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Background and Aim: Direct‐acting antivirals (DAAs) have been accessible in Japan since 2014. The aim of this study is to compare how the prognosis of patients with hepatitis C virus (HCV)‐associated hepatocellular carcinoma (HCV‐HCC) changed before and after DAA development. Methods: A retrospective analysis of 1949 Japanese HCV‐HCC patients from January 2000 to January 2023 categorized them into pre‐DAA (before 2013, n = 1169) and post‐DAA (after 2014, n = 780) groups. Changes in clinical features and prognosis were assessed. Results: Despite no significant differences in BCLC stage between groups, the post‐DAA group exhibited higher rates of sustained virological response (SVR) (45.6% vs. 9.8%), older age (73 vs 69 years), lower levels of AST (40 vs 56 IU/L), ALT (31 vs 46 IU/L), and AFP (11.7 vs 23.6 ng/mL), higher platelet count (13.5 vs 10.8 × 104/μL), better prothrombin time (88.0% vs 81.9%), and better ALBI score (−2.54 vs −2.36) (all P < 0.001). The post‐DAA group also showed higher rates of curative treatments (74.1% vs 65.2%) and significantly improved recurrence‐free survival (median 2.8 vs 2.1 years). Adjusted for inverse probability weighting, overall survival was superior in the post‐DAA group (median 7.4 vs 5.6 years, P < 0.001). Subanalysis within the post‐DAA group revealed significantly shorter overall survival for patients without SVR (median 4.8 years vs NA vs NA) compared to pre‐SVR or post‐SVR patients (both P < 0.001). No significant difference in OS was observed between the pre‐SVR and post‐SVR groups (P = 1.0). Conclusion: The development of DAA therapy has dramatically improved the prognosis of HCV‐HCC patients. [ABSTRACT FROM AUTHOR]

Background and Aim: The study aims to develop a novel predictive model including the fibrosis (FIB)‐3 index for hepatocellular carcinoma (HCC) development in patients with chronic hepatitis C virus (HCV) who achieved sustained virological response (SVR) with direct‐acting antiviral (DAA) therapy. Methods: This study included 2529 patients in whom HCV was eradicated with DAA therapy. The after DAA recommendation for surveillance (ADRES) score, which is based on sex, FIB‐4 index, and α‐fetoprotein, was used to predict HCC development. We developed a modified ADRES (mADRES) score, in which the FIB‐4 index was replaced by the FIB‐3 index, and evaluated its usefulness in predicting HCC development compared with the ADRES score. Results: In the training set (n = 1770), multivariate analysis with Cox proportional hazards modeling showed that male sex (hazard ratio [HR], 2.11; 95% confidence interval [CI], 1.48–3.01), FIB‐3 index (HR, 1.36; 95% CI, 1.28–1.45), and α‐fetoprotein (HR, 1.05; 95% CI, 1.03–1.07) are independently associated with HCC development. The incidence of HCC differed significantly by ADRES or mADRES score in multiple comparisons. Univariate Cox proportional hazards models showed that compared with the mADRES score 0 group, the HR for HCC development was 2.07 (95% CI, 1.02–4.19) for the mADRES score 1 group, 11.37 (95% CI, 5.80–22.27) for the mADRES score 2 group, and 21.95 (95% CI, 10.17–47.38) for the mADRES score 3 group. Similar results were obtained for mADRES score but not for ADRES score in the validation set (n = 759). Conclusion: The mADRES score is useful for predicting HCC development after SVR. [ABSTRACT FROM AUTHOR]

Previous infection with hepatitis B virus (HBV), which is assessed by HBV core antibody (HBcAb) or surface antibody (HBsAb) titres, has reportedly been associated with an increased risk of developing hepatocellular carcinoma (HCC). We investigated the influence of previous HBV infection on the incidence of HCC in patients with hepatitis C virus (HCV) infection who achieved eradication of HCV, that is sustained virologic response (SVR). Both HBcAb and HBsAb were measured in a total of 1214 patients with HCV infection who had not been coinfected with HBV, as determined by both negative HBs antigen and HBV DNA, and in whom SVR was confirmed. Patients were followed up for a median of 5.7 years, and the incidence of post‐SVR HCC was compared based on HBcAb and/or HBsAb. In both univariate and multivariate analyses, the incidence of post‐SVR HCC did not differ based on the presence of HBcAb or HBsAb. In conclusion, previous HBV infection has no impact on the incidence of HCC in patients with HCV after SVR. [ABSTRACT FROM AUTHOR]

Aim: Elastography is an established, noninvasive method for measuring liver stiffness using to 2‐D shear‐wave elastography (2D‐SWE) or magnetic resonance elastography (MRE). The aim of this study was to determine the usefulness of combined measurement using 2D‐SWE and MRE to stratify the risk of developing hepatocellular carcinoma (HCC) in patients who achieved hepatitis C virus eradication. Methods: Five hundred and twenty‐five patients who underwent 2D‐SWE and MRE before antiviral therapy and who achieved eradication were enrolled. The optimal 2D‐SWE and MRE cutoff values were determined using time‐dependent receiver operating characteristic (ROC) curves for predicting HCC development. Inverse probability of treatment weighting (IPTW) and a Cox proportional hazards model were used to adjust the cumulative incidence rate of HCC development for potential imbalances. Results: Time‐dependent ROC analysis showed that the optimal cut‐off values of 2D‐SWE and MRE for predicting HCC development were 11.7 and 4.5 kPa, respectively. The IPTW‐adjusted cumulative incidence rate of HCC development in patients with both an 2D‐SWE value ≥ 11.7 kPa and an MRE value ≥ 4.5 kPa had a higher hazard ratio (28.080; 95% confidence interval, 5.527–132.600; p < 0.001) than those with either an 2D‐SWE value < 11.7 kPa or an MRE value < 4.5 kPa. Conclusions: The combined measurement of 2D‐SWE and MRE was very effective for identifying patients at high risk of HCC development. US‐based elastography should be performed first, and if the 2D‐SWE value is high, MRE should then be carried out to confirm the degree of liver stiffness. [ABSTRACT FROM AUTHOR]

Aim: Fatty liver is the most common liver disease. This study examined fatty liver and advanced fibrosis prevalence in a random sample of the Japanese general population. Methods: A total of 6000 people randomly selected from two cities in Hiroshima Prefecture were invited to participate in this cross‐sectional study originally carried out for hepatitis virus screening. Ultrasonography and FibroScan (controlled attenuation parameter [CAP] and liver stiffness measurement [LSM]) were provided as additional tests. Results: Of 6000 invited individuals, 1043 participated in hepatitis virus screening, of which 488 randomly selected individuals (median age, 56 years; interquartile range, 45–68 years; male participants, 49.8%) underwent ultrasonography, CAP, and LSM. Ultrasonography showed fatty liver in 24.6% and mild fatty liver in 32.8%. Controlled attenuation parameter showed severe steatosis in 27.5%, moderate steatosis in 12.5%, and mild steatosis in 11.1%. Overall, 62.1% were diagnosed with fatty liver based on ultrasonography or CAP. Nonalcoholic fatty liver disease (NAFLD) prevalence was 50.6%. Liver stiffness measurement found cirrhosis in 1.0% and severe fibrosis in 1.8%. Multivariate analysis of risk factors associated with ≥F2 or higher liver fibrosis showed that age ≥60 years and above (adjusted odds ratio [AOR], 3.2; 95% confidence interval [CI], 1.5–6.9; p = 0.0031), hepatitis C virus antibody positivity (AOR, 8.4; 95% CI, 1.0–68.4; p = 0.0467), and fatty liver (AOR, 2.3; 95% CI, 1.1–6.2; p = 0.0317) are independent risk factors. Conclusions: In the general population, 62.1% had fatty liver, and NAFLD prevalence was twice as high as previously reported. Screening that is noninvasive, low‐cost, and does not require special techniques or equipment is needed to detect advanced liver fibrosis. [ABSTRACT FROM AUTHOR]

Background and Aim: The relationship between the characteristics of hepatocellular carcinoma (HCC) diagnosed after sustained virological response (SVR) with direct‐acting antiviral (DAA) therapy and surveillance status has not been sufficiently investigated. This study investigated the clinical risk factors for HCC development and HCC characteristics according to which type of physician performed follow‐up after SVR. Methods: A total of 1070 patients in whom hepatitis C virus (HCV) was eradicated with DAA therapy were evaluated. Results: There were 458 patients followed by hepatologists (specialist group) and 612 followed by non‐hepatologists (non‐specialist group) after SVR. During the follow‐up period, 54 patients developed HCC. The 1‐, 2‐, 3‐, 4‐, and 5‐year cumulative incidence rates of HCC were 1.8, 4.1, 6.9, 10.5, and 17.2%, respectively. Multivariate Cox proportional hazards analysis showed that male sex (hazard ratio [HR], 3.139; 95% confidence interval [CI], 1.732–5.690), α‐fetoprotein level (HR, 1.056; 95% CI, 1.035–1.077), and fibrosis‐4 (FIB‐4) index (HR, 1.051; 95% CI, 1.017–1.085) were significantly associated with HCC development, while the follow‐up physician type after SVR was not. There were 25 patients with stage I HCC, 17 with stage II, 9 with stage III, and 3 with stage IV. Multivariate ordinal logistic regression showed that follow‐up physician type (non‐specialist) (HR, 39.100; 95% CI, 9.350–224.00) was independently associated with HCC stage, while α‐fetoprotein level and FIB‐4 index were not. Conclusion: When patients have more risk factors for HCC development after SVR (i.e., male sex, elevated α‐fetoprotein, or elevated FIB‐4 index), they should be followed by a hepatologist for HCC surveillance. [ABSTRACT FROM AUTHOR]

Non‐hypervascular hypointense nodules (NHHNs) on gadolinium‐ethoxybenzyl‐diethylenetriamine pentaacetic acid–enhanced magnetic resonance imaging (EOB‐MRI) have a high likelihood of hypervascularization progressing to typical hypervascular hepatocellular carcinoma (HCC). NHHNs that were present before the start of anti‐hepatitis C virus (HCV) therapy is a risk marker for HCC development after achieving sustained virologic response (SVR). In this report, we show a patient without a previous history of HCC in whom HCC developed by hypervascularization of NHHN after SVR. This patient achieved SVR more than 8 years before NHHN developed into HCC, and during this time NHHN had been present but had remained unchanged in size and imaging features as shown by repeated EOB‐MRI. Hepatocarcinogenic potential of NHHNs persist for a long time after SVR, despite the eradication of HCV. [ABSTRACT FROM AUTHOR]

The impact of antiviral therapy on clinical outcomes in patients with hepatitis C virus (HCV) infection and mild liver fibrosis (FIB‐4 score <1.45) is not well understood. We aimed to clarify the impact of viral eradication on hepatocarcinogenesis and mortality in patients with mild fibrosis.The subjects were 657 patients who achieved sustained virologic response (SVR) (Clearance group) and 586 patients who did not receive antiviral therapy or did not achieve SVR (No clearance group). We applied inverse probability weighting because the groups had different baseline characteristics. Multivariate proportional hazards models were used to analyse factors associated with hepatocarcinogenesis and mortality using a time‐dependent covariate. In addition, we compared the mortality rate of the Clearance group stratified by age to the mortality rate of the general population.Clearance of HCV RNA was significantly associated with hepatocarcinogenesis and all‐cause, liver‐related and non–liver‐related mortality (adjusted hazard ratios [95% confidence interval], 0.2653 [0.1147–0.6136, p = 0.0019], 0.3416 [0.2157–0.5409, p < 0.0001], 0.2474 [0.0802–0.8917, p = 0.0381] and 0.4118 [0.2449–0.6925, p = 0.0008], respectively). The Clearance group had significantly higher mortality than the general population matched by age, sex and follow‐up duration (p < 0.0001). However, there were no significant differences between patients who achieved SVR before age 50 and the general population matched by age, sex and follow‐up duration (p = 0.1570). HCV eradication in patients with mild fibrosis reduces liver‐related and non–liver‐related mortality. If HCV is eradicated before age 50, prognosis is likely be similar to that of the age‐matched and sex‐matched general population. (249 words). [ABSTRACT FROM AUTHOR]

Aim: The pathogenic process underlying the development of hepatocellular carcinoma (HCC) is not yet clear in patients with chronic hepatitis C virus who receive direct‐acting antiviral therapy and achieve sustained virological response. This study investigated two risk factors for HCC in these patients; specifically, hepatic fibrosis and steatosis. Methods: A total of 355 patients in whom hepatitis C virus was eradicated by direct‐acting antiviral were evaluated. Fibrosis and steatosis were assessed using transient elastography (TE) and the controlled attenuation parameter (CAP). Inverse probability weighting was applied to patient age, sex, albumin–bilirubin, α‐fetoprotein, history of HCC, TE, or CAP. Results: The 12‐, 24‐, and 36‐month cumulative incidence rates of HCC were 0.9%, 2.4%, and 4.1%, respectively. Univariate analysis with the Cox proportional hazards model showed that whereas a high TE value (≥10 kPa) was significantly associated with HCC development (HR 7.861, 95% CI 2.126–29.070; p = 0.002), CAP was not. Additionally, univariate analysis with the Cox proportional hazards model adjusted by inverse probability weighting showed that a high TE value was significantly associated with HCC development (HR 3.980, 95% CI, 1.036–15.290; p = 0.044), whereas CAP was not. The cumulative inverse probability weighting‐adjusted incidence of HCC rates at 12, 24, and 36 months were 0.0%, 0.5%, and 1.7%, respectively, in patients with a low TE value, and 2.5%, 5.1%, and 7.6%, respectively, in those with a high TE value. Conclusion: A high TE value was a risk factor for HCC in hepatitis C virus patients who received direct‐acting antiviral therapy and achieved sustained virological response. [ABSTRACT FROM AUTHOR]

Summary: Background: Identification of risk factors for the development of hepatocellular carcinoma (HCC) after a sustained virologic response (SVR) in patients with chronic hepatitis C virus (HCV) infection is urgently needed for HCC surveillance. Aims: To evaluate whether the presence of non‐hypervascular hypointense nodules (NHHNs) depicted by gadolinium‐ethoxybenzyl‐diethylenetriamine pentaacetic acid‐enhanced magnetic resonance imaging (EOB‐MRI) before direct‐acting antivirals (DAAs) therapy is a risk factor for de novo HCC development after SVR. Methods: The presence of NHHNs was examined with EOB‐MRI before the start of DAA therapy in 383 patients with HCV infection who achieved SVR. The incidence of de novo HCC after SVR was compared between patients with versus without NHHNs. Results: NHHNs were detected before DAA therapy in 32 patients (8.4%). The incidence of de novo HCC after SVR was significantly higher in patients with NHHNs than in those without (1‐, 3‐, 5‐year incidence, 9.8%, 24.2% and 41.6% vs. 0%, 1.2% and 4.4%, P < 0.0001). The presence of NHHNs before DAA therapy (adjusted HR, 10.86; 95% CI, 4.03‐31.64) and cirrhosis (adjusted HR, 7.23; 95% CI, 1.88‐35.85) were independently associated with a higher incidence of HCC after SVR. A higher incidence of de novo HCC after SVR remained after adjustment for age, gender, regular alcohol intake, diabetes, cirrhosis, FIB‐4 index and serum alpha‐foetoprotein with inverse probability of treatment weighting. Conclusions: This study confirmed that the presence of NHHNs before DAA therapy is a strong risk factor for the development of de novo HCC after SVR. [ABSTRACT FROM AUTHOR]

Introduction: In patients with hepatitis C virus (HCV) infection and decompensated cirrhosis (DC), it is uncertain whether viral clearance is clinically meaningful and whether it decreases liver-related and non-liver-related mortality. The aim of this study was to assess whether viral eradication reduced liver-related and non-liver-related mortality in patients with HCV infection and DC. Methods: To clarify the impact of viral eradication on liver-related and non-liver-related mortality, 364 patients with DC who received direct-acting antivirals (DAAs) and achieved sustained virological response (SVR) in the UK (DAA group) were compared with 249 patients with DC who did not receive DAAs and who underwent symptomatic treatment in Japan (non-DAA group). Propensity score matching and inverse probability weighting (IPW) were performed to adjust the baseline characteristics in the DAA and non-DAA groups. Liver-related and non-liver-related mortality were analyzed using the competing risks IPW cumulative incidence functions estimator. Results: The cumulative all-cause mortality rate in the DAA group was significantly lower than that in the non-DAA group (p < 0.0001, IPW-adjusted log-rank test). The cumulative incidence rates of both liver-related and non-liver-related mortality were significantly lower in the DAA group than those in the non-DAA group (p < 0.0001 for both). Conclusion: DAA-mediated viral eradication reduced not only liver-related mortality but also non-liver-related mortality in patients with HCV infection and DC. [ABSTRACT FROM AUTHOR]

To investigate the long‐term prognosis of liver disease in patients with hepatitis C virus (HCV) eradication after antiviral therapy versus those with persistent HCV infection. Four hundred and eighty patients (5259 person‐years [PYs]) who received interferon‐based therapy and achieved sustained virologic response and 848 patients (3853 PYs) with persistent HCV infection were included. In the analysis of 1‐year liver disease state transition probability matrices using Markov chain models, progression to cirrhosis from the chronic hepatitis state was observed (0.00%–0.63%) in patients with HCV eradication. Among patients with chronic hepatitis or cirrhosis and HCV eradication, hepatocellular carcinoma (HCC) development was observed in males aged ≥ 50 years (0.97%–1.96%) and females aged ≥ 60 years (0.26%–5.00%). Additionally, in patients with cirrhosis and HCV eradication, improvement to chronic hepatitis was also observed (4.94%–10.64%). Conversely, in patients with chronic hepatitis and persistent HCV infection, progression to cirrhosis was observed in males aged ≥ 30 years and female aged ≥ 40 years (0.44%–1.99%). In males aged ≥ 40 years and female aged ≥ 50 years with cirrhosis, the transition probability for HCC was relatively high (4.17%–14.02%). Under the assumption of either chronic hepatitis or cirrhosis at age 40 or 60 years as the starting condition for simulation over the next 30 or 40 years, respectively, the probability of HCC was higher in patients with persistent HCV infection than those with HCV eradication. In conclusion, HCV eradication can reduce the risk of developing cirrhosis or HCC in patients with chronic HCV infection. [ABSTRACT FROM AUTHOR]

Background: Even though both interferon (IFN)-based and direct-acting antiviral (DAA) therapies against hepatitis C virus (HCV) reduce the risk of hepatocellular carcinoma (HCC), post-sustained virological response (SVR) patients remain at elevated risk of HCC. Methods: A total of 4620 patients who achieved SVR were enrolled in this retrospective cohort study. After excluding patients who had a history of HCC or developed HCC within 1 year and whose follow-up period was less than 1 year and who were positive for HBsAg, we investigated the association between clinical characteristics and HCC development after SVR in the remaining 3771 patients. Results: Median observation period was 41 months. We confirmed known risk factors. In addition, we found that PNPLA3 and HLA-DQB1 polymorphisms were associated with HCC after SVR. Finally, we propose an estimation model for the incidence of HCC after SVR. Based on gender, FIB-4 index, AFP, and PNPLA3 polymorphism, about 18% of all patients were classified as having high risk, with a cumulative incidence rate (CIR) at 5 years of 16.5%. Another 17% were classified as having moderate risk with a CIR of 7.6%. The remaining 65% showed a CIR of 0.5%. The effect of PNPLA3 polymorphism might be more pronounced in patients with lower body mass index (BMI) and without diabetes mellitus compared to those with higher BMI and diabetes mellitus. Conclusions: We demonstrated that PNPLA3 and HLA-DQB1 polymorphisms were associated with HCC after SVR. These findings might be useful to inform risk stratification for HCC surveillance after SVR. [ABSTRACT FROM AUTHOR]

Aim: The long‐term prognosis of patients with chronic hepatitis C virus (HCV) infection who have received antiviral therapy and who demonstrate HCV eradication remains incompletely characterized. In this study, we investigated the long‐term prognosis of liver disease in patients with eradication of HCV. Methods: A total of 552 patients with chronic HCV infection (6815 person‐years) who were treated with interferon‐based therapy and who achieved sustained virologic response were included. Yearly transition probabilities for each liver state (chronic hepatitis, cirrhosis, and hepatocellular carcinoma [HCC]) were calculated using a Markov chain model. Results: In the analysis of 1‐year liver disease state transition probabilities, progression to cirrhosis occurred in 0.5–2.1% of male patients with chronic hepatitis across all age groups. In male patients with cirrhosis, HCC developed in 0.6–1.9% of patients over the age of 50 years. In female patients with chronic hepatitis, progression to cirrhosis occurred in 0.4–2.1% of patients across all age groups. In addition, in female patients with cirrhosis, HCC developed in those aged 60–69 (0.4%) and 70–79 (0.4%) years. Under the assumption of either a chronic hepatitis or cirrhosis state at age 40 or 60 years as the starting condition for simulation over the next 40 or 20 years, respectively, the probability of HCC gradually increased with age and was higher in male patients. Conclusions: The development or progression of cirrhosis and the development of HCC are risks in HCV patients despite HCV eradication, not only in those with cirrhosis but also in those with chronic hepatitis. [ABSTRACT FROM AUTHOR]

Summary: Background: We conducted a prospective study using gadolinium‐ethoxybenzyl‐diethylenetriamine pentaacetic acid–enhanced magnetic resonance imaging (Gd‐EOB‐MRI) to determine whether sustained virological response (SVR) by direct‐acting anti‐viral (DAA) drugs suppresses hepatocarcinogenesis in patients with hepatitis C virus (HCV) infection. Aim: To use serial Gd‐EOB‐MRI to assess the impact of DAAs on hepatocarcinogenesis. Methods: Between February 2008 and December 2018, 1083 consecutive patients with HCV infection underwent Gd‐EOB‐MRI. Of these, 719 patients were enrolled, including 210 patients in the 'Non‐DAA group', who did not receive DAAs before the introduction of DAAs, and 509 patients in the 'DAA group', who achieved SVR after the introduction of DDAs. Factors associated with hepatocarcinogenesis were analysed by a Cox proportional hazard model. In addition, hepatocarcinogenesis was classified into two types, 'multistep' and 'de novo', on the basis of Gd‐EOB‐MRI findings. Factors associated with each type were analysed by Fine and Gray proportional hazards models. Results: Hepatocarcinogenesis was observed in 67 of 719 (9.3%) patients. Factors associated with hepatocarcinogenesis were male gender, albumin‐bilirubin (ALBI) grade 2 or 3, Lens culinaris agglutinin–reactive fraction of alpha‐fetoprotein (AFP‐L3) ≥5%, the presence of nonhypervascular hypointense nodules (NHHNs) and Non‐DAA group. Of 67 patients, multistep hepatocarcinogenesis occurred in 58 patients (86.6%) and de novo hepatocarcinogenesis occurred in nine patients (13.4%). Factors associated with multistep hepatocarcinogenesis were male gender and Non‐DAA group. Conclusion: The eradication of HCV by DAA therapy reduces multistep hepatocarcinogenesis. [ABSTRACT FROM AUTHOR]

The quantification of hepatitis C virus (HCV) is essential for the management of chronic hepatitis C therapy. We have developed a fully automated microfluidic RT-qPCR system for rapid quantitative detection of HCV RNA in human EDTA-plasma and serum, and the performance of the method was assessed. The platform for the assay, µTASWako g1 Fully Automated Genetic Analyzer, performs automated sample preparation and RNA extraction, followed by amplification and detection on an integrated RT-qPCR-CE (capillary electrophoresis (CE)) microfluidic chip. The total assay time from sample input to data output is less than 120 minutes. The HCV assay has a linear quantitative range of 15 to 107 IU/mL, with a limit of detection (LOD) of 10.65 IU/mL in EDTA-plasma and 12.43 IU/mL in serum. The assay has a reproducibility of SD ≤ 0.16 log10 IU/mL and an accuracy of ≤ 0.22 log10 IU/mL difference when compared to the assigned values. The main HCV genotypes 1 to 6 are detected with an accuracy of ± 0.3 log10 IU/mL. The assay is specific for HCV RNA and is free of interference from non-HCV pathogens, elevated levels of anti-viral and anti-bacterial drugs, and common endogenous interferents. In the linear quantitative range, the assay is highly correlated with the Roche cobas AmpliPrep/cobas TaqMan HCV Test, version 2.0 (r2 = 0.949). As the assay is highly sensitive, accurate and specific, and provides reliable quantification of HCV in plasma and serum, it can potentially be applicable for monitoring the therapy and management of HCV infection. [ABSTRACT FROM AUTHOR]

Summary: Background: Intrahepatic non‐hypervascular hypointense nodules (NHHNs) detected during the hepatobiliary phase of gadolinium‐ethoxybenzyl‐diethylenetriamine pentaacetic acid‐enhanced magnetic resonance imaging (EOB‐MRI) have the potential to transition into typical hypervascular hepatocellular carcinoma (HCC). However, the incidence and risk factors for the emergence of these nodules in patients with chronic hepatitis C virus (HCV) infection are unknown. Aim: To investigate the incidence and risk factors for NHHNs in patients with chronic HCV infection in a longitudinal follow‐up study Methods: EOB‐MRI was performed in 608 patients with chronic HCV infection and no history of HCC. The characteristics of patients with and without NHHNs were compared. In patients without NHHNs at baseline, the incidence of NHHN emergence and associated risk factors were analysed. Results: NHHNs were detected at baseline in 93 of 608 patients (15.3%). Among 515 patients without NHHNs at baseline, the 1‐year, 3‐year and 5‐year incidence of NHHN emergence was 1.8%, 9.8% and 16.4%, respectively. Only FIB‐4 index was independently associated with the emergence of NHHNs in multivariate analyses. Whereas NHHNs emerged in 24.1% of patients with FIB‐4 index ≥ 3.25 at 5 years, none emerged in patients with FIB‐4 index < 1.45. Conclusion: In patients with chronic HCV infection, advanced liver fibrosis is an important risk factor for the presence or emergence of NHHNs. [ABSTRACT FROM AUTHOR]

Background: Long‐term prognosis of patients with chronic hepatitis C infection (HCV) remains incompletely characterized. We investigated the long‐term prognosis of liver disease in patients with chronic HCV infection who have not received antiviral therapy. Methods: A total of 2304 patients with chronic HCV who were not received interferon‐based therapy were included. Results: In the assessment of 1‐year disease state of liver transition probabilities, progression to chronic hepatitis occurred in 12% to 14% of patients across all age groups in male asymptomatic carriers. In male patients with chronic hepatitis, progression to cirrhosis was observed mostly in the 60 to 69 (7.6%) and ≥70 age groups (9.6%). In addition, in male patients with cirrhosis, HCC development occurred in approximately 5% of patients over the age of 40. In female asymptomatic carriers, progression to chronic hepatitis was observed in 6% to 14% of patients across all age groups. In female patients with chronic hepatitis, progression to cirrhosis was observed mostly in the 60 to 69 (8.7%) and ≥70 (7.4%) age groups. In addition, in female patients with cirrhosis, HCC development occurred in 0.9% to 3.3% of patients over the age of 50. Under assumptions of either chronic hepatitis or asymptomatic carrier state at age 40 as the starting condition for simulation over the following 40 years, the probability of HCC gradually increased with age and was higher in male patients. Conclusions: There is a risk of cirrhosis or HCC development in HCV patients with not only chronic hepatitis but the asymptomatic carrier state as well. Highlight: Yearly transition probabilities for each liver state (asymptomatic carrier, chronic hepatitis, cirrhosis, and hepatocellular carcinoma [HCC]) were calculated using a Markov chain model.Poor liver disease outcomes such as the development of cirrhosis or HCC are possible not only in patients with chronic hepatitis but also in patients who are asymptomatic carriers at age ≥40 years. [ABSTRACT FROM AUTHOR]

Background: Little is known about the course of elderly patients with persistent hepatitis C virus (HCV) infection. We investigated the course of HCV infection in this patient population.Methods: Among 9,126 HCV antibody-positive patients who visited our hospital between 1995 and 2015, there were 453 patients with continuous follow-up who survived to age 80. They were included in the study following the inclusion criteria: confirmed persistent detection of HCV RNA, no HCV eradication if anti-HCV therapy occurred before enrollment, and no development of hepatocellular carcinoma (HCC) before enrollment. For all study patients, baseline was defined as the date when they turned 80. Mortality rates after the age of 80 years and cause of death were analyzed.Results: During the study period, 155 patients (34.2%) died. Median survival time (MST) after age 80 was 8.8 years, which was comparable to that of the general population (10.1 years). Among 155 deceased patients, the majority (115 patients, 74.2%) died due to non-liver-related disease, followed by HCC (28 patients, 18.1%) and liver-related disease other than HCC (12 patients, 7.7%). Patients with advanced liver fibrosis (FIB-4 index > 3.25, n = 245) had shorter MST than patients with mild liver fibrosis (FIB-4 index ≤ 3.25, n = 208) (7.1 vs. 10.2 years; p = 0.020) due to a higher mortality rate from liver-related complications, including HCC.Conclusion: Most elderly HCV patients die from non-liver-related disease, especially those with less advanced liver fibrosis. [ABSTRACT FROM AUTHOR]

Aim: Several interferon (IFN)‐free, all‐oral regimens with direct acting antivirals (DAAs) for chronic hepatitis C virus (HCV) infection also include ribavirin (RBV). We investigated the influence of renal dysfunction on virologic efficacy and adverse effects in 189 patients with HCV genotype 2 infection who received combination RBV–DAA regimens. Methods: The incidence of RBV‐induced anemia, RBV dose reduction, and virologic efficacy were compared according to baseline renal function as defined by the estimated glomerular filtration rate (eGFR). Results: Patients with renal dysfunction (eGFR = 30–59 mL/min/1.73 m2) had higher rate of RBV dose reduction and more marked decreases in hemoglobin levels. These findings were more pronounced in patients with the ITPA CC genotype, who are more sensitive to RBV‐induced anemia. Although there were no statistically significant differences in sustained virologic response (SVR) rates according to renal function overall (P = 0.1650), the SVR rate was significantly lower in patients who required RBV dose reduction than in those who did not (P < 0.0001). Conclusions: Baseline renal dysfunction could unfavorably affect the outcomes of RBV–DAA in patients with chronic HCV infection due to the increased risk of RBV dose reduction, even in the era of IFN‐free DAA regimens. [ABSTRACT FROM AUTHOR]

Background & Aims: It remains controversial whether the eradication of hepatitis C virus (HCV) by interferon (IFN)‐free anti‐HCV therapy using direct‐acting antivirals (DAAs) suppresses or promotes hepatocellular carcinoma (HCC) development. We investigated the influence of HCV eradication by DAA therapy on HCC development, by observing changes of non‐hypervascular hypointense nodules (NHHNs) by gadolinium‐ethoxybenzyl‐diethylenetriamine pentaacetic acid‐enhanced magnetic resonance imaging (EOB‐MRI). Methods: A total of 401 patients treated with DAA therapy who did not have a history of HCC were enrolled in this prospective cohort study. All patients underwent EOB‐MRI prior to the start of DAA therapy and were followed up periodically after therapy. The progression of NHHNs detected at baseline to typical HCC, as indicated by hypervascularization and the incidence of newly emergent NHHNs, was analyzed. Results: In comparison of patients who achieved sustained virologic response (SVR) with propensity score‐matched patients with persistent HCV infection, there was no difference in the incidence of hypervascularization of NHHNs to typical HCC among patients who had NHHNs at baseline. Among patients who did not have NHHNs at baseline, the incidence of the new emergence of NHHNs did not differ between study patients and propensity score–matched patients with persistent HCV infection. Conclusions: During a 2‐year observation period after SVR, the eradication of HCV by IFN‐free DAA therapy did not suppress or enhance HCC development. (UMIN000017020). See Editorial on Page 446 [ABSTRACT FROM AUTHOR]

Background and Aim: To develop a scoring method using with common clinical data for predicting hepatocellular carcinoma (HCC) development after sustained virological response at 24 weeks (SVR24) after treatment with direct acting antivirals (DAAs), we retrospectively evaluated clinical features of patients who obtained SVR24. Methods: From October 2014 to December 2017, 1069 hepatitis C virus patients without a past history of HCC, who obtained SVR24 by DAAs at two different areas, were enrolled (the training [n = 484, ChuShikoku‐group] and validation [n = 585, Chubu‐group] sets). All were examined by ultrasonography as surveillance for HCC at the time of starting DAAs and twice a year after SVR24. We identified three parameters at SVR24, male gender, FIB‐4 index > 3.25, and α‐fetoprotein level > 5.0 ng/mL, as risk factors for HCC development and gave them point values, with the sum used as After DAAs Recommendation for Surveillance (ADRES) score. Results: In the ChuShikoku‐group, the respective 1‐/2‐year rates for HCC incidence rates ADRES score 0 were 0.0%/0.0%, for a score 1 were 1.1%/2.1%, score 2 were 8.8%/15.9%, and score 3 were 17.1%/28.1%. On the other hand, those respective scores for the Chubu‐group were 0.0%/0.0%, 0.0%/0.7%, 7.9%/10.6%, and 19.5%/not available. The c‐index of the predictive value for HCC development in the training set after SVR24 was 0.835 while 0.899 in the validation set. Finally, those of the entire cohort were 0.0%/0.0%, 0.5%/1.6%, 8.4%/13.4%, and 18.0%/32.8%. Conclusion: The present ADRES score was simple and easy to use and may be useful for predicting risk of HCC development in short term after reaching SVR24 by DAAs. [ABSTRACT FROM AUTHOR]

Aim: Although the development of new direct‐acting antivirals (DAAs) for the treatment of chronic hepatitis C virus (HCV) infection has markedly advanced, the effects of cirrhosis on DAA treatment remain unclear. We aimed to clarify the impact of cirrhosis on DAA treatment of patients infected with HCV. Methods: This large‐scale, multicenter, retrospective study consisted of 2130 HCV genotype 1b‐infected patients who were treated with one of the following DAA combination therapies: asunaprevir/daclatasvir (ASV/DCV), ledipasvir/sofosbuvir (LDV/SOF), or paritaprevir/ombitasvir/ritonavir (PTV/OBV/r). Ninety‐two patients (4.3%) previously received DAA‐based treatment. Seven hundred and forty‐five patients (34.9%) had cirrhosis. Results: Overall, the sustained virologic response (SVR) rate was 93.0%. The SVR rates in patients who received ASV/DCV, LDV/SOF, or PTV/OBV/r were 90.0%, 96.9%, and 97.6%, respectively. The SVR rate in patients with cirrhosis (89.1%) was significantly lower than that in patients without cirrhosis (95.1%, P = 6.94 × 10–7). In the multivariate analysis for the overall cohort, absence of cirrhosis (P = 1.26 × 10–3), no previous DAA‐based treatment (P = 2.54 × 10–14), low HCV‐RNA levels (P = 1.64 × 10–6), wild‐type non‐structural protein 5A L31/Y93 (P = 7.33 × 10–13), and DAA regimen (LDV/SOF or PTV/OBV/r) (P = 1.92 × 10–14) were independent factors contributing to SVR. Except for patients with DAA‐based treatment history, absence of cirrhosis (P = 2.15 × 10–3; odds ratio, 2.51) was an independent factor contributing to SVR in 2038 DAA‐naïve patients. Conclusion: This study suggests that the presence of cirrhosis reduces the SVR rate of DAA treatment, regardless of the type of DAA treatment. [ABSTRACT FROM AUTHOR]

Summary: The optimal term of follow‐up for patients who achieve sustained virological responses (SVR) is an important topic because of the widespread use of direct‐acting antivirals (DAA), which achieve a high SVR rate. Investigations of long‐term follow‐up among patients with SVR after interferon (IFN) therapy have reported that approximately 80%‐100% of patients maintained SVR. However, the long‐term durability of SVR to DAA treatment is unknown. The aim of this study was to evaluate the incidence of late relapse in patients who achieved SVR with daclatasvir (DCV) and asunaprevir (ASV). Four hundred and thirteen patients infected with hepatitis C virus (HCV) genotype 1b who completed ASV and DCV treatment and achieved SVR were selected. Patients who were persistently negative for serum HCV RNA at 24 weeks after withdrawal of DCV and ASV were considered to have SVR24. Mean follow‐up period was 21.5 months (range, 4.8‐30.3 months) after SVR24. Four patients redeveloped HCV RNA in serum at 6, 12, 12 and 26 months, respectively, after achieving SVR24. Results of molecular analysis by phylogenetic tree of HCV nonstructural protein 3 and 5A regions from late relapse indicated that the same strain was present at pretreatment and late relapse. In conclusion, late relapse by the original HCV strain was confirmed by direct sequencing in 4 of 413 patients with SVR to ASV and DCV. Although a few patients may develop late relapse, SVR achieved with all oral DAA therapy is as durable as that with IFN therapy. [ABSTRACT FROM AUTHOR]

Background and Aim: Amino‐acid substitutions in the interferon sensitivity‐determining region (ISDR) within the NS5A region are known to be associated with responsiveness to interferon (IFN)‐based therapy. Additionally, previous studies reported that the ISDR was related to the development of hepatocellular carcinoma (HCC) in patients infected with hepatitis C virus (HCV). However, the association between substitutions in the ISDR and the development of HCC in patients who achieved sustained virological response (SVR) is unclear. The aim of this study was to clarify the association between amino‐acid substitutions in the ISDR and development of HCC after SVR. Methods: One thousand five hundred eighty‐eight patients infected with HCV who were treated with IFN‐based therapy were enrolled, and 475 patients who achieved SVR and underwent complete virological analysis at pretreatment were investigated. HCV genotypes consisted of 1a (n = 10), 1b (n = 307), 2a (n = 110), 2b (n = 41), and 3a (n = 7), and the ISDR in each genotype was examined by direct sequencing. Results: Nineteen patients developed HCC after SVR. The cumulative incidence of HCC was 2.1% and 15.9% at 5 and 10 years after SVR, respectively. Multivariate analysis indicated older age (≥ 60 years: hazard ratio [HR], 3.23; P = 0.014), higher γ‐glutamyl transpeptidase level (≥ 50 IU/L: HR, 8.42; P < 0.001) and ≥ 3 substitutions in the ISDR (HR, 3.24; P = 0.016) as independent factors that were significantly associated with HCC development. Conclusion: Amino‐acid substitutions in the ISDR are useful to predict not only IFN responsiveness but also HCC development in patients who achieved SVR by IFN‐based therapy. [ABSTRACT FROM AUTHOR]

Background and Aim: On-treatment response of serum hepatitis C virus (HCV) is reportedly less useful to predict the outcome of anti-HCV therapy with interferon (IFN)-free regimen with direct-acting antivirals than with IFN-based regimens in clinical trials. We evaluated the significance of very early viral response after the start of therapy, which indicates direct HCV response to the drugs, on therapeutic outcome. Methods: Reductions in serum HCV-RNA levels were measured at 1 day after the start of therapy in 544 patients who underwent IFN-free direct-acting antiviral regimens. The association between these reductions and the achievement or failure of sustained virologic response (SVR) was evaluated. Results: Patient characteristics did not influence 1-day reduction in serum HCV-RNA except for liver fibrosis. There was no difference in 1-day HCV reduction between SVR and non-SVR patients treated with a 24-week regimen. In contrast, in patients treated with a 12-week regimen, 1-day reduction was significantly greater in SVR than in non-SVR patients (P = 0.0013) and was predictive of SVR versus non-SVR (area under the receiver-operating characteristics curve: 0.80). Conclusions: Whereas the reduction in serum HCV-RNA levels at 1 day after the start of therapy was not associated with treatment outcomes in patients who underwent a 24-week regimen of IFN-free therapy, there was an association in patients receiving a 12-week regimen, and this reduction was predictive of SVR, thus potentially serving as a factor to identify patients at risk of treatment failure. [ABSTRACT FROM AUTHOR]

Background and Aim There is insufficient research on whether direct-acting antiviral (DAA) therapy can improve liver fibrosis in patients with chronic hepatitis C virus (HCV). We evaluated sequential changes in liver stiffness using shear wave elastography in patients with HCV who received DAA therapy. Methods A total of 210 patients with HCV who received daclatasvir and asunaprevir therapy and achieved sustained virological response (SVR) were analyzed. Liver stiffness, as evaluated by shear wave elastography, and laboratory data were assessed before treatment (baseline), at end of treatment (EOT), and at 24 weeks after EOT (SVR24). Results Alanine aminotransferase levels (ALT) decreased over time, and there were significant differences between baseline and EOT and between EOT and SVR24. Although platelet counts did not significantly differ between baseline and EOT, they increased significantly from EOT to SVR24. The median (interquartile range) liver stiffness values at baseline, EOT, and SVR24 were 10.2 (7.7-14.7), 8.8 (7.1-12.1), and 7.6 (6.3-10.3) kPa, respectively ( P < 0.001, baseline vs EOT; P < 0.001, EOT vs SVR24). Additionally, in patients with ALT ≤ 30 (indicating low necroinflammatory activity in the liver) and Fibrosis-4 index > 2.0 ( n = 75), the liver stiffness values at baseline, EOT, and SVR24 were 9.6 (7.7-15.2), 9.2 (7.3-12.1), and 7.7 (6.3-10.1) kPa, respectively ( P < 0.001, baseline vs EOT; P < 0.001, EOT vs SVR24). Conclusion These results suggest that early improvement of liver stiffness starts during the administration of DAAs in patients who achieve SVR, and this effect is particularly pronounced in patients with progressive liver fibrosis. [ABSTRACT FROM AUTHOR]

Background and Aim Eradication of hepatitis C virus (HCV) with interferon (IFN)-based therapy has been reported to reduce all-cause mortality in patients with chronic HCV infection. However, the impact of HCV eradication on non-liver-related mortality and causes of death has not been sufficiently investigated in patients with progressive HCV-related fibrosis. Methods We enrolled 784 chronic HCV patients with progressive liver fibrosis (aspartate aminotransferase to platelet ratio index >1). Cause of death, incidence of hepatocellular carcinoma, and all-cause mortality including non-liver-related mortality were analyzed. Results Of these 784 patients, 170 achieved sustained virological response (SVR) (eradication of HCV) with IFN-based therapy (IFN-SVR), and 614 did not receive IFN-based therapy (non-IFN patients, chronic HCV infection). The median follow-up duration was 10.3 years. Two hundred seventy-three patients died during follow-up (liver-related death, n = 171; non-liver-related death, n = 102). The mortality rate from non-liver-related disease was 63.6% (7/11) in IFN-SVR patients and 36.3% (95/262) in non-IFN patients, respectively. In multivariate analysis, the eradication of HCV associated with not only hepatocellular carcinoma incidence (hazard ratio (HR), 0.162; 95% confidence interval (CI), 0.092-0.284), and all-cause mortality (HR, 0.094; 95% CI, 0.047-0.187), but non-liver-related mortality (HR, 0.286; 95% CI, 0.127-0.644) as well. Conclusions Eradication of HCV reduced both liver-related and non-liver-related mortality in patients with progressive HCV-related fibrosis. [ABSTRACT FROM AUTHOR]

The aim of this study was to determine the efficacy of two hepatitis C virus (HCV) real-time PCR assays, the COBAS AmpliPrep/COBAS TaqMan HCV test (CAP/CTM) and the Abbott RealTime HCV test (ART), for predicting the clinical outcomes of patients infected with HCV who received telaprevir (TVR)-based triple therapy or daclatasvir/asunaprevir (DCV/ASV) dual therapy. The rapid virological response rates in patients receiving TVR-based triple therapy were 92% (23/25) and 40% (10/25) for CAP/CTM and ART, respectively. The false omission rate (FOR) of ART was 93.3% (14/15), indicating that CAP/CTM could accurately predict clinical outcome in the early phase. In an independent examination of 20 patients receiving TVR-based triple therapy who developed viral breakthrough or relapse, the times to HCV disappearance by ART were longer than by CAP/CTM, whereas the times to HCV reappearance were similar. In an independent experiment of WHO standard HCV RNA serially diluted in serum containing TVR, the analytical sensitivities of CAP/CTM and ART were similar. However, cell cultures transfected with HCV and grown in medium containing TVR demonstrated that ART detected HCV RNA for a longer time than CAP/CTM. Similar results were found for 42 patients receiving DCV/ASV dual therapy. The FOR of ART was 73.3% (11/15) at week 8 after initiation of therapy, indicating that ART at week 8 could not accurately predict the clinical outcome. In conclusion, although CAP/CTM and ART detected HCV RNA with comparable analytical sensitivity, CAP/CTM might be preferable for predicting the clinical outcomes of patients receiving protease inhibitor-based therapy. [ABSTRACT FROM AUTHOR]

Aim We investigated the characteristics and prognosis of patients with hepatocellular carcinoma (HCC) diagnosed after sustained virological response (SVR) to antiviral therapy for chronic hepatitis C virus (HCV) infection, namely, the eradication of HCV, according to surveillance status after SVR. Methods In this multicenter study, liver function at HCC diagnosis and progression of HCC among patients with HCC diagnosed after SVR were compared. Outcomes were also investigated. Results In patients not under surveillance after SVR, HCC was significantly more advanced at diagnosis, with tumors that were larger in size and of higher stage than in patients who continued under surveillance after SVR. Survival rates were significantly lower in patients not under surveillance ( P < 0.0001). Among patients who were under surveillance, those with a 6-month surveillance interval had larger and higher stage HCC than patients with a 3-month interval. Recurrence rates in patients with a 6-month surveillance interval were significantly higher than in patients with a 3-month surveillance interval ( P = 0.0417). Conclusion Lack of surveillance after SVR was obviously associated with more advanced HCC at detection, resulting in poor prognosis. More importantly, there may be a difference in the severity of HCC at diagnosis and prognosis based on the surveillance interval after SVR. Establishing guidelines how to survey patients with chronic hepatitis C after SVR is necessary. [ABSTRACT FROM AUTHOR]

Background & Aims Eradication of hepatitis C virus ( HCV) by interferon ( IFN)-based therapy has been reported to reduce all-cause mortality rates in patients with chronic HCV infection. However, the impact of HCV eradication on non-liver-related mortality including the causes of death has not been sufficiently investigated in patients with chronic HCV infection. Methods We enrolled 2743 patients with chronic HCV infection. Causes of death, incidence of hepatocellular carcinoma ( HCC), and all-cause mortality including non-liver-related diseases, were analysed. Results Of these 2743 patients, 587 achieved sustained virological response ( SVR) (eradication of HCV) by IFN-based therapy ( IFN- SVR), 475 did not (without HCV eradication) ( IFN-non- SVR), or 1681 did not receive IFN-based therapy (non- IFN patients) (Cohort 1); of these, 309 were selected from IFN- SVR and non- IFN groups using propensity score matching (Cohort 2).The median follow-up duration was 11.4 years. In Cohort 1 patients, mortality rates from non-liver-related diseases were 71.0% (22/31) in IFN- SVR patients, 34.9% (37/106) in IFN-non- SVR patients and 50.0% (248/496) in non- IFN patients respectively. In Cohort 2 patients, mortality rates from non-liver-related diseases were 72.2% (13/18) in IFN- SVR patients and 46.8% (29/62) in non- IFN patients respectively. The eradication of HCV reduced all-cause mortality (hazard ratio ( HR), 0.265; 95% confidence interval ( CI), 0.058-0.380) including non-liver-related mortality ( HR, 0.439; 95% CI, 0.231-0.834) and the incidence of HCC ( HR, 0.275; 95% CI, 0.156-0.448). Conclusions Eradication of HCV reduced not only liver-related mortality but also non-liver-related mortality in patients with chronic HCV. [ABSTRACT FROM AUTHOR]

Aim Single nucleotide polymorphisms ( SNP) near the interleukin-28 B ( IL28B) gene affect the outcome of 24-week telaprevir-based triple therapy with telaprevir, pegylated interferon-α and ribavirin for chronic hepatitis C virus ( HCV) genotype 1b patients. We aimed to identify factors associated with treatment outcomes in patients with the unfavorable minor IL28B SNP genotype, who have poor response to combination therapy. Methods Pretreatment and on-treatment factors associated with sustained virological response ( SVR) for 24-week telaprevir-based triple therapy were analyzed using multiple logistic regression analysis in 106 HCV genotype 1b patients with the minor IL28B SNP rs8099917 genotype (non- TT). Results Of the 106 non- TT patients, 62 (58.5%) achieved SVR. Of the 44 remaining patients, 22 experienced relapse, 13 experienced viral breakthrough and nine were non-responders. Pretreatment factors such as treatment-naïve/prior treatment response ( P = 0.0041), high fasting serum low-density lipoprotein cholesterol ( LDL- C) concentration ( P = 0.0068) and low serum HCV RNA levels ( P = 0.0088) were significantly and independently associated with SVR. On-treatment factors such as achievement of rapid virological response ( RVR) were significantly and independently associated with SVR ( P = 0.0001). For both pre- and on-treatment factors, treatment-naïve/prior treatment response ( P = 0.0018), low pretreatment serum fasting LDL- C ( P = 0.0062) and achieving RVR ( P = 0.0021) were significantly and independently associated with SVR. Conclusion In HCV genotype 1b patients with the minor IL28B SNP rs8099917 genotype, evaluating prior treatment response and achieving RVR and pretreatment serum fasting LDL- C concentrations were useful for predicting SVR achievement after 24-week telaprevir-based triple therapy. [ABSTRACT FROM AUTHOR]

Background and Aims The population of patients chronically infected with hepatitis C virus ( HCV) is aging, and the number of older patients with HCV-related hepatocellular carcinoma ( HCC) is increasing. The purpose of this study was to elucidate the effects of peginterferon and ribavirin combination therapy on prevention of HCC in older patients with chronic hepatitis C ( CH- C). Methods We compared the sustained virological response ( SVR) and treatment discontinuation rates between older (≥ 65 years) and younger patients (< 65 years) among 1280 CH- C patients treated with peginterferon alfa-2b and ribavirin. Cumulative incidence of HCC was determined by Kaplan- Meier analysis, and factors associated with liver carcinogenesis were analyzed by Cox proportional hazards regression. Results Older patients had a significantly lower SVR rate and a significantly higher discontinuation rate of treatment than younger patients. Fifty patients developed HCC during median follow-up period of 47 months. Cox proportional hazards regression analysis indicated that the following were independent risk factors associated with the development of HCC: older age, male, advanced fibrosis, non- SVR in all patients: higher gamma-glutamyltranspeptidase, and non- SVR in older patients. Older patients who achieved SVR had a significantly reduced rate of HCC compared with those who did not achieve SVR, especially those who had gamma-glutamyltranspeptidase over 44 IU/ L. Conclusions The SVR rate was lower and the combination therapy discontinuation rate was higher in older CH- C patients than in younger patients. However, older patients who achieved SVR had a markedly lower rate of HCC development compared with older patients who did not achieve SVR. [ABSTRACT FROM AUTHOR]

Background and Aim The single nucleotide polymorphism ( SNP) of interleukin 28 B ( IL28B) and the mutations in the NS5A region of hepatitis C virus ( HCV) genotype 1 have been associated with response to interferon ( IFN) therapy. However, these relationships in patients with HCV genotype 2 are not well understood. The aim of this study was to investigate whether the SNP of IL28B (rs8099917) and amino acid substitutions in the NS5A region in patients with HCV genotype 2 affect the response to IFN and ribavirin combination therapy. Methods The study enrolled 286 patients with chronic hepatitis C genotype 2. Patients received pegylated- IFN-alpha 2b once each week plus oral ribavirin daily for 24 weeks. Results Of the 286 patients, 215 (75.2%) achieved sustained virologic response ( SVR). Rate of SVR was similar in patients with IL28B TT allele (76%) and those with TG or GG alleles (72%). Patients with SVR were younger than those without SVR ( P < 0.001). SVR was achieved in 65.9% of patients with wild-type IFN sensitivity-determining region ( ISDR) and 83.5% of patients with mutant type ( P < 0.001). There were no significant differences in other factors, including sex, alanine aminotransferase, platelet count, HCV viral load, HCV genotype, and IL28B genotype. The factors related to SVR on multivariate analysis were age ( P = 0.019) and ISDR ( P = 0.003). Conclusions ISDR sequence variations are significantly associated with IFN responsiveness in patients with HCV genotype 2. The SNP of IL28B was not associated with SVR in patients with HCV genotype 2. [ABSTRACT FROM AUTHOR]

Objective: Some patients with chronic hepatitis C virus (HCV) infection fail to achieve complete early virologic response (EVR) despite a marked decrease in HCV RNA at 4 weeks. We investigated the characteristics and final treatment outcomes of this patient subpopulation. Methods: A total of 516 patients with HCV genotype 1 were enrolled. Background characteristics and final outcomes were compared between patients who achieved complete EVR and those who did not among patients whose HCV RNA levels decreased 3.0 log10 or more at 4 weeks. Results: 78 of 334 patients (23.4%) with a ≥3.0 log10 reduction in HCV RNA levels at 4 weeks failed to achieve complete EVR. Female sex, higher pretreatment HCV RNA levels and lower baseline alanine aminotransferase (ALT) activity were independently associated with failure of complete EVR. The rate of sustained virologic response (SVR) in patients without complete EVR was 47.4%, significantly lower than that in patients with complete EVR (89.7%, p < 0.0001). Conclusions: Female patients, patients with higher pretreatment HCV RNA levels and patients with lower baseline ALT have a high likelihood of failure of complete EVR even when they had a ≥3 log10 reduction of HCV RNA at 4 weeks, resulting in a significantly lower SVR rate. © 2014 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Aim It has been reported that branched-chain amino acids ( BCAA) supplementation can improve nutritional status and reduce liver-related complications in patients with decompensated cirrhosis. BCAA supplementation reportedly reduces the incidence of hepatocellular carcinoma ( HCC) in obese cirrhotic patients infected with hepatitis C virus ( HCV). We investigated the effects of oral supplementation with BCAA granules on hepatocarcinogenesis in patients with HCV-related cirrhosis using propensity score matching. Methods A total of 60 patients with HCV-related cirrhosis and without history of HCC who were selected by one-to-one matching of propensity scores: 30 patients receiving 12 g/day of BCAA granules for 3 months or more ( BCAA group) and 30 being observed without BCAA supplementation (control group). The impact of BCAA supplementation was analyzed on the incidence of HCC. Results The 3- and 5-year rates of HCC development were 13.7% and 13.7% in the BCAA group and 35.1% and 44.5% in the control group, respectively. The BCAA group had a significantly lower rate of HCC than the control group ( P = 0.032). Multivariate analysis for factors that were associated with hepatocarcinogenesis indicated that BCAA supplementation was independently associated with a reduced incidence of HCC (hazard ratio 0.131; 95% confidence interval, 0.032-0.530; P = 0.004) along with sex and serum α-fetoprotein. Obesity (body mass index, ≥25 kg/m2) was not significantly associated with an increased incidence of HCC. Conclusion Oral supplementation with BCAA granules is associated with a reduced incidence of HCC in patients with HCV-related cirrhosis regardless of the presence of obesity based on the propensity score analysis. [ABSTRACT FROM AUTHOR]

Aim Previous studies have suggested that patients with chronic hepatitis C with a low pretreatment hepatitis C virus ( HCV) level have a high sustained virological response ( SVR) rate, and that there would be a subpopulation of patients in which HCV can be eradicated with pegylated interferon ( PEG IFN) alone without a decrease in SVR. However, the efficacy of PEG IFN monotherapy in patients with low HCV RNA levels is unclear. Several studies have reported that interferon sensitivity-determining region ( ISDR) and the single-nucleotide polymorphism ( SNP) of interleukin-28 B ( IL-28B) contribute to IFN response, but these relationships are controversial. The aim of this study was to determine whether the SNP of IL-28B (rs8099917) and amino acid substitutions in the ISDR among patients with low HCV levels affect the response to PEG IFN monotherapy. Methods One hundred and four patients with low-level HCV infection were studied. Low HCV level was defined as 100 KIU/m L or less. Results SVR was achieved in 94 patients (92.2%). HCV levels (≤50 KIU/m L) and ISDR (≥2 mutations) were associated with SVR on univariate analysis. The rates of SVR in the patients with IL-28B genotypes TT, TG and GG were 94.5%, 77.8% and 100%, respectively. The G allele tended to be associated with poor response to IFN therapy ( P = 0.0623). On multivariate analysis, the ISDR was the factor predictive of SVR ( P = 0.004). Conclusion The ISDR is significantly associated with a good response to PEG IFN monotherapy in patients with low HCV levels. [ABSTRACT FROM AUTHOR]

Background and Aim The average age of hepatitis C virus ( HCV)-related hepatocellular carcinoma ( HCC) patients has been rising in Japan. We evaluate characteristics of HCV-positive patients who develop HCC in older age to determine an optimal surveillance strategy. Methods A total of 323 patients with three or more years of follow-up before HCC diagnosis and 323 propensity-matched controls without HCC were studied. HCC patients were classified into four groups according to age at the time of HCC diagnosis: group A (≤ 60 years, n = 36), group B (61-70 years, n = 115), group C (71-80 years, n = 143), and group D (> 80 years, n = 29). Clinical and laboratory data were compared. Results Platelet counts were significantly higher in the older groups at HCC diagnosis ( P < 0.0001). The rate of platelet counts decline was lower in older groups ( P = 0.0107). The average integration value of serum alanine aminotransferase ( ALT) in groups A, B, C, and D were 80.9 IU/L, 62.3 IU/L, 59.0 IU/L, and 44.9 IU/L, respectively ( P < 0.0001). In older patients (≥ 65 years old), cirrhosis and average integration value of ALT were significantly associated with hepatocarcinogenesis, but platelet count was not. Conclusion Elderly HCV-positive patients (≥ 65 years old) with low ALT values developed HCC regardless of their platelet counts. These findings should be taken into account when designing the most suitable HCC surveillance protocol for this population. [ABSTRACT FROM AUTHOR]

Background and aims: Mutations in the core and NS5A region of hepatitis C virus (HCV) genotype 1b have been associated with response to interferon (IFN) therapy. Genome-wide association studies have revealed that the single-nucleotide polymorphism (SNP) of interleukin 28B (IL28B) contributes to IFN response. The aim of this study was to investigate whether the SNP of IL28B (rs8099917) and amino acid substitutions in the core and NS5A region affect the response to IFN therapy. Methods: A total of 299 patients (157 men, 142 women; mean age, 55.9 ± 10.3 years) infected with HCV genotype 1b were studied. The fibrosis stage was diagnosed as F0 ( n=23), F1 ( n=121), F2 ( n=62), F3 ( n=32) and F4 ( n=7) by liver biopsy. Results: Of the 299 patients, 138 achieved sustained virological response (SVR). On univariate analysis, predictors of SVR were age <60 years, male gender, higher platelet count, lack of fibrosis, non-Q at core 70, mutant-type interferon sensitivity-determining region (ISDR) and IL28B genotype TT. The factors related to SVR on multivariate analysis were IL28B ( P=0.0001), fibrosis ( P=0.0111) and mutations in the core region70 ( P=0.0267) and ISDR ( P=0.0408). The best SVR was achieved in patients with non-Q70, mutant-type ISDR and T allele (74.5%), and the worst was achieved in patients with Q70, wild-type ISDR and G allele (8.1%). Conclusions: The SNP of IL28B and mutations in the core region and NS5A are associated with IFN responsiveness. Both host and viral factors might be useful for predicting IFN response. [ABSTRACT FROM AUTHOR]

Background: Increases in tumor markers are sometimes seen in patients with chronic liver disease without hepatocellular carcinoma (HCC). The aim of this study was to determine the relationship between the levels of three tumor markers [alpha-fetoprotein (AFP), Lens culinaris agglutinin-reactive fraction of AFP (AFP-L3%), and des-γ-carboxy prothrombin (DCP)] and hepatic carcinogenesis to identify hepatitis C virus (HCV) carriers at high risk for cancer development. Methods: A total of 623 consecutive HCV carriers with follow-up periods of >3 years were included. The average integration values were calculated from biochemical tests, and tumor markers, including AFP, AFP-L3%, and DCP, and factors associated with the cumulative incidence of HCC were analyzed. Results: HCC developed in 120 (19.3%) of the 623 patients. Age >65 years [adjusted relative risk, 2.303 (95% confidence interval, 1.551-3.418), P < 0.001], low platelet count [3.086 (1.997-4.768), P < 0.001], high aspartate aminotransferase value [3.001 (1.373-6.562), P < 0.001], high AFP level [≥10, <20 ng/mL: 2.814 (1.686-4.697), P < 0.001; ≥20 ng/mL: 3.405 (2.087-5.557), P < 0.001] compared to <10 ng/mL, and high AFP-L3% level [≥5, <10%: 2.494 (1.291-4.816), P = 0.007; ≥10%: 3.555 (1.609-7.858), P < 0.001] compared to <5% were significantly associated with an increased incidence of HCC on multivariate analysis. Conclusions: Increased AFP or AFP-L3% levels were significantly associated with an increased incidence of HCC. Among HCV carriers, patients with ≥10 ng/mL AFP or patients with ≥5% AFP-L3% are at very high risk for the development of HCC even if AFP is less than 20 ng/mL or AFP-L3% is less than 10%, which are the most commonly reported cutoff values. [ABSTRACT FROM AUTHOR]

Background and Aim: We prospectively compared the sensitivity to interferon (IFN) and the efficacy of antiviral combination therapy with peginterferon (PEG-IFN) and ribavirin for chronic hepatitis C virus (HCV) genotype 1b infection according to the amino acid sequences of the HCV core, E1, and NS5A regions reported to be associated with the outcome of antiviral therapy. Methods: A total of 107 patients with HCV genotype 1b were investigated. All patients received combination therapy with PEG-IFN alpha-2b and ribavirin. Amino acids 70 and 91 (core), 139 (E1), and 2209–2248 (NS5A) of HCV were analyzed by direct nucleotide sequencing. Results: The reduction in HCV RNA concentration at 24 h after a single administration of conventional IFN-alpha and after the start of combination therapy was significantly less marked, and rates of complete early virologic response, end-of-treatment response, and sustained virologic response (SVR) were significantly lower (all P < 0.0001) in patients with glutamine at amino acid 70 ( n = 29) than in those with arginine at that position ( n = 70). We found no differences associated with the other amino acid positions. Amino acid 70 was an independent factor for the responses to the therapy in multivariate analysis. Conclusion: The identity of amino acid 70 of the HCV core region affected the sensitivity to IFN; patients with glutamine at amino acid 70 of HCV showed resistance to IFN. Consequently, it strongly affected the outcome of combination therapy with PEG-IFN and ribavirin in Japanese patients with HCV genotype 1b. [ABSTRACT FROM AUTHOR]

Objectives: The aim of this study was to evaluate the efficacy and indication of combination therapy with ribavirin plus peginterferon-α-2b in chronic hepatitis C virus (HCV) patients aged 65 years and older. Methods: Five hundred and ninety-one consecutive HCV patients were treated with combination therapy. These patients were divided into elder patients (≥65 years) ( n=115) and younger patients (<65 years) ( n=476). The clinical characteristics, sustained virological response (SVR) rates and discontinuation rates were compared between the two groups. Results: Compared with younger patients, baseline haemoglobin levels and baseline platelet counts were significantly lower ( P<0.0001, P=0.013 respectively) and fibrosis was more advanced in elderly patients ( P=0.0310). Moreover, the SVR rate was significantly lower (37.4 vs. 51.5%; P=0.0067) while the combination therapy discontinuation rate was significantly higher (32.2 vs. 17.0%; P=0.0003) in elderly patients. A multivariate analysis revealed that HCV load and genotype were significantly associated with an SVR in elderly patients. An SVR was achieved in over 50% of elderly male patients with genotype 1 and HCV RNA concentrations under 2 000 000 IU/ml. In contrast, the SVR rate was under 30% in elderly male patients with genotype 1 and with HCV RNA concentrations over 2 000 000 IU/ml and in all elderly female patients with genotype 1. Conclusions: The SVR rate was lower in elderly patients than in younger patients. However, in elderly patients combination therapy was most beneficial for genotype 1 patients, male patients with HCV RNA concentrations <2 000 000 IU/ml and patients with genotype 2. [ABSTRACT FROM AUTHOR]

Abstract: Background: The “response-guided therapy” based on response of hepatitis C virus (HCV) during antiviral combination therapy with peginterferon and ribavirin is important for patients with HCV genotype 1. However, the sensitivity of previous assays for serum HCV RNA is limited. Objectives: We evaluated the changes in serum HCV RNA during the combination therapy using a novel method for measurement based on real-time PCR. Study design: Changes in serum HCV RNA during the combination therapy were reanalyzed using TaqMan PCR assay in 144 patients with chronic HCV genotype 1b infection who underwent the therapy under HCV RNA monitoring with the Amplicor Monitor assay. Treatment duration was elongated from 48 weeks to 72 weeks in 17 patients based on the time when serum HCV RNA became negative. Results: In 9 of 144 (6.3%) patients, serum HCV RNA transiently appeared again on the TaqMan PCR assay after having previously become negative. At the point of reappearance, the Amplicor Monitor assay gave a negative result in all patients, and no flare of alanine aminotransferase activity was observed. Each of the 9 patients achieved an end-of-treatment response but relapsed after the end of treatment, including 3 patients in whom the treatment duration was elongated to 72 weeks. Conclusions: Attention should be paid to this phenomenon in the antiviral treatment for patients with HCV infection. The transient reappearance of HCV RNA in the serum indicates a high likelihood of relapse, and is likely to be missed without frequent measurements by a sensitive detection method. [Copyright &y& Elsevier]

Background/Aims: This study sought to identify the independent risk factors involved in the development of hepatocellular carcinoma (HCC) in patients with chronic hepatitis C virus (HCV) infection who have normal alanine aminotransferase (ALT) levels. Methods: A total of 519 patients with average ALT integration values less than or equal to 40 IU/L over 10 years were included. Baseline ultrasound was done in all patients and 68 patients underwent liver biopsy at the start of this study. Factors associated with the cumulative incidence of HCC were determined. Results: HCC occurred in 48 of 519 patients (9.2%). The following factors were significantly associated with the incidence of HCC: age>65 years (adjusted hazard ratio: 2.006 [95% confidence interval: 1.078–3.733]), ALT>20 IU/L (6.242 [1.499–25.987]), platelet count<15.0×104/m3 (2.675 [1.407–5.085]), total bilirubin>1.2mg/dL (2.798 [1.257–6.228]), ALP>338 IU/L (2.486 [1.327–4.657]), and total albumin<3.5g/dl (2.707 [1.177–6.223]). The 5- and 10-year cumulative incidences of HCC were 4.4% and 26.5% in patients with ALT>20 IU/L and platelet count<15.0×104/m3, respectively. Conclusions: High ALT level and low platelet count are closely associated with the development of hepatocarcinogenesis. Therefore, individuals within this group are candidates for antiviral therapy. [Copyright &y& Elsevier]