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Background: The Wisteria floribunda agglutinin-positive human Mac-2-binding protein (WFA(+) -M2BP) is a new liver fibrosis glycobiomarker with unique fibrosis-related glyco-alteration. WFA(+) -M2BP is also a useful surrogate marker for the risk of developing hepatocellular carcinoma and for the liver functional reserve., Aim: To evaluate the diagnostic ability of WFA(+) -M2BP for liver fibrosis in the clinical setting and the clinical utility of WFA(+) -M2BP for predicting the efficacy of direct-acting anti-viral (DAA) treatment for chronic hepatitis C patients., Methods: The study included 159 genotype 1 hepatitis C patients who received DAA-based treatment (telaprevir or simeprevir) combined with pegylated-interferon alpha plus ribavirin (108 telaprevir- and 51 simeprevir-based triple treatment). The relation between baseline serum WFA(+) -M2BP and treatment efficacy was evaluated., Results: The serum WFA(+) -M2BP level significantly increased with the progress of liver fibrosis. Area under the receiver operating characteristic curve analysis identified 2.17 as the cut-off index (COI) for WFA(+) -M2BP for diagnosing advanced fibrosis. The sustained virological response (SVR) rate was significantly, negatively correlated with the serum WFA(+) -M2BP level. Multiple logistic regression analysis found a low serum WFA(+) -M2BP level (<2.17 COI) to be independently associated with SVR (odds ratio, 4.35, P = 0.027). Even for prior nonresponders and patients with the interleukin-28B minor allele or histological advanced fibrosis, treatment outcome was favourable for patients with a low serum WFA(+) -M2BP level., Conclusion: Serum WFA(+) -M2BP is a non-invasive liver fibrosis marker useful for predicting the efficacy of DAA-based triple therapy for chronic hepatitis C patients., (© 2015 John Wiley & Sons Ltd.)

Favourable efficacy and safety profiles for simeprevir in combination with pegylated interferon alpha (PEG-IFNα) and ribavirin (triple therapy) have been shown in clinical trials. This study was carried out to evaluate the effectiveness of simeprevir-based triple therapy for patients with prior telaprevir treatment failure. This multicentre, observational cohort consisted of 345 consecutive Japanese patients infected with HCV genotype 1b, including 20 who had experienced telaprevir-based triple therapy. Amino acid substitutions in the NS3/4A region were identified by direct sequencing at the time of relapse or breakthrough in treatment with telaprevir and at the initiation of treatment with simeprevir. Patients were stratified according to prior response to PEG-IFNα and ribavirin. Of the 20 patients with telaprevir treatment failure, 10 (50.0%) achieved sustained virological response at week 12 after the end of treatment (SVR12). For patients treatment naïve [3/4 (75.0%)] or with prior relapse [1/1 (100%)] or partial response [5/6 (83.3%)] to PEG-IFNα and ribavirin, almost all achieved SVR12, mainly because of the improvement of treatment adherence, especially to direct-acting antiviral agent and ribavirin. However, of the nine patients with prior null response to PEG-IFNα and ribavirin, only one (11.1%) achieved SVR12, despite all having received an adequate treatment dosage, and five (55.6%) achieved rapid virological response. The treatment outcome of simeprevir-based triple therapy for HCV genotype 1b patients with prior telaprevir failure depended on the prior response to PEG-IFNα and ribavirin. For patients with prior null response to PEG-IFNα and ribavirin, retreatment with simeprevir-based triple therapy is not a useful option., (© 2015 John Wiley & Sons Ltd.)

In Japan, the human immunodeficiency virus (HIV) and hepatitis C virus (HCV) coinfection of some patients with hemophilia was caused by the transfusion of imported blood products, such as unheated coagulation factor. With the development of antiretroviral therapy (ART) for HIV, chronic HCV infection has become a major cause of liver disease and mortality for hemophiliac patients coinfected with HCV/HIV. Data is limited regarding the efficacy and safety of antiviral therapy with the HCV protease inhibitor telaprevir (TVR) in combination with pegylated interferon-α (PegIFN-α) and ribavirin (RBV) for hemophilia patients coinfected with HCV/HIV. We report a case of a Japanese patient with hemophilia and HCV/HIV coinfection who had partial response to prior to PegIFN-α and RBV therapy. This is the first published report of 24-week TVR-based triple therapy for a hemophilia patient coinfected with HCV/HIV. The patient had HCV genotype 1a infection with a high viral load. His single-nucleotide polymorphism of the interleukin 28B (rs8099917) gene was the TT major allele. He presented with undetectable HIV RNA and a high CD4(+) T cell counts by taking ART including tenofovir, emtricitabine and raltegravir. He was again treated for HCV with TVR plus PegIFN-α2b and RBV for the first 12 weeks, followed by the continuation of PegIFN-α2b and RBV for 12 additional weeks while continuing ART. He had rapid virological response and achieved sustained virological response with the 24-week treatment. No serious adverse events such as skin rash, severe anemia or exacerbated bleeding tendency were observed, only a mild headache. No dose adjustment was necessary when tenofovir and raltegravir were used in combined with TVR, and no HIV breakthrough was observed. TVR-based triple therapy with ART could can an effective treatment for hemophilia patients coinfected with HCV (genotype 1)/HIV regardless of prior response. TVR can be used in combination with tenofovir, emtricitabine and raltegravir for patients with hemophilia. Furthermore, patients with undetectable HCV RNA at week 4 could be successfully treated with a 24-week regimen., (Copyright © 2013 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Objectives: This prospective, pharmacokinetic study was done to investigate the impact of telaprevir plasma trough concentration (Ctrough) in the early stage of treatment on the response to telaprevir-based triple therapy for chronic hepatitis C patients., Methods: Participants were 70 chronic hepatitis C patients infected with genotype 1. All patients received 12 week triple therapy that included telaprevir (2250 mg/day), pegylated interferon-α2b (pegylated-IFNα2b) (60-150 μg/week) and ribavirin (600-1000 mg/day) followed by a 12 week dual therapy that included pegylated-IFNα2b and ribavirin. Plasma telaprevir Ctrough was determined by a validated assay using HPLC at days 3, 7 and 14. The study was registered as a clinical trial on the University Hospital Medical Information Network (ID 000009656)., Results: The rates of undetectable hepatitis C virus RNA at week 4 [rapid virological response (RVR)] and at 24 weeks after therapy [sustained virological response (SVR)] were 71.4% and 82.9%, respectively. Of the patients with RVR, 90% achieved SVR. The mean telaprevir Ctrough levels at days 3, 7 and 14 of SVR patients (2.748, 2.733 and 2.999 μg/mL, respectively) were significantly higher than those of non-SVR patients (1.616, 1.788 and 2.314 μg/mL, respectively) (all P < 0.05). Multiple logistic regression analysis of possible predictors of SVR extracted higher telaprevir Ctrough at day 3 (OR 1.012 by 0.001 μg/mL, P < 0.0001) and interleukin 28B (rs8099917) TT allele (OR 6.16 versus non-TT alleles, P < 0.0001)., Conclusions: Therapeutic drug monitoring of telaprevir in the early stage of treatment is useful in clinical practice for predicting the virological response of patients receiving telaprevir-based triple therapy.

Thrombocytopenia in patients with chronic hepatitis C may represent an obstacle for the initiation of antiviral treatment. The aim of this study was to evaluate factors predictive of successful pegylated interferon (PEG-IFN) α2b and ribavirin (RBV) treatment for patients with thrombocytopenia with no history of splenectomy or partial splenic embolization. One hundred and fifty-one chronic hepatitis C patients (genotype 1: n = 110, genotype 2: n = 41) with TCP (<100 × 10(9) /L) at baseline were enrolled. Pretreatment variables included interleukin 28B (IL28B) genotype (rs8099917) and homoeostasis model assessment of insulin resistance score (HOMA-IR). The kinetics of haemoglobin and platelets according to the inosine triphosphatase (ITPA) genotype (rs1127354) were investigated. Sustained virological response (SVR) was significantly more frequent in hepatitis C virus (HCV) genotype 2 (65.9%) than in genotype 1 (34.5%) patients (P < 0.0001). Multiple logistic regression analysis of HCV genotype 1 extracted IL28B TT genotype [odds ratio (OR) 5.97, P = 0.006] and HOMA-IR <2.5 (OR 7.14, P = 0.0016) as significant independent pretreatment predictors of SVR. The analyses of HCV genotype 2 showed that HOMA-IR was significantly related to SVR, but IL28B genotype was not. Patients with ITPA CC genotype showed a significant haemoglobin reduction and lower degree of platelets decrease than those with ITPA CA/AA genotypes. The most common reason for premature discontinuation of treatment was the development of hepatocellular carcinoma (n = 8, 5.3%). In conclusion, HOMA-IR is a useful predictor of SVR for patients with thrombocytopenia infected with HCV genotype 1 or 2 treated with PEG-IFNα2b and RBV. The inclusion of IL28B, ITPA genotypes and HOMA-IR adds valuable therapeutic information., (© 2013 John Wiley & Sons Ltd.)

Aim: To investigate and clarify, for the first time, the role of inosine triphosphate pyrophosphatase (ITPA) polymorphism in Egyptian chronic hepatitis C virus (HCV) patients., Methods: The human genomic DNA of all patients was extracted from peripheral blood cells in order to determine the single nucleotide polymorphism (SNP) of ITPA (rs1127354). SNP genotyping was performed by real time polymerase chain reaction (PCR, ABI TaqMan allelic discrimination kit) for 102 treatment-naive Egyptian patients with chronic HCV. All patients had no evidence of cardiovascular or renal diseases. They received a combination treatment of pegylated interferon α (PEG-IFNα) as a weekly subcutaneous dose plus an oral weight-adjusted dose of ribavirin (RBV). The majority received PEG-IFNα2a (70.6%) while 29.4% received PEG-IFNα2b. The planned duration of treatment was 24-48 wk according to the viral kinetics throughout the course of treatment. Pre-treatment liver biopsy was done for each patient for evaluation of fibrosis stage and liver disease activity. The basal viral load level was detected quantitatively by real time PCR while viral load throughout the treatment course was performed qualitatively by COBAS TaqMan assay., Results: Ninety-three patients (91.2%) had ITPA SNP CC genotype and 9 (8.8%) had non-CC genotype (CA and AA). The percentage of hemoglobin (Hb) decline was higher for CC patients than for non-CC patients, particularly at weeks 4 and 8 (P = 0.047 and 0.034, respectively). During the first 12 wk of treatment, CC patients had significantly more Hb decline > 3 g/dL than non-CC patients: 64.5% vs 22.2% at weeks 8 and 12, respectively, (P = 0.024 and 0.038). Reduction of the amount of the planned RBV dose was significantly higher for CC patients than non-CC patients during the first 12 wk (18% ± 12.1% vs 8.5% ± 10.2%, P = 0.021). The percentage of CC patients with RBV dose reduction was significantly greater than that of non-CC patients (77.4% vs 44.4%, P = 0.044). Multivariate analysis identified only the percentage of RBV dose as a predictor for Hb decline. Platelet decline was significantly higher in non-CC patients than CC patients at weeks 12, 24 and 48 (P = 0.018, 0.009 and 0.026, respectively)., Conclusion: Rs1127354 ITPA polymorphism plays a decisive role in protecting against treatment-induced anemia and the need for RBV dose reduction in Egyptian HCV patients.

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., (Copyright © 2012 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

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.

Background & Aims: Recent studies have suggested that insulin resistance exerts a strong influence on chronic hepatitis C virus (HCV) infection. We analyzed pretreatment factors useful for predicting sustained virological response (SVR), especially interleukin (IL) 28B polymorphism and Homeostasis Model Assessment of Insulin Resistance (HOMA-IR)., Methods: This cohort study consisted of 328 chronic hepatitis C patients with HCV genotype 1 who were treated for 48 weeks with pegylated interferon (PegIFN) α-2b and ribavirin (RBV). Genotyping of the polymorphisms in the IL28B gene region (rs8099917) on chromosome 19 was performed on DNA collected from each patient., Results: No significant difference in IL28B genotype distribution was found according to HOMA-IR. Multivariate analysis identified the IL28B TT genotype (OR=5.97, 95% CI 2.15-16.55, p=0.0006) and the baseline HOMA-IR (OR=0.65, 95% CI 0.48-0.87, p=0.0044) as significant, independent pretreatment predictors of SVR. Receiver operating characteristic analyses to determine the optimal threshold values of HOMA-IR for predicting SVR showed that the areas under the curve (AUC) were high for both IL28B TT (AUC=0.774, HOMA-IR cut-off value: 2.45) and IL28B TG/GG genotypes (AUC=0.772, HOMA-IR cut-off value: 1.55)., Conclusions: For HCV genotype 1, both IL28B and baseline HOMA-IR are independent pretreatment predictors of SVR in patients treated with PegIFNα-2b and RBV. Insulin resistance undermines the advantages of IL28B polymorphism to obtain SVR., (Copyright © 2012 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

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., (© 2011 Journal of Gastroenterology and Hepatology Foundation and Blackwell Publishing Asia Pty Ltd.)

Background and Aim: We intended to determine whether laparoscopic splenectomy (Lap-Sp) contributes to treatment with interferon therapy in hepatitis C virus (HCV)-cirrhotic patients with thrombocytopenia caused by hypersplenism., Methods: From December 2004 to August 2008, 100 cirrhotic patients (54 men and 46 women) underwent Lap-Sp for a clinical application of interferon therapy. All the patients were Child-Pugh class A or B with thrombocytopenia (average platelet count, 56 × 10(3) /mm(3)). The HCV genotype was type 1 in 80 patients and type 2 in 20 patients., Results: Pure laparoscopic or hand-assisted laparoscopy was performed in 78 and 22 patients, respectively, without mortality. Conversion to open surgery was not required in any of the patients. The platelet counts improved (mean platelet count 172 × 10(3) /mm(3) 1 month after surgery) and interferon (IFN) therapy was started in 97 patients. In this study period, 36 patients obtained a sustained virologic response. Eight patients discontinued IFN therapy because of depression, neutropenia or other reasons., Conclusions: Lap-Sp permits most patients with HCV cirrhosis and hypersplenism to receive sufficient IFN therapy. Therefore, Lap-Sp can become a strong supportive surgery for cirrhotic patients who require antiviral therapy., (© 2011 Journal of Gastroenterology and Hepatology Foundation and Blackwell Publishing Asia Pty Ltd.)

Objectives: The current standard of care for chronic hepatitis C patients is a pegylated interferon-α plus ribavirin combination treatment. This study was carried out to determine the relationship between ribavirin concentration in the later stages of treatment and virological relapse., Patients and Methods: Serum ribavirin concentration of 183 chronic hepatitis C patients (genotype 1) treated with pegylated interferon-α2b plus ribavirin for 48 weeks was prospectively measured by HPLC at weeks 4, 12, 24, 36 and 48. Patients with undetectable serum hepatitis C virus (HCV) RNA 24 weeks after the end of treatment were designated as having sustained virological response (SVR). Patients with undetectable HCV RNA during the treatment but with virological relapse after the end of treatment were designated relapse., Results: The mean ribavirin concentration at each testing point of patients with SVR (1401, 1725, 1803, 1811 and 1901 ng/mL) was significantly higher than that of relapse patients (998, 704, 607, 643 and 654 ng/mL) at weeks 4, 12, 24, 36 and 48, respectively (all P < 0.001). Multivariate regression analysis for relapse extracted ribavirin concentration at week 36, but not cumulative ribavirin dosage. The cut-off value by receiver operating curve analysis for predicting a relapse was 1503 and 1562 ng/mL at weeks 36 and 48, respectively., Conclusions: Ribavirin concentration in the later stages of treatment is an important marker of viral relapse.

Aim: To analyze the efficacy and safety of a combination therapy of pegylated interferon (PEG-IFN) α-2b plus ribavirin (RBV) in older Japanese patients (65 years or older) infected with hepatitis C virus (HCV)., Methods: This multicenter study included 938 patients with HCV genotype 1 who received 1.5 μg/kg per week PEG-IFN α-2b plus RBV 600-1000 mg/d for 48 wk and 313 HCV genotype 2 patients who received this treatment for 24 wk., Results: At 24 wk after the end of combination therapy, the overall sustained virological response (SVR) for genotypes 1 and 2 were 40.7% and 79.6%, respectively. The SVR rate decreased significantly with age in each genotype, and was markedly reduced in genotype 1 (P < 0.001). Moreover, the SVR was significantly higher in patients with genotype 1 who were less than 65 years (47.3% of 685) than in those 65 years or older (22.9% of 253) (P < 0.001) and was higher in patients with genotype 2 who were less than 65 years (82.9% of 252) than in those 65 years or older (65.6% of 61) (P = 0.004). When patients received a dosage at least 80% or more of the target dosage of PEG-IFN α-2b and 60% or more of the target dosage of RBV, the SVR rate significantly increased to 66.5% in patients less than 65 years and to 45.2% in those 65 years or older (P < 0.001). Adverse effects resulted in treatment discontinuation more often in patients with genotype 1 (14.4%) than in patients with genotype 2 (7.3%), especially by patients 65 years or older (24.1%)., Conclusion: PEG-IFN α-2b plus RBV treatment was effective in chronic hepatitis C patients 65 years or older who completed treatment with at least the minimum acceptable treatment dosage.

Background: An early virological response (EVR) after the start of interferon (IFN) treatment for chronic hepatitis C leads to a successful virological outcome. To analyze an association between sustained virological response (SVR) and EVR by comparing TaqMan with Amplicor assays in HCV genotype 1-infected patients treated with pegylated (PEG)-IFN alpha-2b plus ribavirin (RBV)., Methods: We retrospectively analyzed a total of 80 HCV genotype 1 patients (39 SVR and 41 non-SVR patients), who received an enough dosage and a complete 48-week treatment of PEG-IFN alpha-2b plus RBV. Serum HCV RNA levels were measured by both TaqMan and Amplicor assays for each patients at Weeks 2, 4, 8 and 12 after the start of the antiviral treatment., Results: Of the 80 patients with undetectable HCV RNA by Amplicor, 17 (21.3%) patients were positive for HCV RNA by TaqMan at Weeks 12. The quantification results showed that no significant difference in the decline of HCV RNA level between TaqMan and Amplicor 10-fold method assays within the initial 12 weeks of the treatment was found. However, the qualitative analysis showed significant differences of the positive predictive rates for SVR were found between TaqMan (100% at weeks 4 and 100% at weeks 8) and Amplicor (80.0% and 69.6%, respectively)., Conclusions: The COBAS TaqMan HCV assay is very useful for monitoring HCV viremia during antiviral treatment to predict a SVR in HCV genotype 1 patients.

The aim of this study was to assess the association between liver stiffness measured by transient elastography (FibroScan) and the efficacy of pegylated interferon alpha-2b plus ribavirin combination treatment for patients with chronic hepatitis C virus (HCV) infection. We prospectively studied 145 Japanese patients with chronic HCV infection. FibroScan was done at baseline, at the end of treatment, and at 48 and 96 weeks after the end of treatment. The FibroScan values were significantly decreased for sustained virological response (SVR) patients (the mean rate of change; -16.2%, -32.2% and -43.5%) in comparison with non-SVR patients (-7.2%, -2.1% and +17.3%) at the end of treatment (P=0.0127), and 48 weeks (P<0.0001) and 96 weeks (P<0.0001) after the end of treatment. Among the non-SVR patients, the FibroScan values were significantly decreased for patients with biochemical response (BR) (-17.9%, -30.0% and -27.1%) in comparison with non-BR (-4.1%, +6.4% and +30.6%) at the end of treatment (P=0.0270), and 48 weeks (P<0.0001) and 96 weeks (P<0.0001) after the end of treatment. The FibroScan values may predict a progressively better clinical outcome for patients with successful virological and biochemical responses.

Aim: The aim of the present study was to investigate the association between the length of the treatment period and the cumulative dose of pegylated interferon alpha-2b (peg-IFN alpha-2b) plus ribavirin (RBV) and their effectiveness in the treatment of chronic hepatitis C., Methods: Seven hundred and fifteen patients received peg-IFN alpha-2b plus RBV treatment for 48 weeks and 24 weeks for genotypes 1 (n = 586) and 2 (n = 129), respectively., Results: Sustained virological responses (SVR), defined as serum hepatitis C virus (HCV)-RNA undetectable at 24 weeks after the end of treatment, were 42.4% and 74.4% in genotypes 1 and 2, respectively, on an intention-to-treat analysis. SVR significantly increased with treatment length (4.7%, 36.4%, and 51.8% for < 24 weeks, 24-47 weeks, and 48 weeks, respectively, for genotype 1; and 28.6%, 57.1%, 78.3% for < 12 weeks, 12-23 weeks, and 24 weeks, respectively, for genotype 2). SVR significantly increased with total cumulative treatment dose (21.1%, 36.5%, and 52.9% with < 60%, 60-79%, and >or= 80% in peg-IFN dose; 29.6%, 51.1%, and 59.2% with < 60%, 60-79%, and >or= 80% in RBV dose) in genotype 1, although it did not differ significantly for genotype 2., Conclusions: In peg-IFN alpha-2b plus RBV treatment for chronic hepatitis C, it is important to complete the target length of treatment and to continue the target dosage to achieve SVR, especially for genotype 1 patients.

Type I interferon (IFN) possesses antiviral and antitumor activities and also having an immune regulatory effect, activating cellular immune response and upregulating several cytokines. Recent study has shown that type I IFN upregurates the dendritic cell production of IL-15 capable of activating natural killer cells and CD8+ memory T lymphocytes. However, it is still unknown if type I IFN induces IL-15 production in non-immune cells and if type I IFN affects IL-15 production in vivo. The present study investigated the effect of type I IFNs on IL-15 expression in hepatocellular carcinoma (HCC) cell lines in vitro and in patients with chronic hepatitis C in vivo. When three HCC cell lines, Huh7, HepG2, and JHH4 were cultured in vitro, IFN upregulation of IL-15 expression was observed at both the mRNA and protein levels. In experiments using Huh7 cells, upregulation of IL-15 expression occurred within 24 h of the start of IFN stimulation, and both IFN-alpha and -beta dose-dependently increased IL-15 production in the range from 100 U/ml to 10,000 U/ml of concentration. IFN-beta showed stronger activity in IL-15 production induction in vitro than IFN-alpha. For in vivo examination, sera were obtained from 21 chronic hepatitis C patients treated with IFN and 29 healthy individuals, and the serum IL-15 level was quantified by ELISA. The serum IL-15 level of chronic hepatitis C patients before IFN treatment was similar to that of the healthy controls and significantly increased only during the IFN administration period. These results confirm that IFN-alpha/beta induce IL-15 production and also suggest that IL-15 may be associated with type I IFN-induced immune response.

The antiviral, antiproliferative and immunomodulatory effects of type I interferons (IFNs) are well documented, however, few studies have been published concerning differences in the antitumor effects of IFN-alpha and beta. In the present study, differences in antitumor effect, including the antiproliferative effect, cell cycle change, apoptosis, and the IFN-stimulated gene (ISG) were examined by flow cytometry between IFN-alpha and beta on three human hepatocellular carcinoma (HCC) cell lines (HepG2, Huh7 and JHH4). The antiproliferative effect of both IFNs on the HCC cell lines was time- and dose-dependent, and IFN-beta was significantly stronger than IFN-alpha. The cell cycle effect by both IFNs was an S-phase accumulation, with IFN-beta having a tendency to increase the S-phase ratio more strongly than IFN-alpha, especially in Huh7. Apoptosis marker expression, Fas antigen and intracellular active caspase-3, was increased after the addition of IFNs, especially of IFN-beta. The expression of human leukocyte antigen-class I molecules, ISG-encoded protein, was increased after the addition of IFNs, especially of IFN-beta. These data suggest that IFN-beta has a greater antitumor effect than IFN-alpha on HCC of a very early stage in patients with chronic hepatitis C.

Aim: To determine the efficacy of an interferon alpha and ribavirin combination treatment for Japanese patients infected with hepatitis C virus (HCV) of genotype 2, a multi-center study was retrospectively analyzed., Methods: In total, 173 patients with HCV genotype 2 started to receive interferon-alpha subcutaneously thrice a week and 600-800 mg of ribavirin daily for 24 wk., Results: The overall sustained virological response (SVR), defined as undetectable HCV RNA in serum, 24 wk after the end of treatment, was remarkably high by 84.4%, (146/173) by an intention-to-treat analysis. A significant difference in SVR was found between patients with and without the discontinuation of ribavirin (46.9% vs 92.9%), but no difference was found between those with and without a dose reduction of ribavirin. A significant difference in SVR was also found between patients with less than 16 wk and patients with 16 or more weeks of ribavirin treatment (34.8% vs 92.0%)., Conclusion: The 24-wk interferon and ribavirin treatment is highly effective for Japanese patients with HCV genotype 2. The significant predictor of SVR is continuation of the ribavirin treatment for up to 16 weeks.

The viral genotype and serum viral level influence the response to interferon (IFN) treatment in patients with chronic hepatitis C virus (HCV) viremia. The aim of this study was to investigate a possible relationship between early virological response and helper T (Th) cell cytokine expansion by 4 weeks of ribavirin (RIB) alone followed by IFN and RIB combined in patients with genotype 1b and a high HCV RNA level, patients reported not to respond well to IFN treatment. Eighty-one patients with genotype 1b and a high HCV RNA level, over 100 international unit per milliliter (KIU/mL) (by Amplicor HCV Monitor), were assigned to two groups: Group A (N = 40) with a 4-week RIB administration followed by a 24-week combination treatment, and Group B (N = 41) with a 24-week combination treatment only. Blood was obtained from each patient on the following schedule: at Baseline (4 weeks before day 0), on day 0 (initiation day of the RIB and IFN combination treatment), weeks 4 (4 weeks after the start of the combination treatment), and at the end of the combination treatment. Flow cytometry was used to investigate sequential changes of IFN-gamma producing (Th1) and interleukin-4 producing (Th2) cells from whole blood samples after stimulation with PMA and ionomycin. Serum HCV RNA clearances were 32.5% at week 4, 43.2% at week 8, 85.7% at the end of the combination treatment, and 22.9% within the 24-week follow-up in Group A; and 17.1%, 27.0%, 66.7% and 19.4% in Group B, respectively. The mean Th1/Th2 ratio significantly increased from 15.9 at baseline to 17.6 at day 0 with a decrease of Th2 cells, and then significantly decreased from 17.6 at day 0 to 15.5 at week 4 in Group A, while there was no significant change in Group B between baseline and day 0. In Group A, 13 patients with HCV RNA clearance within 4 weeks had a significantly increased Th1/Th2 ratio, from 14.0 at baseline to 22.1 at day 0, and then a significantly decreased ratio, from 22.1 at day 0 to 15.0 at week 4, while the others had no significant change in the ratio. RIB administration preceding combined treatment of RIB with IFN was more effective in Th2 cell expansion than the usual combined treatment of IFN with RIB and led to a relatively early virological clearance in chronic hepatitis C patients with genotype 1b and a high HCV RNA level.

To investigate differences in the effect of interferon (IFN) -alpha and IFN-beta treatment for hepatitis C on hepatocellular carcinoma (HCC) development, we prospectively followed 351 consecutive patients (median age, 56.6 years; mean follow-up, 5.7 +/- 2.6 years) with chronic hepatitis C virus (HCV) viremia. Of 260 IFN-alpha and 91 IFN-beta treated patients, 17 (6.5%) and 4 (4.4%), respectively, developed HCC. Virological response (VR) was defined as persistent HCV RNA disappearance from serum, and biochemical response (BR) as persistent alanine aminotransferase (ALT) normalization after treatment. No significant between-group differences in HCC development were found between those with and without VR. Although the HCC development rate in patients without BR was significantly higher than that in patients with BR in the IFN-alpha group (11.4% and 0.8%; P << 0.05), no significant difference was found in the IFN-beta group (6.3% and 2.3%). Similar rates of HCC development were found in patients with chronic HCV viremia treated with either IFN-alpha or IFN-beta.

Using first- and second-generation branched-DNA probe assays (1st- and 2nd-bDNA), we investigated the predictors of favorable clinical response to interferon (IFN) treatment in patients with chronic HCV viremia. A total of 122 patients (85 genotype lb and 37 genotype 2a) with chronic HCV viremia received 24-week IFN-alpha treatment. Patients with sustained clearance of serum HCV RNA by polymerase chain reaction at six months after IFN treatment were defined as having a sustained response (SR). HCV RNA level was determined by 1st- and 2nd-bDNA assays prior to treatment. Mean HCV RNA level by 1st-bDNA was significantly higher in genotype lb patients [5.4 x 10(6) HCV genome equivalent (Meq)/ ml] than in genotype 2a patients (0.9 Meq/ml) (P < 0.05). There was no significant difference between patients with these genotypes in the level by 2nd-bDNA (1b: 5.2 Meq/ml and 2a: 3.1 Meq/ml). SR was achieved by 43 (35.2%) of 122 patients. Mean HCV RNA levels by both the 1st- and 2nd-bDNA of SR patients (1.0 and 1.9 Meq/ml) were significantly lower than those of non-SR patients (5.3 and 6.0 Meq/ml) (both P < 0.05). The SR rate in genotype 2a patients (59.5%) was significant higher than in genotype lb patients (24.7%) (P < 0.05). Stepwise logistic regression analysis showed that HCV RNA level < or = 1.0 Meq/ml by 2nd-bDNA (odds ratio = 7.6, compared to level > 1.0 Meq/ml, P < 0.05) was a significant predictive cutoff for SR. Using 2nd-bDNA, a significantly higher rate of SR was found in genotype lb patients with level < or = 1.0 Meq/ml (57.6%) than in those with level > 1.0 Meq/ml (3.8%) (P < 0.05). The SR rate of genotype 2a patients with level >1.0 Meq/ml (68.6%) was somewhat higher than for those with level < or = 1.0 Meq/ml (52.4%). These findings suggested that, using 2nd-bDNA, a low HCV RNA level of < or = 1.0 Meq/ml was the most favorable marker of successful IFN treatment and that patients with genotype 2a, even those with level >1.0 Meq/ml, had a high rate of SR to IFN treatment.

To determine the effects of interferon treatment, we studied 77 Japanese patients with hepatitis C virus (HCV) infection and normal alanine aminotransferase (ALT). Of 77 patients, 37 were given natural interferon-alpha for 24 weeks, and 40 not given interferon acted as controls. Serum samples were tested for HCV RNA and genotypes by polymerase chain reaction (PCR). HCV RNA levels were measured by competitive PCR. Of 37 treated patients, 11 (29.7%) had sustained elimination throughout a six-month follow-up, while HCV RNA was not eliminated in any untreated patients. At 24 months, the number of patients with elevated ALT was not significantly different between treated (13.5%) and untreated patients (15%). Interferon eliminates HCV RNA in patients with normal ALT without severe side effects. The natural history of HCV infection should be clarified so that the interferon treatment regimen can be tailored to the needs of each patient.

To compare virological, biochemical, and immune responses to human lymphoblastoid interferon (IFN-alpha) and human fibroblast interferon (IFN-beta) in patients with chronic hepatitis C virus (HCV) infection, 120 patients were randomly assigned to three groups (group A, 60 patients receiving IFN-alpha, 6 million units (MU) once a day, daily for one month and thrice weekly for five months; group B, 40 patients receiving 6 MU IFN-beta once a day daily for two months; and group C, 20 patients receiving 3 MU IFN-beta twice a day (6 MU/day) daily for two months). Serum soluble interleukin-2 receptor (sIL-2R) and interleukin-6 (IL-6) levels were measured by enzyme-linked immunosorbent assay. Patients with sustained clearance of serum HCV RNA detected by polymerase chain reaction (PCR) at six months after IFN treatment were defined as having complete response to IFN treatment. A low level of HCV RNA (< or = 10(4) copies/50 microl, measured by competitive PCR) and HCV RNA of genotype 2a were favorable factors for a complete response to both IFNs. Complete response in group A treatment was strongly associated with early HCV RNA clearance, in contrast with group B. A significantly higher HCV RNA negativity at the second week from start of treatment was noted in group C (80.0%), compared with groups A (41.6%) and B (27.5%). sIL-2R levels rose in each group during IFN administration. In group C, alanine aminotransferase (ALT) and IL-6 levels were remarkably elevated. These findings indicate that timing of serum HCV RNA negativity in sustained response differs between IFN-alpha and IFN-beta administrations and that early HCV RNA clearance was induced by twice-a-day IFN-beta treatment.

To determine the role of serum soluble interleukin-2 receptor (sIL-2R) in chronic hepatitis B virus (HBV) infection, the level of serum sIL-2R was measured in sera of 105 patients with chronic HBV infection and in 21 healthy controls, using enzyme-linked immunosorbent assay. Serum sIL-2R levels were significantly higher in chronic HBV-infected patients with chronic hepatitis (508+/-310 units/ml) and liver cirrhosis (543+/-283 units/ml) than in healthy controls (331+/-106 units/ml, P < 0.05). Moreover, serum sIL-2R levels were significantly higher in patients with chronic hepatitis or liver cirrhosis than in asymptomatic HBV carriers (341+/-150 units/ml, P < 0.01). There was no difference in serum sIL-2R levels between asymptomatic HBV carriers and healthy controls or between patients with chronic hepatitis and liver cirrhosis. A significant relationship was found between serum sIL-2R and ALT levels (P < 0.05) in patients with chronic HBV infection, although there was no correlation between sIL-2R and HBV DNA levels. Serum sIL-2R levels in most patients decreased to the same level as asymptomatic HBV carriers and healthy controls at 48 weeks after the end of treatment, and serum ALT and HBV DNA levels were decreased to within the normal range at 96 weeks. Thus, serum sIL-2R levels indicate the degree of liver damage among patients with chronic HBV infection. The serum sIL-2R levels one year after interferon administration may be a useful marker of determined at the effectiveness by this treatment.

We investigated the timing of the disappearance and reappearance of serum hepatitis C viral (HCV) RNA in patients with chronic hepatitis C during interferon treatment and follow-up. Serum samples were tested for HCV RNA by polymerase chain reaction in 62 patients with chronic hepatitis C treated with interferon-alpha for 24 weeks. We found that 17 patients obtained complete response, with absence of serum HCV RNA for 6 months after the treatment. Twenty-nine patients had a partial response, with reappearance of serum HCV RNA within 6 months of follow-up, and 16 patients were nonresponders who were positive for serum HCV RNA throughout the observation period. HCV RNA disappeared within 2 weeks of treatment in 31 patients, including all 17 (100%) complete responders and 14 (48.3%) of the 29 partial responders. The patients remaining positive for HCV RNA at the second week were 15 (51.7%) of the 29 partial responders and the 16 nonresponders. In all of the 29 partial responders, viremia recurred within 1 month after the treatment. These results indicate that the status of HCV RNA at the second week of treatment is a useful predictor of effective treatment, whereas status at the first month after cessation of treatment is useful for assessing the effectiveness of interferon itself.

To compare hepatitis C virus (HCV) RNA levels determined by branched DNA probe assay and by competitive polymerase chain reaction (PCR) as predictive markers of the response to interferon for treatment of patients with chronic HCV infection, we studied data on 140 patients treated for six months with natural interferon-alpha. Serum samples were tested for HCV RNA by PCR. HCV RNA was grouped into four genotypes by PCR with type-specific primers, and HCV RNA level was measured by branched DNA probe assay and by competitive PCR. HCV RNA was detected in all patients prior to initiation of the treatment. A complete response, sustained elimination of HCV RNA, occurred in 51 patients (36.4%). With multiple logistic regression analysis assessment, when using competitive PCR, a low level of HCV RNA (P < 0.0001), younger age (P = 0.0054) and genotype 2a and 2b (P < 0.0158) were significant predictive markers for a complete response to interferon treatment. When using branched DNA probe assay, a low level of HCV RNA (P < 0.0001) and age (P = 0.0089) were predictive markers, but genotype was not. The branched DNA probe assay had a narrower linear range for quantitation of HCV RNA level than competitive PCR. In conclusion, HCV RNA level determined by branched DNA probe assay proved to be useful for prediction of effects of interferon and it is cost effective as a marker of complete response to interferon treatment for patients with chronic HCV infection.

Background: Interferon alfa is used widely for patients with chronic hepatitis C virus (HCV) infection. Little is known, however, of the relationship between patients' sex and the effectiveness of interferon alfa treatment in these patients., Methods: We treated 311 patients (199 men and 112 women) with human lymphoblastoid interferon (6 million units subcutaneously every day for 2 weeks and 3 times a week for 22 weeks) and observed them for an additional 6 months. Serum HCV RNA levels and genotype were tested by polymerase chain reaction before treatment. A liver biopsy was also done. For the purposes of this study, a complete response was defined as the elimination of HCV RNA for at least 6 months after the termination of treatment., Results: The rate of complete response was 27.1% for men and 24.1% for women. With multiple logistic regression analysis, the HCV RNA level (P < .001), genotype (P < .001), patients' sex (P < .05), and the interaction between sex and age were associated with a complete response to interferon alfa. The rate of complete response was 33.3% in men aged 39 years and younger, 25.0% in men aged 40 years and older. 75.0% in women aged 39 years and younger, and 15.6% in women aged 40 years and older. The odds ratio by group was 1.00, 0.72, 4.38, and 0.21, respectively., Conclusions: Our finding that women aged 39 years and younger are responsive to interferon alfa treatment suggests that hormonal activity, in particular the level of estrogen, may be associated with the sustained elimination of HCV.

To evaluate the efficacy of large dose interferon treatment for patients with chronic hepatitis C virus (HCV) infection, we studied 99 Japanese patients treated with either 6 million units (MU) or 9 MU natural interferon alpha. Serum samples were tested for HCV RNA by polymerase chain reaction (PCR). HCV RNA genotypes were determined by PCR with type-specific preimers, and the HCV RNA level was measured by competitive PCR. HCV RNA was detected in all patients, prior to the initiation of treatment. We examined interleukin-1 receptor antagonist (IL-1 Ra) by enzyme-linked immunosorbent assay. Forty-four patients were treated with 9 MU natural interferon alpha for 24 weeks (group A), and fifty-five patients were treated with 6 MU natural interferon alpha for 24 weeks (group B). There were no significant differences in HCV RNA levels, HCV RNA genotype or histological activity index (HAI) score between the two groups. Of the 94 patients who completed this treatment, nine (23.1%) in group A and 14 (25.5%) in group B sustained elimination of HCV RNA throughout a 6-month follow-up. There were no differences in the rate of complete response when comparing HCV RNA genotype, levels and HAI score and no significant differences in elevation of IL-1 Ra levels between the two groups. Five of group A patients refused further treatment because of severe side effects such as retinal hemorrhage, while no patient in group B had severe side effects. Thus, large dose natural interferon alpha treatment confers no additional benefit to the patient, compared with the current use of a lower dose.

To evaluate the efficacy and safety of human lymphoblastoid interferon treatment (interferon alfa) for patients with compensated cirrhosis caused by hepatitis C virus (HCV) infection, we randomly assigned 82 cirrhotic patients with chronic HCV infection (44 men, 38 women; mean age, 58.6 years) to two groups: 41 patients were treated with interferon alfa (480 million U over 6 months), and the other patients received no drug treatment. HCV RNA genotypes were determined by polymerase chain reaction (PCR) testing using type-specific primers. HCV RNA levels were measured by competitive PCR testing. No untreated patients eliminated HCV RNA from the serum or had a decrease in the level of alanine aminotransferase to normal during the observation period. Of the 34 patients who completed interferon alfa treatment, 6 (17.6%) who were considered complete responders eliminated HCV RNA from the serum by the end of treatment and sustained this elimination throughout a 6-month follow-up period. Complete responders constituted 6 (46.2%) of 13 patients with HCV RNA levels < or = 10(5) copies/50 microL, but none of the 21 patients with levels > 10(5) copies/50 microL were complete responders. Two (7.1%) of 28 patients with genotype 1b infection and 4 (66.7%) of 6 with genotype 2a were complete responders. Five patients withdrew because of interferon alfa-induced side effects (1 for thrombocytopenia, 3 for severe general malaise, and 1 for impotence), and 2 withdrew after being diagnosed with hepatocellular carcinoma. Hepatic failure did not occur in any treated patient in the present study. These findings indicate that interferon alfa treatment is useful for compensated cirrhosis caused by HCV infection if the HCV RNA levels are low and the infection is of genotype 2a.