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A woman in her late 70 s was diagnosed with liver injury at a health examination. Despite treatment with ursodeoxycholic acid at a nearby hospital, her transaminase levels elevated in two peaks. She was transferred to our hospital 77 days after the health examination. She weighed 42 kg and had a low body mass index of 19.8 kg/m

Hepatitis E virus (HEV) causes acute or chronic hepatitis in humans. Pigs are the primary reservoir for zoonotic HEV genotypes 3 and 4 worldwide. This study investigated the infection dynamics and genomic mutations of HEV in domestic pigs on a farrow-to-finish pig farm in Japan between 2012 and 2021. A high prevalence of anti-HEV IgG antibodies was noted among pigs on this farm in 2012, when the survey started, and persisted for at least nine years. During 2012–2021, HEV RNA was detected in both serum and fecal samples, indicating active viral replication. Environmental samples, including slurry samples in manure pits, feces on the floor, floor and wall swabs in pens, and dust samples, also tested positive for HEV RNA, suggesting potential sources of infection within the farm environment. Indeed, pigs raised in HEV-contaminated houses had a higher rate of HEV infection than those in an HEV-free house. All 104 HEV strains belonged to subgenotype 3b, showing a gradual decrease in nucleotide identities over time. The 2012 (swEJM1201802S) and 2021 (swEJM2100729F) HEV strains shared 97.9% sequence identity over the entire genome. Importantly, the swEJM2100729F strain efficiently propagated in human hepatoma cells, demonstrating its infectivity. These findings contribute to our understanding of the prevalence, transmission dynamics, and genetic characteristics of HEV in domestic pigs, emphasizing the potential risks associated with HEV infections and are crucial for developing effective strategies to mitigate the risk of HEV infection in both animals and humans.

Objective One of the therapeutic goals for chronic infection with hepatitis B virus is the clearance of hepatitis B surface antigen (HBsAg) from the blood, as a high load of HBsAg has been proposed to induce antigen-specific immunotolerance. To achieve HBsAg reduction, Pegylated interferon and nucleos (t) ide analogs are used to treat chronic hepatitis B. Following the coronavirus disease 2019 (COVID-19) outbreak, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has rapidly spread worldwide, and vaccination with mRNA COVID-19 vaccines has been conducted since 2021 in Japan. We experienced three clinical cases in which HBsAg levels rapidly decreased after injection of the COVID-19 vaccine without any incentive. Method To examine whether the vaccine administration was involved in the HBsAg reduction, the number of patients with chronic hepatitis B showing a change in the HBsAg levels during the period before the commencement of the COVID-19 vaccination program in Japan (i.e. until the end of 2020; pre-vaccination-program period) was compared to the number of those who showed a change in HBsAg levels after the initiation of the program (i.e. 2021 onwards; post-vaccination-program period). Results The number of patients whose HBsAg levels was reduced by50% per year was prominent after the initiation of the vaccination program. Although the involvement of vaccination in HBsAg reduction was not statistically proven (p=0.0532), the result suggests that the administration of COVID-19 vaccines may have been involved in HBsAg reduction in patients with chronic hepatitis B. Conclusion COVID-19 vaccines may be involved in HBsAg reduction.

ObjectiveThis study aimed to evaluate the safety and tolerability of OP-724, a CREB-binding protein/β-catenin inhibitor, in patients with advanced primary biliary cholangitis (PBC).DesignAn open-label, non-randomised, phase 1 trial was conducted at two hospitals in Japan. Patients with advanced PBC classified as stage III or higher according to the Scheuer classification by liver biopsy between 4 September 2019 and 21 September 2021 were enrolled. Seven patients received intravenous OP-724 infusions at escalating dosages of 280 and 380 mg/m2/4 hours two times weekly for 12 weeks. The primary endpoint was the incidence of serious adverse events (SAEs). The secondary endpoints were the incidence of AEs and the improvement in the modified Histological Activity Index (mHAI) score.ResultsSeven patients (median age, 68 years) were enrolled. Of these seven patients, five completed twelve cycles of treatment, one discontinued prematurely for personal reasons in the 280 mg/m2/4 hours cohort, and one in the 380 mg/m2/4 hours cohort was withdrawn from the study due to drug-induced liver injury (grade 2). Consequently, the recommended dosage was determined to be 280 mg/m2/4 hours. SAEs did not occur. The most common AEs were abdominal discomfort (29%) and abnormal hepatic function (43%). OP-724 treatment was associated with histological improvements in the fibrosis stage (2/5 (40%)) and mHAI score (3/5 (60%)) on histological analysis.ConclusionAdministration of intravenous OP-724 infusion at a dosage of 280 mg/m2/4 hours two times weekly for 12 weeks was well tolerated by patients with advanced PBC. However, further evaluation of antifibrotic effects in patients with PBC is warranted.Trial registration numberNCT04047160.

Background Vonoprazan has been more widely used for artificial ulcers after endoscopic submucosal dissection (ESD) for early gastric cancer; however, no reports have examined intragastric pH during ESD. The present study aimed to measure gastric pH at the time of ESD and the clinical course afterwards for patients treated with vonoprazan the night before undergoing ESD. Materials and methods We examined medication status regarding gastric acid secretion and antithrombotic drugs, post-ESD bleeding as a perioperative complication, and the timing of upper gastrointestinal endoscopy after ESD and ulcer healing in 156 patients who underwent gastric ESD at our hospital from January 2014 to December 2019. The gastric pH was measured at the time of ESD after administration of 20 mg vonoprazan on the night before gastric ESD. Results There were 14 cases of post-ESD bleeding in patients treated with proton-pump inhibitors (PPIs), including oozing during second-look endoscopy compared to only 1 case of bleeding with vonoprazan administration (p, Highlights • Post-ESD bleeding was reduced vonoprazan treated in patient. • Gastric pH at ESD was high after vonoprazan treatment on the night before ESD. • Post-ESD ulcer healing was improved vonoprazan treated in patient.

Cronkhite-Canada syndrome (CCS) is a rare disease characterized by diffuse gastrointestinal polyposis with chronic diarrhea and ectodermal change, but its etiology is unknown. We present a case at the age of 26 years complaining of epigastralgia and weight loss. Endoscopic examination revealed extensive diffuse polypoid lesions of the stomach and the terminal ileum, all of which showed hyperplastic polyps pathologically. There were no polypoid lesions in his colon. He has no family history of diffuse gastrointestinal polyposis. Diffuse gastrointestinal hyperplastic polyposis without any hereditary association led us to suspect this case as CCS although he did not show chronic diarrhea and any ectodermal symptoms such as onychodystrophy, alopecia, and hyperpigmentation. After initiation of a corticosteroid therapy, his epigastralgia disappeared and he gained appetite and weight, accompanied by normalization of serum albumin levels. Endoscopic examination 1 year after initiation of corticosteroid therapy revealed a decrease in the number of gastric polyposis and those inflammations. This rare young case may suggest that early therapeutic intervention with corticosteroids could improve the prognosis of CCS, preventing not only malnutrition but also appearance of several ectodermal symptoms.

Background and aims Current treatment with nucleos(t)ide analogs (NUCs) safely controls the replication of hepatitis B virus (HBV) and improves prognosis in patients with HBV. However, the inability to completely clear HBV is problematic, and novel therapies are desired. It has been believed that all NUCs have similar functions to inhibit HBV reverse transcriptase. However, our recent findings that only acyclic nucleoside phosphonates (ANPs; adefovir dipivoxil and tenofovir disoproxil fumarate) had an additional effect of inducing interferon (IFN)-λ3 in the gastrointestinal tract suggests that ANPs are not only distinct from nucleoside analogs (lamivudine and entecavir) in their structures but also in their functions. Because enteric lipopolysaccharide (LPS) can cross the intestine and affect peripheral blood mononuclear cells (PBMCs), we hypothesized that orally administered ANPs could have further additional effects to modulate LPS-mediated cytokine profile in PBMCs. Approach and results This study showed that pretreatment of PBMCs, from either healthy volunteers or patients with HBV, with ANPs inhibited LPS-mediated interleukin (IL)-10 production, which reciprocally induced IL-12p70 and tumor necrosis factor-α production in a dose-dependent manner. Furthermore, the combination of IFN-α and ANPs synergistically enhanced LPS-mediated IL-12p70 production in PBMCs. Mechanistic analyses revealed that cellular metabolites of ANPs directly bound the Akt protein, inhibiting its translocation to the plasma membrane, thereby impairing Akt phosphorylation. Therefore, pretreatment of PBMCs with ANPs impairs LPS-mediated IL-10 production. Conclusions Among NUCs, only ANPs have an additional pharmacological effect modulating LPS-mediated cytokine production, which is expected to produce favorable immune responses toward HBV elimination. This additional immunomodulation by ANPs in PBMCs, as well as IFN-λ3 induction in the gastrointestinal tract, provides insights into HBV treatment.

Hepatitis E virus (HEV) is a quasi-enveloped virus with a single-stranded positive-sense RNA genome belonging to the family Hepeviridae. Studies of the molecular aspects of HEV and drug screening have benefited from the discovery of bioluminescent reporter genes. However, the stability of large foreign genes is difficult to maintain after insertion into the viral genome. Currently, ribavirin is used to treat HEV-infected patients who require antiviral therapy. This has several major drawbacks. Thus, the development of novel anti-HEV drugs is of great importance. We developed a system consisting of recombinant infectious HEV harboring a small luciferase gene (nanoKAZ) in the hypervariable region (HVR) of the open reading frame 1 (ORF1) (HEV-nanoKAZ). It replicated efficiently in cultured cells, was genetically stable, and had morphological characteristics similar to those of the parental virus. Both membrane-associated (eHEV-nanoKAZ) and membrane-unassociated (neHEV-nanoKAZ) particles were infectious. HEV particles circulating in the bloodstream and attaching to hepatocytes in HEV-infected patients are membrane-associated; thus, eHEV-nanoKAZ was applied in drug screening. The eHEV-nanoKAZ system covers at least the inhibitor of HEV entry and inhibitor of HEV RNA replication. Four drugs with anti-HEV activity were identified. Their effectiveness in cultured cells was confirmed in naive and HEV-producing PLC/PRF/5 cells. Two hit drugs (azithromycin and ritonavir) strongly inhibited HEV production in culture supernatants, as well as intracellular expression of ORF2 protein, and may therefore be candidate novel anti-HEV drugs. The HEV-nanoKAZ system was developed and applied in drug screening and is expected to be useful for investigating the HEV life cycle. IMPORTANCE Bioluminescent reporter viruses are essential tools in molecular virological research. They have been widely used to investigate viral life cycles and in the development of antiviral drugs. For drug screening, the use of a bioluminescent reporter virus helps shorten the time required to perform the assay. A system, consisting of recombinant infectious HEV harboring the nanoKAZ gene in the HVR of ORF1 (HEV-nanoKAZ), was developed in this study and was successfully applied to drug screening in which four hit drugs with anti-HEV activity were identified. The results of this study provide evidence supporting the use of this system in more variable HEV studies. In addition, both forms of viral particles (eHEV-nanoKAZ and neHEV-nanoKAZ) are infectious, which will enable their application in HEV studies requiring both forms of viral particles, such as in the investigation of unknown HEV receptors and the elucidation of host factors important for HEV entry.

Benefits of nucleos(t)ide analogs (NAs) on hepatitis B surface antigen (HBsAg) reduction and interferon-lambda3 (IFN-λ3) induction are still not known. This study aimed to investigate the effects of NAs on HBsAg reduction and association with serum IFN-λ3 levels in chronic hepatitis B (CHB) patients.A total of 91 patients [51 treated with nucleoside analog entecavir hydrate (ETV) and 40 treated with nucleotide analog adefovir dipivoxil (ADV) or tenofovir disoproxil fumarate (TDF)] with clinically evident CHB (chronic hepatitis, 57; liver cirrhosis, 34) were enrolled in this study. Serum IFN-λ3 levels among patients receiving ETV and ADV/TDF were measured before the initiation of therapy and 1, 3, and 5 years post-therapy.The change (mean ± standard deviation) in serum HBsAg levels from baseline to year five was -0.38 ± 0.46 and -0.84 ± 0.64 logNucleotide analog (ADV/TDF) treatment reduced HBsAg levels greater compared with nucleoside analog (ETV) in parallel with IFN-λ3 induction.

A case of subclinical hepatitis E virus (HEV) infection was detected by nucleic acid amplification test on blood donation. The patient was followed-up until day 220 after the blood donation but showed no symptoms throughout the observation period. Aspartate aminotransferase and alanine aminotransferase levels reached the maximum values on day 37 with a slight increase but remained in normal ranges from day 67 to 220. The quantity of HEV RNA at the initial examination on day 13 was 1.1 × 10

Rat hepatitis E virus (HEV-C1) in the Orthohepevirus C species has been reported to cause zoonotic infection and hepatitis in humans. HEV-C1 strains have been detected from wild rats in many countries in Europe, Asia, and North America. However, in Japan, no HEV-C1 strains have been identified. In the present study, 5 (1.2%) of 428 wild rats (Rattus norvegicus or R. rattus) were positive for anti-HEV-C1 IgG. Although all 428 rat sera were negative for HEV-C1 RNA, it was detectable in 20 (19.8%) of 101 rat fecal samples collected on a swine farm, where HEV (genotype 3b, HEV-3b) was prevalent and wild rats were present. In addition, HEV-C1 RNA was detectable in the intestinal contents and liver tissues of 7 (18.9%) of 37 additional rats captured on the same farm. The HEV-C1 strain (ratEJM1703495L) obtained in this study shared only 75.8-84.7% identity with reported HEV-C1 strains over the entire genome but propagated efficiently in cultured cells. HEV-3b strains were detected in the rats' intestinal contents, with 97.3-99.5% identity to those in pigs on the same farm, but were undetectable in rat liver tissues, suggesting that wild rats do not support the replication of HEV-3b of swine origin.

A 66-year-old man, who had undergone plasma exchange 30 years previously in Egypt for the treatment of falciparum malaria, was referred to our hospital for treatment of chronic hepatitis C (HCV). An analysis of the 655-nucleotide 5'-untranslated region-core region sequence revealed infection with HCV subtype 1g. A phylogenetic analysis of the full-length HCV genome confirmed that the patient's HCV was subtype 1g, which was the first case identified in Japan. Although his HCV possessed several naturally occurring resistance-associated substitutions in the nonstructural (NS) 3 and NS5A regions, he was successfully treated by combination therapy with glecaprevir/pibrentasvir.

Hepatitis E virus (HEV) is a zoonotic agent mainly transmitted through the consumption of uncooked or undercooked meat products derived from infected animals. In Japan, domestic pigs and wild boars are the major animal reservoirs, and whether or not deer are an HEV reservoir remains controversial. We analyzed 395 serum and 199 liver samples from 405 sika deer (Cervus nippon) caught in the wild between 1997 and 2020 in 11 prefectures of Japan for markers of HEV infection. Overall, 17 deer had anti-HEV IgG (4.3%), while 1 (0.2%) had HEV RNA (genotype 3b), indicating the occurrence of ongoing HEV infection in wild deer in Japan. An analysis of the complete HEV genome (deJOI_14) recovered from a viremic deer in Oita Prefecture revealed only 88.8% identity with the first HEV strain in sika deer (JDEER-Hyo03L) in Japan, being closest (96.3%) to the HEV obtained from a hepatitis patient living in the same prefecture. Of note, the deJOI_14 strain was 8.7-9.0% different from the wild boar HEV strains obtained in the same habitat and the same year, suggesting that difference in infected HEV strains between boar and deer may be explained by the limited possibility of close contact with each other, although boars are a known source of HEV infection. Increased numbers of hepatitis E cases after consumption of raw or undercooked meat products of wild deer have been reported in Japan. These results suggest a low but nonnegligible zoonotic risk of HEV infection in wild deer in this country.

A 76-year-old woman with spontaneous reactivation of hepatitis B virus (HBV) without any immunosuppressants who had been successfully treated with tenofovir alafenamide fumarate (TAF) was reported. The patient was admitted to our hospital because of acute exacerbation of the liver function and jaundice. She had been found to have chronic HBV infection with a normal liver function and had been treated for lifestyle-related diseases, such as diabetes mellitus, dyslipidemia and hypertension, for over 10 years at a local clinic. At admission, her serum HBV DNA was high (7.3 log IU/mL), and anti-hepatitis B core protein immunoglobulin M was slightly elevated (1.47 S/CO). Due to the absence of known risk factors for HBV reactivation, the reactivation was regarded as "spontaneous". After the initiation of the nucleotide analog TAF, her liver function gradually improved with a decrease in the HBV DNA load. Her HBV genome was typed as subgenotype B1 and possessed a frameshift mutation due to an insertion of T after nucleotide (nt) 1817 and G to A mutations at nt 1896 and nt 1899 (G1896A/G1899A) in the precore region as well as serine to glutamine substitution of amino acid 21 in the core protein. In addition to these viral mutations, aging and complications of lifestyle-related diseases in the present case may have been responsible for the spontaneous HBV reactivation. Careful observation and management of aged HBV carriers with underlying diseases are needed even when persistent HBV infection is free from symptoms and liver dysfunction and no immunosuppressive conditions are involved.

We report a novel pegivirus in pet cats (Felis silvestris catus) in Japan. This virus was only 44.0–49.6 % identical to the reported viruses in the 11 current Pegivirus species and an unclassified pegivirus in dolphins within the entire protein-coding nucleotide sequence and was detected in 1.6 % of pet cats.

The entire genome sequences of two pegivirus strains recovered from serum samples of wild rats (Rattus rattus) in Indonesia were determined. They possessed 11,013 to 11,014 nucleotides and differed from the reported rodent pegivirus strains within the Pegivirus J species of the genus Pegivirus by 12.7% to 40.9% in the near-entire coding region sequences.

Hepatitis E virus (HEV) infects humans and a wide variety of other mammalian hosts. Recently, HEV strains belonging to genotype 8 (G8) within the Orthohepevirus A species of the Hepeviridae family, were identified in Bactrian camels (Camelus bactrianus) in China. The Bactrian camel (also known as the Mongolian camel) is native to the steppes of Central Asia. However, the HEV strains of Mongolian camels have not been examined. Among 200 serum samples from domestic Bactrian camels raised on 6 farms, in 6 soums in 3 provinces; 71 (35.5 %) were positive for anti-HEV IgG, with prevalence differing by farm (soum) (4.2−75.0 %); and 2 camels (1.0 %) that had been raised in Bogd, Bayankhongor Province, which had the highest seroprevalence among the six studied areas, were positive for HEV RNA. The two HEV strains (BcHEV-MNG140 and BcHEV-MNG146) obtained from the viremic camels in the present study shared 97.7 % nucleotide identity. They were closest to the reported G8 Chinese camel HEV strains but differed from them by 13.9−14.3 % over the entire genome, with a nucleotide difference of 24.0−26.5 % from the reported G1−G7 HEV strains. A phylogenetic tree indicated that the BcHEV-MNG140 and BcHEV-MNG146 strains were located upstream of a clade consisting of the Chinese camel HEV strains and formed a cluster with them, with a bootstrap value of 100 %, suggesting that they may represent a novel subtype within G8. These results indicate a high prevalence of HEV infection in Mongolian camels and suggest that the variability of camel HEV genomes is markedly high.

A married couple who developed hepatitis was referred to our hospital. The husband was diagnosed with acute hepatitis C virus (HCV) infection based on HCV RNA positivity and seroconversion to HCV antibody. The wife was also diagnosed with HCV-related hepatitis; however, she could not be confirmed to have acute hepatitis due to the lack of information on her HCV negativity just before this event. The HCV strains recovered from the couple were genotype 2b and shared 100% identities within the 5’-untranslated region-core region sequence (655 nucleotides/nt) and non-structural (NS)5B region sequence (502 nt). The amplified hypervariable region 1 (HVR-1) sequence indicated that all 10 clones from the wife shared 100% identity and were identical to 3 of 10 heterogeneous clones (separable into 4 groups) from the husband. The husband had a history of intravenous drug use. These results suggested that one of four quasispecies 2b HCV strains was transmitted from the husband to the wife, with the husband being the infectious source for acute HCV infection in the wife, most likely via sexual intercourse. A sequence analysis of the HCV genomes and the further comparison of the HVR-1 amino acid sequence variability may be useful for defining the infectious source of HCV, especially in couples or cluster cases.

[BACKGROUND & AIMS] Primary biliary cholangitis (PBC) is a chronic liver disease in which autoimmune destruction of the small intra-hepatic bile ducts eventually leads to cirrhosis. Many patients have inadequate response to licensed medications, motivating the search for novel therapies. Previous genome-wide association studies (GWAS) and meta-analyses (GWMA) of PBC have identified numerous risk loci for this condition, providing insight into its aetiology. We undertook the largest GWMA of PBC to date, aiming to identify additional risk loci and prioritise candidate genes for in silico drug efficacy screening. [METHODS] We combined new and existing genotype data for 10, 516 cases and 20, 772 controls from five European and two East Asian cohorts. [RESULTS] We identified 56 genome-wide significant loci (20 novel) including 46 in European, 13 in Asian, and 41 in combined cohorts; and a 57th genome-wide significant locus (also novel) in conditional analysis of the European cohorts. Candidate genes at newly identified loci include FCRL3, INAVA, PRDM1, IRF7, CCR6, CD226, and IL12RB1, each having key roles in immunity. Pathway analysis reiterated the likely importance of pattern recognition receptor and TNF signalling, Jak-STAT signalling, and differentiation of TH1 and TH17 cells in the pathogenesis of this disease. Drug efficacy screening identified several medications predicted to be therapeutic in PBC, some well-established in the treatment of other autoimmune disorders. [CONCLUSIONS] This study has identified additional risk loci for PBC, provided a hierarchy of agents that could be trialled in this condition, and emphasised the value of genetic and genomic approaches to drug discovery in complex disorders. [Lay summary] Primary biliary cholangitis (PBC) is a chronic liver disease that eventually leads to cirrhosis. In this study, we analysed genetic information from 10, 516 people with PBC and 20, 772 healthy individuals recruited in Canada, China, Italy, Japan, UK, or USA. We identified several genetic regions associated with PBC. Each of these regions contains several genes. For each region, we used diverse sources of evidence to help us choose the gene most likely to be involved in causing PBC. We used these ‘candidate genes’ to help us identify medications that are currently used for treatment of other conditions, which might also be useful for treatment of PBC., 原発性胆汁性胆管炎のゲノムワイド関連解析 --国際メタ解析による新規疾患感受性遺伝子と治療薬候補の同定--. 京都大学プレスリリース. 2021-06-28.

A preliminary metagenomic analysis of the virome of wild sika deer (Cervus nippon) blood in Japan resulted in the identification of a novel parvovirus. The virus was closest, but only 44.7-60.7% identical to 17 reported strains belonging to the genus Copiparvovirus within the subfamily Parvovirinae, over the near-entire genomic sequence. The sika deer copiparvovirus DNA was detected in 15% (31/206) of sika deer captured in 7 prefectures of Japan, and a region-dependent prevalence of 0-66.7% was noted, with a biased distribution in the southern part of Japan. The observed biased distribution of sika deer copiparvovirus may be due to the habitat density of deer and the number of ticks, which might play a role in the transmission of the virus.

We have performed a genome-wide association study (GWAS) including 473 Japanese HBV (hepatitis B virus)-positive HCC (hepatocellular carcinoma) patients and 516 HBV carriers including chronic hepatitis and asymptomatic carrier individuals to identify new host genetic factors associated with HBV-derived HCC in Japanese and other East Asian populations. We identified 65 SNPs with P values −4 located within the HLA class I region and three SNPs were genotyped in three independent population-based replication sets. Meta-analysis confirmed the association of the three SNPs (rs2523961: OR = 1.73, P = 7.50 × 10−12; rs1110446: OR = 1.79, P = 1.66 × 10−13; and rs3094137: OR = 1.73, P = 7.09 × 10−9). We then performed two-field HLA genotype imputation for six HLA loci using genotyping data to investigate the association between HLA alleles and HCC. HLA allele association testing revealed that HLA-A * 33:03 (OR = 1.97, P = 4.58 × 10−4) was significantly associated with disease progression to HCC. Conditioning analysis of each of the three SNPs on the HLA class I region abolished the association of HLA-A*33:03 with disease progression to HCC. However, conditioning the HLA allele could not eliminate the association of the three SNPs, suggesting that additional genetic factors may exist in the HLA class I region.

Approximately 5-10% of individuals who are vaccinated with a hepatitis B (HB) vaccine designed based on the hepatitis B virus (HBV) genotype C fail to acquire protective levels of antibodies. Here, host genetic factors behind low immune response to this HB vaccine were investigated by a genome-wide association study (GWAS) and Human Leukocyte Antigen (HLA) association tests. The GWAS and HLA association tests were carried out using a total of 1,193 Japanese individuals including 107 low responders, 351 intermediate responders, and 735 high responders. Classical HLA class II alleles were statistically imputed using the genome-wide SNP typing data. The GWAS identified independent associations of HLA-DRB1-DQB1, HLA-DPB1 and BTNL2 genes with immune response to a HB vaccine designed based on the HBV genotype C. Five HLA-DRB1-DQB1 haplotypes and two DPB1 alleles showed significant associations with response to the HB vaccine in a comparison of three groups of 1,193 HB vaccinated individuals. When frequencies of DRB1-DQB1 haplotypes and DPB1 alleles were compared between low immune responders and HBV patients, significant associations were identified for three DRB1-DQB1 haplotypes, and no association was identified for any of the DPB1 alleles. In contrast, no association was identified for DRB1-DQB1 haplotypes and DPB1 alleles in a comparison between high immune responders and healthy individuals. Conclusion: The findings in this study clearly show the importance of HLA-DR-DQ (i.e., recognition of a vaccine related HB surface antigen (HBsAg) by specific DR-DQ haplotypes) and BTNL2 molecules (i.e., high immune response to HB vaccine) for response to a HB vaccine designed based on the HBV genotype C. (Hepatology 2018).

Eosinophilic esophagitis (EoE) is a chronic inflammatory disease associated with eosinophilic infiltration of the esophageal mucosa mostly due to exposure to allergens. However, the causes and pathogenesis of EoE are not fully understood. We encountered a case of EoE that was triggered by sublingual immunotherapy (SLIT) for cedar pollen allergy. A 40-year-old man who was treated with Japanese cedar pollen tablet SLIT for cedar pollen allergy developed heartburn 3 weeks after the initiation of the treatment. He took vonoprazan for the heartburn, but the heartburn did not improve. Then, esophagogastroduodenoscopy was performed; it revealed longitudinal furrows and white spots on the esophageal mucosa, decreased vascular permeability, and erosions. Consequently, the patient was diagnosed with EoE. Heartburn and chest discomfort disappeared 1 week after the discontinuation of Japanese cedar pollen tablet SLIT, and the patient tested positive for drug allergy to Japanese cedar pollen tablet SLIT. In this study, we found that if heartburn persists during SLIT for cedar pollen allergy, and does not improve on administration of vonoprazan or proton pump inhibitors, EoE should be suspected. In addition, the occurrence of EoE due to drug allergy is indicated.

Rat hepatitis E virus (HEV) has been isolated from wild rats worldwide and the potential of zoonotic transmission has been documented. Escherichia coli (E. coli) is utilized as an effective system for producing HEV-like particles. However, the production of rat HEV ORF2 proteins in E. coli forming virus-like particles (VLPs) has not yet been reported. In this study, nine rat HEV ORF2 proteins of the ratELOMB-131L strain with truncated N- and C-termini (amino acids 339-594, 349-594, 351-594, 354-594, 357-594, 357-599, 357-604, 357-609, and 357-614 of ORF2 protein) were expressed in E. coli and the 357-614 protein self-assembled most efficiently. A bioanalyzer showed that the purified 357-614 protein has a molecular weight of 33.5 kDa and a purity of 93.2%. Electron microscopy revealed that the purified 33.5 kDa protein formed VLPs with a diameter of 21-52 (average 32) nm, and immunoelectron microscopy using an anti-rat HEV ORF2 monoclonal antibody (TA7014) indicated that the observed VLPs were derived from rat HEV ORF2. The VLPs attached to and entered the PLC/PRF/5 cells and blocked the neutralization of rat HEV by TA7014, suggesting that the VLPs possess the antigenic structure of infectious rat HEV particles. In addition, rat HEV VLPs showed high immunogenicity in mice. The present results would be useful for future studies on the development of VLP-based vaccines for HEV prevention in a rat model and for the prevention of rat HEV infection in humans.

We previously reported that hepatocellular carcinoma (HCC) changes to a phenotype producing des-γ-carboxy prothrombin (DCP) during epithelial mesenchymal transition (EMT) in vitro. To confirm this change in vivo, we evaluated the association between DCP production and HCC hemodynamics in patients undergoing resection as EMT and hemodynamic changes are closely associated with each other. We evaluated HCC hemodynamics by employing Sonazoid-enhanced ultrasound (SEUS) before surgical resection, and sought associations with histological grade and immunohistochemical staining of DCP in 19 areas from 11 patients. In 10 HCC areas showing early washout (3 min ≥) using SEUS, three areas corresponded to poorly differentiated HCC and the remaining seven areas corresponded to moderately differentiated HCC, and positive DCP staining was observed in only two of the seven moderately differentiated HCC areas, whereas no staining was observed in poorly differentiated HCC areas. Six HCC areas showing intermediate washout (3–10 min) using SEUS were moderately differentiated, of which five demonstrated positive DCP staining (83.3%, 5/6). However, all HCC areas without enhancement in the arterial phase were well-differentiated and did not show DCP staining. Our preliminary findings suggest that HCC hemodynamics evaluated by SEUS are associated with histological grade and/or DCP production.

This prospective cohort study searched for factors associated with a response to nucleos(t)ide analogue/peg-interferon (NUC/peg-IFN) sequential therapy. A total of 95 patients with chronic hepatitis B being treated with NUCs were enrolled. Immediately following NUC cessation, peg-IFN was administered at 180 µg/dose weekly for 48 weeks. Twenty-six patients (27%) were judged to be responders at 48 weeks after the completion of peg-IFN. Analysis of baseline factors revealed that hepatitis B surface antigen (HBsAg)

Aim Interferon (IFN)-λ3 is known to have antiviral effects against various pathogens. Recently, it has been reported that the production of IFN-λ3 in colon cells after the administration of nucleotide analogs is expected to reduce hepatitis B surface antigen in chronic hepatitis B patients. Here, we aimed to prove the antiviral effects of IFN-λ3 on hepatitis B virus (HBV) by using an in vitro HBV production and infection system. Methods We used HepG2.2.15-derived HBV as an inoculum and the replication-competent molecular clone of HBV as a replication model. Results By administering IFN-λ3 to HepG2 cells transfected with the HBV molecular clone, the production of hepatitis B surface antigen and hepatitis B core-related antigen was reduced dose-dependently. IFN-λ3 treatment also reduced the number of HBV-positive cells and the synthesis of covalently closed circular DNA after infection of HepG2.2.15-derived HBV to sodium taurocholate cotransporting polypeptide-transduced HepG2 cells. The inhibitory effect on HBV infection by IFN-λ3 was confirmed by using a recombinant a HBV reporter virus system. To elucidate the underlying mechanisms of the anti-HBV effect of IFN-λ3, we assessed the transcription of HBV RNA and the production of core-associated HBV DNA in HBV molecular clone-transfected HepG2 cells, and found that both parameters were reduced by IFN-λ3. Conclusions We observed that the administration of IFN-λ3 inhibits HBV infection and the production of HBV proteins at the HBV RNA transcription level. This finding provides novel insight into the treatment of chronic hepatitis B patients with the administration or induction of IFN-λ3.

Article, Scientific reports.9 :102(2019)

Telaprevir (TVR) remarkably improves the efficacy of interferon treatment for chronic hepatitis C. Interleukin-28B (IL28B) genotype and interferon-gamma-inducible protein-10 (IP-10) level predict virologic response to peg-interferon (Peg-IFN)/ribavirin (RBV) therapy. We aimed to investigate the usefulness of pretreatment serum IP-10 levels and IL28B genotyping in predicting sustained virologic response (SVR) to TVR-based triple therapy.In this multi-center study, patients infected with hepatitis C virus genotype 1 with high viral load (⩾5.0logIU/mL) were treated with TVR for 12weeks and Peg-IFN/RBV for 24weeks in Japan. IL28B genotype, serum IP-10 levels, other clinical parameters, and drug dosages were assessed before treatment.We included 121 patients who were treated with TVR for at least 8weeks and Peg-IFN/RBV for 24weeks. The median IP-10 levels were significantly lower in rapid virologic response (RVR) or SVR in the IL28B non-TT genotype group, with no significant difference in the TT genotype group. RVR rates were significantly lower in the group with higher serum IP-10 levels (450pg/mL). In the non-TT IL28B genotype group, RVR and SVR rates were significantly lower in the group with higher IP-10 levels. SVR rates in the group with lower IP-10 levels (450pg/mL) increased to 82% for those showing RVR, but reduced to 27% in the group with higher IP-10 levels for those not showing RVR.Determination of serum IP-10 levels before treatment could be useful for predicting favorable virologic response to TVR-based triple therapy, especially in patients with IL28B non-TT genotype.

ObjectiveThe clinical significance of polymorphisms in the interleukin-28B gene encoding interferon (IFN)-λ3, which has antiviral effects, is known in chronic HCV but not in HBV infection. Thus, we measured IFN-λ3 levels in patients with HBV and investigated its clinical significance and association with nucleos(t)ide (NUC) analogue administration.DesignSerum IFN-λ3 level was measured in 254 patients with HBV with varying clinical conditions using our own high sensitivity method. The resulting values were compared with various clinical variables. In addition, cell lines originating from various organs were cultured with NUCs, and the production of IFN-λ3 was evaluated.ResultsHigher serum IFN-λ3 levels were detected in the patients treated with nucleotide analogues (adefovir or tenofovir) compared with those treated with nucleoside analogues (lamivudine or entecavir). There were no other differences in the clinical background between the two groups. A rise in the serum IFN-λ3 levels was observed during additional administration of the nucleotide analogues. In vitro experiments showed that the nucleotide analogues directly and dose-dependently induced IFN-λ3 production only in colon cancer cells. Furthermore, the supernatant from cultured adefovir-treated colon cancer cells significantly induced IFN-stimulated genes (ISGs) and inhibited hepatitis B surface antigen (HBsAg) production in hepatoma cells, as compared with the supernatant from entecavir-treated cells.ConclusionsWe discovered that the nucleotide analogues show an additional pharmacological effect by inducing IFN-λ3 production, which further induces ISGs and results in a reduction of HBsAg production. These findings provide novel insights for HBV treatment and suggest IFN-λ3 induction as a possible target.

AIM Few studies concerning the protective management of hepatitis B virus (HBV) infection among health-care personnel (HCP), excluding occult HBV or carriers, have been reported. Therefore, we undertook a cross-sectional study of the updated status of HBV vaccine management by measuring the antibody to hepatitis B surface antigen (anti-HBs) along with the antibody to hepatitis B core antigen (anti-HBc). METHODS Both anti-HBs and anti-HBc were assessed in 1085 HCP employed by our institute. Hepatitis B virus vaccination-related histories were recorded using self-administered questionnaires. RESULTS Of 1085 HCP, 27 (2.5%) were positive for anti-HBc, and its positive rate increased with age. Of the 1058 subjects with negative anti-HBc, 879 (83.1%) were positive for anti-HBs. The median titer of anti-HBs was 71.1 mIU/mL, which was higher in female subjects (P = 0.037). By age group, the positive rate of anti-HBs were 77.5%, 89.3%, 90.8%, and 81.6% in the groups aged ≤29, 30-39, 40-49, and ≥50 years, respectively (P