Hiroshi Yatsuhashi

Anti‐gp210 and anti‐centromere antibodies are different risk factors for the progression of primary biliary cirrhosis

The predictive role of antinuclear antibodies (ANAs) remains elusive in the long‐term outcome of primary biliary cirrhosis (PBC). The progression of PBC was evaluated in association with ANAs using stepwise Cox proportional hazard regression and an unconditional stepwise logistic regression model based on the data of 276 biopsy‐proven, definite PBC patients who have been registered to the National Hospital Organization Study Group for Liver Disease in Japan (NHOSLJ). When death of hepatic failure/liver transplantation (LT) was defined as an end‐point, positive anti‐gp210 antibodies (Hazard ratio (HR) = 6.742, 95% confidence interval (CI): 2.408, 18.877), the late stage (Scheuers stage 3, 4) (HR = 4.285, 95% CI:1.682,10.913) and male sex (HR = 3.266, 95% CI: 1.321,8.075) were significant risk factors at the time of initial liver biopsy. When clinical progression to death of hepatic failure/LT (i.e., hepatic failure type progression) or to the development of esophageal varices or hepatocellular carcinoma without developing jaundice (Total bilirubin < 1.5 mg/dL) (i.e., portal hypertension type progression) was defined as an end‐point in the early stage (Scheuers stage 1, 2) PBC patients, positive anti‐gp210 antibodies was a significant risk factor for hepatic failure type progression [odds ratio (OR) = 33.777, 95% CI: 5.930, 636.745], whereas positive anti‐centromere antibodies was a significant risk factor for portal hypertension type progression (OR = 4.202, 95% CI: 1.307, 14.763). Histologically, positive anti‐gp210 antibodies was most significantly associated with more severe interface hepatitis and lobular inflammation, whereas positive anticentromere antibodies was most significantly associated with more severe ductular reaction. Conclusion: These results indicate 2 different progression types in PBC, hepatic failure type and portal hypertension type progression, which may be represented by positive‐anti‐gp210 and positive‐anticentromere antibodies, respectively. (HEPATOLOGY 2007;45:118–127.)

Ledipasvir and sofosbuvir fixed-dose combination with and without ribavirin for 12 weeks in treatment-naive and previously treated Japanese patients with genotype 1 hepatitis C: an open-label, randomised, phase 3 trial

BACKGROUND Compared with other countries, patients with chronic hepatitis C infection in Japan tend to be older, have more advanced liver disease, and are more likely to have been previously treated for hepatitis C. We aimed to assess the efficacy and safety of an all-oral, fixed-dose combination of the hepatitis C virus NS5A inhibitor ledipasvir and the NS5B nucleotide polymerase inhibitor sofosbuvir with and without ribavirin for 12 weeks in treatment-naive and previously treated Japanese patients with chronic genotype 1 hepatitis C virus infection. METHODS In this randomised, open-label study, we enrolled patients from 19 clinical Japanese centres. Patients were randomly assigned (1:1) to receive either ledipasvir (90 mg) and sofosbuvir (400 mg) or ledipasvir, sofosbuvir, and ribavirin (dosed according to the Japanese Copegus product label-ie, patients ≤60 kg received 600 mg daily, patients >60 kg to ≤80 kg received 800 mg daily, and patients >80 kg received 1000 mg daily) orally once daily for 12 weeks. After completion or early discontinuation of treatment, patients were followed up off-treatment for 24 weeks. Eligible patients were at least 20 years of age with chronic genotype 1 hepatitis C virus infection with serum hepatitis C virus RNA concentrations of at least 5 log10 IU/mL, creatinine clearance of at least 1·0 mL/s, and a platelet count of at least 50 × 10(9) per L. An interactive web response system was used to manage patient randomisation and treatment assignment. Randomisation was stratified by the presence or absence of cirrhosis for treatment-naive patients and stratified by presence or absence of cirrhosis and by previous treatment category (relapser or breakthrough, non-responder, or interferon-intolerant) for previously treated patients. Within each strata, patients were sequentially assigned to either treatment with ledipasvir-sofosbuvir or ledipasvir-sofosbuvir plus ribavirin in a 1:1 ratio with block size of 4. The primary endpoint was sustained virological response 12 weeks after completion of treatment (SVR12) assessed in all patients who were randomly assigned and received at least one dose of study drug; safety outcomes were assessed in all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT01975675. FINDINGS Between Oct 15, 2013 and Dec 13, 2013, 341 patients were randomly assigned to treatment groups and received at least one dose of study treatment. SVR12 was achieved in all 171 (100%) patients (83 of 83 treatment naive and 88 of 88 treatment experienced) receiving ledipasvir-sofosbuvir (95% CI 98-100) and 167 (98%) of 170 patients (80 of 83 treatment naive and 87 of 87 treatment experienced) receiving ledipasvir-sofosbuvir plus ribavirin (95% CI 95-100). Of the 76 patients with baseline NS5A resistant variants, 75 (99%) achieved SVR12. Two (1·2%) of 170 patients in the ledipasvir-sofosbuvir plus ribavirin group discontinued treatment because of adverse events. The most common adverse events were nasopharyngitis (50 [29·2%] of 171), headache (12 [7·0%] of 171), and malaise (nine [5·3%] of 171) in patients receiving ledipasvir-sofosbuvir; and nasopharyngitis (40 [23·5%] of 170), anaemia (23 [13·5%] of 170), and headache in those receiving ledipasvir-sofosbuvir and ribavirin (15 [8·8%] of 170). INTERPRETATION Although existing regimens for the treatment of hepatitis C virus are effective for many patients, medical needs remain unmet, particularly in Japan where the population with hepatitis C virus genotype 1 is generally older and treatment-experienced, with advanced liver disease. The efficacy, tolerability, and absence of drug-drug interactions of ledipasvir-sofosbuvir suggest that it could be an important option for treatment of genotype 1 hepatitis C virus in Japanese patients. FUNDING Gilead Sciences.

Influence of genotypes and precore mutations on fulminant or chronic outcome of acute hepatitis B virus infection.

The outcome of acute hepatitis B virus (HBV) infection is variable, influenced by host and viral factors. From 1982 through 2004, 301 patients with acute HBV infection entered a multi‐center cross‐sectional study in Japan. Patients with fulminant hepatitis (n = 40) were older (44.7 ± 16.3 vs. 36.0 ± 14.3 years, P < .0017), less predominantly male (43% vs. 71%, P = .0005), less positive for hepatitis B e antigen (HBeAg) (23% vs. 60%, P < .0001), less infected with subgenotype Ae (0% vs. 13%, P < .05), and more frequently with Bj (30% vs. 4%, P < .0001) than those with acute self‐limited hepatitis (n = 261). Precore (G1896A) and core‐promoter (A1762T/G1764A) mutations were more frequent in patients with fulminant than acute self‐limited hepatitis (53% vs. 9% and 50% vs. 17%, P < .0001 for both). HBV infection persisted in only three (1%) patients, and they represented 2 of the 23 infected with Ae and 1 of the 187 with the other subgenotypes (9% vs. 0.5%, P = .032); none of them received antiviral therapy. In multivariate analysis, age 34 years or older, Bj, HBeAg‐negative, total bilirubin 10.0 mg/dL or greater, and G1896A mutation were independently associated with the fulminant outcome. In in vitro transfection experiments, the replication of Bj clone was markedly enhanced by introducing either G1896A or A1762T/G1764A mutation. In conclusion, persistence of HBV was rare (1%) and associated with Ae, whereas fulminant hepatitis was frequent (13%) and associated with Bj and lack of HBeAg as well as high replication due to precore mutation in patients with acute HBV infection. (HEPATOLOGY 2006;44:326–334.)

Serum cytokine and soluble cytokine receptor levels in patients with non-alcoholic steatohepatitis

Abstract: Background: Although the pathogenesis of non‐alcoholic steatohepatitis (NASH) remains poorly understood, proinflammatory cytokines seem to play an important role in the process of NASH. We have undertaken this study in order to elucidate the role of proinflammatory cytokines and their soluble receptors in NASH patients.

Influence of interleukin-10 gene promoter polymorphisms on disease progression in patients chronically infected with hepatitis B virus

OBJECTIVES:The role of host genetic factors in chronic hepatitis B virus (HBV) infection is not fully understood. We studied the influence of tumor necrosis factor-α (TNF-α) and interleukin-10 (IL-10) gene promoter polymorphisms on disease progression in HBV carriers.METHODS:The sample population included 213 Japanese HBV carriers and 52 healthy volunteers. Of 213 HBV carriers, 66 were considered to be asymptomatic carriers based on the sustained normalization of serum ALT together with seropositivity for the antibody to hepatitis B e antigen (anti-HBe), and 147 were found to have chronic progressive liver disease including cirrhosis. Five biallelic polymorphisms in the TNF-α gene promoter and three biallelic polymorphisms in the IL-10 gene promoter were analyzed by polymerase chain reaction in combination with direct sequencing or restriction fragment length polymorphism assay.RESULTS:Allelic distributions of both gene promoters were not significantly different between HBV carriers and healthy volunteers. In HBV carriers, the TNF-α gene promoter polymorphisms were not linked to disease progression. In contrast, allelic frequencies of T and A at positions −819 and −592, respectively, in the IL-10 gene promoter, as well as the frequencies of ATA haplotype at positions −1082/− 819/− 592 (which is characterized with low capacity for IL-10 production), were significantly higher in asymptomatic carriers than in patients with chronic progressive liver disease. Even after adjusting for individuals positive for anti-HBe, such a relationship could be found between the two groups.CONCLUSION:In chronic HBV infection, inheritance of the IL-10 gene promoter polymorphisms is involved in a host genetic factor that is relevant to disease progression.

Simeprevir with peginterferon/ribavirin for treatment-naïve hepatitis C genotype 1 patients in Japan: CONCERTO-1, a phase III trial

BACKGROUND & AIMS In a Japanese Phase II study, the hepatitis C virus NS3/4A protease inhibitor simeprevir demonstrated potent antiviral activity and significantly improved sustained virologic response rates when added to peginterferon α-2a/ribavirin in treatment-naïve patients infected with hepatitis C virus genotype 1. METHODS CONCERTO-1 was a Phase III, randomized, double-blind, placebo-controlled trial. Treatment-naïve adults (⩽ 70 years) with chronic hepatitis C virus genotype 1 infection (hepatitis C virus RNA ⩾ 5 log10 IU/ml) were randomized (2:1) to simeprevir 100mg once-daily with peginterferon α-2a/ribavirin for 12 weeks then response-guided therapy with peginterferon α-2a/ribavirin for 12 or 36 weeks, or to placebo with peginterferon α-2a/ribavirin for 12 weeks then peginterferon α-2a/ribavirin for 36 weeks. RESULTS Overall, 183 patients were treated. Sustained virologic response 12 weeks after treatment end (primary efficacy endpoint) was achieved in 88.6% of simeprevir- and 61.7% of placebo-treated patients (p<0.0001 for stratum-adjusted between-group difference). Overall, 91.9% of simeprevir-treated patients met response-guided therapy criteria and completed treatment at week 24; sustained virologic response rate at 12 weeks in these patients was 92.0%. One simeprevir- (0.8%) and two placebo-treated patients (3.3%) experienced viral breakthrough; respective viral relapse rates were 7.6% and 30.6%. Overall adverse event profile in simeprevir-treated patients was comparable to that in patients who received peginterferon α-2a/ribavirin alone. CONCLUSIONS Simeprevir once daily with peginterferon α-2a/ribavirin significantly improved sustained virologic response rate 12 weeks after treatment end in treatment-naïve patients with chronic hepatitis C virus genotype 1 infection, with a shorter 24-week treatment duration in most patients.

Prospective analysis of risk factors for early intrahepatic recurrence of hepatocellular carcinoma following ethanol injection

BACKGROUND/AIM Time-dependent intrahepatic recurrence of hepatocellular carcinoma is frequent after different treatment modalities, including percutaneous ethanol injection. We attempted to prospectively analyze the possible risk factors for early intrahepatic recurrence of hepatocellular carcinoma after percutaneous ethanol injection. METHODS Sixty-five patients with 65 solitary hepatocellular carcinoma nodules < or =6 cm in diameter underwent initial treatment with percutaneous ethanol injection and were examined to ascertain the factors related to recurrence, local and distant, within the liver. A number of clinical and tumor parameters were analyzed. RESULTS Cumulative overall recurrence rates 12 and 24 months after percutaneous ethanol injection were 15.6% and 45.1%, respectively, irrespective of clinical and tumor parameters. Overall recurrence rates 12 and 24 months after percutaneous ethanol injection were 40% and 67.5%, for tumor > or =3 cm and 7.5% and 37.5%, for tumor <3 cm. Cumulative local recurrence rates at 12 and 24 months were 26.3% and 43.5%, respectively, for tumor > or =3 cm and 11.7% and 18.2%, respectively, for tumor <3 cm. The log-rank test indicated that a tumor size of > or =3 cm and the presence of capsule for a tumor of <3 cm in diameter were significant risk factors for intrahepatic recurrence. A pretreatment serum PIVKA-II level of > or =0.02 AU/ml was the only clinical parameter associated with overall recurrence (p=0.0041) and distant intrahepatic recurrence (p=0.0307). Distant intrahepatic recurrence rates 12 and 24 months after percutaneous ethanol injection were 22.5% and 31.4%, respectively, for PIVKA-II levels of > or =0.02 AU/ml and 8% and 17.8%, for PIVKA-II of <0.02 AU/ml. Coxs proportional hazard model identified that tumor size, tumor capsule and baseline serum PIVKA-II levels were independently related to intrahepatic recurrence. CONCLUSIONS These data demonstrate that tumor size and peritumoral capsule were associated with overall and local recurrence of hepatocellular carcinoma. Moreover, pretreatment serum levels of PIVKA-II can indicate the risk of early intrahepatic recurrence and may assist in patient selection and appropriate therapy.

Sofosbuvir plus ribavirin in Japanese patients with chronic genotype 2 HCV infection: an open‐label, phase 3 trial

Genotype 2 hepatitis C virus (HCV) accounts for up to 30% of chronic HCV infections in Japan. The standard of care for patients with genotype 2 HCV – peginterferon and ribavirin for 24 weeks – is poorly tolerated, especially among older patients and those with advanced liver disease. We conducted a phase 3, open‐label study to assess the efficacy and safety of an all‐oral combination of the NS5B polymerase inhibitor sofosbuvir and ribavirin in patients with chronic genotype 2 HCV infection in Japan. We enrolled 90 treatment‐naïve and 63 previously treated patients at 20 sites in Japan. All patients received sofosbuvir 400 mg plus ribavirin (weight‐based dosing) for 12 weeks. The primary endpoint was sustained virologic response at 12 weeks after therapy (SVR12). Of the 153 patients enrolled and treated, 60% had HCV genotype 2a, 11% had cirrhosis, and 22% were over the aged 65 or older. Overall, 148 patients (97%) achieved SVR12. Of the 90 treatment‐naïve patients, 88 (98%) achieved SVR12, and of the 63 previously treated patients, 60 (95%) achieved SVR12. The rate of SVR12 was 94% in patients with cirrhosis and in those aged 65 and older. No patients discontinued study treatment due to adverse events. The most common adverse events were nasopharyngitis, anaemia and headache. Twelve weeks of sofosbuvir and ribavirin resulted in high rates of SVR12 in treatment‐naïve and previously treated patients with chronic genotype 2 HCV infection. The treatment was safe and well tolerated by patients, including the elderly and those with cirrhosis.

Elevated serum levels of Wisteria floribunda agglutinin-positive human Mac-2 binding protein predict the development of hepatocellular carcinoma in hepatitis C patients

The Wisteria floribunda agglutinin‐positive human Mac‐2‐binding protein (WFA+‐M2BP) was recently shown to be a liver fibrosis glycobiomarker with a unique fibrosis‐related glycoalteration. We evaluated the ability of WFA+‐M2BP to predict the development of hepatocellular carcinoma (HCC) in patients who were infected with the hepatitis C virus (HCV). A total of 707 patients who had been admitted to our hospital with chronic HCV infection without other potential risk factors were evaluated to determine the ability of WFA+‐M2BP to predict the development of HCC; factors evaluated included age, sex, viral load, genotypes, fibrosis stage, aspartate and alanine aminotransferase levels, bilirubin, albumin, platelet count, alpha‐fetoprotein (AFP), WFA+‐M2BP, and the response to interferon (IFN) therapy. Serum WFA+‐M2BP levels were significantly increased according to the progression of liver fibrosis stage (P < 0.001). In each distinctive stage of fibrosis (F0‐F1, F2, F3, and F4), the risk of development of HCC was increased according to the elevation of WFA+‐M2BP. Multivariate analysis identified age >57 years, F4, AFP >20 ng/mL, WFA+‐M2BP ≥4, and WFA+‐M2BP 1‐4 as well as the response to IFN (no therapy vs. sustained virological response) as independent risk factors for the development of HCC. The time‐dependent areas under the receiver operating characteristic curve demonstrated that the WFA+‐M2BP assay predicted the development of HCC with higher diagnostic accuracy than AFP. Conclusion: WFA+‐M2BP can be applied as a useful surrogate marker for the risk of HCC development, in addition to liver biopsy. (Hepatology 2014;60:1563–1570)

Risk factors for development of hepatocellular carcinoma in patients with chronic hepatitis C after sustained response to interferon.

BackgroundInterferon (IFN) is expected to prevent the progression of hepatitis C virus infection to cirrhosis and the development of hepatocellular carcinoma (HCC), but there have been several reports of the development of HCC after a sustained response to IFN. Our aim was to elucidate the incidence and clinical features of, and risk factors for, HCC in sustained responders to IFN, taken for the treatment of chronic hepatitis C.MethodsWe designed a retrospective cohort study conducted at 16 major Hospitals. The subjects were a total of 1056 patients showing sustained responses, 29 of whom developed HCC.ResultsThe incidence of HCC per 100 person-years was 0.56 (95% confidence interval, 0.35–0.76) in sustained responders. By the Cox proportional hazard model, we found that older age, higher serum aspartate aminotransferase level, and lower platelet count before IFN therapy were independent risk factors associated with the development of HCC. A risk index of HCC development, based on the coefficients of these risk factors, was used to classify patients into three groups, with low, intermediate, and high risk. The incidence rates of HCC for these three groups were 0.11, 0.44, and 1.98 per 100 person-years, respectively. The median period to the development of HCC was 4.6 years (range, 1.4–9.0 years), and there were no other specific clinical features of the HCC that developed in these patients.ConclusionsThis study suggests that the risk of development of HCC is not completely eliminated in sustained responders to IFN. These findings may be useful in determining a follow-up strategy after a sustained response to IFN.