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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.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.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 × 10This study suggests that the presence of cirrhosis reduces the SVR rate of DAA treatment, regardless of the type of DAA treatment.

The aim of this study was to clarify the effects and safety of ombitasvir/paritaprevir/ritonavir (OBT/PTV/r) therapy in genotype 1b chronic hepatitis C patients with non-dialysis chronic kidney disease (CKD).This retrospective, multicenter study of 12-week OBT/PTV/r therapy included genotype 1b patients with non-dialysis CKD. Chronic kidney disease was defined as an estimated glomerular filtration rate (eGFR)60 mL/min/1.73 mTwo hundred and thirty-five patients with a median age of 67 years (range, 27-89 years) were enrolled, consisting of 181 patients without CKD and 54 patients with CKD. Overall, the rates of rapid virologic response (RVR), end of treatment response (ETR), and sustained virologic response (SVR) were 78.7%, 98.7%, and 98.7%, respectively. Among the 181 non-CKD patients, the rates were 77.3% (140/181), 98.9% (179/181), and 98.9% (179/181), respectively. Among the 54 CKD patients, the rates were 83.3% (45/54), 98.1% (53/54), and 98.1% (53/54), respectively. There were no significant differences in the virologic response rates between the two groups (P = 0.449 for RVR, 0.545 for ETR, and 0.545 for SVR). In the CKD group, the eGFR level did not significantly change throughout the treatment period. There was no significant difference in the incidence of TEAEs or treatment discontinuation due to TEAEs between the two groups.The present study showed that the effects and safety of OBV/PTV/r therapy in genotype 1b chronic hepatitis C patients with non-dialysis CKD were not inferior to those in patients without CKD.

From a pharmacokinetic viewpoint, the use of ombitasvir/paritaprevir/ritonavir, one of the standards of care for genotype 1b chronic hepatitis C in Japan, could be possible in patients with impaired renal function. The aim of this study was to assess the efficacy and safety of this combination that have not yet been addressed in patients undergoing dialysis.A retrospective, multicenter study evaluated the outcome of 12-week ombitasvir (non-structural protein [NS]5A inhibitor)/paritaprevir (NS3/4A protease inhibitor)/ritonavir combination therapy for dialysis patients. The primary end-point was sustained virologic response 12 weeks after therapy (SVR12).The subjects were 31 patients with a median age of 64 years (range, 49-85 years), including 10 cirrhotic patients. All of the 31 patients had an estimated glomerular filtration rate level 15 mL/min/1.73 mThe present study suggests that ombitasvir/paritaprevir/ritonavir combination therapy is effective and safe for genotype 1b chronic hepatitis C patients undergoing dialysis due to ESRD.

Protease inhibitors with pegylated interferon (PEG IFN)/ribavirin improve a sustained virological response (SVR) rate to approximately 90% in chronic hepatitis C genotype 1b patients with IL28B rs8099917 genotype TT, but yield only approximately 50% in those with the unfavorable non-TT. Among such treatment-refractory patients, serum vitamin D levels could influence the SVR rate. This randomized controlled trial was conducted to assess the effect of native vitamin D supplementation in simeprevir with PEG IFN/ribavirin for 1b patients with non-TT.Patients were randomly assigned to receive simeprevir (100 mg/day) for 12 weeks plus PEG IFN/ribavirin for 24 weeks (control group, n = 58), or vitamin D (2000 IU/day) for 16 weeks including a lead-in phase plus PEG IFN/ribavirin for 24 weeks (vitamin D group, n = 57). The primary end-point was sustainably undetectable viremia 24 weeks after the end of treatment (SVR).SVR rates were 37.9% in the control group and 70.2% in the vitamin D group. In subgroup analysis, SVR rates of prior null responders were 11.8% and 54.5%, respectively. SVR rates for advanced fibrosis were 28.6% and 65.4%. SVR rates for patients with vitamin D3 deficiency at the baseline were 25.0% in the control group and 66.7% in the vitamin D group. Overall, the SVR rate was significantly higher in patients with high serum 25(OH)D3 levels at the beginning of combination therapy than in those with low serum 25(OH)D3 levels.Native vitamin D3 supplementation improved SVR rates in simeprevir with PEG IFN/ribavirin for chronic hepatitis C genotype 1b patients with refractory factors.

Proton beam therapy is safe and more effective than conventional radiation therapy for the local control of nodular hepatocellular carcinoma (HCC). However, evaluating therapeutic response by imaging is not accurate during the early post-irradiation period. Therefore, we examined whether the histopathological study of biopsy specimens obtained at 3 weeks after irradiation can be used to more accurately assess therapeutic response.Fifteen HCC lesions from 13 patients were treated with proton beam irradiation. Tissue biopsy samples were obtained using abdominal ultrasound-guided percutaneous fine-needle aspiration from the center of the tumor before, 3 weeks after and 1 year post-proton therapy. The specimens were examined after staining with hematoxylin-eosin (HE) and a MIB-1 antibody.MIB-1 labeling indices (LI) before treatment were 13.0 ± 8.5% (mean ± SD; range, 0.6-27.0), whereas those 3 weeks after proton therapy were significantly reduced to 3.2 ± 2.4% (range, 0.6-8.9) (P 0.05). Although the tumor size was reduced, we did not observe a reduction in tumor blood flow by dynamic computed tomography or degenerative changes by HE. All lesions that displayed reduced MIB-1 LI at 3 weeks post-proton treatment were ultimately diagnosed as complete response at 1 year after treatment. In contrast, one case with increased MIB-1 LI at 3 weeks had significant tumor size progression at 1 year post-treatment.The percutaneous fine-needle aspiration biopsy of HCC is a safe and useful tool that can be used to evaluate the response to proton irradiation. In particular, MIB-1 LI may provide additional information to assess the therapeutic response of HCC during the early post-irradiated period.

Non-alcoholic fatty liver disease (NAFLD) that encompasses a spectrum of liver disorders characterized by simple steatosis, non-alcoholic steatohepatitis (NASH) through cirrhosis, is becoming an important chronic liver disease in Japan. Currently, there is no proven therapy for NASH. In this study, we assessed the efficacy of statin therapy in NASH patients with dyslipidemia. Twenty patients with biopsy-proven NASH with dyslipidemia who agreed to participate in this multicentric prospective study were enrolled. The patients were treated for 12 months with pitavastatin 2 mg/day. Clinical and histological alterations were comparatively evaluated before and after treatment. Standard weight loss counseling was continued during the treatment period. Follow-up liver biopsy was performed in 13 patients. Twenty-five percent of patients had hyperlipoproteinemia type IIa and 75% had hyperlipoproteinemia type IIb at baseline. The levels of alanine aminotransferase, γ-glutamyl transpeptidase and lipid profiles were significantly improved by the treatment with pitavastatin for 12 months. Especially, these improvements were prominent in NASH patients with hyperlipoproteinemia type IIb. While non-alcoholic fatty liver disease activity score and fibrosis stage did not change significantly in all patients, they did improve in 54% and 42% in individual patients, respectively. NASH-related metabolic parameters improved with therapy including histology in some patients. However, three of 13 patients had progression of fibrosis during the treatment. Our pilot study demonstrated the efficacy of pitavastatin for the treatment of NASH with dyslipidemia, especially with hyperlipoproteinemia type IIb and controlled trials are needed in the future.

Cholesterol is an essential molecule for the life cycle of the hepatitis C virus (HCV). This review focuses on the roles of cholesterol in HCV infection and introduces HCV events related to cholesterol metabolism and applications for cholesterol metabolism as a therapeutic target. HCV appears to alter host lipid metabolism into its preferable state, which is clinically recognized as steatosis and hypocholesterolemia. While hepatic fatty acid and triglyceride syntheses are upregulated in chronic hepatitis C patients, no direct evidence of increased hepatic de novo cholesterol biosynthesis has been obtained. Impaired VLDL secretion from hepatocytes is suggested to increase intracellular cholesterol concentrations, which may lead to hypocholesterolemia. Clinically, lower serum cholesterol levels are associated with lower rates of sustained virological responses (SVR) to pegylated-interferon plus ribavirin therapy, but the reason remains unclear. Clinical trials targeting HMG-CoA reductase, the rate-limiting enzyme in the cholesterol biosynthetic pathway, are being conducted using statins. Anti-HCV actions by statins appear to be caused by the inhibition of geranylgeranyl pyrophosphate synthesis rather than their cholesterol lowering effects. Other compounds that block various steps of cholesterol metabolic pathways have also been studied to develop new strategies for the complete eradication of this virus.

Infection with hepatitis C virus (HCV) is the leading cause of liver cirrhosis that develops into hepatocellular carcinoma. Previous studies have shown in vitro that lipids within hepatocytes are crucially important for a series of HCV infection-proliferation-release processes. On the other hand, in the patients with HCV, the serum total cholesterol (Total-C) and low-density lipoprotein cholesterol (LDL-C) levels have been reported to be lower. We conducted an epidemiological survey of a large cohort and investigated whether the lower serum lipid levels were caused by a direct or the secondary effects of HCV infection (i.e. hepatic damage or nutritional disorder). Among 146 857 participants (male, 34%; female, 66%) undergoing public health examinations between 2002 and 2007 in Ibaraki Prefecture, Japan, the HCV positive rates determined by HCV antibody/antigen and/or RNA tests were 1.37% and 0.67% in males and females, respectively. In addition to Total-C and LDL-C, serum high-density lipoprotein cholesterol and triglyceride concentrations were also significantly lower in the HCV positive subjects compared with the negative subjects, regardless of sex, age or nutritional state evaluated by body mass index. Multivariate analysis showed that HCV infection was the strongest among the factors to be significantly associated with the lower level of these lipids. Particularly, the hypolipidemia was also confirmed in the HCV positive subjects with normal aminotransferase levels (alanine aminotransferase ≤30 and aspartate aminotransferase ≤30). This epidemiological survey in a large Japanese cohort suggests that the HCV infection itself might directly cause hypolipidemia, irrespective of host factors including age, hepatic damage and nutritional state.

Aim: We have previously reported in mice the hepatic inflammatory in graft versus host response (GVHR) model due to the disparity of major histocompatibility complex class-II. The regulatory T (Treg) cells have been reported to control excessive immune response and prevent immune-related diseases. This study aimed to investigate the pathogenesis profiles of chronic GVHR progression, focusing on the Treg cells. Methods: GVHR mice induced by parental spleen CD4+ T cell injection were sacrificed after 0, 2, 4, and 8 weeks (G0, G2, G4, G8). Further, one GVHR group received anti-IL-10 antibody in advance and were maintained for 2 weeks. Pathologic profiles of hepatic infiltrating inflammatory cells were evaluated by haematoxylin and eosin and immunohistochemistry staining with surface markers including Treg cell markers. Results: Remarkable hepatic inflammatory in G2 significantly and gradually improved over time up to G8. In immunohistochemical staining, the increased IL-10 receptor β+ Tr1 cells in G2 were maintained through to G8; although other inflammatory cells decreased from G2 to G8. By contrast, in the anti-IL-10 antibody received-GVHR mice, the Tr1 cells were not detectable with significant inflammatory aggravation, while FoxP3+ Treg cells significantly enhanced. Conclusions: These findings in the GVHR mice suggest that the expression and activity of Treg cells, especially the Tr1 cells, might be key factors for pathologic alteration in immune-related liver disease.

Aim A large cohort study in Japan revealed that the specific viral profile may influence the fulminant outcome in acute hepatitis B virus (HBV) infections, while the genetic influence on outcome has not been clarified in patients with acute exacerbation of chronic liver disease caused by HBV. We experienced a case of fatal liver failure that developed as the result of chronic HBV infection. To determine possible genetic factor involving acute exacerbation, genetic analysis of serum from the patient and his siblings was performed. Methods HBV subgenotype as well as pre-core/core-promoter mutations of samples mentioned above were determined. Results Patient had HBV-Bj with pre-core (1896/1899) and core-promoter (1762/1764) mutations, the genomic profile frequently seen in fulminant hepatitis caused by acute HBV infection. Conclusion This result suggests that determination of the HBV subgenotype and pre-core/core promoter mutations could provide a rationale for development of a treatment strategy in asymptomatic HBV carriers.

Ursodeoxycholic acid (UDCA) is used in the treatment of cholestatic liver diseases, gallstone dissolution, and for patients with hepatitis C virus infection to ameliorate elevated alanine aminotransferase levels. The efficacy of UDCA treatment has been debated and the mechanisms of action in humans have still not defined. Suggested mechanisms include the improvement of bile acid transport and/or detoxification, cytoprotection, and anti-apoptotic effects. In this review, we summarize the proposed molecular mechanisms for the action of UDCA, especially in hepatocytes, and also discuss the putative future clinical usage of this unique drug.

Ribavirin-induced hemolytic anemia is one of the important adverse effects for the premature cessation of interferon and ribavirin combination therapy for hepatitis C virus clearance. To elucidate the mechanism of this matter, we examined the effects of plasma and erythrocyte ribavirin concentration on hemoglobin (Hb) reduction to assess hemolytic anemia in this combination therapy.Nineteen patients, treated with the interferon alpha-2b and ribavirin combination therapy, were included. Plasma and erythrocyte ribavirin concentrations were monitored for the first 28 days of the combination therapy, in relation to changes in hematological parameters, Hb and hematocrit values. The initial dose of ribavirin was 11.5+/-1.5mg/kg/day.Steady-state plasma and erythrocyte ribavirin concentrations were 8.9+/-2.6 and 1218+/-270muM, respectively. Significant correlation was observed between erythrocyte ribavirin and Hb reduction (r=0.360, p0.05), but not between plasma ribavirin and Hb reduction. The patients with higher levels of erythrocyte ribavirin (/=1000muM) had greater Hb reduction compared to those with lower levels (1000muM) (3.8+/-1.2g/dL versus 2.6+/-0.9g/dL, p0.05). Nine cases out of 12 patients who developed anemia within the first 28 days of the combination therapy had higher levels of erythrocyte ribavirin (/=1000muM).We confirmed that erythrocyte ribavirin was strongly associated with Hb reduction in interferon and ribavirin combination therapy.

A 39-year-old Japanese women who has been jaundiced since childhood and indicative of Dubin-Johnson syndrome (DJS) underwent MRP2/ABCC2 mutation analysis. The results of the analysis revealed two novel mutations, C298T and C3928T, and two single nucleotide polymorphisms (SNPs), C3972T and C-24T. One of the two mutations (C298T) is in the transmembrane domain. The other mutation (C3928T) and the SNP (C3972T) are in the cytoplasmaic domain which are concentrated in the second adenosine triphosphate (ATP)-binding cassette. Both of the mutations, C298T and C3928T, are immature stop codons. C298T, C-24T and C3972T (originating from the mother) and C3928T (from the father) were observed to be heterozygous in this patient. Light-microscopy examination of the liver biopsy specimens revealed the accumulation of dark pigment granules in most of the hepatocytes. In the immunohistochemistry using pAb recognizing the C-terminal of the human MRP2, no staining of MRP2 in the canalicular membrane domain was observed in the liver sections from this patient. In this patient, the mutations with immature stop codons presumably resulted in instability of MRP2 mRNA and/or defective synthesis of the truncated protein, which may underlie the loss of the expression of functional MRP2 protein.

In human liver cirrhosis (LC), the Fischer ratio (branched-chain amino acid (BCAA)/aromatic amino acid (AAA)) is used as a marker of hepatic encephalopathy. Similarly, the plasma BCAA levels decrease while AAA levels increase in LC rats. However the BCAA and AAA ratio and the influence of exercise on this ratio remains to be clarified in various tissues of the LC rat model. Normal and LC rats received 2-weekly injections of olive oil or CCl(4) for 10 weeks, respectively, and half of the rats from each group were subjected to one time exercise on a treadmill. BCAA, AAA, glutamate (GLU) and glutamine (GLN) concentrations were measured in plasma, liver, brain, heart and skeletal muscles. Decreased BCAA and increased AAA concentrations in brain and heart were also observed in LC rats and these changes were significantly amplified by exercise. The Fischer ratio in the LC group with and without exercise was decreased in skeletal muscles, while it remained unchanged in the liver. Decreased GLU and increased GLN concentrations were shown in most LC samples following exercise. In conclusion, specific alterations of the amino acid patterns were observed in various tissues in the LC group. These alterations were further emphasized by exercise.

C57BL/6 (B6) spleen T cells which were injected into major histocompatibility complex (MHC) class II-disparate (B6.C-H-2(bm/2)xB6) F1 hybrid mice induced autoimmune graft-versus-host reaction (GVHR). Early production of interferon (IFN)-gamma and delayed production of interleukin (IL)-10 might play an important role in the formation of GVHR hepatic lesions. To clarify whether blocking of IL-10 deteriorate autoimmune-mediated hepatic lesions induced by GVHR, and to elucidate the change of the T helper (Th)1/Th2 cytokines in the liver, anti-IL-10 monoclonal antibodies (mAbs, 500mgr;g) were given 4 h before the induction of GVHR. We evaluated the change of splenomegaly and GVHR-induced hepatic lesions. The changes of the expressions of IFN-gamma and IL-4 mRNA isolated from liver-infiltrating lymphocytes were measured by real-time polymerase chain reaction (PCR). In GVHR with anti-IL-10 mAbs mice splenomegaly and periportal cellular infiltration was significantly increased compared with those of GVHR mice. In these mice, both IFN-gamma and IL-4 mRNA expression levels were significantly elevated by the neutralization of IL-10. These findings suggest an important role of IL-10 in murine GVHR due to MHC class II disparity. IL-10 may play a crucial role in down-regulating autoimmune-related hepatic lesions.