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Sy A, McCabe L, Hudson E, Ansari AM, Pedergnana V, Lin SK, Santana S, Fiorino M, Ala A, Stone B, Smith M, Nelson M, Barclay ST, McPherson S, Ryder SD, Collier J, Barnes E, Walker AS, Pett SL, Cooke G, on behalf of the STOP-HCV-1 trial team. Utility of a buccal swab point-of-care test for the IFNL4 genotype in the era of direct acting antivirals for hepatitis C virus. PLoS One 2023; 18:e0280551. [PMID: 36689413 PMCID: PMC9870125 DOI: 10.1371/journal.pone.0280551] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Accepted: 01/03/2023] [Indexed: 01/24/2023] Open
Abstract
BACKGROUND The CC genotype of the IFNL4 gene is known to be associated with increased Hepatitis C (HCV) cure rates with interferon-based therapy and may contribute to cure with direct acting antivirals. The Genedrive® IFNL4 is a CE marked Point of Care (PoC) molecular diagnostic test, designed for in vitro diagnostic use to provide rapid, real-time detection of IFNL4 genotype status for SNP rs12979860. METHODS 120 Participants were consented to a substudy comparing IFNL4 genotyping results from a buccal swab analysed on the Genedrive® platform with results generated using the Affymetix UK Biobank array considered to be the gold standard. RESULTS Buccal swabs were taken from 120 participants for PoC IFNL4 testing and a whole blood sample for genetic sequencing. Whole blood genotyping vs. buccal swab PoC testing identified 40 (33%), 65 (54%), and 15 (13%) had CC, CT and TT IFNL4 genotype respectively. The Buccal swab PoC identified 38 (32%) CC, 64 (53%) CT and 18 (15%) TT IFNL4 genotype respectively. The sensitivity and specificity of the buccal swab test to detect CC vs non-CC was 90% (95% CI 76-97%) and 98% (95% CI 91-100%) respectively. CONCLUSIONS The buccal swab test was better at correctly identifying non-CC genotypes than CC genotypes. The high specificity of the Genedrive® assay prevents CT/TT genotypes being mistaken for CC, and could avoid patients being identified as potentially 'good responders' to interferon-based therapy.
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Affiliation(s)
- Aminata Sy
- MRC Clinical Trials Unit, University College London, London, United Kingdom
| | - Leanne McCabe
- MRC Clinical Trials Unit, University College London, London, United Kingdom
| | - Emma Hudson
- Peter Medawar Building for Pathogen Research, Oxford, United Kingdom
| | - Azim M. Ansari
- Peter Medawar Building for Pathogen Research, Oxford, United Kingdom
| | | | - Shang-Kuan Lin
- Peter Medawar Building for Pathogen Research, Oxford, United Kingdom
| | - S. Santana
- Peter Medawar Building for Pathogen Research, Oxford, United Kingdom
| | - Marzia Fiorino
- Mortimer Market Centre, Central and NorthWest London NHS Foundation Trust, London, United Kingdom
- Institute for Global Health, University College London, London, United Kingdom
| | - Aftab Ala
- Clinical and Experimental Medicine, University of Surrey, Guilford, United Kingdom
| | - Ben Stone
- Infectious Diseases, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, United Kingdom
| | - M. Smith
- Hepatology, Brighton and Sussex Medical School, Brighton, United Kingdom
| | - Mark Nelson
- HIV Medicine, Chelsea & Westminster NHS Trust, London, United Kingdom
| | | | - Stuart McPherson
- Hepatology, Newcastle Upon Tyne Hospitals NHS Trust, Newcastle upon Tyne, United Kingdom
| | - Stephen D. Ryder
- Hepatology, Nottingham University Hospitals NHS Trust, Nottingham, United Kingdom
| | - Jane Collier
- Translational Gastroenterology Unit, John Radcliffe Hospital, Oxford, United Kingdom
| | - Eleanor Barnes
- Peter Medawar Building for Pathogen Research, Oxford, United Kingdom
- Translational Gastroenterology Unit, John Radcliffe Hospital, Oxford, United Kingdom
| | - Ann Sarah Walker
- MRC Clinical Trials Unit, University College London, London, United Kingdom
| | - Sarah L. Pett
- MRC Clinical Trials Unit, University College London, London, United Kingdom
- Mortimer Market Centre, Central and NorthWest London NHS Foundation Trust, London, United Kingdom
- Institute for Global Health, University College London, London, United Kingdom
| | - Graham Cooke
- Department of Infectious Disease, Imperial College London, London, United Kingdom
- NIHR Biomedical Research Centre, Imperial College NHS Trust, London, United Kingdom
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Role of IL-28B polymorphisms in virologic response to combined pegylated interferon and ribavirin therapy in genotype 4 chronic HCV infected patients with and without cirrhosis. ALEXANDRIA JOURNAL OF MEDICINE 2019. [DOI: 10.1016/j.ajme.2014.09.005] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
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Attallah AM, Omran D, Omran MM, Abdelrazek MA, Zayed R, Essawey RE, Saif S, Farid A, Hassany M, Yosry A, Omar A. Extracellular Matrix Proteins Substantiate IL-28B T allele Effect on Histological Outcome of Chronic Hepatitis C. Ann Hepatol 2018; 17:569-576. [PMID: 29893697 DOI: 10.5604/01.3001.0012.0918] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
INTRODUCTION AND AIM The correlation between interleukin-28B (IL-28B) polymorphisms and chronic hepatitis C (CHC) progression is debatable. Here, we aimed to evaluate the relation between IL-28B C/T genotypes and the development of cirrhotic liver. Extracellular matrix (ECM) proteins, FibroScan and model for end-stage liver disease (MELD) were used to substantiate the severity of liver disease. MATERIAL AND METHODS IL-28B rs12979860, liver stiffness and ECM proteins were assessed in 272 CHC patients. RESULTS Cirrhosis percentage increased to 10%, 52% and 96% with the increasing number of T alleles (CC, CT and TT, respectively). Also, elevated ECM proteins levels were correlated with the increasing number of T alleles. Interestingly, among cirrhotic patients, liver stiffness, MELD and ECM proteins were significantly (P < 0.0001) higher in patients with TT more than CT genotype. FibroScan, hyaluronic acid, Laminin, Collagen IV and the N-terminal pro-peptide of collagen type III have high accuracy to differentiate liver status in CC from TT genotype. Area under receiver-operating characteristic curve (95% CI) were 1.0 (1.0-1.0), 0.97 (0.96- 1.0), 0.93 (0.85-1.0), 0.98 (0.97-1.0) and 0.93 (0.91-0.97), respectively. CONCLUSION This study suggests that IL-28B T allele affects the natural course of CHC type 4 and also suggests that carriage of the IL-28B C allele protects from unfavorable clinical outcomes in CHC as coexistence of C allele with T allele reduced cirrhosis severity.
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Affiliation(s)
- Abdelfattah M Attallah
- Research & Development Department, Biotechnology Research Center, New Damietta City, Egypt
| | - Dalia Omran
- Department of Endemic Medicine and Hepatology, Faculty of Medicine, Cairo University, Egypt
| | | | - Mohamed A Abdelrazek
- Research & Development Department, Biotechnology Research Center, New Damietta City, Egypt
| | - Rania Zayed
- Department of Clinical and Chemical Pathology, Faculty of Medicine, Cairo University, Egypt
| | - Riham El Essawey
- Department of Clinical and Chemical Pathology, Faculty of Medicine, Cairo University, Egypt
| | - Sameh Saif
- National Hepatology and Tropical Medicine Research Institute, Egypt
| | - Azza Farid
- National Hepatology and Tropical Medicine Research Institute, Egypt
| | - Mohamed Hassany
- National Hepatology and Tropical Medicine Research Institute, Egypt
| | - Ayman Yosry
- Department of Endemic Medicine and Hepatology, Faculty of Medicine, Cairo University, Egypt
| | - Ashraf Omar
- Department of Endemic Medicine and Hepatology, Faculty of Medicine, Cairo University, Egypt
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Karkhane M, Marzban A, Lashgarian HE, Zali MR. Genetic Variations in Host Factors and their Critical Role on HCV Medication. RESEARCH IN MOLECULAR MEDICINE 2017. [DOI: 10.29252/rmm.5.1.6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
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The influence of anti-HBc status on the sustained virological response rate in HCV-infected patients treated with pegylated interferon alfa 2 and ribavirin. Clin Exp Hepatol 2016; 2:155-160. [PMID: 28856281 PMCID: PMC5497428 DOI: 10.5114/ceh.2016.63873] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2016] [Accepted: 10/16/2016] [Indexed: 12/19/2022] Open
Abstract
Aim of the study To determine the influence of HBsAg and HBeAg negative but anti-HBc positive status on the sustained virological response (SVR) rate in HCV-infected patients treated with pegylated interferon alfa 2 (Peg-IFNα-2) and ribavirin (RBV). Material and methods The study was based on the retrospective analysis of medical records of HCV-infected patients who started Peg-IFNα and RBV treatment between 1 January 2011 and 31 December 2013 at the 1st and 2nd Department of Infectious Diseases of the Regional Hospital in Wrocław, Poland. Results Among 240 patients included in the analysis 99 were anti-HBc positive and 141 anti-HBc negative. In the genotype 1, anti-HBc positive group the SVR rate was 47% and in the anti-HBc negative group it was 42.7% (p = 0.591). In the genotype 3, anti-HBc positive group the SVR rate was 60% and in anti-HBc negative patients it was 63.2% (p = 0.79). Differences in SVR rates between anti-HBc positive and negative groups were not statistically significant. None of the anti-HBc positive patients developed reactivation of HBV infection during or in the 24 weeks following the end of treatment. Conclusions Anti-HBc determination does not seem to be useful in predicting treatment outcome of conventional Peg-IFNα/RBV therapy in patients infected with HCV genotypes 1 and 3.
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Esmail MA, Hassuna NA, Amr KS, Ghazawy ER, Abdel-Hamid M. Polymorphisms at IL28B gene as predictors of viral relapse in genotype 4 Egyptian hepatitis C patients. J Med Virol 2016; 88:481-6. [PMID: 26280154 DOI: 10.1002/jmv.24354] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/07/2015] [Indexed: 12/23/2022]
Abstract
Chronic HCV is one of the commonest causes of chronic liver disease worldwide with about 15% of population infected in Egypt. Certain single nucleotide polymorphisms (SNPs) lying near the IL28B gene were found to affect the spontaneous clearance as well as treatment outcome of HCV. To examine the association between different IL28B variants and the relapse of HCV infection after combined therapy with ribavirin and pegylated interferon (pegIFN). Hundered HCV genotype four patients received 1.5 mg/kg/week peginterferon alfa-2b plus 800-1400 mg/d ribavirin (weight-adjusted) for 48 weeks. IL28B polymorphisms (rs12980275, rs12979860, and 1 rs8099917) were studied in responders and relapsers at week 72. Out of 69 patients receiving treatment, 13 (18.8%) were relapsers. By stratifying patients on the basis of the IL-28/60 genotype (CC vs. CT/TT), CC patients showed lower relapse rates (2.3%) compared with CT/TT patients (46.2%) (P < 0.001). On the basis of the IL-28/75 genotype (GG vs. GA/AA), the GG patients achieved higher relapse rates (62.5%) compared with GA/AA patients (13.1%) (P = 0.004). Moreover, no statistical significant difference was observed between the TT patients compared with GG/GT patients on the basis of the IL-28/17 genotype. SNPs at IL-28/60 and IL-28/75 are possible predictors of relapse in patients receiving dual treatment.
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Affiliation(s)
| | - Noha A Hassuna
- Microbiology and Immunology Department, Faculty of Medicine, Minia University, Egypt
| | | | | | - Mohamed Abdel-Hamid
- Microbiology and Immunology Department, Faculty of Medicine, Minia University, Egypt
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Cariani E, Roli L, Missale G, Villa E, Ferrari C, Trenti T. Interleukin 28B polymorphisms as predictors of sustained virological response in chronic hepatitis C: systematic review and meta-analysis. THE PHARMACOGENOMICS JOURNAL 2016; 16:18-29. [PMID: 25918016 DOI: 10.1038/tpj.2015.28] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/23/2014] [Revised: 02/05/2015] [Accepted: 03/02/2015] [Indexed: 12/11/2022]
Abstract
Polymorphism of interleukin 28B gene represents a powerful outcome predictor for interferon-based regimens in hepatitis C virus infection. However, some studies report conflicting results. The predictive value of interleukin 28B genotype over the outcome interferon-α/ribavirin treatment was thoroughly evaluated and compared with virological predictors of response. Literature revision was performed on PubMed. Pooled odds ratios (ORs) were calculated by fixed- or random-effects models. Heterogeneity and publication bias were also assessed. Sixty-two eligible papers including 20 290 patients were retrieved. Both polymorphisms (rs12979860 and rs8099917) were strongly associated with response (OR=4.09 and 4.00, respectively), however, the association was weaker for subjects infected with viral genotypes 2 and 3 (OR=1.52 and 1.49, respectively). Compared with interleukin 28B genotype, the association with response was lower for baseline viremia (OR=2.15) and higher for rapid virological response (OR=13.86). These results provide a critical evaluation of interleukin 28B genotype as a pharmacogenetic predictor in hepatitis C patients.
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Affiliation(s)
- E Cariani
- Department of Laboratory Medicine, Clinical Pathology-Toxicology, Ospedale S Agostino-Estense, Modena, Italy
| | - L Roli
- Department of Laboratory Medicine, Clinical Pathology-Toxicology, Ospedale S Agostino-Estense, Modena, Italy
| | - G Missale
- UO Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria, Parma, Italy
| | - E Villa
- Department of Gastroenterology, University of Modena and Reggio Emilia, Modena, Italy
| | - C Ferrari
- UO Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria, Parma, Italy
| | - T Trenti
- Department of Laboratory Medicine, Clinical Pathology-Toxicology, Ospedale S Agostino-Estense, Modena, Italy
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Biasiolo A, Martini A, Pontisso P. New biomarkers for clinical management of hepatitis C virus infected patients. World J Clin Infect Dis 2015; 5:59-66. [DOI: 10.5495/wjcid.v5.i4.59] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2015] [Revised: 08/28/2015] [Accepted: 10/19/2015] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the third most frequent oncological cause of death worldwide, principally a consequence of hepatitis C virus (HCV) infection and its prognosis is mostly poor. For early identification and surveillance of HCV patients with liver disease progression, the availability of suitable diagnostic and prognostic biomarkers is still an unmet clinical need. Alfa-fetoprotein together with imaging techniques is commonly used, however its specificity and sensitivity are not satisfactory. Several clinical and serological data have been proposed to define the risk of disease progression in HCV infected patients and new biomarkers have been proposed, including post-transcriptionally modified molecules and genetic biomarkers. The present editorial article attempts to summarize the current knowledge on the new promising tools for effective early diagnosis of HCV-related liver disease progression and for the surveillance of HCC.
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Olmedo DB, Cader SA, Porto LC. IFN-λ gene polymorphisms as predictive factors in chronic hepatitis C treatment-naive patients without access to protease inhibitors. J Med Virol 2015; 87:1702-15. [PMID: 25970604 DOI: 10.1002/jmv.24227] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/02/2015] [Indexed: 12/16/2022]
Abstract
The single nucleotides polymorphisms analyses in the regions near the IL28B gene in patients chronically infected with genotype 1 hepatitis C virus (HCV) are an important predictive factor for sustained virological response (SVR). The aim was to assess the predictive value of the polymorphisms of the IL28B/IFNL3 gene in patients chronically infected with genotype 1 for the viral clearance obtained after initial treatment including admixed populations. A systematic review was conducted, using a meta-analysis in the PubMed, Embase, LILACS, and SCIELO using MesH and DECS in 42 studies. The parameters were IL28B polymorphisms, rs12979860, rs8099917, and rs12980275, SVR ratio, and OR (odds ratio). OR and confidence Interval of 95% (95%CI), were calculated by fixed or random effects models. Heterogeneity, sensitivity analysis, and publication bias were also performed. Significant differences were noted between carriers groups with the major versus minor allele at rs12979860 CC versus CT/TT-genotype (OR = 4.18; 95%CI = 3.37-5.17), rs8099917 TT versus TG/GG-genotype (OR = 4.07; 95%CI = 2.94-5.63), and rs12980275 AA versus AA/AG-genotype (OR = 5.34; 95%CI = 1.60-17.82). There was selection bias in the rs8099917 analysis (Egger's regression P = 0.049), which reversed after performing a sensitivity analysis (P = 0.510). The incorporation of SNP analyses in IL28B/IFNL3 gene during the diagnosis process in Brazil should be used as a complementary tool to determine the appropriate treatment for HCV genotype 1. Here, we confirm that the rs12979860 CC, rs8099917 TT, and rs12980275 AA genotype-carriers have favorable responses to standard therapy, including two studies with Brazilian population, and this information should be considered.
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Affiliation(s)
- Daniele Blasquez Olmedo
- Histocompatibility and Cryopreservation Laboratory, Rio de Janeiro State University, Rio de Janeiro, Brazil
| | - Samária Ali Cader
- Histocompatibility and Cryopreservation Laboratory, Rio de Janeiro State University, Rio de Janeiro, Brazil
| | - Luís Cristóvão Porto
- Histocompatibility and Cryopreservation Laboratory, Rio de Janeiro State University, Rio de Janeiro, Brazil
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Haj-sheykholeslami A, Keshvari M, Sharafi H, Pouryasin A, Hemmati K, Mohammadzadehparjikolaei F. Interferon-λ polymorphisms and response to pegylated interferon in Iranian hepatitis C patients. World J Gastroenterol 2015; 21:8935-8942. [PMID: 26269684 PMCID: PMC4528037 DOI: 10.3748/wjg.v21.i29.8935] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2014] [Revised: 02/10/2015] [Accepted: 04/09/2015] [Indexed: 02/06/2023] Open
Abstract
AIM To evaluate the efficacy of pegylated interferon in Iranian chronic hepatitis C patients in relation to interferon-λ (IFNL) polymorphisms. METHODS This study enrolled patients with chronic hepatitis C referred to the Tehran Blood Transfusion Hepatitis Clinic in 2011. Patients were included in the study if they had no concomitant hepatic illness, were negative for human immunodeficiency virus antibodies, and had no prior history of treatment with any type of pegylated interferon. Patients were treated with 180 μg pegylated interferon alpha-2a (Pegaferon(®)) weekly and 800-1200 mg ribavirin daily for 24 or 48 wk depending on weight and hepatitis C virus (HCV) genotype. Blood samples were collected from patients to obtain DNA for determination of IFNL rs12979860 and rs8099917 polymorphisms. The virologic response in patients was then evaluated and compared between the different IFNL genotypes. RESULTS A total of 152 patients with a mean age of 41.9 ± 10.0 years were included in the study, of which 141/152 were men (92.8%). The most frequent HCV genotype was type-1, infecting 93/152 (61.2%) patients. Sustained virologic response (SVR) was achieved in 81.9% of patients with HCV genotype-1 and 91.1% of patients with HCV genotype-3. Treatment success was achieved in 91.2% (52/57) of patients with the IFNL rs12979860 CC genotype and 82.1% (78/95) in those with other genotypes. Similar treatment response rates were also observed in patients with rs8099917 TT (39/45; 86.7%) and non-TT (61/68; 89.7%) genotypes. Univariate analyses identified the following factors which influenced treatment response for inclusion in a multivariate analysis: age, HCV RNA level, stage of liver fibrosis, rs12979860 CC genotype, and aspartate transaminase level. A logistic regression analysis revealed that only the rs12979860 CC genotype was significantly associated with achievement of SVR (OR = 6.2; 95%CI: 1.2-31.9; P = 0.03). CONCLUSION The rs12979860 CC genotype was associated with SVR in patients receiving pegylated interferon plus ribavirin, however, the SVR rate in other rs12979860 genotypes was also relatively high.
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Kaczor MP, Seczyńska M, Szczeklik W, Sanak M. IL28B polymorphism (rs12979860) associated with clearance of HCV infection in Poland: systematic review of its prevalence in chronic hepatitis C patients and general population frequency. Pharmacol Rep 2015; 67:260-6. [PMID: 25712648 DOI: 10.1016/j.pharep.2014.10.006] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2014] [Revised: 09/26/2014] [Accepted: 10/08/2014] [Indexed: 12/25/2022]
Abstract
BACKGROUND A common single nucleotide polymorphism (rs12979860) of the interleukin-28B (IL28B) gene is strongly associated with spontaneous and treatment-related eradication of HCV infection. In this study we estimated rs12979860 genotypes distribution among chronic hepatitis C patients in Poland using a systematic review of published studies and compared this data with the prevalence of rs12979860 variants of IL28B in representative sample of the Southern Poland population. METHODS Systematic review on rs12979860 variant prevalence in the Polish chronic HCV subjects was performed. Additionally, age- and gender-stratified population sample was recruited from inhabitants of Kraków using a randomized municipal census data, DNA samples available for 538 individuals were genotyped using a real-time PCR method. RESULTS The frequency of homozygotes TT was from 15 to 27% and carriers of unfavorable T alleles (genotypes CT and TT) were present in 70-80% of chronic HCV subjects. In the general population, 47% individuals were CC homozygous, 42% CT heterozygous and 11% TT homozygous. The population frequency of T allele was 0.318 (95% CI: 0.291-0.347) and the variant was in Hardy-Weinberg equilibrium. Distributions of IL28B genotypes in chronic HCV patients were characterized by a departure from the genetic equilibrium and differed significantly from the random population sample. CONCLUSIONS Events of spontaneous viral clearance can fully explain differences between genotype distributions in general population and chronic HCV subjects and a departure from the genetic equilibrium. This is the first study estimating the prevalence of IL28B rs12979860 SNP in the Southern Poland population based on a random representative sample.
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Affiliation(s)
- Marcin P Kaczor
- Department of Medicine, Jagiellonian University Medical College, Kraków, Poland.
| | - Marta Seczyńska
- Department of Medicine, Jagiellonian University Medical College, Kraków, Poland.
| | - Wojciech Szczeklik
- Department of Medicine, Jagiellonian University Medical College, Kraków, Poland.
| | - Marek Sanak
- Department of Medicine, Jagiellonian University Medical College, Kraków, Poland.
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Xu Y, Qi W, Wang X, Zhao P, Zhang Y, Zhang Q, Qin S, Wang J. Pegylated interferon α-2a plus ribavirin for decompensated hepatitis C virus-related cirrhosis: relationship between efficacy and cumulative dose. Liver Int 2014; 34:1522-31. [PMID: 25453135 DOI: 10.1111/liv.12417] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
BACKGROUND & AIMS A combination of pegylated interferon alpha-2a (Peg-IFNα-2a) and ribavirin (RBV) achieves a sustained virological response (SVR) in 40-50% of patients infected with genotype 1 hepatitis C virus (HCV), but efficacy rates are significantly lower in patients with decompensated HCV-induced cirrhosis. The efficacy and tolerability of Peg-IFNα-2a and RBV, the cumulative dose effect, time to achieve planned cumulative dose and role of HCV phenotype on treatment response were determined in patients with decompensated HCV-induced cirrhosis. METHODS In this case-controlled study, 257 patients with decompensated HCV-induced cirrhosis were enrolled, including patients treated with partial splenic embolization for leukopaenia. Of patients with sufficient blood cell counts, 130 patients opted for antiviral therapy (treatment group) consisting of 180 μg/kg Peg-IFNα-2a for 48 weeks with 800-1200 mg/day RBV; the remaining 127 were considered the control group. Primary endpoints were SVR and absence of relapse; the secondary end point was assessment of disease progression. RESULTS Sustained virological response was highest and relapse rates were lowest when cumulative doses of Peg-IFNα-2a and RBV were both ≥80% of the prescribed dose. Patients achieving ≥80% of the planned cumulative doses in 48 weeks had a significantly higher SVR compared with patients achieving this in 72 weeks. Patients with HCV genotype 1 had significantly lower SVR compared with patients with HCV genotype 2 (19.7% vs. 42.9%, respectively; P = 0.008). Treatment group patients had a significantly lower rate of SVR-independent liver disease-related mortality. CONCLUSIONS Our findings provide additional evidence to support the use of Peg-IFNα-2a and RBV therapy for decompensated HCV-induced cirrhosis.
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Affiliation(s)
- Yan Xu
- Department of Digestive; China-Japan Union Hospital affiliated to Jilin University; Changchun China
| | - Wenqian Qi
- Department of Digestive; China-Japan Union Hospital affiliated to Jilin University; Changchun China
| | - Xu Wang
- Department of Digestive; China-Japan Union Hospital affiliated to Jilin University; Changchun China
| | - Ping Zhao
- Department of Digestive; China-Japan Union Hospital affiliated to Jilin University; Changchun China
| | - Yonggui Zhang
- Department of Digestive; China-Japan Union Hospital affiliated to Jilin University; Changchun China
| | - Qian Zhang
- Department of Digestive; China-Japan Union Hospital affiliated to Jilin University; Changchun China
| | - Shaoyou Qin
- Department of Digestive; China-Japan Union Hospital affiliated to Jilin University; Changchun China
| | - Jiangbin Wang
- Department of Digestive; China-Japan Union Hospital affiliated to Jilin University; Changchun China
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Gatselis NK, Zachou K, Saitis A, Samara M, Dalekos GN. Individualization of chronic hepatitis C treatment according to the host characteristics. World J Gastroenterol 2014; 20:2839-53. [PMID: 24659876 PMCID: PMC3961989 DOI: 10.3748/wjg.v20.i11.2839] [Citation(s) in RCA: 7] [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: 09/19/2013] [Revised: 11/19/2013] [Accepted: 01/06/2014] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) infection is a global health problem that affects more than 170 million people worldwide. It is a major cause of cirrhosis and hepatocellular carcinoma, making the virus the most common cause of liver failure and transplantation. The standard-of-care treatment for chronic hepatitis C (CHC) has been changed during the last decade and direct acting antiviral drugs have already been used. Besides, understanding of the pathogenesis of CHC has evolved rapidly during the last years and now several host factors are known to affect the natural history and response to treatment. Recent genome-wide association studies have shown the important role of interleukin-28B and inosine triphosphatase in HCV infection. The present review article attempts to summarize the current knowledge on the role of host factors towards individualization of HCV treatment.
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Jiménez-Sousa MA, Berenguer J, Fernández-Rodríguez A, Micheloud D, Guzmán-Fulgencio M, Miralles P, Pineda-Tenor D, García-Álvarez M, López JC, Aldámiz-Echevarria T, Carrero A, Resino S. IL28RA polymorphism (rs10903035) is associated with insulin resistance in HIV/HCV-coinfected patients. J Viral Hepat 2014; 21:189-97. [PMID: 24438680 DOI: 10.1111/jvh.12130] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2013] [Accepted: 05/01/2013] [Indexed: 12/18/2022]
Abstract
Hepatitis C virus (HCV) infection is associated with insulin resistance (IR), although mechanisms leading to IR in these patients are not completely understood. The aim of this study was to evaluate the association of interleukin 28B (IL28B) and interleukin 28 receptor alpha (IL28RA) polymorphisms with IR among human immunodeficiency virus (HIV)/HCV-coinfected patients. We carried out a cross-sectional study on 203 patients. IL28B (rs8099917) and IL28RA (rs10903035) polymorphisms were genotyped by GoldenGate(®) assay. IR was defined as homeostatic model assessment (HOMA) values ≥3.00. Univariate and multivariate generalized linear models (GLM) were used to compare HOMA values and the percentage of patients with IR according to IL28B and IL28RA genotypes. In total, 32% (n = 65/203) of the patients had IR. IL28B rs8099917 TT was not significantly associated with HOMA values and IR. In contrast, rs10903035 AA was significantly associated with high HOMA values taking into account all patients (P = 0.024), as well as the subgroups of patients with significant fibrosis (P = 0.047) and infected with HCV genotype 3 (P = 0.024). Additionally, rs10903035 AA was significantly associated with IR (HOMA ≥3.00) in all patients (adjusted odds ratio (aOR) = 2.02; P = 0.034), in patients with significant fibrosis (aOR = 2.86; P = 0.039) and HCV genotype 3 patients (aOR = 4.89; P = 0.031). In conclusions, IL28RA polymorphism (rs10903035) seems to be implicated in the glucose homeostasis because AA genotype increases the likelihood of IR, but this association was different depending on hepatic fibrosis and HCV genotype.
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Affiliation(s)
- M A Jiménez-Sousa
- Unit of Viral Infection and Immunity, National Centre of Microbiology, Instituto de Salud Carlos III, Majadahonda, Spain
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Derbala M, Rizk NM, Al-Kaabi S, John A, Sharma M, El-dweik N, Yakoob R, Pasic F, Almohanadi M, Alejji K, Abdelmola A, Butt M. The predictive value of IL28B rs12979860, rs11881222 and rs8099917 polymorphisms and IP-10 in the therapeutic response of Egyptian genotype 4 patients. Virology 2013; 444:292-300. [PMID: 23866096 DOI: 10.1016/j.virol.2013.06.025] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2013] [Revised: 04/12/2013] [Accepted: 06/24/2013] [Indexed: 02/07/2023]
Abstract
UNLABELLED Interleukin-28B (IL28B) polymorphisms have previously been reported to be strongly associated with spontaneous and treatment-induced HCV viral clearance. AIM To assess the impact of four different IL28B polymorphisms and their haplotype combination and interferon-c inducible protein 10 (IP-10) in response to treatment in Egyptian genotype 4 patients. METHOD 159 HCV-genotype 4 patients were included. All patients were treated with Peginterferon alph2a/Ribavirin for 48 wk. The following polymorphisms rs12979860, rs11881222, rs8103142 and rs8099917 and rs80803142 of Il-28 were known to be associated with the sustained virological response. They were genotyped using the TaqMan assay. IP-10 was assessed by Eliza. RESULTS The data indicated that all SNPs are within the Hardy-Weinberg Equilibrium (HWE) except for rs8103142 (p=6.255(-9)), therefore it was excluded from the study since it deviates from HWE-P. The CC, AA and TT genotypes of rs12979860, rs11881222 and rs8099917 were the more frequent genotypes among the responders at RVR, EVR, ETR and SVR, respectively. The frequency of CC, CT, and TT genotype was 46.4%, 38.1% and 15.5% among responders of RVR, and was 46.9%, 45.9% and 7.2 among responders of SVR for rs12979860, respectively. The relapse rate was 18.0% and 16.0 % during EVR and ETR, while the response rate was 52.8%, 58.5%, 59.7% and 61.6% after 4, 12, 48 and 72 weeks of treatment. The transient virological response (TVR) was 6.9% among HCV patients. The results showed that the odds ratio and 95% CI of HCV genotype 4 patients to have a better sustained response to treatment (SVR) was 2.92, (1.83-4.68, p=2.01(-5)), 2.89 (1.79-4.70, p=2.53(-5)), and 2.73 (0.21-0.65, p=0.0007) for those with the major allele "C" of rs12979860, the "A" allele of rs11881222, and the "T" allele of rs8099917, respectively. Furthermore, the positive predictive value (PPV) of the major homozygous alleles for SVR with better response to therapy was in the following order: 78.69%, 68.42%, and 32.14% with a positive likelihood ratio of 1.95, 1.25, and 0.86 for rs12979860, rs11881222 and rs8099917, respectively. The haplotype formed between the 3 studied SNPs (rs12979860, rs11881222 and rs8099917) showed that two haplotypes (TGG and TGT) increased the probability of a poor response to therapy, but the CAT haplotype had the opposite effect. Multinomial logistic regression analysis revealed that the viral load and rs12979860 are the only significant actors involved in the efficacy of the treatment response among the cohort study. In addition, patients with SVR had significantly lower values of IP-10 than non-responder patients (NR), with a P-value<=0.001. CONCLUSIONS In genotype 4 cases, the IL28B SNPs rs12979860 rs8099917, and rs11881222 are the strongest predictors of a response, while IP-10 is a strong negative biomarker of a response. Accounting for this factor is important in the individualization of treatment and enhances the degree of predictiveness of the IL28 polymorphism in the final treatment outcome. The frequent distribution of C, A and T alleles of IL28 polymorphism are higher among TVR, which may reflect sensitivity to prolonged course.
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Affiliation(s)
- Moutaz Derbala
- Gastroenterology and Hepatology Department, Hamad Hospital, Doha, Qatar.
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Khairy M, Fouad R, Mabrouk M, El-Akel W, Awad AB, Salama R, Elnegouly M, Shaker O. The impact of interleukin 28b gene polymorphism on the virological response to combined pegylated interferon and ribavirin therapy in chronic HCV genotype 4 infected egyptian patients using data mining analysis. HEPATITIS MONTHLY 2013; 13:e10509. [PMID: 24065997 PMCID: PMC3776149 DOI: 10.5812/hepatmon.10509] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/31/2013] [Revised: 04/10/2013] [Accepted: 05/25/2013] [Indexed: 12/11/2022]
Abstract
BACKGROUND Chronic HCV represents one of the common causes of chronic liver disease worldwide with Egypt having the highest prevalence, namely genotype 4. Interleukin IL-28B gene polymorphism has been shown to relate to HCV treatment response, mainly in genotype1. OBJECTIVES We aim to evaluate the predictive power of the rs12979860 IL28B SNP and its protein for treatment response in genotype 4 Egyptian patients by regression analysis and decision tree analysis. PATIENTS AND METHODS The study included 263 chronic HCV Egyptian patients receiving peg-interferon and ribavirin therapy. Patients were classified into 3 groups; non responders (83patients), relapsers (76patients) and sustained virological responders (104 patients). Serum IL 28 B was performed, DNA was extracted and analyzed by direct sequencing of the SNP rs 12979860 of IL28B gene. RESULTS CT, CC and TT represented 56 %, 25 % and 19% of the patients, respectively. Absence of C allele (TT genotype) was significantly correlated with the early failure of response while CC was associated with sustained virological response. The decision tree showed that baseline alpha fetoprotein (AFP ≤ 2.68 ng/ml) was the variable of initial split (the strongest predictor of response) confirmed by regression analysis. Patients with TT genotype had the highest probability of failure of response. CONCLUSIONS Absence of the C allele was significantly associated with failure of response. The presence of C allele was associated with a favorable outcome. AFP is a strong baseline predictor of HCV treatment response. A decision tree model is useful for predicting the probability of response to therapy.
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Affiliation(s)
- Marwa Khairy
- Endemic Medicine Department and Hepatology Unit, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Rabab Fouad
- Endemic Medicine Department and Hepatology Unit, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Mahassen Mabrouk
- Endemic Medicine Department and Hepatology Unit, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Wafaa El-Akel
- Endemic Medicine Department and Hepatology Unit, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Abu Bakr Awad
- Bioinformatic and Statistic Department, Faculty of Computer Sciences, Cairo University, Cairo, Egypt
| | - Rabab Salama
- Endemic Medicine Department and Hepatology Unit, Faculty of Medicine, Cairo University, Cairo, Egypt
- Corresponding author: Rabab Salama, Endemic Medicine and Hepatology Department, Kasr El-Aini Faculty of Medicine, Cairo University, Cairo, Egypt. Tel: +20-25262555, Fax: +20-25326439, E-mail:
| | - Mayada Elnegouly
- Endemic Medicine Department and Hepatology Unit, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Olfat Shaker
- Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Cairo University, Cairo, Egypt
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Yu ML, Liu CH, Huang CF, Tseng TC, Huang JF, Dai CY, Lin ZY, Chen SC, Wang LY, Juo SHH, Chuang WL, Kao JH. Revisiting the stopping rule for hepatitis C genotype 1 patients treated with peginterferon plus ribavirin. PLoS One 2012; 7:e52048. [PMID: 23284866 PMCID: PMC3528729 DOI: 10.1371/journal.pone.0052048] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2012] [Accepted: 11/08/2012] [Indexed: 12/23/2022] Open
Abstract
BACKGROUND The current stopping rule for peginterferon/ribavirin therapy in hepatitis C virus genotype-1 (HCV-1) patients is based on an early virological response (EVR, defined as >2 log(10) viral reduction at treatment week 12). We aimed to explore rapid stopping rules at week 4. METHODS We randomly allocated 528 HCV-1 patients into training and validation sets (at a 1∶2 ratio). The interleukin-28B rs8099917 genotypes and on-treatment virological responses were evaluated to determine the negative predictive value (NPV) for achieving a sustained virological response (SVR, defined as undetectable HCV RNA 24 weeks after end-of-treatment). The study was approved by the ethics committees of the participating hospitals. All of the patients gave written informed consent before enrollment. RESULTS A poor week 4 response (W4R), defined as a HCV RNA reduction of <1 log(10) IU/mL at week 4 or a week 4 HCV RNA>10,000 IU/mL with interleukin-28B non-TT genotype, had the highest NPV (95%). In the complete sample, poor W4R could identify 43.4% (59/136) of the non-responders, with an NPV of 95% and a false negative rate of only 0.8% (3/396). The multivariate analysis revealed that a poor W4R was the most important negative predictor (odds ratio/95% confidence intervals: 49.01/13.70-175.37), followed by the lack of an EVR. In addition to HCV RNA<1 log(10) IU/mL reduction, using the criteria of HCV RNA>10,000 IU/mL/non-TT genotype helped identifying an additional one-third of non-SVR patients at W4.Using the strategy of sequential rapid stopping rule strategy could identify 53.7% (73/136) of the non-responders (43.4% at week 4 and an addition 11.3% at week 12), as compared to 40.4% for the classical week-12 early stopping rule. CONCLUSIONS Sequential rapid stopping rules using on-treatment virological responses and interleukin-28B genotype can rapidly identify additional peginterferon/ribavirin non-responders.
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Affiliation(s)
- Ming-Lung Yu
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Department of Internal Medicine, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- Faculty of Internal Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Chen-Hua Liu
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Chung-Feng Huang
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Department of Occupational Medicine, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Tai-Chung Tseng
- Department of Internal Medicine, Buddhist Tzu Chi General Hospital, Taipei Branch, Taipei, Taiwan
| | - Jee-Fu Huang
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Faculty of Internal Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Internal Medicine, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Chia-Yen Dai
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Faculty of Internal Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Zu-Yau Lin
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Faculty of Internal Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Shinn-Cherng Chen
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Faculty of Internal Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Liang-Yen Wang
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Faculty of Internal Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Suh-Hang Hank Juo
- Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Department of Medical Genetics and Department of Neurology, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Wan-Long Chuang
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Faculty of Internal Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Jia-Horng Kao
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
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