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Simple Summary: The Barcelona clinic liver cancer (BCLC) system is used widely for staging hepatocellular carcinomas (HCCs). However, it is questionable that for patients classified as BCLC stage C, control of intrahepatic targets using various treatment procedures is not the main topic of discussion, whereas the importance of intrahepatic tumor control in patients with extrahepatic tumor spread is reviewed. Therefore, this study analyzed the data of 64 consecutive BCLC stage C patients with intrahepatic target nodules who received systemic therapy and evaluated the efficacy of the combined use of systemic sequential therapy, including more than two agents, and locoregional treatment administered after initiation of systemic therapy. We showed that the combined use of systemic sequential therapy of more than two agents and locoregional-treatment improved overall survival in BCLC stage C HCC patients with intrahepatic target nodules who had previously received systemic therapy-based treatment. Background: The aim of this study was to evaluate the clinical impact of a combination of systemic sequential therapy and locoregional therapy on the long-term survival of patients with Barcelona Clinic Liver Cancer (BCLC) stage C hepatocellular carcinoma (HCC). Methods: Sixty-four consecutive patients with intrahepatic target nodules who had initially received systemic therapy (lenvatinib and atezolizumab plus bevacizumab) were reviewed. The clinical impact of the combined use of systemic sequential therapy and locoregional therapy was evaluated by determining overall survival (OS). The combined use of systemic sequential therapy with more than two agents and locoregional treatment was defined as multidisciplinary combination therapy (MCT), while only systemic sequential therapy and repeated locoregional-treatment was defined as a single treatment procedure (STP). Results: R0 resection, MCT, and STP resulted in significantly better OS compared with no additional treatment (median OS, not reached vs. 18.2 months and 12.6 vs. 8.1 months, respectively; p = 0.002). Multivariate analysis confirmed that the use of R0 resection and MCT were associated with better OS (hazard ratio [HR]; 0.053, p = 0.006 and 0.189, p < 0.001, respectively) compared with that for STP (HR; 0.279, p = 0.003). Conclusions: MCT is may effective in patients with BCLC stage C HCC and intrahepatic target nodules who have previously received systemic therapy-based treatment. [ABSTRACT FROM AUTHOR]

Introduction: When lenvatinib is administered to people with hepatocellular carcinoma (HCC), tumor blood flow is reduced due to the inhibition of the vascular endothelial growth factor receptor (VEGFR) and fibroblast growth factor receptor (FGFR). Few studies have examined the decrease in tumor blood flow with respect to changes in tumor blood vessels (TBVs) in clinical practice. We investigated the mechanism of tumor blood flow control by investigating changes in the diameter of relatively large TBVs in large-sized lesions with high blood flow. Methods: From January 2011 to October 2021, patients receiving lenvatinib for unresectable intrahepatic HCC at Toranomon Hospital, Tokyo, Japan, were considered for inclusion. We investigated the TBV diameter in the arterial phase of dynamic computed tomography before treatment and its change over time (2–12 weeks after lenvatinib initiation). The relationship between changes in TBV diameter and prognosis was also examined. Results: Of 114 patients treated with lenvatinib for HCC, 26 patients who had intrahepatic lesions with a tumor diameter of 30 mm or more enrolled in the study. The median tumor and TBV diameters before treatment were 58 mm and 2.55 mm, respectively. Twenty-five patients (96%) had a shrinkage in TBV diameter 2–12 weeks after lenvatinib administration. The maximum TBV diameter shrinkage of 20% or more was observed in 19 patients (73%), and progression-free survival was prolonged in these patients compared to the group with less than 20% TBV diameter shrinkage (p = 0.039). Discussion/Conclusion: Due to the antiangiogenic effect of lenvatinib, a shrinkage in the TBV diameter of HCC was observed. The shrinkage of TBV may be regarded as a process of normalization of TBVs. The shrinkage of TBVs in imaging analysis may be associated with improved prognosis; however, additional studies are still required. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Hepatitis C virus is the leading cause of liver cirrhosis and hepatocellular carcinoma in Japan. We aimed to examine the long-term (> 20 years) mortality and hepatocellular carcinoma rates and associated risk factors in 1412 Japanese patients with decompensated hepatitis C virus-related cirrhosis (Child-Pugh B or C).Methods: Cumulative survival and hepatocellular carcinoma rates were determined using Kaplan-Meier analysis. Independent risk factors were identified by multivariate analysis. A two-tailed P-value of < 0.05 was considered significant.Results: The patients were followed up for a median of 2 years (range 0.5-24.2 years). In total, 62.3%, 41.7%, 4.7%, and 68.3% of the patients had a history of hepatocellular carcinoma, ascites, hepatic encephalopathy, and esophageal varices, respectively. The 1-, 5-, 10-, and 20-year cumulative overall survival rates in the total cohort was 74.9%, 29.0%, 9.1%, and 1.4%, respectively. The 1-, 3-, 5-, and 10-year cumulative survival rates for patients without hepatocellular carcinoma were 93.1%, 54.4%, 18.2%, and 4.0%, respectively, and the corresponding cumulative post-decompensation hepatocellular carcinoma rates were 14.0%, 31.6%, 46.1%, and 66.2%, respectively. The independent risk factors for mortality were older age, Child-Pugh C cirrhosis, the presence of hepatocellular carcinoma, low estimated glomerular filtration rate, low serum sodium level, low platelet count, and high γ-glutamyl transferase and α-fetoprotein levels for all patients and older age, Child-Pugh C cirrhosis, and low estimated glomerular filtration rate for patients without hepatocellular carcinoma. Overall, 1035 patients (73.3%) died; the causes of death were liver failure with/without hepatocellular carcinoma, pneumonia, sepsis, cardiovascular disease, and non-hepatocellular carcinoma malignancies. The corresponding morality rates per person-year were 133.4, 59.9, 10.9, 10.6, 9.0, and 5.2, respectively.Conclusions: Among Japanese patients with decompensated hepatitis C virus-related cirrhosis, hepatocellular carcinoma is associated with poor prognosis. Our results highlight the importance of managing liver-related events, including hepatocellular carcinoma, in these patients. [ABSTRACT FROM AUTHOR]

Aims: Rifaximin (RFX), a non‐systemic antibiotic, improves liver/neuropsychological functions in patients with hepatic encephalopathy (HE). We aimed to investigate the clinical profiles associated with gut bacterial loads using exploratory data analysis and the effects of RFX on the gut microbiota of patients with HE. Methods: We analyzed the data from 17 patients with HE who underwent fecal microbiota examination in phase II/III trials in Japan. Profiles associated with genera Streptococcus, Veillonella, and Lactobacillus loads were analyzed using classification and regression trees (CART). Changes in gut microbial consortia of seven patients with HE were then assessed 2 weeks after RFX treatment by principal component analysis. Results: In the CART, the first and second divergence variables for each higher bacterial load were as follows: (i) in Streptococcus, the number connection test‐A ≥39.55 s and presence of portal‐systemic shunt; (ii) in Veillonella, serum potassium levels <4.75 mEq/L and total cholesterol level <129.5 mg/dL; and (iii) in Lactobacillus, white blood cell counts ≥3.4 × 103/μL and aspartate aminotransferase level ≥44.5 U/L. There was no significant change in total bacterial load before and after RFX treatment; however, there was a decrease in Streptococcus, Veillonella, and Lactobacillus counts after RFX treatment. Conclusion: We report clinical profiles associated with gut bacterial loads in patients with HE, and showed that RFX altered gut microbiota components associated with liver/neuropsychological functions. Thus, RFX could improve liver/neuropsychological functions through the regulation of the gut microbial consortia in patients with HE. [ABSTRACT FROM AUTHOR]

Background: We determined the antiviral potency and viral breakthrough rate after 10 years of continuous entecavir treatment in patients with chronic hepatitis B (CHB) infection.Methods: The cumulative rates of undetectable hepatitis B virus DNA (HBV-DNA, < 2.1 log copies/mL), alanine aminotransferase (ALT) normalization, hepatitis B e antigen (HBeAg) seroclearance, hepatitis B surface antigen (HBsAg) seroclearance, and viral breakthrough of 1094 nucleos(t)ide analogue-naïve CHB patients (HBeAg-positive: 47%) who were on continuous entecavir treatment for 10 years were calculated.Results: The median age was 50 years and follow-up period was 5.5 years, with 999, 804, 591, 390, 182 and 87 patients followed up for at least 1, 3, 5, 7, 9 and 10 years, respectively. Incremental increases were noted in the rates of undetectable HBV-DNA, ALT normalization, HBeAg seroclearance, and HBsAg seroclearance, reaching 96, 79, 38 and 3.7%, respectively, by the tenth year. The mean decline in HBsAg level from baseline was - 0.08 log IU/mL/year. Multivariate analysis identified HBsAg level and genotype (A) as independent predictors of HBsAg seroclearance. Sixteen patients experienced viral breakthrough. The cumulative percentages of patients with viral breakthrough analyzed by the Kaplan-Meier test were 1.5 and 2.5% at years 5 and 10, respectively. There were no serious adverse events during treatment.Conclusions: Long-term entecavir treatment of nucleos(t)ide analogue-naïve CHB patients was associated with an excellent viral response and a low rate of entecavir-resistant mutations at 10 years. Baseline HBsAg levels and genotype were predictors of HBsAg seroclearance during entecavir treatment. [ABSTRACT FROM AUTHOR]

Introduction: In Japan, hepatitis C virus (HCV) genotype (GT) 2 accounts for approximately 32% of HCV infections. Limited treatment options exist in Japan for HCV GT2-infected patients. GIFT-II was a phase 3, randomized, open-label study evaluating the efficacy and safety of 16- and 12-week regimens of co-formulated ombitasvir (OBV)/paritaprevir (PTV)/ritonavir (r) plus ribavirin (RBV) in Japanese adults with HCV GT2 infection.Methods: Patients were randomized in a 1:1 ratio to once-daily, co-formulated OBV/PTV/r (25/150/100 mg) with weight-based RBV for 16 or 12 weeks. The primary efficacy endpoint was the sustained virologic response at 12 weeks post-treatment (SVR12) rate in the primary efficacy population of non-cirrhotic treatment-naive patients.Results: A total of 171 patients were randomized to OBV/PTV/r + RBV. In the primary efficacy population, SVR12 rates were 91.5% (43/47; 95% confidence interval 83.5-99.5%) and 75.0% (36/48; 95% confidence interval 62.8-87.2%) in the 16-week arm and 12-week arm, respectively. No patient in the 16-week arm relapsed by post-treatment week 12. Among non-cirrhotic treatment-experienced patients, the overall SVR rate in the 16-week arm was 75.8% (25/33) and was highest [93.8% (15/16)] among those who had relapsed after previous interferon-based therapy. SVR12 rates were consistently higher in patients with HCV GT2a infection versus HCV GT2b infection [16-week treatment arm: 93.9% (31/33) versus 85.7% (12/14) and 93.8% (15/16) versus 56.3% (9/16) among non-cirrhotic treatment-naive and treatment-experienced patients, respectively]. No patient discontinued treatment because of an adverse event. The most common adverse events were anemia, increased blood bilirubin, and nasopharyngitis.Conclusions: OBV/PTV/r + RBV for 16 weeks resulted in high SVR12 rates in non-cirrhotic Japanese patients infected with HCV GT2 who were treatment-naive or who had relapsed after an interferon-based therapy. Higher SVR12 rates were observed among patients with HCV GT2a infection versus those with GT2b infection. This regimen demonstrated a favorable safety profile.Trial Registration: ClinicalTrials.gov identifier, NCT02023112.Funding: AbbVie. [ABSTRACT FROM AUTHOR]

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 (SVR24) 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. [ABSTRACT FROM AUTHOR]

Background: The significance of HBV reactivation during immunosuppressive therapy was evaluated in three nationwide cohorts including patients with previously resolved HBV (prHBV) infection.Methods: The clinical features of 1061 patients with acute liver failure (ALF) or late-onset hepatic failure (LOHF) were retrospectively examined, focusing on those who experienced HBV reactivation. Additionally, 420 patients with prHBV infection were prospectively enrolled: 203 received immunosuppressive therapies immediately after enrollment, while the remaining 217 were enrolled after having received immunosuppressive therapies without the occurrence of HBV reactivation. The serum HBV-DNA levels were prospectively monitored every month, and the incidences of HBV reactivation, defined as a serum HBV-DNA level of 1.3 log IU/ml or more, were evaluated.Results: In the retrospective study, persistent HBV infection was found in 90 patients, and HBV reactivation was responsible for liver injuries in 50 patients including 23 receiving immunosuppressive therapies (26 with HBs-antigen positivity, 7 with prHBV infection). None of seven patients with prHBV infection were rescued. In the prospective studies, HBV reactivation occurred in ten patients, but preemptive entecavir administration prevented liver injury. The cumulative reactivation rate was 3.2 % at 6 months, and the increase of the rate compared to that at 6 months was +1.5 % at 48 months.Conclusions: HBV reactivation during immunosuppression was responsible for liver injuries in a quarter of the ALF/LOHF patients with persistent HBV infection. Early serum HBV-DNA monitoring may improve patient prognosis, since HBV reactivation typically occurs within 6 months of the start of immunosuppressive therapies in patients with prHBV infection. [ABSTRACT FROM AUTHOR]

Background and Aims: A sustained virological response (SVR) decreases the incidence of hepatocellular carcinoma (HCC) in patients with hepatitis C. We investigated the longterm outcomes of patients who developed HCC after achieving SVR with interferon therapy. Patients: Of 75 patients who developed HCC after SVR, 40 patients underwent radical therapies (SVR group). From 436 patients undergoing surgical resection for hepatitis C virus-positive HCC, 80 patients were randomly chosen as a control cohort, after adjusting for age, gender, and extent of hepatic fibrosis (non- SVR group). Patients were observed for a median of 5.08 years. Results: HCC recurrence was found in 16 SVR patients and in 66 non-SVR patients. The respective HCC recurrence rates of SVR and non-SVR patients were 23 and 56% at 3 years, 42 and 77% at 5 years, and 53 and 90% at 10 years (p = 0.001). The respective overall survival rates in the SVR and non-SVR groups were 93 and 68% at 5 years, 88 and 34% at 10 years, and 53 and 21% at 15 years (p = 0.001). Conclusion: Although SVR patients had a significantly lower HCC recurrence rate than the non-SVR patients, the cumulative recurrence rate of SVR patients increased to 86% at 15 years. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objectives: A randomized controlled trial was conducted to evaluate the efficacy of impedance control of a radiofrequency interstitial thermal ablation system (RITA) used to treat hepatocellular carcinoma (HCC). Methods: Fifteen patients with hypervascular HCCs <20 mm in diameter were randomly treated with radiofrequency ablation (RFA) using conventional temperature control (group A) or impedance control methods (group B). RITA needle electrodes were used in all cases. We compared ablation time, extent of lesion ablation, and energy use between the two groups. Results: The median long and short diameters of the axial cross sections of radiofrequency-induced necrotic areas visualized by CT were 32 mm (range, 26-36) and 25 mm (20-31) in group A and 32 mm (28-40) and 31 mm (24-37) in group B, respectively. The short diameter of group B patients was significantly greater than that of group A patients (p = 0.029). The median ablation time was 18.8 min in group A and 13.4 min in group B, thus significantly shorter in group B (p = 0.001). The energy requirement did not differ significantly between the groups. Conclusions: Impedance control of the RITA system resulted in an increased size of the ablation zone and a decreased ablation time. © 2015 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: The significance of anti-inflammatory therapy has not been fully evaluated in hepatitis C virus (HCV)-related cirrhosis. Patients and Methods: We analyzed stepwise progression rates from cirrhosis to hepatocellular carcinoma (HCC) and to death using a Markov model in 1,280 patients with HCV-related cirrhosis. During the observation period, 303 patients received interferon and 736 received glycyrrhizin injections as anti-inflammatory therapy. Results: In the entire group, annual progression rates from cirrhosis to HCC and from cirrhosis to death were 6.8 and 1.9%, and the rate from HCC to death was 19.0%. When sustained virological response (SVR) or biochemical response (BR) was attained with interferon, the annual rate to HCC decreased to 2.6%. On the contrary, the progression rates to HCC and to death in the patients without SVR and BR were 7.2 and 2.0%, respectively (p < 0.0001). Continuous interferon administration significantly decreased the carcinogenesis rate to 5.5% (p = 0.0087). In the analysis of the remaining patients with high alanine transaminase of 75 IU/l or more but without interferon response or without interferon administration, glycyrrhizin injection significantly decreased annual non-progression probability (no glycyrrhizin 88.0% vs. glycyrrhizin therapy 92.3%, p = 0.00055). Conclusion: Glycyrrhizin injection therapy is useful in the prevention of disease progression in interferon-resistant or intolerant patients with HCV-related cirrhosis. © 2014 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: Few studies have investigated the long-term effects of interferon (IFN) therapy for chronic hepatitis B (CHB). In this retrospective study, we investigated the efficacy of and predictors of response to IFN therapy in CHB patients. Methods: We analyzed data for 615 Japanese CHB patients (hepatitis B e antigen [HBeAg]-positive 414, HBeAg-negative 201) treated with IFN, and conducted follow up for a median duration of 8.1 years (range 0.5-23.2). Responders were defined as patients who showed continuously normalized alanine transaminase (ALT) levels, HBeAg clearance, and low hepatitis B virus (HBV) DNA levels at 6 months post-treatment or for a span of more than 6 months until each test point at 1, 3, 5, and 10 years. Results: The IFN response rates of all patients were 21, 18, 21, 23, and 25% at 6 months and 1, 3, 5, and 10 years, respectively. On multivariate analysis, significant determinants of the outcome of IFN therapy were as follows: at 6 months and 1 year, young age, low HBV DNA levels, and long duration of treatment; at 3 years, long duration of treatment, young age, and high level of albumin; at 5 years, high level of albumin, female, and pretreated with IFN; and at 10 years, HBeAg-negative. Sixty-nine of the 615 patients (11%) achieved seroclearance of hepatitis B surface antigen (HBsAg). On multivariate analysis, age ≥30 years, HBV genotype A, and male were all independent factors predicting the achievement of HBsAg seroclearance. Conclusion: HBeAg, HBV DNA level, age, sex, albumin, duration of treatment, pretreatment with IFN, and HBV genotype were important factors in determining long-term response to IFN therapy. [ABSTRACT FROM AUTHOR]

Aim: Malignancies that include hepatocellular carcinoma often occurred in patients with chronic liver disease. The aim of this retrospective match control study was to assess the cumulative development incidence and predictive factors for total malignancies in elderly Japanese patients with non-alcoholic hepatic diseases (NAFLD) or hepatitis C virus (HCV). Methods: A total of 1600 NAFLD patients with age of ≥60 years were enrolled, and 1600 HCV patients with age of ≥60 years were selected as control by matching 1:1 with NAFLD group for age, sex, and follow-up period. The primary goal is the first development of malignancies. Evaluation was performed by the use of the Wilcoxon rank sum test, the Kaplan-Meier method, and Cox proportional hazard model. The mean observation period is 8.2 years in both NAFLD and HCV group, respectively. Results: The number of patients with the development of malignancies was 167 in the NAFLD group and 395 in the HCV group. The 10th development rate of malignancies was 13.9% in the NAFLD group and 28.2% in the HCV group (risk ratio 2.27; P < 0.001). The incident rates of hepatocellular carcinoma in all the malignancies were 6.0% (10/167) in the NAFLD group and 67.6% (267/395) in the HCV group ( P < 0.001). The malignancies in the NAFLD group were observed in the following order: gastric cancer 34 cases (20.4%) > colon cancer 31 cases (18.6%) > prostate cancer 21 cases (12.6%). Conclusions: The incident rates of hepatocellular carcinoma in all the malignancies were approximately 6% in the NAFLD group and two-thirds in the HCV group. [ABSTRACT FROM AUTHOR]

OBJECTIVES:The aim of this study was to determine the incidence and risk factors of hepatocellular carcinoma (HCC), and to elucidate the utility of two non-invasive predictive procedures for liver fibrosis: the aspartate aminotransferase (AST) to platelet ratio index (APRI) and the BARD score (which includes the following three variables: body mass index, AST/alanine aminotransferase ratio, and diabetes) in the prediction of HCC in a large population of Japanese patients with non-alcoholic fatty liver disease (NAFLD).METHODS:This was a retrospective cohort study conducted at a public hospital. Study subjects included 6,508 patients with NAFLD diagnosed by ultrasonography. The median follow-up period was 5.6 years. The primary end point was the onset of HCC. Evaluation was performed using Kaplan-Meier methodology and Cox's proportional hazards analysis.RESULTS:In all, 16 (0.25%) new cases with HCC were diagnosed during the study. The cumulative rates of NAFLD-related HCC were 0.02% at year 4, 0.19% at year 8, and 0.51% at year 12. The annual rate of new HCC was 0.043%. Multivariate analysis identified serum AST level ≥40 IU/L (hazard ratio (HR): 8.20; 95% confidence interval (95% CI): 2.56-26.26; P<0.001), platelet count <150 × 103/μl (HR: 7.19; 95% CI: 2.26-23.26; P=0.001), age ≥60 years (HR: 4.27; 95% CI: 1.30-14.01; P=0.017), and diabetes (HR: 3.21; 95% CI: 1.09-9.50; P=0.035) as independent risk factors for HCC. With regard to the APRI, 184 patients (2.83%) were considered to have significant fibrosis (equivalent to non-alcoholic steatohepatitis (NASH) stage 3-4). The cumulative rate of HCC was significantly higher in this group (HR: 25.03; 95% CI: 9.02-69.52; P<0.001). In contrast, regarding the BARD score, 3,841 (59%) patients were considered to have advanced fibrosis (NASH stage 3-4). However, no significant associations between the BARD score and the incidence of HCC were observed (HR: 1.16; 95% CI: 0.40-3.37; P=0.780).CONCLUSIONS:This retrospective study indicates that the annual incidence rate of HCC among Japanese NAFLD patients is low. Elderly NAFLD patients with diabetes, elevated serum AST, and especially thrombocytopenia (suggested to be associated with advanced liver fibrosis) should be monitored carefully during follow-up that includes using the APRI to ensure early diagnosis and treatment of HCC. [ABSTRACT FROM AUTHOR]

The consensus meeting for the diagnosis, management and treatment for hepatitis C was held in 45th annual meeting for the Japan Society of Hepatology (JSH) in June 2009 where the recommendations and informative statements were discussed including organizers and presenters. The Several important informative statements and recommendations have been shown. This was the fourth JSH consensus meeting of hepatitis C, however, the recommendations have not been published in English previously. Thus, this is the first report of JSH consensus of hepatitis C. The rate of development of hepatocellular carcinoma (HCC) in HCV-infected patients in Japan is higher than in the USA, because the average age of the HCV-infected patients is greater and there are more patients with severe fibrosis of the liver than in the USA. In Japan, more than 60% of HCV-infected patients are genotype 1b infection, and they show lower response to perinterferon and ribavirin combination treatment. To improve the response rate is also an important issue in our country. To establish the original recommendations and informative statements to prevent the development of HCC is a very important issue in Japan. [ABSTRACT FROM AUTHOR]

In the 2008 guidelines for the treatment of patients with cirrhosis, who are infected with hepatitis B virus (HBV), the main goal is to normalize levels of alanine and aspartate aminotransferases by eliminating HBV or reducing viral loads. In patients with compensated cirrhosis, the clearance of HBV from serum is aimed for by entecavir, as the main resort, for histological improvement toward the prevention of hepatocellular carcinoma (HCC). In patients with decompensated cirrhosis, by contrast, meticulous therapeutic strategies are adopted for the reversal to compensation, toward the eventual goal of decreasing the risk of HCC. For maintaining liver function and preventing HCC, branched chain amino acids and nutrient supplements are applied, in addition to conventional liver supportive therapies. For patients with chronic hepatitis B, separate guidelines are applied to those younger than 35 years and those aged 35 years or older. Even for patients with chronic hepatitis who are negative for hepatitis e antigen (HBeAg), but who harbor HBV DNA in titers of 7 log copies/mL or more, a “drug-free state” is aimed for by sequential treatment with interferon (IFN) plus entecavir as the first line. For patients with chronic hepatitis B aged 35 years or older, who are HBeAg-negative and carry HBV DNA in titers of less than 7 log copies/mL, long-term IFN for 24–48 weeks is adopted anew. To HBeAg-negative patients who have either or both platelet counts of less than 150 × 103/mm3 and less than 7 log copies of HBV DNA, also, long-term IFN for 24–48 weeks is indicated. [ABSTRACT FROM AUTHOR]

In the 2008 guidelines for the treatment of patients with chronic hepatitis C, pegylated interferon (Peg-IFN) combined with ribavirin for 48 weeks are indicated for treatment-naive patients infected with hepatitis C virus (HCV) of genotype 1. Treatment is continued for an additional 24 weeks (72 weeks total) in the patients who have remained positive for HCV RNA detectable by the real-time polymerase chain reaction at 12 weeks after the start of treatment, but who turn negative for HCV RNA during 13–36 weeks on treatment. Re-treatment is aimed to either eradicate HCV or normalize transaminase levels for preventing the development of hepatocellular carcinoma (HCC). For patients with compensated cirrhosis, the clearance of HCV RNA is aimed toward improving histological damages and decreasing the development of HCC. The recommended therapeutic regimen is the initial daily dose of 6 million international units (MIU) IFN continued for 2–8 weeks that is extended to longer than 48 weeks, if possible. IFN dose is reduced to 3 MIU daily in patients who fail to clear HCV RNA by 12 weeks for preventing the development of HCC. Splenectomy or embolization of the splenic artery is recommended to patients with platelet counts of less than 50 × 103/mm3 prior to the commencement of IFN treatment. When the prevention of HCC is at issue, not only IFN, but also liver supportive therapy such as stronger neo-minophagen C, ursodeoxycholic acid, phlebotomy, branched chain amino acids (BCAA), either alone or in combination, are given. In patients with decompensated cirrhosis, by contrast, reversal to compensation is attempted. [ABSTRACT FROM AUTHOR]

Background and Aim: Entecavir is a potent inhibitor of both wild-type and lamivudine-resistant hepatitis B virus (HBV) with proven clinical efficacy. We conducted a randomized, double-blind, multicenter study in Japan (ETV-052) evaluating the efficacy and safety of two doses of entecavir in adult patients with lamivudine-refractory chronic hepatitis B infection. Methods: Eighty-four patients with chronic hepatitis B who were refractory to lamivudine therapy were switched from lamivudine to daily oral doses of 0.5 mg entecavir (41 patients) or 1 mg entecavir (43 patients) for 52 weeks. Results: The proportions of patients achieving the primary end-point (≥2 log10 reduction in HBV-DNA from baseline by polymerase chain reaction assay or undetectable HBV-DNA levels [<400 copies/mL] at week 48) were 90% and 93% for entecavir 0.5 mg and 1 mg, respectively, with 33% of patients in each dosing group achieving <400 copies/mL. The mean reduction in HBV-DNA from baseline was 3.58 and 3.75 log10 copies/mL for entecavir 0.5 mg and 1 mg, respectively. High proportions of patients achieved alanine aminotransferase normalization at week 48 (0.5 mg 86%, 1 mg 78%). Histological improvement was observed in most patients (0.5 mg 52%, 1 mg 60%). Virological breakthrough (increase in HBV-DNA of ≥1 log10 copies/mL from nadir) was observed in one patient but was not associated with selection of entecavir-associated resistance substitutions. Entecavir was well tolerated, with no patients discontinuing study drug due to adverse events. Conclusions: These findings indicate that entecavir is safe and effective for the treatment of Japanese adults with lamivudine-refractory chronic hepatitis B. [ABSTRACT FROM AUTHOR]

Background: The anticarcinogenic capacity of interferon (IFN) was assessed in a cohort of Japanese patients with chronic hepatitis C en masse. Patients and Methods: The rate of hepatocarcinogenesis was analyzed in 2,166 patients with chronic hepatitis C, of whom 1,654 had received IFN therapy while 512 had not. Results: Crude rates of hepatocarcinogenesis in treated and untreated patients were 2.6 and 4.6% at the end of the 5th year, 5.8 and 12.7% at the 10th year and 13.9 and 23.9% at the 15th year (after completion of IFN therapy for those treated) (p < 0.001). IFN decreased the hazard ratio of carcinogenesis to 0.42 (p < 0.001) in multivariate analysis with adjustments for significant covariates including fibrotic stage, γ-glutamyl transpeptidase level, gender, platelet count and age. Among the 1,654 patients treated with IFN, 606 (36.6%) achieved persistent loss of hepatitis C virus (HCV) RNA and an additional 266 (16.1%) gained normal levels of alanine aminotransferase without loss of HCV RNA for 6 months or longer after the completion of IFN therpay. Cumulative rates of hepatocarcinogenesis in sustained virological responders and biochemical responders were 1.4 and 2.0% at the end of the 5th year, 1.9 and 3.6% at the 10th year and 1.9 and 7.5% at the 15th year, respectively. The hazard ratio of sustained virological response was 0.10 (p < 0.001), and that of biochemical response was 0.12 (p < 0.001). Normalization of aminotransferase levels after IFN therapy without loss of serum HCV RNA decreased hepatocarcinogenesis. Conclusion: IFN significantly decreased the rate of hepatocarcinogenesis in patients with chronic hepatitis C as a whole in Japan, even in those who fail to clear HCV RNA from serum. Copyright © 2006 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background. In Japan, there are few studies of long-term (more than 1 month)interferon (IFN) therapy for chronic hepatitis B (CHB). In this retrospective study, we investigated the efficacy and predictors of response to 6-month IFN therapy. Methods. We analyzed 66 Japanese patients with CHB who were treated with IFN for 6 months. They comprised patients who were hepatitis B e antigen (HBeAg)-positive (n = 45) and -negative (n = 21). One (2%), 8 (12%), and 51 (77%) patients were infected with hepatitis B virus (HBV) genotypes A, B, and C, respectively. Responders in patients positive for HBeAg were defined as those who showed normalization of serum alanine aminotransferase (ALT) level, HBeAg loss, and HBV DNA negativity at 6 months after completion of IFN therapy. In patients negative for HBeAg, responders were defined as those patients who showed normalization of ALT level and HBV DNA negativity at the same 6-month time point. Results. Of the 45 patients with HBeAg at the commencement of IFN therapy, 9 (20%) were responders. Young patients, especially those with a high serum ALT level, were significantly more likely to respond to IFN therapy. Of the 21 patients negative for HBeAg, 13 (62%) were responders. There were no significant differences in clinical characteristics between responders and nonresponders among patients negative for HBeAg. Multivariate analyses identified HbeAg negativity and young age as independent factors associated with a positive response to 6-month IFN therapy. However, long-term follow-up of the treated patients showed a fall in the response rate. Conclusions. The response rate to 6-month IFN therapy among HbeAgpositive patients was low. However, young patients may require long-term IFN therapy. [ABSTRACT FROM AUTHOR]

The article presents a study on infection with hepatitis B virus genotype A (HBV) in Tokyo, Japan, during the period between 1976 to 2001. In the present study, 68 Japanese patients infected with HBV/A who visited Toranomon Hospital in the Tokyo metropolitan area during 1976 through 2001 were examined along with their clinicopathological characteristics and virological features. It has been found that HBV/A infection has become more frequent during recent years, predominantly presenting as acute hepatitis, while subtype A' is uncommon in the Tokyo metropolitan area.

Objective: Several reports have examined the efficacy of long-term lamivudine therapy and the risk factors involved in emergence of viral resistance in Japanese patients with hepatitis B virus (HBV) infection. However, the patient cohorts in such studies are relatively small. Methods: We analyzed 234 chronically HBV-infected Japanese patients who were treated with lamivudine for more than 12 months. They comprised patients with HBV genotype A (n = 8), genotype B (n = 21), genotype C (n = 203) and other HBV genotypes (n = 2). Results: In most patients, lamivudine resulted in normalization of alanine transaminase (ALT) levels at 6 and 12 months, and suppression of serum HBV DNA to undetectable levels by the branched chain DNA probe assay (bDNA). Rates of ALT normalization and non-detection of HBV DNA were higher among patients with genotype B than genotype C disease. The proportions of patients who achieved HBeAg loss were 27, 42 and 45% after 6 months, 1 year and 2 years, respectively. The emergence of mutations was not different among genotypes A, B and C by the Kaplan-Meier method. Multivariate analyses identified high HBV DNA level (bDNA ≥ 100 MEq/ml) as an independent factor associated with emergence of the YMDD motif mutation in all patients. Among patients with genotype C disease, which is the predominant HBV genotype in Japan, multivariate analysis also identified high HBV DNA level and HBeAg positivity as factors associated with emergence of resistance. Conclusion: Patients exhibiting these factors at the commencement of lamivudine treatment must be monitored carefully at regular intervals for emergence of viral resistance. [ABSTRACT FROM AUTHOR]

Investigates the role of interferon (IFN) in cancer prevention in liver cirrhosis type C en masse on Japanese patients in Japan. Efficacy of IFN in reducing serum alanine aminotransferase and hepatitis C virus; Factors affecting hepatocellular carcinogenesis; Rates of crude hepatocellular carcinogenesis.

Studies serum thrombopoietin levels in patients with chronic hepatitis and liver cirrhosis by researchers from Japan. Presentation of thrombocytopenia as a manifestation of cirrhosis; Examination of the relationship between serum thrombopoietin concentrations, circulating platelet levels and the stage of hepatic fibrosis in patients with chronic viral hepatitis; Indications showing an elevation of serum thrombopoietin levels in patients with an early stage of chronic viral hepatitis.

Introduction: It is unclear whether the relationships between changes in fibrosis and circulating microRNA-122 (miR-122) dynamics might influence the prognosis of nonalcoholic fatty liver disease (NAFLD)., Methods: This study investigates the impact of serum miR-122 dynamics and histological changes on the incidence of liver cancer and mortality in 81 Japanese NAFLD patients who underwent serial liver biopsies. The median interval between the first and second liver biopsies was 2.9 years., Results: The fibrosis stage scores indicated progression, no change, and improvement (a decrease of one point or more) in 21.0%, 56.8%, and 22.2% of the patients, respectively. There were 64 patients in the high-risk group who had no improvement in stage scores. Among these, the miR-122 levels were significantly lower in 7 patients with liver cancer than those of the 54 patients who had no liver cancer at the second liver biopsy. The cumulative rates of liver cancer were significantly higher in cases with miR-122 ratios <0.5 (serum miR-122 level at second biopsy to that at first biopsy) than those with ratios ≥0.5. The cumulative survival rates in cases with miR-122 ratios <0.5 tended to be lower than those with ratios ≥0.5. Of the 64 high-risk patients, 39 indicated stage 2 or greater (severe fibrosis stage) at the first liver biopsy and also showed similar results of cumulative liver cancer and survival rates., Conclusions: Longitudinal examination of serial liver biopsies indicated that the circulating miR-122 dynamics might be useful in predicting the prognosis for NAFLD patients with severe fibrosis stage and no improvement of the stage scores., (© 2021 The Author(s). Published by S. Karger AG, Basel.)

Background: Reliable noninvasive predictors of the top three causes of death [cardiovascular diseases (CVDs), malignancies, and liver-related events in patients with non-alcoholic fatty liver disease (NAFLD)] have not yet been determined., Methods: We retrospectively investigated the incidence of three complications [CVDs, malignancy (except for liver cancer), and liver-related events] in 477 Japanese patients with histo-pathologically confirmed NAFLD for a median follow-up of 5.9 years. In addition to histological findings, we also investigated noninvasive predictors., Results: A score of ≥ 2.67 for the noninvasive diagnosis of stage 4 fibrosis based on the Fibrosis-4 (FIB-4) index indicated a high level area under the receiver operating characteristic (AUROC) curve (0.90), sensitivity (82.9%), specificity (86.4%), and negative predictive value [(NPV) of 98.5%]. The yearly incidence rates of CVDs, malignancies, and liver-related events were found to be 1.04%, 0.83%, and 0.30%, respectively. Multivariate analysis identified a FIB-4 index ≥ 2.67 score as a significant and independent, noninvasive predictor of these three complications. Furthermore, the cumulative incidence rates of CVDs were significantly different among the three genotypes of PNPLA3. PNPLA3 genotype CC, chronic kidney disease (CKD), and FIB-4 index ≥ 2.67 was could be attributed to these three significant CVD risk factors. The rates of CVDs were significantly different among the three subgroups based on the combination of risk factors. In malignancy (except for liver cancer), the incidence rate of colon cancer was 25.0%; in particular, the rate in females was 53.8%., Conclusions: Our results highlighted the importance of the PNPLA3 genotype and FIB-4 index ≥ 2.67 on the incidence of complications in Japanese patients with NAFLD, especially the incidence of CVDs. Early diagnosis, based on the presence of one or more risk factors, and early treatment might improve the prognosis for NAFLD patients., (© 2021. The Author(s).)

Objective The aim of this study was to determine the long-term effects of a sodium-glucose cotransporter 2 inhibitor (SGLT2i) in nonalcoholic fatty liver disease (NAFLD) patients with type 2 diabetes mellitus (T2DM) on the clinical features and liver histopathology. Methods In this retrospective study, the long-term histological impacts of SGLT2i in NAFLD patients with T2DM were investigated. Patients Seven patients with NAFLD and T2DM were treated for the long term with 100 mg/day canagliflozin, an SGLT2i, and liver biopsies were obtained at the 3 points of pretreatment, 24 weeks, and ≥1 year (third liver biopsy) after the start of treatment. Six of seven patients were evaluated with third liver biopsy at the point of three or more years. The primary outcome was liver histopathological changes (defined as a decrease in the NAFLD activity score of one point or more without worsening of the fibrosis stage, compared to pretreatment). Results All 7 patients showed worsening of body mass index and waist circumference at the third liver biopsy compared to 24 weeks. However, the scores of steatosis, lobular inflammation, ballooning, and fibrosis stage improved at the third liver biopsy in 57%, 43%, 14%, and 29% of the patients, respectively, compared to pretreatment. One of the seven patients showed histopathological worsening at the third liver biopsy compared to pretreatment, but the improvement was maintained in the other six patients. Conclusion The long-term treatment of NAFLD complicated by T2DM using an SGLT2i is associated with long-term improvement in liver histopathology despite the worsening of clinical features.

Objective The correlation between the insulin secretion levels and the risk of hepatocarcinogenesis is clinically important. The aim of the present study was to determine the effects of various clinical parameters on C-peptide (CPR) levels in patients with non-alcoholic fatty liver disease (NAFLD). Methods In this retrospective cohort study, the effects of clinical parameters on insulin resistance (HOMA-IR) and insulin secretion levels (HOMA-β and fasting CPR) were investigated. Patients A total of 244 Japanese patients with histopathologically confirmed NAFLD were evaluated. Of these, 77 underwent the meal tolerance test (MTT) to evaluate the association of various clinical parameters with the CPR levels at 120 minutes. Results A multivariate analysis identified fasting plasma glucose (FPG) (≥110 mg/dL), aspartate aminotransferase (≥1.0×ULN IU/L), and a large waist circumference as independent predictors of insulin resistance (HOMA-IR ≥2.5) or high fasting CPR levels. Significant parameters for a low insulin secretion capacity (HOMA-β <30%) were not detected, except for the parameters mentioned in the diagnostic criteria of diabetes mellitus. Regarding the MTT, the CPR levels at 120 minutes were significantly higher in patients with fibrosis stage 3-4 than in those with stage 0-2. Body composition and genetic variation did not affect the CPR levels at 120 minutes. A multivariate analysis identified fibrosis stage (3-4), hyperuricemia, FPG (≥110 mg/dL), and procollagen III peptide (>1.0 U/mL) as independent predictors of high CPR levels at 120 minutes. Conclusion The present study showed that high plasma glucose levels and severe liver fibrosis stage influence insulin secretion levels in Japanese patients with NAFLD. Conservation of delayed insulin secretion levels was confirmed in patients with severe liver fibrosis.

Background: Safety and effectiveness of daclatasvir (DCV)/asunaprevir (ASV) dual therapy were demonstrated in Japanese patients with chronic hepatitis C (CHC) genotype (GT) 1b in phase III studies. This postmarketing surveillance (PMS) was conducted to assess the safety and effectiveness of DCV/ASV in Japanese patients with GT-1 CHC treated in routine clinical practice., Methods: This PMS was conducted between September 2014 and February 2017 at 261 centers in Japan. Patients with GT-1 CHC with or without compensated cirrhosis starting DCV and ASV dual therapy were observed from treatment initiation until 24 weeks after completing treatment. Safety and effectiveness assessments included incidence of adverse drug reactions (ADRs) and sustained viral response (SVR) rates at 24 weeks (SVR24)., Results: Of 2820 patients (median age, 71.0 years; ≥ 65 years, 73.1%; female, 56.1%; with compensated cirrhosis, 39.1%) in the safety population, 726 (25.7%) experienced 1063 ADRs and 47 (1.7%) experienced 55 serious ADRs. Overall, 532 hepatic ADRs were reported; most hepatic ADRs occurred between > 4 and ≤ 12 weeks after treatment initiation. Subgroup analysis showed a higher incidence of ADRs in female, elderly, underweight, and renal function-impaired patients. SVR24 and SVR at 12 weeks (SVR12) were 87.3% (2216/2538) and 88.4% (2284/2584), respectively. Patients without (SVR12, 89.1%; SVR24, 87.9%) and with (SVR12, 87.3%; SVR24, 86.3%) compensated cirrhosis had similar SVR rates., Conclusion: Results from this large PMS indicate that DCV and ASV dual therapy is generally well tolerated and effective in routine clinical practice in Japanese patients with GT-1 CHC with or without compensated cirrhosis.

Background & Aims: It is important to investigate the treatment outcomes in patients excluded from clinical trials (CTR). The aims of this study were to evaluate the efficacy and safety of a 24-week daclatasvir (DCV) and asunaprevir (ASV) therapy for patients with chronic hepatitis C virus (HCV)-1b infection., Methods: A total of 651 HCV-1b patients started dual oral therapy with DCV and ASV for 24 weeks in Toranomon Hospital, Tokyo. Among them, 276 patients met phase III CTR inclusion criteria. The sustained virological response (SVR) rate after treatment and the adverse events during therapy were compared between CTR-met (patients who met the inclusion criteria) and CTR-unmet (patients who did not meet the inclusion criteria) groups., Results: SVR12 was achieved in 87.0% (240/276) and 86.7% (325/375) in CTR-met and CTR-unmet patients respectively. SVR12 rate in simeprevir-experienced patients was 52.9% (9/17). SVR12 rate in patients without resistance-associated variant (RAV) of NS3 or NS5A loci was 93.7% (416/444). However, the SVR12 rates in patients with NS3-D168, NS5A-L31 and Y93 single RAV at baseline were 55.0% (11/20), 73.9% (17/23) and 65.6% (63/96) respectively. The safety profiles in both CTR-met and CTR-unmet patients were similar. The discontinuation rate as a result of alanine aminotransferase (ALT) elevation was only 2.9%. Seven (2.5%) patients in CTR-met group and 20 (5.3%) in CTR-unmet group discontinued therapy because of adverse events other than the ALT elevation., Conclusions: Dual oral therapy with DCV and ASV in real-life settings was well tolerated with a similar safety profile and achieved similar SVR12 rates as that of CTR., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background & Aims: Genome-wide association studies (GWAS) recently indicated that polymorphisms in the human leucocyte antigen (HLA)-DP genes were associated with risk of persistent hepatitis B virus (HBV) infection and clearance of HBV, but the effect of HLA-DP gene polymorphisms on the effect of antiviral therapy was unknown. We here investigated whether such polymorphisms were associated with decreases in HBsAg levels and seroclearance in patients who received long-term lamivudine (LAM) treatment., Methods: Japanese patients (202) who were hepatitis B e antigen positive at baseline, received LAM as first-line treatment, and consented to HLA-DP genotyping (HLA-DPA1 rs3077 and HLA-DPB1 rs9277535) were categorized into two cohorts, viz., a cohort who achieved virological response without rescue therapy (cohort 1) and those who did so with rescue therapy (cohort 2)., Results: Serum HBsAg levels declined significantly between year 3 and 9 from baseline among cohort 1 patients possessing ≥2 A-alleles at rs3077 and rs9277535. The percentages of such patients in cohort 1 patients with decreases in HBsAg ≥0.5 log IU/ml were higher than those with <2 A-alleles (71.8% [28/39] vs. 38.9% [23/59]; P = 0.004). However, there was no significant difference in cumulative HBsAg seroclearance rates between patients with ≥2 and those with <2 A-alleles in cohort 1. In cohort 2, HBsAg seroclearance rates were higher in patients with ≥2 A-alleles than in those with <2 A-alleles (P = 0.003)., Conclusion: We found an association between HLA-DP polymorphisms and decreases in HBsAg levels and seroclearance among HBeAg-positive patients treated with LAM., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background and Aim: Currently, non-alcoholic steatohepatitis (NASH) can only be diagnosed histopathologically. Our objective was to establish a new scoring system for the fibrotic stage of NASH., Methods: We enrolled 139 patients with histologically proven NASH and divided them into two groups to construct (n = 90) and validate (n = 49) a fibrotic score for NASH (FSN). We used 17 variables and their natural logarithmic transformations in the multivariate analysis. To assess the accuracy of the FSN in determining NASH advanced fibrosis (stages 3-4), we compared various fibrotic scores for NASH., Results: In the construct group, multivariate regression analysis ultimately obtained the following function: z = 1.022 × ln (type IV collagen 7S) (ng/mL) - 0.00680 × (platelet count) (×10(9)/L) + 1.925 × ln (AST) (IU/L) - 1.239 × ln (ALT) (IU/L) + 0.249. Median values of the FSN for stages 1, 2, 3 and 4 were 1.87, 2.14, 3.26 and 3.89, respectively. The multiple regression coefficient and coefficient of determination were 0.70 and 0.46, respectively. In the validation group, the median value was 2.00, 2.83, 3.08 and 4.37 in each stage. With regard to the utility of the FSN for predicting advanced fibrosis of NASH (stage ≥3), the area under the receiver operating characteristic curves (AUROC), 0.909 (95% CI 0.847-0.970, p < 0.001), was higher than that for the other fibrotic scores (APRI, NAFLD fibrosis score, FIB-4 index, BARD score, NIKEI) in the construct group., Conclusions: This simple scoring system accurately predicts fibrotic stage and discriminates patients with advanced fibrosis of NASH.

Objective: The aim of this study was to clarify the indications for oral glucose tolerance tests (OGTT) in non-alcoholic fatty liver disease (NAFLD) subjects with a HbA1c level of ≤6.4%, fasting plasma glucose (FPG) level of <126 mg/dL and no history of diabetes., Patients: A total of 569 NAFLD subjects underwent 75-g OGTT. The plasma glucose and insulin levels were analyzed periodically for three hours during the OGTT examinations. Impaired fasting glucose (IFG) was defined as a plasma glucose level of ≥100 mg/dL to <126 mg/dL. Diabetes was defined as a two-hour post-load plasma glucose level of ≥200 mg/dL. Elevated insulin resistance was defined as a homeostasis model assessment-insulin resistance (HOMA-IR) of ≥2.5. Insulin secretory insufficiency was defined as an insulinogenic index of <0.4., Results: The prevalence of diabetes on the OGTT was 7.7% (44/569) among the NAFLD patients with an HbA1c level of ≤6.4%, FPG level of <126 mg/dL and no history of diabetes. A multivariate analysis showed that diabetes occurred more frequently when the subjects had IFG [odds ratio (OR) 5.13; 95% confidential interval (CI) 3.01-8.76; p<0.001] and an HbA1c level of 5.7-6.4% (OR 5.45; 95% CI 3.33-8.93; p<0.001). Of the NAFLD subjects with both IFG and an HbA1c level of 5.7-6.4%, 22.8% (28/123) exhibited a pattern of diabetes on OGTT. Regarding insulin dynamics, among the NAFLD subjects with both IFG and an HbA1c level of 5.7-6.4%, 25.2% (31/123) had elevated IR alone, 25.2% (31/123) had insulin secretory deficiency alone and 27.6% (34/123) had both elevated insulin resistance and insulin secretory deficiency., Conclusion: NAFLD subjects with IFG and an HbA1c level of 5.7-6.4% should undergo OGTT in order to determine whether they have diabetes and/or abnormal insulin dynamics.

Using ultra-deep sequencing technology, the present study was designed to investigate the evolution of simeprevir-resistant variants (amino acid substitutions of aa80, aa155, aa156, and aa168 positions in HCV NS3 region) over time. In Toranomon Hospital, 18 Japanese patients infected with HCV genotype 1b, received triple therapy of simeprevir/PEG-IFN/ribavirin (DRAGON or CONCERT study). Sustained virological response rate was 67%, and that was significantly higher in patients with IL28B rs8099917 TT than in those with non-TT. Six patients, who did not achieve sustained virological response, were tested for resistant variants by ultra-deep sequencing, at the baseline, at the time of re-elevation of viral loads, and at 96 weeks after the completion of treatment. Twelve of 18 resistant variants, detected at re-elevation of viral load, were de novo resistant variants. Ten of 12 de novo resistant variants become undetectable over time, and that five of seven resistant variants, detected at baseline, persisted over time. In one patient, variants of Q80R at baseline (0.3%) increased at 96-week after the cessation of treatment (10.2%), and de novo resistant variants of D168E (0.3%) also increased at 96-week after the cessation of treatment (9.7%). In conclusion, the present study indicates that the emergence of simeprevir-resistant variants after the start of treatment could not be predicted at baseline, and the majority of de novo resistant variants become undetectable over time. Further large-scale prospective studies should be performed to investigate the clinical utility in detecting simeprevir-resistant variants., (© 2014 Wiley Periodicals, Inc.)

Background: Rate of hepatitis B surface antigen (HBsAg) seroclearance was determined in 2,112 Japanese patients with chronic hepatitis B who were followed up for at least 15 years., Methods: Patients had a median age of 37 years and included 1,431 (67.8 %) men. Median values were AST/ALT, 43/62 IU/L; platelet counts, 182 × 10(3)/mm(3); HBsAg, 3,400 IU/mL; and hepatitis B virus (HBV) DNA, 6.2 log copies/mL. Factors influencing HBsAg seroclearance were evaluated by the Cox proportional model and annual rate of HBsAg seroclearance by the Kaplan-Meier life table method., Results: The overall annual rate of HBsAg seroclearance was 1.75 % in 2,112 patients; it was 1.65 % in 1,130 untreated and 2.05 % in 982 treated patients (p = 0.289). In untreated patients, seroclearance was influenced by age, no HBV infections in third-degree or closer relatives, and HBsAg levels in univariate analysis. Seroclearance was influenced by a median age ≥50 years [relative risk (RR) 1.61 (p = 0.018)] and HBsAg ≤2,000 IU/mL [RR 1.77 (p = 0.014)] in multivariate analysis. In treated patients, age, male gender, no HBV infections in third-degree or closer relatives, interferon therapy, chronic hepatitis, high AST and γ-GTP levels, low platelet counts, hepatitis B e antigen (HBeAg)-negative status, low HBsAg levels and the wild-type precore sequence significantly influenced HBsAg seroclearance. In multivariate analysis, no family history [RR 2.22 (p = 0.006)], interferon treatment [RR 3.15 (p < 0.001)], and HBeAg-negative status [RR 3.75 (p < 0.001)] significantly influenced HBsAg seroclearance., Conclusions: In this retrospective cohort study, the annual rate of HBsAg seroclearance was 1.65 % in untreated patients and 2.05 % in treated patients.

The aim of this retrospective cohort study was to assess the cumulative incidence and predictive factors for intracerebral hemorrhagic stroke after the termination of interferon (IFN) therapy in Japanese patients with hepatitis C virus (HCV). A total of 4,649 HCV-positive patients treated with IFN were enrolled. The primary goal is the first onset of intracerebral hemorrhagic stroke. The mean observation period was 8.0 years. Evaluation was performed using the Kaplan-Meier method and the Cox proportional hazard model. A P-value of less than 0.05 was considered statistically significant. A total of 28 developed intracerebral hemorrhagic stroke. The cumulative incidence of intracerebral hemorrhagic stroke was 0.3% at 5 years, 0.8% at 10 years, and 1.7% at 15 years. Intracerebral hemorrhagic stroke occurred when patients had age increments of 10 years (hazard ratio: 2.77; 95% confidence interval (CI) 1.48-5.18; P = 0.001), hypertension (hazard ratio: 2.30; 95% CI 1.09-4.83; P = 0.021), liver cirrhosis (hazard ratio: 4.50; 95% CI 2.07-9.78; P < 0.001), and HCV non-clearance (hazard ratio: 3.22; 95% CI 1.22-8.53; P = 0.018). On the intracerebral hemorrhagic stroke based on the difference of liver fibrosis and efficacy of IFN therapy, HCV clearance reduced to 24.3% (1/4.11) compared to HCV non-clearance in cirrhotic patients (P = 0.040). In conclusion, HCV clearance reduced the development of intracerebral hemorrhagic stroke. In particular, HCV clearance reduced intracerebral hemorrhagic stroke to about one-fourth in cirrhotic patients., (© 2013 Wiley Periodicals, Inc.)

The clinical usefulness of detecting telaprevir-resistant variants is unclear. Two hundred fifty-two Japanese patients infected with hepatitis C virus (HCV) genotype 1b received triple therapy with telaprevir-peginterferon (PEG-IFN)-ribavirin and were evaluated for telaprevir-resistant variants by direct sequencing at baseline and at the time of reelevation of the viral load. An analysis of the entire group indicated that 76% achieved a sustained virological response. Multivariate analysis identified a PEG-IFN dose of <1.3 μg/kg of body weight, an IL28B rs8099917 genotype (genotype non-TT), detection of telaprevir-resistant variants of amino acid (aa) 54 at baseline, nonresponse to prior treatment, and a leukocyte count of <5,000/mm(3) as significant pretreatment factors for detection of telaprevir-resistant variants at the time of reelevation of the viral load. In 63 patients who showed nonresponse to prior treatment, a higher proportion of patients with no detected telaprevir-resistant variants at baseline (54%) achieved a sustained virological response than did patients with detected telaprevir-resistant variants at baseline (0%). Furthermore, 2 patients who did not have a sustained virological response from the first course of triple therapy with telaprevir received a second course of triple therapy with telaprevir. These patients achieved a sustained virological response by the second course despite the persistence of very-high-frequency variants (98.1% for V36C) or a history of the emergence of variants (0.2% for R155Q and 0.2% for A156T) by ultradeep sequencing. In conclusion, this study indicates that the presence of telaprevir-resistant variants at the time of reelevation of viral load can be predicted by a combination of host, viral, and treatment factors. The presence of resistant variants at baseline might partly affect treatment efficacy, especially in those with nonresponse to prior treatment.

The prevalence of hepatitis C virus (HCV) infection in elderly patients has been increasing in Japan. However, there are no reports on the safety and efficacy of the triple therapy of telaprevir, peginterferon, and ribavirin for elderly patients with chronic HCV infection. This study evaluated the safety and efficacy of triple therapy [12 weeks of telaprevir 1,500 mg/day, reduction dose, and 24 weeks of peginterferon and ribavirin] in 18 elderly Japanese patients aged >65 years, with chronic infection with HCV genotype 1b. Four patients received triple therapy with telaprevir 2,250 mg/day and the other 14 patients received telaprevir 1,500 mg/day. Sustained virological response-12 (HCV RNA negativity at 12 weeks after completion of therapy) was 50% (9 of 18 patients); while 4 of 18 (22%) patients discontinued triple therapy due to adverse events (skin rashes, anemia, poor appetite). The dose of telaprevir did not affect HCV RNA clearance rates. Regardless of the dose, 50% of the treated patients achieved sustained virological response-12, evaluated by intention-to-treat analysis. Furthermore, the fall in hemoglobin and the rise in serum creatinine were significantly milder in the telaprevir 1,500 mg group than the telaprevir 2,250 mg/day group. Further analysis showed that 67% (6 of 9 elderly patients) with IL28B gene (rs8099917) genotype TT, treated with telaprevir 1,500 mg, achieved sustained virological response-12. These results suggest that 24-week triple therapy with telaprevir 1,500 mg seems safe and efficacious for elderly Japanese patients infected with HCV genotype 1b., (Copyright © 2013 Wiley Periodicals, Inc.)

The impacts of IL28B genotype to treatment response of hepatitis C virus (HCV) genotype 2 are still not clear. A total of 381 consecutive Japanese patients infected with HCV genotype 2, who could complete combination therapy with interferon (IFN) plus ribavirin for 24 weeks, were evaluated to investigate pretreatment predictors. Patients, who could not achieve sustained virological response at the first course of 24-week IFN plus ribavirin, were recruited into the study protocol of total 48-week IFN plus ribavirin. In 24-week regimen, rates of sustained virological response and rapid virological response were 82% and 50%, respectively. There were no significant differences in rates of sustained virological response and rapid virological response, according to IL28B genotype. Multivariate analysis identified younger age, higher level of albumin, absence of past history of IFN, and lower level of viremia as significant determinants of sustained virological response. As significant or marginal significant determinants of non-sustained virological response regardless of rapid virological response, multivariate analysis identified IL28B rs8099917 genotype TG + GG and lower level of albumin. In 48-week regimen to 10 patients of non-sustained virological response at the first course of 24-week regimen, sustained virological response rates were 70%. All of six patients, with IL28B TT and relapse at the first course of 24-week regimen, could achieve sustained virological response, but two patients with IL28B TG could not achieve sustained virological response. In conclusion, the present results suggest that IL28B genotype might partly affect viral response of HCV genotype 2 to combination therapy., (Copyright © 2012 Wiley Periodicals, Inc.)

Patients who do not achieve sustained virological response to telaprevir/peginterferon (PEG-IFN)/ribavirin need to be identified. Predictive factors of virological response to the triple therapy in non-responders to previous PEG-IFN/ribavirin therapy are not clear. The aims of this study were to determine the predictive factors of virological response to a 24-week regimen of triple therapy in 15 non-responders to previous PEG-IFN/ribavirin therapy among 61 Japanese adults infected with HCV genotype 1. Overall, sustained virological response and end-of-treatment response were achieved by 27% and 60%, respectively. Telaprevir-resistant variants (by direct sequencing) appeared during or after treatment in 82% of patients who did not show sustained virological response, but disappeared at the end of study, except for one patient with resistant variant at baseline. Substitution at aa 70 (Arg70) and type of previous response to PEG-IFN/ribavirin (partial response) were identified as significant determinants of sustained virological response. In addition, alpha-fetoprotein level (<10 µg/L) and type of previous response (partial response) were identified as significant determinants of end-of-treatment response. Prediction of response to therapy based on the combination of these factors had high sensitivity, specificity, positive, and negative predictive values. In conclusion, this study identified amino acid substitution of the core region, alpha-fetoprotein level, and type of previous response as predictors of virological response to telaprevir/PEG-IFN/ribavirin in patients infected with HCV genotype 1b who had not responded to previous PEG-IFN/ribavirin therapy., (Copyright © 2012 Wiley Periodicals, Inc.)

Background: Stage progression of 374 small hepatocellular carcinomas (HCC) was retrospectively analysed., Patients and Methods: During 8 years, 236 patients with the early stage of HCC received radiofrequency ablation (RFA), and 138 underwent surgery as an initial therapy. More patients of young age and with better liver function tended to undergo surgical treatment. Based on 1892 patient-year data, the Markov model analysed the stepwise progression of early stage (multiple up to three nodules, 3 cm or less each) to intermediate stage (four nodules or more, or larger than 3 cm), to advanced stage (portal invasion, extrahepatic metastasis or Child-Pugh C) and to death., Results: The recurrence rates after RFA and surgery were 53.3 and 40.6% in the third year. The annual progression rates from the early stage to the intermediate stage, advanced stage and death were 5.40, 1.63 and 1.73% in the RFA group and 3.90, 1.87 and 0.62% in the surgery group respectively. The progression rate from the early to the intermediate stage was significantly lower (2.34% annually) in the younger patient group (<60 years) than that in the older group (≥ 60 years, 5.70%, P=0.0053). In contrast, the progression rate from the intermediate to the advanced stage was significantly higher in the younger patient group (<60 years, 37.50% annually) than that in the older groups (60-69 years, 30.30%, 70 years or older 22.09%, P=0.0011). Multivariate hazard analysis showed that initial treatment did not significantly affect the stage progression rate (hazard ratio of RFA 1.09, P=0.70) and the survival rate (hazard ratio of RFA 1.09, P=0.73)., Conclusion: Although the recurrence rate was slightly higher in the RFA group, additional ablation procedures could control the progression of HCC, with a rate comparable to the surgical group., (© 2011 John Wiley & Sons A/S.)

Objective Chronic kidney disease (CKD) is present in patients with nonalcoholic fatty liver disease (NAFLD). The aim of this retrospective study was to assess the cumulative development incidence and predictive factors for new onset of CKD in Japanese patients with NAFLD. Methods A total of 5,561 NAFLD patients without CKD were enrolled. CKD was defined as either an estimated glomerular filtration rate of <60 mL/min/1.73 m(2) or dipstick proteinuria (≥+1). A blood sample and a urine sample were taken for routine analyses during follow-up. The mean observation period was 5.5 years. The primary goal is the new development of CKD. Independent factors associated with new development of CKD were analyzed by using the Kaplan-Meyer method and the Cox proportional hazards model. Results Of 5.561 NAFLD patients, 263 patients developed CKD. The cumulative development rate of CKD was 3.1% at the 5th year and 12.2% at the 10th year. Multivariate Cox proportional hazards analysis showed that CKD development in patients with NAFLD occurred when patient had low level of GFR of 60-75 mL/min/1.73 m(2) [hazard ratio:2.75; 95% confidence interval (CI)=1.93-3.94; p<0.001], age of ≥50 years (hazard ratio: 2.67; 95% CI=2.06-3.46; p<0.001), diabetes (hazard ratio: 1.92; 95% CI=1.45-2.54; p<0.001), hypertension (hazard ratio: 1.69; 95% CI=1.25-2.29; p<0.001), and elevated serum gamma-glutamyltransferase of ≥109 IU/L (hazard ratio: 1.35; 95% CI=1.02-1.78; p=0.038). Conclusion Our retrospective study indicates that the annual incidence of CKD in Japanese patients with NAFLD is about 1.2%. Five factors of low eGFR level, aging, type 2 diabetes, hypertension, and elevated gamma-glutamyltransferase, increases the risk of the development of CKD.

Background/aims: The recurrence rate of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) is high even in patients receiving curative therapy. In this study, we analysed the risk factors for tumour recurrence after curative therapy for HBV-related HCC while under treatment with nucleot(s)ide analogues (NAs) by measuring serum HBcrAg and intrahepatic covalently closed circular DNA (cccDNA) levels to elucidate the viral status associated with HCC recurrence., Methods: We enrolled 55 patients who developed HCC during NA therapy and underwent either curative resection or percutaneous ablation for HCC., Results: Hepatocellular carcinoma recurred in 21 (38%) of the patients over a period of 2.2 (range, 0.2-7.4) years. In multivariate analysis, serum HBcrAg levels ≥4.8 log U/ml at the time of HCC diagnosis (hazard ratio, 8.96; 95% confidential interval, 1.94-41.4) and portal vein invasion (3.94, 1.25-12.4) were independent factors for HCC recurrence. The recurrence-free survival rates of the high cccDNA group were significantly lower than those of the low cccDNA group only in patients who underwent resection (P=0.0438). A positive correlation (P=0.028; r=0.479) was observed between the intrahepatic cccDNA and the serum HBcrAg levels at the incidence of HCC., Conclusion: HBcrAg is a predictor of the post-treatment recurrence of HCC during antiviral therapy. Serum HBcrAg and intrahepatic cccDNA suppression by NAs may be important to prevent HCC recurrence., (© 2010 John Wiley & Sons A/S.)

Background and Aims: To assess the efficacy of switching Japanese chronic hepatitis B patients from lamivudine monotherapy to entecavir 0.5 mg/day., Methods: A retrospective analysis was conducted on 134 patients switched to entecavir between September 2006 and February 2008 for 6 months or more. Patients were divided into three groups based on viral load at entecavir switching point (baseline < 2.6, 2.6-5.0 and > 5.0 log(10) copies/mL)., Results: At baseline, detection of lamivudine-resistant virus was highest in patients with higher hepatitis B virus (HBV) DNA (76% vs 23% in > or = 2.6 and < 2.6 log(10) copies/mL, respectively), and in patients with longest previous exposure to lamivudine (52%, 28% and 24% for > 3 years, 1-3 years and < 1 year, respectively). Two years after entecavir switching, HBV DNA suppression to less than 2.6 log(10) copies/mL was achieved in 100% (32/32), 92% (12/13) and 44% (4/9) of patients in the less than 2.6, 2.6-5.0 and more than 5.0 log(10) copies/mL baseline groups, respectively. Alanine aminotransferase (ALT) normalization occurred in 76-96% and 90-100% of patients following 1 and 2 years of entecavir treatment, respectively. One patient (2.6-5.0 log(10) copies/mL) with lamivudine-resistant mutants at baseline developed entecavir resistance at week 48 during follow up., Conclusion: Switching to entecavir 0.5 mg/day achieves or maintains undetectable HBV DNA levels and ALT normalization over 2 years, especially in patients with viral load less than 5.0 log(10) copies/mL.

Previous studies provided a direct experimental evidence for the contribution of HCV core protein in the development of insulin resistance (IR), but the clinical impact of HCV core region on IR is still not clear. The present study evaluated the impact of Amino acid (aa) substitutions of HCV-1b core region on IR in 123 Japanese patients infected with HCV-1b without cirrhosis and diabetes mellitus, and investigated the treatment efficacy of 48-week pegylated interferon (PEG-IFN) plus ribavirin (RBV) according to HOMA-IR values. Patients with IR (HOMA-IR > or = 2.5) and severe IR (HOMA-IR > or = 3.5) were present in 51.2% and 27.6%, respectively. Multivariate analysis identified body mass index (> or = 25 kg/m(2)) and hepatocyte steatosis (> or = 5%) as significant determinants of IR. Furthermore, multivariate analysis identified hepatocyte steatosis (> or = 5%), aa substitutions of the core region (Gln70 (His70) and/or Met91), and age (> or = 55 years) as significant determinants of severe IR. Especially, significantly lower proportions of patients with Gln70 (His70) and/or Met91 were noted among those without severe IR (59.6%) than those with severe IR (82.4%). The rates of sustained virological response in patients with IR (50.0%) were not significantly different from those without IR (52.9%). Furthermore, the rates of non-virological response in patients with IR (28.9%) were not significantly also different from those without IR (20.6%). In conclusion, the present study indicated that substitutions of HCV-1b core region were the important predictor of severe IR in patients without cirrhosis and diabetes mellitus, but HOMA-IR values might be not useful as predictors of 48-week PEG-IFN plus RBV therapy.

Background: The significance of antiviral therapy for elderly patients with chronic hepatitis C virus (HCV) infection has not been elucidated., Patients and Methods: Among 5645 patients with HCV-related chronic liver disease, the prognosis of 1917 elderly patients aged 60 years or more was analyzed. A total of 454 patients underwent interferon (IFN) therapy. By using multivariate analysis, carcinogenesis and survival were analyzed according to initial findings., Results: At 10 and 15 years, cumulative survivals in untreated elderly patients were 90.7% and 72.7% in the high platelet (>or=150,000/mm(3)) group, 78.6% and 47.8% in the intermediate (100,000-149,000/mm(3)) group, and 52.5% and 25.0% in the low platelet group (<100,000/mm(3)), respectively. At 5 and 10 years, hepatocarcinogenesis rates in the intermediate and low platelet groups were 10.9% and 21.6% in the IFN group (N=217) and 19.5% and 43.0% in the untreated group (N=459), respectively (P=.0005). IFN independently decreased carcinogenesis risk with a hazard ratio of 0.56 (P=.035). In the high platelet group, 5- and 10-year carcinogenesis rates were 3.7% and 8.3% in the IFN-treated group (N=228) and 5.1% and 14.0% in the untreated group (N=585), respectively (P=.69). IFN treatment significantly increased cumulative survivals in the lower platelet subgroup (P=.0001) but did not affect the higher platelet subgroup (P=.08). IFN was independently associated with a longer survival in the lower platelet subgroup (hazard ratio 2.33, P=.005)., Conclusion: In elderly patients with chronic HCV, IFN for a subgroup with intermediate and low platelet counts had significant advantages in regard to hepatocarcinogenesis and survival.

Unlabelled: Diabetes is present in patients with chronic hepatitis C virus infection. The aim of this retrospective cohort study was to assess the cumulative development incidence and predictive factors for type 2 diabetes after the termination of interferon therapy in Japanese patients positive for hepatitis C virus (HCV). A total of 2,842 HCV-positive patients treated with interferon (IFN) monotherapy or combination therapy with IFN and ribavirin were enrolled. The mean observation period was 6.4 years. An overnight (12-hour) fasting blood sample or a casual blood sample was taken for routine analyses during follow-up. The primary goal was the onset of type 2 diabetes. Evaluation was performed by using the Kaplan-Meier method and Cox proportional hazard analysis. Of 2,842 HCV patients, 143 patients developed type 2 diabetes. The cumulative development rate of type 2 diabetes was 3.6% at 5 years, 8.0% at 10 years, and 17.0% at 15 years. Multivariate Cox proportional hazard analysis revealed that type 2 diabetes development after the termination of IFN therapy occurred when histological staging was advanced (hazard ratio 3.30; 95% confidence interval [CI] 2.06-5.28; P < 0.001), sustained virological response was not achieved (hazard ratio 2.73; 95% CI 1.77-4.20; P < 0.001), the patient had pre-diabetes (hazard ratio 2.19; 95% CI 1.43-3.37; P < 0.001), and age was >or=50 years (hazard ratio 2.10; 95% CI 1.38-3.18; P < 0.001)., Conclusion: Our results indicate sustained virological response causes a two-thirds reduction in the risk of type 2 diabetes development in HCV-positive patients treated with IFN.