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The factors associated with sustained virologic response (SVR) in chronic hepatitis C (CH-C) genotype 1 patients treated with simeprevir (SMV), pegylated interferon (Peg-IFN) plus ribavirin (RBV) triple therapy have not been fully investigated. Two hundred and twenty-nine treatment-naïve CH-C patients treated with SMV triple therapy were enrolled in this study. The overall SVR rate was 87% in per-protocol analysis. In multivariate analysis, the interleukin (IL) 28B genotype (rs8099917, TT vs. non-TT, odds ratio [OR]: 0.044, P = 0.001) and RBV dose (< 10/10-12/ ≥ 12 mg/kg/day, OR: 4.513, P = 0.041) were significant factors associated with SVR. In patients with the IL28B non-TT genotype, RBV dose affected SVR dose-dependently in stratified analysis of RBV dose (P = 0.015); it was 44% (8/18) for patients administered <10 mg/kg/day of RBV, 78% (14/18) for those administered 10-12 mg/kg/day of RBV, and 100% (3/3) for those administered ≥12 mg/kg/day of RBV, whereas in patients with the IL28B TT genotype, a significant correlation between SVR and RBV dose was not observed (P = 0.229). Regarding RBV dose reduction of less than 10 mg/kg/day, the inosine triphosphate pyrophosphatase (ITPA) genotype (rs1127354, CC vs. non-CC, OR: 0.239, P = 0.003) and age (by 1 y.o., OR: 1.084, P = 0.002) were significant independent factors. RBV dosage affected SVR dose-dependently in patients with the IL28B non-TT genotype treated with SMV triple therapy. Special attention to anemia progression and RBV dosage should be paid to aged patients with the ITPA CC genotype. J. Med. Virol. 88:1776-1784, 2016. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

The use of pegylated interferon (Peg-IFN) plus ribavirin combination therapy for chronic hepatitis C patients who received curative treatment for hepatocellular carcinoma is controversial. This study tried to clarify this. Ninety-nine chronic hepatitis C patients who received curative resection or radiofrequency ablation for primary hepatocellular carcinoma, met the Milan criteria and were treated with Peg-IFN plus ribavirin therapy were enrolled (75 males, 24 females; mean age, 65.0 ± 5.9 years; 79 HCV genotype 1, 20 genotype 2). Among them, 40 patients who had received curative treatment for a single carcinoma were analyzed for recurrence (observation period: 27.6 ± 18.1 months). The factors associated with recurrence were examined using a log-rank test and a Cox proportional-hazards model. The discontinuation rate of the Peg-IFN plus ribavirin combination therapy was 25% (25/99). Among the patients who completed the therapy, the sustained virologic response rates were 35% for the genotype 1 patients and 56% for the genotype 2 patients. The cumulative incidence rates of recurrence were 10.0% at 1 year and 40.8% at 3 years. On multivariate analysis, a virologic response and platelet counts served as independent factors of recurrence (sustained virologic response, hazard ratio = 0.190, P = 0.029; platelet counts <12 × 10(4) /mm(3), hazard ratio = 3.19, P = 0.019). It is concluded that patients with chronic hepatitis C virus infection after curative treatment for hepatocellular carcinoma can be candidates for anti-viral therapy to reduce the recurrence of hepatocellular carcinoma, especially patients with low platelet counts., (© 2015 Wiley Periodicals, Inc.)

Triple therapy with telaprevir, pegylated interferon and ribavirin has been reported to improve antiviral efficacy but have potentially severe adverse effects in patients with chronic hepatitis C. To avoid the severe effects of telaprevir, lowering the dose has been suggested. However, impact of dosage changes on antiviral and adverse effects remains unclear. One hundred and sixty-six Japanese patients with HCV genotype 1 were treated with triple therapy. The drug exposure of each medication was calculated by averaging the dose actually taken. The overall SVR rate was 82%. The telaprevir discontinuation rate was 26%. The factors associated with discontinuation were an older age (≥65 y.o.) and a higher average dose during treatment. The telaprevir discontinuation rates were 42%, 25% and 14% in patients at ≥35, 25-35 and <25 mg/kg/day of telaprevir and 58% in older patients at ≥35 mg/kg/day of TVR. The factors associated with SVR were treatment-naïve, relapse to previous treatment, higher average telaprevir dose during treatment and completion of treatment. The SVR rate was higher, at 91%, in patients at 25-35 mg/kg/day of telaprevir than the 71% and 78% observed in those at <25 and ≥35 mg/kg/day of drug. In Japanese patients, a mean telaprevir dose of 25-35 mg/kg/day during treatment can augment its efficacy in triple therapy for patients with HCV genotype 1., (© 2014 John Wiley & Sons Ltd.)

Background: Triple therapy with telaprevir (TVR), pegylated interferon and ribavirin has improved antiviral efficacy in patients with chronic hepatitis C (CH-C). However, the severe adverse effects caused by TVR are important to resolve. In this prospective, randomized, multicenter, open-label study, the antiviral efficacy and safety in the reduced administration of TVR were examined., Methods: A total of 81 CH-C Japanese patients with HCV genotype 1 were randomized into two regimens of TVR 2250 mg (TVR-2250) or 1500 mg (TVR-1500) and treated with triple therapy for 24 weeks., Results: The mean HCV RNA at start, 2 and 4 weeks of treatment were 6.69 ± 0.70, 1.05 ± 0.74, 0.22 ± 0.48 log10 IU/ml in the TVR-2250 group and 6.70 ± 0.62, 1.02 ± 0.62, 0.13 ± 0.41 log10 IU/ml in the TVR-1500 group. The SVR rates were 85% in both groups (35/41 and 34/40, respectively). There were no patients with viral breakthrough in either group. As for adverse effects, rash more than moderate and severe anemia with <8.5 g/dl of hemoglobin were higher in the TVR-2250 group than in the TVR-1500 group (p = 0.046, p < 0.001, respectively). The increase in serum creatinine levels and decrease in estimated glomerular filtration rates were higher in the TVR-2250 group than in the TVR-1500 group., Conclusions: The lower dose of TVR (1500 mg/day) can result in similar SVR rates and lower treatment-related adverse effects compared to the higher dose of TVR (2250 mg/day) in triple therapy (UMIN: 000007313, 000007330).

The antiviral therapy for patients with chronic hepatitis C virus(HCV) infection has changed from interferon(IFN) monotherapy to dual therapy with IFN plus ribavirin(RBV), moreover pegylated IFN(Peg-IFN) plus RBV. The sustained virologic response(SVR), defined as HCV RNA negativiation at 24 weeks after the treatment, were obtained 50% among the patients with genotype 1 (48 weeks treatment) and 80% among those with genotype 2 (24 weeks treatment) in Peg-IFN plus RBV combination therapy. The baseline host factors such as age, the degree of liver fibrosis progression and a genetic polymorphism near the IL28B gene, the viral factors such as HCV genotype, mutant virus at HCV core region and interferon sensitivity determining region, the treatment factors such as drug adherence and treatment duration have been reported to be associated with SVR. The risk for hepatocellular carcinoma (HCC) incidence was significantly lower in SVR patients than non-SVR patients. Especially, alpha-fetoprotein (AFP) levels decreased through therapy, and the patients with < 5 ng/mL had a low potential of HCC incidence regardless of HCV eradication. It is suggested that AFP levels at 24 weeks after the treatment can be a good surrogate marker for HCC incidence irrespective of the virologic response.

Pegylated interferon (Peg-IFN) plus ribavirin combination therapy is effective in patients with hepatitis C virus (HCV) infection and normal alanine aminotransferase levels (NALT). However, it remains unclear whether the risk of hepatocellular carcinoma (HCC) incidence is actually reduced in virological responders. In this study, HCC incidence was examined for 809 patients with NALT (ALT ≤ 40 IU/mL) treated with Peg-IFN alpha-2b and ribavirin for a mean observation period of 36.2 ± 16.5 months. The risk factors for HCC incidence were analysed by Kaplan-Meier method and Cox proportional hazards model. On multivariate analysis among NALT patients, the risk of HCC incidence was significantly reduced in patients with sustained virological response (SVR) or relapse compared with those showing nonresponse (NR) (SVR vs NR, hazard ratio (HR): 0.16, P = 0.009, relapse vs NR, HR: 0.11, P = 0.037). Other risk factors were older age (≥65 years vs <60 years, HR: 6.0, P = 0.032, 60-64 vs <60 years, HR: 3.2, P = 0.212) and male gender (HR: 3.9, P = 0.031). Among 176 patients with PNALT (ALT ≤ 30 IU/mL), only one patient developed HCC and no significant risk factors associated with HCC development were found. In conclusion, antiviral therapy for NALT patients with HCV infection can lower the HCC incidence in responders, particularly for aged and male patients. The indication of antiviral therapy for PNALT (ALT ≤ 30 IU/mL) patients should be carefully determined., (© 2013 John Wiley & Sons Ltd.)

Background: HCV kinetics during treatment demonstrated strong association with the antiviral outcome of patients treated with pegylated interferon (Peg-IFN) plus ribavirin. However, the relationship between HCV kinetics and pre-treatment factors remains unclear., Methods: Of 547 patients with HCV genotype 1 treated with Peg-IFN alfa-2b plus ribavirin, 401 completed the response-guided therapy and were assessed for per protocol analysis., Results: The sustained virologic response (SVR) rate was 53 % for all patients, 60 % for those with genotype TT, and 19 % for those with genotype TG/GG according to IL28B (rs8099917) single nucleotide polymorphisms. The SVR rates increased with HCV decrease at week 4; 4 % (2/56) with <1 log10 decrease, 13 % (7/56) with 1-2 log10 decrease, 51 % (44/87) with 2-3 log10 decrease, 64 % (56/87) with 3-4 log10 decrease, 88 % (72/82) with more than 4 log10 decrease but with detectable HCV RNA and 100 % (33/33) with undetectable HCV RNA (p < 0.001). Similarly, SVR rates increased step-by-step in proportion to HCV decrease in both IL28B TT and TG/GG groups, showing almost the same SVR rates for the same conditions. In multivariate analysis, age (p = 0.005) and the magnitude of HCV decrease at week 4 (p < 0.001) but not IL28B were associated with SVR. Advanced liver fibrosis (p = 0.004) and the magnitude of HCV decrease at week 4 (p < 0.001) but not IL28B were associated with non-response., Conclusions: The magnitude of the HCV decrease at week 4 seems to be the most reliable marker for predicting antiviral outcome after starting Peg-IFN plus ribavirin therapy.

Background: The timing to the first undetectable hepatitis C virus (HCV) RNA level is strongly associated with sustained virologic response in pegylated interferon (Peg-IFN) plus ribavirin combination therapy for patients with chronic hepatitis C (CH-C) with genotype 1. This study was conducted to clarify the impact of drug exposure to Peg-IFN on the timing of HCV RNA negativity in Peg-IFN plus ribavirin combination therapy for CH-C patients with genotype 1., Methods: A total of 1409 patients treated with Peg-IFN alfa-2b plus ribavirin were enrolled and classified into four categories according to the Peg-IFN dosage. Furthermore, 100 patients were extracted from each Peg-IFN dosage category to adjust for characteristic factors, using the propensity score method., Results: Peg-IFN exposure was dose-dependently associated with the timing of HCV RNA negativity (p ≤ 0.001). The HCV RNA negative rate at week 4 decreased from 12% with a Peg-IFN dose of >1.5 μg/kg/week to 1-3% with a dose of <1.5 μg/kg/week (p ≤ 0.001), and at week 12 the rate had decreased from 44% with a dose of ≥1.2 μg/kg/week to 18% with a dose of <1.2 μg/kg/week (p = 0.001). Treatment failure (patients without a 1-log decrease of HCV RNA at week 4 or a 2-log decrease of HCV RNA at week 12, or positive at week 24) was found in 54-66% of patients given <1.2 μg/kg/week (p ≤ 0.001), and these patients accounted for 64% of the non-responders., Conclusions: The timing of HCV RNA negativity depends significantly on the Peg-IFN dose. Reducing the Peg-IFN dose can induce a later virologic response or non-response in HCV genotype 1 patients treated with Peg-IFN plus ribavirin.

Background: For the treatment of chronic hepatitis C, a combination of pegylated interferon-α (PEG-IFNα) and ribavirin has been widely used as a standard of care. Enhancement of immune response against hepatitis C virus (HCV) is known to be involved in the efficacy of the combination therapy. Our aim was to elucidate whether or not the frequency or function of blood cells is related to the outcome of the therapy., Methods: Sixty-seven chronic hepatitis C patients with high viral load of HCV genotype 1 infection who underwent 48 weeks of PEG-IFNα2b and ribavirin therapy were examined. During the treatment, frequencies of myeloid or plasmacytoid dendritic cells, Th1, Th2 cells, NK cells, and regulatory T cells were phenotypically determined., Results: Among the patients enrolled, 29 showed a sustained virological response (SVR), 18 a transient response (TR) and 17 no response (NR). The clinical and immunological markers were compared between the SVR and non-SVR patients, including TR and NR. Based on clinical, histological, immunological parameters, and cumulative dosage of PEG-IFNα2b and ribavirin, multivariate analyses revealed that higher platelet counts and higher regulatory T cell frequency at week 12 are indicative of SVR. Even in patients who attained complete early virological response at week 12, multivariate analyses disclosed that higher platelet counts and higher plasmacytoid dendritic cell frequency are indicative of SVR., Conclusions: In PEG-IFNα and ribavirin combination therapy for chronic hepatitis C patients, the increments of regulatory T cells and plasmacytoid dendritic cell frequency are independently related to favorable virological response to the therapy.

Background: This study aimed to define factors associated with relapse among responders to pegylated interferon (PEG-IFN) plus ribavirin (RBV) therapy in chronic hepatitis C., Methods: A cohort of genotype 1b chronic hepatitis C patients treated with PEG-IFN plus RBV and who had an undetectable HCV RNA by week 12 (n=951) were randomly assigned to model derivation (n=636) or internal validation (n=315) groups. An independent cohort (n=598) were used for an external validation. A decision tree model for relapse was explored using data mining analysis., Results: The data mining analysis defined five subgroups of patients with variable rates of relapse ranging from 13% to 52%. The reproducibility of the model was confirmed by internal and external validations (r(2)=0.79 and 0.83, respectively). Patients with undetectable HCV RNA at week 4 had the lowest risk of relapse (13%), followed by patients <60 years with undetectable HCV RNA at week 5-12 who received ≥3.0 g/kg of body weight of RBV (16%). Older patients with a total RBV dose <3.0 g/kg had the highest risk of relapse (52%). Higher RBV dose beyond 3.0 g/kg was associated with further decrease of relapse rate among patients <60 years (up to 11%) but not among older patients whose relapse rate remained stable around 30%., Conclusions: Data mining analysis revealed that time to HCV RNA negativity, age and total RBV dose was associated with relapse. To prevent relapse, ≥3.0 g/kg of RBV should be administered. Higher dose of RBV may be beneficial in patients <60 years.

Background: The antiviral effect of pegylated interferon (Peg-IFN) plus ribavirin combination therapy in chronic hepatitis C (CHC) patients with normal alanine aminotransferase (ALT) levels (N-ALT) has been reported to be equivalent to that for patients with elevated ALT levels (E-ALT). However, the actual antiviral effect in N-ALT patients remains obscure because efficacy can be overestimated in patients with an advantageous background., Methods: In this study, 386 patients were extracted, for a matched case-control study, from 1320 CHC patients treated with Peg-IFN alpha-2b plus ribavirin combination therapy; 193 N-ALT patients [116 with hepatitis C virus genotype 1 (HCV-1), 77 with HCV genotype 2 (HCV-2)] were matched with 193 E-ALT patients by a propensity score method using the variables of age, sex, IFN treatment history, body mass index, and platelet counts., Results: On multivariate analysis for sustained virological response (SVR) in N-ALT patients, younger age, low HCV RNA level at baseline, and HCV-2 were significant factors. The matched case-control study showed that the SVR rates of N-ALT patients were equivalent to those of E-ALT patients; at 49 and 40% in the HCV-1 group (P = 0.146), and 78 and 81% in the HCV-2 group (P = 0.691). However, in N-ALT patients with non-SVR, approximately 40% showed ALT elevation at 24 weeks post-treatment., Conclusion: Our findings indicate that the antiviral effect of Peg-IFN plus ribavirin therapy in N-ALT patients is comparable to that for E-ALT patients irrespective of their advantageous background; however, the application of this therapy for N-ALT patients, especially for those with HCV-1, should be considered carefully.

Background: This study aimed to develop a model to predict the development of severe anemia during pegylated interferon alpha-2b plus ribavirin combination therapy., Methods: Data were collected from 1081 genotype 1b chronic hepatitis C patients who were treated at 6 hospitals in Japan. These patients were randomly assigned to a model-building group (n = 691) or an internal validation group (n = 390). Factors predictive of severe anemia (hemoglobin, Hb < 8.5 g/dl) were explored using data-mining analysis., Results: Hb values at baseline, creatinine clearance (Ccr), and an Hb concentration decline by 2 g/dl at week 2 were used to build a decision-tree model, in which the patients were divided into 5 subgroups based on variable rates of severe anemia ranging from 0.4 to 11.8%. The reproducibility of the model was confirmed by the internal validation group (r² = 0.96). The probability of severe anemia was high in patients whose Hb value was <14 g/dl before treatment (6.5%), especially (a) in those whose Ccr was <80 ml/min (11.8%) and (b) those whose Ccr was ≥ 80 ml/min but whose Hb concentration decline at week 2 was ≥ 2 g/dl (11.5%). The probability of severe anemia was low in the other patients (0.4-2.5%)., Conclusions: The decision-tree model that included Hb values at baseline, Ccr, and an Hb concentration decline by 2 g/dl at week 2 was useful for predicting the probability of severe anemia, and has the potential to support clinical decisions regarding early dose reduction of ribavirin.

Background: It is still not known which patients with chronic hepatitis C who failed to respond to previous pegylated interferon (Peg-IFN) plus ribavirin therapy can benefit from re-treatment., Methods: Seventy-four patients (HCV genotype 1, n = 56, genotype 2, n = 18) were re-treated with Peg-IFN plus ribavirin., Results: On re-treatment, the sustained virologic response (SVR) rate was 41% for genotype 1 and 56% for genotype 2. With genotype 1, the factors associated with an SVR were previous treatment response and the serum hepatitis C virus (HCV) RNA level at the start of re-treatment. Patients with a ≥ 2-log decrease in HCV RNA at week 12 (partial early virologic response, p-EVR) in previous treatment had significantly higher SVR rates than those without these decreases (p < 0.001); no patient without a p-EVR in the previous treatment attained an SVR with re-treatment (0/16). All patients with <5 log(10) IU/ml of HCV RNA at the start of re-treatment attained an SVR (6/6), while only 33% (15/45) of those patients with ≥ 5 log(10) IU/ml of HCV RNA attained an SVR (p < 0.01). Among the patients with relapse in the previous treatment, those who attained an SVR on re-treatment required a longer duration of re-treatment than the duration of the previous treatment (re-treatment, 63.8 ± 13.0 weeks vs. previous treatment, 53.9 ± 13.5 weeks, p = 0.01)., Conclusions: Re-treatment of genotype 1 patients should be limited to patients with a p-EVR in the previous treatment and a low HCV RNA level at the start of re-treatment. In re-treatment with Peg-IFN plus ribavirin, longer treatment duration can contribute to increasing the anti-viral effect.

Background: Which patients with hepatitis C virus (HCV) genotype 1 can benefit from extended treatment with pegylated interferon (Peg-IFN) plus ribavirin is unknown, although the overall sustained virologic response (SVR) rate has been shown to improve in patients with a late virologic response (LVR), defined as detectable serum HCV RNA at week 12 and undetectable at week 24., Methods: Among 1163 chronic hepatitis C patients with genotype 1 treated with Peg-IFN plus ribavirin combination therapy, 213 patients with an LVR were examined in this study. In addition, we selected 81 patients of matched sex and age from each of the 48- and 72-week treatment groups, using the propensity score, to compare the efficacy of the two treatment durations., Results: With 72-week treatment, the timing of HCV RNA disappearance and the hemoglobin level at baseline showed a strong correlation with the SVR on multivariate analysis. Earlier HCV RNA disappearance was associated with a better SVR rate, regardless of the ribavirin dose (HCV RNA disappearance at week 16, 74%; at week 20, 52%; and at week 24, 31%, p = 0.01). The SVR rate with 72-week treatment was higher than that with 48-week treatment, irrespective of age, sex, or the platelet value, and, especially in aged patients (≥65 years old), the SVR rate increased markedly with 72-week treatment (48 weeks, 25% vs. 72 weeks, 56%; p < 0.05)., Conclusions: An earlier response predicts a higher SVR rate in patients with an LVR given 72-week treatment. Extended treatment with Peg-IFN plus ribavirin for patients with an LVR improved the treatment efficacy, even for aged patients.

Background & Aims: This study investigated the efficacy and adverse effects of pegylated interferon (Peg-IFN) plus ribavirin therapy in aged patients with chronic hepatitis C (CH-C)., Methods: A total of 1040 naïve patients with CH-C (genotype 1, n=759; genotype 2, n=281), of whom 240 (23%) over 65 years old (y.o.), were treated with Peg-IFN alfa-2b plus ribavirin and assessed after being classified into five categories, according to age., Results: The discontinuance rate was higher for patients over 70 y.o. (36%), the most common reason being anemia. In the presence of genotype 1, the SVR rate was similar (42-46%) among patients under 65 y.o. and declined (26-29%) among patients over 65 y.o. For patients over 65 y.o., being male (Odds ratio, OR, 3.5, p=0.035) and EVR (OR, 83.3, p<0.001) were significant factors for SVR, in multivariate analysis. The Peg-IFN dose was related to EVR, and when EVR was attained, 76-86% of patients over 65 y.o. achieved SVR. SVR was not achieved (0/35, 0/38, respectively) if a 1-log decrease and a 2-log decrease were not attained at week 4 and week 8, respectively. In the presence of genotype 2, the SVR rate was similar (70-71%) among patients under 70 y.o. and declined among patients over 70 y.o. (43%)., Conclusions: Aged patients up to 65 y.o. with genotype 1 and 70 y.o. with genotype 2 can be candidates for Peg-IFN plus ribavirin therapy. The response-guided therapy can be applied for aged patients with genotype 1., (Copyright © 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background: This study aimed to develop a model for the pre-treatment prediction of sustained virological response (SVR) to peg-interferon plus ribavirin therapy in chronic hepatitis C., Methods: Data from 800 genotype 1b chronic hepatitis C patients with high viral load (>100,000 IU/ml) treated by peg-interferon plus ribavirin at 6 hospitals in Japan were randomly assigned to a model building (n = 506) or an internal validation (n = 294). Data from 524 patients treated at 29 hospitals in Japan were used for an external validation. Factors predictive of SVR were explored using data mining analysis., Results: Age (<50 years), alpha-fetoprotein (AFP) (<8 ng/mL), platelet count (≥ 120 × 10(9)/l), gamma-glutamyltransferase (GGT) (<40 IU/l), and male gender were used to build the decision tree model, which divided patients into 7 subgroups with variable rates of SVR ranging from 22 to 77%. The reproducibility of the model was confirmed by the internal and external validation (r (2) = 0.92 and 0.93, respectively). When reconstructed into 3 groups, the rate of SVR was 75% for the high probability group, 44% for the intermediate probability group and 23% for the low probability group. Poor adherence to drugs lowered the rate of SVR in the low probability group, but not in the high probability group., Conclusions: A decision tree model that includes age, gender, AFP, platelet counts, and GGT is useful for predicting the probability of response to therapy with peg-interferon plus ribavirin and has the potential to support clinical decisions regarding the selection of patients for therapy.

Previous reports demonstrated that amino acid (aa) substitutions in the hepatitis C virus (HCV) core protein are predictors of non-virological responses to pegylated interferon (Peg-IFN) and ribavirin combination therapy. The aim of this study was to investigate the impact of core aa substitutions on viral kinetics during the treatment and relapse after the treatment. The 187 patients with HCV genotype 1 enrolled in this study were categorized into four groups according to core aa substitution patterns: double-wild group (n=92), Arg70/Leu91; 70-mutant group (n=42), Gln70/Leu91; 91-mutant group (n=31), Arg70/Met91; and double-mutant group (n=22), Gln70/Met91. The relationship between the core aa substitutions and the virological response was examined. Multivariate logistic regression analyses showed that substitution at aa 70 was significantly associated with a poor virological response during the first 12 weeks (decline of <1 log from baseline at week 4, <2 log at week 12), and substitution at aa 91 was significantly associated with detectable HCV RNA at week 24. With respect to relapse, only the ribavirin exposure (odds ratio (OR), 0.77; 95% confidence interval (CI), 0.60-0.98) and HCV RNA disappearance between weeks 13 and 24 (OR, 23.69; 95% CI, 5.44-103.08) were associated independently with relapse, with no correlation being found with the core aa substitutions and relapse. In conclusion, the results showed that core aa substitutions can be strong predictive factors at pretreatment of the non-response, but not for relapse, for virological responders with HCV RNA disappearance during treatment., (Copyright © 2011 Wiley-Liss, Inc.)

The aim of the present study was to clarify the significance of viral factors for pretreatment prediction of sustained virological response to pegylated-interferon (PEG-IFN) plus ribavirin (RBV) therapy for chronic hepatitis C using data mining analysis. Substitutions in the IFN sensitivity-determining region (ISDR) and at position 70 of the HCV core region (Core70) were determined in 505 patients with genotype 1b chronic hepatitis C treated with PEG-IFN plus RBV. Data mining analysis was used to build a predictive model of sustained virological response in patients selected randomly (n = 304). The reproducibility of the model was validated in the remaining 201 patients. Substitutions in ISDR (odds ratio = 9.92, P < 0.0001) and Core70 (odds ratio = 1.92, P = 0.01) predicted sustained virological response independent of other covariates. The decision-tree model revealed that the rate of sustained virological response was highest (83%) in patients with two or more substitutions in ISDR. The overall rate of sustained virological response was 44% in patients with a low number of substitutions in ISDR (0-1) but was 83% in selected subgroups of younger patients (<60 years), wild-type sequence at Core70, and higher level of low-density lipoprotein cholesterol (LDL-C) (≥ 120 mg/dl). Reproducibility of the model was validated (r(2) = 0.94, P < 0.001). In conclusion, substitutions in ISDR and Core70 of HCV are significant predictors of response to PEG-IFN plus RBV therapy. A decision-tree model that includes these viral factors as predictors could identify patients with a high probability of sustained virological response., (Copyright © 2011 Wiley-Liss, Inc.)

Reducing the dose of drug affects treatment efficacy in pegylated interferon (Peg-IFN) and ribavirin combination therapy for patients with hepatitis C virus (HCV) genotype 1. The aim of this study was to investigate the impact of drug exposure, as well as the baseline factors and the virological response on the treatment efficacy for genotype 2 patients. Two-hundred and fifty patients with genotype 2 HCV who were to undergo combination therapy for 24 weeks were included in the study, and 213 completed the treatment. Significantly more patients who achieved a rapid virological response (RVR), defined as HCV RNA negativity at week 4, achieved a sustained virological response (SVR) (92%, 122/133) compared with patients who failed to achieve RVR (48%, 38/80) (P < 0.0001). Multivariate logistic-regression analysis showed that only platelet counts [odds ratio (OR), 1.68; confidence interval (CI), 1.002-1.139] and RVR (OR, 11.251; CI, 5.184-24.419) were independently associated with SVR, with no correlation being found for the mean dose of Peg-IFN and ribavirin for RVR and SVR. Furthermore, in the stratification analysis of the timing of viral clearance, neither mean dose of Peg-IFN (P = 0.795) nor ribavirin (P = 0.649) affected SVR in each group. Among the patients with RVR, the lowest dose group of Peg-IFN (0.77 +/- 0.10 microg/kg/week) and ribavirin (6.9 +/- 0.90 mg/kg/day) showed 100% and 94% of SVR. Hence, RVR served as an important treatment predictor, and drug exposure had no impact on both SVR and RVR in combination therapy for genotype 2 patients.

The impact of ribavirin exposure on virologic relapse remains controversial in combination therapy with pegylated interferon (Peg-IFN) and ribavirin for patients with chronic hepatitis C (CH-C) genotype 1. The present study was conducted to investigate this. Nine hundred and eighty-four patients with CH-C genotype 1 were enrolled. The drug exposure of each medication was calculated by averaging the dose actually taken. For the 472 patients who were HCV RNA negative at week 24 and week 48, multivariate logistic regression analysis showed that the degree of fibrosis (P = 0.002), the timing of HCV RNA negativiation (P < 0.001) and the mean doses of ribavirin (P < 0.001) were significantly associated with relapse, but those of Peg-IFN were not. Stepwise reduction of the ribavirin dose was associated with a stepwise increase in relapse rate from 11% to 60%. For patients with complete early virologic response (c-EVR) defined as HCV RNA negativity at week 12, only 4% relapse was found in patients given > or = 12 mg/kg/day of ribavirin and ribavirin exposure affected the relapse even after treatment week 12, while Peg-IFN could be reduced to 0.6 microg/kg/week after week 12 without the increase of relapse rate. Ribavirin showed dose-dependent correlation with the relapse. Maintaining as high a ribavirin dose as possible (> or = 12 mg/kg/day) during the full treatment period can lead to suppression of the relapse in HCV genotype 1 patients responding to Peg-IFN alpha-2b plus ribavirin, especially in c-EVR patients.

Chronic hepatitis C (CH-C) genotype 1 patients who achieved early virologic response have a high probability of sustained virologic response (SVR) following pegylated interferon (Peg-IFN) plus ribavirin therapy. This study was conducted to evaluate how reducing drug doses affects complete early virologic response (c-EVR) defined as hepatitis C virus (HCV) RNA negativity at week 12. Nine hundred eighty-four patients with CH-C genotype 1 were enrolled. Drug doses were evaluated independently on a body weight base from doses actually taken. From multivariate analysis, the mean dose of Peg-IFN alpha-2b during the first 12 weeks was the independent factor for c-EVR (P = 0.02), not ribavirin. The c-EVR rate was 55% in patients receiving > or = 1.2 microg/kg/week of Peg-IFN, and declined to 38% at 0.9-1.2 microg/kg/week, and 22% in patients given <0.9 microg/kg/week (P < 0.0001). Even with stratified analysis according to ribavirin dose, the dose-dependent effect of Peg-IFN on c-EVR was observed, and similar c-EVR rates were obtained if the dose categories of Peg-IFN were the same. Furthermore, the mean dose of Peg-IFN during the first 12 weeks affected HCV RNA negativity at week 24 (P < 0.0001) and SVR (P < 0.0001) in a dose-dependent manner. Our results suggest that Peg-IFN was dose-dependently correlated with c-EVR, independently of ribavirin dose. Thus, maintaining the Peg-IFN dose as high as possible during the first 12 weeks can yield HCV RNA negativity and higher c-EVR rates, leading to better SVR rates in patients with CH-C genotype 1.

A combination of pegylated interferon alpha (PEG-IFNalpha) and ribavirin has been used widely. Enhancement of immune response against hepatitis C virus (HCV) is known to be involved in the efficacy of the combination therapy. The aim of the study was to elucidate whether the frequency or function of immunocompetent blood cells is related to the outcome of the therapy. Twenty-five chronic hepatitis C patients with high viral load of HCV genotype 1 who underwent 48 weeks of PEG-IFNalpha2b and ribavirin therapy were examined. During the treatment, frequencies of dendritic cell subsets, helper T cell subsets, and NK cells were phenotypically determined. In some patients, the ability of dendritic cells to stimulate allogeneic CD4(+)T cells was examined at the end and after the therapy. Among the 25 patients, 11 showed a sustained virological response, 11 a transient response, and 3 no response. In comparison with sustained virological responders, non-sustained virological responders showed impaired dendritic cell function at the end and after the treatment. The transient responders showed a decline of plasmacytoid dendritic cell frequency from Weeks 1-12 and impaired dendritic cell function as well. Even in patients who attained negative serum HCV RNA at Week 12, the transient responders showed a significant decrease of plasmacytoid dendritic cell frequency and impaired dendritic cell function. In conclusion, in PEG-IFNalpha and ribavirin combination therapy for chronic hepatitis C patients, the early-phase plasmacytoid dendritic cell frequency and/or end-of-treatment dendritic cell function are related to the virological outcome of the therapy.

Background: The aim of this study was to examine the factors correlated with the progression of ribavirin-induced hemolytic anemia in patients with chronic hepatitis C treated by interferon and ribavirin combination therapy., Methods: This study was conducted on 505 patients by the Osaka Liver Disease Study Group. A decline of hemoglobin (Hb) concentration by 2 g/dl at the end of 2 weeks from the start of the treatment ("2 by 2" standard) was adopted as a predictive factor for progression to severe anemia. The ribavirin apparent clearance (CL/F) was also examined., Results: Of 482 patients whose Hb value was more than 12 g/dl before the treatment, 68 patients (14%) had to discontinue ribavirin owing to severe anemia. Patients in the "2 by 2"-positive group (Hb decline over 2 g/dl) and the group with lower CL/F were significantly more likely to discontinue ribavirin owing to severe anemia. Discontinuation was more common among patients aged 60 years or older than for those under 60 years old (21% vs. 9%, P < 0.001). Among patients aged 60 years or older, only the "2 by 2" standard was significantly associated with the discontinuance of ribavirin owing to severe anemia in a multivariate analysis (odds ratio, 4.18; P < 0.001)., Conclusions: The "2 by 2" standard of Hb decline can be used to identify patients likely to develop severe anemia. The early reduction of ribavirin can help prevent progression to severe anemia, thus allowing ribavirin therapy to be completed even in older patients.

Chronic hepatitis C (CH-C) genotype 1 patients who achieved early virologic response have a high probability of sustained virologic response (SVR) following pegylated interferon (Peg-IFN) plus ribavirin therapy. This study was conducted to evaluate how reducing drug doses affects complete early virologic response (c-EVR) defined as hepatitis C virus (HCV) RNA negativity at week 12. Nine hundred eighty-four patients with CH-C genotype 1 were enrolled. Drug doses were evaluated independently on a body weight base from doses actually taken. From multivariate analysis, the mean dose of Peg-IFN α-2b during the first 12 weeks was the independent factor for c-EVR ( P = 0.02), not ribavirin. The c-EVR rate was 55% in patients receiving ≥1.2 μg/kg/week of Peg-IFN, and declined to 38% at 0.9–1.2 μg/kg/week, and 22% in patients given <0.9 μg/kg/week ( P < 0.0001). Even with stratified analysis according to ribavirin dose, the dose-dependent effect of Peg-IFN on c-EVR was observed, and similar c-EVR rates were obtained if the dose categories of Peg-IFN were the same. Furthermore, the mean dose of Peg-IFN during the first 12 weeks affected HCV RNA negativity at week 24 ( P < 0.0001) and SVR ( P < 0.0001) in a dose-dependent manner. Our results suggest that Peg-IFN was dose-dependently correlated with c-EVR, independently of ribavirin dose. Thus, maintaining the Peg-IFN dose as high as possible during the first 12 weeks can yield HCV RNA negativity and higher c-EVR rates, leading to better SVR rates in patients with CH-C genotype 1. [ABSTRACT FROM AUTHOR]

In interferon-alpha (IFN- α)/ribavirin combination therapy for chronic hepatitis C (CHC), an enhanced T helper 1 (Th1) response is essential for the eradication of hepatitis C virus (HCV). We aimed to elucidate the role of IFN- α or IFN- α/ribavirin in dendritic cell (DC) ability to induce Th1 response in HCV infection. We generated monocyte-derived DC from 20 CHC patients and 15 normal subjects driven by granulocyte–macrophage colony-stimulating factor and interleukin 4 (IL-4) without IFN- α (GM/4-DC), with IFN- α (IFN-DC), with ribavirin (R-DC) or with IFN- α/ribavirin (IFN/R-DC) and compared their phenotypes and functions between the groups. We also compared them in 14 CHC patients between who subsequently attained sustained virological response (SVR) and who did not (non-SVR) by 24 weeks of IFN- α/ribavirin therapy. Compared with GM/4-DC, IFN-DC displayed higher CD86 expression, but lesser ability to secrete IL-10 and were more potent to prime CD4+ T cells to secrete IFN- γ and IL-2. Such differences were more significant in healthy subjects than in CHC patients. No additive effect of ribavirin was observed in DC phenotypes and functions in vitro either which was used alone or in combined with IFN- α. However, in the SVR patients, an ability of IFN/R-DC to prime T cells to secrete IFN- γ and IL-2 was higher than those of IFN-DC and those of IFN/R-DC in the non-SVR group, respectively. In conclusion, DC from CHC patients are impaired in the ability to drive Th1 in response to IFN- α. Such DC impairment is restored in vitro by the addition of ribavirin in not all but some patients who cleared HCV by the combination therapy. [ABSTRACT FROM AUTHOR]