Chronic hepatitis B virus (HBV) infection leads to cirrhosis and hepatocellular carcinoma (HCC). Antiviral agents are thought to reduce HCC development, but agents such as lamivudine (LAM) have a high rate of drug resistance. We compared the incidence of HCC in 472 entecavir (ETV)-treated patients and 1,143 nontreated HBV patients (control group). Propensity score matching eliminated the baseline differences, resulting in a sample size of 316 patients per cohort. The drug mutation resistance was 0.8% (4/472) in the ETV group. The cumulative HCC incidence rates at 5 years were 3.7% and 13.7% for the ETV and control groups, respectively (P < 0.001). Cox proportional hazard regression analysis, adjusted for a number of known HCC risk factors, showed that patients in the ETV group were less likely to develop HCC than those in the control group (hazard ratio: 0.37; 95% confidence interval: 0.15-0.91; P 5 0.030). Both cohorts were applied in three previously reported risk scales and risk scores were generated based on age, gender, cirrhosis status, levels of alanine aminotransferase, hepatitis B e antigen, baseline HBV DNA, albumin, and bilirubin. The greatest HCC risk reduction occurred in high-risk patients who scored higher on respective risk scales. In sub analyses, we compared treatment effect between nucleos(t)ide analogs, which included matched LAM-treated patients without rescue therapy (n 5 182). We found HCC suppression effect greater in ETV-treated (P < 0.001) than nonrescued LAM-treated (P 5 0.019) cirrhosis patients when they were compared with the control group. Conclusion: Long-term ETV treatment may reduce the incidence of HCC in HBV-infected patients. The treatment effect was greater in patients at higher risk of HCC. (HEPATOLOGY 2013;58:98-107) See Editorial on Page 18 M ore than 2 billion people worldwide have been exposed to hepatitis B virus (HBV) and about 350 million people are chronically infected, the majority of whom are in Asia (75%). The prevalence of HBV in Japan is 0.8%, which is lower than other Asian countries such as Taiwan (>10%) and China.1-3 As chronic HBV infection leads to cirrhosis and hepatocellular carcinoma (HCC), published studies have shown that up to 25% of chronically infected patients eventually die of liver cirrhosis or HCC. 4A large-scale longitudinal epidemiologic study has shown that a patient's baseline HBV DNA level is an independent predictor for the development of HCC. 5Studies have begun to show that treatment to decrease HBV DNA reduces the risk of HCC development in HBV patients with cirrhosis or advanced fibrosis or in chronic HBV patients. 6,7 Within the past 10 years, new antiviral therapies, including nucleos(t)ide analogs (NAs), have been approved and were successful in suppressing circulating serum viral loads. Studies that have examined the relationship between NA therapy and HCC almost exclusively used older drugs such as lamivudine and/or adefovir. Although results of long-term studies showed the importance of antiviral suppression, HCC risk among p...

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Objective: Patients with high titer (≧100 kIU/ml) of hepatitis C virus (HCV) genotype 1b do not achieve highly sustained virological response rates to combination therapy with interferon plus ribavirin. Non-virological responders (NVRs, namely ultimate resistant cases) who do not achieve HCV-RNA negativity during treatment are also encountered. We investigated the pretreatment virological features of NVRs. Methods: We evaluated 50 consecutive Japanese adults with high titer of HCV genotype 1b who received combination therapy for 48 weeks. We investigated the pretreatment substitution patterns in amino acids 1–191 of the core region and amino acids 2209–2248 of NS5A, and early viral kinetics. Results: Overall, a non-virological response was noted in 12 (24%) patients. Multivariate analysis identified serum albumin <3.9 g/dl, substitutions of amino acid 70 in the core region, and substitutions of amino acid 91 as independent and significant factors associated with a non-virological response. Especially, substitutions of arginine (R) by glutamine (Q) at amino acid 70, and/or leucine (L) by methionine (M) at amino acid 91 were significantly more common in NVRs. The falls in HCV-RNA levels during treatment in patients with specific substitutions in the core region were significantly less than in those without such substitutions. Conclusions: Our results suggest that serum albumin and amino acid substitution patterns in the core region in patients with high titers of HCV genotype 1b may have an effect on combination therapy in NVRs. Further large-scale studies are required to examine the role of amino acid substitutions specific to a non-virological response to combination therapy.

This retrospective study indicates that the annual incidence rate of HCC among Japanese NAFLD patients is low. Elderly NAFLD patients with diabetes, elevated serum AST, and especially thrombocytopenia (suggested to be associated with advanced liver fibrosis) should be monitored carefully during follow-up that includes using the APRI to ensure early diagnosis and treatment of HCC.

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. (HEPATOLOGY 2010;52:421-429) H epatitis C virus (HCV) usually causes chronic infection that can result in chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma (HCC).1,2 At present, treatments based on interferon (IFN), in combination with ribavirin, are the mainstay for combating HCV infection. In Japan, HCV genotype 1b (HCV-1b) in high viral loads (>100 KIU/ mL) accounts for more than 70% of HCV infections, making it difficult to treat patients with chronic hepatitis C.3 Such background calls for efficient treatments of Japanese patients with chronic HCV infection.Even with pegylated IFN (PEG-IFN) combined with ribavirin, a sustained virological response lasting over 24 weeks after the withdrawal of treatment is achieved in at most 50% of the patients infected with HCV-1b and high viral loads. 4,5 Recently, a new strategy was introduced in the treatment of chronic HCV infection by

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 >50 years (hazard ratio 2.10; 95% CI 1.38-3.18; P < 0.001). H epatitis C virus (HCV) is one of the more common causes of chronic liver disease in world. Chronic hepatitis C is an insidiously progressive form of liver disease that relentlessly but silently progresses to cirrhosis in 20% to 50% of cases over a period of 10 to 30 years. [1][2][3] In addition, HCV is a major risk for hepatocellular carcinoma (HCC). 4-8 Moreover, chronic HCV infection has been associated with a variety of extrahepatic complications such as essential mixed cryoglobulinemia, porphyria cutanea tarda, membranoproliferative glomerulonephritis, autoimmune thyroiditis, sialadenitis, and cardiomyopathy. [9][10][11][12][13] Lately, data supporting a link between type 2 diabetes mellitus (T2DM) and chronic hepatitis C infection have been reported. 14,15 Although there is growing evidence to support the concept that HCV infection is a risk factor for developing T2DM, there have been a few interventional studies confirming this issue. This issue needs to be confirmed with a long-term follow-up of patients with high risk of developing diabetes. Thus, prospective studies including metabolic evaluations are clearly needed to clarify these issues.With this background in mind, the cohort study was initiated to investigate the cumulative incidence and risk factors of T2DM after prolonged follow-up in HCV-infected patients treated with interferon (IFN) monotherapy or combination therapy with IFN and ribavirin. The strengths of the current study are the large numbers of patients included and the long-term follow-up of patients. Patients and MethodsPatients. There were 5,890 patients diagnosed with chronic ...

Fatigue is one of the most frequent symptoms in cancer patients. However, the precise causes of this fatigue are still unknown, and this situation makes it difficult to combat the problem. The present study was conducted to investigate factors correlated with fatigue in disease-free breast cancer patients. A group of 134 randomly selected ambulatory breast cancer patients who had undergone successful surgical treatment participated. They completed the Cancer Fatigue Scale, the Hospital Anxiety and Depression Scale, the Mental Adjustment to Cancer Scale, and an ad hoc questionnaire detailing physical symptoms, social support, and demographic variables at home and returned them by mail the following day. Multiple regression analysis revealed that fatigue was significantly correlated with dyspnea, insufficient sleep, and depression, and that these three variables accounted for a total of 46% of variance in fatigue. Factors concerned with the cancer and treatment, such as disease stage, lymph node metastasis, number of days since operation, past intravenous chemotherapy, radiotherapy, current use of fluoropyrimidine compounds, and current use of tamoxifen citrate were not correlated with fatigue. The results suggest that fatigue in this population is determined by current physical and psychological distress rather than by the cancer itself and prior cancer treatments, and that the management of dyspnea, insomnia, and depression might be important in reducing fatigue in this population.