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Real-world efficacy and safety of glecaprevir/pibrentasvir in Japanese adolescents with chronic hepatitis C: a prospective multicenter study. J Gastroenterol 2023; 58:405-412. [PMID: 36790540 DOI: 10.1007/s00535-023-01968-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Accepted: 02/05/2023] [Indexed: 02/16/2023]
Abstract
BACKGROUND Part 1 of the DORA study, a 2019 international clinical trial of glecaprevir and pibrentasvir (G/P) treatment in adolescents with chronic hepatitis C virus (HCV) infection, demonstrated high efficacy and safety. However, few reports have considered real-world experience with G/P treatment in adolescents with chronic HCV. The present prospective multicenter study assessed real-world efficacy and safety of G/P treatment in Japanese adolescents with chronic HCV. METHODS Subjects between 12 and 17 years old who were treatment-naïve or previously managed with interferon-based regimens were prospectively enrolled and treated with G/P (300 mg/120 mg) once daily for 8 or 12 weeks. The primary efficacy endpoint was sustained virologic response at 12 weeks after treatment completion (SVR12). Adverse effects and laboratory abnormalities were assessed. RESULTS Twenty-five Japanese patients (15 female) were enrolled from 13 pediatric centers in Japan. Median age was 13 years (range 12-17). Numbers of patients with genotypes 1b, 2a, 2b, and 2b/1b were 6, 12, 6, and 1, respectively. Twenty-two were treatment-naïve, while three had experienced interferon-based treatments. All patients completed G/P treatment (24 for 8 weeks and 1 for 12). Twenty-four achieved SVR12 (96%). Most adverse events were mild. None were serious. G/P significantly decreased serum alanine aminotransferase, γ-glutamyltransferase, and Wisteria floribunda agglutinin-positive Mac-2-binding protein concentrations. No negative effects on growth or maturation were apparent at 12 weeks. CONCLUSIONS Under real-world conditions, G/P treatment of Japanese adolescents with chronic HCV was highly efficacious and well tolerated.
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Hou W, Qiao K, Huo Z, Du Y, Wang C, Syn WK. Association of IFNL3 rs12979860 polymorphism with HCV-related hepatocellular carcinoma susceptibility in a Chinese population. Clin Exp Gastroenterol 2019; 12:433-439. [PMID: 31807049 PMCID: PMC6842746 DOI: 10.2147/ceg.s206194] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2019] [Accepted: 08/19/2019] [Indexed: 12/12/2022] Open
Abstract
Background The association between interferon lambda-3 (IFNL3，also known as interleukin 28B, IL28B) rs12979860 polymorphism and the development of hepatocellular carcinoma (HCC) has been investigated in recent studies with inconclusive and inconsistent results. IFNL3 rs12979860 polymorphism has been shown a marked differential distribution with regional and ethnic variation. Whether this single nucleotide polymorphism influences susceptibility to hepatitis C virus (HCV)-related HCC remains elusive. Methods In this case–control study, a total of 157 Chinese Han patients with chronic HCV infection were enrolled, including 62 HCV-related HCC patients and 95 chronic hepatitis C (CHC) patients without HCC, and the genetic polymorphism of IFNL3 rs12979860 was genotyped via a DNA microarray-based assay. The logistic regression analysis was employed to determine the correlation between the genetic polymorphism and risk of HCV-related HCC. Results A higher proportion of CT/TT genotype and T allele was observed in HCC patients compared to the CHC group. Under the genetic model of allele frequency, the T allele was associated with elevated risk of HCV-related HCC in the Chinese population compared to C allele after an adjustment for age, gender, body mass index, HCV infection duration, and HCV genotypes (P=0.046). In the subgroup analysis stratified by HCV genotype, subjects with CHC genotype 1b infection carrying rs12979860 T allele and CT+TT genotype had higher susceptibility to HCC than those with C allele and CC genotype (P=0.020, P=0.037, respectively). Conclusion IFNL3 rs12979860 polymorphism with T allele could be a factor that increases the risk of HCV-related HCC in the Chinese population, especially those subjects with CHC genotype 1b infection.
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Affiliation(s)
- Wei Hou
- Tianjin Second People's Hospital and Tianjin Institute of Hepatology, Tianjin, People's Republic of China.,Division of Gastroenterology and Hepatology, Department of Medicine, Medical University of South Carolina, Charleston, SC, USA
| | - Kunyan Qiao
- Tianjin Second People's Hospital and Tianjin Institute of Hepatology, Tianjin, People's Republic of China
| | - Zhixiao Huo
- Tianjin Second People's Hospital and Tianjin Institute of Hepatology, Tianjin, People's Republic of China
| | - Yanan Du
- Department of Biomedical Engineering, School of Medicine, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Tsinghua University, Beijing, People's Republic of China
| | - Cindy Wang
- Division of Gastroenterology and Hepatology, Department of Medicine, Medical University of South Carolina, Charleston, SC, USA
| | - Wing-Kin Syn
- Division of Gastroenterology and Hepatology, Department of Medicine, Medical University of South Carolina, Charleston, SC, USA.,Section of Gastroenterology, Ralph H Johnson Veterans Affairs Medical Center, Charleston, SC, USA
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Qin S, Wang J, Zhou C, Xu Y, Zhang Y, Wang X, Wang S. The influence of interleukin 28B polymorphisms on the risk of hepatocellular carcinoma among patients with HBV or HCV infection: An updated meta-analysis. Medicine (Baltimore) 2019; 98:e17275. [PMID: 31568008 PMCID: PMC6756689 DOI: 10.1097/md.0000000000017275] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2018] [Revised: 06/14/2019] [Accepted: 08/28/2019] [Indexed: 12/22/2022] Open
Abstract
Single nucleotide polymorphisms (SNPs) of the interleukin 28B (IL28B) gene has proven to be associated with the clinical outcome of patients with chronic hepatitis virus B or C (HBV or HCV) infections. However, whether IL28B SNPs have an influence on the risk of hepatocellular carcinoma (HCC) among patients with HBV or HCV infection remains controversial. Therefore, this study aims to determine the association between IL28B polymorphisms and the risk of HCC in individuals with HBV or HCV infection.PubMed, EMBASE, and Chinese National Knowledge Infrastructure (CNKI) databases were used to identify studies meeting the selection requirements using the terms "interleukin 28B", "IFN-lambda-3", "IFNL3", "single nucleotide polymorphisms", "SNPs", "hepatocellular carcinoma", "HCC", "liver cancer".A total of 24 eligible original studies (1 cohort study and 23 case-control studies) involved 20238 individuals (HCC group = 8725 vs control group = 11,513) were included. Both IL28B rs12979860 CC and rs8099917 TT genotypes were significantly associated with a decreased risk of HCC among patients with HBV or HCV infection (OR = 0.71, 95% CI = 0.57-0.88; OR = 0.82, 95% CI = 0.72-0.94, respectively). Egger test and Begg test revealed no' publication bias (P > .05). Sensitivity analyses suggested the robustness of the results in this meta-analysis.Both IL28B rs12979860 CC and rs8099917 TT genotypes are protective factors for the development of HCC among patients with HBV or HCV infection. Future prospective studies examining the impact of IL28B polymorphisms on the risk of HCC and investigating the underlying mechanism for the protective role of IL28B polymorphisms in HCC development are warranted.
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Affiliation(s)
- Shaoyou Qin
- Department of Gastroenterology and Hepatology, China-Japan Union Hospital of Jilin University
| | - Jiangbin Wang
- Department of Gastroenterology and Hepatology, China-Japan Union Hospital of Jilin University
| | - Changyu Zhou
- Department of Gastroenterology and Hepatology, China-Japan Union Hospital of Jilin University
| | - Yan Xu
- Department of Gastroenterology and Hepatology, China-Japan Union Hospital of Jilin University
| | - Yonggui Zhang
- Department of Gastroenterology and Hepatology, China-Japan Union Hospital of Jilin University
| | - Xu Wang
- Department of Gastroenterology and Hepatology, China-Japan Union Hospital of Jilin University
| | - Song Wang
- Department of Urology, the First Hospital of Jilin University, Changchun, China
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Kim SU, Seo YS, Lee HA, Kim MN, Lee YR, Lee HW, Park JY, Kim DY, Ahn SH, Han KH, Hwang SG, Rim KS, Um SH, Tak WY, Kweon YO, Kim BK, Park SY. A multicenter study of entecavir vs. tenofovir on prognosis of treatment-naïve chronic hepatitis B in South Korea. J Hepatol 2019; 71:456-464. [PMID: 30959156 DOI: 10.1016/j.jhep.2019.03.028] [Citation(s) in RCA: 123] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2019] [Revised: 03/22/2019] [Accepted: 03/26/2019] [Indexed: 12/22/2022]
Abstract
BACKGROUND & AIMS It is currently unclear which antiviral agent, entecavir (ETV) or tenofovir disoproxil fumarate (TDF), is superior for improving prognosis in patients with chronic hepatitis B (CHB). Here, we assessed the ability of these 2 antivirals to prevent liver-disease progression in treatment-naïve patients with CHB. METHODS From 2012 to 2014, treatment-naïve patients with CHB who received ETV or TDF as a first-line antiviral agent were recruited from 4 academic teaching hospitals. Patients with decompensated cirrhosis or hepatocellular carcinoma (HCC) at enrollment were excluded. Cumulative probabilities of HCC and death or orthotopic liver transplant (OLT) were assessed. RESULTS In total, 2,897 patients (1,484 and 1,413 in the ETV and TDF groups, respectively) were recruited. The annual HCC incidence was not statistically different between the ETV and TDF groups (1.92 vs. 1.69 per 100 person-years [PY], respectively; adjusted hazard ratio [HR] 0.975 [p = 0.852] by multivariate analysis). Propensity score (PS)-matched and inverse probability of treatment weighting (ITPW) analyses yielded similar patterns of results (HR 1.021 [p = 0.884] and 0.998 [p = 0.988], respectively). The annual incidence of death or OLT was not statistically different between the ETV and TDF groups (0.52 vs. 0.53 per 100 PY, respectively; adjusted HR 1.202 [p = 0.451]). PS-matched and ITPW analyses yielded similar patterns of results (HR 1.248 [p = 0.385] and 1.239 [p = 0.360], respectively). These findings were consistently reproduced in patients with compensated cirrhosis (all p >0.05). CONCLUSIONS The overall prognosis in terms of HCC and death or OLT was not statistically different between the ETV and TDF groups. Further studies are needed to validate our results. LAY SUMMARY It is currently unclear which antiviral agent, entecavir or tenofovir disoproxil fumarate, is superior for improving prognosis in patients with chronic hepatitis B virus infection. In this analysis we found that there was no difference in terms of overall prognosis, including risk of hepatocellular carcinoma, death, or the need for a liver transplant, in patients receiving either antiviral.
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Affiliation(s)
- Seung Up Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea; Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea; Yonsei Liver Center, Severance Hospital, Seoul, Republic of Korea
| | - Yeon Seok Seo
- Department of Internal Medicine, Korea University College of Medicine, Seoul, Republic of Korea
| | - Han Ah Lee
- Department of Internal Medicine, Korea University College of Medicine, Seoul, Republic of Korea
| | - Mi Na Kim
- Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam, Republic of Korea
| | - Yu Rim Lee
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, Republic of Korea
| | - Hye Won Lee
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea; Yonsei Liver Center, Severance Hospital, Seoul, Republic of Korea
| | - Jun Yong Park
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea; Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea; Yonsei Liver Center, Severance Hospital, Seoul, Republic of Korea
| | - Do Young Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea; Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea; Yonsei Liver Center, Severance Hospital, Seoul, Republic of Korea
| | - Sang Hoon Ahn
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea; Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea; Yonsei Liver Center, Severance Hospital, Seoul, Republic of Korea
| | - Kwang-Hyub Han
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea; Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea; Yonsei Liver Center, Severance Hospital, Seoul, Republic of Korea
| | - Seong Gyu Hwang
- Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam, Republic of Korea
| | - Kyu Sung Rim
- Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam, Republic of Korea
| | - Soon Ho Um
- Department of Internal Medicine, Korea University College of Medicine, Seoul, Republic of Korea
| | - Won Young Tak
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, Republic of Korea
| | - Young Oh Kweon
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, Republic of Korea
| | - Beom Kyung Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea; Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea; Yonsei Liver Center, Severance Hospital, Seoul, Republic of Korea.
| | - Soo Young Park
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, Republic of Korea.
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Complex Association of Virus- and Host-Related Factors with Hepatocellular Carcinoma Rate following Hepatitis C Virus Clearance. J Clin Microbiol 2019; 57:JCM.01463-18. [PMID: 30381417 DOI: 10.1128/jcm.01463-18] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2018] [Accepted: 10/23/2018] [Indexed: 02/07/2023] Open
Abstract
Little is known about the effects of virus- and host-related factors on hepatocarcinogenesis in patients who show viral clearance after HCV RNA eradication by direct-acting antivirals (DAAs). The subjects of this retrospective study were 1,922 patients with HCV genotype 1 (HCV-1)- or HCV-2-related chronic liver disease who showed a sustained virological response (SVR; defined as negative results for HCV RNA at 12 weeks after the cessation of all-oral DAAs). All patients were confirmed to be hepatocellular carcinoma (HCC) free before and during DAAs. HCC was diagnosed in 43 patients during the follow-up, with an incidence rate per 1,000 person years of 9.44. The cumulative HCC rates were 1.2, 2.0, and 3.1% at the end of 1, 2, and 3 years, respectively. The annual rate of HCC during the first 3 years was 1.0%. The incidence rate was significantly higher in patients infected with the HCV-1b core amino acid (aa) 70 mutant than in those infected with HCV-2a/2b, and the rate in patients infected with the HCV-1b core aa 70 wild type tended to be higher than that in patients infected with HCV-2a/2b. The rate in patients infected with the HCV-1b NS5A aa 93 mutant was significantly higher than that in patients infected with HCV-2a/2b. However, the rate was not different between patients infected with the IL28B rs8099917 TT genotype and patients infected with the non-TT genotype. Multivariate analysis identified a Wisteria floribunda agglutinin-positive Mac-2 binding protein (WFA+M2BP) cutoff index (COI) of ≥2.5 and infection with the HCV-1b core aa 70 mutant subgroup to be pretreatment predictors of posttreatment HCC. The same analysis identified an alpha-fetoprotein concentration of ≥5 μg/liter and an WFA+M2BP COI of ≥1.0 to be predictors of HCC at 24 weeks after the end of antiviral therapy. We conclude that both virus- and host-related factors seem to influence the development of HCC after HCV RNA eradication.
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Attallah AM, Omran D, Marie MS, Abdelrazek M, Salama A, El Essawey R, Mobarak L, Maklad S, Omar A. IL-28B rs12979860 polymorphism affect the course of chronic hepatitis and the development of HCC in Egyptian patients with hepatitis C type 4. Br J Biomed Sci 2018; 75:157-162. [PMID: 29914308 DOI: 10.1080/09674845.2018.1489599] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2018] [Accepted: 05/07/2018] [Indexed: 12/16/2022]
Abstract
BACKGROUND A single nucleotide polymorphism (SNP) in the interleukin 28B (IL28B) gene may alter the trajectory of hepatitis C virus (HCV) chronic infection. Several studies have sought to determine a link between IL28B rs12979860 SNP and the development of HCV-related hepatocellular carcinoma (HCC), but with variable results, and consensus is awaited. We hypothesised that IL28B rs12979860 SNP is linked to HCC in patients with HCV type 4. METHODS IL28B genotyping of 300 patients with HCV-related fibrosis (n = 100), cirrhosis (n = 100) and HCC (n = 100) was carried out and the results were analysed to determine the association between the IL28B genotype and clinical outcome. RESULTS In IL28B TT genotype carriers, the proportions of moderate/severe fibrosis, advanced cirrhosis (Child B-C) and HCC (50%, 84% and 60.2%, respectively) were higher (p < 0.05) than in CC/CT (4.3%, 46% and 23%, respectively). IL-28B SNP was linked significantly (p < 0.05) with cirrhosis progression and HCC advanced stages. Moreover, HCC advanced Child, Okuda and CLIP stages were associated with T allele carriage (73.9%, 82.6% and 78.3% vs. 44.2%, 50.6% and 46.8% in CC/CT). The percentage of large tumour size (> 3cm) increased (p = 0.028) in TT genotype carriers (81.8% vs.52.6% in CC/CT). CONCLUSION IL-28B rs12979860 TT genotype is more prevalent in patients with advanced fibrosis, cirrhosis and HCC stages. Thus, it seems to be associated with poor outcomes in chronic HCV patients and to augment the risk of developing HCC.
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Affiliation(s)
- A M Attallah
- a Research & Development Department , Biotechnology Research Center , New Damietta , Egypt
| | - D Omran
- b Department of Endemic Medicine and Hepatology, Faculty of Medicine , Cairo University , Cairo , Egypt
| | - M S Marie
- b Department of Endemic Medicine and Hepatology, Faculty of Medicine , Cairo University , Cairo , Egypt
| | - Mohamed Abdelrazek
- a Research & Development Department , Biotechnology Research Center , New Damietta , Egypt
| | - A Salama
- b Department of Endemic Medicine and Hepatology, Faculty of Medicine , Cairo University , Cairo , Egypt
| | - R El Essawey
- c Department of Clinical and Chemical pathology, Faculty of Medicine , Cairo University , Cairo , Egypt
| | - L Mobarak
- d National Hepatology and Tropical Medicine Research Institute , Cairo , Egypt
| | - S Maklad
- d National Hepatology and Tropical Medicine Research Institute , Cairo , Egypt
| | - A Omar
- b Department of Endemic Medicine and Hepatology, Faculty of Medicine , Cairo University , Cairo , Egypt
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Molecular Mechanisms of Hepatocarcinogenesis Following Sustained Virological Response in Patients with Chronic Hepatitis C Virus Infection. Viruses 2018; 10:v10100531. [PMID: 30274202 PMCID: PMC6212901 DOI: 10.3390/v10100531] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2018] [Revised: 09/25/2018] [Accepted: 09/27/2018] [Indexed: 02/07/2023] Open
Abstract
Despite the success of direct-acting antiviral (DAA) agents in treating chronic hepatitis C virus (HCV) infection, the number of cases of HCV-related hepatocellular carcinoma (HCC) is expected to increase over the next five years. HCC develops over the span of decades and is closely associated with fibrosis stage. HCV both directly and indirectly establishes a pro-inflammatory environment favorable for viral replication. Repeated cycles of cell death and regeneration lead to genomic instability and loss of cell cycle control. DAA therapy offers >90% sustained virological response (SVR) rates with fewer side effects and restrictions than interferon. While elimination of HCV helps to restore liver function and reverse mild fibrosis, post-SVR patients remain at elevated risk of HCC. A series of studies reporting higher than expected rates of HCC development among DAA-treated patients ignited debate over whether use of DAAs elevates HCC risk compared to interferon. However, recent prospective and retrospective studies based on larger patient cohorts have found no significant difference in risk between DAA and interferon therapy once other factors are taken into account. Although many mechanisms and pathways involved in hepatocarcinogenesis have been elucidated, our understanding of drivers specific to post-SVR hepatocarcinogenesis is still limited, and lack of suitable in vivo and in vitro experimental systems has hampered efforts to examine etiology-specific mechanisms that might serve to answer this question more thoroughly. Further research is needed to identify risk factors and biomarkers for post-SVR HCC and to develop targeted therapies based on more complete understanding of the molecules and pathways implicated in hepatocarcinogenesis.
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Sedeno-Monge V, Vallejo-Ruiz V, Sosa-Jurado F, Santos-Lopez G. Polymorphisms in the hepatitis C virus core and its association with development of hepatocellular carcinoma. J Biosci 2018; 42:509-521. [PMID: 29358564 DOI: 10.1007/s12038-017-9695-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Little is known about the mechanisms underlying hepatocellular carcinoma (HCC). Some studies have focused on the role of HCV viral proteins in hepatocyte transformation. In this work we have compiled and analysed current articles regarding the impact of polymorphisms in the HCV core gene and protein on the development of HCC. An exhaustive search for fulltext articles until November 2016 in PubMed database was performed using the MeSH keywords: 'hepatitis C', 'polymorphisms', 'core', 'hepatocellular cancer' and 'hepatocarcinogenesis'. Nineteen full-text articles published between 2000 and 2016 were considered. Different articles associate not only the HCC development with polymorphisms at residues 70 and 91 in the core protein, but more with mortality and treatment response. Also, different polymorphisms were found in core and other viral proteins related to HCC development. Eleven articles reported that HCC development is significantly associated with Gln/His70, four associated it with Leu91 and two more associated it with both markers together. Additional studies are necessary, including those in different types of populations worldwide, to validate the possibility of the usability and influence in chronically HCV-infected patients as well as to observe their interaction with other risk factors or prognosis and genetic markers of the host.
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Affiliation(s)
- Virginia Sedeno-Monge
- Departamento de Ciencias de la Salud, Universidad Popular Autonoma del Estado de Puebla, Puebla, Mexico
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Matsuura K, Tanaka Y. Host genetic variations associated with disease progression in chronic hepatitis C virus infection. Hepatol Res 2018; 48:127-133. [PMID: 29235266 DOI: 10.1111/hepr.13042] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2017] [Revised: 12/04/2017] [Accepted: 12/05/2017] [Indexed: 12/19/2022]
Abstract
Treatment with recently developed interferon-free oral regimens combining direct-acting antiviral agents (DAAs) results in the elimination of hepatitis C virus (HCV) in almost all chronic hepatitis C (CHC) patients. In the era of DAAs, surveillance of hepatocellular carcinoma (HCC) after eradication of HCV by anti-HCV therapy is particularly important. As is well known, an advanced state of hepatic fibrosis is the major risk factor for developing HCC. Therefore, an increased understanding of various factors associated with disease progression and development of HCC in CHC patients is essential for implementing personalized treatment and surveillance of disease progression and HCC. Recent genome-wide association studies (GWAS) have identified several host genetic variants influencing treatment efficacy or clinical course in HCV infection. This review focuses on these host genetic variations recently identified, mainly by GWAS, which are associated with the clinical course of chronic HCV infection, especially disease progression and hepatocarcinogenesis.
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Affiliation(s)
- Kentaro Matsuura
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.,Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Yasuhito Tanaka
- Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
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Irshad M, Gupta P, Irshad K. Molecular basis of hepatocellular carcinoma induced by hepatitis C virus infection. World J Hepatol 2017; 9:1305-1314. [PMID: 29359013 PMCID: PMC5756719 DOI: 10.4254/wjh.v9.i36.1305] [Citation(s) in RCA: 43] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2017] [Revised: 11/08/2017] [Accepted: 12/05/2017] [Indexed: 02/06/2023] Open
Abstract
Present study outlines a comprehensive view of published information about the underlying mechanisms operational for progression of chronic hepatitis C virus (HCV) infection to development of hepatocellular carcinoma (HCC). These reports are based on the results of animal experiments and human based studies. Although, the exact delineated mechanism is not yet established, there are evidences available to emphasize the involvement of HCV induced chronic inflammation, oxidative stress, insulin resistance, endoplasmic reticulum stress, hepato steatosis and liver fibrosis in the progression of HCV chronic disease to HCC. Persistent infection with replicating HCV not only initiates several liver alterations but also creates an environment for development of liver cancer. Various studies have reported that HCV acts both directly as well as indirectly in promoting this process. Whereas HCV related proteins, like HCV core, E1, E2, NS3 and NS5A, modulate signal pathways dysregulating cell cycle and cell metabolism, the chronic infection produces similar changes in an indirect way. HCV is an RNA virus and does not integrate with host genome and therefore, HCV induced hepatocarcinogenesis pursues a totally different mechanism causing imbalance between suppressors and proto-oncogenes and genomic integrity. However, the exact mechanism of HCC inducement still needs a full understanding of various steps involved in this process.
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Affiliation(s)
- Mohammad Irshad
- Clinical Biochemistry Division, Department of Laboratory Medicine, All India Institute of Medical Sciences, New Delhi 110029, India.
| | - Priyanka Gupta
- Clinical Biochemistry Division, Department of Laboratory Medicine, All India Institute of Medical Sciences, New Delhi 110029, India
| | - Khushboo Irshad
- Clinical Biochemistry Division, Department of Laboratory Medicine, All India Institute of Medical Sciences, New Delhi 110029, India
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Sultana C, Oprişan G, Teleman MD, Dinu S, Oprea C, Voiculescu M, Ruta S. Impact of hepatitis C virus core mutations on the response to interferon-based treatment in chronic hepatitis C. World J Gastroenterol 2016; 22:8406-8413. [PMID: 27729747 PMCID: PMC5055871 DOI: 10.3748/wjg.v22.i37.8406] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2016] [Revised: 08/09/2016] [Accepted: 08/23/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To determine whether hepatitis C virus (HCV) core substitutions play a role in the response to interferon-based treatment in Caucasian patients. METHODS One hundred eight HCV chronically infected patients initiating treatment with pegylated IFN plus ribavirin for 48 wk were tested for baseline substitutions at codons 70 and 91 of the viral core protein (BigDye Terminator vers.3.1, Applied Biosystems,) and for genetic polymorphisms in host IL28B gene rs12979860 (Custom TaqMan 5' allelic discrimination assay; Applied Biosystems). RESULTS Of the patients, all were infected with HCV genotype 1b, 44.4% had low baseline HCV viral load, and 37.9% had mild/moderate fibrosis. Only 38.9% achieved therapeutic success, defined as sustained virological response (SVR). Eighty-eight percent of the patients presented at least one substitution at core position 70 (R70Q/H) or/and position 91 (L91M). The favorable IL28B CC polymorphism was detected in only 17.6% of the patients. In the univariate analysis, young age (P < 0.001), urban residence (P = 0.004), IL28B CC genotype (P < 0.001), absence of core mutations (P = 0.005), achievement of rapid virologic response (P < 0.001) and early virological response (P < 0.001) were significantly correlated with SVR. A multivariate analysis revealed three independent predictors of therapeutic success: young age (P < 0.001), absence of core substitutions (P = 0.04) and IL28B CC genotype (P < 0.001); the model correctly classified 75.9% of SVR cases with a positive predictive value of 80.7%. CONCLUSION HCV core mutations can help distinguish between patients who can still benefit from the affordable IFN-based therapy from those who must be treated with DAAs to prevent the evolution towards end-stage liver disease.
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12
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Molecular mechanisms of hepatitis C virus-induced hepatocellular carcinoma. Clin Microbiol Infect 2016; 22:853-861. [PMID: 27476823 DOI: 10.1016/j.cmi.2016.07.019] [Citation(s) in RCA: 101] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2016] [Revised: 07/09/2016] [Accepted: 07/16/2016] [Indexed: 02/06/2023]
Abstract
Hepatitis C virus (HCV) is a major leading cause of hepatocellular carcinoma (HCC). HCV-induced hepatocarcinogenesis is a multistep process resulting from a combination of pathway alterations that are either caused directly by viral factors or immune mediated as a consequence of a chronic state of inflammation. Host genetic variation is now emerging as an additional element that contribute to increase the risk of developing HCC. The advent of direct-acting antiviral agents foresees a rapid decline of HCC rate in HCV patients. However, a full understanding of the HCV-mediated tumourigenic process is required to elucidate if pro-oncogenic signatures may persist after virus clearance, and to identify novel tools for HCC prevention and therapy. In this review, we summarize the current knowledge of the molecular mechanisms responsible for HCV-induced hepatocarcinogenesis.
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Moreira JP, Malta FDM, Diniz MA, Kikuchi L, Chagas AL, Lima LDSB, Gomes-Gouvêa MS, de Castro VFD, Santana RAF, Sumita NM, Paranagua Vezozzo DC, Carrilho FJ, Pinho JRR. Interferon lambda and hepatitis C virus core protein polymorphisms associated with liver cancer. Virology 2016; 493:136-41. [PMID: 27035616 DOI: 10.1016/j.virol.2016.03.008] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2016] [Revised: 03/06/2016] [Accepted: 03/09/2016] [Indexed: 02/07/2023]
Abstract
BACKGROUND Hepatitis C virus (HCV) infection is often persistent and gradually advances from chronic hepatitis to liver cirrhosis and hepatocellular carcinoma (HCC). Worldwide, hepatocellular carcinoma is the fifth most common neoplasm. METHOD OF STUDY the Interferon lambda (IFNL) polymorphisms genotypes (rs8099917, rs12979860 and rs12980275) and the presence of mutations in HCV core protein were analyzed in 59 patients with HCC, and also in 50 cirrhotic patients (without HCC). RESULTS the rs12980275-AG genotype was associated with HCC on age-adjusted analysis (OR 2.42, 95% CI 1.03-5.69, P=0.043). Core substitutions R70Q and L91M were mainly found in genotype 1b isolates. Furthermore, a borderline level of statistical significance association was found among the presence of amino acid Glutamine (Q) in the position 70 and IFNL3 genotype AG (P=0.054). CONCLUSIONS the screening of these polymorphisms and functional studies would be useful in clinical practice for identifying groups at high risk of HCC development.
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Affiliation(s)
- João Paulo Moreira
- Laboratory of Tropical Gastroenterology and Hepatology "João Alves de Queiroz and Castorina Bittencourt Alves", LIM-07, Institute of Tropical Medicine, University of São Paulo, São Paulo, Brazil; Department of Gastroenterology, University of São Paulo, School of Medicine, São Paulo, Brazil
| | - Fernanda de Mello Malta
- Laboratory of Tropical Gastroenterology and Hepatology "João Alves de Queiroz and Castorina Bittencourt Alves", LIM-07, Institute of Tropical Medicine, University of São Paulo, São Paulo, Brazil; Department of Gastroenterology, University of São Paulo, School of Medicine, São Paulo, Brazil.
| | - Márcio Augusto Diniz
- Department of Gastroenterology, University of São Paulo, School of Medicine, São Paulo, Brazil; Samuel Oschin Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United States
| | - Luciana Kikuchi
- Department of Gastroenterology, University of São Paulo, School of Medicine, São Paulo, Brazil
| | - Aline Lopes Chagas
- Department of Gastroenterology, University of São Paulo, School of Medicine, São Paulo, Brazil
| | - Livia de Souza Botelho Lima
- Laboratory of Tropical Gastroenterology and Hepatology "João Alves de Queiroz and Castorina Bittencourt Alves", LIM-07, Institute of Tropical Medicine, University of São Paulo, São Paulo, Brazil; Department of Gastroenterology, University of São Paulo, School of Medicine, São Paulo, Brazil
| | - Michele Soares Gomes-Gouvêa
- Laboratory of Tropical Gastroenterology and Hepatology "João Alves de Queiroz and Castorina Bittencourt Alves", LIM-07, Institute of Tropical Medicine, University of São Paulo, São Paulo, Brazil; Department of Gastroenterology, University of São Paulo, School of Medicine, São Paulo, Brazil
| | | | | | - Nairo Massakazu Sumita
- Central Laboratory Division of Hospital das Clínicas, University of São Paulo, School of Medicine, São Paulo, Brazil
| | | | - Flair José Carrilho
- Department of Gastroenterology, University of São Paulo, School of Medicine, São Paulo, Brazil
| | - João Renato Rebello Pinho
- Laboratory of Tropical Gastroenterology and Hepatology "João Alves de Queiroz and Castorina Bittencourt Alves", LIM-07, Institute of Tropical Medicine, University of São Paulo, São Paulo, Brazil; Department of Gastroenterology, University of São Paulo, School of Medicine, São Paulo, Brazil; Hospital Israelita Albert Einstein, São Paulo, Brazil
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Kadjbaf D, Keshvari M, Alavian SM, Pouryasin A, Behnava B, Salimi S, Mehrnoush L, Karimi Elizee P, Sharafi H. The Prevalence of Hepatitis C Virus Core Amino Acid 70 Substitution and Genotypes of Polymorphisms Near the IFNL3 Gene in Iranian Patients With Chronic Hepatitis C. HEPATITIS MONTHLY 2016; 16:e37011. [PMID: 27630727 PMCID: PMC5010881 DOI: 10.5812/hepatmon.37011] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/09/2016] [Revised: 03/06/2016] [Accepted: 03/18/2016] [Indexed: 12/11/2022]
Abstract
BACKGROUND Molecular studies have demonstrated that the hepatitis C virus (HCV) genotype and host genetics play predictive roles in the management of patients infected with HCV. OBJECTIVES This study aimed to investigate the HCV genotype, core amino acid (aa) 70 substitution, and polymorphisms near the IFNL3 gene (including rs12979860 and rs8099917) among Iranian patients with chronic hepatitis C (CHC). PATIENTS AND METHODS In this cross-sectional study, the molecular profiles of the HCV genotype, core aa 70 substitution, and rs12979860 and rs8099917 polymorphisms and plasma HCV RNA levels were determined in 429 CHC patients including 141 hemophilic, 84 thalassemic, and 204 non-hemophilic, non-thalassemic patients. RESULTS The hepatitis C virus subtype 1a was the most common subtype in the study population. Core aa substitution Arg70Gln was strongly associated with cirrhosis (OR = 2.49; 95% CI = 1.13 - 5.50; P = 0.020). Core aa 70 substitutions were more frequently observed in patients with the HCV subtype 1b than in patients with any other HCV subtypes (P < 0.001). Core aa 70 substitutions were also more common in patients with the rs12979860 TT genotype than in patients with non-TT genotypes (17.3% vs. 8.5%, P = 0.022) and also in rs8099917 non-TT genotypes than in the TT genotype (14.0% vs. 7.0%, P = 0.026). The HCV genotypes and rs8099917 polymorphisms were correlated in which HCV subtype 1b was in favor of rs8099917 GG and HCV subtype 3a favored rs8099917 TT (P = 0.021). Furthermore, the rs12979860 TT and rs8099917 GG genotypes showed significantly lower HCV RNA levels than the other genotypes (P < 0.001). CONCLUSIONS There is an as yet unexplained association between HCV and host parameters with unknown mechanisms in patients with chronic HCV infection. The assessments of core aa 70 substitution and polymorphisms near the IFNL3 gene could offer promising steps to improve the management of patients with HCV.
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Affiliation(s)
- Danesh Kadjbaf
- Baqiyatallah Research Center for Gastroenterology and Liver Diseases, Baqiyatallah University of Medical Sciences, Tehran, IR Iran
- School of Medicine, Tehran University of Medical Sciences (TUMS), Tehran, IR Iran
| | - Maryam Keshvari
- Blood Transfusion Research Center, High Institute for Research and Education in Transfusion Medicine, Tehran, IR Iran
| | - Seyed Moayed Alavian
- Baqiyatallah Research Center for Gastroenterology and Liver Diseases, Baqiyatallah University of Medical Sciences, Tehran, IR Iran
- Middle East Liver Disease (MELD) Center, Tehran, IR Iran
| | - Ali Pouryasin
- Armin Pathobiology Laboratory, Tehran, IR Iran
- Department of Biology, Arsanjan Branch, Islamic Azad University, Arsanjan, IR Iran
| | - Bita Behnava
- Baqiyatallah Research Center for Gastroenterology and Liver Diseases, Baqiyatallah University of Medical Sciences, Tehran, IR Iran
- Middle East Liver Disease (MELD) Center, Tehran, IR Iran
| | - Shima Salimi
- Baqiyatallah Research Center for Gastroenterology and Liver Diseases, Baqiyatallah University of Medical Sciences, Tehran, IR Iran
- Middle East Liver Disease (MELD) Center, Tehran, IR Iran
| | - Leila Mehrnoush
- Baqiyatallah Research Center for Gastroenterology and Liver Diseases, Baqiyatallah University of Medical Sciences, Tehran, IR Iran
- Middle East Liver Disease (MELD) Center, Tehran, IR Iran
| | | | - Heidar Sharafi
- Baqiyatallah Research Center for Gastroenterology and Liver Diseases, Baqiyatallah University of Medical Sciences, Tehran, IR Iran
- Middle East Liver Disease (MELD) Center, Tehran, IR Iran
- Armin Pathobiology Laboratory, Tehran, IR Iran
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Matsuura K, Tanaka Y. Host genetic variants influencing the clinical course of hepatitis C virus infection. J Med Virol 2015. [PMID: 26211651 DOI: 10.1002/jmv.24334] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
The clinical course of hepatitis C virus (HCV) infection greatly differs in individuals. Various viral, host, and environmental factors influence the natural history of HCV infection. Recent genome-wide association studies identified several host genetic factors influencing treatment efficacy or clinical course in HCV infection. A landmark discovery was that IFNL3-IFNL4 variants are strongly associated with responses to interferon-based treatment. Genetic variants in IFNL3-IFNL4 as well as those in HLA class II loci influence the spontaneous clearance of acute HCV infection. Interestingly, these genetic variants also affect the activity of hepatitis, or disease progression in chronic hepatitis C. In addition, polymorphisms in apoptosis-related genes such as RNF7, TULP1, and MERTK are associated with fibrosis progression, and DEPDC5 and MICA variants are associated with HCV-related hepatocellular carcinoma. Understanding the genetic factors associated with the clinical course of HCV infection is essential for personalized treatment and surveillance of disease progression and hepatocellular carcinoma.
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Affiliation(s)
- Kentaro Matsuura
- Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan.,Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan.,Department of Transfusion Medicine, Clinical CenterInfectious Disease and Immunogenetics Section, National Institutes of Health, Bethesda, Maryland
| | - Yasuhito Tanaka
- Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan
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Chang KC, Tseng PL, Wu YY, Hung HC, Huang CM, Lu SN, Wang JH, Lee CM, Chen CH, Tsai MC, Yen YH, Lin MT, Wu CK, Huang CC, Chen HH, Hu TH. A polymorphism in interferon L3 is an independent risk factor for development of hepatocellular carcinoma after treatment of hepatitis C virus infection. Clin Gastroenterol Hepatol 2015; 13:1017-24. [PMID: 25460552 DOI: 10.1016/j.cgh.2014.10.035] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2014] [Revised: 10/12/2014] [Accepted: 10/17/2014] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Polymorphisms in interferon (IFN)L3 (encodes IFNλ3 or interleukin 28B) are associated with outcomes of treatment for hepatitis C virus (HCV) infection. However, there is controversy regarding how polymorphisms in IFNL3 affect the risk for development of hepatocellular carcinoma (HCC) in patients treated with pegylated interferon and ribavirin. METHODS In a retrospective study, we analyzed data from 1118 patients with HCV infection (589 men; median age, 60 y; 49.9% infected with genotype 1; 51.3% with advanced fibrosis) treated with pegylated interferon and ribavirin from March 2000 through October 2009 at the Chang Gung Memorial Hospital in Kaohsiung, Taiwan (71.64% achieved sustained virologic response [SVR]). Baseline samples were collected before therapy. Starting 24 weeks after treatment, clinical and biochemical features were assessed every 3 to 6 months and patients underwent ultrasound examinations. Lesions detected were examined by computed tomography, angiography, or fine-needle aspiration biopsy analyses. Patients were followed up from the initiation of HCV therapy until a diagnosis of HCC (based on published guidelines), death, or March 31, 2013 (median, 60 mo). DNA samples from each patient were analyzed for rs12979860 in IFNL3. Kaplan-Meier analysis was used to determine the risk for development of HCC. RESULTS The percentages of patients with the IFNL3 rs12979860 CC, CT, and TT genotypes were 86.4%, 13.2%, and 0.3%, respectively. A total of 108 patients (9.66%) developed HCC. The IFNL3 rs12979860 CT and TT genotypes correlated with high baseline levels of α-fetoprotein (AFP; ≥20 ng/mL), advanced stage of fibrosis, diabetes, or lack of an SVR (all P < .05). Based on multivariate Cox regression analysis, age 60 years and older, low platelet count (<15 × 10(9) cells/L), AFP level of 20 ng/mL or greater, advanced stage fibrosis, diabetes, lack of an SVR, and the IFNL3 rs12979860 CT and TT genotypes were significant risk factors for HCC (P < .05). Age 60 years and older, low numbers of platelets or high AFP level, and advanced fibrosis were risk factors for HCC among patients with a SVR. The IFNL3 rs12979860 genotype did not have a significant effect on risk for HCC among patients with SVRs, although some of these patients (with the CT or TT genotype) did develop HCC. Among patients without SVRs, only fibrosis stage and the IFNL3 rs12979860 CT and TT genotypes (hazard ratio, 1.80; 95% confidence interval, 1.06-3.07; P = .030) were independent risk factors for HCC. CONCLUSIONS Based on a retrospective study of patients treated for HCV infection, the IFNL3 rs12979860 CT and TT polymorphisms are associated with a risk for HCC, especially in patients without a SVR.
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Affiliation(s)
- Kuo-Chin Chang
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Po-Lin Tseng
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Yi-Ying Wu
- Division of Biostatistics, Graduate Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan
| | - Hung-Chao Hung
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Chao-Min Huang
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Sheng-Nan Lu
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Jing-Houng Wang
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Chuan-Mo Lee
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Chien-Hung Chen
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Ming-Chao Tsai
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Yi-Hao Yen
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Ming-Tsung Lin
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Cheng-Kun Wu
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Chao-Cheng Huang
- Department of Pathology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan; School of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Hsiu-Hsi Chen
- Division of Biostatistics, Graduate Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan
| | - Tsung-Hui Hu
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan.
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Echeverría N, Moratorio G, Cristina J, Moreno P. Hepatitis C virus genetic variability and evolution. World J Hepatol 2015; 7:831-845. [PMID: 25937861 PMCID: PMC4411526 DOI: 10.4254/wjh.v7.i6.831] [Citation(s) in RCA: 74] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2014] [Revised: 12/22/2014] [Accepted: 02/11/2015] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) has infected over 170 million people worldwide and creates a huge disease burden due to chronic, progressive liver disease. HCV is a single-stranded, positive sense, RNA virus, member of the Flaviviridae family. The high error rate of RNA-dependent RNA polymerase and the pressure exerted by the host immune system, has driven the evolution of HCV into 7 different genotypes and more than 67 subtypes. HCV evolves by means of different mechanisms of genetic variation. On the one hand, its high mutation rates generate the production of a large number of different but closely related viral variants during infection, usually referred to as a quasispecies. The great quasispecies variability of HCV has also therapeutic implications since the continuous generation and selection of resistant or fitter variants within the quasispecies spectrum might allow viruses to escape control by antiviral drugs. On the other hand HCV exploits recombination to ensure its survival. This enormous viral diversity together with some host factors has made it difficult to control viral dispersal. Current treatment options involve pegylated interferon-α and ribavirin as dual therapy or in combination with a direct-acting antiviral drug, depending on the country. Despite all the efforts put into antiviral therapy studies, eradication of the virus or the development of a preventive vaccine has been unsuccessful so far. This review focuses on current available data reported to date on the genetic mechanisms driving the molecular evolution of HCV populations and its relation with the antiviral therapies designed to control HCV infection.
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Miura M, Maekawa S, Sato M, Komatsu N, Tatsumi A, Takano S, Amemiya F, Nakayama Y, Inoue T, Sakamoto M, Enomoto N. Deep sequencing analysis of variants resistant to the non-structural 5A inhibitor daclatasvir in patients with genotype 1b hepatitis C virus infection. Hepatol Res 2014; 44:E360-7. [PMID: 24612030 DOI: 10.1111/hepr.12316] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2013] [Revised: 02/12/2014] [Accepted: 02/14/2014] [Indexed: 12/11/2022]
Abstract
AIM Daclatasvir, a non-structural (NS)5A replication complex inhibitor, is a potent and promising direct antiviral agent (DAA) for hepatitis C virus (HCV), being most effective in genotype 1b infection. Although it is known that genotype 1b viruses with Y93H and/or L31M/V/F mutations have strong resistance to daclatasvir, it is not known whether there are some clinical background conditions that favor the occurrence of HCV carrying those NS5A mutations. METHODS In this study, we carried out deep sequencing analysis of stored sera to determine the presence and significance of daclatasvir-resistant mutants in 110 genotype 1b HCV-infected patients with no previous daclatasvir treatment. RESULTS Deep sequencing analysis revealed that the NS5A L31M/V/F and Y93H mutations were present in 13 (11.8%) and 34 (30.9%) of the 110 patients, respectively, and significantly more frequently than in the control plasmid. Simultaneous L31M/V/F and Y93H mutations were detected in four of the 110 patients (3.6%). When the clinical relevance of NS5A resistance was investigated, Y93H was significantly correlated with the IL28B major (TT) genotype of the host (P = 0.042). CONCLUSION Y93H was detected frequently by deep sequencing in daclatasvir treatment-naïve patients. Importantly, it seems that the IL28B status of the patients may influence the presence of Y93H mutations, resulting in different treatment responses to daclatasvir.
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Affiliation(s)
- Mika Miura
- First Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, Chuo, Yamanashi, Japan
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HCV genome-wide genetic analyses in context of disease progression and hepatocellular carcinoma. PLoS One 2014; 9:e103748. [PMID: 25079603 PMCID: PMC4117537 DOI: 10.1371/journal.pone.0103748] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2014] [Accepted: 07/01/2014] [Indexed: 12/20/2022] Open
Abstract
Hepatitis C virus (HCV) is a major cause of hepatitis and hepatocellular carcinoma (HCC) world-wide. Most HCV patients have relatively stable disease, but approximately 25% have progressive disease that often terminates in liver failure or HCC. HCV is highly variable genetically, with seven genotypes and multiple subtypes per genotype. This variation affects HCV's sensitivity to antiviral therapy and has been implicated to contribute to differences in disease. We sequenced the complete viral coding capacity for 107 HCV genotype 1 isolates to determine whether genetic variation between independent HCV isolates is associated with the rate of disease progression or development of HCC. Consensus sequences were determined by sequencing RT-PCR products from serum or plasma. Positions of amino acid conservation, amino acid diversity patterns, selection pressures, and genome-wide patterns of amino acid covariance were assessed in context of the clinical phenotypes. A few positions were found where the amino acid distributions or degree of positive selection differed between in the HCC and cirrhotic sequences. All other assessments of viral genetic variation and HCC failed to yield significant associations. Sequences from patients with slow disease progression were under a greater degree of positive selection than sequences from rapid progressors, but all other analyses comparing HCV from rapid and slow disease progressors were statistically insignificant. The failure to observe distinct sequence differences associated with disease progression or HCC employing methods that previously revealed strong associations with the outcome of interferon α-based therapy implies that variable ability of HCV to modulate interferon responses is not a dominant cause for differential pathology among HCV patients. This lack of significant associations also implies that host and/or environmental factors are the major causes of differential disease presentation in HCV patients.
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Sato M, Kato N, Tateishi R, Muroyama R, Kowatari N, Li W, Goto K, Otsuka M, Shiina S, Yoshida H, Omata M, Koike K. IL28B minor allele is associated with a younger age of onset of hepatocellular carcinoma in patients with chronic hepatitis C virus infection. J Gastroenterol 2014; 49:748-754. [PMID: 23689989 DOI: 10.1007/s00535-013-0826-x] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2012] [Accepted: 04/22/2013] [Indexed: 02/04/2023]
Abstract
BACKGROUND IL28B polymorphisms were shown to be associated with a response to peg-interferon-based treatment in chronic hepatitis C (CHC) and spontaneous clearance. However, little is known about how this polymorphism affects the course of CHC, including the development of hepatocellular carcinoma (HCC). We evaluated the influence of IL28B polymorphisms on hepatocarcinogenesis in CHC patients. METHODS We genotyped the rs8099917 single-nucleotide polymorphism in 351 hepatitis C-associated HCC patients without history of IFN-based treatment, and correlated the age at onset of HCC in patients with each genotype. RESULTS Frequencies of TT, TG, and GG genotypes were 74.3 % (261/351), 24.8 % (87/351), and 0.9 % (3/351), respectively. The mean ages at onset of HCC for TT, TG, and GG genotypes were 69.9, 67.5 and 66.8, respectively. In multivariate analysis, IL28B minor allele (TG and GG genotypes) was an independent risk factor for younger age at onset of HCC (P = 0.02) in males (P < 0.001) with higher body mass index (BMI; P = 0.009). The IL28B minor allele was also associated with a lower probability of having aspartate aminotransferase-to-platelet ratio index (APRI) >1.5 (minor vs. major, 46.7 vs. 58.6 %; P = 0.01), lower AST (69.1 vs. 77.7 IU/L, P = 0.02), lower ALT (67.8 vs. 80.9 IU/L, P = 0.002), higher platelet count (12.8 vs. 11.2 × 10(4)/μL, P = 0.002), and higher prothrombin time (79.3 vs. 75.4 %, P = 0.002). CONCLUSIONS The IL28B minor allele was associated with lower inflammatory activity and less progressed fibrosis of the liver; however, it constituted a risk factor for younger-age onset of HCC in CHC patients.
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Affiliation(s)
- Masaya Sato
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
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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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Matsuura K, Watanabe T, Tanaka Y. Role of IL28B for chronic hepatitis C treatment toward personalized medicine. J Gastroenterol Hepatol 2014; 29:241-9. [PMID: 24325405 DOI: 10.1111/jgh.12475] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/13/2013] [Indexed: 02/06/2023]
Abstract
Genome-wide association studies recently revealed that certain interleukin-28B (IL28B) polymorphisms are strongly associated with responses to pegylated interferon (PEG-IFN) and ribavirin (RBV) therapy in patients chronically infected with hepatitis C virus (HCV) genotype 1, as well as with spontaneous clearance of HCV. Subsequent reports revealed that IL28B genotypes also affect treatment efficacy in chronic infection with other HCV genotypes. Furthermore, there have been several reports that implicate IL28B genotypes in inflammatory status, progression of fibrosis and adverse clinical outcomes in chronic hepatitis C (CHC). Therapy of CHC recently entered a new era with the deployment of direct-acting antivirals. These include nonstructural 3/4A protease inhibitors which have shown promise in combination with PEG-IFN/RBV in several clinical trials. IFN-free therapy is expected to be useful especially in IFN-resistant patients and may become the standard of care in the future. Several clinical trials have revealed an association between IL28B genotype and treatment efficacy in triple therapy or IFN-free regimens. On the other hand the mechanism of the effect of IL28B on HCV infection has not yet been elucidated. Recently, it was shown that the polymorphism of IFN-lambda 4 (IFNL4) is in high linkage disequilibrium with that of near IL28B, and more strongly associated with spontaneous or treatment-induced HCV clearance than IL28B genotypes, especially in individuals of African ancestry. This finding provides new insights into the genetic regulation of HCV clearance and its clinical management. IL28B genotyping will be also useful for personalized CHC treatment in the forthcoming era of direct-acting antivirals.
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Affiliation(s)
- Kentaro Matsuura
- Department of Virology, Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan; Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan; Infectious Disease and Immunogenetics Section, Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland, United States
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23
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Deep-sequencing analysis of the association between the quasispecies nature of the hepatitis C virus core region and disease progression. J Virol 2013; 87:12541-51. [PMID: 23946458 DOI: 10.1128/jvi.00826-13] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Variation of core amino acid (aa) 70 of hepatitis C virus (HCV) has been shown recently to be closely correlated with liver disease progression, suggesting that the core region might be present as a quasispecies during persistent infection and that this quasispecies nature might have an influence on the progression of disease. In our investigation, the subjects were 79 patients infected with HCV genotype 1b (25 with chronic hepatitis [CH], 29 with liver cirrhosis [LC], and 25 with hepatocellular carcinoma [HCC]). Deep sequencing of the HCV core region was carried out on their sera by using a Roche 454 GS Junior pyrosequencer. Based on a plasmid containing a cloned HCV sequence (pCV-J4L6S), the background error rate associated with pyrosequencing, including the PCR procedure, was calculated as 0.092 ± 0.005/base. Deep sequencing of the core region in the clinical samples showed a mixture of "mutant-type" Q/H and "wild-type" R at the core aa 70 position in most cases (71/79 [89.9%]), and the ratio of mutant residues to R in the mixture increased as liver disease advanced to LC and HCC. Meanwhile, phylogenetic analysis of the almost-complete core region revealed that the HCV isolates differed genetically depending on the mutation status at core aa 70. We conclude that the core aa 70 mixture ratio, determined by deep sequencing, reflected the status of liver disease, demonstrating a significant association between core aa 70 and disease progression in CH patients infected with HCV genotype 1b.
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24
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Toyoda H, Kumada T, Kiriyama S, Tanikawa M, Hisanaga Y, Kanamori A, Tada T, Kitabatake S, Murakami Y. Association between hepatic steatosis and hepatic expression of genes involved in innate immunity in patients with chronic hepatitis C. Cytokine 2013; 63:145-50. [PMID: 23673288 DOI: 10.1016/j.cyto.2013.04.012] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2013] [Revised: 03/13/2013] [Accepted: 04/10/2013] [Indexed: 12/21/2022]
Abstract
BACKGROUNDS/AIMS We investigated the association between hepatic steatosis and hepatic expression of genes involved in innate immunity, both of which are reportedly associated with resistance to peginterferon (PEG-IFN) and ribavirin combination therapy for hepatitis C virus (HCV) infection. METHODS A total of 122 patients infected with HCV genotype 1b who underwent and completed PEG-IFN and ribavirin combination therapy were studied. Hepatic steatosis was evaluated on the basis of the liver specimen biopsied prior to antiviral therapy. The levels of mRNA of innate immunity genes (RIG-I, MDA5, LGP2, Cardif, RNF125, ISG15, and USP18) were measured by real-time polymerase chain reaction in RNA extracted from biopsied liver tissue and compared between patients with and without hepatic steatosis. RESULTS The proportion of patients with hepatic steatosis, the hepatic expression levels of RIG-I gene, and RIG-I/Cardif and RIG-I/RNF125 ratios were significantly higher in patients in whom serum HCV RNA did not disappear throughout the treatment period. Hepatic expression of RIG-I and the ratios of RIG-I/Cardif and RIG-I/RNF125 were significantly higher in patients with steatosis than those without. CONCLUSIONS Changes in hepatic expression of some genes involved in innate immunity were observed along with hepatic steatosis, possibly playing a mechanistic role in resistance to IFN-based therapy in patients with hepatic steatosis.
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MESH Headings
- Adaptor Proteins, Signal Transducing/blood
- Adaptor Proteins, Signal Transducing/genetics
- Antiviral Agents/therapeutic use
- DEAD Box Protein 58
- DEAD-box RNA Helicases/blood
- DEAD-box RNA Helicases/genetics
- Drug Resistance, Viral/genetics
- Drug Therapy, Combination
- Fatty Liver/genetics
- Fatty Liver/metabolism
- Female
- Genotype
- Hepacivirus/classification
- Hepacivirus/drug effects
- Hepacivirus/genetics
- Hepatitis C, Chronic/drug therapy
- Hepatitis C, Chronic/genetics
- Hepatitis C, Chronic/pathology
- Humans
- Immunity, Innate/genetics
- Interferon alpha-2
- Interferon-alpha/therapeutic use
- Liver
- Male
- Middle Aged
- Polyethylene Glycols/therapeutic use
- RNA, Messenger/biosynthesis
- Receptors, Immunologic
- Recombinant Proteins/therapeutic use
- Ribavirin/therapeutic use
- Ubiquitin-Protein Ligases/blood
- Ubiquitin-Protein Ligases/genetics
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Affiliation(s)
- Hidenori Toyoda
- Department of Gastroenterology, Ogaki Municipal Hospital, 4-86 Minaminokawa, Ogaki, Gifu 503-8502, Japan.
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Khaliq S, Latief N, Jahan S. Role of different regions of the hepatitis C virus genome in the therapeutic response to interferon-based treatment. Arch Virol 2013; 159:1-15. [PMID: 23851652 DOI: 10.1007/s00705-013-1780-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2013] [Accepted: 05/28/2013] [Indexed: 12/21/2022]
Abstract
Hepatitis C virus (HCV) is considered a significant risk factor in HCV-induced liver diseases and development of hepatocellular carcinoma (HCC). Nucleotide substitutions in the viral genome result in its diversification into quasispecies, subtypes and distinct genotypes. Different genotypes vary in their infectivity and immune response due to these nucleotide/amino acid variations. The current combination treatment for HCV infection is pegylated interferon α (PEG-IFN-α) with ribavirin, with a highly variable response rate mainly depending upon the HCV genotype. Genotypes 2 and 3 are found to respond better than genotypes 1 and 4, which are more resistant to IFN-based therapies. Different studies have been conducted worldwide to explore the basis of this difference in therapy response, which identified some putative regions in the HCV genome, especially in Core and NS5a, and to some extent in the E2 region, containing specific sequences in different genotypes that act differently with respect to the IFN response. In the review, we try to summarize the role of HCV proteins and their nucleotide sequences in association with treatment outcome in IFN-based therapy.
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Affiliation(s)
- Saba Khaliq
- Department of Immunology, University of Health Sciences, Lahore, Pakistan,
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26
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Selimovic D, El-Khattouti A, Ghozlan H, Haikel Y, Abdelkader O, Hassan M. Hepatitis C virus-related hepatocellular carcinoma: An insight into molecular mechanisms and therapeutic strategies. World J Hepatol 2012; 4:342-55. [PMID: 23355912 PMCID: PMC3554798 DOI: 10.4254/wjh.v4.i12.342] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2012] [Revised: 11/17/2012] [Accepted: 11/24/2012] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) infects more than 170 million people worldwide, and thereby becomes a series global health challenge. Chronic infection with HCV is considered one of the major causes of end-stage liver disease including cirrhosis and hepatocellular carcinoma. Although the multiple functions of the HCV proteins and their impacts on the modulation of the intracellular signaling transduction processes, the drive of carcinogenesis during the infection with HCV, is thought to result from the interactions of viral proteins with host cell proteins. Thus, the induction of mutator phenotype, in liver, by the expression of HCV proteins provides a key mechanism for the development of HCV-associated hepatocellular carcinoma (HCC). HCC is considered one of the most common malignancies worldwide with increasing incidence during the past decades. In many countries, the trend of HCC is attributed to several liver diseases including HCV infection. However, the development of HCC is very complicated and results mainly from the imbalance between tumor suppressor genes and oncogenes, as well as from the alteration of cellular factors leading to a genomic instability. Besides the poor prognosis of HCC patients, this type of tumor is quite resistance to the available therapies. Thus, understanding the molecular mechanisms, which are implicated in the development of HCC during the course of HCV infection, may help to design a general therapeutic protocol for the treatment and/or the prevention of this malignancy. This review summarizes the current knowledge of the molecular mechanisms, which are involved in the development of HCV-associated HCC and the possible therapeutic strategies.
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Affiliation(s)
- Denis Selimovic
- Denis Selimovic, Youssef Haikel, Mohamed Hassan, Institut National de la Santé et de la Recherche Médicale, U 977, 67000 Strasbourg, France
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27
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Kozuka R, Enomoto M, Hai H, Ogawa T, Nakaya M, Hagihara A, Fujii H, Kobayashi S, Iwai S, Morikawa H, Tamori A, Kawada N. Changes in sequences of core region, interferon sensitivity-determining region and interferon and ribavirin resistance-determining region of hepatitis C virus genotype 1 during interferon-alpha and ribavirin therapy, and efficacy of retreatment. Hepatol Res 2012; 42:1157-67. [PMID: 22672644 DOI: 10.1111/j.1872-034x.2012.01046.x] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
AIM Some regions associated with sensitivity to interferon-α and ribavirin have been identified in the hepatitis C virus (HCV) genome, including amino acid 70 in the core region (core a.a. 70), a.a. 2209-2248 (interferon sensitivity-determining region, ISDR) and a.a. 2334-2379 (interferon and ribavirin resistance-determining region, IRRDR). METHODS We examined changes in the sequences of these regions in 25 patients with chronic HCV genotype 1 infection who had not had sustained virological response (SVR) to interferon-α and ribavirin for 24-48 weeks and subsequently received retreatment for 48-72 weeks. RESULTS At baseline, the core a.a. 70 was mutant (resistant) type in seven patients. At the start of retreatment, the core a.a. 70 had changed from sensitive to resistant type in 2 patients, and SVR was not achieved by retreatment. The ISDR variations were resistant type (0-1 mutations) in 17 patients at baseline. After 2 weeks of treatment, amino acid change was found in two patients; in one, the substitutions returned to baseline status after treatment, and in the other, the substitution persisted. At the start of retreatment, ISDR sequences had changed from resistant to sensitive type in two patients and SVR was achieved and from sensitive to resistant type in three patients and SVR was not achieved. The IRRDR variations were resistant type (<6 mutations) in 19 patients at baseline and at the start of retreatment. CONCLUSION Sequences of the core region and ISDR sometimes change during anti-HCV therapy, potentially affecting the outcomes of retreatment.
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Affiliation(s)
- Ritsuzo Kozuka
- Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka Center for the Advancement of Higher Education, Faculty of Engineering, Kinki University, Hiroshima, Japan
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Agúndez JA, García-Martin E, Maestro ML, Cuenca F, Martínez C, Ortega L, Carballo M, Vidaurreta M, Agreda M, Díaz-Zelaya G, Suárez A, Díaz-Rubio M, Ladero JM. Relation of IL28B gene polymorphism with biochemical and histological features in hepatitis C virus-induced liver disease. PLoS One 2012; 7:e37998. [PMID: 22666430 PMCID: PMC3362530 DOI: 10.1371/journal.pone.0037998] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2012] [Accepted: 04/27/2012] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND/AIMS Polymorphism at the IL28B gene may modify the course of hepatitis C virus (HCV) chronic infection. Our aim was to study the influence of IL28B rs12979860 gene polymorphism on the biochemistry and pathology of HCV-induced disease in the clinical course from mild chronic hepatitis C to hepatocellular carcinoma. METHODS We have determined the rs12979860 single nucleotide polymorphism (SNP) upstream IL28B gene in two groups of patients with HCV-induced chronic liver disease: 1) 268 patients (159 men) with biopsy-proven chronic hepatitis C, to analyse its relation with biochemical, virological and histological features; and 2) 134 patients (97 men) with HCV-related hepatocellular carcinoma. The distribution of the analysed SNP in hepatocellular carcinoma patients was compared with that found in untreated chronic hepatitis C patients. All patients were white and most were Spaniards. RESULTS In multivariate analysis ALT values were higher (P = 0.001) and GGT values were lower (P<0.001) in chronic hepatitis C patients homozygotes for the major rs12979860C allele as compared with carriers of the mutated rs12979860T allele. Steatosis was more frequent (Odds ratio = 1.764, 95% C.I. 1.053-2.955) and severe (P = 0.026) in carriers of the rs12979860T allele. No relation was found between the analysed SNP and METAVIR scores for necroinflammation and fibrosis, and there were no differences in the distribution of the analysed SNP between hepatocellular carcinoma and untreated chronic hepatitis C patients. CONCLUSION The IL28B rs12979860 polymorphism correlates with the biochemical activity and the presence and severity of liver steatosis in chronic hepatitis C.
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Affiliation(s)
- José A. Agúndez
- Department of Pharmacology, University of Extremadura, Cáceres, Spain
| | - Elena García-Martin
- Department of Biochemistry & Molecular Biology, University of Extremadura, Cáceres, Spain
| | - María L. Maestro
- Genomics Unit, Service of Clinical Biochemistry, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain
| | - Francisca Cuenca
- Liver Unit, Service of Gastroenterology, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain
| | - Carmen Martínez
- Department of Pharmacology, University of Extremadura, Cáceres, Spain
| | - Luis Ortega
- Service of Pathology, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain
| | - Miguel Carballo
- Laboratory of Molecular Genetics, Hospital de Terrassa, Terrassa (Barcelona), Spain
| | - Marta Vidaurreta
- Genomics Unit, Service of Clinical Biochemistry, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain
| | - Marta Agreda
- Liver Unit, Service of Gastroenterology, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain
| | - Gabriela Díaz-Zelaya
- Service of Pathology, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain
| | - Avelina Suárez
- Service of Clinical Microbiology, Hospital Clínico San Carlos (IdISCC), Madrid, Spain
| | - Manuel Díaz-Rubio
- Liver Unit, Service of Gastroenterology, Hospital Clínico San Carlos, Department of Medicine, Medical School, Universidad Complutense, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain
| | - José M. Ladero
- Liver Unit, Service of Gastroenterology, Hospital Clínico San Carlos, Department of Medicine, Medical School, Universidad Complutense, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain
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IL28B, HCV core mutations, and hepatocellular carcinoma: does host genetic make-up shape viral evolution in response to immunity? Hepatol Int 2011. [PMID: 26201341 DOI: 10.1007/s12072-011-9327-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Mutations in the core sequence of the HCV genome have been reported to influence treatment response, fibrosis progression, and hepatocarcinogenesis in Asian patients with genotype-1 chronic hepatitis C (CHC). In this issue, Miura et al. report data consistent with a causal relationship between the R70 → Q70 core variant and hepatocellular carcinoma (HCC) risk in CHC genotype-1b patients, by the prospective evaluation of changes in the consensus sequence in the entire open reading frame between treatment failure and HCC development or end of follow-up, and validation of the initial findings in a confirmatory cohort. Furthermore, they observed an association between the IL28B genotype, which is believed to influence the immune response to viral infection, and the direction of time-dependent changes in core residue 70, with unfavorable IL28B genotypes linked to a preferential shift to the 70Q associated with HCC. Although this association needs to be validated in independent cohorts, and IL28B variants did not influence HCC risk, these results suggest that IL28B genotype might not only influence the behavior of the innate immune system in the presence of HCV genotype-1 infection but also shape the resultant viral evolution, with possible consequences on major clinical outcomes, such as HCC development, and treatment response.
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