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Substitution of amino acid (aa) 70 and/or 91 in the core region of HCV genotype 1b (HCV-1b) is an important predictor of hepatocarcinogenesis, but its impact on the development of hepatocellular carcinoma (HCC) following eradication of HCV RNA by antiviral therapy is not clear. 1,273 patients with HCV-related chronic liver disease, with sustained virological response, defined as negative HCV RNA at 24 weeks after cessation of interferon monotherapy or interferon plus ribavirin combination therapy, were included in a follow-up study to evaluate the impact of aa substitution in the core region on hepatocarcinogenesis. Twenty six patients developed HCC during the follow-up. The cumulative rates of new HCC were 3.2%, 4.8%, and 8.6% at the end of 5, 10, and 15 years, respectively. The rates in patients infected with HCV-1b/Gln70(His70) [glutamine (histidine) at aa 70] were significantly higher than in patients infected with HCV-1b/Arg70 (arginine at aa 70) (P = 0.007; log-rank test) and HCV-2a/2b (P < 0.001; log-rank test). The rates in patients infected with HCV-1b/Arg70 were not significantly higher than in those infected with HCV-2a/2b (P = 0.617; log-rank test). Multivariate analysis identified HCV-1b/Gln70(His70) (HR 10.5, P < 0.001), advanced fibrosis (HR 9.03, P = 0.002), and old age (HR 3.09, P = 0.066) as determinants of hepatocarcinogenesis. In conclusion, aa substitution in the core region of HCV-1b at the start of antiviral therapy is an important predictor of HCC following eradication of HCV RNA. This study emphasizes the importance of detection of aa substitutions in the core region before antiviral therapy., (Copyright © 2011 Wiley-Liss, Inc.)

Unlabelled: Polymorphisms of the inosine triphosphatase (ITPA) gene influence anemia during pegylated interferon (PEG-IFN) and ribavirin (RBV) therapy, but their effects during triple therapy with PEG-IFN, RBV, and telaprevir are not known. Triple therapy for 12 weeks, followed by PEG-IFN and RBV for 12 weeks, was given to 49 patients with RBV-sensitive (CC at rs1127354) and 12 with RBV-resistant (CA/AA) ITPA genotypes who had been infected with hepatitis C virus (HCV) of genotype 1. Decreases in hemoglobin levels were greater in patients with CC than CA/AA genotypes at week 2 (-1.63 ± 0.92 vs. -0.48 ± 0.75 g/dL, P = 0.001) and week 4 (-3.5 ± 1.1 vs. -2.2 ± 0.96, P = 0.001), as well as at the end of treatment (-2.9 ± 1.1 vs. -2.0 ± 0.86, P = 0.013). Risk factors for hemoglobin <11.0 g/dL at week 4 were female gender, age >50 years, body mass index (BMI) <23, and CC at rs1127354 by multivariate analysis. RBV dose during the first 12 weeks was smaller in patients with CC than CA/AA genotypes (52 ± 14% vs. 65 ± 21% of the target dose, P = 0.039), but the total RBV dose was no different between them (49 ± 17% and 54 ± 18% of the target, P = 0.531). Sustained virological response (SVR) was achieved in 70% and 64% of them, respectively (P = 0.724)., Conclusion: ITPA polymorphism influences hemoglobin levels during triple therapy, particularly during the first 12 weeks while telaprevir is given. With careful monitoring of anemia and prompt adjustment of RBV dose, SVR can be achieved comparably frequently between patients with CC and CA/AA genotypes., (Copyright © 2010 American Association for the Study of Liver Diseases.)

Unlabelled: Genetic variation near the IL28B gene and substitution of amino acid (aa) 70 and 91 in the core region of hepatitis C virus (HCV) genotype 1b can predict the response to pegylated interferon (PEG-IFN)/ribavirin combination therapy, but its impact on triple therapy of telaprevir/PEG-IFN/ribavirin is not clear. The aims of this study were to investigate the predictive factors of sustained virological response to a 12-week or 24-week regimen of triple therapy in 72 of 81 Japanese adults infected with HCV genotype 1. Overall, sustained virological response and end-of-treatment response were achieved by 61% and 89%, respectively. Especially, the sustained virological response was achieved by 45% and 67% in the 12- and 24-week regimens, respectively. Multivariate analysis identified rs8099917 near the IL28B gene (genotype TT) and substitution at aa 70 (Arg70) as significant determinants of sustained virological response. Prediction of response to therapy based on a combination of these factors had high sensitivity, specificity, and positive and negative predictive values. The efficacy of triple therapy was high in the patients with genotype TT, who accomplished sustained virological response (84%), irrespective of substitution of core aa 70. In the patients having genotype non-TT, those of Arg70 gained high sustained virological response (50%), and sustained virological response (12%) was the worst in patients who possessed both genotype non-TT and Gln70(His70)., Conclusion: This study identified genetic variation near the IL28B gene and aa substitution of the core region as predictors of sustained virological response to a triple therapy of telaprevir/PEG-IFN/ribavirin in Japanese patients infected with HCV genotype 1b.

Osteoporosis is often present in postmenopausal women. The aim of this retrospective cohort study was to assess the cumulative incidence and predictive factors for bone fracture after cessation of interferon (IFN) in postmenopausal women with osteoporosis and chronic liver disease caused by hepatitis C virus (HCV). A total of 420 postmenopausal women treated with IFN monotherapy were enrolled. The mean observation period was 7.2 years. The primary goal was the development of bone fracture. Evaluation was carried out by using the Kaplan-Meier method and the Cox proportional hazards analysis. Thirty-one out of 420 patients sustained bone fracture. The cumulative development rate of bone fracture was 3.6% at 5th year, 9.2% at 10th year, and 17.4% at 15th year. Multivariate Cox proportional hazards analysis showed that bone fracture after cessation of IFN therapy occurred when histological staging of the liver was advanced (hazard ratio (HR): 2.54; 95% confidence interval (CI) = 1.21-5.31; P = 0.013), serum albumin level was < 3.5g/dl (HR: 2.25; 95% CI = 1.10-4.59; P = 0.026), and virus clearance was not achieved (HR: 3.65; 95% CI = 1.11-12.05; P = 0.033). The results indicate that virus clearance causes a reduction of two-thirds in the risk of bone fracture after cessation of IFN therapy in postmenopausal women with osteoporosis and chronic liver disease caused by HCV. J. Med. Virol. 82:390-395, 2010. (c) 2010 Wiley-Liss, Inc.

Here, we describe for the first time a case of sustained virological response (SVR) achieved in a patient with chronic hepatitis C (CH-C) by monotherapy with a NS3-4A protease inhibitor, telaprevir, without interferon therapy. A 59-year-old treatment-naïve Japanese man was enrolled in a phase II trial of telaprevir by repeat oral administration at a dose of 750mg every 8h for 24 weeks. At the start of treatment, he exhibited a low-level viremia with genotype 1b of the hepatitis C virus (HCV). After the first week of treatment with telaprevir, serum HCV RNA was undetectable, and negativity remained until the end of treatment. Moreover, he was evaluated as having a SVR after the post-treatment 24-week follow-up program. Two characteristics may explain the strong antiviral activity of telaprevir in the present case. First, although pre-treatment PCR-direct sequencing and cloning for the N-terminal in the NS3 region showed a protease inhibitor-resistant variant (T54A) in 1 of 32 independent clones, the T54A substitution has only a low-level resistance to protease inhibitors and his viral load was low. Second, when compared to a consequence sequence of 35 treatment-naïve patients with HCV genotype 1b, R130K and Q195K substitutions were unique to the present case. Although it is presently unknown whether the R130K and Q195K substitutions are related to SVR, this case suggests that long-term telaprevir monotherapy may be effective in CH-C patients with genotype 1 and a low viral load., (Copyright (c) 2009 Elsevier B.V. All rights reserved.)

Objective: The aim of this study was to evaluate the efficacy of combination therapy of natural human interferon-beta and ribavirin in patients infected with hepatitis C virus (HCV) genotype 2 and high virus load., Methods: Inclusion criteria were HCV-genotype 2, serum HCV RNA level of >or=100 KIU/mL before combination therapy. A total of 24 were enrolled in this retrospective cohort study. The treatment period of combination therapy was 24 weeks., Results: Of the 24 study patients, no patient stopped the treatment due to treatment-related adverse events. The dose of drugs were reduced in 8 patients. Twenty-one of 24 patients (87.5%) had sustained virological response (SVR) by the intention to treat analysis. The rate of negative HCV RNA at 8 week after the initiation of treatment was 18/21 (86%) in patients with SVR and 1/3 (33%) in patients with non-SVR. Logistic regression analysis showed that SVR occurred when serum HCV RNA at 8 week after the initiation of combination therapy was negative (hazard ratio: 40.0; 95% confidence interval=1.75-914.78; p=0.021), Conclusion: The combination therapy of IFN-beta and ribavirin offers sufficient safety and efficacy in chronic hepatitis C patients with genotype 2 and high virus load.

Objective: The aim of this study was to evaluate the efficacy of combination therapy of natural human interferon-beta and ribavirin in patients infected with hepatitis C virus (HCV) genotype 1b., Methods: Inclusion criteria were HCV-genotype 1b, serum HCV RNA level of >or=100 KIU/ml before the initiation of treatment. A total of 40 patients were enrolled in this retrospective cohort study. The treatment period of combination therapy was 48 weeks. Nonparametric procedures were employed for the analysis of background features of the patients with SVR and without SVR. A p value of <0.05 was considered to indicate a significant difference., Results: Of the 40 study patients, ten had mental disorders before the initiation of combination therapy. One of the patients stopped the treatment due to exacerbation of depression and another patient stopped due to a skin rash. Three patients suspended the therapy due to an insufficient response of positive serum HCV RNA at 24 weeks after the initiation of treatment. Thus, 34 patients completed combination therapy. Fifteen had sustained virological response (SVR). The SVR rate in patients who showed negative HCV RNA 8 weeks after the initiation of combination therapy was 86.7% (13/15). On the other hand, the SVR rate in patients who showed positive HCV RNA at 8 weeks was 8% (2/25) (p<.001). Continuous period of negative serum HCV RNA was 33.1 weeks in SVR groups, and 12.5 weeks in non-SVR groups (p<.001)., Conclusion: The combination therapy of IFN-beta and ribavirin is a possible therapy selection for patients with type C hepatitis of genotype 1b and high virus load.

Objective: In treatment-resistant patients with genotype 2 chronic hepatitis C the suitable treatment duration is still unclear. The aims were to investigate extending combination therapy with peginterferon plus ribavirin for genotype 2., Methods: 7 patients infected with genotype 2 at a high viral load and who did not achieve a sustained virological response (SVR) with the first course of 24-week IFN plus ribavirin were recruited into the study protocol with a total of 48 weeks of peginterferon plus ribavirin therapy., Results: SVR was achieved in 5 of 7 patients (71%). All 4 patients (100%) who were in relapse with the first course achieved SVR. Only 1 of 3 patients (33%) who had a non-virological response (NVR) with the first course achieved SVR. All 4 patients who had an early virological response (EVR) with the first course achieved EVR and SVR. Two of 3 patients who had no EVR with the first course also did not achieve EVR and SVR. One patient who had no EVR or a NVR during the first course achieved EVR and SVR with the second course., Conclusions: Our results suggest that extending combination therapy for genotype 2 chronic hepatitis C might be useful for patients who relapse following 24-week combination therapy., (2010 S. Karger AG, Basel.)

The aim of this retrospective cohort study is to assess the cumulative development incidence and predictive factors for type 2 diabetes (T2DM) in HCV positive and hypertensive patients treated with losartan. Eighty Japanese patients were given 50 mg of losartan per day after diagnosis of hypertension (losartan group). Another 160 treated with spironolactone were selected as control (spironolactone group). Patients in spironolactone group were matched 1:2 with losartan group for age and sex. The mean observation period was 5.2 years in losartan group and 5.4 years in spironolactone group. An overnight (12 hr) fasting blood sample or a casual blood sample was taken for routine analyses during follow-up. The primary goal is the onset of T2DM. Evaluation was performed by using the Kaplan-Meier method and the cox proportional hazards analysis. Three patients in losartan group and 20 in spironolactone group developed T2DM. The 5th year cumulative appearance rates of T2DM were 5.4% in losartan group and 14.4% in spironolactone group. Multivariate cox proportional hazards analysis showed that T2DM development after the initiation of anti-hypertensive drugs occurred when anti-hypertensive drug was spironolactone (hazard ratio: 6.10; 95% confidence interval = 1.78-20.84; P = 0.004), histological staging was advanced (hazard ratio: 4.31; 95% confidence interval = 1.94-9.60; P < 0.001), fatty liver was present (hazard ratio: 3.28; 95% confidence interval = 1.47-7.27; P = 0.004), and patient had pre-diabetes (hazard ratio: 2.47; 95% confidence interval = 1.08-5.63; P = 0.032). Our results indicate losartan causes about 60% reduction of the onset of T2DM compared to patients treated with spironolactone.

Unlabelled: Diabetes is present in patients with chronic hepatitis C virus infection. The aim of this retrospective cohort study was to assess the cumulative development incidence and predictive factors for type 2 diabetes after the termination of interferon therapy in Japanese patients positive for hepatitis C virus (HCV). A total of 2,842 HCV-positive patients treated with interferon (IFN) monotherapy or combination therapy with IFN and ribavirin were enrolled. The mean observation period was 6.4 years. An overnight (12-hour) fasting blood sample or a casual blood sample was taken for routine analyses during follow-up. The primary goal was the onset of type 2 diabetes. Evaluation was performed by using the Kaplan-Meier method and Cox proportional hazard analysis. Of 2,842 HCV patients, 143 patients developed type 2 diabetes. The cumulative development rate of type 2 diabetes was 3.6% at 5 years, 8.0% at 10 years, and 17.0% at 15 years. Multivariate Cox proportional hazard analysis revealed that type 2 diabetes development after the termination of IFN therapy occurred when histological staging was advanced (hazard ratio 3.30; 95% confidence interval [CI] 2.06-5.28; P < 0.001), sustained virological response was not achieved (hazard ratio 2.73; 95% CI 1.77-4.20; P < 0.001), the patient had pre-diabetes (hazard ratio 2.19; 95% CI 1.43-3.37; P < 0.001), and age was >or=50 years (hazard ratio 2.10; 95% CI 1.38-3.18; P < 0.001)., Conclusion: Our results indicate sustained virological response causes a two-thirds reduction in the risk of type 2 diabetes development in HCV-positive patients treated with IFN.

Substitution of amino acid (aa) 70 and 91 in the core region of HCV genotype 1b is a useful pretreatment predictor of efficacy of 48-week peginterferon (PEG-IFN) plus ribavirin (RBV) therapy. Here, we determined the efficacy of 72-week PEG-IFN/RBV and the predictive factors to such therapy in a case-control study matched for sex, age, and periods from the start of treatment to initial point of HCV RNA-negative. We compared the treatment efficacy of 72-week regimen in 65 patients with that of 48-week in 130 patients, who were infected with HCV genotype 1b and treated with PEG-IFN/RBV. They consisted mainly of late virological responders (LVR) (HCV RNA-positive at 12 weeks and negative at 24 weeks after start of treatment). Sustained virological response (SVR) was achieved by 61.5% and 32.3% of patients of the 72- and 48-week groups, respectively, while non-virological response was noted in 9.2% and 29.2% of the respective groups. Multivariate analysis identified substitution of aa 70 and 91 (Arg70 and/or Leu91) and duration of treatment (72-week) as independent parameters that significantly influenced SVR. For Arg70 and/or Leu91 of core region, SVR rate was significantly higher in 72- (68.0%) than 48-week group (37.8%). For wild-type of ISDR, SVR rate was significantly higher in 72- (61.2%) than in 48-week group (29.3%). We conclude that 72-week PEG-IFN/RBV improves SVR rate for LVR, especially those with Arg70 and/or Leu91 of core region or wild-type of ISDR. Substitution of aa 70 and 91 is also a useful pretreatment predictor of response to 72-week PEG-IFN/RBV., (Copyright 2009 Wiley-Liss, Inc.)

Background: Substitution of amino acids (aa) 70 and 91 in the core region of HCV genotype 1b is a useful pretreatment predictor of poor response to interferon + ribavirin combination therapy, but the impacts of aa substitutions in the core region of HCV genotype 2a are still not clear., Methods: 154 consecutive Japanese adults with a high viral load (> or =100 kIU/ml) of genotype 2a who could complete combination therapy for 24 weeks were evaluated. To examine the differences in virological characteristics between non-sustained virological response (non-SVR) and rapid responder (SVR patients who could achieve a HCV-RNA-negative status within 8 weeks), 86 patients could be analyzed by pretreatment substitution patterns of the core region., Results: SVR was achieved in 127 of 154 patients (83%), and rapid response in 113 of 127 (90%). In all 154 patients, multivariate analysis identified younger age, lower level of viremia, and higher level of albumin as significant determinants of SVR. As significant determinants of rapid response in 86 patients, multivariate analysis identified substitution of aa 4 (non-asparagine) in addition to the significant determinants of SVR., Conclusions: Our results suggest that the aa substitution pattern of the core region in patients with a high titer of genotype 2a may partly affect the virological response to combination therapy., (Copyright 2009 S. Karger AG, Basel.)

Aims: We showed previously that amino acid (aa) substitutions in HCV genotype 1b (HCV-1b) core region are negative predictors of virological response to peginterferon + ribavirin therapy, and also risk factors of hepatocarcinogenesis. The aim of this study was to evaluate the impact of core aa substitutions on mortality in elderly patients., Methods: We compared the characteristics and survival of 92 elderly (> or =75 years) patients with HCV-related hepatocellular carcinoma (HCC) (including 62 patients with HCV-1b) with those of 44 younger patients (<50 years, 34 patients with HCV-1b)., Results: For all patients, univariate analysis identified female sex, history of blood transfusion, preserved liver function and glucose metabolism as significant variables in the elderly patients. In patients with HCV-1b-related HCC, univariate analysis identified preserved lipid metabolism as significant variable in addition to significant variables in overall patients. In elderly patients with HCV-1b-related HCC, multivariate analysis identified male sex, methionine of core aa91, and non-radical therapy as factors that influenced mortality after first treatment for HCC., Conclusions: Our results characterized elderly patients who develop HCC after HCV-1b infection, and suggested that aa substitutions of HCV-1b core region correlate with mortality of patients after first treatment for HCC., (Copyright 2009 S. Karger AG, Basel.)

Objective: The aim of this study was to evaluate the efficacy of combination therapy of peginterferon and ribavirin in patients infected with hepatitis C virus (HCV) genotype 1b and low virus load., Methods: Inclusion criteria were HCV-genotype 1b, serum HCV RNA level of < 100 KIU/mL at the initiation time of treatment. A total of 60 were enrolled in this retrospective cohort study. The treatment period of combination therapy was 39.8+/-16.1 weeks., Results: Of the 60 study patients, 47 had sustained virological response (SVR) by the intention to treat analysis. SVR occurred when serum HCV RNA was negative 8 weeks after the initiation of the treatment (p=0.004) and continuance of negative HCV RNA during treatment was > or = 30 week (p=0.016). In rapid virological response, all of seven patients with continuance of negative HCV RNA 20 to 29 weeks during treatment had SVR. In early virological response nine of 10 patients with continuance of negative HCV RNA of 30 to 39 week during treatment had SVR., Conclusion: The duration of combination therapy for chronic hepatitis C should be determined based on the time of attainment of negative HCV RNA in patients with genotype 1b and low-virus load.

Aim: To investigate the cumulative development incidence and predictive factors for idiopathic pulmonary fibrosis in hepatitis C virus (HCV) positive patients., Methods: We studied 6150 HCV infected patients who were between 40-70 years old (HCV-group). Another 2050 patients with hepatitis B virus (HBV) were selected as control (HBV-group). The mean observation period was 8.0 +/- 5.9 years in HCV-group and 6.3 +/- 5.5 years in HBV-group. The primary goal is the development ofidiopathic pulmonary fibrosis (IPF) in both groups. The cumulative appearance rate of IPF and independent factors associated with the incidence rate of IPF were calculated using the Kaplan-Meier method and the Cox proportional hazard model. All of the studies were performed retrospectively by collecting and analyzing data from the patient records in our hospital., Results: Fifteen patients in HCV-group developed IPF. On the other hand, none of the patients developed IPF in HBV-group. In HCV-group, the cumulative rates of IPF development were 0.3% at 10th year and 0.9% at 20th year. The IPF development rate in HCV-group was higher than that in HBV-group (P = 0.021). The IPF development rate in patients with HCV or HBV was high with statistical significance in the following cases: (1) patients > or = 55 years (P < 0.001); (2) patients who had smoking index (package per day multiply year) of > or = 20 (P = 0.002); (3) patients with liver cirrhosis (P = 0.042)., Conclusion: Our results indicate that age, smoking and liver cirrhosis enhance the development of IPF in HCV positive patients.

Objective: Interferon (IFN) therapy reduces the incidence of hepatocarcinogenesis in patients with hepatitis C viral (HCV) infection who achieve a sustained virological response (SVR). The aim of the present study was to determine the rate of hepatocarcinogenesis and the risk factor in sustained virological responders., Patients and Method: The study subjects were 1,193 patients with HCV-related chronic liver disease and IFN- or IFN plus ribavirin-induced SVR. The age, male/female ratio, and liver fibrosis stage [(F0-F3)/LC] were 15-83 years, 808/385, and 1106/41, respectively. Patients were followed-up for 8.3 years (range, 0 to 19.0 years) and the incidence of hepatocellular carcinoma was recorded., Results: Hepatocellular carcinogenesis was detected in 23 patients during the follow-up. The crude rates of hepatocarcinogenesis at 5, 10, and 15 years were 1.5%, 2.4% and 4.1%, respectively. Multivariate analysis identified cirrhosis, male sex and age older than 50 years as determinants of hepatocarcinogenesis with hazard ratios of 12.9 (p<0.001), 6.45 (p=0.012), and 20.2 (p=0.004), respectively., Conclusion: Long-term follow-up of patients with chronic HCV infection is necessary even in those who show SVR, especially in male elderly patients with cirrhosis.

Objective: The aim of this study was to elucidate efficacy after dose reduction in combination therapy of peginterferon and ribavirin for chronic hepatitis C., Methods: Inclusion criteria were hepatitis C virus (HCV) genotype 1b, serum HCV RNA level of >/=100 KIU/ml, dose reduction of peginterferon and/or ribavirin between the first 4 weeks and 20 weeks after the initiation of treatment. 164 patients were enrolled in this retrospective cohort study. Predictive factors for sustained viral response (SVR) after dose reduction were examined., Results: Out of the 146 patients treated with dose reduction, 57 had SVR. Multivariate analysis showed that SVR occurred when serum HCV RNA at the time of dose reduction was negative (p < 0.001) and total ribavirin dose was >/=100% of the anticipated total dose (p < 0.001). 57% (55/97) of patients with undetectable serum HCV RNA at the time of dose reduction had SVR. In contrast, only 4% (2/49) of patients with detectable serum HCV RNA at the time of dose reduction had SVR., Conclusions: On dose reduction of combination therapy for chronic hepatitis C, undetectable serum HCV RNA at the time of dose reduction and attainment of the total ribavirin dose of >/=100% enhance SVR., (Copyright (c) 2008 S. Karger AG, Basel.)

Objectives: The aim of this study was to elucidate the efficacy of interferon (IFN) therapy in liver cirrhosis Japanese patients with genotype 1b and low virus load., Methods: The present study was a retrospective cohort study. Inclusion criteria were liver cirrhosis, HCV genotype 1b, HCV RNA of <100 KIU/ml, and natural IFN-alpha monotherapy for 24 weeks. In 23 consecutive patients who satisfied the above criteria the efficacy and side effects of IFN were examined. Independent factors that might have influenced a sustained virologic response (SVR) were studied using logistic regression analysis., Results: The clinical patient profiles were as follows: median (range) age 52 (37-69) years; male/female 18/5, and median (range) HCV RNA 52 (<5-92) KIU/ml. Eight of the 23 patients (34.8%) had SVR by intention-to-treat analysis. Logistic analysis indicated that an HCV RNA level of <50 KIU/ml was associated with SVR (p = 0.049). The median (range) HCV RNA levels were 28 (<5-68) KIU/ml in patients with SVR and 60 (6-92) KIU/ml in patients without SVR., Conclusions: 24-week IFN monotherapy is a suitable therapy for type C cirrhotic patients with genotype 1b and an HCV RNA level of <50 KIU/ml., (Copyright 2008 S. Karger AG, Basel.)