|
1
|
Giampaoli O, Sciubba F, Biliotti E, Spagnoli M, Calvani R, Tomassini A, Capuani G, Miccheli A, Taliani G. Precision Medicine: Determination of Ribavirin Urinary Metabolites in Relation to Drug Adverse Effects in HCV Patients. Int J Mol Sci 2022; 23:ijms231710043. [PMID: 36077436 PMCID: PMC9456413 DOI: 10.3390/ijms231710043] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2022] [Revised: 08/26/2022] [Accepted: 08/31/2022] [Indexed: 11/25/2022] Open
Abstract
The most commonly used antiviral treatment against hepatitis C virus is a combination of direct-acting antivirals (DAAs) and ribavirin (RBV), which leads to a shortened duration of therapy and a sustained virologic response until 98%. Nonetheless, several dose-related side effects of RBV could limit its applications. This study aims to measure the urinary concentration of RBV and its main metabolites in order to evaluate the drug metabolism ability of HCV patients and to evaluate the adverse effects, such as anemia, with respect to RBV metabolite levels. RBV and its proactive and inactive metabolites were identified and quantified in the urine of 17 HCV males with severe liver fibrosis using proton nuclear magnetic resonance (1H-NMR) at the fourth week (TW4) and at the twelfth week of treatment (EOT). Four prodrug urinary metabolites, including RBV, were identified and three of them were quantified. At both the TW4 and EOT stages, six HCV patients were found to maintain high concentrations of RBV, while another six patients maintained a high level of RBV proactive metabolites, likely due to nucleosidase activity. Furthermore, a negative correlation between the reduction in hemoglobin (Hb) and proactive forms was observed, according to RBV-triphosphate accumulation causing the hemolysis. These findings represent a proof of concept regarding tailoring the drug dose in relation to the specific metabolic ability of the individual, as expected by the precision medicine approach.
Collapse
Affiliation(s)
- Ottavia Giampaoli
- NMR-Based Metabolomics Laboratory (NMLab), Sapienza University of Rome, 00185 Rome, Italy
- Department of Environmental Biology, Sapienza University of Rome, 00185 Rome, Italy
| | - Fabio Sciubba
- NMR-Based Metabolomics Laboratory (NMLab), Sapienza University of Rome, 00185 Rome, Italy
- Department of Environmental Biology, Sapienza University of Rome, 00185 Rome, Italy
| | - Elisa Biliotti
- Department of Clinical Medicine, Policlinico Umberto I, Sapienza University of Rome, 00161 Rome, Italy
| | - Mariangela Spagnoli
- Department of Occupational Medicine, Epidemiology and Hygiene, INAIL, Monte Porzio Catone, 00078 Rome, Italy
| | - Riccardo Calvani
- Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy
| | - Alberta Tomassini
- NMR-Based Metabolomics Laboratory (NMLab), Sapienza University of Rome, 00185 Rome, Italy
- Department of Chemistry, Sapienza University of Rome, 00185 Rome, Italy
| | - Giorgio Capuani
- NMR-Based Metabolomics Laboratory (NMLab), Sapienza University of Rome, 00185 Rome, Italy
- Department of Chemistry, Sapienza University of Rome, 00185 Rome, Italy
| | - Alfredo Miccheli
- NMR-Based Metabolomics Laboratory (NMLab), Sapienza University of Rome, 00185 Rome, Italy
- Department of Environmental Biology, Sapienza University of Rome, 00185 Rome, Italy
- Correspondence:
| | - Gloria Taliani
- Department of Clinical Medicine, Policlinico Umberto I, Sapienza University of Rome, 00161 Rome, Italy
| |
Collapse
|
|
2
|
Akutagawa M, Ide K, Kawasaki Y, Yamanaka M, Iketani R, Yamada H, Masaki N. Safety Profile of Telaprevir-Based Triple Therapy in Elderly Patients: A Real-World Retrospective Cohort Study. Biol Pharm Bull 2017; 40:1525-1529. [PMID: 28603159 DOI: 10.1248/bpb.b17-00354] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
To compare the rate of treatment discontinuation due to adverse events for telaprevir-based triple (T/PR) and pegylated interferon-alfa-2b and ribavirin (PR) therapy for the treatment of hepatitis C virus (HCV) infection in patients over the age of 65 years, in Japan. Retrospective analysis of the health data of patients over the age of 65 years treated for a HCV infection genotype 1 using T/PR or PR therapy, from 38 prefectures in Japan. The primary outcome was the rate of treatment discontinuation due to adverse events for T/PR and PR. The secondary outcome was to evaluate the prevalence and type of adverse events during the treatment period that resulted in treatment discontinuation for both therapies. For comparison, the T/PR and PR populations were matched using the propensity score method, and adjusted odds ratios (ORs) for treatment discontinuation calculated by multivariate logistic regression analysis. The study group included 1330 patients, 328 in the T/PR group and 1002 in the PR group. The rate of treatment discontinuation due to adverse events in the matched population was lower for T/PR (19.82%) than PR (35.98%) therapy, (adjusted OR, 0.418; 95% confidence interval, 0.292-0.599; p<0.01). Malaise was the principal cause of treatment discontinuation in both groups (T/PR, 30.77%, and PR, 42.37%). Using real-world health data of elderly individuals in Japan, we identified a lower rate of treatment discontinuation for T/PR than PR. Our outcomes provide information for a segment of the population that is generally excluded for clinical trials.
Collapse
Affiliation(s)
- Maiko Akutagawa
- Department of Drug Evaluation & Informatics, Graduate School of Pharmaceutical Sciences, University of Shizuoka
| | - Kazuki Ide
- Department of Drug Evaluation & Informatics, Graduate School of Pharmaceutical Sciences, University of Shizuoka.,Department of Pharmacoepidemiology, Graduate School of Medicine and Public Health, Kyoto University.,Center for the Promotion of Interdisciplinary Education and Research, Kyoto University
| | - Yohei Kawasaki
- Department of Drug Evaluation & Informatics, Graduate School of Pharmaceutical Sciences, University of Shizuoka.,Department of Pharmacoepidemiology, Graduate School of Medicine and Public Health, Kyoto University
| | - Mie Yamanaka
- Department of Drug Evaluation & Informatics, Graduate School of Pharmaceutical Sciences, University of Shizuoka
| | - Ryo Iketani
- Department of Drug Evaluation & Informatics, Graduate School of Pharmaceutical Sciences, University of Shizuoka
| | - Hiroshi Yamada
- Department of Drug Evaluation & Informatics, Graduate School of Pharmaceutical Sciences, University of Shizuoka
| | - Naohiko Masaki
- Laboratory Testing Department, National Center for Global Health and Medicine
| |
Collapse
|
|
3
|
El Raziky M, Zayed NA, Abdel Baki A, Mansour SA, Shahin RMH. ITPA gene polymorphism (94C>A) effects on ribavirin-induced anemia during therapy in Egyptian patients with chronic hepatitis C. J Med Virol 2017; 89:1823-1829. [PMID: 28480960 DOI: 10.1002/jmv.24844] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2017] [Accepted: 04/11/2017] [Indexed: 12/13/2022]
Abstract
Inosine triphosphatase (ITPA) gene variants can protect against ribavirin (RBV)-induced anemia in patients treated for chronic hepatitis C. The aim of this study was to determine the relationship between genetic variants of ITPA polymorphism, anemia, RBV dose reduction, and treatment response in hepatitis C virus (HCV)-infected patients. This study was conducted on 97 Egyptian chronic HCV patients who were scheduled for pegylated-interferon (PEG-INF) /RBV therapy. ITPA genotypes rs1127354 were determined by Real Time PCR melting curve analysis. Effects of ITPA polymorphism on hemoglobin (Hb) levels, RBV dose reduction and treatment response were analyzed. The homozygous wild genotype (CC) was associated with Hb reduction at week 4 (P = 0.004). The minor allele protected against Hb reduction. No association with sustained virological response was observed (P = 0.492). Female gender; lower baseline Hb and higher baseline WBC were associated with week 4 anemia (P = 0.04; P = 0.023; 0.033, respectively). The ITPA gene polymorphism rs1127354 heterozygous genotype (CA) may influence Hb levels and protect against hemolytic anemia during RBV-containing regimens for HCV. However, such findings were not significantly related to treatment outcomes. Patients with wild ITPA genotype (CC) experienced a more Hb drop and RBV dose reductions more frequently.
Collapse
Affiliation(s)
- Maissa El Raziky
- Department of Endemic Medicine and Hepatology, Kasr Al Ainy Hospital, School of Medicine, Cairo University, Cairo, Egypt
| | - Naglaa A Zayed
- Department of Endemic Medicine and Hepatology, Kasr Al Ainy Hospital, School of Medicine, Cairo University, Cairo, Egypt
| | - Amin Abdel Baki
- Department of Tropical Medicine, National Hepatology and Tropical Medicine Research Institute (NHTMRI), Cairo, Egypt
| | - Shimaa A Mansour
- Department of Tropical Medicine, National Hepatology and Tropical Medicine Research Institute (NHTMRI), Cairo, Egypt
| | - Rasha M H Shahin
- Department of Clinical Pathology, Kasr Al Ainy, School of Medicine, Cairo University, Cairo, Egypt
| |
Collapse
|
|
4
|
Kanda T, Nakamura M, Yasui S, Haga Y, Tawada A, Suzuki E, Ooka Y, Takahashi K, Sasaki R, Wu S, Nakamoto S, Arai M, Imazeki F, Yokosuka O. Treatment of Real-World HCV Genotype 2-Infected Japanese Patients with Sofosbuvir plus Ribavirin. BIOLOGY 2017; 6:biology6020030. [PMID: 28486403 PMCID: PMC5485477 DOI: 10.3390/biology6020030] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/01/2017] [Revised: 05/04/2017] [Accepted: 05/06/2017] [Indexed: 12/23/2022]
Abstract
The aim of this study was to characterize the treatment response and tolerability of sofosbuvir plus ribavirin therapies in Japanese patients infected with hepatitis C virus (HCV) genotype (GT)-2. This retrospective study analyzed 114 Japanese HCV GT-2 patients treated for 12 weeks with 400 mg of sofosbuvir plus weight-based ribavirin daily. This treatment led to higher sustained virologic response at 12-weeks post-treatment (SVR12) rates in both treatment-naïve and treatment-experienced patients. The efficacy of this treatment in compensated cirrhotics was the same as that in patients with chronic hepatitis. HCV GT-2a infection and lower estimated glomerular filtration rates (eGFR) tended to be associated with SVR12. Of 114 patients, 113 completed the combination of sofosbuvir plus ribavirin for 12 weeks. Seven patients without SVR12 did not have HCV NS5B-S282 mutations. The overall SVR12 rate was 90.4% (103 of 114). More effective therapeutic options with less adverse events are desired to achieve higher SVR rates in HCV GT-2 Japanese patients.
Collapse
Affiliation(s)
- Tatsuo Kanda
- Department of Gastroenterology and Nephrology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.
| | - Masato Nakamura
- Department of Gastroenterology and Nephrology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.
| | - Shin Yasui
- Department of Gastroenterology and Nephrology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.
| | - Yuki Haga
- Department of Gastroenterology and Nephrology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.
| | - Akinobu Tawada
- Safety and Health Organization, Chiba University, 1-33 Yayoicho, Inage-ku, Chiba 263-8522, Japan.
| | - Eiichiro Suzuki
- Department of Gastroenterology and Nephrology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.
| | - Yoshihiko Ooka
- Department of Gastroenterology and Nephrology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.
| | - Koji Takahashi
- Department of Gastroenterology and Nephrology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.
| | - Reina Sasaki
- Department of Gastroenterology and Nephrology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.
| | - Shuang Wu
- Department of Gastroenterology and Nephrology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.
| | - Shingo Nakamoto
- Department of Molecular Virology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.
| | - Makoto Arai
- Department of Gastroenterology and Nephrology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.
| | - Fumio Imazeki
- Safety and Health Organization, Chiba University, 1-33 Yayoicho, Inage-ku, Chiba 263-8522, Japan.
| | - Osamu Yokosuka
- Department of Gastroenterology and Nephrology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.
| |
Collapse
|
|
5
|
Kanda T, Yasui S, Nakamura M, Suzuki E, Arai M, Ooka Y, Ogasawara S, Chiba T, Saito T, Haga Y, Takahashi K, Sasaki R, Wu S, Nakamoto S, Tawada A, Maruyama H, Imazeki F, Kato N, Yokosuka O. Real-World Experiences with the Combination Treatment of Ledipasvir plus Sofosbuvir for 12 Weeks in HCV Genotype 1-Infected Japanese Patients: Achievement of a Sustained Virological Response in Previous Users of Peginterferon plus Ribavirin with HCV NS3/4A Inhibitors. Int J Mol Sci 2017; 18:E906. [PMID: 28441362 PMCID: PMC5454819 DOI: 10.3390/ijms18050906] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2017] [Revised: 04/19/2017] [Accepted: 04/21/2017] [Indexed: 12/14/2022] Open
Abstract
The aim of this study was to characterize the treatment response and serious adverse events of ledipasvir plus sofosbuvir therapies in Japanese patients infected with hepatitis C virus (HCV) genotype 1 (GT1). This retrospective study analyzed 240 Japanese HCV GT1 patients treated for 12 weeks with 90 mg of ledipasvir plus 400 mg of sofosbuvir daily. Sustained virological response at 12 weeks post-treatment (SVR12) was achieved in 236 of 240 (98.3%) patients. Among treatment-naïve patients, SVR12 was achieved in 136 of 138 (98.6%) patients, and among treatment-experienced patients, SVR12 was achieved in 100 of 102 (98.0%) patients. In patients previously treated with peginterferon plus ribavirin with various HCV NS3/4A inhibitors, 100% SVR rates (25/25) were achieved. Two relapsers had HCV NS5A resistance-associated variants (RAVs), but no HCV NS5B-S282 was observed after they relapsed. We experienced two patients with cardiac events during treatment. In conclusion, combination of ledipasvir plus sofosbuvir for 12 weeks is a potential therapy for HCV GT1 patients. Caution is needed for HCV NS5A RAVs, which were selected by HCV NS5A inhibitors and cardiac adverse events.
Collapse
Affiliation(s)
- Tatsuo Kanda
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.
| | - Shin Yasui
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.
| | - Masato Nakamura
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.
| | - Eiichiro Suzuki
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.
| | - Makoto Arai
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.
| | - Yoshihiko Ooka
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.
| | - Sadahisa Ogasawara
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.
| | - Tetsuhiro Chiba
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.
| | - Tomoko Saito
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.
| | - Yuki Haga
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.
| | - Koji Takahashi
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.
| | - Reina Sasaki
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.
| | - Shuang Wu
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.
| | - Shingo Nakamoto
- Department of Molecular Virology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.
| | - Akinobu Tawada
- Safety and Health Organization, Chiba University, 1-33 Yayoicho, Inage-ku, Chiba 263-8522, Japan.
| | - Hitoshi Maruyama
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.
| | - Fumio Imazeki
- Safety and Health Organization, Chiba University, 1-33 Yayoicho, Inage-ku, Chiba 263-8522, Japan.
| | - Naoya Kato
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.
| | - Osamu Yokosuka
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.
| |
Collapse
|
|
6
|
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.
Collapse
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
| |
Collapse
|
|
7
|
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.
Collapse
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.
| |
Collapse
|
|
8
|
Kanda T, Nakamoto S, Yokosuka O. Is the use of IL28B genotype justified in the era of interferon-free treatments for hepatitis C? World J Virol 2015; 4:178-184. [PMID: 26279979 PMCID: PMC4534809 DOI: 10.5501/wjv.v4.i3.178] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2015] [Revised: 06/25/2015] [Accepted: 07/23/2015] [Indexed: 02/05/2023] Open
Abstract
In 2009, several groups reported that interleukin-28B (IL28B) genotypes are associated with the response to peginterferon plus ribavirin therapy for chronic hepatitis C virus (HCV) infection in a genome-wide association study, although the mechanism of this association is not yet well understood. However, in recent years, tremendous progress has been made in the treatment of HCV infection. In Japan, some patients infected with HCV have the IL28B major genotype, which may indicate a favorable response to interferon-including regimens; however, certain patients within this group are also interferon-intolerant or ineligible. In Japan, interferon-free 24-wk regimens of asunaprevir and daclatasvir are now available for HCV genotype 1b-infected patients who are interferon-intolerant or ineligible or previous treatment null-responders. The treatment response to interferon-free regimens appears better, regardless of IL28B genotype. Maybe other interferon-free regimens will widely be available soon. In conclusion, although some HCV-infected individuals have IL28B favorable alleles, importance of IL28B will be reduced with availability of oral interferon free regimen.
Collapse
|
|
9
|
Ampuero J, Del Campo JA, Rojas L, Calleja JL, Cabezas J, Lens S, Crespo J, Forns X, Andrade RJ, Fernández I, Buti M, Millán R, Romero-Gómez M. Role of ITPA and SLC28A2 genes in the prediction of anaemia associated with protease inhibitor plus ribavirin and peginterferon in hepatitis C treatment. J Clin Virol 2015; 68:56-60. [PMID: 26071337 DOI: 10.1016/j.jcv.2015.05.010] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2015] [Revised: 05/07/2015] [Accepted: 05/11/2015] [Indexed: 01/26/2023]
Abstract
BACKGROUND Anaemia is a common side-effect of ribavirin (RBV) use that overwhelms management of hepatitis C when protease inhibitors are added. AIM To assess the pharmacogenomic impact of candidate genes SLC28A2, SLC28A3 and ITPA on anaemia in patients receiving triple therapy. METHODS Patients (n=161) with chronic hepatitis C genotype 1 treated with telaprevir (n=95) or boceprevir (n=66) were included. Using RT-PCR we genotyped ITPA (rs1127354, rs7270101) and SLC28A3 (rs56350726, rs10868138) and SLC28A2 (rs11854484). Clinically significant anaemia (CSA) was diagnosed when at least one of the following criteria was observed: (a) haemoglobin <8.5g/dL during treatment; (b) blood transfusion required; (c) erythropoietin administered. RESULTS CSA occurred in 44% (69/157) of patients and was associated with SLC28A2 rs11854484 [CC/CT genotypes: 33% (26/78) vs. TT genotype: 56% (36/64); p=0.006]. Further, the needed for blood transfusion was related to genotype [CC: 0% (0/18) vs. CT: 13% (8/61) vs. TT: 27% (17/64); p=0.016]. Similarly, ITPA rs1127354 genotypes [AA/AC: 19% (3/16) vs. CC: 45% (61/135; p=0.060] were linked to CSA. In multivariate analysis, SLC28A2 rs11854484 TT genotype (OR:2.33;95%CI:1.10-4.95; p=0.027), female sex (OR:2.54;95% CI:1.13-5.71;p=0.024) and Hb drop at week 4) OR: 1.36; 95CI%: 1.11-1.67; p=0.003) were independently associated with CSA. Similarly, ITPA rs1127354 genotypes [AA/AC: 16% (3/19) vs. CC: 63% (85/134); p=0.0001] and ITPA rs6051702 genotypes [CC/CA: 46% (26/57) vs. CC: 65% (60/93); p=0.023] were related to Hb drop of >3g/dL at week 4. CONCLUSIONS In patients receiving first generation protease inhibitors, genotype SLC28A2 rs11854484 predicts CSA, and helps to identify a subgroup of patients with better tolerance of triple therapy.
Collapse
Affiliation(s)
- Javier Ampuero
- Unit for the Clinical Management of Digestive Diseases, Valme University Hospital & CIBERehd, Sevilla, Spain
| | - José Antonio Del Campo
- Unit for the Clinical Management of Digestive Diseases, Valme University Hospital & CIBERehd, Sevilla, Spain
| | - Lourdes Rojas
- Unit for the Clinical Management of Digestive Diseases, Valme University Hospital & CIBERehd, Sevilla, Spain
| | | | - Joaquín Cabezas
- Digestive Department, Hospital Marqués de Valdecilla, Santander, Spain
| | - Sabela Lens
- Hepatology Unit, Hospital Clinic and IDIBAPS & CIBERehd, Barcelona, Spain
| | - Javier Crespo
- Digestive Department, Hospital Marqués de Valdecilla, Santander, Spain
| | - Xavier Forns
- Hepatology Unit, Hospital Clinic and IDIBAPS & CIBERehd, Barcelona, Spain
| | - Raúl J Andrade
- Digestive Unit, Hospital Virgen de la Victoria & CIBERehd, Málaga, Spain
| | | | - María Buti
- Hepatology Unit, Hospital Vall d'Hebron & CIBERehd, Barcelona, Spain
| | - Raquel Millán
- Unit for the Clinical Management of Digestive Diseases, Valme University Hospital & CIBERehd, Sevilla, Spain
| | - Manuel Romero-Gómez
- Unit for the Clinical Management of Digestive Diseases, Valme University Hospital & CIBERehd, Sevilla, Spain
| |
Collapse
|
|
10
|
Gatselis NK, Zachou K, Saitis A, Samara M, Dalekos GN. Individualization of chronic hepatitis C treatment according to the host characteristics. World J Gastroenterol 2014; 20:2839-53. [PMID: 24659876 PMCID: PMC3961989 DOI: 10.3748/wjg.v20.i11.2839] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2013] [Revised: 11/19/2013] [Accepted: 01/06/2014] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) infection is a global health problem that affects more than 170 million people worldwide. It is a major cause of cirrhosis and hepatocellular carcinoma, making the virus the most common cause of liver failure and transplantation. The standard-of-care treatment for chronic hepatitis C (CHC) has been changed during the last decade and direct acting antiviral drugs have already been used. Besides, understanding of the pathogenesis of CHC has evolved rapidly during the last years and now several host factors are known to affect the natural history and response to treatment. Recent genome-wide association studies have shown the important role of interleukin-28B and inosine triphosphatase in HCV infection. The present review article attempts to summarize the current knowledge on the role of host factors towards individualization of HCV treatment.
Collapse
|
|
11
|
Lee TH, Tillmann HL, Patel K. Individualized therapy for hepatitis C infection: focus on the interleukin-28B polymorphism in directing therapy. Mol Diagn Ther 2014; 18:25-38. [PMID: 24022240 DOI: 10.1007/s40291-013-0053-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Hepatitis C virus—a major global cause of chronic hepatitis, cirrhosis, and hepatocellular carcinoma—affects millions of people worldwide. Pegylated interferon (Peg-IFN) and ribavirin (RBV) had been the standard treatment for a decade until availability of the protease inhibitors in 2011. However, current antiviral therapy is still IFN-based and is associated with significant side effects and variable treatment response. Thus, various host and viral factors have been evaluated before and during treatment for the prediction of sustained virologic response to antiviral therapy. In 2009, genome-wide association studies found the single-nucleotide polymorphisms, located near the host interleukin-28B (IL28B) gene that encodes IFN-λ3, to be the best pretreatment predictor of virologic response to Peg-IFN and RBV therapy in chronic hepatitis C genotype 1 patients. Additionally, inosine triphosphatase (ITPA) gene variants were found to be associated with RBV-induced hemolytic anemia, which could affect treatment dose for selected patients. IL28B, ITPA, and other treatment predictors allowed for a potential individualized approach to treat hepatitis C. In the era of increased overall virologic response rates and good tolerability of the rapidly developing non-IFN oral direct-acting antiviral therapy regimens, the need for individualized treatment is likely to diminish. Various predictors of response, including IL28B will likely be of reduced importance in the near future.
Collapse
|
|
12
|
IFNL4 ss469415590 Variant Is Associated with Treatment Response in Japanese HCV Genotype 1 Infected Individuals Treated with IFN-Including Regimens. Int J Hepatol 2014; 2014:723868. [PMID: 25548683 PMCID: PMC4274707 DOI: 10.1155/2014/723868] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2014] [Accepted: 11/24/2014] [Indexed: 12/24/2022] Open
Abstract
Aim. Eradication of hepatitis C virus (HCV) is still challenging even if interferon- (IFN-) free regimens with direct-acting antiviral agents (DAAs) for HCV-infected individuals are available in clinical practice. IFNL4 is a newly described protein, associated with human antiviral defenses. We investigated whether IFNL4 ss469415590 variant has an effect on the prediction of treatment response in HCV-infected patients treated with IFN-including regimens. Patients and Methods. In all, 185 patients infected with HCV genotype 1 treated with peg-IFN plus ribavirin, with or without telaprevir, were genotyped for IFNL4 ss469415590. We retrospectively investigated whether the role of IFNL4 ss469415590 variant and other factors could predict sustained virological response (SVR) in Japanese patients infected with HCV genotype 1. Results. There were 65.7%, 31.5%, and 2.8% patients in the IFNL4 ss469415590 TT/TT, TT/-G, and -G/-G groups, respectively. SVR rates were 82.1% or 49.3% in patients treated with peg-IFN plus ribavirin with or without telaprevir, respectively. IFNL4 ss469415590 variant and HCV viral loads or IFNL4 ss469415590 variant and early virological response were better predictors of SVR in patients treated with peg-IFN plus ribavirin with or without telaprevir, respectively. Conclusion. In the era of DAAs, measurement of IFNL4 ss469415590 variant could help the prediction of SVR in Japanese HCV genotype 1 infected individuals treated with IFN-including regimens.
Collapse
|
|
13
|
Wu S, Kanda T, Nakamoto S, Imazeki F, Yokosuka O. Hepatitis C virus protease inhibitor-resistance mutations: Our experience and review. World J Gastroenterol 2013; 19:8940-8948. [PMID: 24379619 PMCID: PMC3870547 DOI: 10.3748/wjg.v19.i47.8940] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2013] [Accepted: 12/04/2013] [Indexed: 02/06/2023] Open
Abstract
Direct-acting antiviral agents (DAAs) for hepatitis C virus (HCV) infection are one of the major advances in its medical treatment. The HCV protease inhibitors boceprevir and telaprevir were the first approved DAAs in the United States, Europe, and Japan. When combined with peginterferon plus ribavirin, these agents increase sustained virologic response rates to 70%-80% in treatment-naïve patients and previous-treatment relapsers with chronic HCV genotype 1 infection. Without peginterferon plus ribavirin, DAA mono-therapies increased DAA-resistance mutations. Several new DAAs for HCV are now in clinical development and are likely to be approved in the near future. However, it has been reported that the use of these drugs also led to the emergence of DAA-resistance mutations in certain cases. Furthermore, these mutations exhibit cross-resistance to multiple drugs. The prevalence of DAA-resistance mutations in HCV-infected patients who were not treated with DAAs is unknown, and it is as yet uncertain whether such variants are sensitive to DAAs. We performed a population sequence analysis to assess the frequency of such variants in the sera of HCV genotype 1-infected patients not treated with HCV protease inhibitors. Here, we reviewed the literature on resistance variants of HCV protease inhibitors in treatment naïve patients with chronic HCV genotype 1, as well as our experience.
Collapse
|
|
14
|
Nakamura M, Kanda T, Nakamoto S, Miyamura T, Jiang X, Wu S, Yokosuka O. No correlation between PNPLA3 rs738409 genotype and fatty liver and hepatic cirrhosis in Japanese patients with HCV. PLoS One 2013; 8:e81312. [PMID: 24349054 PMCID: PMC3859490 DOI: 10.1371/journal.pone.0081312] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2013] [Accepted: 10/21/2013] [Indexed: 02/07/2023] Open
Abstract
Background Hepatitis C virus (HCV) infection is associated with the development of cirrhosis and hepatocellular carcinoma and is also related to fatty change of the liver. Variation in patatin-like phospholipase domain-containing 3 (PNPLA3) gene is associated with disease progression in nonalcoholic fatty liver disease (NAFLD). Recent reports have suggested that PNPLA3, IL28B and TLR4-associated single nucleotide polymorphisms (SNPs) may have an impact on hepatic steatosis or fibrosis in patients with chronic HCV infection. Methods and Findings Four SNPs (PNPLA3 rs738409, TLR4 rs4986790, TLR4 rs4986791, IL28B rs8099917) were identified in Japanese patients infected with HCV. We examined the association between the distribution of these SNP alleles and fatty change of the liver or existence of hepatic cirrhosis diagnosed by ultrasonography, one of the widely accessible and easy-to-use methods. PNPLA3 rs738409 G-allele and IL28B rs 8099917 minor allele were found in 70.0% and 31.1%, respectively. These two TLR4 SNPs were uniform in Japanese. Fatty change of the liver developed independent of the abscence of hepatic cirrhosis on sonographic findings and younger age. Hepatic cirrhosis was associated with a higher aspartate aminotransferase/platelet ratio index (APRI), no fatty change of the liver, higher BMI and higher AFP levels. No association between PNPLA3 rs738409/IL28B rs8099917 genotypes and hepatic steatosis or liver fibrosis was observed. Conclusions According to ultrasound examinations, no association between PNPLA3 rs738409 genotype and fatty change of the liver or hepatic cirrhosis was found in Japanese patients infected with HCV. Together, our results suggested that the mechanism of hepatic steatosis underlying HCV infection might differ from that of NAFLD and should be explored.
Collapse
Affiliation(s)
- Masato Nakamura
- Department of Gastroenterology and Nephrology, Chiba University, Graduate School of Medicine, Chiba, Japan
| | - Tatsuo Kanda
- Department of Gastroenterology and Nephrology, Chiba University, Graduate School of Medicine, Chiba, Japan
- * E-mail:
| | - Shingo Nakamoto
- Department of Gastroenterology and Nephrology, Chiba University, Graduate School of Medicine, Chiba, Japan
- Department of Molecular Virology, Chiba University, Graduate School of Medicine, Chiba, Japan
| | - Tatsuo Miyamura
- Department of Gastroenterology and Nephrology, Chiba University, Graduate School of Medicine, Chiba, Japan
| | - Xia Jiang
- Department of Gastroenterology and Nephrology, Chiba University, Graduate School of Medicine, Chiba, Japan
| | - Shuang Wu
- Department of Gastroenterology and Nephrology, Chiba University, Graduate School of Medicine, Chiba, Japan
| | - Osamu Yokosuka
- Department of Gastroenterology and Nephrology, Chiba University, Graduate School of Medicine, Chiba, Japan
| |
Collapse
|
|
15
|
No correlation between PNPLA3 rs738409 genotype and fatty liver and hepatic cirrhosis in Japanese patients with HCV. PLoS One 2013. [PMID: 24349054 DOI: 10.1371/journal.pone.0081312.] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
BACKGROUND Hepatitis C virus (HCV) infection is associated with the development of cirrhosis and hepatocellular carcinoma and is also related to fatty change of the liver. Variation in patatin-like phospholipase domain-containing 3 (PNPLA3) gene is associated with disease progression in nonalcoholic fatty liver disease (NAFLD). Recent reports have suggested that PNPLA3, IL28B and TLR4-associated single nucleotide polymorphisms (SNPs) may have an impact on hepatic steatosis or fibrosis in patients with chronic HCV infection. METHODS AND FINDINGS Four SNPs (PNPLA3 rs738409, TLR4 rs4986790, TLR4 rs4986791, IL28B rs8099917) were identified in Japanese patients infected with HCV. We examined the association between the distribution of these SNP alleles and fatty change of the liver or existence of hepatic cirrhosis diagnosed by ultrasonography, one of the widely accessible and easy-to-use methods. PNPLA3 rs738409 G-allele and IL28B rs 8099917 minor allele were found in 70.0% and 31.1%, respectively. These two TLR4 SNPs were uniform in Japanese. Fatty change of the liver developed independent of the abscence of hepatic cirrhosis on sonographic findings and younger age. Hepatic cirrhosis was associated with a higher aspartate aminotransferase/platelet ratio index (APRI), no fatty change of the liver, higher BMI and higher AFP levels. No association between PNPLA3 rs738409/IL28B rs8099917 genotypes and hepatic steatosis or liver fibrosis was observed. CONCLUSIONS According to ultrasound examinations, no association between PNPLA3 rs738409 genotype and fatty change of the liver or hepatic cirrhosis was found in Japanese patients infected with HCV. Together, our results suggested that the mechanism of hepatic steatosis underlying HCV infection might differ from that of NAFLD and should be explored.
Collapse
|
|
16
|
Kanda T, Nakamoto S, Wu S, Yokosuka O. Role of IL28B genotype in older hepatitis C virus-infected patients. World J Immunol 2013; 3:54-61. [DOI: 10.5411/wji.v3.i3.54] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2013] [Revised: 09/02/2013] [Accepted: 10/16/2013] [Indexed: 02/05/2023] Open
Abstract
The average age of hepatitis C virus (HCV)-infected individuals is becoming increasingly higher in Japan and steps should be taken to treat older individuals infected with HCV. Until an interferon-free regimen becomes available, peginterferon plus ribavirin will play a critical role in the treatment. The perception that older HCV-infected patients may be at higher risk than younger patients for adverse events from peginterferon plus ribavirin treatment but may obtain less clinical benefit from it may be based on the underrepresentation of older patients in clinical trials. A recent genome-wide association study revealed that interleukin-28B (IL28B) genotype closely correlates with the treatment response against HCV. The relationship of IL28B genotype with the treatment response in older HCV-infected patients is also unknown. In this review, we focused on the treatment response in older patients infected with HCV and the effects of IL28B genotype. IL28B major genotype is a useful predictor of sustained virological response in the interferon-including treatment of older patients infected with HCV. It also seems useful for avoiding adverse events, although the mechanisms of the effects of IL28B genotype on the treatment outcome are still poorly understood and are currently under investigation. Further studies will be needed.
Collapse
|
|
17
|
Miyamura T, Kanda T, Nakamura M, Jiang X, Wu S, Nakamoto S, Mikami S, Takada N, Imazeki F, Yokosuka O. IL-28B polymorphisms and treatment response in hepatitis C virus patients with persistently normal alanine aminotransferase. World J Hepatol 2013; 5:635-641. [PMID: 24303092 PMCID: PMC3847947 DOI: 10.4254/wjh.v5.i11.635] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2013] [Revised: 10/07/2013] [Accepted: 11/05/2013] [Indexed: 02/06/2023] Open
Abstract
AIM: To examine the association between the interleukin 28B (IL-28B) genotype and treatment response in hepatitis C virus (HCV)-infected patients with persistently normal alanine aminotransferase (PNALT).
METHODS: We compared the treatment response of HCV-infected patients with PNALT to that of patients with non-PNALT. Between February 2010 and April 2013, 278 patients infected with HCV were enrolled in this study. All of the patients were treated with peginterferon-alpha 2a or 2b plus ribavirin. In addition, 180 μg of peginterferon alpha-2a or 1.5 μg/kg peginterferon alpha-2b per week plus weight-based ribavirin (600-1000 mg/d) were typically administered for 24 wk to HCV genotype 2-infected patients or for 48-72 wk to HCV genotype 1-infected patients. In all of the patients, the IL-28B rs8099917 genotype was determined using a TaqMan single-nucleotide polymorphism assay. HCV RNA was measured using the COBAS TaqMan HCV test.
RESULTS: Female patients were dominant in the PNALT group (P < 0.0001). Among 72 HCV genotype 1-infected patients with PNALT, the early virologic response (EVR) rates (P < 0.01) and the sustained virologic response (SVR) rates (P < 0.01) were higher in patients with the IL-28B TT genotype than in those with the IL-28B TG/GG genotype. In HCV genotype 1-infected patients with PNALT, multivariate logistic-regression analysis showed that SVR was independently predicted by the IL-28B rs8099917 TT type (P < 0.05) and having an EVR (P < 0.01). The IL-28B rs8099917 TT genotype strongly correlated with treatment response in HCV genotype 1-infected Asian patients with PNALT.
CONCLUSION: The IL-28B genotype may be useful for selecting HCV genotype 1-infected patients with PNALT who should receive interferon-based treatment.
Collapse
|
|
18
|
Kanda T, Jiang X, Nakamoto S, Nakamura M, Miyamura T, Wu S, Yokosuka O. Different effects of three interferons L on Toll-like receptor-related gene expression in HepG2 cells. Cytokine 2013; 64:577-83. [PMID: 24041672 DOI: 10.1016/j.cyto.2013.08.010] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2013] [Revised: 08/07/2013] [Accepted: 08/16/2013] [Indexed: 02/07/2023]
Abstract
IFNL1 (IL29), IFNL2 (IL28A) and IFNL3 (IL28B) might play important roles in anti-viral defense. IFNL3 genotypes have been shown to be associated with hepatitis C spontaneous and treatment-induced viral clearance. The effects of IFNL1, IFNL2 and IFNL3 on innate immunity including Toll-like receptor (TLR)-related pathway in human hepatocytes were examined. After G418 screening, we established the human hepatoma stable cell lines HepG2-IL28A, HepG2-IL28B, and HepG2-IL29, expressing IFNL2, IFNL3, and IFNL1 in conditioned medium, respectively, and a control cell line, HepG2-pcDNA3.1. We performed real-time RT-PCR to investigate 84 Toll-like receptor-related gene expressions in triplicate and, using ddCt methods, compared these gene expressions in each cell line. IFNL2, IFNL3 and IFNL1 were respectively detected by ELISA in HepG2-IL28A, HepG2-IL28B and HepG2-IL29. Compared to HepG2-pcDNA3.1 cells, 17 (20.2%), 11 (13.0%) and 16 genes (19.0%) were up-regulated 1.5-fold or more (p<0.05); 10 (11.9%), 2 (2.3%) and 10 genes (11.9%) were 1.5-fold or more down-regulated (p<0.05) in HepG2-IL28A, HepG2-IL28B and HepG2-IL29, respectively. EIF2AK2 and SARM1 were up-regulated among all cells. Of interest, TLR3, TLR4 and related molecules CXCL10 (IP10), IL6, EIF2K2, IFNB1, and IRF1, important genes in the progression of HCV-related pathogenesis and antiviral activities against HCV, in HepG2-IL28B, presented different profiles from those of HepG2-IL28A and HepG2-IL29. IFNL3 induces interferon-stimulated genes (ISGs) that are reportedly associated with the progression of HCV-related pathogenesis and antiviral activities against HCV. IFNL is a powerful modulator of innate immune response and it is supposed that the 3 IFNLs may play different roles in the antiviral activity against HBV and HCV.
Collapse
Affiliation(s)
- Tatsuo Kanda
- Department of Gastroenterology and Nephrology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8677, Japan.
| | | | | | | | | | | | | |
Collapse
|
|
19
|
Derbala M, Rizk NM, Al-Kaabi S, John A, Sharma M, El-dweik N, Yakoob R, Pasic F, Almohanadi M, Alejji K, Abdelmola A, Butt M. The predictive value of IL28B rs12979860, rs11881222 and rs8099917 polymorphisms and IP-10 in the therapeutic response of Egyptian genotype 4 patients. Virology 2013; 444:292-300. [PMID: 23866096 DOI: 10.1016/j.virol.2013.06.025] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2013] [Revised: 04/12/2013] [Accepted: 06/24/2013] [Indexed: 02/07/2023]
Abstract
UNLABELLED Interleukin-28B (IL28B) polymorphisms have previously been reported to be strongly associated with spontaneous and treatment-induced HCV viral clearance. AIM To assess the impact of four different IL28B polymorphisms and their haplotype combination and interferon-c inducible protein 10 (IP-10) in response to treatment in Egyptian genotype 4 patients. METHOD 159 HCV-genotype 4 patients were included. All patients were treated with Peginterferon alph2a/Ribavirin for 48 wk. The following polymorphisms rs12979860, rs11881222, rs8103142 and rs8099917 and rs80803142 of Il-28 were known to be associated with the sustained virological response. They were genotyped using the TaqMan assay. IP-10 was assessed by Eliza. RESULTS The data indicated that all SNPs are within the Hardy-Weinberg Equilibrium (HWE) except for rs8103142 (p=6.255(-9)), therefore it was excluded from the study since it deviates from HWE-P. The CC, AA and TT genotypes of rs12979860, rs11881222 and rs8099917 were the more frequent genotypes among the responders at RVR, EVR, ETR and SVR, respectively. The frequency of CC, CT, and TT genotype was 46.4%, 38.1% and 15.5% among responders of RVR, and was 46.9%, 45.9% and 7.2 among responders of SVR for rs12979860, respectively. The relapse rate was 18.0% and 16.0 % during EVR and ETR, while the response rate was 52.8%, 58.5%, 59.7% and 61.6% after 4, 12, 48 and 72 weeks of treatment. The transient virological response (TVR) was 6.9% among HCV patients. The results showed that the odds ratio and 95% CI of HCV genotype 4 patients to have a better sustained response to treatment (SVR) was 2.92, (1.83-4.68, p=2.01(-5)), 2.89 (1.79-4.70, p=2.53(-5)), and 2.73 (0.21-0.65, p=0.0007) for those with the major allele "C" of rs12979860, the "A" allele of rs11881222, and the "T" allele of rs8099917, respectively. Furthermore, the positive predictive value (PPV) of the major homozygous alleles for SVR with better response to therapy was in the following order: 78.69%, 68.42%, and 32.14% with a positive likelihood ratio of 1.95, 1.25, and 0.86 for rs12979860, rs11881222 and rs8099917, respectively. The haplotype formed between the 3 studied SNPs (rs12979860, rs11881222 and rs8099917) showed that two haplotypes (TGG and TGT) increased the probability of a poor response to therapy, but the CAT haplotype had the opposite effect. Multinomial logistic regression analysis revealed that the viral load and rs12979860 are the only significant actors involved in the efficacy of the treatment response among the cohort study. In addition, patients with SVR had significantly lower values of IP-10 than non-responder patients (NR), with a P-value<=0.001. CONCLUSIONS In genotype 4 cases, the IL28B SNPs rs12979860 rs8099917, and rs11881222 are the strongest predictors of a response, while IP-10 is a strong negative biomarker of a response. Accounting for this factor is important in the individualization of treatment and enhances the degree of predictiveness of the IL28 polymorphism in the final treatment outcome. The frequent distribution of C, A and T alleles of IL28 polymorphism are higher among TVR, which may reflect sensitivity to prolonged course.
Collapse
Affiliation(s)
- Moutaz Derbala
- Gastroenterology and Hepatology Department, Hamad Hospital, Doha, Qatar.
| | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
20
|
Kanda T, Kato K, Tsubota A, Takada N, Nishino T, Mikami S, Miyamura T, Maruoka D, Wu S, Nakamoto S, Arai M, Fujiwara K, Imazeki F, Yokosuka O. Platelet count and sustained virological response in hepatitis C treatment. World J Hepatol 2013; 5:182-188. [PMID: 23671722 PMCID: PMC3648649 DOI: 10.4254/wjh.v5.i4.182] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2012] [Revised: 10/31/2012] [Accepted: 01/30/2013] [Indexed: 02/06/2023] Open
Abstract
AIM: To examine the epidemiological data, hematological safety and treatment responses of peginterferon-alpha 2a plus ribavirin therapy for hepatitis C.
METHODS: Between March 2008 and February 2011, 196 hepatitis C virus (HCV) genotype 1 infected Japanese (127 treatment-naive and 69 treatment-experienced patients) patients treated with peginterferon-alpha 2a plus ribavirin were enrolled. We examined the epidemiological data and treatment responses were retrospectively analyzed in terms of hematological safety. HCV RNA was measured by the COBAS TaqMan HCV test.
RESULTS: Overall sustained virological response (SVR) rates of treatment-naive and treatment-experienced patients were 56% and 39%, respectively. Multivariate logistic regression analysis showed that SVR was attained independently of early virological response in both treatment-naive and treatment-experienced patients. SVR rates did not differ between the pretreatment hemoglobin < 13 g/dL and ≥ 13 g/dL groups. However, in treatment-naive patients, the SVR rate of the pretreatment platelet count < 130000/µL group was significantly lower than that of the pretreatment platelet count ≥ 130000/µL group.
CONCLUSION: Attention should be paid to potential thrombocytopenia in the treatment of chronic hepatitis C patients.
Collapse
|
|
21
|
Kanda T, Yokosuka O, Omata M. Treatment of hepatitis C virus infection in the future. Clin Transl Med 2013; 2:9. [PMID: 23577631 PMCID: PMC3637513 DOI: 10.1186/2001-1326-2-9] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2013] [Accepted: 04/08/2013] [Indexed: 12/13/2022] Open
Abstract
Two direct-acting antivirals (DAAs) against hepatitis C virus (HCV): telaprevir and boceprevir, are now available in combination with peginterferon plus ribavirin for the treatment of chronic hepatitis C infection. Although these drugs are potent inhibitors of HCV replication, they occasionally result in severe adverse events. In the present clinical trials, in their stead, several second-generation DAAs are being investigated. Most of them are being viewed with high expectations, but they also require the combination with peginterferon plus ribavirin. In the near future, we might be using all-oral DAAs and interferon-free regimens for the treatment of HCV-infected patients, and these would be potent inhibitors of HCV and have less adverse events.
Collapse
Affiliation(s)
- Tatsuo Kanda
- Department of Gastroenterology and Nephrology, Chiba University, Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba (260-8670), Japan.
| | | | | |
Collapse
|
|
22
|
Nakamura M, Kanda T, Miyamura T, Wu S, Nakamoto S, Yokosuka O. Alanine aminotransferase elevation during peginterferon alpha-2a or alpha-2b plus ribavirin treatment. Int J Med Sci 2013; 10:1015-21. [PMID: 23801888 PMCID: PMC3691800 DOI: 10.7150/ijms.6402] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2013] [Accepted: 06/09/2013] [Indexed: 02/07/2023] Open
Abstract
Alanine aminotransferase (ALT) elevation was occassionally observed during the treatment with combination peginterferon alpha plus ribavirin. Two forms of peginterferon are currently available as a standard of care with or without direct-acting antivirals against hepatitis C virus (HCV). Until the appearance of interferon-sparing regimen, peginterferon alpha plus ribavirin will play a central role in the eradication of HCV. In the present study, we compared ALT elevations in response to peginterferon alpha-2a plus ribavirin or peginterferon alpha-2b plus ribavirin in HCV genotype-1-infected patients. There were no significant differences in ALT elevations between treatments with the two peginterferons, but in a comparison of the proportions of patients with transient ALT elevation from baseline between the two groups, transient ALT elevation was observed more in sustained virological response (SVR) patients treated with peginterferon alpha-2a than with peginterferon alpha-2b. However, no patients discontinued treatment due to ALT elevation. Patients with transient ALT elevation from baseline during the treatment had less favorable IL28B rs8099917 genotype in the peginterferon alpha-2b group. Patients achieving SVR tended to have lower ALT levels, although some had persistent ALT elevation during treatment. In conclusion, clinicians should pay attention to possible ALT elevation during the treatment of chronic hepatitis C patients.
Collapse
Affiliation(s)
- Masato Nakamura
- Department of Gastroenterology and Nephrology, Chiba University, Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan
| | | | | | | | | | | |
Collapse
|