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Sasaki R, Kanda T, Kato N, Yokosuka O, Moriyama M. Hepatitis C virus-associated hepatocellular carcinoma after sustained virologic response. World J Hepatol 2018; 10:898-906. [PMID: 30631394 PMCID: PMC6323517 DOI: 10.4254/wjh.v10.i12.898] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2018] [Revised: 11/08/2018] [Accepted: 11/15/2018] [Indexed: 02/06/2023] Open
Abstract
The introduction of a direct-acting antiviral (DAA) for patients with hepatitis C virus (HCV) infection, could lead to higher sustained virologic response (SVR) rates with fewer adverse events, and it could shorten the treatment duration relative to the interferon era. Although most recent clinical studies have demonstrated that the occurrence rates of hepatocellular carcinoma (HCC) are decreased by SVR with both interferon-based and interferon-free-regimens, there are several reports about the unexpected observation of high rates of early tumor occurrence and recurrence in patients with HCV-related HCC undergoing interferon-free therapy despite SVR. Several mechanisms of HCC occurrence and rapid immunological changes, including cytokines and chemokines during and after DAA treatment, have also been reported. We focused on the possibilities that HCC occurs or recurs during and after DAA treatment, based on the reported clinical and basic studies. Further studies and observations will be needed to determine the short-term and long-term effects on hepatocarcinogenesis caused by the eradication of HCV with DAAs. New serum biomarkers and a follow-up system for HCV-patients with SVR should be established.
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Affiliation(s)
- Reina Sasaki
- Department of Gastroenterology and Nephrology, Chiba University, Graduate School of Medicine, Chiba 260-8670, Japan
| | - Tatsuo Kanda
- Department of Gastroenterology and Nephrology, Chiba University, Graduate School of Medicine, Chiba 260-8670, Japan
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Tokyo, Itabashi-ku 173-8610, Japan.
| | - Naoya Kato
- Department of Gastroenterology and Nephrology, Chiba University, Graduate School of Medicine, Chiba 260-8670, Japan
| | - Osamu Yokosuka
- Department of Gastroenterology and Nephrology, Chiba University, Graduate School of Medicine, Chiba 260-8670, Japan
| | - Mitsuhiko Moriyama
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Tokyo, Itabashi-ku 173-8610, Japan
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Chen Y, Yuan J, Han X, Liu X, Han X, Ye H. Coexpression Analysis of Transcriptome on AIDS and Other Human Disease Pathways by Canonical Correlation Analysis. Int J Genomics 2017; 2017:9163719. [PMID: 28695125 PMCID: PMC5488239 DOI: 10.1155/2017/9163719] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2016] [Revised: 02/24/2017] [Accepted: 03/08/2017] [Indexed: 11/17/2022] Open
Abstract
Acquired immune deficiency syndrome is a severe disease in humans caused by human immunodeficiency virus. Several human genes were characterized as host genetic factors that impact the processes of AIDS disease. Recent studies on AIDS patients revealed a series disease is complicating with AIDS. To resolve gene interaction between AIDS and complicating diseases, a canonical correlation analysis was used to identify the global correlation between AIDS and other disease pathway genes expression. The results showed that HLA-B, HLA-A, MH9, ZNED1, IRF1, TLR8, TSG101, NCOR2, and GML are the key AIDS-restricted genes highly correlated with other disease pathway genes. Furthermore, pathway genes in several diseases such as asthma, autoimmune thyroid disease, and malaria were globally correlated with ARGs. It suggests that these diseases are a high risk in AIDS patients as complicating diseases.
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Affiliation(s)
- Yahong Chen
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou 350025, China
- Infectious Diseases Hospital of Fuzhou, Fuzhou 350025, China
| | - Jinjin Yuan
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou 350025, China
- Infectious Diseases Hospital of Fuzhou, Fuzhou 350025, China
| | - Xianlin Han
- Department of General Surgery, Peking Union Medical College Hospital, Beijing, China
| | - Xiaolong Liu
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou 350025, China
- Infectious Diseases Hospital of Fuzhou, Fuzhou 350025, China
| | - Xiao Han
- Biotechnology Research Institute, Chinese Academy of Agricultural Sciences, Beijing 100081, China
| | - Hanhui Ye
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou 350025, China
- Infectious Diseases Hospital of Fuzhou, Fuzhou 350025, China
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Kanda T, Nakamoto S, Sasaki R, Nakamura M, Yasui S, Haga Y, Ogasawara S, Tawada A, Arai M, Mikami S, Imazeki F, Yokosuka O. Sustained Virologic Response at 24 Weeks after the End of Treatment Is a Better Predictor for Treatment Outcome in Real-World HCV-Infected Patients Treated by HCV NS3/4A Protease Inhibitors with Peginterferon plus Ribavirin. Int J Med Sci 2016; 13:310-315. [PMID: 27076789 PMCID: PMC4829545 DOI: 10.7150/ijms.14953] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2016] [Accepted: 03/15/2016] [Indexed: 01/01/2023] Open
Abstract
BACKGROUND Direct-acting antiviral agents against HCV with or without peginterferon plus ribavirin result in higher eradication rates of HCV and shorter treatment duration. We examined which is better for predicting persistent virologic response, the assessment of serum HCV RNA at 12 or 24 weeks after the end of treatment for predicting sustained virologic response (SVR12 or SVR24, respectively) in patients treated by HCV NS3/4A protease inhibitors with peginterferon plus ribavirin. METHODS In all, 149 Japanese patients infected with HCV genotype 1b treated by peginterferon plus ribavirin with telaprevir or simeprevir were retrospectively analyzed: 59 and 90 patients were treated with telaprevir- and simeprevir-including regimens, respectively. HCV RNA was measured by TaqMan HCV Test, version 2.0, real-time PCR assay. SVR12 or SVR24, respectively, was defined as HCV RNA negativity at 12 or 24 weeks after ending treatment. RESULTS Total SVR rates were 78.0% and 66.7% in the telaprevir and simeprevir groups, respectively. In the telaprevir group, all 46 patients with SVR12 finally achieved SVR24. In the simeprevir group, 60 (93.8%) of the total 64 patients with SVR12 achieved SVR24, with the other 4 patients all being previous-treatment relapsers. CONCLUSIONS SVR12 was suitable for predicting persistent virologic response in almost all cases. In simeprevir-including regimens, SVR12 could not always predict persistent virologic response. Clinicians should use SVR24 for predicting treatment outcome in the use of HCV NS3/4A protease inhibitors with peginterferon plus ribavirin for any group of real-world patients chronically infected with HCV.
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Affiliation(s)
- Tatsuo Kanda
- 1. Department of Gastroenterology and Nephrology, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Shingo Nakamoto
- 2. Department of Molecular Virology, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Reina Sasaki
- 1. Department of Gastroenterology and Nephrology, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Masato Nakamura
- 1. Department of Gastroenterology and Nephrology, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Shin Yasui
- 1. Department of Gastroenterology and Nephrology, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Yuki Haga
- 1. Department of Gastroenterology and Nephrology, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Sadahisa Ogasawara
- 1. Department of Gastroenterology and Nephrology, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Akinobu Tawada
- 1. Department of Gastroenterology and Nephrology, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Makoto Arai
- 1. Department of Gastroenterology and Nephrology, Chiba University Graduate School of Medicine, Chiba, Japan
| | | | - Fumio Imazeki
- 4. Safety and Health Organization, Chiba University, Chiba, Japan
| | - Osamu Yokosuka
- 1. Department of Gastroenterology and Nephrology, Chiba University Graduate School of Medicine, Chiba, Japan
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Olmedo DB, Cader SA, Porto LC. IFN-λ gene polymorphisms as predictive factors in chronic hepatitis C treatment-naive patients without access to protease inhibitors. J Med Virol 2015; 87:1702-15. [PMID: 25970604 DOI: 10.1002/jmv.24227] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/02/2015] [Indexed: 12/16/2022]
Abstract
The single nucleotides polymorphisms analyses in the regions near the IL28B gene in patients chronically infected with genotype 1 hepatitis C virus (HCV) are an important predictive factor for sustained virological response (SVR). The aim was to assess the predictive value of the polymorphisms of the IL28B/IFNL3 gene in patients chronically infected with genotype 1 for the viral clearance obtained after initial treatment including admixed populations. A systematic review was conducted, using a meta-analysis in the PubMed, Embase, LILACS, and SCIELO using MesH and DECS in 42 studies. The parameters were IL28B polymorphisms, rs12979860, rs8099917, and rs12980275, SVR ratio, and OR (odds ratio). OR and confidence Interval of 95% (95%CI), were calculated by fixed or random effects models. Heterogeneity, sensitivity analysis, and publication bias were also performed. Significant differences were noted between carriers groups with the major versus minor allele at rs12979860 CC versus CT/TT-genotype (OR = 4.18; 95%CI = 3.37-5.17), rs8099917 TT versus TG/GG-genotype (OR = 4.07; 95%CI = 2.94-5.63), and rs12980275 AA versus AA/AG-genotype (OR = 5.34; 95%CI = 1.60-17.82). There was selection bias in the rs8099917 analysis (Egger's regression P = 0.049), which reversed after performing a sensitivity analysis (P = 0.510). The incorporation of SNP analyses in IL28B/IFNL3 gene during the diagnosis process in Brazil should be used as a complementary tool to determine the appropriate treatment for HCV genotype 1. Here, we confirm that the rs12979860 CC, rs8099917 TT, and rs12980275 AA genotype-carriers have favorable responses to standard therapy, including two studies with Brazilian population, and this information should be considered.
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Affiliation(s)
- Daniele Blasquez Olmedo
- Histocompatibility and Cryopreservation Laboratory, Rio de Janeiro State University, Rio de Janeiro, Brazil
| | - Samária Ali Cader
- Histocompatibility and Cryopreservation Laboratory, Rio de Janeiro State University, Rio de Janeiro, Brazil
| | - Luís Cristóvão Porto
- Histocompatibility and Cryopreservation Laboratory, Rio de Janeiro State University, Rio de Janeiro, Brazil
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Kanda T, Nakamoto S, Yokosuka O. Is the use of IL28B genotype justified in the era of interferon-free treatments for hepatitis C? World J Virol 2015; 4:178-184. [PMID: 26279979 PMCID: PMC4534809 DOI: 10.5501/wjv.v4.i3.178] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2015] [Revised: 06/25/2015] [Accepted: 07/21/2015] [Indexed: 02/05/2023] Open
Abstract
In 2009, several groups reported that interleukin-28B (IL28B) genotypes are associated with the response to peginterferon plus ribavirin therapy for chronic hepatitis C virus (HCV) infection in a genome-wide association study, although the mechanism of this association is not yet well understood. However, in recent years, tremendous progress has been made in the treatment of HCV infection. In Japan, some patients infected with HCV have the IL28B major genotype, which may indicate a favorable response to interferon-including regimens; however, certain patients within this group are also interferon-intolerant or ineligible. In Japan, interferon-free 24-wk regimens of asunaprevir and daclatasvir are now available for HCV genotype 1b-infected patients who are interferon-intolerant or ineligible or previous treatment null-responders. The treatment response to interferon-free regimens appears better, regardless of IL28B genotype. Maybe other interferon-free regimens will widely be available soon. In conclusion, although some HCV-infected individuals have IL28B favorable alleles, importance of IL28B will be reduced with availability of oral interferon free regimen.
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Sato M, Kondo M, Tateishi R, Fujiwara N, Kato N, Yoshida H, Taguri M, Koike K. Impact of IL28B genetic variation on HCV-induced liver fibrosis, inflammation, and steatosis: a meta-analysis. PLoS One 2014; 9:e91822. [PMID: 24637774 PMCID: PMC3956722 DOI: 10.1371/journal.pone.0091822] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2013] [Accepted: 02/15/2014] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND & AIMS IL28B polymorphisms were shown to be strongly associated with the response to interferon therapy in chronic hepatitis C (CHC) and spontaneous viral clearance. However, little is known about how these polymorphisms affect the natural course of the disease. Thus, we conducted the present meta-analysis to assess the impact of IL28B polymorphisms on disease progression. METHODS A literature search was conducted using MEDLINE, EMBASE, and the Cochrane Library. Integrated odds ratios (OR) were calculated with a fixed-effects or random-effects model based on heterogeneity analyses. RESULTS We identified 28 studies that included 10,024 patients. The pooled results indicated that the rs12979860 genotype CC was significantly associated (vs. genotype CT/TT; OR, 1.122; 95%CI, 1.003-1.254; P = 0.044), and that the rs8099917 genotype TT tended to be (vs. genotype TG/GG; OR, 1.126; 95%CI, 0.988-1.284; P = 0.076) associated, with an increased possibility of severe fibrosis. Both rs12979860 CC (vs. CT/TT; OR, 1.288; 95%CI, 1.050-1.581; P = 0.015) and rs8099917 TT (vs. TG/GG; OR, 1.324; 95%CI, 1.110-1.579; P = 0.002) were significantly associated with a higher possibility of severe inflammation activity. Rs8099917 TT was also significantly associated with a lower possibility of severe steatosis (vs. TG/GG; OR, 0.580; 95%CI, 0.351-0.959; P = 0.034), whereas rs12979860 CC was not associated with hepatic steatosis (vs. CT/TT; OR, 1.062; 95%CI, 0.415-2.717; P = 0.901). CONCLUSIONS IL28B polymorphisms appeared to modify the natural course of disease in patients with CHC. Disease progression seems to be promoted in patients with the rs12979860 CC and rs8099917 TT genotypes.
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Affiliation(s)
- Masaya Sato
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
| | - Mayuko Kondo
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
| | - Ryosuke Tateishi
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
| | - Naoto Fujiwara
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
| | - Naoya Kato
- Unit of Disease Control Genome Medicine, Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan
| | - Haruhiko Yoshida
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
| | - Masataka Taguri
- Department of Biostatistics and Epidemiology, Yokohama City University Medical Center, Yokohama, Kanagawa, Japan
| | - Kazuhiko Koike
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
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IFNL4 ss469415590 Variant Is Associated with Treatment Response in Japanese HCV Genotype 1 Infected Individuals Treated with IFN-Including Regimens. Int J Hepatol 2014; 2014:723868. [PMID: 25548683 PMCID: PMC4274707 DOI: 10.1155/2014/723868] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2014] [Accepted: 11/24/2014] [Indexed: 12/24/2022] Open
Abstract
Aim. Eradication of hepatitis C virus (HCV) is still challenging even if interferon- (IFN-) free regimens with direct-acting antiviral agents (DAAs) for HCV-infected individuals are available in clinical practice. IFNL4 is a newly described protein, associated with human antiviral defenses. We investigated whether IFNL4 ss469415590 variant has an effect on the prediction of treatment response in HCV-infected patients treated with IFN-including regimens. Patients and Methods. In all, 185 patients infected with HCV genotype 1 treated with peg-IFN plus ribavirin, with or without telaprevir, were genotyped for IFNL4 ss469415590. We retrospectively investigated whether the role of IFNL4 ss469415590 variant and other factors could predict sustained virological response (SVR) in Japanese patients infected with HCV genotype 1. Results. There were 65.7%, 31.5%, and 2.8% patients in the IFNL4 ss469415590 TT/TT, TT/-G, and -G/-G groups, respectively. SVR rates were 82.1% or 49.3% in patients treated with peg-IFN plus ribavirin with or without telaprevir, respectively. IFNL4 ss469415590 variant and HCV viral loads or IFNL4 ss469415590 variant and early virological response were better predictors of SVR in patients treated with peg-IFN plus ribavirin with or without telaprevir, respectively. Conclusion. In the era of DAAs, measurement of IFNL4 ss469415590 variant could help the prediction of SVR in Japanese HCV genotype 1 infected individuals treated with IFN-including regimens.
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Wu S, Kanda T, Nakamoto S, Imazeki F, Yokosuka O. Hepatitis C virus protease inhibitor-resistance mutations: our experience and review. World J Gastroenterol 2013; 19:8940-8948. [PMID: 24379619 PMCID: PMC3870547 DOI: 10.3748/wjg.v19.i47.8940] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2013] [Revised: 11/08/2013] [Accepted: 12/03/2013] [Indexed: 02/06/2023] Open
Abstract
Direct-acting antiviral agents (DAAs) for hepatitis C virus (HCV) infection are one of the major advances in its medical treatment. The HCV protease inhibitors boceprevir and telaprevir were the first approved DAAs in the United States, Europe, and Japan. When combined with peginterferon plus ribavirin, these agents increase sustained virologic response rates to 70%-80% in treatment-naïve patients and previous-treatment relapsers with chronic HCV genotype 1 infection. Without peginterferon plus ribavirin, DAA mono-therapies increased DAA-resistance mutations. Several new DAAs for HCV are now in clinical development and are likely to be approved in the near future. However, it has been reported that the use of these drugs also led to the emergence of DAA-resistance mutations in certain cases. Furthermore, these mutations exhibit cross-resistance to multiple drugs. The prevalence of DAA-resistance mutations in HCV-infected patients who were not treated with DAAs is unknown, and it is as yet uncertain whether such variants are sensitive to DAAs. We performed a population sequence analysis to assess the frequency of such variants in the sera of HCV genotype 1-infected patients not treated with HCV protease inhibitors. Here, we reviewed the literature on resistance variants of HCV protease inhibitors in treatment naïve patients with chronic HCV genotype 1, as well as our experience.
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Nakamura M, Kanda T, Nakamoto S, Miyamura T, Jiang X, Wu S, Yokosuka O. No correlation between PNPLA3 rs738409 genotype and fatty liver and hepatic cirrhosis in Japanese patients with HCV. PLoS One 2013; 8:e81312. [PMID: 24349054 PMCID: PMC3859490 DOI: 10.1371/journal.pone.0081312] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2013] [Accepted: 10/21/2013] [Indexed: 02/07/2023] Open
Abstract
Background Hepatitis C virus (HCV) infection is associated with the development of cirrhosis and hepatocellular carcinoma and is also related to fatty change of the liver. Variation in patatin-like phospholipase domain-containing 3 (PNPLA3) gene is associated with disease progression in nonalcoholic fatty liver disease (NAFLD). Recent reports have suggested that PNPLA3, IL28B and TLR4-associated single nucleotide polymorphisms (SNPs) may have an impact on hepatic steatosis or fibrosis in patients with chronic HCV infection. Methods and Findings Four SNPs (PNPLA3 rs738409, TLR4 rs4986790, TLR4 rs4986791, IL28B rs8099917) were identified in Japanese patients infected with HCV. We examined the association between the distribution of these SNP alleles and fatty change of the liver or existence of hepatic cirrhosis diagnosed by ultrasonography, one of the widely accessible and easy-to-use methods. PNPLA3 rs738409 G-allele and IL28B rs 8099917 minor allele were found in 70.0% and 31.1%, respectively. These two TLR4 SNPs were uniform in Japanese. Fatty change of the liver developed independent of the abscence of hepatic cirrhosis on sonographic findings and younger age. Hepatic cirrhosis was associated with a higher aspartate aminotransferase/platelet ratio index (APRI), no fatty change of the liver, higher BMI and higher AFP levels. No association between PNPLA3 rs738409/IL28B rs8099917 genotypes and hepatic steatosis or liver fibrosis was observed. Conclusions According to ultrasound examinations, no association between PNPLA3 rs738409 genotype and fatty change of the liver or hepatic cirrhosis was found in Japanese patients infected with HCV. Together, our results suggested that the mechanism of hepatic steatosis underlying HCV infection might differ from that of NAFLD and should be explored.
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Affiliation(s)
- Masato Nakamura
- Department of Gastroenterology and Nephrology, Chiba University, Graduate School of Medicine, Chiba, Japan
| | - Tatsuo Kanda
- Department of Gastroenterology and Nephrology, Chiba University, Graduate School of Medicine, Chiba, Japan
- * E-mail:
| | - Shingo Nakamoto
- Department of Gastroenterology and Nephrology, Chiba University, Graduate School of Medicine, Chiba, Japan
- Department of Molecular Virology, Chiba University, Graduate School of Medicine, Chiba, Japan
| | - Tatsuo Miyamura
- Department of Gastroenterology and Nephrology, Chiba University, Graduate School of Medicine, Chiba, Japan
| | - Xia Jiang
- Department of Gastroenterology and Nephrology, Chiba University, Graduate School of Medicine, Chiba, Japan
| | - Shuang Wu
- Department of Gastroenterology and Nephrology, Chiba University, Graduate School of Medicine, Chiba, Japan
| | - Osamu Yokosuka
- Department of Gastroenterology and Nephrology, Chiba University, Graduate School of Medicine, Chiba, Japan
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No correlation between PNPLA3 rs738409 genotype and fatty liver and hepatic cirrhosis in Japanese patients with HCV. PLoS One 2013. [PMID: 24349054 DOI: 10.1371/journal.pone.0081312.] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
BACKGROUND Hepatitis C virus (HCV) infection is associated with the development of cirrhosis and hepatocellular carcinoma and is also related to fatty change of the liver. Variation in patatin-like phospholipase domain-containing 3 (PNPLA3) gene is associated with disease progression in nonalcoholic fatty liver disease (NAFLD). Recent reports have suggested that PNPLA3, IL28B and TLR4-associated single nucleotide polymorphisms (SNPs) may have an impact on hepatic steatosis or fibrosis in patients with chronic HCV infection. METHODS AND FINDINGS Four SNPs (PNPLA3 rs738409, TLR4 rs4986790, TLR4 rs4986791, IL28B rs8099917) were identified in Japanese patients infected with HCV. We examined the association between the distribution of these SNP alleles and fatty change of the liver or existence of hepatic cirrhosis diagnosed by ultrasonography, one of the widely accessible and easy-to-use methods. PNPLA3 rs738409 G-allele and IL28B rs 8099917 minor allele were found in 70.0% and 31.1%, respectively. These two TLR4 SNPs were uniform in Japanese. Fatty change of the liver developed independent of the abscence of hepatic cirrhosis on sonographic findings and younger age. Hepatic cirrhosis was associated with a higher aspartate aminotransferase/platelet ratio index (APRI), no fatty change of the liver, higher BMI and higher AFP levels. No association between PNPLA3 rs738409/IL28B rs8099917 genotypes and hepatic steatosis or liver fibrosis was observed. CONCLUSIONS According to ultrasound examinations, no association between PNPLA3 rs738409 genotype and fatty change of the liver or hepatic cirrhosis was found in Japanese patients infected with HCV. Together, our results suggested that the mechanism of hepatic steatosis underlying HCV infection might differ from that of NAFLD and should be explored.
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Miyamura T, Kanda T, Nakamura M, Jiang X, Wu S, Nakamoto S, Mikami S, Takada N, Imazeki F, Yokosuka O. IL-28B polymorphisms and treatment response in hepatitis C virus patients with persistently normal alanine aminotransferase. World J Hepatol 2013; 5:635-641. [PMID: 24303092 PMCID: PMC3847947 DOI: 10.4254/wjh.v5.i11.635] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2013] [Revised: 10/07/2013] [Accepted: 11/02/2013] [Indexed: 02/06/2023] Open
Abstract
AIM To examine the association between the interleukin 28B (IL-28B) genotype and treatment response in hepatitis C virus (HCV)-infected patients with persistently normal alanine aminotransferase (PNALT). METHODS We compared the treatment response of HCV-infected patients with PNALT to that of patients with non-PNALT. Between February 2010 and April 2013, 278 patients infected with HCV were enrolled in this study. All of the patients were treated with peginterferon-alpha 2a or 2b plus ribavirin. In addition, 180 μg of peginterferon alpha-2a or 1.5 μg/kg peginterferon alpha-2b per week plus weight-based ribavirin (600-1000 mg/d) were typically administered for 24 wk to HCV genotype 2-infected patients or for 48-72 wk to HCV genotype 1-infected patients. In all of the patients, the IL-28B rs8099917 genotype was determined using a TaqMan single-nucleotide polymorphism assay. HCV RNA was measured using the COBAS TaqMan HCV test. RESULTS Female patients were dominant in the PNALT group (P < 0.0001). Among 72 HCV genotype 1-infected patients with PNALT, the early virologic response (EVR) rates (P < 0.01) and the sustained virologic response (SVR) rates (P < 0.01) were higher in patients with the IL-28B TT genotype than in those with the IL-28B TG/GG genotype. In HCV genotype 1-infected patients with PNALT, multivariate logistic-regression analysis showed that SVR was independently predicted by the IL-28B rs8099917 TT type (P < 0.05) and having an EVR (P < 0.01). The IL-28B rs8099917 TT genotype strongly correlated with treatment response in HCV genotype 1-infected Asian patients with PNALT. CONCLUSION The IL-28B genotype may be useful for selecting HCV genotype 1-infected patients with PNALT who should receive interferon-based treatment.
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Affiliation(s)
- Tatsuo Miyamura
- Tatsuo Miyamura, Tatsuo Kanda, Masato Nakamura, Xia Jiang, Shuang Wu, Shingo Nakamoto, Osamu Yokosuka, Department of Gastroenterology and Nephrology, Chiba University, Graduate School of Medicine, Chiba 260-8677, Japan
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Kanda T, Jiang X, Nakamoto S, Nakamura M, Miyamura T, Wu S, Yokosuka O. Different effects of three interferons L on Toll-like receptor-related gene expression in HepG2 cells. Cytokine 2013; 64:577-583. [PMID: 24041672 DOI: 10.1016/j.cyto.2013.08.010] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2013] [Revised: 08/07/2013] [Accepted: 08/16/2013] [Indexed: 02/07/2023]
Abstract
IFNL1 (IL29), IFNL2 (IL28A) and IFNL3 (IL28B) might play important roles in anti-viral defense. IFNL3 genotypes have been shown to be associated with hepatitis C spontaneous and treatment-induced viral clearance. The effects of IFNL1, IFNL2 and IFNL3 on innate immunity including Toll-like receptor (TLR)-related pathway in human hepatocytes were examined. After G418 screening, we established the human hepatoma stable cell lines HepG2-IL28A, HepG2-IL28B, and HepG2-IL29, expressing IFNL2, IFNL3, and IFNL1 in conditioned medium, respectively, and a control cell line, HepG2-pcDNA3.1. We performed real-time RT-PCR to investigate 84 Toll-like receptor-related gene expressions in triplicate and, using ddCt methods, compared these gene expressions in each cell line. IFNL2, IFNL3 and IFNL1 were respectively detected by ELISA in HepG2-IL28A, HepG2-IL28B and HepG2-IL29. Compared to HepG2-pcDNA3.1 cells, 17 (20.2%), 11 (13.0%) and 16 genes (19.0%) were up-regulated 1.5-fold or more (p<0.05); 10 (11.9%), 2 (2.3%) and 10 genes (11.9%) were 1.5-fold or more down-regulated (p<0.05) in HepG2-IL28A, HepG2-IL28B and HepG2-IL29, respectively. EIF2AK2 and SARM1 were up-regulated among all cells. Of interest, TLR3, TLR4 and related molecules CXCL10 (IP10), IL6, EIF2K2, IFNB1, and IRF1, important genes in the progression of HCV-related pathogenesis and antiviral activities against HCV, in HepG2-IL28B, presented different profiles from those of HepG2-IL28A and HepG2-IL29. IFNL3 induces interferon-stimulated genes (ISGs) that are reportedly associated with the progression of HCV-related pathogenesis and antiviral activities against HCV. IFNL is a powerful modulator of innate immune response and it is supposed that the 3 IFNLs may play different roles in the antiviral activity against HBV and HCV.
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Affiliation(s)
- Tatsuo Kanda
- Department of Gastroenterology and Nephrology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8677, Japan.
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Nakamura M, Kanda T, Miyamura T, Wu S, Nakamoto S, Yokosuka O. Alanine aminotransferase elevation during peginterferon alpha-2a or alpha-2b plus ribavirin treatment. Int J Med Sci 2013; 10:1015-1021. [PMID: 23801888 PMCID: PMC3691800 DOI: 10.7150/ijms.6402] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2013] [Accepted: 06/09/2013] [Indexed: 02/07/2023] Open
Abstract
Alanine aminotransferase (ALT) elevation was occassionally observed during the treatment with combination peginterferon alpha plus ribavirin. Two forms of peginterferon are currently available as a standard of care with or without direct-acting antivirals against hepatitis C virus (HCV). Until the appearance of interferon-sparing regimen, peginterferon alpha plus ribavirin will play a central role in the eradication of HCV. In the present study, we compared ALT elevations in response to peginterferon alpha-2a plus ribavirin or peginterferon alpha-2b plus ribavirin in HCV genotype-1-infected patients. There were no significant differences in ALT elevations between treatments with the two peginterferons, but in a comparison of the proportions of patients with transient ALT elevation from baseline between the two groups, transient ALT elevation was observed more in sustained virological response (SVR) patients treated with peginterferon alpha-2a than with peginterferon alpha-2b. However, no patients discontinued treatment due to ALT elevation. Patients with transient ALT elevation from baseline during the treatment had less favorable IL28B rs8099917 genotype in the peginterferon alpha-2b group. Patients achieving SVR tended to have lower ALT levels, although some had persistent ALT elevation during treatment. In conclusion, clinicians should pay attention to possible ALT elevation during the treatment of chronic hepatitis C patients.
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Affiliation(s)
- Masato Nakamura
- 1. Department of Gastroenterology and Nephrology, Chiba University, Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan
| | - Tatsuo Kanda
- 1. Department of Gastroenterology and Nephrology, Chiba University, Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan
| | - Tatsuo Miyamura
- 1. Department of Gastroenterology and Nephrology, Chiba University, Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan
| | - Shuang Wu
- 1. Department of Gastroenterology and Nephrology, Chiba University, Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan
| | - Shingo Nakamoto
- 1. Department of Gastroenterology and Nephrology, Chiba University, Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan
- 2. Department of Molecular Virology, Chiba University, Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan
| | - Osamu Yokosuka
- 1. Department of Gastroenterology and Nephrology, Chiba University, Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan
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Kanda T, Yokosuka O, Omata M. Treatment of hepatitis C virus infection in the future. Clin Transl Med 2013; 2:9. [PMID: 23577631 PMCID: PMC3637513 DOI: 10.1186/2001-1326-2-9] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2013] [Accepted: 04/08/2013] [Indexed: 12/13/2022] Open
Abstract
Two direct-acting antivirals (DAAs) against hepatitis C virus (HCV): telaprevir and boceprevir, are now available in combination with peginterferon plus ribavirin for the treatment of chronic hepatitis C infection. Although these drugs are potent inhibitors of HCV replication, they occasionally result in severe adverse events. In the present clinical trials, in their stead, several second-generation DAAs are being investigated. Most of them are being viewed with high expectations, but they also require the combination with peginterferon plus ribavirin. In the near future, we might be using all-oral DAAs and interferon-free regimens for the treatment of HCV-infected patients, and these would be potent inhibitors of HCV and have less adverse events.
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Affiliation(s)
- Tatsuo Kanda
- Department of Gastroenterology and Nephrology, Chiba University, Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba (260-8670), Japan.
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15
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Hodo Y, Honda M, Tanaka A, Nomura Y, Arai K, Yamashita T, Sakai Y, Yamashita T, Mizukoshi E, Sakai A, Sasaki M, Nakanuma Y, Moriyama M, Kaneko S. Association of interleukin-28B genotype and hepatocellular carcinoma recurrence in patients with chronic hepatitis C. Clin Cancer Res 2013; 19:1827-37. [PMID: 23426277 DOI: 10.1158/1078-0432.ccr-12-1641] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
PURPOSE Several single-nucleotide polymorphisms (SNP) in the interleukin-28B (IL-28B) locus have recently been shown to be associated with antiviral treatment efficacy for chronic hepatitis C (CHC). However, such an association with hepatocellular carcinoma (HCC) is unkno3 we investigated the association between the IL-28B genotype and the biology and clinical outcome of patients with HCC receiving curative treatment. EXPERIMENTAL DESIGN Genotyping of 183 patients with HCC with CHC who were treated with hepatic resection or radiofrequency ablation (RFA) was carried out, and the results were analyzed to determine the association between the IL-28B genotype (rs8099917) and clinical outcome. Gene expression profiles of 20 patients with HCC and another series of 91 patients with CHC were analyzed using microarray analysis and gene set enrichment analysis. Histologic and immunohistochemical analyses were also conducted. RESULTS The TT, TG, and GG proportions of the rs8099917 genotype were 67.8% (124 of 183), 30.6% (56 of 183), and 1.6% (3 of 183), respectively. Multivariate Cox proportional hazard analysis showed that the IL-28B TT genotype was significantly associated with HCC recurrence (P = 0.007; HR, 2.674; 95% confidence interval, 1.16-2.63). Microarray analysis showed high expression levels of IFN-stimulated genes in background liver samples and immune-related genes in tumor tissues of the IL-28B TG/GG genotype. Histologic findings showed that more lymphocytes infiltrated into tumor tissues in the TG/GG genotype. CONCLUSIONS The IL-28B genotype is associated with HCC recurrence, gene expression, and histologic findings in patients with CHC.
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Affiliation(s)
- Yuji Hodo
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Science, Kanazawa, Ishikawa, Japan
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Luo Y, Jin C, Ling Z, Mou X, Zhang Q, Xiang C. Association study of IL28B: rs12979860 and rs8099917 polymorphisms with SVR in patients infected with chronic HCV genotype 1 to PEG-INF/RBV therapy using systematic meta-analysis. Gene 2013; 513:292-296. [PMID: 23142377 DOI: 10.1016/j.gene.2012.10.030] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2012] [Accepted: 10/21/2012] [Indexed: 12/22/2022]
Abstract
Recently, genome-wide associated studies (GWAS) have identified that host genetics IL28B SNPs rs12979860 and rs8099917 were significantly associated with SVR in patients infected with chronic HCV genotype 1 to PEG-INF/RBV therapy. Results from these studies remain conflicting. We conducted this meta-analysis to estimate the overall association of SVR with rs12979860 and rs8099917. We searched the PubMed, Embase, Scholar Google, ISI Web of Knowledge, and Chinese National Knowledge Infrastructure (CNKI) databases for all articles before July 30, 2012. The odds ratio (OR) corresponding to the 95% confidence interval (CI) was used to assess the association. The statistical heterogeneity among studies was assessed with the I(2) statistics. Begg's test and Egger's test were performed to evaluate the publication bias. Eventually, twenty studies were selected for the meta-analysis. The IL-28B SNPs rs12979860 genotype CC and rs8099917 genotype TT significantly positive associated with SVR in patients infected chronic HCV genotype 1 to PEG-INF/RBV therapy (OR=4.473, 95% CI=3.814-5.246, OR=5.171, 95% CI=4.372-6.117 respectively). The results suggested that rs12979860 genotype CC and rs8099917 genotype TT could be used as independent predictors of the HCV-1 infected patients.
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Affiliation(s)
- Yueqiu Luo
- State Key Laboratory for Diagnosis and Treatment of Infectious Disease, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang province 310003, PR China
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Jiménez-Sousa MA, Fernández-Rodríguez A, Guzmán-Fulgencio M, García-Álvarez M, Resino S. Meta-analysis: implications of interleukin-28B polymorphisms in spontaneous and treatment-related clearance for patients with hepatitis C. BMC Med 2013; 11:6. [PMID: 23298311 PMCID: PMC3570369 DOI: 10.1186/1741-7015-11-6] [Citation(s) in RCA: 71] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2012] [Accepted: 01/08/2013] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Since 2009, several studies have identified single-nucleotide polymorphisms (SNPs) near the gene encoding for interleukin (IL)-28 (IL28B) that are strongly associated with spontaneous and treatment-induced hepatitis C virus (HCV) clearance. Because this large amount of data includes some inconsistencies, we consider assessment of the global estimate for each SNP to be essential. METHODS Relevant studies assessing IL28B polymorphisms associated with sustained virologic response (SVR) and spontaneous clearance (SC) were identified from a literature search of PubMed up to 9 July, 2012. Studies were eligible studies if they included patients infected with HCV or HCV/HIV, or assessed any SNP located within or near the IL28B gene, SVR data available under standard treatment, and/or SC data in patients with acute HCV infection. Pooled odds ratios were estimated by fixed or random effects models when appropriate. Variables such as HCV genotype, ethnicity, and type of co-infection were studied. RESULTS Of 282 screened studies, 67 were selected for SVR and 10 for SC. In total, 20,163 patients were studied for SVR and 3,554 for SC. For SVR, we found that all SNPs showed strong associations in patients with HCV genotypes 1 and 4, whereas the pooled ORs were almost three times lower for genotypes 2 and 3 (rs12979860 and rs8099917). Regarding ethnicity, the SNP most associated with SVR was rs12979860 in white patients, whereas in East Asians it seemed to be rs8099917. The most studied SNP (rs12979860) showed similar results for patients co-infected with HCV/HIV, as for those infected with HCV only. Finally, rs12979860 and rs8099917 both appeared to be associated with SC. CONCLUSIONS IL28B polymorphisms influence both the outcome of interferon treatment and the natural clearance of HCV. However we did not identify a universal predictor SNP, as the best genetic markers differed depending on patient ethnicity, genotype, and type of infection. Nevertheless, our results may be useful for more precise treatment decision-making.
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Affiliation(s)
- María A Jiménez-Sousa
- Unit of HIV/Hepatitis Coinfection, National Center for Microbiology, Health Institute Carlos III (ISCIII), 28220 Majadahonda, Madrid, Spain
| | - Amanda Fernández-Rodríguez
- Unit of HIV/Hepatitis Coinfection, National Center for Microbiology, Health Institute Carlos III (ISCIII), 28220 Majadahonda, Madrid, Spain
| | - María Guzmán-Fulgencio
- Unit of HIV/Hepatitis Coinfection, National Center for Microbiology, Health Institute Carlos III (ISCIII), 28220 Majadahonda, Madrid, Spain
| | - Mónica García-Álvarez
- Unit of HIV/Hepatitis Coinfection, National Center for Microbiology, Health Institute Carlos III (ISCIII), 28220 Majadahonda, Madrid, Spain
| | - Salvador Resino
- Unit of HIV/Hepatitis Coinfection, National Center for Microbiology, Health Institute Carlos III (ISCIII), 28220 Majadahonda, Madrid, Spain
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18
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Hung MY, Hsu KH, Hu WS, Chang NC, Huang CY, Hung MJ, Miyamura T, Maruoka D, Wu S, Tanaka T, Arai M, Mikami S, Fujiwara K, Imazeki F, Yokosuka O. Gender-specific prognosis and risk impact of C-reactive protein, hemoglobin and platelet in the development of coronary spasm. Int J Med Sci 2013; 10:255-64. [PMID: 23372432 PMCID: PMC3558714 DOI: 10.7150/ijms.5383] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2012] [Accepted: 01/09/2013] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Scarce data are available on hemoglobin and platelet in relation to coronary artery spasm (CAS) development. We sought to determine the roles that high-sensitivity C-reactive protein (hs-CRP), hemoglobin and platelet play in CAS patients. METHODS Patients (337 women and 532 men) undergoing coronary angiography with or without CAS but without obstructive coronary artery disease were evaluated during a 12-year period. RESULTS Among women with high hemoglobin levels, the odds ratios (OR) from the lowest (<1 mg/l) to the highest tertiles (>3 mg/l) of hs-CRP were 1.21, 2.15, and 5.93 (p=0.009). In women with low hemoglobin levels, an elevated risk was found from the middle to the highest tertiles of hs-CRP (OR 0.59 to 3.85) (p=0.004). This relationship was not observed in men. In men, platelet count was the most significant risk factor for CAS (p=0.004). The highest likelihood of developing CAS was found among women with the highest hs-CRP tertile and low platelet counts (OR 8.77; 95% confidence interval [CI] 2.20-35.01) and among men with the highest hs-CRP tertile and high platelet counts (OR 4.58; 95% CI 0.48-43.97). Neither hemoglobin level nor platelet count was associated with frequent recurrent angina in both genders with CAS whereas death and myocardial infarction were rare. CONCLUSIONS There are positive interactions among hs-CRP, hemoglobin and platelet in women with this disease, but not in men. While hemoglobin is a modifier in CAS development in women, platelet count is an independent risk factor for men. Both women and men have good prognosis of CAS.
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Affiliation(s)
- Ming-Yow Hung
- Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
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Kanda T, Nakamoto S, Wu S, Yokosuka O. Role of IL28Bgenotype in older hepatitis C virus-infected patients. World J Immunol 2013; 3:54. [DOI: 10.5411/wji.v3.i3.54] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2013] [Revised: 09/02/2013] [Accepted: 10/16/2013] [Indexed: 02/05/2023] Open
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Kanda T, Nakamoto S, Nishino T, Takada N, Tsubota A, Kato K, Miyamura T, Maruoka D, Wu S, Tanaka T, Arai M, Mikami S, Fujiwara K, Imazeki F, Yokosuka O. Peginterferon Alfa-2a plus ribavirin in Japanese patients infected with hepatitis C virus genotype 2 who failed previous interferon therapy. Int J Med Sci 2012; 10:43-49. [PMID: 23289004 PMCID: PMC3534876 DOI: 10.7150/ijms.5358] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2012] [Accepted: 12/02/2012] [Indexed: 01/07/2023] Open
Abstract
Some patients infected with hepatitis C virus (HCV) genotype 2 could be cured with treatment shorter than 24 weeks using peginterferon plus ribavirin, but there are still treatment-refractory patients. Direct-acting antivirals (DAAs) are not currently available for HCV genotype 2 patients, different from genotype 1 patients, in clinical practice. We investigated 29 HCV genotype 2-infected Japanese patients who had been previously treated and failed to clear HCV. We retreated them with peginterferon alfa-2a plus ribavirin and measured HCV RNA level to assess the efficacy and safety of this treatment in patients who had failed previous therapy. We found that retreatment of HCV genotype 2-infected Japanese patients with peginterferon alfa-2a plus ribavirin for 24-48 weeks led to 60 to 66.6% sustained virological response (SVR) in patients previously treated with (peg-)interferon monotherapy and to 69.9% SVR in relapsers previously treated with peginterferon plus ribavirin. Attention should be paid to certain patients with unique features. Selection of patients according to their previous treatment could lead to optimal therapy in HCV genotype 2 treatment-experienced patients.
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Affiliation(s)
- Tatsuo Kanda
- Department of Gastroenterology and Nephrology, Graduate School of Medicine, Chiba University, Inohana, Chuo-ku, Chiba, Japan.
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21
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Rau M, Baur K, Geier A. Host genetic variants in the pathogenesis of hepatitis C. Viruses 2012; 4:3281-302. [PMID: 23342360 PMCID: PMC3528266 DOI: 10.3390/v4123281] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2012] [Revised: 11/17/2012] [Accepted: 11/17/2012] [Indexed: 02/06/2023] Open
Abstract
Direct-acting antiviral drugs (DAAs) are currently replacing antiviral therapy for Hepatitis C infection. Treatment related side effects are even worse and the emergence of resistant viruses must be avoided because of the direct-antiviral action. Altogether it remains a challenge to take treatment decisions in a clinical setting with cost restrictions. Genetic host factors are hereby essential to implement an individualized treatment concept. In recent years results on different genetic variants have been published with a strong association with therapy response, fibrosis and treatment-related side effects. Polymorphisms of the IL28B gene were identified as accurate predictors for therapy response and spontaneous clearance of HCV infection and are already used for diagnostic decisions. For RBV-induced side effects, such as hemolytic anemia, associations to genetic variants of inosine triphosphatase (ITPA) were described and different SLC28 transporters for RBV-uptake have been successfully analyzed. Fibrosis progression has been associated with variants of Vitamin D receptor (VDR) and ABCB11 (bile salt export pump). Cirrhotic patients especially have a high treatment risk and low therapy response, so that personalized antiviral treatment is mandatory. This review focuses on different host genetic variants in the pathogenesis of Hepatitis C at the beginning of a new area of treatment.
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Affiliation(s)
- Monika Rau
- Division of Hepatology, Department of Internal Medicine II, University Hospital Würzburg, Oberdürrbacherstraße 6, 97080 Würzburg, Germany;
| | - Katharina Baur
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Rämistrasse 100, 8091 Zurich, Switzerland;
| | - Andreas Geier
- Division of Hepatology, Department of Internal Medicine II, University Hospital Würzburg, Oberdürrbacherstraße 6, 97080 Würzburg, Germany;
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Rämistrasse 100, 8091 Zurich, Switzerland;
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22
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Kanda T, Wu S, Kiyohara T, Nakamoto S, Jiang X, Miyamura T, Imazeki F, Ishii K, Wakita T, Yokosuka O. Interleukin-29 suppresses hepatitis A and C viral internal ribosomal entry site-mediated translation. Viral Immunol 2012; 25:379-386. [PMID: 23035851 DOI: 10.1089/vim.2012.0021] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Our aim was to investigate the effects of interferons (IFNs)-λ (interleukin-29 [IL-29], IL-28A, and IL-28B) on hepatitis C virus (HCV) and hepatitis A virus (HAV) internal ribosomal entry site (IRES)-mediated translation. The effects of these IFNs on HCV/HAV translation from HAV/HCV IRES were investigated using bicistronic reporter constructs. We transfected HCV/HAV IRES constructs into these IFN-expressing cell lines. IL-29 showed stronger inhibition of their IRES-mediated translation. Combining IL-29 with IFN-α or amantadine resulted in stronger inhibition of HAV IRES activity. Our findings demonstrated a novel antiviral effect of IFNs-λ against HAV and HCV through the suppression of IRES-mediated translation.
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Affiliation(s)
- Tatsuo Kanda
- Department of Medicine and Clinical Oncology, Chiba University Graduate School of Medicine, Chiba, Japan.
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Miyamura T, Kanda T, Nakamoto S, Wu S, Jiang X, Arai M, Fujiwara K, Imazeki F, Yokosuka O. Roles of ITPA and IL28B genotypes in chronic hepatitis C patients treated with peginterferon plus ribavirin. Viruses 2012; 4:1264-1278. [PMID: 23012624 PMCID: PMC3446761 DOI: 10.3390/v4081264] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2012] [Revised: 07/27/2012] [Accepted: 08/06/2012] [Indexed: 12/12/2022] Open
Abstract
It has been reported that inosine triphosphatase (ITPA) gene variants protect against ribavirin-induced anemia in patients treated for chronic hepatitis C. IL28B variants also influence the treatment response of peginterferon plus ribavirin treatment in these patients. In the present study, we examined how ITPA and IL28B genotypes have clinical impacts on treatment-induced hematotoxicities and treatment response in HCV-infected patients treated with peginterferon plus ribavirin. ITPA genotypes (rs1127354 and rs6051702) and IL28B genotype (rs8099917) were determined by TaqMan SNP assay. We compared clinical background, treatment course and treatment response in terms of these genotypes. Only IL28B rs8099917 major type could predict sustained virological response. ITPA rs1127354 major type leads to significantly greater ribavirin-induced anemia than ITPA rs1127354 minor type between days 0 and 84. We noticed that IL28B rs8099917 minor genotype was associated with higher reduction of neutrophils and platelets. ITPA rs1127354 is useful for the prediction of ribavirin-induced anemia in the early phase after the commencement of peginterferon plus ribavirin treatment and IL28B rs8099917 is useful for the prediction of sustained virological response. Use of the combination of these two genotypes could lead to safe and effective treatment of chronic hepatitis C patients.
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Affiliation(s)
- Tatsuo Miyamura
- Department of Medicine and Clinical Oncology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8677, Japan; (T.M.); (S.N.); (S.W.); (X.J.); (M.A.); (K.F.); (F.I.); (O.Y.)
| | - Tatsuo Kanda
- Department of Medicine and Clinical Oncology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8677, Japan; (T.M.); (S.N.); (S.W.); (X.J.); (M.A.); (K.F.); (F.I.); (O.Y.)
| | - Shingo Nakamoto
- Department of Medicine and Clinical Oncology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8677, Japan; (T.M.); (S.N.); (S.W.); (X.J.); (M.A.); (K.F.); (F.I.); (O.Y.)
- Department of Molecular Virology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8677, Japan;
| | - Shuang Wu
- Department of Medicine and Clinical Oncology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8677, Japan; (T.M.); (S.N.); (S.W.); (X.J.); (M.A.); (K.F.); (F.I.); (O.Y.)
| | - Xia Jiang
- Department of Medicine and Clinical Oncology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8677, Japan; (T.M.); (S.N.); (S.W.); (X.J.); (M.A.); (K.F.); (F.I.); (O.Y.)
| | - Makoto Arai
- Department of Medicine and Clinical Oncology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8677, Japan; (T.M.); (S.N.); (S.W.); (X.J.); (M.A.); (K.F.); (F.I.); (O.Y.)
| | - Keiichi Fujiwara
- Department of Medicine and Clinical Oncology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8677, Japan; (T.M.); (S.N.); (S.W.); (X.J.); (M.A.); (K.F.); (F.I.); (O.Y.)
| | - Fumio Imazeki
- Department of Medicine and Clinical Oncology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8677, Japan; (T.M.); (S.N.); (S.W.); (X.J.); (M.A.); (K.F.); (F.I.); (O.Y.)
| | - Osamu Yokosuka
- Department of Medicine and Clinical Oncology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8677, Japan; (T.M.); (S.N.); (S.W.); (X.J.); (M.A.); (K.F.); (F.I.); (O.Y.)
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Messori A, Fadda V, Maratea D, Trippoli S. Effect of discounting on estimation of benefits determined by hepatitis C treatment. World J Gastroenterol 2012; 18:3032-4. [PMID: 22736930 PMCID: PMC3380334 DOI: 10.3748/wjg.v18.i23.3032] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2011] [Revised: 02/27/2012] [Accepted: 03/20/2012] [Indexed: 02/06/2023] Open
Abstract
The combination of either boceprevir or telaprevir with ribavirin and interferon (triple therapy) has been shown to be more effective than ribavirin+interferon (dual therapy) for the treatment of genotype 1 hepatitis C. Since the benefit of these treatments takes place after years, simulation models are needed to predict long-term outcomes. In simulation models, the choice of different values of yearly discount rates (e.g., 6%, 3.5%, 2%, 1.5% or 0%) influences the results, but no studies have specifically addressed this issue. We examined this point by determining the long-term benefits under different conditions on the basis of standard modelling and using quality-adjusted life years (QALYs) to quantify the benefits. In our base case scenario, we compared the long-term benefit between patients given a treatment with a 40% sustained virologic response (SVR) (dual therapy) and patients given a treatment with a 70% SVR (triple therapy), and we then examined how these specific yearly discount rates influenced the incremental benefit. The gain between a 70% SVR and a 40% SVR decreased from 0.45 QALYs with a 0% discount rate to 0.22 QALYs with a 6% discount rate (ratio between the two values = 2.04). Testing the other discounting assumptions confirmed that the discount rate has a marked impact on the magnitude of the model-estimated incremental benefit. In conclusion, the results of our analysis can be helpful to better interpret cost-effectiveness studies evaluating new treatment for hepatitis C.
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