|
1
|
Frías M, Rivero-Juárez A, Machuca I, Camacho Á, Rivero A. The outlook for precision medicine for the treatment of chronic hepatitis C infection: challenges and opportunities. EXPERT REVIEW OF PRECISION MEDICINE AND DRUG DEVELOPMENT 2020. [DOI: 10.1080/23808993.2020.1764346] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Affiliation(s)
- Mario Frías
- Clinical Virology and Zoonoses, Hospital Universitario Reina Sofía de Córdoba. Instituto Maimonides de Investigación Biomédica de Córdoba (IMIBIC), Universidad de Córdoba, Spain
| | - Antonio Rivero-Juárez
- Clinical Virology and Zoonoses, Hospital Universitario Reina Sofía de Córdoba. Instituto Maimonides de Investigación Biomédica de Córdoba (IMIBIC), Universidad de Córdoba, Spain
| | - Isabel Machuca
- Clinical Virology and Zoonoses, Hospital Universitario Reina Sofía de Córdoba. Instituto Maimonides de Investigación Biomédica de Córdoba (IMIBIC), Universidad de Córdoba, Spain
| | - Ángela Camacho
- Clinical Virology and Zoonoses, Hospital Universitario Reina Sofía de Córdoba. Instituto Maimonides de Investigación Biomédica de Córdoba (IMIBIC), Universidad de Córdoba, Spain
| | - Antonio Rivero
- Clinical Virology and Zoonoses, Hospital Universitario Reina Sofía de Córdoba. Instituto Maimonides de Investigación Biomédica de Córdoba (IMIBIC), Universidad de Córdoba, Spain
| |
Collapse
|
|
2
|
Frias M, Rivero-Juárez A, López-López P, Rivero A. Pharmacogenetics and the treatment of HIV-/HCV-coinfected patients. Pharmacogenomics 2018; 19:979-995. [PMID: 29992850 DOI: 10.2217/pgs-2018-0046] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
This review will summarize the role of pharmacogenetics in the natural history of hepatitis C, particularly in patients with HIV/HCV and will take the perspective of pharmacogenetics and its influence on the response to antiviral therapy and the susceptibility to develop adverse effects. This review will also devote a section to host genetics in other clinical situations, such as disease progression and acute HCV infection, which may determine whether treatment of HIV-/HCV-coinfected patients is implemented or deferred.
Collapse
Affiliation(s)
- Mario Frias
- Department of Clinical Virology & Zooneses, Hospital Universitario Reina Sofía de Córdoba, Instituto Maimonides de Investigación Biomédica de Córdoba (IMIBIC), Universidad de Córdoba. Córdoba, 14004, Spain
| | - Antonio Rivero-Juárez
- Department of Clinical Virology & Zooneses, Hospital Universitario Reina Sofía de Córdoba, Instituto Maimonides de Investigación Biomédica de Córdoba (IMIBIC), Universidad de Córdoba. Córdoba, 14004, Spain
| | - Pedro López-López
- Department of Clinical Virology & Zooneses, Hospital Universitario Reina Sofía de Córdoba, Instituto Maimonides de Investigación Biomédica de Córdoba (IMIBIC), Universidad de Córdoba. Córdoba, 14004, Spain
| | - Antonio Rivero
- Department of Clinical Virology & Zooneses, Hospital Universitario Reina Sofía de Córdoba, Instituto Maimonides de Investigación Biomédica de Córdoba (IMIBIC), Universidad de Córdoba. Córdoba, 14004, Spain
| |
Collapse
|
|
3
|
Yamagiwa S, Ishikawa T, Waguri N, Sugitani S, Wakabayashi H, Ohkoshi S, Tsukishiro T, Takahashi T, Watanabe T, Terai S. Efficacy and safety of telaprevir- and simeprevir-based triple therapies for older patients with chronic hepatitis C. World J Hepatol 2017; 9:252-262. [PMID: 28261382 PMCID: PMC5316845 DOI: 10.4254/wjh.v9.i5.252] [Citation(s) in RCA: 2] [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: 08/22/2016] [Revised: 12/29/2016] [Accepted: 01/11/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To evaluate and compare the efficacy and safety of telaprevir (TVR)-and simeprevir (SMV)-based triple therapies in elderly patients, specifically patients aged 66 years or older. METHODS The present study enrolled 112 and 76 Japanese patients with chronic hepatitis C virus genotype 1b infection who were treated with a 12-wk TVR-based or SMV-based triple therapy, respectively, followed by a dual therapy that included pegylated interferon α and ribavirin (RBV) for 12 wk. The patients were categorized into two groups according to age as follows: A younger group of patients aged ≤ 65 years old and an older group of patients aged > 65 years old. Among the patients treated with TVR-based triple therapy, 34 patients were included in the older group. The median ages were 56 years (range: 28-65 years) in the younger group and 69 years (range: 66-81 years) in the older group. Among the patients treated with SMV-based triple therapy, 39 patients were included in the older group. The median ages were 59 years (range: 36-65 years) in the younger group and 71 years (range: 66-86 years) in the older group. The clinical, biochemical and virological data were analyzed before and during treatment. RESULTS Among the patients treated with the TVR-based triple therapy, no significant difference in the sustained virological response (SVR) was found between the younger (80.8%) and older (88.2%) groups. The SVR rates for patients with the interleukin 28B (IL28B) (rs8099917) TG/GG-genotypes (73.9% and 60.0% in the younger and older groups, respectively) were significantly lower than for patients with the IL28B TT-genotype (86.3% and 92.9%, respectively). The cumulative exposure to RBV for the entire 24-wk treatment period (as a percentage of the target dose) was significantly higher in the younger group than in the older group (91.7% vs 66.7%, respectively, P < 0.01), but the cumulative exposure to TVR was not significantly different between the younger and older groups (91.6% vs 81.9%, respectively). A multivariate analysis identified the TT-genotype of IL28B (OR = 8.160; 95%CI: 1.593-41.804, P = 0.012) and the adherence of RBV (> 60%) (OR = 11.052; 95%CI: 1.160-105.273, P = 0.037) as independent factors associated with the SVR. Adverse events resulted in discontinuation of the treatment in 11.3% and 14.7% of the younger and older groups, respectively. Among the patients treated with the SMV-based triple therapy, no significant difference in the SVR rare was found between the younger (81.1%) and older (82.1%) groups. The SVR rates for patients with the IL28B TG/GG-genotypes (77.8% and 64.7% in the younger and older groups, respectively) were significantly lower than for patients with the IL28B TT-genotype (88.2% and 100%, respectively). A multivariate analysis identified the TT-genotype of IL28B as an independent factor associated with the SVR (OR = 9.677; 95%CI: 1.114-84.087, P = 0.040). Adverse events resulted in discontinuation of the treatment in 7.0% and 14.3% of patients in the younger and older groups, respectively. CONCLUSION Both TVR- and SMV-based triple therapies can be successfully used to treat patients aged 66 years or older with genotype 1b chronic hepatitis C. Genotyping of the IL28B indicates a potential to achieve SVR in these difficult-to-treat elderly patients.
Collapse
Affiliation(s)
- Satoshi Yamagiwa
- Satoshi Yamagiwa, Shuji Terai, Division of Gastroenterology and Hepatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan
| | - Toru Ishikawa
- Satoshi Yamagiwa, Shuji Terai, Division of Gastroenterology and Hepatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan
| | - Nobuo Waguri
- Satoshi Yamagiwa, Shuji Terai, Division of Gastroenterology and Hepatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan
| | - Soichi Sugitani
- Satoshi Yamagiwa, Shuji Terai, Division of Gastroenterology and Hepatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan
| | - Hiroto Wakabayashi
- Satoshi Yamagiwa, Shuji Terai, Division of Gastroenterology and Hepatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan
| | - Shogo Ohkoshi
- Satoshi Yamagiwa, Shuji Terai, Division of Gastroenterology and Hepatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan
| | - Takashi Tsukishiro
- Satoshi Yamagiwa, Shuji Terai, Division of Gastroenterology and Hepatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan
| | - Toru Takahashi
- Satoshi Yamagiwa, Shuji Terai, Division of Gastroenterology and Hepatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan
| | - Toshiaki Watanabe
- Satoshi Yamagiwa, Shuji Terai, Division of Gastroenterology and Hepatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan
| | - Shuji Terai
- Satoshi Yamagiwa, Shuji Terai, Division of Gastroenterology and Hepatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan
| |
Collapse
|
|
4
|
Novotny D, Roubalova L, Aiglova K, Bednarikova J, Bartkova M. IL28B genotyping and treatment of HCV infected subjects. ASIAN BIOMED 2017. [DOI: 10.5372/1905-7415.0804.313] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
AbstractBackground: Chronic hepatitis C is a common cause of advanced liver disease and appropriate treatment has been complex and a challenge. Reaction of individual genotypes to classical pegylated interferon-ribavirin therapy differs and no success has been achieved in some even after repeated therapy cycles. New types of so called directly acting antivirals (DAAs) are hopeful, as shown in many recent clinical studies, and triple therapy regimens involving DAA are becoming the new standard of care.Objective: To summarize knowledge about the relationship between HCV therapeutic regimens and the genetic background of the host represented by interleukin 28B (IL28B) gene polymorphisms. In the first part, the host basic mechanisms in specific and innate immunity are introduced. The IL28B genotype and its role in the course of HCV treatment are described in the second part.Methods: We searched and summarized publications on HCV therapeutic regimens and host IL28B polymorphisms.Results: Compared to classical regimens, the association between IL28B polymorphism and treatment outcome of HCV infected patients is weaker in triple therapy using first generation DAAs boceprevir and telaprevir.Conclusions: The association between IL28B polymorphism and treatment outcome is lessened with availability of new therapeutic regimens. Nevertheless, IL28B genotyping may still be useful for individualization of treatment strategies.
Collapse
Affiliation(s)
- Dalibor Novotny
- PhD, Department of Clinical Biochemistry, University Hospital Olomouc, 77520 Olomouc, Czechia
| | - Lucie Roubalova
- Department of Clinical Biochemistry, University Hospital Olomouc, Olomouc 77520, Czechia
| | - Kvetoslava Aiglova
- Department of Internal Medicine, Faculty of Medicine and Dentistry, Palacky University Olomouc and University Hospital Olomouc, Olomouc 77520, Czechia
| | - Jana Bednarikova
- Department of Clinical Biochemistry, University Hospital Olomouc, Olomouc 77520, Czechia
| | - Margita Bartkova
- Department of Clinical Biochemistry, University Hospital Olomouc, Olomouc 77520, Czechia
| |
Collapse
|
|
5
|
Ning G, Lin CS. History and future of antiviral therapy of chronic hepatitis C. Shijie Huaren Xiaohua Zazhi 2016; 24:2117-2130. [DOI: 10.11569/wcjd.v24.i14.2117] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) infection often leads to chronic diseases, and antiviral therapy is an important way to prevent chronic hepatitis C from progressing to end-stage liver disease. Up to now, hepatitis C antiviral therapy has successively experienced eras of interferon monotherapy, interferon and ribavirin combination therapy, and combination therapy of pegylated-interferon (PEG-IFN) and ribavirin. Now we are entering into a new era of direct-acting antiviral agents (DAAs). Just like acquired immune deficiency syndrome (AIDS) cocktails, combination therapy consists of two or more antiviral agents. DAAs will be the primary antiviral therapy for hepatitis C in the future for their better tolerance, lower drug resistance, higher sustained virological response and shorter treatment course. In this article, we review the history and future of antiviral therapy of HCV infection.
Collapse
|
|
6
|
About F, Oudot-Mellakh T, Niay J, Rabiéga P, Pedergnana V, Duffy D, Sultanik P, Cagnot C, Carrat F, Marcellin P, Zoulim F, Larrey D, Hézode C, Fontaine H, Bronowicki JP, Pol S, Albert ML, Theodorou I, Cobat A, Abel L, ANRS CO20-CUPIC study group. Impact of IL28B, APOH and ITPA Polymorphisms on Efficacy and Safety of TVR- or BOC-Based Triple Therapy in Treatment-Experienced HCV-1 Patients with Compensated Cirrhosis from the ANRS CO20-CUPIC Study. PLoS One 2015; 10:e0145105. [PMID: 26670100 PMCID: PMC4682920 DOI: 10.1371/journal.pone.0145105] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2015] [Accepted: 11/29/2015] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Human genetic factors influence the outcome of pegylated interferon and ribavirin hepatitis C therapy. We explored the role of IL28B, APOH and ITPA SNPs on the outcomes of triple therapy including telaprevir or boceprevir in patients with compensated cirrhosis chronically infected with HCV-1. PATIENTS AND METHODS A total of 256 HCV-1 Caucasian treatment-experienced patients with compensated cirrhosis from the ANRS CO20-CUPIC cohort were genotyped for a total of 10 candidate SNPs in IL28B (rs12979860 and rs368234815), APOH (rs8178822, rs12944940, rs10048158, rs52797880, rs1801689 and rs1801690) and ITPA (rs1127354 and rs7270101). We tested the association of IL28B and APOH SNPs with sustained virological response and of ITPA SNPs with anemia related phenotypes by means of logistic regression assuming an additive genetic model. RESULTS None of the six APOH SNPs were associated with sustained virological response. The favorable alleles of the IL28B SNPs rs12979860 and rs368234815 were associated with sustained virological response (rs12979860: OR = 2.35[1.50-3.70], P = 2x10(-4)). Refined analysis showed that the effect of IL28B SNPs on sustained virological response was restricted to prior PegIFN/RBV relapse (OR = 3.80[1.82-8.92], P = 8x10(-4)). We also confirmed the association between ITPA low activity alleles and protection against early hemoglobin decline in triple therapy (P = 2x10(-5)). CONCLUSION Our results suggest that the screening of rs12979860 may remain interesting for decision making in prior relapse HCV-1 Caucasian patients with compensated cirrhosis eligible for a telaprevir- or boceprevir-based therapy.
Collapse
Affiliation(s)
- Frédégonde About
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale (INSERM) U1163, Paris, France
- Paris Descartes University, Imagine Institute, Paris, France
| | - Tiphaine Oudot-Mellakh
- Laboratory of Immunity and Infection, Centre d’Immunologie et des Maladies Infectieuses de Paris (CIMI), INSERM U1135, Groupe Hospitalier Pitié Salpétrière, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France
- Plateforme Génomique Inserm-ANRS, Groupe Hospitalier Pitié Salpétrière, AP-HP, UPMC Université Paris 6, Paris, France
| | - Jonathan Niay
- Laboratory of Immunity and Infection, Centre d’Immunologie et des Maladies Infectieuses de Paris (CIMI), INSERM U1135, Groupe Hospitalier Pitié Salpétrière, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France
- Plateforme Génomique Inserm-ANRS, Groupe Hospitalier Pitié Salpétrière, AP-HP, UPMC Université Paris 6, Paris, France
| | - Pascaline Rabiéga
- Sorbonne Universités, UPMC Université Paris 06, INSERM, Institut Pierre Louis d’épidémiologie et de Santé Publique (IPLESP UMRS 1136), Paris, France
| | - Vincent Pedergnana
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale (INSERM) U1163, Paris, France
- Paris Descartes University, Imagine Institute, Paris, France
- Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom
| | - Darragh Duffy
- Centre for Human Immunology, Department of Immunology, Institut Pasteur, Paris, France
- The Laboratory of Dendritic Cell Biology, Department of Immunology, Institut Pasteur, INSERM U818, Paris, France
| | - Philippe Sultanik
- Département d'Hépatologie, Hôpital Cochin, AP-HP, Université Paris Descartes, Paris, France
- INSERM UMS20, Institut Pasteur, Paris, France
| | - Carole Cagnot
- Unit for Basic and Clinical research on Viral Hepatitis, Inserm-ANRS (France REcherche Nord & sud Sida-HIV Hépatites-FRENSH), Paris, France
| | - Fabrice Carrat
- Sorbonne Universités, UPMC Université Paris 06, INSERM, Institut Pierre Louis d’épidémiologie et de Santé Publique (IPLESP UMRS 1136), Paris, France
- Service de Santé Publique, Hôpital Saint Antoine, AP-HP, Paris, France
| | | | - Fabien Zoulim
- Centre de recherche en cancérologie de Lyon (CRCL), INSERM UMR I 1052/CNRS 5286, Lyon cedex 03, France
- Université Claude-Bernard Lyon 1, Villeurbanne, France
- Hospices civils de Lyon, Hôpital de la Croix-Rousse, service d'hépatologie et de gastroentérologie, Lyon, France
| | | | - Christophe Hézode
- Department of Hepatology and Gastroenterology, Hôpital Henri Mondor, AP-HP, Université Paris-Est Créteil (UPEC), Créteil, France
- Institut Mondor de Recherche Biomédicale (IMRB), INSERM U955, UPEC, Créteil, France
| | - Hélène Fontaine
- Département d'Hépatologie, Hôpital Cochin, AP-HP, Université Paris Descartes, Paris, France
- INSERM UMS20, Institut Pasteur, Paris, France
| | - Jean-Pierre Bronowicki
- Department of Hepatogastroenterology, INSERM U954, CHU de Nancy, Université de Lorraine, Vandoeuvre-Lès-Nancy, France
| | - Stanislas Pol
- Département d'Hépatologie, Hôpital Cochin, AP-HP, Université Paris Descartes, Paris, France
- INSERM UMS20, Institut Pasteur, Paris, France
| | - Matthew L. Albert
- Centre for Human Immunology, Department of Immunology, Institut Pasteur, Paris, France
- The Laboratory of Dendritic Cell Biology, Department of Immunology, Institut Pasteur, INSERM U818, Paris, France
- INSERM UMS20, Institut Pasteur, Paris, France
| | - Ioannis Theodorou
- Laboratory of Immunity and Infection, Centre d’Immunologie et des Maladies Infectieuses de Paris (CIMI), INSERM U1135, Groupe Hospitalier Pitié Salpétrière, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France
- Plateforme Génomique Inserm-ANRS, Groupe Hospitalier Pitié Salpétrière, AP-HP, UPMC Université Paris 6, Paris, France
| | - Aurélie Cobat
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale (INSERM) U1163, Paris, France
- Paris Descartes University, Imagine Institute, Paris, France
| | - Laurent Abel
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale (INSERM) U1163, Paris, France
- Paris Descartes University, Imagine Institute, Paris, France
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, United States of America
| | | |
Collapse
|
|
7
|
Shuldiner SR, Gong L, Muir AJ, Altman RB, Klein TE. PharmGKB summary: peginterferon-α pathway. Pharmacogenet Genomics 2015; 25:465-74. [PMID: 26111151 PMCID: PMC4757589 DOI: 10.1097/fpc.0000000000000158] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Affiliation(s)
| | - Li Gong
- Department of Genetics, Stanford University, Stanford, California
| | - Andrew J. Muir
- Duke Clinical Research Institute, Duke University, Durham, North Carolina, USA
| | - Russ B. Altman
- Department of Genetics, Stanford University, Stanford, California
- Department of Bioengineering, Stanford University, Stanford, California
| | - Teri E. Klein
- Department of Genetics, Stanford University, Stanford, California
| |
Collapse
|
|
8
|
Bailly F, Virlogeux V, Dufour C, Pradat P, Hézode C, Larrey D, Alric L, Samuel D, Bourlière M, Métivier S, Zarski JP, Fontaine H, Loustaud-Ratti V, Serfaty L, Bronowicki JP, Carrat F, Zoulim F. Early virological assessment during telaprevir- or boceprevir-based triple therapy in hepatitis C cirrhotic patients who failed a previous interferon based regimen - The ANRS CO20-CUPIC study. Clin Res Hepatol Gastroenterol 2015; 39:443-50. [PMID: 25636238 DOI: 10.1016/j.clinre.2014.12.007] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2014] [Revised: 12/09/2014] [Accepted: 12/15/2014] [Indexed: 02/04/2023]
Abstract
BACKGROUND AND OBJECTIVE To assess within the ANRS CO20-CUPIC cohort whether the viral load (VL) at week 2/week 6 for telaprevir/boceprevir-based triple therapy, respectively, was predictive of sustained virological response (SVR) in patients with hepatitis C virus (HCV) infection and to study the relevance of this measurement to early diagnose drug resistance. METHODS Observational study of HCV genotype 1 patients with compensated cirrhosis (Child-Pugh A), non-responders to a prior course of interferon (IFN)-based therapy and who started triple therapy. Patients received either 12 weeks of telaprevir in combination with PEG-IFN/ribavirin (RBV), then 36 weeks of PEG-IFN/RBV, or 4 weeks of PEG-IFN/RBV, then 44 weeks of PEG-IFN/RBV and boceprevir. RESULTS A total of 262 patients were analyzed. For telaprevir-treated patients, 28% had undetectable VL at W2 of whom 81% achieved SVR12 whereas 67% had undetectable VL at W4 of whom 67% achieved SVR12. For boceprevir-treated patients 20% had undetectable VL at W6 and 86% of them achieved SVR12 whereas 36% had undetectable VL at W8 among whom 73% achieved SVR12. Five telaprevir-treated patients had a VL increase between W2 and W4 after a decrease between D0 and W2. Four of them did not achieve SVR12. Similarly, six boceprevir-treated patients had a VL increase between W6 and W8 after a decrease between D0 and W6. Five did not reach SVR12. CONCLUSIONS The assessment of HCV RNA level after two weeks of triple therapy in cirrhotic non-responder patients is a good predictor of SVR. This assessment was useful to do an early diagnosis of viral breakthrough.
Collapse
Affiliation(s)
- François Bailly
- Department of Hepatology, Hôpital de la Croix-Rousse, Hospices Civils de Lyon, 69004 Lyon, France; Inserm U1052, 69003 Lyon, France; Université Lyon I, 69622 Villeurbanne, France
| | - Victor Virlogeux
- Department of Hepatology, Hôpital de la Croix-Rousse, Hospices Civils de Lyon, 69004 Lyon, France; École Normale Supérieure, 69007 Lyon, France
| | - Cécilie Dufour
- Inserm UMR-S 707, Université Pierre-et-Marie-Curie Paris 6, 75012 Paris, France
| | - Pierre Pradat
- Department of Hepatology, Hôpital de la Croix-Rousse, Hospices Civils de Lyon, 69004 Lyon, France; Inserm U1052, 69003 Lyon, France; Université Lyon I, 69622 Villeurbanne, France
| | | | - Dominique Larrey
- Hépato-gastroentérologie, CHU de Montpellier, Hôpital Saint-Éloi, 34090 Montpellier, France
| | - Laurent Alric
- Pôle Digestif, CHU Purpan, UMR 152, Université Toulouse 3, 31059 Toulouse, France
| | - Didier Samuel
- Centre Hépato-Biliaire, AP-HP Hôpital Paul-Brousse, 94870 Villejuif, France; Unité 785, Inserm, 94870 Villejuif, France; Université Paris-Sud, 94270 Le Kremlin-Bicêtre, France
| | - Marc Bourlière
- Department of Hepatology and Gastroenterology, Hôpital Saint-Joseph, 13285 Marseille, France
| | - Sophie Métivier
- Pôle Digestif-Gastro-entérologie-Hépatologie, CHU Purpan, 31059 Toulouse, France
| | - Jean-Pierre Zarski
- Clinique universitaire d'Hépato-Gastroentérologie, CHRU Michallon, 38043 Grenoble, France
| | - Hélène Fontaine
- Hôpital Cochin, AP-HP, Université Paris-René Descartes, Inserm U1016, 75014 Paris, France
| | | | - Lawrence Serfaty
- Hépato-gastro-entérologie orienté en hépatologie, CHU Saint-Antoine, 75012 Paris, France
| | - Jean-Pierre Bronowicki
- Department of Hepatology and Gastroenterology, CHU de Nancy, Université de Lorraine, Inserm U954, 54500 Vandœuvre-lès-Nancy, France
| | - Fabrice Carrat
- Inserm UMR-S 707, Université Pierre-et-Marie-Curie Paris 6, 75012 Paris, France
| | - Fabien Zoulim
- Department of Hepatology, Hôpital de la Croix-Rousse, Hospices Civils de Lyon, 69004 Lyon, France; Inserm U1052, 69003 Lyon, France; Université Lyon I, 69622 Villeurbanne, France.
| | | |
Collapse
|
|
9
|
Salmerón J, Vinaixa C, Berenguer R, Pascasio JM, Sánchez Ruano JJ, Serra M&A, Gila A, Diago M, Romero-Gómez M, Navarro JM, Testillano M, Fernández C, Espinosa D, Carmona I, Pons JA, Jorquera F, Rodriguez FJ, Pérez R, Montero JL, Granados R, Fernández M, Martín AB, Muñoz de Rueda P, Quiles R, Alhambra Spanish Study Group. Effectiveness and safety of first-generation protease inhibitors in clinical practice: Hepatitis C virus patients with advanced fibrosis. World J Gastroenterol 2015; 21:9163-9174. [PMID: 26290644 PMCID: PMC4533049 DOI: 10.3748/wjg.v21.i30.9163] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2015] [Revised: 04/29/2015] [Accepted: 06/26/2015] [Indexed: 02/06/2023] Open
Abstract
AIM To evaluates the effectiveness and safety of the first generation, NS3/4A protease inhibitors (PIs) in clinical practice against chronic C virus, especially in patients with advanced fibrosis. METHODS Prospective study and non-experimental analysis of a multicentre cohort of 38 Spanish hospitals that includes patients with chronic hepatitis C genotype 1, treatment-naïve (TN) or treatment-experienced (TE), who underwent triple therapy with the first generation NS3/4A protease inhibitors, boceprevir (BOC) and telaprevir (TVR), in combination with pegylated interferon and ribavirin. The patients were treatment in routine practice settings. Data on the study population and on adverse clinical and virologic effects were compiled during the treatment period and during follow up. RESULTS One thousand and fifty seven patients were included, 405 (38%) were treated with BOC and 652 (62%) with TVR. Of this total, 30% (n = 319) were TN and the remaining were TE: 28% (n = 298) relapsers, 12% (n = 123) partial responders (PR), 25% (n = 260) null-responders (NR) and for 5% (n = 57) with prior response unknown. The rate of sustained virologic response (SVR) by intention-to-treatment (ITT) was greater in those treated with TVR (65%) than in those treated with BOC (52%) (P < 0.0001), whereas by modified intention-to-treatment (mITT) no were found significant differences. By degree of fibrosis, 56% of patients were F4 and the highest SVR rates were recorded in the non-F4 patients, both TN and TE. In the analysis by groups, the TN patients treated with TVR by ITT showed a higher SVR (P = 0.005). However, by mITT there were no significant differences between BOC and TVR. In the multivariate analysis by mITT, the significant SVR factors were relapsers, IL28B CC and non-F4; the type of treatment (BOC or TVR) was not significant. The lowest SVR values were presented by the F4-NR patients, treated with BOC (46%) or with TVR (45%). 28% of the patients interrupted the treatment, mainly by non-viral response (51%): this outcome was more frequent in the TE than in the TN patients (57% vs 40%, P = 0.01). With respect to severe haematological disorders, neutropaenia was more likely to affect the patients treated with BOC (33% vs 20%, P ≤ 0.0001), and thrombocytopaenia and anaemia, the F4 patients (P = 0.000, P = 0.025, respectively). CONCLUSION In a real clinical practice setting with a high proportion of patients with advanced fibrosis, effectiveness of first-generation PIs was high except for NR patients, with similar SVR rates being achieved by BOC and TVR.
Collapse
|
|
10
|
Calisti G, Tavares A, Macartney MJ, McCormick A, Labbett W, Jacobs M, Dusheiko G, Rosenberg WM, Haque T. IL28B genotype predicts response to chronic hepatitis C triple therapy with telaprevir or boceprevir in treatment naïve and treatment-experienced patients other than prior partial- and null-responders. SPRINGERPLUS 2015; 4:357. [PMID: 26191484 PMCID: PMC4503705 DOI: 10.1186/s40064-015-1137-x] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/16/2015] [Accepted: 07/03/2015] [Indexed: 01/26/2023]
Abstract
Single nucleotide polymorphisms (SNPs) in the IL28B gene were shown to have limited utility in predicting response to telaprevir and boceprevir in treatment of chronic HCV infection in clinical trials. Data outside of the clinical trial setting are lacking. We assessed the value of single and combined IL28B SNPs rs12979860 and rs8099917 genotypes in predicting sustained virological response 12 weeks after cessation of triple therapy (SVR12) with telaprevir or boceprevir in a single-centre cohort of treatment-naïve and treatment-experienced patients with genotype 1 HCV mono-infection (n = 105). The overall SVR12 rate was 65.7%. By unadjusted bivariate logistic regression analysis, rs12979860-CC and rs8099917-TT were significantly associated with SVR12 in the subgroup of patients including all naïve patients and all treatment-experienced patients with the exception of partial- and null-responders to previous HCV therapy. The predictive value of rs12979860-CC was stronger than rs8099917-TT and only rs12979860-CC remained significantly predictive of treatment success when the two variants were assessed by adjusted logistic regression analysis in the whole study cohort. In patients presenting the rs12979860-CC variant, the additional determination of rs8099917 genotype had no value. IL28B rs12979860-CC remained significantly associated with SVR12 also in the multivariate analysis including the other baseline characteristics associated to SVR12 in the bivariate analysis (i.e., female gender, HCV genotype 1b, baseline viral load <800,000 IU/mL, advanced liver fibrosis and prior partial- or null-response to HCV therapy). Our study suggests that testing for the IL28B rs12979860 genotype may still be useful in predicting response to triple therapy with boceprevir and telaprevir in naïve patients and treatment-experienced patients other than partial and null-responders.
Collapse
Affiliation(s)
- Giorgio Calisti
- Department of Virology, Royal Free London NHS Foundation Trust, Pond Street, London, NW5 4AP UK
| | - Amanda Tavares
- Department of Virology, Royal Free London NHS Foundation Trust, Pond Street, London, NW5 4AP UK
| | - Malcolm J Macartney
- Department of Virology, Royal Free London NHS Foundation Trust, Pond Street, London, NW5 4AP UK
| | - Adele McCormick
- Department of Virology, Royal Free London NHS Foundation Trust, Pond Street, London, NW5 4AP UK
| | - Wendy Labbett
- Department of Virology, Royal Free London NHS Foundation Trust, Pond Street, London, NW5 4AP UK
| | - Michael Jacobs
- The UCL Institute for Liver and Digestive Health/Royal Free London NHS Foundation Trust Viral Hepatitis Service, London, UK
| | - Geoffrey Dusheiko
- The UCL Institute for Liver and Digestive Health/Royal Free London NHS Foundation Trust Viral Hepatitis Service, London, UK
| | - William M Rosenberg
- The UCL Institute for Liver and Digestive Health/Royal Free London NHS Foundation Trust Viral Hepatitis Service, London, UK
| | - Tanzina Haque
- Department of Virology, Royal Free London NHS Foundation Trust, Pond Street, London, NW5 4AP UK
| |
Collapse
|
|
11
|
Bailly F, Pradat P, Virlogeux V, Zoulim F. Antiviral Therapy in Patients with Hepatitis C Virus-Induced Cirrhosis. Dig Dis 2015; 33:613-23. [PMID: 26159282 DOI: 10.1159/000375359] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
BACKGROUND Opportunities to treat infection with hepatitis C virus (HCV) are evolving rapidly. From the introduction of interferon (IFN)-α monotherapy in the early 1990s to the approval of telaprevir- and boceprevir-based triple therapies with pegylated (PEG)-IFN-α and ribavirin (RBV) in 2011, the chances of curing patients infected with HCV genotype 1 have improved dramatically to reach approximately 70%. Significant further improvements that may cure virtually all HCV patients with an all-oral, IFN-free regimen are becoming progressively available. Key Messages: Historically, a PEG-IFN/RBV combination therapy of patients with liver cirrhosis was associated with lower virological rates and a worse safety profile. The advent of the first protease inhibitor-based triple therapy was long expected, but the promise fell rapidly because of the numerous side effects and the requirement for intensive clinical management in cirrhotic patients. The newer direct-acting antivirals (DAAs) target the viral polymerase with either nucleos(t)ide analogues or nonnucleosidic inhibitors, the viral protease and the viral NS5A protein. Several clinical trials have now shown that a combination of sofosbuvir (nucleosidic polymerase inhibitor) with daclatasvir or ledipasvir (NS5A inhibitors), or sofosbuvir with simeprevir (protease inhibitor), or a combination of ABT-450 (protease inhibitor) with ritonavir (ABT-450/r), the nonnucleosidic polymerase inhibitor ABT-333 and the NS5A inhibitor ABT-267, can achieve a sustained virological response in up to 95% of naive patients or previously treated patients, even in those who failed prior treatment with first-generation protease inhibitors. The best treatment regimens enable the achievement of comparable results even in cirrhotics, while other regimens still require RBV or a longer treatment duration to achieve optimal results. This improved risk/benefit ratio justifies early access programs of IFN-free regimens for cirrhotic patients. The remaining difficult-to-treat patients are cirrhotics infected with HCV genotype 3 and those with decompensated cirrhosis, for whom novel DAA combinations should be evaluated in clinical trials. CONCLUSIONS As new DAAs are becoming available in early access treatment programs, treatment strategy studies are being performed to optimize treatment regimens with respect to the choice of DAAs and treatment duration, based on viral genotypes, prior treatment response and the presence of liver cirrhosis. In the near future, this should allow: (i) a decrease in the complications of HCV-induced cirrhosis, (ii) liver transplantations to be performed in virally cured patients, and (iii) the rescue of patients in the worst clinical situation (decompensated cirrhosis and HCV recurrence on liver graft).
Collapse
Affiliation(s)
- François Bailly
- Hepatology Department, Hospices Civils de Lyon, Lyon, France
| | | | | | | |
Collapse
|
|
12
|
Sultanik P, Mallet V, Lagaye S, Casrouge A, Dorival C, Barthe Y, Fontaine H, Hézode C, Mottez E, Bronowicki JP, Carrat F, Theodorou I, Abel L, Gayat E, Fontanet A, Pol S, Albert ML. Plasma apolipoprotein H limits HCV replication and associates with response to NS3 protease inhibitors-based therapy. Liver Int 2015; 35:1833-44. [PMID: 25556540 DOI: 10.1111/liv.12759] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2014] [Accepted: 11/20/2014] [Indexed: 12/17/2022]
Abstract
BACKGROUND & AIMS Chronic infection with HCV remains a public health problem with approximately 150 million people infected worldwide. HCV intersects with lipid metabolism for replication and entry; and plasma concentrations of apolipoproteins have been identified as predictors for response to therapy. Herein, we conducted a screen of plasma proteins, including all apolipoproteins, to identify correlates of response to pegylated-interferon/ribavirin (PR) and HCV non-structural protein 3 (NS3) inhibitors (i.e., telaprevir/boceprevir) therapy in treatment-experienced cirrhotic patients from the ANRS CUPIC cohort. METHODS We analysed 220 baseline plasma protein concentrations in 189 patients using Luminex technology and analyzed results. RESULTS We identified baseline levels of apolipoprotein H (apoH) as a surrogate marker for sustained virological response (SVR). Notably, increased plasma concentration of apoH, used in combination with known clinical parameters, established a robust model with improved classification of patients as likely to achieve SVR (AUC = 0.77, Se = 66%, Sp = 72%, NRI = 39%). Moreover, we provide mechanistic information that indicates a previously unidentified role for apoH during viral entry. Using a human liver slices HCV infection model, we demonstrate that apoH limits replication. CONCLUSION These data support testing of new biomarker strategies for the management of cirrhotic HCV patients and expand our understanding of how apoH may intersect with HCV infection.
Collapse
Affiliation(s)
- Philippe Sultanik
- Department of Hepatology, Hôpital Cochin, AP-HP, Paris, France.,INSERM U 1016, CNRS UMR 8104, Université Paris Descartes UMR-S 1016, Paris, France
| | - Vincent Mallet
- Department of Hepatology, Hôpital Cochin, AP-HP, Paris, France.,INSERM U 1016, CNRS UMR 8104, Université Paris Descartes UMR-S 1016, Paris, France
| | - Sylvie Lagaye
- INSERM U 1016, CNRS UMR 8104, Université Paris Descartes UMR-S 1016, Paris, France
| | - Armanda Casrouge
- The laboratory of Dendritic Cell Biology, Departement of Immunology, Institut Pasteur, INSERM U818, Paris, France
| | - Céline Dorival
- UMR-S 707, Université Pierre et Marie Curie-Paris 6 & INSERM, Paris, France
| | - Yoann Barthe
- UMR-S 707, Université Pierre et Marie Curie-Paris 6 & INSERM, Paris, France
| | - Hélène Fontaine
- Department of Hepatology, Hôpital Cochin, AP-HP, Paris, France.,INSERM U 1016, CNRS UMR 8104, Université Paris Descartes UMR-S 1016, Paris, France
| | - Christophe Hézode
- Department of Hepatology and Gastroenterology, Hôpital Henri Mondor, AP-HP, Université Paris-Est, Créteil, France
| | - Estelle Mottez
- Centre for Human Immunology, Departement of Immunology, Institut Pasteur, INSERM S20, Paris, France
| | - Jean-Pierre Bronowicki
- Centre Hospitalier Universitaire de Nancy, Université de Lorraine, INSERM U954, Vandoeuvre-les-Nancy, France
| | - Fabrice Carrat
- UMR-S 707, Université Pierre et Marie Curie-Paris 6 & INSERM, Paris, France.,Department of Public Health, Hôpital Saint-Antoine, AP-HP, Paris, France
| | - Ioannis Theodorou
- Laboratory of Immunity and Infection, Groupe Hospitalier Pitié-Salpêtrière AP-HP, INSERM UMR-S 945, UPMC Université Paris 6, Paris, France
| | - Laurent Abel
- Laboratory of Human Genetics of Infectious Diseases, Necker branch, INSERM U1163, Paris, France.,University Paris Descartes, Sorbonne Paris Cité, Imagine Institute, Paris, France.,Laboratory of Human Genetics of Infectious Diseases, Rockefeller branch, The Rockefeller University, New-York, USA
| | - Etienne Gayat
- Department of Anesthesiology and Critical Care Medicine - Mobile Care Unit, Hôpital Lariboisière, AP-HP, Paris, France.,Biomarkers and cardiac diseases, Hôpital Lariboisière, INSERM U942, Paris, France
| | - Arnaud Fontanet
- Departement of Epidemiology of Infectious Disease, Institut Pasteur, Paris, France
| | - Stanislas Pol
- Department of Hepatology, Hôpital Cochin, AP-HP, Paris, France.,INSERM U 1016, CNRS UMR 8104, Université Paris Descartes UMR-S 1016, Paris, France
| | - Matthew L Albert
- The laboratory of Dendritic Cell Biology, Departement of Immunology, Institut Pasteur, INSERM U818, Paris, France.,Centre for Human Immunology, Departement of Immunology, Institut Pasteur, INSERM S20, Paris, France
| | | |
Collapse
|
|
13
|
Cavalcante LN, Lyra AC. Predictive factors associated with hepatitis C antiviral therapy response. World J Hepatol 2015; 7:1617-31. [PMID: 26140082 PMCID: PMC4483544 DOI: 10.4254/wjh.v7.i12.1617] [Citation(s) in RCA: 61] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2014] [Revised: 12/16/2014] [Accepted: 05/05/2015] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) infection may lead to significant liver injury, and viral, environmental, host, immunologic and genetic factors may contribute to the differences in the disease expression and treatment response. In the early 2000s, dual therapy using a combination of pegylated interferon plus ribavirin (PR) became the standard of care for HCV treatment. In this PR era, predictive factors of therapy response related to virus and host have been identified. In 2010/2011, therapeutic regimens for HCV genotype 1 patients were modified, and the addition of NS3/4a protease inhibitors (boceprevir or telaprevir) to dual therapy increased the effectiveness and chances of sustained virologic response (SVR). Nevertheless, the first-generation triple therapy is associated with many adverse events, some of which are serious and associated with death, particularly in cirrhotic patients. This led to the need to identify viral and host predictive factors that might influence the SVR rate to triple therapy and avoid unnecessary exposure to these drugs. Over the past four years, hepatitis C treatment has been rapidly changing with the development of new therapies and other developments. Currently, with the more recent generations of pangenotipic antiviral therapies, there have been higher sustained virologic rates, and prognostic factors may not have the same importance and strength as before. Nonetheless, some variables may still be consistent with the low rates of non-response with regimens that include sofosbuvir, daclatasvir and ledipasvir. In this manuscript, we review the predictive factors of therapy response across the different treatment regimens over the last decade including the new antiviral drugs.
Collapse
Affiliation(s)
- Lourianne Nascimento Cavalcante
- Lourianne Nascimento Cavalcante, André Castro Lyra, Hospital Sao Rafael - Gastro-Hepatology Service, Salvador, Bahia 41253-190, Brazil
| | - André Castro Lyra
- Lourianne Nascimento Cavalcante, André Castro Lyra, Hospital Sao Rafael - Gastro-Hepatology Service, Salvador, Bahia 41253-190, Brazil
| |
Collapse
|
|
14
|
Sultanik PS, Casrouge A, Alanio C, Mottez E, Rosa-Hézode I, Hézode C, Renard P, Bousquet L, Pellet P, Uzé G, Pol S, Albert ML, Mallet V. Baseline sensitivity of T cells to alpha-IFN correlates with sustained virological response to IFN-based triple therapy in HCV infection. J Viral Hepat 2015; 22:524-34. [PMID: 25382001 DOI: 10.1111/jvh.12355] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2014] [Accepted: 10/04/2014] [Indexed: 01/22/2023]
Abstract
Chronic infection with HCV is a public health problem with approximately 170 million people infected worldwide. Interferon alpha (IFNα) sensitivity in liver and IL28B genotype has been identified as important determinants of HCV clearance in the setting of pegylated interferon/ribavirin treatment. Herein, we explored IFNα sensitivity in PBMC from 21 healthy donors and 21 HCV-infected patients treated with pegylated interferon/ribavirin and HCV nonstructural protein-3 inhibitors (i.e. telaprevir/boceprevir). We explored phospho-STAT1 level as read-out for IFN signalling pathway activation in PBMC, T cells and monocytes and correlated results with virological response. We found that PBMC from healthy donors are desensitized to IFNα after priming and challenged with IFNα, with a subsequent decrease of phospho-STAT1 and interferon-stimulated genes. Furthermore, we show that CD3+ T cells, but not monocytes, become desensitized after 4 weeks of treatment, with a significant decrease of phospho-STAT1 after ex vivo IFNα stimulation. Finally, we identified baseline phospho-STAT1 level in CD3+ T cells as a potential biomarker of sustained virological response, regardless of the IL28B genotype. In the upcoming costly era of IFN-sparing regimen, baseline IFNα sensitivity could act as biomarker to define cost-effectiveness strategies of treatment by identifying patients who will or will not respond to IFN-based treatments.
Collapse
Affiliation(s)
- P-S Sultanik
- INSERM (UMR-S 1016), Université Paris Descartes, Assistance Publique-Hôpitaux de Paris, Centre Hospitalier Universitaire Cochin-Port Royal, Service d'hépatologie, Paris, France
| | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
15
|
Abstract
Liver-related biomarkers have been developed and validated mainly in patients with chronic hepatitis C for the prediction of liver fibrosis or cirrhosis, which is a final pathway of chronic liver injury. They are noninvasive, traceable, and easy-to-use. Biomarkers provide implications related to screening, diagnosis, treatment, and prognosis of chronic hepatitis. For the improvement of performance and coverage, biomarker panels, imaging biomarkers, and even genetic biomarkers have been developed. With the advancement of genomics and proteomics, earlier and more precise prediction is expected in the near future. In this review, multiple biomarker panels for the estimation of the degree of fibrosis in chronic hepatitis C, biomarkers for the screening and diagnosis of hepatitis C, biomarkers for the treatment of hepatitis C, biomarkers for the prediction of complications related to the chronic hepatitis C, and future perspectives will be summarized.
Collapse
Affiliation(s)
- Seung Ha Park
- Department of Internal Medicine, Inje University College of Medicine, Busan, South Korea
| | - Chang Seok Bang
- Department of Internal Medicine, Hallym University College of Medicine, Chuncheon, South Korea
| | - Dong Joon Kim
- Department of Internal Medicine, Hallym University College of Medicine, Chuncheon, South Korea.
| |
Collapse
|
|
16
|
Abe H, Tsubota A, Shimada N, Atsukawa M, Kato K, Takaguchi K, Asano T, Chuganji Y, Sakamoto C, Toyoda H, Kumada T, Ide T, Sata M, Aizawa Y. Factors associated with sustained virological response in 24-week telaprevir-based triple therapy for chronic hepatitis C genotype 1b patients with the IL28B minor genotype. Hepatol Res 2015; 45:387-396. [PMID: 24849518 DOI: 10.1111/hepr.12360] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2013] [Revised: 03/11/2014] [Accepted: 05/15/2014] [Indexed: 02/08/2023]
Abstract
AIM Single nucleotide polymorphisms (SNP) near the interleukin-28B (IL28B) gene affect the outcome of 24-week telaprevir-based triple therapy with telaprevir, pegylated interferon-α and ribavirin for chronic hepatitis C virus (HCV) genotype 1b patients. We aimed to identify factors associated with treatment outcomes in patients with the unfavorable minor IL28B SNP genotype, who have poor response to combination therapy. METHODS Pretreatment and on-treatment factors associated with sustained virological response (SVR) for 24-week telaprevir-based triple therapy were analyzed using multiple logistic regression analysis in 106 HCV genotype 1b patients with the minor IL28B SNP rs8099917 genotype (non-TT). RESULTS Of the 106 non-TT patients, 62 (58.5%) achieved SVR. Of the 44 remaining patients, 22 experienced relapse, 13 experienced viral breakthrough and nine were non-responders. Pretreatment factors such as treatment-naïve/prior treatment response (P = 0.0041), high fasting serum low-density lipoprotein cholesterol (LDL-C) concentration (P = 0.0068) and low serum HCV RNA levels (P = 0.0088) were significantly and independently associated with SVR. On-treatment factors such as achievement of rapid virological response (RVR) were significantly and independently associated with SVR (P = 0.0001). For both pre- and on-treatment factors, treatment-naïve/prior treatment response (P = 0.0018), low pretreatment serum fasting LDL-C (P = 0.0062) and achieving RVR (P = 0.0021) were significantly and independently associated with SVR. CONCLUSION In HCV genotype 1b patients with the minor IL28B SNP rs8099917 genotype, evaluating prior treatment response and achieving RVR and pretreatment serum fasting LDL-C concentrations were useful for predicting SVR achievement after 24-week telaprevir-based triple therapy.
Collapse
Affiliation(s)
- Hiroshi Abe
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Jikei University School of Medicine Katsushika Medical Center, Tokyo, Japan
| | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
17
|
Buchanan R, Hydes T, Khakoo SI. Innate and adaptive genetic pathways in HCV infection. TISSUE ANTIGENS 2015; 85:231-40. [PMID: 25708172 DOI: 10.1111/tan.12540] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Infection with hepatitis C virus (HCV) leads to a wide spectrum of clinical manifestations. This heterogeneity is underpinned by the host immune response and the genetic factors that govern it. Polymorphisms affecting both the innate and adaptive immunity determine the outcome of exposure. However the innate immune system appears to play a greater role in determining treatment-associated responses. Overall the effects of IFNL3/4 appear dominant over other polymorphic genes. Understanding how host genetics determines the disease phenotype has not been as intensively studied. This review summarizes our current understanding of innate and adaptive immunogenetic factors in the outcome of HCV infection. It focuses on how they relate to resolution and the progression of HCV-related liver disease, in the context of current and future treatment regimes.
Collapse
Affiliation(s)
- R Buchanan
- Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK
| | | | | |
Collapse
|
|
18
|
Bertol BC, Moreira S, Garcia RFL, Ferreira LE, Debortoli G, Pinho MDSL, Amendola-Pires M, Maciel AMDA, Brandço-Mello CE, de França PHC. IL28B gene polymorphisms in mono- and HIV-coinfected chronic hepatitis C patients. Front Microbiol 2015; 6:153. [PMID: 25788894 PMCID: PMC4349181 DOI: 10.3389/fmicb.2015.00153] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2014] [Accepted: 02/10/2015] [Indexed: 12/19/2022] Open
Abstract
Introduction: Single-nucleotide polymorphisms (SNPs) associated with hepatitis C virus (HCV) clearance were identified near the IL28B gene. Coinfection by the human immunodeficiency virus (HIV) influences the course of HCV contributing to liver damage. Nevertheless, little is known about the relationship between these SNPs and HCV/HIV coinfection. Our aim was to estimate the frequencies of the allelic and genotypic variants of the IL28B polymorphisms rs12979860 (C/T) and rs8099917 (T/G) and their possible association with the establishment of HCV infection. Methodology: A total of 199 non-infected controls and 230 patients with chronic hepatitis C, including 53 coinfected with HIV, participated in the study. Genotyping consisted of polymerase chain reaction and subsequent analysis of the restriction patterns resulting from exposure to endonucleases. Results: Among the controls with established results, 47.4% (90/190) exhibited the rs12979860 CC genotype, 43.7 CT, and 8.9% TT, whereas 29.1% (66/227), 51.5%, and 19.4% of the patients exhibited the CC, CT, and TT genotypes, respectively. With respect to rs8099917, 66.8% (133/199) of the controls exhibited the TT genotype, 31.2% TG, and 2.0% GG, whereas 56.1% (129/230), 40.9%, and 3.0% of the patients exhibited the TT, TG, and GG genotypes, respectively. Conclusion: The frequencies of the rs12979860 C allele and CC genotype and of the rs8099917 T allele and TT genotype were significantly higher among controls compared with patients, thus confirming the suggested protective effect against HCV infection. No significant difference was observed in the genotype and allelic distributions between the mono- and coinfected patients.
Collapse
Affiliation(s)
- Bruna C Bertol
- Laboratory of Molecular Biology, Department of Medicine, Universidade da Região de Joinville Joinville, Brazil
| | - Simone Moreira
- Laboratory of Molecular Biology, Department of Medicine, Universidade da Região de Joinville Joinville, Brazil
| | - Raquel F L Garcia
- Laboratory of Molecular Biology, Department of Medicine, Universidade da Região de Joinville Joinville, Brazil ; Hospital Municipal São José, Joinville Brazil
| | - Leslie E Ferreira
- Laboratory of Molecular Biology, Department of Medicine, Universidade da Região de Joinville Joinville, Brazil
| | - Guilherme Debortoli
- Laboratory of Molecular Biology, Department of Medicine, Universidade da Região de Joinville Joinville, Brazil
| | - Mauro de Souza Leite Pinho
- Laboratory of Molecular Biology, Department of Medicine, Universidade da Região de Joinville Joinville, Brazil ; Hospital Municipal São José, Joinville Brazil
| | - Marcia Amendola-Pires
- Hospital Universitário Gaffrée Guinle - Universidade Federal do Estado do Rio de Janeiro, Rio de Janeiro Brazil
| | | | - Carlos E Brandço-Mello
- Hospital Universitário Gaffrée Guinle - Universidade Federal do Estado do Rio de Janeiro, Rio de Janeiro Brazil
| | - Paulo H C de França
- Laboratory of Molecular Biology, Department of Medicine, Universidade da Região de Joinville Joinville, Brazil
| |
Collapse
|
|
19
|
Virolés Torrent S, López Nuñez C, Hombrados Verde M, Figa Francesch M, Ferri Iglesias MJ, Louvriex Freire R, Acero Fernández D. La interrupción precoz del tratamiento triple con telaprevir de la hepatitis crónica C por efecto adverso grave no presupone necesariamente el fracaso del tratamiento. GASTROENTEROLOGIA Y HEPATOLOGIA 2015; 38:78-81. [DOI: 10.1016/j.gastrohep.2014.04.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/22/2014] [Revised: 04/21/2014] [Accepted: 04/24/2014] [Indexed: 10/25/2022]
|
|
20
|
Berg T, Andreone P, Pol S, Roberts S, Younossi Z, Diago M, Lawitz EJ, Focaccia R, Foster GR, Horban A, Lonjon-Domanec I, DeMasi R, Picchio G, Luo D, De Meyer S, Zeuzem S. Low-density lipoprotein and other predictors of response with telaprevir-based therapy in treatment-experienced HCV genotype 1 patients: REALIZE study. Liver Int 2015; 35:448-454. [PMID: 25319731 DOI: 10.1111/liv.12703] [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: 01/22/2014] [Accepted: 10/10/2014] [Indexed: 01/05/2023]
Abstract
BACKGROUND & AIMS Predictors of response to treatment with peginterferon plus ribavirin are well established. In these post-hoc analyses of the REALIZE study, we sought to identify predictors of response for telaprevir-based triple therapy. METHODS Patients from the REALIZE study with baseline data for all predictors evaluated (including baseline disease characteristics and demographics, prior treatment response and baseline laboratory assessments) were included in the post-hoc analyses (n = 465). Univariate and multivariate analyses were used to evaluate factors predicting treatment outcomes. RESULTS Sustained viral response (SVR) rates were 86% in prior relapsers, 63% in prior partial responders and 32% in prior null-responders. In the final multivariate analysis, baseline factors predicting SVR were prior response to treatment [Odds ratio (OR) = 2.80; 95% confidence interval (CI), 2.13-3.69], low-density lipoprotein (LDL) (≥2.6 mmol/L) (OR = 2.11; 95% CI, 1.52-2.93), HCV genotype (OR = 0.58; 95% CI, 0.36-0.93), and maximum alanine amino transferase and aspartate amino transferase (OR = 0.62; 95% CI, 0.40-0.97). CONCLUSIONS Prior response to peginterferon plus ribavirin treatment and LDL levels are the main independent predictive markers of response with telaprevir-based triple therapy.
Collapse
Affiliation(s)
- Thomas Berg
- Universitätsklinikum Leipzig, Sektion Hepatologie, Klinik für Gastroenterologie und Rheumatologie, Leipzig, Germany
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
21
|
Neukam K, Munteanu D, Haubitz S, Mira JA, Ingiliz P, Rivero-Juárez A, Lutz T, de los Santos-Gil I, Scholten S, Márquez M, Rauch A, Rockstroh JK, Pineda JA. Impact of IL28B genotype on first-week response to telaprevir-based therapy in HIV-HCV coinfection. Antivir Ther 2014; 20:407-13. [PMID: 25470790 DOI: 10.3851/imp2921] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/11/2014] [Indexed: 10/24/2022]
Abstract
BACKGROUND IL28B genotype predicts response to treatment against HCV with pegylated interferon/ribavirin (PR) and impacts on the outcome of therapy including telaprevir (TVR). This study aimed to determine the influence of the favourable IL28B genotype on early viral kinetics during therapy with TVR/PR in HIV-HCV-coinfected patients. METHODS All HIV-HCV genotype 1 coinfected subjects who received TVR/PR for at least 4 weeks were included from populations prospectively followed in 22 centres throughout Germany, Switzerland and Spain. RESULTS Of the 129 subjects included, 38 (29.5%) presented with IL28B genotype CC and 94 (72.9%) were treatment-experienced. A total of 96 (73.8%) patients showed undetectable plasma HCV RNA at treatment week (W)4: 30 (78.9%) of the IL28B-CC carriers and 65 (71.4%) of the non-CC carriers (P=0.377). Among treatment-naive patients, proportions of undetectable HCV RNA among IL28B-CC versus non-CC carriers were 8/9 (88.9%) versus 3/9 (33.3%; P=0.016) and 14/17 (82.4%) versus 11/18 (61.1%; P=0.164) at W2 and W4. The decrease of HCV RNA at W2 and W4 was similar among the IL28B carriers. CONCLUSIONS IL28B genotype does not predict W4 response to TVR/PR in HIV-HCV-coinfected patients, regardless of their treatment history. However, there is evidence of an impact on response during the first weeks in treatment-naive patients.
Collapse
Affiliation(s)
- Karin Neukam
- Unit of Infectious Diseases and Microbiology, Valme University Hospital, Seville, Spain.
| | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
22
|
Shimada N, Tsubota A, Atsukawa M, Abe H, Ide T, Takaguchi K, Chuganji Y, Toyoda H, Yoshizawa K, Ika M, Sato Y, Kato K, Kumada T, Sakamoto C, Aizawa Y, Sata M. A 48-week telaprevir-based triple combination therapy improves sustained virological response rate in previous non-responders to peginterferon and ribavirin with genotype 1b chronic hepatitis C: A multicenter study. Hepatol Res 2014; 44:E386-E396. [PMID: 24606109 DOI: 10.1111/hepr.12323] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2014] [Revised: 03/02/2014] [Accepted: 03/05/2014] [Indexed: 02/08/2023]
Abstract
AIM The sustained virological response (SVR) rate of non-responders to peginterferon and ribavirin therapy (PR) is low for 24-week telaprevir-based triple combination therapy (T12PR24), compared to that of treatment-naïve patients or previous-treatment relapsers. This study investigated which characteristics of non-responders were associated with a better SVR rate to 48-week therapy (T12PR48). METHODS A total of 103 Japanese non-responders with genotype 1b chronic hepatitis C received telaprevir-based therapy. Among them, 81 patients (50 partial and 31 null responders) received T12PR24 and 22 (seven partial and 15 null responders) who agreed to the extended therapy received T12PR48. RESULTS Multivariate logistic regression analysis for SVR identified the interleukin-28B (IL28B) rs8099917 TT genotype (P = 0.0005, odds ratio [OR] = 10.38), extended rapid virological response (P = 0.0008, OR = 7.02), T12PR48 regimen (P = 0.0016, OR = 9.31) and previous partial responders (P = 0.0022, OR = 5.89). Among partial responders, the SVR rate did not differ significantly between T12PR48 (85.7%) and T12PR24 (70.0%). Among null responders, the SVR rate was significantly higher with T12PR48 than T12PR24 (66.7% vs 22.6%, P = 0.0037). Among patients with the IL28B non-TT genotype, the SVR rate was significantly higher with T12PR48 than T12PR24 (68.8% vs 37.7%, P = 0.0288). Moreover, among null responders with the non-TT genotype, the SVR rate was significantly higher with T12PR48 than T12PR24 (66.7% vs 9.1%, P = 0.0009). CONCLUSION T12PR48 improves the SVR rate in null responders, patients with the non-TT genotype, and null responders with a non-TT genotype.
Collapse
Affiliation(s)
- Noritomo Shimada
- Division of Gastroenterology and Hepatology, Shinmatsudo Central General Hospital, Matsudo, Japan
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
23
|
Susser S, Herrmann E, Lange C, Hamdi N, Müller T, Berg T, Perner D, Zeuzem S, Sarrazin C. Predictive value of interferon-lambda gene polymorphisms for treatment response in chronic hepatitis C. PLoS One 2014; 9:e112592. [PMID: 25393304 PMCID: PMC4231027 DOI: 10.1371/journal.pone.0112592] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2014] [Accepted: 10/10/2014] [Indexed: 01/23/2023] Open
Abstract
BACKGROUND IL28B gene polymorphism is the best baseline predictor of response to interferon alfa-based antiviral therapies in chronic hepatitis C. Recently, a new IFN-L4 polymorphism was identified as first potential functional variant for induction of IL28B expression. Individualization of interferon alfa-based therapies based on a combination of IL28B/IFN-L4 polymorphisms may help to optimize virologic outcome and economic resources. METHODS Optimization of treatment outcome prediction was assessed by combination of different IL28B and IFN-L4 polymorphisms in patients with chronic HCV genotype 1 (n = 385), 2/3 (n = 267), and 4 (n = 220) infection treated with pegylated interferon alfa (PEG-IFN) and ribavirin with (n = 79) or without telaprevir. Healthy people from Germany (n = 283) and Egypt (n = 96) served as controls. RESULTS Frequencies of beneficial IL28B rs12979860 C/C genotypes were lower in HCV genotype 1/4 infected patients in comparison to controls (20-35% vs. 46-47%) this was also true for ss469415590 TT/TT (20-35% vs. 45-47%). Single interferon-lambda SNPs (rs12979860, rs8099917, ss469415590) correlated with sustained virologic response (SVR) in genotype 1, 3, and 4 infected patients while no association was observed for genotype 2. Interestingly, in genotype 3 infected patients, best SVR prediction was based on IFN-L4 genotype. Prediction of SVR with high accuracy (71-96%) was possible in genotype 1, 2, 3 and 4 infected patients who received PEG-IFN/ribavirin combination therapy by selection of beneficial IL28B rs12979860 C/C and/or ss469415590 TT/TT genotypes (p<0.001). For triple therapy with first generation protease inhibitors (PIs) (boceprevir, telaprevir) prediction of high SVR (90%) rates was based on the presence of at least one beneficial genotype of the 3 IFN-lambda SNPs. CONCLUSION IFN-L4 seems to be the best single predictor of SVR in genotype 3 infected patients. For optimized prediction of SVR by treatment with dual combination or first generation PI triple therapies, grouping of interferon-lambda haplotypes may be helpful with positive predictive values of 71-96%.
Collapse
Affiliation(s)
- Simone Susser
- Medical Department 1, Goethe-University Hospital Frankfurt/Main, Frankfurt, Germany
| | - Eva Herrmann
- Institute of Biostatistics and Mathematical Modeling, Goethe-University Hospital Frankfurt/Main, Frankfurt, Germany
| | - Christian Lange
- Medical Department 1, Goethe-University Hospital Frankfurt/Main, Frankfurt, Germany
| | - Nabila Hamdi
- Department of Pharmacology and Toxicology, German University in Cairo, Cairo, Egypt
| | - Tobias Müller
- Clinic for Gastroenterology, Section Hepatology, University Hospital Leipzig, Leipzig, Germany
| | - Thomas Berg
- Clinic for Gastroenterology, Section Hepatology, University Hospital Leipzig, Leipzig, Germany
| | - Dany Perner
- Medical Department 1, Goethe-University Hospital Frankfurt/Main, Frankfurt, Germany
| | - Stefan Zeuzem
- Medical Department 1, Goethe-University Hospital Frankfurt/Main, Frankfurt, Germany
| | - Christoph Sarrazin
- Medical Department 1, Goethe-University Hospital Frankfurt/Main, Frankfurt, Germany
| |
Collapse
|
|
24
|
Shimada N, Toyoda H, Tsubota A, Ide T, Takaguchi K, Kato K, Kondoh M, Matsuyama K, Kumada T, Sata M. Baseline factors and very early viral response (week 1) for predicting sustained virological response in telaprevir-based triple combination therapy for Japanese genotype 1b chronic hepatitis C patients: a multicenter study. J Gastroenterol 2014; 49:1485-94. [PMID: 24287582 DOI: 10.1007/s00535-013-0918-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2013] [Accepted: 11/11/2013] [Indexed: 02/07/2023]
Abstract
BACKGROUND Genetic polymorphisms near Interleukin 28B (IL28B) (rs8099917) and a rapid virological response (RVR) have been reported as predictors for a sustained virological response (SVR) to telaprevir (TVR)-based triple combination therapy. However, the association between SVR and viral kinetics earlier than week 4 after initiation of therapy remains unclear. Thus, we evaluated the SVR prediction ability of baseline factors and reduced hepatitis C virus (HCV) RNA levels at week 1 after the initiation of TVR-based therapy in Japanese genotype-1b chronic hepatitis C (CHC) patients. METHODS A total of 156 Japanese CHC patients received a 24-week regimen of TVR-based therapy. Baseline factors and reduction in HCV RNA levels at weeks 1 and 4 after the initiation of therapy were analyzed for SVR prediction. RESULTS Multiple logistic regression analysis for SVR in TVR-based therapy identified the IL28B TT genotype, a reduction of ≥ 4.7 log10 IU/mL in HCV RNA levels at week 1, RVR, and treatment-naïve/relapse. Whereas the SVR rate was higher than 90 % regardless of the reduction in HCV RNA levels at week 1 in patients with the TT genotype, a reduction of ≥ 4.7 log10 IU/mL in HCV RNA levels at week 1 was the strongest predictor of SVR in patients with the non-TT genotype, as determined by multiple logistic regression analysis (P = 0.0043). CONCLUSIONS The IL28B TT genotype is the most important baseline factor for predicting SVR, and a ≥ 4.7 log10 IU/mL reduction in HCV RNA at week 1 is a useful very early on-treatment predictor of SVR, especially in the non-TT genotype.
Collapse
Affiliation(s)
- Noritomo Shimada
- Division of Gastroenterology and Hepatology, Shinmatsudo Central General Hospital, 1-380 Shinmatsudo, Matsudo, Chiba, 270-0034, Japan,
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
25
|
Mechie NC, Röver C, Cameron S, Amanzada A. Predictability of IL-28B-polymorphism on protease-inhibitor-based triple-therapy in chronic HCV-genotype-1 patients: A meta-analysis. World J Hepatol 2014; 6:759-765. [PMID: 25349647 PMCID: PMC4209421 DOI: 10.4254/wjh.v6.i10.759] [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: 06/06/2014] [Revised: 07/29/2014] [Accepted: 09/10/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the predictability of interleukin-28B single nucleotide polymorphism rs12979860 with respect to sustained virological response (SVR) in chronically hepatitis C virus (HCV) genotype-1 patients treated with a protease-inhibitor and pegylated interferon-α (Peg-INF-α) based triple-therapy.
METHODS: We searched PubMed, the Cochrane Library and Web of Knowledge for studies regarding the interleukin 28B (IL-28B)-genotype and protease-inhibitor based triple-therapy. Ten studies with 2707 patients were included into this meta-analysis. We used regression methods in order to investigate determinants of SVR.
RESULTS: IL-28B-CC-genotype patients achieved higher SVR rates (odds 5.34, 95%CI: 3.81-7.49) than IL-28B-non-CC-genotype patients (1.88, 95%CI: 1.43-2.48) receiving triple-therapy. The line of therapy (treatment-naïve or -experienced for Peg-INF-α) did not affect the predictive value of IL-28B (P = 0.1). IL-28B-CC-genotype patients treated with protease inhibitor-based triple-therapy consisting of Boceprevir, Simeprevir, Telaprevir or Vaniprevir showed odds of 3.38, 14.66, 7.84 and 2.91, respectively. The odds for CC genotype patients treated with Faldaprevir cannot be quantified, as only a single study with a 100% SVR rate was available.
CONCLUSION: IL-28B-SNP predicts the outcome for chronic HCV genotype-1 patients receiving protease inhibitor-based triple-therapy. The predictive value varies between the different protease inhibitors.
Collapse
|
|
26
|
Cotte L, Braun J, Lascoux-Combe C, Vincent C, Valantin MA, Sogni P, Lacombe K, Neau D, Aumaitre H, Batisse D, de Truchis P, Gervais A, Michelet C, Morlat P, Vittecoq D, Rosa I, Bertucci I, Chevaliez S, Aboulker JP, Molina JM, Aumaitre H, Batisse D, Bernard L, Cheret A, Cotte L, de Truchis P, Dellamonica P, Dominguez S, Gervais A, Girard PM, Lucht F, Metivier S, Michelet C, Molina JM, Morlat P, Neau D, Pageaux GP, Pol S, Rosa I, Rosenthal E, Vittecoq D, Valantin MA, Zucman D. Telaprevir for HIV/Hepatitis C Virus-Coinfected Patients Failing Treatment With Pegylated Interferon/Ribavirin (ANRS HC26 TelapreVIH): An Open-Label, Single-Arm, Phase 2 Trial. Clin Infect Dis 2014; 59:1768-76. [DOI: 10.1093/cid/ciu659] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
|
|
27
|
Abe H, Tsubota A, Shimada N, Atsukawa M, Kato K, Takaguchi K, Asano T, Chuganji Y, Sakamoto C, Toyoda H, Kumada T, Ide T, Sata M, Aizawa Y. Predictors of response to 24-week telaprevir-based triple therapy for treatment-naïve genotype 1b chronic hepatitis C patients. Gastroenterol Res Pract 2014; 2014:549709. [PMID: 25197269 PMCID: PMC4150495 DOI: 10.1155/2014/549709] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2014] [Revised: 07/19/2014] [Accepted: 08/04/2014] [Indexed: 01/20/2023] Open
Abstract
We evaluated the genetic variation in rs8099917, substitutions in core amino acid (aa) 70, and the number of aa substitutions in the interferon sensitivity-determining region (ISDR) on the prediction of sustained virological response (SVR) in treatment-naïve hepatitis C virus (HCV) genotype 1b (G1b) patients. This multicenter study involved 150 Asian treatment-naïve patients infected with HCV G1b who received 12 weeks of telaprevir in combination with 24 weeks of peginterferon-α-2b and ribavirin. The baseline and treatment-related factors potentially associated with SVR were determined by multivariate logistic regression analysis. Virological response was analyzed on an intent-to-treat basis. Cessation of the therapy due to adverse effects occurred in only 2 patients, who discontinued the trial at 10 weeks and at 2 weeks due to cerebral infarction and renal impairment, respectively. Among the 150 patients in whom the final virological response was determined, only genotype TT in rs8099917 was identified as a pretreatment predictor (P = 7.38 × 10(-4)). Achievement of a rapid virological response (RVR), defined as undetectable HCV RNA at week 4 of treatment, was identified as an after-starting-treatment predictor (P = 2.47 × 10(-5)). However, neither a substitution in core aa 70 nor the number of substitutions in the ISDR affected treatment outcome.
Collapse
Affiliation(s)
- Hiroshi Abe
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Jikei University School of Medicine Katsushika Medical Center, 6-41-2 Aoto, Katsushika-ku, Tokyo 125-0062, Japan
| | - Akihito Tsubota
- Institute of Clinical Medicine and Research, The Jikei University School of Medicine, Kashiwa, Chiba, Japan
| | - Noritomo Shimada
- Department of Gastroenterology and Hepatology, Shinmatsudo Central General Hospital, Matsudo, Chiba, Japan
| | - Masanori Atsukawa
- Division of Gastroenterology, Department of Internal Medicine, Nippon Medical School Chiba Hokusoh Hospital, Inzai, Chiba, Japan
| | - Keizo Kato
- Department of Gastroenterology and Hepatology, Shinmatsudo Central General Hospital, Matsudo, Chiba, Japan
| | - Koichi Takaguchi
- Department of Hepatology, Kagawa Prefectural Central Hospital, Takamatsu, Kagawa, Japan
| | - Toru Asano
- Department of Gastroenterology, Tokyo Metropolitan Bokutoh Hospital, Sumida-ku, Tokyo, Japan
| | - Yoshimichi Chuganji
- Department of Gastroenterology, Tokyo Metropolitan Bokutoh Hospital, Sumida-ku, Tokyo, Japan
| | - Choitsu Sakamoto
- Department of Gastroenterology, Nippon Medical School, Graduate School of Medicine, Tokyo, Japan
| | - Hidenori Toyoda
- Department of Gastroenterology, Ogaki Municipal Hospital, Ogaki, Gifu, Japan
| | - Takashi Kumada
- Department of Gastroenterology, Ogaki Municipal Hospital, Ogaki, Gifu, Japan
| | - Tatsuya Ide
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Fukuoka, Japan
| | - Michio Sata
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Fukuoka, Japan
| | - Yoshio Aizawa
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Jikei University School of Medicine Katsushika Medical Center, 6-41-2 Aoto, Katsushika-ku, Tokyo 125-0062, Japan
| |
Collapse
|
|
28
|
Indolfi G, Azzari C, Resti M. Polymorphisms in the IFNL3/IL28B gene and hepatitis C: from adults to children. World J Gastroenterol 2014; 20:9245-52. [PMID: 25071317 PMCID: PMC4110554 DOI: 10.3748/wjg.v20.i28.9245] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2013] [Revised: 02/24/2014] [Accepted: 05/23/2014] [Indexed: 02/06/2023] Open
Abstract
The purpose of the present review is to summarise the current knowledge on the association between single nucleotide polymorphisms (SNPs) in the interferon L3 (IFNL3) gene and hepatitis C virus (HCV) infection in children. Many studies in adults have demonstrated that genetic variation in IFNL3 is a strong predictor of the virological response in treatment-naive patients with HCV genotype 1 who were treated with Pegylated-IFN-α and ribavirin. Genetic variation in IFNL3 is also associated with the spontaneous clearance of HCV. Thus far, few paediatric studies have explored the association between variations in the IFNL3 gene and either spontaneous or treatment-induced clearance of HCV. The CC genotype of the rs12979860 SNP is associated with the spontaneous clearance of HCV in children independently of HCV genotype. Four paediatric studies have shown that both the CC genotype of the rs12979860 SNP and the TT genotype of the rs8099917 SNP are associated with the treatment-induced (IFN monotherapy and Pegylated-IFN-α and ribavirin association) clearance of HCV, while the rs12980275 SNP did not affect the virological response. The possible role of IFNL3 gene variation as a pre-treatment and on-treatment predictor of virological response in children is highly attractive but still undetermined. Further paediatric studies are needed to evaluate if testing for SNPs in IFNL3, either alone or together with other predictors of response to treatment, could be used to direct treatment strategies, including an avoidance of unnecessary protease inhibitor therapy and the duration of treatment.
Collapse
|
|
29
|
Abstract
Hepatitis C virus (HCV) infection is a substantial health problem worldwide. Most patients infected with HCV remain chronically infected, with an increased risk of cirrhosis and hepatocellular carcinoma. Although they are associated with toxicities and low sustained viral response rates, interferon alfa and ribavirin have been the mainstay of treatment until recently. New direct acting antivirals, specifically designed to inhibit three viral proteins (the NS3/4A protease, the NS5A protein, and the NS5B RNA dependent RNA polymerase) are now becoming available. The NS3/4A inhibitor simeprevir and NS5B inhibitor sofosbuvir have recently been licensed and can reduce the length of antiviral treatment, improve response rates, and allow for interferon-free regimens for some HCV genotypes. Several other newer direct acting antivirals have shown promise in clinical studies and are likely to be licensed soon. These agents seem to facilitate the use of shortened courses of combination interferon-free therapy, which are associated with high (>95%) sustained response rates and relatively few toxicities. These regimens have also been successful in patients who were previously difficult to treat, including those with cirrhosis, HIV coinfection, and those who have undergone liver transplantation. The high cost of these agents may be the biggest challenge to their implementation worldwide.
Collapse
Affiliation(s)
- Eoin R Feeney
- Division of Infectious Diseases, Massachusetts General Hospital, Boston, USA
| | - Raymond T Chung
- Division of Gastroenterology, Massachusetts General Hospital, Boston MA 02114, USA
| |
Collapse
|
|
30
|
Thomas BS, Joyce MA, Levin A, Tyrrell DLJ. Validation of TaqMan® SNP genotyping specificity for rs12979860 of IL-28B: modeling primer specificity in vitro. J Virol Methods 2014; 203:39-47. [PMID: 24681052 DOI: 10.1016/j.jviromet.2014.03.016] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2013] [Revised: 03/15/2014] [Accepted: 03/18/2014] [Indexed: 02/08/2023]
Abstract
Members of the type III interferon gene family arose by gene duplication events and have retained a high percent identity both in their coding and non-coding regions. In this study, the specificity of a widely used TaqMan(®) SNP genotyping assay for rs12979860 is validated. The 66 bp template for SNP genotyping has only 3 bp at one 5' end that vary between IL-28B and IL-28A; excluding the rs12979860 SNP itself. Conflicting annealing temperatures were found for the mismatched 19 bp primer to IL-28B and IL-28A with in silico melting temperature algorithms, or with in vitro dissociation curves. In order to prove specificity for IL-28B, an in vitro competition assay was setup with genomic DNA and synthetic oligonucleotides. When genomic DNA, containing equimolar concentrations of rs12979860 and the homologous region of IL-28A are present, no off-target amplification was observed. This SNP genotyping assay is therefore specific for rs12979860 and all previously reported results are valid. Finally, using a completely synthetic in vitro competition assay it was possible to calculate the amount of off-target template that will produce 1/2 the maximum on-target (VIC) fluorescent signal, a value that is between a C/C genotype and a T/T genotype. This value is defined in the manuscript as the half maximum positive value, KHPV, and in the present assay KHPV is 15.75±0.0721, represented as the relative fold increase in the amount of IL-28A over rs12979860. This method will be of interest to those performing genotyping on highly conserved gene families.
Collapse
Affiliation(s)
- Brad S Thomas
- Department of Medical Microbiology and Immunology, Li Ka Shing Institute of Virology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2E1, Canada.
| | - Michael A Joyce
- Department of Medical Microbiology and Immunology, Li Ka Shing Institute of Virology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2E1, Canada
| | - Aviad Levin
- Department of Medical Microbiology and Immunology, Li Ka Shing Institute of Virology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2E1, Canada
| | - D Lorne J Tyrrell
- Department of Medical Microbiology and Immunology, Li Ka Shing Institute of Virology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2E1, Canada.
| |
Collapse
|
|
31
|
Wehmeyer MH, Eißing F, Jordan S, Röder C, Hennigs A, Degen O, Hüfner A, Hertling S, Schmiedel S, Sterneck M, van Lunzen J, Lohse AW, Schulze zur Wiesch J, Lüth S. Safety and efficacy of protease inhibitor based combination therapy in a single-center "real-life" cohort of 110 patients with chronic hepatitis C genotype 1 infection. BMC Gastroenterol 2014; 14:87. [PMID: 24884400 PMCID: PMC4102246 DOI: 10.1186/1471-230x-14-87] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2013] [Accepted: 04/28/2014] [Indexed: 12/22/2022] Open
Abstract
Background The combination of boceprevir or telaprevir with peginterferon-alfa and ribavirin for the treatment of patients infected with HCV genotype 1 has led to significantly increased rates of sustained virological response (SVR) in phase III trials. There is only limited data regarding the safety and efficacy in a “real-life” cohort. Methods We analyzed a cohort of 110 unselected HCV patients who started triple therapy from September 2011 to February 2013 by chart review with focus on the individual course of treatment, complications and outcome. We excluded 8 patients from analysis because of HIV-coinfection (N = 6) or status post liver transplant (N = 2). Importantly, 41 patients displayed F3 or F4 fibrosis, 10 patients had a history of treatment with protease/polymerase inhibitors and 15 patients were prior partial- or null-responder. Results SVR12 was achieved in 62 of the 102 patients (60.8%). A high rate of serious adverse events (N = 30) was observed in 22 patients including 2 fatalities in cirrhotic diabetes patients. Age >50 years, liver cirrhosis, bilirubin >1.1 mg/dl (P < 0.01, each), platelets <100,000/μl (P = 0.01), ASAT >100 U/l (P = 0.03) and albumin ≤35 g/l (P = 0.04) at baseline were associated with occurence of a SAE. Conclusions The frequency of SVR in a “real-life” treatment setting is slightly lower as compared to the results of the phase III trials for telaprevir or boceprevir. Importantly, we observed a high frequency of SAE in triple therapy, especially in patients with liver cirrhosis.
Collapse
Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | | | - Julian Schulze zur Wiesch
- I, Medizinische Klinik und Poliklinik, Universitätsklinikum Hamburg-Eppendorf, Martinistr, 52, Hamburg 20246, Germany.
| | | |
Collapse
|
|
32
|
Stättermayer AF, Scherzer T, Beinhardt S, Rutter K, Hofer H, Ferenci P. Review article: genetic factors that modify the outcome of viral hepatitis. Aliment Pharmacol Ther 2014; 39:1059-1070. [PMID: 24654629 PMCID: PMC7159786 DOI: 10.1111/apt.12717] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2013] [Revised: 12/10/2013] [Accepted: 03/01/2014] [Indexed: 12/16/2022]
Abstract
BACKGROUND Genetic factors can play an important role for treatment response and disease progression in chronic viral hepatitis. AIM To review the influence of host genetic factors on the clinical course as well as on treatment response in patients with viral hepatitis. METHODS Review of the literature. RESULTS A landmark genome-wide association study (GWAS) identified polymorphisms in the IL28B gene on chromosome 19 (19q13.13) associated with response to therapy with pegylated interferon-α (PEG-IFN) and ribavirin (RBV) and spontaneous viral clearance in acute hepatitis C. Furthermore, IL28B genotype is associated with changes of lipid metabolism and insulin resistance. A further GWAS demonstrated that ITPA genetic variants protect HCV genotype 1 patients from RBV-induced anaemia. Another polymorphism in the patatin-like phospholipase domain containing 3 (PNPLA3) is associated with hepatic steatosis. Difficult-to-treat hepatitis C patients homozygous for GG had an up to five-fold lower chance of viral clearance on PEG/RBV than non-GG patients. In chronic hepatitis B patients treated with PEG-IFN several retrospective analyses of IL28B rs12980275 and rs12979860 genotypes yielded conflicting results which can be explained by the heterogeneity between the study populations. Some variants of the HLA-DP locus (HLA-DPA1 A allele and HLA-DPB1) protect against progression of chronic hepatitis B infection. CONCLUSIONS The determination of IL28B polymorphisms may be useful to individualise treatment options when using PEG/RBV based therapies for chronic hepatitis C infection. In contrast, so far identified genetic factors play only a minor role in chronic hepatitis B infection.
Collapse
Affiliation(s)
- A. F. Stättermayer
- Division of Gastroenterology and HepatologyDepartment of Internal Medicine IIIMedical University of ViennaViennaAustria
| | - T. Scherzer
- Division of Gastroenterology and HepatologyDepartment of Internal Medicine IIIMedical University of ViennaViennaAustria
| | - S. Beinhardt
- Division of Gastroenterology and HepatologyDepartment of Internal Medicine IIIMedical University of ViennaViennaAustria
| | - K. Rutter
- Division of Gastroenterology and HepatologyDepartment of Internal Medicine IIIMedical University of ViennaViennaAustria
| | - H. Hofer
- Division of Gastroenterology and HepatologyDepartment of Internal Medicine IIIMedical University of ViennaViennaAustria
| | - P. Ferenci
- Division of Gastroenterology and HepatologyDepartment of Internal Medicine IIIMedical University of ViennaViennaAustria
| |
Collapse
|
|
33
|
Izumi N, Hayashi N, Kumada H, Okanoue T, Tsubouchi H, Yatsuhashi H, Kato M, Ki R, Komada Y, Seto C, Goto S. Once-daily simeprevir with peginterferon and ribavirin for treatment-experienced HCV genotype 1-infected patients in Japan: the CONCERTO-2 and CONCERTO-3 studies. J Gastroenterol 2014; 49:941-53. [PMID: 24626851 DOI: 10.1007/s00535-014-0949-8] [Citation(s) in RCA: 74] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2013] [Accepted: 02/14/2014] [Indexed: 02/04/2023]
Abstract
BACKGROUND Efficacy of available therapies for patients with HCV who have previously failed treatment is limited. Two Phase III, open-label trials in Japan investigated efficacy and safety of simeprevir and peginterferon-α-2a/ribavirin (PR) combination therapy in treatment-experienced patients with genotype 1 HCV infection. METHODS In CONCERTO-2, prior non-responders to IFN-based therapy (N = 106) received simeprevir (TMC435) 100 mg QD with PR for 12 (SMV12, n = 53) or 24 weeks (SMV24, n = 53) followed by response-guided therapy (RGT) with PR for 12/36 (SMV12) or 0/24 (SMV24) weeks. In CONCERTO-3, relapsers after IFN-based therapy (N = 49) received simeprevir 100 mg QD with PR for 12 weeks followed by RGT with PR for 12/36 weeks. Primary endpoints were the rates of sustained virologic response 12 weeks after treatment end (SVR12). RESULTS SVR12 rates were 52.8% (SMV12) and 35.8% (SMV24) for prior non-responders, and 95.9% for prior relapsers (SMV12; p ≤ 0.0001 vs null hypothesis, respectively). Most prior non-responders (SMV12: 81.1%; SMV24: 73.6%) and prior relapsers (95.9%) met RGT criteria and completed PR to Week 24. Of these, 60.5%, 48.7%, and 95.7%, respectively, achieved SVR12. Viral breakthrough occurred in 13.2 % (SMV12) and 11.3% (SMV24) of prior non-responders; no viral breakthrough occurred in prior relapsers. Viral relapse occurred in 38.6% (SMV12) and 51.1% (SMV24) of prior non-responders and 8.2% of prior relapsers. Simeprevir with PR was generally well tolerated in both studies. CONCLUSION Re-treatment with 12 weeks of simeprevir QD with PR provided high SVR in treatment-experienced patients with chronic HCV genotype 1 infection, and allowed most patients to complete treatment in 24 weeks.
Collapse
|
|
34
|
Coppola N, Pisaturo M, Sagnelli C, Sagnelli E, Angelillo IF. Peg-interferon plus ribavirin with or without boceprevir or telaprevir for HCV genotype 1: a meta-analysis on the role of response predictors. PLoS One 2014; 9:e94542. [PMID: 24728219 PMCID: PMC3984165 DOI: 10.1371/journal.pone.0094542] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2013] [Accepted: 03/18/2014] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND & AIM To compare the efficacy of pegylated-interferon (Peg-IFN) α-2a or α-2b and ribavirin given as dual therapy versus triple therapy (Peg-IFN and ribavirin plus boceprevir or telaprevir) in patients with HCV-1 chronic hepatitis naïve for anti-HCV therapy or relapsers to dual therapy in relation to the presence of constitutional, clinical and virological predictors of treatment response. METHODS Included in the meta-analysis were studies meeting these criteria: original data from randomized trials on the efficacy of dual versus triple therapy in therapy-naïve patients or relapsers; at least one primary outcome clearly defined: sustained virological response in patients with or without rapid virological response (RVR), with genotype 1a or 1b, low or high HCV load, IL28-B CC or non-CC genotype, mild or severe fibrosis; odds ratio estimates of relative risk (RR) and 95% confidence intervals; English language; and published up to the end of June 2013. RESULTS Seven original studies met the inclusion criteria, allowing a meta-analysis on 3,652 patients. Triple therapy was more effective than dual, regardless of IL-28B genotype, HCV sub-genotype, liver fibrosis, and baseline HCV load. In 1,045 patients who achieved RVR, SVR was more frequently achieved with dual therapy (RR = 1.11; p = 0.002) than triple. The same results were achieved when only the therapy-naïve patients were considered. CONCLUSIONS Triple therapy provides a significantly higher SVR rate than dual therapy, but dual therapy obtains a significantly higher SVR rate in patients with RVR. The data stress the clinical importance of a 4-week lead-in phase in direct-acting antiviral-based treatment.
Collapse
Affiliation(s)
- Nicola Coppola
- Department of Mental Health and Public Medicine, Section of Infectious Diseases, Second University of Naples, Naples, Italy
| | - Mariantonietta Pisaturo
- Department of Mental Health and Public Medicine, Section of Infectious Diseases, Second University of Naples, Naples, Italy
| | - Caterina Sagnelli
- Department of Clinical and Experimental Medicine and Surgery “F. Magrassi e A. Lanzara”, Second University of Naples, Naples, Italy
| | - Evangelista Sagnelli
- Department of Mental Health and Public Medicine, Section of Infectious Diseases, Second University of Naples, Naples, Italy
| | - Italo F. Angelillo
- Department of Experimental Medicine, Second University of Naples, Naples, Italy
| |
Collapse
|
|
35
|
Genebat M, Vera F, Hernández-Quero J, Domingo P, Guardiola JM, Martínez-Madrid O, Martínez L, de la Llana FG, Sánchez-Villegas J, Álvarez H, Mariño A, Lluch JF, Martínez-Pérez MA, Marín J, Ruiz-Mateos E, Leal M. Efficacy and tolerability after 24weeks of treatment with telaprevir, pegylated interferon and ribavirin in cirrhotic HIV–HCV coinfected subjects. Antiviral Res 2014; 104:59-61. [DOI: 10.1016/j.antiviral.2014.01.019] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2013] [Revised: 01/14/2014] [Accepted: 01/23/2014] [Indexed: 01/18/2023]
|
|
36
|
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.
Collapse
|
|
37
|
Shimada N, Tsubota A, Atsukawa M, Abe H, Ika M, Kato K, Sato Y, Kondo C, Sakamoto C, Tanaka Y, Aizawa Y. α-Fetoprotein is a surrogate marker for predicting treatment failure in telaprevir-based triple combination therapy for genotype 1b chronic hepatitis C Japanese patients with the IL28B minor genotype. J Med Virol 2014; 86:461-472. [PMID: 24166425 DOI: 10.1002/jmv.23824] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/27/2013] [Indexed: 12/14/2022]
Abstract
Even when treated with telaprevir-based triple therapy, some patients fail to achieve a sustained virological response. This study identified factors related closely to treatment failure. A total of 146 Japanese genotype 1b chronic hepatitis C patients were enrolled in this prospective, multicenter study and received a 24-week regimen of triple therapy. The end-of-treatment response rate was significantly lower in patients with the interleukin 28B (IL28B) (rs8099917) non-TT genotype (85.2%) than in those with the TT genotype (100%, P = 0.0002). Multiple logistic regression analysis identified high α-fetoprotein levels as an independent factor related to non-end-of-treatment response in patients with the non-TT genotype. A cut-off value of 20 ng/ml was determined for a non-end-of-treatment response; sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy were 75.0%, 95.7%, 75.0%, 75.0%, and 92.6%, respectively. Multiple logistic regression analysis for a sustained virological response identified the IL28B TT genotype, low α-fetoprotein levels, non-responders, and a rapid virological response. The sustained virological response rate was significantly lower in patients with the non-TT genotype (59.3%) than in those with the TT genotype (96.7%, P < 0.0001). In patients with the non-TT genotype, α-fetoprotein was the most significant predictor for non-sustained virological response by univariate analysis. A cut-off value of 7.4 ng/ml α-fetoprotein was determined for non-sustained virological response; sensitivity, specificity, PPV, NPV, and accuracy were 63.6%, 87.5%, 77.8%, 77.8%, and 77.8%, respectively. For the non-TT patients, serum α-fetoprotein levels may be a surrogate marker for predicting treatment failure in telaprevir-based therapy for genotype 1b chronic hepatitis C.
Collapse
Affiliation(s)
- Noritomo Shimada
- Division of Gastroenterology and Hepatology, Shinmatsudo Central General Hospital, Matsudo, Chiba, Japan
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
38
|
Schneider MD, Sarrazin C. Antiviral therapy of hepatitis C in 2014: do we need resistance testing? Antiviral Res 2014; 105:64-71. [PMID: 24583028 DOI: 10.1016/j.antiviral.2014.02.011] [Citation(s) in RCA: 71] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2013] [Revised: 02/10/2014] [Accepted: 02/13/2014] [Indexed: 12/15/2022]
Abstract
The treatment of chronic hepatitis C has fundamentally changed since the approval of the first direct-acting antivirals (DAA) in 2011. In addition to telaprevir and boceprevir, in 2014 two new NS3 protease inhibitors (simeprevir and faldaprevir), one non-nucleoside polymerase inhibitor (sofosbuvir) and one NS5a replication complex inhibitor (daclatasvir) have expanded the treatment options for chronic hepatitis C. Resistance-associated variants (RAV) are naturally produced during the HCV life cycle. The frequency of RAVs within HCV quasispecies mainly depends on their replicational fitness. Variants conferring resistance to nucleos(t)ide analogues have not been detected, and the majority of NS3 protease-resistant variants are present at low frequencies (0.1-3%) before initiation of DAA-based therapies. However, the Q80K variant conferring resistance to simeprevir has been observed in 9-48% of untreated HCV genotype 1a-infected patients, leading to reduced SVR rates. Resistant variants are detectable in the majority of patients with treatment failure to NS3 protease inhibitor- or NS5a inhibitor-based antiviral therapy. Long-term follow-up studies by population-based sequence analysis have shown the disappearance of resistant variants in the majority of patients, with median times to loss of mutations of 4-64weeks. For the nucleotide analogue sofosbuvir, the emergence of the S282T resistant variant has been observed only in single patients, with reversion to wild-type within several weeks. Data are sparse on retreatment of patients with the same DAA or the same class of DAAs. However, retreatment with a different class of DAAs after failure of NS3 protease inhibitor-based therapy has been successful in small studies. This article forms part of a symposium in Antiviral Research on "Hepatitis C: next steps toward global eradication."
Collapse
Affiliation(s)
- Maximilian David Schneider
- J. W. Goethe University Hospital, Department of Internal Medicine I, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany
| | - Christoph Sarrazin
- J. W. Goethe University Hospital, Department of Internal Medicine I, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany.
| |
Collapse
|
|
39
|
Zeuzem S, Berg T, Gane E, Ferenci P, Foster GR, Fried MW, Hezode C, Hirschfield GM, Jacobson I, Nikitin I, Pockros PJ, Poordad F, Scott J, Lenz O, Peeters M, Sekar V, De Smedt G, Sinha R, Beumont-Mauviel M. Simeprevir increases rate of sustained virologic response among treatment-experienced patients with HCV genotype-1 infection: a phase IIb trial. Gastroenterology 2014; 146:430-41.e6. [PMID: 24184810 DOI: 10.1053/j.gastro.2013.10.058] [Citation(s) in RCA: 185] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2013] [Revised: 10/24/2013] [Accepted: 10/29/2013] [Indexed: 01/05/2023]
Abstract
BACKGROUND & AIMS Simeprevir (TMC435) is an oral NS3/4 protease inhibitor in phase III trials for chronic hepatitis C virus (HCV) infection. We performed a phase IIb, randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of the combination of simeprevir, peginterferon-α2a (PegIFN), and ribavirin (RBV) in patients with HCV genotype-1 infection previously treated with PegIFN and RBV. METHODS We analyzed data from patients who did not respond (null response), had a partial response, or relapsed after treatment with PegIFN and RBV, randomly assigned to receive simeprevir (100 or 150 mg, once daily) for 12, 24, or 48 weeks plus PegIFN and RBV for 48 weeks (n = 396), or placebo plus PegIFN and RBV for 48 weeks (n = 66). All patients were followed for 24 weeks after planned end of treatment; the primary end point was the proportion of patients with sustained virologic response (SVR; undetectable HCV RNA) at that time point. RESULTS Overall, rates of SVR at 24 weeks were significantly higher in the groups given simeprevir than those given placebo (61%-80% vs 23%; P < .001), regardless of prior response to PegIFN and RBV (simeprevir vs placebo: prior null response, 38%-59% vs 19%; prior partial response, 48%-86% vs 9%; prior relapse, 77%-89% vs 37%). All groups had comparable numbers of adverse events; these led to discontinuation of simeprevir or placebo and/or PegIFN and RBV in 8.8% of patients given simeprevir and 4.5% of those given placebo. CONCLUSIONS In treatment-experienced patients, 12, 24, or 48 weeks simeprevir (100 mg or 150 mg once daily) in combination with 48 weeks PegIFN and RBV significantly increased rates of SVR at 24 weeks compared with patients given placebo, PegIFN, and RBV and was generally well tolerated. ClinicalTrials.gov number: NCT00980330.
Collapse
Affiliation(s)
| | | | - Edward Gane
- Auckland Clinical Studies, Auckland, New Zealand
| | - Peter Ferenci
- Universitätsklinik für Innere Medizin III, Wien, Austria
| | | | - Michael W Fried
- University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | | | - Gideon M Hirschfield
- NIHR Biomedical Research Unit, Centre for Liver Research, University of Birmingham, United Kingdom
| | - Ira Jacobson
- Weill Cornell Medical College, New York, New York
| | - Igor Nikitin
- Russian State Medical University, Moscow, Russia
| | | | - Fred Poordad
- The Texas Liver Institute/University of Texas Health Science Center, San Antonio, Texas
| | - Jane Scott
- Janssen Global Services LLC, High Wycombe, Buckinghamshire, United Kingdom
| | - Oliver Lenz
- Janssen Infectious Diseases BVBA, Beerse, Belgium
| | | | - Vanitha Sekar
- Janssen Research & Development, Titusville, New Jersey
| | | | - Rekha Sinha
- Janssen Infectious Diseases BVBA, Beerse, Belgium
| | | |
Collapse
|
|
40
|
Lee TH, Tillmann HL, Patel K. Individualized therapy for hepatitis C infection: focus on the interleukin-28B polymorphism in directing therapy. Mol Diagn Ther 2014; 18:25-38. [PMID: 24022240 DOI: 10.1007/s40291-013-0053-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Hepatitis C virus—a major global cause of chronic hepatitis, cirrhosis, and hepatocellular carcinoma—affects millions of people worldwide. Pegylated interferon (Peg-IFN) and ribavirin (RBV) had been the standard treatment for a decade until availability of the protease inhibitors in 2011. However, current antiviral therapy is still IFN-based and is associated with significant side effects and variable treatment response. Thus, various host and viral factors have been evaluated before and during treatment for the prediction of sustained virologic response to antiviral therapy. In 2009, genome-wide association studies found the single-nucleotide polymorphisms, located near the host interleukin-28B (IL28B) gene that encodes IFN-λ3, to be the best pretreatment predictor of virologic response to Peg-IFN and RBV therapy in chronic hepatitis C genotype 1 patients. Additionally, inosine triphosphatase (ITPA) gene variants were found to be associated with RBV-induced hemolytic anemia, which could affect treatment dose for selected patients. IL28B, ITPA, and other treatment predictors allowed for a potential individualized approach to treat hepatitis C. In the era of increased overall virologic response rates and good tolerability of the rapidly developing non-IFN oral direct-acting antiviral therapy regimens, the need for individualized treatment is likely to diminish. Various predictors of response, including IL28B will likely be of reduced importance in the near future.
Collapse
|
|
41
|
Abstract
Hepatitis C virus infection is a growing, global health problem, with mortality expected to reach a peak in the next ten years in many western countries. A number of host and viral factors have been established as useful predictors of treatment response in the context of interferon and ribavirin. Several new markers have recently been identified that improve our understanding of treatment response. The addition of protease inhibitors to treatment regimens has highlighted the importance of viral kinetics on-treatment in predicting response to treatment. Many new classes of direct acting anti-virals are currently being developed and expected to be clinically available in the near future. Current predictors of treatment response will be redefined in the context of interferon free regimens.
Collapse
Affiliation(s)
- Louise Berry
- Department of Microbiology, Nottingham University Hospitals NHS Trust, Nottingham, NG7 2UH, UK
| | | |
Collapse
|
|
42
|
Pár A, Pár G, Tornai I, Szalay F, Várszegi D, Fráter E, Papp M, Lengyel G, Fehér J, Varga M, Gervain J, Schuller J, Nemes Z, Péterfi Z, Tusnádi A, Hunyady B, Haragh A, Szinku Z, Vincze Á, Szereday L, Kisfali P, Melegh B. IL28B and IL10R -1087 polymorphisms are protective for chronic genotype 1 HCV infection and predictors of response to interferon-based therapy in an East-Central European cohort. BMC Res Notes 2014; 7:12. [PMID: 24398031 PMCID: PMC3896726 DOI: 10.1186/1756-0500-7-12] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2013] [Accepted: 01/03/2014] [Indexed: 01/23/2023] Open
Abstract
BACKGROUND Previous studies have shown that single nucleotide polymorphisms (SNP) in IL28B and IL10R are associated with sustained virological response (SVR) in chronic hepatitis C patients treated with pegilated interferon plus ribavirin (P/R). The present study extends our earlier investigations on a large East-Central European cohort. The allele frequencies of IL28B and IL10R in genotype 1 HCV infection were compared with that of healthy controls for the purpose of examining the relationship between the polymorphisms and the SVR to P/R treatment. METHODS A total of 748 chronic HCV1 infected patients (365 male, 383 female; 18-82 years) and 105 voluntary blood donors as controls were enrolled. Four hundred and twenty HCV patients were treated with P/R for 24-72 weeks, out of them 195 (46.4%) achieved SVR. The IL28 rs12979860 SNP was determined using Custom Taqman SNP Genotyping Assays. The IL10R -1087 (also known as IL10R -1082 (rs1800896) promoter region SNP was determined by RT-PCR and restriction fragment length polymorphism analysis. RESULTS The IL28B CC genotype occurred with lower frequency in HCV patients than in controls (26.1% vs 51.4%, p<0.001). P/R treated patients with the IL28B CC genotype achieved higher SVR rate, as compared to patients with CT (58.6% vs 40.8%, p=0.002). The prevalence of IL10R -1087 GG genotype was lower in patients than in controls (31.8 % vs 52.2%, p<0.001). Among patients achieving SVR, the IL10R -1087 GG genotype occurred with higher frequency than the AA (32.0% vs 17.4%, p=0.013). The IL28B T allele plus IL10R A allele combination was found with higher prevalence in patients than in controls (52% vs 20.7%, p<0.001). The IL28B CC plus IL10R A allele combination occurred with higher frequency among patients with SVR than in non-responders (21.3% vs 12.8%, p=0.026). Both the IL28B CC plus IL10R GG and the IL28B CC plus IL10R A allele combinations occurred with lower frequency in patients than in controls. CONCLUSIONS In our HCV1 patients, both the IL28B CC and IL10R GG genotypes are associated with clearance of HCV. Moreover, distinct IL28B and IL10R allele combinations appear to be protective against chronic HCV1 infection and predictors of response to P/R therapy.
Collapse
MESH Headings
- Adolescent
- Adult
- Aged
- Aged, 80 and over
- Antiviral Agents/therapeutic use
- Drug Resistance, Multiple, Viral
- Drug Therapy, Combination
- Female
- Gene Frequency
- Genotype
- Hepacivirus/drug effects
- Hepacivirus/genetics
- Hepatitis C, Chronic/drug therapy
- Hepatitis C, Chronic/epidemiology
- Hepatitis C, Chronic/genetics
- Hepatitis C, Chronic/prevention & control
- Humans
- Hungary
- Interferon alpha-2
- Interferon-alpha/therapeutic use
- Interferons
- Interleukins/genetics
- Male
- Middle Aged
- Patient Selection
- Polyethylene Glycols/therapeutic use
- Polymorphism, Single Nucleotide
- Promoter Regions, Genetic/genetics
- Receptors, Interleukin-10/genetics
- Recombinant Proteins/therapeutic use
- Ribavirin/therapeutic use
- Treatment Outcome
- Young Adult
Collapse
Affiliation(s)
- Alajos Pár
- First Department of Medicine, University of Pécs, Rákóczi u. 2, 7623 Pécs, Hungary
| | - Gabriella Pár
- First Department of Medicine, University of Pécs, Rákóczi u. 2, 7623 Pécs, Hungary
| | - István Tornai
- Second Department of Medicine, University of Debrecen, 4012 Debrecen, Hungary
| | - Ferenc Szalay
- First Department of Medicine, Semmelweis University, 1082 Budapest, Hungary
| | - Dalma Várszegi
- Department of Dermatology, University of Pécs, 7627 Pécs, Hungary
| | - Edit Fráter
- Second Department of Medicine, University of Debrecen, 4012 Debrecen, Hungary
| | - Mária Papp
- Second Department of Medicine, University of Debrecen, 4012 Debrecen, Hungary
| | - Gabriella Lengyel
- Second Department of Medicine, Semmelweis University, 1088 Budapest, Hungary
| | - János Fehér
- Second Department of Medicine, Semmelweis University, 1088 Budapest, Hungary
| | - Márta Varga
- Réthy Pál Hospital, 5600 Békéscsaba, Hungary
| | | | - János Schuller
- United Szent István and Szent László Hospital, 1097 Budapest, Hungary
| | - Zsuzsanna Nemes
- First Department of Medicine, University of Pécs, Rákóczi u. 2, 7623 Pécs, Hungary
| | - Zoltán Péterfi
- First Department of Medicine, University of Pécs, Rákóczi u. 2, 7623 Pécs, Hungary
| | | | - Béla Hunyady
- First Department of Medicine, University of Pécs, Rákóczi u. 2, 7623 Pécs, Hungary
| | - Attila Haragh
- Kaposi Mór Teaching Hospital, 7400 Kaposvár, Hungary
| | - Zsolt Szinku
- Kaposi Mór Teaching Hospital, 7400 Kaposvár, Hungary
| | - Áron Vincze
- First Department of Medicine, University of Pécs, Rákóczi u. 2, 7623 Pécs, Hungary
| | - László Szereday
- Department of Medical Microbiology and Immunology, University of Pécs, 7624 Pécs, Hungary
| | - Péter Kisfali
- Department of Medical Genetics, University of Pécs, 7624 Pécs, Hungary
| | - Béla Melegh
- Department of Medical Genetics, University of Pécs, 7624 Pécs, Hungary
| |
Collapse
|
|
43
|
Tsubota A, Shimada N, Atsukawa M, Abe H, Kato K, Ika M, Matsudaira H, Nagatsuma K, Matsuura T, Aizawa Y. Impact of IL28B polymorphisms on 24-week telaprevir-based combination therapy for Asian chronic hepatitis C patients with hepatitis C virus genotype 1b. J Gastroenterol Hepatol 2014; 29:144-150. [PMID: 24117654 DOI: 10.1111/jgh.12402] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/05/2013] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIM The aim of this study was to clarify which or how factors could influence the probability of sustained virological response (SVR) in 24-week telaprevir-based triple combination therapy for East Asian chronic hepatitis C patients infected with hepatitis C virus genotype 1b. METHODS Of 140 patients who were enrolled in this study, 137 received 12-week telaprevir combined with 24-week pegylated interferon alpha-2b plus ribavirin and were subjected to the analysis. Factors associated with SVR were analyzed by multiple logistic regression analysis. RESULTS Of the 137 patients, 112 (82%) achieved SVR. Of 87 patients with IL28B single nucleotide polymorphism rs8099917 genotype TT, 84 (97%) achieved SVR. By contrast, 28 of 50 (56%) patients with the genotype TG/GG had SVR (P = 3.29 × 10(-9) ). Fifty-three of 60 (88%) naïve patients and 50 of 54 (93%) prior relapsers achieved SVR. Nine of 13 (69%) prior partial responders and none of 10 (0%) prior null responders achieved SVR. Multivariable analysis identified four independent factors that were significantly associated with SVR: IL28B SNP rs8099917 genotype (P = 6.90 × 10(-5) ), pre-existence of cirrhosis (P = 3.99 × 10(-3) ), prior treatment response (P = 0.0126), and rapid virological response (P = 0.0239). CONCLUSIONS The IL28B single nucleotide polymorphism still remained informative as a predictor of SVR to 24-week telaprevir-based triple combination therapy for East Asian patients infected with hepatitis C virus genotype 1b.
Collapse
Affiliation(s)
- Akihito Tsubota
- Institute of Clinical Medicine and Research (ICMR), Jikei University School of Medicine, Kashiwa, Chiba, Japan; Division of Gastroenterology and Hepatology, Kashiwa Hospital, Jikei University School of Medicine, Kashiwa, Chiba, Japan
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
44
|
Abstract
Despite the incontestable benefits of telaprevir and boceprevir-based triple therapy in patients infected with genotype 1, the practitioner faces a number of new challenges. In daily clinical practice, a checklist approach may facilitate the management of triple therapy. Before initiation, several specific issues should be reviewed with the patient in order to optimize adherence and treatment outcome: potential drug to drug interaction, treatment duration and stopping rules, possible treatment outcomes, side effects, dose and administration with food advice, management of side effects. Because treatment failure is associated with the emergence of resistance-associated variants with reduced sensitivity to protease inhibitors, adherence is of major importance. In this setting, the role of educational nurse should be emphasized for the management of triple therapy in daily clinical practice.
Collapse
Affiliation(s)
- Lawrence Serfaty
- Assistance Publique Hôpitaux de Paris, Université Pierre et Marie Curie, Service d'Hépatologie, INSERM UMR_938, Hôpital Saint-Antoine, Paris, France.
| |
Collapse
|
|
45
|
Liu CH, Kao JH. IL28B Genotype on HCV Infection in Asia. CURRENT HEPATITIS REPORTS 2013; 12:149-156. [DOI: 10.1007/s11901-013-0176-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
|
|
46
|
Pár A, Pár G, Tornai I, Szalay F, Várszegi D, Fráter E, Papp M, Lengyel G, Fehér J, Varga M, Gervain J, Schuller J, Nemes Z, Péterfi Z, Tusnádi A, Hunyady B, Haragh A, Szinku Z, Pálinkás L, Berki T, Vincze A, Kisfali P, Melegh B. [IL28B CC genotype: a protective factor and predictor of the response to interferon treatment in chronic hepatitis C virus infection]. Orv Hetil 2013; 154:1261-8. [PMID: 23916907 DOI: 10.1556/oh.2013.29680] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2023]
Abstract
INTRODUCTION In chronic hepatitis C-virus infection the possible role of gene variants encoding cytokines has become the focus of interest. AIM The aim of the study was to investigate the effect of IL28B polymorphisms on the outcome of chronic hepatitis C-virus genotype 1 infection in the Hungarian population. In addition, the association between IL28B genotypes and the Th1/Th2 cytokine production of activated peripheral blood monocytes and lymphocytes was evaluated. METHOD Total of 748 chronic hepatitis C-virus genotype 1 positive patients (365 males and 383 females, aged between 18 and 82 years; mean age, 54±10 years) were enrolled, of which 420 patients were treated with pegylated interferon plus ribavirin for 24-72 weeks. Of the 420 patients, 195 patients (46.4%) achieved sustained virological response. The IL28B rs12979860 polymorphism was determined using Custom Taqman SNP Genotyping Assays (Applied Biosystems, Life Technologies, Foster, CA, USA). For cytokine studies, tumour necrosis factor-α, interleukin-2, interferon-γ, interleukin-2 and interleukin-4 production by LPS-stimulated monocytes and PMA-ionomycine activated lymphocytes were measured from the supernatant of the cells obtained from 40 hepatitis C-virus infected patients, using FACS-CBA Becton Dickinson test. The cytokine levels were compared in patients with different (CC, CT, TT) IL28B genotypes. RESULTS The IL28B rs12979860 CC genotype occurred in lower frequency in hepatitis C-virus infected patients than in healthy controls (26.1% vs 51.4%, OR 0.333, p<0.001). Patients carried the T allele with higher frequency than controls (73.9%, vs 48.6%, OR 3.003, p<0.001). Pegylated interferon plus ribavirin treated patients with the IL28B CC genotype achieved higher sustained virological response rate than those with the CT genotype (58.6% vs 40.8%, OR 2.057, p = 0.002), and those who carried the T allele (41.8%, OR1.976, p = 0.002). LPS-induced TLR-4 activation of monocytes resulted in higher tumour necrosis factor-α production in patients with the IL28B CC genotype compared to non-CC individuals (p<0.01). Similarly, increased tumour necrosis factor-α, interleukin-2 and interferon-γ production by lymphocytes was found in the IL28B CC carriers (p<0.01) CONCLUSIONS: The IL28B CC genotype exerts protective effect against chronic hepatitis C-virus infection and may be a pretreatment predictor of sustained virological response during interferon-based antiviral therapy. The IL28B CC polymorphism is associated with increased Th1 cytokine production of activated peripheral blood monocytes and lymphocytes, which may play a role in interferon-induced rapid immune control and sustained virological response of pegylated interferon plus ribavirin treated patients.
Collapse
Affiliation(s)
- Alajos Pár
- Pécsi Tudományegyetem, Általános Orvostudományi Kar, Orvos- és Egészségtudományi Centrum I. Belgyógyászati Klinika.
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
47
|
King LY, Chung RT. IL28B testing in a rapidly changing world: Still relevant? J Hepatol 2013; 58:847-9. [PMID: 23416431 DOI: 10.1016/j.jhep.2013.02.002] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2013] [Revised: 02/08/2013] [Accepted: 02/11/2013] [Indexed: 12/21/2022]
|
|
48
|
Kanda T, Nakamoto S, Wu S, Yokosuka O. Role of IL28Bgenotype in older hepatitis C virus-infected patients. World J Immunol 2013; 3:54. [DOI: 10.5411/wji.v3.i3.54] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2013] [Revised: 09/02/2013] [Accepted: 10/16/2013] [Indexed: 02/05/2023] Open
|