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1
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Nakamura T, Shirouzu T. Antibody-Mediated Rejection and Recurrent Primary Disease: Two Main Obstacles in Abdominal Kidney, Liver, and Pancreas Transplants. J Clin Med 2021; 10:5417. [PMID: 34830699 PMCID: PMC8619797 DOI: 10.3390/jcm10225417] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2021] [Revised: 11/17/2021] [Accepted: 11/18/2021] [Indexed: 02/08/2023] Open
Abstract
The advances in acute phase care have firmly established the practice of organ transplantation in the last several decades. Then, the next issues that loom large in the field of transplantation include antibody-mediated rejection (ABMR) and recurrent primary disease. Acute ABMR is a daunting hurdle in the performance of organ transplantation. The recent progress in desensitization and preoperative monitoring of donor-specific antibodies enables us to increase positive outcomes. However, chronic active ABMR is one of the most significant problems we currently face. On the other hand, recurrent primary disease is problematic for many recipients. Notably, some recipients, unfortunately, lost their vital organs due to this recurrence. Although some progress has been achieved in these two areas, many other factors remain largely obscure. In this review, these two topics will be discussed in light of recent discoveries.
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Affiliation(s)
- Tsukasa Nakamura
- Department of Organ Transplantation and General Surgery, Kyoto Prefectural University of Medicine, Kajii-cho 465, Kamigyo-ku, Kyoto 602-8566, Japan
| | - Takayuki Shirouzu
- Molecular Diagnositcs Division, Wakunaga Pharmaceutical Co., Ltd., 13-4 Arakicho, shinjyuku-ku, Tokyo 160-0007, Japan;
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Tahata Y, Sakamori R, Takehara T. Treatment progress and expansion in Japan: From interferon to direct-acting antiviral. Glob Health Med 2021; 3:321-334. [PMID: 34782876 DOI: 10.35772/ghm.2021.01083] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Revised: 08/24/2021] [Accepted: 09/10/2021] [Indexed: 12/17/2022]
Abstract
Hepatitis C virus (HCV) was first discovered in 1989, and patients infected with HCV were initially treated with interferon (IFN) monotherapy. In the 2000s, pegylated IFN combined with ribavirin was the mainstay of therapy for infected patients, but the sustained virologic response (SVR) rate was less than 50% for patients with HCV genotype 1. To further improve the therapeutic effect, direct-acting antiviral (DAA) was developed, and combination therapy with DAA and IFN has been available since 2011. In addition, IFN-free DAA therapy became available in 2014, and SVR was achieved in more than 95% of patients with chronic hepatitis and compensated cirrhosis. Thus, in just 30 years since the discovery of HCV, we aim to eliminate HCV in almost all patients. However, there are remaining issues to be addressed. Many of the patients who achieved SVR with DAA therapy had advanced liver fibrosis, and it is necessary to verify to what extent DAA therapy improves their prognosis in terms of liver function, hepatocellular carcinoma occurrence, and mortality. Resistance-associated substitutions can cause failure of DAA therapy, and the search for an effective therapy for high-level resistant viruses such as P32 deletion is particularly important. DAA therapy was approved for use in patients with decompensated cirrhosis in Japan in 2019, which is an unmet need so far. It is also important to verify the efficacy and safety in real-world settings. The World Health Organization aims to eliminate HCV by 2030, and Japan must tackle its remaining issues to achieve this goal.
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Affiliation(s)
- Yuki Tahata
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Ryotaro Sakamori
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Tetsuo Takehara
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
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3
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Yoshioka M, Sawada Y, Saito-Sasaki N, Yoshioka H, Hama K, Omoto D, Ohmori S, Okada E, Nakamura M. High S100A2 expression in keratinocytes in patients with drug eruption. Sci Rep 2021; 11:5493. [PMID: 33750880 PMCID: PMC7943585 DOI: 10.1038/s41598-021-85009-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2020] [Accepted: 02/17/2021] [Indexed: 11/09/2022] Open
Abstract
Telaprevir used as a protease inhibitor against hepatitis C virus is frequently associated with cutaneous adverse reactions. To explore a histological biomarker of cutaneous adverse events induced by telaprevir, we systematically searched for genes that were dysregulated by telaprevir in normal human epidermal keratinocytes (NHEKs). Microarray analysis and real-time polymerase chain reaction (PCR) revealed the significant increase in the expression of S100 calcium-binding protein A2 (S100A2) gene following treatment of NHEKs with telaprevir. Immunohistochemical analysis demonstrated that the expression of S100A2 was dominant in the spinous layer of the epidermis in patients with telaprevir-mediated severe-type drug eruptions and limited to the basal layer of the epidermis in healthy subjects. Furthermore, S100A2 expression increased after treatment with trichloroethylene and other medications, and the degree of S100A2 expression correlated with the severity of cutaneous adverse events. S100A2 expression also significantly increased in the skin of patients with atopic dermatitis and psoriasis. Taken together, S100A2 is highly expressed in the epidermis under inflammatory conditions and drug eruptions and may serve as a marker for keratinocyte damage in response to any inflammatory or toxic condition.
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Affiliation(s)
- Manabu Yoshioka
- Department of Dermatology, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu, 807-8555, Japan
| | - Yu Sawada
- Department of Dermatology, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu, 807-8555, Japan.
| | - Natsuko Saito-Sasaki
- Department of Dermatology, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu, 807-8555, Japan
| | - Haruna Yoshioka
- Department of Dermatology, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu, 807-8555, Japan
| | - Kayo Hama
- Department of Dermatology, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu, 807-8555, Japan
| | - Daisuke Omoto
- Department of Dermatology, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu, 807-8555, Japan
| | - Shun Ohmori
- Department of Dermatology, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu, 807-8555, Japan
| | - Etsuko Okada
- Department of Dermatology, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu, 807-8555, Japan
| | - Motonobu Nakamura
- Department of Dermatology, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu, 807-8555, Japan.
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Iwamoto T, Saeki I, Hidaka I, Ishikawa T, Takami T, Sakaida I. Novel Therapeutic Strategy Using Interventional Radiology (IVR) for Hepatitis C Virus (HCV)-Related Decompensated Liver Cirrhosis: A Case Report. AMERICAN JOURNAL OF CASE REPORTS 2019; 20:1699-1704. [PMID: 31738743 PMCID: PMC6878963 DOI: 10.12659/ajcr.919240] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Patient: Male, 72 Final Diagnosis: Decompensated liver cirrhosis Symptoms: Disturbance of consciousness Medication: — Clinical Procedure: PSE • BRTO • HCV treatment Specialty: Radiology
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Affiliation(s)
- Takuya Iwamoto
- Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan
| | - Issei Saeki
- Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan
| | - Isao Hidaka
- Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan
| | - Tsuyoshi Ishikawa
- Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan
| | - Taro Takami
- Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan
| | - Isao Sakaida
- Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan
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Oh JY, Kim BS, Lee CH, Song JE, Lee HJ, Park JG, Hwang JS, Chung WJ, Jang BK, Kweon YO, Tak WY, Park SY, Jang SY, Suh JI, Kwak SG. Daclatasvir and asunaprevir combination therapy for patients with chronic hepatitis C virus genotype 1b infection in real world. Korean J Intern Med 2019; 34:794-801. [PMID: 29792020 PMCID: PMC6610199 DOI: 10.3904/kjim.2017.368] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2017] [Accepted: 01/29/2018] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND/AIMS Previous studies have reported a high rate of sustained virologic response (SVR) and a low rate of serious adverse events with the use of daclatasvir (DCV) and asunaprevir (ASV) combination therapy. We evaluated the efficacy and safety of DCV and ASV combination therapy for patients with chronic hepatitis C virus (HCV) genotype 1b infection in real world. METHODS We enrolled 278 patients (184 treatment-naïve patients) from five hospitals in Daegu and Gyeongsangbuk-do. We evaluated the rates of rapid virologic response (RVR), end-of-treatment response (ETR), and SVR at 12 weeks after completion of treatment (SVR12). Furthermore, we investigated the rate of adverse events and predictive factors of SVR12 failure. RESULTS The mean age of patients was 59.5 ± 10.6 years, and 140 patients (50.2%) were men. Seventy-seven patients had cirrhosis. Baseline information regarding nonstructural protein 5A (NS5A) sequences was available in 268 patients. Six patients presented with pretreatment NS5A resistance-associated variants. The RVR and the ETR rates were 96.6% (258/267) and 95.2% (223/232), respectively. The overall SVR12 rate was 91.6% (197/215). Adverse events occurred in 17 patients (7.9%). Six patients discontinued treatment because of liver enzyme elevation (n = 4) and severe nausea (n = 2). Among these, four achieved SVR12. Other adverse events observed were fatigue, headache, diarrhea, dizziness, loss of appetite, skin rash, and dyspnea. Univariate analysis did not show significant predictive factors of SVR12 failure. CONCLUSION DCV and ASV combination therapy showed high rates of RVR, ETR, and SVR12 in chronic HCV genotype 1b-infected patients in real world and was well tolerated without serious adverse events.
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Affiliation(s)
- Jae Young Oh
- Department of Internal Medicine, Catholic University of Daegu School of Medicine, Daegu, Korea
| | - Byung Seok Kim
- Department of Internal Medicine, Catholic University of Daegu School of Medicine, Daegu, Korea
- Correspondence to Byung Seok Kim, M.D. Department of Internal Medicine, Catholic University of Daegu School of Medicine, 33 Duryugongwon-ro 17-gil, Nam-gu, Daegu 42472, Korea Tel: +82-53-650-4090 Fax: +82-53-656-3281 E-mail:
| | - Chang Hyeong Lee
- Department of Internal Medicine, Catholic University of Daegu School of Medicine, Daegu, Korea
| | - Jeong Eun Song
- Department of Internal Medicine, Catholic University of Daegu School of Medicine, Daegu, Korea
| | - Heon Ju Lee
- Department of Internal Medicine, Yeungnam University College of Medicine, Daegu, Korea
| | - Jung Gil Park
- Department of Internal Medicine, Yeungnam University College of Medicine, Daegu, Korea
| | - Jae Seok Hwang
- Department of Internal Medicine, Keimyung University School of Medicine, Daegu, Korea
| | - Woo Jin Chung
- Department of Internal Medicine, Keimyung University School of Medicine, Daegu, Korea
| | - Byoung Kuk Jang
- Department of Internal Medicine, Keimyung University School of Medicine, Daegu, Korea
| | - Young Oh Kweon
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, Korea
| | - Won Young Tak
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, Korea
| | - Soo Young Park
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, Korea
| | - Se Young Jang
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, Korea
| | - Jeong Ill Suh
- Department of Internal Medicine, Dongguk University College of Medicine, Gyeongju, Korea
| | - Sang Gyu Kwak
- Department of Medical Statistics, Catholic University of Daegu School of Medicine, Daegu, Korea
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Leahy J, Thom H, Jansen JP, Gray E, O'Leary A, White A, Walsh C. Incorporating single-arm evidence into a network meta-analysis using aggregate level matching: Assessing the impact. Stat Med 2019; 38:2505-2523. [PMID: 30895655 DOI: 10.1002/sim.8139] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2017] [Revised: 11/27/2018] [Accepted: 02/14/2019] [Indexed: 01/21/2023]
Abstract
Increasingly, single-armed evidence is included in health technology assessment submissions when companies are seeking reimbursement for new drugs. While it is recognized that randomized controlled trials provide a higher standard of evidence, these are not available for many new agents that have been granted licenses in recent years. Therefore, it is important to examine whether alternative strategies for assessing this evidence may be used. In this work, we examine approaches to incorporating single-armed evidence formally in the evaluation process. We consider matching aggregate level covariates to comparator arms or trials and including this evidence in a network meta-analysis. We consider two methods of matching: (i) we include the chosen matched arm in the data set itself as a comparator for the single-arm trial; (ii) we use the baseline odds of an event in a chosen matched trial to use as a plug-in estimator for the single-arm trial. We illustrate that the synthesis of evidence resulting from such a setup is sensitive to the between-study variability, formulation of the prior for the between-design effect, weight given to the single-arm evidence, and extent of the bias in single-armed evidence. We provide a flowchart for the process involved in such a synthesis and highlight additional sensitivity analyses that should be carried out. This work was motivated by a hepatitis C data set, where many agents have only been examined in single-arm studies. We present the results of our methods applied to this data set.
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Affiliation(s)
- Joy Leahy
- School of Computer Science and Statistics, Trinity College Dublin, The University of Dublin, Dublin, Ireland
- National Centre for Pharmacoeconomics, St. James's Hospital, Dublin, Ireland
| | - Howard Thom
- Bristol Medical School: Population Health Sciences, University of Bristol, Bristol, UK
| | - Jeroen P Jansen
- Department of Health Research and Policy Epidemiology, Stanford University School of Medicine, Stanford, California
| | - Emma Gray
- School of Medicine, Trinity College Dublin, The University of Dublin, Dublin, Ireland
| | - Aisling O'Leary
- National Centre for Pharmacoeconomics, St. James's Hospital, Dublin, Ireland
| | - Arthur White
- School of Computer Science and Statistics, Trinity College Dublin, The University of Dublin, Dublin, Ireland
- National Centre for Pharmacoeconomics, St. James's Hospital, Dublin, Ireland
| | - Cathal Walsh
- National Centre for Pharmacoeconomics, St. James's Hospital, Dublin, Ireland
- Department of Mathematics and Statistics, Health Research Institute and MACSI, University of Limerick, Limerick, Ireland
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Taki S, Tamai H, Ida Y, Shingaki N, Kawashima A, Shimizu R, Moribata K, Maekita T, Iguchi M, Kato J, Nakao T, Kitano M. The Real-World Safety and Efficacy of Daclatasvir and Asunaprevir for Elderly Patients. Gut Liver 2018; 12:86-93. [PMID: 28798288 PMCID: PMC5753689 DOI: 10.5009/gnl17048] [Citation(s) in RCA: 5] [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: 01/25/2017] [Revised: 03/22/2017] [Accepted: 03/22/2017] [Indexed: 01/10/2023] Open
Abstract
Background/Aims Although daclatasvir with asunaprevir was approved in Japan for interferon ineligible or intolerant patients, patients aged ≥75 years were excluded in the phase III trial. The present study aimed to evaluate the safety and efficacy of this therapy for elderly patients aged ≥75 years and to clarify whether an extremely high sustained virological response (SVR) rate can be achieved, even in a real-world setting when patients with resistance-associated substitutions (RASs) to nonstructural protein 5A (NS5A) inhibitors or prior simeprevir failure are excluded. Methods Daclatasvir (60 mg) and asunaprevir (100 mg) were orally administered daily for 24 weeks. Patients without pre-existing NS5A RASs and simeprevir failure were enrolled in this study. Results Overall, 110 patients were treated. The median age was 73 years old. The SVR rates of total patients, those aged ≥75 years, and those aged <75 years were 97% (107/110), 98% (46/47), and 97% (61/63), respectively. The treatment of two patients (2%) was discontinued because of adverse events. Conclusions Daclatasvir with asunaprevir was a safe treatment, even in patients aged ≥75 years. When patients without pre-existing NS5A RASs and prior simeprevir failure were selected, an extremely high SVR rate could be achieved irrespective of age.
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Affiliation(s)
- Shinya Taki
- Second Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan
| | - Hideyuki Tamai
- Second Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan
| | - Yoshiyuki Ida
- Second Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan
| | - Naoki Shingaki
- Second Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan
| | - Akira Kawashima
- Department of Internal Medicine, Naga Municipal Hospital, Wakayama, Japan
| | - Ryo Shimizu
- Second Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan
| | - Kosaku Moribata
- Second Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan
| | - Takao Maekita
- Second Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan
| | - Mikitaka Iguchi
- Second Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan
| | - Jun Kato
- Second Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan
| | - Taisei Nakao
- Department of Internal Medicine, Naga Municipal Hospital, Wakayama, Japan
| | - Masayuki Kitano
- Second Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan
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8
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Suda G, Ogawa K, Morikawa K, Sakamoto N. Treatment of hepatitis C in special populations. J Gastroenterol 2018; 53:591-605. [PMID: 29299684 PMCID: PMC5910474 DOI: 10.1007/s00535-017-1427-x] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2017] [Accepted: 12/19/2017] [Indexed: 02/08/2023]
Abstract
Hepatitis C virus (HCV) infection is one of the primary causes of liver cirrhosis and hepatocellular carcinoma. In hemodialysis patients, the rate of HCV infection is high and is moreover associated with a poor prognosis. In liver transplantation patients with HCV infection, recurrent HCV infection is universal, and re-infected HCV causes rapid progression of liver fibrosis and graft loss. Additionally, in patients with HCV and human immunodeficiency virus (HIV) co-infection, liver fibrosis progresses rapidly. Thus, there is an acute need for prompt treatment of HCV infection in these special populations (i.e., hemodialysis, liver transplantation, HIV co-infection). However, until recently, the standard anti-HCV treatment involved the use of interferon-based therapy. In these special populations, interferon-based therapies could not achieve a high rate of sustained viral response and moreover were associated with a higher rate of adverse events. With the development of novel direct-acting antivirals (DAAs), the landscape of anti-HCV therapy for special populations has changed dramatically. Indeed, in special populations treated with interferon-free DAAs, the sustained viral response rate was above 90%, with a lower incidence and severity of adverse events.
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Affiliation(s)
- Goki Suda
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, North 15, West 7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan.
| | - Koji Ogawa
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, North 15, West 7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan
| | - Kenichi Morikawa
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, North 15, West 7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan
| | - Naoya Sakamoto
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, North 15, West 7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan
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Tamai H, Ida Y, Kawashima A, Shingaki N, Shimizu R, Moribata K, Nasu T, Maekita T, Iguchi M, Kato J, Nakao T, Kitano M. Simeprevir-Based Triple Therapy with Reduced Doses of Pegylated Interferon α-2a Plus Ribavirin for Interferon Ineligible Patients with Genotype 1b Hepatitis C Virus. Gut Liver 2018; 11:551-558. [PMID: 28506030 PMCID: PMC5491091 DOI: 10.5009/gnl16525] [Citation(s) in RCA: 3] [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: 10/26/2016] [Revised: 12/10/2016] [Accepted: 12/23/2016] [Indexed: 12/28/2022] Open
Abstract
Background/Aims The present study aimed to evaluate the safety and efficacy of simeprevir-based triple therapy with reduced doses of pegylated interferon (PEG-IFN) and ribavirin for interferon (IFN) ineligible patients, such as elderly and/or cirrhotic patients, and to elucidate the factors contributing to a sustained virologic response (SVR). Methods One hundred IFN ineligible patients infected with genotype 1b hepatitis C virus (HCV) were treated. Simeprevir (100 mg) was given orally together with reduced doses of PEG-IFN-α 2a (90 μg), and ribavirin (200 mg less than the recommended dose). Results The patients’ median age was 70 years, and 70 patients were cirrhotic. Three patients (3%) discontinued treatment due to adverse events. The SVR rate was 64%. Factors that significantly contributed to the SVR included the γ-glutamyl transferase and α-fetoprotein levels, interleukin-28B (IL28B) polymorphism status, and the level and reduction of HCV RNA at weeks 2 and 4. The multivariate analysis showed that the IL28B polymorphism status was the only independent factor that predicted the SVR, with a positive predictive value of 77%. Conclusions Simeprevir-based triple therapy with reduced doses of PEG-IFN and ribavirin was safe and effective for IFN ineligible patients infected with genotype 1b HCV. IL28B polymorphism status was a useful predictor of the SVR.
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Affiliation(s)
- Hideyuki Tamai
- Second Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan
| | - Yoshiyuki Ida
- Second Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan
| | - Akira Kawashima
- Department of Internal Medicine, Naga Municipal Hospital, Wakayama, Japan
| | - Naoki Shingaki
- Second Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan
| | - Ryo Shimizu
- Second Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan
| | - Kosaku Moribata
- Second Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan
| | - Tetsushi Nasu
- Department of Internal Medicine, Naga Municipal Hospital, Wakayama, Japan
| | - Takao Maekita
- Second Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan
| | - Mikitaka Iguchi
- Second Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan
| | - Jun Kato
- Second Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan
| | - Taisei Nakao
- Department of Internal Medicine, Naga Municipal Hospital, Wakayama, Japan
| | - Masayuki Kitano
- Second Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan
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10
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Tadokoro T, Morishita A, Fujita K, Oura K, Sakamoto T, Nomura T, Tani J, Yoneyama H, Masaki T. Severe Steroid-responsive Skin Disorders Related to Ledipasvir and Sofosbuvir for HCV. Intern Med 2018; 57:1101-1104. [PMID: 29279506 PMCID: PMC5938499 DOI: 10.2169/internalmedicine.9744-17] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Combination therapy with ledipasvir and sofosbuvir (LDV/SOF), direct-acting antiviral agents, is highly effective against hepatitis C virus genotype 1 infection. Although LDV/SOF is safer than conventional treatment, reports have indicated that LDV/SOF was discontinued in certain cases due to severe skin disorders. A 68-year-old woman presented with a rash after starting LDV/SOF treatment. We interrupted LDV/SOF and began the oral administration of prednisolone (PSL). After the rash improved, we re-started LDV/SOF with PSL. After treatment, the rash clearly improved; we checked for a sustained virologic response 12 weeks after treatment. Steroids may therefore be an effective treatment option for controlling the side effects of LDV/SOF.
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Affiliation(s)
- Tomoko Tadokoro
- Department of Gastroenterology and Neurology, Kagawa University, Japan
| | - Asahiro Morishita
- Department of Gastroenterology and Neurology, Kagawa University, Japan
| | - Koji Fujita
- Department of Gastroenterology and Neurology, Kagawa University, Japan
| | - Kyoko Oura
- Department of Gastroenterology and Neurology, Kagawa University, Japan
| | - Teppei Sakamoto
- Department of Gastroenterology and Neurology, Kagawa University, Japan
| | - Takako Nomura
- Department of Gastroenterology and Neurology, Kagawa University, Japan
| | - Joji Tani
- Department of Gastroenterology and Neurology, Kagawa University, Japan
| | - Hirohito Yoneyama
- Department of Gastroenterology and Neurology, Kagawa University, Japan
| | - Tsutomu Masaki
- Department of Gastroenterology and Neurology, Kagawa University, Japan
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11
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Suda G, Ito J, Nagasaka A, Yamamoto Y, Furuya K, Okamoto M, Terashita K, Kobayashi T, Tsunematsu I, Yoshida J, Meguro T, Ohara M, Kawagishi N, Kimura M, Umemura M, Izumi T, Tsukuda Y, Nakai M, Sho T, Natsuizaka M, Morikawa K, Ogawa K, Sakamoto N. Add-on effects of fluvastatin in simeprevir/pegylated-interferon/ribavirin combination therapy for patients with genotype 1 hepatitis C virus infection: A randomized controlled study. Hepatol Res 2018; 48:E146-E154. [PMID: 28722780 DOI: 10.1111/hepr.12938] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2017] [Revised: 07/11/2017] [Accepted: 07/12/2017] [Indexed: 02/08/2023]
Abstract
BACKGROUND The Japan Society of Hepatology guidelines indicate that hepatitis C virus (HCV) protease inhibitor combination therapy with simeprevir (SMV), pegylated-interferon (Peg-IFN), and ribavirin (RBV) is a therapeutic option for patients who fail to respond to a direct direct-acting antiviral-containing regimen. However, treatment outcomes have room for improvement. Fluvastatin (FLV) add-on treatment in Peg-IFN and RBV combination therapy for HCV-infected patients significantly improved the sustained virologic response (SVR), but the add-on effect of FLV on SMV combination therapy is not well understood. METHODS This was a prospective, randomized, multicenter study in which a total of 61 HCV genotype 1b-infected patients were recruited and 60 eligible patients were randomly allocated to two groups that received 12 weeks of SMV/Peg-IFN/RBV followed by 12 weeks of Peg-IFN/RBV with or without 24 weeks of FLV. The SVR rate and adverse events were compared between the two groups. RESULTS Thirty-one patients were allocated to the FLV add-on group and 29 patients were allocated to the control group. Baseline clinical factors, including median age, baseline platelet count, alanine aminotransferase level, HCV RNA titer, Fibrosis-4 index, and rate of IL28B minor genotype, were all similar between the two groups. The rapid virologic response, end-of-treatment response rates, SVR rates at 24 weeks after treatment, and safety profiles were also similar between the two groups. CONCLUSIONS This prospective, randomized, multicenter study indicated that FLV had no add-on effect when given with SMV/Peg-IFN/RBV combination therapy for genotype 1b HCV-infected patients.
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Affiliation(s)
- Goki Suda
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Jun Ito
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | | | | | | | | | - Katsumi Terashita
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan.,Kushiro Rosai Hospital, Kushiro, Japan
| | - Tomoe Kobayashi
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan.,Tomakomai City Hospital, Tomakomai, Japan
| | | | | | | | - Masatsugu Ohara
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Naoki Kawagishi
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Megumi Kimura
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Machiko Umemura
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Takaaki Izumi
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Yoko Tsukuda
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan.,Sapporo City General Hospital, Sapporo, Japan
| | - Masato Nakai
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Takuya Sho
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Mitsuteru Natsuizaka
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Kenichi Morikawa
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Koji Ogawa
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Naoya Sakamoto
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
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12
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Kumada H, Mochida S, Nakamuta M, Suzuki F, Yagi T, Takasaki R, Okai M, Kamiya N, Okada Y, Hirota S, Orihashi M, Ochi M, Chayama K. Efficacy and safety of telaprevir with natural human interferon-β and ribavirin in Japanese chronic hepatitis C patients with depression. Hepatol Res 2018; 48:184-192. [PMID: 28497489 DOI: 10.1111/hepr.12914] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2016] [Revised: 03/16/2017] [Accepted: 05/09/2017] [Indexed: 12/16/2022]
Abstract
AIM To assess the efficacy and safety of telaprevir (TVR) when used in combination with natural human interferon-β (IFN-β) and ribavirin (RBV) for genotype 1 patients with depression compared to IFN-β/RBV therapy in Japan. We also examined the efficacy of the TVR/IFN-β/RBV therapy in treatment failure genotype 2 patients with depression. METHODS For the genotype 1 patients, 30 patients received TVR (750 mg every 8 h) for 12 weeks combined with IFN-β and RBV for 24 weeks (Group A), and 30 received IFN-β and RBV for 48 weeks (Group B). For the genotype 2 patients, 14 patients were dosed only with the TVR-based regimen. RESULTS The sustained virologic response (SVR) rates for Group A and Group B were 63.3% and 20.0%, respectively (P = 0.001, likelihood ratio test). The SVR rate for genotype 2 patients previously treated with pegylated IFN and/or RBV was 71.4%. No patient dropped out due to exacerbation of depression. The trend of platelet counts after the drugs were given was similar in the TVR/IFN-β/RBV therapy group and the IFN-β/RBV therapy group. Common resistance-associated variants of TVR were identified in 4 of the 13 patients who did not achieve SVR. CONCLUSION This study showed that an addition of TVR to IFN-β/RBV therapy raised SVR in previously treated and untreated genotype 1 patients and previously treated genotype 2 patients with chronic hepatitis C and depression.
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Affiliation(s)
| | - Satoshi Mochida
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Saitama Medical University, Saitama, Japan
| | - Makoto Nakamuta
- Department of Gastroenterology, Kyushu Medical Center, Clinical Research Center, National Hospital Organization, Fukuoka, Japan
| | | | - Takashi Yagi
- Pharmaceutical Clinical Research Department, Toray Industries, Inc., Tokyo, Japan
| | - Ryuji Takasaki
- Pharmaceutical Clinical Research Department, Toray Industries, Inc., Tokyo, Japan
| | - Masao Okai
- Pharmaceutical Clinical Research Department, Toray Industries, Inc., Tokyo, Japan
| | - Naohiro Kamiya
- SOHYAKU. Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, Tokyo, Japan
| | - Yasushi Okada
- IKUYAKU. Integrated Value Development Division, Mitsubishi Tanabe Pharma Corporation, Tokyo, Japan
| | - Saya Hirota
- SOHYAKU. Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, Tokyo, Japan
| | - Madori Orihashi
- SOHYAKU. Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, Tokyo, Japan
| | - Miyoko Ochi
- SOHYAKU. Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, Tokyo, Japan
| | - Kazuaki Chayama
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical and Health Science, Hiroshima University, Hiroshima, Japan
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13
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Kaneko R, Nakazaki N, Omori R, Yano Y, Ogawa M, Sato Y. Efficacy of direct-acting antiviral treatment for chronic hepatitis C: A single hospital experience. World J Hepatol 2018; 10:88-94. [PMID: 29399282 PMCID: PMC5787689 DOI: 10.4254/wjh.v10.i1.88] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2017] [Revised: 12/04/2017] [Accepted: 12/13/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To evaluate the efficacy of direct-acting antivirals (DAAs) in Kanto Rosai Hospital.
METHODS All patients with hepatitis C virus (HCV) who underwent DAA prescription were enrolled in this study. The present study was a single center retrospective analysis using patients infected with HCV genotype 1 or 2. Resistance analysis was performed by using direct sequencing and cycleave PCR in genotype 1 patients treated with interferon (IFN)-free DAA. The primary endpoint was sustained virologic response at 12 wk after therapy (SVR12).
RESULTS A total of 117 patients participated in the study, including 135 with genotype 1 and 42 with genotype 2. Of the 135 patients with genotype 1, 16 received protease inhibitor + IFN + ribavirin and all achieved SVR. Of the 119 patients who received IFN-free DAA (in different combinations), 102 achieved SVR and 9 failed (7/9 were on daclatasvir/asunaprevir and 2/9 on ledipasvir/sofosbuvir). Efficacy analysis was done only for 43 patients who received daclatasvir/asunaprevir. From this analysis, Y93 resistance-associated substitutions were significantly correlated with SVR.
CONCLUSION The SVR rate was 98% for genotype 1 and 100% for genotype 2. However, caution is needed for HCV NS5A resistance-associated substitutions that are selected by HCV NS5A inhibitors because cerebrovascular adverse events are induced by some DAA drugs.
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Affiliation(s)
- Rena Kaneko
- Department of Gastroenterology, Japan Organization of Occupational Health and Safety Kanto Rosai Hospital, Nakahara Kawasaki City, Kanagawa 211-8510, Japan
| | - Natsuko Nakazaki
- Department of Gastroenterology, Japan Organization of Occupational Health and Safety Kanto Rosai Hospital, Nakahara Kawasaki City, Kanagawa 211-8510, Japan
| | - Risa Omori
- Department of Gastroenterology, Japan Organization of Occupational Health and Safety Kanto Rosai Hospital, Nakahara Kawasaki City, Kanagawa 211-8510, Japan
| | - Yuichiro Yano
- Department of Gastroenterology, Japan Organization of Occupational Health and Safety Kanto Rosai Hospital, Nakahara Kawasaki City, Kanagawa 211-8510, Japan
| | - Masazumi Ogawa
- Department of Gastroenterology, Japan Organization of Occupational Health and Safety Kanto Rosai Hospital, Nakahara Kawasaki City, Kanagawa 211-8510, Japan
| | - Yuzuru Sato
- Department of Gastroenterology, Japan Organization of Occupational Health and Safety Kanto Rosai Hospital, Nakahara Kawasaki City, Kanagawa 211-8510, Japan
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14
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Kaneko R, Nakazaki N, Omori R, Yano Y, Ogawa M, Sato Y. The Effect of New Therapeutic and Diagnostic Agents on the Prognosis of Hepatocellular Carcinoma in Japan – An Analysis of Data from the Kanagawa Cancer Registry. Asian Pac J Cancer Prev 2017; 18:2471-2476. [PMID: 28952279 PMCID: PMC5720653 DOI: 10.22034/apjcp.2017.18.9.2471] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Objective: Notable advances in diagnostic imaging modalities and therapeutic agents have contributed to
improvement in the prognosis of hepatocellular carcinoma (HCC) over the past decade. However, knowledge concerning
their epidemiological contribution remains limited. The present study investigated the effect of emerging diagnostic
and therapeutic agents on HCC prognosis, using the largest regional cancer registry in Japan. Methods: Using data
from the Kanagawa Cancer Registry, the five-year survival rate of patients with liver cancer was estimated according
to the International Statistical Classification of Diseases and Related Health Problems (10th Edition). Result: A total of
40,276 cases of HCC (from 1976 to 2013) were identified. The prognosis markedly improved after the introduction of
new devices into the diagnosis and treatment of HCC (p<0.01). The trend of survival rate varied significantly between
institutions with many registered patients (high-volume centers) (p<0.01). Conclusion: The five-year survival rate of
patients with HCC in Kanagawa has markedly improved in recent years. This improvement in survival may be attributed
to the advances in surveillance and intervention for the treatment of HCC.
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Affiliation(s)
- Rena Kaneko
- Department of Gastroenterology, Japan Organization of Occupational Health and Safety Kanto Rosai Hospital, Japan.
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15
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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] [MESH Headings] [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.
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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
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16
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Sezaki H, Suzuki F, Hosaka T, Akuta N, Fujiyama S, Kawamura Y, Kobayashi M, Suzuki Y, Saitoh S, Arase Y, Ikeda K, Kobayashi M, Kumada H. The efficacy and safety of dual oral therapy with daclatasvir and asunaprevir for genotype 1b in Japanese real-life settings. Liver Int 2017; 37:1325-1333. [PMID: 28178397 DOI: 10.1111/liv.13384] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2016] [Accepted: 02/01/2017] [Indexed: 01/17/2023]
Abstract
BACKGROUND & AIMS It is important to investigate the treatment outcomes in patients excluded from clinical trials (CTR). The aims of this study were to evaluate the efficacy and safety of a 24-week daclatasvir (DCV) and asunaprevir (ASV) therapy for patients with chronic hepatitis C virus (HCV)-1b infection. METHODS A total of 651 HCV-1b patients started dual oral therapy with DCV and ASV for 24 weeks in Toranomon Hospital, Tokyo. Among them, 276 patients met phase III CTR inclusion criteria. The sustained virological response (SVR) rate after treatment and the adverse events during therapy were compared between CTR-met (patients who met the inclusion criteria) and CTR-unmet (patients who did not meet the inclusion criteria) groups. RESULTS SVR12 was achieved in 87.0% (240/276) and 86.7% (325/375) in CTR-met and CTR-unmet patients respectively. SVR12 rate in simeprevir-experienced patients was 52.9% (9/17). SVR12 rate in patients without resistance-associated variant (RAV) of NS3 or NS5A loci was 93.7% (416/444). However, the SVR12 rates in patients with NS3-D168, NS5A-L31 and Y93 single RAV at baseline were 55.0% (11/20), 73.9% (17/23) and 65.6% (63/96) respectively. The safety profiles in both CTR-met and CTR-unmet patients were similar. The discontinuation rate as a result of alanine aminotransferase (ALT) elevation was only 2.9%. Seven (2.5%) patients in CTR-met group and 20 (5.3%) in CTR-unmet group discontinued therapy because of adverse events other than the ALT elevation. CONCLUSIONS Dual oral therapy with DCV and ASV in real-life settings was well tolerated with a similar safety profile and achieved similar SVR12 rates as that of CTR.
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Affiliation(s)
- Hitomi Sezaki
- Department of Hepatology, Toranomon Hospital, Tokyo, Japan
| | - Fumitaka Suzuki
- Department of Hepatology, Toranomon Hospital, Tokyo, Japan.,Okinaka Memorial Institute for Medical Research, Tokyo, Japan
| | - Tetsuya Hosaka
- Department of Hepatology, Toranomon Hospital, Tokyo, Japan
| | - Norio Akuta
- Department of Hepatology, Toranomon Hospital, Tokyo, Japan
| | | | | | | | | | - Satoshi Saitoh
- Department of Hepatology, Toranomon Hospital, Tokyo, Japan
| | - Yasuji Arase
- Department of Hepatology, Toranomon Hospital, Tokyo, Japan
| | - Kenji Ikeda
- Department of Hepatology, Toranomon Hospital, Tokyo, Japan
| | - Mariko Kobayashi
- Research Institute for Hepatology, Toranomon Hospital, Tokyo, Japan
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17
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Morishita N, Hiramatsu N, Oze T, Urabe A, Tahata Y, Yamada R, Yakushijin T, Hosui A, Iio S, Yamada A, Hagiwara H, Mita E, Yamada Y, Ito T, Inada M, Katayama K, Yabuuchi I, Imai Y, Hikita H, Sakamori R, Yoshida Y, Tatsumi T, Hayashi N, Takehara T. Ultra-deep sequencing analysis of resistance-associated variants during retreatment with simeprevir-based triple therapy after failure of telaprevir-based triple therapy in patients with genotype 1 hepatitis C virus infection. Hepatol Res 2017; 47:773-782. [PMID: 27593967 DOI: 10.1111/hepr.12817] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2016] [Revised: 07/15/2016] [Accepted: 08/31/2016] [Indexed: 01/13/2023]
Abstract
AIM Simeprevir (SMV)-based triple therapy is an effective retreatment option following failure of telaprevir (TVR)-based triple therapy. However, it is unclear whether the persistence of resistance-associated variants (RAVs) induced by TVR-based therapy may reduce the treatment effect of SMV-based therapy. METHODS The factors associated with the treatment effect, including RAVs in the NS3 region, were examined in 21 patients with genotype 1b HCV infection who were treated with SMV-based therapy after failure of TVR-based therapy. Ultra-deep sequencing was carried out to detect RAVs. RESULTS With the exception of one patient who discontinued treatment owing to adverse events, the sustained virologic response (SVR) rate was 50% (10/20). Ultra-deep sequencing at the start of SMV-based therapy revealed that TVR-resistant variants were detected in six patients (29%), and no variants were observed at position 168. Cross-resistance between TVR and SMV with low frequency was detected in only one patient, and this patient achieved SVR. Higher SVRs for SMV-based therapy were attained in patients who discontinued treatment owing to the adverse effects of prior TVR-based therapy (discontinuation 100% vs. non-discontinuation 29%, P = 0.005), and patients who relapsed following prior pegylated interferon plus ribavirin therapy (relapse 100% vs. non-response 20%, P = 0.007). CONCLUSIONS In this study, ultra-deep sequencing analysis revealed that TVR and/or SMV-resistant variants may have no influence on the effect of SMV-based therapy after failure of TVR-based therapy. Patients who discontinued treatment owing to adverse effects of TVR-based therapy and relapsers to previous pegylated interferon/ribavirin therapy would be good candidates for retreatment with SMV-based therapy.
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Affiliation(s)
- Naoki Morishita
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Naoki Hiramatsu
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Tsugiko Oze
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Ayako Urabe
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Yuki Tahata
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Ryoko Yamada
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Takayuki Yakushijin
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | | | - Sadaharu Iio
- Higashiosaka City General Hospital, Higashiosaka, Japan
| | | | | | - Eiji Mita
- National Hospital Organization Osaka National Hospital, Osaka, Japan
| | | | - Toshifumi Ito
- Japan Community Health Care Organization Osaka Hospital, Osaka, Japan
| | | | - Kazuhiro Katayama
- Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan
| | - Iwao Yabuuchi
- National Hospital Organization Minami Wakayama Medical Center, Tanabe, Japan
| | | | - Hayato Hikita
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Ryotaro Sakamori
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Yuichi Yoshida
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Tomohide Tatsumi
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
| | | | - Tetsuo Takehara
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan
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18
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Mawatari S, Oda K, Tabu K, Ijuin S, Kumagai K, Inada Y, Uto H, Hiramine Y, Kure T, Fujisaki K, Hashiguchi M, Hori T, Oshige A, Imanaka D, Saishoji A, Taniyama O, Sakae H, Tamai T, Moriuchi A, Ido A. New resistance-associated substitutions and failure of dual oral therapy with daclatasvir and asunaprevir. J Gastroenterol 2017; 52:855-867. [PMID: 28078469 DOI: 10.1007/s00535-016-1303-0] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2016] [Accepted: 11/22/2016] [Indexed: 02/04/2023]
Abstract
BACKGROUND Daclatasvir (DCV) and asunaprevir (ASV) combination therapy has been primarily used in patients without NS5A L31 or Y93 resistance-associated substitutions (RASs) before treatment. We examined the characteristics of patients without these baseline RASs who did not achieve hepatitis C virus eradication with DCV and ASV combination therapy and identified new baseline NS5A RASs that are closely associated with failure of combination therapy. METHODS Three hundred thirty-five patients with hepatitis C virus genotype 1 infection with no NS5A L31, NS5A Y93, and NS3 D168 RASs before DCV and ASV combination therapy and no history of protease inhibitor therapy were enrolled. All RASs were evaluated by direct sequencing. RESULTS Sustained virologic response at 12 weeks (SVR12) was achieved in 297 patients (89%). Patients with NS5A Q24, L28, and/or R30 RASs or concomitant NS5A F37 and Q54 RASs had a significantly lower SVR12 rate than patients without these RASs (70% vs 92%, p < 0.001 and 79% vs 92%, p = 0.002 respectively). Multivariate analysis showed that NS5A Q24, L28, and/or R30 RASs and concomitant NS5A F37 and Q54 RASs were significantly associated with virologic failure. The SVR12 rate in patients without NS5A Q24, L28, and/or R30 RASs and concomitant NS5A F37 and Q54 RASs was 96.2% (202/210). CONCLUSIONS In patients without NS5A L31 or Y93 RASs, the presence of NS5A Q24, L28, and/or R30 RASs and concomitant NS5A F37 and Q54 RASs at the baseline was associated with failure of DCV and ASV combination therapy. The coexistence of baseline RASs other than NS5A L31 and Y93 may affect the therapeutic effectiveness of DCV and ASV combination therapy.
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Affiliation(s)
- Seiichi Mawatari
- Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima, 890-8544, Japan.
| | - Kohei Oda
- Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima, 890-8544, Japan
| | - Kazuaki Tabu
- Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima, 890-8544, Japan
| | - Sho Ijuin
- Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima, 890-8544, Japan
| | - Kotaro Kumagai
- Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima, 890-8544, Japan
| | - Yukiko Inada
- Center for Digestive and Liver Diseases, Miyazaki Medical Center Hospital, 2-16 Takamatsu-cho, Miyazaki, 880-0003, Japan
| | - Hirofumi Uto
- Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima, 890-8544, Japan.,Center for Digestive and Liver Diseases, Miyazaki Medical Center Hospital, 2-16 Takamatsu-cho, Miyazaki, 880-0003, Japan
| | - Yasunari Hiramine
- Department of Internal Medicine, Kagoshima Kouseiren Hospital, 22-25 Tenpozan-cho, Kagoshima, 890-0061, Japan
| | - Takeshi Kure
- Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima, 890-8544, Japan.,Department of Internal Medicine, Kagoshima Kouseiren Hospital, 22-25 Tenpozan-cho, Kagoshima, 890-0061, Japan
| | - Kunio Fujisaki
- Department of Hepatology, Kirishima Medical Center, 3320 Hayato-cho, Kirishima, Kagoshima, 899-5112, Japan
| | - Masafumi Hashiguchi
- Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima, 890-8544, Japan.,Department of Hepatology, Kirishima Medical Center, 3320 Hayato-cho, Kirishima, Kagoshima, 899-5112, Japan
| | - Takeshi Hori
- Department of Gastroenterology and Hepatology, Kagoshima City Hospital, 37-1 Uearata-cho, Kagoshima, 890-8760, Japan
| | - Akihiko Oshige
- Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima, 890-8544, Japan.,Department of Gastroenterology and Hepatology, Kagoshima City Hospital, 37-1 Uearata-cho, Kagoshima, 890-8760, Japan
| | - Dai Imanaka
- Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima, 890-8544, Japan.,Department of Gastroenteroloby, Ikeda Hospital, 1830 Shimoharaigawa-cho, Kanoya, Kagoshima, 893-0024, Japan
| | - Akiko Saishoji
- Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima, 890-8544, Japan.,Department of Hepatology, Kagoshima Teishin Hospital, 1-12-1 Shimoishiki, Kagoshima, 890-8798, Japan
| | - Oki Taniyama
- Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima, 890-8544, Japan
| | - Haruka Sakae
- Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima, 890-8544, Japan
| | - Tsutomu Tamai
- Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima, 890-8544, Japan
| | - Akihiro Moriuchi
- Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima, 890-8544, Japan
| | - Akio Ido
- Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima, 890-8544, Japan
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A NEW HEALTH TECHNOLOGY ASSESSMENT SYSTEM FOR JAPAN? SIMULATING THE POTENTIAL IMPACT ON THE PRICE OF SIMEPREVIR. Int J Technol Assess Health Care 2017; 33:121-127. [DOI: 10.1017/s0266462317000174] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
Objectives:Japanese authorities have announced a plan to introduce a health technology assessment (HTA) system in 2016. This study assessed the potential impact of such a policy on the price of the antivirologic drug simeprevir.Methods:Taking the antivirologic drug simeprevir as an example, we compared the current Japanese price with hypothetical prices that might result if a U.K. (cost-utility) or German (efficiency frontier) style HTA assessment was in place.Results:The simeprevir unit price under the current Japanese pricing scheme is 13,122 Japanese yen (equivalent to 109.35 U.S. dollars as of April 2015). Depending on the selection of comparators and the pricing method, and assuming that HTA will be used as a basis for price setting, the estimated prices of simeprevir vary up to four times higher than under the current Japanese pricing scheme.Conclusions:Although the analysis is based on only one drug, it cannot be taken for granted that a new HTA system would reduce public healthcare expenditure in Japan.
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Iketani R, Ide K, Yamada H, Kawasaki Y, Masaki N. The Safety Profile of Telaprevir-Based Triple Therapy in Clinical Practice: A Retrospective Cohort Study. Biol Pharm Bull 2017; 40:687-692. [PMID: 28179602 DOI: 10.1248/bpb.b16-00989] [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] [Indexed: 11/22/2022]
Abstract
This study was designed to evaluate the safety profile of adding telaprevir to therapy using pegylated interferon-alfa-2b and ribavirin (PR) using real world patient data obtained from a nationwide Japanese interferon database. This retrospective cohort study compared telaprevir-based triple therapy (T/PR) with PR therapy. The study population comprised patients with genotype 1 chronic hepatitis C represented in the database between December 2009 and August 2015. The primary endpoint was dropout from treatment due to adverse events during the relevant standard treatment duration based on guidelines from the Japan Society of Hepatology. The dropout odds ratio (OR) and 95% confidence interval (95% CI) were calculated using univariate logistic regression analysis. Covariates were detected using a stepwise logistic regression analysis, and the adjusted OR and 95% CI were calculated. A total of 25989 patients were registered, and 4619 patients (T/PR: 1334, PR: 3285) were appropriate for primary endpoint analysis. The dropout rate due to adverse events was lower in the T/PR group (13.4%) than in the PR group (22.6%) (OR: 0.530; 95% CI, 0.444-0.633). After adjustment for the covariates detected by stepwise selection, the OR was 0.529 (95% CI, 0.441-0.634). Our study showed that there was a difference in dropout rate between real world T/PR and PR therapy in Japan. Although the addition of telaprevir to PR therapy may improve treatment continuity under the care of hepatologists, this study could not fully determine which therapy was safer or the factors influencing this result. Therefore, additional research will be required to confirm this.
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Affiliation(s)
- Ryo Iketani
- 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
| | - Hiroshi Yamada
- Department of Drug Evaluation & Informatics, Graduate School of Pharmaceutical Sciences, University of Shizuoka
| | - 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
| | - Naohiko Masaki
- Laboratory Testing Department, National Center for Global Health and Medicine
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21
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Ide K, Kawasaki Y, Iketani R, Masaki N. Risk Factors for Treatment Discontinuation Caused by Adverse Events When Using Telaprevir, Peginterferon, and Ribavirin to Treat Chronic Hepatitis C: A Real-World Retrospective Cohort Study. Biol Pharm Bull 2017; 40:645-649. [PMID: 28216512 DOI: 10.1248/bpb.b16-00941] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
In this study, a nationwide database was used to identify the risk factors for treatment discontinuation due to adverse events during telaprevir, peginterferon, and ribavirin (T/PR) treatment, and estimate the increase in the occurrence of adverse events when patients have multiple risk factors at the same time. The risk factors were identified using univariate logistic regression analysis, and a Cochran-Armitage trend test was used to analyze the correlation between the number of risk factors and treatment discontinuation due to adverse events. Of the 25989 individuals registered in the database, 1668 (age, mean±standard deviation (S.D.): 58.0±9.9) were included in the study. Of these, 188 (11.3%) discontinued T/PR therapy due to adverse events. In the univariate logistic regression analysis, sex, age, aspartate aminotransferase (AST) level, and platelet count were found to significantly affect the incidence of T/PR treatment discontinuation (p<0.05). Furthermore, the incidence of treatment discontinuation gradually increased from 4.6 to 27.2% as the number of risk factors increased from 0 to 4, and the Cochran-Armitage trend test showed a significant correlation (p<0.001). In conclusion, this study not only revealed the risk factors for treatment discontinuation but also showed that patients with multiple risk factors are more likely to discontinue treatment due to adverse events compared to patients with fewer risk factors.
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Affiliation(s)
- Kazuki Ide
- Department of Pharmacoepidemiology, Graduate School of Medicine and Public Health, Kyoto University
- Center for the Promotion of Interdisciplinary Education and Research, Kyoto University
- Department of Drug Evaluation & Informatics, Graduate School of Pharmaceutical Sciences, University of Shizuoka
| | - Yohei Kawasaki
- Department of Pharmacoepidemiology, Graduate School of Medicine and Public Health, Kyoto University
- 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
| | - Naohiko Masaki
- The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine
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Kumada H, Suzuki F, Kamiya N, Orihashi M, Nakayasu Y, Yamada I. Efficacy and safety of telaprevir with pegylated interferon α-2a and ribavirin in Japanese patients. Hepatol Res 2017; 47:514-521. [PMID: 27062488 DOI: 10.1111/hepr.12722] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2016] [Revised: 03/16/2016] [Accepted: 04/04/2016] [Indexed: 01/01/2023]
Abstract
AIM To assess the efficacy and safety of telaprevir (TVR) in combination with pegylated interferon α-2a (PEG-IFNα-2a) and ribavirin (RBV) for treatment-naïve patients and relapsed patients compared to previous TVR-based triple therapy in Japan. METHODS The study group included 35 treatment-naïve (median age, 55 years) and 19 relapsed (median age, 55 years) patients with genotype 1 hepatitis C virus infection. Patients received TVR (750 mg every 8 h) for 12 weeks, in combination with PEG-IFNα-2a and RBV. RESULTS The sustained virological response (SVR24 ) rates for naïve and relapsed patients were 85.7% (30/35) and 94.7% (18/19), respectively. The discontinuation rate of all study drugs due to adverse events was 5.6% (3/54). Among the 54 patients, grade 3 skin disorders and grade 3 anemia (<8.0 g/dL) were reported in 2 (3.7%) and 6 patients (11.1%), respectively. Although the overall safety profiles were similar for the TVR/PEG-IFNα-2a/RBV and TVR/PEG-IFNα-2b/RBV regimens (previous study), the proportion of patients discontinuing all study drugs due to adverse events was lower in the patients treated with the TVR/PEG-IFNα-2a/RBV regimen (3/54, 5.6%) than TVR/PEG-IFNα-2b/RBV regimen (44/267, 16.5%). CONCLUSION Telaprevir in combination with PEG-IFNα-2a/RBV provided a high sustained virological response rate for the treatment of genotype 1 hepatitis C virus in both treatment-naïve and relapsed patients in Japan. Telaprevir-based therapy may provide a useful treatment option for patients who are difficult to treat due to NS5A (Y93, L31) and NS3/4A (D168) variants.
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Affiliation(s)
| | | | - Naohiro Kamiya
- SOUYAKU, Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, Tokyo, Japan
| | - Madori Orihashi
- SOUYAKU, Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, Tokyo, Japan
| | - Yoshiyuki Nakayasu
- SOUYAKU, Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, Tokyo, Japan
| | - Ichimaro Yamada
- IKUYAKU, Integrated Value Development Division, Mitsubishi Tanabe Pharma Corporation, Tokyo, Japan
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23
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Morio R, Imamura M, Kawakami Y, Morio K, Kobayashi T, Yokoyama S, Kimura Y, Nagaoki Y, Kawaoka T, Tsuge M, Hiramatsu A, Nelson Hayes C, Aikata H, Takahashi S, Miki D, Ochi H, Mori N, Takaki S, Tsuji K, Chayama K. Safety and efficacy of dual therapy with daclatasvir and asunaprevir for older patients with chronic hepatitis C. J Gastroenterol 2017; 52:504-511. [PMID: 27631593 DOI: 10.1007/s00535-016-1255-4] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2016] [Accepted: 08/25/2016] [Indexed: 02/04/2023]
Abstract
BACKGROUND Daclatasvir and asunaprevir combination therapy has shown a high virological response for chronic genotype 1 hepatitis C virus (HCV)-infected patients. However, the safety and efficacy of the therapy for older patients are unknown. METHODS One hundred seventy patients younger than 75 years and 139 patients aged 75 years or older with genotype 1 HCV infection were treated for 24 weeks with daclatasvir plus asunaprevir. Pretreatment drug-resistance-associated variants at NS5A-L31 and NS5A-Y93 were determined by the Invader assay. Virological response and adverse events according to age were analyzed. RESULTS The sustained virological response (SVR) rate for older patients was similar to that for younger patients (97.1 and 92.4 % respectively). In multivariate regression analysis, prior simeprevir treatment (odds ratio 56.6 for absence; P < 0.001) was identified as a significant independent predictor of SVR. The SVR rate for patients with pretreatment resistance-associated variants (RAVs) at a low population frequency (less than 25 %) was similar to that for patients with no detectable RAVs. The frequency of adverse events was similar between younger and older patients. All 19 very elderly patients (85 years or older) completed the 24 weeks of treatment and achieved SVR. CONCLUSIONS Older patients have a virological response and tolerance of daclatasvir plus asunaprevir therapy similar to those of younger patients. Even though RAVs were detected, virological response similar to that for patients with no detectable RAVs may still be expected for patients with RAVs as long as the population frequency is low.
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Affiliation(s)
- Reona Morio
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Michio Imamura
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Yoshiiku Kawakami
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Kei Morio
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Tomoki Kobayashi
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Satoe Yokoyama
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Yuki Kimura
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Yuko Nagaoki
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Tomokazu Kawaoka
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Masataka Tsuge
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Akira Hiramatsu
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - C Nelson Hayes
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Hiroshi Aikata
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Shoichi Takahashi
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Daiki Miki
- Laboratory for Digestive Diseases, SNP Research Center, The Institute of Physical and Chemical Research (RIKEN), Hiroshima, Japan
| | - Hidenori Ochi
- Laboratory for Digestive Diseases, SNP Research Center, The Institute of Physical and Chemical Research (RIKEN), Hiroshima, Japan
| | - Nami Mori
- Hiroshima Red Cross Hospital & Atomic-Bomb Survivors Hospital, Hiroshima, Japan
| | - Shintaro Takaki
- Hiroshima Red Cross Hospital & Atomic-Bomb Survivors Hospital, Hiroshima, Japan
| | - Keiji Tsuji
- Hiroshima Red Cross Hospital & Atomic-Bomb Survivors Hospital, Hiroshima, Japan
| | - Kazuaki Chayama
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical & Health Sciences, 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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Inoue T, Hmwe SS, Shimada N, Kato K, Ide T, Torimura T, Kumada T, Toyoda H, Tsubota A, Takaguchi K, Wakita T, Tanaka Y. Clinical Significance of Two Real-Time PCR Assays for Chronic Hepatitis C Patients Receiving Protease Inhibitor-Based Therapy. PLoS One 2017; 12:e0170667. [PMID: 28118381 PMCID: PMC5261727 DOI: 10.1371/journal.pone.0170667] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2016] [Accepted: 01/09/2017] [Indexed: 12/20/2022] Open
Abstract
The aim of this study was to determine the efficacy of two hepatitis C virus (HCV) real-time PCR assays, the COBAS AmpliPrep/COBAS TaqMan HCV test (CAP/CTM) and the Abbott RealTime HCV test (ART), for predicting the clinical outcomes of patients infected with HCV who received telaprevir (TVR)-based triple therapy or daclatasvir/asunaprevir (DCV/ASV) dual therapy. The rapid virological response rates in patients receiving TVR-based triple therapy were 92% (23/25) and 40% (10/25) for CAP/CTM and ART, respectively. The false omission rate (FOR) of ART was 93.3% (14/15), indicating that CAP/CTM could accurately predict clinical outcome in the early phase. In an independent examination of 20 patients receiving TVR-based triple therapy who developed viral breakthrough or relapse, the times to HCV disappearance by ART were longer than by CAP/CTM, whereas the times to HCV reappearance were similar. In an independent experiment of WHO standard HCV RNA serially diluted in serum containing TVR, the analytical sensitivities of CAP/CTM and ART were similar. However, cell cultures transfected with HCV and grown in medium containing TVR demonstrated that ART detected HCV RNA for a longer time than CAP/CTM. Similar results were found for 42 patients receiving DCV/ASV dual therapy. The FOR of ART was 73.3% (11/15) at week 8 after initiation of therapy, indicating that ART at week 8 could not accurately predict the clinical outcome. In conclusion, although CAP/CTM and ART detected HCV RNA with comparable analytical sensitivity, CAP/CTM might be preferable for predicting the clinical outcomes of patients receiving protease inhibitor-based therapy.
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Affiliation(s)
- Takako Inoue
- Department of Clinical Laboratory, Nagoya City University Hospital, Nagoya, Japan
| | - Su Su Hmwe
- Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan
| | - Noritomo Shimada
- Ootakanomori Hospital, Kashiwa, Japan
- Division of Gastroenterology and Hepatology, Shin-Matsudo Central General Hospital, Matsudo, Japan
| | - Keizo Kato
- Division of Gastroenterology and Hepatology, Shin-Matsudo Central General Hospital, Matsudo, Japan
| | - Tatsuya Ide
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Takuji Torimura
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Takashi Kumada
- Department of Gastroenterology and Hepatology, Ogaki Municipal Hospital, Ogaki, Japan
| | - Hidenori Toyoda
- Department of Gastroenterology and Hepatology, Ogaki Municipal Hospital, Ogaki, Japan
| | - Akihito Tsubota
- Institute of Clinical Medicine and Research, The Jikei University School of Medicine, Kashiwa, Japan
| | - Koichi Takaguchi
- Department of Hepatology, Kagawa Prefectural Central Hospital, Takamatsu, Japan
| | - Takaji Wakita
- Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan
| | - Yasuhito Tanaka
- Department of Clinical Laboratory, Nagoya City University Hospital, Nagoya, Japan
- Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
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Suda G, Ogawa K, Kimura M, Nakai M, Sho T, Morikawa K, Sakamoto N. Novel Treatment of Hepatitis C Virus Infection for Patients with Renal Impairment. J Clin Transl Hepatol 2016; 4:320-327. [PMID: 28097101 PMCID: PMC5225152 DOI: 10.14218/jcth.2016.00032] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2016] [Revised: 11/21/2016] [Accepted: 12/07/2016] [Indexed: 12/11/2022] Open
Abstract
Prevalence of hepatitis C virus (HCV) infection is high in patients with end-stage renal dysfunction, including patients undergoing hemodialysis (HD). The HCV infection itself can cause glomerulonephritis and puts individuals at increased risk of developing end-stage renal disease; fortunately, successful HCV eradication sometimes restore HCV-related renal dysfunction. Moreover, the prognosis of dialysis patients infected with HCV is significantly worse and the renal allograft survival in HCV-infected patients is also worse than in dialysis patients without HCV infection. If life prognosis is favorable, therefore, anti-HCV therapy is strongly recommended for HCV-infected patients with severe renal dysfunction. The standard therapy for HCV-infected patients with severe renal dysfunction has historically been interferon-based therapy. However, this therapy remains ineffective in achieving high, sustained viral response rates and the rate of adverse events and treatment discontinuation due to treatment-induced adverse events continues to be high in patients with severe renal dysfunction. Safe and effective anti-HCV therapies are urgently needed, and crucial, for patients with severe renal dysfunction. Recently, direct-acting antivirals (DAAs) that specifically target viral proteins have been developed, and these targets include the NS3, NS5A, and NS5B of HCV. Clinical trials have revealed high efficacy and safety of the DAA-based therapies, but patients with severe renal dysfunction were not included in the majority of these trials. However, several recent reports have shown high efficacy and safety for some regimens of DAA combination therapy for HCV-infected patients with severe renal dysfunction. In this review, we discuss novel treatments for HCV-infected patients with severe renal dysfunction and the pharmacokinetics of these drugs.
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Affiliation(s)
- Goki Suda
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Hokkaido, Japan
| | - Koji Ogawa
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Hokkaido, Japan
| | - Megumi Kimura
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Hokkaido, Japan
| | - Masato Nakai
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Hokkaido, Japan
| | - Takuya Sho
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Hokkaido, Japan
| | - Kenichi Morikawa
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Hokkaido, Japan
| | - Naoya Sakamoto
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Hokkaido, Japan
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26
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Kumada H. [111th Scientific Meeting of the Japanese Society of Internal Medicine: Invited Lecture; 5. New strategy of hepatitis C virus of treatment]. ACTA ACUST UNITED AC 2016; 103:2084-97. [PMID: 27522756 DOI: 10.2169/naika.103.2084] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
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27
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Ueda Y, Ikegami T, Soyama A, Akamatsu N, Shinoda M, Ishiyama K, Honda M, Marubashi S, Okajima H, Yoshizumi T, Eguchi S, Kokudo N, Kitagawa Y, Ohdan H, Inomata Y, Nagano H, Shirabe K, Uemoto S, Maehara Y. Simeprevir or telaprevir with peginterferon and ribavirin for recurrent hepatitis C after living-donor liver transplantation: A Japanese multicenter experience. Hepatol Res 2016; 46:1285-1293. [PMID: 26899352 DOI: 10.1111/hepr.12684] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/24/2015] [Revised: 02/10/2016] [Accepted: 02/12/2016] [Indexed: 02/08/2023]
Abstract
AIM This study aimed to clarify the efficacy and safety of simeprevir, a second-generation NS3/4A inhibitor, with peginterferon and ribavirin for recurrent hepatitis C after liver transplantation. METHODS A retrospective cohort study of living-donor liver transplant recipients with recurrent hepatitis C with the hepatitis C virus genotype 1 treated with either simeprevir- or telaprevir-based triple therapy was carried out at eight Japanese liver transplant centers. RESULTS Simeprevir- and telaprevir-based triple therapies were given to 79 and 36 patients, respectively. Of the 79 patients treated with simeprevir-based triple therapy, 44 (56%) achieved sustained virological response 12 weeks (SVR12) after treatment ended, and there was no significant difference in the SVR12 between the simeprevir- and telaprevir-based triple therapy groups (69%). The rates of adverse events were not significantly different between the simeprevir- and telaprevir-based triple therapy groups, although the rate of patients who received blood cell transfusion and erythropoietin due to anemia and had renal insufficiency were significantly higher in the telaprevir group than in the simeprevir group. Three baseline factors, the presence of prior dual therapy with peginterferon and ribavirin (P = 0.001), a non-responder to the prior dual therapy (P < 0.001), and male sex (P = 0.040), were identified as significant predictive factors for non-SVR with simeprevir-based triple therapy. CONCLUSION Simeprevir-based triple therapy for recurrent hepatitis C after living-donor liver transplantation resulted in a high SVR rate and good tolerability, especially in treatment-naïve patients.
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Affiliation(s)
- Yoshihide Ueda
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University
| | - Toru Ikegami
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka
| | - Akihiko Soyama
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki
| | - Nobuhisa Akamatsu
- Division of Artificial Organ and Transplantation, Department of Surgery, University of Tokyo
| | - Masahiro Shinoda
- Department of Surgery, Keio University School of Medicine, Tokyo
| | - Kohei Ishiyama
- Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Masaki Honda
- Department of Transplantation and Pediatric Surgery, Kumamoto University, Kumamoto
| | - Shigeru Marubashi
- Department of Surgery, Osaka University Graduate School of Medicine, Osaka
| | - Hideaki Okajima
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Tomoharu Yoshizumi
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka
| | - Susumu Eguchi
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki
| | - Norihiro Kokudo
- Division of Artificial Organ and Transplantation, Department of Surgery, University of Tokyo
| | - Yuko Kitagawa
- Department of Surgery, Keio University School of Medicine, Tokyo
| | - Hideki Ohdan
- Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Yukihiro Inomata
- Department of Transplantation and Pediatric Surgery, Kumamoto University, Kumamoto
| | - Hiroaki Nagano
- Department of Surgery, Osaka University Graduate School of Medicine, Osaka
| | - Ken Shirabe
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka
| | - Shinji Uemoto
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Yoshihiko Maehara
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka
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Yamagiwa Y, Asano M, Kawasaki Y, Korenaga M, Murata K, Kanto T, Mizokami M, Masaki N. Pretreatment serum levels of interferon-gamma-inducible protein-10 are associated with virologic response to telaprevir-based therapy. Cytokine 2016; 88:29-36. [PMID: 27541605 DOI: 10.1016/j.cyto.2016.07.004] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2016] [Revised: 07/03/2016] [Accepted: 07/05/2016] [Indexed: 01/16/2023]
Abstract
AIM Telaprevir (TVR) remarkably improves the efficacy of interferon treatment for chronic hepatitis C. Interleukin-28B (IL28B) genotype and interferon-gamma-inducible protein-10 (IP-10) level predict virologic response to peg-interferon (Peg-IFN)/ribavirin (RBV) therapy. We aimed to investigate the usefulness of pretreatment serum IP-10 levels and IL28B genotyping in predicting sustained virologic response (SVR) to TVR-based triple therapy. METHODS In this multi-center study, patients infected with hepatitis C virus genotype 1 with high viral load (⩾5.0logIU/mL) were treated with TVR for 12weeks and Peg-IFN/RBV for 24weeks in Japan. IL28B genotype, serum IP-10 levels, other clinical parameters, and drug dosages were assessed before treatment. RESULTS We included 121 patients who were treated with TVR for at least 8weeks and Peg-IFN/RBV for 24weeks. The median IP-10 levels were significantly lower in rapid virologic response (RVR) or SVR in the IL28B non-TT genotype group, with no significant difference in the TT genotype group. RVR rates were significantly lower in the group with higher serum IP-10 levels (>450pg/mL). In the non-TT IL28B genotype group, RVR and SVR rates were significantly lower in the group with higher IP-10 levels. SVR rates in the group with lower IP-10 levels (<450pg/mL) increased to 82% for those showing RVR, but reduced to 27% in the group with higher IP-10 levels for those not showing RVR. CONCLUSIONS Determination of serum IP-10 levels before treatment could be useful for predicting favorable virologic response to TVR-based triple therapy, especially in patients with IL28B non-TT genotype.
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Affiliation(s)
- Yoko Yamagiwa
- The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Japan.
| | - Mai Asano
- The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Japan
| | - Youhei Kawasaki
- Department of Drug Evaluation & Informatics, Graduate School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Shizuoka 422-8526, Japan
| | - Masaaki Korenaga
- The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Japan
| | - Kazumoto Murata
- The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Japan
| | - Tatsuya Kanto
- The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Japan
| | - Masashi Mizokami
- The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Japan
| | - Naohiko Masaki
- The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Japan
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29
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Gray E, Norris S, Schmitz S, O'Leary A. Do disparities between populations in randomized controlled trials and the real world lead to differences in outcomes? J Comp Eff Res 2016; 6:65-82. [PMID: 27854129 DOI: 10.2217/cer-2016-0042] [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] [Indexed: 02/06/2023] Open
Abstract
AIM To conduct a systematic review investigating reasons for the disparity between the efficacy and effectiveness rates reported in randomized controlled trials (RCTs) and observational studies of direct-acting antiviral treatment regimens licensed for use in genotype1 hepatitis C virus-infected individuals. METHODS This systematic review was conducted in accordance with the criteria of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses group. RESULTS Statistically significant (p < 0.05) differences in the baseline demographics and sustained virological response rates were observed between RCT and observational studies. CONCLUSION In order for outcomes from RCTs to be generalizable to the real world, greater consideration needs to be taken to include patient populations that are more representative of those awaiting treatment in the clinical setting.
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Affiliation(s)
- Emma Gray
- School of Medicine, Trinity College Dublin, Dublin, Ireland
| | - Suzanne Norris
- School of Medicine, Trinity College Dublin, Dublin, Ireland.,Departmentof Hepatology, St James' Hospital, Dublin, Ireland
| | - Susanne Schmitz
- HealthEconomics & Evidence Synthesis Research Unit, Department of PopulationHealth, Luxembourg Health Institute, Luxembourg
| | - Aisling O'Leary
- Schoolof Pharmacy, Royal College of Surgeons of Ireland, Dublin, Ireland.,NationalCentre for Pharmacoeconomics, St James' Hospital, Dublin, Ireland
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30
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Morio K, Imamura M, Kawakami Y, Morio R, Hatooka M, Kan H, Fujino H, Fukuhara T, Kobayashi T, Masaki K, Ono A, Nakahara T, Urabe A, Yokoyama S, Nagaoki Y, Kawaoka T, Hiraga N, Tsuge M, Hiramatsu A, Hayes CN, Aikata H, Ochi H, Chayama K. Effects of ITPA polymorphism on decrease of hemoglobin during simeprevir, peg-interferon, and ribavirin combination treatment for chronic hepatitis C. Hepatol Res 2016; 46:1256-1263. [PMID: 26916827 DOI: 10.1111/hepr.12681] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2015] [Revised: 02/14/2016] [Accepted: 02/15/2016] [Indexed: 02/08/2023]
Abstract
AIM Polymorphisms in the ITPA gene influence anemia during peg-interferon (PEG-IFN) and ribavirin (RBV) therapy, but their effects during triple therapy with simeprevir, PEG-IFN, and RBV are not sufficiently known. METHODS We analyzed 212 patients with genotype 1 chronic hepatitis C, who were treated with simeprevir plus PEG-IFN/RBV triple therapy, and assessed the effect of the ITPA polymorphism on hemoglobin levels and RBV dose reduction. ITPA (rs1127354) and IFNL4 (ss469415590) polymorphisms were genotyped using the Invader assay. A stepwise multivariate regression analysis was carried out to identify factors associated with outcome of the therapy. RESULTS Reduction of hemoglobin levels was similar between patients treated with simeprevir plus PEG-IFN/RBV and those treated with PEG-IFN/RBV therapy. In simeprevir plus PEG-IFN/RBV-treated patients, decreases in hemoglobin levels were faster and greater, and the cumulative proportion of patients with ribavirin dose reduction was significantly greater in ITPA genotype CC patients than in CA/AA patients. The total dose of simeprevir and PEG-IFN was similar between ITPA genotype CC and CA/AA patients. In contrast, the total dose of RBV was lower in patients with the CC genotype. Multivariate analysis showed that the IFNL4 TT/TT genotype, but not the ITPA SNP genotype, treatment history (treatment-naive or relapse during prior treatment), and treatment completion were significantly associated with outcome of therapy. CONCLUSION ITPA polymorphism influences hemoglobin levels and incidence of RVB dose reduction during simeprevir triple therapy, indicating the importance of monitoring anemia during treatment, particularly for ITPA genotype CC patients.
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Affiliation(s)
- Kei Morio
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Michio Imamura
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Yoshiiku Kawakami
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Reona Morio
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Masahiro Hatooka
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Hiromi Kan
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Hatsue Fujino
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Takayuki Fukuhara
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Tomoki Kobayashi
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Keiichi Masaki
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Atsushi Ono
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Takashi Nakahara
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Ayako Urabe
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Satoe Yokoyama
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Yuko Nagaoki
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Tomokazu Kawaoka
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Nobuhiko Hiraga
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Masataka Tsuge
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Akira Hiramatsu
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - C Nelson Hayes
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Hiroshi Aikata
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Hidenori Ochi
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.,Laboratory for Digestive Diseases, SNP Research Center, The Institute of Physical and Chemical Research (RIKEN), Hiroshima, Japan
| | - Kazuaki Chayama
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.,Laboratory for Digestive Diseases, SNP Research Center, The Institute of Physical and Chemical Research (RIKEN), Hiroshima, Japan
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Network meta-analysis of first- and second-generation protease inhibitors for chronic hepatitis C genotype 1: efficacy based on RVR and SVR 24. Eur J Clin Pharmacol 2016; 73:1-14. [PMID: 27757504 DOI: 10.1007/s00228-016-2146-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2016] [Accepted: 10/07/2016] [Indexed: 12/17/2022]
Abstract
PURPOSE This study aimed to compare the efficacy among direct-acting antiviral agents (first and second-generation direct-acting antiviral agents (DAAs)) with placebo and with standard dual therapy (pegylated interferon + ribavirin (Peg-IFN + RBV)) in terms of rapid virologic response (RVR) and sustained virologic response (SVR) in chronic hepatitis C genotype 1 treatment. METHODS We performed a systematic review of randomized controlled trials (RCTs) in MEDLINE, International Pharmaceutical Abstracts, Cochrane Library, SCIELO, and Scopus and conducted a network meta-analysis to compare the efficacy of boceprevir (BOC), daclatasvir (DCV), grazoprevir, simeprevir (SMV) and telaprevir (TVR), in treatment-naive and treatment-experienced patients. RESULTS Sixteen studies encompassing 7171 patients were analysed. Associations between DAAs therapies (IFN-free regimens) could not be addressed since no common comparator was found in the RCTs among these associations and the other agents included in the present analysis. All agents were more efficacious than placebo or Peg-IFN + RBV in terms of RVR, while only BOC and SMV showed statistically significant superiority for the SVR outcome when compared to placebo or standard dual therapy. No significant differences between the DAAs were observed. The analysis prioritized treatment with DCV for both efficacy outcomes. Node-splitting analysis showed that our networks are robust (p > 0.05). CONCLUSIONS The superiority of DAAs over placebo or standard dual therapy with Peg-IFN + RBV was confirmed, indicating the greater efficacy of DCV. This study is the first network meta-analysis that included RVR as an outcome in the evaluation of these agents via indirect comparison. Further investigation should be carried out addressing safety and tolerability outcomes.
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32
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Hagiwara S, Nishida N, Watanabe T, Sakurai T, Ida H, Minami Y, Takita M, Minami T, Iwanishi M, Chishina H, Ueshima K, Komeda Y, Arizumi T, Kudo M. Outcome of Asunaprevir/Daclatasvir Combination Therapy for Chronic Liver Disease Type C. Dig Dis 2016; 34:620-626. [PMID: 27750228 DOI: 10.1159/000448822] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
OBJECTIVE Treatment for chronic hepatitis C has recently developed in a very rapid manner. In Japan, in September 2014, IFN-free asunaprevir (ASV) and daclatasvir (DCV) became available for combination therapy. We report the treatment outcomes achieved at our hospital using this combination therapy. METHODS Sustained virological response (SVR) 24 could be evaluated in 120 of 125 patients with chronic liver disease type C who visited our hospital and were treated with ASV/DCV after September 2014, and these patients were analyzed. RESULTS SVR24 was achieved in 106 patients (88%). End-of-treatment response was not achieved in 10 patients (8.3%). Five of them carried multiple-resistant NS3/4A or NS5A region, and administration was discontinued early in 4 patients due to adverse effects. After ASV/DCV treatment, hepatocellular carcinoma (HCC) developed in 2 patients (1.7%) and recurred in 5 (4.2%). CONCLUSIONS ASV/DCV treatment achieved favorable SVR in elderly and hepatic cirrhosis patients and patients in whom HCC was cured. However, an increase in the incidence of HCC development in patients who markedly respond to direct-acting antivirals treatment is expected and surveillance of HCC becomes more important.
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33
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Ozeki I, Nakajima T, Yamaguchi M, Kimura M, Arakawa T, Kuwata Y, Ohmura T, Sato T, Hige S, Karino Y, Toyota J. Successful achievement of sustained virological response to triple combination therapy containing simeprevir in two patients with chronic hepatitis C who had failed asunaprevir:Daclatasvir combination therapy. Hepatol Res 2016; 46:1162-1167. [PMID: 26857426 DOI: 10.1111/hepr.12667] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2015] [Revised: 01/09/2016] [Accepted: 02/01/2016] [Indexed: 12/13/2022]
Abstract
Patients 1 and 2 were treatment-naive women who had genotype 1b chronic hepatitis C. Both had IL-28B genotype TT, and amino acid substitutions of core 70 and 91 were both wild type. Search for the presence of resistance-associated variants (RAV) in non-structural (NS)3 and NS5A regions confirmed wild-type D168 and L31, along with Y93H, in both patients. These patients participated in a Japanese phase III clinical study of asunaprevir and daclatasvir at the age of 52 and 67 years, respectively, and were treated with the combination regimen for 24 weeks. However, both experienced post-treatment relapse, and then treated with triple combination therapy with simeprevir, pegylated interferon (IFN) and ribavirin at the age of 53 and 68 years, respectively, and achieved sustained virological response. A search for RAV prior to simeprevir treatment identified multiple resistance including D168E, Y93H and L31V in both patients. It has been demonstrated that, in many cases, a treatment failure with a combination of asunaprevir and daclatasvir results in acquisition of RAV in NS3 and NS5A regions and that drug-resistant mutants, particularly those in the NS5A region, survive for a long time. In these cases, direct-acting antivirals targeted towards the NS5A region may have a limited efficacy. The present case report is based on an idea that a regimen containing IFN with simeprevir could be a therapeutic option particularly for those who are likely to be highly sensitive and tolerable to IFN.
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Affiliation(s)
- Itaru Ozeki
- Department of Gastroenterology, Sapporo Kosei General Hospital, Sapporo, Japan.
| | - Tomoaki Nakajima
- Department of Gastroenterology, Sapporo Kosei General Hospital, Sapporo, Japan
| | - Masakatsu Yamaguchi
- Department of Gastroenterology, Sapporo Kosei General Hospital, Sapporo, Japan
| | - Mutsuumi Kimura
- Department of Gastroenterology, Sapporo Kosei General Hospital, Sapporo, Japan
| | - Tomohiro Arakawa
- Department of Gastroenterology, Sapporo Kosei General Hospital, Sapporo, Japan
| | - Yasuaki Kuwata
- Department of Gastroenterology, Sapporo Kosei General Hospital, Sapporo, Japan
| | - Takumi Ohmura
- Department of Gastroenterology, Sapporo Kosei General Hospital, Sapporo, Japan
| | - Takahiro Sato
- Department of Gastroenterology, Sapporo Kosei General Hospital, Sapporo, Japan
| | - Shuhei Hige
- Department of Gastroenterology, Sapporo Kosei General Hospital, Sapporo, Japan
| | - Yoshiyasu Karino
- Department of Gastroenterology, Sapporo Kosei General Hospital, Sapporo, Japan
| | - Joji Toyota
- Department of Gastroenterology, Sapporo Kosei General Hospital, Sapporo, Japan
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34
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Pecoraro V, Cariani E, Villa E, Trenti T. Optimisation of triple therapy for patients with chronic hepatitis C: a systematic review. Eur J Clin Invest 2016; 46:737-48. [PMID: 27376688 DOI: 10.1111/eci.12656] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2016] [Accepted: 02/11/2016] [Indexed: 12/15/2022]
Abstract
BACKGROUND Triple therapy with Pegylated-Interferon α (PEG-IFNα)/Ribavirin (RBV) and Boceprevir (Boc) or Telaprevir (Tel) significantly improved sustained virological response (SVR) rates for patients with genotype 1 HCV infection compared to PEG-IFNα/RBV alone (dual therapy). However, less is known about factors associated with rates of SVR and of adverse events (AEs). MATERIAL AND METHODS The aim of this systematic review was to evaluate the evidence regarding the factors affecting response and rate of AEs associated with triple therapy. We performed systematic electronic searches in Medline, Embase, Scopus and Central as well as a list of reference literature. We included randomised controlled trials examining triple therapy compared with dual therapy and reporting data according to patients features and about AEs. Odds ratios (OR) were pooled using either fixed or random effect model, as appropriate. RESULTS We included data from 14 studies. Treatment with triple therapy increased SVR rate compared to dual therapy especially in patients previously treated with PEG-IFNα/RBV and with increased pretreatment alanine aminotransferase (ALT) levels. Higher rate of serious AEs and treatment discontinuation due to AEs was also observed particularly in treatment-experienced patients. CONCLUSIONS The present study shows how improved results of triple therapy are mainly observed in some patients' subsets and are accompanied by increased risk of AEs compared to dual therapy. These results might be useful for optimising treatment of chronic hepatitis C when IFN-free regimens are unavailable.
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Affiliation(s)
- Valentina Pecoraro
- Clinical Pathology - Toxicology, Ospedale Civile Sant'Agostino Estense, Modena, Italy
| | - Elisabetta Cariani
- Clinical Pathology - Toxicology, Ospedale Civile Sant'Agostino Estense, Modena, Italy
| | - Erica Villa
- Division of Gastroenterology, AOU Modena, Modena, Italy
| | - Tommaso Trenti
- Clinical Pathology - Toxicology, Ospedale Civile Sant'Agostino Estense, Modena, Italy
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35
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Ishikawa T, Abe S, Watanabe T, Nozawa Y, Sano T, Iwanaga A, Seki K, Honma T, Yoshida T. Clinical efficacy of the highly sensitive hepatitis C virus RNA quantitative assay in patients with relapse following interferon-based therapy with second-generation direct-acting antivirals. Biomed Rep 2016; 4:664-666. [PMID: 27313853 PMCID: PMC4888019 DOI: 10.3892/br.2016.660] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2016] [Accepted: 04/05/2016] [Indexed: 11/06/2022] Open
Abstract
For refractory chronic hepatitis C, interferon (IFN)-based triple-agent combination therapy with second-generation direct-acting antivirals (DAAs) has been established as the standard treatment method. The rate of decrease in the viral load and the negative conversion of hepatitis C virus (HCV) RNA in the early phase following treatment initiation are considered important factors for predicting the therapeutic outcome. In the present study, the Roche Cobas AmpliPrep/COBAS TaqMan (CAP/CTM) HCV v2.0 assay and the AccuGENE m-HCV RNA quantitative assay [Abbott RealTime HCV (ART) assay] were analyzed for their clinical efficacy and ability to predict therapeutic outcomes in the early phase in patients with relapse following IFN-based second-generation DAA therapy. Of the 56 patients who received IFN-based second-generation DAA therapy since December 2013, 6 achieved an end-of-treatment response (ETR), but subsequently experienced relapse. In these 6 patients, fluctuations in viral loads in the early phase detected by the CAP/CTM and ART assays were compared. At 4 weeks after treatment initiation, 4 of the 6 patients were diagnosed as negative by the CAP/CTM assay, whereas 2 of these 4 patients were not identified as negative by the ART assay. Of the 2 patients, one was signal-positive with an HCV RNA load <1.08 Log IU/ml, and the other patient had a viral load of 1.12 Log IU/ml. At 8 weeks after treatment initiation, 1 patient was found to be negative by the CAP/CTM assay, but signal-positive with a viral load <1.08 Log IU/ml by the ART assay. From 4 to 8 weeks after treatment initiation, 3 of the 6 patients appeared to be discrepant cases. In conclusion, of the 6 patients who achieved an ETR, 4 were determined to have achieved a rapid virological response (RVR) by the CAP/CTM assay, but may not have actually become negative. The ART assay is highly sensitive, has a wide measurement range, may be suitable for monitoring HCV RNA loads, and is expected to have an important role in providing a predictive marker for early therapeutic outcomes. In discrepant cases in which no RVR is proved by either assay, it was assumed important to consider continuation of treatment and to attempt to achieve a sustained virological response.
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Affiliation(s)
- Toru Ishikawa
- Department of Gastroenterology and Hepatology, Saiseikai Niigata Daini Hospital, Niigata 950-1104, Japan
| | - Satoshi Abe
- Department of Gastroenterology and Hepatology, Saiseikai Niigata Daini Hospital, Niigata 950-1104, Japan
| | - Takayuki Watanabe
- Department of Gastroenterology and Hepatology, Saiseikai Niigata Daini Hospital, Niigata 950-1104, Japan
| | - Yujiro Nozawa
- Department of Gastroenterology and Hepatology, Saiseikai Niigata Daini Hospital, Niigata 950-1104, Japan
| | - Tomoe Sano
- Department of Gastroenterology and Hepatology, Saiseikai Niigata Daini Hospital, Niigata 950-1104, Japan
| | - Akito Iwanaga
- Department of Gastroenterology and Hepatology, Saiseikai Niigata Daini Hospital, Niigata 950-1104, Japan
| | - Keiichi Seki
- Department of Gastroenterology and Hepatology, Saiseikai Niigata Daini Hospital, Niigata 950-1104, Japan
| | - Terasu Honma
- Department of Gastroenterology and Hepatology, Saiseikai Niigata Daini Hospital, Niigata 950-1104, Japan
| | - Toshiaki Yoshida
- Department of Gastroenterology and Hepatology, Saiseikai Niigata Daini Hospital, Niigata 950-1104, Japan
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36
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Nagaoki Y, Aikata H, Nakano N, Shinohara F, Nakamura Y, Hatooka M, Morio K, Kan H, Fujino H, Kobayashi T, Fukuhara T, Masaki K, Ono A, Nakahara T, Kawaoka T, Miki D, Tsuge M, Hiramatsu A, Imamura M, Takahashi S, Kawakami Y, Ochi H, Chayama K. Development of hepatocellular carcinoma in patients with hepatitis C virus infection who achieved sustained virological response following interferon therapy: A large-scale, long-term cohort study. J Gastroenterol Hepatol 2016; 31:1009-15. [PMID: 26584407 DOI: 10.1111/jgh.13236] [Citation(s) in RCA: 48] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2015] [Revised: 10/01/2015] [Accepted: 11/08/2015] [Indexed: 12/30/2022]
Abstract
BACKGROUND We assessed the risk factors for the development of hepatocellular carcinoma (HCC) following successful eradication of hepatitis C virus (HCV) with interferon (IFN) therapy in a long-term, large-scale cohort study. METHODS We reviewed 1094 consecutive patients with HCV who achieved sustained virological response (SVR) following IFN therapy between January 1995 and September 2013. RESULTS During the observation period (median 50 months: range 13-224), 36 (3%) of 1094 patients developed HCC after SVR. The median period from SVR to diagnosis of HCC was 37 months (range 17-141), and the cumulative rates of HCC at 5, 10, and 15 years were 4%, 6%, and 12%, respectively. Multivariate analysis identified old age (≥60 years, HR, 3.1: 95%CI, 1.3-6.6: P = 0.009), male sex (HR, 12.0: 95%CI, 2.8-50.0: P < 0.0001), advanced fibrosis stage (F3/4, HR, 3.2: 95%CI, 1.6-7.2: P < 0.0001), and alpha-fetoprotein ≥10 ng/mL at 1 year after SVR (HR, 7.8: 95%CI, 2.9-16.8: P < 0.0001) as significant and independent risk factors for post-SVR HCC. CONCLUSIONS Older age and male sex (host factors), advanced fibrosis stage (pre-IFN treatment factor), and higher alpha-fetoprotein values (post-treatment factor) were significantly associated with HCC development after HCV eradication.
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Affiliation(s)
- Yuko Nagaoki
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan
| | - Hiroshi Aikata
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan
| | - Norihito Nakano
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan
| | - Fumi Shinohara
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan
| | - Yuki Nakamura
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan
| | - Masahiro Hatooka
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan
| | - Kei Morio
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan
| | - Hiromi Kan
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan
| | - Hatsue Fujino
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan
| | - Tomoki Kobayashi
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan
| | - Takayuki Fukuhara
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan
| | - Keiichi Masaki
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan
| | - Atsushi Ono
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan
| | - Takashi Nakahara
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan
| | - Tomokazu Kawaoka
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan
| | - Daiki Miki
- Laboratory for Digestive Diseases, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
| | - Masataka Tsuge
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan
| | - Akira Hiramatsu
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan
| | - Michio Imamura
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan
| | - Shoichi Takahashi
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan
| | - Yoshiiku Kawakami
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan
| | - Hidenori Ochi
- Laboratory for Digestive Diseases, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
| | - Kazuaki Chayama
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan.,Laboratory for Digestive Diseases, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
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Watanabe T, Joko K, Seike H, Michitaka K, Horiike N, Kisaka Y, Tanaka Y, Nakanishi S, Nakanishi K, Nonaka T, Yamauchi K, Onji M, Ohno Y, Tokumoto Y, Hirooka M, Abe M, Hiasa Y. Simeprevir with peginterferon/ribavirin for patients with hepatitis C virus genotype 1: high frequency of viral relapse in elderly patients. SPRINGERPLUS 2016; 5:518. [PMID: 27186482 PMCID: PMC4844583 DOI: 10.1186/s40064-016-2190-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/17/2015] [Accepted: 04/20/2016] [Indexed: 02/07/2023]
Abstract
Purpose The tolerability and efficacy of simeprevir in combination with peginterferon and ribavirin in patients infected with hepatitis C virus (HCV) genotype 1 under actual clinical conditions were investigated. Methods A total of 176 patients with chronic HCV genotype 1 infection were treated with simeprevir for 12 weeks plus Peg-IFN/RBV for 24 weeks. Overall, 107 (60.7 %) patients were aged 60 years or more, and 16 (9 %) patients were aged 70 years or more. Treatment discontinuation, sustained virological response 12 (SVR12), and viral relapse were evaluated and compared between younger patients and elderly patients. Results The rates of undetectable HCV RNA at the end of treatment were 95.8, 100 and 93.1 % in treatment-naïve, prior relapse, and prior non-responders, respectively. However, the rates of SVR12 were 82.4, 88.2 and 69.2 %, respectively. Especially in prior non-responders, viral relapse was relatively frequent. Treatment discontinuation and SVR12 were not different between patients aged <70 and ≥70 years, but viral relapse after completing treatment was significantly more frequent in patients aged ≥70 years (p = 0.012). Conclusions In simeprevir with peginterferon and ribavirin therapy, viral relapse was relatively frequent. Especially in elderly patients, the relapse rate was high after completing treatment, instead of low frequency of discontinuation by the adverse events.
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Affiliation(s)
- Takao Watanabe
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime 791-0295 Japan
| | - Kouji Joko
- Center for Liver-Biliary-Pancreatic Diseases, Matsuyama Red Cross Hospital, 1 Bunkyocho, Matsuyama, Ehime 790-8524 Japan
| | - Hirotaka Seike
- Department of Gastroenterology, Uwajima City Hospital, 1-1 Gotenmachi, Uwajima, Ehime 798-0061 Japan
| | - Kojiro Michitaka
- Department of Gastroenterology, Ehime Prefectural Central Hospital, 83 Kasugamachi, Matsuyama, Ehime 790-0024 Japan
| | - Norio Horiike
- Department of Gastroenterology, Saiseikai Imabari Hospital, 7-1-6 Kitamura, Imabari, Ehime 799-1502 Japan
| | - Yoshiyasu Kisaka
- Department of Gastroenterology, Matsuyama Shimin Hospital, 2-6-5 Ootemachi, Matsuyama, Ehime 790-0067 Japan
| | - Yoshinori Tanaka
- Department of Gastroenterology, Matsuyama Shimin Hospital, 2-6-5 Ootemachi, Matsuyama, Ehime 790-0067 Japan
| | - Seiji Nakanishi
- Department of Gastroenterology, Ehime Prefectural Imabari Hospital, 4-5-5 Ishiicho, Imabari, Ehime 794-0006 Japan
| | - Kimio Nakanishi
- Department of Internal Medicine, Shiritsu Oozu Hospital, 570 Kou Nishioozu, Oozu, Ehime 795-0013 Japan
| | - Takashi Nonaka
- Department of Internal Medicine, Ehime Prefectural Niihama Hospital, 3-1-1 Hongo, Niihama, Ehime 792-0042 Japan
| | - Kazuhiko Yamauchi
- Department of Gastroenterology, National Hospital Organization Ehime Medical Center, 366 Yokogawara, Toon, Ehime 791-0203 Japan
| | - Morikazu Onji
- Department of Gastroenterology, Saiseikai Imabari Hospital, 7-1-6 Kitamura, Imabari, Ehime 799-1502 Japan
| | - Yoshinori Ohno
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime 791-0295 Japan
| | - Yoshio Tokumoto
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime 791-0295 Japan
| | - Masashi Hirooka
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime 791-0295 Japan
| | - Masanori Abe
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime 791-0295 Japan
| | - Yoichi Hiasa
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime 791-0295 Japan
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Hayashi N, Nakamuta M, Takehara T, Kumada H, Takase A, Howe AYM, Ludmerer SW, Mobashery N. Vaniprevir plus peginterferon alfa-2b and ribavirin in treatment-naive Japanese patients with hepatitis C virus genotype 1 infection: a randomized phase III study. J Gastroenterol 2016; 51:390-403. [PMID: 26403160 PMCID: PMC4805724 DOI: 10.1007/s00535-015-1120-x] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2015] [Accepted: 08/27/2015] [Indexed: 02/04/2023]
Abstract
BACKGROUND Vaniprevir is a potent macrocyclic hepatitis C virus (HCV) nonstructural protein 3/4A protease inhibitor. This phase III study evaluated the safety and efficacy of vaniprevir in combination with peginterferon alfa-2b and ribavirin (PR) for 24 weeks compared with PR alone for 48 weeks in treatment-naive Japanese patients with HCV genotype 1 infection. METHODS Treatment-naive Japanese patients with HCV genotype 1 infection were randomly assigned to receive vaniprevir (300 mg twice daily) plus PR for 12 weeks then PR alone for 12 weeks, vaniprevir (300 mg twice daily) plus PR for 24 weeks, or PR alone for 48 weeks. The primary end point was sustained virologic response 24 weeks after completion of treatment (SVR24). RESULTS In total, 294 patients were randomly assigned to receive treatment. Most patients had HCV genotype 1b infection (98 %, 288 of 294 patients). SVR24 was achieved in 83.7, 84.5, and 55.1 % of the patients in the vaniprevir 12-week, vaniprevir 24-week, and control arms, respectively. The difference in SVR24 rates between each vaniprevir arm and the control arm was statistically significant (p < 0.001 for both). Relapse was commoner in the control arm (29.5 %) than in the vaniprevir arms (8.6 % and 10.5 % for the 12-week and 24-week arms, respectively). Commonly reported adverse events were generally similar across treatment arms, with the exception of an increase in the incidence of gastrointestinal adverse events such as nausea, diarrhea, and vomiting in patients receiving vaniprevir. These events were considered manageable. CONCLUSION Vaniprevir is a valuable addition to the therapeutic options available to Japanese patients with HCV genotype 1 infection who are eligible for interferon-based treatment. CLINICALTRIALS. GOV IDENTIFIER NCT01370642.
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Affiliation(s)
- Norio Hayashi
- Kansai Rosai Hospital, 1-69 Inabasou 3-chome, Amagasaki, Hyogo, 660-8511, Japan.
| | - Makoto Nakamuta
- Department of Gastroenterology, National Hospital Organization Kyushu Medical Center, 1-8-1 Jigyohama, Chuo-Ku, Fukuoka, 810-8563, Japan
| | - Tetsuo Takehara
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Hiromitsu Kumada
- Department of Hepatology, Toranomon Hospital, 1-3-1 Kajigaya, Takatsu-ku, Kawasaki, 213-8587, Japan
| | - Akiko Takase
- MSD K.K., 1-13-12 Kudan-kita, Chiyoda-Ku, Tokyo, 102-8667, Japan
| | | | - Steven W Ludmerer
- Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ, 07033, USA
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Matsumoto N, Ikeda H, Shigefuku R, Hattori N, Watanabe T, Matsunaga K, Hiraishi T, Tamura T, Noguchi Y, Fukuda Y, Ishii T, Okuse C, Sato A, Suzuki M, Itoh F. Hemoglobin Decrease with Iron Deficiency Induced by Daclatasvir plus Asunaprevir Combination Therapy for Chronic Hepatitis C Virus Genotype 1b. PLoS One 2016; 11:e0151238. [PMID: 26990758 PMCID: PMC4798293 DOI: 10.1371/journal.pone.0151238] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2015] [Accepted: 02/25/2016] [Indexed: 01/02/2023] Open
Abstract
Background Decreased hemoglobin (Hb) level has been supposed to be a relatively rare side effect of a combination therapy against hepatitis C virus that consists of the NS5A inhibitor daclatasvir (DCV) and the NS3/4A protease inhibitor asunaprevir (ASV). Methods The study was conducted in 75 patients with genotype 1b chronic hepatitis C virus infection who had started combination therapy with DCV and ASV at St. Marianna University School of Medicine Hospital between September 2014 and December 2014. Results Among the patients examined, decreased Hb level by ≥1.5 g/dL from the values at treatment initiation was observed in 11 individuals. This was accompanied by decreased mean corpuscular volume, and iron and ferritin levels. Conclusions These findings suggest that the mechanism of the phenomenon is caused by iron deficiency. The underlying mechanism and clinical impacts will need to be further examined.
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Affiliation(s)
- Nobuyuki Matsumoto
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-ku, Kawasaki City, Kanagawa, 216–8511, Japan
- * E-mail:
| | - Hiroki Ikeda
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-ku, Kawasaki City, Kanagawa, 216–8511, Japan
| | - Ryuta Shigefuku
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-ku, Kawasaki City, Kanagawa, 216–8511, Japan
| | - Nobuhiro Hattori
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-ku, Kawasaki City, Kanagawa, 216–8511, Japan
| | - Tsunamasa Watanabe
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-ku, Kawasaki City, Kanagawa, 216–8511, Japan
| | - Kotaro Matsunaga
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-ku, Kawasaki City, Kanagawa, 216–8511, Japan
| | - Tetsuya Hiraishi
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-ku, Kawasaki City, Kanagawa, 216–8511, Japan
| | - Tomohiro Tamura
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-ku, Kawasaki City, Kanagawa, 216–8511, Japan
| | - Yohei Noguchi
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-ku, Kawasaki City, Kanagawa, 216–8511, Japan
| | - Yasunobu Fukuda
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-ku, Kawasaki City, Kanagawa, 216–8511, Japan
| | - Toshiya Ishii
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-ku, Kawasaki City, Kanagawa, 216–8511, Japan
| | - Chiaki Okuse
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-ku, Kawasaki City, Kanagawa, 216–8511, Japan
| | - Akira Sato
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-ku, Kawasaki City, Kanagawa, 216–8511, Japan
| | - Michihiro Suzuki
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-ku, Kawasaki City, Kanagawa, 216–8511, Japan
| | - Fumio Itoh
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-ku, Kawasaki City, Kanagawa, 216–8511, Japan
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Kohjima M, Kurokawa M, Enjoji M, Yoshimoto T, Nakamura T, Ohashi T, Fukuizumi K, Harada N, Murata Y, Matsunaga K, Kato M, Kotoh K, Nakamuta M. Analysis of renal function during telaprevir-based triple therapy for chronic hepatitis C. Exp Ther Med 2016; 11:1781-1787. [PMID: 27168803 DOI: 10.3892/etm.2016.3133] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2015] [Accepted: 11/05/2015] [Indexed: 12/23/2022] Open
Abstract
Telaprevir (TVR) is used for the treatment of chronic hepatitis C in a combination therapy with pegylated-interferon and ribavirin. Although renal dysfunction is one of the critical adverse outcomes of this treatment, little is known regarding the mechanism of its onset. The present study assessed the association of renal function with TVR dose and viral response. Hematological, biochemical, urinary and virological parameters of renal function were examined during the TVR-based triple therapy of patients infected with hepatitis C virus (HCV) genotype 1b. Serum creatinine levels were increased and the estimated glomerular filtration rate (eGFR) was decreased in every patient during TVR administration, but these values recovered to normal levels following cessation of TVR. Fractional excretion of sodium was <1% at days 3 and 7, appearing similar regardless of baseline renal function. Urinary β2-microglobulin levels were elevated and were significantly higher in patients with renal dysfunction, as compared with those not exhibiting renal dysfunction (P<0.05). The reduction in renal function was milder in patients treated with a reduced TVR dose, and these patients had a significantly lower risk of developing renal dysfunction (P<0.05). Using a multivariate analysis, TVR dose and eGFR at the initiation of treatment were identified as significant contributory factors in the development of renal dysfunction. Reduction in TVR dose did not lead to a significant increase in the viral kinetics of HCV or detrimental effects on the sustained viral response (SVR) rate. It is hypothesized that renal dysfunction during TVR treatment is caused by damage of the renal tubule, in addition to pre-renal dysfunction, and that reduction in TVR dose reduces the rate of renal dysfunction without causing a significant decrease in the SVR rate.
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Affiliation(s)
- Motoyuki Kohjima
- Department of Gastroenterology, National Hospital Organization Kyushu Medical Center, Fukuoka 810-8563, Japan
| | - Miho Kurokawa
- Department of Gastroenterology, National Hospital Organization Kyushu Medical Center, Fukuoka 810-8563, Japan
| | - Munechika Enjoji
- Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka 814-0180, Japan
| | - Tsuyoshi Yoshimoto
- Department of Gastroenterology, National Hospital Organization Kyushu Medical Center, Fukuoka 810-8563, Japan
| | - Tsukasa Nakamura
- Department of Gastroenterology, National Hospital Organization Kyushu Medical Center, Fukuoka 810-8563, Japan
| | - Tomoko Ohashi
- Department of Gastroenterology, National Hospital Organization Kyushu Medical Center, Fukuoka 810-8563, Japan
| | - Kunitaka Fukuizumi
- Department of Gastroenterology, National Hospital Organization Kyushu Medical Center, Fukuoka 810-8563, Japan
| | - Naohiko Harada
- Department of Gastroenterology, National Hospital Organization Kyushu Medical Center, Fukuoka 810-8563, Japan
| | - Yusuke Murata
- Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka 814-0180, Japan
| | - Kazuhisa Matsunaga
- Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka 814-0180, Japan
| | - Masaki Kato
- Department of Medicine and Bioregulatory Science, Kyushu University, Fukuoka 812-8582, Japan
| | - Kazuhiro Kotoh
- Department of Medicine and Bioregulatory Science, Kyushu University, Fukuoka 812-8582, Japan
| | - Makoto Nakamuta
- Department of Gastroenterology, National Hospital Organization Kyushu Medical Center, Fukuoka 810-8563, Japan
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HCV evolutionary genetics of SVR versus virologic failure assessed from the vaniprevir phase III registration trials. Antiviral Res 2016; 130:118-29. [PMID: 26947564 DOI: 10.1016/j.antiviral.2016.03.004] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2015] [Revised: 02/05/2016] [Accepted: 03/02/2016] [Indexed: 01/20/2023]
Abstract
UNLABELLED In the phase III registration studies conducted in Japan, Japanese HCV gt1 patients administered vaniprevir 300 mg twice daily plus pegylated interferon/ribavirin for 12 or 24 weeks achieved SVR24 rates of 83.7-84.5% among treatment-naïve patients, and 92.0-96.2% and 61.9% among breakthrough/relapsers or null-responders to prior interferon based therapy. As evidenced by direct sequencing, patients who did not achieve SVR24 principally failed due to treatment-emerging mutations at D168 or in a few cases R155. In this work, additional sequence analysis was conducted to address whether there were baseline polymorphisms associated with failure, evaluate the persistence of resistant virus among treatment failures, and assess for evidence of second site co-evolution with R155 or D168 mutations. To accomplish this, clonal sequencing (up to 40 clones per sample) was conducted on baseline, failure, and follow-up samples from all 38 patients among the vaniprevir treatment arms who met virologic failure criteria (37 gt1b, 1 gt1a, herein referred to as virologic failures) and baseline samples from 41 vaniprevir-treated SVR24 patients (all gt1b) selected among the three studies. SVR24 and virologic failure patients showed similar distributions of baseline polymorphisms previously associated with failure to one or more protease inhibitors. Furthermore, there was no evidence for baseline polymorphisms or a genetic signature across the NS3 protease domain specific to virologic failure patients, and which distinguishes them from baseline SVR24 sequences beyond a chance distribution. 24 of 32 virologic failures for whom baseline, failure, and follow-up samples were available showed reduced prevalence of the resistant virus first observed at the time of failure during the protocol-defined follow-up period of 24 weeks. Finally, pairwise analysis using either alignment or phylogenetic based methodologies provided no evidence for second site evolution with either the R155 or D168 mutations attributed to failure. This work supports and extends earlier findings based upon direct sequencing that attributed virologic failure to vaniprevir in the Phase III studies solely to the emergence of R155 or D168 mutations, with no apparent influence by other residues within the NS3 protease domain on treatment outcome. CLINICALTRIALS. GOVIDENTIFIERS NCT01370642, NCT01405937, NCT01405560.
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Ikegami T, Yoshizumi T, Yoshida Y, Kurihara T, Harimoto N, Itoh S, Shimokawa M, Fukuhara T, Shirabe K, Maehara Y. Telaprevir versus simeprevir for the treatment of recurrent hepatitis C after living donor liver transplantation. Hepatol Res 2016; 46:E136-45. [PMID: 26096514 DOI: 10.1111/hepr.12546] [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: 03/28/2015] [Revised: 06/16/2015] [Accepted: 06/16/2015] [Indexed: 12/17/2022]
Abstract
AIM Our aim was to evaluate the clinical outcomes of telaprevir (TVR)- or simeprevir (SMV)-based triple therapy for recurrent hepatitis C after living donor liver transplantation. METHODS Twenty-six patients received antiviral therapy, consisting of either TVR (n = 12) or SMV (n = 14) in combination with pegylated interferon and ribavirin, plus cyclosporin. RESULTS More patients had a dose reduction of the direct-acting agent (36.3% vs 0.0%, P = 0.02) or required blood transfusion for anemia (58.3% vs 7.1%, P < 0.01) in the TVR group. The cyclosporin trough/dose ratio increased significantly from week 0 to week 4 in the TVR group (1.6 ± 0.4 to 5.1 ± 2.0, P < 0.01), but not in the SMV group (1.2 ± 0.3 to 1.3 ± 0.2, P = 0.68). The 24-week cumulative viral clearance rate was 91.7% and 85.7% in the TVR and in SMV groups, respectively. The early viral response and sustained viral response rates were 91.7% and 83.3%, respectively, in the TVR group, compared with 85.7% and 64.3%, respectively, in the SMV group. Interferon-mediated graft dysfunction occurred in four and five patients in the TVR and SMV groups, respectively; two patients were treated by oral steroids, five by steroid pulse and two by thymoglobulin, resulting in viral breakthrough in one case. CONCLUSION SMV-based triple therapy was associated with fewer adverse events and drug interactions with cyclosporin, and possibly less antiviral properties to TVR. Interferon-mediated graft dysfunction is a significant clinical problem that warrants particular caution following living donor liver transplantation.
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Affiliation(s)
- Toru Ikegami
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Tomoharu Yoshizumi
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yoshihro Yoshida
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Takeshi Kurihara
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Norifumi Harimoto
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Shinji Itoh
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Masahiro Shimokawa
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Takasuke Fukuhara
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Ken Shirabe
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yoshihiko Maehara
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
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Uchida Y, Kouyama JI, Naiki K, Sugawara K, Ando S, Nakao M, Motoya D, Inao M, Imai Y, Nakayama N, Mochida S. Significance of variants associated with resistance to NS5A inhibitors in Japanese patients with genotype 1b hepatitis C virus infection as evaluated using cycling-probe real-time PCR combined with direct sequencing. J Gastroenterol 2016; 51:260-70. [PMID: 26245700 DOI: 10.1007/s00535-015-1106-8] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2015] [Accepted: 07/13/2015] [Indexed: 02/04/2023]
Abstract
BACKGROUND Dual oral therapy with daclatasvir plus asunaprevir yielded an SVR rate of 85% among patients with genotype 1b HCV. Treatment failure mainly occurred in patients with pre-existing HCV with NS5A-Y93H mutation. The significance of the mutation was evaluated. METHODS The percent of serum NS5A-Y93H strains relative to the total strains was quantified using cycling-probe real-time PCR combined with direct sequencing in 444 patients with genotype 1b HCV, and the factors associated with mutation were analyzed. The mutation rates during interferon therapy were measured sequentially. RESULTS NS5A-Y93H strains (1-100% of the total strains) were detected in 87 patients (19.6%). Mutant strains were detected more frequently among women than among men, in patients with a favorable allele in the IL28B-related gene SNP than among those with unfavorable alleles, and among patients without HCC and/or with serum AFP levels less than 6.0 ng/ml than among those with HCC and/or levels of 6.0 ng/ml or more. A multivariate analysis revealed that IL28B-related gene polymorphisms were significant factors associated with mutant strains. Although the frequency of patients with mutant strains was equivalent among patients depending on their previous interferon therapies, a sequential analysis during the interferon administrations revealed that the mutant strains disappeared earlier than the wild-type strains. CONCLUSIONS NS5A-Y93H mutation was associated with sex, serum AFP levels, and IL28B-related gene polymorphisms in patients infected with genotype 1b HCV. The indications for NS5A inhibitor use should be determined based on these factors, since mutant strains seem to be sensitive to interferon.
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Affiliation(s)
- Yoshihito Uchida
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Saitama Medical University, 38 Morohongo, Moroyama-Machi, Iruma-Gun, Saitama, 350-0495, Japan
| | - Jun-Ichi Kouyama
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Saitama Medical University, 38 Morohongo, Moroyama-Machi, Iruma-Gun, Saitama, 350-0495, Japan
| | - Kayoko Naiki
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Saitama Medical University, 38 Morohongo, Moroyama-Machi, Iruma-Gun, Saitama, 350-0495, Japan
| | - Kayoko Sugawara
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Saitama Medical University, 38 Morohongo, Moroyama-Machi, Iruma-Gun, Saitama, 350-0495, Japan
| | - Satsuki Ando
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Saitama Medical University, 38 Morohongo, Moroyama-Machi, Iruma-Gun, Saitama, 350-0495, Japan
| | - Masamitsu Nakao
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Saitama Medical University, 38 Morohongo, Moroyama-Machi, Iruma-Gun, Saitama, 350-0495, Japan
| | - Daisuke Motoya
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Saitama Medical University, 38 Morohongo, Moroyama-Machi, Iruma-Gun, Saitama, 350-0495, Japan
| | - Mie Inao
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Saitama Medical University, 38 Morohongo, Moroyama-Machi, Iruma-Gun, Saitama, 350-0495, Japan
| | - Yukinori Imai
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Saitama Medical University, 38 Morohongo, Moroyama-Machi, Iruma-Gun, Saitama, 350-0495, Japan
| | - Nobuaki Nakayama
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Saitama Medical University, 38 Morohongo, Moroyama-Machi, Iruma-Gun, Saitama, 350-0495, Japan
| | - Satoshi Mochida
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Saitama Medical University, 38 Morohongo, Moroyama-Machi, Iruma-Gun, Saitama, 350-0495, Japan.
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Jovanovic-Cupic S, Glisic S, Stanojevic M, Nozic D, Petrovic N, Mandusic V, Krajnovic M. The influence of host factors and sequence variability of the p7 region on the response to pegylated interferon/ribavirin therapy for chronic hepatitis C genotype 1b in patients from Serbia. Arch Virol 2016; 161:1189-98. [PMID: 26860912 DOI: 10.1007/s00705-016-2777-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2014] [Accepted: 01/27/2016] [Indexed: 12/31/2022]
Abstract
The goal of this study was to identify host and viral factors affecting the response to pegylated interferon/ribavirin (PEG-IFN/RBV) treatment in patients with chronic hepatitis C genotype 1b. Baseline characteristics of the patients and sequences within the p7 region were analyzed in pre-treatment serum samples from 53 individuals with chronic hepatitis C genotype 1b and related to the outcome of therapy. We found a significant correlation between age and response to therapy (p < 0.001). Furthermore, the pre-treatment viral load was closely associated with the stage of liver fibrosis (p < 0.001). The presence of fewer than 4 mutations and age above 40 were significantly associated with non-response (NR) (p < 0.001). Our findings may be useful for estimating the likelihood of achieving a sustained virologic response (SVR) in patients who are chronically infected with hepatitis C virus genotype 1b.
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Affiliation(s)
- Snezana Jovanovic-Cupic
- Laboratory for Radiobiology and Molecular Genetics, Institute of Nuclear Sciences, Vinca, University of Belgrade, P.O. Box 522, Belgrade, Serbia.
| | - Sanja Glisic
- Center for Multidisciplinary Research, Institute of Nuclear Sciences, Vinca, University of Belgrade, P.O. Box 522, Belgrade, Serbia
| | - Maja Stanojevic
- Institute of Microbiology and Immunology, Faculty of Medicine, University of Belgrade, 11000, Belgrade, Serbia
| | - Darko Nozic
- Clinics of Infectious and Tropical Diseases, Military Medical Academy, 11000, Belgrade, Serbia
| | - Nina Petrovic
- Laboratory for Radiobiology and Molecular Genetics, Institute of Nuclear Sciences, Vinca, University of Belgrade, P.O. Box 522, Belgrade, Serbia
| | - Vesna Mandusic
- Laboratory for Radiobiology and Molecular Genetics, Institute of Nuclear Sciences, Vinca, University of Belgrade, P.O. Box 522, Belgrade, Serbia
| | - Milena Krajnovic
- Laboratory for Radiobiology and Molecular Genetics, Institute of Nuclear Sciences, Vinca, University of Belgrade, P.O. Box 522, Belgrade, Serbia
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Asahina Y, Izumi N, Hiromitsu K, Kurosaki M, Koike K, Suzuki F, Takikawa H, Tanaka A, Tanaka E, Tanaka Y, Tsubouchi H, Hayashi N, Hiramatsu N, Yotsuyanagi H. JSH Guidelines for the Management of Hepatitis C Virus Infection: A 2016 update for genotype 1 and 2. Hepatol Res 2016; 46:129-65. [PMID: 26876581 DOI: 10.1111/hepr.12645] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Affiliation(s)
- Yasuhiro Asahina
- Department of Gastroenterology and Hepatology, School of Medicine, Tokyo Medical and Dental University
| | - Namiki Izumi
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital
| | | | - Masayuki Kurosaki
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital
| | - Kazuhiko Koike
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo
| | | | - Hajime Takikawa
- Department of Medicine, Teikyo University School of Medicine
| | - Atsushi Tanaka
- Department of Medicine, Teikyo University School of Medicine
| | - Eiji Tanaka
- The Second Department of Internal Medicine, Shinshu University School of Medicine
| | - Yasuhito Tanaka
- Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Science
| | | | | | - Naoki Hiramatsu
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine
| | - Hiroshi Yotsuyanagi
- Department of Infectious Diseases, Graduate School of Medicine, The University of Tokyo
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46
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Kinoshita K, Iwasa T, Takase A, Nakamura K. [Preclinical and clinical properties of vaniprevir (VANIHEP® Capsules 150 mg), a novel therapeutic agent for hepatitis C]. Nihon Yakurigaku Zasshi 2016; 146:159-70. [PMID: 26354016 DOI: 10.1254/fpj.146.159] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
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Broglio KR, Daar ES, Quintana M, Yuan Y, Kalsekar A, Spellberg B, Lewis RJ, Akker DVD, Detry MA, Le T, Berry SM. A meta-analysis platform methodology for determining the comparative effectiveness of antihepatitis C virus regimens. J Comp Eff Res 2016; 4:101-14. [PMID: 25825840 DOI: 10.2217/cer.14.69] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
AIM Many hepatitis C virus regimens are unlikely to be compared head to head. In more difficult to treat populations where there is no standard of care, trials are single arm. We describe a flexible meta-analysis platform in this setting. METHODS Our meta-analysis is literature based. We illustrate our methodology and show how inference can be extended to single-arm trials. RESULTS As an example, in the single arm setting, a regimen with response rates of 84, 72 and 54% in genotype 1a across treatment naive, previous partial responders and previous null responders, respectively, would have 95% probability of superiority to IFN-α + RBV + TPV. CONCLUSION This is a rigorous approach to comparative effectiveness that accounts for varying patient populations and plans for the incorporation of emerging treatments.
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48
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Swallow E, Kelley C, Signorovitch J, Wygant G, McPhee F. Daclatasvir + asunaprevir versus sofosbuvir/ledipasvir for hepatitis C genotype 1 in Japanese patients: an indirect comparison. J Comp Eff Res 2016; 5:273-9. [PMID: 26793987 DOI: 10.2217/cer.15.69] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023] Open
Abstract
AIM To compare daclatasvir + asunaprevir (DCV + ASV) versus sofosbuvir/ledipasvir (SOF/LDV) for hepatitis C virus genotype 1b in Japanese patients without NS5A polymorphisms at L31 and Y93H. PATIENTS & METHODS All Phase III trials of SOF/LDV and DCV + ASV conducted in Japan were included. To adjust for cross-trial differences, DCV + ASV patients were weighted to match reported SOF/LDV summary baseline characteristics. RESULTS After adjustment, the rate of SVR12 (99.3 vs 100%; p = 0.398) and discontinuation due to adverse events (1.3 vs 0.0%; p = 0.327) were similar between patients treated with DCV + ASV (n = 252) and SOF/LDV (n = 171). CONCLUSION After adjusting for cross-trial differences in baseline characteristics, DCV + ASV and SOF/LDV were associated with similar efficacy and discontinuation due to adverse events in the treatment of hepatitis C virus genotype 1b in Japanese patients without NS5A polymorphisms.
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Affiliation(s)
- Elyse Swallow
- Analysis Group Inc., 111 Huntington Avenue, 10th floor, Boston, MA 02199, USA
| | - Caroline Kelley
- Analysis Group Inc., 111 Huntington Avenue, 10th floor, Boston, MA 02199, USA
| | - James Signorovitch
- Analysis Group Inc., 111 Huntington Avenue, 10th floor, Boston, MA 02199, USA
| | - Gail Wygant
- Bristol-Myers Squibb, 100 Nassau Park Boulevard, Princeton, NJ 08540, USA
| | - Fiona McPhee
- Bristol-Myers Squibb, 100 Nassau Park Boulevard, Princeton, NJ 08540, USA
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49
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50
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Matsuoka S, Fujikawa H, Hasegawa H, Ochiai T, Watanabe Y, Moriyama M. Onset of Tuberculosis from a Pulmonary Latent Tuberculosis Infection during Antiviral Triple Therapy for Chronic Hepatitis C. Intern Med 2016; 55:2011-7. [PMID: 27477407 DOI: 10.2169/internalmedicine.55.6448] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
A 62-year-old man was diagnosed with the onset of tuberculosis (Tb) from a pulmonary latent tuberculosis infection (LTBI) during triple therapy with pegylated interferon α2a, ribavirin, and telaprevir for a chronic hepatitis C infection in 2013 before interferon (IFN)-free anti-viral therapy was introduced in Japan. A liver biopsy before IFN treatment revealed the presence of epithelioid cell granulomas (ECGs). IFN may also be employed for chronic hepatitis B infection and malignant tumors, thus, special attention must be paid to the development of Tb from a LTBI when ECGs are observed before treatment. It is also necessary to review the significance of the liver biopsy.
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Affiliation(s)
- Shunichi Matsuoka
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Japan
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