Keiji Tsuji

Dose-finding trial of tolvaptan in liver cirrhosis patients with hepatic edema: A randomized, double-blind, placebo-controlled trial

Liver cirrhosis represents the end stage of any chronic liver disease, and it is associated with hepatic edema such as ascites. Many patients with ascites do not respond to diuretic therapy or require administration of diuretics at high doses that can cause adverse events. This 7‐day, multicenter, double‐blind trial of tolvaptan was designed to determine the optimal dose of tolvaptan for producing the intended pharmacological effect in hepatic edema.

Comparison of hepatic arterial infusion chemotherapy versus sorafenib monotherapy in patients with advanced hepatocellular carcinoma

Sorafenib is the standard treatment for advanced hepatocellular carcinoma (HCC) with distant metastasis, unresectable HCC, and those refractory to transcatheter arterial chemoembolization (TACE) or with macroscopic vascular invasion (MVI). The application of sorafenib has been approved by the Japanese Government‐sponsored Medicare for unresectable HCC. In this retrospective cohort study we aimed to compare various aspects of HAIC with sorafenib in the treatment of Child–Pugh A patients with advanced HCC who were otherwise free of extrahepatic metastasis.

Liver disease in hepatitis C virus carriers identified at blood donation and their outcomes with or without interferon treatment: Study on 1019 carriers followed for 5-10 years.

Aim:  To portray liver disease and project outcomes in carriers of hepatitis C virus (HCV) in the general population.

Real-World Efficacy and Safety of Daclatasvir and Asunaprevir Therapy for Hepatitis C Virus-Infected Cirrhosis Patients.

Daclatasvir and asunaprevir combination therapy has shown a high virological response for chronic genotype 1 hepatitis C virus (HCV) infected‐patients. However, the real‐world efficacy and safety of the therapy for patients with cirrhosis are unknown.

Eicosapentaenoic Acid Could Permit Maintenance of the Original Ribavirin Dose in Chronic Hepatitis C Virus Patients during the First 12 Weeks of Combination Therapy with Pegylated Interferon-α and Ribavirin

Objective: To evaluate the efficacy of eicosapentaenoic acid (EPA) against ribavirin (RBV)-associated hemolytic anemia during the first 12 weeks in chronic hepatitis C virus (HCV) combination therapy. Methods: This study was a prospective open-label, randomized controlled trial. 100 HCV patients were randomized to either the EPA group (n = 49) or non-EPA group (n = 51) who received combination therapy with or without EPA. We compared the changes in hemoglobin level and RBV plasma concentrations at week 12 in each group with RBV dose reduction rate and performed multivariate analysis to identify independent variables associated with RBV dose reduction. Results: 8 patients (17%) in the EPA group and 20 patients (29%) in the non-EPA group required RBV dose reduction, respectively. The cumulative RBV reduction rate was significantly lower in the EPA group than in the non-EPA group (p = 0.017), while the decrease of hemoglobin and RBV plasma concentrations from baseline was not significantly different. However, in the multivariate analysis, treatment with EPA showed significant variables for the reduction of RBV dose (odds ratio 3.235, p = 0.023). Conclusion: EPA could prevent the RBV dose reduction during the first 12 weeks in combination therapy, although further large-scale double-blind randomized controlled trials are required.

Dose comparison study of pegylated interferon-α-2b plus ribavirin in naïve Japanese patients with hepatitis C virus genotype 2: A randomized clinical trial

Background and Aim:  To compare the efficacy and safety of pegylated interferon (PEG‐I) at 1 and 1.5 µg/kg, and in combination with ribavirin (RBV) for 24 weeks in naïve Japanese patients infected with hepatitis C virus genotype 2.

Prospective study of short‐term peginterferon‐α‐2a monotherapy in patients who had a virological response at 2 weeks after initiation of interferon therapy

Background and Aims:  Long‐term interferon (IFN) therapy is effective in eliminating hepatitis C virus (HCV). However, it carries the risk of adverse effects and reduced quality of life. To assess whether short‐term IFN therapy effectively eliminates HCV, we performed a prospective pilot study of pegylated (peg)IFN‐α‐2a therapy for 8 or 24 weeks.

Does interferon-free direct-acting antiviral therapy for hepatitis C after curative treatment for hepatocellular carcinoma lead to unexpected recurrences of HCC? A multicenter study by the Japanese Red Cross Hospital Liver Study Group

Background and aim This study aimed to elucidate whether interferon (IFN)-free direct-acting antiviral (DAA) therapy for hepatitis C after curative treatment of hepatocellular carcinoma (HCC) promotes HCC recurrence in a real-world large-scale cohort. Methods This multicenter study was conducted by the Japanese Red Cross Hospital Liver Study Group. This retrospective study analyzed 516 patients who underwent antiviral treatment for hepatitis C with either IFN (n = 148) or IFN-free DAA (n = 368) after curative HCC treatment; 78 IFN-treated patients and 347 IFN-free DAA-treated patients achieved sustained virological response (SVR). The recurrence rate of HCC was compared between the antiviral therapies. Logistic analysis and Cox proportional hazards analysis identified factors associated with early recurrence of HCC within 24 weeks of antiviral therapy and recurrence throughout the observation period, respectively. Results AFP at the completion of antiviral therapy, clinical stage of HCC, and non-SVR were independent factors associated with early recurrence of HCC. Among patients who had achieved SVR, the clinical stage of HCC and the level of AFP at completion of antiviral therapy were independent factors associated with early recurrence of HCC. For recurrence throughout the observation period in SVR patients, AFP at completion of antiviral therapy, duration between last HCC treatment to antiviral therapy, and the number of treatments were independent factors. There was no significant difference in the rate of early recurrence of HCC or recurrence throughout the observation period between IFN and IFN-free DAA treated patients. Conclusions There were no differences in the early recurrence rate of HCC between patients who underwent IFN and those who underwent IFN-free DAA as antiviral therapies.

Emergence of drug resistance‐associated variants and changes in serum lipid profiles in sofosbuvir plus ledipasvir‐treated chronic hepatitis C patients

Combination of sofosbuvir plus ledipasvir therapy has been expected to enhance sustained virological response (SVR) rates in hepatitis C virus (HCV) genotype 1 chronic infected patients. We analyzed the emergence of drug resistance‐associated variants (RAVs) in treatment failure and changes in lipid profiles in sofosbuvir/ledipasvir‐treated patients. A total of 176 patients with chronic HCV genotype 1 infection without decompensated liver cirrhosis were treated with sofosbuvir/ledipasvir for 12 weeks. NS5A and NS5B RAVs were determined by either Invader assay or direct sequencing. Serum lipid‐related markers were measured at the start of treatment and at week 4 in patients who received sofosbuvir/ledipasvir and ombitasvir/paritaprevir/ritonavir therapies. SVR was achieved in 94.9% (167 out of 176) of patients. SVR12 rate was 97.1% for patietns with low frequncy (<25%) of baseline NS5A RAVs, but 82.8% for patients with high frequency (>75%) of NS5A RAVs. In multivariate regression analysis, higher albumin (odds ratio [OR] = 0.020 for presence; P = 0.007), and NS5A‐L31/Y93 RAVs with a population frequency <75% (OR = 29.860 for presence; P = 0.023) were identified as significant independent predictors for SVR12. NS5A‐Y93H substitutions were detected in all nine treatment failures at HCV relapse, and three out of six patients with NS5A inhibitor‐naïve patients achieved additional NS5A RAVs. Serum low‐density lipoprotein cholesterol and apolipoprotein B levels were significantly elevated at week 4 in sofosbuvir/ledipasvir‐treated patients. These elevations were greater than in ombitasvir/paritaprevir/ritonavir‐treated patients. In conclusion, NS5A multi‐RAVs are likely to develop in patients who fail to respond to sofosbuvir/ledipasvir therapy. Inhibition of HCV replication with sofosbuvir might affect lipid metabolism.

IFNL4 polymorphism effects on outcome of simeprevir, peginterferon, and ribavirin therapy for older patients with genotype 1 chronic hepatitis C

Older patients with chronic hepatitis C have a lower virological response to interferon (IFN)‐based treatments compared to younger patients. A single nucleotide polymorphism in the IFN‐λ‐4 (IFNL4) gene has a potent predictive effect on treatment response to IFN‐based treatments. The efficacy of simeprevir (SMV) plus pegylated‐IFN (PEG‐IFN) and ribavirin therapy and the predictive value of IFNL4 on the outcome of therapy for older patients have not been addressed.