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1
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Murray M. Mechanisms and Clinical Significance of Pharmacokinetic Drug Interactions Mediated by FDA and EMA-approved Hepatitis C Direct-Acting Antiviral Agents. Clin Pharmacokinet 2023; 62:1365-1392. [PMID: 37731164 DOI: 10.1007/s40262-023-01302-x] [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: 08/28/2023] [Indexed: 09/22/2023]
Abstract
The treatment of patients infected with the hepatitis C virus (HCV) has been revolutionised by the development of direct-acting antiviral agents (DAAs) that target specific HCV proteins involved in viral replication. The first DAAs were associated with clinical problems such as adverse drug reactions and pharmacokinetic drug-drug interactions (DDIs). Current FDA/EMA-approved treatments are combinations of DAAs that simultaneously target the HCV N5A-protein, the HCV N5B-polymerase and the HCV NS3/4A-protease. Adverse events and DDIs are less likely with these DAA combinations but several DDIs of potential clinical significance remain. Much of the available information on the interaction of DAAs with CYP drug-metabolising enzymes and influx and efflux transporters is contained in regulatory summaries and is focused on DDIs of likely clinical importance. Important DDIs perpetrated by current DAAs include increases in the pharmacokinetic exposure to statins and dabigatran. Some mechanistic information can be deduced. Although the free concentrations of DAAs in serum are very low, a number of these DDIs are likely mediated by the inhibition of systemic influx transporters, especially OATP1B1/1B3. Other DDIs may arise by DAA-mediated inhibition of intestinal efflux transporters, which increases the systemic concentrations of some coadministered drugs. Conversely, DAAs are victims of DDIs mediated by cyclosporin, ketoconazole, omeprazole and HIV antiretroviral drug combinations, especially when boosted by ritonavir and, to a lesser extent, cobicistat. In addition, concurrent administration of inducers, such as rifampicin, carbamazepine and efavirenz, decreases exposure to some DAAs. Drug-drug interactions that increase the accumulation of HCV N3/4A-protease inhibitors like grazoprevir may exacerbate hepatic injury in HCV patients.
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Affiliation(s)
- Michael Murray
- School of Pharmacy, Faculty of Medicine and Health, University of Sydney, New South Wales, 2006, Australia.
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2
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McKay LGA, Thomas J, Albalawi W, Fattaccioli A, Dieu M, Ruggiero A, McKeating JA, Ball JK, Tarr AW, Renard P, Pollakis G, Paxton WA. The HCV Envelope Glycoprotein Down-Modulates NF-κB Signalling and Associates With Stimulation of the Host Endoplasmic Reticulum Stress Pathway. Front Immunol 2022; 13:831695. [PMID: 35371105 PMCID: PMC8964954 DOI: 10.3389/fimmu.2022.831695] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Accepted: 02/21/2022] [Indexed: 11/13/2022] Open
Abstract
Following acute HCV infection, the virus establishes a chronic disease in the majority of patients whilst few individuals clear the infection spontaneously. The precise mechanisms that determine chronic HCV infection or spontaneous clearance are not completely understood but are proposed to be driven by host and viral genetic factors as well as HCV encoded immunomodulatory proteins. Using the HIV-1 LTR as a tool to measure NF-κB activity, we identified that the HCV E1E2 glycoproteins and more so the E2 protein down-modulates HIV-1 LTR activation in 293T, TZM-bl and the more physiologically relevant Huh7 liver derived cell line. We demonstrate this effect is specifically mediated through inhibiting NF-κB binding to the LTR and show that this effect was conserved for all HCV genotypes tested. Transcriptomic analysis of 293T cells expressing the HCV glycoproteins identified E1E2 mediated stimulation of the endoplasmic reticulum (ER) stress response pathway and upregulation of stress response genes such as ATF3. Through shRNA mediated inhibition of ATF3, one of the components, we observed that E1E2 mediated inhibitory effects on HIV-1 LTR activity was alleviated. Our in vitro studies demonstrate that HCV Env glycoprotein activates host ER Stress Pathways known to inhibit NF-κB activity. This has potential implications for understanding HCV induced immune activation as well as oncogenesis.
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Affiliation(s)
- Lindsay G. A. McKay
- Department of Clinical Infection, Microbiology and Immunology, Institute of Veterinary and Ecological Sciences, University of Liverpool, Liverpool, United Kingdom
| | - Jordan Thomas
- Department of Clinical Infection, Microbiology and Immunology, Institute of Veterinary and Ecological Sciences, University of Liverpool, Liverpool, United Kingdom
| | - Wejdan Albalawi
- Department of Clinical Infection, Microbiology and Immunology, Institute of Veterinary and Ecological Sciences, University of Liverpool, Liverpool, United Kingdom
| | - Antoine Fattaccioli
- Laboratory of Biochemistry and Cell Biology (URBC), Namur Research Institute for Life Sciences (NARILIS), University of Namur (UNamur), Namur, Belgium
| | - Marc Dieu
- MaSUN, Mass Spectrometry Facility, University of Namur (UNamur), Namur, Belgium
| | - Alessandra Ruggiero
- Department of Clinical Infection, Microbiology and Immunology, Institute of Veterinary and Ecological Sciences, University of Liverpool, Liverpool, United Kingdom
| | - Jane A. McKeating
- Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
| | - Jonathan K. Ball
- Wolfson Centre for Global Virus Research and School of Life Sciences, University of Nottingham, Nottingham, United Kingdom
| | - Alexander W. Tarr
- Wolfson Centre for Global Virus Research and School of Life Sciences, University of Nottingham, Nottingham, United Kingdom
| | - Patricia Renard
- Laboratory of Biochemistry and Cell Biology (URBC), Namur Research Institute for Life Sciences (NARILIS), University of Namur (UNamur), Namur, Belgium,MaSUN, Mass Spectrometry Facility, University of Namur (UNamur), Namur, Belgium
| | - Georgios Pollakis
- Department of Clinical Infection, Microbiology and Immunology, Institute of Veterinary and Ecological Sciences, University of Liverpool, Liverpool, United Kingdom
| | - William A. Paxton
- Department of Clinical Infection, Microbiology and Immunology, Institute of Veterinary and Ecological Sciences, University of Liverpool, Liverpool, United Kingdom,*Correspondence: William A. Paxton,
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Envelope-Specific IgG3 and IgG1 Responses Are Associated with Clearance of Acute Hepatitis C Virus Infection. Viruses 2020; 12:v12010075. [PMID: 31936235 PMCID: PMC7019651 DOI: 10.3390/v12010075] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2019] [Revised: 12/18/2019] [Accepted: 01/06/2020] [Indexed: 12/16/2022] Open
Abstract
Hepatitis C virus (HCV) can be cleared naturally in a subset of individuals. However, the asymptomatic nature of acute HCV infection makes the study of the early immune response and defining the correlates of protection challenging. Despite this, there is now strong evidence implicating the humoral immune response, specifically neutralising antibodies, in determining the clearance or chronicity outcomes of primary HCV infection. In general, immunoglobulin G (IgG) plays the major role in viral neutralisation. However, there are limited investigations of anti-HCV envelope protein 2 (E2) isotypes (IgM, IgG, IgA) and IgG subclasses (IgG1-4) in early HCV infection. In this study, using a rare cohort of 14 very recently HCV-infected individuals (4-45 days) with varying disease outcome (n = 7 clearers), the timing and potency of anti-HCV E2 isotypes and IgG subclasses were examined longitudinally, in relation to neutralising antibody activity. Clearance was associated with anti-E2 IgG, specifically IgG1 and IgG3, and appeared essential to prevent the emergence of new HCV variants and the chronic infection outcome. Interestingly, these IgG responses were accompanied by IgM antibodies and were associated with neutralising antibody activity in the subjects who cleared infection. These findings provide novel insights into the early humoral immune response characteristics associated with HCV disease outcome.
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Rossotti R, Puoti M. Sexually Transmitted Hepatitis. Sex Transm Infect 2020. [DOI: 10.1007/978-3-030-02200-6_13] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
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Ali Q, Jamal A, Imran M, Ullah S, Kalam I, Ullah S, Waqar AB. Correlation of IL28B rs12979860 genotype and gender with spontaneous clearance of HCV infection: a Pakistani cross-section study. Per Med 2018; 15:495-502. [PMID: 30398404 DOI: 10.2217/pme-2018-0016] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
AIM There is a strong correlation of IL28B rs12979860 genetic variations and gender with spontaneous clearance of hepatitis C virus (HCV) infection. MATERIALS & METHODS HCV-infected subjects were categorized into HCV spontaneous clearance (SC) group and chronic hepatitis C (CHC) group on the basis of anti-HCV antibodies and HCV RNA level and follow-up of 6 months. 35 subjects were classified in SC group and 165 subjects were classified in CHC group. IL28B rs12979860 genotypes were determined by allele-specific PCR. RESULTS & CONCLUSION Multinominal logistic regression analyses revealed that both genders favor IL28B rs12979860 CT genotype (OR: 4.80; CI: 2.22-10.35; p = 0.0005) and (OR: 3.47; CI: 1.63-7.43; p = 0.001) for male and female, respectively, are significant in spontaneous clearance of HCV infection.
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Affiliation(s)
- Qaisar Ali
- Faculty of Allied and Health Sciences, Imperial College of Business & Studies, Lahore, Pakistan 53720
| | - Arshad Jamal
- Faculty of Allied and Health Sciences, Imperial College of Business & Studies, Lahore, Pakistan 53720
| | - Muhammad Imran
- Department of Microbiology, University of Health Sciences, Lahore, Pakistan 54000
| | - Sajjad Ullah
- Faculty of Allied and Health Sciences, Imperial College of Business & Studies, Lahore, Pakistan 53720
| | - Irfan Kalam
- Faculty of Allied and Health Sciences, Imperial College of Business & Studies, Lahore, Pakistan 53720
| | - Shafi Ullah
- Faculty of Allied and Health Sciences, Imperial College of Business & Studies, Lahore, Pakistan 53720
| | - Ahmed B Waqar
- Faculty of Allied and Health Sciences, Imperial College of Business & Studies, Lahore, Pakistan 53720
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6
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Wei L, Wedemeyer H, Liaw YF, Chan HLY, Piratvisuth T, Marcellin P, Jia J, Tan D, Chow WC, Brunetto MR, Diago M, Gurel S, Morozov V, He H, Zhu Y, Wat C, Surujbally B, Thompson AJ. No association between IFNL3 (IL28B) genotype and response to peginterferon alfa-2a in HBeAg-positive or -negative chronic hepatitis B. PLoS One 2018; 13:e0199198. [PMID: 30016335 PMCID: PMC6049926 DOI: 10.1371/journal.pone.0199198] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2017] [Accepted: 05/22/2018] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND & AIMS It has yet to be firmly established whether host IFNL3 (IL28B) genotype influences interferon responsiveness in patients with chronic hepatitis B. We investigated associations between single-nucleotide polymorphisms (SNPs) in the IFNL3 region and response to peginterferon alfa-2a in 701 patients enrolled in three large, randomized, international studies. METHODS Responses were defined as hepatitis B surface antigen (HBsAg) loss and/or hepatitis B e antigen (HBeAg) seroconversion plus hepatitis B virus (HBV) DNA <2000 IU/ml in HBeAg-positive patients, and HBsAg loss and/or HBV DNA <2000 IU/ml in HBeAg-negative patients (24 weeks after end of treatment). Associations between treatment response and the number of copies of the poor-response allele at three SNPs (rs8099917, rs12980275, rs12979860) were explored with logistic regression models in Asian and white patients. RESULTS The HBeAg-positive and -negative populations comprised 465 (92% Asian, 50% HBV genotype C) and 236 (79% Asian, 41% HBV genotype C) patients, respectively, and had respective response rates of 26% and 47%. The IFNL3 genotype was strongly associated with ethnicity. There was no association between IFNL3 genotype and treatment response in HBeAg-positive or -negative patients. Independent predictors of treatment response were: sex, HBV DNA level and alanine aminotransferase level in HBeAg-positive Asian patients; age in HBeAg-negative Asian patients; and HBV DNA in HBeAg-negative white patients. CONCLUSIONS This is the largest analysis to date of associations between IFNL3 genotype and peginterferon response in patients with chronic hepatitis B. The data suggest that IFNL3 polymorphism is not a major determinant of the response to peginterferon alfa-2a in either HBeAg-positive or HBeAg-negative patients.
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Affiliation(s)
- Lai Wei
- Peking University People’s Hospital, Peking University Hepatology Institute, Beijing, China
| | - Heiner Wedemeyer
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Yun-Fan Liaw
- Liver Research Unit, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei, Taiwan
| | - Henry Lik-Yuen Chan
- Department of Medicine and Therapeutics, Institute of Digestive Disease and State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, China
| | - Teerha Piratvisuth
- NKC Institute of Gastroenterology and Hepatology, Prince of Songkla University, Songklanagarind Hospital, Songkhla, Thailand
| | - Patrick Marcellin
- Service d’Hépatologie and INSERM CRB3/U773, Université Paris-Diderot, Clichy, France
| | - Jidong Jia
- Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Deming Tan
- Xiangya Hospital, Central South University, Changsha, Hunan Province, China
| | - Wan-Cheng Chow
- Department of Gastroenterology & Hepatology, Singapore General Hospital, Singapore, Singapore
| | | | | | - Selim Gurel
- Department of Gastroenterology, Medical Faculty, Uludag University, Bursa, Turkey
| | | | - Hua He
- Roche Products Ltd, Welwyn, United Kingdom
| | - Yonghong Zhu
- Genentech Inc., San Francisco, California, United States of America
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7
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Martinello M, Hajarizadeh B, Grebely J, Dore GJ, Matthews GV. Management of acute HCV infection in the era of direct-acting antiviral therapy. Nat Rev Gastroenterol Hepatol 2018; 15:412-424. [PMID: 29773899 DOI: 10.1038/s41575-018-0026-5] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The management of acute HCV infection has not been standardized following the availability of direct-acting antiviral agents (DAAs) for chronic HCV infection, and substantial uncertainty exists regarding the optimal treatment regimen and duration. Despite the lack of direct evidence, the 2016 American Association for the Study of Liver Diseases (AASLD)-Infectious Diseases Society of America (IDSA) guidelines supported "the same regimens for acute HCV as recommended for chronic HCV infection … owing to high efficacy and safety", whereas the 2016 European Association for the Study of the Liver (EASL) guidelines recommended sofosbuvir-ledipasvir, sofosbuvir-velpatasvir or sofosbuvir plus daclatasvir for 8 weeks in acute HCV infection, with a longer duration of 12 weeks recommended for those infected with HIV and/or baseline HCV RNA levels >1,000,000 IU/ml. This Review outlines the epidemiology, natural history and diagnosis of acute HCV infection and provides contemporary information on DAAs for acute and recent HCV infection. The Review also discusses the 2016 AASLD-IDSA and EASL recommendations for acute HCV infection management in light of available evidence and highlights key differences in study populations and design that influence interpretation. We focus on populations at high risk of HCV transmission and acquisition, including people who inject drugs and HIV-positive men who have sex with men, and highlight the potential effects of diagnosis and treatment of acute HCV infection in contributing to HCV elimination.
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Affiliation(s)
- Marianne Martinello
- Viral Hepatitis Clinical Research Program, Kirby Institute, UNSW, Sydney, NSW, Australia.
| | - Behzad Hajarizadeh
- Viral Hepatitis Clinical Research Program, Kirby Institute, UNSW, Sydney, NSW, Australia
| | - Jason Grebely
- Viral Hepatitis Clinical Research Program, Kirby Institute, UNSW, Sydney, NSW, Australia
| | - Gregory J Dore
- Viral Hepatitis Clinical Research Program, Kirby Institute, UNSW, Sydney, NSW, Australia
| | - Gail V Matthews
- Viral Hepatitis Clinical Research Program, Kirby Institute, UNSW, Sydney, NSW, Australia
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8
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Aisyah DN, Shallcross L, Hully AJ, O'Brien A, Hayward A. Assessing hepatitis C spontaneous clearance and understanding associated factors-A systematic review and meta-analysis. J Viral Hepat 2018; 25:680-698. [PMID: 29345844 DOI: 10.1111/jvh.12866] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2017] [Accepted: 12/14/2017] [Indexed: 12/11/2022]
Abstract
New advances in the treatment of hepatitis C provide high levels of sustained viral response but their expense limits availability in publicly funded health systems. The aim of this review was to estimate the proportion of patients who will spontaneously clear HCV, to identify factors that are associated with clearance and to support better targeting of directly acting antivirals. We searched Ovid EMBASE, Ovid MEDLINE and PubMed from 1 January 1994 to 30 June 2015 for studies reporting hepatitis C spontaneous clearance and/or demographic, clinical and behavioural factors associated with clearance. We undertook meta-analyses to estimate the odds of clearance for each predictor. Forty-three studies met the inclusion criteria, representing 20 110 individuals, and 6 of these studies included sufficient data to estimate spontaneous clearance. The proportion achieving clearance within 3, 6, 12 and 24 months following infection were, respectively, 19.8% (95% CI: 2.6%-47.5%), 27.9% (95% CI: 17.2%-41.8%), 36.1% (95% CI: 23.5%-50.9%) and 37.1% (95% CI: 23.7%-52.8%). Individuals who had not spontaneously cleared by 12 months were unlikely to do so. The likelihood of spontaneous clearance was lower in males and individuals with HIV co-infection, the absence of HBV co-infection, asymptomatic infection, black or nonindigenous race, nongenotype 1 infection, older age and alcohol or drug problems. This study suggests that patients continue to spontaneously clear HCV for at least 12 months following initial infection. However, injecting drug users are comparatively less likely to achieve clearance; thus, they should be considered a priority for early treatment given the continuing risks that these individuals pose for onwards transmission.
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Affiliation(s)
- D N Aisyah
- UCL Infectious Disease Informatics, Farr Institute of Health Informatics, London, UK.,Faculty of Public Health, Universitas Indonesia, Depok, Indonesia
| | - L Shallcross
- UCL Infectious Disease Informatics, Farr Institute of Health Informatics, London, UK
| | - A J Hully
- Kings College London School of Medicine, London, UK
| | - A O'Brien
- UCL Division of Medicine, London, UK
| | - A Hayward
- UCL Infectious Disease Informatics, Farr Institute of Health Informatics, London, UK.,Institute of Epidemiology and Health Care, University College London, London, UK
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9
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Yan Z, Wang Y. Viral and host factors associated with outcomes of hepatitis C virus infection (Review). Mol Med Rep 2017; 15:2909-2924. [PMID: 28339063 DOI: 10.3892/mmr.2017.6351] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2016] [Accepted: 02/13/2017] [Indexed: 11/05/2022] Open
Abstract
Hepatitis C virus (HCV) infection is a major health issue globally. Owing to the progress made in host genetics and HCV molecular virology, emerging data have suggested that the natural course and treatment response in patients with HCV infection are largely determined by complex host‑viral interactions. HCV genotype is the most important viral factor predicting the response to pegylated interferon‑α plus ribavirin therapy. The subtype of HCV genotype 1 is the key viral factor that predicts the efficacy of direct‑acting antiviral therapy. HCV genome heterogeneity and baseline viral load are additionally associated with the treatment response. Multiple host genetic variants localized in genes associated with the immune response have been identified as predictors of spontaneous disease course and therapy outcome in chronic HCV. However, most findings from candidate gene association studies have not been proven universal for all investigated populations and independent studies. Previous findings in independent large genome wide association studies confirmed that interferon‑λ3 gene polymorphisms are associated with spontaneous clearance and treatment responsiveness. A polymorphism of the inosine triphosphatase gene has been identified as a protective factor against ribavirin‑induced anemia and dose reductions. Another genetic variant in the patatin‑like phospholipase domain containing 3 genes is associated with hepatic steatosis and fibrosis in patients with HCV. The present review focused on the identified viral and host factors associated with outcomes of patients with HCV, and assessed the involvement of viral and host genetics in the natural history and treatment outcomes of HCV infection. This will provide novel ideas concerning personalized prevention and individualized clinical management.
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Affiliation(s)
- Zehui Yan
- Department of Infectious Diseases, Southwest Hospital, Third Military Medical University, Shapingba, Chongqing 400038, P.R. China
| | - Yuming Wang
- Department of Infectious Diseases, Southwest Hospital, Third Military Medical University, Shapingba, Chongqing 400038, P.R. China
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10
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Association of Genotype and Haplotype of IL-28B Gene with Hepatitis C Infection Outcome in Iran: Spontaneous Clearance Versus Chronic Infection. HEPATITIS MONTHLY 2017. [DOI: 10.5812/hepatmon.45745] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/13/2023]
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11
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Czupryna P, Parczewski M, Grygorczuk S, Pancewicz S, Zajkowska J, Dunaj J, Kondrusik M, Krawczuk K, Moniuszko-Malinowska A. Analysis of the relationship between single nucleotide polymorphism of the CD209, IL-10, IL-28 and CCR5 D32 genes with the human predisposition to developing tick-borne encephalitis. POSTEP HIG MED DOSW 2017; 71:788-796. [PMID: 28894041 DOI: 10.5604/01.3001.0010.3856] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
<b>Introduction: </b>It is known that in the pathogenesis of tick-borne encephalitis (TBE) various molecules play a significant role. The most prominent factors include IL-10, IL-28B, CD-209 and CCR5. It is reasonable to search for genetic predispositions to the development of various clinical forms of TBE related to the genetic variation of IL-10, IL-28B, CD-209 and CCR5. In this study we aimed to search for the relationship between single nucleotide polymorphism in the promoter region of the CD209, IL-10, IL-28 and 32 base pair deletion in CCR5 coding region (Δ 32) with the human predisposition to development of various clinical presentations of TBE. We tried to assess the relation between the presence of particular alleles and genotypes with laboratory and clinical parameters. <b>Material/Methods </b>59 patients with TBE and 57 people, bitten by a tick who never developed TBE (Polish cohort), were included in the study. To assess the distribution of single nucleotide polymorphisms, TaqMan SNP genotyping assays were used for IL10: rs1800872 and rs1800896, for CD 209 rs4804803 and rs2287886, rs12979860 for IL 28B SNPs according to the manufacturer's protocol using real-time PCR technology on the StepOne thermal cycler. <b>Results </b>Comparison between TBE patients and CG showed that in SNP rs2287886 CD 209 AG heterozygotes were more frequent in the TBE group, while homozygotes GG were more frequent in the CG group. <b>Conclusions </b> SNP rs2287886 CD 209 AG heterozygotes predispose humans to develop TBE. Single nucleotide polymorphism in the promoter region of the CD209, IL-10, IL-28 and CCR5 D32 genes does not correlate with the severity of TBE.
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Affiliation(s)
- Piotr Czupryna
- Department of Infectious Diseases and Neuroinfections, Medical University in Białystok, Poland
| | - Miłosz Parczewski
- Department of Infectious, Tropical Diseases and Immune Deficiency, Pomeranian Medical University, Szczecin, Poland
| | - Sambor Grygorczuk
- Department of Infectious Diseases and Neuroinfections, Medical University in Białystok, Poland
| | - Sławomir Pancewicz
- Department of Infectious Diseases and Neuroinfections, Medical University in Białystok, Poland
| | - Joanna Zajkowska
- Department of Infectious Diseases and Neuroinfections, Medical University in Białystok, Poland
| | - Justyna Dunaj
- Department of Infectious Diseases and Neuroinfections, Medical University in Białystok, Poland
| | - Maciej Kondrusik
- Department of Infectious Diseases and Neuroinfections, Medical University in Białystok, Poland
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Landaverde C, Wells J, Hamner R, Goldstein JL. Dual therapy of grazoprevir and elbasvir for the treatment of hepatitis C infection. Expert Rev Gastroenterol Hepatol 2016; 10:419-29. [PMID: 26818134 DOI: 10.1586/17474124.2016.1147346] [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] [Indexed: 01/04/2023]
Abstract
The impact of chronic hepatitis C (HCV) worldwide is expected to increase as the population infected with HCV ages and more undiagnosed individuals are identified and linked to care through nation-wide initiatives. The development of interferon-free regimens involving the use of direct-acting antiviral agents, which disrupt key steps in viral replication, has revolutionized the treatment of chronic HCV infection. However, there remains a great medical need for HCV therapy that is of shorter duration, all-oral, with a high barrier to resistance, and highly effective for all patient populations including those with end-stage renal disease (ESRD) and cirrhosis. Grazoprevir, an HCV NS3/4A protease inhibitor and elbasvir, an NS5A inhibitor, have broad in vitro activity against most HCV genotypes and retain in vitro activity against many clinically relevant resistance-associated variants. The once daily regimen is well-tolerated and highly efficacious across wide-ranging patient populations including those with ESRD on hemodialysis.
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Affiliation(s)
- Carmen Landaverde
- a Metabolic Liver Disease Program , Texas Liver Institute , Austin , TX , USA.,b University of Texas Health Sciences Center San Antonio (UTHSCSA) , San Antonio , TX , USA.,c Dell Medical School , UT Austin , Austin , TX , USA
| | - Jennifer Wells
- b University of Texas Health Sciences Center San Antonio (UTHSCSA) , San Antonio , TX , USA.,c Dell Medical School , UT Austin , Austin , TX , USA.,d Regenerative Liver and Neoplasia , Texas Liver Institute , Austin , TX , USA
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Boesecke C, Ingiliz P, Reiberger T, Stellbrink HJ, Bhagani S, Page E, Mauss S, Lutz T, Voigt E, Guiguet M, Valantin MA, Baumgarten A, Nelson M, Vogel M, Rockstroh JK. Dual treatment of acute HCV infection in HIV co-infection: influence of HCV genotype upon treatment outcome. Infection 2016; 44:93-101. [PMID: 26481253 DOI: 10.1007/s15010-015-0856-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2015] [Accepted: 10/07/2015] [Indexed: 12/13/2022]
Abstract
PURPOSE With DAAs still only being licensed for chronic HCV infection, the ongoing epidemic of acute hepatitis C (AHC) infection among MSM highlights the need to identify factors allowing for optimal HCV treatment outcome. METHODS 303 HIV-infected patients from 4 European countries with diagnosed acute HCV infection were treated early with pegylated interferon (pegIFN) and ribavirin (RBV) (n = 273) or pegylated interferon alone (n = 30). RESULTS All patients were male, median age was 39 years. Main routes of transmission were MSM (95%) and IVDU (3%). 69% of patients were infected with HCV GT 1, 4.3% with GT 2, 10.6% with GT 3, 16.1% with GT 4. Overall SVR rate was 69.3% (210/303). RVR (p ≤ 0.001), 48-w treatment duration (p ≤ 0.001) and GT 2/3 (p = 0.024) were significantly associated with SVR. SVR rates were significantly higher in HCV GT 2/3 receiving pegIFN and RBV (33/35) when compared with pegIFN mono-therapy (6/10) (94% vs. 60 % respectively; p = 0.016). In multivariate analysis, pegIFN/RBV combination therapy (p = 0.017) and rapid virological response (RVR) (p = 0.022) were significantly associated with SVR in HCV GT 2/3. In HCV GT 1/4, RVR (p ≤ 0.001) and 48-w treatment duration (p ≤ 0.001) were significantly associated with SVR. CONCLUSIONS Treatment of AHC GT 2 and 3 infections with pegIFN/RBV is associated with higher SVR rates suggesting different cure rates depending on HCV genotype similar to the genotype effects seen previously in chronic HCV under pegIFN/RBV. With pegIFN/RBV still being the gold standard of AHC treatment and in light of cost issues around DAAs and very limited licensed interferon-free DAA treatment options for chronic HCV GT 3 infection AHC GT 3 patients might benefit most from early interferon-containing treatment.
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Sulejmani N, Jafri SM, Gordon SC. Pharmacodynamics and pharmacokinetics of elbasvir and grazoprevir in the treatment of hepatitis C. Expert Opin Drug Metab Toxicol 2016; 12:353-61. [PMID: 26849059 DOI: 10.1517/17425255.2016.1148685] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
INTRODUCTION Approximately 130 - 150 million people have chronic hepatitis C virus (HCV) infection and upwards of 500,000 deaths annually are attributed to HCV related liver disease worldwide. Pegylated interferon and ribavirin have been the mainstay of treatment for greater than 25 years until recent advent of protease inhibitors which has led to all oral HCV treatment regimens that have changed the outlook of hepatitis C treatment. AREAS COVERED This review provides summary of pharmacokinetics, pharmacodynamics, efficacy and safety of grazoprevir/elbasvir therapy for treatment of HCV infection. EXPERT OPINION Grazoprevir/elbasvir provides an all-oral once daily treatment option for HCV infection with high rates of efficacy and tolerability in a pangenotypic fashion. It highly efficacious in treating patients with cirrhosis, patients who have previously failed treatment with pegylated interferon and ribavirin, and patients with HIV co-infection. Grazoprevir/elbasvir has demonstrated higher barrier to resistance even in the presence of variants associated with resistance such as Q41R, F43S, R155K, V36M, T54S, and D168. It is one of only few HCV treatment regimens evaluated for use in patients with advanced chronic kidney disease and dialysis. It is a very promising regimen for treatment of HCV infection.
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Affiliation(s)
- Nimisha Sulejmani
- a Department of Pharmacy , Henry Ford Hospital , Detroit , MI , USA.,b Division of Gastroenterology , Henry Ford Hospital , Detroit , MI , USA
| | | | - Stuart C Gordon
- b Division of Gastroenterology , Henry Ford Hospital , Detroit , MI , USA
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15
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El Kassas M, Elbaz T, Abd El Latif Y, Esmat G. Elbasvir and grazoprevir for chronic hepatitis C genotypes 1 and 4. Expert Rev Clin Pharmacol 2016; 9:1413-1421. [PMID: 27603877 DOI: 10.1080/17512433.2016.1233813] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
INTRODUCTION During the last few years, treatment of hepatitis C virus (HCV) revolutionized with the appearance of direct antiviral agents especially for patients with HCV genotypes 1 and 4 infections. Elbasvir (NS5A inhibitor) and grazoprevir (NS3/4A protease inhibitor) are newly developed drugs that are presented in fixed dose combination tablets. Areas covered: This review covers the mechanism of action, pharmacokinetic and pharmacodynamics properties, clinical uses, safety and efficacy of elbasvir/grazoprevir in managing a wide variety of easy and difficult to treat populations (such as presence of cirrhosis, treatment experienced, co-infection with HIV and patients with inherited blood disorders). Expert commentary: Elbasvir/grazoprevir combination showed great efficacy with high rates of sustained virological response rates in genotypes 1 and 4 HCV infection. In addition, it retained a good safety profile and is generally well tolerated.
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Affiliation(s)
- Mohamed El Kassas
- a Endemic Medicine Department, Faculty of Medicine , Helwan University , Cairo , Egypt
| | - Tamer Elbaz
- b Endemic Hepatogastroenterology, Faculty of Medicine , Cairo University , Cairo , Egypt
| | - Yasmeen Abd El Latif
- c Tropical Medicine Department, Faculty of Medicine , Ain Shams University , Cairo , Egypt
| | - Gamal Esmat
- b Endemic Hepatogastroenterology, Faculty of Medicine , Cairo University , Cairo , Egypt
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16
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Abstract
PURPOSE OF REVIEW Modern interferon (IFN)-free, and potentially also ribavirin-free, combinations consisting of two or three direct-acting antivirals (DAAs) are highly efficacious in treating chronic hepatitis C virus (HCV) infection with treatment durations being much shorter and with much more favorable toxicity profiles. With the acute HCV (AHC) epidemic among men who have sex with men (MSM) still ongoing, the question remains should we be using DAAs in the acute phase of the infection? RECENT FINDINGS To date, none of the currently available DAAs has been licensed for use in the setting of AHC infection. Thus, the current gold standard of treatment still is a combination of pegylated interferon (pegIFN) and weight-adapted ribavirin (RBV). However, with less patients being treated in the acute phase, the current epidemic of AHC in HIV-positive MSM will continue. SUMMARY A decision to treat AHC with pegIFN and RBV can currently only be made on an individual basis in an open discussion between patient and physician which will need to weigh up the risk and benefits of a rather toxic and lengthy treatment now versus the likely available options in the chronic phase. Therefore, studies with IFN-free DAA combinations remain of great urgency to further evaluate the role of DAAs in the treatment of AHC.
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17
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Page K, Mirzazadeh A, Rice TM, Grebely J, Kim AY, Cox AL, Morris MD, Hellard M, Bruneau J, Shoukry NH, Dore GJ, Maher L, Lloyd AR, Lauer G, Prins M, McGovern BH. Interferon Lambda 4 Genotype Is Associated With Jaundice and Elevated Aminotransferase Levels During Acute Hepatitis C Virus Infection: Findings From the InC3 Collaborative. Open Forum Infect Dis 2016; 3:ofw024. [PMID: 26973850 PMCID: PMC4785397 DOI: 10.1093/ofid/ofw024] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2015] [Accepted: 01/21/2016] [Indexed: 01/29/2023] Open
Abstract
Symptomatic acute HCV infection and interferon lambda 4 (IFNL4) genotypes are important predictors of spontaneous viral clearance. Using data from a multicohort database (Injecting Cohorts [InC3] Collaborative), we establish an independent association between host IFNL4 genotype and symptoms of acute hepatitis C virus infection. This association potentially explains the higher spontaneous clearance observed in some patients with symptomatic disease.
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Affiliation(s)
- Kimberly Page
- Division of Epidemiology, Biostatistics and Preventive Medicine, University ofNew Mexico Health Sciences Center, Albuquerque, New Mexico
| | - Ali Mirzazadeh
- Department of Epidemiology and Biostatistics, University of California San Francisco
| | - Thomas M. Rice
- Department of Epidemiology and Biostatistics, University of California San Francisco
| | - Jason Grebely
- The Kirby Institute for Infection and Immunity in Society
| | | | - Andrea L. Cox
- Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, Maryland
| | - Meghan D. Morris
- Department of Epidemiology and Biostatistics, University of California San Francisco
| | | | - Julie Bruneau
- Centre Hospitalier de l'Université de Montréal, Quebec, Canada
| | | | | | - Lisa Maher
- The Kirby Institute for Infection and Immunity in Society
| | - Andrew R. Lloyd
- School of Medical Sciences, University of New South Wales, Sydney, Australia
| | - Georg Lauer
- Harvard Medical School, Boston, Massachusetts
| | - Maria Prins
- GGD Public Health Service of Amsterdam, the Netherlands
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18
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Doyle JS, Deterding K, Grebely J, Wedemeyer H, Sacks-Davis R, Spelman T, Matthews G, Rice TM, Morris MD, McGovern BH, Kim AY, Bruneau J, Lloyd AR, Page K, Manns MP, Hellard ME, Dore GJ. Response to treatment following recently acquired hepatitis C virus infection in a multicentre collaborative cohort. J Viral Hepat 2015; 22:1020-32. [PMID: 26098993 PMCID: PMC4618180 DOI: 10.1111/jvh.12429] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2015] [Accepted: 05/06/2015] [Indexed: 12/21/2022]
Abstract
Pegylated interferon therapy is highly effective in recently acquired HCV. The optimal timing of treatment, regimen and influence of host factors remains unclear. We aimed to measure sustained virological response (SVR) during recent HCV infection and identify predictors of response. Data were from five prospective cohorts of high-risk individuals in Australia, Canada, Germany and the United States. Individuals with acute or early chronic HCV who commenced pegylated interferon therapy were included. The main outcome was SVR, and predictors were assessed using logistic regression. Among 516 with documented recent HCV infection, 237 were treated (pegylated interferon n = 161; pegylated interferon/ribavirin n = 76) (30% female, median age 35 years, 56% ever injected drugs, median duration of infection 6.2 months). Sixteen per cent (n = 38) were HIV/HCV co-infected. SVR among those with HCV mono-infection was 64% by intention to treat; SVR was 68% among HCV/HIV co-infection. Independent predictors of SVR in HCV mono-infection were duration of HCV infection (the odds of SVR declined by 8% per month of infection, aOR 0.92, 95% CI 0.85-0.99, P = 0.033), IFNL4 genotype (adjusted OR 2.27, 95% CI 1.13-4.56, P = 0.021), baseline HCV RNA <400 000 IU/mL (aOR 2.06, 95% CI 1.03-4.12, P = 0.041) and age ≥40 years (vs <30: aOR 2.92, 95% CI 1.31-6.49, P = 0.009), with no difference by drug regimen, HCV genotype, symptomatic infection or gender. The effect of infection duration on odds of SVR was greater among genotype-1 infection. Interferon-based HCV treatment is highly effective in recent HCV infection. Duration of infection, IFNL4 genotype and baseline HCV RNA levels can predict virological response and may inform clinical decision-making.
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Affiliation(s)
- Joseph S. Doyle
- Centre for Population Health, Burnet Institute, Melbourne, Australia,School of Population Health and Preventive Medicine, Monash University, Melbourne, Australia,Department of Infectious Diseases, The Alfred Hospital, Melbourne, Australia
| | - Katja Deterding
- Hannover Medical School, Hannover, Germany,Hep-Net Study House: German Network of Competence on Viral Hepatitis, Germany
| | | | - Heiner Wedemeyer
- Hannover Medical School, Hannover, Germany,Hep-Net Study House: German Network of Competence on Viral Hepatitis, Germany,German Centre for Infection Research (DZIF), Hannover-Braunschweig, Germany
| | - Rachel Sacks-Davis
- Centre for Population Health, Burnet Institute, Melbourne, Australia,School of Population Health and Preventive Medicine, Monash University, Melbourne, Australia
| | - Tim Spelman
- Centre for Population Health, Burnet Institute, Melbourne, Australia
| | | | - Thomas M. Rice
- Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, USA
| | - Meghan D. Morris
- Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, USA
| | | | | | | | - Andrew R. Lloyd
- School of Medical Sciences, UNSW Australia, Sydney, Australia
| | - Kimberly Page
- Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, USA
| | - Michael P. Manns
- Hannover Medical School, Hannover, Germany,Hep-Net Study House: German Network of Competence on Viral Hepatitis, Germany,German Centre for Infection Research (DZIF), Hannover-Braunschweig, Germany
| | - Margaret E. Hellard
- Centre for Population Health, Burnet Institute, Melbourne, Australia,School of Population Health and Preventive Medicine, Monash University, Melbourne, Australia,Department of Infectious Diseases, The Alfred Hospital, Melbourne, Australia
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19
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Zheng H, Li M, Chi B, Wu XX, Wang J, Liu DW. IL28B rs12980275 variant as a predictor of sustained virologic response to pegylated-interferon and ribavirin in chronic hepatitis C patients: A systematic review and meta-analysis. Clin Res Hepatol Gastroenterol 2015; 39:576-83. [PMID: 25769643 DOI: 10.1016/j.clinre.2015.01.009] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2014] [Revised: 11/05/2014] [Accepted: 01/26/2015] [Indexed: 02/07/2023]
Abstract
BACKGROUND AND OBJECTIVE The IL-28B rs12979860 CC and rs8099917 TT genotypes were proved to be predictor for pegylated-interferon (PEG-IFN)/ribavirin (RBV)-treated hepatitis C virus (HCV) patients. However, there were no identical conclusions on rs12980275 polymorphism. Our aim is to perform a meta-analysis in order to determine the association between rs12980275 polymorphism of IL28B and the sustain viral response (SVR) of HCV patients with PEG-IFN/RBV therapy. METHODS Studies were retrieved from PubMed and Chinese China National Knowledge Infrastructure (CNKI). Data were extracted by two investigators and analyzed using Stata 11.0 software. RESULTS Sixteen articles, containing 19 independent studies were included in the analysis. The results showed that patients with AA genotype of rs12980275 achieved higher SVR than patients with AG/GG genotypes. The overall OR (95% CI) was 3.118 (2.146, 4.529). In subgroup analysis by ethnicity, the ORs (95% CIs) were 3.084 (1.454, 6.542) and 2.736 (1.863, 4.018) in Asian and Caucasian population, respectively. Another subgroup analysis by HCV genotype, the ORs (95% CIs) were 3.976 (2.568, 6.158), 1.462 (0.504, 4.240) and 1.489 (0.916, 2.421) in patients with HCV genotype 1/4, mix genotype, and HCV genotype 2/3, respectively. CONCLUSION AA genotype of rs12980275 was a predictive factor for SVR in HCV patients with PEG-IFN/RBV treatment, especially in HCV genotype 1/4.
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Affiliation(s)
- Hao Zheng
- Department of Ultrasonography, Hebei Chest Hospital, Shijiazhuang, 050041 Hebei Province, China
| | - Man Li
- Department of Epidemiology and Biostatistics, School of Public Health, Hebei Medical University, Zhongshan East Road 361#, Shijiazhuang, 050017 Hebei Province, China
| | - Bing Chi
- Department of Epidemiology and Biostatistics, School of Public Health, Hebei Medical University, Zhongshan East Road 361#, Shijiazhuang, 050017 Hebei Province, China
| | - Xiao-xue Wu
- Department of Epidemiology and Biostatistics, School of Public Health, Hebei Medical University, Zhongshan East Road 361#, Shijiazhuang, 050017 Hebei Province, China
| | - Jia Wang
- Department of Epidemiology and Biostatistics, School of Public Health, Hebei Medical University, Zhongshan East Road 361#, Shijiazhuang, 050017 Hebei Province, China
| | - Dian-Wu Liu
- Department of Epidemiology and Biostatistics, School of Public Health, Hebei Medical University, Zhongshan East Road 361#, Shijiazhuang, 050017 Hebei Province, China.
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20
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Coppola N, Pisaturo M, Sagnelli C, Onorato L, Sagnelli E. Role of genetic polymorphisms in hepatitis C virus chronic infection. World J Clin Cases 2015; 3:807-822. [PMID: 26380828 PMCID: PMC4568530 DOI: 10.12998/wjcc.v3.i9.807] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2014] [Revised: 12/09/2014] [Accepted: 06/08/2015] [Indexed: 02/05/2023] Open
Abstract
AIM: To analyze the host genetics factors influencing the clinical course and the response to antiviral treatment in patients with chronic hepatitis C (CHC).
METHODS: We conducted an electronic search on the PubMed and MEDLINE (2000-2014) databases and Cochrane library (2000-2014). A total of 73 articles were retrieved and their data were extensively evaluated and discussed by the authors and then analyzed in this review article.
RESULTS: Several studies associated polymorphisms in the interleukin 28B gene on chromosome 19 (19q13.13) with a spontaneous viral clearance in acute hepatitis C and with the response to pegylated interferon (Peg-IFN)-based treatment in chronic hepatitis C patients. Other investigations demonstrated that inosine triphosphate pyrophosphatase genetic variants protect hepatitis C virus-genotype-1 CHC patients from ribavirin-induced anemia, and other studies that a polymorphism in the patatin-like phospholipase domain-containing protein 3 was associated with hepatic steatosis in CHC patients. Although not conclusive, some investigations suggested that the vitamin D-associated polymorphisms play an important role in the achievement of sustained virologic response in CHC patients treated with Peg-IFN-based antiviral therapy. Several other polymorphisms have been investigated to ascertain their possible impact on the natural history and on the response to treatment in patients with CHC, but the data are preliminary and warrant confirmation.
CONCLUSION: Several genetic polymorphisms seem to influence the clinical course and the response to antiviral treatment in patients with CHC, suggesting individualized follow up and treatment strategies.
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21
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Hajarizadeh B, Grady B, Page K, Kim AY, McGovern BH, Cox AL, Rice TM, Sacks-Davis R, Bruneau J, Morris M, Amin J, Schinkel J, Applegate T, Maher L, Hellard M, Lloyd AR, Prins M, Geskus RB, Dore GJ, Grebely J. Factors associated with hepatitis C virus RNA levels in early chronic infection: the InC3 study. J Viral Hepat 2015; 22:708-17. [PMID: 25580520 PMCID: PMC4496327 DOI: 10.1111/jvh.12384] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2014] [Accepted: 12/09/2014] [Indexed: 02/06/2023]
Abstract
Improved understanding of natural history of hepatitis C virus (HCV) RNA levels in chronic infection provides enhanced insights into immunopathogenesis of HCV and has implications for the clinical management of chronic HCV infection. This study assessed factors associated with HCV RNA levels during early chronic infection in a population with well-defined early chronic HCV infection. Data were from an international collaboration of nine prospective cohorts studying acute HCV infection (InC(3) study). Individuals with persistent HCV and detectable HCV RNA during early chronic infection (one year [±4 months] postinfection) were included. Distribution of HCV RNA levels during early chronic infection was compared by selected host and virological factors. A total of 308 individuals were included. Median HCV RNA levels were significantly higher among males (vs females; 5.15 vs 4.74 log IU/mL; P < 0.01) and among individuals with HIV co-infection (vs no HIV; 5.89 vs 4.86; P = 0.02). In adjusted logistic regression, male sex (vs female, adjusted odds ratio [AOR]: 1.93; 95%CI: 1.01, 3.69), interferon lambda 4 (IFNL4) rs12979860 CC genotype (vs TT/CT; AOR: 2.48; 95%CI: 1.42, 4.35), HIV co-infection (vs no HIV; AOR: 3.27; 95%CI: 1.35, 7.93) and HCV genotype G2 (vs G3; AOR: 5.40; 95%CI: 1.63, 17.84) were independently associated with high HCV RNA levels (>5.6 log IU/mL = 400 000 IU/mL). In conclusion, this study demonstrated that IFNL4 rs12979860 CC genotype, male sex, HIV co-infection and HCV genotype G2 are associated with high HCV RNA levels in early chronic infection. These factors exert their role as early as one year following infection.
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Affiliation(s)
| | - Bart Grady
- Cluster Infectious Diseases, GGD Public Health Service of Amsterdam, Amsterdam, The Netherlands
| | - Kimberly Page
- Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA
| | | | | | - Andrea L. Cox
- Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, MD, USA
| | - Thomas M. Rice
- Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA
| | - Rachel Sacks-Davis
- Burnet Institute, Melbourne, VIC, Australia,Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Australia
| | - Julie Bruneau
- CRCHUM, Université de Montréal, Montreal, QC, Canada
| | - Meghan Morris
- Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA
| | - Janaki Amin
- The Kirby Institute, UNSW Australia, Sydney, NSW, Australia
| | | | | | - Lisa Maher
- The Kirby Institute, UNSW Australia, Sydney, NSW, Australia
| | - Margaret Hellard
- Burnet Institute, Melbourne, VIC, Australia,Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Australia
| | - Andrew R. Lloyd
- Inflammation and Infection Research Centre, School of Medical Sciences, UNSW Australia, Sydney, NSW, Australia
| | - Maria Prins
- Cluster Infectious Diseases, GGD Public Health Service of Amsterdam, Amsterdam, The Netherlands,Academic Medical Center, Amsterdam, The Netherlands
| | - Ronald B Geskus
- Cluster Infectious Diseases, GGD Public Health Service of Amsterdam, Amsterdam, The Netherlands,Academic Medical Center, Amsterdam, The Netherlands
| | | | - Jason Grebely
- The Kirby Institute, UNSW Australia, Sydney, NSW, Australia
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22
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Haj-sheykholeslami A, Keshvari M, Sharafi H, Pouryasin A, Hemmati K, Mohammadzadehparjikolaei F. Interferon-λ polymorphisms and response to pegylated interferon in Iranian hepatitis C patients. World J Gastroenterol 2015; 21:8935-8942. [PMID: 26269684 PMCID: PMC4528037 DOI: 10.3748/wjg.v21.i29.8935] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2014] [Revised: 02/10/2015] [Accepted: 04/09/2015] [Indexed: 02/06/2023] Open
Abstract
AIM To evaluate the efficacy of pegylated interferon in Iranian chronic hepatitis C patients in relation to interferon-λ (IFNL) polymorphisms. METHODS This study enrolled patients with chronic hepatitis C referred to the Tehran Blood Transfusion Hepatitis Clinic in 2011. Patients were included in the study if they had no concomitant hepatic illness, were negative for human immunodeficiency virus antibodies, and had no prior history of treatment with any type of pegylated interferon. Patients were treated with 180 μg pegylated interferon alpha-2a (Pegaferon(®)) weekly and 800-1200 mg ribavirin daily for 24 or 48 wk depending on weight and hepatitis C virus (HCV) genotype. Blood samples were collected from patients to obtain DNA for determination of IFNL rs12979860 and rs8099917 polymorphisms. The virologic response in patients was then evaluated and compared between the different IFNL genotypes. RESULTS A total of 152 patients with a mean age of 41.9 ± 10.0 years were included in the study, of which 141/152 were men (92.8%). The most frequent HCV genotype was type-1, infecting 93/152 (61.2%) patients. Sustained virologic response (SVR) was achieved in 81.9% of patients with HCV genotype-1 and 91.1% of patients with HCV genotype-3. Treatment success was achieved in 91.2% (52/57) of patients with the IFNL rs12979860 CC genotype and 82.1% (78/95) in those with other genotypes. Similar treatment response rates were also observed in patients with rs8099917 TT (39/45; 86.7%) and non-TT (61/68; 89.7%) genotypes. Univariate analyses identified the following factors which influenced treatment response for inclusion in a multivariate analysis: age, HCV RNA level, stage of liver fibrosis, rs12979860 CC genotype, and aspartate transaminase level. A logistic regression analysis revealed that only the rs12979860 CC genotype was significantly associated with achievement of SVR (OR = 6.2; 95%CI: 1.2-31.9; P = 0.03). CONCLUSION The rs12979860 CC genotype was associated with SVR in patients receiving pegylated interferon plus ribavirin, however, the SVR rate in other rs12979860 genotypes was also relatively high.
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23
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Matsuura K, Tanaka Y. Host genetic variants influencing the clinical course of hepatitis C virus infection. J Med Virol 2015. [PMID: 26211651 DOI: 10.1002/jmv.24334] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
The clinical course of hepatitis C virus (HCV) infection greatly differs in individuals. Various viral, host, and environmental factors influence the natural history of HCV infection. Recent genome-wide association studies identified several host genetic factors influencing treatment efficacy or clinical course in HCV infection. A landmark discovery was that IFNL3-IFNL4 variants are strongly associated with responses to interferon-based treatment. Genetic variants in IFNL3-IFNL4 as well as those in HLA class II loci influence the spontaneous clearance of acute HCV infection. Interestingly, these genetic variants also affect the activity of hepatitis, or disease progression in chronic hepatitis C. In addition, polymorphisms in apoptosis-related genes such as RNF7, TULP1, and MERTK are associated with fibrosis progression, and DEPDC5 and MICA variants are associated with HCV-related hepatocellular carcinoma. Understanding the genetic factors associated with the clinical course of HCV infection is essential for personalized treatment and surveillance of disease progression and hepatocellular carcinoma.
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Affiliation(s)
- Kentaro Matsuura
- Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan.,Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan.,Department of Transfusion Medicine, Clinical CenterInfectious Disease and Immunogenetics Section, National Institutes of Health, Bethesda, Maryland
| | - Yasuhito Tanaka
- Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan
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24
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Rönsholt FF, Gerstoft J. Grazoprevir and elbasvir: a second-generation protease inhibitor and a second-generation NS5A inhibitor in a combination regimen for treatment of chronic hepatitis C. Future Virol 2015. [DOI: 10.2217/fvl.15.40] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
ABSTRACT The emergence of direct acting antivirals against HCV infection has provided the opportunity for interferon free, all oral treatments for HCV infection in patients with HCV genotype 1 (GT1). This review describes the current data on the combination of grazoprevir and elbasvir, a second-generation NS3/4A inhibitor and a second-generation NS5A inhibitor, respectively. The regimen has shown promising results in Phase II trials in patients with GT1 with response rates >90%, even in patient groups that have been challenging to treat, such as patients with cirrhosis, HIV co-infection and previous null responders to treatment with pegylated IFN-α + ribavirin. Grazoprevir + elbasvir treatment is well tolerated. Phase III trials and trials including infections with GT2–4 + 6 are ongoing.
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Affiliation(s)
| | - Jan Gerstoft
- Department of Infectious Diseases, 8632 Rigshospitalet, Copenhagen, Denmark
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25
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Sacks-Davis R, Grebely J, Dore GJ, Osburn W, Cox AL, Rice TM, Spelman T, Bruneau J, Prins M, Kim AY, McGovern BH, Shoukry NH, Schinkel J, Allen TM, Morris M, Hajarizadeh B, Maher L, Lloyd AR, Page K, Hellard M. Hepatitis C Virus Reinfection and Spontaneous Clearance of Reinfection--the InC3 Study. J Infect Dis 2015; 212:1407-19. [PMID: 25883387 DOI: 10.1093/infdis/jiv220] [Citation(s) in RCA: 73] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2014] [Accepted: 03/30/2015] [Indexed: 12/27/2022] Open
Abstract
BACKGROUND We aimed to characterize the natural history of hepatitis C virus (HCV) reinfection and spontaneous clearance following reinfection (reclearance), including predictors of HCV reclearance. METHODS Data were synthesized from the 9 prospective cohorts of the International Collaboration of Incident Human Immunodeficiency Virus and HCV in Injecting Cohorts study, which evaluated HCV infection outcomes among people who inject drugs. Participants with primary HCV infection were classified as having achieved viral suppression if they had negative results of at least 1 subsequent HCV RNA test. Those with positive results of an HCV RNA test following viral suppression were investigated for reinfection. Viral sequence analysis was used to identify reinfection (defined as detection of heterologous virus with no subsequent detection of the original viral strain). RESULTS Among 591 participants with acute primary HCV infection, 118 were investigated for reinfection. Twenty-eight participants were reinfected (12.3 cases/100 person-years; 95% confidence interval [CI], 8.5-17.8). Peak HCV RNA level was lower during reinfection than primary infection (P = .011). The proportion of individuals with reclearance 6 months after reinfection was 52% (95% CI, 33%-73%). After adjustment for study site, females with the IFNL4 (formerly IFNL3 and IL28B) rs12979860 CC genotype detected were more likely to have reclearance (hazard ratio, 4.16; 95% CI, 1.24-13.94; P = .021). CONCLUSIONS Sex and IFNL4 genotype are associated with spontaneous clearance after reinfection.
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Affiliation(s)
- Rachel Sacks-Davis
- Burnet Institute, Monash University, Melbourne Department of Epidemiology and Preventive Medicine, Monash University, Melbourne
| | - Jason Grebely
- The Kirby Institute, University of New South Wales, Sydney, Australia
| | - Gregory J Dore
- The Kirby Institute, University of New South Wales, Sydney, Australia
| | - William Osburn
- Department of Medicine, Johns Hopkins University, Baltimore, Maryland
| | - Andrea L Cox
- Department of Medicine, Johns Hopkins University, Baltimore, Maryland
| | - Thomas M Rice
- Department of Epidemiology and Biostatistics, University of California-San Francisco
| | - Timothy Spelman
- Burnet Institute, Monash University, Melbourne Department of Epidemiology and Preventive Medicine, Monash University, Melbourne
| | | | - Maria Prins
- GGD Public Health Service of Amsterdam, Amsterdam, The Netherlands Academic Medical Center, Amsterdam, The Netherlands
| | | | | | | | | | | | - Meghan Morris
- Department of Epidemiology and Biostatistics, University of California-San Francisco
| | | | - Lisa Maher
- The Kirby Institute, University of New South Wales, Sydney, Australia
| | - Andrew R Lloyd
- School of Medical Sciences, University of New South Wales, Sydney, Australia
| | - Kimberly Page
- Department of Epidemiology and Biostatistics, University of California-San Francisco
| | - Margaret Hellard
- Burnet Institute, Monash University, Melbourne Department of Epidemiology and Preventive Medicine, Monash University, Melbourne
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Hajarizadeh B, Grady B, Page K, Kim AY, McGovern BH, Cox AL, Rice TM, Sacks-Davis R, Bruneau J, Morris M, Amin J, Schinkel J, Applegate T, Maher L, Hellard M, Lloyd AR, Prins M, Dore GJ, Grebely J. Patterns of hepatitis C virus RNA levels during acute infection: the InC3 study. PLoS One 2015; 10:e0122232. [PMID: 25837807 PMCID: PMC4383375 DOI: 10.1371/journal.pone.0122232] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2014] [Accepted: 02/10/2015] [Indexed: 01/14/2023] Open
Abstract
BACKGROUND Understanding the patterns of HCV RNA levels during acute hepatitis C virus (HCV) infection provides insights into immunopathogenesis and is important for vaccine design. This study evaluated patterns of HCV RNA levels and associated factors among individuals with acute infection. METHODS Data were from an international collaboration of nine prospective cohorts of acute HCV (InC3 Study). Participants with well-characterized acute HCV infection (detected within three months post-infection and interval between the peak and subsequent HCV RNA levels ≤ 120 days) were categorised by a priori-defined patterns of HCV RNA levels: i) spontaneous clearance, ii) partial viral control with persistence (≥ 1 log IU/mL decline in HCV RNA levels following peak) and iii) viral plateau with persistence (increase or <1 log IU/mL decline in HCV RNA levels following peak). Factors associated with HCV RNA patterns were assessed using multinomial logistic regression. RESULTS Among 643 individuals with acute HCV, 162 with well-characterized acute HCV were identified: spontaneous clearance (32%), partial viral control with persistence (27%), and viral plateau with persistence (41%). HCV RNA levels reached a high viraemic phase within two months following infection, with higher levels in the spontaneous clearance and partial viral control groups, compared to the viral plateau group (median: 6.0, 6.2, 5.3 log IU/mL, respectively; P = 0.018). In the two groups with persistence, Interferon lambda 3 (IFNL3) CC genotype was independently associated with partial viral control compared to viral plateau (adjusted odds ratio [AOR]: 2.75; 95%CI: 1.08, 7.02). In the two groups with viral control, female sex was independently associated with spontaneous clearance compared to partial viral control (AOR: 2.86; 95%CI: 1.04, 7.83). CONCLUSIONS Among individuals with acute HCV, a spectrum of HCV RNA patterns is evident. IFNL3 CC genotype is associated with initial viral control, while female sex is associated with ultimate spontaneous clearance.
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Affiliation(s)
- Behzad Hajarizadeh
- The Kirby Institute, UNSW Australia (University of New South Wales), Sydney, NSW, Australia
| | - Bart Grady
- Cluster Infectious Diseases, GGD Public Health Service of Amsterdam, Amsterdam, The Netherlands
| | - Kimberly Page
- Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California, United States of America
| | - Arthur Y. Kim
- Harvard Medical School, Boston, Massachusetts, United States of America
| | - Barbara H. McGovern
- Tufts Medical School, Boston, Massachusetts, United States of America
- Abbvie, Chicago, Illinois, United States of America
| | - Andrea L. Cox
- Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, Maryland, United States of America
| | - Thomas M. Rice
- Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California, United States of America
| | - Rachel Sacks-Davis
- Burnet Institute, Melbourne, VIC, Australia
- Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Australia
| | - Julie Bruneau
- CRCHUM, Université de Montréal, Montreal, QC, Canada
| | - Meghan Morris
- Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California, United States of America
| | - Janaki Amin
- The Kirby Institute, UNSW Australia (University of New South Wales), Sydney, NSW, Australia
| | | | - Tanya Applegate
- The Kirby Institute, UNSW Australia (University of New South Wales), Sydney, NSW, Australia
| | - Lisa Maher
- The Kirby Institute, UNSW Australia (University of New South Wales), Sydney, NSW, Australia
| | - Margaret Hellard
- Burnet Institute, Melbourne, VIC, Australia
- Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Australia
| | - Andrew R. Lloyd
- Inflammation and Infection Research Centre, School of Medical Sciences, UNSW Australia, Sydney, NSW, Australia
| | - Maria Prins
- Cluster Infectious Diseases, GGD Public Health Service of Amsterdam, Amsterdam, The Netherlands
- Academic Medical Center, Amsterdam, The Netherlands
| | - Gregory J. Dore
- The Kirby Institute, UNSW Australia (University of New South Wales), Sydney, NSW, Australia
| | - Jason Grebely
- The Kirby Institute, UNSW Australia (University of New South Wales), Sydney, NSW, Australia
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Taheri S, Aygen B, Korkmaz K, Yıldız O, Zararsız G, Canatan H. Characterization of the Interleukin-28B Gene rs12979860 C/T Polymorphism in Turkish Chronic Hepatitis C Patients and Healthy Individuals. Balkan Med J 2015; 32:147-55. [PMID: 26167338 DOI: 10.5152/balkanmedj.2015.15156] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2014] [Accepted: 12/10/2014] [Indexed: 12/28/2022] Open
Abstract
BACKGROUND Host genetic factors can affect the progress of hepatitis-C virus (HCV) infection. Interleukin-28B (IL28B) single nucleotide polymorphisms may play an important role in the clearance of HCV spontaneously or with treatment. AIMS The aim of our study was to evaluate the rate of IL28B genotypes in patients with Chronic Hepatitis-C (CHC) and healthy control subjects and to examine the characteristics of patients in each IL28B subgroup. STUDY DESIGN Case-control study. METHODS IL28B polymorphisms were genotyped by Polymerase Chain Reaction and Restriction Fragment Length Polymorphism (PCR-RFLP) in all subjects. RESULTS The mean age was 52.3±10.9 years (33% female) in the CHC patients and 52.5±11.5 years (39.1% female) in the healthy controls. The percentage of patients with a high baseline viral load (≥400,000 IU/mL) was higher in the CT group (69.8%) compared to the C/C (44.4%) and T/T (50%) groups (p=0.021). There was no significant difference in liver fibrosis and liver necroinflammation distribution among the CC, CT and TT genotypes with mild, moderate and severe groups (p=0.058 and p=0.791, respectively). Mean age, gender ratio, body mass index, viral load at baseline, rate of HCV genotypes, baseline ALT levels were not significantly different among the three IL28B subgroups (p>0.05). A significant increase was observed in the frequencies of IL28B rs12979860 TT genotypes in the CHC patients (20.6%) compared to the healthy control group (8.7%) (p=0.033). CONCLUSION In the patients with chronic HCV-genotype 1b and 4 infections, the IL28B rs12979860 (C>T) gene polymorphism frequency of the TT genotype and T allele was higher than in healthy control subjects. This result indicates that the TT genotype may be more effective in the progression of HCV infection than other genotypes.
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Affiliation(s)
- Serpil Taheri
- Department of Medical Biology, Erciyes University Faculty of Medicine, Kayseri, Turkey ; Betül-Ziya Eren Genome and Stem Cell Center, Erciyes University, Kayseri, Turkey
| | - Bilgehan Aygen
- Department of Infectious Diseases and Clinical Microbiology, Erciyes University Faculty of Medicine, Kayseri, Turkey
| | - Keziban Korkmaz
- Betül-Ziya Eren Genome and Stem Cell Center, Erciyes University, Kayseri, Turkey
| | - Orhan Yıldız
- Department of Infectious Diseases and Clinical Microbiology, Erciyes University Faculty of Medicine, Kayseri, Turkey
| | - Gökmen Zararsız
- Department of Biostatistics, Erciyes University Faculty of Medicine, Kayseri, Turkey
| | - Halit Canatan
- Department of Medical Biology, Erciyes University Faculty of Medicine, Kayseri, Turkey
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Rossotti R, Baiguera C, Travi G, Pazzi A, Orso M, Puoti M. Acute HCV Infection: Diagnosis, Epidemiology and Current Treatment Options. CURRENT TREATMENT OPTIONS IN INFECTIOUS DISEASES 2015. [DOI: 10.1007/s40506-015-0045-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
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Moqueet N, Infante-Rivard C, Platt RW, Young J, Cooper C, Hull M, Walmsley S, Klein MB. Favourable IFNL3 genotypes are associated with spontaneous clearance and are differentially distributed in Aboriginals in Canadian HIV-hepatitis C co-infected individuals. Int J Mol Sci 2015; 16:6496-512. [PMID: 25803108 PMCID: PMC4394544 DOI: 10.3390/ijms16036496] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2015] [Revised: 03/13/2015] [Accepted: 03/13/2015] [Indexed: 12/13/2022] Open
Abstract
Canadian Aboriginals are reported to clear Hepatitis C (HCV) more frequently. We tested the association of spontaneous clearance and three single nucleotide polymorphisms (SNPs) near the Interferon-lambda 3 (IFNL3) gene (rs12979860, rs8099917, functional variant rs8103142) and compared the SNP frequencies between HIV-HCV co-infected whites and Aboriginals from the Canadian Co-infection Cohort. HCV treatment-naïve individuals with at least two HCV RNA tests were included (n = 538). A spontaneous clearance case was defined as someone with two consecutive HCV RNA-negative tests, at least six months apart. Data were analyzed using Cox proportional hazards adjusted for sex and ethnicity. Advantageous variants and haplotypes were more common in Aboriginals than Caucasians: 57% vs. 46% had the rs12979860 CC genotype, respectively; 58% vs. 48%, rs8103142 TT; 74% vs. 67%, the rs12979860 C allele; and 67% vs. 64% the TCT haplotype with three favourable alleles. The adjusted Hazard Ratios (95% CI) for spontaneous clearance were: rs12979860: 3.80 (2.20, 6.54); rs8099917: 5.14 (2.46, 10.72); and rs8103142: 4.36 (2.49, 7.62). Even after adjusting for rs12979860, Aboriginals and females cleared HCV more often, HR (95% CI) = 1.53 (0.89, 2.61) and 1.42 (0.79, 2.53), respectively. Our results suggest that favourable IFNL3 genotypes are more common among Aboriginals than Caucasians, and may partly explain the higher HCV clearance rates seen among Aboriginals.
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Affiliation(s)
- Nasheed Moqueet
- Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, QC H3A 1A2, Canada.
| | - Claire Infante-Rivard
- Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, QC H3A 1A2, Canada.
| | - Robert W Platt
- Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, QC H3A 1A2, Canada.
| | - Jim Young
- Basel Institute for Clinical Epidemiology and Biostatistics, University Hospital Basel, Basel 4031, Switzerland.
- Department of Medicine, Division of Infectious Diseases/Chronic Viral Illness Service, Royal Victoria Hospital, McGill University Health Centre, 3650 Saint-Urbain Street, Montreal, QC H2X 2P4, Canada.
| | - Curtis Cooper
- The Ottawa Hospital-Research Institute, Ottawa, ON K1Y 4E9, Canada.
| | - Mark Hull
- BC Centre for Excellence in HIV/AIDS, Vancouver, BC V6Z 1Y6, Canada.
| | - Sharon Walmsley
- Toronto General Research Institute, University Health Network, University of Toronto, Toronto, ON M5G 2M9, Canada.
| | - Marina B Klein
- Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, QC H3A 1A2, Canada.
- Department of Medicine, Division of Infectious Diseases/Chronic Viral Illness Service, Royal Victoria Hospital, McGill University Health Centre, 3650 Saint-Urbain Street, Montreal, QC H2X 2P4, Canada.
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Grygorczuk S, Parczewski M, Moniuszko A, Świerzbińska R, Kondrusik M, Zajkowska J, Czupryna P, Dunaj J, Boroń-Kaczmarska A, Pancewicz S. Increased concentration of interferon lambda-3, interferon beta and interleukin-10 in the cerebrospinal fluid of patients with tick-borne encephalitis. Cytokine 2015; 71:125-31. [PMID: 25461389 DOI: 10.1016/j.cyto.2014.10.001] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2014] [Revised: 10/01/2014] [Accepted: 10/04/2014] [Indexed: 12/16/2022]
Abstract
Tick-borne encephalitis (TBE) has a wide clinical spectrum, from asymptomatic to severe encephalitis, and host-dependent factors determining the outcome remain elusive. We have measured concentrations of pro-inflammatory/Th1 interferon-γ (IFNγ), immunomodulatory/Th2 interleukin-10 (IL-10), anti-viral type I (IFNβ) and type III (IFNλ3) interferons in cerebrospinal fluid (csf) and serum of 18 TBE patients, simultaneously genotyped for polymorphisms associated with the expression of genes IFNL3 (coding IFNλ3), IL10, CD209 and CCR5. IL-10, IFNβ and IFNλ3 were up-regulated in csf, with IFNλ3 level higher in patients with the milder clinical presentation (meningitis) than in meningoencephalitis. There was an increased serum IFNβ and a tendency for increased serum IL-10 in meningitis patients. Genotype in rs12979860 locus upstream of IFNL3 was associated with IFNλ3 expression and in rs287886 (CD209) - IL-10 expression. IL-10, IFNβ and IFNλ3 are expressed and play a protective role in TBE and their expression in TBE patients is associated with genetic polymorphisms.
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Affiliation(s)
- Sambor Grygorczuk
- Medical University in Białystok, Department of the Infectious Diseases and Neuroinfections, ul. Żurawia 14, 15-540 Białystok, Poland.
| | - Miłosz Parczewski
- Pomeranian Medical University, Department of the Infectious Diseases and Hepatology, ul. Arkońska 4, 71-455 Szczecin, Poland
| | - Anna Moniuszko
- Medical University in Białystok, Department of the Infectious Diseases and Neuroinfections, ul. Żurawia 14, 15-540 Białystok, Poland
| | - Renata Świerzbińska
- Medical University in Białystok, Department of the Infectious Diseases and Neuroinfections, ul. Żurawia 14, 15-540 Białystok, Poland
| | - Maciej Kondrusik
- Medical University in Białystok, Department of the Infectious Diseases and Neuroinfections, ul. Żurawia 14, 15-540 Białystok, Poland
| | - Joanna Zajkowska
- Medical University in Białystok, Department of the Infectious Diseases and Neuroinfections, ul. Żurawia 14, 15-540 Białystok, Poland
| | - Piotr Czupryna
- Medical University in Białystok, Department of the Infectious Diseases and Neuroinfections, ul. Żurawia 14, 15-540 Białystok, Poland
| | - Justyna Dunaj
- Medical University in Białystok, Department of the Infectious Diseases and Neuroinfections, ul. Żurawia 14, 15-540 Białystok, Poland
| | - Anna Boroń-Kaczmarska
- Pomeranian Medical University, Department of the Infectious Diseases and Hepatology, ul. Arkońska 4, 71-455 Szczecin, Poland
| | - Sławomir Pancewicz
- Medical University in Białystok, Department of the Infectious Diseases and Neuroinfections, ul. Żurawia 14, 15-540 Białystok, Poland
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Dong ZX, Zhou HJ, Xiang XG, Guo SM, Zhuang Y, Zhao GD, Xie Q. IL28B genetic variations are associated with treatment response of patients with chronic hepatitis C in a Chinese Han population. J Dig Dis 2015; 16:90-7. [PMID: 25312023 DOI: 10.1111/1751-2980.12202] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES This study aimed to investigate the association between interleukin 28B (IL28B) single nucleotide polymorphisms (SNPs) and sustained virological response (SVR) in Chinese Han patients with chronic hepatitis C (CHC) and to analyze the correlations between IL28B SNPs and their personal, virological and clinical characteristics. METHODS Altogether 631 Chinese Han individuals, including 297 CHC patients treated with pegylated interferon α plus ribavirin, 14 spontaneous responders to hepatitis C virus (HCV) and 320 healthy controls were enrolled in the study. Two main SNPs of IL28B, rs12979860 and rs8099917, were genotyped using an SNaPshot Multiplex Assay. Associations between IL28B, treatment outcomes and the patients' characteristics were assessed by multivariate logistic regression. RESULTS The proportion of individuals with the rs12979860 CC or rs8099917 TT genotype was similar in the healthy controls and the CHC patients, although all spontaneous responders presented with both genotypes. Patients with IL28B genotypes had a significantly high rate of rapid virological response (RVR) and SVR. Multivariate analysis revealed that the IL28B SNP rs12979860 CC genotype, being aged <40 years and having a non-genotype 1 (G1) were independent predictors for SVR. The rs12979860 CC genotype and rs8099917 TT genotypes were predictors for RVR. The rs12979860 CC and rs8099917 TT genotypes were more prevalent in patients with a non-G1 genotype than those with G1 genotype. CONCLUSIONS IL28B rs12979860 CC genotype is a significant predictor for SVR and RVR in Chinese Han patients with CHC. Non-G1 HCV genotype is associated with favourable IL28B genotypes.
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Affiliation(s)
- Zhi Xia Dong
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
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Boesecke C, Rockstroh JK. How will we manage acute HCV in men having sex with men in the era of all oral therapy? J Viral Hepat 2015; 22:2-7. [PMID: 25333810 DOI: 10.1111/jvh.12348] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2014] [Accepted: 09/09/2014] [Indexed: 01/22/2023]
Abstract
With the advent of direct-acting antivirals (DAAs), the treatment of chronic hepatitis C virus (HCV) infection (CHC) has been revolutionized. Modern interferon- and potentially also ribavirin-free combinations consisting of 2 or 3 direct-acting antivirals (DAA) promise sustained virological response rates (SVR) of above 90%. This coincides with much shorter treatment durations and a much more favorable toxicity profile. Some DAAs even work across all HCV genotypes (pangenotypic) [BMJ, 349, 2014, g3308]. And lastly, HCV treatment in HIV-coinfected patients will no longer differ from HCV-monoinfected patients as response rates under DAA in the setting of HCV-HIV coinfection have been as good as in HCV-monoinfected patients [J Hepatol, 61, 2014, 373]. Only drug-drug interactions with the new DAAs and concomitant antiretroviral therapy have to be accounted for due to shared metabolization pathways via the cytochrome p450 system.
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Affiliation(s)
- C Boesecke
- Department of Internal Medicine I, Bonn University Hospital, Bonn, Germany
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Fateh A, Aghasadeghi MR, Keyvani H, Mollaie HR, Yari S, Hadizade Tasbiti AR, Ghazanfari M, Monavari SHR. High resolution melting curve assay for detecting rs12979860 IL28B polymorphisms involved in response of Iranian patients to chronic hepatitis C treatment. Asian Pac J Cancer Prev 2015; 16:1873-80. [PMID: 25773839 DOI: 10.7314/apjcp.2015.16.5.1873] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/13/2023] Open
Abstract
BACKGROUND A recent genome-wide association study (GWAS) on patients with chronic hepatitis C (CHC) treated with peginterferon and ribavirin (pegIFN-α/RBV) identified a single nucleotide polymorphism (SNP) on chromosome 19 (rs12979860) which was strongly associated with a sustained virological response (SVR). The aim of this study was twofold: to study the relationship between IL28B rs12979860 and sustained virological response (SVR) to pegIFN-α/RVB therapy among CHC patients and to detect the rs12979860 polymorphism by high resolution melting curve (HRM) assay as a simple, fast, sensitive, and inexpensive method. MATERIALS AND METHODS The study examined outcomes in 100 patients with chronic hepatitis C in 2 provinces of Iran from December 2011 to June 2013. Two methods were applied to detect IL28B polymorphisms: PCR-sequencing as a gold standard method and HRM as a simple, fast, sensitive, and inexpensive method. RESULTS The frequencies of IL28B rs12979860 CC, CT, and TT alleles in chronic hepatitis C genotype 1a patients were 10% (10/100), 35% (35/100), and 6% (6/100) and in genotype 3a were 13% (13/100), 31% (31/100), and 5% (5/100), respectively. In genotype 3a infected patients, rs12979860 (CC and CT alleles) and in genotype 1a infected patients (CC allele) were significantly associated with a sustained virological response (SVR). The SVR rates for CC, CT and TT (IL28B rs12979860) were 18%, 34% and 4%, respectively. Multiple logistic regression analysis identified two independent factors that were significantly associated with SVR: IL-28B genotype (rs 12979860 CC vs TT and CT; odds ratio [ORs], 7.86 and 4.084, respectively), and HCV subtype 1a (OR, 7.46). In the present study, an association between SVR rates and IL28B polymorphisms was observed. CONCLUSIONS The HRM assay described herein is rapid, inexpensive, sensitive and accurate for detecting rs12979860 alleles in CHC patients. This method can be readily adopted by any molecular diagnostic laboratory with HRM capability and will be clinically beneficial in predicting treatment response in HCV genotype 1 and 3 infected patients. In addition, it was demonstrated that CC and CT alleles in HCV-3a and the CC allele in HCV-1a were significantly associated with response to pegIFN-α/RBV treatment. The present results may help identify subjects for whom the therapy might be successful.
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Affiliation(s)
- Abolfazl Fateh
- Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran E-mail :
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Shaker O, Rashad A, Abd El Aziz G, El Raziky M. Is rs8099917 polymorphism of IL-28B gene a good predictor of response to therapy of HCV than rs12979860? An Egyptian study. Cell Biochem Biophys 2015; 71:307-14. [PMID: 25115611 DOI: 10.1007/s12013-014-0199-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
Hepatitis C virus (HCV) infection is the major etiology of chronic liver disease. Polymorphisms in the IL-28B gene region are important in predicting outcome following therapy for chronic hepatitis C virus infection. The aim of this study was to detect the relationship between IL-28B polymorphism and responses to therapy in patients infected with genotype 4. This study included one hundred chronic hepatitis C patients infected with genotype 4, received PEG-IFNα2b plus ribavirin for 24 weeks, as well as, 20 healthy subjects serving as control. Clinical and laboratory parameters, including genetic variation near the IL-28B gene (rs8099917 and rs12979860), were assessed. The results of this study showed significant difference between responders and non-responders as regard SNPs in the interleukin 28B gene at rs8099917 and rs12979860. In rs8099917, TT genotypes had more frequency in responders than GG genotypes. On the other hand, CC genotype in rs12979860 had more frequency in responders than TT genotype. By multiple regression analysis, rs8099917 (TT), total bilirubin, and prothrombin time were independent factors affecting the response to treatment. This results demonstrate that in HCV genotype 4-infected patients, rs12979860 (CC) and rs8099917 (TT) genotypes may identify patients who are likely to respond to treatment. IL-28B SNPs are good predictors of response to combination therapy of HCV.
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Affiliation(s)
- Olfat Shaker
- Medical Biochemistry and Molecular Biology, Faculty of Medicine, Cairo University, Giza, Egypt,
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Aygen B, Yildiz O, Akhan S, Gunal O, Taheri S, Zararsiz G, Sayan M, Rustemoglu A, Altinok ES. Impact of Interleukin 28B Genotype on the Virological Responses in Chronic Hepatitis C Treatment. Gastroenterology Res 2014; 7:123-130. [PMID: 27785282 PMCID: PMC5040535 DOI: 10.14740/gr629e] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/30/2014] [Indexed: 12/24/2022] Open
Abstract
Background Interleukin (IL) 28B single nucleotide polymorphisms may play a role in the clearance of hepatitis C virus (HCV). We aimed to evaluate the treatment response of chronic HCV infection patients to pegile interferon (pegIFN) and ribavirin treatment with regard to IL28B rs12979860 C/T polymorphism. Methods A total of 186 patients (mean age, 55.6 ± 10 years; 65.1% female) who underwent pegIFN and ribavirin treatment for chronic HCV infection were studied. We analyzed demographics, HCV genotype, baseline alanine aminotransferase (ALT) levels, histopathological data, viral load before treatment and at 4, 12, 24, 48, and 72 weeks from the treatment start, and IL28B genotype. IL28B polymorphism was genotyped using polymerase chain reaction based restriction fragment length polymorphism (PCR-RFLP) in all the subjects. Results One hundred forty-five (86.8%) patients were infected with viral genotype 1b, and 13.2% were infected with viral genotype 4. The rates of C/C, C/T, and T/T genotypes were 22.6%, 52.7%, and 24.7% respectively. The percentage of patients with a viral load over 400,000 IU/mL was higher in the C/T group (P = 0.020). Of the patients, 44.6% provided sustained virological response (SVR) to pegIFN and ribavirin combination treatment. The frequency of T allele was 41% in patients with SVR, whereas 59% patients provided no response (P < 0.001). SVR was obtained in 66.7%, 42.9%, and 28.3% of CC, CT, and TT groups (P = 0.001). The rates of rapid virological response (RVR), early virological response (EVR), end-of-treatment response (ETR), and SVR were higher in the CC group than other groups (P = 0.216, P < 0.001, P = 0.001, P = 0.001, respectively). The relapse and null response (NR) rates were higher in TT group and partial response rate (PR) was higher in CT group. Conclusions IL28B rs12979860 C/T gene polymorphism affects the response to antiviral treatment in the patients with chronic HCV genotypes 1b and 4 infections.
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Affiliation(s)
- Bilgehan Aygen
- Department of Infectious Diseases and Clinical Microbiology, Medical School of Erciyes University, Kayseri, Turkey
| | - Orhan Yildiz
- Department of Infectious Diseases and Clinical Microbiology, Medical School of Erciyes University, Kayseri, Turkey
| | - Sila Akhan
- Kocaeli University Medical Faculty Infectious Diseases and Clinical Microbiology, Kocaeli, Turkey
| | - Ozgur Gunal
- Department of Infectious Diseases and Clinical Microbiology, Medical School of Gaziosmanpasa University, Tokat, Turkey
| | - Serpil Taheri
- Erciyes University Betul Ziya Eren Genome and Stem Cell Center, Kayseri, Turkey
| | - Gokmen Zararsiz
- Department of Biostatistics, Medical School of Erciyes University, Kayseri, Turkey
| | - Murat Sayan
- Department of Infectious Diseases and Clinical Microbiology, Medical School of Kocaeli University, Kocaeli, Turkey
| | - Aydin Rustemoglu
- Gaziosmanpasa University Medical Faculty, Department of Medical Biology, Tokat, Turkey
| | - Elif Sargin Altinok
- Department of Infectious Diseases and Clinical Microbiology, Medical School of Kocaeli University, Kocaeli, Turkey
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Hajarizadeh B, Grady B, Page K, Kim AY, McGovern BH, Cox AL, Rice TM, Sacks-Davis R, Bruneau J, Morris M, Amin J, Schinkel J, Applegate T, Maher L, Hellard M, Lloyd AR, Prins M, Geskus RB, Dore GJ, Grebely J. Interferon lambda 3 genotype predicts hepatitis C virus RNA levels in early acute infection among people who inject drugs: the InC(3) study. J Clin Virol 2014; 61:430-4. [PMID: 25256151 PMCID: PMC4279031 DOI: 10.1016/j.jcv.2014.08.027] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2014] [Revised: 08/25/2014] [Accepted: 08/28/2014] [Indexed: 12/23/2022]
Abstract
BACKGROUND AND OBJECTIVES Hepatitis C virus (HCV) RNA level in acute HCV infection is predictive of spontaneous clearance. This study assessed factors associated with HCV RNA levels during early acute infection among people who inject drugs with well-defined acute HCV infection. STUDY DESIGN Data were from International Collaboration of Incident HIV and Hepatitis C in Injecting Cohorts (InC(3)) Study, an international collaboration of nine prospective cohorts studying acute HCV infection. Individuals with available HCV RNA levels during early acute infection (first two months following infection) were included. The distribution of HCV RNA levels during early acute infection were compared by selected host and virological factors. RESULTS A total of 195 individuals were included. Median HCV RNA levels were significantly higher among individuals with interferon lambda 3 (IFNL3, formerly called IL28B) CC genotype compared to those with TT/CT genotype (6.28 vs. 5.39logIU/mL, respectively; P=0.01). IFNL3 CC genotype was also associated with top tertile HCV RNA levels (≥6.3log IU/mL; vs. TT/CT genotype; adjusted Odds Ratio: 4.28; 95%CI: 2.01, 9.10; P<0.01). CONCLUSIONS This study indicates that IFNL3 CC genotype predicts higher HCV RNA levels in early acute HCV infection.
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Affiliation(s)
| | - Bart Grady
- Cluster Infectious Diseases, GGD Public Health Service of Amsterdam, Amsterdam, The Netherlands
| | - Kimberly Page
- Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA
| | | | | | - Andrea L Cox
- Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, MD, USA
| | - Thomas M Rice
- Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA
| | - Rachel Sacks-Davis
- Burnet Institute, Melbourne, VIC, Australia; Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, VIC, Australia
| | - Julie Bruneau
- CRCHUM, Université de Montréal, Montreal, QC, Canada
| | - Meghan Morris
- Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA
| | - Janaki Amin
- The Kirby Institute, UNSW Australia, Sydney, NSW, Australia
| | | | | | - Lisa Maher
- The Kirby Institute, UNSW Australia, Sydney, NSW, Australia
| | - Margaret Hellard
- Burnet Institute, Melbourne, VIC, Australia; Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, VIC, Australia
| | - Andrew R Lloyd
- Inflammation and Infection Research Centre, School of Medical Sciences, UNSW Australia, Sydney, NSW, Australia
| | - Maria Prins
- Cluster Infectious Diseases, GGD Public Health Service of Amsterdam, Amsterdam, The Netherlands; Academic Medical Center, Amsterdam, The Netherlands
| | - Ronald B Geskus
- Cluster Infectious Diseases, GGD Public Health Service of Amsterdam, Amsterdam, The Netherlands; Academic Medical Center, Amsterdam, The Netherlands
| | - Gregory J Dore
- The Kirby Institute, UNSW Australia, Sydney, NSW, Australia
| | - Jason Grebely
- The Kirby Institute, UNSW Australia, Sydney, NSW, Australia
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Sharafi H, Alavian SM, Behnava B, Pouryasin A, Keshvari M. The Impact of IFNL4 rs12979860 Polymorphism on Spontaneous Clearance of Hepatitis C; A Case-Control Study. HEPATITIS MONTHLY 2014; 14:e22649. [PMID: 25419220 PMCID: PMC4238152 DOI: 10.5812/hepatmon.22649] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/09/2014] [Revised: 09/08/2014] [Accepted: 09/08/2014] [Indexed: 12/11/2022]
Abstract
BACKGROUND About 30% of individuals with hepatitis C virus (HCV) infection are able to clear HCV spontaneously. Differences in host genetics affect the outcome of HCV infection. Single nucleotide polymorphisms (SNPs) of the Interferon lambda (IFNL) genes were associated with spontaneous and treatment-induced clearance of HCV infection. OBJECTIVES The aim of this study was to evaluate the association between the IFNL4 rs12979860 SNP and spontaneous clearance of HCV infection in Iranian population. MATERIALS AND METHODS A case-control study was designed on 91 cases with spontaneous HCV infection clearance and 259 patients with persistent HCV infection as the control group. The rs12979860 SNP was assessed as the most common IFNL polymorphism by PCR-RFLP method. RESULTS Distribution of rs12979860 CC genotype in the spontaneous clearance group was around two folds of its distribution in chronic hepatitis C group (P < 0.001, OR = 4.09, 95% CI = 2.44-6.86). CONCLUSIONS The rs12979860 SNP was observed as a strong host genetic factor associated with spontaneous clearance of hepatitis C infection.
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Affiliation(s)
- Heidar Sharafi
- Iran Hepatitis Network, Tehran, IR Iran
- Middle East Liver Disease (MELD) Center, Tehran, IR Iran
- Armin Pathobiology Laboratory, Tehran, IR Iran
| | - Seyed Moayed Alavian
- Iran Hepatitis Network, Tehran, IR Iran
- Middle East Liver Disease (MELD) Center, Tehran, IR Iran
| | - Bita Behnava
- Iran Hepatitis Network, Tehran, IR Iran
- Middle East Liver Disease (MELD) Center, Tehran, IR Iran
| | - Ali Pouryasin
- Iran Hepatitis Network, Tehran, IR Iran
- Armin Pathobiology Laboratory, Tehran, IR Iran
- Department of Genetics, Islamic Azad University-Arsanjan Branch, Arsanjan, IR Iran
| | - Maryam Keshvari
- Iran Hepatitis Network, Tehran, IR Iran
- Middle East Liver Disease (MELD) Center, Tehran, IR Iran
- Blood Transfusion Research Center, High Institute for Research and Education in Transfusion Medicine, Tehran, IR Iran
- Corresponding Author: Maryam Keshvari, Blood Transfusion Research Center, High Institute for Research and Education in Transfusion Medicine, Tehran, IR Iran. Tel: +98-2188601501, Fax: +98-2166900386, E-mail:
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Ansaldi F, Orsi A, Sticchi L, Bruzzone B, Icardi G. Hepatitis C virus in the new era: Perspectives in epidemiology, prevention, diagnostics and predictors of response to therapy. World J Gastroenterol 2014; 20:9633-9652. [PMID: 25110404 PMCID: PMC4123355 DOI: 10.3748/wjg.v20.i29.9633] [Citation(s) in RCA: 110] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2013] [Revised: 04/18/2014] [Accepted: 05/19/2014] [Indexed: 02/06/2023] Open
Abstract
Despite the great successes achieved in the fields of virology and diagnostics, several difficulties affect improvements in hepatitis C virus (HCV) infection control and eradication in the new era. New HCV infections still occur, especially in some of the poorest regions of the world, where HCV is endemic and long-term sequelae have a growing economic and health burden. An HCV vaccine is still no available, despite years of researches and discoveries about the natural history of infection and host-virus interactions: several HCV vaccine candidates have been developed in the last years, targeting different HCV antigens or using alternative delivery systems, but viral variability and adaption ability constitute major challenges for vaccine development. Many new antiviral drugs for HCV therapy are in preclinical or early clinical development, but different limitations affect treatment validity. Treatment predictors are important tools, as they provide some guidance for the management of therapy in patients with chronic HCV infection: in particular, the role of host genomics in HCV infection outcomes in the new era of direct-acting antivirals may evolve for new therapeutic targets, representing a chance for modulated and personalized treatment management, when also very potent therapies will be available. In the present review we discuss the most recent data about HCV epidemiology, the new perspectives for the prevention of HCV infection and the most recent evidence regarding HCV diagnosis, therapy and predictors of response to it.
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Quiles-Pérez R, Pavón-Castillero EJ, Muñoz-de-Rueda P, Carmona I, Salmerón J. Valor de la genética en la era de la terapia triple frente al virus de la hepatitis C. GASTROENTEROLOGIA Y HEPATOLOGIA 2014; 37:427-37. [PMID: 24948442 DOI: 10.1016/j.gastrohep.2014.04.004] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/29/2014] [Revised: 04/09/2014] [Accepted: 04/15/2014] [Indexed: 12/19/2022]
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Mao XR, Zhang LT, Chen H, Xiao P, Zhang YC. Correlation between the genetic variations in interleukin 28B and chronic hepatitis C virus genotypes in the Chinese population. Mol Med Rep 2014; 10:1037-45. [PMID: 24840747 DOI: 10.3892/mmr.2014.2242] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2013] [Accepted: 03/05/2014] [Indexed: 12/24/2022] Open
Abstract
Genetic variations at the interleukin 28B (IL-28B) locus and chronic hepatitis C virus (HCV) genotypes are significant factors in predicting the therapeutic outcome for HCV infection. The present study aimed to determine the geographical distribution of HCV genotypes and single nucleotide polymorphisms (SNPs) associated with IL-28B in Chinese patients infected with HCV. The gene frequencies of 13 types of IL-28B SNPs and HCV genotypes were investigated in 1,014 patients infected with HCV, who were recruited from varying regions of China. The correlation between the SNPs of IL-28B, the HCV genotypes and age, gender and geographical location were investigated. The data revealed geographical differences in age, gender and HCV genotypes in the Chinese HCV patients. HCV genotype 1 was distributed extensively and had a higher incidence compared with other HCV genotypes in all regions, with the exception of South (38%) and Northwest China (45.6%). A gender differences also existed (P<0.01). The distribution of genotype 6 was lower compared with other HCV genotypes in the majority of the regions (P<0.01). In middle‑aged patients, the number of male patients was higher than the number of female patients in North and South China, which was the opposite of the results found in the other regions. There were no geographical differences in IL-28B SNPs in Chinese HCV‑infected populations. Notably, there were significant differences between HCV genotype 1 and 2 in the genotype percentages of the majority of SNPs (P<0.01). In conclusion, a geographical distribution in HCV genotypes and a correlation between HCV genotypes and IL-28B SNPs have been identified, and indicate that these variants may be associated with spontaneous and treatment-induced HCV clearance.
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Affiliation(s)
- Xiao-Rong Mao
- Department of General Surgery, The Second Hospital of Lanzhou University, Lanzhou, Gansu, P.R. China
| | - Li-Ting Zhang
- Department of Infectious Diseases, The First Hospital of Lanzhou University, Lanzhou, Gansu, P.R. China
| | - Hong Chen
- Department of Infectious Diseases, The First Hospital of Lanzhou University, Lanzhou, Gansu, P.R. China
| | - Ping Xiao
- Department of Infectious Diseases, The First Hospital of Lanzhou University, Lanzhou, Gansu, P.R. China
| | - You-Cheng Zhang
- Department of General Surgery, The Second Hospital of Lanzhou University, Lanzhou, Gansu, P.R. China
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41
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Fernández Rodriguez CM, Gutierrez Garcia ML. [Impact of antiviral therapy on the natural history of hepatitis C virus]. GASTROENTEROLOGIA Y HEPATOLOGIA 2014; 37:583-92. [PMID: 25066318 DOI: 10.1016/j.gastrohep.2014.05.010] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/21/2014] [Accepted: 05/28/2014] [Indexed: 02/08/2023]
Abstract
Chronic hepatitis C virus infection affects around 150 million persons, and 350,000 persons worldwide die of this disease each year. Although the data on its natural history are incomplete, after the acute infection, most patients develop chronic forms of hepatitis C with variable stages of fibrosis. In these patients, continual inflammatory activity can cause significant fibrosis, cirrhosis, decompensation of the liver disease, or hepatocarcinoma. In the next few years, it is expected that hepatitis C virus infection and its complications will significantly increase, as will the incidence of hepatocarcinoma in Spain. This review presents the data on the natural history of hepatitis C virus infection and discusses the potential impact of antiviral therapy on the distinct stages of the disease.
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Hajarizadeh B, Grebely J, Applegate T, Matthews GV, Amin J, Petoumenos K, Hellard M, Rawlinson W, Lloyd A, Kaldor J, Dore GJ. Dynamics of HCV RNA levels during acute hepatitis C virus infection. J Med Virol 2014; 86:1722-9. [PMID: 25042465 DOI: 10.1002/jmv.24010] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/06/2014] [Indexed: 12/20/2022]
Abstract
Understanding viral dynamics during acute hepatitis C virus (HCV) infection can provide important insights into immunopathogenesis and guide early treatment. The aim of this study was to investigate the dynamics of HCV RNA and alanine transaminase (ALT) levels during recent HCV infection in the Australian Trial in Acute Hepatitis C (ATAHC). ATAHC was a prospective study of the natural history of recently acquired HCV infection. Longitudinal HCV RNA and ALT levels were compared among individuals with persistent infection and spontaneous clearance. Among those with HCV persistence (n = 104) and HCV clearance (n = 30), median HCV RNA (5.2 vs. 4.1 log IU/ml, respectively) and ALT levels (779 vs. 1,765 IU/L, respectively) were high during month two following infection, and then declined during months three and four in both groups. Among those with HCV persistence, median HCV RNA was 2.9 log IU/ml during months four, increased to 5.5 log IU/ml during month five, and remained subsequently relatively stable. Among those with HCV clearance, median HCV RNA was undetectable by month five. Median HCV RNA levels were comparable between individuals with HCV persistence and HCV clearance during month three following infection (3.2 vs. 3.5 log IU/ml, respectively; P = 0.935), but markedly different during month five (5.5 vs. 1.0 log IU/ml, respectively; P < 0.001). In conclusion, dynamics of HCV RNA levels in those with HCV clearance and HCV persistence diverged between months three and five following infection, with the latter time-point being potentially useful for commencing early treatment.
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Affiliation(s)
- Behzad Hajarizadeh
- The Kirby Institute, UNSW Australia (The University of New South Wales), Sydney, Australia
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Kamal SM. Pharmacogenetics of hepatitis C: transition from interferon-based therapies to direct-acting antiviral agents. Hepat Med 2014; 6:61-77. [PMID: 25114601 PMCID: PMC4075960 DOI: 10.2147/hmer.s41127] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Hepatitis C virus (HCV) has emerged as a major viral pandemic over the past two decades, infecting 170 million individuals, which equates to approximately 3% of the world’s population. The prevalence of HCV varies according to geographic region, being highest in developing countries such as Egypt. HCV has a high tendency to induce chronic progressive liver damage in the form of hepatic fibrosis, cirrhosis, or liver cancer. To date, there is no vaccine against HCV infection. Combination therapy comprising PEGylated interferon-alpha and ribavirin has been the standard of care for patients with chronic hepatitis C for more than a decade. However, many patients still do not respond to therapy or develop adverse events. Recently, direct antiviral agents such as protease inhibitors, polymerase inhibitors, or NS5A inhibitors have been used to augment PEGylated interferon and ribavirin, resulting in better efficacy, better tolerance, and a shorter treatment duration. However, most clinical trials have focused on assessing the efficacy and safety of direct antiviral agents in patients with genotype 1, and the response of other HCV genotypes has not been elucidated. Moreover, the prohibitive costs of such triple therapies will limit their use in patients in developing countries where most of the HCV infection exists. Understanding the host and viral factors associated with viral clearance is necessary for individualizing therapy to maximize sustained virologic response rates, prevent progression to liver disease, and increase the overall benefits of therapy with respect to its costs. Genome wide studies have shown significant associations between a set of polymorphisms in the region of the interleukin-28B (IL28B) gene and natural clearance of HCV infection or after PEGylated interferon-alpha and ribavirin treatment with and without direct antiviral agents. This paper synthesizes the recent advances in the pharmacogenetics of HCV infection in the era of triple therapies.
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Affiliation(s)
- Sanaa M Kamal
- Department of Medicine, Division of Hepatology, Gastroenterology and Tropical Medicine, Ain Shams Faculty of Medicine, Cairo, Egypt ; Department of Medicine, Salman Bin Abdul Aziz College of Medicine, Kingdom of Saudi Arabia
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Ishikane M, Watanabe K, Tsukada K, Nozaki Y, Yanase M, Igari T, Masaki N, Kikuchi Y, Oka S, Gatanaga H. Acute hepatitis C in HIV-1 infected Japanese Cohort: single center retrospective cohort study. PLoS One 2014; 9:e100517. [PMID: 24945812 PMCID: PMC4063971 DOI: 10.1371/journal.pone.0100517] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2014] [Accepted: 05/25/2014] [Indexed: 01/25/2023] Open
Abstract
OBJECTIVES HCV co-infection is a poor prognostic factor in HIV-1-infected patients. Although the number of newly reported patients who show seroconversion is increasing, the clinical features are still unclear, especially in Asian countries. DESIGN A single-center retrospective cohort study of patients diagnosed between 2001-2012. METHODS Acute hepatitis C (AHC) was diagnosed upon detection of high serum ALT (>100 IU) followed by anti-HCV seroconversion. Clinical characteristics, HIV-1-related immunological status and IL-28B genotypes (rs12979860, rs8099917) were collected. We compared these variables between patients with and without spontaneous clearance of HCV and between responders and non-responders to treatment with pegylated interferon (PEG-IFN) plus ribavirin. RESULTS Thirty-five patients were diagnosed with AHC during the study period. The majority (96.9%) were MSM. Three were lost to follow-up. Seventy-five percent of patients with AHC (24/32) were asymptomatic and found incidentally to have high serum ALT. Compared to those who did not show spontaneous clearance, patients with spontaneous HCV viral clearance showed more symptoms and more severe abnormalities related to acute hepatitis. Spontaneous clearance was seen in 4 out of 28 patients with CC+TT genotype, but not in 6 patients with IL-28B CT+TG genotype. PEG-IFN plus ribavirin treatment was initiated in 12 out of 28 cases without spontaneous clearance. The sustained virological response rate was high (81.8%, 9/11), even in cases with CT+TG genotype infected with HCV genotype 1b (SVR 2/2). CONCLUSIONS Careful attention to AHC is needed in HIV-1-infected MSM. Early diagnosis and PEG-IFN plus ribavirin treatment should be considered for AHC cases.
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Affiliation(s)
- Masahiro Ishikane
- AIDS Clinical Center, National Center for Global Health and Medicine, Tokyo, Japan
- Field Epidemiology Training Program Japan, Infectious Disease Surveillance Center, National Institute of Infectious Diseases, Tokyo, Japan
- Global Infectious Diseases of Infection and Epidemiology, Medical Sciences Doctoral Program, Graduate School of Medicine, Tohoku University, Miyagi, Japan
| | - Koji Watanabe
- AIDS Clinical Center, National Center for Global Health and Medicine, Tokyo, Japan
- Center for AIDS Research, Kumamoto University, Kumamoto, Japan
| | - Kunihisa Tsukada
- AIDS Clinical Center, National Center for Global Health and Medicine, Tokyo, Japan
| | - Yuichi Nozaki
- Department of Gastroenterology, National Center for Global Health and Medicine, Tokyo, Japan
| | - Mikio Yanase
- Department of Gastroenterology, National Center for Global Health and Medicine, Tokyo, Japan
| | - Toru Igari
- Pathology Division of Clinical Laboratory, National Center for Global Health and Medicine, Tokyo, Japan
| | - Naohiko Masaki
- Department of Gastroenterology, National Center for Global Health and Medicine, Tokyo, Japan
- Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Tokyo, Japan
| | - Yoshimi Kikuchi
- AIDS Clinical Center, National Center for Global Health and Medicine, Tokyo, Japan
| | - Shinichi Oka
- AIDS Clinical Center, National Center for Global Health and Medicine, Tokyo, Japan
- Center for AIDS Research, Kumamoto University, Kumamoto, Japan
| | - Hiroyuki Gatanaga
- AIDS Clinical Center, National Center for Global Health and Medicine, Tokyo, Japan
- Center for AIDS Research, Kumamoto University, Kumamoto, Japan
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Fierro NA, Gonzalez-Aldaco K, Torres-Valadez R, Martinez-Lopez E, Roman S, Panduro A. Immunologic, metabolic and genetic factors in hepatitis C virus infection. World J Gastroenterol 2014; 20:3443-3456. [PMID: 24707127 PMCID: PMC3974511 DOI: 10.3748/wjg.v20.i13.3443] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2013] [Revised: 01/16/2014] [Accepted: 03/06/2014] [Indexed: 02/06/2023] Open
Abstract
The mechanisms that regulate disease progression during hepatitis C virus (HCV) infection and the response to treatment are not clearly identified. Numerous studies have demonstrated that a strong host immune response against HCV favors HCV clearance. In addition, genetic factors and metabolic machinery, particularly cholesterol modulation, are involved in HCV infection. It is likely that the interplay between all of these factors contributes to the outcome of HCV infection. In recent years, the world has experienced its largest epidemic of obesity. Mexico and the United States are the leading sufferers from this epidemic at the global level. Obesity is associated with the development of numerous pathologies including hypercholesterolemia which is one of the eight most important risk factors for mortality in Mexico. This may be related to the course of HCV infection in this population. Here, we focus on the urgent need to study the progression of HCV infection in relation to ethnic characteristics. Discoveries are discussed that hold promise in identifying immune, metabolic and genetic factors that, in conjunction, could be therapeutic targets or predictors of the progression of HCV infection.
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Gentile I, Buonomo AR, Borgia F, Zappulo E, Castaldo G, Borgia G. MK-5172 : a second-generation protease inhibitor for the treatment of hepatitis C virus infection. Expert Opin Investig Drugs 2014; 23:719-28. [PMID: 24666106 DOI: 10.1517/13543784.2014.902049] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
INTRODUCTION Approximately 170 million people worldwide are chronic carriers of the hepatitis C virus (HCV). Twenty-five percent of them develop liver cirrhosis and hepatocellular carcinoma during their life. Successful antiviral treatment dramatically reduces the risk of disease progression. HCV infection is treated with pegylated interferon and ribavirin; the addition of a protease inhibitor (boceprevir or telaprevir) can also be considered for patients with genotype 1. AREAS COVERED This review summarizes the data about the pharmacokinetics, pharmacodynamics, efficacy and safety of MK-5172 , a second-generation inhibitor of HCV NS3/4A protease. EXPERT OPINION The pharmacokinetic profile allows for once-a-day administration. Combined with pegylated interferon and ribavirin, MK-5172 results in a high rate of HCV eradication (in about 90% of cases) and a better outcome than boceprevir-based triple therapy. Also in interferon-free combinations, MK-5172-associated eradication rates are very high (89 - 100%). MK-5172 has a higher barrier to resistance than first-generation protease inhibitors and is active against most variants associated with resistance to first-generation protease inhibitors. Tolerability and safety profile are good. Although data are limited, MK-5172 appears to overcome most of the drawbacks of the first-generation protease inhibitors and is thus a very promising agent to be used in combination with other antivirals to eradicate HCV infection.
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Affiliation(s)
- Ivan Gentile
- University of Naples "Federico II", Department of Clinical Medicine and Surgery (Ed. 18) , via S. Pansini 5, I-80131 Naples , Italy +39 0 81 7463178 ; +39 0 81 7463190 ;
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Gatselis NK, Zachou K, Saitis A, Samara M, Dalekos GN. Individualization of chronic hepatitis C treatment according to the host characteristics. World J Gastroenterol 2014; 20:2839-53. [PMID: 24659876 PMCID: PMC3961989 DOI: 10.3748/wjg.v20.i11.2839] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2013] [Revised: 11/19/2013] [Accepted: 01/06/2014] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) infection is a global health problem that affects more than 170 million people worldwide. It is a major cause of cirrhosis and hepatocellular carcinoma, making the virus the most common cause of liver failure and transplantation. The standard-of-care treatment for chronic hepatitis C (CHC) has been changed during the last decade and direct acting antiviral drugs have already been used. Besides, understanding of the pathogenesis of CHC has evolved rapidly during the last years and now several host factors are known to affect the natural history and response to treatment. Recent genome-wide association studies have shown the important role of interleukin-28B and inosine triphosphatase in HCV infection. The present review article attempts to summarize the current knowledge on the role of host factors towards individualization of HCV treatment.
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48
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Sagnelli E, Santantonio T, Coppola N, Fasano M, Pisaturo M, Sagnelli C. Acute hepatitis C: clinical and laboratory diagnosis, course of the disease, treatment. Infection 2014; 42:601-10. [PMID: 24619833 DOI: 10.1007/s15010-014-0608-2] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2013] [Accepted: 02/24/2014] [Indexed: 02/06/2023]
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Abstract
The acute phase of hepatitis C (HCV) infection is typically defined as the initial 6 months following exposure to the virus; however, in some individuals, the acute phase of the infection can last much longer (Orland et al. Hepatology 33:321-27, 2001). Although some patients have symptoms of acute hepatitis, most infected individuals are entirely asymptomatic. As a result, many patients are unaware of the infection until it progresses to chronic infection, and may not develop symptoms until decades later with the onset of decompensated cirrhosis or hepatocellular carcinoma (HCC). A substantial proportion (20-40%) of infected patients clear the virus during the acute phase. Interferon-based treatment is also much more likely to be successful in the acute phase of infection but is relatively poorly tolerated. Therefore, recognition of acute HCV infection is critical to prioritize those patients who do not spontaneously clear the infection for immediate therapy. However, the promise of highly effective well-tolerated all-oral therapies in development may alter the management approach. This review will focus on the epidemiology, natural history, diagnosis, and treatment of acute HCV infection.
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Affiliation(s)
- Suraj A Sharma
- Toronto Center for Liver Disease, Sandra Rotman Centre for Global Health, University Health Network, University of Toronto, 6B-Fell Pavilion, 399 Bathurst Street, Toronto, Ontario, M5T 2S8, Canada
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50
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Arnaud C, Trépo C, Petit MA. Predictors of the therapeutic response in hepatitis C. A 2013 update. Clin Res Hepatol Gastroenterol 2014; 38:12-7. [PMID: 24268305 DOI: 10.1016/j.clinre.2013.08.003] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2013] [Accepted: 08/19/2013] [Indexed: 02/04/2023]
Abstract
Chronic hepatitis C is a major cause of cirrhosis and hepatocellular carcinoma. Current therapy based on pegylated-interferon-α (PEG-IFN) and ribavirin (RBV) combination has limited efficacy and is poorly tolerated. Disease progression is highly variable and pre-therapeutic prediction of response to treatment remains difficult. Although viral kinetics proved most useful to monitor duration of therapy, other predictors would be helpful to identify patients with the best chance of subsequent treatment response prior initiation of antiviral therapy (double or triple therapy). The predictive power of IL28B polymorphism is well-recognized and has become the reference biomarker for clinicians in patients treated with double therapy. The combination of serum IP-10 and IL28B SNPs increases predictive value of treatment response. Recently, anti-E1E2 antibodies appear to closely correlate with therapeutic outcome and predict the complete elimination of HCV. They may represent a new relevant prognostic biomarker of double therapy response. Since the introduction of triple therapy including protease inhibitors (telaprevir/boceprevir), the major priority is to help patients who failed on double therapy, and there is now an urgent need for robust pre-therapeutic predictors of response to better select the patients to treat. Indeed, the relevance of IL28B polymorphism and IP-10 serum concentration are limited in triple therapy. Many new drugs are currently under investigation and there is hope that effective and well-tolerated IFN-free regimens may become a part of future therapy. In this context, this will help to identify the most powerful predictive marker and/or to assess the benefit of anti-E1E2 in decision to treat.
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Affiliation(s)
- Clémence Arnaud
- Inserm U1052/CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon (CRCL), 151, Cours-Albert-Thomas, 69424 Lyon cedex 03, France; Université Claude-Bernard Lyon 1, 69000 Lyon, France
| | - Christian Trépo
- Inserm U1052/CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon (CRCL), 151, Cours-Albert-Thomas, 69424 Lyon cedex 03, France; Université Claude-Bernard Lyon 1, 69000 Lyon, France; Service d'Hépatologie et de Gastroentérologie, Hospices Civils de Lyon, Hôpital de la Croix-Rousse, 69004 Lyon, France
| | - Marie-Anne Petit
- Inserm U1052/CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon (CRCL), 151, Cours-Albert-Thomas, 69424 Lyon cedex 03, France; Université Claude-Bernard Lyon 1, 69000 Lyon, France.
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