis C virus (HCV)-related liver cirrhosis (LC)., Methods: Fourteen collaborating centers provided details of 261 patients with HCV-related LC undergoing treatment with interferon plus ribavirin. Univariate and multivariate analyses were used to establish which factors predicted treatment outcome., Results: Eighty-four patients (32.2%) achieved a sustained virological response (SVR). SVR rates were 21.6% (41/190) in patients with HCV genotype 1 with high viral load (G1H) and 60.6% (43/71) in patients with non-G1H. In patients with non-G1H, treatment outcome was effective irrespective of IL28B polymorphism. In those with G1H, SVR was achieved in 27.1% of patients with the IL28B rs8099917 TT allele compared with 8.8% of those with the TG/GG alleles (P = 0.004). In patients with G1H having TT allele, treatments longer than 48 weeks achieved significantly higher SVR rates than treatments less than 48 weeks (34.6% vs 16.4%, P = 0.042). In patients with G1H having TG/GG alleles, treatments longer than 72 weeks achieved significantly higher SVR rates than treatments less than 72 weeks (37.5% vs 4.1%, P = 0.010)., Conclusion: Interferon plus ribavirin treatment in Japanese patients with non-G1H HCV-related LC was more effective than those with G1H and not influenced by IL28B polymorphism. In those with G1H, IL28B polymorphism may predict SVR and guide treatment duration: SVR rates were higher in those with the TT allele treated for more than 48 weeks and those with the TG/GG alleles treated for more than 72 weeks., (© 2013 The Japan Society of Hepatology.)

Aim: Hepatectomy for hepatocellular carcinoma (HCC) in patients with primary biliary cirrhosis (PBC) has seldom been reported, and the clinical significance of this procedure remains unclear, although HCC has often been observed in end-stage PBC patients., Methods: To understand the characteristics of hepatectomy on HCC in PBC patients, we examined seven cases at our institute, as well as 22 reported hepatectomy cases in the English-language and Japanese published work. Furthermore, to assess the treatment efficacy of hepatectomy for HCC in PBC patients, we compared these patients with viral hepatitis patients who underwent hepatectomies at our institute during the same period., Results: In the review of 29 cases, more than 70% of the patients were aged over 65 years, and the mean Mayo risk score was low at 5.17. The resected tumors were mainly solitary (79%), and the median maximum tumor size was 37 mm. Approximately two-thirds of the patients met the Milan criteria. In the comparison between the PBC and viral hepatitis cases, there were no differences in the postoperative prognoses, although the tumor size was greater in the PBC cases., Conclusion: Hepatectomy for HCC in selected PBC cases is a feasible and potentially curative treatment option, similar to hepatectomy for HCC in viral hepatitis patients. This procedure is particularly useful for patients with preserved liver function who are not ideal candidates for liver transplantation., (© 2013 The Japan Society of Hepatology.)

Aim: In patients with hepatoviral infection, although a wide resection margin can eradicate the microsatellite lesions around hepatocellular carcinoma (HCC), a large-volume hepatectomy may diminish remaining liver function and become an obstacle for treating recurrent HCC. The optimal width of the resection margin for these patients is still controversial. This study was conducted to investigate the optimal resection margin in hepatectomy for hepatoviral infection patients., Methods: We retrospectively investigated the influences of the resection margin status on recurrence patterns and long-term prognosis in a group of 311 HCC patients with hepatoviral infection who had a solitary HCC without perioperative anti-HCC treatment., Results: The resection margin status did not statistically influence the postoperative recurrence-free and overall survival rates (3-year recurrence-free survival of 61.0% vs 55.1%, P = 0.33; 5-year overall survival of 74.9% vs 81.5%, P = 0.77 in without a margin vs with a margin, respectively), although resection without a margin increased the local recurrence with marginal significance (P = 0.055). Regarding the width of the resection margin, in 30-mm or smaller HCC, resection margin did not significantly improve the prognosis among hepatoviral infection patients. However, for tumors larger than 30 mm, a resection margin wider than 3 mm showed significant impacts on the prevention of recurrence in spite of the influence of multicentric carcinogenesis., Conclusion: The resection margin used for eradication of microsatellite lesions showed differences that were dependent on tumor size in hepatoviral infection patients. Resection margin should be based on not only background liver function but also tumor characteristics., (© 2013 The Japan Society of Hepatology.)

Aim: The aim of this case-control study was to assess the efficacy and safety of dipeptidyl peptidase-4 inhibitor (sitagliptin) for type 2 diabetes mellitus (T2DM) with non-alcoholic fatty liver disease (NAFLD)., Methods: Twenty NAFLD patients with T2DM treated by sitagliptin were retrospectively enrolled as the sitagliptin group. These patients were given sitagliptin between January 2010 and July 2011. Another 20 NAFLD patients with T2DM treated only with diet and exercise for 48 weeks were selected as the control group. Serum levels of fasting plasma glucose (FPG), hemoglobin A1C (HbA1c), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were measured before and 12, 24, 36 and 48 weeks after the initiation of treatment., Results: In the sitagliptin group, average HbA1c levels decreased approximately 0.7% at 48 weeks after the initiation of sitagliptin. Next, average FPG levels decreased approximately 15 mg/dL at 48 weeks after the initiation of sitagliptin. The serum levels of HbA1c and FPG in the sitagliptin group decreased with statistical significance compared to those in the control group (P < 0.05). All the patients could take sitagliptin of 50 mg/day without reduction necessitated by sitagliptin-related side-effects. There were no significant changes of average AST and ALT levels during follow up of 48 weeks in both sitagliptin and control groups., Conclusion: Our results indicate sitagliptin is effective and safe for the treatment of T2DM complicated with NAFLD., (© 2013 The Japan Society of Hepatology.)

Aim: Patients with unresectable hepatocellular carcinoma (HCC) often undergo transcatheter arterial chemoembolization (TACE). Miriplatin is a lipophilic cisplatin derivative used in TACE that is effective in HCC. However, the difference in antitumor efficacy between warmed versus room temperature miriplatin is unclear., Methods: Chemotherapy efficacy was evaluated by dynamic computed tomography 1-3 months after TACE, according to the Modified Response Evaluation Criteria in Solid Tumors. A total of 203 patients with HCC who received TACE with miriplatin for the first time were included in a follow-up study to retrospectively investigate its efficacy and safety. Overall, 45 patients underwent TACE with warmed (40°C) miriplatin and 158 patients received TACE with room temperature miriplatin., Results: Seventy patients (44.3%) treated with room temperature miriplatin and 32 patients (71.1%) who received warmed miriplatin experienced complete or partial responses. Multivariate analysis identified miriplatin temperature (warmed miriplatin, risk ratio (RR) = 2.26, P = 0.047), tumor number (solitary, RR = 3.48, P = 0.007), α-fetoprotein (AFP) level (<50 ng/mL, RR = 2.35, P = 0.012) and history of TACE (no history, RR = 2.22, P = 0.041) as predictors of objective response following TACE with miriplatin, and no serious complications were observed., Conclusion: Warm temperature, solitary tumors, low AFP level and first TACE are significant and independent predictors of objective response after TACE using miriplatin. These results suggest that warmed miriplatin can be considered as one of the standard treatments for unresectable HCC., (© 2012 The Japan Society of Hepatology.)

Aim: To evaluate the efficacy of a new ablation procedure for the stepwise hook extension technique using a SuperSlim needle for radiofrequency ablation (RFA) treatment of hepatocellular carcinoma (HCC), a randomized controlled trial was performed., Methods: Thirty patients with HCC measuring 20 mm or less were randomly treated with a conventional four stepwise expansion technique (group 1) and the new stepwise expansion technique (group 2; the electrode was closed in the shaft after the same three steps of the conventional procedure and then fully extended). All patients underwent the RFA procedure using a 10-hook expandable electrode of 17-G diameter (LeVeen SuperSlim 30 mm). We compared the ablation time, required energy and ablated lesions in the two groups., Results: The long and short diameters of RFA-induced necrosis were significantly larger in group 2 (37 and 28 mm) than group 1 (30 and 26 mm, P = 0.001 and =0.045, respectively). Irregular and small needle expansion resulting in the parachute-like or irregularly shaped ablated zone was observed in more cases in group 1 than in group 2. The new technique made all tines expand uniformly and largely, which produced a near-oval ablated zone of which the long axis is perpendicular to the needle shaft., Conclusion: The two kinds of stepwise procedures allow the selection of a more suitable procedure according to the tumor size and shape in each RFA., (© 2013 The Japan Society of Hepatology.)

Aim: Laparoscopy-guided liver biopsy is the most accurate method for assessing liver fibrosis but have several limitations. We designed a non-invasive method, called magnetic resonance laparoscopy (MRL), based on gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging, to assess liver fibrosis in patients with chronic hepatitis B and C virus., Methods: We prospectively analyzed 49 patients with normal liver and 353 patients with chronic viral hepatitis, laparoscopic liver biopsy was performed on 109 patients and 244 patients were diagnosed as having liver cirrhosis clinically. The MRL findings of the liver surface were classified into three categories: (i) smooth (essentially smooth surface of the entire liver or with limited areas of depression); (ii) partially irregular (several interconnected depressions on the surface mainly in the left lobe of the liver); and (iii) diffusely irregular (nodules present on the liver surface). Patients with diffusely irregular liver surface was diagnosed as liver cirrhosis., Results: The liver surface changed with the progression of liver fibrosis from smooth, partially irregular to diffusely irregular, irrespective of viral type. The sensitivity, specificity, positive and negative predictive values for the diagnosis of cirrhosis according to the surface findings on MRL were 96%, 100%, 95% and 95%, respectively. The cirrhotic liver showed: (i) disappearance of impression of the right ribs; (ii) enlargement of the lateral segment; and (iii) atrophy of the right lobe according to Child-Pugh classification., Conclusion: Our data indicated that MRL is a potentially useful non-invasive examination for evaluation of liver fibrosis associated with viral hepatitis., (© 2012 The Japan Society of Hepatology.)

Aim: The aims of this study are to assess the antiviral effects, safety and telaprevir (TVR) pharmacokinetics in two cohorts given TVR every 8 h (q8h) at doses of 500 mg and 750 mg with peginterferon-α-2b and ribavirin in chronic hepatitis C patients., Methods: Twenty chronic hepatitis C (HCV) patients with genotype 1b in high viral loads were randomly assigned to two TVR-based regimens of 750 mg q8h (group A) and 500 mg q8h (group B) in combination with peginterferon-α-2b and ribavirin for 12 weeks., Results: Although the difference was not statistically significant other than trough concentration (Ctrough ) at week 4, the parameters of maximum concentration (Cmax ), the area under the concentration time curve (AUC0-∞ ) and Ctrough tended to be higher in group A than those in group B. The antiviral effects were similar in the two groups (sustained virological response rates [SVR], 40% in group A, 50% in group B). The discontinuation rates by anemia were 30% in group A and 20% in group B. Serum creatinine concentrations were lower in group B than those in group A., Conclusion: Although the exposure to TVR tended to be lower in 500 mg q8h than that in 750 mg q8h, the SVR rates in both groups were similar. The result suggests that the 500 mg q8h dose may be one option for treatment. In addition, the present findings indicate that the development of adverse events which increase with a TVR-based regimen, specifically anemia and creatinine, could be avoided by dose adjustment of TVR., (© 2012 The Japan Society of Hepatology.)

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., (© 2012 The Japan Society of Hepatology.)

Aim: To test if the treatment adherence to branched-chain amino acid (BCAA) granules influences the serum albumin level and prognosis in prospective 2984 patients with decompensated liver cirrhosis who were prescribed BCAA granules containing 952 mg of L-isoleucine, 1904 mg of L-leucine and 1144 mg of L-valine at 4.15 g/sachet three times a day after meals., Methods: The primary end-point was the time to the event defined as "hospital admission due to progression of hepatic failure", and factors affecting this outcome were explored. Changes in serum albumin level were evaluated as the secondary end-point., Results: Patients were divided into the good adherence group (those who reported to have taken "nearly all" prescribed doses) and the poor adherence group (those who reported to have taken "approximately half" or "less" doses), because such stratification was validated by treatment responses in plasma BCAA/tyrosine ratio. Factors related to the primary end-point were age, drug adherence during 6 months of study treatment, previous hepatic cancer, current clinical manifestations, previous clinical manifestations, baseline serum albumin level, platelet count and total bilirubin level. The cumulative event-free survival was significantly higher in the good adherence group. Increase in the serum albumin level was also greater in the good adherence group., Conclusion: Higher BCAA treatment adherence better raised the serum albumin level, leading to improvement of event-free survival. These results indicate the importance of patient instruction for the adequate use of BCAA granules., (© 2012 The Japan Society of Hepatology.)

Aim:   To evaluate the efficacy of reduction therapy of natural human interferon (IFN)-β and ribavirin in elderly patients with hepatitis C virus (HCV) genotype 1b and high viral load who had complications of anemia, low bodyweight (<50 kg), diabetes mellitus and/or hypertension., Methods:   Inclusion criteria were age of 65 years or older, HCV genotype 1b, and serum HCV RNA level of 5.0 logIU/mL or higher. A total of 23 subjects with hemoglobin level of less than 13 g/dL, low bodyweight, diabetes mellitus and/or hypertension were enrolled in this study (reduction-dose group). IFN-β was administrated i.v. at a dose of 6 million units daily for 4 weeks initially, followed by three times a week for 44 weeks. Ribavirin was given daily for 48 weeks at a decreased dose of one tablet per day compared to the ordinary dose described based on bodyweight. As a control, another 22 patients without anemia, low bodyweight and/or complications treated with the standard dose of ribavirin (standard-dose group) were enrolled., Results:   Patients' rates with further dose reduction or discontinuation of treatment was 26.1% (6/23) in the reduction-dose group and 77.3% (17/22) in the standard-dose group. The sustained virological response (SVR) was 39.1% (9/23) in the reduction-dose group and 27.3% (6/22) in the standard-dose group (P = 0.404). Based on genetic variations near the IL28B gene (rs8099917), SVR was 44.1% (15/34) in patients with TT and 0% (0/11) in patients with TG (P = 0.008)., Conclusion:   The reduction therapy of IFN-β and ribavirin in elderly HCV patients with genotype 1b, high viral load, IL28B gene (rs8099917) of TT who had complications of anemia, low bodyweight, diabetes mellitus and/or hypertension is one possible selection of treatment., (© 2012 The Japan Society of Hepatology.)