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Frías M, Rivero-Juárez A, Machuca I, Camacho Á, Rivero A. The outlook for precision medicine for the treatment of chronic hepatitis C infection: challenges and opportunities. EXPERT REVIEW OF PRECISION MEDICINE AND DRUG DEVELOPMENT 2020. [DOI: 10.1080/23808993.2020.1764346] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Affiliation(s)
- Mario Frías
- Clinical Virology and Zoonoses, Hospital Universitario Reina Sofía de Córdoba. Instituto Maimonides de Investigación Biomédica de Córdoba (IMIBIC), Universidad de Córdoba, Spain
| | - Antonio Rivero-Juárez
- Clinical Virology and Zoonoses, Hospital Universitario Reina Sofía de Córdoba. Instituto Maimonides de Investigación Biomédica de Córdoba (IMIBIC), Universidad de Córdoba, Spain
| | - Isabel Machuca
- Clinical Virology and Zoonoses, Hospital Universitario Reina Sofía de Córdoba. Instituto Maimonides de Investigación Biomédica de Córdoba (IMIBIC), Universidad de Córdoba, Spain
| | - Ángela Camacho
- Clinical Virology and Zoonoses, Hospital Universitario Reina Sofía de Córdoba. Instituto Maimonides de Investigación Biomédica de Córdoba (IMIBIC), Universidad de Córdoba, Spain
| | - Antonio Rivero
- Clinical Virology and Zoonoses, Hospital Universitario Reina Sofía de Córdoba. Instituto Maimonides de Investigación Biomédica de Córdoba (IMIBIC), Universidad de Córdoba, Spain
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Echeverría N, Chiodi D, López P, Sanchez Ciceron A, Angulo J, López-Lastra M, Silvera P, Canavesi A, Bianchi C, Colistro V, Cristina J, Hernandez N, Moreno P. IL28B gene polymorphism rs12979860, but not rs8099917, contributes to the occurrence of chronic HCV infection in Uruguayan patients. Virol J 2018; 15:40. [PMID: 29499724 PMCID: PMC5833045 DOI: 10.1186/s12985-018-0946-2] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2017] [Accepted: 02/05/2018] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Host single-nucleotide polymorphisms (SNPs) near the interleukin 28B (IL28B) locus are associated with sustained virological response to antiviral therapy and with spontaneous Hepatitis C Virus (HCV) clearance. Prevalence of these SNPs varies depending on ethnicity. The impact of IL28B SNPs in HCV-infected patients is currently unknown in Uruguay. Therefore, the aim of this study was to evaluate and compare the distribution of polymorphisms in the IL28B gene (rs12979860 and rs8099917) among HCV-infected patients and healthy individuals in Uruguay and thus assess their possible association with the establishment of HCV infection. METHODS DNA was recovered from 92 non-infected individuals and 78 HCV-infected patients and SNPs were determined by RFLP and allelic discrimination by real-time PCR. RESULTS The distribution of rs12979860 genotypes for the infected population was 29.5%-CC, 47.4%-CT and 23.1%-TT and for the control group 45.7%, 42.4% and 11.9%, respectively. Prevalence in both infected and uninfected individuals is similar to that reported in other countries with admixed populations. The distribution of rs8099917 genotypes for the infected population was 57.7%-TT, 27.2%-TG and 14.1%-GG and for the control group 60.9%, 33.7% and 5.4%, respectively. The comparison of rs12979860 genotype distribution between the two populations evidenced a higher prevalence of the favourable genotype (CC) in the uninfected control group (p < 0.05). Additionally, results generated using logistic regression analysis show that individuals carrying rs12979860-TT or CT genotypes have a higher likelihood of developing chronic hepatitis upon infection with HCV, when compared to CC carriers, considering rs8099917 genotype as constant. CONCLUSION Patients with HCV infection have a statistically significant lower prevalence of the favourable rs12979860 genotype when compared to uninfected individuals; therefore we can establish that only IL28B rs12979860-CT and TT genotypes seem to contribute to the occurrence of chronic HCV infection in the cohort of Uruguayan population studied. Considering that a trend towards a higher frequency of "good" response genotypes was observed in responder patients, we believe that IL28B rs12979860 genotyping could be a useful tool for predicting different therapies outcome, including in the DAA era.
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Affiliation(s)
- Natalia Echeverría
- Laboratorio de Virología Molecular, Centro de Investigaciones Nucleares, Facultad de Ciencias, Universidad de la República, 2055 Montevideo, Mataojo Uruguay
| | - Daniela Chiodi
- Clínica de Gastroenterología, Hospital de Clínicas, Facultad de Medicina, Universidad de la República, 11600 Montevideo, Uruguay
| | - Pablo López
- Departamento de Laboratorio Clínico, Hospital de Clínicas, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay
| | - Adriana Sanchez Ciceron
- Clínica de Gastroenterología, Hospital de Clínicas, Facultad de Medicina, Universidad de la República, 11600 Montevideo, Uruguay
| | - Jenniffer Angulo
- Laboratorio de Virología Molecular, Instituto Milenio de Inmunología e Inmunoterapia, Centro de Investigaciones Médicas, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Marcelo López-Lastra
- Laboratorio de Virología Molecular, Instituto Milenio de Inmunología e Inmunoterapia, Centro de Investigaciones Médicas, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Paola Silvera
- Departamento de Laboratorio Clínico, Hospital de Clínicas, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay
| | - Adrian Canavesi
- Clínica de Gastroenterología, Hospital de Clínicas, Facultad de Medicina, Universidad de la República, 11600 Montevideo, Uruguay
| | | | - Valentina Colistro
- Departamento de Genética, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay
| | - Juan Cristina
- Laboratorio de Virología Molecular, Centro de Investigaciones Nucleares, Facultad de Ciencias, Universidad de la República, 2055 Montevideo, Mataojo Uruguay
| | - Nelia Hernandez
- Clínica de Gastroenterología, Hospital de Clínicas, Facultad de Medicina, Universidad de la República, 11600 Montevideo, Uruguay
| | - Pilar Moreno
- Laboratorio de Virología Molecular, Centro de Investigaciones Nucleares, Facultad de Ciencias, Universidad de la República, 2055 Montevideo, Mataojo Uruguay
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Liu CH, Huang CF, Liu CJ, Dai CY, Huang JF, Lin JW, Liang CC, Yang SS, Lin CL, Su TH, Yang HC, Chen PJ, Chen DS, Chuang WL, Kao JH, Yu ML. Peginterferon plus weight-based ribavirin for treatment-naïve hepatitis C virus genotype 2 patients not achieving rapid virologic response: a randomized trial. Sci Rep 2015; 5:11710. [PMID: 26130141 PMCID: PMC4486927 DOI: 10.1038/srep11710] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2015] [Accepted: 06/01/2015] [Indexed: 01/08/2023] Open
Abstract
Hepatitis C virus genotype 2 (HCV-2) slow responders poorly respond to 24 weeks of peginterferon (Peg-IFN) plus ribavirin (RBV). We evaluated the efficacy of extended 48-week regimen and the role of interleukin-28B (IL-28B) genotype in this clinical setting. Treatment-naïve HCV-2 patients not achieving rapid virologic response (RVR) by Peg-IFN alfa-2a 180 μg/week plus weight-based RBV (1,000-1,200 mg/day, cutoff body weight of 75 kg) were randomly assigned to receive a total duration of 48 (n = 94) or 24 (n = 93) weeks of therapy. The primary endpoint was sustained virologic response (SVR). Baseline patient characteristics to predict SVR were analyzed. Patients receiving 48 weeks of treatment had a greater SVR rate than those receiving 24 weeks of treatment (70.2% versus 46.2%, P = 0.001). Compared to patients treated for 24 weeks, the SVR rate in those treated for 48 weeks increased by 10.9% [95% CI: -5.9% to 27.7%] and 65.6% [95% CI: 44.5% to 86.7%] if they had IL-28B rs8099917 TT genotype, and GT/GG genotype, respectively (interaction P = 0.002). In conclusion, 48-week treatment with Peg-IFN plus weight-based RBV provides a greater SVR rate than 24-week treatment in treatment-naïve HCV-2 patients with unfavorable IL-28B genotypes who fail to achieve RVR.
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Affiliation(s)
- Chen-Hua Liu
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
- Department of Internal Medicine, National Taiwan University Hospital, Yun-Lin Branch, Douliou, Taiwan
| | - Chung-Feng Huang
- Institute of Clinical Medicine and Faculty of Internal Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Hepatobiliary Division, Department of Internal Medicine and Hepatitis Center, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Department of Occupational Medicine, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan
| | - Chun-Jen Liu
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Chia-Yen Dai
- Institute of Clinical Medicine and Faculty of Internal Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Hepatobiliary Division, Department of Internal Medicine and Hepatitis Center, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Jee-Fu Huang
- Institute of Clinical Medicine and Faculty of Internal Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Hepatobiliary Division, Department of Internal Medicine and Hepatitis Center, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Jou-Wei Lin
- Department of Internal Medicine, National Taiwan University Hospital, Yun-Lin Branch, Douliou, Taiwan
| | - Cheng-Chao Liang
- Department of Internal Medicine, Far Eastern Memorial Hospital, Taipei, Taiwan
| | - Sheng-Shun Yang
- Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan
| | - Chih-Lin Lin
- Department of Gastroenterology, Taipei City Hospital, Ren-Ai Branch, Taipei, Taiwan
| | - Tung-Hung Su
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Hung-Chih Yang
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
- Department of Microbiology, National Taiwan University College of Medicine and National Taiwan University Hospital, Taipei
| | - Pei-Jer Chen
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Ding-Shinn Chen
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
- Genomics Research Center, Academia Sinica, Taiwan
| | - Wan-Long Chuang
- Institute of Clinical Medicine and Faculty of Internal Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Hepatobiliary Division, Department of Internal Medicine and Hepatitis Center, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Jia-Horng Kao
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Ming-Lung Yu
- Institute of Clinical Medicine and Faculty of Internal Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Hepatobiliary Division, Department of Internal Medicine and Hepatitis Center, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan
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Chen TM, Huang PT, Show BC, Wen CF, Chen YP. Impact of interleukin-28B polymorphism on HCV-1 infected patients treated with response-guided therapy. ADVANCES IN DIGESTIVE MEDICINE 2014. [DOI: 10.1016/j.aidm.2014.11.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
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Riva E, Scagnolari C, Turriziani O, Antonelli G. Hepatitis C virus and interferon type III (interferon-λ3/interleukin-28B and interferon-λ4): genetic basis of susceptibility to infection and response to antiviral treatment. Clin Microbiol Infect 2014; 20:1237-45. [PMID: 25273834 DOI: 10.1111/1469-0691.12797] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2014] [Revised: 08/12/2014] [Accepted: 08/17/2014] [Indexed: 02/06/2023]
Abstract
There has been a significant increase in our understanding of the host genetic determinants of susceptibility to viral infections in recent years. Recently, two single-nucleotide polymorphisms (SNPs), rs12979860 T/C and rs8099917 T/G, upstream of the interleukin (IL)-28B/interferon (IFN)-λ3 gene have been clearly associated with spontaneous and treatment-induced viral clearance in hepatitis C virus (HCV) infection. Because of their power in predicting the response to IFN/ribavirin therapy, the above SNPs have been used as a diagnostic tool, even though their relevance in the management of HCV infection will be blunt in the era of IFN-free regimens. The recent discovery of a new genetic variant, ss469415590 TT/ΔG, upstream of the IL-28B gene, which generates the novel IFN-λ4 protein, has opened up a new and alternative scenario to understand the functional architecture of type III IFN genomic regions and to improve our knowledge of the pathogenetic mechanism of HCV infection. A role of ss469415590 in predicting responsiveness to antiviral therapy has also been observed in HCV-infected patients receiving direct antiviral agents. The underlying biological mechanism that links the above IL-28B polymorphisms (in both IFN-λ3 and IFN-λ4) to spontaneous and treatment-induced clearance of HCV infection remains to be discovered. Despite this, shedding some light on this issue, which is the main aim of this review, may provide new insights into the general topic of 'host genetics and viral infections'.
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Affiliation(s)
- E Riva
- Department of Integrated Research, Virology Section, University Campus Bio-Medico of Rome, Rome, Italy
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Ferenci P, Aires R, Ancuta I, Arohnson A, Cheinquer H, Delic D, Gschwantler M, Larrey D, Tallarico L, Schmitz M, Tatsch F, Ouzan D. A tool for selecting patients with a high probability of sustained virological response to peginterferon alfa-2a (40kD)/ribavirin. Liver Int 2014; 34:1550-1559. [PMID: 24329937 DOI: 10.1111/liv.12439] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2013] [Accepted: 12/07/2013] [Indexed: 02/13/2023]
Abstract
BACKGROUND & AIMS Pretreatment identification of patients likely to achieve a sustained virological response (SVR) with peginterferon alfa-2a/ribavirin would be useful for individualizing treatment choices. The aim of this analysis was to devise a simple scoring system to identify patients with high probability of achieving an SVR with peginterferon alfa-2a/ribavirin. METHODS Using data from 2109 Caucasian treatment-naive hepatitis C virus (HCV) genotype 1 mono-infected patients from the PROPHESYS cohorts, the relationship between favourable baseline characteristics and SVR was explored using generalized additive model analysis, and a scoring system was devised to predict SVR. RESULTS Points were assigned for: age (years) (≤35: 2; >35, ≤45: 1; >45: 0); body mass index (kg/m(2)) (≤20: 2; >20, ≤22: 1; >22: 0); HCV RNA (IU/ml) (≤100,000: 3; >100,000-400,000: 2; >400,000-800,000: 1; >800,000: 0); platelets (>150 ×10(9)/l: 1; ≤150 ×10(9)/l: 0); alanine aminotransferase [×upper limit of normal (ULN)] (>3: 1; ≤3: 0); serum aspartate aminotransferase (×ULN) (≤1: 1; >1: 0). 1029, 698 and 382 patients had scores of 0-2, 3-4 and ≥5, respectively, among whom SVR rates were 35.0, 54.9 and 76.7%. SVR in patients with scores ≥5 and undetectable HCV RNA by week 4 was 86.7%. The score was tested against two databases of patients who received peginterferon alfa-2a/ribavirin in other clinical trials; similar high SVR rates in patients with scores ≥5 were reported. CONCLUSIONS The scoring system can reliably identify treatment-naive HCV genotype 1 mono-infected Caucasian patients who have a high probability of achieving an SVR with peginterferon alfa-2a/ribavirin and will be particularly useful where protease inhibitors are not readily available.
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Trinks J, Hulaniuk ML, Redal MA, Flichman D. Clinical utility of pharmacogenomics in the management of hepatitis C. PHARMACOGENOMICS & PERSONALIZED MEDICINE 2014; 7:339-47. [PMID: 25382982 PMCID: PMC4222698 DOI: 10.2147/pgpm.s52624] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Hepatitis C virus (HCV) was identified for the first time more than 20 years ago. Since then, several studies have highlighted the complicated aspects of this viral infection in relation to its worldwide prevalence, its clinical presentation, and its therapeutic response. Recently, two landmark scientific breakthroughs have moved us closer to the successful eradication of chronic HCV infection. First, response rates in treatment-naïve patients and in prior non-responders to pegylated-interferon-α and ribavirin therapy are increasing as a direct consequence of the development of direct-acting antiviral drugs. Secondly, the discovery of single-nucleotide polymorphisms near the interleukin 28B gene significantly related to spontaneous and treatment-induced HCV clearance represents a milestone in the HCV therapeutic landscape. The implementation of this pharmacogenomics finding as a routine test for HCV-infected patients has enhanced our understanding of viral pathogenesis, has encouraged the design of ground-breaking antiviral treatment regimens, and has become useful for pretreatment decision making. Nowadays, interleukin 28B genotyping is considered to be a key diagnostic tool for the management of HCV-infected patients and will maintain its significance for new combination treatment schemes using direct-acting antiviral agents and even in interferon-free regimens. Such pharmacogenomics insights represent a challenge to clinicians, researchers, and health administrators to transform this information into knowledge with the aim of elaborating safer and more effective therapeutic strategies specifically designed for each patient. In conclusion, the individualization of treatment regimens for patients with hepatitis C, that may lead to a universal cure in future years, is becoming a reality due to recent developments in biomarker and genomic medicine. In light of these advances, we review the scientific evidence and clinical implications of recent findings related to host genetic factors in the management of HCV infection.
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Affiliation(s)
- Julieta Trinks
- Instituto de Ciencias Básicas y Medicina Experimental, Hospital Italiano de Buenos Aires, Universidad de Buenos Aires, Buenos Aires, Argentina ; National Scientific and Technical Research Council, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - María Laura Hulaniuk
- Instituto de Ciencias Básicas y Medicina Experimental, Hospital Italiano de Buenos Aires, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - María Ana Redal
- Instituto de Ciencias Básicas y Medicina Experimental, Hospital Italiano de Buenos Aires, Universidad de Buenos Aires, Buenos Aires, Argentina ; Instituto Universitario del Hospital Italiano de Buenos Aires, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Diego Flichman
- National Scientific and Technical Research Council, Universidad de Buenos Aires, Buenos Aires, Argentina ; Cátedra de Virología, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina
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Akkarathamrongsin S, Thong VD, Payungporn S, Poovorawan K, Prapunwattana P, Poovorawan Y, Tangkijvanich P. IFNL3 (IL28B) and IFNL4 polymorphisms are associated with treatment response in Thai patients infected with HCV genotype 1, but not with genotypes 3 and 6. J Med Virol 2014; 86:1482-1490. [PMID: 24782280 DOI: 10.1002/jmv.23957] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/24/2014] [Indexed: 12/11/2022]
Abstract
Recent studies have shown an association between single nucleotide polymorphisms (SNPs) in the interferon lambda-3 (IFNL3 or IL-28B) and IFNL4 genes and treatment response to hepatitis C virus genotype 1 (HCV-1) infection. The importance of these SNPs for HCV genotype 3 (HCV-3), and particularly HCV genotype 6 (HCV-6), remains to be elucidated. We analyzed a cohort of 225 Thai individuals with chronic HCV infection treated with pegylated-interferon and ribavirin, of whom 69 (30.7%), 114 (50.7%) and 42 (18.6%) patients were infected with HCV-1, HCV-3, and HCV-6, respectively. DNA extracted from blood samples was analyzed for the SNPs rs12979860 and ss469415590. The distribution of CC, CT, and TT genotypes of rs12979860 was 189 (84%), 28 (12.4%) and 8 (3.6%), respectively, while the distribution of TT/TT, ΔG/TT, and ΔG/ΔG genotypes of ss469415590 was 192(85.3%), 28(12.5%), and 5(2.2%), respectively. Significantly lower frequencies of the favorable genotypes CC (for rs12979860) and TT/TT (for ss469415590) were found in the HCV-1 group in comparison with the other groups. The favorable genotypes were associated significantly with rapid and sustained virological response in the HCV-1 group. However, they were only associated with rapid virological response in the HCV-3 and HCV-6 groups. Furthermore, both SNPs were associated equally with the treatment outcome in the HCV-1 group. In contrast, the role of these SNPs in predicting treatment response was attenuated in the HCV-3 and HCV-6 groups. Thus, identification of these SNPs may be useful only in patients with refractory HCV-1 infection.
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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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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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Mancuso ME, Linari S, Aghemo A, Bartolozzi D, Santagostino E, Rumi MG, Fognani E, Fasulo MR, Gragnani L, Bruno R, Morfini M, Zignego AL, Colombo M. Interferon lambda 3 rs12979860 polymorphism in patients with haemophilia and HCV infection: a predictor of spontaneous viral clearance and sustained virological response. Thromb Haemost 2014; 111:1067-76. [PMID: 24522196 DOI: 10.1160/th13-11-897] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2013] [Accepted: 12/19/2013] [Indexed: 12/19/2022]
Abstract
Chronic hepatitis C is the main cause of morbidity and mortality in adult haemophilic patients who received non-virally inactivated plasma-derived clotting factor concentrates. Overall, spontaneous viral clearance rate is 10-25% and the only approach that can halt disease progression is hepatitis C virus (HCV) eradication by means of antiviral therapy. In non-haemophilic patients a single nucleotide polymorphism located upstream the gene of interferon lambda 3 (IFNλ3) has been associated with both spontaneous viral clearance and sustained virological response after antiviral treatment. The aim of this study was to assess whether the rs12979860 polymorphism was a predictor of spontaneous viral clearance and of sustained virological response after antiviral therapy in a large cohort of haemophilic patients with HCV infection. The rs12979860 polymorphism, defined as CC genotype or T allele, was tested in a cohort of 342 haemophilic patients and evaluated as predictor of spontaneous clearance or response to antiviral therapy. By multivariate regression analysis the IFNλ3 CC genotype was an independent predictor of spontaneous viral clearance (odds ratio: 3.7, 95% confidence interval: 2.0-6.8). Sustained virological response rates were doubled in patients with the CC genotype than in those with the T allele (78% vs 44%; p<0.001), especially in patients with HCV type 1 (67% vs 32%; p<0.001) and higher sustained response rates were observed in patients with the CC genotype who did not achieve rapid virological response (61% vs 30% in T allele patients; p=0.006).
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Affiliation(s)
- Maria Elisa Mancuso
- Maria Elisa Mancuso, MD, PhD, Angelo Bianchi Bonomi Haemophilia and Thrombosis Center, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Via Pace 9, 20122 Milan, Italy, Tel.: +39 02 5503 4072, Fax: +39 02 5503 2072, E-mail:
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Trinks J, Hulaniuk ML, Caputo M, Pratx LB, Ré V, Fortuny L, Pontoriero A, Frías A, Torres O, Nuñez F, Gadano A, Corach D, Flichman D. Distribution of genetic polymorphisms associated with hepatitis C virus (HCV) antiviral response in a multiethnic and admixed population. THE PHARMACOGENOMICS JOURNAL 2014; 14:549-54. [PMID: 24841973 DOI: 10.1038/tpj.2014.20] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/22/2013] [Revised: 03/08/2014] [Accepted: 03/26/2014] [Indexed: 12/19/2022]
Abstract
The prevalence of genetic polymorphisms identified as predictors of therapeutic-induced hepatitis C virus (HCV) clearance differs among ethnic groups. However, there is a paucity of information about their prevalence in South American populations, whose genetic background is highly admixed. Hence, single-nucleotide polymorphisms rs12979860, rs1127354 and rs7270101 were characterized in 1350 healthy individuals, and ethnicity was assessed in 259 randomly selected samples. The frequency of rs12979860CC, associated to HCV treatment response, and rs1127354nonCC, related to protection against hemolytic anemia, were significantly higher among individuals with maternal and paternal Non-native American haplogroups (64.5% and 24.2%), intermediate among admixed samples (44.1% and 20.4%) and the lowest for individuals with Native American ancestry (30.4% and 6.5%). This is the first systematic study focused on analyzing HCV predictors of antiviral response and ethnicity in South American populations. The characterization of these variants is critical to evaluate the risk-benefit of antiviral treatment according to the patient ancestry in admixed populations.
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Affiliation(s)
- J Trinks
- 1] Instituto de Ciencias Básicas y Medicina Experimental (ICBME), Hospital Italiano de Buenos Aires, Buenos Aires, Argentina [2] National Scientific and Technical Research Council (CONICET), Buenos Aires, Argentina
| | - M L Hulaniuk
- Instituto de Ciencias Básicas y Medicina Experimental (ICBME), Hospital Italiano de Buenos Aires, Buenos Aires, Argentina
| | - M Caputo
- 1] Servicio de Huellas Digitales Genéticas, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina [2] National Scientific and Technical Research Council (CONICET), Buenos Aires, Argentina
| | - L Burgos Pratx
- Servicio de Medicina Transfusional, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina
| | - V Ré
- 1] Instituto de Virología Dr José María Vanella, Facultad de Ciencias Médicas de la Universidad Nacional de Córdoba, Córdoba, Argentina [2] National Scientific and Technical Research Council (CONICET), Buenos Aires, Argentina
| | - L Fortuny
- Servicio de Medicina Transfusional, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina
| | - A Pontoriero
- Instituto de Ciencias Básicas y Medicina Experimental (ICBME), Hospital Italiano de Buenos Aires, Buenos Aires, Argentina
| | - A Frías
- Servicio de Medicina Transfusional, Hospital Materno Infantil 'Ramón Sardá', Buenos Aires, Argentina
| | - O Torres
- Servicio de Medicina Transfusional, Hospital Materno Infantil 'Ramón Sardá', Buenos Aires, Argentina
| | - F Nuñez
- Servicio de Medicina Transfusional, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina
| | - A Gadano
- Servicio de Hepatología, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina
| | - D Corach
- 1] Servicio de Huellas Digitales Genéticas, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina [2] National Scientific and Technical Research Council (CONICET), Buenos Aires, Argentina
| | - D Flichman
- 1] Cátedra de Virología, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina [2] National Scientific and Technical Research Council (CONICET), Buenos Aires, Argentina
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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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Ferenci P. Treatment of Chronic Hepatitis C, Genotype 4. CURRENT HEPATITIS REPORTS 2013; 12:246-250. [DOI: 10.1007/s11901-013-0178-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/11/2025]
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15
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Domagalski K, Pawlowska M, Tretyn A, Halota W, Tyczyno M, Kozielewicz D, Dybowska D. Association of IL28B Polymorphisms With the Response to Peginterferon Plus Ribavirin Combined Therapy in Polish Patients Infected With HCV Genotype 1 and 4. HEPATITIS MONTHLY 2013; 13:e13678. [PMID: 24348648 PMCID: PMC3860073 DOI: 10.5812/hepatmon.13678] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/18/2013] [Revised: 08/24/2013] [Accepted: 11/04/2013] [Indexed: 12/11/2022]
Abstract
BACKGROUND Three single nucleotide polymorphisms (SNPs) near interleukin-28B (IL-28B) gene were shown to be highly associated with treatment response (SVR) in patients with chronic hepatitis C virus (HCV) infection. There is limited data about the role of single and combined IL-28B polymorphisms in HCV-infected Polish population. OBJECTIVES This study's aim was to determine predictability of three IL-28B gene polymorphisms and other known prognostic factors on the treatment response in HCV genotype 1 and 4 infected Polish patients. The effect of IL-28B polymorphisms on therapy was also compared with other known prognostic factors. PATIENTS AND METHODS We genotyped IL-28B polymorphisms (rs12979860, rs12980275 and rs8099917) by polymerase chain reaction-based restriction fragment length polymorphism assay in a group of 293 patients from which a selected cohort of 174 treatment-naiev patients underwent treatment. RESULTS We showed that rs12979860 CC [odds ratio (OR) = 4.6, P < 0.001], rs12980275 AA (OR = 2.9, P = 0.002) and rs8099917 TT (OR = 2.2, P = 0.016) genotypes were associated with successful treatment compared to the rs12979860 CT-TT, rs12980275 AG-GG and rs8099917 TG-GG, respectively. Patients bearing of IL-28B profile including the three favourable genotypes do not have much chance of a recovery (OR = 3.4, P = 0.002). Except for IL-28B polymorphisms, there was no association of SVR with any other pretreatment clinical data in analyzed group. The correlation of SNPs with other host and viral factors revealed association of favorable genotypes of IL-28B markers with high levels of alanine aminotransferase and baseline HCV viral load. CONCLUSIONS IL-28B polymorphisms were the strongest pretreatment predictors of response to pegylated interferon and ribavirin in Polish patients chronically infected with HCV genotype 1 and 4. This study confirm the strongest impact of IL-28B rs12979860 on SVR, nevertheless rs12980275 AA seems to be more important than rs8099917 TT in predicting positive treatment response.
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Affiliation(s)
- Krzysztof Domagalski
- Department of Infectious Diseases and Hepatology, Nicolaus Copernicus University, Bydgoszcz, Poland
- Department of Plant Physiology and Biotechnology, Nicolaus Copernicus University, Torun, Poland
| | - Magorzata Pawlowska
- Department of Infectious Diseases and Hepatology, Nicolaus Copernicus University, Bydgoszcz, Poland
- Corresponding author: Magorzata Pawlowska, Department of Infectious Diseases and Hepatology, Nicolaus Copernicus University, Bydgoszcz, Poland. Tel/Fax: +48-523255605, E-mail:
| | - Andrzej Tretyn
- Department of Plant Physiology and Biotechnology, Nicolaus Copernicus University, Torun, Poland
- Centre For Modern Interdisciplinary Technologies, Nicolaus Copernicus University, Torun, Poland
| | - Waldemar Halota
- Department of Infectious Diseases and Hepatology, Nicolaus Copernicus University, Bydgoszcz, Poland
| | - Magorzata Tyczyno
- Department of Infectious Diseases and Hepatology, Nicolaus Copernicus University, Bydgoszcz, Poland
| | - Dorota Kozielewicz
- Department of Infectious Diseases and Hepatology, Nicolaus Copernicus University, Bydgoszcz, Poland
| | - Dorota Dybowska
- Department of Infectious Diseases and Hepatology, Nicolaus Copernicus University, Bydgoszcz, Poland
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Ferenci P, Rutter K. Commentary: durability of SVR in chronic hepatitis C patients treated with peginterferon-a2a/ribavirin in combination with a direct-acting anti-viral--authors' reply. Aliment Pharmacol Ther 2013; 38:558. [PMID: 23937467 DOI: 10.1111/apt.12420] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2013] [Accepted: 06/29/2013] [Indexed: 12/08/2022]
Affiliation(s)
- P Ferenci
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.
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Liu CH, Kao JH. IL28B Genotype on HCV Infection in Asia. CURRENT HEPATITIS REPORTS 2013; 12:149-156. [DOI: 10.1007/s11901-013-0176-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
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Aghemo A, Degasperi E, Rumi MG, Galmozzi E, Valenti L, De Francesco R, De Nicola S, Cheroni C, Grassi E, Colombo M. Cirrhosis and rapid virological response to peginterferon plus ribavirin determine treatment outcome in HCV-1 IL28B rs12979860 CC patients. BIOMED RESEARCH INTERNATIONAL 2013; 2013:580796. [PMID: 23936821 PMCID: PMC3722882 DOI: 10.1155/2013/580796] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/26/2013] [Accepted: 06/19/2013] [Indexed: 12/20/2022]
Abstract
BACKGROUND The rs12979860 CC genotype of the interleukin 28B (IL28B) polymorphism is associated with high rates of sustained virological response (SVR) to peginterferon (PegIFN) and ribavirin (Rbv) in hepatitis C virus genotype-1 (HCV-1) patients. The impact of baseline predictors of treatment outcome and their interplay with viral kinetics in HCV-1 CC patients has not been fully evaluated. AIM To identify baseline and on-therapy predictors of treatment failure in HCV-1 IL28B CC patients. METHODS Treatment-naïve HCV-1 patients, compliant to PegIFN and Rbv who did not discontinue treatment for nonvirological reasons, were analyzed. RESULTS 109 HCV-1 IL28B CC were studied. Sixty were males, 39 with BMI >25, 69 with >600,000 IU/mL HCV RNA, 15 with HCV1a, and 30 with cirrhosis. Overall, 75 (69%) achieved an SVR; cirrhosis was the only baseline predictor of treatment failure (OR: 2.58, 95% CI: 1.07-6.21) as SVR rates were 53% in cirrhotics versus 75% in noncirrhotics (P = 0.03). HCV RNA undetectability (<50 IU/mL) at week 4 (RVR) was achieved by 58 patients (53%). The SVR rates were independent of RVR in noncirrhotics, 76% (34/45) RVR (+) and 74% (25/34) RVR (-) (P = 0.9). In cirrhotic patients, SVR rates were significantly higher in RVR (+) compared to RVR (-) (10/13 (77%) versus 6/17 (35%) P = 0.03). CONCLUSIONS In HCV-1 IL28B CC patients, cirrhosis is the only clinical baseline predictor of PegIFN and Rbv treatment failure. However, in IL28B CC cirrhotics, the achievement of RVR identifies those patients who still have high rates of SVR to Peg-IFN/Rbv therapy.
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Affiliation(s)
- Alessio Aghemo
- Centro AM e A Migliavacca, First Division of Gastroenterology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Milano, Università degli Studi di Milano, Milano, Italy.
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Bucci C, von Delft A, Christian A, Flemming VM, Harrison A, Halliday J, Collier J, Manganis C, Klenerman P, Irving W, Barnes E. 'Favourable' IL28B polymorphisms are associated with a marked increase in baseline viral load in hepatitis C virus subtype 3a infection and do not predict a sustained virological response after 24 weeks of therapy. J Gen Virol 2013; 94:1259-1265. [PMID: 23486666 DOI: 10.1099/vir.0.051052-0] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
IL28B host genetic make-up is known to play a critical role in the outcome of genotype 1 hepatitis C virus (HCV) infection in the context of both primary infection and therapy. However, the role of IL28B in subtype 3a infection remains unclear, and has not yet been assessed in the UK population where subtype 3a is dominant. In this study, we evaluated the role of the IL28B single-nucleotide polymorphism rs8099917 in 201 patients recruited from two well-defined cohorts (from Nottingham and Oxford), treated with the standard-of-care therapy of pegylated interferon and ribavirin for 24 weeks. We showed that the 'favourable' IL28B gene was associated with a rapid virological response to therapy at 4 weeks (P<0.0001), but not with a sustained virological response to therapy. The median viral load at baseline, before therapy, was markedly increased in people with the 'favourable' IL28B genotype [median viral load for the TT allele, 925,961 IU ml(-1) (range 2200-21,116,965 IU ml(-1)), and for the GT or GG allele, 260,284 IU ml(-1) (range 740-7,560,000 IU ml(-1)); P = 0.0010]. Our results suggest that the host genetic response plays an important role in early viral clearance of subtype 3a virus from the blood. However, significant reservoirs of infection must persist, as viral relapse is common, even in those with the favourable host genotype.
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Affiliation(s)
- Cristina Bucci
- The Peter Medawar Building for Pathogen Research, University of Oxford, Oxford, UK
| | - Annette von Delft
- The Peter Medawar Building for Pathogen Research, University of Oxford, Oxford, UK
| | | | - Vicki M Flemming
- The Peter Medawar Building for Pathogen Research, University of Oxford, Oxford, UK
| | - Abby Harrison
- The Peter Medawar Building for Pathogen Research, University of Oxford, Oxford, UK
| | - John Halliday
- The Peter Medawar Building for Pathogen Research, University of Oxford, Oxford, UK
| | | | | | - Paul Klenerman
- NIHR Oxford Biomedical Research Centre, Oxford, UK
- The Peter Medawar Building for Pathogen Research, University of Oxford, Oxford, UK
| | - William Irving
- NIHR Nottingham Digestive Diseases Biomedical Research Unit, Nottingham, UK
| | - Eleanor Barnes
- NIHR Oxford Biomedical Research Centre, Oxford, UK
- The Peter Medawar Building for Pathogen Research, University of Oxford, Oxford, UK
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Abdo AA, Al-Ahdal MN, Khalid SS, Helmy A, Sanai FM, Alswat K, Al-hamoudi W, Ali SM, Al-Ashgar HI, Al-Mdani A, Albenmousa A, Al Faleh FZ, Al-Anazi M, Khalaf N, Al-Qahtani A. IL28B polymorphisms predict the virological response to standard therapy in patients with chronic hepatitis C virus genotype 4 infection. Hepatol Int 2013; 7:533-538. [PMID: 23853698 PMCID: PMC3695682 DOI: 10.1007/s12072-013-9421-8] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2012] [Accepted: 09/20/2012] [Indexed: 01/27/2023]
Abstract
BACKGROUND Genome-wide association studies have recently revealed that several single-nucleotide polymorphisms (SNPs) in the interleukin (IL) 28B genes can predict the sustained virological response (SVR) to pegylated interferon-α2a/b plus ribavirin in hepatitis C virus (HCV)-genotype 1 patients. However, data for patients infected with HCV genotype 4 (HCV-G4) are limited. AIM We analyzed the association of IL28B SNPs (hematological, biochemical, virological, and pathological factors) with SVR in the HCV-G4 monoinfected cohort of patients. PATIENTS AND METHODS One hundred twenty-nine treatment-naïve HCV-G4 patients undergoing treatment were recruited from three tertiary care centers in Saudi Arabia. Five IL28B SNPs (rs12979860, rs12980275, rs8105790, rs8099917, and rs72486680) were identified by polymerase chain reaction and DNA sequencing. SVR was statistically correlated with various clinical, histopathological, virological, and genetic parameters. RESULTS SVR was significantly associated with the CC and AA alleles of rs12979860 (p = 0.008) and rs12980275 (p = 0.004), respectively. Moreover, albumin levels (p = 0.002) and platelet count (p = 0.039) showed significant differences in the SVR and No SVR groups. On multivariate analysis, the CC allele of rs12979860 (OR, 2.89; 95 % CI 1.6-6.2, p = 0.006) and albumin levels (OR, 1.2; 95 % CI 1.1-1.4, p = 0.001) independently predicted SVR. CONCLUSIONS IL28B polymorphism (CC allele of rs12979860) predicts the sustained response to antiviral therapy in HCV-G4.
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Affiliation(s)
- Ayman A. Abdo
- Division of Gastroenterology, Department of Medicine, King Saud University, Riyadh, Kingdom of Saudi Arabia
- Liver Disease Research Centre, King Saud University, Riyadh, Kingdom of Saudi Arabia
| | - Mohammed N. Al-Ahdal
- Department of Infection and Immunity, Research Center, King Faisal Specialist Hospital and Research Center, P.O. Box 3354 (MBC-03), Riyadh, 11211 Kingdom of Saudi Arabia
| | - Saira S. Khalid
- Liver Disease Research Centre, King Saud University, Riyadh, Kingdom of Saudi Arabia
| | - Ahmed Helmy
- Liver Disease Research Centre, King Saud University, Riyadh, Kingdom of Saudi Arabia
- Department of Tropical Medicine and Gastroenterology, Faculty of Medicine, Assiut University Hospitals, Assiut, Egypt
| | - Faisal M. Sanai
- Liver Disease Research Centre, King Saud University, Riyadh, Kingdom of Saudi Arabia
- Department of Hepatobiliary Sciences and Liver Transplantation, King Abdulaziz Medical City, Riyadh, Kingdom of Saudi Arabia
| | - Khalid Alswat
- Division of Gastroenterology, Department of Medicine, King Saud University, Riyadh, Kingdom of Saudi Arabia
- Liver Disease Research Centre, King Saud University, Riyadh, Kingdom of Saudi Arabia
| | - Waleed Al-hamoudi
- Division of Gastroenterology, Department of Medicine, King Saud University, Riyadh, Kingdom of Saudi Arabia
- Liver Disease Research Centre, King Saud University, Riyadh, Kingdom of Saudi Arabia
| | - Safiyya M. Ali
- Liver Disease Research Centre, King Saud University, Riyadh, Kingdom of Saudi Arabia
| | - Hamad I. Al-Ashgar
- Department of Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Kingdom of Saudi Arabia
| | - Abdallah Al-Mdani
- Department of Gastroenterology, Riyadh Military Hospital, Riyadh, Kingdom of Saudi Arabia
| | - Ali Albenmousa
- Department of Gastroenterology, Riyadh Military Hospital, Riyadh, Kingdom of Saudi Arabia
| | - Faleh Z. Al Faleh
- Division of Gastroenterology, Department of Medicine, King Saud University, Riyadh, Kingdom of Saudi Arabia
| | - Mashael Al-Anazi
- Department of Infection and Immunity, Research Center, King Faisal Specialist Hospital and Research Center, P.O. Box 3354 (MBC-03), Riyadh, 11211 Kingdom of Saudi Arabia
| | - Nisreen Khalaf
- Department of Infection and Immunity, Research Center, King Faisal Specialist Hospital and Research Center, P.O. Box 3354 (MBC-03), Riyadh, 11211 Kingdom of Saudi Arabia
| | - Ahmed Al-Qahtani
- Liver Disease Research Centre, King Saud University, Riyadh, Kingdom of Saudi Arabia
- Department of Infection and Immunity, Research Center, King Faisal Specialist Hospital and Research Center, P.O. Box 3354 (MBC-03), Riyadh, 11211 Kingdom of Saudi Arabia
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Komatsu H, Inui A, Tsunoda T, Sogo T, Fujisawa T. Association between an IL-28B genetic polymorphism and the efficacy of the response-guided pegylated interferon therapy in children with chronic hepatic C infection. Hepatol Res 2013; 43:327-338. [PMID: 22970660 DOI: 10.1111/j.1872-034x.2012.01087.x] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2012] [Revised: 07/31/2012] [Accepted: 08/05/2012] [Indexed: 12/13/2022]
Abstract
AIM The relation between interleukin-28B (IL-28B) genotypes and treatment-induced hepatitis C virus (HCV) clearance in children is unknown. This was a retrospective study to evaluate the association between an IL-28B genotype (rs8099917) and pegylated (PEG) interferon (IFN) response. METHODS Sixty-three children (median age, 7 years; range, 3-17 years; 22 with HCV genotype 1 and 41 with genotype non-1) with chronic HCV infection who were treated with response-guided PEG IFN on the basis of viral load were evaluated. RESULTS The duration of treatment with PEG IFN was 24 weeks in one child (2%), 36 weeks in eight children (13%), 48 weeks in 36 children (57%), 60 weeks in 11 children (17%) and 72 weeks in seven children (11%). Of the total 63 children, 54 (86%) were initially treated with PEG IFN-α-2a monotherapy. The remaining nine (14%) received PEG IFN plus ribavirin as the initial therapy. Of the 54 children initially treated with monotherapy, 35 (65%) continued receiving monotherapy until the end of treatment. In the remaining 19 (35%), monotherapy was changed to PEG IFN plus ribavirin at 12 or 24 weeks of treatment. Of the total 63 children, 54 (86%) achieved a sustained virological response (SVR). In univariate analysis, rs8099917 genotype TT (P = 0.075) showed a weak association with SVR. However, the multivariate analysis revealed no predictive factors which had a significant association with SVR. CONCLUSION The IL-28B genotype was not a strong pretreatment predictor for SVR in a mixed genotype cohort of children treated with response-guided PEG IFN therapy.
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Affiliation(s)
- Haruki Komatsu
- Department of Pediatrics, Toho University, Sakura Medical Center, Sakura; Division of Hepatology and Gastroenterology, Department of Pediatrics, Eastern Yokohama Hospital, Yokohama, Japan
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Abstract
Combination therapy with pegylated interferon and ribavirin is the standard of care (SOC) for the treatment of chronic hepatitis C (CHC). Treating CHC with SOC may show a sustained virological response (SVR) in approximately 50-70 % of genotype 1 CHC patients and an SVR in 70-90 % of genotype 2 CHC patients. The genotype, baseline viral load, and viral kinetics (i.e., rapid virologic response and early virologic response) can be used as predictors of response-guided therapy. Nonetheless, host factors, e.g. age, ethnicity, insulin resistance, and genetic variations, may also play important roles in the SVR in CHC patients treated with SOC. Recent genome-wide association studies have demonstrated that single-nucleotide polymorphisms near the interleukin 28B gene (IL28B) were associated with SVR to treatment with SOC in CHC patients. The IL28B polymorphisms may contribute to the viral kinetics during treatment. Asian people have favorable IL28B polymorphisms. This factor may at least partly explain the high eradication rate of hepatitis C by SOC in Asia. Combination therapy with direct-acting antivirals (DAAs) and SOC can increase the SVR rates both in treatment-naïve and treatment-experienced patients. Although the IL28B polymorphisms also affect the SVR of triple therapy with SOC and first-generation protease inhibitors, pilot studies have demonstrated that potent DAAs might overcome the influence of IL28B polymorphisms. Thus, the treatment of hepatitis C virus infection could be simplified in the near future.
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Affiliation(s)
- Wan-Long Chuang
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, No. 100, Shih-Chuan 1st Road, Kaohsiung, Taiwan.
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Abstract
Genome-wide association studies have identified polymorphisms located near the gene encoding IL28B, which turned out to be the best predictor of response to pegylated interferon plus ribavirin for chronic hepatitis C virus (HCV) genotype 1 infection. This association was extended to spontaneous clearance of HCV, suggesting shared mechanisms of treatment and natural control of this virus. In addition to the biologic implications for innate immunity and HCV, a variety of clinical studies have suggested possible translation to a useful genetic test for practitioners. This article reviews the discovery, biology, and potential clinical applications that have stemmed from the seminal observation that IL28B polymorphisms are a main predictor of HCV clearance.
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Affiliation(s)
- Christoph T. Berger
- Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard Medical School
- Department of Internal Medicine and Department of Biomedicine, University Hospital Basel, Switzerland
| | - Arthur Y. Kim
- Division of Infectious Diseases, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA
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Rau M, Baur K, Geier A. Host genetic variants in the pathogenesis of hepatitis C. Viruses 2012; 4:3281-302. [PMID: 23342360 PMCID: PMC3528266 DOI: 10.3390/v4123281] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2012] [Revised: 11/17/2012] [Accepted: 11/17/2012] [Indexed: 02/06/2023] Open
Abstract
Direct-acting antiviral drugs (DAAs) are currently replacing antiviral therapy for Hepatitis C infection. Treatment related side effects are even worse and the emergence of resistant viruses must be avoided because of the direct-antiviral action. Altogether it remains a challenge to take treatment decisions in a clinical setting with cost restrictions. Genetic host factors are hereby essential to implement an individualized treatment concept. In recent years results on different genetic variants have been published with a strong association with therapy response, fibrosis and treatment-related side effects. Polymorphisms of the IL28B gene were identified as accurate predictors for therapy response and spontaneous clearance of HCV infection and are already used for diagnostic decisions. For RBV-induced side effects, such as hemolytic anemia, associations to genetic variants of inosine triphosphatase (ITPA) were described and different SLC28 transporters for RBV-uptake have been successfully analyzed. Fibrosis progression has been associated with variants of Vitamin D receptor (VDR) and ABCB11 (bile salt export pump). Cirrhotic patients especially have a high treatment risk and low therapy response, so that personalized antiviral treatment is mandatory. This review focuses on different host genetic variants in the pathogenesis of Hepatitis C at the beginning of a new area of treatment.
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Affiliation(s)
- Monika Rau
- Division of Hepatology, Department of Internal Medicine II, University Hospital Würzburg, Oberdürrbacherstraße 6, 97080 Würzburg, Germany;
| | - Katharina Baur
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Rämistrasse 100, 8091 Zurich, Switzerland;
| | - Andreas Geier
- Division of Hepatology, Department of Internal Medicine II, University Hospital Würzburg, Oberdürrbacherstraße 6, 97080 Würzburg, Germany;
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Rämistrasse 100, 8091 Zurich, Switzerland;
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Jia Z, Ding Y, Tian S, Niu J, Jiang J. Test of IL28B polymorphisms in chronic hepatitis C patients treated with PegIFN and ribavirin depends on HCV genotypes: results from a meta-analysis. PLoS One 2012; 7:e45698. [PMID: 23029188 PMCID: PMC3448689 DOI: 10.1371/journal.pone.0045698] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2012] [Accepted: 08/22/2012] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Many studies have been published on the association between single nucleotide polymorphisms (SNP) near the IL28B gene and response to the combined treatments of pegylated-interferon (PegIFN) and ribavirin (RBV) in chronic HCV-infected patients, but without identical conclusions. The aim of this study was to assess impact of the IL28B polymorphisms on the effect of HCV standard treatment using meta-analysis based method. METHODS Association studies between polymorphisms of rs12979860 or rs8099917 and response to PegIFN/RBV treatment in chronic HCV patients were retrieved from PubMed. Data of qualified studies on sustained virological response (SVR) in different genotypes were extracted and analyzed using meta-analysis method in Stata 10 software. RESULTS Thirty-four papers, containing 46 independent studies, were included in the analysis. In the HCV G1/4 patients without treatment history, individuals carrying rs12979860 CC genotype were more likely to achieve SVR (OR 3.97, 95%CI 3.29-4.80) compared to those carrying CT/TT genotypes. Similar results were observed in the HCV G1/4 patients with unsuccessful or unknown treatment history (OR 3.76, 95%CI 2.67-5.28) or in the patients co-infected with human immunodeficiency virus (OR 5.20, 95%CI 3.04-8.90). However, associations could not be observed in HCV G2/3 patients. For rs8099917, similar results were obtained for genotype TT compared to genotypes TG/GG, indicating that TT genotype was significantly associated with better treatment response in patients infected with genotype 1 or 4 HCV, but not genotype 2 or 3 HCV. CONCLUSION Polymorphisms of rs12979860 and rs8099917 near IL28B only associate with the treatment response to PegIFN/RBV in patients infected with HCV genotype 1 or 4 but not with genotype 2 or 3, irrespective of the previous treatment history or HIV co-infected status. Therefore, identification of IL28B genotypes is necessary only in patients infected with relatively difficult-to-treat genotype 1 or 4 HCV.
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Affiliation(s)
- Zhifang Jia
- Division of Clinical Epidemiology, First Hospital of Jilin University, Changchun, China
| | - Yanhua Ding
- Department of Phase I Clinical Trials of Medicine, First Hospital of Jilin University, Changchun, China
| | - Suyan Tian
- Division of Clinical Epidemiology, First Hospital of Jilin University, Changchun, China
| | - Junqi Niu
- Department of Hepatology, First Hospital of Jilin University, Changchun, China
| | - Jing Jiang
- Division of Clinical Epidemiology, First Hospital of Jilin University, Changchun, China
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Ferenci P. Response guided therapy in patients with chronic hepatitis C - yesterday, today and tomorrow. Best Pract Res Clin Gastroenterol 2012; 26:463-469. [PMID: 23199505 DOI: 10.1016/j.bpg.2012.09.002] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2012] [Accepted: 09/06/2012] [Indexed: 01/31/2023]
Abstract
The rapidity of viral disappearance on antiviral treatment of chronic hepatitis C with peginterferon/ribavirin correlates with the cure rate. The earlier the virus becomes undetectable, the higher are the response rates. This observation is the basis of response-guided therapy. Viral clearance within the first 4 weeks of treatment is called a rapid virologic response (RVR). The rate of RVR varies among various populations, with the highest one observed in Asian patients and the lowest in African-Americans. This can be partly explained by a polymorphism in the region of the 5IL28B gene. In patients infected with genotypes 1 and 4 with RVR treatment with peginterferon/ribavirin can be shortened to just 24 weeks (with SVR rates of >80%). In contrast, patients with a slow decline in viral load (>2 log drop after 12 weeks with still detectable virus) may benefit from treatment extension to 72 weeks. The virologic response criteria were modified for triple therapy (extended RVR; HCV-RNA undetectable: telaprevir week 4 and 12; boceprevir week 8 and 24). Patients with eRVR can be cured by an abbreviated treatment regime. Further modification and unification of response criteria are needed for the currently evaluated interferon-free treatment regimes.
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Affiliation(s)
- Peter Ferenci
- Internal Medicine 3, Gastroenterology and Hepatology, Medical University of Vienna, Austria.
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Thompson AJ. Genetic factors and hepatitis C virus infection. Gastroenterology 2012; 142:1335-9. [PMID: 22537440 DOI: 10.1053/j.gastro.2012.01.046] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2011] [Revised: 01/27/2012] [Accepted: 01/31/2012] [Indexed: 01/01/2023]
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