Yasuji Arase

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)

Association of Amino Acid Substitution Pattern in Core Protein of Hepatitis C Virus Genotype 1b High Viral Load and Non-Virological Response to Interferon-Ribavirin Combination Therapy

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 (≥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.

Amino acid substitution in hepatitis C virus core region and genetic variation near the interleukin 28B gene predict viral response to telaprevir with peginterferon and ribavirin.

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)

Sustained virological response reduces incidence of onset of type 2 diabetes in chronic hepatitis C

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). 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. (HEPATOLOGY 2009.)

Effect of repeated transcatheter arterial embolization on the survival time in patients with hepatocellular carcinoma. An analysis by the cox proportional hazard model

One hundred fifty‐eight patients with hepatocellular carcinoma (HCC) were treated by transcatheter arterial embolization (TAE) as repeatedly as possible. Survival rates at the end of the first, second, and third year were 76.5%, 54.5%, and 41.1%, respectively. In 142 patients with repeated TAE, a significantly increased number of patients with complete necrosis of tumor was observed after repetition of the therapy. Adjusting the imbalance in prognostic factors among patients by using Cox proportional hazard model, it proved that the best response during the repeated therapy, rather than the first response, was significantly associated with survival period of the patients. Aside from the factor of response to the treatment, tumor size was the worst prognostic factor at the time when diagnosis was made. Other significant factors were portal vein invasion by HCC and bilirubin. The survival period of patients with HCC treated by repeated TAE was, therefore, affected by cancer factors, liver cirrhosis factors, and therapy‐responsiveness factors. It is concluded that even if complete necrosis of tumor is not obtained after the first trial, repetition of TAE is an effective measure for prolonging of survival time in patients with HCC. 68:2150‐2154, 1991.

Genotypic subtyping of hepatitis C virus

Four subtypes of hepatitis C virus (HCV), Pt(I), K1(II), K2a(III) and K2b(IV), have been suggested based on the nucleotide sequences of the non‐structural (NS) 5 region. A fifth subtype from Japanese patients, Tr(V), which shows a less than 68% homology in nucleotide sequence when compared with other subtypes has been identified. A one‐step method which enables a quick determination of subtype using polymerase chain reaction with a mixed primer set deduced from the sequence of each subtype has been developed. Using this technique, the subtypes of 418 out of 478 Japanese patients (87.4%) were determined. The incidence of each subtype in Japan was as follows: K1(II), 307 (73.4%); K2a(III), 74 (17.7%); K2b(IV), 28 (6.7%); and Tr(V), 3 (0.7%). This one‐step subtyping technique should be useful for studying the epidemiology or biology of the HCV.

Interferon decreases hepatocellular carcinogenesis in patients with cirrhosis caused by the hepatitis B virus

To elucidate the influence of long term interferon administration on the rate of occurrence of hepatocellular carcinoma (HCC) in patients with hepatitis B virus (HBV)‐related cirrhosis, the authors analyzed 313 consecutive patients with cirrhosis.

HbA1c 5·7–6·4% and impaired fasting plasma glucose for diagnosis of prediabetes and risk of progression to diabetes in Japan (TOPICS 3): a longitudinal cohort study

BACKGROUND The clinical relevance of the diagnostic criteria for prediabetes to prediction of progression to diabetes has been little studied. We aimed to compare the prevalence of prediabetes when assessed by the new glycated haemoglobin A(1c) (HbA(1c)) 5·7-6·4% criterion or by impaired fasting glucose, and assessed differences in progression rate to diabetes between these two criteria for prediabetes in a Japanese population. METHODS Our longitudinal cohort study included 4670 men and 1571 women aged 24-82 years without diabetes at baseline (diabetes was defined as fasting plasma glucose ≥7·0 mmol/L, self-reported clinician-diagnosed diabetes, or HbA(1c) ≥6·5%) who attended Toranomon Hospital (Tokyo, Japan) for a routine health check between 1997 and 2003. Participants with a baseline diagnosis of prediabetes according to impaired fasting glucose (fasting plasma glucose 5·6-6·9 mmol/L) or HbA(1c) 5·7-6·4%, or both, were divided into four groups on the basis of baseline diagnosis of prediabetes. Rate of progression to diabetes was assessed annually. FINDINGS Mean follow-up was 4·7 (SD 0·7) years. 412 (7%) of 6241 participants were diagnosed with prediabetes on the basis of the HbA(1c) 5·7-6·4% criterion. Screening by HbA(1c) alone missed 1270 (61%) of the 2092 prediabetic individuals diagnosed by a combination of impaired fasting glucose and HbA(1c) 5·7-6·4%. Overall cumulative probability of progression to diabetes did not differ significantly between participants with prediabetes discordantly diagnosed by either HbA(1c) or impaired fasting glucose alone (incidence was 7% for HbA(1c) alone [n=412 individuals and 30 incident cases] and 9% for impaired fasting glucose alone [n=1270, 108 cases]; log-rank test, p=0·3317). Multivariate-adjusted hazard ratios for incident diabetes were 6·16 (95% CI 4·33-8·77) for those diagnosed with prediabetes by impaired fasting glucose alone and 6·00 (3·76-9·56) for diagnosis by HbA(1c) alone, and were substantially increased to 31·9 (22·6-45·0) for diagnosis by both impaired fasting glucose and HbA(1c) compared with normoglycaemic individuals. INTERPRETATION Diagnosis of prediabetes by both the new HbA(1c) criterion and impaired fasting glucose identified individuals with an increased risk of progression to diabetes. Although the new HbA(1c) criterion identified fewer individuals at high risk than did impaired fasting glucose, the predictive value for progression to diabetes assessed by HbA(1c) 5·7-6·4% was similar to that assessed by impaired fasting glucose alone. The two tests used together could efficiently target people who are most likely to develop diabetes and allow for early intervention. FUNDING Japan Society for the Promotion of Science; Ministry of Health Labor and Welfare, Japan.

Histological changes in liver biopsies after one year of lamivudine treatment in patients with chronic hepatitis B infection.

BACKGROUND/AIMS The aim of this study was to examine the histological changes in liver biopsies induced by 52 weeks of lamivudine therapy in patients with e-antigen positive and e-antigen negative chronic hepatitis B infection. METHODS Twenty patients were enrolled into this open-label study. All patients had a liver biopsy within the 4 weeks before starting lamivudine therapy. Lamivudine was given orally at a dose of 100 mg OD for 52 weeks. A second liver biopsy was taken for comparison at the end of week 52. Blinded biopsies were evaluated by a histopathologist and scored according to Knodells histology activity index (HAI). RESULTS Ninety-five percent (19/20) patients had a reduction of their hepatic necroinflammatory HAI score (components 1 through 3) by > or =2 points at the end of 52 weeks of lamivudine therapy compared to their pretreatment values. Not only were improvements in necroinflammatory activity observed, but 7/20 (35%) of patients had improvement in fibrosis. This histologic improvement was independent of the presence or absence of e-antigen. CONCLUSIONS Significant improvements in liver histology can be obtained in the majority of patients when they are treated with lamivudine for 1 year.

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.