Showing papers by "Masashi Mizokami published in 2018"
TL;DR: It is 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.
Abstract: Objective The 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 Design Serum 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 Results Higher 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 Conclusions We 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
124 citations
TL;DR: Mac 2-Binding Protein Gylcan Isomer is shown to be a surrogate marker for assessing HSC activation and may reveal the roles of HSCs in extrahepatic fibrotic disease progression, which is important for predicting the efficacy of antiviral therapy and patient prognosis.
Abstract: Assessing liver fibrosis is important for predicting the efficacy of antiviral therapy and patient prognosis. Liver biopsy is the gold standard for diagnosing liver fibrosis, despite its invasiveness and problematic diagnostic accuracy. Although noninvasive techniques to assess liver fibrosis are becoming important, reliable serum surrogate markers are not available. A glycoproteomics study aimed at identifying such markers discovered Mac 2-Binding Protein Gylcan Isomer (M2BPGi), which is a reliable marker for assessing liver fibrosis in patients with viral hepatitis and other fibrotic liver diseases such as primary biliary cholangitis, biliary atresia, autoimmune hepatitis, and nonalcoholic fatty liver disease. M2BPGi predicts the development of hepatocellular carcinoma (HCC) in patients infected with hepatitis B and C as well as the prognosis of liver cirrhosis in those with HCC after therapy. The unique features of M2BPGi are as follows: (1) cut-off values differ for the same stages of fibrosis according to the cause of fibrosis; and (2) M2BPGi levels rapidly decrease after patients achieve a sustained antiviral response to hepatitis C virus. These observations cannot be explained if M2BPGi levels reflect the amount of fibrotic tissue. Hepatic stellate cells (HSCs) secrete M2BPGi, which may serve as a messenger between HSCs and Kupffer cells via Mac-2 (galectin 3) that is expressed in Kupffer cells during fibrosis progression. Here we show that M2BPGi is a surrogate marker for assessing HSC activation. These findings may reveal the roles of HSCs in extrahepatic fibrotic disease progression.
111 citations
TL;DR: Small macrocyclic peptide inhibitors of HBV entry that target the cell-surface receptor for HBV, sodium taurocholate cotransporting polypeptide (NTCP) exhibited no inhibition of NTCP-mediated bile acid uptake, making them appealing candidates for therapeutic development.
50 citations
01 Jan 2018
TL;DR: Quantitative fibrosis assessment reveals a nonlinear relationship between fibrosis stage and fiber amount, with a marked difference between stage 4 and stage 3 and much smaller differences among stages 0‐3, suggesting a heterogeneity in disease severity within NAFLD‐related cirrhosis.
Abstract: Accurate staging of liver fibrosis is crucial to guide therapeutic decisions for patients with nonalcoholic fatty liver disease (NAFLD). Digital image analysis has emerged as a promising tool for quantitative assessment of fibrosis in chronic liver diseases. We sought to determine the relationship of histologic fibrosis stage with fiber amounts quantified in liver biopsy specimens for the better understanding of NAFLD progression. We measured area ratios of collagen and elastin fibers in Elastica van Gieson-stained biopsy tissues from 289 patients with NAFLD from four hospitals using an automated computational method and examined their correlations with Brunt's fibrosis stage. As a secondary analysis, we performed multivariable logistic regression analysis to assess the associations of the combined area ratios of collagen and elastin with noninvasive fibrosis markers. The combined fiber area ratios correlated strongly with Brunt's stage (Spearman correlation coefficient, 0.78; P < 0.0001), but this relationship was nonlinear (P = 0.007) with striking differences between stage 4 (median area ratios, 12.3%) and stages 0-3 (2.1%, 2.8%, 4.3%, and 4.8%, respectively). Elastin accumulation was common in areas of thick bridging fibrosis and thickened venous walls but not in areas of perisinusoidal fibrosis. The highest tertile of the combined fiber area ratios was associated with the fibrosis-4 index and serum type IV collagen 7s domain (7s collagen) levels, whereas the upper two tertiles of the fiber amounts significantly associated with body mass index, aspartate aminotransferase, and 7s collagen in the multivariable analysis. Conclusion: Quantitative fibrosis assessment reveals a nonlinear relationship between fibrosis stage and fiber amount, with a marked difference between stage 4 and stage 3 and much smaller differences among stages 0-3, suggesting a heterogeneity in disease severity within NAFLD-related cirrhosis. (Hepatology Communications 2018;2:58-68).
42 citations
TL;DR: Sofosbuvir–velpatasvir plus ribavirin was highly effective and well tolerated in Japanese patients who previously failed a DAA-based regimen and the most common adverse events were upper respiratory tract viral infection, anemia, and headache.
Abstract: In Japan, there is a growing population of patients with chronic hepatitis C virus (HCV) infection who failed a direct-acting antiviral (DAA)-based regimen. In this Phase 3 study, we evaluated sofosbuvir–velpatasvir plus ribavirin in Japanese patients with genotype 1 or 2 HCV infection who previously received DAAs. Patients were randomized 1:1 to receive sofosbuvir–velpatasvir plus ribavirin for 12 or 24 weeks. Randomization was stratified by HCV genotype and presence of cirrhosis. The primary endpoint was sustained virologic response 12-week post-treatment (SVR12). Of 117 participants, 81% had HCV genotype 1 infection, 33% had cirrhosis, and 95% had NS5A resistance-associated substitutions (RAS) at baseline. Overall, SVR12 rates were 97% (58/60; 95% CI 88–100%) with 24 weeks of treatment and 82% (47/57; 95% CI 70–91%) with 12 weeks. For HCV genotype 1 and 2 infected patients, the SVR12 rates with 24 weeks of treatment were 98% and 92%, respectively. In both treatment groups, SVR12 rates in HCV genotype 1 patients were statistically superior to a historical control rate of 50% (p < 0.001). For patients with NS5A RASs at baseline, 85% (46/54) in the 12-week group and 96% (54/56) in the 24-week group achieved SVR12. The most common adverse events were upper respiratory tract viral infection, anemia, and headache. Three (2.6%) patients discontinued treatment because of adverse events. Sofosbuvir–velpatasvir plus ribavirin was highly effective and well tolerated in Japanese patients who previously failed a DAA-based regimen. Baseline NS5A RASs did not affect treatment outcomes.
37 citations
TL;DR: The findings in this study clearly show the importance of HLA‐DR‐DQ and BTNL2 molecules for response to a HB vaccine designed based on the HBV genotype C.
36 citations
University of Tokyo1, Kanazawa University2, Hokkaido University3, International University of Health and Welfare4, Kawasaki Medical School5, Shinshu University6, Okayama University7, Osaka City University8, Chiba University9, Yamaguchi University10, Kyoto Prefectural University of Medicine11, Saga University12, Saitama Medical University13, University of Hong Kong14, Chulalongkorn University15
TL;DR: A genome-wide association study including 473 Japanese HBV-positive HCC patients and 516 HBV carriers including chronic hepatitis and asymptomatic carrier individuals to identify new host genetic factors associated withHBV-derived HCC in Japanese and other East Asian populations finds that additional genetic factors may exist in the HLA class I region.
Abstract: 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 < 10-4 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.
32 citations
TL;DR: HBV reactivation was rare in HBsAg‐negative patients treated with DAA therapy, and hepatitis did not occur in HBV‐reactivated patients with a baseline HBV DNA level <2000 IU/mL before DAA Therapy.
Abstract: To determine the clinical characteristics of hepatitis B virus (HBV) reactivation in patients undergoing interferon-free antihepatitis C virus (HCV) therapy, we examined HBV DNA in 25 HBV co-infected patients and 765 patients with resolved HBV infection during and after treatment with direct-acting antiviral agents (DAAs). Among those with HCV genotype 1, asunaprevir plus daclatasvir was administered to 160 patients, sofosbuvir (SOF) plus ledipasvir to 438 patients and paritaprevir plus ombitasvir and ritonavir to 25 patients. In total, 167 patients with genotype 2 were treated with SOF plus ribavirin. Three patients with an HBV DNA level ≥2000 IU/mL were treated with entecavir before anti-HCV therapy, without reactivation of HBV. In 3 of 22 (12%) HBV surface antigen (HBsAg)-positive patients with an HBV DNA level <2000 IU/mL, the viral load increased during treatment. However, hepatitis flare did not occur in these patients. There was no significant difference in clinical history between patients with and without HBV reactivation. Among 765 patients with resolved HBV infection, HBV reactivation occurred in 1 (0.1%) patient after initial resolution, whose HBV DNA level spontaneously decreased after DAA therapy. We compared anti-HBs titres at baseline with those at post-DAA therapy in 123 patients without HBsAg. There was no significant difference in anti-HBs levels between the two points (P = .79). In conclusion, HBV reactivation was rare in HBsAg-negative patients treated with DAA therapy. Additionally, hepatitis did not occur in HBV-reactivated patients with a baseline HBV DNA level <2000 IU/mL before DAA therapy.
30 citations
TL;DR: HLA‐DQB1 was independently associated with HCC; HCV genotypes modified the effects of HLA‐dQB1 on the risk of HCC, andHaplotype analysis supported that DQB1*03:01 and DQB 1*06:02 are primarily protective and susceptible variants, respectively.
27 citations
TL;DR: Elevation of serum CXCL9, C XCL10, CX CL10,CXCL11, CxCL13, and IL-21 might be a hallmark of functional cure of AH or CH patients.
Abstract: Background The clearance of hepatitis B surface antigen (HBsAg) loss, defined as functional cure, is a clinical target in patients with chronic hepatitis B (CH). To understand the immune responses underlying functional cure, we evaluated cytokine and chemokine expression profiles from patients with resolving and nonresolving acute hepatitis B (AH). Methods We cross-sectionally evaluated 41 chemokines and cytokines at the peak of hepatitis in the sera from 41 self-limited AH patients who achieved HBsAg seroconversion, 8 AH patients who failed to clear HBsAg within 1 year after the diagnosis, 8 CH patients with hepatic flare, and 14 healthy volunteers. We longitudinally examined 41 chemokines and cytokines in the sera from 4 self-limited AH patients, 3 chimpanzees inoculated with hepatitis B virus (HBV), and 2 CH patients treated with nucleotide analogs and PEG-IFN-α, one resulting in functional cure. Results In AH patients and HBV-inoculated chimpanzees with HBsAg loss, CXCL9, CXCL10, CXCL11, CXCL13, and IL-21 were elevated at hepatitis with subsequent decline of HBsAg. Interestingly, IL-21 elevation was observed only in resolving AH patients but not in nonresolvers. CXCL13 and IL-21 elevation was not observed in CH patients who failed to attain HBsAg loss, even at hepatic flare. A concomitant increase of CXCL13 and IL-21 was significant in CH patients who attained HBsAg seroconversion with a sequential therapy. Conclusion Elevation of serum CXCL9, CXCL10, CXCL11, CXCL13, and IL-21 might be a hallmark of functional cure of AH or CH patients.
27 citations
TL;DR: An association between Alaska‐specific core mutations and HCC development in young Alaskan Native people infected with genotype F1b is identified; accumulation of these core mutations during the course of chronic infection with genotypes F1B would contribute to H CC development in AN people earlier in life.
TL;DR: Treatment of HCV GT1b with all‐oral direct‐acting anti‐virals in Japan can lead to significant direct and indirect savings related to avoidance of HCC and DCC.
Abstract: Hepatocellular carcinoma (HCC) is a serious complication of hepatitis C virus (HCV) infection. Sustained virologic response (SVR) for HCV is associated with a reduction in cirrhosis, HCC and mortality and their associated costs. Japanese HCV patients are older with higher prevalence of HCC. Here we used a decision-analytic Markov model to estimate the economic benefit of HCV cure by reducing HCC and DCC burden in Japan. A cohort of 10 000 HCV genotype 1b (GT1b) Japanese patients was modelled with a hybrid decision tree and Markov state-transition model capturing natural history of HCV over a lifetime horizon. Treatment options were approved all-oral direct-acting anti-virals (DAAs) vs no treatment. Treatment efficacy was based on clinical trials and transition rates and costs obtained from Japan-specific data. Cases of HCC, decompensated cirrhosis (DCC) and quality-adjusted life years (QALYs) were projected for patients treated with DAAs vs NT. QALYs were monetized using a willingness-to-pay threshold of ¥4-to-¥6 million. Incremental savings with treatment were calculated by adding the projected cost of complications avoided to the monetized gains in QALYs. The model showed that DAA treatment vs no treatment, reduces 2057 cases of HCC and 1478 cases of decompensated cirrhosis and saves ¥850 446.73 and ¥338 229.90 per patient (ppt). Additionally, treatment can lead to additional 2.64 QALYs gained per patient. The indirect economic gains associated with treatment-related QALY improvements were ¥10 576 000, ¥13 220 000 and ¥15 864 000 ppt (willingness-to-pay thresholds of ¥4 million, ¥5 million and ¥6 million). Total economic savings of treatment with DAAs (vs no treatment) was ¥7 526 372.63, ¥10 170 372.63 and ¥12 814 372.63, at these different willingness-to-pay thresholds. In conclusion treatment of HCV GT1b with all-oral DAAs in Japan can lead to significant direct and indirect savings related to avoidance of HCC and DCC.
TL;DR: The virological and clinical characteristics of HBV genotype A will be useful in elucidating the association among persistent viral infection, host genetic factors, and treatment in future studies.
Abstract: Hepatitis B virus (HBV) infection is one of the most prevalent chronic viral infections in humans. The overall prevalence of hepatitis B surface antigen (HBsAg) is reported to be 3.6%; however, it varies depending upon the geographic area. HBV is classified into ten genotypes (A through J) on the basis of an intergroup genomic divergence of > 8%. Specifically, HBV genotype A exhibits several unique virological and clinical characteristics and can be further classified into seven subtypes. Among them, subtype A2 or Ae (A2/[e]) is occasionally responsible for nosocomial infection and among homosexual males. Regarding virological factors, the G1896A precore mutation is rarely observed in genotype A as it would disrupt an essential stem-loop structure in the e signal essential for pregenomic RNA packaging. HBV genotype A also harbors a 6-nucleotide C-terminal insertion in the hepatitis B-e antigen (HBeAg) precursor, resulting in a variable-length HBeAg protein product observed in serum of positive patients. These molecular traits likely contribute to the specific clinical presentation of genotype A-infected patients, such as mild acute hepatitis B (AHB), longer persistence of HBsAg positivity in AHB, and increased chronicity after AHB in adults. However, genotype A shows a better response to interferon than other genotypes in chronic hepatitis B patients. Here, we review the virological and clinical characteristics of HBV genotype A that will be useful in elucidating the association among persistent viral infection, host genetic factors, and treatment in future studies.
TL;DR: There was no correlation between OBI and anti-HBV antibodies, but fewer patients with OBI had high inflammatory activity, suggesting that factors other than inflammation may be involved in HCC carcinogenesis in patients withOBI.
TL;DR: Prevalence of HCV subtypes and RAS in China were investigated and compared to other Asian counties, North America and Europe and differences in the prevalence of GT2 and GT3 sub types and NS5A RAS were observed.
TL;DR: A recombinant reporter HBV bearing the NanoLuc gene is constructed and this system mimics the early stage of the HBV life cycle faithfully, and a quantitative analysis of HBV infectivity to several human hepatocyte cell lines as well as the effect of dimethyl sulfoxide and HBV protein X on the earlyStage HBV proliferation using this system.
Abstract: Chronic infection with Hepatitis B virus (HBV) increases the risk of developing fibrosis, cirrhosis, or hepatocellular carcinoma. Current therapies are limited to type-I interferons and/or nucleos(t)ide analogues; however, these are only partially effective. The development of novel anti-HBV agents for new treatment strategies has been hampered by the lack of a suitable system that allows the in vitro replication of HBV. Studies of virus infection/replication at the molecular level using wild-type HBV are labor-intensive and time-consuming. To overcome these problems, we previously constructed a recombinant reporter HBV bearing the NanoLuc gene and showed its usefulness to identify factors that affect HBV proliferation. Because this system mimics the early stage of HBV life cycle faithfully, we conducted a quantitative analysis of HBV infectivity to several human hepatocyte cell lines as well as the effect of dimethyl sulfoxide and HBV protein X on the early stage of HBV proliferation using this system. Furthermore, we developed a system to produce a reporter HBV expressing a pol gene. These reporter HBVs may provide an opportunity to enhance our understanding of the HBV life cycle and aid strategies for the development of new anti-HBV agents.
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TL;DR: A glycan profiling method for HBsAg on the intact HBV particle and an easy and simple method to enrich Dane particles from patient serum by jacalin fractionation are presented.
Abstract: Hepatitis B virus (HBV) is a double-stranded DNA virus composed of three types of viral particles. The virions are called Dane particles and the others are noninfectious subviral particles (SVPs). In blood, SVPs are detected in abundance, about 1000-10000 fold higher than Dane particles. Dane particles are hazardous because of their strong infectivity, unlike SVPs. Dane particles are covered with an envelope of glycoprotein called HBV surface antigen (HBsAg). HBsAg glycosylation is involved in viral particle formation and secretion. In this study, we established a novel and highly sensitive method for viral glycan profiling of HBsAg using small aliquots of patient serum. Our lectin microarray system could sensitively profile the glycans exposed on HBV while retaining the intact viral particle structure under nonreducing conditions. Several typical lectins were chosen from the lectin microarray results. Specifically, jacalin, which recognizes O-glycan, showed specific and strong reactivity to the M-HBsAg required for Dane particle secretion. Employing the lectin-fractionation method using jacalin, HBV particles were fractionated into jacalin-bound and unbound fractions from patient serum. We measured HBsAg titer and viral DNA load in each fraction using clinical tests. Interestingly, the jacalin-bound fraction contained a major fraction of the HBV viral DNA load. Thus, in this study we have presented a glycan profiling method for HBsAg on the intact HBV particle and an easy and simple method to enrich Dane particles from patient serum by jacalin fractionation.
TL;DR: Patients with resolved hepatitis B virus (HBV) infection following hematopoietic stem cell transplantation (HSCT) are potentially at high risk of HBV reactivation.
TL;DR: Serum WFA+‐M2BP level may elevate before HCC onset and is a short‐term predictor of HCC among patients infected with HCV.
Abstract: Objectives:Wisteria floribunda agglutinin-positive human Mac-2-binding protein (WFA+-M2BP) is a glycomarker. The present community-based long-term follow-up study repeatedly determined the serum WFA+-M2BP level and examined its short- and long-term associations with hepatitis C virus (HCV)-r
TL;DR: SOF/VEL+RBV has the potential to be a safe, well-tolerated, and effective treatment for Japanese patients with and without cirrhosis who have previously failed DAA-based regimens, a group without currently approved retreatment options.
Abstract: Background There is a growing number of Japanese patients with HCV infection who have failed direct acting antiviral (DAA)-based regimens and currently have no salvage therapies available. This Phase 3 study evaluates the efficacy and safety of sofosbuvir/velpatasvir (SOF/VEL) plus ribavirin (RBV) for 12 or 24 weeks in Japanese patients with genotype (GT) 1 or 2 HCV infection who have been previously treated with DAAs. Methods Approximately 110 subjects were randomised 1:1 to receive SOF/VEL+RBV for 12 or 24 weeks. Randomization was stratified by GT and presence of cirrhosis. All subjects must have been previously treated with a DAA for at least 4 weeks. Subjects with GT1 HCV infection must have previously been treated with an NS5A inhibitor. The primary efficacy analysis is a comparison of the SVR12 rates for GT1 patients in each of the two treatment groups to a historical control SVR of 50%. Results Of 117 patients enrolled, 45% were male, 81% had GT1 HCV infection, and 33% had cirrhosis. 84% had previously been treated with at least 2 different DAAs.86% of GT1 patients had previously been treated with daclatasvir plus asunaprevir and 91% of GT2 patients with SOF. Virologic outcomes at post-treatment week 4 are presented in the table below. There were no on-treatment virologic failures. Complete SVR12 and virology data will be presented. Three (3%) patients discontinued study drugs due to adverse events (AEs). One patient in the 12 week arm discontinued study drugs on Day 4 due to rash (related to study drugs). Two patients in the 24 week arm discontinued study drugs; one on Day 85 due to hepatic angiosarcoma (not related) and one on Day 57 due to depression (related). The two latter patients achieved SVR12. No Grade 3 or 4 AEs were considered related to study drugs (table 1). Conclusions SOF/VEL+RBV has the potential to be a safe, well-tolerated, and effective treatment for Japanese patients with and without cirrhosis who have previously failed DAA-based regimens, a group without currently approved retreatment options. Baseline NS5A RASs did not affect treatment outcome.
Patent•
05 Sep 2018