Takeji Umemura

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.

Immunoglobin G4-hepatopathy: Association of immunoglobin G4-bearing plasma cells in liver with autoimmune pancreatitis†

Autoimmune pancreatitis (AIP) is characterized by high serum immunoglobin (Ig) G4 concentrations, lymphoplasmacytic inflammation, and a favorable response to corticosteroid treatment. Since liver dysfunction is frequently seen in AIP patients, we investigated hepatic histopathology and its clinical significance in patients with AIP. We examined the clinical features, histology, and immunoglobin G (IgG)4‐bearing plasma cell infiltration of liver biopsies from 17 patients with AIP and 63 patients with either autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, or chronic viral hepatitis and histological changes in the 7 of 17 livers before and after glucocorticoid therapy. The liver histology of AIP was classified into 5 patterns: evident portal inflammation with or without interface hepatitis (6 cases), large bile‐duct obstructive features (8 cases), portal sclerosis (8 cases), lobular hepatitis (5 cases), and canalicular cholestasis (4 cases); some of the histological features coexisted in the same liver. The number of IgG4‐bearing plasma cells was significantly higher in AIP patients than controls (P < 0.01), and was significantly correlated with serum IgG4 concentration (P = 0.0014, r = 0.709). Glucocorticoid therapy reduced IgG4‐bearing plasma cell infiltration in the liver (P = 0.031) and ameliorated other histological findings. In conclusion, virtually all AIP liver biopsies showed evidence of various pathological changes and infiltration of IgG4‐bearing plasma cells. These features were ameliorated by steroid therapy, suggesting that the liver is concurrently affected in AIP, and that liver biopsies can provide significant information in the clinical evaluation and diagnosis of AIP. (HEPATOLOGY 2007.)

Genomic and Molecular Evolutionary Analysis of a Newly Identified Infectious Agent (SEN Virus) and Its Relationship to the TT Virus Family

A new group of transmissible single-stranded (ss) DNA viruses (SENV) distantly related to the large TT virus (TTV) family was recently identified. Eight different SENV isolates have been found, some with an association with posttransfusion hepatitis. A phylogenetic analysis of near-complete open-reading frame 1, including conserved motifs and excluding recombinant regions, was performed. The analysis used TTV-like minivirus as an outgroup, to determine a root of the phylogenetic tree, and compared 8 SENV isolates, 6 prototype TTV isolates, and 7 TTV variants (including SANBAN, TUS01, PMV, and YONBAN). Four distinct clusters separated by a bootstrap value of 100% were observed. YONBAN isolates formed a distinct outer group, representing the earliest recognized phylogenetic divergence (group 1). Prototype TTV formed group 2, PMV formed group 3, and SENV, SANBAN, and TUS01 isolates formed group 4, the most recently evolved group. This taxonomic classification suggests that these circular ssDNA viruses probably evolved from a common ancestor virus.

Pretreatment prediction of virological response to peginterferon plus ribavirin therapy in chronic hepatitis C patients using viral and host factors

The interferon sensitivity determining region (ISDR) of the hepatitis C virus (HCV) and T‐helper type 1 and type 2 (Th1/Th2) ratio were analyzed along with other host and viral factors for their ability to predict the response of patients with chronic hepatitis C to pegylated interferon alpha‐2b (Peg‐IFN) and ribavirin (RBV) combination therapy. A total of 120 chronic hepatitis C patients with genotype 1 HCV and high baseline viral loads who were to undergo combination therapy scheduled for 48 weeks were enrolled. Sustained virologic response (SVR) was achieved in 54 (45%) of the 120 patients. The pretreatment factors significantly associated with SVR by logistic regression analysis were ISDR mutant [odds ratio (OR) = 86.0, P = 0.0008], Th1/Th2 ratio ≤ 15.5 (OR = 9.6, P = 0.0021), body weight 59 kg, and neutrophil count 2,300/μL. A logistic regression model to estimate SVR before combination therapy was constructed using these four factors. Patients fell into three groups when plotted according to estimated and actual SVR rates: actual SVR rate was 91% (32/35) in the high sensitivity group, 41% (15/37) in the intermediate sensitivity group, and 15% (7/48) in the low sensitivity group. Rapid or early virological responses were seen in 80% of patients with high sensitivity and who achieved SVR but were found in only 40% of patients with intermediate or low sensitivity. Null‐ and very late virological responses were quite rare in the high sensitivity group. In conclusion, a logistic regression model that includes the sequence of ISDR of the HCV, Th1/Th2 ratio, body weight, and neutrophil count can be useful for accurately predicting actual SVR rate before combination therapy. (HEPATOLOGY 2008;48:1753‐1760.)

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.

Association of autoimmune pancreatitis with cytotoxic T-lymphocyte antigen 4 gene polymorphisms in Japanese patients.

OBJECTIVES:Autoimmune pancreatitis (AIP) is characterized by high serum IgG4 concentrations, lymphoplasmacytic inflammation, and a favorable response to corticosteroid treatment. Although the HLA DRB1*0405-DQB1*0401 haplotype and Fc receptor-like 3 polymorphisms have been associated with AIP, the role of other genetic factors is largely unknown. As cytotoxic T-lymphocyte antigen 4 (CTLA4) polymorphisms have recently been linked with several autoimmune diseases, we sought to determine if CTLA4 polymorphisms and serum sCTLA4 levels were associated with AIP as well.METHODS:Five CTLA4 polymorphisms, located at −1722, −658, and −318 in the promoter, +49 in exon 1, and +6230 in the 3′ untranslated region, were genotyped in 59 patients with AIP and 102 healthy subjects. Serum sCTLA4 levels were also determined in cohorts of 52 patients and 32 controls.RESULTS:Compared with healthy subjects, we found a significant increase in the +6230 G/G genotype (64% vs 42%, odds ratio [OR] 2.48, P = 0.011) in AIP patients. Haplotype 2, which had the +6230A, was associated with AIP resistance (OR 0.49, P = 0.011). The +49A/A and +6230A/A genotypes were associated with an enhanced risk of relapse (OR 5.45, P = 0.038 and OR 12.66, P = 0.022). Additionally, median serum sCTLA4 levels were significantly higher in patients with AIP (8.9 ng/mL) compared with healthy subjects (2.9 ng/mL, P < 0.001). The +6230 G/A polymorphism did not influence sCTLA4 levels in AIP patients.CONCLUSIONS:Our findings suggest that AIP is associated with a genetic polymorphism in CTLA4 and is positively correlated with serum sCTLA4 levels.

Mortality secondary to fulminant hepatic failure in patients with prior resolution of hepatitis B virus infection in Japan

Hepatitis B virus (HBV) reactivation in patients with resolved HBV infection was found in 23 (4%) of 552 newly hepatitis B surface antigen-positive patients in Japan. Because one-fourth of cases develop into fulminant hepatic failure and mortality is 100%, management of HBV reactivation in patients with resolved HBV infection should be discussed.

Genetic association of Fc receptor-like 3 polymorphisms with autoimmune pancreatitis in Japanese patients

Autoimmune pancreatitis is characterised by irregular narrowing of the main pancreatic duct, swelling of the pancreas, histological evidence of lymphoplasmacytic inflammation, and high serum immunoglobulin G4 (IgG4) concentration.1–4 Although the human leucocyte antigen DRB1\*0405-DQB1\*0401 haplotype has been associated with autoimmune pancreatitis,5 the role of genetic factors has not yet been fully defined. A new family of genes called Fc receptor-like genes ( FCRL s), which have high structural homology with classical Fcγ receptor genes, has recently been identified.6,7 FCRL3 polymorphisms have been shown to be associated with various autoimmune diseases, such as rheumatoid arthritis, autoimmune thyroid disease, and systemic lupus erythematosus, in Japanese populations.8,9 These polymorphisms alter the binding affinity of nuclear factor κB and regulate FCRL3 expression. FCRL3 expression on B cells has been observed in significant amounts and …

IgG4 associated autoimmune hepatitis: a differential diagnosis for classical autoimmune hepatitis

Autoimmune pancreatitis is characterised by raised serum levels of IgG4 and IgG4-bearing plasma cells in the inflammatory tissue.1 Similar pathology can also occur in the larger bile ducts, resembling sclerosing cholangitis.2 We report a patient with hepatitis and chronic cholecystitis, raised IgG4 level, and IgG4-bearing plasma cells in the liver and gall bladder wall, but no evident pancreatic disease. In January 2003, a cholecystectomy was undertaken on a 54 year old woman for chronic cholecystitis. The extracted gall bladder showed lymphoplasmacytic infiltration and subserosal fibrosis. A liver biopsy was done because of abnormal liver function tests and showed severe lobular hepatitis with mild portal inflammation. Plasma cell infiltration was observed in the portal tracts and parenchyma, though fibrosis was not significant. IgG4 bearing plasma cell infiltration was found both in the liver and the gall bladder wall. After six months, liver function was still abnormal: aspartate …

Two critical genes (HLA-DRB1 and ABCF1)in the HLA region are associated with the susceptibility to autoimmune pancreatitis

We have previously reported that autoimmune pancreatitis (AIP) is a bioclinical entity characterized by high serum immunoglobulin G4 concentrations and association with the HLA-DRB1*0405-DQB1*0401 haplotype. However, the precise identity of gene(s) within this haplotype directly responsible for AIP pathogenesis is yet to be established. To dissect the genetic contribution of the incriminated haplotype, we have now performed an association analysis within the human leukocyte antigen (HLA) region using various types of polymorphic markers. Genomic DNAs from 43 AIP patients and 213 unrelated Japanese controls were used in this analysis. In each DNA sample, we established the genotype of 25 microsatellite markers distributed throughout the HLA region, that of single nucleotide polymorphism within the 5′-flanking regions of the TNFA and IkBLI (also known as NFKBIL1) as well as HLA class I and II genes. The HLA-linked susceptibility regions for AIP were localized to two segments: HLA-DRB1 (*0405; OR = 3.20, P = 0.00063, Pc = 0.0016) -DQB1 (*0401; OR = 3.29, P = 0.00046, Pc = 0.0069) in the HLA class II and C3-2-11microsatellite (allele 219; OR = 2.96, P = 0.0076, Pc = 0.099) in the HLA class I regions. Upon stratification analysis in search for a synergistic effect given the extensive linkage disequilibrium within the major histocompatibility complex, it was established that each segment contributed to disease pathogenesis. The two critical HLA regions for susceptibility to AIP are limited to the HLA-DRB1*0405-DQB1*0401 in the class II and the ABCF1 proximal to C3-2-11, telomeric of HLA-E, in the class I regions.