High prevalence of hepatitis C virus among criminals in rehabilitation facilities in Japan.

OBJECTIVE: There is a high prevalence of hepatitis C virus (HCV) carriers in prison in several developed countries, but the situation in Japan has not been well reported. This study aimed to determine the state of HCV infection among criminals in Japan. METHODS: We enrolled 533 criminals in rehabilitation facilities (354 men and 179 women) who underwent a medical check-up from April 2014 to March 2022. Their records of blood tests, medical history, and drug injection use were retrospectively analyzed. RESULTS: The HCV-antibody positive rate was 11.1 % (59/533), with rates of 8.2 % (29/354) in men and 16.8 % (30/179 in women. Approximately half of the HCV-infected residents had a history of drug injection, and this rate did not vary by age or by sex. Although an opportunity to treat HCV infection with medical assistance from government was provided to all residents who were positive for HCV RNA, 26.5 % of them abandoned the treatment. CONCLUSION: In spite of the generous economical support to treat HCV infection by the government and the free access system in Japan, eliminating HCV in criminals appears to be difficult. The reason for this problem might be the criminals' negligent attitude to life.

Effectiveness and safety of daclatasvir plus asunaprevir for patients with hepatitis C virus genotype 1b aged 75 years and over with or without cirrhosis.

AIM: The aim of this study was to evaluate the efficacy and safety of 24-week daclatasvir (NS5A inhibitor) plus asunaprevir (NS3/4 A protease inhibitor) treatment for elderly patients with hepatitis C virus (HCV) genotype 1b infection. METHODS: This prospective, multicenter study consisted of 321 Japanese HCV genotype 1b patients who were interferon-ineligible/intolerant or non-responders to interferon-based regimens, including 103 (32.1%) aged ≥75 years and 127 (39.6%) with cirrhosis. Sustained virological response (SVR) at 24 weeks after the end of treatment and adverse effects were analyzed according to age. RESULTS: The overall SVR rate was 90.3%. In terms of by age, 94.5% (69/73), 88.3% (128/145), and 90.3% (93/103) of the patients aged <65, 65-74, and ≥75 years, respectively, achieved SVR. For the entire cohort, pre-existent NS5A resistance-associated variants and prior simeprevir failure were independently associated with treatment failure. According to the analysis of patients without these unfavorable pretreatment factors, 90.8% (89/98) aged ≥75 years achieved SVR, although this was significantly lower than for those aged <65 years (98.5%, 66/67) (P < 0.05). The frequency of adverse effects was comparable for the <75 and ≥75 age groups, the most common being an elevated alanine aminotransferase level (>150 U/L, 8.7%), however, no decompensating events were seen. CONCLUSIONS: Daclatasvir plus asunaprevir for HCV genotype 1b was well tolerated and effective for patients without pre-existent NS5A resistance-associated variants or simeprevir failure, irrespective of fibrosis status. However, it was less effective for very old patients aged ≥75 years compared to those aged <65.

Spalt-like transcription factor 4 immunopositivity is associated with epithelial cell adhesion molecule expression in combined hepatocellular carcinoma and cholangiocarcinoma.

AIM: Combined hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC) (cHCC-CC) is a rare biphasic liver cancer. Recent studies have demonstrated that cHCC-CC originates from hepatic progenitor cells (HPCs). Spalt-like transcription factor 4 (SALL4) is a marker for a progenitor subclass of HCC with an aggressive phenotype. However, little has been revealed about SALL4 expression in cHCC-CC. The aims of this study were to report SALL4 immunopositivity and the results of clinicopathological analysis in cHCC-CC, and to examine the two different nuclear immunostaining patterns for SALL4. METHODS AND RESULTS: We defined the diffuse finely granular nuclear immunostaining pattern as immunopositive for SALL4; this was observed in eight (8.9%) of 90 cHCC-CCs. SALL4 immunopositivity was significantly associated with immunopositivity for α-fetoprotein, glypican 3, and epithelial cell adhesion molecule (EpCAM). There was no relationship between SALL4 immunopositivity and prognosis. We confirmed SALL4 mRNA expression in samples with a punctuate/clumped immunostaining pattern, which showed a significantly lower rate of immunopositivity for EpCAM than those with a diffuse finely granular pattern. CONCLUSIONS: SALL4 immunopositivity is not a prognostic factor in cHCC-CC; however, it is associated with α-fetoprotein, glypican 3 and EpCAM immunopositivity, indicating the mechanism of carcinogenesis. Further study is necessary to interpret the immunostaining pattern for SALL4.

Low-grade elevation of fibrinogen-degradation products is an important parameter to identify acute presentation of autoimmune hepatitis.

OBJECTIVE: Diagnosing early-stage acute autoimmune hepatitis (AIH) without pathological findings is difficult. Recent reports indicated that macrophages are not activated during disease development, unlike in other acute liver injuries. We suggest that hepatitis without macrophage activation should lack sinusoidal fibrin deposition, which might help diagnose the acute presentation of AIH. MATERIAL AND METHODS: To test this hypothesis, 295 consecutive patients with acute liver injury enrolled into this study. Their clinical data on admission were analyzed to verify the differences between acute presentation of AIH and other liver injuries. RESULTS: The distribution of plasma fibrinogen degradation products (FDP) showed two clusters: patients without elevated FDP and those with measurable FDP levels of various degrees. Most AIH patients are included in the former. Multivariate logistic analysis of patients' laboratory data was performed for useful parameters to identify the acute presentation of AIH. FDP, alanine transaminase, zinc sulfate turbidity test and HBsAg levels were significant. Based on the odds ratio obtained from the analysis, we assigned each result individual points and constructed a convenient scoring system, which showed high sensitivity and specificity to identify AIH. Additionally, the area under the receiver operating characteristic curve was 0.928. CONCLUSIONS: Our results indicated that the process of macrophage activation and subsequent sinusoidal fibrin deposition was not involved in the development of the acute presentation of AIH. Our new scoring system including FDP levels could contribute to rapid diagnosis of the acute presentation of AIH without liver biopsy.

Efficacy of interferon-beta plus ribavirin combination treatment on the development of hepatocellular carcinoma in Japanese patients with chronic hepatitis C.

AIM: Although there is much evidence of an antitumor effect of pegylated interferon (IFN)-α-based treatment, limited data is available about that of IFN-ß-based treatment. Our goal was to evaluate the impact of IFN-ß plus ribavirin (RBV) treatment on the suppression of hepatocellular carcinoma (HCC). METHODS: This retrospective, multicenter study consisted of 124 chronic hepatitis C patients who were treated with IFN-ß plus RBV treatment, including 61 with advanced fibrosis and five with pretreatment HCC. All participants were followed for a median of 2.8 years (range, 2.2-3.2) after the end of their antiviral treatment. The data of 112 patients who finished the treatment were available for analysis. Cox proportional hazard analyses were performed to determine factors significantly associated with HCC development. Cumulative incidence curves for HCC were plotted using the Kaplan-Meier method and differences between groups were assessed using the log-rank test. RESULTS: The 2.9% rate of HCC development of patients with sustained virological response (SVR) was significantly lower (P = 0.027) than the 15.9% of non-SVR patients. Interestingly, no significant difference was observed between the rates of HCC development of patients with and without advanced fibrosis (P = 0.733), even though the SVR rate of patients with advanced fibrosis was significantly lower than that of those without advanced fibrosis (P < 0.001). Stepwise multivariable Cox analysis extracted that only SVR was significantly associated with HCC development (hazard ratio, 0.20; 95% confidence interval, 0.03-0.84, P = 0.027). CONCLUSION: SVR was significantly associated with a lower risk of HCC development after IFN-ß plus RBV treatment.

T1 ρ Relaxation of the liver: A potential biomarker of liver function.

PURPOSE: To investigate the diagnostic potential of T1 ρ relaxation for assessing liver function, liver fibrosis, or liver necroinflammation in patients with chronic liver disease (CLD). MATERIALS AND METHODS: We obtained T1 ρ maps of the liver for 53 patients with or without CLD. We measured the T1 ρ values of the liver and correlated them with the results of laboratory tests and histological examinations. Pearson's correlation coefficients (r) were calculated between the T1 ρ values and blood serum parameters including the retention rates at 15 minutes after an injection of indocyanine green (ICG-R15). Spearman's rank correlation coefficients were calculated between the T1 ρ values and the scores of liver fibrosis or liver necroinflammation. RESULTS: The T1 ρ values showed significant positive correlations with the serum levels of total bilirubin (r = 0.31, P < 0.05), direct bilirubin (r = 0.32, P < 0.05), and ICG-R15 (r = 0.46, P < 0.05), and significant negative correlations with the serum levels of albumin (r = -0.33, P < 0.05) and γ-glutamyl transpeptidase (r = -0.28, P < 0.05). However, there were no significant correlations between the T1 ρ value and the scores of liver fibrosis (P = 0.95) or liver necroinflammation (P = 0.86). CONCLUSION: T1 ρ relaxation has potential as a biomarker of liver function in patients with CLD. However, it may not be suitable to estimate liver fibrosis or liver necroinflammation.

Pathophysiological analysis of primary biliary cirrhosis focusing on choline/phospholipid metabolism.

BACKGROUND & AIMS: Injury to biliary epithelial cells caused by disorders in bile composition may be the initial step in the pathogenesis of primary biliary cirrhosis (PBC). We therefore examined choline/phospholipid metabolism in livers of patients with PBC. METHODS: Hepatic levels of mRNA encoded by choline metabolism-related genes in early stage PBC patients were quantified by real-time RT-PCR. Serum cholesterol and triglyceride concentrations in each lipoprotein compartment and serum/tissue choline levels were also measured. OCT1 expression was quantified by genotype (rs683369 and rs622342). RESULTS: Serum choline concentrations were significantly higher in PBC patients than in normal individuals, with the concentrations in the former lowered by treatment with fibrates. Hepatic choline levels were markedly lower in PBC patients than in controls. The levels of expression of genes associated with choline uptake (OCT1 and CTL1), phosphatidylcholine synthesis (PEMT and BHMT), and phosphatidylcholine transport (MDR3) were significantly upregulated in PBC compared with control livers. Serum cholesterol concentrations and the cholesterol/triglyceride ratio in serum very low density lipoprotein were markedly higher in PBC patients than in controls. In PBC liver, OCT1 protein levels were lower in patients with minor (CG/GG at rs683369 and/or CC at rs622342) than major (CC at rs683369 and AA at rs622342) genotypes of the OCT1 gene. CONCLUSION: During early stage PBC, hepatocellular choline uptake and PC synthesis become dysregulated. OCT1 genotypes may influence the pathogenesis of PBC.

Comparative effectiveness and safety study of triple therapy with simeprevir or telaprevir for non-cirrhotic patients with chronic hepatitis C virus genotype 1b infection.

BACKGROUND AND AIM: The addition of hepatitis C virus (HCV) NS3/4A protease inhibitors to pegylated-interferon alpha (PEG-IFNα) and ribavirin (triple therapy) has greatly improved treatment outcome. The aim of this study was to compare the effectiveness and safety of simeprevir-based or telaprevir-based triple therapy for non-cirrhotic patients in real-world clinical practice. METHODS: This multicenter study consisted of 835 consecutive Japanese HCV genotype 1b patients treated in a clinical setting, 716 of whom were enrolled (simeprevir = 256 and telaprevir = 460). Logistic regression was carried out after propensity score matching to assess the sustained virological response at week 12 after the end of treatment (SVR12). RESULTS: In the propensity-matched cohort (253 matched pairs), the SVR12 rates of the patients who underwent simeprevir-based or telaprevir-based triple therapy were 85.0% and 84.2%, respectively, by intention-to-treat analysis. Prior treatment response to PEG-IFNα/ribavirin and IL28B genotype was independently associated with SVR12 in both groups. No significant differences in the SVR12 rates stratified by prior treatment response to PEG-IFNα/ribavirin were found between the simeprevir (treatment-naïve 89.1%, prior relapse 94.3%, prior partial response 65.0%, and prior null response 33.3%) and telaprevir (treatment-naïve 87.8%, prior relapse 90.1%, prior partial response 68.4%, and prior null response 50.0%) groups. The incidence of adverse effects, such as anemia, severe rash, and the elevation of serum creatinine, was markedly higher in the telaprevir group. CONCLUSIONS: Considering the effectiveness and safety, simeprevir-based triple therapy will continue to be a useful treatment option in Japan for treatment-naïve or prior relapse patients with a favorable IL28B genotype.

Comparative safety study on severe anemia by simeprevir versus telaprevir-based triple therapy for chronic hepatitis C.

BACKGROUND AND AIM: The addition of hepatitis C virus (HCV) NS3/4A protease inhibitors to the pegylated interferon (PEG-IFN) α and ribavirin combination regimen (triple therapy) has dramatically improved treatment outcome. Unfortunately, anemia remains a common adverse effect. This study was done to compare the development of severe anemia during simeprevir- or telaprevir-based triple therapy. METHODS: This retrospective multicenter study consisted of 837 consecutive Japanese HCV genotype 1 patients treated in a real-world clinical setting, 811 of whom were enrolled (simeprevir 281, telaprevir 530). The inosine triphosphate pyrophosphatase (ITPA) genotype at rs1127354 was determined for all studied patients. Logistic regression was done after propensity score matching to assess the risk of development of severe anemia. RESULTS: Propensity score matching of the entire study population yielded 266 matched pairs. Severe anemia (nadir hemoglobin < 9.0 g/dL) was developed during the treatment period by 81 (30.5%) and 144 (54.1%) patients treated with simeprevir and telaprevir, respectively. Treatment with simeprevir was independently associated with a lower risk of severe anemia (odds ratio 0.25, 95% confidence interval 0.16-0.38, P < 0.0001). Moreover, ITPA genotype, age, hemoglobin level, and estimated glomerular filtration rate at baseline were also independent factors associated with the development of severe anemia. CONCLUSIONS: Patients treated with simeprevir-based triple therapy have a lower risk of the development of severe anemia than those treated with telaprevir. Moreover, ITPA genotype and age may be useful for individualizing treatment to reduce the risk of anemia-related adverse effects.

Efficacy and safety of splenectomy in telaprevir-based triple therapy for chronic hepatitis C patients with thrombocytopenia and advanced fibrosis.

BACKGROUND AND AIM: Thrombocytopenia (TCP) of chronic hepatitis C patients with cirrhosis has a negative impact on the management of interferon-based treatment. The aim of this study is to evaluate the efficacy and safety of telaprevir-based triple therapy for patients who have undergone splenectomy (Spx). METHODS: This prospective, multicenter study consisted of 80 patients, including 32 Spx and 48 non-Spx/TCP (platelet count: 60-99 × 10(9) /L) patients with advanced fibrosis infected with hepatitis C virus genotype 1b. All received 12 weeks of telaprevir in combination with 24 weeks of pegylated interferon (PEG-IFN) α2b and ribavirin. RESULTS: The sustained virological response (SVR) rate of the Spx group (75.0%) was significantly higher than that of the non-Spx/TCP group (52.1%) (P < 0.05). Under favorable conditions such as treatment-naïve/prior relapse and interleukin-28B (IL28B) TT allele (rs8099917), the SVR rates of the Spx group were significantly higher than those of the non-Spx/moderate TCP (60-79 × 10(9) /L) groups (91.3% vs 50.0% and 93.8% vs 37.5%, respectively; both P < 0.05). Adequate PEG-IFNα2b adherence was associated with SVR. However, the percentage of patients who achieved 80% adherence to PEG-IFNα2b in the non-Spx/moderate TCP (42.9%) group was significantly lower than that of the Spx (79.3%) and non-Spx/mild TCP (80-99 × 10(9) /L) (80.0%) groups. Treatment discontinuation due to adverse effects and the development of bacterial infection did not differ between the Spx and non-Spx/TCP groups. CONCLUSION: The increase of platelet count after Spx contributed to treatment success, especially for moderate to severe TCP patients who are treatment-naïve/prior relapse or IL28B TT allele.

Efficacy of pegylated interferon alpha-2b and ribavirin treatment on the risk of hepatocellular carcinoma in patients with chronic hepatitis C: a prospective, multicenter study.

BACKGROUND & AIMS: The effects of pegylated interferon (PegIFN) α and ribavirin (RBV) treatment of chronic hepatitis C on the incidence of hepatocellular carcinoma (HCC) have not been well established. This study investigated the impact of treatment outcome on the development of HCC by chronic hepatitis C patients treated with PegIFNα2b and RBV. METHODS: This large-scale, prospective, multicenter study consisted of 1013 Japanese chronic hepatitis C patients with no history of HCC (non-cirrhosis, n=863 and cirrhosis, n=150). All patients were treated with PegIFNα2b and RBV and the follow-up period started at the end of the antiviral treatment (median observation period of 3.6 years). The cumulative incidence rate of HCC was estimated using the Kaplan-Meier method, according to treatment outcome. RESULTS: Forty-seven patients (4.6%) developed HCC during the observation period. In the non-cirrhosis group, the 5-year cumulative incidence rates of HCC for the sustained virological response (SVR) (1.7%) and transient virological response (3.2%) (TVR: defined as relapse or breakthrough) groups were significantly lower than those of the non-virological response (NVR) group (7.6%) (p=0.003 and p=0.03, respectively). A significantly low rate of incidence of HCC by TVR patients in comparison with NVR patients was found for patients aged 60 years and over, but not for those under 60 years of age. In the cirrhosis group, the 5-year cumulative incidence rates of HCC for the SVR (18.9%) and TVR groups (20.8%) were also significantly lower than those of the NVR group (39.4%) (p=0.03 and p=0.04, respectively). CONCLUSIONS: SVR and complete viral suppression during treatment with relapse (TVR) were associated with a lower risk of HCC development when compared with NVR.

Clinical milestones for the prediction of severe anemia by chronic hepatitis C patients receiving telaprevir-based triple therapy.

BACKGROUND & AIMS: Anemia is a common adverse effect of telaprevir (TVR) in combination with pegylated interferon (PegIFN)α and ribavirin (RBV) therapy. It occurs at a higher incidence with the TVR relative to PegIFNα and RBV alone. We herein evaluate the baseline and on-treatment predictors of the development of severe anemia by chronic hepatitis C virus (HCV) patients receiving TVR-based triple therapy. METHODS: This prospective, multicenter study consisted of 292 patients (median age: 62 years) infected with HCV genotype 1. All received 12 weeks of TVR in combination with 24 weeks of PegIFNα2b and RBV. The definition of severe anemia during antiviral treatment is hemoglobin (Hb)<85 g/L. RESULTS: 101 (34.6%) patients developed severe anemia during the treatment period. Multivariable logistic regression analysis of possible pretreatment predictors of the development of severe anemia extracted baseline Hb < 135 g/L (Hazard ratio [HR], 2.53; p = 0.0013), estimated glomerular filtration rate <80 ml/min/1.73 m(2) (HR, 1.83; p = 0.0265), and inosine triphosphatase (ITPA) CC genotype (rs1127354) (HR, 2.91; p = 0.0024). For patients with ITPA CC (n = 227), multivariable logistic regression analysis of possible pretreatment and on-treatment predictors of the development of severe anemia extracted Hb level at week 2 (HR, 0.96; p = 0.0085) and the initial four weeks of weight-adjusted TVR (HR, 1.05; p = 0.0281). CONCLUSIONS: Anemia remains a risk for all patients treated with TVR-based triple therapy. However, ITPA polymorphism (rs1127354) is useful for predicting the development of severe anemia and will be helpful in the management of treatment.

Telaprevir can be successfully and safely used to treat older patients with genotype 1b chronic hepatitis C.

BACKGROUND & AIMS: This study was performed to evaluate the efficacy of a triple therapy in older Japanese patients; telaprevir (TVR) was added to pegylated interferon α2b and ribavirin. METHODS: This prospective study enrolled 120 genotype 1b patients with chronic hepatitis C who received 12 weeks of triple therapy followed by a 12-week dual therapy that included pegylated interferon α2b and ribavirin. Patients were categorized according to age: group A, 64 patients aged >60 and group B, 56 patients aged ⩽60. Serum HCV RNA levels were monitored by COBAS TaqMan HCV test. RESULTS: The rates of undetectable HCV RNA at week 4 (rapid virological response, RVR) were 73.4% in group A and 73.2% in group B. No significant difference in sustained virological response (SVR) was found between groups A (76.6%) and B (83.9%) (p=0.314). The SVR rates for patients with interleukin 28B (IL28B) (rs8099917) TT allele (89.4% and 91.9% for groups A and B) were significantly higher than for those with the IL28B TG/GG allele (41.2% and 68.4%, respectively) (both p<0.05). Multivariate analysis extracted IL28B TT and RVR as independent factors associated with SVR. Adverse effects resulted in treatment discontinuation by 12.5% in each group. Hemoglobin decrease significantly differed between groups A and B: the decrease to ≤100 g/L, to 85 - <100g/L, and to <85 g/L, was 9.4%, 40.6%, and 50% in group A patients, respectively, and 41.1%, 25%, and 33.9% in group B patients, respectively (p=0.0006). CONCLUSIONS: TVR-based triple therapy can be successfully used to treat older patients with genotype 1b chronic hepatitis C.

Add-on therapy of pitavastatin and eicosapentaenoic acid improves outcome of peginterferon plus ribavirin treatment for chronic hepatitis C.

Despite the use of pegylated-interferon (peg-IFN) plus ribavirin combination therapy, many patients infected with hepatitis C virus (HCV)-1b remain HCV-positive. To determine whether addition of pitavastatin and eicosapentaenoic acid (EPA) is beneficial, the "add-on" therapy option (add-on group) was compared retrospectively with unmodified peg-IFN/ribavirin therapy (standard group). Association of host- or virus-related factors with sustained virological response was assessed. In HCV replicon cells, the effects of pitavastatin and/or EPA on HCV replication and expression of innate-immunity- and lipid-metabolism-associated genes were investigated. In patients infected with HCV-1b, sustained virological response rates were significantly higher in the add-on than standard group. In both groups, sustained virological response rates were significantly higher in patients with genotype TT of IL-28B (rs8099917) than in those with non-TT genotype. Among the patients with non-TT genotype, sustained virological response rates were markedly higher in the add-on than standard group. By multivariate analysis, genome variation of IL28B but not add-on therapy remained as a predictive factor of sustained virological response. In replicon cells, pitavastatin and EPA suppressed HCV replication. Activation of innate immunity was obvious in pitavastatin-treated cells and EPA suppressed the expression of sterol regulatory element binding protein-1c and low-density lipoprotein receptor. Addition of pitavastatin and EPA to peg-IFN/ribavirin treatment improved sustained virological response in patients infected with HCV-1b. Genotype variation of IL-28B is a strong predictive factor in add-on therapy.

Early extensive viremia, but not rs8099917 genotype, is the only predictor for cholestatic hepatitis C after living-donor liver transplantation.

AIM: Cholestatic hepatitis C is one of the most serious but still unaddressed disorders after liver transplantation. METHODS: In this study, we analyzed 49 patients who underwent living-donor liver transplantation (LDLT) to treat hepatitis C virus (HCV) infection. RESULTS: Five patients developed cholestatic hepatitis C, with total bilirubin of 15.2 ± 3.1 mg/dL at diagnosis 6.2 ± 1.0 weeks after LDLT. Univariate analysis showed that larger graft to standard liver volume ratio, higher HCV RNA titer at 2 weeks, earlier peak HCV RNA titer and cytomegalovirus infection were the significant risk factors. The development of cholestatic hepatitis C was not significantly associated with interleukin-28B genotype (rs8099917); four out of five affected patients had the T/T genotype. Multivariate analysis showed that higher HCV RNA titer at 2 weeks was the only significant factor (P = 0.026) for the development of cholestatic hepatitis C. Receiver-operator curve analysis showed that that HCV RNA titer of more than 7.2 log10 IU/mL was the optimal cut-off for characterizing cholestatic hepatitis C. All of the patients were serum HCV RNA negative after treatment with pegylated interferon and ribavirin and all the patients are alive. CONCLUSION: Early extensive viremia, but not the rs8099917 genotype, was the only predictor for cholestatic hepatitis C after LDLT.

Evaluation of the adverse effect of premature discontinuation of pegylated interferon α-2b and ribavirin treatment for chronic hepatitis C virus infection: results from Kyushu University Liver Disease Study.

BACKGROUND AND AIMS: Pegylated interferon (PEG-IFN) α-2b and ribavirin (RBV) treatment of chronic hepatitis C virus (HCV) infection is associated with a substantially elevated risk of discontinuation. The aim of this study is to evaluate the reason for premature discontinuation during PEG-IFN α-2b and RBV treatment due to adverse effects in patients with chronic HCV infection. METHODS: A total of 2871 Japanese patients who had chronic HCV infection treated with PEG-IFN α-2b and RBV were screened. We prospectively investigated the reasons for premature discontinuation of treatment classified by sex and age, and analyzed the timing of discontinuation. RESULTS: Of the 2871 patients, 250 (8.7%) discontinued treatment because of adverse effects. The main reasons for premature discontinuation were neurovegetative symptoms (n = 77, 30.8%), depression-related syndrome (n = 46, 18.4%), hematologic effects (n = 41, 16.4%) and dermatologic effects (n = 27, 10.8%). The rate of discontinuation of treatment for patients aged ≥ 65 years was significantly higher than for patients aged < 65 years, for both men (P < 0.0001) and women (P = 0.0121). Moreover, the frequency of discontinuation due to neurovegetative symptoms, depression-related syndrome, and hematologic effects for men aged ≥ 65 years was significantly higher than for those aged < 65 years (P = 0.0001, P = 0.0016, and P = 0.0170, respectively), but not for women. CONCLUSION: Premature discontinuation due to the adverse effects of PEG-IFN α-2b and RBV treatment by patients with chronic HCV infection is mainly due to neuropsychiatric symptoms and is more common for older than for younger patients.

An inadequate dose of ribavirin is related to virological relapse by chronic hepatitis C patients treated with pegylated interferon alpha-2b and ribavirin.

The aim of this large-scale analysis was to assess the effect of 48-week pegylated interferon (PEG-IFN) α-2b and ribavirin (RBV) therapy on virological relapse by patients infected with hepatitis C virus (HCV) genotype 1. The relationship between virological relapse and the dose of PEG-IFNα-2b and RBV was investigated in 619 patients who had once cleared HCV RNA during PEG-IFNα-2b and RBV treatment for 48 weeks. The overall virological relapse rate was 34.1% (211 of 619). The relapse rate was 59.5% (22 of 37) for patients who received <6 mg/kg/day of RBV, even if a sufficient dose of PEG-IFNα-2b (≥1.5 µg/kg/day) was received. In contrast, the relapse rate was 28.1% (16 of 57) for patients who received ≥12 mg/kg/day of RBV, irrespective of the PEG-IFNα-2b dose. The relapse rates were significantly increased with the reduction of the RBV dose for both PEG-IFNα-2b doses of ≥1.2 and <1.2 µg/kg/week (P < 0.0001 and P = 0.0006, respectively). Moreover, the relapse rate was 41.2% (35 of 85) for patients with an early virological response (EVR) who received <6 mg/kg/day of RBV. The relapse rates were significantly increased with the reduction of the RBV dose in both those patients with an EVR and those with a late virological response (P = 0.0006 and P = 0.0088, respectively). To summarize, for HCV genotype 1 patients treated with PEG-IFNα-2b and RBV, the virological relapse of HCV was RBV dose-dependent, irrespective of the dose of PEG-IFNα or the effect of early viral kinetics.

Radiological catheter placement for transcatheter arterial steroid injection therapy to treat severe acute hepatic failure: technical feasibility and efficacy.

BACKGROUND: Severe acute hepatic failure (SAHF), which progresses to fulminant form in some cases, is a life-threatening disease. PURPOSE: To assess the technical feasibility and the efficacy of transcatheter arterial steroid injection therapy (TASIT) for SAHF. MATERIAL AND METHODS: Twenty-seven patients with SAHF, 10 of whom had variant anatomy of the hepatic artery, underwent radiologic placement of an indwelling catheter in the hepatic artery, and TASIT was subsequently performed for three days. The tips of the catheters were inserted as follows: common hepatic artery (n = 18), proper hepatic artery (n = 4), and replaced right hepatic artery (n = 5). The clinical success rate of TASIT and the prognosis after TASIT were evaluated. RESULTS: In one patient, intimal injury of the left hepatic artery was encountered; however, TASIT could be resumed and completed via intrahepatic arterial collaterals. In two patients, the catheter tip placement was corrected on the following day because of dislocation. Finally, TASIT could be carried out in all patients. Twenty-two patients (81.5%) responded to TASIT but five patients (18.5%) did not. Among the five non-responders, two patients were transferred to liver transplantation and survived, and three patients died. There was no significant difference in the response rates to TASIT among locations of catheter tip (P > 0.05) and extent of drug distribution in the liver (P > 0.05). CONCLUSION: TASIT is a feasible and efficient treatment option for SAHF regardless of the anatomic variation of the hepatic artery. Careful manipulation during the procedure to prevent injury of the hepatic artery may be the most essential factor not only for successful TASIT but also for liver transplantation, which may be performed on TASIT non-responders.

Potential role of branched-chain amino acids in glucose metabolism through the accelerated induction of the glucose-sensing apparatus in the liver.

Branched-chain amino acids (BCAAs) have a potential to improve glucose metabolism in cirrhotic patients; however, the contribution of liver in this process has not been clarified. To estimate the effect of BCAA on glucose metabolism in liver, we evaluated the mRNA expression levels of glucose-sensing apparatus genes in HepG2 cells and in rat liver after oral administration of BCAA. HepG2 cells were cultured in low glucose (100 mg/dl) or high glucose (400 mg/dl) in the absence or presence of BCAA. The mRNA expression levels and protein levels of GLUT2 and liver-type glucokinase (L-GK) were estimated using RT-PCR and immunoblotting. The expression levels of transcriptional factors, including SREBP-1c, ChREBP, PPAR-γm and LXRα, were estimated. The mRNA expression levels of transcriptional factors, glycogen synthase, and genes involved in gluconeogenesis were evaluated in rat liver at 3 h after the administration of BCAA. BCAA accelerated the expression of GLUT2 and L-GK in HepG2 cells in high glucose. Expression levels of ChREBP, SREBP-1c, and LXRα were also increased in this condition. BCAA administration enhanced the mRNA expression levels of L-GK, SREBP-1c, and LXRα and suppressed the expression levels of G-6-Pase in rat liver, without affecting the expression levels of glycogen synthase or serum glucose concentrations. BCAA administration enhanced the bioactivity of the glucose-sensing apparatus, probably via the activation of a transcriptional mechanism, suggesting that these amino acids may improve glucose metabolism through the accelerated utility of glucose and glucose-6-phosphate in the liver.