Katsuhisa Nakatsuka

Effects of terlipressin on systemic, hepatic and renal hemodynamics in patients with cirrhosis

Background and Aim:  Terlipressin has been shown to be effective in the management of hepatorenal syndrome. However, how terlipressin exerts its effect on the renal artery is unknown. The aim of the present study was to assess the effects of terlipressin on systemic, hepatic and renal hemodynamics in cirrhosis.

A randomized clinical trial comparing transjugular intrahepatic portosystemic shunt with endoscopic sclerotherapy in the long-term management of patients with cirrhosis after recent variceal hemorrhage

The aim of this study was to compare the efficacy of transjugular intrahepatic portosystemic shunt (TIPS) with that of endoscopic sclerotherapy (ES) in the long-term management of patients with cirrhosis after variceal bleeding. Seventy-eight consecutive cirrhotic patients with recent variceal bleeding were randomly allocated to either TIPS (n=38) or ES (n=40). All patients were in good condition at randomization. The mean follow-up was 1116+/-92 days in the TIPS group and 1047+/-102 days in the ES group. Differences in rebleeding from any source (18.4% vs. 32.5%) and esophageal variceal rebleeding (15.7% vs. 27.5%) were not significantly different between the two groups (P>0.05). The mortality rates were similar in both treatment groups. Shunt dysfunction was noted in 27 patients (71%) in the TIPS group. There were more numbers of rehospitalization during follow-up in the TIPS group than in the ES group (2.6+/-0.4 vs. 1.1+/-0.2) (P<0.01). TIPS and ES are equally effective in the prevention of variceal rebleeding. However, TIPS is associated with high incidence of shunt dysfunction, which lead to more rehospitalization. Therefore, TIPS may not be a first-line treatment for the prevention of variceal rebleeding in cirrhotic patients who are in stable condition.

An open-label randomized controlled study of pegylated interferon/ribavirin combination therapy for chronic hepatitis C with versus without fluvastatin.

Summary.  Pegylated interferon (PEG‐IFN)/ribavirin combination therapy is the standard‐of‐care (SOC) treatment for chronic hepatitis C patients infected with hepatitis C virus (HCV) genotype 1b and high viral load. The addition of fluvastatin to SOC treatment has been suggested to be effective for better outcome in retrospective pilot analyses. We investigated whether the combination of fluvastatin with PEG‐IFN/ribavirin could actually improve sustained viral response (SVR) in patients with HCV genotype 1b and high viral load. A randomized, open‐labeled, controlled study was conducted between July 2008 and December 2009 in 101 chronic hepatitis C patients allocated to PEG‐IFN/ribavirin combination therapy with or without fluvastatin. SVR rates were calculated in groups, stratifying host and viral factors. We also analyzed predictive factors for SVR among patients on fluvastatin with multivariate regression analysis. Rapid and early virological, and end of treatment response rates in the fluvastatin group were not significantly different from those in the non‐fluvastatin group. Notwithstanding, SVR rate was significantly higher in the fluvastatin group than in the non‐fluvastatin group (63.0%vs 41.7%, P = 0.0422). Comparison of the two groups stratifying demographic data and HCV characteristics showed significantly higher SVR rates to more than 80% in males, more than two mutations in the interferon sensitivity determining region (ISDR), and a history of relapse among the fluvastatin group than the non‐fluvastatin group. Being male and major genotype IL28B single nucleotide polymorphisms (SNPs) were independent predictive factors for SVR among patients on fluvastatin with multivariate analysis. Fluvastatin‐combined with PEG‐IFN/ribavirin therapy significantly improves SVR rates in patients with HCV genotype 1b and high viral load. Male and major genotype IL28B SNPs were independent predictors for SVR among patients on fluvastatin combination therapy.

Ribavirin downmodulates inducible costimulator on CD4+ T cells and their interleukin-10 secretion to assist in hepatitis C virus clearance.

Background and Aim:  The immunological mechanism by which ribavirin (RBV) polarizes the T‐helper (Th) 1/2 balance toward Th1 predominancy is not fully understood. We therefore examined whether RBV affects costimulatory signaling, which is known to be essential for regulating the Th1/2 balance.

Purification of antigenic peptide from murine hepatoma cells recognized by Class-I major histocompatibility complex molecule-restricted cytotoxic T-lymphocytes induced with B7-1-gene-transfected hepatoma cells

BACKGROUND/AIM It has been reported that expression of costimulatory molecules, such as B7, on tumors is essential for priming tumor-specific cytotoxic T-lymphocytes (CTLs). Here, we have attempted to induce murine hepatoma-specific CTLs by immunizing with the B7-1-gene-expressing hepatoma cells, and to identify the epitope(s) presented on the hepatoma cells. METHODS The B7-1-gene encoding plasmid was transferred into the murine hepatoma cell line, Hepa1-6. Syngeneic C57BL/6 mice were immunized with the B7-1-transfected cells via various routes to prime CTLs. The mild acid elution method was used to isolate antigenic fractions from the class-I major histocompatibility complex (MHC) molecules on the Hepa1-6 cells. Cytotoxicity was measured by standard 51Cr-releasing assay. The effect of the CTLs on hepatoma growth was evaluated in hepatoma-bearing SCID mice to which the cells were preadministered. RESULTS A clone, termed L1, highly expressing the B7-1-gene, has been established. Killer cells generated from mice immunized intraperitoneally with L1 cells eliminated both L1 and Hepa1-6 cells, and also another syngeneic hepatoma cell line, Hepa1-clc7. The killer cells were CD8+ and the class-I MHC molecule-restricted CTLs which might recognize hepatoma-specific antigenic peptide(s) in association with the D(b)class-I MHC molecules. A functional peptide fraction was obtained from eluted fluid of the Hepa1-6 cells. In addition, intravenous preadministration of the CTLs inhibited the hepatoma growth in SCID mice. CONCLUSIONS The hepatoma epitope-specific CTLs which suppressed hepatoma growth in vivo could be generated with the B7-1-gene-transfected hepatoma cells. These results will be useful in establishing immunotherapy against hepatocellular carcinoma.

Combination of fluvastatin with pegylated interferon/ribavirin therapy reduces viral relapse in chronic hepatitis C infected with HCV genotype 1b

Although the anti‐hepatitis C virus (HCV) effect of statins in vitro and clinical efficacy of fluvastatin combined with Pegylated interferon (PEG‐IFN)/ribavirin therapy for chronic hepatitis C (CHC) have been reported, the details of clinical presentation are largely unknown. We focused on viral relapse that influences treatment outcome, and performed a post‐hoc analysis by using data from a randomized controlled trial.

Ribavirin modulates the conversion of human CD4 + CD25 T cell to CD4 + CD25 + FOXP3 + T cell via suppressing interleukin-10-producing regulatory T cell

Because regulatory T (Treg) cells play an important role in modulating the immune system response against both endogenous and exogenous antigens, their control is critical to establish immunotherapy against autoimmune disorders, chronic viral infections and tumours. Ribavirin (RBV), an antiviral reagent used with interferon, is known to polarize the T helper (Th) 1/2 cell balance toward Th1 cells. Although the immunoregulatory mechanisms of RBV are not fully understood, it has been expected that RBV would affect T reg cells to modulate the Th1/2 cell balance. To confirm this hypothesis, we investigated whether RBV modulates the inhibitory activity of human peripheral CD4+ CD25+ CD127− T cells in vitro. CD4+ CD25+ CD127− T cells pre‐incubated with RBV lose their ability to inhibit the proliferation of CD4+ CD25− T cells. Expression of Forkhead box P3 (FOXP3) in CD4+ CD25− T cells was down‐modulated when they were incubated with CD4+ CD25+ CD127− T cells pre‐incubated with RBV without down‐modulating CD45RO on their surface. In addition, transwell assays and cytokine‐neutralizing assays revealed that this effect depended mainly on the inhibition of interleukin‐10 (IL‐10) produced from CD4+ CD25+ CD127− T cells. These results indicated that RBV might inhibit the conversion of CD4+ CD25− FOXP3− naive T cells into CD4+ CD25+ FOXP3+ adaptive Treg cells by down‐modulating the IL‐10‐producing Treg 1 cells to prevent these effector T cells from entering anergy and to maintain Th1 cell activity. Taken together, our findings suggest that RBV would be useful for both elimination of long‐term viral infections such as hepatitis C virus infection and for up‐regulation of tumour‐specific cellular immune responses to prevent carcinogenesis, especially hepatocellular carcinoma.

Effect of native vitamin D3 supplementation on refractory chronic hepatitis C patients in simeprevir with pegylated interferon/ribavirin

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.

Serum 25-hydroxyvitamin D3 levels affect treatment outcome in pegylated interferon/ribavirin combination therapy for compensated cirrhotic patients with hepatitis C virus genotype 1b and high viral load

Much is unknown about the effect of 25‐hydroxyvitamin D3 levels on the outcome of pegylated interferon/ribavirin (PEG IFN/RBV) therapy for hepatitis C virus‐related cirrhosis. The purpose of the present study was to analyze and elucidate factors, including 25‐hydroxyvitamin D3, that contribute to a sustained virological response (SVR) in patients with cirrhosis.

EFFICACY OF ALFACALCIDOL ON PEG-IFN/ RIBAVIRIN COMBINATION THERAPY FOR ELDERLY PATIENTS WITH CHRONIC HEPATITIS C: A PILOT STUDY

Background Serum vitamin D concentration is reported to show a decrease in older age. Patients with chronic hepatitis C (CHC) in Japan are older on average than those in Western countries. Moreover, the outcome of pegylated-interferon (PEG-IFN)/ ribavirin therapy combined with vitamin D in elderly patients is unclear. Objectives This pilot study explored the efficacy and safety of alfacalcidol as vitamin D source in PEG-IFN/ ribavirin combination therapy for elderly CHC patients infected with hepatitis C virus genotype 1b. Patients and Methods Consecutive twenty CHC patients aged ≥ 65 years were enrolled in this pilot study. Fifteen patients met the inclusion criteria and received PEG-IFN/ ribavirin therapy combined with alfacalcidol. Four-week lead-in of oral alfacalcidol was conducted, and it was subsequently and concurrently administered in PEG-IFN/ ribavirin combination therapy (vitamin D group). Age, gender, and IL28B genotype-matched patients, who received PEG-IFN/ ribavirin alone, were saved as control group (n = 15) to compare the treatment outcome with the vitamin D group. Results Subjects consisted of 14 males and 16 females, with a median age of 70 years (65-78). The serum 25 (OH) D3 concentration in females (20 ng/ml, 11-37) was significantly lower than males (27 ng/mL, 13-49) (P = 0.004). Sustained virological response (SVR) rates were 33.3% (5/15) in the control group and 80.0% (12/15) in the vitamin D group, respectively (P = 0.025). While no significant difference was shown in the (SVR) rate between the two groups among males (P = 0.592), in females the SVR rate was significantly higher in the vitamin D group (87.5%, 7/8) than the control group (25.0%, 2/8) (P = 0.041). The relapse rates in the groups with and without alfacalcidol were 7.7% (1/13) and 61.5% (8/13), respectively (P = 0.011). Interestingly, in females, the relapse in the control group was shown in 5 of 7 (71.4%), whereas in the vitamin D group the relapse rate was decreased (1/8, 12.5%) (P = 0.041). No specific adverse events were observed in the vitamin D group. Conclusions PEG-IFN/ ribavirin combined with alfacalcidol may be effective and safe in elderly CHC patients. In particular, concomitant administration of alfacalcidol may lead to a reduced relapse rate, and consequently improving the SVR rate in elderly females.