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Liu YC, Jeng WJ, Cheng YT, Hsieh YC, Teng W, Chen YC, Lin CY, Chien RN, Sheen IS. Incidence and predictors for abnormal liver function during direct-acting antiviral agents in chronic hepatitis C patients. Medicine (Baltimore) 2020; 99:e21898. [PMID: 32925725 PMCID: PMC7489670 DOI: 10.1097/md.0000000000021898] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
Abrupt alanine aminotransferase (ALT) elevation during direct-acting antiviral agents (DAA) treatment is an uncommon but noticeable adverse event in chronic hepatitis C (CHC) patients, which may lead to early termination of treatment. This study aims to investigate the incidence, outcome and predictors of the on-treatment ALT elevation during DAA therapy.CHC patients treated with DAA regimen in Chang Gung Memorial Hospital, Linkou branch during March 2015 to March 2019 were recruited. Prospective scheduled ALT assessment at baseline, 2nd, 4th, 8th, and 12th/24th weeks were recorded. Pretherapy host and viral factors were compared between patients with and without on-treatment ALT elevation. Multivariate logistic regression was used for independent factors for on-treatment ALT elevation.A total of 1563 CHC patients treated with grazoprevir/elbasvir, glecaprevir/pibrentasvir and sofosbuvir-based regimen were analyzed. On-treatment ALT elevation occurred in 10.9% patients while those treated with glecaprevir/pibrentasvir had the least possibility (5.4%). Only 1.4% patients had ≥grade 3 ALT elevation events. The presence of such events had no impact on sustained virological response 12 rates. Hepatitis B virus coinfection (aOR: 3.599, P < 0.001) and higher pretherapy ALT (1-5x, ≥5x upper limit of normal: aOR: 2.632, P = 0.024, aOR: 4.702, P = .011, respectively) were significant predictors for ALT elevation.On-treatment ALT elevation occurred in one-tenth CHC patients treated with preferred DAAs but had no impact on sustained virological response rate.
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Affiliation(s)
- Yen-Chun Liu
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou branch
- College of Medicine, Chang Gung University, Taiwan
| | - Wen-Juei Jeng
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou branch
- College of Medicine, Chang Gung University, Taiwan
| | - Ya-Ting Cheng
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou branch
- College of Medicine, Chang Gung University, Taiwan
| | - Yi-Chung Hsieh
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou branch
- College of Medicine, Chang Gung University, Taiwan
| | - Wei Teng
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou branch
- College of Medicine, Chang Gung University, Taiwan
| | - Yi-Cheng Chen
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou branch
- College of Medicine, Chang Gung University, Taiwan
| | - Chun-Yen Lin
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou branch
- College of Medicine, Chang Gung University, Taiwan
| | - Rong-Nan Chien
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou branch
- College of Medicine, Chang Gung University, Taiwan
| | - I-Shyan Sheen
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou branch
- College of Medicine, Chang Gung University, Taiwan
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Baudy AR, Otieno MA, Hewitt P, Gan J, Roth A, Keller D, Sura R, Van Vleet TR, Proctor WR. Liver microphysiological systems development guidelines for safety risk assessment in the pharmaceutical industry. LAB ON A CHIP 2020; 20:215-225. [PMID: 31799979 DOI: 10.1039/c9lc00768g] [Citation(s) in RCA: 89] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/10/2023]
Abstract
The liver is critical to consider during drug development because of its central role in the handling of xenobiotics, a process which often leads to localized and/or downstream tissue injury. Our ability to predict human clinical safety outcomes with animal testing is limited due to species differences in drug metabolism and disposition, while traditional human in vitro liver models often lack the necessary in vivo physiological fidelity. To address this, increasing numbers of liver microphysiological systems (MPS) are being developed, however the inconsistency in their optimization and characterization often leads to models that do not possess critical levels of baseline performance that is required for many pharmaceutical industry applications. Herein we provide a guidance on best approaches to benchmark liver MPS based on 3 stages of characterization that includes key performance metrics and a 20 compound safety test set. Additionally, we give an overview of frequently used liver injury safety assays, describe the ideal MPS model, and provide a perspective on currently best suited MPS contexts of use. This pharmaceutical industry guidance has been written to help MPS developers and end users identify what could be the most valuable models for safety risk assessment.
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Affiliation(s)
| | - Monicah A Otieno
- Janssen Pharmaceutical Research and Development, Spring House, PA, USA
| | | | - Jinping Gan
- Bristol-Myers Squibb, New York City, NY, USA
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Matsumoto J, San SN, Fujiyoshi M, Kawauchi A, Chiba N, Tagai R, Sanbe R, Yanaka S, Sakaue H, Kato Y, Nakamura H, Yamada H, Ariyoshi N. Effect of CYP3A5*3 genetic variant on the metabolism of direct-acting antivirals in vitro: a different effect on asunaprevir versus daclatasvir and beclabuvir. J Hum Genet 2019; 65:143-153. [PMID: 31645655 DOI: 10.1038/s10038-019-0685-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2019] [Revised: 09/29/2019] [Accepted: 10/02/2019] [Indexed: 12/18/2022]
Abstract
Direct-acting antivirals, asunaprevir (ASV), daclatasvir (DCV), and beclabuvir (BCV) are known to be mainly metabolized by CYP3A enzymes; however, the differences in the detailed metabolic activities of CYP3A4 and CYP3A5 on these drugs are not well clarified. The aim of the present study was to elucidate the relative contributions of CYP3A4 and CYP3A5 to the metabolism of ASV, DCV, and BCV, as well as the effect of CYP3A5*3 genetic variant in vitro. The amount of each drug and their major metabolites were determined using LC-MS/MS. Recombinant CYP3As and CYP3A5*3-genotyped human liver microsomes (CYP3A5 expressers or non-expressers) were used for the determination of their metabolic activities. The contribution of CYP3A5 to ASV metabolism was considerable compared to that of CYP3A4. Consistently, ASV metabolic activity in CYP3A5 expressers was higher than those in CYP3A5 non-expresser. Moreover, CYP3A5 expression level was significantly correlated with ASV metabolism. In contrast, these observations were not found in DCV and BCV metabolism. To our knowledge, this is the first study to directly demonstrate the effect of CYP3A5*3 genetic variants on the metabolism of ASV. The findings of the present study may provide basic information on ASV, DCV, and BCV metabolisms.
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Affiliation(s)
- Jun Matsumoto
- Department of Personalized Medicine and Preventive Healthcare Sciences, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan.
| | - Su Nwe San
- Department of Pharmacokinetics, Pharmaceutical Sciences, International University of Health and Welfare, Tochigi, Japan
| | - Masachika Fujiyoshi
- Department of Personalized Medicine and Preventive Healthcare Sciences, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
| | - Ayano Kawauchi
- Department of Pharmacokinetics, Pharmaceutical Sciences, International University of Health and Welfare, Tochigi, Japan
| | - Natsumi Chiba
- Department of Pharmacokinetics, Pharmaceutical Sciences, International University of Health and Welfare, Tochigi, Japan
| | - Ran Tagai
- Department of Pharmacokinetics, Pharmaceutical Sciences, International University of Health and Welfare, Tochigi, Japan
| | - Ryoko Sanbe
- Department of Pharmacokinetics, Pharmaceutical Sciences, International University of Health and Welfare, Tochigi, Japan
| | - Shiho Yanaka
- Department of Pharmacokinetics, Pharmaceutical Sciences, International University of Health and Welfare, Tochigi, Japan
| | - Hiroaki Sakaue
- Department of Biochemistry, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan
| | - Yoshinori Kato
- Department of Pharmacokinetics, Pharmaceutical Sciences, International University of Health and Welfare, Tochigi, Japan
| | - Hiroyoshi Nakamura
- Department of Pharmacokinetics, Pharmaceutical Sciences, International University of Health and Welfare, Tochigi, Japan.,Division of Pharmacy, International University of Health and Welfare Mita Hospital, Tokyo, Japan
| | - Harumi Yamada
- Department of Pharmacokinetics, Pharmaceutical Sciences, International University of Health and Welfare, Tochigi, Japan
| | - Noritaka Ariyoshi
- Department of Personalized Medicine and Preventive Healthcare Sciences, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
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Kato K, Shimada N, Atsukawa M, Abe H, Itokawa N, Matsumoto Y, Agata R, Tsubota A. Single nucleotide polymorphisms associated with elevated alanine aminotransferase in patients receiving asunaprevir plus daclatasvir combination therapy for chronic hepatitis C. PLoS One 2019; 14:e0219022. [PMID: 31291311 PMCID: PMC6619746 DOI: 10.1371/journal.pone.0219022] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2019] [Accepted: 06/14/2019] [Indexed: 12/12/2022] Open
Abstract
Aims Drug-induced liver damage characterized by serum alanine aminotransferase (ALT) elevation often occurs in direct-acting antiviral (DAA) combination therapy for chronic hepatitis C virus (HCV) infection. This study explored single nucleotide polymorphisms (SNPs) at drug metabolism- or transport-related genes that were associated with ALT elevation in asunaprevir plus daclatasvir therapy. Methods Subjects were 185 Japanese patients with chronic HCV genotype 1b infection who received asunaprevir plus daclatasvir therapy. Tag SNPs at possible metabolizing enzyme and transporter genes, which were involved in the pharmacokinetics of asunaprevir and daclatasvir, were selected. Results Among the tag SNPs analyzed, CYP3A4 rs4646437 was significantly associated with ALT elevation (p = 0.013): maximum ALT values in patients with genotype CC were higher than those in patients with genotype non-CC (allele T). The proportion of grades 2–4 in genotype CC patients were significantly greater than those in genotype non-CC patients (p = 0.028). No patients with genotype non-CC showed grade ≥2 ALT elevation. In multivariate analysis, rs4646437 genotype CC and cirrhosis were significant, independent factors associated with grade ≥1 ALT elevation (odds ratio, 2.83 and 1.88; p = 0.040 and 0.045, respectively). In exploratory analyses, although serum concentrations of asunaprevir and daclatasvir were not correlated with maximum ALT values or rs4646437 genotypes, asunaprevir concentrations in patients with grade ≥1 ALT elevation were significantly higher than those in patients with grade <1 ALT elevation (P = 0.023). Conclusions CYP3A4 rs4646437 was found to be significantly and independently associated with ALT elevation in Japanese patients receiving ASV plus DCV therapy. Notably, none of the patients with rs4646437 genotype non-CC (allele T) had grade ≥2 ALT elevation. SNP genotyping prior to treatment might be useful for carefully monitoring patients to complete treatment safely.
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Affiliation(s)
- Keizo Kato
- Liver Disease Control Science, Graduate School of Organic Pathology and Therapeutics, The Jikei University School of Medicine, Minato-ku, Tokyo, Japan
- Division of Gastroenterology and Hepatology, Shinmatsudo Central General Hospital, Matsudo, Chiba, Japan
| | - Noritomo Shimada
- Division of Gastroenterology and Hepatology, Ootakanomori Hospital, Kashiwa, Chiba, Japan
| | - Masanori Atsukawa
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Nippon Medical School, Bunkyo-ku, Tokyo, Japan
| | - Hiroshi Abe
- Division of Gastroenterology and Hepatology, Shinmatsudo Central General Hospital, Matsudo, Chiba, Japan
| | - Norio Itokawa
- Division of Gastroenterology, Department of Internal Medicine, Nippon Medical School Chiba Hokusoh Hospital, Inzai, Chiba, Japan
| | - Yoshihiro Matsumoto
- Division of Gastroenterology and Hepatology, The Jikei University School of Medicine, Kashiwa Hospital, Chiba, Japan
| | - Rie Agata
- Core Research Facilities, Research Center for Medical Sciences, The Jikei University School of Medicine, Minato-ku, Tokyo, Japan
| | - Akihito Tsubota
- Liver Disease Control Science, Graduate School of Organic Pathology and Therapeutics, The Jikei University School of Medicine, Minato-ku, Tokyo, Japan
- Core Research Facilities, Research Center for Medical Sciences, The Jikei University School of Medicine, Minato-ku, Tokyo, Japan
- * E-mail:
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Uchida Y, Naiki K, Kouyama JI, Sugawara K, Nakao M, Motoya D, Inao M, Nakayama N, Imai Y, Tomiya T, Mochida S. Serum asunaprevir concentrations showing correlation with the extent of liver fibrosis as a factor inducing liver injuries in patients with genotype-1b hepatitis C virus receiving daclatasvir plus asunaprevir therapy. PLoS One 2018; 13:e0205600. [PMID: 30308053 PMCID: PMC6181393 DOI: 10.1371/journal.pone.0205600] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2018] [Accepted: 09/27/2018] [Indexed: 12/14/2022] Open
Abstract
AIMS Liver injury can occur during antiviral therapies with direct-acting antivirals (DAAs), potentially necessitating discontinuation of the therapies, with consequent worsening of the sustained viral response (SVR) rates, in patients with hepatitis C virus (HCV). To clarify the mechanisms involved in serum transaminase level elevation, we performed a retrospective evaluation of the serum concentrations of daclatasvir and asunaprevir, both classified as DAAs, in patients receiving treatment with a combination of the two drugs. METHODS Subjects were 278 Japanese patients with genotype-1b HCV who received daclatasvir plus asunaprevir therapy for more than 4 weeks. Serum concentrations of both the DAAs were measured at 4 weeks after the initiation of therapy. RESULT Liver injuries including serum AST and/or ALT level elevation to 150 U/L or over were found in 34 patients (12.2%). Multivariate logistic regression analysis identified serum asunaprevir concentrations as being significantly associated with developing liver injury, with an odds ratio of 1.046 (95% confidence interval 1.011-1.082, p<0.05). Serum asunaprevir concentrations showed correlation with the extent of liver fibrosis, estimated by peripheral platelets counts and serum albumin levels and baseline and FIB4 index and serum Mac-2 binding protein glycosylation isomer (M2BPGi) levels at 4 weeks of the therapy; the concentrations were significantly higher among patients showing 3.0 or more of M2BPGi levels than among those with the levels less than 3.0; on the other hand, no such correlation/difference was found in serum daclatasvir concentrations. CONCLUSION High serum concentrations of serum asunaprevir, which were associated with the extent of liver fibrosis, appear to provoke the occurrence of liver injury in patients with genotype-1b HCV receiving combined daclatasvir plus asunaprevir therapy.
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Affiliation(s)
- Yoshihito Uchida
- Department of Gastroenterology & Hepatology, Faculty of Medicine, Saitama Medical University, Moroyama, Saitama, Japan
| | - Kayoko Naiki
- Department of Gastroenterology & Hepatology, Faculty of Medicine, Saitama Medical University, Moroyama, Saitama, Japan
| | - Jun-ichi Kouyama
- Department of Gastroenterology & Hepatology, Faculty of Medicine, Saitama Medical University, Moroyama, Saitama, Japan
| | - Kayoko Sugawara
- Department of Gastroenterology & Hepatology, Faculty of Medicine, Saitama Medical University, Moroyama, Saitama, Japan
| | - Masamitsu Nakao
- Department of Gastroenterology & Hepatology, Faculty of Medicine, Saitama Medical University, Moroyama, Saitama, Japan
| | - Daisuke Motoya
- Department of Gastroenterology & Hepatology, Faculty of Medicine, Saitama Medical University, Moroyama, Saitama, Japan
| | - Mie Inao
- Department of Gastroenterology & Hepatology, Faculty of Medicine, Saitama Medical University, Moroyama, Saitama, Japan
| | - Nobuaki Nakayama
- Department of Gastroenterology & Hepatology, Faculty of Medicine, Saitama Medical University, Moroyama, Saitama, Japan
| | - Yukinori Imai
- Department of Gastroenterology & Hepatology, Faculty of Medicine, Saitama Medical University, Moroyama, Saitama, Japan
| | - Tomoaki Tomiya
- Department of Gastroenterology & Hepatology, Faculty of Medicine, Saitama Medical University, Moroyama, Saitama, Japan
| | - Satoshi Mochida
- Department of Gastroenterology & Hepatology, Faculty of Medicine, Saitama Medical University, Moroyama, Saitama, Japan
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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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Safety and effectiveness of daclatasvir and asunaprevir dual therapy in patients with genotype 1 chronic hepatitis C: results from postmarketing surveillance in Japan. Hepatol Int 2018; 12:244-253. [DOI: 10.1007/s12072-018-9872-z] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2018] [Accepted: 05/16/2018] [Indexed: 12/26/2022]
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Association between alanine aminotransferase elevation and UGT1A1*6 polymorphisms in daclatasvir and asunaprevir combination therapy for chronic hepatitis C. J Gastroenterol 2018; 53:780-786. [PMID: 29094205 DOI: 10.1007/s00535-017-1405-3] [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: 07/07/2017] [Accepted: 10/20/2017] [Indexed: 02/04/2023]
Abstract
BACKGROUND Liver damage presented as alanine aminotransferase (ALT) elevation and high ALT-caused treatment discontinuation occurs with high frequency in Japanese patients receiving daclatasvir plus asunaprevir (DCV/ASV) therapy for hepatitis C virus (HCV) infection, and its mechanism is unknown. METHODS A total of 247 Japanese patients consisting of two independent cohorts with genotype-1b HCV infection receiving DCV/ASV therapy were included. The association of ALT levels during therapy and single nucleotide polymorphisms (SNP) of five drug-metabolizing enzyme loci selected for their possible influence on NS3/4A and NS5A inhibitors was investigated. RESULTS Among five SNPs, we found a significant correlation between the presence of the UGT1A1 rs4148323 A allele and ALT elevation (Grade 3 elevation in AA 57%, AG 18%, and GG 4%, P = 8.4E - 06) and drug discontinuation (AA 22%, AG 11%, and GG 2.5%, P = 8.7E - 04), while no association was observed with ALT values at baseline (Grade 3 elevation AA 0%, AG 4%, and GG 2%, P = 0.5). In contrast, patients with risk A allele for drug-induced ALT elevation had a tendency to respond more favorably to treatment (AA 100%, AG 93%, and GG 90%, P = 0.29). CONCLUSIONS Through the analysis we suggest that the A allele in UGT1A1 rs4148323 (UGT1A1*6), which is highly prevalent in the Japanese population, should be considered a risk for the development of DCV/ASV therapy-induced ALT elevation. Pretreatment SNP testing of UGT1A1*6 might be beneficial for the prediction of liver damage induced by DCV/ASV or even by DCV/ASV plus beclabuvir.
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Fujii H, Umemura A, Nishikawa T, Yamaguchi K, Moriguchi M, Nakamura H, Yasui K, Minami M, Tanaka S, Ishikawa H, Kimura H, Takami S, Nagao Y, Shima T, Itoh Y. Real-world efficacy of daclatasvir and asunaprevir with respect to resistance-associated substitutions. World J Hepatol 2017; 9:1064-1072. [PMID: 28951778 PMCID: PMC5596313 DOI: 10.4254/wjh.v9.i25.1064] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2017] [Revised: 05/17/2017] [Accepted: 07/17/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate daclatasvir (DCV) and asunaprevir (ASV) efficacy in hepatitis C (HCV) patients, with respect to resistance-associated substitutions (RASs).
METHODS A total of 392 HCV-infected patients from multiple centers were included in this study. We evaluated their clinical courses and sustained virologic responses (SVR) according to pretreatment factors (gender, age, history of interferon-based regimens, platelet counts, level of viremia, pretreatment NA5A:L31, and Y93 substitutions). We also analyzed the pretreatment and post-treatment major RASs of NS3:D168, NS5A:L31 and Y93 substitutions using a direct-sequencing method in 17 patients who were unable to achieve SVR at 12 wk after treatment completion (SVR12).
RESULTS The overall SVR12 rate was 88.3%. Thirty-one patients discontinued treatment before 24 wk because of adverse events, 23 of whom achieved SVR12. There were no significant differences in SVR12 rates with respect to gender, age, history of interferon-based regimens, and platelet counts. The SVR12 rate in patients with viral loads of ≥ 6.0 log IU/mL was significantly lower than those with viral loads of < 6.0 log IU/mL (P < 0.001). The SVR12 rate in patients with Y93 substitution-positive was significantly lower than those with Y93 substitution-negative (P < 0.001). The L31 substitution-positive group showed a lower SVR12 rate than the L31 substitution-negative group, but the difference was not statistically significant. Seventeen patients who did not achieve SVR12 and had available pretreatment and post-treatment sera had additional RASs in NS3:D168, NS5:L31, and Y93 substitution at treatment failure.
CONCLUSION Combination of DCV and ASV is associated with a high SVR rate. Baseline RASs should be thoroughly assessed to avoid additional RASs after treatment failure.
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Affiliation(s)
- Hideki Fujii
- Department of Gastroenterology, Japanese Red Cross Kyoto Daiichi Hospital, Kyoto 6050981, Japan
| | | | | | | | | | - Hideki Nakamura
- Department of Gastroenterology and Hepatology, North Medical Center, Kyoto Prefectural University of Medicine, Kyoto 6292261, Japan
| | | | - Masahito Minami
- Department of Internal Medicine, Aiseikai Yamashina Hospital, Kyoto 6078086, Japan
| | - Saiyu Tanaka
- Center for Digestive and Liver Diseases, Nara City Hospital, Nara 6308305, Japan
| | - Hiroki Ishikawa
- Department of Gastroenterology and Hepatology, Omihachiman Community Medical Center, Shiga 5230082, Japan
| | - Hiroyuki Kimura
- Department of Gastroenterology, Japanese Red Cross Kyoto Daiichi Hospital, Kyoto 6050981, Japan
| | - Shiro Takami
- Department of Gastroenterology, Otsu Municipal Hospital, Otsu 5200804, Japan
| | - Yasuyuki Nagao
- Department of Gastroenterology, Matsushita Memorial Hospital, Moriguchi 5708540, Japan
| | - Toshihide Shima
- Center of Gastroenterology and Hepatology, Saiseikai Suita Hospital, Suita 5640013, Japan
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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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11
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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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12
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Mishra P, Chen M. Direct-Acting Antivirals for Chronic Hepatitis C: Can Drug Properties Signal Potential for Liver Injury? Gastroenterology 2017; 152:1270-1274. [PMID: 28327365 DOI: 10.1053/j.gastro.2017.03.012] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/02/2022]
Affiliation(s)
- Poonam Mishra
- US Food and Drug Administration, Silver Spring, Maryland
| | - Minjun Chen
- US Food and Drug Administration, Jefferson, Arkansas.
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13
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Morio K, Imamura M, Kawakami Y, Morio R, Kobayashi T, Yokoyama S, Nagaoki Y, Kawaoka T, Tsuge M, Hiramatsu A, Makokha GN, Hayes CN, Aikata H, Miki D, Ochi H, Honda Y, Mori N, Takaki S, Tsuji K, Chayama K. Real-world efficacy and safety of daclatasvir and asunaprevir therapy for hepatitis C virus-infected cirrhosis patients. J Gastroenterol Hepatol 2017; 32:645-650. [PMID: 27513614 DOI: 10.1111/jgh.13511] [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] [Accepted: 08/07/2016] [Indexed: 12/24/2022]
Abstract
BACKGROUND AND AIMS Daclatasvir and asunaprevir combination therapy has shown a high virological response for chronic genotype 1 hepatitis C virus (HCV) infected-patients. However, the real-world efficacy and safety of the therapy for patients with cirrhosis are unknown. METHODS A total of 252 patients with genotype 1 HCV infection (158 with chronic hepatitis and 94 with compensated liver cirrhosis) were treated with 24 weeks of daclatasvir and asunaprevir combination therapy. Plasma concentrations of daclatasvir and asunaprevir at day 5 of treatment, end-of-treatment response, sustained virological response (SVR), and the frequencies of adverse events were analyzed. RESULT Plasma asunaprevir concentration was significantly higher, and daclatasvir concentration tended to be higher, in cirrhosis patients compared with chronic hepatitis patients. End-of-treatment response was achieved in 95.6% and 94.7% of chronic hepatitis and cirrhosis patients, respectively, and SVR was achieved in 94.3% and 92.6%. Although pre-treatment NS5A drug resistant-associated variants were detected, a high SVR rate was achieved when the population frequency of the variant was low. The frequencies of treatment-related adverse events in cirrhosis patients were similar to those in chronic hepatitis patients. Treatment discontinuation due to adverse events occurred in three and two patients in chronic hepatitis and cirrhosis groups, respectively; however, four out of five patients with treatment discontinuation nonetheless achieved SVR. CONCLUSION Patients with compensated liver cirrhosis have similar virological response and tolerance for daclatasvir plus asunaprevir therapy to patients with chronic hepatitis. This combination therapy might offer a safe and effective treatment for chronic HCV infected-patients with compensated cirrhosis.
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Affiliation(s)
- Kei Morio
- 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
| | - Yoshiiku Kawakami
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan
| | - Reona Morio
- 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
| | - Satoe Yokoyama
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan
| | - Yuko Nagaoki
- 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
| | - 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
| | - Grace Naswa Makokha
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan
| | - C Nelson Hayes
- 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
| | - 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
| | - Yoji Honda
- Hiroshima Red Cross Hospital & Atomic-bomb Survivors Hospital, 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 Science, Institute of Biomedical & Health Science, 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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14
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Hayes CN, Imamura M, Chayama K. The practical management of chronic hepatitis C infection in Japan - dual therapy of daclatasvir + asunaprevir. Expert Rev Gastroenterol Hepatol 2017; 11:103-113. [PMID: 27936974 DOI: 10.1080/17474124.2017.1270205] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Without treatment, many of the 200 million people worldwide with chronic hepatitis C virus (HCV) infection will develop cirrhosis or liver cancer. Japan was the first nation to approve an interferon-free therapy for HCV, and sustained viral response (SVR) rates >90% have been achieved with asunaprevir, a protease inhibitor, plus daclatasvir, an inhibitor of the non-structural 5A (NS5A) protein. Areas covered: This review provides an overview of the results from both clinical trials and real world experience with asunaprevir and daclatasvir therapy focused primarily on Japan. A literature search using the keywords 'asunaprevir,' 'daclatasvir,' 'interferon-free therapy,' and 'direct-acting antiviral drugs' was initially used to select relevant literature for inclusion in the review. Expert commentary: While not approved in the United States, dual therapy with asunaprevir plus daclatasvir has already been successfully used in Japan and throughout East Asia to treat many thousands of patients. Pre-existing or treatment-emergent NS5A-Y93 or -L31 resistance-associated variants (RAVs) may lead to viral breakthrough, and alternative therapies should be considered for these patients, but patients who harbor NS5A RAVs only at low frequency are likely to achieve SVR. The therapy has also been shown to be safe and effective with renal dysfunction or liver cirrhosis.
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Affiliation(s)
- C Nelson Hayes
- a Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences , Hiroshima University , Minami-ku , Hiroshima , Japan.,b Liver Research Project Center , Hiroshima University , Hiroshima , Japan
| | - Michio Imamura
- a Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences , Hiroshima University , Minami-ku , Hiroshima , Japan.,b Liver Research Project Center , Hiroshima University , Hiroshima , Japan
| | - Kazuaki Chayama
- a Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences , Hiroshima University , Minami-ku , Hiroshima , Japan.,b Liver Research Project Center , Hiroshima University , Hiroshima , Japan.,c Laboratory for Digestive Diseases , Center for Genomic Medicine, RIKEN , Hiroshima , Japan
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15
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Iio E, Shimada N, Abe H, Atsukawa M, Yoshizawa K, Takaguchi K, Eguchi Y, Nomura H, Kuramitsu T, Kang JH, Matsui T, Hirashima N, Tsubota A, Kusakabe A, Hasegawa I, Miyaki T, Shinkai N, Fujiwara K, Nojiri S, Tanaka Y. Efficacy of daclatasvir/asunaprevir according to resistance-associated variants in chronic hepatitis C with genotype 1. J Gastroenterol 2017; 52:94-103. [PMID: 27236547 DOI: 10.1007/s00535-016-1225-x] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2016] [Accepted: 05/11/2016] [Indexed: 02/04/2023]
Abstract
BACKGROUND The present study explored the treatment outcome of daclatasvir (DCV) and asunaprevir (ASV) therapy combining oral direct-acting antiviral agents (DAAs) for chronic hepatitis C (HCV) including liver cirrhosis according to resistance-associated variants (RAVs) in NS3/NS5A region. METHODS Overall, 641 patients enrolled in Japan with HCV-1b received DCV and ASV for 24 weeks. Baseline drug-resistant mutations L31F/I/M/V, Q54H, P58S, A92K, and Y93H in the HCV NS5A region and V36A, T54A/S, Q80K/L/R, R155K/T/Q, A156S/V/T, and D168A/E/H/T/V in the HCV NS3/4A region were assessed by direct sequencing. RESULTS Overall, 86.9 % (543/625) of patients had SVR12, which was significantly higher in NS5A 93Y (wild) (88.3 %) compared with NS5A 93H at baseline (48.0 %), indicating the SVR12 rate was significantly lower in patients with 93H mutations. Additionally, 66.7 % (18/27) of patients with prior triple therapy including simeprevir (SMV) failure had virological failure. The virological failure rate of DCV/ASV therapy after SMV failure was significantly higher in those with preexisting NS3/4A 168 substitutions compared with without substitutions at baseline [84.2 % (16/19) vs. 28.6 % (2/7), p = 0.014]. The number of patients with multiple RAVs or deletions in NS5A increased from 0 to 85 % in failed patients. Alanine aminotransferase elevation was a frequent adverse event causing discontinuation of DCV/ASV therapy, although 87.5 % (14/16) patients achieved SVR12, subsequently. CONCLUSIONS History of SMV therapy and pre-existing NS5A Y93H were associated with virological failure of DCV/ASV therapy, resulting in the emergence of multiple RAVs. Patients with RAVs at baseline should be assessed to optimize future DAA therapies.
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Affiliation(s)
- Etsuko Iio
- Nagoya City University Graduate School of Medical Sciences, Kawasumi, Mizuho, Nagoya, Aichi, Japan
| | | | - Hiroshi Abe
- Jikei University School of Medicine Katsushika Medical Center, Tokyo, Japan
| | | | | | | | | | | | | | | | | | - Noboru Hirashima
- National Hospital Organization Nagoya Medical Center, Nagoya, Japan
| | | | | | - Izumi Hasegawa
- Japan Community Health Care Organization, Chukyo Hospital, Nagoya, Japan
| | | | - Noboru Shinkai
- Nagoya City University Graduate School of Medical Sciences, Kawasumi, Mizuho, Nagoya, Aichi, Japan
| | - Kei Fujiwara
- Nagoya City University Graduate School of Medical Sciences, Kawasumi, Mizuho, Nagoya, Aichi, Japan
| | - Shunsuke Nojiri
- Nagoya City University Graduate School of Medical Sciences, Kawasumi, Mizuho, Nagoya, Aichi, Japan
| | - Yasuhito Tanaka
- Nagoya City University Graduate School of Medical Sciences, Kawasumi, Mizuho, Nagoya, Aichi, Japan.
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16
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Evaluation of Resistance-Associated Substitutions in NS5A Using Direct Sequence and Cycleave Method and Treatment Outcome with Daclatasvir and Asunaprevir for Chronic Hepatitis C Genotype 1. PLoS One 2016. [PMID: 27684567 DOI: 10.1371/journal.pone.0163884pone-d-16-27137] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND The aim of this study was to evaluate the efficacy of daclatasvir plus asunaprevir therapy in patients infected with hepatitis C virus and determine its relevance to resistant variants. METHODS A total of 629 consecutive patients infected with hepatitis C virus genotype 1 were assessed. Daclatasvir (60 mg/day) plus asunaprevir (200 mg/day) was given for 24 weeks. The virological responses and resistance-associated substitutions of hepatitis C virus mutants were examined by the direct sequence and cycleave methods were evaluated. RESULTS Overall, 89.4% (555/621) of patients exhibited a sustained virological response (SVR). The SVR rates in the patients with wild type, mixed, and mutant type Y93 by direct sequencing were 92.5% (520/562), 70.3% (26/37), and 42.9% (9/21), respectively. The SVR rates in the patients with 100%, 90%, 80%-30%, and 20%-0% Y93 wild by the cycleave method were 93.4% (456/488), 88.2%(30/34), 56.0%(14/25), and 36.8%(7/19), respectively. In contrast, the SVR rates for the wild type and mixed/mutant type L31 by direct sequencing were 90.2% (534/592) and 72.4% (21/29), respectively. In the multivariate analyses, the wild type Y93, no history of simeprevir therapy, the wild type L31, and low HCV RNA level were independent factors of SVR. CONCLUSION NS5A resistance-associated substitutions, especially Y93H, were major factors predicting the SVR. Although direct sequencing can predict the SVR rate, the cycleave method is considered to be more useful for predicting the SVR when used in combination.
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17
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Ide T, Eguchi Y, Harada M, Ishii K, Morita M, Morita Y, Sugiyama G, Fukushima H, Yano Y, Noguchi K, Nakamura H, Hisatomi J, Kumemura H, Shirachi M, Iwane S, Okada M, Honma Y, Arinaga-Hino T, Miyajima I, Ogata K, Kuwahara R, Amano K, Kawaguchi T, Kuromatsu R, Torimura T. Evaluation of Resistance-Associated Substitutions in NS5A Using Direct Sequence and Cycleave Method and Treatment Outcome with Daclatasvir and Asunaprevir for Chronic Hepatitis C Genotype 1. PLoS One 2016; 11:e0163884. [PMID: 27684567 PMCID: PMC5042440 DOI: 10.1371/journal.pone.0163884] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2016] [Accepted: 09/15/2016] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND The aim of this study was to evaluate the efficacy of daclatasvir plus asunaprevir therapy in patients infected with hepatitis C virus and determine its relevance to resistant variants. METHODS A total of 629 consecutive patients infected with hepatitis C virus genotype 1 were assessed. Daclatasvir (60 mg/day) plus asunaprevir (200 mg/day) was given for 24 weeks. The virological responses and resistance-associated substitutions of hepatitis C virus mutants were examined by the direct sequence and cycleave methods were evaluated. RESULTS Overall, 89.4% (555/621) of patients exhibited a sustained virological response (SVR). The SVR rates in the patients with wild type, mixed, and mutant type Y93 by direct sequencing were 92.5% (520/562), 70.3% (26/37), and 42.9% (9/21), respectively. The SVR rates in the patients with 100%, 90%, 80%-30%, and 20%-0% Y93 wild by the cycleave method were 93.4% (456/488), 88.2%(30/34), 56.0%(14/25), and 36.8%(7/19), respectively. In contrast, the SVR rates for the wild type and mixed/mutant type L31 by direct sequencing were 90.2% (534/592) and 72.4% (21/29), respectively. In the multivariate analyses, the wild type Y93, no history of simeprevir therapy, the wild type L31, and low HCV RNA level were independent factors of SVR. CONCLUSION NS5A resistance-associated substitutions, especially Y93H, were major factors predicting the SVR. Although direct sequencing can predict the SVR rate, the cycleave method is considered to be more useful for predicting the SVR when used in combination.
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Affiliation(s)
- Tatsuya Ide
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Fukuoka, Japan
- * E-mail:
| | - Yuichiro Eguchi
- Department of Internal Medicine, Saga Medical School, Saga, Japan
| | - Masaru Harada
- Third Department of Internal Medicine, University of Occupational and Environmental Health, Fukuoka, Japan
| | | | | | | | - Gen Sugiyama
- Kurume University Medical Center, Fukuoka, Japan
| | | | | | | | | | | | | | | | - Shinji Iwane
- Department of Internal Medicine, Saga Medical School, Saga, Japan
| | - Michiaki Okada
- Department of Internal Medicine, Saga Medical School, Saga, Japan
| | - Yuichi Honma
- Third Department of Internal Medicine, University of Occupational and Environmental Health, Fukuoka, Japan
| | - Teruko Arinaga-Hino
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Fukuoka, Japan
| | - Ichiro Miyajima
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Fukuoka, Japan
| | - Kei Ogata
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Fukuoka, Japan
| | - Reiichiro Kuwahara
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Fukuoka, Japan
| | - Keisuke Amano
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Fukuoka, Japan
| | - Toshihiro Kawaguchi
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Fukuoka, Japan
| | - Ryoko Kuromatsu
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Fukuoka, Japan
| | - Takuji Torimura
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Fukuoka, Japan
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18
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Baba H, Tajiri K, Nagata K, Kawai K, Minemura M, Sugiyama T. Hyperbilirubinemia without Transaminitis during Combined Therapy with Daclatasvir and Asunaprevir. Case Rep Gastroenterol 2016; 10:352-359. [PMID: 27504082 PMCID: PMC4965544 DOI: 10.1159/000447486] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2016] [Accepted: 06/07/2016] [Indexed: 02/05/2023] Open
Abstract
Daclatasvir (DCV) and asunaprevir (ASV) are direct-acting antivirals (DAAs) used in the treatment of chronic hepatitis C virus (HCV) infection. Combined therapy with DCV and ASV shows high efficacy and safety even in patients with cirrhosis. We encountered a patient exhibiting severe hyperbilirubinemia during combined therapy, which is an unreported side effect of DCV and ASV. A 78-year-old woman with cirrhosis developed hyperbilirubinemia >10 mg/dl without transaminitis 3 weeks after starting combined therapy. We suspected DAAs-induced liver disorder and discontinued treatment, which resulted in the improvement of hyperbilirubinemia. Caution is required in the use of DAAs for patients with advanced cirrhosis.
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Affiliation(s)
- Hayato Baba
- The Third Department of Internal Medicine, Toyama University Hospital, Toyama, Japan
- Department of Education and Clinical Training, Toyama University Hospital, Toyama, Japan
| | - Kazuto Tajiri
- The Third Department of Internal Medicine, Toyama University Hospital, Toyama, Japan
| | - Kohei Nagata
- The Third Department of Internal Medicine, Toyama University Hospital, Toyama, Japan
| | - Kengo Kawai
- The Third Department of Internal Medicine, Toyama University Hospital, Toyama, Japan
| | - Masami Minemura
- The Third Department of Internal Medicine, Toyama University Hospital, Toyama, Japan
| | - Toshiro Sugiyama
- The Third Department of Internal Medicine, Toyama University Hospital, Toyama, Japan
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Sato A, Ishii T, Adachi K, Kumon D, Tamura T, Noguchi Y, Matsumoto N, Okuse C. Sustained virological response after a 17-day treatment with daclatasvir plus asunaprevir in a cirrhotic patient with hepatitis C virus genotype 1b and null response for peginterferon ribavirin therapy. Clin J Gastroenterol 2016; 9:89-92. [PMID: 26896968 DOI: 10.1007/s12328-016-0630-2] [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: 10/26/2015] [Accepted: 02/05/2016] [Indexed: 11/29/2022]
Abstract
Daclatasvir (DCV) plus asunaprevir (ASV) treatment, an oral therapy for chronic hepatitis C virus (HCV) genotype 1b infection, can achieve a high sustained viral response (SVR) rate within a 24-week treatment period. A 55-year-old Japanese female with cirrhosis and null response for peginterferon plus ribavirin therapy received DCV plus ASV therapy, but she reported a slight fever beginning on treatment day 4. The fever increased to >38.0 °C beginning on treatment day 15 and could not be controlled with antipyretics; thus, the treatment was discontinued on day 17. Although the patient was still positive for HCV RNA 6 days after treatment discontinuation, she achieved an SVR at week 24 after treatment cessation. In some patients with HCV genotype 1b infection, an SVR can be achieved with short-term DCV plus ASV treatment, and HCV RNA positivity at the end of treatment does not always indicate virological failure.
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Affiliation(s)
- Akira Sato
- Division of Gastroenterology, Department of Internal Medicine, St. Marianna University School of Medicine Yokohama City Seibu Hospital, 1197-1 Yasashicho Asahi-ku, Yokohama, 241-0811, Japan.
| | - Toshiya Ishii
- Division of Gastroenterology, Department of Internal Medicine, St. Marianna University School of Medicine Yokohama City Seibu Hospital, 1197-1 Yasashicho Asahi-ku, Yokohama, 241-0811, Japan
| | - Kayo Adachi
- Division of Gastroenterology, Department of Internal Medicine, St. Marianna University School of Medicine Yokohama City Seibu Hospital, 1197-1 Yasashicho Asahi-ku, Yokohama, 241-0811, Japan
| | - Daisuke Kumon
- Division of Gastroenterology, Department of Internal Medicine, St. Marianna University School of Medicine Yokohama City Seibu Hospital, 1197-1 Yasashicho Asahi-ku, Yokohama, 241-0811, Japan
| | - Tomohiro Tamura
- Division of Gastroenterology, Department of Internal Medicine, St. Marianna University School of Medicine Yokohama City Seibu Hospital, 1197-1 Yasashicho Asahi-ku, Yokohama, 241-0811, Japan
| | - Youhei Noguchi
- Division of Gastroenterology, Department of Internal Medicine, St. Marianna University School of Medicine Yokohama City Seibu Hospital, 1197-1 Yasashicho Asahi-ku, Yokohama, 241-0811, Japan
| | - Nobuyuki Matsumoto
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-ku, Kawasaki, 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, 216-8511, Japan
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