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Teixeira AP, Franko N, Fussenegger M. Engineering Gene and Protein Switches for Regulation of Lineage-Specifying Transcription Factors. Biotechnol Bioeng 2025; 122:1051-1061. [PMID: 39801452 DOI: 10.1002/bit.28920] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2024] [Revised: 12/16/2024] [Accepted: 12/16/2024] [Indexed: 03/12/2025]
Abstract
Human pluripotent stem cells (hPSCs) can be differentiated in vitro to an increasing number of mature cell types, presenting significant promise for addressing a wide range of diseases and studying human development. One approach to further enhance stem cell differentiation methods would be to coordinate multiple inducible gene or protein switches to operate simultaneously within the same cell, with minimal cross-interference, to precisely regulate a network of lineage-specifying transcription factors (TFs) to guide cell fate decisions. Therefore, in this study, we designed and tested various mammalian gene and protein switches responsive to clinically safe small-molecule inhibitors of viral proteases. First, we leveraged hepatitis C virus and human rhinovirus proteases to control the activity of chimeric transcription factors, enabling gene expression activation exclusively in the presence of protease inhibitors and achieving high fold-inductions in hPSC lines. Second, we built single-chain protein switches regulating the activity of three differentiation-related pancreatic TFs, MafA, Pdx1, and Ngn3, each engineered with a protease cleavage site within its structure and having the corresponding protease fused at one terminus. While variants lacking the protease retained most of the unmodified TF activity, the attachment of the protease significantly decreased the activity, which could be rescued upon addition of the corresponding protease inhibitor. We confirmed the functionality of these protein switches for simultaneously controlling the activity of three TFs with a common input molecule, as well as the orthogonality of each protease-based system to independently regulate two TFs. Finally, we validated these very compact systems for precisely controlling TF activity in hPSCs. Our results suggest that they will be valuable tools for research in both developmental biology and regenerative medicine.
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Affiliation(s)
- Ana P Teixeira
- Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland
| | - Nik Franko
- Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland
| | - Martin Fussenegger
- Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland
- Faculty of Science, University of Basel, Basel, Switzerland
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Manna S, Das K, Santra S, Nosova EV, Zyryanov GV, Halder S. Structural and Synthetic Aspects of Small Ring Oxa- and Aza-Heterocyclic Ring Systems as Antiviral Activities. Viruses 2023; 15:1826. [PMID: 37766233 PMCID: PMC10536032 DOI: 10.3390/v15091826] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Revised: 08/17/2023] [Accepted: 08/21/2023] [Indexed: 09/29/2023] Open
Abstract
Antiviral properties of different oxa- and aza-heterocycles are identified and properly correlated with their structural features and discussed in this review article. The primary objective is to explore the activity of such ring systems as antiviral agents, as well as their synthetic routes and biological significance. Eventually, the structure-activity relationship (SAR) of the heterocyclic compounds, along with their salient characteristics are exhibited to build a suitable platform for medicinal chemists and biotechnologists. The synergistic conclusions are extremely important for the introduction of a newer tool for the future drug discovery program.
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Affiliation(s)
- Sibasish Manna
- Department of Chemistry, Visvesvaraya National Institute of Technology, Nagpur 440010, India
| | - Koushik Das
- Department of Chemistry, Visvesvaraya National Institute of Technology, Nagpur 440010, India
| | - Sougata Santra
- Department of Organic and Biomolecular Chemistry, Chemical Engineering Institute, Ural Federal University, 19 Mira Street, 620002 Yekaterinburg, Russia; (S.S.); (E.V.N.); (G.V.Z.)
| | - Emily V. Nosova
- Department of Organic and Biomolecular Chemistry, Chemical Engineering Institute, Ural Federal University, 19 Mira Street, 620002 Yekaterinburg, Russia; (S.S.); (E.V.N.); (G.V.Z.)
- I. Ya. Postovskiy Institute of Organic Synthesis, Ural Division of the Russian Academy of Sciences, 22 S. Kovalevskoy Street, 620219 Yekaterinburg, Russia
| | - Grigory V. Zyryanov
- Department of Organic and Biomolecular Chemistry, Chemical Engineering Institute, Ural Federal University, 19 Mira Street, 620002 Yekaterinburg, Russia; (S.S.); (E.V.N.); (G.V.Z.)
- I. Ya. Postovskiy Institute of Organic Synthesis, Ural Division of the Russian Academy of Sciences, 22 S. Kovalevskoy Street, 620219 Yekaterinburg, Russia
| | - Sandipan Halder
- Department of Chemistry, Visvesvaraya National Institute of Technology, Nagpur 440010, India
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Sofia MJ. Curing Hepatitis C with Direct‐Acting Antiviral Therapy. METHODS AND PRINCIPLES IN MEDICINAL CHEMISTRY 2022:13-57. [DOI: 10.1002/9783527810697.ch2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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Tojima H, Kakizaki S, Takakusagi S, Hoshino T, Naganuma A, Nagashima T, Namikawa M, Ueno T, Shimada Y, Hatanaka T, Takizawa D, Arai H, Sato K, Takagi H, Uraoka T. Follow-up after Direct-acting Antiviral Treatment for Chronic Hepatitis C Virus Infection: Most Patients Are Followed Appropriately. Intern Med 2021; 60:3061-3070. [PMID: 34602520 PMCID: PMC8545640 DOI: 10.2169/internalmedicine.6591-20] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2020] [Accepted: 02/16/2021] [Indexed: 12/16/2022] Open
Abstract
Objective Chronic hepatitis C virus (HCV) infection carries a residual risk of hepatocarcinogenesis even after viral elimination, so appropriate follow-up is necessary. The present study investigated the current hospital visits and hepatocarcinogenesis status of patients who received daclatasvir plus asunaprevir treatment (DCV+ASV) to determine whether or not appropriate follow-up was being performed. Methods We retrospectively analyzed hepatocarcinogenesis, the overall survival, and the length of hospital visits in 442 patients who applied for the medical expense subsidy system for viral hepatitis and received DCV+ASV treatment in Gunma Prefecture between October 2014 and December 2015. This also included 61 patients who had a history of hepatocellular carcinoma (HCC). Results Among 442 patients, 388 achieved a sustained viral response (SVR) by DCV+ASV therapy (87.8%), and 95.9% achieved an SVR if additional treatment was included. HCC was found in 75 cases (17.0%). A history of HCC, the FIB-4 index and the treatment effect SVR were determined to be factors affecting the incidence of HCC. Regarding the follow-up rate, 89.9% of patients continued to regularly visit the hospital after 5 years of treatment. However, patients ≤60 years old had significantly lower persistence rates than older patients. The persistence rate of hospital visits to the same institution was 67.7% over a 5-year period, which was significantly better in small and medium-sized institutions than in large, specialized institutions (71.7% vs. 63.9%, p=0.039). Conclusion Patients with direct-acting antiviral treatment generally received adequate follow-up, but younger patients had a slightly higher rate of follow-up interruption and were considered to need support.
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Affiliation(s)
- Hiroki Tojima
- Department of Gastroenterology and Hepatology, Gunma University Graduate School of Medicine, Japan
| | - Satoru Kakizaki
- Department of Gastroenterology and Hepatology, Gunma University Graduate School of Medicine, Japan
- Department of Clinical Research, National Hospital Organization Takasaki General Medical Center, Japan
| | | | - Takashi Hoshino
- Department of Gastroenterology, National Hospital Organization Takasaki General Medical Center, Japan
| | - Atsushi Naganuma
- Department of Gastroenterology, National Hospital Organization Takasaki General Medical Center, Japan
| | - Tamon Nagashima
- Department of Gastroenterology, National Hospital Organization Shibukawa Medical Center, Japan
| | - Masashi Namikawa
- Department of Internal Medicine, Kiryu Kosei General Hospital, Japan
| | - Takashi Ueno
- Department of Internal Medicine, Isesaki Municipal Hospital, Japan
| | - Yasushi Shimada
- Department of Internal Medicine, Isesaki Municipal Hospital, Japan
| | - Takeshi Hatanaka
- Department of Gastroenterology, Gunma Saiseikai Maebashi Hospital, Japan
| | - Daichi Takizawa
- Department of Gastroenterology, Maebashi Red Cross Hospital, Japan
| | - Hirotaka Arai
- Department of Gastroenterology, Maebashi Red Cross Hospital, Japan
| | - Ken Sato
- Department of Gastroenterology and Hepatology, Gunma University Graduate School of Medicine, Japan
| | - Hitoshi Takagi
- Department of Gastroenterology, Kusunoki Hospital, Japan
| | - Toshio Uraoka
- Department of Gastroenterology and Hepatology, Gunma University Graduate School of Medicine, Japan
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Lim YS, Nguyen LP, Lee GH, Lee SG, Lyoo KS, Kim B, Hwang SB. Asunaprevir, a Potent Hepatitis C Virus Protease Inhibitor, Blocks SARS-CoV-2 Propagation. Mol Cells 2021; 44:688-695. [PMID: 34518443 PMCID: PMC8490202 DOI: 10.14348/molcells.2021.0076] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Revised: 07/19/2021] [Accepted: 07/20/2021] [Indexed: 11/27/2022] Open
Abstract
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has become a global health concern. Various SARS-CoV-2 vaccines have been developed and are being used for vaccination worldwide. However, no therapeutic agents against coronavirus disease 2019 (COVID-19) have been developed so far; therefore, new therapeutic agents are urgently needed. In the present study, we evaluated several hepatitis C virus direct-acting antivirals as potential candidates for drug repurposing against COVID-19. Theses include asunaprevir (a protease inhibitor), daclatasvir (an NS5A inhibitor), and sofosbuvir (an RNA polymerase inhibitor). We found that asunaprevir, but not sofosbuvir and daclatasvir, markedly inhibited SARS-CoV-2-induced cytopathic effects in Vero E6 cells. Both RNA and protein levels of SARS-CoV-2 were significantly decreased by treatment with asunaprevir. Moreover, asunaprevir profoundly decreased virion release from SARS-CoV-2-infected cells. A pseudoparticle entry assay revealed that asunaprevir blocked SARS-CoV-2 infection at the binding step of the viral life cycle. Furthermore, asunaprevir inhibited SARS-CoV-2 propagation in human lung Calu-3 cells. Collectively, we found that asunaprevir displays broad-spectrum antiviral activity and therefore might be worth developing as a new drug repurposing candidate for COVID-19.
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Affiliation(s)
- Yun-Sook Lim
- Laboratory of RNA Viral Diseases, Korea Zoonosis Research Institute, Jeonbuk National University, Iksan 54531, Korea
| | - Lap P. Nguyen
- Laboratory of RNA Viral Diseases, Korea Zoonosis Research Institute, Jeonbuk National University, Iksan 54531, Korea
- Ilsong Institute of Life Science, Hallym University, Seoul 07247, Korea
| | - Gun-Hee Lee
- Korea Zoonosis Research Institute, Jeonbuk National University, Iksan 54531, Korea
| | - Sung-Geun Lee
- Korea Zoonosis Research Institute, Jeonbuk National University, Iksan 54531, Korea
| | - Kwang-Soo Lyoo
- Korea Zoonosis Research Institute, Jeonbuk National University, Iksan 54531, Korea
| | - Bumseok Kim
- College of Veterinary Medicine, Jeonbuk National University, Iksan 54531, Korea
| | - Soon B. Hwang
- Laboratory of RNA Viral Diseases, Korea Zoonosis Research Institute, Jeonbuk National University, Iksan 54531, Korea
- Ilsong Institute of Life Science, Hallym University, Seoul 07247, Korea
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Yoneyama H, Morishita A, Iwama H, Fujita K, Masaki T, Tani J, Tadokoro T, Nomura T, Sakamoto T, Oura K, Takuma K, Nakahara M, Mimura S, Deguchi A, Oryu M, Tsutsui K, Himoto T, Shimotohno K, Wakita T, Kobara H, Masaki T. Identification of microRNA associated with the elimination of hepatitis C virus genotype 1b by direct-acting antiviral therapies. J Gastroenterol Hepatol 2021; 36:1126-1135. [PMID: 32839985 DOI: 10.1111/jgh.15224] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2019] [Revised: 08/06/2020] [Accepted: 08/12/2020] [Indexed: 12/15/2022]
Abstract
BACKGROUND AND AIM Direct-acting antiviral (DAA) therapies have been proven to be highly effective for the eradication of hepatitis C virus (HCV) without resistance-associated substitutions (RASs). However, even in cases with no detected RASs, treatment sometimes fails, suggestive of the existence of some host-related factors involved in HCV eradication by DAAs. To explore such factors, we analyzed the serum microRNAs (miRNAs) of patients who received DAA treatment. METHODS The serum miRNA expression levels of 39 patients with chronic HCV infection without any detectable RASs, who achieved sustained virological response with asunaprevir/daclatasvir or grazoprevir/elbasvir therapy, were investigated cyclopedically, using oligonucleotide microarrays. The effects of specific miRNAs on the replication of HCV were measured in the HCV genomic replicon containing Huh-7 hepatoma cells. RESULTS Along with the disappearance of HCV, the expression quantiles of 16 miRNAs in the asunaprevir/daclatasvir group and 18 miRNAs in the grazoprevir/elbasvir group showed a tendency to increase or decrease. Among these molecules, adjustments for multiple testing yielded a significant differential expression at a false discovery rate of less than 5% for only one molecule, hsa-miR-762. Its expression quantile increased after HCV exclusion in all patients who had achieved sustained virological response. Quantitative polymerase chain reaction analysis validated a significant increase in the serum hsa-miR-762 after disappearance of HCV. On the contrary, hsa-miR-762 was decreased in the relapse and breakthrough of HCV in DAA failures. Transfection of hsa-miR-762 into cultured HCV-infected hepatocytes significantly decreased HCV-RNA replication. CONCLUSION These data suggest that hsa-miR-762 is one of the host factors participating in HCV exclusion by DAA therapy.
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Affiliation(s)
- Hirohito Yoneyama
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki, Kagawa, Japan
| | - Asahiro Morishita
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki, Kagawa, Japan
| | - Hisakazu Iwama
- Life Science Research Center, Kagawa University, Miki, Kagawa, Japan
| | - Koji Fujita
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki, Kagawa, Japan
| | - Takahiro Masaki
- Department of Laboratory Medicine, Jikei University School of Medicine, Tokyo, Japan
| | - Joji Tani
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki, Kagawa, Japan
| | - Tomoko Tadokoro
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki, Kagawa, Japan
| | - Takako Nomura
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki, Kagawa, Japan
| | - Teppei Sakamoto
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki, Kagawa, Japan
| | - Kyoko Oura
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki, Kagawa, Japan
| | - Kei Takuma
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki, Kagawa, Japan
| | - Mai Nakahara
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki, Kagawa, Japan
| | - Shima Mimura
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki, Kagawa, Japan
| | - Akihiro Deguchi
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki, Kagawa, Japan
| | - Makoto Oryu
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki, Kagawa, Japan
| | - Kunihiko Tsutsui
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki, Kagawa, Japan
| | - Takashi Himoto
- Department of Medical Technology, Kagawa Prefectural University of Health Sciences, Takamatsu, Kagawa, Japan
| | - Kunitada Shimotohno
- Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Chiba, Japan
| | - Takaji Wakita
- Department of Virology II, National Institute of Infectious Diseases, Toyama, Tokyo, Japan
| | - Hideki Kobara
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki, Kagawa, Japan
| | - Tsutomu Masaki
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki, Kagawa, Japan
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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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Tsai MC, Hung CH, Lu SN, Wang JH, Chen CH, Kee KM, Chang KC, Chao TL, Hu TH. The incidence of resistance-associated variants to NS5A in HCV subtypes 1a and 1b in Taiwan. Biomed J 2020; 44:S126-S131. [PMID: 35123932 PMCID: PMC9038949 DOI: 10.1016/j.bj.2020.08.004] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2018] [Revised: 01/01/2020] [Accepted: 08/06/2020] [Indexed: 11/23/2022] Open
Abstract
Background Resistance-associated variants (RAVs) to direct-antiviral agents (DAAs) may hamper treatment. There was a lack of data on the natural prevalence of RAVs in Taiwanese HCV-infected patients. We investigated the real-life presence of RAVs in the nonstructural 5A (NS5A) region in HCV genotype 1a and 1b in chronically infected individuals in Taiwan. Methods In this single-center cohort study, nested polymerase chain reaction and direct sequencing analysis was used to determine the frequency of RAVs in the HCV NS5A region in patients with HCV genotype 1a (n = 55) and 1b (n = 525). Results In genotype 1a strains, the incidence of RAVs was 16.4% (9/55) in the NS5A region (M28V/T, n = 6, 10.9%; Q30L, n = 1, 1.8%; Y93N/H, n = 3, 5.5%). In genotype 1b, the incidence of RAVs was 17.5% (92/525) in the NS5A region (L31I/M/V, n = 7, 1.3%; Y93 H/S, n = 87, 16.5%). Patients with RAVs had significantly higher HCV RNA levels (6.1 ± 0.7 vs 5.9 ± 0.8 log IU/mL, p = 0.001) and lower rGT levels (28.9 ± 18.9 vs. 42.9 ± 57.0 U/L, p = 0.001) compared to those without RAVs. Multivariate analysis identified HCV RNA levels (odds ratio = 1.145, 95% CI: 1.060–1.237, p = 0.001) and rGT (OR = 0.989, 95% CI: 0.978–0.999, p = 0.035) as risk factors that are associated with the presence of RAVs. Importantly, there is no association between the presence of RAVs and no SVR (3.8% in patients with RAVs, 15.9% in patients without RAVs, p = 0.32). Conclusion RAVs, especially M28V and Y93H in the NS5A region, were highly prevalent in patients with genotype 1a and 1b HCV, respectively, in Taiwan, and they were linked to high HCV RNA levels and low rGT levels. Before using the NS5A inhibitors, the presence of mutated HCV variants should be taken into consideration.
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Pre-existing minor variants with NS5A L31M/V-Y93H double substitution are closely linked to virologic failure with asunaprevir plus daclatasvir treatment for genotype 1b hepatitis C virus infection. PLoS One 2020; 15:e0234811. [PMID: 32544182 PMCID: PMC7297368 DOI: 10.1371/journal.pone.0234811] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2020] [Accepted: 06/02/2020] [Indexed: 12/15/2022] Open
Abstract
Background L31 and Y93 in the NS5A region of the hepatitis C virus (HCV) are the most important substitution positions associated with resistance to direct-acting antiviral (DAA) treatment. Methods We analyzed the frequency of NS5A L31M/V and Y93/H in NS5A inhibitor-naive HCV genotype 1 patients who received asunaprevir plus daclatasvir combination treatment using a conventional sequencing method and a deep sequencing method that can distinguish a single substitution at either position and a double substitution at both positions with a 0.1% detection threshold. Results The frequency of substitutions at both sites using the conventional method was very low, with 1 in 14 non-responders and 0 in 42 randomly selected responder patients. On the other hand, for the deep sequencing method, cases with double substitutions in the tandem sequence were detected in 8/14 non-responders and 1/42 responders (p<0.0001). For the conventional method, substitutions were detected at any position in 6/14 non-responders and 2/42 responders (p = 0.0019), with a clear difference between the two groups. The difference was also clear with the deep sequencing method, with 11/14 non-responders and 8/42 responders. Interestingly, for the deep sequencing method, the single substitution of L31 was found in 6/14 non-responders and 7/42 responders, whereas single substitutions of Y93 or double substitutions were found in 7/14 vs. 1/42 and 8/14 vs. 1/42 patients, respectively. Conclusions NS5A L31 and Y93 substitutions were detected in tandem by the deep sequencing methods in several genotype 1 patients, who may be more resistant to DAA treatment containing an NS5A inhibitor.
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Tojima H, Kakizaki S, Takakusagi S, Hoshino T, Naganuma A, Nagashima T, Namikawa M, Ueno T, Shimada Y, Hatanaka T, Takizawa D, Arai H, Sato K, Takagi H, Uraoka T. Favorable outcome of retreatment by direct-acting antivirals for hepatitis C patients with daclatasvir plus asunaprevir combination therapy failure. Hepatol Res 2020; 50:303-312. [PMID: 31750974 DOI: 10.1111/hepr.13462] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2019] [Revised: 10/23/2019] [Accepted: 11/01/2019] [Indexed: 12/13/2022]
Abstract
AIM In patients with hepatitis C virus, treatment failure of daclatasvir plus asunaprevir combination therapy (DCV + ASV) seems to become intractable due to the induction of resistance-associated substitutions. This study aimed to investigate the outcomes of retreatment with direct-acting antivirals (DAAs) in patients with DCV + ASV therapy failure, as well as changes in drug resistance mutations. METHODS We retrospectively analyzed 44 patients re-treated with DAAs after DCV + ASV failure between December 2015 and April 2018. All patients were analyzed for amino acid substitutions, and additional treatment regimens were selected based on the results and current treatment guidelines. RESULTS The sustained virological response rate with second-line treatment was 81.8% (36/44), and relapse occurred in five of 16 patients who received sofosbuvir/ledipasvir and three of seven patients who received DCV/ASV/beclabuvir. Third- and fourth-line treatments were also tried in relapsed cases, and the overall sustained virological response rates were 90.9% (40/44) and 93.2% (41/44), respectively. A high rate of viral clearance was eventually observed. Before second-line treatment, the prevalence of mutations in the NS5A and NS3/4A regions was 100% (44/44) and 86.4% (38/44), respectively. There was no significant increase in the number of amino acid substitutions in patients for whom second-line treatment failed. CONCLUSIONS Amino acid substitutions were frequently observed in patients with DCV + ASV failure, but most patients achieved a sustained virological response after retreatment with DAAs. Although the spread of drug-resistant viruses due to unsuccessful DAA treatment was a matter of concern, most cases of DCV + ASV failure were overcome with additional treatment.
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Affiliation(s)
- Hiroki Tojima
- Department of Gastroenterology and Hepatology, Gunma University Graduate School of Medicine, Maebashi, Japan
| | - Satoru Kakizaki
- Department of Gastroenterology and Hepatology, Gunma University Graduate School of Medicine, Maebashi, Japan
| | | | - Takashi Hoshino
- Department of Gastroenterology, National Hospital Organization Takasaki General Medical Center, Takasaki, Japan
| | - Atsushi Naganuma
- Department of Gastroenterology, National Hospital Organization Takasaki General Medical Center, Takasaki, Japan
| | - Tamon Nagashima
- Department of Gastroenterology, National Hospital Organization Shibukawa Medical Center, Shibukawa, Japan
| | - Masashi Namikawa
- Department of Internal Medicine, Kiryu Kosei General Hospital, Kiryu, Japan
| | - Takashi Ueno
- Department of Internal Medicine, Isesaki Municipal Hospital, Isesaki, Japan
| | - Yasushi Shimada
- Department of Internal Medicine, Isesaki Municipal Hospital, Isesaki, Japan
| | - Takeshi Hatanaka
- Department of Gastroenterology, Gunma Saiseikai Maebashi Hospital, Maebashi, Japan
| | - Daichi Takizawa
- Department of Gastroenterology, Maebashi Red Cross Hospital, Maebashi, Japan
| | - Hirotaka Arai
- Department of Gastroenterology, Maebashi Red Cross Hospital, Maebashi, Japan
| | - Ken Sato
- Department of Gastroenterology and Hepatology, Gunma University Graduate School of Medicine, Maebashi, Japan
| | - Hitoshi Takagi
- Department of Gastroenterology, Kusunoki Hospital, Fujioka, Japan
| | - Toshio Uraoka
- Department of Gastroenterology and Hepatology, Gunma University Graduate School of Medicine, Maebashi, Japan
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Mashiba T, Joko K, Kurosaki M, Ochi H, Hasebe C, Akahane T, Sohda T, Tsuji K, Mitsuda A, Kimura H, Narita R, Ogawa C, Furuta K, Shigeno M, Okushin H, Ito H, Kusakabe A, Satou T, Kawanami C, Nakata R, Kobashi H, Tamada T, Ide Y, Yagisawa H, Morita A, Matsushita T, Okada K, Izumi N. Real-world efficacy of elbasvir and grazoprevir for hepatitis C virus (genotype 1): A nationwide, multicenter study by the Japanese Red Cross Hospital Liver Study Group. Hepatol Res 2019; 49:1114-1120. [PMID: 31077527 PMCID: PMC6899599 DOI: 10.1111/hepr.13362] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2019] [Revised: 04/23/2019] [Accepted: 05/04/2019] [Indexed: 12/13/2022]
Abstract
AIM The present study aimed to determine the real-world efficacy and safety of the non-structural protein (NS)5A inhibitor elbasvir (EBR) combined with the NS3/4A protease inhibitor grazoprevir (GZR) in patients with hepatitis C virus (HCV) genotype 1 (GT1) infection. METHODS This study retrospectively evaluated the rate of sustained virologic response at 12 weeks post-treatment (SVR12) and the safety of EBR/GZR treatment in 159 men and 194 women with a median age of 72 years, and it assessed factors associated with the SVR12 rate. The attending physicians were responsible for selecting candidate patients for EBR/GZR in this retrospective study. RESULTS Treatment outcomes for EBR/GZR were good in direct-acting antiviral (DAA)-naïve patients, of whom 99.4% achieved SVR. Of 353 patients, 10 (2.9%) had treatment failure. Of these patients, eight previously underwent DAA therapy, and the remaining two had NS5A-L31/Y93 double mutation. The SVR rate was 50% (8/16 patients) in patients who previously underwent DAA therapy, and 18.2% (2/11 patients) in patients with NS5A-L31/Y93 double mutation. On multivariate logistic regression analysis, NS5A-Y31/Y93 double mutation (odds ratio 356.3; 95% confidence interval, 23.91-16 940; P < 0.0001) was identified as an independent predictor of treatment failure. No serious adverse events were observed with EBR/GZR therapy. CONCLUSIONS The SVR rate of EBR/GZR would have been 100% in patients without either a history of DAA therapy or double mutation. This combination of drugs could be safely given and is, thus, considered a highly useful first-line treatment for DAA-naïve patients with HCV.
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Affiliation(s)
- Toshie Mashiba
- Center for Liver‐Biliary‐Pancreatic DiseaseMatsuyama Red Cross HospitalEhimeJapan
| | - Kouji Joko
- Center for Liver‐Biliary‐Pancreatic DiseaseMatsuyama Red Cross HospitalEhimeJapan
| | - Masayuki Kurosaki
- Department of Gastroenterology and HepatologyMusashino Red Cross HospitalTokyoJapan
| | - Hironori Ochi
- Center for Liver‐Biliary‐Pancreatic DiseaseMatsuyama Red Cross HospitalEhimeJapan
| | - Chitomi Hasebe
- Department of GastroenterologyJapanese Red Cross Asahikawa HospitalHokkaidoJapan
| | - Takehiro Akahane
- Department of GastroenterologyIshinomaki Red Cross HospitalMiyagiJapan
| | - Tetsuro Sohda
- Hepatology DivisionJapanese Red Cross Fukuoka HospitalFukuokaJapan
| | - Keiji Tsuji
- Department of GastroenterologyHiroshima Red Cross Hospital and Atomic‐bomb Survivors HospitalHiroshimaJapan
| | - Akeri Mitsuda
- Department of Internal MedicineJapanese Red Cross Tottori HospitalTottoriJapan
| | - Hiroyuki Kimura
- Department of GastroenterologyJapanese Red Cross Kyoto Daiichi HospitalKyotoJapan
| | - Ryoichi Narita
- Department of GastroenterologyOita Red Cross HospitalOitaJapan
| | - Chikara Ogawa
- Department of GastroenterologyTakamatsu Red Cross HospitalKagawaJapan
| | - Koichiro Furuta
- Department of Internal MedicineMasuda Red Cross HospitalShimaneJapan
| | - Masaya Shigeno
- Department of GastroenterologyJapanese Red Cross Nagasaki Genbaku HospitalNagasakiJapan
| | - Hiroaki Okushin
- Department of GastroenterologyJapanese Red Cross Society Himeji HospitalHyogoJapan
| | - Hiroshi Ito
- Department of GastroenterologyFukaya Red Cross HospitalSaitamaJapan
| | - Atsunori Kusakabe
- Department of GastroenterologyJapanese Red Cross Nagoya Daini HospitalNagoyaAichiJapan
| | - Takashi Satou
- Department of GastroenterologyNasu Red Cross HospitalTochigiJapan
| | | | - Ryo Nakata
- Department of GastroenterologyJapanese Red Cross Medical CenterTokyoJapan
| | - Haruhiko Kobashi
- Department of GastroenterologyJapanese Red Cross Okayama HospitalOkayamaJapan
| | - Takashi Tamada
- Department of GastroenterologyTakatsuki Red Cross HospitalTakatsukiJapan
| | - Yasushi Ide
- Department of Internal MedicineKaratsu Red Cross HospitalSagaJapan
| | - Hitoshi Yagisawa
- Department of GastroenterologyJapanese Red Cross Akita HospitalAkitaJapan
| | - Atsuhiro Morita
- Department of GastroenterologyJapanese Red Cross Kyoto Daini HospitalKyotoJapan
| | | | - Kazuhiko Okada
- Department of GastroenterologyToyama Red Cross HospitalToyamaJapan
| | - Namiki Izumi
- Department of Gastroenterology and HepatologyMusashino Red Cross HospitalTokyoJapan
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12
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Sofia MJ. The Discovery and Development of Daclatasvir: An Inhibitor of the Hepatitis C Virus NS5A Replication Complex. ACTA ACUST UNITED AC 2019. [PMCID: PMC7122418 DOI: 10.1007/7355_2018_47] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
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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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14
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Yeh TK, Kang IJ, Hsu TA, Lee YC, Lee CC, Hsu SJ, Tian YW, Yang HY, Chen CT, Chao YS, Yueh A, Chern JH. A novel, potent, and orally bioavailable thiazole HCV NS5A inhibitor for the treatment of hepatitis C virus. Eur J Med Chem 2019; 167:245-268. [PMID: 30772607 DOI: 10.1016/j.ejmech.2019.02.016] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2018] [Revised: 02/02/2019] [Accepted: 02/04/2019] [Indexed: 12/24/2022]
Abstract
A medicinal chemistry program based on the small-molecule HCV NS5A inhibitor daclatasvir has led to the discovery of dimeric phenylthiazole compound 8, a novel and potent HCV NS5A inhibitor. The subsequent SAR studies and optimization revealed that the cycloalkyl amide derivatives 27a-29a exhibited superior potency against GT1b with GT1b EC50 values at picomolar concentration. Interestingly, high diastereospecificity for HCV inhibition was observed in this class with the (1R,2S,1'R,2'S) diastereomer displaying the highest GT1b inhibitory activity. The best inhibitor 27a was found to be 3-fold more potent (GT1b EC50 = 0.003 nM) than daclatasvir (GT1b EC50 = 0.009 nM) against GT1b, and no detectable in vitro cytotoxicity was observed (CC50 > 50 μM). Pharmacokinetic studies demonstrated that compound 27a had an excellent pharmacokinetic profiles with a superior oral exposure and desired bioavailability after oral administration in both rats and dogs, and therefore it was selected as a developmental candidate for the treatment of HCV infection.
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Affiliation(s)
- Teng-Kuang Yeh
- Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 350, Taiwan, ROC
| | - Iou-Jiun Kang
- Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 350, Taiwan, ROC
| | - Tsu-An Hsu
- Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 350, Taiwan, ROC
| | - Yen-Chun Lee
- Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 350, Taiwan, ROC
| | - Chung-Chi Lee
- Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 350, Taiwan, ROC
| | - Sheng-Ju Hsu
- Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 350, Taiwan, ROC
| | - Ya-Wen Tian
- Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 350, Taiwan, ROC
| | - Hui-Yun Yang
- Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 350, Taiwan, ROC
| | - Chiung-Tong Chen
- Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 350, Taiwan, ROC
| | - Yu-Sheng Chao
- Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 350, Taiwan, ROC
| | - Andrew Yueh
- Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 350, Taiwan, ROC
| | - Jyh-Haur Chern
- Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 350, Taiwan, ROC.
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15
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Ueno T, Osawa M, Shiozaki T, Green M, Garimella T. Exposure-Response Analysis for Efficacy of Daclatasvir, Asunaprevir, and Beclabuvir Combinations in HCV-Infected Patients. Clin Pharmacol Drug Dev 2019; 8:903-913. [PMID: 30667592 DOI: 10.1002/cpdd.646] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2018] [Accepted: 12/03/2018] [Indexed: 12/21/2022]
Abstract
The combination regimen of daclatasvir, asunaprevir, and beclabuvir (3DAA regimen) was developed as a fixed-dose combination for the treatment of hepatitis C virus (HCV) infection in Japan. The objectives of this analysis were to characterize the relationship between drug exposure and sustained virologic response at posttreatment week 12 (SVR12) in HCV-infected subjects and to evaluate the impact of demographic covariates and clinical factors on the exposure-response (E-R) relationship. The E-R efficacy analysis was performed with data from phase 2 and phase 3 studies in HCV-infected subjects treated with the 3DAA regimen. The relationship between the probability of achieving SVR12 and exposure to daclatasvir, asunaprevir, and beclabuvir was described using a logistic regression model and included assessments of the potential covariate effects. The impacts of the covariates on the rate of SVR12 and interactions of covariates with the individual drug effects were tested. The final model for SVR12 included effects of non-genotype-1a status, resistance-associated NS5A-Q30 substitution in genotype-1a subjects, and baseline RNA level on the intercept, and effect of prior peg-interferon failure on the beclabuvir slope. Sex, race, age, weight, fibrosis score, alanine transaminase, and cirrhosis status had no statistically significant impact on the rate of SVR12. The individual E-R relationships with each drug, were relatively flat, and the effects of exposure were not significant. With the exception of the NS5A-Q30 substitution in genotype-1a subjects, statistically significant covariate effects had little impact on SVR12 rates. Overall, the E-R model was developed that captured the high SVR12 rates and the effect of covariates for the 3DAA regimen in HCV-infected patients.
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Affiliation(s)
- T Ueno
- Bristol-Myers Squibb KK, Tokyo, Japan
| | - M Osawa
- Bristol-Myers Squibb KK, Tokyo, Japan
| | | | - M Green
- Certara, Menlo Park, CA, USA
| | - T Garimella
- Bristol-Myers Squibb Research and Development, Lawrenceville, NJ, USA
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16
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Sofia MJ. The Discovery and Early Clinical Evaluation of the HCV NS3/4A Protease Inhibitor Asunaprevir (BMS-650032). TOPICS IN MEDICINAL CHEMISTRY 2019. [PMCID: PMC7123690 DOI: 10.1007/7355_2018_58] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/02/2022]
Abstract
The discovery of asunaprevir (1) began with the concept of engaging the small and well-defined S1’ pocket of the hepatitis C virus (HCV) NS3/4A protease that was explored in the context of tripeptide carboxylic acid-based inhibitors. A cyclopropyl-acyl sulfonamide moiety was found to be the optimal element at the P1-P1’ interface enhancing the potency of carboxylic acid-based prototypes by 10- to >100-fold, dependent upon the specific background. Optimization for oral bioavailability identified a 1-substituted isoquinoline-based P2* element that conferred a significant exposure advantage in rats compared to the matched 4-substituted quinoline isomer. BMS-605339 (30) was the first cyclopropyl-acyl sulfonamide derivative advanced into clinical trials that demonstrated dose-related reductions in plasma viral RNA in HCV-infected patients. However, 30 was associated with cardiac events observed in a normal healthy volunteer (NHV) and an HCV-infected patient that led to the suspension of the development program. Using a Langendorff rabbit heart model, a limited structure-cardiac liability relationship was quickly established that led to the discovery of 1. This compound, which differs from 30 only by changes in the substitution pattern of the P2* isoquinoline heterocycle and the addition of a single chlorine atom to the molecular formula, gave a dose-dependent reduction in plasma viral RNA following oral administration to HCV-infected patients without the burden of the cardiac events that had been observed with 30. A small clinical trial of the combination of 1 with the HCV NS5A inhibitor daclatasvir (2) established for the first time that a chronic genotype 1 (GT-1) HCV infection could be cured by therapy with two direct-acting antiviral agents in the absence of exogenous immune-stimulating agents. Development of the combination of 1 and 2 was initially focused on Japan where the patient population is predominantly infected with GT-1b virus, culminating in marketing approval which was granted on July 4, 2014. In order to broaden therapy to include GT-1a infections, a fixed dose triple combination of 1, 2, and the allosteric NS5B inhibitor beclabuvir (3) was developed, approved by the Japanese health authorities for the treatment of HCV GT-1 infection on December 20, 2016 and marketed as Ximency®.
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17
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Liverton NJ. Evolution of HCV NS3/4a Protease Inhibitors. TOPICS IN MEDICINAL CHEMISTRY 2019. [DOI: 10.1007/7355_2018_39] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
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Sagnelli E, Starace M, Minichini C, Pisaturo M, Macera M, Sagnelli C, Coppola N. Resistance detection and re-treatment options in hepatitis C virus-related chronic liver diseases after DAA-treatment failure. Infection 2018; 46:761-783. [PMID: 30084057 DOI: 10.1007/s15010-018-1188-3] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2018] [Accepted: 07/30/2018] [Indexed: 12/12/2022]
Abstract
BACKGROUND Introduced in 2013-2014, the second- and third-wave directly acting antivirals (DAAs) have strongly enhanced the efficacy and tolerability of anti-HCV treatment, with a sustained virological response (SVR) in 90-95% of cases treated. The aim of this paper was to focus on the type and prevalence of viral strains with a reduced sensitivity to DAAs and on treatment choices for DAA-experienced patients. METHODS The Medline was searched for "HCV infection", "HCV treatment", "Directly acting antivirals","HCV resistance". RESULTS Most patients who did not achieve an SVR have been found to be infected with HCV mutant strains with a reduced susceptibility to these drugs. These mutants occur frequently in the NS5A region, with a moderate frequency in the NS3/4A regions and rarely in the NS5B region. Treatment-induced mutants resistant to NS5A DAAs persist for years after treatment discontinuation, whereas those resistant to the NS3 DAAs have a shorter duration. CONCLUSIONS Patients who have failed HCV treatment with DAA agents have several re-treatment options, but re-treatment selection may be intricate and resistance testing is recommended to optimize this choice. It is, therefore, important to bear in mind that the correct determination of HCV genotype and subtype and the identification of RASs are essential elements for choosing the optimal re-treatment. It is supposed that it is useful to give readers some other suggestions regarding therapeutic reprocessing.
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Affiliation(s)
- Evangelista Sagnelli
- Section of Infectious Diseases, Department of Mental Health and Public Medicine, University of Campania Luigi Vanvitelli, Via: L. Armanni 5, 80131, Naples, Italy.
| | - Mario Starace
- Section of Infectious Diseases, Department of Mental Health and Public Medicine, University of Campania Luigi Vanvitelli, Via: L. Armanni 5, 80131, Naples, Italy
| | - Carmine Minichini
- Section of Infectious Diseases, Department of Mental Health and Public Medicine, University of Campania Luigi Vanvitelli, Via: L. Armanni 5, 80131, Naples, Italy
| | - Mariantonietta Pisaturo
- Section of Infectious Diseases, Department of Mental Health and Public Medicine, University of Campania Luigi Vanvitelli, Via: L. Armanni 5, 80131, Naples, Italy
| | - Margherita Macera
- Section of Infectious Diseases, Department of Mental Health and Public Medicine, University of Campania Luigi Vanvitelli, Via: L. Armanni 5, 80131, Naples, Italy
| | - Caterina Sagnelli
- Section of Infectious Diseases, Department of Mental Health and Public Medicine, University of Campania Luigi Vanvitelli, Via: L. Armanni 5, 80131, Naples, Italy
| | - Nicola Coppola
- Section of Infectious Diseases, Department of Mental Health and Public Medicine, University of Campania Luigi Vanvitelli, Via: L. Armanni 5, 80131, Naples, Italy
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19
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Minosse C, Selleri M, Giombini E, Bartolini B, Capobianchi MR, Cerilli S, Loiacono L, Taibi C, D'Offizi G, McPhee F, Garbuglia A. Clinical and virological properties of hepatitis C virus genotype 4 infection in patients treated with different direct-acting antiviral agents. Infect Drug Resist 2018; 11:2117-2127. [PMID: 30464554 PMCID: PMC6223400 DOI: 10.2147/idr.s179158] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Background The efficacy of direct-acting antivirals (DAAs) depends on the hepatitis C virus (HCV) genotype 4 (GT4) subtype which are used in the treatment of HCV. We aimed to retrospectively investigate the baseline prevalence of HCV NS5A and NS5B polymorphisms and their impact on virological outcome in GT4-infected patients treated with various DAA regimens. Patients and methods Available plasma samples from HCV GT4-infected patients treated with different DAA regimens were analyzed at baseline and after treatment failure, where applicable. Sanger sequencing of patient-derived NS5A and NS5B regions was performed on all available samples, while ultradeep pyrosequencing (UDPS) of NS5A and NS5B regions was performed only on samples from treatment failures at different time points. Results Sustained virological response (SVR) was achieved by 96% (48/50) of patients. Of 16 patients with baseline NS5A sequence, polymorphisms at amino acid positions associated with drug resistance were detected only at position 58: P58 (69.2%) and T58 (30.8%). Of 21 patients with baseline NS5B sequence, N142S was detected only in the two treatment failures, both with GT4d were treated with sofosbuvir (SOF)-based regimens, suggesting a potential involvement in SOF efficacy. Two patients (patient 1 [Pt1] and patient 2 [Pt2]) relapsed. In Pt1, NS5A-T56I and NS5A-Y93H/S emerged. In Pt2, NS5A-L28F emerged and a novel NS5B resistance-associated substitution (RAS), L204F, representing 1.5% of the viral population at baseline, enriched to 71% and 91.6% during and after treatment failure, respectively. UDPS of NS5B from Pt2 indicated a mixed infection of approximately 1:5, GT1a:GT4d, at baseline and GT4d during failure. Phylogenetic analysis of NS5A sequences indicated no clustering of HCV strains from patients achieving SVR vs patients who relapsed. The mean genetic distance in NS5A sequences was 5.8%, while a lower genetic distance (3.1%) was observed in NS5B sequences. Conclusion Results from these analyses confirm the importance of UDPS in the analysis of viral quasispecies variability and the identification of novel RASs potentially associated with DAA treatment failure in HCV GT4-infected patients.
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Affiliation(s)
- Claudia Minosse
- Department of Pre-clinical Research Epidemiology and Advanced Diagnostics, Laboratory of Virology, National Institute for Infectious Diseases "Lazzaro Spallanzani" - IRCCS, Rome, Italy
| | - Marina Selleri
- Department of Pre-clinical Research Epidemiology and Advanced Diagnostics, Laboratory of Virology, National Institute for Infectious Diseases "Lazzaro Spallanzani" - IRCCS, Rome, Italy
| | - Emanuela Giombini
- Department of Pre-clinical Research Epidemiology and Advanced Diagnostics, Laboratory of Virology, National Institute for Infectious Diseases "Lazzaro Spallanzani" - IRCCS, Rome, Italy
| | - Barbara Bartolini
- Department of Pre-clinical Research Epidemiology and Advanced Diagnostics, Laboratory of Virology, National Institute for Infectious Diseases "Lazzaro Spallanzani" - IRCCS, Rome, Italy
| | - Maria Rosaria Capobianchi
- Department of Pre-clinical Research Epidemiology and Advanced Diagnostics, Laboratory of Virology, National Institute for Infectious Diseases "Lazzaro Spallanzani" - IRCCS, Rome, Italy
| | - Stefano Cerilli
- Clinical Department, Infectious Disease-Hepatology Unit, National Institute for Infectious Diseases, "Lazzaro Spallanzani" - IRCCS, Rome, Italy,
| | - Laura Loiacono
- Clinical Department, Infectious Disease-Hepatology Unit, National Institute for Infectious Diseases, "Lazzaro Spallanzani" - IRCCS, Rome, Italy,
| | - Chiara Taibi
- Clinical Department, Infectious Disease-Hepatology Unit, National Institute for Infectious Diseases, "Lazzaro Spallanzani" - IRCCS, Rome, Italy,
| | - Gianpiero D'Offizi
- Clinical Department, Infectious Disease-Hepatology Unit, National Institute for Infectious Diseases, "Lazzaro Spallanzani" - IRCCS, Rome, Italy,
| | - Fiona McPhee
- Bristol-Myers Squibb Research and Development, Wallingford, CT, USA
| | - AnnaRosa Garbuglia
- Department of Pre-clinical Research Epidemiology and Advanced Diagnostics, Laboratory of Virology, National Institute for Infectious Diseases "Lazzaro Spallanzani" - IRCCS, Rome, Italy
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Tsuji K, Kurosaki M, Itakura J, Mori N, Takaki S, Hasebe C, Akahane T, Joko K, Yagisawa H, Takezawa J, Nakata R, Kusakabe A, Kojima Y, Kimura H, Tamada T, Kobashi H, Mitsuda A, Kondou M, Ogawa C, Uchida Y, Sohda T, Narita R, Izumi N. Real-world efficacy and safety of ledipasvir and sofosbuvir in patients with hepatitis C virus genotype 1 infection: a nationwide multicenter study by the Japanese Red Cross Liver Study Group. J Gastroenterol 2018; 53:1142-1150. [PMID: 29626296 DOI: 10.1007/s00535-018-1455-1] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2018] [Accepted: 03/23/2018] [Indexed: 02/04/2023]
Abstract
BACKGROUND We aimed to describe the real-world efficacy and safety of combination therapy with ledipasvir and sofosbuvir (LDV/SOF) for chronic hepatitis C virus (HCV) genotype 1 (GT1) infection. METHODS This retrospective analysis of a prospective, nationwide, multicenter registry included GT1-infected patients treated with LDV/SOF for 12 weeks. We assessed the rate of sustained virological response at 12 weeks post-treatment (SVR12), incidence of adverse events, and serum markers of hepatocellular carcinoma (HCC). RESULTS Among the 1461 patients included (mean age, 69 years; 29.5% aged > 75 years; cirrhosis, 23.8%; history of treatment for HCC, 10.9%), the overall SVR12 rate was 98.4% (1438/1461). Factors associated with treatment failure were cirrhosis (odds ratio, 4.19; p = 0.014) and resistance-associated substitutions (RASs) in NS5A at baseline (odds ratio, 7.78; p = 0.0004). The SVR12 rate in patients with cirrhosis and NS5A RASs was 93.0% compared to 100% in patients without cirrhosis or NS5A RASs. In patients with SVR, the levels of alpha-fetoprotein (AFP), AFP-L3, and Mac-2 binding protein glycosylation isomer (M2BPGi) decreased from baseline to end of treatment (from 13.4 ± 37.6 to 6.0 ± 10.6 ng/mL, p < 0.0001; from 2.2 ± 4.9 to 1.5 ± 6.3%, p < 0.005; and from 3.6 ± 3.7 to 2.0 ± 3.5 cut-off index, p < 0.0001; respectively). Adverse events were rare and not associated with age. No decrease in estimated glomerular filtration rate was observed in patients with baseline chronic kidney disease stage 3. CONCLUSIONS LDV/SOF therapy is highly effective and safe in elderly Japanese patients with HCV GT1, even in the presence of cirrhosis or NS5A RASs. Patients with SVR may have a lower risk of HCC.
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Affiliation(s)
- Keiji Tsuji
- Department of Gastroenterology, Hiroshima Red Cross Hospital and Atomic-bomb Survivors Hospital, Hiroshima, Hiroshima, Japan
| | - Masayuki Kurosaki
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, 1-26-1 Kyonan-cho, Musashino-shi, Tokyo, 180-8610, Japan
| | - Jun Itakura
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, 1-26-1 Kyonan-cho, Musashino-shi, Tokyo, 180-8610, Japan
| | - Nami Mori
- Department of Gastroenterology, Hiroshima Red Cross Hospital and Atomic-bomb Survivors Hospital, Hiroshima, Hiroshima, Japan
| | - Shintaro Takaki
- Department of Gastroenterology, Hiroshima Red Cross Hospital and Atomic-bomb Survivors Hospital, Hiroshima, Hiroshima, Japan
| | - Chitomi Hasebe
- Department of Gastroenterology, Japanese Red Cross Asahikawa Hospital, Asahikawa, Hokkaido, Japan
| | - Takehiro Akahane
- Department of Gastroenterology, Japanese Red Cross Ishinomaki Hospital, Ishinomaki, Miyagi, Japan
| | - Kouji Joko
- Center for Liver-Biliary-Pancreatic Disease, Matsuyama Red Cross Hospital, Matsuyama, Ehime, Japan
| | - Hitoshi Yagisawa
- Department of Gastroenterology, Japanese Red Cross Akita Hospital, Akita, Akita, Japan
| | - Jirou Takezawa
- Department of Internal Medicine, Japanese Red Cross Haramachi Hospital, Haramachi, Gunma, Japan
| | - Ryou Nakata
- Department of Gastroenterology, Japanese Red Cross Medical Center, Shibuya-ku, Tokyo, Japan
| | - Atsunori Kusakabe
- Department of Gastroenterology, Japanese Red Cross Nagoya Daini Hospital, Nagoya, Aichi, Japan
| | - Yuji Kojima
- Department of Hepatology, Japanese Red Cross Ise Hospital, Ise, Mie, Japan
| | - Hiroyuki Kimura
- Department of Gastroenterology, Japanese Red Cross Kyoto Daiichi Hospital, Kyoto, Japan
| | - Takashi Tamada
- Department of Gastroenterology, Takatsuki Red Cross Hospital, Takatsuki, Osaka, Japan
| | - Haruhiko Kobashi
- Department of Gastroenterology, Japanese Red Cross Okayama Hospital, Okayama, Okayama, Japan
| | - Akeri Mitsuda
- Department of Gastroenterology, Japanese Red Cross Tottori Hospital, Tottori, Tottori, Japan
| | - Masahiko Kondou
- Department of Gastroenterology, Japanese Red Cross Otsu Hospital, Otsu, Shiga, Japan
| | - Chikara Ogawa
- Department of Gastroenterology, Takamatsu Red Cross Hospital, Takamatsu, Kagawa, Japan
| | - Yasushi Uchida
- Department of Gastroenterology, Matsue Red Cross Hospital, Matsue, Shimane, Japan
| | - Tetsuro Sohda
- Department of Hepatology, Japanese Red Cross Fukuoka Hospital, Fukuoka, Fukuoka, Japan
| | - Ryouichi Narita
- Department of Gastroenterology, Oita Red Cross Hospital, Oita, Oita, Japan
| | - Namiki Izumi
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, 1-26-1 Kyonan-cho, Musashino-shi, Tokyo, 180-8610, Japan.
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Fujii H, Kimura H, Kurosaki M, Hasebe C, Akahane T, Yagisawa H, Kato K, Yoshida H, Itakura J, Sakita S, Satou T, Okada K, Kusakabe A, Kojima Y, Kondo M, Morita A, Nasu A, Tamada T, Okushin H, Kobashi H, Tsuji K, Joko K, Ogawa C, Uchida Y, Mitsuda A, Sohda T, Ide Y, Izumi N. Efficacy of daclatasvir plus asunaprevir in patients with hepatitis C virus infection undergoing and not undergoing hemodialysis. Hepatol Res 2018; 48:746-756. [PMID: 29480939 DOI: 10.1111/hepr.13070] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2017] [Revised: 02/01/2018] [Accepted: 02/17/2018] [Indexed: 02/08/2023]
Abstract
AIM To evaluate the virologic responses and clinical course of daclatasvir plus asunaprevir treatment in non-hemodialysis (non-HD) and hemodialysis (HD) patients infected with genotype 1 hepatitis C virus (HCV). METHODS A total of 1113 non-HD patients and 67 HD patients were assessed. To evaluate pretreatment factors contributing to sustained virological response at 12 weeks (SVR12), univariate and multivariate analyses were carried out. To adjust for differences in patient background, propensity score matching was undertaken. RESULTS The overall SVR12 rates were 91.6% in non-HD patients and 95.5% in HD patients. Compared with non-HD patients, HD patients were younger, were more likely to be male, were less likely to have received interferon-based pretreatment, had a lower viral load, and had lower levels of alanine transaminase, hemoglobin, and α-fetoprotein. Multivariate analysis revealed that viral load, α-fetoprotein, L31 substitution negative, and Y93 substitution negative were independent predictive factors for SVR12 in non-HD patients. The proportion of patients with undetectable HCV-RNA during the initial 4 weeks was significantly higher in HD patients than in non-HD patients. The SVR12 rate was clearly higher in HD patients than in non-HD patients, although the difference was not statistically significant. After propensity score matching to adjust for viral load, α-fetoprotein, L31 substitution, and Y93 substitution, these trends disappeared. CONCLUSIONS For treatment of HCV genotype 1 infection, daclatasvir plus asunaprevir is useful not only in non-HD patients but also in HD patients. Viral load, α-fetoprotein levels, L31 substitution, and Y93 substitution influence treatment course and outcome.
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Affiliation(s)
- Hideki Fujii
- Department of Gastroenterology, Japanese Red Cross Kyoto Daiichi Hospital, Kyoto, Japan
| | - Hiroyuki Kimura
- Department of Gastroenterology, Japanese Red Cross Kyoto Daiichi Hospital, Kyoto, Japan
| | - Masayuki Kurosaki
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Musashino, Japan
| | - Chitomi Hasebe
- Department of Gastroenterology, Asahikawa Red Cross Hospital, Asahikawa, Japan
| | - Takehiro Akahane
- Department of Gastroenterology, Japanese Red Cross Ishinomaki Hospital, Ishinomaki, Japan
| | - Hitoshi Yagisawa
- Department of Gastroenterology, Japanese Red Cross Akita Hospital, Akita, Japan
| | - Keizo Kato
- Department of Gastroenterology, Narita Red Cross Hospital, Narita, Japan
| | - Hideo Yoshida
- Department of Gastroenterology, Japanese Red Cross Medical Center, Tokyo, Japan
| | - Jun Itakura
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Musashino, Japan
| | - Shinya Sakita
- Department of Gastroenterology, Yokohama City Minato Red Cross Hospital, Yokohama, Japan
| | - Takashi Satou
- Department of Gastroenterology, Nasu Red Cross Hospital, Otawara, Tochigi, Japan
| | - Kazuhiko Okada
- Department of Gastroenterology, Toyama Red Cross Hospital, Toyama, Japan
| | - Atsunori Kusakabe
- Department of Gastroenterology, Nagoya Daini Red Cross Hospital, Nagoya, Japan
| | - Yuji Kojima
- Department of Gastroenterology and Hepatology, Japanese Red Cross Ise Hospital, Ise, Japan
| | - Masahiko Kondo
- Department of Gastroenterology, Otsu Red Cross Hospital, Siga, Japan
| | - Atsuhiro Morita
- Department of Gastroenterology, Kyoto Second Red Cross Hospital Gastroenterology, Kyoto, Japan
| | - Akihiro Nasu
- Department of Gastroenterology and Hepatology, Osaka Red Cross Hospital, Osaka, Japan
| | - Takashi Tamada
- Department of Gastroenterology and Hepatology, Takatsuki Red Cross Hospital, Osaka, Japan
| | - Hiroaki Okushin
- Department of Hepatology, Japanese Red Cross Society Himeji Hospital, Himeji, Japan
| | - Haruhiko Kobashi
- Department of Hepatology, Japanese Red Cross Okayama Hospital, Okayama, Japan
| | - Keiji Tsuji
- Department of Gastroenterology, Hiroshima Red Cross Hospital and Atomic-bomb Survivors Hospital, Hiroshima, Japan
| | - Kouji Joko
- Center for Liver-Biliary-Pancreatic Diseases, Matsuyama Red Cross Hospital, Ehime
| | - Chikara Ogawa
- Department of Gastroenterology and Hepatology, Takamatsu Red Cross Hospital, Takamatsu, Japan
| | - Yasushi Uchida
- Department of Gastroenterology, Matsue Red Cross Hospital, Matsue, Japan
| | - Akeri Mitsuda
- Department of Gastroenterology, Japanese Red Cross Tottori Hospital, Tottori, Japan
| | - Tetsuro Sohda
- Hepatology Division, Japanese Red Cross Fukuoka Hospital, Fukuoka, Japan
| | - Yasushi Ide
- Department of Gastroenterology, Japanese Red Cross Karatsu Hospital, Karatsu, Japan
| | - Namiki Izumi
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Musashino, Japan
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Osawa M, Ueno T, Ishikawa H, Imai Y, Garimella T. Population Pharmacokinetic Analysis for Daclatasvir and Asunaprevir in Japanese Subjects With Chronic Hepatitis C Virus Infection. J Clin Pharmacol 2018; 58:1468-1478. [PMID: 30063254 PMCID: PMC6174986 DOI: 10.1002/jcph.1274] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2018] [Accepted: 05/18/2018] [Indexed: 12/21/2022]
Abstract
Daclatasvir is a nonstructural protein 5A replication complex inhibitor, and asunaprevir is a nonstructural protein 3 protease inhibitor for hepatitis C virus (HCV). In 2014, the combination therapy of daclatasvir and asunaprevir received the first global approval in Japan as the first nonribavirin, all‐oral therapy for HCV treatment. The population pharmacokinetics (popPK) of daclatasvir and asunaprevir were characterized by nonlinear mixed‐effects modeling using 3801 and 2626 concentration data from 336 and 265 Japanese HCV subjects, respectively. The plasma pharmacokinetic profiles of daclatasvir and asunaprevir were described by a 1‐compartment model. Parameter estimates (interindividual variability) of daclatasvir apparent clearance (CL/F) and apparent volume of the central compartment (V/F) were 5.29 L/h (39.4%) and 64.2 L (38.1%). The effects of all statistically significant covariates on daclatasvir PK parameters were within or overlapped the 80% to 125% boundaries, suggesting a lack of clinical relevance. Parameter estimates (interindividual variability) of asunaprevir CL/F and V/F were 52.1 L/h (41.5%) and 75.1 L (93.4%), respectively. Baseline and time‐varying aspartate aminotransferase (AST) and cirrhosis on CL/F and formulation (soft‐gel capsule or tablet) on F were included as significant covariates in the asunaprevir popPK model. The effects of all covariates exceeded the 80% to 125% boundaries, indicating that the asunaprevir soft‐gel capsule had higher bioavailability than the tablet and that asunaprevir exposure increased with cirrhosis and increasing baseline and time‐varying AST values. The popPK models adequately described the PK profiles of daclatasvir and asunaprevir in Japanese HCV subjects.
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Ueno T, Osawa M, Imai Y, Ishikawa H, Garimella T. Exposure-Response (Efficacy) Analysis of Daclatasvir and Asunaprevir in Japanese Patients With Hepatitis C Virus Infection. J Clin Pharmacol 2018; 58:1479-1488. [PMID: 30063245 PMCID: PMC6175176 DOI: 10.1002/jcph.1262] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2018] [Accepted: 04/19/2018] [Indexed: 12/12/2022]
Abstract
The treatment of hepatitis C virus (HCV) infection has been revolutionized by the development of all-oral combination regimens of direct-acting antiviral agents. The current analysis characterized the relationship between exposures of daclatasvir (DCV; tablets) and asunaprevir (ASV; capsules) and sustained virologic response (SVR) in Japanese patients who are HCV genotype (GT) 1b nonresponders to pegylated interferon (IFN) α/ribavirin or IFNβ/ribavirin, and IFN-based therapy-ineligible naive/intolerant patients receiving DCV and ASV, and provided insight into patient covariates that were most closely associated with efficacy. The relationship between the probability of achieving SVR at 12 weeks after treatment (SVR12) and average steady-state plasma concentrations estimated from population pharmacokinetic models for DCV and ASV is described using a logistic regression model with data from a phase 2 and a phase 3 study in Japanese patients infected with HCV GT 1b (N=265). The functional form characterization, which describes a relationship between DCV and ASV average steady-state plasma concentrations and SVR12, as well as covariate identification (demographic, laboratory, and prognostic and treatment covariates) were investigated during model development. The presence of the signature nonstructural protein 5A Y93H mutation at baseline was the only significant parameter of SVR12 in the final exposure-response model. Model evaluation plots demonstrate that the final model was able to predict the observed SVR rates. Exposure-response analysis supports the clinical utility of the combination regimen of 60-mg once-daily DCV and 100-mg twice-daily ASV in Japanese patients infected with HCV GT 1b.
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24
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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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Eley T, Garimella T, Li W, Bertz RJ. Asunaprevir: An HCV Protease Inhibitor With Preferential Liver Distribution. Clin Pharmacol Drug Dev 2018; 6:195-200. [PMID: 28263460 DOI: 10.1002/cpdd.315] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2015] [Accepted: 09/15/2016] [Indexed: 12/24/2022]
Abstract
Asunaprevir is an inhibitor of the hepatitis C virus (HCV) NS3/4A protease, demonstrating efficacy in clinical studies in patients infected with HCV genotype 1 or 4, with either peginterferon/ribavirin or combinations of direct-acting antivirals. Because of preferential distribution of asunaprevir to the liver via organic anion-transporting polypeptide (OATP)-mediated transport, asunaprevir demonstrates high apparent oral clearance and very low plasma concentrations. Asunaprevir plasma concentrations are markedly increased by single-dose rifampin (an OATP inhibitor) and in subjects with moderate to severe hepatic impairment. In addition, modestly higher plasma concentrations of asunaprevir have been noted in subjects infected with HCV relative to healthy subjects and in Asian subjects relative to whites. At the marketed dose, infrequent hepatic transaminase abnormalities were poorly predicted by plasma concentrations. For a compound with these characteristics, hepatic concentrations may have provided an improved understanding of the in vivo pharmacokinetic and pharmacodynamic data to support decision making during development.
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Affiliation(s)
- Timothy Eley
- Research and Development, Bristol-Myers Squibb, Princeton, NJ, USA
| | - Tushar Garimella
- Research and Development, Bristol-Myers Squibb, Princeton, NJ, USA
| | - Wenying Li
- Research and Development, Bristol-Myers Squibb, Princeton, NJ, USA
| | - Richard J Bertz
- Research and Development, Bristol-Myers Squibb, Princeton, NJ, USA
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26
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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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Lee HW, Oh SR, Kim DY, Jeong Y, Kim S, Kim BK, Kim SU, Kim DY, Ahn SH, Han KH, Park JY. Daclatasvir Plus Asunaprevir for the Treatment of Patients with Hepatitis C Virus Genotype 1b Infection: Real-World Efficacy, Changes in Liver Stiffness and Fibrosis Markers, and Safety. Gut Liver 2018; 12:324-330. [PMID: 29409309 PMCID: PMC5945264 DOI: 10.5009/gnl17298] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2017] [Revised: 09/20/2017] [Accepted: 09/20/2017] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND/AIMS The treatment with daclatasvir plus asunaprevir (DCV+ASV) is associated with potent antiviral effects in patients with genotype 1b hepatitis C virus (HCV) infection. We investigated the real-world efficacy, changes in liver stiffness and noninvasive fibrosis markers, and the safety of DCV+ASV treatment in Korean patients. METHODS In total, 363 patients with chronic hepatitis C were treated with DCV+ASV between August 2015 and January 2017. Finally, we analyzed the data of 270 patients who were monitored for at least 12 weeks after the end of treatment. RESULTS The mean age was 60.7 years, and females predominated (60.4%). Most patients (64.8%) were treatment-naïve, and 56 patients (20.7%) had cirrhosis. Two hundred fifty-seven (95.2%) and 251 (93.0%) patients achieved end-of-treatment responses and sustained virological responses at 12 weeks posttreatment (SVR12), respectively. The SVR12 rates were higher in patients who were ＜65 years of age, males, without cirrhosis and had lower HCV RNA levels. All LS values and fibrosis-4 and aspartate aminotransferase-to-platelet ratio index values declined from baseline to the time of assessment of SVR12. CONCLUSIONS The DCV+ASV therapy resulted in a high SVR12 and improved liver fibrosis; the treatment was well tolerated in patients with genotype 1b HCV infections.
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Affiliation(s)
- Hye Won Lee
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul,
Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul,
Korea
- Yonsei Liver Center, Severance Hospital, Yonsei University College of Medicine, Seoul,
Korea
| | - Se Rim Oh
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul,
Korea
| | - Dong Yun Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul,
Korea
| | - Yechan Jeong
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul,
Korea
- Brain Korea 21 PLUS Project for Medical Science College of Medicine, Seoul,
Korea
| | - Seungtaek Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul,
Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul,
Korea
- Yonsei Liver Center, Severance Hospital, Yonsei University College of Medicine, Seoul,
Korea
| | - Beom Kyung Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul,
Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul,
Korea
- Yonsei Liver Center, Severance Hospital, Yonsei University College of Medicine, Seoul,
Korea
| | - Seung Up Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul,
Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul,
Korea
- Yonsei Liver Center, Severance Hospital, Yonsei University College of Medicine, Seoul,
Korea
| | - Do Young Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul,
Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul,
Korea
- Yonsei Liver Center, Severance Hospital, Yonsei University College of Medicine, Seoul,
Korea
| | - Sang Hoon Ahn
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul,
Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul,
Korea
- Yonsei Liver Center, Severance Hospital, Yonsei University College of Medicine, Seoul,
Korea
| | - Kwang-Hyub Han
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul,
Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul,
Korea
- Yonsei Liver Center, Severance Hospital, Yonsei University College of Medicine, Seoul,
Korea
| | - Jun Yong Park
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul,
Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul,
Korea
- Yonsei Liver Center, Severance Hospital, Yonsei University College of Medicine, Seoul,
Korea
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Hirayama T, Ikegami T, Honda A, Miyazaki T, Yara SI, Kohjima M, Nakamuta M, Matsuzaki Y. Differences in the Serum 4β-hydroxycholesterol Levels of Patients with Chronic Hepatitis C Virus (HCV) Infection: A Possible Impact on the Efficacy and Safety of Interferon (IFN)-free Treatment. Intern Med 2018; 57:1219-1227. [PMID: 29279486 PMCID: PMC5980801 DOI: 10.2169/internalmedicine.9479-17] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/05/2022] Open
Abstract
Objective Since the majority of direct-acting antivirals (DAAs) that are used in the treatment of hepatitis C virus (HCV) infection are mainly metabolized by CYP3A4, it is hypothesized that inter-individual differences in CYP3A4 activity may be associated with the bioavailability of these agents. Methods The level of serum 4β-hydroxycholesterol (4βHC), a surrogate marker of CYP3A4 activity, was determined by LC-MS/MS in samples obtained from patients with HCV infection (CHCs) as well as healthy control subjects (CTLs). Serum samples obtained from patients treated with either asunaprevir/daclatasvir (ASV/DCV) or ombitasvir/paritaprevir/ritonavir (OTV/PTV/r) were used for additional assays. Results The serum 4βHC level in CHCs was significantly higher than that in CTLs, and a gender difference was seen among CHCs. In patients treated with OTV/PTV/r, the serum 4βHC level was observed to gradually decrease during the treatment period. In the cohort treated with ASV/DCV, 4 of 83 patients showed virological treatment failure. In pretreatment testing, an Invader assay detected a low prevalence of resistance-associated variants in these four patients. The average serum concentration of DCV/ASV in the treatment-failed group tended to be lower than that in the sustained virological response (SVR) group. The pretreatment serum 4βHC level in patients with treatment failure was significantly higher than that in patients with an SVR but in whom the prevalence of resistance-associated variants was low in the pretreatment setting. Conclusion The evaluation of CYP3A4 activity by measuring 4βHC before treatment may provide additional information that can potentially be used to select cost- and efficacy-optimized treatment of HCV.
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Affiliation(s)
- Takeshi Hirayama
- Division of Gastroenterology and Hepatology, Tokyo Medical University Ibaraki Medical Center, Japan
| | - Tadashi Ikegami
- Division of Gastroenterology and Hepatology, Tokyo Medical University Ibaraki Medical Center, Japan
| | - Akira Honda
- Division of Gastroenterology and Hepatology, Tokyo Medical University Ibaraki Medical Center, Japan
- Joint Research Center, Tokyo Medical University Ibaraki Medical Center, Japan
| | - Teruo Miyazaki
- Joint Research Center, Tokyo Medical University Ibaraki Medical Center, Japan
| | - Sho-Ichiro Yara
- Division of Gastroenterology and Hepatology, Tokyo Medical University Ibaraki Medical Center, Japan
| | - Motoyuki Kohjima
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Japan
| | - Makoto Nakamuta
- Department of Gastroenterology, National Hospital Organization Kyushu Medical Center, Japan
| | - Yasushi Matsuzaki
- Division of Gastroenterology and Hepatology, Tokyo Medical University Ibaraki Medical Center, Japan
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Reddy KR, Pol S, Thuluvath PJ, Kumada H, Toyota J, Chayama K, Levin J, Lawitz EJ, Gadano A, Ghesquiere W, Gerken G, Brunetto MR, Peng C, Silva M, Strasser SI, Heo J, McPhee F, Liu Z, Yang R, Linaberry M, Noviello S. Long-term follow-up of clinical trial patients treated for chronic HCV infection with daclatasvir-based regimens. Liver Int 2018; 38:821-833. [PMID: 28941023 PMCID: PMC5947593 DOI: 10.1111/liv.13596] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2017] [Accepted: 09/18/2017] [Indexed: 12/29/2022]
Abstract
BACKGROUND & AIMS Daclatasvir has achieved high sustained virologic response (SVR) rates in diverse hepatitis C virus (HCV) populations. This study evaluated the long-term efficacy and safety of daclatasvir-based regimens administered during clinical studies. METHODS Patients enrolled within 6 months of parent study completion or protocol availability at the study sites. The primary objective was durability of SVR at follow-up Week 12 (SVR12). Secondary objectives included analysing HCV sequences in non-responders or responders who relapsed, and characterization of liver disease progression. RESULTS Between 24 February 2012 and 17 July 2015, this study enrolled and began following 1503 recipients of daclatasvir-based regimens (follow-up cut-off, 13 October 2015); 60% were male, 18% aged ≥65 years, 87% had genotype-1a (42%) or -1b (45%) infection, and 18% had cirrhosis. Median follow-up from parent study follow-up Week 12 was 111 (range, 11-246) weeks. 1329/1489 evaluable patients were SVR12 responders; 1316/1329 maintained SVR until their latest visit. Twelve responders relapsed by (n = 9) or after (n = 3) parent study follow-up Week 24; one was reinfected. Relapse occurred in 3/842 (0.4%) and 9/487 (2%) responders treated with interferon-free or interferon-containing regimens, respectively. Hepatic disease progression and new hepatocellular carcinoma were diagnosed in 15 and 23 patients, respectively. Among non-responders, emergent non-structural protein-5A (NS5A) and -3 (NS3) substitutions were replaced by wild-type sequences in 27/157 (17%) and 35/47 (74%) patients, respectively. CONCLUSIONS SVR12 was durable in 99% of recipients of daclatasvir-based regimens. Hepatic disease progression and new hepatocellular carcinoma were infrequent. Emergent NS5A substitutions persisted longer than NS3 substitutions among non-responders.
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Affiliation(s)
| | | | | | | | | | | | | | - Eric J. Lawitz
- Texas Liver InstituteUniversity of Texas Health Sciences CenterSan AntonioTXUSA
| | - Adrian Gadano
- Hospital Italiano de Buenos AiresBuenos AiresArgentina
| | - Wayne Ghesquiere
- Vancouver Island Health AuthorityUniversity of British ColumbiaVictoriaBCCanada
| | | | | | | | | | | | - Jeong Heo
- College of MedicineMedical Research InstitutePusan National University HospitalPusan National UniversityBusanKorea
| | | | | | - Rong Yang
- Bristol‐Myers SquibbWallingfordCTUSA
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30
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Kawakami Y, Ochi H, Hayes CN, Imamura M, Tsuge M, Nakahara T, Katamura Y, Kohno H, Kohno H, Tsuji K, Takaki S, Mori N, Honda Y, Arataki K, Takahashi S, Kira S, Tamura T, Masuda K, Nakamura T, Kikkawa M, Chayama K. Efficacy and safety of ledipasvir/sofosbuvir with ribavirin in chronic hepatitis C patients who failed daclatasvir/asunaprevir therapy: pilot study. J Gastroenterol 2018; 53:548-556. [PMID: 28815329 DOI: 10.1007/s00535-017-1380-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2017] [Accepted: 08/04/2017] [Indexed: 02/04/2023]
Abstract
BACKGROUND In Japan, daclatasvir (DCV) and asunaprevir (ASV) therapy was the first IFN-free treatment to be approved, and thousands of patients have since been successfully treated, with an SVR rate of around 90%. The converse, however, is that around 10% of patients fail to achieve viral eradication and must be retreated using a different approach. This study is to evaluate treatment efficacy of ledipasvir/sofosbuvir and ribavirin in patients who failed to respond to DCV and ASV therapy. METHODS Thirty patients were treated with 12 weeks of ledipasvir/sofosbuvir and ribavirin. We evaluated the rate of sustained virological response 12 weeks after the end of treatment (SVR12) and examined the incidence of adverse events during ledipasvir/sofosbuvir and ribavirin treatment. NS5A and NS5B resistance-associated variants (RAVs) in treatment failure cases were examined. RESULTS The overall SVR12 rate was 86.7% (26/30). Large decreases in mean log10 HCV RNA levels were observed in patients without cirrhosis, and the SVR12 rate for these patients was 100% (12/12). In cases of cirrhosis, SVR12 rate was 72.2% (13/18). The common factors in treatment failure cases were the presence of liver cirrhosis and both NS5A L31M/I and Y93H RAVs. The frequency of RAVs did not change before and after treatment among patients who relapsed. CONCLUSION Ledipasvir/sofosbuvir with ribavirin is an effective retreatment option for patients with chronic hepatitis C who failed to respond to prior daclatasvir and asunaprevir therapy.
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Affiliation(s)
- Yoshiiku Kawakami
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
- Department of Center for Integrated Medical Research, Hiroshima University, Hiroshima, Japan
- Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Hidenori Ochi
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
- Liver Research Project Center, Hiroshima University, Hiroshima, Japan
- Laboratory for Digestive Diseases, RIKEN Center for Integrative Medical Sciences, The Institute of Physical and Chemical Research (RIKEN), Hiroshima, Japan
| | - Clair Nelson Hayes
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
- Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Michio Imamura
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
- Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Masataka Tsuge
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
- Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Takashi Nakahara
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
- Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | | | | | | | - Keiji Tsuji
- Hiroshima Red Cross Hospital and Atomic-bomb Survivors Hospital, Hiroshima, Japan
| | - Shintaro Takaki
- Hiroshima Red Cross Hospital and Atomic-bomb Survivors Hospital, Hiroshima, Japan
| | - Nami Mori
- Hiroshima Red Cross Hospital and Atomic-bomb Survivors Hospital, Hiroshima, Japan
| | - Yohji Honda
- Hiroshima Red Cross Hospital and Atomic-bomb Survivors Hospital, Hiroshima, Japan
| | | | | | | | | | | | | | | | - Kazuaki Chayama
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.
- Liver Research Project Center, Hiroshima University, Hiroshima, Japan.
- Laboratory for Digestive Diseases, RIKEN Center for Integrative Medical Sciences, The Institute of Physical and Chemical Research (RIKEN), Hiroshima, Japan.
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Honda K, Seike M, Oribe J, Endo M, Arakawa M, Tokoro M, Iwao M, Mori T, Nishimura J, Takahashi Y, Omori K, Yamashita T, Muro T, Murakami K. Usefulness of semiquantitative PCR-Invader assay for selecting candidates for daclatasvir plus asunaprevir combination therapy among patients with hepatitis C virus genotype 1b. Hepatol Res 2018; 48:255-263. [PMID: 29080280 DOI: 10.1111/hepr.12994] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2017] [Revised: 10/13/2017] [Accepted: 10/24/2017] [Indexed: 02/06/2023]
Abstract
AIMS PCR-Invader is a highly sensitive assay for detecting non-structural protein 5A (NS5A) resistance-associated variants (RAVs) of hepatitis C virus (HCV). Here, we validated the accuracy of the semiquantitative PCR-Invader (SQ-PI) assay compared to direct sequencing (DS) for identifying NS5A RAVs, and we evaluated the treatment efficacy of daclatasvir plus asunaprevir (DCV + ASV) for patients judged to be non-positive for NS5A RAVs by SQ-PI. METHODS Detection rates of NS5A RAVs by SQ-PI and DS were compared for 204 patients with HCV genotype 1b. Patients with non-positive results for NS5A RAVs by SQ-PI were treated by DCV + ASV, and the efficacy of this treatment was examined. RESULTS All samples judged as negative for NS5A RAVs by SQ-PI were similarly judged by DS. However, 29.7% of samples judged as negative for Y93H by DS were judged as weakly positive or positive by SQ-PI. Among 108 patients who were judged as negative by SQ-PI and treated by DCV + ASV, rates of sustained virologic response at 24 weeks (SVR24) were 96.3% in intention-to-treat analysis and 99.0% in patients who completed treatment. Among patients who were weakly positive for Y93H on SQ-PI, the SVR24 rate was 95.0% (19/20). This rate was 100% (78/78) in patients who were negative for Y93H on SQ-PI and completed treatment. CONCLUSION Treatment efficacy of DCV + ASV was extremely high among patients who were non-positive for NS5A RAVs on SQ-PI, especially for patients with negative results.
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Affiliation(s)
- Koichi Honda
- Department of Gastroenterology, Faculty of Medicine, Oita University, Yufu City, Japan
| | - Masataka Seike
- Department of Gastroenterology, Faculty of Medicine, Oita University, Yufu City, Japan
| | - Junya Oribe
- Department of Gastroenterology, Faculty of Medicine, Oita University, Yufu City, Japan
| | - Mizuki Endo
- Department of Gastroenterology, Faculty of Medicine, Oita University, Yufu City, Japan
| | - Mie Arakawa
- Department of Gastroenterology, Faculty of Medicine, Oita University, Yufu City, Japan
| | - Masanori Tokoro
- Department of Gastroenterology, Faculty of Medicine, Oita University, Yufu City, Japan
| | - Masao Iwao
- Department of Gastroenterology, Faculty of Medicine, Oita University, Yufu City, Japan
| | | | - Junko Nishimura
- Department of Gastroenterology, Oita Cardiovascular Hospital, Oita City, Japan
| | - Yukou Takahashi
- Department of Gastroenterology, Oita Cardiovascular Hospital, Oita City, Japan
| | - Kaoru Omori
- Department of Internal Medicine, Sato Daiichi Hospital, Usa City, Japan
| | - Tsutomu Yamashita
- Department of Gastroenterology and Hepatology, National Hospital Organization Oita Medical Center, Oita City, Japan
| | - Toyokichi Muro
- Department of Gastroenterology and Hepatology, National Hospital Organization Oita Medical Center, Oita City, Japan
| | - Kazunari Murakami
- Department of Gastroenterology, Faculty of Medicine, Oita University, Yufu City, Japan
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Efficacy of daclatasvir-based quadruple therapy in nonresponder patients infected by hepatitis C virus genotype 4: the ANRS HC32 QUATTRO study. Eur J Gastroenterol Hepatol 2018; 30:302-309. [PMID: 29271782 DOI: 10.1097/meg.0000000000001035] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND A few direct antiviral agents have been studied in difficult-to-treat patients infected by hepatitis C virus (HCV) genotype 4 (GT4). The efficacy of daclatasvir (DCV), asunaprevir (ASV), pegylated interferon and ribavirin (Peg-IFN/RBV) association was investigated in these patients. PATIENTS AND METHODS This open-label, single-arm, phase 2 study was conducted in HCV GT4 patients who were null or partial responders to Peg-IFN/RBV. Patients received 24 weeks of DCV (60 mg, once daily), ASV (100 mg, twice daily) and Peg-IFN/RBV. The primary endpoint was sustained virologic response at post-treatment week 12 [sustained virologic response (SVR)12]. RESULTS Sixty patients were included; 45 (75%) were previous null responders and 27 (45%) had cirrhosis. The most frequent subtypes were GT4a (48%) and GT4d (27%) with 25% of the patients being infected with other subtypes such as 4c, 4r, 4f, 4k, 4j and 4q. The global SVR12 was 95% (90% confidence interval: 90.4-99.6) and 96.3% (90% confidence interval: 87.5-99.5) in cirrhotic patients. All patients achieving SVR12 also achieved SVR24. Previous Peg-IFN/RBV response, IL28b genotype, cirrhosis status or GT4 subtypes did not influence SVR12 rates. Serious adverse events occurred in 13% of the patients, four being cirrhotic and four noncirrhotic. Three (5%) patients stopped HCV therapy prematurely: one because of virologic breakthrough and two because of serious adverse events. Grade 3/4 laboratory abnormalities included leukopenia (33%), neutropenia (27%), thrombocytopenia (4%) and transaminases increase (2%). CONCLUSION Association of DCV plus ASV and peg-IFN/RBV for 24 weeks demonstrated a high rate of SVR12 in HCV GT4-infected prior nonresponders, independently of the cirrhotic status or the GT4 subtype. The safety profile was acceptable, even in cirrhotic patients.
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Sorbo MC, Cento V, Di Maio VC, Howe AYM, Garcia F, Perno CF, Ceccherini-Silberstein F. Hepatitis C virus drug resistance associated substitutions and their clinical relevance: Update 2018. Drug Resist Updat 2018. [PMID: 29525636 DOI: 10.1016/j.drup.2018.01.004] [Citation(s) in RCA: 150] [Impact Index Per Article: 21.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Nowadays, due to the development of potent Direct-Acting Antiviral Agents (DAAs) that specifically target NS3, NS5A and NS5B viral proteins, several new and highly efficacious options to treat chronic Hepatitis C virus (HCV) infection are available. The natural presence of resistance associated substitutions (RASs), as well as their rapid emergence during incomplete drug-pressure, are intrinsic characteristics of HCV that greatly affect treatment outcome and the chances to achieve a virolgical cure. To date, a high number of RASs in NS3, NS5A, and NS5B have been associated in vivo and/or in vitro with reduced susceptibility to DAAs, but no comprehensive RASs list is available. This review thus provides an updated, systematic overview of the role of RASs to currently approved DAAs or in phase II/III of clinical development against HCV-infection, discriminating their impact in different HCV-genotypes and DAAs, providing assistance for a fruitful use of HCV resistance testing in clinical practice.
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Affiliation(s)
- Maria C Sorbo
- Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, Rome, Italy
| | - Valeria Cento
- Residency program in Microbiology and Virology, Università degli Studi di Milano. Milan, Italy.
| | - Velia C Di Maio
- Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, Rome, Italy
| | - Anita Y M Howe
- Centre for Excellence in HIV/AIDS, St Paul's Hospital, Vancouver, BC, Canada
| | - Federico Garcia
- Clinical Microbiology Service, Hospital Universitario San Cecilio, Granada, Spain
| | - Carlo F Perno
- Department of Oncology and Oncohematology, Università degli Studi di Milano. Milan, Italy.
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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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Haga Y, Kanda T, Yasui S, Nakamura M, Ooka Y, Takahashi K, Wu S, Nakamoto S, Arai M, Chiba T, Maruyama H, Yokosuka O, Takada N, Moriyama M, Imazeki F, Kato N. Successful retreatment with sofosbuvir plus ledipasvir for cirrhotic patients with hepatitis C virus genotype 1b, who discontinued the prior treatment with asunaprevir plus daclatasvir: A case series and review of the literature. Oncotarget 2018; 9:5509-5513. [PMID: 29435197 PMCID: PMC5797068 DOI: 10.18632/oncotarget.23768] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2017] [Accepted: 12/23/2017] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND Interferon-free treatment results in higher sustained virologic response (SVR) rates, with no serious adverse events in hepatitis C virus (HCV)-infected patients. However, in some patients with treatment-failure in HCV NS5A inhibitor-including interferon-free regimens, the treatment-emergent HCV NS5A resistance-associated variants (RAVs), which are resistant to interferon-free retreatment including HCV NS5A inhibitors, are observed. In HCV-infected Japanese patients with daclatasvir and asunaprevir treatment failure, retreatment with sofosbuvir and ledipasvir could lead to only ∼70% SVR rates. CASE SUMMARY Three HCV genotype (GT)-1b-infected cirrhotic patients who discontinued the combination of daclatasvir and asunaprevir due to adverse drug reactions within 4 weeks; retreatment with sofosbuvir and ledipasvir combination could result in SVR in these patients without RAVs. One HCV GT-1b-infected cirrhotic patient who discontinued the combination of daclatasvir and asunaprevir due to viral breakthrough at week 10; retreatment with sofosbuvir and ledipasvir combination for this patient with the treatment-emergent HCV NS5A RAV-Y93H resulted in viral relapse at week 4 after the end of the treatment. CONCLUSION Retreatment with sofosbuvir and ledipasvir is effective for HCV GT-1b patients who discontinue the combination of daclatasvir and asunaprevir within 4 weeks. The treatment response should be related to the existence of treatment-emergent HCV NS5A RAVs, but may not be related to the short duration of treatment.
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Affiliation(s)
- Yuki Haga
- Department of Gastroenterology, Chiba University, Graduate School of Medicine, Inohana, Chuo-ku, Chiba, Japan
| | - Tatsuo Kanda
- Department of Gastroenterology, Chiba University, Graduate School of Medicine, Inohana, Chuo-ku, Chiba, Japan
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo, Japan
| | - Shin Yasui
- Department of Gastroenterology, Chiba University, Graduate School of Medicine, Inohana, Chuo-ku, Chiba, Japan
| | - Masato Nakamura
- Department of Gastroenterology, Chiba University, Graduate School of Medicine, Inohana, Chuo-ku, Chiba, Japan
| | - Yoshihiko Ooka
- Department of Gastroenterology, Chiba University, Graduate School of Medicine, Inohana, Chuo-ku, Chiba, Japan
| | - Koji Takahashi
- Department of Gastroenterology, Chiba University, Graduate School of Medicine, Inohana, Chuo-ku, Chiba, Japan
| | - Shuang Wu
- Department of Gastroenterology, Chiba University, Graduate School of Medicine, Inohana, Chuo-ku, Chiba, Japan
| | - Shingo Nakamoto
- Department of Gastroenterology, Chiba University, Graduate School of Medicine, Inohana, Chuo-ku, Chiba, Japan
- Department of Molecular Virology, Chiba University, Graduate School of Medicine, Inohana, Chuo-ku, Chiba, Japan
| | - Makoto Arai
- Department of Gastroenterology, Chiba University, Graduate School of Medicine, Inohana, Chuo-ku, Chiba, Japan
| | - Tetsuhiro Chiba
- Department of Gastroenterology, Chiba University, Graduate School of Medicine, Inohana, Chuo-ku, Chiba, Japan
| | - Hitoshi Maruyama
- Department of Gastroenterology, Chiba University, Graduate School of Medicine, Inohana, Chuo-ku, Chiba, Japan
| | - Osamu Yokosuka
- Department of Gastroenterology, Chiba University, Graduate School of Medicine, Inohana, Chuo-ku, Chiba, Japan
| | - Nobuo Takada
- Department of Internal Medicine, Toho University Sakura Medical Center, Shimoshizu, Sakura, Japan
| | - Mitsuhiko Moriyama
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo, Japan
| | - Fumio Imazeki
- Department of Gastroenterology, Chiba University, Graduate School of Medicine, Inohana, Chuo-ku, Chiba, Japan
- Safety and Health Organization, Chiba University, Yayoicho, Inage-ku, Chiba, Japan
| | - Naoya Kato
- Department of Gastroenterology, Chiba University, Graduate School of Medicine, Inohana, Chuo-ku, Chiba, Japan
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Integrated pharmacokinetic/viral dynamic model for daclatasvir/asunaprevir in treatment of patients with genotype 1 chronic hepatitis C. Acta Pharmacol Sin 2018; 39:140-153. [PMID: 28880015 DOI: 10.1038/aps.2017.84] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2016] [Accepted: 04/27/2017] [Indexed: 12/12/2022]
Abstract
In order to develop an integrated pharmacokinetic/viral dynamic (PK/VD) model to predict long-term virological response rates to daclatasvir (DCV) and asunaprevir (ASV) combination therapy in patients infected with genotype 1 (GT1) chronic hepatitis C virus (HCV), a systematic publication search was conducted for DCV and ASV administered alone and/or in combination in healthy subjects or patients with GT1 HCV infection. On the basis of a constructed meta-database, an integrated PK/VD model was developed, which adequately described both DCV and ASV PK profiles and viral load time curves. The IC50 values of DCV and ASV were estimated to be 0.041 and 2.45 μg/L, respectively, in GT1A patients. A sigmoid Emax function was applied to describe the antiviral effects of DCV and ASV, depending on the drug concentrations in the effect compartment. An empirical exponential function revealed that IC50 changing over time described drug resistance in HCV GT1A patients during DCV or ASV monotherapy. Finally, the PK/VD model was evaluated externally by comparing the expected and observed virological response rates during and post-treatment with DCV and ASV combination therapy in HCV GT1B patients. Both the rates were in general agreement. Our PK/VD model provides a useful platform for the characterization of pharmacokinetic/pharmacodynamic relationships and the prediction of long-term virological response rates to aid future development of direct acting antiviral drugs.
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Hayashi K, Ishigami M, Ishizu Y, Kuzuya T, Honda T, Kawashima H, Ishikawa T, Tachi Y, Hattori M, Katano Y, Goto H, Hirooka Y. Comparison of direct sequencing and Invader assay for Y93H mutation and response to interferon-free therapy in hepatitis C virus genotype 1b. J Gastroenterol Hepatol 2018; 33:249-255. [PMID: 28440885 DOI: 10.1111/jgh.13809] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2017] [Revised: 04/03/2017] [Accepted: 04/11/2017] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIM Virologic failure of interferon-free therapy has been associated with Y93H mutation in the non-structure 5A region in hepatitis C virus (HCV) genotype 1b, and screening is recommended. A simple assay based on Q-Invader technology was developed for Y93H mutant screening to reduce cost and effort. The present study sought to compare two methods of detection of Y93H mutation and to evaluate the effect of Y93H mutation on response to interferon-free therapy. METHODS Y93H mutation was examined in 258 patients with HCV genotype 1b using both direct sequencing analysis and the polymerase chain reaction (PCR)-Invader assay. Daclatasvir and asunaprevir or ledipasvir and sofosbuvir therapy was administered to 205 patients whose sustained virological responses (SVR) were checked. RESULTS Hepatitis C virus was detected in 232 of 258 patients by direct sequencing and in 236 of 258 patients by the PCR-Invader assay. Forty of 231 cases were defined as Y93 mutation by direct sequencing, and 46 of 236 cases were defined as Y93 mutation by the PCR-Invader assay. SVR of patients who were Y93H by direct sequencing, Y93H by the PCR-Invader assay, and Y93H by both methods was 62.5%, 82.4%, and 50%, respectively. CONCLUSIONS The sensitivity of the PCR-Invader assay was similar to that of direct sequencing analysis; however, the PCR-Invader assay had a better ability to detect minor strains. Combination of the two assays would improve prediction of the response to daclatasvir and asunaprevir, but Y93H mutation had little effect on SVR in ledipasvir and sofosbuvir therapy.
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Affiliation(s)
- Kazuhiko Hayashi
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Masatoshi Ishigami
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yoji Ishizu
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Teiji Kuzuya
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Takashi Honda
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Hiroki Kawashima
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Tetsuya Ishikawa
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yoshihiko Tachi
- Department of Gastroenterology, Komaki City Hospital, Komaki, Japan
| | - Masashi Hattori
- Department of Gastroenterology, Yamashita Hospital, Ichinomiya, Japan
| | - Yoshiaki Katano
- Department of Internal Medicine, Banbuntane Hotokukai Hospital, Fujita Health University, Nagoya, Japan
| | - Hidemi Goto
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yoshiki Hirooka
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
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Otsuka T, Kawaguchi Y, Mizuta T, Ide Y, Koga F, Kumagai T, Yoshioka W, Murayama K, Rikitake O, Ikeda Y, Ozaki I. Asunaprevir and daclatasvir in hemodialysis patients with chronic hepatitis C virus genotype 1b infection. JGH OPEN 2017; 1:148-152. [PMID: 30483552 PMCID: PMC6207006 DOI: 10.1002/jgh3.12026] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/30/2017] [Accepted: 10/12/2017] [Indexed: 12/16/2022]
Abstract
Background and Aim Patients requiring hemodialysis show high morbidity with hepatitis C virus (HCV) infection, but there are difficulties associated with interferon‐based therapies. Asunaprevir and daclatasvir could help patients with HCV genotype 1b because the drugs have a nonrenal metabolism and show good viral eradication. We evaluated the efficacy and safety of combined asunaprevir and daclatasvir therapy. Methods This was a multicenter prospective trial of patients with chronic hepatitis or compensated cirrhosis from HCV genotype 1b who had end‐stage renal disease requiring chronic hemodialysis. Asunaprevir and daclatasvir were administered orally (100 mg twice daily and 60 mg once daily, respectively) for 24 weeks. The primary end‐point was the proportion of patients achieving sustained virological response 12, defined as HCV RNA <15 IU/mL undetectable at 12 weeks after completion of asunaprevir and daclatasvir treatment. Results Between December 2014 and December 2015, 23 dialysis patients were enrolled, and 22 patients completed the protocol therapy. Sustained virological response 12 rates were 91.3% (95% confidence interval: 72.0–98.9) in the intention‐to‐treat and 95.5% (95% confidence interval: 77.2–99.9) in the per‐protocol populations. Serum aminotransferase significantly decreased after initiation of asunaprevir and daclatasvir (P < 0.01), although the level was low at baseline. Asunaprevir and daclatasvir were well tolerated; however, one patient could not continue because of infective endocarditis and cerebral infarction. Conclusions Asunaprevir and daclatasvir could help patients with chronic hepatitis C receiving hemodialysis. Close collaboration with dialysis physicians is important when treating these patients because hemodialysis carries life‐threatening risks.
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Affiliation(s)
- Taiga Otsuka
- Department of Internal Medicine, Division of Hepatology Saga University Hospital Saga Japan
| | - Yasunori Kawaguchi
- Hepato-Biliary and Pancreatology Division Saga Medical Center Koseikan Saga Japan
| | - Toshihiko Mizuta
- Department of Internal Medicine Imari-Arita Kyoritsu Hospital Saga Japan
| | - Yasushi Ide
- Department of Internal Medicine Karatsu Red Cross Hospital Saga Japan
| | - Futa Koga
- Department of Internal Medicine, Division of Hepatology Saga University Hospital Saga Japan
| | | | - Wataru Yoshioka
- Department of Internal Medicine, Division of Hepatology Saga University Hospital Saga Japan
| | - Kenichiro Murayama
- Department of Internal Medicine, Division of Hepatology Saga University Hospital Saga Japan
| | - Osamu Rikitake
- Department of Internal Medicine Rikitake Clinic Saga Japan
| | - Yuji Ikeda
- Department of Internal Medicine, Division of Nephrology Saga University Hospital Saga Japan
| | - Iwata Ozaki
- Department of Internal Medicine, Division of Hepatology Saga University Hospital Saga Japan
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Suda G, Ogawa K, Yamamoto Y, Katagiri M, Furuya K, Kumagai K, Konno J, Kimura M, Kawagishi N, Ohara M, Umemura M, Ito J, Izumi T, Nakai M, Sho T, Natsuizaka M, Morikawa K, Tsubota A, Shimada N, Iio E, Tanaka Y, Sakamoto N. Retreatment with sofosbuvir, ledipasvir, and add-on ribavirin for patients who failed daclatasvir and asunaprevir combination therapy. J Gastroenterol 2017; 52:1122-1129. [PMID: 28315983 DOI: 10.1007/s00535-017-1328-z] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2017] [Accepted: 03/02/2017] [Indexed: 02/04/2023]
Abstract
BACKGROUND The optimal retreatment regimen for patients with hepatitis C virus (HCV) infection who failed interferon-free, direct-acting antiviral (DAA) therapy is undetermined. In this study, we aimed to evaluate the efficacy and safety of 12-week retreatment with ledipasvir (LDV) and sofosbuvir (SOF) with add-on ribavirin (RBV) for patients who previously failed to respond to HCV-NS5A inhibitor, daclatasvir (DCV), and HCV-NS3 inhibitor, asunaprevir (ASV), therapy. METHODS This multicenter, prospective study enrolled 15 patients with genotype-1 HCV infection who failed DCV/ASV combination therapy. They were retreated with SOF, LDV, and RBV for 12 weeks and underwent physical examinations and blood tests at baseline, during treatment, and after therapy. At baseline and relapse, NS3/NS5A and NS5B resistance-associated variants (RAVs) were evaluated. RESULTS Of the 15 enrolled patients, 73.3% (11/15), 86.7% (13/15), and 0% (0/15) had RAVs in NS3 D168A/V/T/E, NS5A L31I/M/F/V plus Y93H, and NS5B S282T, respectively. Overall, 86.7% (13/15) of patients achieved a sustained viral response, and all patients completed therapy. No patients experienced severe adverse events. Two patients who failed to respond to SOF, LDV, and RBV combination therapy were elderly women, had the IL28B non-TT genotype, and NS5A RAVs in L31I/Y93H or NS5A A92 K at baseline. CONCLUSIONS This study revealed that SOF, LDV, and RBV combination therapy was effective and well-tolerated for patients with genotype-1 HCV infection who failed DCV and ASV combination therapy. Thus, RBV added to DAA therapy for difficult-to-treat patients might improve treatment outcomes.
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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
| | | | | | - Ken Furuya
- JCHO Hokkaido Hospital, Sapporo, Hokkaido, Japan
| | - Kenichi Kumagai
- Mori City National Health Insurance Hospital, Mori, Hokkaido, Japan
| | - Jun Konno
- Hakodate Central General Hospital, Hakodate, Hokkaido, Japan
| | - Megumi Kimura
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, North 15, West 7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan
| | - Naoki Kawagishi
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, North 15, West 7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan
| | - Masatsugu Ohara
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, North 15, West 7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan
| | - Machiko Umemura
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, North 15, West 7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan
| | - Jun Ito
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, North 15, West 7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan
| | - Takaaki Izumi
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, North 15, West 7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan
| | - Masato Nakai
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, North 15, West 7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan
| | - Takuya Sho
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, North 15, West 7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan
| | - Mitsuteru Natsuizaka
- 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
| | - Akihito Tsubota
- Core Research Facilities for Basic Science, Division of Molecular Cell Biology, Research Center for Medical Science, The Jikei University School of Medicine, Tokyo, Japan
| | - Noritomo Shimada
- Division of Gastroenterology and Hepatology, Ootakanomori Hospital, Chiba, Japan
| | - Etsuko Iio
- Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Yasuhito Tanaka
- Nagoya City University Graduate School of Medical Sciences, Nagoya, 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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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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Yoshikawa A, Terashita K, Morikawa K, Matsuda S, Yamamura T, Sarashina K, Nakano S, Kobayashi Y, Sogabe S, Takahashi K, Haba S, Oda H, Takahashi T, Miyagishima T, Sakamoto N. Interferon-free therapy with sofosbuvir plus ribavirin for successful treatment of genotype 2 hepatitis C virus with lichen planus: a case report. Clin J Gastroenterol 2017; 10:270-273. [PMID: 28447325 DOI: 10.1007/s12328-017-0742-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2017] [Accepted: 04/18/2017] [Indexed: 12/27/2022]
Abstract
Hepatitis C virus (HCV) infection remains the main cause of liver disease and can lead to chronic hepatitis, cirrhosis, and hepatocellular carcinoma. HCV may also develop extrahepatic manifestations in the skin, eyes, joints, kidneys, nervous system, and immune system. In fact, several studies reported that up to 70% of HCV patients experienced extrahepatic manifestations. Lichen planus (LP), which is an immune system disorder that is triggered by viral infections, allergens, and stress, can affect the skin, mouth, nails, and scalp. The association of LP with HCV has been reported, but the effect of HCV treatment on LP remission is controversial. We encountered a 53-year-old man with HCV genotype 2a and LP that were successfully treated with sofosbuvir and ribavirin for 12 weeks. After treatment, he achieved sustained virological response against HCV and remission of erosive LP lesions on the lip. In the era of interferon (IFN)-based treatment for HCV, exacerbation of autoimmune diseases is a common adverse event. Therefore, use of an IFN-free regimen of direct-acting antivirals for HCV might prevent the extrahepatic manifestation of an immune disorder.
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Affiliation(s)
- Ayumu Yoshikawa
- Department of Internal Medicine, Kushiro Rosai Hospital, Kushiro, Japan
| | - Katsumi Terashita
- Department of Internal Medicine, Kushiro Rosai Hospital, Kushiro, Japan
| | - Kenichi Morikawa
- Division of Gastroenterology and Hepatology, Hokkaido University Hospital, Sapporo, Japan.
| | - Soichiro Matsuda
- Department of Internal Medicine, Kushiro Rosai Hospital, Kushiro, Japan
| | - Takahiro Yamamura
- Department of Internal Medicine, Kushiro Rosai Hospital, Kushiro, Japan
| | | | - Shintaro Nakano
- Department of Internal Medicine, Kushiro Rosai Hospital, Kushiro, Japan
| | | | - Susumu Sogabe
- Department of Internal Medicine, Kushiro Rosai Hospital, Kushiro, Japan
| | | | - Shin Haba
- Department of Internal Medicine, Kushiro Rosai Hospital, Kushiro, Japan
| | - Hisashi Oda
- Department of Internal Medicine, Kushiro Rosai Hospital, Kushiro, Japan
| | | | | | - Naoya Sakamoto
- Division of Gastroenterology and Hepatology, Hokkaido University Hospital, Sapporo, Japan
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Kanda T, Yasui S, Nakamura M, Suzuki E, Arai M, Ooka Y, Ogasawara S, Chiba T, Saito T, Haga Y, Takahashi K, Sasaki R, Wu S, Nakamoto S, Tawada A, Maruyama H, Imazeki F, Kato N, Yokosuka O. Real-World Experiences with the Combination Treatment of Ledipasvir plus Sofosbuvir for 12 Weeks in HCV Genotype 1-Infected Japanese Patients: Achievement of a Sustained Virological Response in Previous Users of Peginterferon plus Ribavirin with HCV NS3/4A Inhibitors. Int J Mol Sci 2017; 18:906. [PMID: 28441362 PMCID: PMC5454819 DOI: 10.3390/ijms18050906] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2017] [Revised: 04/19/2017] [Accepted: 04/21/2017] [Indexed: 12/14/2022] Open
Abstract
The aim of this study was to characterize the treatment response and serious adverse events of ledipasvir plus sofosbuvir therapies in Japanese patients infected with hepatitis C virus (HCV) genotype 1 (GT1). This retrospective study analyzed 240 Japanese HCV GT1 patients treated for 12 weeks with 90 mg of ledipasvir plus 400 mg of sofosbuvir daily. Sustained virological response at 12 weeks post-treatment (SVR12) was achieved in 236 of 240 (98.3%) patients. Among treatment-naïve patients, SVR12 was achieved in 136 of 138 (98.6%) patients, and among treatment-experienced patients, SVR12 was achieved in 100 of 102 (98.0%) patients. In patients previously treated with peginterferon plus ribavirin with various HCV NS3/4A inhibitors, 100% SVR rates (25/25) were achieved. Two relapsers had HCV NS5A resistance-associated variants (RAVs), but no HCV NS5B-S282 was observed after they relapsed. We experienced two patients with cardiac events during treatment. In conclusion, combination of ledipasvir plus sofosbuvir for 12 weeks is a potential therapy for HCV GT1 patients. Caution is needed for HCV NS5A RAVs, which were selected by HCV NS5A inhibitors and cardiac adverse events.
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Affiliation(s)
- Tatsuo Kanda
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.
| | - Shin Yasui
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.
| | - Masato Nakamura
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.
| | - Eiichiro Suzuki
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.
| | - Makoto Arai
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.
| | - Yoshihiko Ooka
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.
| | - Sadahisa Ogasawara
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.
| | - Tetsuhiro Chiba
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.
| | - Tomoko Saito
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.
| | - Yuki Haga
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.
| | - Koji Takahashi
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.
| | - Reina Sasaki
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.
| | - Shuang Wu
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.
| | - Shingo Nakamoto
- Department of Molecular Virology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.
| | - Akinobu Tawada
- Safety and Health Organization, Chiba University, 1-33 Yayoicho, Inage-ku, Chiba 263-8522, Japan.
| | - Hitoshi Maruyama
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.
| | - Fumio Imazeki
- Safety and Health Organization, Chiba University, 1-33 Yayoicho, Inage-ku, Chiba 263-8522, Japan.
| | - Naoya Kato
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.
| | - Osamu Yokosuka
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.
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Tarao K, Tanaka K, Nozaki A, Sato A, Ishii T, Komatsu H, Ikeda T, Komatsu T, Matsushima S, Oshige K. Efficacy and safety of dual therapy with daclatasvir and asunaprevir in elderly patients. World J Hepatol 2017; 9:544-550. [PMID: 28469810 PMCID: PMC5395803 DOI: 10.4254/wjh.v9.i11.544] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2016] [Revised: 01/19/2017] [Accepted: 02/08/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To survey the efficacy and safety of dual therapy with daclatasvir and asunaprevir in the elderly hepatitis C virus (HCV) patients multicentricity. METHODS Interferon-ineligible/intolerant patients and non-responders to previous pegylated-interferon/ribavirin therapy with chronic HCV genotype 1b infection were enrolled. Child B, C cirrhotic patients were excluded. Patients received oral direct acting antiviral treatment consisting of 60 mg daclatasvir once daily plus 200 mg asunaprevir twice daily for 24 wk. We divided the patients into two groups of 56 elderly patients (≥ 75 years-old) and 141 non-elderly patients (< 75 years old) and compared the efficacy and safety. RESULTS Ninety-one point one percent of elderly patients and 90.1% of non-elderly patients achieved sustained virological response at 24 wk (SVR24). In the former, 1.8% experienced viral breakthrough, as compared with 3.5% in the latter (not significant). Adverse events occurred in 55.4% of the former and 56.0% of the latter. In the former, 7 cases (12.5%) were discontinued due to adverse events, and in the latter 9 cases were discontinued (6.4%, not significant). CONCLUSION Dual therapy with daclatasvir and asunaprevir achieved the same high rates of SVR24 in HCV elderly patients without more adverse events than in the non-elderly patients.
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Affiliation(s)
- Kazuo Tarao
- Kazuo Tarao, Tarao's Gastroenterological Clinic, Yokohama 241-0821, Japan
| | - Katsuaki Tanaka
- Kazuo Tarao, Tarao's Gastroenterological Clinic, Yokohama 241-0821, Japan
| | - Akito Nozaki
- Kazuo Tarao, Tarao's Gastroenterological Clinic, Yokohama 241-0821, Japan
| | - Akira Sato
- Kazuo Tarao, Tarao's Gastroenterological Clinic, Yokohama 241-0821, Japan
| | - Toshiya Ishii
- Kazuo Tarao, Tarao's Gastroenterological Clinic, Yokohama 241-0821, Japan
| | - Hirokazu Komatsu
- Kazuo Tarao, Tarao's Gastroenterological Clinic, Yokohama 241-0821, Japan
| | - Takaaki Ikeda
- Kazuo Tarao, Tarao's Gastroenterological Clinic, Yokohama 241-0821, Japan
| | - Tatsuji Komatsu
- Kazuo Tarao, Tarao's Gastroenterological Clinic, Yokohama 241-0821, Japan
| | - Shozo Matsushima
- Kazuo Tarao, Tarao's Gastroenterological Clinic, Yokohama 241-0821, Japan
| | - Kenji Oshige
- Kazuo Tarao, Tarao's Gastroenterological Clinic, Yokohama 241-0821, Japan
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Serti E, Park H, Keane M, O’Keefe AC, Rivera E, Liang TJ, Ghany M, Rehermann B. Rapid decrease in hepatitis C viremia by direct acting antivirals improves the natural killer cell response to IFNα. Gut 2017; 66:724-735. [PMID: 26733671 PMCID: PMC6886885 DOI: 10.1136/gutjnl-2015-310033] [Citation(s) in RCA: 49] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2015] [Revised: 11/23/2015] [Accepted: 11/24/2015] [Indexed: 12/26/2022]
Abstract
OBJECTIVE Chronic HCV infection is characterised by innate immune activation with increased interferon-stimulated genes (ISG) expression and by an altered phenotype of interferon-responsive natural killer (NK) cells. Here, we asked whether a rapid reduction in viremia by daclatasvir (DCV) and asunaprevir (ASV) improves the response to pegylated interferon (PegIFN) in patients who had previously failed a standard course of PegIFN/ribavirin (RBV) therapy. DESIGN Twenty-two HCV-infected non-responders to previous PegIFN/RBV therapy were studied for IFN-responsiveness of NK cells during quadruple (QUAD) therapy with DCV, ASV, PegIFN and RBV. A direct comparison of early NK cell responses in PegIFN/RBV therapy and QUAD therapy was performed for seven patients using paired cryopreserved peripheral blood mononuclear cells (PBMC) from both treatment courses. As a validation cohort, nine DCV/ASV-treated patients were studied for their NK cell response to in vitro stimulation with IFNα. RESULTS The 24 h virological response to QUAD therapy correlated with an increase in signal transducer and activator of transcription 1 (STAT1), phosphorylated STAT1 (pSTAT1) and tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) expression in NK cells, and the STAT1/pSTAT1/TRAIL induction was greater during QUAD therapy than during previous PegIFN/RBV therapy. Successful QUAD therapy as well as successful IFN-free DCV/ASV regimen resulted in an improved functional NK cell response (degranulation and TRAIL expression) to in vitro stimulation with IFNα. CONCLUSIONS IFN-responsiveness can be improved by inhibiting HCV replication and reducing the HCV-induced activation of the innate immune response. This may provide a rationale for clinical trials of a brief period of direct acting antiviral therapy followed by PegIFN/RBV therapy to reduce the overall treatment costs in low-income and middle-income countries. TRIAL REGISTRATION NUMBERS NCT01888900 and NCT00718172.
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Affiliation(s)
- Elisavet Serti
- Immunology Section, National Institutes of Health, DHHS, Bethesda, MD, USA
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, DHHS, Bethesda, MD, USA
| | - Heiyoung Park
- Immunology Section, National Institutes of Health, DHHS, Bethesda, MD, USA
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, DHHS, Bethesda, MD, USA
| | - Meghan Keane
- Immunology Section, National Institutes of Health, DHHS, Bethesda, MD, USA
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, DHHS, Bethesda, MD, USA
| | - Ashley C. O’Keefe
- Immunology Section, National Institutes of Health, DHHS, Bethesda, MD, USA
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, DHHS, Bethesda, MD, USA
| | - Elenita Rivera
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, DHHS, Bethesda, MD, USA
| | - T. Jake Liang
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, DHHS, Bethesda, MD, USA
| | - Marc Ghany
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, DHHS, Bethesda, MD, USA
| | - Barbara Rehermann
- Immunology Section, National Institutes of Health, DHHS, Bethesda, MD, USA
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, DHHS, Bethesda, MD, USA
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Toyota J, Karino Y, Suzuki F, Ikeda F, Ido A, Tanaka K, Takaguchi K, Naganuma A, Tomita E, Chayama K, Fujiyama S, Inada Y, Yoshiji H, Watanabe H, Ishikawa H, Hu W, McPhee F, Linaberry M, Yin PD, Swenson ES, Kumada H. Daclatasvir/asunaprevir/beclabuvir fixed-dose combination in Japanese patients with HCV genotype 1 infection. J Gastroenterol 2017; 52:385-395. [PMID: 27502287 DOI: 10.1007/s00535-016-1245-6] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2016] [Accepted: 07/16/2016] [Indexed: 02/04/2023]
Abstract
BACKGROUND DCV-TRIO, a fixed-dose combination of daclatasvir (pangenotypic NS5A inhibitor), asunaprevir (NS3/4A protease inhibitor), and beclabuvir (non-nucleoside NS5B inhibitor), has achieved high rates of sustained virologic response at post-treatment Week 12 (SVR12) in phase 3 studies. METHODS In this phase 3 study, DCV-TRIO for 12 weeks and daclatasvir plus asunaprevir (DUAL) for 24 weeks were studied in Japanese patients infected with HCV genotype 1 (99 % genotype 1b). RESULTS SVR12 rates ≥95 % were achieved in both treatment-naive (N = 152) and interferon-experienced (N = 65) cohorts treated with DCV-TRIO for 12 weeks and were comparable across patient subgroups, including patients aged ≥65 years and those with cirrhosis. DUAL recipients (N = 75) had an SVR12 rate of 87 %. In the absence of baseline resistance-associated polymorphisms at positions NS5A-Y93H or -L31, SVR12 rates were 98 % with DCV-TRIO or DUAL. Among genotype 1b-infected patients with baseline Y93H or L31 polymorphisms, 35/38 (92 %) DCV-TRIO recipients, and 7/16 (44 %) DUAL recipients achieved SVR12. Adverse events, mostly liver related, led to treatment discontinuation in 10 % of DCV-TRIO recipients. In this group, SVR12 was achieved by 3/9 patients who discontinued before Week 4 and by 12/12 patients who completed ≥4 weeks of DCV-TRIO. Treatment-related serious adverse events occurred in 4 and 3 % of DCV-TRIO and DUAL recipients, respectively. Seven patients (9 %) discontinued DUAL due to adverse events. No deaths occurred. CONCLUSION SVR12 was achieved by 96 % of Japanese patients with HCV genotype 1 infection after 12 weeks of treatment with the DCV-TRIO regimen. DCV-TRIO and DUAL exhibited comparable safety profiles.
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Affiliation(s)
- Joji Toyota
- Department of Gastroenterology, Sapporo-Kosei General Hospital, 8-5 Higashi Kita-3-jo Chuo-ku, Sapporo-shi, Hokkaido, Japan.
| | - Yoshiyasu Karino
- Department of Gastroenterology, Sapporo-Kosei General Hospital, 8-5 Higashi Kita-3-jo Chuo-ku, Sapporo-shi, Hokkaido, Japan
| | - Fumitaka Suzuki
- Toranomon Hospital, 2-2-2 Toranomon, Minato-ku, Tokyo, Japan
| | - Fusao Ikeda
- Okayama University, 2-5-1 Shikata-cho, Kita-ku, Okayama-shi, Okayama, Japan
| | - Akio Ido
- Kagoshima University, 8-35-1 Sakuragoka, Kagoshima-shi, Kagoshima, Japan
| | - Katsuaki Tanaka
- Yokohama City University Medical Center, 4-57 Urafune-cho, Minami-ku, Yokohama, Kanagawa, Japan
| | - Koichi Takaguchi
- Kagawa Prefectural Central Hospital, 1-2-1 Asahimachi, Takamatsu-shi, Kagawa, Japan
| | - Atsushi Naganuma
- Takasaki General Medical Center, 36 Takamatsu-cho, Takasaki-shi, Gunma, Japan
| | - Eiichi Tomita
- Gifu Municipal Hospital, 7-1 Kashima-cho, Gifu-shi, Gifu, Japan
| | - Kazuaki Chayama
- Hiroshima University, 1-2-3 Kasumi, Minami-Ku, Hiroshima-shi, Hiroshima, Japan
| | - Shigetoshi Fujiyama
- Kumamoto Shinto General Hospital, 1-17-27 Shinyashiki, Chuo-ku, Kumamoto, Kumamoto, Japan
| | - Yukiko Inada
- Miyazaki Medical Center Hospital, 2-16 Takamatsu-cho, Miyazaki-shi, Miyazaki, Japan
| | - Hitoshi Yoshiji
- Nara Medical University, 840 Shijocho, Kashihara-shi, Nara, Japan
| | - Hideaki Watanabe
- Bristol-Myers Squibb K.K., 5-1 Nishi-Shinjuku 6-chome, Shinjuku-ku, Tokyo, Japan
| | - Hiroki Ishikawa
- Bristol-Myers Squibb K.K., 5-1 Nishi-Shinjuku 6-chome, Shinjuku-ku, Tokyo, Japan
| | - Wenhua Hu
- Bristol-Myers Squibb, 5 Research Parkway, Wallingford, CT, USA
| | - Fiona McPhee
- Bristol-Myers Squibb, 5 Research Parkway, Wallingford, CT, USA
| | - Misti Linaberry
- Bristol-Myers Squibb, 100 Nassau Park Blvd, Princeton, NJ, USA
| | - Philip D Yin
- Bristol-Myers Squibb, 5 Research Parkway, Wallingford, CT, USA
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Sohda T, Yamauchi E, Anan A, Yokoyama K, Fukunaga A, Yamauchi R, Fukuda S, Takata K, Tanaka T, Hanano T, Kitamura Y, Morihara D, Takeyama Y, Irie M, Shakado S, Sakisaka S. Non-response to daclatasvir and asunaprevir therapy in patients co-infected with hepatitis C virus genotypes 1 and 2. Hepatol Res 2017; 47:364-367. [PMID: 27260815 DOI: 10.1111/hepr.12758] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2015] [Revised: 06/01/2016] [Accepted: 06/02/2016] [Indexed: 02/08/2023]
Abstract
Direct-acting antiviral agents for hepatitis C virus (HCV) have been developed such as combined daclatasvir (DCV) and asunaprevir (ASV) treatment. This typically enables HCV serotype 1 patients to achieve a high sustained virological response rate, but a small number of such patients fail to respond to therapy. We investigated three HCV patients who showed no response to DCV and ASV therapy. Hepatitis C genotyping was undertaken in the three patients using nested polymerase chain reaction and polymerase chain reaction direct sequencing in the core region of the HCV genome. All three patients possessed HCV serotype 1, and no mutations were identified in either the non-structural protein 3 or 5A region. The three patients were shown to be co-infected with HCV genotypes 1 and 2 because genotypes 2a and 2b were also identified. This is the first report into failed response to DCV and ASV therapy in patients co-infected with HCV genotypes 1 and 2.
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Affiliation(s)
- Tetsuro Sohda
- Department of Gastroenterology, Faculty of Medicine, Fukuoka University, Fukuoka, Japan
| | - Eri Yamauchi
- Department of Gastroenterology, Faculty of Medicine, Fukuoka University, Fukuoka, Japan
| | - Akira Anan
- Department of Gastroenterology, Faculty of Medicine, Fukuoka University, Fukuoka, Japan
| | - Keiji Yokoyama
- Department of Gastroenterology, Faculty of Medicine, Fukuoka University, Fukuoka, Japan
| | - Atsushi Fukunaga
- Department of Gastroenterology, Faculty of Medicine, Fukuoka University, Fukuoka, Japan
| | - Ryo Yamauchi
- Department of Gastroenterology, Faculty of Medicine, Fukuoka University, Fukuoka, Japan
| | - Sho Fukuda
- Department of Gastroenterology, Faculty of Medicine, Fukuoka University, Fukuoka, Japan
| | - Kazuhide Takata
- Department of Gastroenterology, Faculty of Medicine, Fukuoka University, Fukuoka, Japan
| | - Takashi Tanaka
- Department of Gastroenterology, Faculty of Medicine, Fukuoka University, Fukuoka, Japan
| | - Takayuki Hanano
- Department of Gastroenterology, Faculty of Medicine, Fukuoka University, Fukuoka, Japan
| | - Yuji Kitamura
- Department of Gastroenterology, Faculty of Medicine, Fukuoka University, Fukuoka, Japan
| | - Daisuke Morihara
- Department of Gastroenterology, Faculty of Medicine, Fukuoka University, Fukuoka, Japan
| | - Yasuaki Takeyama
- Department of Gastroenterology, Faculty of Medicine, Fukuoka University, Fukuoka, Japan
| | - Makoto Irie
- Department of Gastroenterology, Faculty of Medicine, Fukuoka University, Fukuoka, Japan
| | - Satoshi Shakado
- Department of Gastroenterology, Faculty of Medicine, Fukuoka University, Fukuoka, Japan
| | - Shotaro Sakisaka
- Department of Gastroenterology, Faculty of Medicine, Fukuoka University, Fukuoka, Japan
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Koizumi Y, Ohashi H, Nakajima S, Tanaka Y, Wakita T, Perelson AS, Iwami S, Watashi K. Quantifying antiviral activity optimizes drug combinations against hepatitis C virus infection. Proc Natl Acad Sci U S A 2017; 114:1922-1927. [PMID: 28174263 PMCID: PMC5338374 DOI: 10.1073/pnas.1610197114] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
With the introduction of direct-acting antivirals (DAAs), treatment against hepatitis C virus (HCV) has significantly improved. To manage and control this worldwide infectious disease better, the "best" multidrug treatment is demanded based on scientific evidence. However, there is no method available that systematically quantifies and compares the antiviral efficacy and drug-resistance profiles of drug combinations. Based on experimental anti-HCV profiles in a cell culture system, we quantified the instantaneous inhibitory potential (IIP), which is the logarithm of the reduction in viral replication events, for both single drugs and multiple-drug combinations. From the calculated IIP of 15 anti-HCV drugs from different classes [telaprevir, danoprevir, asunaprevir, simeprevir, sofosbuvir (SOF), VX-222, dasabuvir, nesbuvir, tegobuvir, daclatasvir, ledipasvir, IFN-α, IFN-λ1, cyclosporin A, and SCY-635], we found that the nucleoside polymerase inhibitor SOF had one of the largest potentials to inhibit viral replication events. We also compared intrinsic antiviral activities of a panel of drug combinations. Our quantification analysis clearly indicated an advantage of triple-DAA treatments over double-DAA treatments, with triple-DAA treatments showing enhanced antiviral activity and a significantly lower probability for drug resistance to emerge at clinically relevant drug concentrations. Our framework provides quantitative information to consider in designing multidrug strategies before costly clinical trials.
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Affiliation(s)
- Yoshiki Koizumi
- School of Medicine, College of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Ishikawa 920-8640, Japan
| | - Hirofumi Ohashi
- Department of Virology II, National Institute of Infectious Diseases, Tokyo 162-8640, Japan
- Department of Applied Biological Sciences, Faculty of Science and Technology, Tokyo University of Sciences, Chiba 278-8510, Japan
| | - Syo Nakajima
- Department of Virology II, National Institute of Infectious Diseases, Tokyo 162-8640, Japan
- Department of Applied Biological Sciences, Faculty of Science and Technology, Tokyo University of Sciences, Chiba 278-8510, Japan
| | - Yasuhito Tanaka
- Department of Virology and Liver Unit, Nagoya City University Graduate School of Medicinal Sciences, Nagoya 467-8601, Japan
| | - Takaji Wakita
- Department of Virology II, National Institute of Infectious Diseases, Tokyo 162-8640, Japan
| | - Alan S Perelson
- Theoretical Biology and Biophysics Group, Los Alamos National Laboratory, Los Alamos, NM 87545
| | - Shingo Iwami
- Mathematical Biology Laboratory, Department of Biology, Faculty of Sciences, Kyushu University, Fukuoka 812-8581, Japan;
- Precursory Research for Embryonic Science and Technology (PRESTO), Japan Science and Technology Agency, Saitama 332-0012, Japan
- Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency, Saitama 332-0012, Japan
| | - Koichi Watashi
- Department of Virology II, National Institute of Infectious Diseases, Tokyo 162-8640, Japan;
- Department of Applied Biological Sciences, Faculty of Science and Technology, Tokyo University of Sciences, Chiba 278-8510, Japan
- Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency, Saitama 332-0012, Japan
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Mull ES, Sun LQ, Zhao Q, Eggers B, Pokornowski K, Zhai G, Rajamani R, Jenkins S, Kramer M, Wang YK, Fang H, Tenney D, Baldick CJ, Cockett MI, Meanwell NA, Scola PM. Functionalized triazines as potent HCV entry inhibitors. Bioorg Med Chem Lett 2017; 27:1089-1093. [PMID: 28089701 DOI: 10.1016/j.bmcl.2016.12.038] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2016] [Revised: 12/13/2016] [Accepted: 12/14/2016] [Indexed: 01/29/2023]
Abstract
A series of potent and novel acylsulfonamide-bearing triazines were synthesized and the structure-activity relationships (SARs) as HCV entry inhibitors were evaluated. This acylsulfonamide series was derived from an early lead, 4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoic acid wherein the carboxylic acid was replaced with an acylsulfonamide moiety. This structural modification provided a class of compounds which projected an additional vector off the terminus of the acylsulfonamide functionality as a means to drive activity. This effort led to the discovery of potent analogues within this series that demonstrated sub-nanomolar EC50 values in the HCV pseudotype particle (HCVpp) assay.
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Affiliation(s)
- Eric S Mull
- Department of Discovery Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States.
| | - Li-Qiang Sun
- Department of Discovery Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States
| | - Qian Zhao
- Department of Discovery Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States
| | - Betsy Eggers
- Department of Virology Discovery Biology, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States
| | - Kevin Pokornowski
- Department of Virology Discovery Biology, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States
| | - Guangzhi Zhai
- Department of Virology Discovery Biology, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States
| | - Ramkumar Rajamani
- Department of Computer-Assisted Drug Design, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States
| | - Susan Jenkins
- Department of Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States
| | - Melissa Kramer
- Department of Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States
| | - Ying-Kai Wang
- Department of Lead Evaluation, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States
| | - Hua Fang
- Department of Lead Evaluation, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States
| | - Daniel Tenney
- Department of Virology Discovery Biology, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States
| | - Carl J Baldick
- Department of Virology Discovery Biology, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States
| | - Mark I Cockett
- Department of Virology Discovery Biology, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States
| | - Nicholas A Meanwell
- Department of Discovery Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States
| | - Paul M Scola
- Department of Discovery Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States
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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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Iwata H, Ishikawa H. [Pharmacological properties and clinical efficacy of Ximency ® Combination Tablets]. Nihon Yakurigaku Zasshi 2017; 150:153-164. [PMID: 28890478 DOI: 10.1254/fpj.150.153] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/07/2023]
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