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Introduction and Objectives: We examined whether Mac-2-binding protein glycosylation isomer (M2BPGi) levels could be a predictive marker for the presence of esophagogastric varices (EGV) in cirrhotic patients after hepatitis C virus (HCV) eradication with direct-acting antivirals (DAAs)., Patients and Methods: A total of 102 cirrhotic patients with HCV infection treated with DAAs were enrolled. Esophagogastroduodenoscopy was performed in 84 of the patients before treatment (Cohort A), in 66 after treatment (Cohort B), and in 48 at both time points (Cohort C). We examined factors associated with EGV before and after DAA treatment., Results: In Cohort A, M2BPGi levels and liver stiffness were significantly higher in the EGV-positive group than the EGV-negative group (p=0.034, and p=0.042, respectively). The proportion of EGV-positive patients with before-treatment levels of M2BPGi ≧ 7.3 C.O.I. was significantly higher than in patients with M2BPGi levels<7.3 C.O.I. (p=0.015). In Cohort B, M2BPGi levels were significantly higher in the EGV-positive group than EGV-negative group (p=0.003). The proportion of EGV-positive patients with after-treatment levels of M2BPGi ≧ 3.4 C.O.I. was significantly higher than in patients with M2BPGi levels<3.4C.O.I. (p=0.001). In Cohort C, M2BPGi levels decreased during DAA treatment regardless of EGV development, but there was no significant difference in the reduction of M2BPGi among the EGV-improvement, EGV-invariant, and EGV-exacerbation groups (p=0.659)., Conclusions: M2BPGi levels may be a novel serum marker for the presence of EGV before and after DAA treatment., (Copyright © 2020 Fundación Clínica Médica Sur, A.C. Published by Elsevier España, S.L.U. All rights reserved.)

It is unclear whether multiple nonstructural (NS) 5A resistance-associated substitutions (RASs) correlate with the outcome of sofosbuvir (SOF) and ledipasvir (LDV) therapy. We investigated the effects of multiple NS5A RASs in NS5A inhibitor-naïve patients with chronic hepatitis C virus genotype 1b infection treated with SOF/LDV. In 313 patients treated with SOF/LDV, we assessed the effects of multiple NS5A RASs on the sustained virological response (SVR). RASs at L28, R30, L31, Q54, P58, Q62, A92, and Y93 in the NS5A region were examined by direct sequencing. The prevalence of RASs was as follows: 2.6% at L28, 8.7% at R30, 6.1% at L31, 48.7% at Q54, 9.9% at P58, 9.9% at Q62, 5.1% at A92, 13.8% at Y93, and 19.2% at L31 or Y93. A total of 133 patients had no RASs. SVR was achieved in 98.7% of the patients. SVR rates significantly differed between patients with and without the L31 or Y93 RAS (93.0% [53/57] vs 100% [250/250], P = .0011). In addition, among patients with the L31 or Y93 RAS, 29.8%, 45.6% and 24.6% had one, two and three or more NS5A RASs, respectively. The SVR rate was significantly lower in patients with the L31 or Y93 RAS with more than three NS5A RASs compared to those with fewer than three NS5A RASs (71.4% [10/14] vs 100% [43/43], P = .0025). Although the prevalence of multiple NS5A RASs at baseline was low in NS5A inhibitor-naïve patients, the presence of multiple NS5A RASs was associated with the effectiveness of SOF/LDV therapy., (© 2017 John Wiley & Sons Ltd.)

Recently, the MICA rs2596542 and DEPDC5 rs1012068 variants in Japanese individuals as well as the HCP5 rs2244546 and PNPLA3 rs738409 variants in European individuals have been found associated with hepatocellular carcinoma (HCC). The present study determined which single nucleotide polymorphism (SNP) is the most predictive for developing hepatitis C virus (HCV)-related HCC in a Japanese cohort. Of the 4 SNPs analysed, only the MICA genotypes were significantly associated with development of HCC (p = 0.0185). The major (MA), hetero (HE), and minor (MI) genotypes occurred in 40%, 41%, and 19% of HCC patients and in 43%, 47%, and 10% of non-HCC patients, respectively. Interestingly, the MICA genotype was significantly correlated with MICA mRNA and soluble protein levels. In patients older than 70 years, the MI genotype was significantly associated with HCC development. In addition, the MI genotype was related to HCC development when the platelet count range was 10-15 × 10 4 /μL, corresponding with the fibrosis stage; but not when the range was less than 10, indicating advanced fibrosis; or greater than 15 × 10 4 /μL, as mild fibrosis. Thus, polymorphisms in MICA, but not in DEPDC5, HCP5 or PNPLA3, are associated with HCC development in Japanese patients with chronic HCV infection.

Background: The efficacy and safety of asunaprevir + daclatasvir combination therapy for treatment of hepatitis C virus (HCV) in compensated cirrhotic patients was not fully evaluated in real-world. Outcomes were assessed in cirrhotic patients with sustained viral response (SVR)., Material and Methods: A total of 145 patients without resistance-associated substitutions (RASs) at L31 and Y93 in the nonstructural protein 5A of HCV genotype 1b, consisting of 49 hepatic cirrhotic and 96 non-cirrhotic patients, were enrolled to the therapy. The patients were treated with 100 mg asunaprevir twice daily plus 60 mg daclatasvir once daily for 24 weeks. The primary endpoint was SVR 24 weeks after completing treatment. In addition, we evaluated the improvement of liver function and development of HCC for 1 year from the end of treatment (EOT)., Results: The SVR24 rate was 96% (47/49) in the cirrhotic group and 96% (91/95) in the non-cirrhotic group (p = 0.69). During treatment, grade III/IV adverse events occurred more frequently in cirrhotic patients (10/49; 20.4%) than in non-cirrhotic patients (10/96; 10.4%) (p = 0.099). After EOT, alanine aminotransferase and AFP levels were significantly decreased in cirrhotic patients with SVR. In addition, serum levels of albumin and platelet counts were significantly increased. On the other hand, the rates of HCC recurrence (43%) and development (7.4%) were higher in cirrhotic patients than in the non-cirrhotic patients (12.5% and 1.1%, respectively)., Conclusion: RAS-oriented asunaprevir/daclatasvir therapy has a strong anti-HCV effect in patients with HCV genotype 1b. However, careful management is necessary in patients with cirrhosis.

Background and Aim: It is unclear whether polymorphism in the inosine triphosphatase (ITPA) gene correlates to the reduction in hemoglobin (Hb) concentrations during sofosbuvir (SOF) and ribavirin (RBV) therapy. This study investigated the effects of the ITPA polymorphism on Japanese patients with chronic hepatitis C virus genotype 2 infection treated with SOF/RBV therapy., Methods: In 106 patients treated with SOF/RBV therapy, this study assessed the effects of the ITPA polymorphism (rs1127354) on anemia, RBV dose reduction, and sustained virological response., Results: Of the 106 patients, 80 had the CC genotype, whereas 26 had a non-CC genotype in ITPA. Patients with the CC genotype had significantly larger reductions in Hb concentrations than those with a non-CC genotype throughout the treatment course. RBV dose reduction was required in 18/106 (17.0%) patients, with a significantly higher frequency in patients with the CC genotype than in those with a non-CC genotype (P = 0.010). In multivariate analysis, age ≥ 65 years (P = 0.011) and the ITPA CC genotype (P < 0.0001) were factors significantly associated with anemia throughout the treatment course. Sustained virological response was achieved in 99.0% of all patients: 98.7% of patients with the CC genotype and 100% of patients with a non-CC genotype., Conclusions: Inosine triphosphatase polymorphism appeared to correlate with anemia incidence and RBV dose reduction during SOF/RBV therapy, but not the clinical outcome. Careful monitoring of Hb concentrations and prompt adjustment of RBV doses are required for successful treatment, particularly in patients harboring the ITPA CC genotype or age ≥ 65 years., (© 2017 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

We evaluated the transition of dominant resistance-associated substitutions (RASs) in hepatitis C virus during long-term follow-up after the failure of DAAs (direct acting antivirals)-based therapy. RASs in non-structure (NS)3/4A, NS5A, NS5B, and deletions in NS5A from 20 patients who failed simeprevir/pegylated-interferon/ribavirin (SMV/PEG-IFN/RBV) and 25 patients who failed daclatasvir/asunaprevir (DCV/ASV) treatment were examined by direct sequencing. With respect to SMV/PEG-IFN/RBV treatment, RAS was detected at D168 in NS3/4A but not detected in NS5A and NS5B at treatment failure in 16 of 20 patients. During the median follow-up period of 64 weeks, the RAS at D168 became less dominant in 9 of 16 patients. Among 25 DCV/ASV failures, RASs at D168, L31, and Y93 were found in 57.1%, 72.2%, and 76.9%, respectively. NS5A deletions were detected in 3 of 10 patients treated previously with SMV/PEG-IFN/RBV. The number of RASs in the breakthrough patients exceeded that in relapsers (mean 3.9 vs. 2.7, p < 0.05). RAS at D168 in NS3/4A became less dominant in 6 of 15 patients within 80 weeks. Y93H emerged at the time of relapse, then decreased gradually by 99% at 130 weeks post-treatment. Emerged RASs were associated with the clinical course of treatment and could not be detected during longer follow-up.

Aim: Anemia is the most common adverse event in patients with chronic hepatitis C virus (HCV) treated with telaprevir (TVR) combined triple therapy. We examined the effects of drug dose adjustment on anemia and a sustained viral response (SVR) during combination therapy., Material and Methods: This study enrolled 62 patients treated with TVR (2,250 mg) for 12 weeks plus pegylated interferon-alpha-2b and ribavirin for 24 weeks. The patients were assigned randomly to the TVR-standard or -reduced groups before treatment. At the occurrence of anemia (hemoglobin < 12 g/dL), the TVR-reduced group received 1500 mg TVR plus the standard dose of ribavirin, whereas the TVR-standard group received the standard TVR dose (2,250 mg) and a reduced dose of ribavirin (200 mg lower than prescribed originally). The safety and SVR at 24 weeks were compared between the TVR-standard (n = 28) and TVR-reduced (n = 25) groups., Results: No differences in the proportion of patients who became HCV RNA-negative were detected between the TVR-standard and -reduced groups (72 and 72% at week 4, 79 and 84% at the end of treatment, and 76 and 80% at SVR24, respectively). Two groups had comparable numbers of adverse events, which led to the discontinuation of TVR in 14 patients of TVR-standard group and in 14 of TVR-reduced group. A lower incidence of renal impairment was observed in the TVR-reduced group (6%) than the TVR-standard group (11%, not statistically significant)., Conclusions: TVR dose adjustment could prevent anemia progression without weakening the anti-viral effect during triple therapy in HCV-patients.

Background and Aim: It is not yet clear which factors are associated with the outcome of 72-week treatment with pegylated-interferon and ribavirin (RBV) in patients with chronic hepatitis C virus (HCV) infection., Methods: In 66 patients with HCV genotype 1 who had a late viral response (LVR) to 72-week treatment of pegylated-interferon and RBV, we examined the factors that determined the outcome, including single nucleotide polymorphisms of interleukin-28B and inosine triphosphatase (ITPA) genes., Results: Thirty seven of 66 (56%) patients with LVR achieved a sustained viral response (SVR). The mean age of these 37 SVR patients was 55, compared with 61 in 29 relapsed patients (P = 0.009). Twenty six of 54 (48%) patients with the CC genotype and 11 of 12 (92%) with the CA/AA genotype of ITPA rs1127354 achieved SVR (P = 0.006). The SVR rates were 79%, 40%, 60%, and 33% in patients with undetectable HCV RNA on weeks 16, 20, 24, and 28 or later, respectively (P = 0.014). Finally, serum RBV concentration at week 44 of treatment was significantly higher in the SVR group (2651 ng/mL) than in the relapse group (1989 ng/mL, P = 0.002). In contrast, the rate of the interleukin-28B genotype was not different between the groups. Multiple regression analysis showed that age < 60 years, ITPA CA/AA genotype, and serum RBV concentration were significant independent predictive factors for SVR., Conclusions: Our findings elucidated the association of four factors, including ITPA genotype, with the outcome of 72-week treatment in LVR patients., (© 2013 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.)

Background: The real-time PCR, such as Abbott RealTime assay, have replaced end-point PCR, such as Amplicor assays, for the measurement of HCV RNA. However, 'response-guided therapy' to use on-treatment response for tailoring the duration of treatment with peginterferon-alpha and ribavirin has not been fully evaluated for real-time PCR., Methods: 43 patients with HCV genotype 1 (24 who had complete early virological responses (cEVR) on Amplicor assay and received 48-week therapy, and 19 who had late virological responses (LVR) and received 72-week therapy) were recruited. Using a RealTime assay, we retrospectively measured HCV RNA in stored sera., Results: In 10 samples obtained during therapy, HCV RNA was undetectable on the Amplicor assay, but detectable on the RealTime assay. Among patients with cEVR on the Amplicor assay, those with detectable HCV RNA on the RealTime assay at week 12 were less likely to have a sustained virological response (SVR) than those without (2/4 vs 17/20, p = 0.116). Among patients with LVR on the Amplicor assay, those with HCV RNA detectable on the RealTime assay at week 24 were significantly less likely to have SVR than those without (1/4 vs 12/15, p = 0.041)., Conclusions: The RealTime assay may be useful for tailoring duration of treatment for the patient with HCV genotype 1.

Background and Objectives: Gastroparesis, a gastrointestinal autonomic neuropathy, is a common adverse reaction in chronic hepatitis C (CHC) patients receiving interferon therapy. Current therapeutic options are limited. We evaluated the efficacy of mosapride for IFN-induced gastroparesis., Methods: Twenty-four consecutive CHC patients were randomly assigned to either the control group, which received pegylated interferon α-2b at 1.5 μg/kg/week and ribavirin at 600-1,000 mg/day, depending on body weight (PegIFN/RBV), or the mosapride group, which received PegIFN/RBV plus mosapride at 15 mg/person/day. The solid-phase gastric emptying half-times (T1/2) of the total, proximal, and distal stomach (scintigraphy) and digestive symptoms (questionnaire) were measured within one week before and four weeks after initiation of the assigned therapy. The test meal comprised a 200-g pancake containing Tc-99m diethylenetriamine pentaacetic acid., Results: In the control group, after PegIFN/RBV initiation, a significant increase was observed in the total T1/2 (before: 84.0 ± 22.1 min versus after: 100.8 ± 28.9 min, P = 0.03), the distal T1/2 (before: 95.3 ± 32.2 min versus after: 115.3 ± 41.4 min, P = 0.03), and digestive symptom score (before: 3.2 ± 1.4 versus after: 8.1 ± 4.8, P = 0.02); proximal T1/2 change was not significant. In the mosapride group, no significant delays were observed in the total, proximal, and distal T1/2 values; the change in symptom scores was not significant., Conclusions: Mosapride improved total and distal gastric motility in IFN-induced gastroparesis, and consequently relieved symptoms.

Background: Although histopathological examination by "invasive" liver biopsy remains the gold standard for evaluating disease progression in chronic liver disease, noninvasive tools have appeared and have led to great progress in diagnosing the stage of hepatic fibrosis. The aim of this study was to assess the value of real-time tissue elastography, using an instrument made in Japan, for the visible measurement of liver elasticity; in particular, comparing the results with those of transient elastography (Fibroscan)., Methods: Real-time tissue elastography (RTE), transient elastography (Fibroscan), liver biopsy, and routine laboratory analyses were performed in 101 patients with chronic hepatitis C. The values for tissue elasticity obtained using novel software (Elasto&#95;ver 1.5.1) connected to RTE were transferred to four image features, Mean, Standard Deviation (SD), Area, and Complexity. Their association with the stage of fibrosis at biopsy and with liver stiffness (kPa) obtained by Fibroscan was analyzed., Results: Colored images obtained by RTE were classified into diffuse soft, intermediate, and patchy hard patterns and the calculated elasticity differed significantly between patients according to and correlated with the stages of fibrosis (p < 0.0001). Mean, SD, Area, and Complexity showed significant differences between the stages of fibrosis (Tukey-Kramer test, p < 0.05). In discriminating patients with cirrhosis, the areas under the receiver operating characteristic curves (AUC) were 0.91 for Mean, 0.84 for SD, 0.91 for Area, 0.93 for Complexity, and 0.95 for Fibroscan., Conclusions: RTE is a noninvasive instrument for the colored visualization of liver elasticity in patients with chronic liver disease.

Hepatitis C virus (HCV) infection is the most common cause of chronic hepatitis, which frequently progresses to hepatocellular carcinoma. The pathogenesis of its persistent infection and tumour progression has not been fully characterized yet. The RCK gene was previously cloned at the breakpoint of the t(11;14)(q23;q32) chromosome translocation observed in human B-cell lymphoma cell line RC-K8. The RCK protein, rck/p54, which is a 54-kDa cytoplasmic protein belonging to the DEAD box/RNA helicase family, is considered to facilitate the translation of mRNA(s) of genes for cell proliferation and malignant transformation not only in B-cell lymphomas having the t(11;14) translocation but also in other solid tumours. The aim of this work was to examine the involvement of rck/p54 in carcinogenesis of hepatocellular carcinoma from HCV-related chronic hepatitis. We examined the expression of rck/p54 in 29 cases of HCV-related chronic hepatitis and eight cases of hepatocellular carcinoma by immunohistochemistry and Western blot analysis. Twenty-six of 29 cases with HCV-related chronic hepatitis and all cases with hepatocellular carcinoma tested overexpressed rck/p54 protein. The expression of rck/p54 was lowered by treatment with IFN-alpha in two cases who showed the decrease in HCV RNA levels. These findings suggest that rck/p54 protein is possibly involved in the replication of HCV genomes in hepatocytes and in tumourigenesis of hepatocellular carcinomas.