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Background and Aim: Liver function can be improved in patients with chronic hepatitis C virus (HCV) infection who achieved sustained virologic response (SVR) with direct-acting antiviral (DAA) treatment. However, to our knowledge, the impact of liver function improvement after SVR on prognosis has not been investigated., Methods: A total of 716 patients with chronic HCV infection and compensated advanced liver fibrosis who began receiving DAA treatment between September 2014 and August 2018 in 25 Japanese hospitals and achieved SVR were enrolled., Results: The median age was 73 years, and 336 (47%) and 380 (53%) patients had albumin-bilirubin (ALBI) grade 1 and grade 2, respectively. Improvement to ALBI grade 1 at 1 year after the end of treatment (EOT) was observed in 76% of the patients with baseline ALBI grade 2. Among 380 patients with baseline ALBI grade 2, alanine aminotransferase (ALT) levels ≥ 40 U/L (p < 0.001) and modified ALBI (mALBI) grade 2a (p < 0.001) were significantly associated with improvement to ALBI grade 1 at 1 year after EOT in multivariate analysis. During the median observation period of 51.8 months, 4 and 10 patients with baseline ALBI grade 1 and 2, respectively, died. In patients with baseline ALBI grade 2, only the absence of improvement to ALBI grade 1 at 1 year after EOT was significantly associated with all-cause mortality in univariate analysis., Conclusions: Baseline ALT levels and mALBI grade were significantly associated with improvement in liver function after SVR. Patients whose liver function improved after SVR could have better prognosis., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

We evaluated the value of secreted glycoprotein thrombospondin-2 (TSP-2) to predict hepatocellular carcinoma (HCC) occurrence in chronic hepatitis C (CHC) patients after Hepatitis C virus (HCV) elimination by direct-acting antiviral agents (DAAs). A total of 786 CHC patients without an HCC history who achieved a sustained virological response (SVR) with DAAs were randomly assigned 2:1, with 524 patients as the derivation cohort and 262 patients as the validation cohort. Serum TSP-2 levels at the end of treatment were measured by enzyme-linked immunosorbent assay (ELISA). In the derivation cohort, the cumulative HCC rate was significantly higher in the high TSP-2 group than in the low TSP-2 group. Multivariate Cox proportional hazards analysis revealed that TSP-2, α-fetoprotein (AFP), and the fibrosis-4 (FIB-4) index were independent HCC risk factors. The area under the receiver operating characteristic curve (AUROC) of the score calculated from these three factors (AFT score) for predicting HCC was 0.83, which was significantly higher than that of each factor alone (TSP-2: 0.70, AFP: 0.72, FIB-4: 0.69). The AFT score was used to stratify patients according to the risk of HCC occurrence in the validation cohort. Lastly, in patients with a FIB-4 index < 3.25, the serum TSP-2 levels could be used to identify those patients with a high risk of HCC occurrence. Serum TSP-2 levels are a predictive biomarker of HCC occurrence in CHC patients after HCV elimination by DAA treatment. The AFT score using TSP-2, AFP, and the FIB-4 index may identify those who require HCC surveillance.

Aim: Hepatocellular carcinoma (HCC) after sustained virologic response (SVR) has been observed even in hepatitis C virus (HCV) patients without advanced liver fibrosis. Identifying predictors for HCC incidence in patients without advanced liver fibrosis will enable efficient post-SVR HCC surveillance. This study aimed to develop a scoring system to predict the incidence of HCC after SVR in HCV patients without advanced liver fibrosis., Methods: A total of 1682 HCV patients without advanced liver fibrosis (defined as Fibrosis-4 index <3.25) with no history of HCC who initiated direct-acting antiviral treatment between September 2014 and October 2020 at 26 institutions, and achieved SVR24, were included. We divided 1682 patients into training (1122) and validation (560) cohorts., Results: In the multivariate analysis, baseline age ≥ 65 years (p = 0.030), alanine aminotransferase (ALT) levels at SVR24 ≥ 30 U/l (p = 0.001), and α-fetoprotein (AFP) levels at SVR24 ≥ 5.0 ng/ml (p = 0.001) were independent predictors for HCC incidence in the training cohort. We developed a scoring system to predict HCC incidence after SVR24 using these three factors (1 point was added for each factor). The cumulative HCC incidence rates at 5 years were 7.1% in patients who scored 2 or 3, and no patients developed HCC in those who scored 0 in the validation cohort., Conclusions: Our scoring system using the three factors of baseline age, ALT levels at SVR, and AFP levels at SVR is useful for post-SVR HCC surveillance of patients without advanced liver fibrosis., (© 2022 Japan Society of Hepatology.)

Background: After hepatitis C virus (HCV) elimination, patients should be followed up due to risk of hepatocellular carcinoma (HCC). Growth differentiation factor 15 (GDF15) is a cytokine induced by mitochondrial dysfunction or oxidative stress. Aim To evaluate the prognostic value of GDF15 for HCC occurrence after HCV elimination., Methods: We measured GDF15 levels in stored serum from patients with chronic HCV infection without a history of HCC who had achieved sustained virological response with direct-acting antiviral agents (DAAs). The patients were randomly divided into derivation (n = 964) and validation (n = 642) cohorts., Results: In the derivation cohort, serum GDF15 levels were higher in those with HCC occurrence after DAA treatment than in those without. Multivariate Cox proportional hazards analysis revealed baseline GDF15 (>1350 pg/mL, HR 2.54), AFP (>5 ng/mL, HR 2.00), and the FIB-4 index (>3.25, HR 2.69) to be independent risk factors for HCC. Scoring based on GDF15, AFP and the FIB-4 index stratified HCC occurrence risk. In the validation cohort, the cumulative HCC occurrence rate at 3 years was 0.64%, 3.27% and 15.3% in low-score (N = 171), medium-score (N = 300) and high-score (N = 166) groups, respectively. In the total cohort, scoring divided patients with a FIB-4 index ≤3.25, whose HCC occurrence rate was 2.0% at 3 years, into medium-score and low-score groups with HCC occurrence rates at 3 years of 3.76% and 0.24%, respectively., Conclusions: Serum GDF15 predicts de novo HCC occurrence. Scoring using GDF15, AFP, and the FIB-4 index can predict de novo HCC occurrence risk after HCV elimination., (© 2021 John Wiley & Sons Ltd.)

Background: Several factors associated with hepatocellular carcinoma (HCC) occurrence after sustained virological response (SVR) in patients with hepatitis C have been reported. However, few validation studies have been performed in the era of direct-acting anti-virals (DAAs)., Aims: To develop a prediction model for HCC occurrence after DAA-mediated SVR and validate its usefulness., Methods: We analysed 2209 patients with SVR and without a history of HCC who initiated DAA treatment at 24 Japanese hospitals. These patients were divided into a training set (1473 patients) and a validation set (736 patients)., Results: In the training set, multivariate Cox proportional hazards analysis showed that the baseline BMI (≥25.0 kg/m 2 , P = 0.024), baseline fibrosis-4 (FIB-4) index (≥3.25, P = 0.001), albumin level at SVR (<4.0 g/dL, P = 0.010) and alpha-foetoprotein level at SVR (≥5.0 ng/mL, P = 0.006) were significantly associated with HCC occurrence. We constructed a prediction model for HCC occurrence with these four factors (2 points were added for the FIB-4 index, and 1 point was added for each of the other three factors). Receiver operating characteristics curve analysis identified a score of 2 as the optimal cut-off value for the prediction model (divided into 0-1 and 2-5). In the validation set, the sensitivity and negative predictive value for HCC occurrence were 87.5% and 99.7%, respectively, at 2 years and 71.4% and 98.0%, respectively, at 3 years., Conclusion: A prediction model combining these four factors contributes to an efficient surveillance strategy for HCC occurrence after DAA-mediated SVR., (© 2021 John Wiley & Sons Ltd.)

Aim: Several studies have recently reported that hepatocellular carcinoma (HCC) occurrence does not differ between hepatitis C virus patients receiving interferon (IFN)-based and IFN-free treatments considering the patients' backgrounds. However, liver fibrosis was not directly considered in these studies., Methods: In total, 3972 patients without a history of HCC who started IFN-based or IFN-free treatment between August 2002 and April 2017 at 30 Japanese hospitals and achieved a sustained virologic response were included. Propensity score matching considering liver histology was performed., Results: The median age and percentage of patients with advanced liver fibrosis (F3/4) were 58 years and 11.4% in the IFN-based group, and 68 years and 18.9% in the IFN-free group, respectively. The HCC occurrence rates at 1 year and 2 years were 0.4% and 1.1% in the IFN-based group, and 1.6% and 4.1% in the IFN-free group, respectively, and HCC occurrence in the IFN-free group was significantly higher than that in the IFN-based group (P < 0.001). The characteristics of the HCC occurrence patterns did not differ between the two groups. After propensity score matching, among 764 patients, the HCC occurrence rates at 1 year and 2 years were 0.5% and 1.9% in the IFN-based group and 1.1% and 3.0% in the IFN-free group, respectively, and no significant difference was observed between the two groups (P = 0.489)., Conclusions: HCC occurrence in sustained virologic response patients does not differ between IFN-based and IFN-free treatment considering liver fibrosis stage. The degree of its progress at diagnosis does not differ between the two groups., (© 2019 The Japan Society of Hepatology.)

Aim: Sofosbuvir (SOF) and ribavirin (RBV) combination therapy has improved the sustained virologic response (SVR) rate and shortened the treatment duration for patients with chronic hepatitis C virus (HCV) genotype 2 infection. Ribavirin-induced hemolytic anemia is one of the most troublesome side-effects of SOF/RBV therapy; however, factors associated with this condition have not been fully elucidated. We aimed to identify a safer way to complete treatment with SOF/RBV therapy by examining factors related to RBV-induced hemolytic anemia and identifying patients who did not develop anemia., Methods: Two hundred and one patients with genotype 2 chronic hepatitis C treated with SOF/RBV therapy were studied. Significant factors associated with the decline in hemoglobin (Hb) levels from the baseline were analyzed., Results: The SVR rate was 96.5% (194 out of 201 patients) based on intent-to-treat analysis. In multivariate analysis, inosine triphosphatase (ITPA) gene variation (P < 0.0001) and estimated glomerular filtration rate (eGFR) (0.001) were significantly associated with a decrease in Hb levels less than 2 g/dL. All patients were divided into four groups by ITPA and eGFR at baseline, and we identified patients with ITPA CA/AA and eGFR >75 as a group that did not develop anemia., Conclusions: The results presented here suggest that patients with ITPA CA/AA and eGFR >75 had no reduction in Hb levels during the treatment with SOF/RBV in HCV genotype 2-infected patients. Adding RBV to direct-acting antiviral therapy might not be problematic in certain patients, at least in terms of the occurrence of anemia., (© 2019 The Japan Society of Hepatology.)

Aim: In patients with chronic hepatitis C, hepatocellular carcinoma (HCC) occurs at a certain frequency, even if a sustained virologic response (SVR) is achieved by antiviral treatment. Old age, liver fibrosis, and high post-treatment α-fetoprotein (AFP) level are typical risk factors of post-SVR HCC. We examined whether the frequencies and factors of HCC in patients with an SVR achieved from interferon treatment changed. Methods Among patients prospectively registered for pegylated interferon and ribavirin treatment, 2021 with an SVR without HCC development during the treatment period were followed up. The mean observation period was 49.5 ± 26.2 months., Results: The multivariable Cox regression analysis showed that older age, diabetes mellitus, advanced liver disease, and higher post-treatment AFP level were the independent risk factors throughout the observation period. The annual occurrence rate of HCC was 0.74% in the third year, 0.54% in the fourth year, and 0.40% in the fifth year; it gradually decreased from the third year. Because the time course hazards for HCC changed at 48 months, we separately analyzed its risk factors before and after this change point. The multivariable Cox regression analysis showed that the four above-mentioned factors were significantly related to HCC development within 4 years. Conversely, the univariable Cox regression analysis only identified diabetes mellitus as a significant factor for HCC development after 4 years., Conclusion: The frequency of HCC in hepatitis C patients who achieved an SVR from interferon treatment decreased during the observation period, and its risk factors changed between the early and late periods., (© 2019 The Japan Society of Hepatology.)

Combination treatment of ledipasvir and sofosbuvir (LDV/SOF) is first-line treatment for patients with chronic hepatitis C genotype 1 in the United States, Europe, and Japan. However, the influence of LDV/SOF on the cardiovascular system is poorly characterized. A total of 470 chronic hepatitis C patients who started LDV/SOF treatment between September 2015 and February 2016 at nine hospitals in Japan were prospectively enrolled in this study. Corrected QT (QTc) prolongation was defined as a QTc interval ≥450 milliseconds. The sustained virologic response rate was 96.0% (451/470), and the discontinuance rate due to adverse effects was 0.9% (4/470). Among 395 patients whose electrocardiogram was evaluated over time and compared with baseline, the QTc interval was significantly prolonged during treatment and returned to baseline levels 12 weeks after the end of treatment. Twenty-four of 376 patients with baseline QTc intervals <450 milliseconds experienced on-treatment QTc prolongation. Higher aspartate aminotransferase-to-platelet ratio index scores (≥0.76; odds ratio, 4.375; P = 0.005) and longer QTc intervals (≥416 milliseconds; odds ratio, 4.823; P = 0.003) at baseline were significantly associated with on-treatment QTc prolongation on multivariate analysis. Patients with cirrhosis showed significantly longer QTc intervals than those without cirrhosis during treatment but not at baseline, and they developed on-treatment QTc prolongation at a higher rate than patients without cirrhosis. No cardiovascular events occurred, except for 1 patient who developed paroxysmal supraventricular tachycardia. Conclusion : Newly developed QTc prolongation was observed in 6.4% of Japanese patients during treatment and was associated with more advanced fibrosis. ( Hepatology Communications 2018; 00:000-000).

Background: Hyperbilirubinemia, mild or moderate, is a commonly observed laboratory abnormality in chronic hepatitis C patients treated with simeprevir with pegylated interferon (Peg-IFN) plus ribavirin. In this prospective, multicenter study, we aimed to investigate the clinical features and factors associated with bilirubin increases during the therapy., Methods: A total of 192 patients with chronic hepatitis C who were treated with simeprevir with Peg-IFN plus ribavirin were analyzed., Results: The mean serum bilirubin level increased significantly during the initial 12 weeks of simeprevir administration and peaked at 2 weeks after the administration. Hyperbilirubinemia of more than 2 mg/dl developed in 18% of the patients; in 85% of those patients, the bilirubin levels peaked within 6 weeks and gradually decreased thereafter. A univariable analysis revealed that an increase in serum total bilirubin of 1.0 mg/dl or more from baseline was significantly associated with the sex, red blood cell count, serum hemoglobin level, serum alanine aminotransferase level, serum creatinine level and inosine triphosphate pyrophosphatase (ITPA) genotype. In the multivariable analysis, the ITPA genotype (CC odds ratio 4.990, p = 0.011) was found to be the only independent factor. Consistent with this result, there was a significant correlation between hyperbilirubinemia and the degree of hemolytic anemia., Conclusions: Hyperbilirubinemia develops at early time points after simeprevir administration in most cases and is dependent on the ITPA genotype. Careful attention should be paid to hyperbilirubinemia, which occurs at later time points or in patients with an ITPA non-CC genotype so that a diagnosis of liver damage with hyperbilirubinemia is not missed.

Background: Previous genome-wide association studies have evaluated the impact of common genetic variants and identified several non-HLA risk loci associated with autoimmune liver diseases. More recent genome-wide association studies and replication analyses reported an association between variants of the CARD10 polymorphism rs6000782 and risk of type 1 autoimmune hepatitis (AIH). In this case-control study, we genotyped 326 Japanese AIH patients and 214 control subjects., Results: Genomic DNA from 540 individuals of Japanese origin, including 326 patients with type-1 AIH and 214 healthy controls, was analyzed for two single nucleotide polymorphisms (SNPs) in the CARD10 gene. We selected CARD10 rs6000782 SNPs and genotyped these using PCR-RFLP method and direct sequencing. The Chi square test revealed that the rs6000782 variant alle (c) was not associated with the susceptibility for AIH in a Japanese population [p = 0.376, odds ratio (OR) 1.271, 95 % confidence interval (CI) 0.747-2.161] in an allele model. Our data also showed that CARD10 rs6000782 variants were not associated with AIH or with the clinical parameters of AIH., Conclusions: In this study we examined an association between rs6000782 SNPs in the CARD10 gene and type-1 AIH. Results showed no significant association of rs62000782 with type-1 AIH in a Japanese population. This study demonstrated no association between CARD10 rs6000782 variants and AIH in a Japanese population.

Recent studies have demonstrated that micro (mi)RNA molecules can be detected in the circulation and can serve as potential biomarkers of various diseases. This study used microarray analysis to identify aberrantly expressed circulating miRNAs in patients with type 1 autoimmune hepatitis (AIH) compared with healthy controls. Patients with well-documented and untreated AIH were selected from the National Hospital Organization (NHO)-AIH-liver-network database. They underwent blood sampling and liver biopsy with inflammation grading and fibrosis staging before receiving treatment. To further confirm the microarray data, circulating expression levels of miR-21 and miR-122 were quantified by real-time quantitative polymerase chain reaction in 46 AIH patients, 40 patients with chronic hepatitis C (CHC), and 13 healthy controls. Consistent with the microarray data, serum levels of miR-21 were significantly elevated in AIH patients compared with CHC patients and healthy controls. miR-21 and miR-122 serum levels correlated with alanine aminotransferase levels. Circulating levels of miR-21 and miR-122 were significantly reduced in AIH patients with liver cirrhosis, and were inversely correlated with increased stages of fibrosis. By contrast, levels of circulating miR-21 showed a significant correlation with the histological grades of inflammation in AIH. We postulate that aberrantly expressed serum miRNAs are potential biomarkers of AIH and could be implicated in AIH pathogenesis. Alternations of miR-21 and miR-122 serum levels could reflect their putative roles in the mediation of inflammatory processes in AIH.

Background: Entecavir (ETV) is one of the first-line nucleoside analogs for treating patients with chronic hepatitis B virus (HBV) infection. However, the hepatocellular carcinoma (HCC) risk for ETV-treated patients remains unclear., Methods: A total of 496 Japanese patients with chronic HBV infection undergoing ETV treatment were enrolled in this study. The baseline characteristics were as follows: age 52.6 ± 12.0 years, males 58%, positive for hepatitis B e antigen 45 %, cirrhosis 19%, and median HBV DNA level 6.9 log copies (LC) per milliliter. The mean treatment duration was 49.9 ± 17.5 months., Results: The proportions of HBV DNA negativity (below 2.6 LC/mL) were 68% at 24 weeks and 86% at 1 year, and the rates of alanine aminotransferase (ALT) level normalization were 62 and 72%, respectively. The mean serum alpha-fetoprotein (AFP) levels decreased significantly at 24 weeks after ETV treatment initiation (from 29.0 ± 137.1 to 5.7 ± 27.9 ng/mL, p < 0.001). The cumulative incidence of HCC at 3, 5, and 7 years was 6.0, 9.6, and 17.2%, respectively, among all enrolled patients. In a multivariate analysis, advanced age [55 years or older, hazard ratio (HR) 2.84; p = 0.018], cirrhosis (HR 5.59, p < 0.001), and a higher AFP level (10 ng/mL or greater) at 24 weeks (HR 2.38, p = 0.034) were independent risk factors for HCC incidence. HCC incidence was not affected by HBV DNA negativity or by ALT level normalization at 24 weeks., Conclusions: The AFP level at 24 weeks after ETV treatment initiation can be the on-treatment predictive factor for HCC incidence among patients with chronic HBV infection.