|
1
|
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.
Collapse
Affiliation(s)
- Virginia Sedeno-Monge
- Departamento de Ciencias de la Salud, Universidad Popular Autonoma del Estado de Puebla, Puebla, Mexico
| | | | | | | |
Collapse
|
|
2
|
Gewaid H, Mesalam AA, Ibrahim AA, Abdel Shafy DN, Abdel Shafy RN, Emara N, Hamdy SM, Gewaid M, Bahgat MM. Establishment of a platform for molecular and immunological characterization of the RNA-dependent-RNA-polymerase NS5B of an Egyptian HCV isolate. J Med Virol 2017; 90:545-558. [PMID: 29064582 DOI: 10.1002/jmv.24977] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2017] [Accepted: 10/16/2017] [Indexed: 11/09/2022]
Abstract
The present work aimed at establishing a platform to enable frequent characterization of the HCV RNA-dependent-RNA-polymerase from Egyptian clinical isolates. Subjecting amplified HCV-NS5B coding gene from Egyptian patient's serum to sequencing, multiple alignment, and phylogenetic analysis confirmed its subtype 4a origin. Nucleotide sequence analysis revealed presence of an additional start codon at the beginning of the NS5B gene. Peptide sequence alignment demonstrated presence of unique amino acid residues in our 4a-NS5B sequence distinct from the JFH-1-NS5B sequence as well as unique amino acids compared to other genotypes. The distinct molecular structure of the herein characterized 4a-NS5B from the 2a-JFH-1-NS5B was further demonstrated both in the built 3D models and the Ramachandran plots corresponding to each structure. Both the unique amino acid residues and 3D structure of the 4a-NS5B may influence both genotype 4a replication rate and response to therapy in comparison to other genotypes. Many resistance mutations to polymerase inhibitors were found both in ours and other genotypes' sequences. The presence of the required amino acid motifs for the RNA dependent RNA polymerase activity encouraged to clone the NS5B570-encoding sequence downstream CMV promotor in a mammalian expression vector. Such construct was used for both prokaryotic expression in bacteria and for DNA immunization. Successful mammalian expression and induction of specific immune response were demonstrated by ELISA and Western blotting. The potential of both the raised antibodies and the expressed NS5B to differentiate between HCV-infected and control human sera were demonstrated which reflect their diagnostic value.
Collapse
Affiliation(s)
- Hossam Gewaid
- Research Group Immune- and Bio-markers for Infection, the Center of Excellence for Advanced Sciences, the National Research Center, Cairo, Egypt.,Therapeutic Chemistry Department, the National Research Center, Cairo, Egypt
| | - Ahmed A Mesalam
- Research Group Immune- and Bio-markers for Infection, the Center of Excellence for Advanced Sciences, the National Research Center, Cairo, Egypt.,Therapeutic Chemistry Department, the National Research Center, Cairo, Egypt
| | - Ahmed A Ibrahim
- Research Group Immune- and Bio-markers for Infection, the Center of Excellence for Advanced Sciences, the National Research Center, Cairo, Egypt.,Therapeutic Chemistry Department, the National Research Center, Cairo, Egypt
| | - Dina N Abdel Shafy
- Research Group Immune- and Bio-markers for Infection, the Center of Excellence for Advanced Sciences, the National Research Center, Cairo, Egypt.,Water Pollution Research Department, the National Research Center, Cairo, Egypt
| | - Rola N Abdel Shafy
- Research Group Immune- and Bio-markers for Infection, the Center of Excellence for Advanced Sciences, the National Research Center, Cairo, Egypt.,Therapeutic Chemistry Department, the National Research Center, Cairo, Egypt
| | - Nahed Emara
- Clinical and Chemical Pathology Department, the National Research Center, Cairo, Egypt
| | - Soha M Hamdy
- Division of Biochemistry, Faculty of Science, Fayoum University, Cairo, Egypt
| | | | - Mahmoud M Bahgat
- Research Group Immune- and Bio-markers for Infection, the Center of Excellence for Advanced Sciences, the National Research Center, Cairo, Egypt.,Therapeutic Chemistry Department, the National Research Center, Cairo, Egypt
| |
Collapse
|
|
3
|
Tasaka-Fujita M, Sugiyama N, Kang W, Masaki T, Masaski T, Murayama A, Yamada N, Sugiyama R, Tsukuda S, Watashi K, Asahina Y, Sakamoto N, Wakita T, Shin EC, Kato T. Amino Acid Polymorphisms in Hepatitis C Virus Core Affect Infectious Virus Production and Major Histocompatibility Complex Class I Molecule Expression. Sci Rep 2015; 5:13994. [PMID: 26365522 PMCID: PMC4568458 DOI: 10.1038/srep13994] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2015] [Accepted: 08/13/2015] [Indexed: 02/06/2023] Open
Abstract
Amino acid (aa) polymorphisms in the hepatitis C virus (HCV) genotype 1b core protein have been reported to be a potent predictor for poor response to interferon (IFN)-based therapy and a risk factor for hepatocarcinogenesis. We investigated the effects of these polymorphisms with genotype 1b/2a chimeric viruses that contained polymorphisms of Arg/Gln at aa 70 and Leu/Met at aa 91. We found that infectious virus production was reduced in cells transfected with chimeric virus RNA that had Gln at aa 70 (aa70Q) compared with RNA with Arg at aa 70 (aa70R). Using flow cytometry analysis, we confirmed that HCV core protein accumulated in aa70Q clone transfected cells, and it caused a reduction in cell-surface expression of major histocompatibility complex (MHC) class I molecules induced by IFN treatment through enhanced protein kinase R phosphorylation. We could not detect any effects due to the polymorphism at aa 91. In conclusion, the polymorphism at aa 70 was associated with efficiency of infectious virus production, and this deteriorated virus production in strains with aa70Q resulted in the intracellular accumulation of HCV proteins and attenuation of MHC class I molecule expression. These observations may explain the strain-associated resistance to IFN-based therapy and hepatocarcinogenesis of HCV.
Collapse
Affiliation(s)
- Megumi Tasaka-Fujita
- Department of Virology II, National Institute of Infectious Diseases, Tokyo 162-8640, Japan.,Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo 113-8519, Japan.,Center for Interprofessional Education, Tokyo Medical and Dental University, Tokyo 113-8510, Japan
| | - Nao Sugiyama
- Department of Virology II, National Institute of Infectious Diseases, Tokyo 162-8640, Japan
| | - Wonseok Kang
- Laboratory of Immunology and Infectious Diseases, Graduate School of Medical Science and Engineering, KAIST, Daejeon 305-701, Korea
| | - Takahiro Masaki
- Department of Virology II, National Institute of Infectious Diseases, Tokyo 162-8640, Japan
| | | | - Asako Murayama
- Department of Virology II, National Institute of Infectious Diseases, Tokyo 162-8640, Japan
| | - Norie Yamada
- Department of Virology II, National Institute of Infectious Diseases, Tokyo 162-8640, Japan
| | - Ryuichi Sugiyama
- Department of Virology II, National Institute of Infectious Diseases, Tokyo 162-8640, Japan
| | - Senko Tsukuda
- Department of Virology II, National Institute of Infectious Diseases, Tokyo 162-8640, Japan
| | - Koichi Watashi
- Department of Virology II, National Institute of Infectious Diseases, Tokyo 162-8640, Japan
| | - Yasuhiro Asahina
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo 113-8519, Japan.,Department of Liver Disease Control, Tokyo Medical and Dental University, Tokyo 113-8519, Japan
| | - Naoya Sakamoto
- Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan
| | - Takaji Wakita
- Department of Virology II, National Institute of Infectious Diseases, Tokyo 162-8640, Japan
| | - Eui-Cheol Shin
- Laboratory of Immunology and Infectious Diseases, Graduate School of Medical Science and Engineering, KAIST, Daejeon 305-701, Korea
| | - Takanobu Kato
- Department of Virology II, National Institute of Infectious Diseases, Tokyo 162-8640, Japan
| |
Collapse
|
|
4
|
Kosaka K, Imamura M, Hayes CN, Abe H, Hiraga N, Yoshimi S, Murakami E, Kawaoka T, Tsuge M, Aikata H, Miki D, Ochi H, Matsui H, Kanai A, Inaba T, Chayama K. Emergence of resistant variants detected by ultra-deep sequencing after asunaprevir and daclatasvir combination therapy in patients infected with hepatitis C virus genotype 1. J Viral Hepat 2015; 22:158-65. [PMID: 24943406 DOI: 10.1111/jvh.12271] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Daclatasvir (DCV) and asunaprevir (ASV) are NS5A and NS3 protease-targeted antivirals respectively, currently under development for the treatment of chronic hepatitis C virus (HCV) infection. We analysed the relationship between pre-existing drug-resistant variants and clinical outcome of the combination treatment with DCV and ASV. Ten patients with HCV genotype 1b were orally treated with a combination of ASV and DCV for 24 weeks. The frequencies of amino acid (aa) variants at NS3 aa positions 155, 156 and 168 and at NS5A aa31 and 93 before and after treatment were analysed by ultra-deep sequencing. We established a minimum variant frequency threshold of 0.3% based on plasmid sequencing. Sustained virological response (SVR) was achieved in 8 out of 10 patients (80%), and relapse of HCV RNA after cessation of the treatment and viral breakthrough occurred in the other two patients. Pre-existing DCV-resistant variants (L31V/M and/or Y93H; 0.9-99.4%) were detected in three out of eight patients who achieved SVR. Pre-existing DCV-resistant variants were detected in a relapsed patient (L31M, Y93H) and in a patient with viral breakthrough (Y93H); however, no ASV-resistant variants were detected. In these patients, HCV RNA rebounded with ASV- and DCV- double resistant variants (NS3 D168A/V plus NS5A L31M and Y93H). While pre-existing DCV-resistant variants might contribute to viral breakthrough in DCV and ASV combination therapy, the effectiveness of prediction of the outcome of therapy based on ultra-deep sequence analysis of pre-existing resistant variants appears limited.
Collapse
Affiliation(s)
- K Kosaka
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
5
|
El-Shamy A, Hotta H. Impact of hepatitis C virus heterogeneity on interferon sensitivity: an overview. World J Gastroenterol 2014; 20:7555-69. [PMID: 24976696 PMCID: PMC4069287 DOI: 10.3748/wjg.v20.i24.7555] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2013] [Revised: 02/18/2014] [Accepted: 04/21/2014] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) is a major cause of liver disease worldwide. HCV is able to evade host defense mechanisms, including both innate and acquired immune responses, to establish persistent infection, which results in a broad spectrum of pathogenicity, such as lipid and glucose metabolism disorders and hepatocellular carcinoma development. The HCV genome is characterized by a high degree of genetic diversity, which can be associated with viral sensitivity or resistance (reflected by different virological responses) to interferon (IFN)-based therapy. In this regard, it is of importance to note that polymorphisms in certain HCV genomic regions have shown a close correlation with treatment outcome. In particular, among the HCV proteins, the core and nonstructural proteins (NS) 5A have been extensively studied for their correlation with responses to IFN-based treatment. This review aims to cover updated information on the impact of major HCV genetic factors, including HCV genotype, mutations in amino acids 70 and 91 of the core protein and sequence heterogeneity in the IFN sensitivity-determining region and IFN/ribavirin resistance-determining region of NS5A, on virological responses to IFN-based therapy.
Collapse
|
|
6
|
Shaker O, El-Shehaby A, Fayez S, Zahra A, Marzouk S, El Raziky M. Osteopontin gene polymorphisms as predictors for the efficacy of interferon therapy in chronic hepatitis C Egyptian patients with genotype 4. Cell Biochem Funct 2013; 31:620-5. [PMID: 23400862 DOI: 10.1002/cbf.2954] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2012] [Revised: 12/05/2012] [Accepted: 01/02/2013] [Indexed: 12/16/2022]
Abstract
This study aimed to determine the relationship between osteopontin gene polymorphisms and its protein level and the efficacy of interferon-based therapies in Hepatitis C virus (HCV) patients. Hundreds HCV patients genotype 4, treated with pegylated interferon alfa-2b plus ribavirin and 60 healthy subjects were enrolled. All individuals were subjected to clinical and laboratory parameters, including hepatitis markers and HCV quantitation by real-time polymerase chain reaction. Single nucleotide polymorphisms (SNPs) of osteopontin (OPN) gene (nucleotide -155, -443 and -1748) were analysed by direct sequencing in addition to estimation of serum level of OPN. SNP at -443 (C/C versus C/T, T/T) was found to represent predictors for treatment response by univariate logistic regression analysis. OPN serum level was independent predictors for treatment response by both univariate and multivariate logistic regression analysis. SNP at nucleotide -443 and serum OPN protein levels could be used as useful markers to predict the efficacy of treatment.
Collapse
Affiliation(s)
- Olfat Shaker
- Departments of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Cairo University, Cairo, Egypt
| | | | | | | | | | | |
Collapse
|
|
7
|
Kawaoka T, Takahashi S, Takaki S, Hiramatsu A, Waki K, Hiraga N, Miki D, Tsuge M, Imamura M, Kawakami Y, Aikata H, Ochi H, Onoe T, Tashiro H, Ohdan H, Chayama K. Interleukin-28B single nucleotide polymorphism of donors and recipients can predict viral response to pegylated interferon/ribavirin therapy in patients with recurrent hepatitis C after living donor liver transplantation. J Gastroenterol Hepatol 2012; 27:1467-72. [PMID: 22432893 DOI: 10.1111/j.1440-1746.2012.07129.x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
BACKGROUND AND AIM Interleukin-28B (IL28B) single nucleotide polymorphism (SNP) influences viral response (VR) to interferon (IFN) therapy in patients with hepatitis C. We studied the relationship between VR and the IL28B polymorphism (rs8099917) in patients on long-term pegylated IFN plus ribavirin (PEGIFN/RBV) therapy for recurrent hepatitis C after living-donor liver transplantation (LDLT). METHODS Thirty-five patients with recurrent hepatitis C after LDLT were treated with PEGIFN/RBV. We evaluated the effect of IL28B SNP on the outcome in 20 patients infected with hepatitis C virus genotype 1 who completed IFN therapy. RESULTS The sustained VR (SVR) rate was 54% (19/35) for all patients; 46% (13/28) for genotype 1. The SVR rate of donors' TT group (major genotype) was higher than that of donors' TG+GG group (minor genotype) (73% vs 20%), while that of recipients' TT group was similar to that of recipients' TG+GG group (64% vs 50%). With regard to the combined effect of donors' and recipients' IL28B SNP, the SVR rates of TT:TT (donors':recipients'), TT:TG+GG, TG+GG:any group were 81%, 50%, and 20%, respectively. The VR rate of TT:TT, TT:TG+GG and TG+GG:any group at 12 weeks were 28%, 0%, and 0%; those at 48weeks were 70%, 50%, 20%, and those at the end of treatment were 100%, 50%, 20%, respectively. The multivariate analysis identified IL28B of donors:recipients (TT:TT) as the only independent determinant of SVR (odds ratio 15.0, P=0.035). CONCLUSION Measurement of donors' and recipients' IL28B SNP can predict the response to PEGIFN/RBV therapy, and the donors' IL28B SNP might be a more significant predictor than that of the recipients.
Collapse
Affiliation(s)
- Tomokazu Kawaoka
- Department of Medicine and Molecular Science, Hiroshima University, Hiroshima, Japan
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
8
|
Kawaoka T, Aikata H, Takaki S, Hiramatsu A, Waki K, Hiraga N, Miki D, Tsuge M, Imamura M, Kawakami Y, Takahashi S, Ochi H, Tashiro H, Ohdan H, Chayama K. IL28B polymorphism may guide pegylated interferon plus ribavirin therapy even after curative treatment for hepatitis C virus-related hepatocellular carcinoma. J Viral Hepat 2011; 18:e550-60. [PMID: 21914076 DOI: 10.1111/j.1365-2893.2011.01468.x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
The present study was designed to determine the predictive factors for the viral response to pegylated interferon-alpha plus ribavirin combination therapy (PEGIFN/RBV) administered after curative treatment for hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC). The study group was 78 patients treated between January 2005 and January 2009. The sustained viral response (SVR) rate was 25.8% (15/58) in patients infected with HCV-genotype 1 and 55.0% (11/20) in those with genotype 2. Among the 78 patients, 32 (41.0%) could not complete the treatment protocol, and this was because of HCC recurrence in 17 (53%) of them. Multivariate analysis identified partial early viral response (pEVR) as the only independent determinant of SVR [odds ratio (OR) 14.73, P = 0.013] for patients with genotype 1. Multivariate analysis identified male gender (OR 8.72, P = 0.001) and interleukin-28B (IL-28B) genotype (rs8099917) TT (OR 7.93, P = 0.007) as independent predictors of pEVR. Multivariate analysis also identified IL-28B genotype GG+TG (OR 14.1, P = 0.021) and α-fetoprotein >30 (OR 5.4, P = 0.031) as independent predictors of null response. Patients with SVR showed a better survival rate than those without SVR (P = 0.034). The second HCC recurrence rate tended to be lower in patients with SVR than in those without SVR (P = 0.054). With regard to the prognosis of patients with SVR, it is desirable to achieve SVR with interferon therapy even when administered after HCC treatment. IL-28B genotype is a potentially useful marker for the response to PEGIFN/RBV therapy administered after curative treatment of HCV-related HCC.
Collapse
Affiliation(s)
- T Kawaoka
- Department of Medicine and Molecular Science, Division of Frontier Medical Science, Minami-ku, Hiroshima University, Hiroshima, Japan
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
9
|
Hiraga N, Abe H, Imamura M, Tsuge M, Takahashi S, Hayes CN, Ochi H, Tateno C, Yoshizato K, Nakamura Y, Kamatani N, Chayama K. Impact of viral amino acid substitutions and host interleukin-28b polymorphism on replication and susceptibility to interferon of hepatitis C virus. Hepatology 2011; 54:764-71. [PMID: 21618576 DOI: 10.1002/hep.24453] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2011] [Accepted: 05/14/2011] [Indexed: 12/11/2022]
Abstract
UNLABELLED Amino acid (aa) substitutions of core 70 and 91 and in the NS5A (nonstructural protein 5A) interferon sensitivity determining region (ISDR) as well as genetic polymorphisms in the host interleukin-28B (IL28B) locus affect the outcome of interferon (IFN)-based therapies for patients with chronic hepatitis C. The combination of these factors and the quasispecies nature of the virus complicate understanding of the underlying mechanism. Using infectious hepatitis C virus (HCV) genotype 1b clone HCV-KT9, we introduced substitutions at both core aa70 (Arg to Gln) and aa91 (Leu to Met). We also introduced four and nine ISDR aa substitutions into core mutant HCV-KT9. Using human hepatocyte chimeric mice with different IL28B genotypes, we examined the infectivity, replication ability, and susceptibility to IFN of these clones. Although aa substitutions in the ISDR significantly impaired infectivity and replication ability of the virus, core aa70 and 91 substitutions did not. The effect of IFN treatment was similar in core wild-type and mutant viruses. Interestingly, virus titer was significantly higher in mice with the favorable IL28B allele (rs8099917 TT and rs12979860 CC) in the transplanted hepatocytes than in mice with hepatocytes from rs8099917 TG and rs12979860 TT donors (P < 0.001). However, the effect of IFN was significantly greater, and intrahepatic expression levels of IFN-stimulated genes were significantly higher in mice with the favorable IL28B allele. CONCLUSION Our data suggest that HCV replication levels and response to IFN are affected by human hepatocyte IL28B single-nucleotide polymorphism genotype and mutations in the ISDR. The mechanism underlying the clinically observed association of wild-type core protein in eradication-favorable host cells should be investigated further.
Collapse
Affiliation(s)
- Nobuhiko Hiraga
- Department of Medicine and Molecular Science, Division of Frontier Medical Science, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan
| | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
10
|
Akuta N, Suzuki F, Hirakawa M, Kawamura Y, Sezaki H, Suzuki Y, Hosaka T, Kobayashi M, Kobayashi M, Saitoh S, Arase Y, Ikeda K, Chayama K, Nakamura Y, Kumada H. Amino acid substitution in HCV core/NS5A region and genetic variation near IL28B gene affect treatment efficacy to interferon plus ribavirin combination therapy. Intervirology 2011; 55:231-41. [PMID: 21734353 DOI: 10.1159/000328327] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2010] [Accepted: 03/28/2011] [Indexed: 12/14/2022] Open
Abstract
OBJECTIVE To evaluate predictive factors of treatment efficacy to interferon (IFN)/ribavirin in patients infected with HCV genotype 1b (HCV-1b). METHODS This study investigated pretreatment predictors, including viral- (aa substitutions in core aa 70/91 and NS5A-ISDR/IRRDR) and host-related factors (genetic variation near IL28B gene), to 48-week IFN/ribavirin in 490 Japanese adults infected with HCV-1b. RESULTS The proportion of patients who showed end-of-treatment response (ETR), sustained virological response (SVR), and SVR after ETR was 76, 54, and 76%, respectively. There was a significant positive correlation between the number of aa substitutions in ISDR and those in IRRDR. Concerning the substitution of core aa 91, the number of aa substitutions in ISDR/IRRDR of patients with Leu91 was significantly higher than that of patients with Met91. Furthermore, levels of viremia were influenced by aa substitutions in core aa 91 and ISDR/IRRDR. By multivariate analysis, rs8099917 genotype was an important predictor of ETR and SVR. With regard to viral factors, core aa 70/91 was an important predictor of ETR, and SVR after ETR. ISDR was an important predictor of SVR, and SVR after ETR. CONCLUSION aa substitution in core/NS5A region and genetic variation near IL28B were important predictors of treatment efficacy to IFN/ribavirin.
Collapse
Affiliation(s)
- Norio Akuta
- Department of Hepatology, Toranomon Hospital, Tokyo, Japan.
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
11
|
Hashimoto Y, Ochi H, Abe H, Hayashida Y, Tsuge M, Mitsui F, Hiraga N, Imamura M, Takahashi S, Nelson Hayes C, Ohishi W, Kubo M, Tsunoda T, Kamatani N, Nakamura Y, Chayama K. Prediction of response to peginterferon-alfa-2b plus ribavirin therapy in Japanese patients infected with hepatitis C virus genotype 1b. J Med Virol 2011; 83:981-8. [PMID: 21503910 DOI: 10.1002/jmv.22028] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2023]
Abstract
Variation at the IL-28B locus was recently reported to be a significant predictive factor of viral response to pegylated-interferon plus ribavirin combination therapy against chronic hepatitis C. Predictive factors for the effect of therapy, including IL-28B polymorphism rs8099917 and viral and clinical factors were investigated. A total of 288 patients were enrolled who were chronically infected with hepatitis C virus (HCV) genotype 1b and treated with combination therapy. Among them, 87 patients completed 48 weeks of therapy without dose reduction or discontinuation. In multivariate regression analysis, the rs8099917 TT genotype was the only independent factor significantly associated with sustained viral response (P = 0.016, OR 61.5), whereas substitutions at amino acid 70 (aa 70) of the HCV core protein (P = 0.038, OR 5.9) and non-TT genotypes (P = 0.002, OR 17.2) were associated with nonvirological response. Both factors were also associated with viral dynamics during the initial stage of the therapy. Correlation analysis revealed that rs8099917 genotype was correlated with γ-glutamyl transpeptidase, hyaluronic acid, and HCV core aa 70. In conclusion, host (IL-28B polymorphism) and viral (aa 70) factors independently affect response to combination therapy.
Collapse
Affiliation(s)
- Yoshimasa Hashimoto
- Division of Frontier Medical Science, Department of Medical and Molecular Science, Programs for Biomedical Research, Graduate School of Biomedical Science, Hiroshima University, Hiroshima, Japan
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
12
|
Chayama K, Hayes CN, Yoshioka K, Moriwaki H, Okanoue T, Sakisaka S, Takehara T, Oketani M, Toyota J, Izumi N, Hiasa Y, Matsumoto A, Nomura H, Seike M, Ueno Y, Yotsuyanagi H, Kumada H. Factors predictive of sustained virological response following 72 weeks of combination therapy for genotype 1b hepatitis C. J Gastroenterol 2011; 46:545-555. [PMID: 21246384 DOI: 10.1007/s00535-010-0358-6] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2010] [Accepted: 11/25/2010] [Indexed: 02/04/2023]
Abstract
BACKGROUND Treatment of genotype 1b chronic hepatitis C virus (HCV) infection has been improved by extending peg-interferon plus ribavirin combination therapy to 72 weeks, but predictive factors are needed to identify those patients who are likely to respond to long-term therapy. METHODS We analyzed amino acid (aa) substitutions in the core protein and the interferon sensitivity determining region (ISDR) of nonstructural protein (NS) 5A in 840 genotype 1b chronic hepatitis C patients with high viral load. We used logistic regression and classification and regression tree (CART) analysis to identify predictive factors for sustained virological response (SVR) for patients undergoing 72 weeks of treatment. RESULTS When patients were separately analyzed by treatment duration using multivariate logistic regression, several factors, including sex, age, viral load, and core aa70 and ISDR substitutions (P = 0.0003, P = 0.02, P = 0.01, P = 0.0001, and P = 0.0004, respectively) were significant predictive factors for SVR with 48 weeks of treatment, whereas age, previous interferon treatment history, and ISDR substitutions (P = 0.03, P = 0.01, and P = 0.02, respectively) were the only significant predictive factors with 72 weeks of treatment. Using CART analysis, a decision tree was generated that identified age, cholesterol, sex, treatment length, and aa70 and ISDR substitutions as the most important predictive factors. The CART model had a sensitivity of 69.2% and specificity of 60%, with a positive predictive value of 68.4%. CONCLUSIONS Complementary statistical and data mining approaches were used to identify a subgroup of patients likely to benefit from 72 weeks of therapy.
Collapse
Affiliation(s)
- Kazuaki Chayama
- Department of Medical and Molecular Science, Division of Frontier Medical Science, Programs for Biomedical Research, Graduate School of Biomedical Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan.
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
13
|
Yoneda S, Umemura T, Katsuyama Y, Kamijo A, Joshita S, Komatsu M, Ichijo T, Matsumoto A, Yoshizawa K, Ota M, Tanaka E. Association of serum cytokine levels with treatment response to pegylated interferon and ribavirin therapy in genotype 1 chronic hepatitis C patients. J Infect Dis 2011; 203:1087-95. [PMID: 21398397 DOI: 10.1093/infdis/jiq165] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND We sought to clarify the associations among serum cytokines, amino acid substitutions in the interferon sensitivity-determining region (ISDR) and core region, and treatment outcome of pegylated interferon and ribavirin therapy in genotype 1 hepatitis C virus (HCV)-infected patients. METHODS We quantified a total of 8 serum cytokines before, during, and after treatment in 79 genotype 1 chronic HCV patients. Viral ISDR and core region variants were determined by direct sequencing. RESULTS High levels of interleukin (IL)-12 and IL-18 and more than 2 mutations in the ISDR were associated with a sustained virological response (SVR). Conversely, high baseline IL-10 levels and glutamine at amino acid 70 of the HCV core protein (Gln70) were significantly associated with a nonresponse to treatment, and patients with Gln70 had significantly higher IL-10 levels. In multivariate analysis, low IL-10, high IL-12, and high IL-18 levels were independently associated with an SVR. These 3 cytokine levels were decreased from baseline levels 4 weeks into treatment and remained low in patients with an SVR. CONCLUSION Serum IL-10, IL-12, and IL-18 levels are predictive of the response to HCV treatment with pegylated interferon and ribavirin and are associated with amino acid substitutions in the ISDR and core region.
Collapse
Affiliation(s)
- Suguru Yoneda
- Department of Medicine, Division of Hepatology and Gastroenterology, Shinshu University School of Medicine, Matsumoto, Japan
| | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
14
|
Kurosaki M, Tanaka Y, Nishida N, Sakamoto N, Enomoto N, Honda M, Sugiyama M, Matsuura K, Sugauchi F, Asahina Y, Nakagawa M, Watanabe M, Sakamoto M, Maekawa S, Sakai A, Kaneko S, Ito K, Masaki N, Tokunaga K, Izumi N, Mizokami M. Pre-treatment prediction of response to pegylated-interferon plus ribavirin for chronic hepatitis C using genetic polymorphism in IL28B and viral factors. J Hepatol 2011; 54:439-448. [PMID: 21129805 DOI: 10.1016/j.jhep.2010.07.037] [Citation(s) in RCA: 97] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2010] [Revised: 06/22/2010] [Accepted: 07/07/2010] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Pegylated interferon and ribavirin (PEG-IFN/RBV) therapy for chronic hepatitis C virus (HCV) genotype 1 infection is effective in 50% of patients. Recent studies revealed an association between the IL28B genotype and treatment response. We aimed to develop a model for the pre-treatment prediction of response using host and viral factors. METHODS Data were collected from 496 patients with HCV genotype 1 treated with PEG-IFN/RBV at five hospitals and universities in Japan. IL28B genotype and mutations in the core and IFN sensitivity determining region (ISDR) of HCV were analyzed to predict response to therapy. The decision model was generated by data mining analysis. RESULTS The IL28B polymorphism correlated with early virological response and predicted null virological response (NVR) (odds ratio=20.83, p<0.0001) and sustained virological response (SVR) (odds ratio=7.41, p<0.0001) independent of other covariates. Mutations in the ISDR predicted relapse and SVR independent of IL28B. The decision model revealed that patients with the minor IL28B allele and low platelet counts had the highest NVR (84%) and lowest SVR (7%), whereas those with the major IL28B allele and mutations in the ISDR or high platelet counts had the lowest NVR (0-17%) and highest SVR (61-90%). The model had high reproducibility and predicted SVR with 78% specificity and 70% sensitivity. CONCLUSIONS The IL28B polymorphism and mutations in the ISDR of HCV were significant pre-treatment predictors of response to PEG-IFN/RBV. The decision model, including these host and viral factors may support selection of optimum treatment strategy for individual patients.
Collapse
MESH Headings
- Aged
- Alleles
- Antiviral Agents/therapeutic use
- Data Mining
- Decision Trees
- Drug Resistance, Viral/genetics
- Female
- Genes, Viral
- Genotype
- Hepacivirus/drug effects
- Hepacivirus/genetics
- Hepatitis C, Chronic/drug therapy
- Hepatitis C, Chronic/genetics
- Hepatitis C, Chronic/immunology
- Hepatitis C, Chronic/virology
- Humans
- Interferon Type I/therapeutic use
- Interferons
- Interleukins/genetics
- Japan
- Logistic Models
- Male
- Middle Aged
- Models, Biological
- Mutation
- Polymorphism, Single Nucleotide
- Prognosis
- RNA, Viral/blood
- RNA, Viral/genetics
- Recombinant Proteins
- Retrospective Studies
- Ribavirin/therapeutic use
- Treatment Outcome
- Viral Core Proteins/genetics
- Viral Load
Collapse
Affiliation(s)
- Masayuki Kurosaki
- Division of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Musashino-shi, Tokyo, Japan
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
15
|
Kawaoka T, Hayes CN, Ohishi W, Ochi H, Maekawa T, Abe H, Tsuge M, Mitsui F, Hiraga N, Imamura M, Takahashi S, Kubo M, Tsunoda T, Nakamura Y, Kumada H, Chayama K. Predictive value of the IL28B polymorphism on the effect of interferon therapy in chronic hepatitis C patients with genotypes 2a and 2b. J Hepatol 2011; 54:408-14. [PMID: 21112660 DOI: 10.1016/j.jhep.2010.07.032] [Citation(s) in RCA: 71] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2010] [Revised: 07/01/2010] [Accepted: 07/02/2010] [Indexed: 12/13/2022]
Abstract
BACKGROUND & AIMS Common IL28B locus polymorphisms (SNPs rs8099917 and rs12979860) have been reported to affect peg-interferon plus ribavirin combination therapy (PEG-RBV) for hepatitis C virus (HCV) genotype 1b, but few reports have examined their effect on other two common genotypes, 2a and 2b. METHODS We analyzed predictive factors for sustained virological response (SVR) in a retrospective study of 719 patients with either genotype 2a (530) or 2b (189). Of these patients, 160 were treated with PEG-RBV and 559 were treated with interferon monotherapy. We evaluated predictive factors including HCV RNA, histological findings, IL28B SNP genotypes (rs8099917, rs12979860, and rs12980275), and the effect of treatment regimen and prior treatment history. RESULTS HCV RNA viral load, treatment regimen, and rs8099917 genotypes independently contributed to the effect of the therapy. For patients treated with PEG-RBV, rs8099917 and viral load were independent predictive factors for SVR in genotype 2b but not in genotype 2a. Conversely, in patients treated with interferon monotherapy, viral load and rs8099917 were independent predictive factors for SVR in genotype 2a but not in genotype 2b. The favorable rs8099917 genotype is also associated with a steep decline in viral load by the second week of treatment. CONCLUSIONS Initial viral load and rs8099917 genotype are significant independent predictors of SVR in genotype 2 patients.
Collapse
Affiliation(s)
- Tomokazu Kawaoka
- Laboratory for Digestive Diseases, Center for Genomic Medicine, RIKEN (The Institute of Physical and Chemical Research), 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
16
|
Tavis JE, Donlin MJ, Aurora R, Fan X, Di Bisceglie AM. Prospects for personalizing antiviral therapy for hepatitis C virus with pharmacogenetics. Genome Med 2011; 3:8. [PMID: 21345258 PMCID: PMC3092093 DOI: 10.1186/gm222] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Chronic hepatitis C virus (HCV) infection is a major cause of liver disease worldwide. HCV infection is currently treated with IFNα plus ribavirin for 24 to 48 weeks. This demanding therapy fails in up to 50% of patients, so the use of pharmacogenetic biomarkers to predict the outcome of treatment would reduce futile treatment of non-responders and help identify patients in whom therapy would be justified. Both IFNα and ribavirin primarily act by modulating the immune system of the patient, and HCV uses multiple mechanisms to counteract the antiviral effects stimulated by therapy. Therefore, response to therapy is influenced by variations in human genes governing the immune system and by differences in HCV genes that blunt antiviral immune responses. This article summarizes recent advances in understanding how host and viral genetic variation affect outcome of therapy. The most notable human associations are polymorphisms within the IL28B gene, but variations in human leukocyte antigen and cytokine genes have also been associated with treatment outcome. The most prominent viral genetic association with outcome of therapy is that HCV genotype 1 is much less sensitive to treatment than genotypes 2 and 3, but genetic differences below the genotype level also influence outcome of therapy, presumably by modulating the ability of viral genes to blunt antiviral immune responses. Pharmacogenetic prediction of the outcome of IFN-based therapy for HCV will require integrating the efficacies of the immunosuppressive mechanisms of a viral isolate, and then interpreting the viral resistance potential in context of the genetic profile of the patient at loci associated with outcome of therapy. Direct-acting inhibitors of HCV that will be used in combination with IFNα are nearing approval, so genetic prediction for anti-HCV therapy will soon need to incorporate viral genetic markers of viral resistance to the new drugs.
Collapse
Affiliation(s)
- John E Tavis
- Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, Saint Louis, MO 63104, USA.
| | | | | | | | | |
Collapse
|
|
17
|
Chayama K, Hayes CN. Hepatitis C virus: How genetic variability affects pathobiology of disease. J Gastroenterol Hepatol 2011; 26 Suppl 1:83-95. [PMID: 21199518 DOI: 10.1111/j.1440-1746.2010.06550.x] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
As an RNA virus, hepatitis C virus (HCV) shows a characteristically high level of nucleotide diversity. Accumulation of nucleotide substitutions in the virus has resulted in diversification into quasispecies, subtypes and distinct genotypes. Pathobiological studies linking nucleotide and amino acid sequences with clinical findings have identified relationships between certain genotypes and characteristic biological properties. Genotype 3 HCV infection was found to be associated with a high level of liver steatosis. Genotypes 1 and 4 were found to be more resistant to interferon (IFN) based therapies than genotypes 2 and 3. Studies of genotype 1 sequences obtained from patients treated with IFN have identified a relationship between favorable response to interferon therapy and amino acid substitutions in the NS5A region (interferon response determining region; ISDR). Further studies have identified a relationship between the effect of IFN therapy and other regions of the NS5A protein. More recently, a relationship has been found between poor response to peg-IFN plus ribavirin combination therapy and substitutions at amino acid 70 and 91 in the core protein. Furthermore, a correlation between human genetic variation in the IL28B (IFN-lamda 3) locus and core amino acid substitutions has been characterized. In this review we briefly summarize the discovery, classification and nomenclature of HCV genotypes and subtypes. We also discuss amino acid substitutions within specific regions that have been reported to be associated with outcome of IFN and peg-IFN plus ribavirin combination therapy.
Collapse
Affiliation(s)
- Kazuaki Chayama
- Department of Medicine and Molecular Science, Hiroshima University, Japan.
| | | |
Collapse
|
|
18
|
Chayama K, Hayes CN, Yoshioka K, Moriwaki H, Okanoue T, Sakisaka S, Takehara T, Oketani M, Toyota J, Izumi N, Hiasa Y, Matsumoto A, Nomura H, Seike M, Ueno Y, Yotsuyanagi H, Kumada H. Accumulation of refractory factors for pegylated interferon plus ribavirin therapy in older female patients with chronic hepatitis C. Hepatol Res 2010; 40:1155-1167. [PMID: 21040273 DOI: 10.1111/j.1872-034x.2010.00726.x] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
AIM Several host and viral factors have been reported to influence the effectiveness of pegylated interferon plus ribavirin combination therapy for chronic hepatitis C. In Japan, where the age of treated patients is comparatively high, recent studies have reported poor response to treatment in older female patients, but little is known about the relationship between advanced age in women and previously reported factors. METHODS Using a database of 1167 patients chronically infected with hepatitis C virus (HCV) genotype 1b, we analyzed the amino acid sequences of the HCV core protein and interferon sensitivity determining region (ISDR) and examined the relationships among predictive factors. RESULTS The proportion of patients with substitutions at core 70, which is associated with poor response to pegylated interferon plus ribavirin therapy, increased with age only in female patients. A similar trend was observed for ISDR wild type (wt). We also found that core 70 wt is associated with core 91 wt (P = 5.4 × 10(-9) ) as well as ISDR wt (P = 0.025). HCV RNA levels were higher in patients with core and ISDR wt (P < 0.001). Furthermore, core amino acid mutations were associated with advanced fibrosis and higher inflammatory activity (P = 0.028 and 0.048, respectively) as well as higher gamma-glutamyltranspeptidase, alanine aminotransferase and low-density lipoprotein cholesterol levels (P < 0.001, 0.006 and 0.001, respectively). CONCLUSION A combination of factors account for poor response rate in older female patients in Japan. Elucidating the relationship between amino acid substitutions and metabolic alteration is an important step in understanding the mechanism of HCV interferon resistance.
Collapse
Affiliation(s)
- Kazuaki Chayama
- Department of Medicine and Molecular Science, Division of Frontier Medical Science, Programs for Biomedical Research, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
19
|
Suzuki H, Kakizaki S, Horiguchi N, Ichikawa T, Sato K, Takagi H, Mori M. Clinical characteristics of null responders to Peg-IFNα2b/ribavirin therapy for chronic hepatitis C. World J Hepatol 2010; 2:401-405. [PMID: 21173908 PMCID: PMC3004033 DOI: 10.4254/wjh.v2.i11.401] [Citation(s) in RCA: 5] [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: 08/12/2010] [Revised: 11/04/2010] [Accepted: 11/11/2010] [Indexed: 02/06/2023] Open
Abstract
AIM To predict which chronic hepatitis C patients are likely to be late-responders, we herein investigated the clinical characteristics of null-responders at 36 wk with hepatitis C virus (HCV) genotype Ib and a high viral load during the course of pegylated interferon (Peg-IFN)/ribavirin therapy. METHODS One hundred forty-two patients with genotype Ib HCV and a high viral load were included in this study. Peg-IFNα2b (1.5 μg/kg once a week) and ribavirin (600-1000 mg per day according to body weight) were administered for 48 wk. We defined null-responders as the cases that never cleared serum HCV RNA as determined using RT-PCR until 36 wk. Other patients were defined as responders. We compared the clinical characteristics (age, gender, body mass index, previous treatment) and HCV RNA titer during the therapy between null-responders and responders. RESULTS The HCV RNA clearance rate was 17.9% (24/134), 46.3% (62/134), 60.6% (86/142), 86.6% (123/142), and 88.0% (125/142) at 4, 8, 12, 24, and 36 wk, respectively. There were 17 patients (12.0%) who were still null-responders at 36 wk. There were no differences in the clinical characteristics between the responders and null-responders except for the titer and decline rates of HCV RNA at 1 wk and 4 wk. The HCV RNA titers at 1 wk and after 4 wk of treatment were significantly higher in the null-responders in comparison to the responders (P <0.01). The serum HCV RNA titers of the responders decreased by 1.3 log after 1 wk of treatment, and 1.6 log after 4 wk of treatment, respectively. On the other hand, the titers of the null responders decreased by only 0.5 log after 1 wk, and 0.7 log after 4 wk of treatment, respectively. The decrease rates of HCV RNA after 1 and 4 wk of treatment were significantly worse for null responders than for the responders (P <0.01). CONCLUSION The HCV RNA titer at 1 wk and 4 wk after initiating treatment may be useful for predicting null-responders to Peg-IFNα2b/ribavirin therapy. However, further investigation is needed to determine the optimal time at which the decision to discontinue the Peg-IFNα2b/ribavirin therapy for null-responders can be made.
Collapse
Affiliation(s)
- Hideyuki Suzuki
- Hideyuki Suzuki, Satoru Kakizaki, Norio Horiguchi, Takeshi Ichikawa, Ken Sato, Hitoshi Takagi, Masatomo Mori, Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan
| | | | | | | | | | | | | |
Collapse
|
|
20
|
Jin YJ, Park YK, Yun GJ, Lee HC, Jeong SH, Kim GM, Lim YS, Chung YH, Lee YS, Suh DJ. [Mutations within the interferon sensitivity determining region in Korean patients infected with hepatitis C virus genotype 1b]. THE KOREAN JOURNAL OF HEPATOLOGY 2010; 16:158-67. [PMID: 20606500 DOI: 10.3350/kjhep.2010.16.2.158] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
BACKGROUND/AIMS The treatment response to interferon could differ with mutations in the interferon-sensitivity-determining region (ISDR) in patients infected with hepatitis C virus (HCV) genotype-1b (HCV-Ib). We examined the pattern of ISDR mutations and analyzed whether the number of amino acid substitutions influences the treatment response to peginterferon plus ribavirin in chronic hepatitis or cirrhotic patients infected with HCV-Ib. METHODS The study population comprised 52 patients who visited Seoul Asan Medical Center and Seoul National University Bundang Hospital from January 2006 to December 2008 and who received peginterferon alpha-2a (n=37) or -2b (n=15) plus ribavirin, and whose serum was stored. We analyzed the early virologic response, end-of-treatment response, and sustained virologic response (SVR), and examined the ISDR using direct sequencing. RESULTS The proportions of patients with ISDR mutation types of wild (0 mutations), intermediate (1-3 mutations), and mutant (> or =4 mutations) were 50.0%, 42.3%, and 7.7%, respectively, and the corresponding SVR rates were 63%, 50%, and 67% (p>0.05). The SVR rates were 59.4% and 50.0% in patients with <2 and > or =2 mutations, respectively (p>0.05). On univariate analysis, age was the only predictive factor for SVR (p=0.016). The pretreatment HCV RNA titer tended to be lower in those with SVR, but without statistical significance (p=0.069). CONCLUSIONS The frequency of ISDR mutations was low in our cohort of Korean patients infected with HCV-Ib. Therefore, ISDR mutations might not contribute to the response to treatment with peginterferon plus ribavirin.
Collapse
Affiliation(s)
- Young-Joo Jin
- Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
21
|
Nakagawa M, Sakamoto N, Ueyama M, Mogushi K, Nagaie S, Itsui Y, Azuma S, Kakinuma S, Tanaka H, Enomoto N, Watanabe M. Mutations in the interferon sensitivity determining region and virological response to combination therapy with pegylated-interferon alpha 2b plus ribavirin in patients with chronic hepatitis C-1b infection. J Gastroenterol 2010; 45:656-65. [PMID: 20112032 DOI: 10.1007/s00535-009-0195-7] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2009] [Accepted: 12/11/2009] [Indexed: 02/04/2023]
Abstract
BACKGROUND Pegylated-interferon-alpha 2b (PEG-IFN) plus ribavirin (RBV) therapy is currently the de-facto standard treatment for hepatitis C virus (HCV) infection. The aims of this study were to analyze the clinical and virological factors associated with a higher rate of response in patients with HCV genotype 1b infection treated with combination therapy. METHODS We analyzed, retrospectively, 239 patients with chronic hepatitis C-1b infection who received 48 weeks of combination therapy. We assessed clinical and laboratory parameters, including age, gender, pretreatment hemoglobin, platelet counts, HCV RNA titer, liver histology, the number of interferon sensitivity determining region (ISDR) mutations and substitutions of the core amino acids 70 and 91. Drug adherence was monitored in each patient. We carried out univariate and multivariate statistical analyses of these parameters and clinical responses. RESULTS On an intention-to-treat (ITT) analysis, 98 of the 239 patients (41%) had sustained virological responses (SVRs). Patients with more than two mutations in the ISDR had significantly higher SVR rates (P<0.01). Univariate analyses showed that stage of fibrosis, hemoglobin, platelet counts, ISDR mutations, serum HCV RNA level, and adherence to PEG-IFN plus RBV were significantly correlated with SVR rates. Multivariate analysis in subjects with good drug adherence extracted the number of ISDR mutations (two or more: odds ratio [OR] 5.181). CONCLUSIONS The number of mutations in the ISDR sequence of HCV-1b (>or=2) is the most effective parameter predicting a favorable clinical outcome of 48-week PEG-IFN plus RBV therapy in patients with HCV genotype 1b infection.
Collapse
Affiliation(s)
- Mina Nakagawa
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
22
|
Toyoda H, Kumada T, Tada T, Arakawa T, Hayashi K, Honda T, Katano Y, Goto H. Association between HCV amino acid substitutions and outcome of peginterferon and ribavirin combination therapy in HCV genotype 1b and high viral load. J Gastroenterol Hepatol 2010; 25:1072-8. [PMID: 20594221 DOI: 10.1111/j.1440-1746.2010.06240.x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
BACKGROUND AND AIM We prospectively compared the sensitivity to interferon (IFN) and the efficacy of antiviral combination therapy with peginterferon (PEG-IFN) and ribavirin for chronic hepatitis C virus (HCV) genotype 1b infection according to the amino acid sequences of the HCV core, E1, and NS5A regions reported to be associated with the outcome of antiviral therapy. METHODS A total of 107 patients with HCV genotype 1b were investigated. All patients received combination therapy with PEG-IFN alpha-2b and ribavirin. Amino acids 70 and 91 (core), 139 (E1), and 2209-2248 (NS5A) of HCV were analyzed by direct nucleotide sequencing. RESULTS The reduction in HCV RNA concentration at 24 h after a single administration of conventional IFN-alpha and after the start of combination therapy was significantly less marked, and rates of complete early virologic response, end-of-treatment response, and sustained virologic response (SVR) were significantly lower (all P < 0.0001) in patients with glutamine at amino acid 70 (n = 29) than in those with arginine at that position (n = 70). We found no differences associated with the other amino acid positions. Amino acid 70 was an independent factor for the responses to the therapy in multivariate analysis. CONCLUSION The identity of amino acid 70 of the HCV core region affected the sensitivity to IFN; patients with glutamine at amino acid 70 of HCV showed resistance to IFN. Consequently, it strongly affected the outcome of combination therapy with PEG-IFN and ribavirin in Japanese patients with HCV genotype 1b.
Collapse
Affiliation(s)
- Hidenori Toyoda
- Department of Gastroenterology, Ogaki Municipal Hospital, Ogaki, Gifu, Japan.
| | | | | | | | | | | | | | | |
Collapse
|
|
23
|
González-Candelas F, López-Labrador FX. Clinical relevance of genetic heterogeneity in HCV. Future Virol 2010. [DOI: 10.2217/fvl.09.63] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
Infection by HCV affects an estimated 170 million people worldwide and it represents one of the major causes of liver transplantation and a heavy burden to healthcare systems. As with many other RNA viruses, HCV is characterized by very high levels of genetic variation, which have been associated to differences in disease progression and efficiency of antiviral treatment. Studies show many contradictory results and little consensus on such associations. Nevertheless, some general guidelines translating research results to clinical practice have been postulated. Here, we review the main research results obtained on HCV variation so far and explore the reasons for their lack of congruence under a population genetics framework. Understanding the factors responsible for the variable dynamics of HCV diversity in human populations and variation within infected individuals is even more necessary in face of the soon-to-arrive new HCV therapies.
Collapse
Affiliation(s)
- Fernando González-Candelas
- Institut Cavanilles de Biodiversitat i Biologia Evolutiva, Universitat de València, Apartado Oficial 22085, 46071-Valencia, Spain
| | - F Xavier López-Labrador
- Genomics and Health Area, CSISP – Centre for Public Health Research, Public Health Department, Generalitat Valenciana, Av. Catalunya, 21, 46020 Valencia, Spain
| |
Collapse
|
|
24
|
Kitamura S, Tsuge M, Hatakeyama T, Abe H, Imamura M, Mori N, Saneto H, Kawaoka T, Mitsui F, Hiraga N, Takaki S, Kawakami Y, Aikata H, Takahashi S, Ohishi W, Ochi H, Hayes CN, Chayama K. Amino acid substitutions in core and NS5A regions of the HCV genome can predict virological decrease with pegylated interferon plus ribavirin therapy. Antivir Ther 2010; 15:1087-97. [DOI: 10.3851/imp1674] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
|
|
25
|
Viral factors influencing the response to the combination therapy of peginterferon plus ribavirin in chronic hepatitis C. J Gastroenterol 2009; 44:1009-15. [PMID: 19756352 DOI: 10.1007/s00535-009-0126-7] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2009] [Accepted: 08/13/2009] [Indexed: 02/04/2023]
Abstract
Hepatitis C virus (HCV) is a single-stranded RNA virus known for its high genetic variability owing to the lack of a proofreading mechanism of its RNA dependent RNA polymerase. Until now, numerous studies have been undertaken to clarify the correlation between pretreatment HCV genetic variability and the therapeutic response. Even with the recent combination therapy of peginterferon plus ribavirin for chronic hepatitis C, viral response is variable, and only half of treated patients could clear the virus [sustained viral response (SVR)]. In this review, the contribution of viral genetic variability affecting the treatment outcome is discussed according to each HCV genomic region.
Collapse
|