Yuya Seko

Long‐term entecavir treatment reduces hepatocellular carcinoma incidence in patients with hepatitis B virus infection

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 = 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 = 182). We found HCC suppression effect greater in ETV‐treated (P < 0.001) than nonrescued LAM‐treated (P = 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)

Large-Scale Long-Term Follow-Up Study of Japanese Patients With Non-Alcoholic Fatty Liver Disease for the Onset of Hepatocellular Carcinoma

OBJECTIVES:The aim of this study was to determine the incidence and risk factors of hepatocellular carcinoma (HCC), and to elucidate the utility of two non-invasive predictive procedures for liver fibrosis: the aspartate aminotransferase (AST) to platelet ratio index (APRI) and the BARD score (which includes the following three variables: body mass index, AST/alanine aminotransferase ratio, and diabetes) in the prediction of HCC in a large population of Japanese patients with non-alcoholic fatty liver disease (NAFLD).METHODS:This was a retrospective cohort study conducted at a public hospital. Study subjects included 6,508 patients with NAFLD diagnosed by ultrasonography. The median follow-up period was 5.6 years. The primary end point was the onset of HCC. Evaluation was performed using Kaplan–Meier methodology and Coxs proportional hazards analysis.RESULTS:In all, 16 (0.25%) new cases with HCC were diagnosed during the study. The cumulative rates of NAFLD-related HCC were 0.02% at year 4, 0.19% at year 8, and 0.51% at year 12. The annual rate of new HCC was 0.043%. Multivariate analysis identified serum AST level ≥40 IU/L (hazard ratio (HR): 8.20; 95% confidence interval (95% CI): 2.56–26.26; P<0.001), platelet count <150 × 103/μl (HR: 7.19; 95% CI: 2.26–23.26; P=0.001), age ≥60 years (HR: 4.27; 95% CI: 1.30–14.01; P=0.017), and diabetes (HR: 3.21; 95% CI: 1.09–9.50; P=0.035) as independent risk factors for HCC. With regard to the APRI, 184 patients (2.83%) were considered to have significant fibrosis (equivalent to non-alcoholic steatohepatitis (NASH) stage 3–4). The cumulative rate of HCC was significantly higher in this group (HR: 25.03; 95% CI: 9.02–69.52; P<0.001). In contrast, regarding the BARD score, 3,841 (59%) patients were considered to have advanced fibrosis (NASH stage 3–4). However, no significant associations between the BARD score and the incidence of HCC were observed (HR: 1.16; 95% CI: 0.40–3.37; P=0.780).CONCLUSIONS: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.

Prevalence of hepatitis C virus variants resistant to NS3 protease inhibitors or the NS5A inhibitor (BMS-790052) in hepatitis patients with genotype 1b

BACKGROUND Hepatitis C virus (HCV) of genotype 1b is the most prevalent worldwide, and the least responsive to interferon-based treatments. A combination therapy with two direct-acting antivirals has shown promising results in patients with HCV-1b, but the prevalence of drug-resistant variants before treatment is not known in the Japanese population. OBJECTIVES To detect HCV variants resistant to NS3 protease inhibitors or the NS5A inhibitor (BMS-790052) in hepatitis patients infected with HCV-1b. STUDY DESIGN Drug-resistant mutations were determined in the 362 hepatitis patients infected with HCV-1b who had not received direct-acting antivirals before. RESULTS Amino-acid substitutions resistant to NS3 inhibitors (V36A, T54S, Q80H and D168E) were detected in 15 of the 307 (4.9%) patients, who had been examined, and T54S (3.3%) predominated over V36A (0.3%), Q80R (0.7%) and D168E (0.7%) in them. Amino-acid substitutions resistant to BMS-790052 (L31M and/or Y93H) were detected in 33 of the 294 (11.2%) patients, and Y93H (8.2%) predominated over L31M (2.7%). One of the 239 (0.4%) patients, who had been examined for amino-acid substitutions in both NS3 and NS5A regions, possessed HCV-1b variants resistant to NS3 inhibitors (T54S) and BMS-790052 (L31M). CONCLUSIONS Mutations conferring resistance to NS3 inhibitors or BMS-790052 were frequent in our treatment-naive study population, but double mutants with possible resistance to both drugs were rare. Since single mutations did not result in treatment failure in a previous pilot trial combining BMS-790052 and an NS3 inhibitor, larger trials of this drug regimen appear warranted in the Japanese population.

Complicated relationships of amino acid substitution in hepatitis C virus core region and IL28B genotype influencing hepatocarcinogenesis

The impact of amino acid (aa) 70 substitution in the core region on hepatocarcinogenesis and survival for liver‐related death in patients of hepatitis C virus (HCV) genotype 1b (HCV‐1b), who had not received antiviral therapy, is unknown. The relationships among aa 70 substitution, IL28B genotype, and hepatocarcinogenesis are also not clear. A total of 1,181 consecutive HCV‐infected patients, who had not received antiviral therapy, were included in a follow‐up study to determine predictive factors of hepatocarcinogenesis and survival for liver‐related death. The cumulative hepatocarcinogenesis rates in HCV‐1b of Gln70(His70) (glutamine (histidine) at aa 70) were significantly higher than those in HCV‐1b of Arg70 (arginine at aa 70) and HCV‐2a/2b. The cumulative survival rates for liver‐related death in HCV‐1b of Gln70(His70) were significantly lower than those in HCV‐1b of Arg70 and HCV‐2a/2b. Multivariate analysis identified gender (male), age (≥60 years), albumin (<3.9 g/dL), platelet count (<15.0 × 104/mm3), aspartate aminotransferase (≥67 IU/L), and HCV subgroup (HCV‐1b of Gln70(His70)) as determinants of both hepatocarcinogenesis and survival rates for liver‐related death. In HCV‐1b patients, the cumulative change rates from Arg70 to Gln70(His70) by direct sequencing were significantly higher than those from Gln70(His70) to Arg70. In patients of Arg70 at the initial visit, the cumulative change rates from Arg70 to Gln70(His70) in IL28B rs8099917 non‐TT genotype were significantly higher than those in the TT genotype. Conclusion: Substitution of aa 70 in the core region of HCV‐1b is an important predictor of hepatocarcinogenesis and survival for liver‐related death in HCV patients who had not received antiviral therapy. The IL28B genotype might partly affect changes over time of dominant amino acid in core aa 70 of HCV‐1b. (HEPATOLOGY 2012;56:2134–2141)

Highly sensitive AFP-L3% assay is useful for predicting recurrence of hepatocellular carcinoma after curative treatment pre- and postoperatively

Aim:  The micro‐total analysis system (µTAS), a fully automated immunoassay system using microchip capillary electrophoresis, is highly sensitive and able to quickly assay the AFP‐L3%. The clinical usefulness of this system was studied.

Emergence of telaprevir-resistant variants detected by ultra-deep sequencing after triple therapy in patients infected with HCV genotype 1

Using ultra‐deep sequencing technology, the present was designed to investigate whether the emergence of telaprevir‐resistant variants (amino acid substitutions of aa36, aa54, aa155, aa156, and aa170 positions in HCV NS3 region) after commencement of triple therapy of telaprevir/peginterferon (PEG‐IFN)/ribavirin could be predicted at baseline in previous non‐responders to dual therapy. Fourteen patients infected with HCV genotype 1 who did not respond to previous PEG‐IFN/ribavirin, received a 24‐week regimen of triple therapy, and were evaluated for appearance of telaprevir‐resistant variants (amino acid substitutions of more than 0.2% among the total coverage) by ultra‐deep sequencing. The sustained virological response rate was 28.6% (4 of 14 patients), which was significantly higher in patients with Arg70 (substitution at core aa70) and partial response (type of previous response to PEG‐IFN/ribavirin) than in other patients. Telaprevir‐resistant variants at baseline were detected in 7.1% (1 of 14 patients) by direct sequencing and in 21.4% (3 of 14 patients) by ultra‐deep sequencing. The appearance of telaprevir‐resistant variants was examined by ultra‐deep sequencing in 10 who did not show sustained virological responders. De novo variants emerged at re‐elevation of viral load, regardless of variant frequencies at baseline (one patient with very high frequency variants [T54S: 99.9%], two patients with very low frequency variants [V36A: 0.2%; and V170A: 0.4%], and seven patients of undetectable variants). It is concluded that it is difficult to predict at baseline the emergence of telaprevir‐resistant variants after commencement of triple therapy in prior non‐responders of HCV genotype 1, even with the use of ultra‐deep sequencing. J. Med. Virol. 85: 1028–1036, 2013.

Heterogeneous Type 4 Enhancement of Hepatocellular Carcinoma on Dynamic CT Is Associated With Tumor Recurrence After Radiofrequency Ablation

OBJECTIVE The aim of this study was to predict recurrence of hepatocellular carcinoma (HCC) from baseline dynamic CT images. MATERIALS AND METHODS This retrospective study included 191 consecutive patients who underwent surgical resection or radiofrequency ablation (RFA) between January 2005 and September 2009 for the treatment of HCC. Enhancement on pretreatment arterial and portal phase dynamic CT images was classified into one of the four following enhancement patterns: Types 1 and 2 are homogeneous enhancement patterns without or with increased arterial blood flow, respectively; type 3 is a heterogeneous enhancement pattern with septations; and type 4 is an irregularly shaped ring structure enhancement pattern. Predictive factors for tumor recurrence including dynamic CT enhancement pattern were also evaluated. Moreover, risk factors including recurrence type (i.e., tumor number ≥ 10, portal vein invasion, or both) were evaluated in RFA-treated cases. RESULTS Among 60 patients who underwent surgical resection, no statistical association was observed between dynamic CT enhancement patterns and recurrence rate. In contrast, in the 131 patients who underwent RFA, cumulative recurrence rates for each enhancement pattern were significantly different: Recurrence rates 2 years after RFA for patients with type 1, 2, 3, and 4 were 26.6%, 46.9%, 38.6%, and 77.8%, respectively (p = 0.042). Recurrence, which was defined as the presence of 10 or more nodules, portal vein invasion, or both occurred in nine of 131 patients (6.9%) in the RFA group. A multivariate Cox proportional hazards analysis revealed that the type 4 dynamic CT enhancement pattern is an independent factor for HCC recurrence (hazard ratio, 27.68; 95% CI, 6.82-112.33; p < 0.001). CONCLUSION The pretreatment type 4 dynamic CT enhancement pattern can potentially be used to predict recurrence of HCC after RFA treatment.

Lower levels of insulin‐like growth factor‐1 standard deviation score are associated with histological severity of non‐alcoholic fatty liver disease

Growth hormone (GH) deficiency may be associated with histological progression of non‐alcoholic fatty liver disease (NAFLD) which includes non‐alcoholic fatty liver (NAFL) and non‐alcoholic steatohepatitis (NASH). Insulin‐like growth factor 1 (IGF‐1) is mainly produced by hepatocytes and its secretion is stimulated by GH. Our aim was to determine whether more histologically advanced NAFLD is associated with low circulating levels of IGF‐1 in Japanese patients.

Blockade of interleukin 6 signalling ameliorates systemic insulin resistance through upregulation of glucose uptake in skeletal muscle and improves hepatic steatosis in high‐fat diet fed mice

Mice fed high‐fat diet (HFD) demonstrate obesity‐related systemic insulin resistance (IR). Aim of this study is to clarify the role of interleukin (IL)‐6 in IR in vivo focusing on skeletal muscle, adipose tissue and liver.

Exploratory study on telaprevir given every 8 h at 500 mg or 750 mg with peginterferon‐alpha‐2b and ribavirin in hepatitis C patients

The aims of this study are to assess the antiviral effects, safety and telaprevir (TVR) pharmacokinetics in two cohorts given TVR every 8 h (q8h) at doses of 500 mg and 750 mg with peginterferon‐α‐2b and ribavirin in chronic hepatitis C patients.