Machine learning for individualized prediction of hepatocellular carcinoma development after the eradication of hepatitis C virus with antivirals.

BACKGROUND AND AIMS: Accurate risk stratification for hepatocellular carcinoma (HCC) after achieving a sustained viral response (SVR) is necessary for optimal surveillance. We aimed to develop and validate a machine learning (ML) model to predict the risk of HCC after achieving an SVR in individual patients. METHODS: In this multicenter cohort study, 1742 patients with chronic hepatitis C who achieved an SVR were enrolled. Five ML models were developed including DeepSurv, gradient boosting survival analysis, random survival forest (RSF), survival support vector machine, and a conventional Cox proportional hazard model. Model performance was evaluated using Harrel' c-index and was externally validated in an independent cohort (977 patients). RESULTS: During the mean observation period of 5.4 years, 122 patients developed HCC (83 in the derivation cohort and 39 in the external validation cohort). The RSF model showed the best discrimination ability using seven parameters at the achievement of an SVR with a c-index of 0.839 in the external validation cohort and a high discriminative ability when the patients were categorized into three risk groups (P <0.001). Furthermore, this RSF model enabled the generation of an individualized predictive curve for HCC occurrence for each patient with an app available online. CONCLUSIONS: We developed and externally validated an RSF model with good predictive performance for the risk of HCC after an SVR. The application of this novel model is available on the website. This model could provide the data to consider an effective surveillance method. Further studies are needed to make recommendations for surveillance policies tailored to the medical situation in each country. IMPACT AND IMPLICATIONS: A novel prediction model for HCC occurrence in patients after hepatitis C virus eradication was developed using machine learning algorithms. This model, using seven commonly measured parameters, has been shown to have a good predictive ability for HCC development and could provide a personalized surveillance system.

Characteristics of patients aged over 75 years with hepatitis C virus infection treated with direct-acting antivirals in Japan: Evidence based on the nationwide, real-world database in Japan.

AIM: Direct-acting antivirals (DAAs) have dramatically changed the treatment of chronic hepatitis C. Their high efficacy helps in eradicating hepatitis C virus with few adverse events. Information on real-world use of DAAs therapy in patients aged 75 years and older is inadequate. METHODS: The Japanese DAAs database was constructed in 2014 as a cooperative system between 18 prefectures. The medical reports filled in by doctors and anonymized at the local government office were collected. The patients' demographic features, viral factors, and treatment characteristics were compared among three groups stratified by age when therapy was initiated: Group A (<60 years old), Group B (60-74 years old), and Group C (≥75 years old). RESULTS: Out of the 22,454 patients whose age upon starting therapy could be identified, 24.8% (n = 5597) belonged to Group C, which was ten times the number in the Japanese Interferon Database. Female patients, advanced stages of liver fibrosis, and past history of hepatocellular carcinoma treatment were significantly higher in the older age groups (Group A < B < C), whereas sustained virologic response (SVR) rates were not different (91%-93%). In Group C, multivariate logistic regression analysis revealed that predicting factors for virologic response varied among DAAs regimens. However, the completion of DAAs therapy commonly contributed to SVR, regardless of DAAs regimen. CONCLUSIONS: DAAs therapy is associated with high SVR rates, even in the oldest age group, and therapy should not be withheld on the basis of old age.

Nationwide survey on activities of regional core centers for the management of liver disease in Japan: Cumulative analyses by the Hepatitis Information Center 2009-2017.

AIM: Regional core centers for the management of liver disease, which are located in every prefecture in Japan, not only take the lead in hepatitis care in their respective regions, but also serve a wide range of other functions, such as education, promotion of hepatitis testing, treatment, and research. METHOD: Since fiscal year 2010, the Hepatitis Information Center has conducted surveys of regional core centers throughout Japan regarding information about their facilities, programs for patient support, training, and education of medical personnel. RESULTS: By compiling and analyzing the results of these surveys, we have elucidated the status of regional core centers and the issues they currently have. We found that regional core centers have come to play widely varied roles in hepatitis treatment and have expanded their programs. These surveys also suggest that uniform accessibility of hepatitis treatment has been implemented throughout Japan. CONCLUSION: To continue serving their diverse roles, regional core centers require further development of hepatitis care networks that include specialized institutions, primary care physicians, and local and central governments; as well as collaboration with other professions and groups.

Clinical features of hepatocellular carcinoma in nonalcoholic fatty liver disease patients without advanced fibrosis.

BACKGROUND AND AIM: The prevalence of hepatocellular carcinoma (HCC) associated with nonalcoholic fatty liver disease (NAFLD-HCC) is increasing. Unfortunately, NAFLD frequently develops into HCC without liver cirrhosis. Therefore, we investigated the clinical features of HCC in NAFLD patients without advanced fibrosis. METHODS: We compared clinical characteristics, survival rates, and recurrence rates between 104 NAFLD-HCC patients diagnosed between January 2000 and December 2016, including 35 without (F0-2) and 69 with advanced fibrosis (F3-F4). Risk factors associated with survival and recurrence were evaluated. RESULTS: In total, 66.3% of those diagnosed had advanced fibrosis, 58.8% in men and 80.5% in women (men vs women, P = 0.03). In NAFLD-HCC without advanced fibrosis, tumor size was significantly larger and liver histological activity was lower than those in patients with advanced fibrosis. Survival rates between the two groups did not differ. Among those achieving curative treatment, the recurrence rate was significantly lower in NAFLD-HCC without advanced fibrosis (P < 0.01). Risk factors of recurrence were male gender, lower serum albumin, and advanced fibrosis. CONCLUSIONS: In men, HCC tended to develop from NAFLD without advanced fibrosis. Although tumor size in NAFLD-HCC without advanced fibrosis is significantly larger, the recurrence rate is significantly lower. Surgical therapy should be strongly considered in these cases.

Medication Adherence Among Patients With Chronic Hepatitis Receiving Antiviral Treatment.

This study aimed to evaluate medication adherence and associated factors among patients with chronic viral hepatitis. A cross-sectional questionnaire survey was conducted in 171 outpatients receiving antiviral treatment of chronic viral hepatitis at 6 national/regional liver disease treatment centers in Japan. Medication adherence was calculated as the subject-reported number of antiviral tablets taken in the past 2 weeks compared with the prescribed number of tablets. Subjects were divided according to 100% adherence or nonadherence. The impact of items pertaining to everyday experiences and perceptions regarding medication adherence were examined. Factors associated with medication adherence were identified via multiple logistic regression. The mean medication adherence rate was 95.8% ± 9.5% (range = 0%-100%), although a smaller proportion (95 subjects; 55.6%) was 100% adherent. Multiple logistic regression indicated a greater "lack of understanding of need for medication" (1 point: odds ratio (OR) = 1.51, 95% confidence interval (CI) [1.30, 1.76], p ≤ .01) and greater "restriction in life due to medication" (1 point: OR = 1.26, 95% CI [1.03, 1.54], p = 0.03) as associated with nonadherence. In conclusion, to improve medication adherence, healthcare professionals should improve patients' understanding of the need for medication and minimization of life restrictions.

Factors improving the utility of antiviral therapy for chronic hepatitis B: A nationwide multicenter study in Japan.

AIM: The consideration of patients' needs in terms of research outcomes is emphasized in research promotion to eradicate hepatitis B virus according to the Basic Act on Hepatitis Measures in Japan. This study analyzed patients' attitudes toward experienced antiviral therapies for chronic hepatitis B and their need for future therapies. METHODS: A self-administered questionnaire comprising 124 questions was completed among patients with chronic hepatitis B from 61 core-center hospitals designated to implement and research policies on hepatitis in 47 prefectures from August 2013 to January 2014 (n = 3021, response rate = 51%). RESULTS: In decision-tree models with 333 variables generated from the questionnaire data, patients' satisfaction with therapy and reduction in anxiety about therapy were dependent on favorable therapeutic effects, sufficient information provided by the physician, and fewer lifestyle disturbances. Medical expenses were not selected at a superior branch because subsidy for antiviral therapy started in 2010. In correspondence analysis of free text answers, patients' need for therapy and support mechanisms differed among their attributes, including a great need for novel therapy in older men, hope for avoidance of lifestyle disturbance in younger men, and alleviation of painful experience with the disease in women. CONCLUSIONS: Continual provision of sufficient information is necessary to improve the utility of antiviral therapy for chronic hepatitis B as well as for favorable therapeutic effects. The patients believed that novel drugs and support would reduce the diverse burden of the disease on their lives.

The Safety Profile of Telaprevir-Based Triple Therapy in Clinical Practice: A Retrospective Cohort Study.

This study was designed to evaluate the safety profile of adding telaprevir to therapy using pegylated interferon-alfa-2b and ribavirin (PR) using real world patient data obtained from a nationwide Japanese interferon database. This retrospective cohort study compared telaprevir-based triple therapy (T/PR) with PR therapy. The study population comprised patients with genotype 1 chronic hepatitis C represented in the database between December 2009 and August 2015. The primary endpoint was dropout from treatment due to adverse events during the relevant standard treatment duration based on guidelines from the Japan Society of Hepatology. The dropout odds ratio (OR) and 95% confidence interval (95% CI) were calculated using univariate logistic regression analysis. Covariates were detected using a stepwise logistic regression analysis, and the adjusted OR and 95% CI were calculated. A total of 25989 patients were registered, and 4619 patients (T/PR: 1334, PR: 3285) were appropriate for primary endpoint analysis. The dropout rate due to adverse events was lower in the T/PR group (13.4%) than in the PR group (22.6%) (OR: 0.530; 95% CI, 0.444-0.633). After adjustment for the covariates detected by stepwise selection, the OR was 0.529 (95% CI, 0.441-0.634). Our study showed that there was a difference in dropout rate between real world T/PR and PR therapy in Japan. Although the addition of telaprevir to PR therapy may improve treatment continuity under the care of hepatologists, this study could not fully determine which therapy was safer or the factors influencing this result. Therefore, additional research will be required to confirm this.

Risk Factors for Treatment Discontinuation Caused by Adverse Events When Using Telaprevir, Peginterferon, and Ribavirin to Treat Chronic Hepatitis C: A Real-World Retrospective Cohort Study.

In this study, a nationwide database was used to identify the risk factors for treatment discontinuation due to adverse events during telaprevir, peginterferon, and ribavirin (T/PR) treatment, and estimate the increase in the occurrence of adverse events when patients have multiple risk factors at the same time. The risk factors were identified using univariate logistic regression analysis, and a Cochran-Armitage trend test was used to analyze the correlation between the number of risk factors and treatment discontinuation due to adverse events. Of the 25989 individuals registered in the database, 1668 (age, mean±standard deviation (S.D.): 58.0±9.9) were included in the study. Of these, 188 (11.3%) discontinued T/PR therapy due to adverse events. In the univariate logistic regression analysis, sex, age, aspartate aminotransferase (AST) level, and platelet count were found to significantly affect the incidence of T/PR treatment discontinuation (p<0.05). Furthermore, the incidence of treatment discontinuation gradually increased from 4.6 to 27.2% as the number of risk factors increased from 0 to 4, and the Cochran-Armitage trend test showed a significant correlation (p<0.001). In conclusion, this study not only revealed the risk factors for treatment discontinuation but also showed that patients with multiple risk factors are more likely to discontinue treatment due to adverse events compared to patients with fewer risk factors.

Cost-Outcome Description of PEG-IFN-α2b+RBV for Hepatitis C: Results Based on the Interferon Database.

Economic evaluation of drugs is used in decision-making on medical care and public policy. Recently, real-world data (RWD) have been used in the analysis. In this study, we discuss the risk and benefits of using RWD for economic evaluation. We conducted a cost-outcome description with RWD from a nationwide registry providing information on hepatitis treatment in Japan and estimated the utility of the analysis. We evaluated the cost-outcome description of peginterferon plus ribavirin (PEG-IFN-α2b+RBV) treatment in hepatitis C virus (HCV)-infected patients. Simulations were based on a Markov model. The cohorts were set using data from the registry and we assumed a societal perspective for the calculation of costs. The dose and drug cost were chosen based on the Japanese Guidelines for the Management of Hepatitis C Virus Infection or package inserts. Model details and parameters were as described in previous studies. The simulations were performed for a period of 10 years with no discount rate. We estimated 2.5 million JPY per Quality Adjusted Life Year (QALY) in 48-week PEG-IFN-α2b+RBV treatment for a period of 10 years. The results of this study are in agreement with previous HCV treatment economic evaluation studies in Japan. We analyzed the statistics of the HCV-infected patients at each disease stage using the data in our registry and calculated the costs. The results of this study more closely reflect a real-world clinical situation compared to the widely used randomized clinical trial method, which estimates clinical trial results and scenarios.

Safety Profile of Telaprevir-Based Triple Therapy in Elderly Patients: A Real-World Retrospective Cohort Study.

To compare the rate of treatment discontinuation due to adverse events for telaprevir-based triple (T/PR) and pegylated interferon-alfa-2b and ribavirin (PR) therapy for the treatment of hepatitis C virus (HCV) infection in patients over the age of 65 years, in Japan. Retrospective analysis of the health data of patients over the age of 65 years treated for a HCV infection genotype 1 using T/PR or PR therapy, from 38 prefectures in Japan. The primary outcome was the rate of treatment discontinuation due to adverse events for T/PR and PR. The secondary outcome was to evaluate the prevalence and type of adverse events during the treatment period that resulted in treatment discontinuation for both therapies. For comparison, the T/PR and PR populations were matched using the propensity score method, and adjusted odds ratios (ORs) for treatment discontinuation calculated by multivariate logistic regression analysis. The study group included 1330 patients, 328 in the T/PR group and 1002 in the PR group. The rate of treatment discontinuation due to adverse events in the matched population was lower for T/PR (19.82%) than PR (35.98%) therapy, (adjusted OR, 0.418; 95% confidence interval, 0.292-0.599; p<0.01). Malaise was the principal cause of treatment discontinuation in both groups (T/PR, 30.77%, and PR, 42.37%). Using real-world health data of elderly individuals in Japan, we identified a lower rate of treatment discontinuation for T/PR than PR. Our outcomes provide information for a segment of the population that is generally excluded for clinical trials.

Pretreatment serum levels of interferon-gamma-inducible protein-10 are associated with virologic response to telaprevir-based therapy.

AIM: Telaprevir (TVR) remarkably improves the efficacy of interferon treatment for chronic hepatitis C. Interleukin-28B (IL28B) genotype and interferon-gamma-inducible protein-10 (IP-10) level predict virologic response to peg-interferon (Peg-IFN)/ribavirin (RBV) therapy. We aimed to investigate the usefulness of pretreatment serum IP-10 levels and IL28B genotyping in predicting sustained virologic response (SVR) to TVR-based triple therapy. METHODS: In this multi-center study, patients infected with hepatitis C virus genotype 1 with high viral load (⩾5.0logIU/mL) were treated with TVR for 12weeks and Peg-IFN/RBV for 24weeks in Japan. IL28B genotype, serum IP-10 levels, other clinical parameters, and drug dosages were assessed before treatment. RESULTS: We included 121 patients who were treated with TVR for at least 8weeks and Peg-IFN/RBV for 24weeks. The median IP-10 levels were significantly lower in rapid virologic response (RVR) or SVR in the IL28B non-TT genotype group, with no significant difference in the TT genotype group. RVR rates were significantly lower in the group with higher serum IP-10 levels (>450pg/mL). In the non-TT IL28B genotype group, RVR and SVR rates were significantly lower in the group with higher IP-10 levels. SVR rates in the group with lower IP-10 levels (<450pg/mL) increased to 82% for those showing RVR, but reduced to 27% in the group with higher IP-10 levels for those not showing RVR. CONCLUSIONS: Determination of serum IP-10 levels before treatment could be useful for predicting favorable virologic response to TVR-based triple therapy, especially in patients with IL28B non-TT genotype.

Hepatitis B virus vaccination-related seroprevalence among health-care personnel in a Japanese tertiary medical center.

AIM: Few studies concerning the protective management of hepatitis B virus (HBV) infection among health-care personnel (HCP), excluding occult HBV or carriers, have been reported. Therefore, we undertook a cross-sectional study of the updated status of HBV vaccine management by measuring the antibody to hepatitis B surface antigen (anti-HBs) along with the antibody to hepatitis B core antigen (anti-HBc). METHODS: Both anti-HBs and anti-HBc were assessed in 1085 HCP employed by our institute. Hepatitis B virus vaccination-related histories were recorded using self-administered questionnaires. RESULTS: Of 1085 HCP, 27 (2.5%) were positive for anti-HBc, and its positive rate increased with age. Of the 1058 subjects with negative anti-HBc, 879 (83.1%) were positive for anti-HBs. The median titer of anti-HBs was 71.1 mIU/mL, which was higher in female subjects (P = 0.037). By age group, the positive rate of anti-HBs were 77.5%, 89.3%, 90.8%, and 81.6% in the groups aged ≤29, 30-39, 40-49, and ≥50 years, respectively (P < 0.001). Of the 908 subjects who reported receiving HBV vaccination, 6 (0.7%) were positive for anti-HBc. Among them, one subject was suspected to have a possible subclinical HBV infection after the HBV vaccination. CONCLUSION: We report the current HBV vaccination-related seroprevalence of anti-HBs along with anti-HBc in a Japanese tertiary medical institution consisting of more than 1000 HCP, which was an level comparable to similar sized hospitals in developed countries. Anti-HBc would be important for understanding HBV status, but not necessary for general HBV vaccine management for HCP.

Geographic distribution and characteristics of genotype A hepatitis B virus infection in acute and chronic hepatitis B patients in Japan.

BACKGROUND AND AIMS: The prevalence of sexually transmitted acute infections of the genotype A hepatitis B virus (HBV) has been increasing in Japan. Genotype A HBV is associated with an increased risk of HBV progression to chronic infection after acute hepatitis B (AHB) in adults. A nationwide survey was conducted to evaluate the geographic distribution, clinical, and virologic characteristics of genotype A AHB and chronic hepatitis B (CHB) in Japan. METHODS: Five hundred seventy AHB patients were recruited between 2005 and 2010, and 3682 CHB patients were recruited between 2010 and 2011. HBV genotypes were determined for 552 and 3619 AHB and CHB patients, respectively. Clinical characteristics were compared among different genotypes in AHB and CHB patients. Genomic characteristics of HBV genotype A were examined by molecular evolutionary analysis. RESULTS: Hepatitis B virus genotype A was the predominant genotype for AHB between 2005 and 2010. Phylogenetic analysis showed that all strains in the AHB patients with genotype A were classified into subtype Ae. Among CHB patients, the occurrence of genotype A was 4.1%, and genotype A was spreading in young adults. In genotype A CHB patients, early stage liver diseases were predominant, although liver diseases progressed to cirrhosis or hepatocellular carcinoma in some patients. CONCLUSIONS: The distribution of HBV genotypes is quite different between AHB and CHB in Japanese patients. Genotype A infection is spreading in young adults of Japanese CHB patients. Sequences derived from Japanese AHB patients were identical to or closely resembled the sequences derived from other Japanese AHB patients.

Regional Differences in Hepatitis C Treatment with Peginterferon and Ribavirin in Japan in Both Genotype 1 and Genotype 2: A Retrospective Cohort Study.

There has been no report on the genotype-dependent regional, especially prefectural, differences in hepatitis C treatment in Japan. We conducted a retrospective cohort study using the nationwide database. The registration period of the database was from December 2009 to April 2013. Individuals with chronic hepatitis C were identified from the database. The sustained virologic response (SVR) rates in each prefecture were calculated stratified by genotype. Confounding variables were identified using stepwise logistic regression analysis. The range of the point estimate of the adjusted odds ratio explained prefectural differences in treatment outcomes. During the registration period, 36 prefectures registered cases to the database. A total of 16349 cases were registered and 11653 cases were included in the analysis. The mean age was 57.9±10.5 years; 7950 (68.2%) had hepatitis C virus (HCV) genotype 1 and 3703 (31.8%) had HCV genotype 2. The range in SVR rates was 30.0 to 63.0% for genotype 1 and 55.0 to 100.0% for genotype 2. In the multivariate analysis, the ranges of the adjusted odds ratio of each prefecture were 0.658 to 2.125 for genotype 1 and 0.364 to 2.630 for genotype 2. Our results suggest that regional, particularly prefectural, differences in chronic hepatitis C treatment with peg-interferon (IFN) and ribavirin (RBV) exist in Japan and that these regional differences may similarly exist both in HCV genotypes 1 and 2. Additional studies using these methods, considering medical situations in each prefecture and new treatments regimens, could greatly contribute to improving and standardizing chronic hepatitis C treatment.

Comparison of the Safety Profiles of Pegylated Interferon α-2a and α-2b Administered in Combination with Ribavirin for Chronic Hepatitis C Infection: A Real-World Retrospective Cohort Study.

This study compares the safety profiles of pegylated interferon (PEG-IFN) α-2a and α-2b administered in combination with ribavirin, based on the variable of time to withdrawal from treatment due to adverse events. We conducted a real-world retrospective cohort study using the Japanese interferon database. Based on eligibility criteria, individuals with chronic hepatitis C virus (HCV) infection were identified in the database covering the period December 2009 to August 2015. The primary outcome measure was defined as difference in time to withdrawal from treatment due to adverse events between patients receiving PEG-IFN α-2a combined with ribavirin and those receiving PEG-IFN α-2b combined with ribavirin. The difference was analyzed using the multivariate Cox proportional hazards regression model. A frailty model was also applied to consider regional (prefectural) variation. After eligibility evaluation, 11058 individuals were included in the analysis. 3774 were treated with PEG-IFN α-2a, and 6764 with PEG-IFN α-2b, with 11.84 and 12.30% respectively withdrawing from treatment due to adverse events. The Cox model showed no significant difference between the two groups (hazard ratio (HR), 95%CI; 0.918, 0.817 to 1.031; p=0.1475). The results were consistent even when regional variation and other confounding variables were adjusted in the frailty model. In conclusion, there may be no difference in time to withdrawal from treatment due to adverse events between PEG-IFN α-2a and PEG-IFN α-2b combined with ribavirin. Applying the method used here to future studies using novel treatment regimens may also provide important information for the treatment of chronic HCV infection in clinical practice.

Genome-wide association study identifies a PSMD3 variant associated with neutropenia in interferon-based therapy for chronic hepatitis C.

Cytopenia during interferon-based (IFN-based) therapy for chronic hepatitis C (CHC) often necessitates reduction of doses of drugs and premature withdrawal from therapy resulting in poor response to treatment. To identify genetic variants associated with IFN-induced neutropenia, we conducted a genome-wide association study (GWAS) in 416 Japanese CHC patients receiving IFN-based therapy. Based on the results, we selected 192 candidate single nucleotide polymorphisms (SNPs) to carry out a replication analysis in an independent set of 404 subjects. The SNP rs2305482, located in the intron region of the PSMD3 gene on chromosome 17, showed a strong association when the results of GWAS and the replication stage were combined (OR = 2.18, P = 3.05 × 10(-7) in the allele frequency model). Logistic regression analysis showed that rs2305482 CC and neutrophil count at baseline were independent predictive factors for IFN-induced neutropenia (OR = 2.497, P = 0.0072 and OR = 0.998, P < 0.0001, respectively). Furthermore, rs2305482 genotype was associated with the doses of pegylated interferon (PEG-IFN) that could be tolerated in hepatitis C virus genotype 1-infected patients treated with PEG-IFN plus ribavirin, but not with treatment efficacy. Our results suggest that genetic testing for this variant might be useful for establishing personalized drug dosing in order to minimize drug-induced adverse events.

Risk factors for long-term persistence of serum hepatitis B surface antigen following acute hepatitis B virus infection in Japanese adults.

UNLABELLED: The proportion of patients who progress to chronicity following acute hepatitis B (AHB) varies widely worldwide. Moreover, the association between viral persistence after AHB and hepatitis B virus (HBV) genotypes in adults remains unclear. A nationwide multicenter study was conducted throughout Japan to evaluate the influence of clinical and virological factors on chronic outcomes in patients with AHB. For comparing factors between AHB patients with viral persistence and those with self-limited infection, 212 AHB patients without human immunodeficiency virus (HIV) coinfection were observed in 38 liver centers until serum hepatitis B surface antigen (HBsAg) disappeared or a minimum of 6 months in cases where HBsAg persisted. The time to disappearance of HBsAg was significantly longer for genotype A patients than that of patients infected with non-A genotypes. When chronicity was defined as the persistence of HBsAg positivity for more than 6 or 12 months, the rate of progression to chronicity was higher in patients with genotype A, although many cases caused by genotype A were prolonged cases of AHB, rather than chronic infection. Multivariate logistic regression analysis revealed only genotype A was independently associated with viral persistence following AHB. A higher peak level of HBV DNA and a lower peak of alanine aminotransferase (ALT) levels were characteristics of AHB caused by genotype A. Treatment with nucleotide analogs (NAs) did not prevent progression to chronic infection following AHB overall. Subanalysis suggested early NA initiation may enhance the viral clearance. CONCLUSION: Genotype A was an independent risk factor for progression to chronic infection following AHB. Our data will be useful in elucidating the association between viral persistence after AHB, host genetic factors, and treatment with NAs in future studies.

Deficiency of eNOS exacerbates early-stage NAFLD pathogenesis by changing the fat distribution.

BACKGROUND: Although many factors and molecules that are closely associated with non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH) have been reported, the role of endothelial nitric oxide synthase (eNOS)-derived nitric oxide (NO) in the pathogenesis of NAFLD/NASH remains unclear. We therefore investigated the role of eNOS-derived NO in NAFLD pathogenesis using systemic eNOS-knockout mice fed a high-fat diet. METHODS: eNOS-knockout and wild-type mice were fed a basal diet or a high-fat diet for 12 weeks. Lipid accumulation and inflammation were evaluated in the liver, and various factors that are closely associated with NAFLD/NASH and hepatic tissue blood flow were analyzed. RESULTS: Lipid accumulation and inflammation were more extensive in the liver and lipid accumulation was less extensive in the visceral fat tissue in eNOS-knockout mice, compared with wild-type mice, after 12 weeks of being fed a high-fat diet. While systemic insulin resistance was comparable between the eNOS-knockout and wild-type mice fed a high-fat diet, hepatic tissue blood flow was significantly suppressed in the eNOS-knockout mice, compared with the wild-type mice, in mice fed a high-fat diet. The microsomal triglyceride transfer protein activity was down-regulated in eNOS-knockout mice, compared with wild-type mice, in mice fed a high-fat diet. CONCLUSIONS: A deficiency of eNOS-derived NO may exacerbate the early-stage of NASH pathogenesis by changing the fat distribution in a mouse model via the regulation of hepatic tissue blood flow.

Deficiency of iNOS-derived NO accelerates lipid accumulation-independent liver fibrosis in non-alcoholic steatohepatitis mouse model.

BACKGROUND: Although many of the factors and molecules closely associated with non-alcoholic steatohepatitis (NASH) have been reported, the role of inducible nitric oxide synthase (iNOS)-derived nitric oxide (NO) on the progression of NASH remains unclear. We therefore investigated the role of iNOS-derived NO in NASH pathogenesis with a long-term follow-up study using systemic iNOS-knockout mice under high-fat diet (HFD) conditions. METHODS: iNOS-knockout and wild-type mice were fed a basal or HFD for 10 or 48 weeks. Lipid accumulation, fibrosis, and inflammation were evaluated, and various factors and molecules closely associated with NASH were analyzed. RESULTS: Marked fibrosis and inflammation (indicators of NASH) were observed in the livers of iNOS-knockout mice compared to wild-type mice after 48 weeks of a HFD; however, lipid accumulation in iNOS-knockout mice livers was less than in the wild-type. Increased expressions of various cytokines that are transcriptionally controlled by NF-kB in iNOS-deficient mice livers were observed during HFD conditions. CONCLUSIONS: iNOS-derived NO may play a protective role against the progression to NASH during an HFD by preventing fibrosis and inflammation, which are mediated by NF-kB activation in Kupffer cells. A lack of iNOS-derived NO accelerates progression to NASH without excessive lipid accumulation.

Efficacy and safety of interferon treatment in elderly patients with chronic hepatitis C in Japan: A retrospective study using the Japanese Interferon Database.

AIM: Although interferon (IFN) treatment in elderly patients with chronic hepatitis C virus (HCV) infection has increased with the aging Japanese population, few studies have examined the efficacy and safety of IFN treatment in this population. We investigated the efficacy and safety of IFN treatment in elderly patients with chronic HCV infection using the Japanese Interferon Database. METHODS: Records of IFN treatment in 36 prefectures in Japan from December 2009 to April 2013 were examined. Patients with HCV infection who received IFN treatment were selected. We compared the sustained virological response (SVR) rate and the withdrawal from treatment proportion among elderly patients (≥75 years) with those among younger patients (<65 years, 65-74 years). RESULTS: We identified 15 267 patients with chronic HCV infection as the study cohort from the database. Of these, 310 patients were elderly with a mean age of 76.7 ± 1.95 years (2.03%; men, 155; women, 155), and the majority (87%) were treated with pegylated IFN. Lower SVR rates (aged <64 years, 65.3%; aged 65-74 years, 49.6%; aged ≥75 years, 46.5%; P < 0.001) and higher withdrawal from treatment proportions (aged <64 years, 15.0%; aged 65-74 years, 21.5%; aged ≥75 years, 32.4%; P < 0.001) were observed with aging. CONCLUSION: We conclude that elderly patients with chronic HCV infection taking IFN therapy achieved lower SVR rates and a higher withdrawal from treatment proportion than younger patients.