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Amjed S, Saleem HGM, Ullah S, Latif S, Shabana, Jafar J, Waqar AB. Impact of ITPA gene polymorphism for predicting anemia and treatment outcome in HCV infected patients taking Sofosbuvir Ribavirin therapy. BMC Infect Dis 2024; 24:301. [PMID: 38468199 PMCID: PMC10926675 DOI: 10.1186/s12879-024-09188-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Accepted: 03/03/2024] [Indexed: 03/13/2024] Open
Abstract
BACKGROUND Globally, 80 million people are suffering from chronic Hepatitis C virus (HCV) infection. Sofosbuvir ribavirin-based anti-HCV therapy is associated with anemia and other adverse effects. Polymorphisms of Inosine triphosphatase (ITPA) gene may cause functional impairment in the Inosine triphosphate pyrophosphatase enzyme, resulting in enhanced sustained viral response (SVR) and protection from ribavirin-associated anemia in patients on therapy. The study objective was to investigate the effect of Inosine triphosphatase gene polymorphism on SVR achievement, hemoglobin decline and ribavirin dose reduction in patients on therapy. METHODS This prospective cohort study was of 170 hepatitis C infected patients received 6-month sofosbuvir ribavirin therapy. Patient viral load, reduction in ribavirin amount, liver function test, and complete blood count were noted monthly. Inosine triphosphatase variants rs1127354 and rs7270101 were assessed through the restriction fragment length polymorphism and confirmed using Sanger sequencing. The impact of polymorphism on cumulative reduction of ribavirin, and anti-HCV therapy outcome were studied. RESULTS A total of 74.3% of patients had ITPA rs1127354 CC genotype, 25.7% were CA and AA 0%. The frequency of ITPA genotype rs7270101-AA was 95%, AC 5%, and CC was 0%. ITPA rs1127354-CA had a notably positive impact on SVR achievement with a zero-relapse rate. ITPA rs1127354-CA genotype was significantly (P ˂0.05) protective against ≥ 2 g/dl Hb reduction from baseline to 1st, 2nd and 6th months of therapy. During treatment, Hb reduction ≥ 10 g/dl was frequently observed in rs1127354-CC genotype and rs7270101-AA genotype patients. Ribavirin dose reduction was significantly (P ˂0.05) high in rs1127354-CC genotype as compared to genotype CA whereas no significant difference was observed in ribavirin dose reduction in rs7270101 AA and non-AA genotype. Patient baseline characteristics such as age, body mass index, rs1127354-CC genotype, and baseline Hb were significantly associated with significant Hb reduction. CONCLUSION Pretreatment evaluation of ITPA polymorphism can be a diagnostic tool to find out patients at risk of anemia and improve treatment adherence. ITPA genotype rs1127354-CA contributes to improved compliance with ribavirin dose and protects against hemoglobin decline in HCV patients while taking ribavirin-based therapy. However, ITPA rs1127354, rs7270101 polymorphism have no significant impact on SVR achievement.
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Affiliation(s)
- Sameen Amjed
- University Institute of Medical Laboratory Technology, Faculty of Allied Health Sciences, The University of Lahore, Raiwind Road Campus, Lahore, Pakistan.
- Medical Laboratory Technology Department, Faculty of Rehabilitation and Allied Health Sciences, RIPHAH International University, Gulberg Campus, Lahore, Pakistan.
| | - Hafiz Ghulam Murtaza Saleem
- University Institute of Medical Laboratory Technology, Faculty of Allied Health Sciences, The University of Lahore, Raiwind Road Campus, Lahore, Pakistan
- Medical Laboratory Technology Department, Faculty of Rehabilitation and Allied Health Sciences, RIPHAH International University, Gulberg Campus, Lahore, Pakistan
| | - Sajjad Ullah
- University Institute of Medical Laboratory Technology, Faculty of Allied Health Sciences, The University of Lahore, Raiwind Road Campus, Lahore, Pakistan
| | - Shahzad Latif
- Gastroenterology Department, Akthar Saeed Medical and Dental College, Lahore, Pakistan
| | - Shabana
- Department of Microbiology and Molecular Genetics, University of the Punjab, Lahore, Pakistan
| | - Junaid Jafar
- Specilized Health Care and Medical Education Department, Lahore, Punjab, Pakistan
| | - Ahmad Bilal Waqar
- University Institute of Medical Laboratory Technology, Faculty of Allied Health Sciences, The University of Lahore, Raiwind Road Campus, Lahore, Pakistan
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Ma Z, Sun Y, Du P, Li X. Association between inosine triphosphatase rs1127354 polymorphisms and ribavirin-induced anaemia and outcome in hepatitis C virus-infected patients: A meta-analysis. J Clin Pharm Ther 2020; 45:1218-1227. [PMID: 32735044 DOI: 10.1111/jcpt.13232] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2020] [Revised: 06/15/2020] [Accepted: 06/26/2020] [Indexed: 11/27/2022]
Abstract
WHAT IS KNOWN AND OBJECTIVES The association between inosine triphosphatase (ITPA) rs1127354 polymorphisms in HCV-infected patients receiving ribavirin (RBV)-based therapy, and the risk of adverse drug reaction and outcomes is still unclear. A meta-analysis was conducted to summarize and clarify this association systematically. METHODS A comprehensive search was performed in PubMed, Embase and Web of Sciences, and twenty-two studies were selected from the literature search. Pooled odds ratio (OR) and 95% confidence interval (95% CI) were estimated by either fixed- or random-effects models. RESULTS Four outcomes were evaluated: (a) haemoglobin decline: significant associations with haemoglobin decline were found for rs1127354 CC VS CA + AA (OR = 10.59, 95% CI = 6.39-17.54); (b) severe anaemia: significant association with severe anaemia was observed for rs1127354 CC VS CA + AA (OR = 16.24, 95% CI = 6.21-42.43); (c) sustained virological response (SVR): CC genotype carriers had a decrease SVR during treatment (OR = 0.65, 95% CI = 0.52-0.81); (d) RBV dose reduction or stopping treatment: although statistical evidence of an association was found between the polymorphism and RBV dose reduction during treatment (OR = 1.80, 95% CI = 1.03-3.13), the sensitivity analysis suggested this result was not robust. WHAT IS NEW AND CONCLUSION Patients with ITPA rs1127354 CC polymorphism are more likely to develop haemolytic anaemia, severe anaemia and decreased SVR. Testing for this genetic polymorphism may benefit patients.
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Affiliation(s)
- Zhichao Ma
- Department of Pharmacy, Affiliated Hospital of Chifeng University, Chifeng, China
| | - Yi Sun
- Department of Pharmacy, Affiliated Hospital of Chifeng University, Chifeng, China
| | - Pengqiang Du
- Department of Pharmacy, Fuwai Central China Cardiovascular Hospital, Central China Fuwai Hospital of Zhengzhou University, Henan Provincial People's Hospital, Zhengzhou, China
| | - Xingang Li
- Department of Pharmacy, Beijing Friendship Hospital, Capital Medical University, Beijing, China
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Impact of hepatitis C virus genotype 3 on liver disease progression in a Chinese national cohort. Chin Med J (Engl) 2020; 133:253-261. [PMID: 31934936 PMCID: PMC7004615 DOI: 10.1097/cm9.0000000000000629] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Supplemental Digital Content is available in the text Background: Hepatitis C virus (HCV) genotype 3, particularly subtype 3b, is increasing in prevalence and distribution in China. This study evaluated the prevalence, regional distribution, clinical characteristics, host factors, treatment outcomes, and disease progression of patients with HCV genotype 3 in China. Methods: A 5-year follow-up was preceded by a cross-sectional study. Treatment choices were at the discretion of treating physicians. Estimated infection time to overall-disease-progression (defined by ≥1 of: newly diagnosed cirrhosis; cirrhosis at baseline, Child-Turcotte-Pugh score increased 2 points or more; progression from compensated cirrhosis to decompensated cirrhosis; hepatocellular carcinoma; liver transplantation; or death) was calculated using the Kaplan-Meier method. Cox regression analyses were conducted to evaluate the risk factors for disease progression. Results: The cross-sectional study enrolled 997 patients, including 91 with HCV genotype 3 infection. Among them, subtype 3b (57.1%) was more dominant than subtype 3a (38.5%). Five hundred and twelve patients were included into the follow-up phase. Among patients analyzed for estimated infection time to overall-disease-progression, 52/304 (17.1%) patients with HCV genotype 1 and 4/41 (9.8%) with HCV genotype 3 (4/26 with genotype 3b, 0/13 with genotype 3a, and 0/2 with undefined subtype of genotype 3) experienced overall-disease-progression. Patients with HCV genotype 3 were younger than those with genotype 1 (mean age: 39.5 ± 8.7 vs. 46.9 ± 13.6 years) and demonstrated more rapid disease progression (mean estimated infection time to overall-disease-progression 27.1 vs. 35.6 years). Conclusions: HCV genotype 3, specifically subtype 3b, is associated with more rapid progression of liver disease. Further analysis to compare HCV subtype 3a and 3b is needed in high prevalence regions. Trial registration: NCT01293279, https://clinicaltrials.gov/ct2/show/NCT01293279; NCT01594554, https://clinicaltrials.gov/ct2/show/NCT01594554.
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Chi X, Wang M, Pan Y, Jiang J, Jiang T, Yan H, Wu R, Wang X, Gao X, Niu J. Inosine triphosphate pyrophosphatase polymorphisms are predictors of anemia in Chinese patients with chronic hepatitis C during therapy with ribavirin and interferon. J Gastroenterol Hepatol 2020; 35:97-103. [PMID: 31359493 DOI: 10.1111/jgh.14812] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2019] [Revised: 06/26/2019] [Accepted: 07/21/2019] [Indexed: 12/14/2022]
Abstract
BACKGROUND AND AIM Polymorphisms of inosine triphosphate pyrophosphatase (rs1127354 and rs6051702) and interferon lambda 4 (IFLN4) (rs12979860) are indicators of anemia and/or sustained virological response (SVR) in patients with chronic hepatitis C on ribavirin/interferon. The study aims to investigate the associations of rs1127354, rs6051702, and rs12979860 with hemoglobin levels and SVR in patients on ribavirin/interferon. METHODS Polymorphisms were detected by pyrosequencing. Levels of hemoglobin and hepatitis C virus (HCV) RNA were measured at weeks 2, 4, 12, 24, 36, 48, and 72 of treatment. RESULTS A total of 351 patients (median age, 50 years; male, 71.2%) were recruited and had HCV genotypes 1b (55.8%) or 2a (37.0%). Vedian baseline hemoglobin and HCV RNA were 155 g/dL and 6.07 log10 IU/mL. Major allele homozygosity was observed in 76.3% for rs1127354 (CC), 70.9% for rs6051702 (AA), and 89.7% for rs12979860 (CC). At 4 weeks of ribavirin/interferon treatment, a more significant reduction in hemoglobin was observed with rs112754 CC than with AC/AA (P < 0.05). A decline ≥3 g/dL was more common in patients with the rs112754 CC than with the other two polymorphisms. No significant change was observed regarding rs6051702 and rs12979860 variants. In the multivariable analysis, rs1127354 AA/AC (vs CC) were independently associated with lower odds of hemoglobin decline of > 3 g/dL at 4 weeks (odds ratio, 0.21; 95% CI, 0.09-0.46; P < 0.0001). In 258 patients with 72-week outcome data available, rs1127354, rs6051702, and rs12979860 were not associated with SVR (all P > 0.05). CONCLUSION rs1127354 polymorphisms are associated with hemoglobin levels in Chinese patients with chronic hepatitis C treated with ribavirin/interferon.
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Affiliation(s)
- Xiumei Chi
- Department of Hepatology, The First Hospital of Jilin University, Changchun, China
| | - Moli Wang
- Department of Hepatology, The Fourth Hospital of Jilin University, Changchun, China
| | - Yu Pan
- Department of Hepatology, The First Hospital of Jilin University, Changchun, China
| | - Jing Jiang
- Department of Clinical Epidemiology, The First Hospital of Jilin University, Changchun, China
| | - Tao Jiang
- Infectious Disease Hospital of Jilin Province, Changchun, China
| | - Hongqing Yan
- Department of Hepatology, The First Hospital of Jilin University, Changchun, China
| | - Ruihong Wu
- Department of Hepatology, The First Hospital of Jilin University, Changchun, China
| | - Xiaomei Wang
- Department of Hepatology, The First Hospital of Jilin University, Changchun, China
| | - Xiuzhu Gao
- Department of Hepatology, The First Hospital of Jilin University, Changchun, China
| | - Junqi Niu
- Department of Hepatology, The First Hospital of Jilin University, Changchun, China
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McGarvey PB, Nightingale A, Luo J, Huang H, Martin MJ, Wu C, Consortium U. UniProt genomic mapping for deciphering functional effects of missense variants. Hum Mutat 2019; 40:694-705. [PMID: 30840782 PMCID: PMC6563471 DOI: 10.1002/humu.23738] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2018] [Revised: 12/17/2018] [Accepted: 02/17/2019] [Indexed: 01/08/2023]
Abstract
Understanding the association of genetic variation with its functional consequences in proteins is essential for the interpretation of genomic data and identifying causal variants in diseases. Integration of protein function knowledge with genome annotation can assist in rapidly comprehending genetic variation within complex biological processes. Here, we describe mapping UniProtKB human sequences and positional annotations, such as active sites, binding sites, and variants to the human genome (GRCh38) and the release of a public genome track hub for genome browsers. To demonstrate the power of combining protein annotations with genome annotations for functional interpretation of variants, we present specific biological examples in disease-related genes and proteins. Computational comparisons of UniProtKB annotations and protein variants with ClinVar clinically annotated single nucleotide polymorphism (SNP) data show that 32% of UniProtKB variants colocate with 8% of ClinVar SNPs. The majority of colocated UniProtKB disease-associated variants (86%) map to 'pathogenic' ClinVar SNPs. UniProt and ClinVar are collaborating to provide a unified clinical variant annotation for genomic, protein, and clinical researchers. The genome track hubs, and related UniProtKB files, are downloadable from the UniProt FTP site and discoverable as public track hubs at the UCSC and Ensembl genome browsers.
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Affiliation(s)
- Peter B. McGarvey
- Innovation Center for Biomedical InformaticsGeorgetown University Medical CenterWashingtonDC
- Protein Information ResourceGeorgetown Medical CenterWashingtonDC
| | - Andrew Nightingale
- European Molecular Biology LaboratoryEuropean Bioinformatics Institute, Wellcome Genome CampusHinxtonUnited Kingdom
| | - Jie Luo
- European Molecular Biology LaboratoryEuropean Bioinformatics Institute, Wellcome Genome CampusHinxtonUnited Kingdom
| | - Hongzhan Huang
- Center for Bioinformatics and Computational BiologyUniversity of DelawareNewarkDelaware
| | - Maria J. Martin
- European Molecular Biology LaboratoryEuropean Bioinformatics Institute, Wellcome Genome CampusHinxtonUnited Kingdom
| | - Cathy Wu
- Center for Bioinformatics and Computational BiologyUniversity of DelawareNewarkDelaware
| | - UniProt Consortium
- European Molecular Biology LaboratoryEuropean Bioinformatics Institute, Wellcome Genome CampusHinxtonUnited Kingdom
- Swiss Institute of BioinformaticsCentre Medical UniversitaireGenevaSwitzerland
- Protein Information ResourceGeorgetown Medical CenterWashingtonDC
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Safety of Sofosbuvir and Ribavirin Combination Therapy in a Patient Who Developed Anemia due to Ribavirin. Case Reports Hepatol 2018; 2017:8793895. [PMID: 29375917 PMCID: PMC5742439 DOI: 10.1155/2017/8793895] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2017] [Revised: 11/12/2017] [Accepted: 11/20/2017] [Indexed: 11/17/2022] Open
Abstract
Interferon (IFN) and ribavirin (RBV) combination therapy was previously the standard of care for treatment of hepatitis C virus (HCV) genotype 2 infection. But, it often induced hemolytic anemia. In 2014, sofosbuvir (SOF) was approved for the treatment of chronic HCV genotype 2 in Japan. SOF/RBV therapy is more effective against genotype 2 than IFN/RBV therapy. We report a case of a 74-year-old woman with chronic HCV genotype 2b infection. She received five treatments including RBV and IFN therapy before SOF was approved and all of them were ineffective. Therapies that included RBV induced severe anemia and led to discontinuation of treatment. With pegylated IFN/RBV therapy, the maximum change in hemoglobin (Hb) from baseline was -3.7 g/dL. However, SOF/RBV therapy was effective and she achieved sustained virologic response (SVR) with a maximum change in Hb from baseline of only -1.2 g/dL. We also found reticulocyte count was very low during treatment in this case and speculate it was one of the reasons that she developed hemolytic anemia with RBV. In conclusion, SOF/RBV therapy is effective and allowed the patient to achieve SVR. An SOF/RBV regimen is safe and effective for patients who have or are at risk of anemia induced by RBV.
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Kozuka R, Hai H, Teranishi Y, Motoyama H, Kawamura E, Hagihara A, Uchida-Kobayashi S, Morikawa H, Enomoto M, Murakami Y, Kawada N, Tamori A. Correlation between polymorphism in the inosine triphosphatase and the reductions in hemoglobin concentration and ribavirin dose during sofosbuvir and ribavirin therapy. J Gastroenterol Hepatol 2017; 32:1495-1502. [PMID: 28109022 DOI: 10.1111/jgh.13743] [Citation(s) in RCA: 9] [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] [Received: 10/11/2016] [Revised: 11/28/2016] [Accepted: 01/04/2017] [Indexed: 01/17/2023]
Abstract
BACKGROUND AND AIM It is unclear whether polymorphism in the inosine triphosphatase (ITPA) gene correlates to the reduction in hemoglobin (Hb) concentrations during sofosbuvir (SOF) and ribavirin (RBV) therapy. This study investigated the effects of the ITPA polymorphism on Japanese patients with chronic hepatitis C virus genotype 2 infection treated with SOF/RBV therapy. METHODS In 106 patients treated with SOF/RBV therapy, this study assessed the effects of the ITPA polymorphism (rs1127354) on anemia, RBV dose reduction, and sustained virological response. RESULTS Of the 106 patients, 80 had the CC genotype, whereas 26 had a non-CC genotype in ITPA. Patients with the CC genotype had significantly larger reductions in Hb concentrations than those with a non-CC genotype throughout the treatment course. RBV dose reduction was required in 18/106 (17.0%) patients, with a significantly higher frequency in patients with the CC genotype than in those with a non-CC genotype (P = 0.010). In multivariate analysis, age ≥ 65 years (P = 0.011) and the ITPA CC genotype (P < 0.0001) were factors significantly associated with anemia throughout the treatment course. Sustained virological response was achieved in 99.0% of all patients: 98.7% of patients with the CC genotype and 100% of patients with a non-CC genotype. CONCLUSIONS Inosine triphosphatase polymorphism appeared to correlate with anemia incidence and RBV dose reduction during SOF/RBV therapy, but not the clinical outcome. Careful monitoring of Hb concentrations and prompt adjustment of RBV doses are required for successful treatment, particularly in patients harboring the ITPA CC genotype or age ≥ 65 years.
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Affiliation(s)
- Ritsuzo Kozuka
- Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Hoang Hai
- Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Yuga Teranishi
- Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Hiroyuki Motoyama
- Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Etsushi Kawamura
- Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Atsushi Hagihara
- Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | | | - Hiroyasu Morikawa
- Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Masaru Enomoto
- Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Yoshiki Murakami
- Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Norifumi Kawada
- Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Akihiro Tamori
- Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka, Japan
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Morio K, Imamura M, Kawakami Y, Nakahara T, Nagaoki Y, Kawaoka T, Tsuge M, Hiramatsu A, Aikata H, Hayes CN, Makokha GN, Ochi H, Amano H, Arataki K, Moriya T, Ito H, Tsuji K, Kohno H, Waki K, Tamura T, Nakamura T, Chayama K. ITPA polymorphism effects on decrease of hemoglobin during sofosbuvir and ribavirin combination treatment for chronic hepatitis C. J Gastroenterol 2017; 52:746-753. [PMID: 27822709 DOI: 10.1007/s00535-016-1279-9] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2016] [Accepted: 10/19/2016] [Indexed: 02/04/2023]
Abstract
BACKGROUND Polymorphisms in the inosine triphosphatase (ITPA) gene is associated with anemia induced by peg-interferon (PEG-IFN) plus ribavirin (RBV) treatment for patients with chronic hepatitis C virus (HCV) infection. However, the effect of ITPA polymorphism on sofosbuvir plus RBV treatment is unknown. METHODS Two hundred and forty-four patients with chronic HCV genotype 2 infection without decompensated liver cirrhosis were treated with sofosbuvir plus RBV for 12 weeks. The effects of ITPA polymorphism on hemoglobin levels and RBV dose reduction and treatment response were analyzed. ITPA (rs1127354) was genotyped using the Invader assay. Multivariate regression analysis was performed to identify factors associated with sustained virological response (SVR). RESULTS Overall, SVR12 was achieved in 231 (94.7%) patients, based on intention to treat analysis. During the therapy, reduction of hemoglobin levels was significantly greater in ITPA genotype CC patients than CA/AA patients. Therefore, the cumulative proportion of patients with RBV dose reduction was significantly higher and total dose of RBV was significantly lower in patients with CC genotype compared to CA/AA genotypes. SVR12 rates were similar between ITPA genotypes CC and CA/AA (94.7 and 94.4%, respectively, P = 0.933). Multivariate logistic regression analysis identified FIB4 index <3.25 (odds ratio [OR], 9.388 for ≥3.25; P = 0.005) and low body weight (OR, 1.059, for high body weight; P = 0.017) as independent predictors for SVR12. CONCLUSIONS ITPA polymorphism influences hemoglobin levels and incidence of RBV dose reduction during sofosbuvir plus RBV therapy. However, ITPA genotype CC patients can expect a curative effect equivalent to CA/AA patients for chronic HCV genotype 2 infection.
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Affiliation(s)
- Kei Morio
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical and Health Science, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Michio Imamura
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical and Health Science, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Yoshiiku Kawakami
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical and Health Science, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Takashi Nakahara
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical and Health Science, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Yuko Nagaoki
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical and Health Science, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Tomokazu Kawaoka
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical and Health Science, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Masataka Tsuge
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical and Health Science, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Akira Hiramatsu
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical and Health Science, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Hiroshi Aikata
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical and Health Science, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Clair Nelson Hayes
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical and Health Science, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Grace Naswa Makokha
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical and Health Science, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Hidenori Ochi
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical and Health Science, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
- Laboratory for Digestive Diseases, SNP Research Center, The Institute of Physical and Chemical Research (RIKEN), Hiroshima, Japan
| | | | | | | | | | - Keiji Tsuji
- Hiroshima Red Cross Hospital, Hiroshima, Japan
| | | | - Koji Waki
- Hiroshima City Asa Hospital, Hiroshima, Japan
| | | | | | - Kazuaki Chayama
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical and Health Science, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.
- Laboratory for Digestive Diseases, SNP Research Center, The Institute of Physical and Chemical Research (RIKEN), Hiroshima, Japan.
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Jimmerson LC, Clayton CW, MaWhinney S, Meissner EG, Sims Z, Kottilil S, Kiser JJ. Effects of ribavirin/sofosbuvir treatment and ITPA phenotype on endogenous purines. Antiviral Res 2017; 138:79-85. [PMID: 27956135 PMCID: PMC10837792 DOI: 10.1016/j.antiviral.2016.12.005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2016] [Revised: 11/23/2016] [Accepted: 12/03/2016] [Indexed: 12/15/2022]
Abstract
Ribavirin (RBV), a purine analog, causes hemolytic anemia in some patients. In vitro, anemia appears to result from depletion of endogenous purines, but there are limited data in vivo. Single nucleotide polymorphisms in the gene encoding the inosine triphosphatase (ITPA) enzyme have been associated with protection against RBV-induced anemia and may mediate the effect of RBV treatment on endogenous purines. The purpose of this work was to determine the effect of RBV treatment on endogenous purine concentrations in individuals being treated for chronic hepatitis C virus (HCV) infection. Adenosine triphosphate (ATP), guanosine triphosphate (GTP), inosine triphosphate (ITP) and ribavirin triphosphate (RTP) were measured in whole blood obtained from 47 HCV-infected individuals at day zero (baseline), day three, day 28 and day 84 of RBV/sofosbuvir (SOF) treatment. ATP decreased -35.1% and -38.6% (p < 0.0001) at day 28 and day 84 of treatment, respectively compared to baseline. The decrease in ATP was greater in patients with ≤60% ITPA activity compared to those with 100% ITPA activity (-29.4% vs. -9.6%). GTP did not change during treatment but was 16.5% (p = 0.01) higher per 100 pmol/106 cells RTP in those with 100% ITPA activity. No significant change or effect of RTP or ITPA phenotype was noted for ITP. In summary, only ATP was reduced by RBV/SOF treatment and ITPA variants had larger reductions in ATP suggesting RBV-induced anemia is due to a different mechanism than predicted from in-vitro studies. These data emphasize the importance of characterizing the effect of nucleos(t)ide analog treatment on endogenous purines in-vivo.
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Affiliation(s)
- Leah C Jimmerson
- University of Colorado, Skaggs School of Pharmacy and Pharmaceutical Sciences Aurora, CO, USA
| | | | | | - Eric G Meissner
- Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, MD, USA
| | - Zayani Sims
- Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, MD, USA
| | - Shyamasundaran Kottilil
- Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, MD, USA
| | - Jennifer J Kiser
- University of Colorado, Skaggs School of Pharmacy and Pharmaceutical Sciences Aurora, CO, USA.
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Jimmerson LC, Urban TJ, Truesdale A, Baouchi-Mokrane F, Kottilil S, Meissner EG, Sims Z, Langness JA, Hodara A, Aquilante CL, Kiser JJ. Variant Inosine Triphosphatase Phenotypes Are Associated With Increased Ribavirin Triphosphate Levels. J Clin Pharmacol 2017; 57:118-124. [PMID: 27349952 PMCID: PMC10725569 DOI: 10.1002/jcph.783] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2016] [Accepted: 06/09/2016] [Indexed: 12/26/2022]
Abstract
Individuals with lower inosine triphosphatase (ITPA) enzyme activity have a reduced likelihood of experiencing hemolytic anemia during hepatitis C virus (HCV) treatment containing ribavirin (RBV). Because ITPA degrades purines and RBV is a purine analogue, it is conceivable that ITPA activity may affect intracellular RBV concentrations. Here we assessed the association between ITPA activity phenotype and concentrations of RBV triphosphate (RBV-TP) in red blood cells (RBCs) during HCV treatment. RBV-TP was quantified in the RBCs of 177 HCV-infected individuals at a median (range) of 84 (19 to 336) days into HCV treatment that included RBV. Mean (SD) RBV-TP concentrations were 92.8 (51.6), 101.3 (53.5), 184.8 (84.5), and 197.7 (64.6) pmol/106 cells for 100%, 60%, 30%, and ≤10% ITPA activity groups, respectively. Overall, RBV-TP was approximately 2-fold higher in patients with ≤30% ITPA activity compared to 100% activity (P < .0001). Despite higher RBV-TP levels, individuals with variant ITPA phenotypes had less anemia. The 100% activity group had, on average, a -2.20 g/dL drop in hemoglobin vs -1.43 g/dL (P = .04) for 60% activity, -1.14 g/dL (P = .008) for 30% activity, and -0.70 g/dL (P = .06) for ≤10% activity. This finding of higher RBV-TP concentrations in RBCs in ITPA variants was unexpected given that ITPA activity-deficient individuals have a reduced likelihood of RBV-induced anemia. It also refutes the hypothesis that the mechanism by which ITPA variants are protected against anemia is due to lower RBV-TP levels in RBCs.
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Affiliation(s)
- Leah C. Jimmerson
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Denver, Aurora, Colorado
| | - Thomas J. Urban
- Division of Pharmacotherapy and Experimental Therapeutics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | | | | | - Shyam Kottilil
- Division of Clinical Care and Research, Institute of Human Virology, University of Maryland, Baltimore, Maryland
- Critical Care Medicine Department, Clinical Center, National Institute of Health, Bethesda, Maryland
| | - Eric G. Meissner
- Division of Infectious Diseases, Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina
- Critical Care Medicine Department, Clinical Center, National Institute of Health, Bethesda, Maryland
| | - Zayani Sims
- Critical Care Medicine Department, Clinical Center, National Institute of Health, Bethesda, Maryland
| | - Jacob A. Langness
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Denver, Aurora, Colorado
- Department of Pharmacy, University of Colorado Hospital, Aurora, Colorado
| | - Ariel Hodara
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Denver, Aurora, Colorado
| | - Christina L. Aquilante
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Denver, Aurora, Colorado
| | - Jennifer J. Kiser
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Denver, Aurora, Colorado
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11
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Kheloufi F, Poizot-Martin I, Garraffo R, Tavenard A, Quaranta S, Renault A, Lavrut T, Bourlière M, Halfon P, Piroth L, Bellissant E, Lacarelle B, Molina JM, Solas C. ITPA deficiency and ribavirin level are still predictive of anaemia in HCV-HIV-coinfected patients receiving ribavirin combined with a first-generation DAA (ANRS HC27 study). Antivir Ther 2016; 22:461-469. [PMID: 27583701 DOI: 10.3851/imp3074] [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: 08/11/2016] [Indexed: 10/21/2022]
Abstract
BACKGROUND We aimed to determine the impact of inosine triphosphatase (ITPA) deficiency on ribavirin (RBV)-induced anaemia in HIV-HCV-coinfected patients receiving a triple therapy including the haematotoxic direct-acting antiviral agent boceprevir (BOC). METHODS Patients of the ANRS HC27 BocepreVIH study were genotyped for two ITPA single nucleotide polymorphisms involved in ITPA deficiency. RBV trough concentration (Ctrough) was determined at week (W)4 and W8. Impact of ITPA deficiency on anaemia, RBV Ctrough, response and haematotoxicity (grade 3/4 anaemia, erythropoietin [EPO] use, RBV dose reduction or transfusion between day [D]0 and W8) was evaluated. Impact of RBV Ctrough on anaemia was also studied. RESULTS Among the 63 genotyped patients, 33% had a predicted ITPA deficiency. ITPA deficiency was associated with a lower haemoglobin (Hb) decline both at W4 (-1.0 g/dl versus -2.1 g/dl; P=0.02) and W8 (-2.7 g/dl versus -4.1 g/dl; P=0.05). None of the patients with ITPA deficiency received EPO between D0-W8 versus 26% of patients without ITPA deficiency (P=0.01). RBV Ctrough was associated with Hb decrease both at W4 and W8 and an RBV Ctrough cutoff value of 2 µg/ml was significantly associated with a W4 Hb decline >2 g/dl. Haematotoxicity was significantly associated with a lower W4 Hb level (P=0.017), absence of ITPA deficiency (P=0.018) and higher RBV Ctrough (P=0.012). ITPA deficiency, W4 RBV Ctrough and gender were independent predictors of anaemia at W4. ITPA deficiency was not associated with virological response. CONCLUSIONS ITPA deficiency and RBV Ctrough are still predictive of RBV-induced anaemia in HIV-HCV-coinfected patients treated with RBV combined with a first-generation direct antiviral agent.
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Affiliation(s)
- Farid Kheloufi
- Aix Marseille University, APHM Timone, Service de Pharmacocinétique et Toxicologie, Marseille, France
- CRO2 INSERM U911, Marseille, France
- Centre Régional de Pharmacovigilance Marseille Provence Corse, Service de pharmacologie clinique et pharmacovigilance, APHM Sainte-Marguerite, Marseille, France
| | - Isabelle Poizot-Martin
- Aix Marseille University, APHM Sainte-Marguerite, Service d'Immuno-hématologie clinique, Marseille, France
- INSERM, UMR912 (SESSTIM), 13006, Marseille, France
| | - Rodolphe Garraffo
- Faculty of Medicine of Nice, Hôpital Pasteur, Laboratoire de Pharmacologie, Nice, France
| | - Aude Tavenard
- Rennes 1 University, Rennes, France
- Rennes University Hospital, Department of Clinical Pharmacology, Rennes, France
- INSERM 1414 CIC-P Clinical Investigation Centre, Rennes, France
| | - Sylvie Quaranta
- Aix Marseille University, APHM Timone, Service de Pharmacocinétique et Toxicologie, Marseille, France
| | - Alain Renault
- Rennes 1 University, Rennes, France
- Rennes University Hospital, Department of Clinical Pharmacology, Rennes, France
- INSERM 1414 CIC-P Clinical Investigation Centre, Rennes, France
| | - Thibault Lavrut
- Faculty of Medicine of Nice, Hôpital Pasteur, Laboratoire de Pharmacologie, Nice, France
| | - Marc Bourlière
- Service d'Hépato-Gastro-Entérologie, Hôpital Saint-Joseph, Marseille, France
| | | | - Lionel Piroth
- Infectious Diseases Department, University Hospital, and UMR 1347, University of Burgundy, Dijon, France
| | - Eric Bellissant
- Rennes 1 University, Rennes, France
- Rennes University Hospital, Department of Clinical Pharmacology, Rennes, France
- INSERM 1414 CIC-P Clinical Investigation Centre, Rennes, France
| | - Bruno Lacarelle
- Aix Marseille University, APHM Timone, Service de Pharmacocinétique et Toxicologie, Marseille, France
- CRO2 INSERM U911, Marseille, France
| | - Jean-Michel Molina
- Infectious Diseases Unit - INSERM U941, Assistance Publique Hôpitaux de Paris (AP-HP) - Saint-Louis Hospital, Paris, France
- Paris VII - Denis Diderot University, Paris, France
| | - Caroline Solas
- Aix Marseille University, APHM Timone, Service de Pharmacocinétique et Toxicologie, Marseille, France
- CRO2 INSERM U911, Marseille, France
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12
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Mei R, Chi X, Wu R, Xu H, Wang X, Gao X, Sun H, Lv J, Yu G, Kong F, Jiang J, Sun B, Zhong J, Pan Y, Niu J. Sustained viral response and treatment-induced cytopenia correlate with SLCs and KLF12 genotypes in interferon/ribavirin-treated Chinese chronic hepatitis C patients. J Gastroenterol Hepatol 2016; 31:1489-97. [PMID: 26750805 DOI: 10.1111/jgh.13290] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2015] [Revised: 01/01/2016] [Accepted: 01/06/2016] [Indexed: 01/14/2023]
Abstract
BACKGROUND AND AIM Genetic variations in solute carrier (SLC) genes are associated with liver diseases, and Kruppel-like factor 12 (KLF12) affects the b chain of hemoglobin. We investigated possible correlations of SLC and KLF12 polymorphisms with viral clearance (spontaneous and treatment-induced) and adverse effects in Chinese chronic hepatitis C (CHC) patients. METHODS We genotyped the single nucleotide polymorphisms in 525 CHC patients, 137 patients with spontaneous clearance, and 207 healthy controls. Three hundred fifty-seven CHC patients received recombinant interferon-alpha2b/ribavirin (IFN-α2b/RBV) treatment, and 175 patients were chosen for analysis of drug-induced cytopenia. All raw P-values were corrected by the Bonferroni method. RESULTS A higher rate of sustained viral response was detected in patients with SLC4A11 rs3810560 CC variant versus TT/TC variant (76.9% vs 59.2%; OR, 2.42; 95% CI, 1.06-5.56, P = 0.037 after adjustment), but there was no significant difference among different hepatitis C virus genotypes. RBV-induced anemia was independently correlated with SLC29A1 rs760370 AA genotype (OR, 2.90; 95% CI, 1.29-6.54, P = 0.010), and the severity of IFN-induced thrombocytopenia was related to GG genotype (OR, 4.98; 95% CI, 1.27-19.61; P = 0.021); the detected effects held true for HCV-2a patients but weakened in HCV-1b patients. A reactive increase in platelet count was closely associated with KLF12 rs9543524 TT variant. CONCLUSION SLC4A11 rs3810560 polymorphism independently affected the sustained viral response rates in CHC patients, whereas SLC29A1 rs760370 and KLF12 rs9543524 single nucleotide polymorphisms correlated with treatment-induced adverse events. Clearly, the predictive power varied with HCV genotypes and the reason for genotype-dependent discrepancy was not fully understood.
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Affiliation(s)
- Ruqi Mei
- Department of Hepatology, First Hospital of Jilin University, Changchun, Jilin Province, China
| | - Xiumei Chi
- Department of Hepatology, First Hospital of Jilin University, Changchun, Jilin Province, China
| | - Ruihong Wu
- Department of Hepatology, First Hospital of Jilin University, Changchun, Jilin Province, China
| | - Hongqin Xu
- Department of Hepatology, First Hospital of Jilin University, Changchun, Jilin Province, China
| | - Xiaomei Wang
- Department of Hepatology, First Hospital of Jilin University, Changchun, Jilin Province, China
| | - Xiuzhu Gao
- Department of Hepatology, First Hospital of Jilin University, Changchun, Jilin Province, China
| | - Haibo Sun
- Department of Hepatology, First Hospital of Jilin University, Changchun, Jilin Province, China
| | - Juan Lv
- Department of Hepatology, First Hospital of Jilin University, Changchun, Jilin Province, China
| | - Ge Yu
- Department of Hepatology, First Hospital of Jilin University, Changchun, Jilin Province, China
| | - Fei Kong
- Department of Hepatology, First Hospital of Jilin University, Changchun, Jilin Province, China
| | - Jing Jiang
- Department of Clinical Epidemiology, First Hospital of Jilin University, Changchun, Jilin Province, China
| | - Bing Sun
- Institute Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.,Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Jin Zhong
- Institute Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.,Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Yu Pan
- Department of Hepatology, First Hospital of Jilin University, Changchun, Jilin Province, China
| | - Junqi Niu
- Department of Hepatology, First Hospital of Jilin University, Changchun, Jilin Province, China
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D'Avolio A, Cusato J, De Nicolò A, Allegra S, Di Perri G. Pharmacogenetics of ribavirin-induced anemia in HCV patients. Pharmacogenomics 2016; 17:925-41. [PMID: 27248282 DOI: 10.2217/pgs.16.22] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Dual therapy (pegylated interferon plus ribavirin) was considered the standard of care for hepatitis C virus (HCV) treatment until 2011, when the first-wave direct-acting antivirals were added to this regimen for HCV genotype-1 patients to increase the sustained virological response rate. The second-wave direct-acting antivirals entered the clinical use also in some ribavirin (RBV)- and/or interferon-free combinations. Nevertheless, since some of the new therapeutic regimens also include RBV and its use results still associated with hemolytic anemia, this requires countermeasures to be prevented. These include the identification of several host predictive factors involved in RBV absorption, distribution, metabolism, elimination and many others that might influence this toxic effect. For this reason, we provided an overview of the potential role of pharmacogenomics in predisposing RBV-treated HCV patients to anemia.
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Affiliation(s)
- Antonio D'Avolio
- Unit of Infectious Diseases, Department of Medical Sciences, Amedeo di Savoia Hospital, University of Turin, Turin, Italy
| | - Jessica Cusato
- Unit of Infectious Diseases, Department of Medical Sciences, Amedeo di Savoia Hospital, University of Turin, Turin, Italy
| | - Amedeo De Nicolò
- Unit of Infectious Diseases, Department of Medical Sciences, Amedeo di Savoia Hospital, University of Turin, Turin, Italy
| | - Sarah Allegra
- Unit of Infectious Diseases, Department of Medical Sciences, Amedeo di Savoia Hospital, University of Turin, Turin, Italy
| | - Giovanni Di Perri
- Unit of Infectious Diseases, Department of Medical Sciences, Amedeo di Savoia Hospital, University of Turin, Turin, Italy
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14
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Ribavirin. MEYLER'S SIDE EFFECTS OF DRUGS 2016. [PMCID: PMC7151912 DOI: 10.1016/b978-0-444-53717-1.01403-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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Nemr N, Kishk R, Mandour M. Role of ITPA gene polymorphism in ribavirin-induced anemia and thrombocytopenia in Egyptian patients with chronic hepatitis C. Indian J Gastroenterol 2016; 35:7-13. [PMID: 26880169 DOI: 10.1007/s12664-016-0618-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2015] [Accepted: 01/10/2016] [Indexed: 02/04/2023]
Abstract
BACKGROUND Ribavirin (RBV)-induced anemia is one of the major causes of dose reduction and discontinuation of therapy for chronic hepatitis C (CHC) patients. We investigated the role of inosine triphosphate pyrophosphatase (ITPA) single nucleotide polymorphism (SNP) (rs1127354) in predicting RBV-induced anemia and thrombocytopenia among Egyptian patients with CHC genotype 4 infection. METHODS One hundred and twenty Egyptian patients with CHC genotype 4 who had received standard of care combination therapy were enrolled in this study. Single nucleotide polymorphism at ITPA (rs1127354) was genotyped by real-time detection polymerase chain reaction. RESULTS Hb levels between CC and non-CC groups were significantly different at weeks 4, 8, and 12. Hemoglobin decline was significantly higher among CC patient than non-CC patients at week 4 and week 8 of treatment. The RBV dose reduction was higher in CC than non-CC group. Platelet decline was significantly lower in CC patients than non-CC patients at baseline, 4, 12 weeks only. CONCLUSION Rs1127354 ITPA polymorphism was associated with RBV-induced anemia and thrombocytopenia in Egyptian patients with hepatitis C virus genotype 4 infection.
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Affiliation(s)
- Nader Nemr
- Department of Endemic and Infectious Diseases, Faculty of Medicine, Suez Canal University, Ismailia, Egypt
| | - Rania Kishk
- Department of Microbiology and Immunology, Faculty of Medicine, Suez Canal University, Ismailia, Egypt.
| | - Mohamed Mandour
- Department of Clinical Pathology, Faculty of Medicine, Suez Canal University, Ismailia, Egypt
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16
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Hwang JJ, Lo CC, Lin CH, Cheng HS, Hung IW, Tsai WJ, Hung CH. Association between IPTA gene polymorphisms and hematological abnormalities in hepatitis C virus-infected patients receiving combination therapy. Gut Liver 2015; 9:214-23. [PMID: 25287171 PMCID: PMC4351029 DOI: 10.5009/gnl14095] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
Background/Aims Hematological abnormalities during hepatitis C virus (HCV) combination therapy with pegylated interferon α and ribavirin often necessitate dose reduction. Variants of the ITPA gene have been reported to protect against anemia during the early stages of HCV combination treatments but have also been associated with larger decreases in platelet counts. We aimed to identify the association between specific ITPA gene polymorphisms and hematological abnormalities in patients undergoing HCV combination therapy. Methods In this retrospective study, 175 patients treated with HCV combination therapy were enrolled at St. Martin De Porres Hospital in Taiwan between 2006 and 2012. Two single nucleotide polymorphisms (SNP) within or adjacent to the ITPA gene (rs1127354, rs6051702) were genotyped. We investigated the effect of ITPA gene variants on hematological abnormalities during the therapy. Results The ITPA rs1127354 minor variants were significantly associated with protection against anemia at week 4 (p=1.86×10−6) and with more severe decreases in platelet counts during HCV combination therapy. SNP rs6051702 was not associated with the hemoglobin decline to >3 g/dL at week 4 in our study (p=0.055). Conclusions The ITPA SNP rs1127354 is a useful predictor of ribavirin-induced anemia in Taiwanese patients and may be related to more severe decreases in platelet counts during the early stage of HCV combination therapy.
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Affiliation(s)
- Jow Jyh Hwang
- Section of Gastroenterology and Hepatology, Department of Internal Medicine, St. Martin De Porres Hospital and Graduate Institute of Clinical Medical Sciences, Chang Gung University College of Medicine, Chiayi, Taiwan
| | - Ching Chu Lo
- Section of Gastroenterology and Hepatology, Department of Internal Medicine, St. Martin De Porres Hospital, Chiayi, Taiwan
| | - Chien Hung Lin
- Section of Gastroenterology and Hepatology, Department of Internal Medicine, St. Martin De Porres Hospital, Chiayi, Taiwan
| | - Hsu Sheng Cheng
- Section of Gastroenterology and Hepatology, Department of Internal Medicine, St. Martin De Porres Hospital, Chiayi, Taiwan
| | - I Wen Hung
- Outpatient Nursing Section, St. Martin De Porres Hospital, Chiayi, Taiwan
| | - Wan Ju Tsai
- Graduate Institute of Clinical Medical Sciences, Chang Gung University College of Medicine, Chiayi, Taiwan
| | - Chien Hui Hung
- Graduate Institute of Clinical Medical Sciences, Chang Gung University College of Medicine, Chiayi, Taiwan
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17
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Peltenburg NC, Bakker JA, Vroemen WHM, de Knegt RJ, Leers MPG, Bierau J, Verbon A. Inosine triphosphate pyrophosphohydrolase activity: more accurate predictor for ribavirin-induced anemia in hepatitis C infected patients than ITPA genotype. Clin Chem Lab Med 2015; 53:2021-9. [PMID: 25968438 DOI: 10.1515/cclm-2015-0057] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2015] [Accepted: 04/14/2015] [Indexed: 12/11/2022]
Abstract
BACKGROUND ITPA polymorphisms have been associated with protection against ribavirin-induced anemia in chronic hepatitis C (HCV) patients. Here we determined the association of inosine triphosphate pyrophosphohydrolase (inosine triphosphatase or ITPase) enzyme activity with ITPA genotype in predicting ribavirin-induced anemia. METHODS In a cohort of 106 HCV patients, hemoglobin (Hb) values were evaluated after 4 weeks (T4) and at the time of lowest Hb value (Tnadir). ITPase activity was measured and ITPA genotype determined. Single-nucleotide polymorphisms (SNPs) tested were c.124+21A>C and c.94C>A. ITPase activity ≥1.11 mU/mol Hb was considered as normal. RESULTS After 4 weeks of treatment, 78% of the patients with normal ITPase activity were anemic and 21% of the patients with low ITPase activity (p<0.001). Stratified by genotype, the percentages of anemic patients were: wt/wt 76%, wt/c.124+21A>C 46% (p=0.068), and wt/c.94C>A 29% (p=0.021). At Tnadir, virtually all patients with normal ITPase activity were anemic, compared to only 64% of the patients with low activity (p=0.02). Thirteen patients had wt/c.124+241A>C genotype. Within this group all five patients with normal ITPase activity and only four of eight with decreased activity developed anemia. Presence of HCV RNA did not influence ITPase activity. CONCLUSIONS This study is the first to report that ITPase activity predicts the development of anemia during ribavirin treatment. ITPase activity and ITPA genotype have high positive predictive values for development of ribavirin-induced anemia at any time during treatment, but ITPase activity predicts ribavirin-induced anemia more accurately.
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18
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Pineda-Tenor D, García-Álvarez M, Jiménez-Sousa MA, Vázquez-Morón S, Resino S. Relationship between ITPA polymorphisms and hemolytic anemia in HCV-infected patients after ribavirin-based therapy: a meta-analysis. J Transl Med 2015; 13:320. [PMID: 26438033 PMCID: PMC4595047 DOI: 10.1186/s12967-015-0682-y] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2015] [Accepted: 09/25/2015] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND There is growing evidence that variations in the gene encoding inosine triphosphate pyrophosphohydrolase (ITPase), known as inosine triphosphatase (ITPA), are related to hemolytic anemia, which is frequently observed among hepatitis C virus (HCV)-infected patients receiving ribavirin (RBV)-based therapy. We performed a meta-analysis of all eligible studies assessing ITPA gene polymorphisms related to RBV-induced hemolytic anemia in HCV-infected patients published in PubMed, Embase and the Cochrane library prior to the end of 2014. METHODS Three outcomes were evaluated: (1) hemoglobin decline, (2) severe anemia, and (3) RBV dose reduction or treatment discontinuation. Pooled odds ratio (OR) and 95 % confidence interval (95 % CI) were estimated by either fixed or random effects models. RESULTS Twenty-nine studies were selected from the literature search: 20 references involving 6533 individuals for hemoglobin decline, 13 references on 3764 patients for severe anemia, and 16 references on 3918 patients for RBV dose reduction or discontinuation. Significant associations with hemoglobin decline were found for rs1127354 CC [OR = 12.84 (95 % CI 7.44; 22.17)], rs7270101 AA [OR = 3.41 (95 % CI 2.08; 5.59)] and rs6051702 AA [OR = 4.43 (95 % CI 2.80; 7.00)] genotypes. Moreover, significant associations with hemoglobin decline were also found for absent [OR = 6.01 (95 % CI 4.84; 7.46)] and mild [OR = 4.68 (95 % CI 2.83; 7.74)] ITPase deficiency haplotypes. The ITPA rs1127354 CC genotype and absent ITPase deficiency haplotype were also associated with severe anemia {[OR = 7.77 (95 % CI 5.03; 12.00)] and [OR = 4.79 (95 % CI 1.69; 13.56)], respectively}. Additionally, the rs1127354 CC genotype showed significant association with RBV dose reduction or stopping treatment (OR = 2.24; 95 % CI 1.79; 2.81). CONCLUSIONS ITPA polymorphisms increase the likelihood of developing hemolytic anemia for HCV-infected patients on RBV-based therapy, particularly rs1127354 CC and rs7270101 AA genotypes, suggesting the utility of screening for ITPA polymorphisms to avoid hematological toxicity and increase adherence to RBV-based therapy.
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Affiliation(s)
- Daniel Pineda-Tenor
- Servicio de Laboratorio Clínico, Hospital Universitario de Fuenlabrada, Fuenlabrada, Madrid, Spain.
| | - Mónica García-Álvarez
- Unidad de Infección Viral e Inmunidad, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Majadahonda-Pozuelo, km 2.2, Majadahonda, 28220, Madrid, Spain.
| | - María A Jiménez-Sousa
- Unidad de Infección Viral e Inmunidad, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Majadahonda-Pozuelo, km 2.2, Majadahonda, 28220, Madrid, Spain.
| | - Sonia Vázquez-Morón
- Unidad de Infección Viral e Inmunidad, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Majadahonda-Pozuelo, km 2.2, Majadahonda, 28220, Madrid, Spain.
| | - Salvador Resino
- Unidad de Infección Viral e Inmunidad, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Majadahonda-Pozuelo, km 2.2, Majadahonda, 28220, Madrid, Spain.
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Olmedo DB, Cader SA, Porto LC. IFN-λ gene polymorphisms as predictive factors in chronic hepatitis C treatment-naive patients without access to protease inhibitors. J Med Virol 2015; 87:1702-15. [PMID: 25970604 DOI: 10.1002/jmv.24227] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/02/2015] [Indexed: 12/16/2022]
Abstract
The single nucleotides polymorphisms analyses in the regions near the IL28B gene in patients chronically infected with genotype 1 hepatitis C virus (HCV) are an important predictive factor for sustained virological response (SVR). The aim was to assess the predictive value of the polymorphisms of the IL28B/IFNL3 gene in patients chronically infected with genotype 1 for the viral clearance obtained after initial treatment including admixed populations. A systematic review was conducted, using a meta-analysis in the PubMed, Embase, LILACS, and SCIELO using MesH and DECS in 42 studies. The parameters were IL28B polymorphisms, rs12979860, rs8099917, and rs12980275, SVR ratio, and OR (odds ratio). OR and confidence Interval of 95% (95%CI), were calculated by fixed or random effects models. Heterogeneity, sensitivity analysis, and publication bias were also performed. Significant differences were noted between carriers groups with the major versus minor allele at rs12979860 CC versus CT/TT-genotype (OR = 4.18; 95%CI = 3.37-5.17), rs8099917 TT versus TG/GG-genotype (OR = 4.07; 95%CI = 2.94-5.63), and rs12980275 AA versus AA/AG-genotype (OR = 5.34; 95%CI = 1.60-17.82). There was selection bias in the rs8099917 analysis (Egger's regression P = 0.049), which reversed after performing a sensitivity analysis (P = 0.510). The incorporation of SNP analyses in IL28B/IFNL3 gene during the diagnosis process in Brazil should be used as a complementary tool to determine the appropriate treatment for HCV genotype 1. Here, we confirm that the rs12979860 CC, rs8099917 TT, and rs12980275 AA genotype-carriers have favorable responses to standard therapy, including two studies with Brazilian population, and this information should be considered.
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Affiliation(s)
- Daniele Blasquez Olmedo
- Histocompatibility and Cryopreservation Laboratory, Rio de Janeiro State University, Rio de Janeiro, Brazil
| | - Samária Ali Cader
- Histocompatibility and Cryopreservation Laboratory, Rio de Janeiro State University, Rio de Janeiro, Brazil
| | - Luís Cristóvão Porto
- Histocompatibility and Cryopreservation Laboratory, Rio de Janeiro State University, Rio de Janeiro, Brazil
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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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Kucherenko A, Pampukha V, Bobrova I, Moroz L, Livshits L. ITPA gene variant may protect against anemia induced during pegylated interferon Alfa and Ribavirin combination treatment in Ukrainian patients with chronic hepatitis C. CYTOL GENET+ 2015. [DOI: 10.3103/s009545271502005x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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Chen SH, Peng CY, Lai HC, Su WP, Lin CH, Li YF, Chuang PH, Chen CH. An index to predict ribavirin-induced anemia in asian patients with chronic genotype 1 hepatitis C. HEPATITIS MONTHLY 2015; 15:e27148. [PMID: 25834588 PMCID: PMC4377223 DOI: 10.5812/hepatmon.27148] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/22/2015] [Revised: 02/10/2015] [Accepted: 02/21/2015] [Indexed: 12/11/2022]
Abstract
BACKGROUND Single-nucleotide polymorphisms (SNP) in the inosine triphosphate pyrophosphatase (ITPA) gene correlate with ribavirin (RBV)-induced anemia in patients with chronic hepatitis C (CHC) receiving combination therapy. Managing anemia is an early priority in the treatment process. OBJECTIVES The aim was to develop a predictive index based on ITPA SNP status to identify CHC patients at risk of anemia. PATIENTS AND METHODS A total of 418 eligible East Asian patients diagnosed with CHC genotype 1 (G1) received combination therapy in this study. Participant DNA was genotyped for a functional ITPA SNP (C/C, A/A or C/A) on chromosome 20 at rs1127354. A predictive index was constructed by incorporating independent factors identified for severe anemia events (hemoglobin < 10 g/dL). Areas under the receiver-operating characteristic curves (AUCs) represented the diagnostic accuracies of the predictive index in randomly assigned development and validation cohorts. RESULTS Multiple logistic regressions identified age (≥ 50 y: OR = 9.7, 95% CI = 5.0 - 18.6), ITPA rs1127354 (C/C: OR = 3.3, 95% CI = 1.8 - 5.8) and baseline hemoglobin (< 14.0 g/dL: OR 6.4, 95% CI = 3.3 - 12.1; 14.0 - 14.9: OR = 2.4, 95% CI = 1.2 - 4.6) as predictors of severe anemia throughout the treatment. For severe anemia, the predictive index incorporating age, ITPA SNP status and baseline hemoglobin yielded diagnostic accuracies (AUCs) of 0.830 (95% CI = 0.783 - 0.871) in the development (n = 324) and 0.902 (0.826 - 0.925) in the validation (n = 81) cohorts. CONCLUSIONS In patients with CHC G1 and receiving combination therapy, ITPA SNP-based index was an accurate and practical solution for prediction of severe anemia.
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Affiliation(s)
- Sheng-Hung Chen
- Institute of Clinical Medical Science, School of Medicine, China Medical University, Taichung, Taiwan
- School of Medicine, China Medical University, Taichung, Taiwan
- Division of Hepatogastroenterology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Cheng-Yuan Peng
- School of Medicine, China Medical University, Taichung, Taiwan
- Division of Hepatogastroenterology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
- Corresponding Author: Cheng-Yuan Peng, Division of Hepatogastroenterology, Department of Internal Medicine, China Medical University Hospital, China Medical University, Taiwan. Tel: +88-6422052121, E-mail:
| | - Hsueh-Chou Lai
- Institute of Clinical Medical Science, School of Medicine, China Medical University, Taichung, Taiwan
- Division of Hepatogastroenterology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
- College of Chinese Medicine, China Medical University, Taichung, Taiwan
| | - Wen-Pang Su
- Division of Hepatogastroenterology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Chia-Hsin Lin
- Division of Hepatogastroenterology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Yu-Fen Li
- Institute of Biostatistics, China Medical University, Taichung, Taiwan
| | - Po-Heng Chuang
- Division of Hepatogastroenterology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Ching-Hsiang Chen
- Division of Hepatogastroenterology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
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Matsuura K, Tanaka Y, Watanabe T, Fujiwara K, Orito E, Kurosaki M, Izumi N, Sakamoto N, Enomoto N, Yatsuhashi H, Kusakabe A, Shinkai N, Nojiri S, Joh T, Mizokami M. ITPA genetic variants influence efficacy of PEG-IFN/RBV therapy in older patients infected with HCV genotype 1 and favourable IL28B type. J Viral Hepat 2014; 21:466-474. [PMID: 24750345 DOI: 10.1111/jvh.12171] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2013] [Accepted: 07/18/2013] [Indexed: 01/22/2023]
Abstract
Inosine triphosphatase (ITPA) genetic variants are strongly associated with ribavirin (RBV)-induced anaemia during pegylated interferon (PEG-IFN) plus RBV therapy. However, the treatment efficacy of ITPA genetic variants has not been fully explored. We enrolled 309 individuals infected with hepatitis C virus genotype 1, who were treated with PEG-IFN plus RBV for 48 weeks. The ITPA SNP: rs1127354 and IL28B SNP: rs8099917 were genotyped. We examined the risk factors for severe anaemia up to week 12 after the start of treatment and treatment efficacy. The incidence of severe anaemia, ≥ 3 g/dL reduction or <10 g/dL of haemoglobin (Hb) up to week 12, was more frequent in patients with CC at rs1127354 [65% (145/224), 33% (73/224)] than in those with CA/AA [25% (21/85), 6% (8/85)] (P < 0.0001). ITPA genotype, pretreatment Hb level and age were independent predictive factors for severe anaemia: Hb < 10 g/dL. In IL28B favourable type, the sustained virologic response rate was higher in ≥ 60-year-old patients with CA/AA than in those with CC [71% (22/31) vs 40% (26/65), P = 0.005], although there was no significant difference in treatment efficacy according to ITPA genetic variants in the <60-year-old patients. The proportion of patients administered ≥ 80% of the dosage of RBV was significantly higher in the patients with CA/AA than in those with CC (P = 0.025), resulting in a lower relapse rate. In conclusion, ITPA genetic variants were associated with severe RBV-induced anaemia and could influence the efficacy of PEG-IFN plus RBV treatment among elderly patients with IL28B favourable type.
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Affiliation(s)
- K Matsuura
- Department of Virology, Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan; Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
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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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Kawaguchi-Suzuki M, Frye RF. The role of pharmacogenetics in the treatment of chronic hepatitis C infection. Pharmacotherapy 2014; 34:185-201. [PMID: 24114761 DOI: 10.1002/phar.1349] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Hepatitis C virus (HCV) chronically infects 170 million people worldwide. Until recently, combination therapy with peginterferon-α (pegIFN) and ribavirin (RBV) has been the standard of care. However, for many patients, especially those infected with the most common HCV genotype 1 (HCV-1), this treatment has resulted in unsatisfactory treatment response rates. Many clinical factors, including pharmacogenetics, influence the treatment response rate. Genetic variation in the interleukin 28B (IL28B) gene is the major determinant of treatment response, a finding that has been replicated in multiple independent cohorts. This review focuses on the association between pharmacogenetics and conventional pegIFN/RBV therapy in patients infected with HCV non-genotype 1; patients reinfected with HCV after liver transplantation; and patients coinfected with HCV and human immunodeficiency virus. We also review the pharmacogenetic data for boceprevir and telaprevir triple therapy in patients with HCV-1 infection, as well as viral genomic polymorphisms and genetic variants that may protect against anemia. Pharmacogenetic information offers a personalized medicine approach to help clinicians and patients make better informed decisions to maximize response and minimize toxicity for the treatment of chronic HCV infection.
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Affiliation(s)
- Marina Kawaguchi-Suzuki
- Department of Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, Gainesville, Florida
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Hai H, Tamori A, Enomoto M, Morikawa H, Uchida-Kobayashi S, Fujii H, Hagihara A, Kawamura E, Thuy LTT, Tanaka Y, Kawada N. Relationship between inosine triphosphate genotype and outcome of extended therapy in hepatitis C virus patients with a late viral response to pegylated-interferon and ribavirin. J Gastroenterol Hepatol 2014; 29:201-207. [PMID: 23980585 DOI: 10.1111/jgh.12376] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/12/2013] [Indexed: 01/15/2023]
Abstract
BACKGROUND AND AIM It is not yet clear which factors are associated with the outcome of 72-week treatment with pegylated-interferon and ribavirin (RBV) in patients with chronic hepatitis C virus (HCV) infection. METHODS In 66 patients with HCV genotype 1 who had a late viral response (LVR) to 72-week treatment of pegylated-interferon and RBV, we examined the factors that determined the outcome, including single nucleotide polymorphisms of interleukin-28B and inosine triphosphatase (ITPA) genes. RESULTS Thirty seven of 66 (56%) patients with LVR achieved a sustained viral response (SVR). The mean age of these 37 SVR patients was 55, compared with 61 in 29 relapsed patients (P = 0.009). Twenty six of 54 (48%) patients with the CC genotype and 11 of 12 (92%) with the CA/AA genotype of ITPA rs1127354 achieved SVR (P = 0.006). The SVR rates were 79%, 40%, 60%, and 33% in patients with undetectable HCV RNA on weeks 16, 20, 24, and 28 or later, respectively (P = 0.014). Finally, serum RBV concentration at week 44 of treatment was significantly higher in the SVR group (2651 ng/mL) than in the relapse group (1989 ng/mL, P = 0.002). In contrast, the rate of the interleukin-28B genotype was not different between the groups. Multiple regression analysis showed that age < 60 years, ITPA CA/AA genotype, and serum RBV concentration were significant independent predictive factors for SVR. CONCLUSIONS Our findings elucidated the association of four factors, including ITPA genotype, with the outcome of 72-week treatment in LVR patients.
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Affiliation(s)
- Hoang Hai
- Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka, Japan
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Fujino T, Aoyagi Y, Takahashi M, Yada R, Yamamoto N, Ohishi Y, Nishiura A, Kohjima M, Yoshimoto T, Fukuizumi K, Nakashima M, Kato M, Kotoh K, Nakamuta M, Enjoji M. Association of ITPA polymorphism with outcomes of peginterferon-α plus ribavirin combination therapy. World J Gastrointest Pharmacol Ther 2013; 4:54-60. [PMID: 23919217 PMCID: PMC3729868 DOI: 10.4292/wjgpt.v4.i3.54] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2013] [Revised: 04/11/2013] [Accepted: 05/19/2013] [Indexed: 02/06/2023] Open
Abstract
AIM: To analyzed the association between inosine triphosphatase (ITPA) (rs1127354) genotypes and sustained virological response (SVR) rates in peginterferon (Peg-IFN)α + ribavirin (RBV) treatment.
METHODS: Patients who underwent Peg-IFNα + RBV combination therapy were enrolled (n = 120) and they had no history of other IFN-based treatments. Variation in hemoglobin levels during therapy, cumulative reduction of RBV dose, frequency of treatment withdrawal, and SVR rates were investigated in each ITPA genotype.
RESULTS: In patients with ITPA CC genotype, hemoglobin decline was significantly greater and the percentage of patients in whom total RBV dose was < 60% of standard and/or treatment was withdrawn was significantly higher compared with CA/AA genotype. However, SVR rates were equivalent between CC and CA/AA genotypes, and within a subset of patients with Interleukin 28B (IL28B) (rs8099917) TT genotype, SVR rates tended to be higher in patients with ITPA CC genotype, although the difference was not significant.
CONCLUSION: ITPA CC genotype was a disadvantageous factor for Peg-IFNα + RBV treatment in relation to completion rates and RBV dose. However, CC genotype was not inferior to CA/AA genotype for SVR rates. When full-length treatment is accomplished, it is plausible that more SVR is achieved in patients with ITPA CC variant, especially in a background of IL28B TT genotype.
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Zhang XH, Cai QX, Hong CX, Lin CS, Zhao ZX. Prevalence of IL-28B and ITPA genotypes in Chinese Han population infected persistently with hepatitis C virus genotype 6 or HCV-1. J Med Virol 2013; 85:1163-9. [PMID: 23918534 DOI: 10.1002/jmv.23561] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/28/2013] [Indexed: 12/20/2022]
Abstract
The geographic distribution, demographics, epidemiology, host factors, and clinical characteristics of persistent HCV-6 infection in China need further characterization. This multicenter study enrolled 63 patients with persistent HCV-6 infection and 63 patients with persistent HCV-1 infection as controls. Blood biochemistry, quantitation of HCV RNA levels, and identification of host IL-28B genotypes (rs12979860, rs8099917, and rs12980275) and ITPA genotype (rs1127354) were performed to estimate potential variability in host factors that may affect response to treatment. The mean HCV-6 RNA level (3.8E6 IU/ml) was significantly higher than that in patients infected with HCV-1 (1.7E6 IU/ml; P < 0.001). Patients persistently infected with HCV-6 had a high prevalence of IL-28B rs12979860 CC genotype (92.1%), rs8099917 TT genotype (93.7%), and rs12980275 AA genotype (90.5%). Their prevalence in patients infected with HCV-1 was only modestly lower (82.5%, 84.1%, and 82.5%, respectively; P > 0.05). The inosine triphosphate pyrophosphatase (ITPA) SNP rs1127354 CC genotype was present in 66.7% of patients infected with HCV-6, comparable to that of patients infected with HCV-1 (65.1%; P > 0.05). There were no differences in the liver function, proportion of hepatic cirrhosis patients or patients with increased serum glucose between these two groups. Persistent HCV-6 infection in Chinese Han is found mainly in the southern China. Chinese Han with chronic HCV-1 or HCV-6 infection have IL-28B genotypes, suggesting responsiveness to interferon-based pharmacotherapy. Most patients (67%) possess the ITPA genotype associated with susceptibility to ribavirin-induced hemolysis. The routes of transmission for HCV-6 genotype were more diversified than HCV-1 genotype. The outbreak of HCV-6 infection through blood transfusion progressed faster than HCV-1.
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Affiliation(s)
- Xiao-Hong Zhang
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
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Ahmed WH, Furusyo N, Zaky S, Sharaf Eldin A, Aboalam H, Ogawa E, Murata M, Hayashi J. Pre-treatment role of inosine triphosphate pyrophosphatase polymorphism for predicting anemia in Egyptian hepatitis C virus patients. World J Gastroenterol 2013; 19:1387-1395. [PMID: 23538996 PMCID: PMC3602498 DOI: 10.3748/wjg.v19.i9.1387] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2012] [Revised: 10/18/2012] [Accepted: 11/28/2012] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate and clarify, for the first time, the role of inosine triphosphate pyrophosphatase (ITPA) polymorphism in Egyptian chronic hepatitis C virus (HCV) patients.
METHODS: The human genomic DNA of all patients was extracted from peripheral blood cells in order to determine the single nucleotide polymorphism (SNP) of ITPA (rs1127354). SNP genotyping was performed by real time polymerase chain reaction (PCR, ABI TaqMan allelic discrimination kit) for 102 treatment-naive Egyptian patients with chronic HCV. All patients had no evidence of cardiovascular or renal diseases. They received a combination treatment of pegylated interferon α (PEG-IFNα) as a weekly subcutaneous dose plus an oral weight-adjusted dose of ribavirin (RBV). The majority received PEG-IFNα2a (70.6%) while 29.4% received PEG-IFNα2b. The planned duration of treatment was 24-48 wk according to the viral kinetics throughout the course of treatment. Pre-treatment liver biopsy was done for each patient for evaluation of fibrosis stage and liver disease activity. The basal viral load level was detected quantitatively by real time PCR while viral load throughout the treatment course was performed qualitatively by COBAS TaqMan assay.
RESULTS: Ninety-three patients (91.2%) had ITPA SNP CC genotype and 9 (8.8%) had non-CC genotype (CA and AA). The percentage of hemoglobin (Hb) decline was higher for CC patients than for non-CC patients, particularly at weeks 4 and 8 (P = 0.047 and 0.034, respectively). During the first 12 wk of treatment, CC patients had significantly more Hb decline > 3 g/dL than non-CC patients: 64.5% vs 22.2% at weeks 8 and 12, respectively, (P = 0.024 and 0.038). Reduction of the amount of the planned RBV dose was significantly higher for CC patients than non-CC patients during the first 12 wk (18% ± 12.1% vs 8.5% ± 10.2%, P = 0.021). The percentage of CC patients with RBV dose reduction was significantly greater than that of non-CC patients (77.4% vs 44.4%, P = 0.044). Multivariate analysis identified only the percentage of RBV dose as a predictor for Hb decline. Platelet decline was significantly higher in non-CC patients than CC patients at weeks 12, 24 and 48 (P = 0.018, 0.009 and 0.026, respectively).
CONCLUSION: Rs1127354 ITPA polymorphism plays a decisive role in protecting against treatment-induced anemia and the need for RBV dose reduction in Egyptian HCV patients.
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Kurosaki M, Tanaka Y, Nishida N, Sakamoto N, Enomoto N, Matsuura K, Asahina Y, Nakagawa M, Watanabe M, Sakamoto M, Maekawa S, Tokunaga K, Mizokami M, Izumi N. Model incorporating the ITPA genotype identifies patients at high risk of anemia and treatment failure with pegylated-interferon plus ribavirin therapy for chronic hepatitis C. J Med Virol 2013; 85:449-458. [PMID: 23297176 DOI: 10.1002/jmv.23497] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/19/2012] [Indexed: 12/12/2022]
Abstract
This study aimed to develop a model for predicting anemia using the inosine triphosphatase (ITPA) genotype and to evaluate its relationship with treatment outcome. Patients with genotype 1b chronic hepatitis C (n = 446) treated with peg-interferon alpha and ribavirin (RBV) for 48 weeks were genotyped for the ITPA (rs1127354) and IL28B (rs8099917) genes. Data mining analysis generated a predictive model for anemia (hemoglobin (Hb) concentration <10 g/dl); the CC genotype of ITPA, baseline Hb <14.0 g/dl, and low creatinine clearance (CLcr) were predictors of anemia. The incidence of anemia was highest in patients with Hb <14.0 g/dl and CLcr <90 ml/min (76%), followed by Hb <14.0 g/dl and ITPA CC (57%). Patients with Hb ≥ 14.0 g/dl and ITPA AA/CA had the lowest incidence of anemia (17%). Patients with two predictors (high-risk) had a higher incidence of anemia than the others (64% vs. 28%, P < 0.0001). At baseline, the IL28B genotype was a predictor of a sustained virological response [adjusted odds ratio 9.88 (95% confidence interval 5.01-19.48), P < 0.0001]. In patients who achieved an early virological response, the IL28B genotype was not associated with a sustained virological response, while a high risk of anemia was a significant negative predictor of a sustained virological response [0.47 (0.24-0.91), P = 0.026]. For high-risk patients with an early virological response, giving >80% of the planned RBV dose increased sustained virological responses by 24%. In conclusion, a predictive model incorporating the ITPA genotype could identify patients with a high risk of anemia and reduced probability of sustained virological response.
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Affiliation(s)
- Masayuki Kurosaki
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
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Kohjima M, Enjoji M, Yoshimoto T, Yada R, Fujino T, Aoyagi Y, Fukushima N, Fukuizumi K, Harada N, Yada M, Kato M, Kotoh K, Nakashima M, Sakamoto N, Tanaka Y, Nakamuta M. Add-on therapy of pitavastatin and eicosapentaenoic acid improves outcome of peginterferon plus ribavirin treatment for chronic hepatitis C. J Med Virol 2013; 85:250-260. [PMID: 23161429 DOI: 10.1002/jmv.23464] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/09/2012] [Indexed: 12/19/2022]
Abstract
Despite the use of pegylated-interferon (peg-IFN) plus ribavirin combination therapy, many patients infected with hepatitis C virus (HCV)-1b remain HCV-positive. To determine whether addition of pitavastatin and eicosapentaenoic acid (EPA) is beneficial, the "add-on" therapy option (add-on group) was compared retrospectively with unmodified peg-IFN/ribavirin therapy (standard group). Association of host- or virus-related factors with sustained virological response was assessed. In HCV replicon cells, the effects of pitavastatin and/or EPA on HCV replication and expression of innate-immunity- and lipid-metabolism-associated genes were investigated. In patients infected with HCV-1b, sustained virological response rates were significantly higher in the add-on than standard group. In both groups, sustained virological response rates were significantly higher in patients with genotype TT of IL-28B (rs8099917) than in those with non-TT genotype. Among the patients with non-TT genotype, sustained virological response rates were markedly higher in the add-on than standard group. By multivariate analysis, genome variation of IL28B but not add-on therapy remained as a predictive factor of sustained virological response. In replicon cells, pitavastatin and EPA suppressed HCV replication. Activation of innate immunity was obvious in pitavastatin-treated cells and EPA suppressed the expression of sterol regulatory element binding protein-1c and low-density lipoprotein receptor. Addition of pitavastatin and EPA to peg-IFN/ribavirin treatment improved sustained virological response in patients infected with HCV-1b. Genotype variation of IL-28B is a strong predictive factor in add-on therapy.
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Affiliation(s)
- Motoyuki Kohjima
- Department of Gastroenterology, Kyushu Medical Center, Fukuoka, Japan
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Guidelines for the Management of Hepatitis C Virus Infection: First edition, May 2012, The Japan Society of Hepatology. Hepatol Res 2013; 43:1-34. [PMID: 23332085 DOI: 10.1111/hepr.12020] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Affiliation(s)
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- Department of Gastroenterology and Hepatology, Faculty of Medicine, Tokyo Medical and Dental University
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Genetic variants at the ITPA locus protect against ribavirin-induced hemolytic anemia and dose reduction in an HCV G2/G3 cohort. Eur J Gastroenterol Hepatol 2012; 24:890-6. [PMID: 22584257 DOI: 10.1097/meg.0b013e3283546efd] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
OBJECTIVES Two functional genetic variants in the inosine triphosphatase (ITPA) gene have been shown to be strongly associated with protection from ribavirin (RBV)-induced hemolysis. We aimed at evaluating this finding in a chronic hepatitis C genotype 2/3 cohort with a predominance of genotype 3 patients where available data are scarce. A second objective was to determine whether a protective association translated into the need for RBV reduction and hence a possible impact on treatment response. METHODS Overall, 457 patients were recruited from two trials of genotype 2/3 patients treated with pegylated interferon α-2b and weight-based RBV. rs1127354 and rs7270101 were genotyped and a composite ITPAase deficiency variable was graded according to the two single nucleotide polymorphisms. The primary endpoints were hemoglobin (Hb) decline from baseline and Hb decline of more than 3 g/dl at week 4. RESULTS Both single nucleotide polymorphisms and the composite ITPAase deficiency variable were strongly and independently associated with protection from a decline in Hb at week 4 in multivariate linear regression models (Prs1127354=7.0×10, Prs7270101=0.0036, PITPase deficiency variable =6.3×10). Patients with any degree of reduced ITPAase activity were less likely to have their RBV dose reduced (odds ratio 0.39, 95% confidence interval 0.16-0.96, P=0.040), although this did not translate into increased rapid viral response or sustained viral response (Prvr=0.93, Psvr=0.22). CONCLUSION We have confirmed a strong association between functional ITPA variants and RBV-induced hemolysis and showed protection from RBV dose reduction, although this did not translate into increased rapid viral response or sustained viral response.
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Osinusi A, Naggie S, Poonia S, Trippler M, Hu Z, Funk E, Schlaak J, Fishbein D, Masur H, Polis M, Kottilil S. ITPA gene polymorphisms significantly affect hemoglobin decline and treatment outcomes in patients coinfected with HIV and HCV. J Med Virol 2012; 84:1106-14. [PMID: 22585729 PMCID: PMC3518921 DOI: 10.1002/jmv.23302] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Published studies have described a strong association with a single-nucleotide polymorphism (SNP) in the inosine triphosphate pyrophosphatase (ITPA) gene and ribavirin (RBV)-induced hemolytic anemia in HCV-infected patients receiving pegylated interferon (pegIFN) and RBV. This study sought to evaluate the effect of these polymorphisms on anemia, hemoglobin reduction, HCV kinetics, and treatment outcomes. Sixty-three patients coinfected with HIV and HCV and 58 patients infected with HCV only were treated with pegIFN/RBV were genotyped using the ABI TaqMan allelic discrimination kit for the 2 ITPA SNP variants rs1127354 and rs7270101. A composite variable of ITPA deficiency using both SNPs was created as previously reported. Statistical analysis was performed using Mann-Whitney test or Chi square/Fishers exact test for categorical data and mixed model analysis for multiple variables. Thirty-five patients (30%) were predicted to have reduced ITPA activity. ITPA deficiency was found to be protective against the development of hemoglobin reduction >3 g/dl over the course of treatment. The rates of hemoglobin reduction >3 g/dl decreased in correlation with the severity of ITPA deficiency. ITPA deficiency was associated with slower hemoglobin decline early in treatment (week 4, P = 0.020) and rapid virologic response (RVR) at week 4 (P = 0.017) in patients coinfected with HIV and HCV. ITPA polymorphisms are associated with hemoglobin decline and in patients coinfected with HIV and HCV it is also associated with early virologic outcomes. Determination of ITPA polymorphisms may allow prediction of RBV-induced anemia and earlier initiation of supportive care to ensure optimal therapeutic outcomes.
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Affiliation(s)
- Anu Osinusi
- Laboratory of Immunoregulation, National Institute of Allergy and Infectious Disease, NIH, Bethesda, MD, USA.
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Birerdinc A, Estep M, Afendy A, Stepanova M, Younossi I, Baranova A, Younossi ZM. Gene expression profiles associated with anaemia and ITPA genotypes in patients with chronic hepatitis C (CH-C). J Viral Hepat 2012; 19:414-22. [PMID: 22571903 DOI: 10.1111/j.1365-2893.2011.01564.x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Anaemia is a common side effect of ribavirin (RBV) which is used for the treatment of hepatitis C. Inosine triphosphatase gene polymorphism (C to A) protects against RBV-induced anaemia. The aim of our study was to genotype patients for inosine triphosphatase gene polymorphism rs1127354 SNP (CC or CA) and associate treatment-induced anaemia with gene expression profile and genotypes. We used 67 hepatitis C patients with available gene expression, clinical, laboratory data and whole-blood samples. Whole blood was used to determine inosine triphosphatase gene polymorphism rs1127354 genotypes (CC or CA). The cohort with inosine triphosphatase gene polymorphism CA genotype revealed a distinct pattern of protection against anaemia and a lower drop in haemoglobin. A variation in the propensity of CC carriers to develop anaemia prompted us to look for additional predictors of anaemia during pegylated interferon (PEG-IFN) and RBV. Pretreatment blood samples of patients receiving a full course of PEG-IFN and RBV were used to assess expression of 153 genes previously implicated in host response to viral infections. The gene expression data were analysed according to presence of anaemia and inosine triphosphatase gene polymorphism genotypes. Thirty-six genes were associated with treatment-related anaemia, six of which are involved in the response to hypoxia pathway (HIF1A, AIF1, RHOC, PTEN, LCK and PDGFB). There was a substantial overlap between sustained virological response (SVR)-predicting and anaemia-related genes; however, of the nine JAK-STAT pathway-related genes associated with SVR, none were implicated in anaemia. These observations exclude the direct involvement of antiviral response in the development of anaemia associated with PEG-IFN and RBV treatment, whereas another, distinct component within the SVR-associated gene expression response may predict anaemia. We have identified baseline gene expression signatures associated with RBV-induced anaemia and identified its functional pathways. In particular, we identified the hypoxia response pathway and the apoptosis/survival-related gene network, as differentially expressed in chronic hepatitis C patients with anaemia.
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Affiliation(s)
- A Birerdinc
- Center for Liver Disease and Department of Medicine, Inova Fairfax Hospital, Falls Church, VA 22042, USA
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Schlecker C, Ultsch A, Geisslinger G, Lötsch J. The pharmacogenetic background of hepatitis C treatment. MUTATION RESEARCH-REVIEWS IN MUTATION RESEARCH 2012; 751:36-48. [PMID: 22409946 DOI: 10.1016/j.mrrev.2012.02.001] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/06/2011] [Revised: 02/20/2012] [Accepted: 02/24/2012] [Indexed: 12/16/2022]
Abstract
Insufficiently treated hepatitis C virus (HCV) infection remains a major healthcare issue. Individual therapy responses vary considerably from spontaneous clearing of the virus to lethal conditions. Host genetics currently receives a major scientific and clinical interest as an important source of interindividual variability in treatment. Mainly the associations of interleukin 28B gene (IL28B) variants with decreased HCV clearance under standard therapy are considered as "state of the art" of hepatitis C pharmacogenetics. However, a search in PubMed identified 41 genes reportedly modulating the individual therapy response, e.g., genes coding for major histocompatibility complex (HLA), the tumor necrosis factor (TNF), interleukin 10 (IL10), other interferon coding genes than IL28B (e.g., IFNAR1, IFNAR2, IFNG), several components of downstream interferon signaling as well as genes modulating side effects of current anti-HCV therapeutics (e.g., SLC28A3, ITPA involved in ribavirin associated hemolytic effects or SLC6A4 and HTR1A involved in serotonin associated psychiatric side effects). Applying knowledge discovery methods from the area of data mining and machine-learning to this comprehensive set of HCV therapy modulating genes, relating the HCV genes to the world wide knowledge on genes given in the form of the Gene Ontology (GO) knowledge base, found that the relevant genes belong to the GO subcategories of "inflammatory response" and "immune response" and "response to virus". This complex approaches to the pharmacogenomics of HCV may serve to identify future candidates for a personalization of HCV therapy and structured approach to possible new therapeutic targets for the control of hepatitis C virus.
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Affiliation(s)
- Christina Schlecker
- pharmazentrum frankfurt/ZAFES, Institute for Clinical Pharmacology, Goethe University, Theodor-Stern-Kai 7, D-60590 Frankfurt am Main, Germany
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Asahina Y, Izumi N, Oketani M, Kumada H, Koike K, Suzuki F, Takikawa H, Tanaka A, Tsubouchi H, Hayashi N, Hiramatsu N, Yotsuyanagi H. Treatment Guidelines of Hepatitis C. ACTA ACUST UNITED AC 2012. [DOI: 10.2957/kanzo.53.355] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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Lötsch J, Hofmann WP, Schlecker C, Zeuzem S, Geisslinger G, Ultsch A, Doehring A. Single and combined IL28B, ITPA and SLC28A3 host genetic markers modulating response to anti-hepatitis C therapy. Pharmacogenomics 2011; 12:1729-40. [PMID: 22118055 DOI: 10.2217/pgs.11.99] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Advances in hepatitis C pharmacogenomics identified modulations of a sustained virologic response (SVR) by frequent IL28B gene variants and of ribavirin-induced hemolysis by frequent ITPA gene variants. These associations have been widely reproduced in various ethnicities, clinical settings and hepatitis C viral genotypes. The IL28B minor alleles rs8099917G, rs12979860T and rs12980275G have been associated with non-SVR whereas the ITPA minor alleles rs1127354A and rs7270101C were associated with less hemolytic side effects, an effect also attributed to a nucleoside transporter gene SLC28A3 rs10868138G/rs56350726T haplotype. The significance levels of these associations, especially in genome-wide studies, were very high. We nevertheless tested how good clinical outcomes of peginterferon α/ribavirin therapy, such as SVR or hemolytic side effects, were predicted by these variants. An analysis in an example dataset of 115 patients revealed that the prediction of non-SVR or hemolysis by single variants was often only slightly better than guessing. Using combinations of IL28B variants provided a higher accuracy (64.5%) of predicting non-SVR than with single IL28B variants (accuracy 60-63%). Similarly, a decline in blood hemoglobin by ≥3 g/dl could be better predicted at an accuracy of 70% (10% better than guessing) with a combination of an ITPA variant with a nucleoside transporter gene (SLC28A3) haplotype. Thus, genotyping information about single IL28B or ITPA variants is reproducibly and statistically significantly associated with hepatitis C therapy outcomes; however, the clinical predictive utility of single variants can be increased by combinations of genotypes.
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Affiliation(s)
- Jörn Lötsch
- Pharmazentrum Frankfurt/ZAFES, Institute of Clinical Pharmacology, Goethe-University Hospital, Theodor Stern Kai 7, D-60590 Franfurt am Main, Germany.
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Ebinuma H, Saito H, Tada S, Nakamoto N, Ohishi T, Tsunematsu S, Kumagai N, Tsuchimoto K, Tsukada N, Inagaki Y, Horie Y, Takahashi M, Atsukawa K, Okamura Y, Kanai T, Hibi T. Disadvantages of peginterferon and ribavirin treatment in older patients with chronic hepatitis C: an analysis using the propensity score. Hepatol Int 2011; 6:744-52. [PMID: 22020828 DOI: 10.1007/s12072-011-9312-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2011] [Accepted: 08/24/2011] [Indexed: 01/20/2023]
Abstract
PURPOSE Peginterferon (PEG-IFN) and ribavirin (RBV) combination treatment for patients with chronic hepatitis C (CHC), infected by genotype-1 hepatitis C virus with high viral loads, results in a sustained viral response (SVR) in ~50%. However, a trend of decreasing SVR in the older patients has been reported. In the present study, we verified this trend of treatment efficacy in older patients using the propensity score (PS). METHODS We conducted a survey of 327 patients with CHC (genotype 1 and high viral loads) who were treated with PEG-IFN and RBV for 48 weeks. The SVR rate was compared between patients =60 and <60 years of age. Because backgrounds of these patients differed considerably, we verified this efficacy between the older (n = 102) and younger (n = 102) patients matched for gender, body weight, platelets (PLT), and red blood cell (RBC) counts using PS. RESULTS The total SVR rate was 42.9% (161/327); this rate decreased with increasing age and was lower in the older patients (≥60 years: 41.5%, <60 years: 54.3%, P = 0.0245). Moreover, younger age was a significant factor for SVR. After correction by PS, the SVR in older patients remained significantly lower (≥60 years: 43.1%, <60 years: 57.8%, P = 0.0497). In addition, RBC counts and hemoglobin (Hgb) concentrations, as well as RBV adherence in the older patients, decreased with this treatment, although there were no significant differences in pretreatment RBC and Hgb levels. CONCLUSIONS The analysis using PS indicated that RBV adherence in the older patients decreased even if they did not have lower pretreatment RBC and Hgb levels.
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Affiliation(s)
- Hirotoshi Ebinuma
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Hidetsugu Saito
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan. .,Department of Pharmacotherapeutics, Faculty of Pharmacy, Keio University, 1-5-30 Shiba-Kohen, Minato-ku, Tokyo, 105-8512, Japan.
| | - Shinichiro Tada
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Nobuhiro Nakamoto
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Tazuko Ohishi
- The Center for Liver Diseases, Department of Internal Medicine, Kitasato Institute Hospital, Tokyo, Japan
| | - Satoshi Tsunematsu
- The Center for Liver Diseases, Department of Internal Medicine, Kitasato Institute Hospital, Tokyo, Japan
| | - Naoki Kumagai
- The Center for Liver Diseases, Department of Internal Medicine, Kitasato Institute Hospital, Tokyo, Japan
| | - Kanji Tsuchimoto
- The Center for Liver Diseases, Department of Internal Medicine, Kitasato Institute Hospital, Tokyo, Japan
| | - Nobuhiro Tsukada
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Saiseikai Central Hospital, Tokyo, Japan
| | - Yasutaka Inagaki
- Department of Internal Medicine, Nihon Kohkan Hospital, Kawasaki, Japan
| | - Yoshinori Horie
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Eiju General Hospital, Tokyo, Japan
| | - Masahiko Takahashi
- Department of Gastroenterology and Hepatology, National Hospital Organization Tokyo Medical Center, Tokyo, Japan
| | - Kazuhiro Atsukawa
- Department of Gastroenterology and Hepatology, Hiratsuka City Hospital, Hiratsuka, Japan
| | | | - Takanori Kanai
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Toshifumi Hibi
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
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