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Gan C, Yuan Y, Shen H, Gao J, Kong X, Che Z, Guo Y, Wang H, Dong E, Xiao J. Liver diseases: epidemiology, causes, trends and predictions. Signal Transduct Target Ther 2025; 10:33. [PMID: 39904973 PMCID: PMC11794951 DOI: 10.1038/s41392-024-02072-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2024] [Revised: 10/06/2024] [Accepted: 11/12/2024] [Indexed: 02/06/2025] Open
Abstract
As a highly complex organ with digestive, endocrine, and immune-regulatory functions, the liver is pivotal in maintaining physiological homeostasis through its roles in metabolism, detoxification, and immune response. Various factors including viruses, alcohol, metabolites, toxins, and other pathogenic agents can compromise liver function, leading to acute or chronic injury that may progress to end-stage liver diseases. While sharing common features, liver diseases exhibit distinct pathophysiological, clinical, and therapeutic profiles. Currently, liver diseases contribute to approximately 2 million deaths globally each year, imposing significant economic and social burdens worldwide. However, there is no cure for many kinds of liver diseases, partly due to a lack of thorough understanding of the development of these liver diseases. Therefore, this review provides a comprehensive examination of the epidemiology and characteristics of liver diseases, covering a spectrum from acute and chronic conditions to end-stage manifestations. We also highlight the multifaceted mechanisms underlying the initiation and progression of liver diseases, spanning molecular and cellular levels to organ networks. Additionally, this review offers updates on innovative diagnostic techniques, current treatments, and potential therapeutic targets presently under clinical evaluation. Recent advances in understanding the pathogenesis of liver diseases hold critical implications and translational value for the development of novel therapeutic strategies.
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Affiliation(s)
- Can Gan
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Yuan Yuan
- Aier Institute of Ophthalmology, Central South University, Changsha, China
| | - Haiyuan Shen
- Department of Oncology, the First Affiliated Hospital; The Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Medical University, Hefei, China
| | - Jinhang Gao
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Xiangxin Kong
- Engineering and Translational Medicine, Medical College, Tianjin University, Tianjin, China
| | - Zhaodi Che
- Clinical Medicine Research Institute and Department of Anesthesiology, The First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Yangkun Guo
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Hua Wang
- Department of Oncology, the First Affiliated Hospital; The Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Medical University, Hefei, China.
| | - Erdan Dong
- Research Center for Cardiopulmonary Rehabilitation, University of Health and Rehabilitation Sciences Qingdao Hospital, School of Health and Life Sciences, University of Health and Rehabilitation Sciences, Qingdao, China.
- Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, China.
| | - Jia Xiao
- Clinical Medicine Research Institute and Department of Anesthesiology, The First Affiliated Hospital of Jinan University, Guangzhou, China.
- Department of Gastroenterology, Qingdao Central Hospital, University of Health and Rehabilitation Sciences, Qingdao, China.
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Jose-Abrego A, Laguna-Meraz S, Roman S, Mariscal-Martinez IM, Panduro A. Hepatitis C Virus Resistance-Associated Substitutions in Mexico. Viruses 2025; 17:169. [PMID: 40006924 PMCID: PMC11860613 DOI: 10.3390/v17020169] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2024] [Revised: 01/10/2025] [Accepted: 01/13/2025] [Indexed: 02/27/2025] Open
Abstract
Hepatitis C virus (HCV) is susceptible to resistance-associated substitutions (RASs) in the NS3, NS5A, and NS5B nonstructural genes, key targets of the direct-acting antivirals (DAAs). This study aimed to assess the prevalence and distribution of RASs across different HCV subtypes in Mexico. A Genbank dataset of 566 HCV sequences was analyzed. Most sequences were from Mexico City (49.1%, 278/566) and Jalisco (39.4%, 223/566). The NS5B region was the most sequenced (59.7%, 338/566). The most frequent HCV subtypes were 1a (44.0%, 249/566), 1b (28.6%, 162/566), 2b (9.5%, 54/566), and 3a (6.2%, 35/566). Subtypes 1a (57.4%, 128/223) and 3a (12.6%, 28/223) were significantly higher in Jalisco than in Mexico City (34.2%, 95/278 and 2.5%, 7/278), whereas subtype 1b was higher in Mexico City (34.5%, 96/278 vs. 14.8%, 33/223). Subtype 1a increased from 2019 to 2024, representing 49.4% (123/249) of all reported cases. RASs were detected in NS3 (6.7%, 1/15), NS5A (2.9%, 3/102), and NS5B (0.3%, 1/349), with the most frequent mutations being Q80K, Y93H, and S282T, respectively, and detected in subtypes 1b (n = 3), 1a (n = 1), and 2a (n = 1). In conclusion, Mexico's HCV sequencing-based surveillance is limited. Subtype 1a predominated, but frequencies varied across states. The prevalence of RASs varied by gene from 0.3% to 6.7%. Establishing regional sequencing centers for NS3, NS5A, and NS5B is crucial to monitoring Mexico's DAA-resistant mutations and HCV subtype genetic diversity.
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Affiliation(s)
- Alexis Jose-Abrego
- Department of Genomic Medicine in Hepatology, Civil Hospital of Guadalajara, Fray Antonio Alcalde, Guadalajara 44280, Mexico; (A.J.-A.); (S.L.-M.); (S.R.); (I.M.M.-M.)
- Health Sciences Center, University of Guadalajara, Guadalajara 44340, Mexico
| | - Saul Laguna-Meraz
- Department of Genomic Medicine in Hepatology, Civil Hospital of Guadalajara, Fray Antonio Alcalde, Guadalajara 44280, Mexico; (A.J.-A.); (S.L.-M.); (S.R.); (I.M.M.-M.)
- Health Sciences Center, University of Guadalajara, Guadalajara 44340, Mexico
| | - Sonia Roman
- Department of Genomic Medicine in Hepatology, Civil Hospital of Guadalajara, Fray Antonio Alcalde, Guadalajara 44280, Mexico; (A.J.-A.); (S.L.-M.); (S.R.); (I.M.M.-M.)
- Health Sciences Center, University of Guadalajara, Guadalajara 44340, Mexico
| | - Irene M. Mariscal-Martinez
- Department of Genomic Medicine in Hepatology, Civil Hospital of Guadalajara, Fray Antonio Alcalde, Guadalajara 44280, Mexico; (A.J.-A.); (S.L.-M.); (S.R.); (I.M.M.-M.)
- Health Sciences Center, University of Guadalajara, Guadalajara 44340, Mexico
- Doctoral Program Molecular Biology in Medicine, Health Sciences Center, University of Guadalajara, Guadalajara 44340, Mexico
| | - Arturo Panduro
- Department of Genomic Medicine in Hepatology, Civil Hospital of Guadalajara, Fray Antonio Alcalde, Guadalajara 44280, Mexico; (A.J.-A.); (S.L.-M.); (S.R.); (I.M.M.-M.)
- Health Sciences Center, University of Guadalajara, Guadalajara 44340, Mexico
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Smolobochkin A, Gazizov A, Appazov N, Sinyashin O, Burilov A. Progress in the Stereoselective Synthesis Methods of Pyrrolidine-Containing Drugs and Their Precursors. Int J Mol Sci 2024; 25:11158. [PMID: 39456938 PMCID: PMC11508981 DOI: 10.3390/ijms252011158] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2024] [Revised: 10/11/2024] [Accepted: 10/12/2024] [Indexed: 10/28/2024] Open
Abstract
The presented review systematizes and summarizes the data on the synthesis of pyrrolidine derivatives, which are precursors for obtaining drugs. Based on the analysis of published data, the most promising directions in the synthesis of biologically active compounds containing a pyrrolidine ring are identified. Stereoselective synthesis methods are classified based on the source of the pyrrolidine ring. The first group includes methods that use a pyrrolidine ring as the starting compound. The second group combines stereoselective methods of cyclization of acyclic starting compounds, which lead to optically pure pyrrolidine derivatives.
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Affiliation(s)
- Andrey Smolobochkin
- Arbuzov Institute of Organic and Physical Chemistry, FRC Kazan Scientific Center, Russian Academy of Sciences, Arbuzov Str., 8, Kazan 420088, Russia; (A.G.); (O.S.); (A.B.)
| | - Almir Gazizov
- Arbuzov Institute of Organic and Physical Chemistry, FRC Kazan Scientific Center, Russian Academy of Sciences, Arbuzov Str., 8, Kazan 420088, Russia; (A.G.); (O.S.); (A.B.)
| | - Nurbol Appazov
- Laboratory of Engineering Profile, Department of Engineering Technology, Korkyt Ata Kyzylorda University, Aiteke bi Str., 29A, Kyzylorda 120014, Kazakhstan
| | - Oleg Sinyashin
- Arbuzov Institute of Organic and Physical Chemistry, FRC Kazan Scientific Center, Russian Academy of Sciences, Arbuzov Str., 8, Kazan 420088, Russia; (A.G.); (O.S.); (A.B.)
| | - Alexander Burilov
- Arbuzov Institute of Organic and Physical Chemistry, FRC Kazan Scientific Center, Russian Academy of Sciences, Arbuzov Str., 8, Kazan 420088, Russia; (A.G.); (O.S.); (A.B.)
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Ravi V. QSPR analysis of drugs used for treatment of hepatitis via reduced reverse degree-based topological descriptors. PHYSICA SCRIPTA 2024; 99:105236. [DOI: 10.1088/1402-4896/ad729d] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
Abstract
Abstract
Topological indices refer to numerical values that are structure-invariant and are used to quantify the bonding topology of a molecular graph. The primary objective of studying topological indices is to acquire and modify chemical structure data, thereby establishing a mathematical correlation between structures and physico-chemical properties, bio-activities, and other experimental attributes. Several studies show a high intrinsic correlation between the molecular architectures of pharmaceuticals and their boiling and melting temperatures, as well as other chemical properties. Researchers can discover more about the physical characteristics, chemical stability, and bioactivities of these chemical molecular structures by using topological indices. To compensate for the lack of chemical experiments and to give a theoretical foundation for the production of pharmaceuticals and chemical materials, topological indices on the molecular structure of chemicals/drugs are studied. This study evaluates the chemical structures of medications used to treat hepatitis (A, B, C, D, E and G) based on reduced reverse degree-based topological indices. The success of drug design is influenced by factors such as solubility, metabolic stability, toxicity, permeability, and transporter effects, which are contingent upon the physical and chemical characteristics of the medication. In recent times, computational techniques have gained prominence in the field of hepatitis medication discovery and development. Machine learning is employed by certain systems to assess the effectiveness and adverse effects of medications. The primary focus of this article is to examine the chemical applicability of ten reduced reverse degree-based descriptors in predicting the ten physico-chemical properties for the 16 drugs employed in the treatment of hepatitis.
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Liu CH, Chang YP, Kao JH. Cutting-edge pharmacotherapy for hepatitis C virus infection: a comprehensive review. Expert Opin Pharmacother 2024; 25:1691-1706. [PMID: 39169665 DOI: 10.1080/14656566.2024.2396024] [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: 07/17/2024] [Revised: 08/17/2024] [Accepted: 08/20/2024] [Indexed: 08/23/2024]
Abstract
INTRODUCTION Pharmacotherapy against hepatitis C virus (HCV) infection has tremendously improved since the advent of interferon (IFN)-free direct-acting antivirals (DAAs). Additionally, fixed-dose pangenotypic DAAs, which are safe, potent, easy for use, and can cover a wide spectrum of patients, have been recommended by professional guidelines for DAA-naïve and DAA-experienced patients with HCV. AREAS COVERED We review the pharmacokinetics, pharmacodynamics, and potential drug-drug interactions (DDIs) of fixed-dose pangenotypic DAA regimens, including glecaprevir/pibrentasvir (GLE/PIB), sofosbuvir/velpatasvir (SOF/VEL), and sofosbuvir/velpatasvir/voxilaprevir (SOF/VEL/VOX). Additionally, we summarize the efficacy and safety of these regimens in clinical trials as well as real-world studies for treating different populations. Lastly, we discuss unmet medical needs in managing HCV in the era of fixed-dose pangenotypic DAAs. EXPERT OPINION Protease inhibitors (PIs), including GLE and VOX, are prone to have more frequent DDIs, compared to the non-structural (NS) 5A and 5B inhibitors. These regimens are generally well tolerated and can be applied to different populations, except for the contraindicated use of PI-containing DAA regimens in decompensated cirrhosis. Using the first-line GLE/PIB and SOF/VEL can eradicate HCV in more than 95% of DAA-naïve patients across different populations. The viral cure usually exceeds 95% when using the rescue SOF/VEL/VOX regimen for prior DAA failures.
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Affiliation(s)
- Chen-Hua Liu
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
- Department of Internal Medicine, National Taiwan University Hospital, Yun-Lin Branch, Douliou, Taiwan
| | - Yu-Ping Chang
- Department of Internal Medicine, National Taiwan University Biomedical Park Hospital, Hsin-Chu, Taiwan
| | - Jia-Horng Kao
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
- Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan
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Hao D, Niu LN. Computational Study on the Wealth Conformations of Hepatitis C Virus Envelope Glycoprotein 2 and Role of Its Glycan Coat. J Chem Inf Model 2024; 64:4811-4821. [PMID: 38861660 DOI: 10.1021/acs.jcim.4c00521] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/13/2024]
Abstract
Hepatitis C virus (HCV) is a major cause of chronic liver disease and hepatocellular carcinoma. Antibody development efforts mainly revolve around HCV envelope glycoprotein 2 (E2), which mediates host cell entry by interacting with several cell surface receptors, including CD81. We still have limited knowledge about the structural ensembles and the dynamic behavior of both the CD81 binding sites and the glycans on E2. Here, multiple microsecond-long, all-atom molecular dynamics (MD) simulations, as well as a Markov state model (MSM), were performed to provide an atomistic perspective on the dynamic nature of E2 and its glycans. End-to-end accessibility analyses outline a complete overview of the vulnerabilities of the glycan shield of E2, which may be exploited in therapeutic efforts. Additionally, the Markov state model built from the simulation maps four metastable states for AS412 and three metastable states for the front layer in CD81 binding sites, while binding with HEPC3 would induce a conformation selection for both of them. Overall, this work presents hitherto unseen functional and structural insights into E2 and its glycan coat, providing a new theoretical foundation to control the conformational plasticity of E2 that could be harnessed for vaccine development.
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Affiliation(s)
- Dongxiao Hao
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Key Laboratory of Stomatology, Department of Prosthodontics, School of Stomatology, The Fourth Military Medical University, Xi'an 710032, China
- School of Electronics and Information Engineering, Ankang University, Ankang 725000, China
| | - Li-Na Niu
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Key Laboratory of Stomatology, Department of Prosthodontics, School of Stomatology, The Fourth Military Medical University, Xi'an 710032, China
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Schiano Moriello N, Pinchera B, Gentile I. Personalized care approaches to hepatitis C therapy: recent advances and future directions. Expert Rev Anti Infect Ther 2024; 22:139-151. [PMID: 38459735 DOI: 10.1080/14787210.2024.2328336] [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: 05/31/2023] [Accepted: 03/05/2024] [Indexed: 03/10/2024]
Abstract
INTRODUCTION The introduction of direct-acting antivirals (DAAs) has significantly transformed the therapeutic landscape for chronic C hepatitis virus (HCV) infection. However, there is still room for further improvement in optimizing therapy efficacy and minimizing adverse effects. AREAS COVERED This review is devoted to the rationale for adopting a personalized approach to HCV therapy. Specifically, we explore the role of host-related factors, such as sex or the presence of comorbidities. We thoroughly examine the implications of commonly encountered comorbidities, including HIV infection, chronic renal disease, liver cirrhosis, and other chronic viral hepatitis infections. Additionally, we discuss the prevalent drug-to-drug interactions between DAAs and other medications, while providing guidance on their management. Finally, we investigate viral-related issues that can influence treatment outcomes, such as viral genotype, quasi-species, and the presence of resistance-associated mutations. EXPERT OPINION Despite pivotal trials demonstrating efficacy rates exceeding 90% for currently available DAA regimens, there are still opportunities to optimize therapy outcomes and tailor treatment to each patient. This can be achieved through a meticulous evaluation of the patient's specific clinical conditions and comorbidities, a vigilant approach to manage potential drug interactions, and diligent patient follow-up.
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Affiliation(s)
| | - Biagio Pinchera
- Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Ivan Gentile
- Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy
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Zingg SCW, Lemon K. Donor Viral Hepatitis and Liver Transplantation. Surg Clin North Am 2024; 104:67-77. [PMID: 37953041 DOI: 10.1016/j.suc.2023.07.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2023]
Abstract
Despite increasing numbers of organ transplants completed each year, there continues to be an organ shortage in liver transplantation. This has led to the utilization of previously discarded or "marginal" allografts, such as those from donors with hepatitis C virus (HCV) or hepatitis B virus (HBV). The advent of direct acting antivirals and nucleos(t)ide analogs has allowed these allografts to be safely transplanted regardless of the recipients' hepatitis status with comparable graft and patient survival. Recent advances have even allowed usage of actively viremic donors with similar graft and patient outcomes. This article presents an overview of the use of HCV positive and HBV positive allografts.
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Affiliation(s)
- Sara-Catherine Whitney Zingg
- Department of Surgery, University of Cincinnati College of Medicine, 231 Albert Sabin Way, ML 0558, Cincinnati, OH 45267, USA. https://twitter.com/transplant_u
| | - Kristina Lemon
- Department of Surgery, University of Cincinnati College of Medicine, 231 Albert Sabin Way, ML 0558, Cincinnati, OH 45267, USA; Division of Transplantation, University of Cincinnati School of Mediicne, 231 Albert Sabin Way, ML 0558, Cincinnati, OH 45267, USA.
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Flisiak R, Zarębska-Michaluk D, Berak H, Dybowska D, Sitko M, Parfieniuk-Kowerda A, Janocha-Litwin J, Janczewska E, Piekarska A, Lorenc B, Mazur W, Dobrowolska K, Tudrujek-Zdunek M, Klapaczyński J, Jaroszewicz J. Pangenotypic triple versus double therapy in HCV-infected patients after prior failure of direct-acting antivirals. Clin Exp Hepatol 2023; 9:193-201. [PMID: 37790681 PMCID: PMC10544061 DOI: 10.5114/ceh.2023.130935] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2023] [Accepted: 08/20/2023] [Indexed: 10/05/2023] Open
Abstract
Aim of the study Despite the excellent effectiveness of direct-acting antivirals (DAA) in the treatment of hepatitis C virus (HCV) infection, still a few percent of patients fail therapy. The study aimed to determine the effectiveness of triple vs double rescue treatment in such a population. Material and methods The study included all consecutive DAA-experienced patients retreated with pangenotypic options from the EpiTer-2 database, a retrospective national multicenter real-world project evaluating antiviral treatment in HCV-infected patients in 2015-2023. Results The studied population consisted of 269 patients, of whom 208 were treated with the double (P2) and 61 with the triple (P3) pangenotypic option. No statistically significant differences were found between these subpopulations, except a significantly more frequent history of liver transplantation in the P3 group (6.6% vs. 0.5%, p = 0.01). In the P2 group, two-thirds of patients were treated with velpatasvir/sofosbuvir, while in the P3 group the majority of patients received a combination of velpatasvir/sofosbuvir/voxilaprevir. Virological response at the end of therapy was comparable in both analyzed subpopulations, but the sustained virologic response (SVR) rate was significantly higher in triple retherapy, 98.3% vs. 88.7%, p = 0.02, calculated after exclusion of patients lost to follow-up. Lower SVR was achieved in genotype 3-infected men with cirrhosis, 88.9% and 80% in P3 and P2, respectively. Conclusions A comparison of double and triple pangenotypic retherapy in patients after failure of DAA therapy showed a higher sustained virological response in the triple option with a comparable response at the end of therapy. The factors reducing the chances of cure were cirrhosis, genotype 3 infection and male gender.
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Affiliation(s)
- Robert Flisiak
- Department of Infectious Diseases and Hepatology, Medical University of Białystok, Białystok, Poland
| | | | - Hanna Berak
- Outpatient Clinic, Hospital for Infectious Diseases in Warsaw, Warsaw, Poland
| | - Dorota Dybowska
- Department of Infectious Diseases and Hepatology, Faculty of Medicine, Nicolaus Copernicus University, Bydgoszcz, Poland
| | - Marek Sitko
- Department of Infectious and Tropical Diseases, Jagiellonian University, Kraków, Poland
| | - Anna Parfieniuk-Kowerda
- Department of Infectious Diseases and Hepatology, Medical University of Białystok, Białystok, Poland
| | - Justyna Janocha-Litwin
- Department of Infectious Diseases and Hepatology, Wrocław Medical University, Wrocław, Poland
| | - Ewa Janczewska
- Department of Basic Medical Sciences, School of Public Health in Bytom, Medical University of Silesia, Katowice, Poland
| | - Anna Piekarska
- Department of Infectious Diseases and Hepatology, Medical University of Łódź, Poland
| | - Beata Lorenc
- Pomeranian Center of Infectious Diseases, Medical University of Gdańsk, Gdańsk, Poland
| | - Włodzimierz Mazur
- Clinical Department of Infectious Diseases, Medical University of Silesia, Chorzów, Poland
| | | | | | - Jakub Klapaczyński
- Department of Internal Medicine and Hepatology, The National Institute of Medicine of the Ministry of Interior and Administration, Warsaw, Poland
| | - Jerzy Jaroszewicz
- Department of Infectious Diseases and Hepatology, Medical University of Silesia, Katowice, Poland
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Braude M, Ratnam DT, Marsh L, Abasszade JH, Dev AT. Hepatitis C virus treatment with glecaprevir and pibrentasvir in patients co-prescribed carbamazepine: Three case reports. World J Gastrointest Pharmacol Ther 2023; 14:33-38. [PMID: 37484883 PMCID: PMC10359723 DOI: 10.4292/wjgpt.v14.i4.33] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2023] [Revised: 05/26/2023] [Accepted: 06/19/2023] [Indexed: 07/04/2023] Open
Abstract
BACKGROUND Highly effective and well-tolerated direct-acting antiviral (DAA) therapies have revolutionised the management of hepatitis C virus (HCV); however, niche populations face treatment barriers. DAAs co-prescribed with several first-generation anti-epileptic drugs (AEDs) are contraindicated due to drug-drug interactions. A common example is carbamazepine whereby steady-state carbamazepine reduces the maximum concentration and area under the curve of velpatasvir, glecaprevir and pibrentasvir due to potent cytochrome P450 (CYP) 3A4 induction. Carbamazepine also induces P-glycoprotein which reduces glecaprevir and pibrentasvir’s area under curve to infinite time. Sofosbuvir-velpatasvir and glecaprevir-pibrentasvir are contraindicated in patients who are co-prescribed carbamazepine due to the risk of reduced DAA therapeutic effect and consequently, virological treatment failure. This presents a challenge for patients in whom carbamazepine substitution is medically unfeasible, impractical or unacceptable. However, the properties of current generation DAA therapies, including high-potency non-structural protein 5A inhibitory effect, may be sufficient to overcome reduced bioavailability arising from carbamazepine related CYP 3A4 and P-glycoprotein induction.
CASE SUMMARY We present a case series of three patients with non-cirrhotic, treatment-naïve, genotype 1a, 1b, and 3a HCV who were treated with a 12 wk course of glecaprevir-pibrentasvir, while co-prescribed carbamazepine for seizure disorders. Glecaprevir-pibrentasvir combination therapy was chosen due to its potent in vitro activity and low barrier to pan-genotypic resistance associated variants. DAA therapy was dose-separated from carbamazepine to maximise time to peak concentration, and taken with meals to improve absorption. Sustained virological response at 12 wk was achieved in each patient with no adverse outcomes.
CONCLUSION DAA therapies, including glecaprevir-pibrentasvir, warrant consideration as a therapeutic agent in people with HCV who are co-prescribed carbamazepine, particularly if AED substitution is not feasible.
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Affiliation(s)
- Michael Braude
- Department of Gastroenterology and Hepatology, Monash Health, Clayton 3168, VIC, Australia
| | - Dilip T Ratnam
- Department of Gastroenterology and Hepatology, Monash Health, Clayton 3168, VIC, Australia
| | - Louise Marsh
- General Practice, Margaret River Medical Centre, Margaret River 6285, Australia
| | - Joshua H Abasszade
- Department of Gastroenterology and Hepatology, Monash Health, Clayton 3168, VIC, Australia
| | - Anouk T Dev
- Department of Gastroenterology and Hepatology, Monash Health, Clayton 3168, VIC, Australia
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Bhattacharya D, Aronsohn A, Price J, Lo Re V. Hepatitis C Guidance 2023 Update: AASLD-IDSA Recommendations for Testing, Managing, and Treating Hepatitis C Virus Infection. Clin Infect Dis 2023:ciad319. [PMID: 37229695 DOI: 10.1093/cid/ciad319] [Citation(s) in RCA: 66] [Impact Index Per Article: 33.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2023] [Revised: 05/11/2023] [Accepted: 05/23/2023] [Indexed: 05/27/2023] Open
Abstract
The Infectious Diseases Society of America and the American Association for the Study of Liver Diseases have collaboratively developed evidence-based guidance regarding the diagnosis, management, and treatment of hepatitis C virus (HCV) infection since 2013. A panel of clinicians and investigators with extensive infectious diseases or hepatology expertise specific to HCV infection periodically review evidence from the field and update existing recommendations or introduce new recommendations as evidence warrants. This update focuses on changes to the guidance since the previous 2020 published update, including ongoing emphasis on recommended universal screening; management recommendations for incomplete treatment adherence; expanded eligibility for simplified chronic HCV infection treatment in adults with minimal monitoring; updated treatment and retreatment recommendations for children as young as 3 years old; management and treatment recommendations in the transplantation setting; and screening, treatment, and management recommendations for unique and key populations.
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Affiliation(s)
- Debika Bhattacharya
- Department of Medicine, Division of Infectious Diseases, David Geffen School of Medicine at UCLA
| | - Andrew Aronsohn
- Department of Medicine, Section of Gastroenterology, Hepatology and Nutrition, University of Chicago
| | - Jennifer Price
- Division of Medicine, Department of Gastroenterology and Hepatology, University of California, San Francisco
| | - Vincent Lo Re
- Department of Medicine, Division of Infectious Diseases and Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania Perelman School of Medicine
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Schulz P, Wiginton A, Mahgoub A. Newly diagnosed hepatitis C infection after pancreas transplantation with multiple treatment failures. BMJ Case Rep 2023; 16:e254331. [PMID: 37137548 PMCID: PMC10163427 DOI: 10.1136/bcr-2022-254331] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/05/2023] Open
Abstract
This case represents the first report of a detected hepatitis C virus (HCV) infection following a pancreas transplantation that failed two different sofosbuvir (SOF)-based treatments. We present the case of a woman in her 30s with a history of kidney transplantation, who developed viremic symptoms 3 months after pancreas transplantation and with two subsequent negative HCV antibody tests. Further work-up revealed a positive HCV RNA test (genotype 1A, treatment naive). Two different direct-acting antiviral agents regimes with SOF failed in our case, and the patient achieved a sustained virological response with a 16-week course of glecaprevir/pibrentasvir.
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Affiliation(s)
- Philipp Schulz
- Internal Medicine, Texas Tech University Health Sciences Center School of Medicine Permian Basin, Odessa, Texas, USA
| | - Ashley Wiginton
- Transplant Hepatology and Gastroenterology, Baylor University Medical Center, Dallas, Texas, USA
| | - Amar Mahgoub
- Transplant Hepatology and Gastroenterology, Baylor University Medical Center, Dallas, Texas, USA
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13
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Kosloski MP, Li H, Wang S, Mensa F, Kort J, Liu W. Characterizing complex and competing drug-drug interactions between the antiviral regimen of glecaprevir and pibrentasvir with rifampin or carbamazepine. Clin Transl Sci 2023; 16:593-605. [PMID: 36597378 PMCID: PMC10087067 DOI: 10.1111/cts.13471] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2022] [Revised: 12/12/2022] [Accepted: 12/16/2022] [Indexed: 01/05/2023] Open
Abstract
The fixed-dose combination of the direct acting antivirals glecaprevir (GLE) and pibrentasvir (PIB) is an oral, once-daily treatment for all six major genotypes of chronic hepatitis C virus infection. A single and multiple-dose rifampin study (N = 12) and a carbamazepine study (N = 12) were conducted in healthy subjects to evaluate the effects of CYP3A/P-gp induction and OATP inhibition on the pharmacokinetics of GLE and PIB. In study 1, GLE 300 mg + PIB 120 mg was administered as a single dose either alone, after single and multiple daily doses of rifampin 600 mg, or 24 h after the last rifampin dose. In study 2, GLE 300 mg + PIB 120 mg was administered as a single dose either alone or after multiple doses of carbamazepine 200 mg. Relative to GLE + PIB alone, exposure of GLE was significantly increased by the first co-administered rifampin dose due to OATP inhibition, significantly decreased 24 h after the last rifampin dose due to CYP3A/P-gp induction, and slightly increased when co-administered with steady-state rifampin due to a combination of inhibition and induction forces. Exposure of PIB was not affected when co-administered with the first rifampin dose but was significantly decreased with steady-state rifampin co-administration, or 24 h after the last rifampin dose due to P-gp induction. Carbamazepine significantly decreased GLE and PIB exposure, mainly attributed to P-gp induction. The regimens tested were generally well-tolerated by the subjects and no new safety issues were identified.
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Affiliation(s)
| | - Hong Li
- Data and Statistical Sciences, AbbVie Inc., North Chicago, Illinois, USA
| | - Stanley Wang
- Infectious Disease, AbbVie Inc., North Chicago, Illinois, USA
| | - Federico Mensa
- Infectious Disease, AbbVie Inc., North Chicago, Illinois, USA
| | - Jens Kort
- Medical Affairs, AbbVie Inc., North Chicago, Illinois, USA
| | - Wei Liu
- Clinical Pharmacology, AbbVie Inc., North Chicago, Illinois, USA
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14
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Feld JJ, Forns X, Dylla DE, Kumada H, de Ledinghen V, Wei L, Brown RS, Flisiak R, Lampertico P, Thabut D, Bondin M, Tatsch F, Burroughs M, Marcinak J, Zhang Z, Emmett A, Jacobson IM. Safety analysis of glecaprevir/pibrentasvir in patients with markers of advanced liver disease in clinical and real-world cohorts. J Viral Hepat 2022; 29:1050-1061. [PMID: 36036117 PMCID: PMC9827821 DOI: 10.1111/jvh.13738] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Revised: 04/28/2022] [Accepted: 07/06/2022] [Indexed: 01/18/2023]
Abstract
Chronic hepatitis C virus (HCV) infection has the greatest health impact in patients with advanced liver disease. The direct-acting antiviral (DAA) regimen glecaprevir/pibrentasvir (G/P) is approved for treatment of HCV-infected patients without cirrhosis and with compensated cirrhosis. However, events of liver decompensation/failure have been reported in patients treated with protease-inhibitor-containing DAA regimens, often in patients with advanced liver disease. This study examines the safety of on-label G/P treatment in patients with compensated cirrhosis (F4 at baseline) with markers of advanced liver disease. Patients with cirrhosis were categorized into 4 subgroups, based on different noninvasive markers of advanced liver disease identified using laboratory measures: platelet count < or ≥ 100 × 109 /L, and Child-Pugh score 5 or 6. Separate analyses were performed using pooled data from clinical trials and from real-world post-marketing observational studies. G/P was well tolerated in patients with platelet count ≥100 × 109 /L (n = 800), platelet count <100 × 109 /L (n = 215), a Child-Pugh score of 5 (n = 915) and a Child-Pugh score of 6 (n = 95). In the clinical trial and real-world cohorts two patients and no patients experienced a serious adverse event (AE) possibly related to study drug, respectively; three patients and no patients experienced an AE of special interest for hepatic decompensation and hepatic failure. This analysis reaffirms G/P's safety profile in indicated patients with compensated cirrhosis, including those with markers of more advanced liver disease. Increasing the number of patients treated with short-duration G/P therapy may contribute to meeting HCV elimination targets.
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Affiliation(s)
- Jordan J. Feld
- Toronto Centre for Liver DiseaseUniversity Health Network, University of TorontoTorontoOntarioCanada
| | - Xavier Forns
- Liver Unit, Hospital ClinicUniversity of Barcelona, IDIBAPS and CIBEREHDBarcelonaSpain
| | | | | | | | - Lai Wei
- Peking University People's HospitalPeking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver DiseaseBeijingChina,Beijing Tsinghua Changgung HospitalTsinghua UniversityBeijingChina
| | - Robert S. Brown
- Center for Liver Disease and TransplantationWeill Cornell Medical CollegeNew YorkNew YorkUSA
| | - Robert Flisiak
- Department of Infectious Diseases and HepatologyMedical University of Białystok, BiałystokBialystokPoland
| | - Pietro Lampertico
- Division of Gastroenterology and HepatologyFoundation IRCCS Ca’ Granda Ospedale Maggiore Policlinico, CRC “A. M. and A. Migliavacca” Center for Liver DiseaseMilanItaly,Department of Pathophysiology and TransplantationUniversity of MilanMilanItaly
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15
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Hasan SA, Dauner DG, Rajpurohit A, Farley JF. Direct-acting antiviral retreatment patterns for hepatitis C. J Manag Care Spec Pharm 2022; 28:1100-1110. [PMID: 36125057 PMCID: PMC10372973 DOI: 10.18553/jmcp.2022.28.10.1100] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
BACKGROUND: Despite the strong efficacy of direct-acting antivirals (DAAs) against the hepatitis C virus, many patients require a second regimen of DAA treatment. However, limited research exists to characterize rates of retreatment across different DAA agents or potential factors that may increase retreatment risk. OBJECTIVE: To characterize patterns and predictors of DAA retreatment among a large, generalizable, commercially insured US population of patients. METHODS: Using the IBM MarketScan Commercial Claims and Encounters data source, this retrospective cohort study examined retreatment patterns among patients receiving DAAs between 2013 and 2019. Descriptive statistics were used to compare patient characteristics predictive of retreatment risk and to examine rates of retreatment in patients initiating different DAA treatments. RESULTS: Among 31,553 DAA users, a total of 1,017 (3.2%) required DAA retreatment. Among the 1,017 patients re-treated, 44 (4.3%) received a third treatment regimen and 2 patients received a fourth treatment regimen. The average total cost for a retreatment regimen was $109,683, with patient out-of-pocket costs totaling $1,287 Patients requiring retreatment had higher rates of hypertension (32.0% vs 26.7%; P < 0.001), diabetes (16.9% vs 11.9%; P < 0.001), coagulopathy (9.9% vs 4.5%; P < 0.001), deficiency anemia (11.1% vs 7.4%; P < 0.001), alcohol abuse (3.3% vs 2.3%; P = 0.038), prior liver transplantation (3.4% vs 2.3%; P = 0.024), and hepatocellular carcinoma (6.1% vs 1.9%; P < 0.001) compared with patients not requiring retreatment. CONCLUSIONS: Although uncommon, some patients receiving DAAs require a second regimen of DAA treatment at substantial cost to both health plans and patients. These patients tend to have more comorbidities and markers of hepatic disease severity. Patients with high retreatment risk may benefit from careful monitoring for occurrences of retreatment.
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Affiliation(s)
- Shaquib Al Hasan
- Social and Administrative Pharmacy Graduate Program, College of Pharmacy, University of Minnesota, Minneapolis
| | - Daniel G Dauner
- Social and Administrative Pharmacy Graduate Program, College of Pharmacy, University of Minnesota, Minneapolis
| | - Abhijeet Rajpurohit
- Department of Pharmaceutical Care and Health Systems, College of Pharmacy, University of Minnesota, Minneapolis
| | - Joel F Farley
- Department of Pharmaceutical Care and Health Systems, College of Pharmacy, University of Minnesota, Minneapolis
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16
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Okubo H, Atsukawa M, Okubo T, Ando H, Nakadera E, Ikejima K, Nagahara A. Gadoxetic acid-enhanced magnetic resonance imaging predicts hyperbilirubinemia induced by glecaprevir during hepatitis C virus treatment. Sci Rep 2022; 12:7847. [PMID: 35552472 PMCID: PMC9098462 DOI: 10.1038/s41598-022-11707-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2021] [Accepted: 04/25/2022] [Indexed: 02/01/2023] Open
Abstract
Glecaprevir is a substrate for organic anion-transporting polypeptide (OATP) 1B1/1B3, which transports bilirubin. Hyperbilirubinemia is an adverse event during anti-hepatitis C virus treatment with glecaprevir and pibrentasvir. Gadoxetic acid is also transported by OATP1B1/1B3, and we aimed to evaluate whether gadoxetic acid-enhanced magnetic resonance (MR) imaging was associated with glecaprevir trough concentrations (Ctrough). We further determined whether this was predictive of hyperbilirubinemia development in a cohort of 33 patients. The contrast enhancement index (CEI), a measure of hepatic enhancement effect on the hepatobiliary image, was assessed. Glecaprevir Ctrough was determined 7 days after administration. Five of the 33 patients (15%) developed Common Terminology Criteria for Adverse Events grade ≥ 2 hyperbilirubinemia. We found a negative relationship between CEI and Ctrough (r = − 0.726, p < 0.001). The partial correlation coefficient between CEI and Ctrough was − 0.654 (p < 0.001), while excluding the effects of albumin, FIB-4 index, and indirect bilirubin at baseline. The Ctrough was significantly higher in patients with hyperbilirubinemia than in those without (p = 0.008). In multivariate analysis, CEI ≤ 1.71 was an independent factor influencing the development of hyperbilirubinemia (p = 0.046). Our findings indicate that gadoxetic acid MR imaging can help predict glecaprevir concentration and development of hyperbilirubinemia.
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Affiliation(s)
- Hironao Okubo
- Department of Gastroenterology, Juntendo University Nerima Hospital, 3-1-10 Takanodai, Nerima-ku, Tokyo, 177-8521, Japan.
| | - Masanori Atsukawa
- Division of Gastroenterology, Department of Internal Medicine, Nippon Medical School Chiba Hokusoh Hospital, 1715 Kamagari, Inzai, Chiba, 270-1694, Japan.,Division of Gastroenterology, Department of Internal Medicine, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo, 113-8603, Japan
| | - Tomomi Okubo
- Division of Gastroenterology, Department of Internal Medicine, Nippon Medical School Chiba Hokusoh Hospital, 1715 Kamagari, Inzai, Chiba, 270-1694, Japan
| | - Hitoshi Ando
- Department of Cellular and Molecular Function Analysis, Graduate School of Medical Sciences, Kanazawa University, 13-1 Takara-machi, Kanazawa, 920-8640, Japan
| | - Eisuke Nakadera
- Department of Gastroenterology, Juntendo University Nerima Hospital, 3-1-10 Takanodai, Nerima-ku, Tokyo, 177-8521, Japan
| | - Kenichi Ikejima
- Department of Gastroenterology, Graduate School of Medicine, Juntendo University, 3-1-3 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan
| | - Akihito Nagahara
- Department of Gastroenterology, Graduate School of Medicine, Juntendo University, 3-1-3 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan
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17
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Chen JJ, Chiu YC, Lee PL, Tung HD, Chiu HC, Chien SC, Cheng PN. Real-world effectiveness and safety of sofosbuvir/velpatasvir and glecaprevir/pibrentasvir for genotype 6 chronic hepatitis C. J Formos Med Assoc 2022; 121:2265-2272. [PMID: 35581112 DOI: 10.1016/j.jfma.2022.04.020] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2021] [Revised: 04/25/2022] [Accepted: 04/28/2022] [Indexed: 12/29/2022] Open
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18
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Patnaik R, Tsai E. Hepatitis C Virus Treatment and Solid Organ Transplantation. Gastroenterol Hepatol (N Y) 2022; 18:85-94. [PMID: 35505819 PMCID: PMC9053510] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
Hepatitis C virus (HCV) infection is a common indication for liver transplantation. If the patient's HCV is untreated prior to liver transplant, infection of the allograft is nearly universal and can lead to graft failure. The demand for deceased-donor organ transplantation continues to surpass the available supply of donor organs. Waitlist mortality remains an important concern, and several strategies have been enacted to increase organ supply, such as using high-risk donors, including those who are HCV positive. The development of safe and highly effective HCV therapy with direct-acting antiviral agents has revolutionized the management of liver transplant candidates and transplantrecipients. Moreover, thenewer antiviral therapieshave paved the road for use of HCV-viremic organs, effectively expanding the donor pool and changing the landscape of solid organ transplantation. This article reviews the data on HCV treatment prior to and after organ transplantation.
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Affiliation(s)
| | - Eugenia Tsai
- UT Health San Antonio, San Antonio, Texas
- Texas Liver Institute, San Antonio, Texas
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19
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Miyasaka A, Yoshida Y, Murakami A, Hoshino T, Sawara K, Numao H, Takikawa Y. Safety and efficacy of glecaprevir and pibrentasvir in north Tohoku Japanese patients with genotype 1/2 hepatitis C virus infection. Health Sci Rep 2022; 5:e458. [PMID: 35024454 PMCID: PMC8733835 DOI: 10.1002/hsr2.458] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2021] [Revised: 10/03/2021] [Accepted: 11/13/2021] [Indexed: 12/11/2022] Open
Abstract
Background and aims To assess the efficacy and safety of treatment with glecaprevir/pibrentasvir in Japanese patients with genotype (GT) 1/2 hepatitis C virus (HCV) infection in a real‐world clinical setting. Methods A total of 230 patients from 12 centers in northern Tohoku Japan with chronic hepatitis (CH) or compensated liver cirrhosis (LC) and GT1/2 HCV infection were treated with glecaprevir/pibrentasvir and followed up for 12 weeks after treatment completion. Those patients were evaluated by dividing them into the following three groups: CH GT1/2 HCV‐infected, direct‐acting antiviral agents (DAA)‐naive patients received 8 weeks of treatment (8‐week initial treatment group), compensated LC GT1/2 HCV‐infected, DAA‐naive patients received 12 weeks of treatment (12‐week initial treatment group), and GT1/2 HCV‐infected patients with previous failed DAA treatment were assigned to 12‐week treatment (12‐week re‐treatment group). Results The overall sustained virologic response (SVR) rate in the modified intention‐to‐treat population was 99% (222/225). The SVR rate in 8‐week initial treatment group, 12‐week initial treatment group, and 12‐week re‐treatment group were 99% (118/119), 98% (104/106), and 97% (56/58), respectively. SVR rates based on chronic kidney disease (CKD) stage were 99% in stage 1/2, 96% in stage 3, and 100% in stage 4/5 patients. SVR rate among the three treatment groups was not influenced by CKD stage. Furthermore, all 18 patients (six in the 8‐week initial treatment group, 12 in 12‐week initial treatment group) who underwent hemodialysis attained SVR. Serious treatment‐associated adverse events (grade ≥ 3) occurred in 12 patients (5.2%). Five patients (2.2%) discontinued treatment because of adverse events; however, three of these patients achieved SVR. Conclusion Primary treatment and re‐treatment with glecaprevir/pibrentasvir are effective and safe for patients without decompensated LC and GT1/2 HCV infection in a real‐world clinical setting. Furthermore, the SVR rate was not influenced by CKD stage.
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Affiliation(s)
- Akio Miyasaka
- Division of Hepatology, Department of Internal Medicine Iwate Medical University School of Medicine Shiwa-gun Japan
| | - Yuichi Yoshida
- Division of Hepatology, Department of Internal Medicine Iwate Medical University School of Medicine Shiwa-gun Japan
| | - Akihiko Murakami
- Department of Gastroenterology Iwate Prefectural Miyako hospital Miyako Japan
| | - Takao Hoshino
- Department of Gastroenterology Akita Kosei Medical Center Akita Japan
| | - Kei Sawara
- Division of Hepatology, Department of Internal Medicine Iwate Medical University School of Medicine Shiwa-gun Japan.,Department of Gastroenterology Iwate Prefectural Kamaishi Hospital Kamaishi Japan
| | - Hiroshi Numao
- Department of Gastroenterology Aomori Prefectural Central Hospital Aomori Japan
| | - Yasuhiro Takikawa
- Division of Hepatology, Department of Internal Medicine Iwate Medical University School of Medicine Shiwa-gun Japan.,Department of Hepatology San-ai hospital Morioka Japan
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20
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Abstract
In the 1970s, an unknown virus was suspected for documented cases of transfusion-associated hepatitis, a phenomenon called non-A, non-B hepatitis. In 1989, the infectious transmissible agent was identified and named hepatitis C virus (HCV) and, soon enough, the first diagnostic HCV antibody test was developed, which led to a dramatic decrease in new infections. Today, HCV infection remains a global health burden and a major cause of liver cirrhosis, hepatocellular carcinoma and liver transplantation. However, tremendous advances have been made over the decades, and HCV became the first curable, chronic viral infection. The introduction of direct antiviral agents revolutionized antiviral treatment, leading to viral eradication in more than 98% of all patients infected with HCV. This Perspective discusses the history of HCV research, which reads like a role model for successful translational research: starting from a clinical observation, specific therapeutic agents were developed, which finally were implemented in national and global elimination programmes.
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Affiliation(s)
- Michael P. Manns
- grid.10423.340000 0000 9529 9877Hannover Medical School, Hannover, Germany
| | - Benjamin Maasoumy
- grid.10423.340000 0000 9529 9877Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
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21
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Akutsu N, Sasaki S, Matsui T, Akashi H, Yonezawa K, Ishigami K, Tsujisaki M, Isshiki H, Yawata A, Yamaoka S, Ban T, Adachi T, Nakahara S, Takagi H, Nakachi K, Tanaka K, Hirano T, Yamamoto I, Kaneto H, Wagatsuma K, Numata Y, Nakase H. Association of the Low-density Lipoprotein Cholesterol/High-density Lipoprotein Cholesterol Ratio with Glecaprevir-pibrentasvir Treatment. Intern Med 2021; 60:3369-3376. [PMID: 34024854 PMCID: PMC8627811 DOI: 10.2169/internalmedicine.7098-21] [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] [Indexed: 11/06/2022] Open
Abstract
Objective The change in serum lipid levels by direct-acting antiviral (DAA) treatment for chronic hepatitis C varies depending on the type of DAA. How the lipid level changes induced by glecaprevir-pibrentasvir (G/P) treatment contribute to the clinical outcome remains unclear. We conducted a prospective observational study to evaluate the effectiveness of G/P treatment and the lipid level changes. Methods The primary endpoint was a sustained virologic response at 12 weeks (SVR12). The total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglyceride (TG) levels and LDL-C/HDL-C (L/H) ratio were measured every two weeks. Patients This study included 101 patients. Seventeen cases of liver cirrhosis and nine cases of DAA retreatment were registered. The G/P treatment period was 8 weeks in 74 cases and 12 weeks in 27 cases. Results SVR12 was evaluated in 96 patients. The rate of achievement of SVR12 in the evaluable cases was 100%. We found significantly elevated TC and LDL-C levels over the observation period compared to baseline. The serum levels of HDL-C did not change during treatment but were significantly increased after treatment compared to baseline. The L/H ratio was significantly increased two weeks after the start of treatment but returned to the baseline after treatment. Conclusion The primary endpoint of the SVR12 achievement rate was 100%. G/P treatment changed the serum lipid levels. Specifically, the TC and LDL-C levels increased during and after treatment, and the HDL-C levels increased after treatment. G/P treatment may be associated with a reduced thrombotic risk. Therefore, validation in large trials is recommended.
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Affiliation(s)
- Noriyuki Akutsu
- Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, Japan
| | - Shigeru Sasaki
- Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, Japan
| | - Takeshi Matsui
- Department of Gastroenterology, Teine Keijinkai Hospital, Japan
| | - Hirofumi Akashi
- Department of Internal Medicine, Saiseikai Otaru Hospital, Japan
| | - Kazuhiko Yonezawa
- Department of Gastroenterology, Kushiro City General Hospital, Japan
| | - Keisuke Ishigami
- Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, Japan
| | | | - Hiroyuki Isshiki
- Department of Gastroenterology, Hakodate Goryoukaku Hospital, Japan
| | - Atsushi Yawata
- Department of Gastroenterology, Hakodate Goryoukaku Hospital, Japan
| | - Satoshi Yamaoka
- Department of Gastroenterology, Sapporo Satozuka Hospital, Japan
| | - Toshihiro Ban
- Department of Gastroenterology, Sapporo Shirakabadai Hospital, Japan
| | - Takeya Adachi
- Department of Gastroenterology, JR Sapporo Hospital, Japan
| | - Seiya Nakahara
- Department of Gastroenterology, Sapporo Teishinkai Hospital, Japan
| | - Hideyasu Takagi
- Department of Gastroenterology, Sapporo Teishinkai Hospital, Japan
| | - Kohei Nakachi
- Department of Medical Oncology, Tochigi Cancer Center, Japan
| | - Katsunori Tanaka
- Department of Gastroenterology, Sapporo Gekakinen Hospital, Japan
| | - Takehiro Hirano
- Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, Japan
| | - Itaru Yamamoto
- Department of Gastroenterology, Obihiro Kyokai Hospital, Japan
| | - Hiroyuki Kaneto
- Department of Gastroenterology, Muroran City General Hospital, Japan
| | - Kohei Wagatsuma
- Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, Japan
| | - Yasunao Numata
- Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, Japan
| | - Hiroshi Nakase
- Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, Japan
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22
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Delphin M, Desmares M, Schuehle S, Heikenwalder M, Durantel D, Faure-Dupuy S. How to get away with liver innate immunity? A viruses' tale. Liver Int 2021; 41:2547-2559. [PMID: 34520597 DOI: 10.1111/liv.15054] [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: 05/23/2021] [Revised: 08/20/2021] [Accepted: 09/08/2021] [Indexed: 12/24/2022]
Abstract
In their never-ending quest towards persistence within their host, hepatitis viruses have developed numerous ways to counteract the liver innate immunity. This review highlights the different and common mechanisms employed by these viruses to (i) establish in the liver (passive entry or active evasion from immune recognition) and (ii) actively inhibit the innate immune response (ie modulation of pattern recognition receptor expression and/or signalling pathways, modulation of interferon response and modulation of immune cells count or phenotype).
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Affiliation(s)
- Marion Delphin
- International Center for Infectiology Research (CIRI), INSERM U1111, CNRS UMR5308, Université de Lyon (UCBL1), Lyon, France
| | - Manon Desmares
- International Center for Infectiology Research (CIRI), INSERM U1111, CNRS UMR5308, Université de Lyon (UCBL1), Lyon, France
| | - Svenja Schuehle
- Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.,Faculty of Biosciences, Heidelberg University, Heidelberg, Germany
| | - Mathias Heikenwalder
- Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.,Department of Infectious Diseases, Molecular Virology, Heidelberg University, Heidelberg, Germany
| | - David Durantel
- International Center for Infectiology Research (CIRI), INSERM U1111, CNRS UMR5308, Université de Lyon (UCBL1), Lyon, France.,DEVweCAN Laboratory of Excellence, Lyon, France
| | - Suzanne Faure-Dupuy
- Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.,Department of Infectious Diseases, Molecular Virology, Heidelberg University, Heidelberg, Germany
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23
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Feldman TC, Dienstag JL, Mandl KD, Tseng YJ. Machine-learning-based predictions of direct-acting antiviral therapy duration for patients with hepatitis C. Int J Med Inform 2021; 154:104562. [PMID: 34482150 DOI: 10.1016/j.ijmedinf.2021.104562] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Revised: 08/15/2021] [Accepted: 08/16/2021] [Indexed: 02/09/2023]
Abstract
INTRODUCTION Hepatitis C, which affects 71 million persons worldwide, is the most common blood-borne pathogen in the United States. Chronic infections can be treated effectively thanks to the availability of modern direct-acting antiviral (DAA) therapies. Real-world data on the duration of DAA therapy, which can be used to optimize and guide the course of therapy, may also be useful in determining quality of life enhancements based upon total required supply of medication and long-term improvements to quality of life. We developed a machine learning model to identify patient characteristics associated with prolonged DAA treatment duration. METHODS A nationwide U.S. commercial managed care plan with claims data that covers about 60 million beneficiaries from 2009 to 2019 were used in the retrospective study. We examined differences in age, gender, and multiple comorbidities among patients treated with different durations of DAA treatment. We also examined the performance of machine learning models for predicting a prolonged course of DAA based on the area under the receiver operating characteristic curve (AUC). RESULTS We identified 3943 cases with hepatitis C who received sofosbuvir/ledipasvir as the first course of DAA and were eligible for the study. Patients receiving prolonged treatment (n = 240, 6.1%) were more likely to have compensated cirrhosis, decompensated cirrhosis, and other comorbidities (P < 0.001). For distinguishing patients who received prolonged DAA treatment for hepatitis C from patients received standard treatment, the optimal predictive model, constructed with XGBoost, had an AUC of 0.745 ± 0.031 (P < 0.001). CONCLUSIONS The risk of antiviral resistance and the cost of DAA are strong motivators to ensure that first-round DAA therapy is effective. For the dominant DAA treatment during the course of this analysis, we present a model that identifies factors already captured in established guidelines and adds to those age, comorbidity burden, and type 2 diabetes status; patient characteristics that are predictive of extended treatment.
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Affiliation(s)
- Theodore C Feldman
- Computational Health Informatics Program, Boston Children's Hospital, Boston, MA, USA; Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA; VA Boston Healthcare System, Boston, MA, USA
| | - Jules L Dienstag
- Gastrointestinal Unit, Massachusetts Hospital, Boston, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA
| | - Kenneth D Mandl
- Computational Health Informatics Program, Boston Children's Hospital, Boston, MA, USA; Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA; Department of Pediatrics, Harvard Medical School, Boston, MA, USA
| | - Yi-Ju Tseng
- Computational Health Informatics Program, Boston Children's Hospital, Boston, MA, USA; Department of Information Management, National Central University, Taoyuan, Taiwan.
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Higuera-de la Tijera F, Servín-Caamaño A, Servín-Abad L. Progress and challenges in the comprehensive management of chronic viral hepatitis: Key ways to achieve the elimination. World J Gastroenterol 2021; 27:4004-4017. [PMID: 34326610 PMCID: PMC8311524 DOI: 10.3748/wjg.v27.i26.4004] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Revised: 03/04/2021] [Accepted: 06/17/2021] [Indexed: 02/06/2023] Open
Abstract
Chronic viral hepatitis is a significant health problem throughout the world, which already represents high annual mortality. By 2040, chronic viral hepatitis due to virus B and virus C and their complications cirrhosis and hepatocellular carcinoma will be more deadly than malaria, vitellogenesis-inhibiting hormone, and tuberculosis altogether. In this review, we analyze the global impact of chronic viral hepatitis with a focus on the most vulnerable groups, the goals set by the World Health Organization for the year 2030, and the key points to achieve them, such as timely access to antiviral treatment of direct-acting antiviral, which represents the key to achieving hepatitis C virus elimination. Likewise, we review the strategies to prevent transmission and achieve control of hepatitis B virus. Finally, we address the impact that the coronavirus disease 2019 pandemic has had on implementing elimination strategies and the advantages of implementing telemedicine programs.
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MESH Headings
- Antiviral Agents/therapeutic use
- COVID-19
- Hepatitis B, Chronic/diagnosis
- Hepatitis B, Chronic/drug therapy
- Hepatitis B, Chronic/epidemiology
- Hepatitis C, Chronic/diagnosis
- Hepatitis C, Chronic/drug therapy
- Hepatitis C, Chronic/epidemiology
- Hepatitis, Viral, Human/diagnosis
- Hepatitis, Viral, Human/drug therapy
- Hepatitis, Viral, Human/epidemiology
- Humans
- Liver Neoplasms/drug therapy
- Liver Neoplasms/epidemiology
- Liver Neoplasms/prevention & control
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Affiliation(s)
| | | | - Luis Servín-Abad
- Department of Gastroenterology, Saint Cloud Hospital, Saint Cloud, MN 56303, United States
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25
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Tani J, Sakamoto T, Yoshino S, Okada A, Koyama Y, Suetsugu F, Ando T, Matsuoka Y, Masaki T. Efforts to identify HCV antibody-positive patients in a medium-sized hospital by "Team hepatitis" composed of hospital staff with a hepatitis medical care coordinator. KANZO 2021; 62:337-348. [DOI: 10.2957/kanzo.62.337] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Affiliation(s)
- Joji Tani
- Department of Gastroenterology and Neurology, Kagawa University Faculty of Medicine
- Yashima General Hospital
| | | | | | | | | | | | | | | | - Tsutomu Masaki
- Department of Gastroenterology and Neurology, Kagawa University Faculty of Medicine
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Tani J, Senoh T, Moriya A, Ogawa C, Deguchi A, Sakamoto T, Takuma K, Nakahara M, Oura K, Tadokoro T, Mimura S, Fujita K, Yoneyama H, Kobara H, Morishita A, Himoto T, Tsutsui A, Nagano T, Takaguchi K, Masaki T. Long-Term Outcomes and Evaluation of Hepatocellular Carcinoma Recurrence after Hepatitis C Virus Eradication by Direct-Acting Antiviral Treatment: All Kagawa Liver Disease Group (AKLDG) Study. Cancers (Basel) 2021; 13:cancers13092257. [PMID: 34066708 PMCID: PMC8125844 DOI: 10.3390/cancers13092257] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2021] [Revised: 05/01/2021] [Accepted: 05/03/2021] [Indexed: 12/09/2022] Open
Abstract
There are limited studies that have evaluated the long-term outcomes in patients with hepatocellular carcinoma (HCC) recurrence after direct-acting antiviral (DAA) treatment. In this retrospective study, we aimed to investigate the recurrence rates, recurrence factors, and prognosis of 130 patients who were treated with IFN-free DAA treatment after treatment for HCC. The median observation time was 41 ± 13.9 months after DAA treatment. The recurrence rates of HCC were 23.2%, 32.5%, 46.3%, and 59.4% at 6, 12, 24, and 36 months, respectively. A multivariate analysis showed that palliative treatment prior to DAA treatment (HR = 3.974, 95% CI 1.924-8.207, p = 0.0006) and alpha-fetoprotein at sustained virological response 12 (HR = 1.048, 95% CI 1.016-1.077, p = 0.0046) were associated with independent factors for HCC recurrence (HCC-R). The 12-, 24-, and 36-month overall survival rates were 97.6%, 94.0%, and 89.8%, respectively. The 12-, 24-, and 36-month survival rates of the non-recurrence and recurrence groups were 97.7%, 97.7%, and 94.1% and 97.6%, 92.3%, and 87.9%, respectively (p = 0.3404). The size of the main tumor lesion and the serological data were significantly improved at the time of HCC-R after DAA treatment. This study showed an improved prognosis regardless of recurrence rate, which suggests that DAA treatment in HCV patients should be considered.
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Affiliation(s)
- Joji Tani
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa 761-0793, Japan; (K.T.); (M.N.); (K.O.); (T.T.); (S.M.); (K.F.); (H.Y.); (H.K.); (A.M.); (T.M.)
- Correspondence: ; Tel.: +81-87-891-2156
| | - Tomonori Senoh
- Department of Hepatology, Kagawa Prefectural Central Hospital, Kagawa 760-8557, Japan; (T.S.); (A.T.); (T.N.); (K.T.)
| | - Akio Moriya
- Department of Gastroenterology, Mitoyo General Hospital, Kagawa 769-1695, Japan;
| | - Chikara Ogawa
- Department of Gastroenterology and Hepatology, Takamatsu Red Cross Hospital, Kagawa 760-0017, Japan;
| | - Akihiro Deguchi
- Department of Gastroenterology, Kagawa Rosai Hospital, Kagawa 763-8502, Japan;
| | - Teppei Sakamoto
- Department of Internal Medicine, Yashima General Hospital, Kagawa 761-0816, Japan;
| | - Kei Takuma
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa 761-0793, Japan; (K.T.); (M.N.); (K.O.); (T.T.); (S.M.); (K.F.); (H.Y.); (H.K.); (A.M.); (T.M.)
| | - Mai Nakahara
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa 761-0793, Japan; (K.T.); (M.N.); (K.O.); (T.T.); (S.M.); (K.F.); (H.Y.); (H.K.); (A.M.); (T.M.)
| | - Kyoko Oura
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa 761-0793, Japan; (K.T.); (M.N.); (K.O.); (T.T.); (S.M.); (K.F.); (H.Y.); (H.K.); (A.M.); (T.M.)
| | - Tomoko Tadokoro
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa 761-0793, Japan; (K.T.); (M.N.); (K.O.); (T.T.); (S.M.); (K.F.); (H.Y.); (H.K.); (A.M.); (T.M.)
| | - Shima Mimura
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa 761-0793, Japan; (K.T.); (M.N.); (K.O.); (T.T.); (S.M.); (K.F.); (H.Y.); (H.K.); (A.M.); (T.M.)
| | - Koji Fujita
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa 761-0793, Japan; (K.T.); (M.N.); (K.O.); (T.T.); (S.M.); (K.F.); (H.Y.); (H.K.); (A.M.); (T.M.)
| | - Hirohito Yoneyama
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa 761-0793, Japan; (K.T.); (M.N.); (K.O.); (T.T.); (S.M.); (K.F.); (H.Y.); (H.K.); (A.M.); (T.M.)
| | - Hideki Kobara
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa 761-0793, Japan; (K.T.); (M.N.); (K.O.); (T.T.); (S.M.); (K.F.); (H.Y.); (H.K.); (A.M.); (T.M.)
| | - Asahiro Morishita
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa 761-0793, Japan; (K.T.); (M.N.); (K.O.); (T.T.); (S.M.); (K.F.); (H.Y.); (H.K.); (A.M.); (T.M.)
| | - Takashi Himoto
- Department of Medical Technology, Kagawa Prefectural University of Health Sciences, Kagawa 761-0123, Japan;
| | - Akemi Tsutsui
- Department of Hepatology, Kagawa Prefectural Central Hospital, Kagawa 760-8557, Japan; (T.S.); (A.T.); (T.N.); (K.T.)
| | - Takuya Nagano
- Department of Hepatology, Kagawa Prefectural Central Hospital, Kagawa 760-8557, Japan; (T.S.); (A.T.); (T.N.); (K.T.)
| | - Koichi Takaguchi
- Department of Hepatology, Kagawa Prefectural Central Hospital, Kagawa 760-8557, Japan; (T.S.); (A.T.); (T.N.); (K.T.)
| | - Tsutomu Masaki
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa 761-0793, Japan; (K.T.); (M.N.); (K.O.); (T.T.); (S.M.); (K.F.); (H.Y.); (H.K.); (A.M.); (T.M.)
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Ohya K, Imamura M, Teraoka Y, Uchida T, Fujino H, Nakahara T, Ono A, Murakami E, Yamauchi M, Kawaoka T, Miki D, Tsuge M, Abe-Chayama H, Hayes CN, Aikata H, Ishida Y, Tateno C, Song H, Miyayama Y, Hijikata M, Chayama K. Novel drug resistance-associated substitutions against pibrentasvir emerged in genotype 1b hepatitis C virus-infected human hepatocyte transplanted mice. Biochem Biophys Res Commun 2021; 559:78-83. [PMID: 33932902 DOI: 10.1016/j.bbrc.2021.04.062] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2021] [Accepted: 04/04/2021] [Indexed: 10/21/2022]
Abstract
Combination therapy with glecaprevir and pibrentasvir (PIB) has high efficacy for patients with hepatitis C virus (HCV) infection except among those who experienced NS5A-P32 deletion (del) mutation during prior DAA treatment failure. However, some patients fail to achieve SVR through combination treatment even in the absence of NS5A-P32del. We analyzed emergence of NS5A resistance-associated substitutions (RASs) against PIB using HCV-infected mice. Male human hepatocyte transplanted mice were infected with genotype 1b wild-type HCV. Mice were treated with PIB, resulting in a transient decrease in serum HCV RNA levels but followed by relapse during the treatment. Direct sequence analysis showed emergences of various mutations in the NS5A region, including L31V/P32del, L31F/P32del/Y93H, NS5A-P29del/Y85C, and NS5A-F37Y. PIB was less effective in mice with NS5A-F37Y mutations compared to mice with wild-type HCV. NS5A-F37Y showed 5.4-fold resistance to PIB relative to wild-type based on analysis using HCV subgenomic replicon systems. The present in vivo and in vitro studies identified NS5A-F37Y as a novel RAS against PIB and showed the possibility of emergence of various NS5A RASs including P29del, P32del and F37Y following PIB treatment. These mutations might emerge and lead to failure to respond to DAA therapies including PIB-based regimens in chronic hepatitis C patients.
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Affiliation(s)
- Kazuki Ohya
- Department of Gastroenterology and Metabolism, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan; Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan
| | - Michio Imamura
- Department of Gastroenterology and Metabolism, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan; Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan
| | - Yuji Teraoka
- Department of Gastroenterology and Metabolism, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan; Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan
| | - Takuro Uchida
- Department of Gastroenterology and Metabolism, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan; Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan
| | - Hatsue Fujino
- Department of Gastroenterology and Metabolism, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan; Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan
| | - Takashi Nakahara
- Department of Gastroenterology and Metabolism, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan; Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan
| | - Atsushi Ono
- Department of Gastroenterology and Metabolism, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan; Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan
| | - Eisuke Murakami
- Department of Gastroenterology and Metabolism, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan; Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan
| | - Masami Yamauchi
- Department of Gastroenterology and Metabolism, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan; Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan
| | - Tomokazu Kawaoka
- Department of Gastroenterology and Metabolism, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan; Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan
| | - Daiki Miki
- Department of Gastroenterology and Metabolism, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan; Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan
| | - Masataka Tsuge
- Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan; Natural Science Center for Basic Research and Development, Hiroshima University, Hiroshima, Japan
| | - Hiromi Abe-Chayama
- Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan; Center for Medical Specialist Graduate Education and Research, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - C Nelson Hayes
- Department of Gastroenterology and Metabolism, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan; Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan
| | - Hiroshi Aikata
- Department of Gastroenterology and Metabolism, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan; Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan
| | - Yuji Ishida
- Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan; PhoenixBio Co., Ltd., Higashihiroshima, Japan
| | - Chise Tateno
- Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan; PhoenixBio Co., Ltd., Higashihiroshima, Japan
| | - HoJoong Song
- Laboratory of Tumor Viruses, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan
| | - Yohei Miyayama
- Laboratory of Tumor Viruses, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan
| | - Makoto Hijikata
- Laboratory of Tumor Viruses, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan
| | - Kazuaki Chayama
- Department of Gastroenterology and Metabolism, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan; Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan; Institute of Physical and Chemical Research (RIKEN) Center for Integrative Medical Sciences, Yokohama, Japan.
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Santander Ballestín S, Gómez Martín D, Lorente Pérez S, Luesma Bartolomé MJ. Hepatitis C: A Pharmacological Therapeutic Update. J Clin Med 2021; 10:1568. [PMID: 33917830 PMCID: PMC8068207 DOI: 10.3390/jcm10081568] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2020] [Revised: 04/04/2021] [Accepted: 04/05/2021] [Indexed: 12/14/2022] Open
Abstract
(1) Background: Hepatitis C is a high-prevalence disease, representing a global impact health problem. Lately, many changes have been made in treatment guidelines because of the commercialization of second-generation direct-acting antivirals due to their high effectiveness, few side effects and pangenotypic action. We address the pharmacological possibilities available and compare them with the current recommendations of the World Health Organization (WHO). (2) Methods: The search for articles was made through the PubMed database using different search strategies and we consulted technical data sheets of the treatments that have been included in the study. (3) Results: Combinations of "glecaprevir/pibrentasvir", "sofosbuvir/velpatasvir" and "sofosbuvir/velpatasvir/voxilaprevir" have been recently incorporated. Phase II studies have shown that they are safe and effective therapies with very comfortable posologies and easy therapeutic adherence; furthermore, they suppose shorter treatment duration. Subsequently, phase III studies have shown they were effective for previously treated or compensated cirrhotic patients that previously had more complex treatment regimens. (4) Conclusions: These results suppose a simplification in Hepatitis C therapeutic approach, and open new study possibilities.
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Affiliation(s)
- Sonia Santander Ballestín
- Department of Pharmacology, Physiology and Legal and Forensic Medicine, Faculty of Medicine, University of Zaragoza, 50009 Zaragoza, Spain;
| | - David Gómez Martín
- Department of Pharmacology, Physiology and Legal and Forensic Medicine, Faculty of Medicine, University of Zaragoza, 50009 Zaragoza, Spain;
| | - Sara Lorente Pérez
- Department of Gastroenterology and Hepatology, Hospital Clinico Universitario Lozano Blesa, 50009 Zaragoza, Spain;
| | - María José Luesma Bartolomé
- Department of Human Anatomy and Histology, Faculty of Science, University of Zaragoza, 50009 Zaragoza, Spain;
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Morgan JR, Savinkina A, Pires Dos Santos AG, Xue Z, Shilton S, Linas B. HCV Viral Load Greater Than 1000 IU/ml at Time of Virologic Failure in Direct-Acting Antiviral-Treated Patients. Adv Ther 2021; 38:1690-1700. [PMID: 33590445 PMCID: PMC7932931 DOI: 10.1007/s12325-021-01647-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2020] [Accepted: 02/02/2021] [Indexed: 11/05/2022]
Abstract
INTRODUCTION One of the remaining barriers to reaching WHO elimination targets of achieving global hepatitis C (HCV) cure is a lack of an established lower limit of detection (LLOD) to confirm cure post-treatment in near-patient technologies. Determining a LLOD at virologic failure aids in increasing testing feasibility through point-of-care assays in resource-limited settings. METHODS We described the level of viremia in 69 patients experiencing virologic failure across 20 clinical trials (ENDURANCE-1, ENDURANCE-2, ENDURANCE-3, ENDURANCE-4, ENDURANCE 5-6, MAGELLAN-1, MAGELLAN-2, EXPEDITION-1, EXPEDITION-2, EXPEDITION-3, EXPEDITION-4, EXPEDITION-5, EXPEDITION-8, SURVEYOR-1, SURVEYOR-2, VOYAGE-1, VOYAGE-2, CERTAIN-1, CERTAIN-2 and APRI). These findings were categorized as on-treatment, post-treatment week (PTW) 4 or PTW12 failures. RESULTS The mean HCV RNA level at baseline in the overall population of 5033 patients was 4,193,712 IU/ml ± 5,955,028 (6.2 log10 IU/ml ± 0.8) compared to 9,585,957 IU/ml ± 8,247,669 (6.8 log10 IU/ml ± 0.5) in 69 patients experiencing virologic failure by PTW12. The mean HCV RNA level at the time of virologic failure for all patients was 6,004,980 IU/ml ± 7,077,728 (6.4 log10 IU/ml ± 0.7). Twenty patients had on-treatment virologic failure with a mean HCV RNA level at the time of failure of 9,136,360 IU/ml ± 8,572,113 (6.7 log10 IU/ml ± 0.7), 36 patients had relapsed by PTW4 with a mean HCV RNA level at the time of relapse of 4,131,344 IU/ml ± 5,246,954 (6.3 log10 IU/ml ± 0.6), and 13 patients, who experienced relapse between PTW4 and PTW12, had a mean HCV RNA at relapse of 6,376,003 IU/ml ± 7,758,968 (6.3 log10 IU/ml ± 1.0). CONCLUSIONS At PTW12, 100% of virologic failures had an HCV RNA > 3.0 log10 IU/ml. The data are encouraging that with a LLOD of 3.0 log10 IU/ml, a point-of-care test could identify all treatment failures accurately; larger studies, including real-world data, are needed to confirm these findings.
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Affiliation(s)
- Jake R Morgan
- Department of Health, Law and Policy Management, Boston University School of Public Health, Boston, MA, USA.
| | - Alexandra Savinkina
- Boston Medical Center, Section of Infectious Diseases, Boston University School of Public Health, Boston, MA, USA
| | | | | | | | - Benjamin Linas
- Boston Medical Center, Section of Infectious Diseases, Boston University School of Public Health, Boston, MA, USA
- Department of Epidemiology, Section of Infectious Diseases, Boston University School of Public Health, Boston, MA, USA
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Beisel C, Herrmann M, Piecha F, Lampalzer S, Buescher G, Pischke S, Schulze zur Wiesch J. Real-world Effectiveness of Glecaprevir/Pibrentasvir (GLE/PIB) for Chronic Hepatitis C Infection: Evidence From a German Single-center Cohort Study. HEPATITIS MONTHLY 2021; 21. [DOI: 10.5812/hepatmon.110077] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
Background: Glecaprevir/pibrentasvir (GLE/PIB) is the latest approved pan-genotypic direct-acting antiviral agent (DAA) for the treatment of chronic hepatitis C virus (HCV) infection. However, real-world data of GLE/PIB in European patient cohorts are limited. Methods: A single-center cohort of 100 unselected HCV patients seen at the Outpatient Clinic of the University Medical Center Hamburg-Eppendorf from October 2017 until September 2019 was retrospectively analyzed by chart review with a special focus on demographic clinical and virologic aspects as well as treatment compliance outcome. Results: A total of 99 patients with chronic HCV infection (genotype (GT) 1 - 6), who started antiviral treatment with GLE/PIB, were included. Treatment duration lasted from 4 to 16 weeks. The primary endpoint was a sustained virological response at week 12 (SVR12) after the end of treatment (EoT). Only three patients (3/100; 3%) were diagnosed with liver cirrhosis by non-invasive measures. Ten patients (10/100; 10%) were pre-treated with Interferon (IFN) containing regiments. Most patients received 8 weeks of treatment (96/100; 96%). One patient discontinued treatment after four weeks due to poor compliance (1/100; 1%). A high number of patients were lost to follow-up (22/100; 22%). All patients who were regularly seen to follow-up visits (76/100; 76%) achieved SVR12 (76/76; 100%). Virological relapse occurred in none of the patients. Adverse events (AEs) were rarely reported (4 patients) (4/100; 4%), and none of these patients discontinued treatment. Conclusions: This study demonstrated that initial and re-treatment with GLE/PIB were effective and safe in a German cohort with chronic HCV infection in real-life settings, regardless of GT.
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Liu X, Hu P. Efficacy and Safety of Glecaprevir/Pibrentasvir in Patients with Chronic HCV Infection. J Clin Transl Hepatol 2021; 9:125-132. [PMID: 33604263 PMCID: PMC7868694 DOI: 10.14218/jcth.2020.00078] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2020] [Revised: 12/03/2020] [Accepted: 12/22/2020] [Indexed: 12/11/2022] Open
Abstract
Hepatitis C virus (HCV) infection is a major cause of end-stage liver disease, including decompensated cirrhosis and hepatocellular carcinoma. Over 95% of patients with HCV infection have achieved sustained virologic response at 12 weeks under the treatment of several pan-genotypic regimens approved for patients with HCV infection. The glecaprevir/pibrentasvir (G/P) regimen has some features that distinguish it from others and is the only 8-week regimen approved for treatment-naive patients and patients experienced in regimens containing (peg)interferon, ribavirin, and/or sofosbuvir, without an HCV NS3/4A protease inhibitor or NS5A inhibitor (except those with genotype 3). This review aims to summarize the efficacy and safety of G/P in HCV-infected patients from clinic trials and real-world studies, including those who have historically been considered difficult to cure.
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Affiliation(s)
| | - Peng Hu
- Correspondence to: Peng Hu, Department of Infectious Diseases, Institute for Viral Hepatitis, The Key Laboratory of Molecular Biology for Infectious Diseases, Chinese Ministry of Education, The Second Affiliated Hospital of Chongqing Medical University, 74 Linjiang Road, Yuzhong District, Chongqing 400010, China. Tel: +86-23-62887083, Fax: +86-23-63703790, E-mail: ,
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Zhang Y, Jiang X, Zhao Y, Xu Y. Effect of baseline resistance-associated substitutions on the efficiency of glecaprevir/pibrentasvir in chronic hepatitis C subjects: A meta-analysis. J Viral Hepat 2021; 28:177-185. [PMID: 32961624 DOI: 10.1111/jvh.13409] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2020] [Revised: 08/16/2020] [Accepted: 08/23/2020] [Indexed: 02/06/2023]
Abstract
The effect of baseline resistance-associated substitutions on the sustained virologic response at 12 weeks in chronic hepatitis C subjects has drawn considerable attention. However, it has been reported that the relationship between such substitutions and sustained virologic response at 12 weeks in chronic hepatitis C subjects is variable in different treatments. This meta-analysis was performed to evaluate this relationship in subjects treated with glecaprevir/pibrentasvir. A systematic literature search up to May 2020 was done, and 17 studies were identified with 6501 chronic hepatitis C subjects. They were reporting relationships between baseline resistance-associated substitutions and sustained virologic response at 12 weeks in chronic hepatitis C subjects treated with glecaprevir/pibrentasvir. The odds ratio (OR) with 95% confidence intervals (CIs) was calculated to evaluate the prognostic role of baseline resistance-associated substitutions on the sustained virologic response at 12 weeks in chronic hepatitis C subjects treated with glecaprevir/pibrentasvir using the dichotomous method with a random or fixed-effect model. Lower sustained virologic response at 12 weeks post-treatment in chronic hepatitis C subjects was significantly related to baseline resistance-associated substitutions in overall genotypes (OR, 0.03; 95% CI, 0.15-0.61, P < .001), baseline NS5a resistance-associated substitutions in genotype-1 (OR, 0.16; 95% CI, 0.04-0.57, P = .005), baseline resistance-associated substitutions in genotype-3 (OR, 0.14; 95% CI, 0.05-0.38, P < .001), and baseline NS5a resistance-associated substitutions in genotype-3 (OR, 0.21; 95% CI, 0.09-0.49, P < .001). Sustained virologic response at 12 weeks in chronic hepatitis C subjects was not significantly related to the baseline NS5a resistance-associated substitutions (OR, 0.61; 95% CI, 0.17-2.22, P = .45), and baseline resistance-associated substitutions in genotype-1 (OR, 0.35; 95% CI, 0.12-1.088, P = .07). In conclusion, the impact of baseline resistance-associated substitutions on the sustained virologic response at 12 weeks in chronic hepatitis C subjects treated with glecaprevir/pibrentasvir may have a great prognostic effect, especially in genotype-3 as a tool to improve treatment prediction. Chronic hepatitis C subjects with baseline resistance-associated substitutions may have an independent risk relationship with poor treatment outcomes. This relationship forces us to recommend testing prior to treatment selection to avoid any possible treatment failure.
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Affiliation(s)
- Yonggui Zhang
- Department of Gastroenterology, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Xuefeng Jiang
- Department of Gastroenterology, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Yuyang Zhao
- Department of Gastroenterology, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Yan Xu
- Department of Gastroenterology, China-Japan Union Hospital of Jilin University, Changchun, China
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Kosloski MP, Oberoi R, Wang S, Viani RM, Asatryan A, Hu B, Ding B, Qi X, Kim EJ, Mensa F, Kort J, Liu W. Drug-Drug Interactions of Glecaprevir and Pibrentasvir Coadministered With Human Immunodeficiency Virus Antiretrovirals. J Infect Dis 2020; 221:223-231. [PMID: 31504702 DOI: 10.1093/infdis/jiz439] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2019] [Accepted: 08/27/2019] [Indexed: 01/27/2023] Open
Abstract
BACKGROUND Treatment of patients coinfected with hepatitis C and human immunodeficiency viruses (HCV; HIV) requires careful consideration of potential drug-drug interactions between HCV direct-acting antiviral agents (DAA) and HIV antiretrovirals. Glecaprevir/pibrentasvir is a fixed-dose combination of an NS3/4A protease inhibitor and an NS5A inhibitor approved for the treatment of chronic HCV genotype 1-6 infection, including patients with HIV coinfection. METHODS A series of phase 1 studies was conducted to evaluate potential interactions of glecaprevir and pibrentasvir with elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide, abacavir/dolutegravir/lamivudine, raltegravir, rilpivirine, atazanavir/ritonavir, darunavir/ritonavir, lopinavir/ritonavir, or efavirenz/emtricitabine/tenofovir disoproxil fumarate. Pharmacokinetics of the antiretrovirals and DAAs were characterized when administered alone and in combination to quantify changes in systemic drug exposure. RESULTS Glecaprevir area under the curve increased >4-fold in the presence of ritonavir-boosted HIV protease inhibitors, while pibrentasvir concentrations were not significantly affected; elevations in alanine transaminase occurred in combination with atazanavir/ritonavir only. Exposures of glecaprevir and pibrentasvir may be significantly decreased by efavirenz. Coadministration with glecaprevir and pibrentasvir did not result in clinically significant changes in the exposure of any antiretroviral agents. CONCLUSIONS Atazanavir is contraindicated with glecaprevir/pibrentasvir and use of boosted protease inhibitors or efavirenz is not recommended. No clinically significant interactions were observed with other studied antiretrovirals.
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Affiliation(s)
| | | | | | | | | | - Beibei Hu
- AbbVie Inc., North Chicago, Illinois
| | | | - Xin Qi
- AbbVie Inc., North Chicago, Illinois
| | | | | | - Jens Kort
- AbbVie Inc., North Chicago, Illinois
| | - Wei Liu
- AbbVie Inc., North Chicago, Illinois
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Xu HQ, Wang CG, Xiao P, Gao YH. Efficacy and Safety of Glecaprevir/Pibrentasvir for Chronic Hepatitis C Patients: A Systematic Review and Meta-analysis. J Clin Transl Hepatol 2020; 8:267-276. [PMID: 33083249 PMCID: PMC7562797 DOI: 10.14218/jcth.2020.00047] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2020] [Revised: 08/10/2020] [Accepted: 08/12/2020] [Indexed: 12/04/2022] Open
Abstract
Background and Aims: Glecaprevir/pibrentasvir is a pangenotypic regimen recently approved for the treatment of chronic hepatitis C virus (HCV) infection. The objective of the present review was to summarize the findings from clinical trials to understand how patient-related factors influence glecaprevir/pibrentasvir efficacy (sustained virologic response rates at 12 weeks' after treatment [referred to as SVR12]) and safety. Methods: Data from 21 phase III clinical trials were analyzed. Results: The integrated efficacy analysis included 4,817 patients. Findings showed 97.5% of all included patients with chronic HCV achieved SVR12 in the intention-to-treat population. SVR12 rate was >95% across subgroups of interest. The integrated safety analysis included 4,015 patients. Findings showed that 64.1% of patients reported an adverse event, and <0.1% of patients reported a serious adverse event related to glecaprevir/pibrentasvir. Conclusions: These results indicate that the 8- or 12-week glecaprevir/pibrentasvir treatment is effective for patients infected with HCV genotypes 1-6 without or with compensated cirrhosis, with good safety profiles, irrespective of treatment-experience. Glecaprevir/pibrentasvir is a good option for patients with human immunodeficiency virus/HCV coinfection and comorbid HCV and severe renal impairment.
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Affiliation(s)
- Hong-Qin Xu
- Department of Hepatology, The First Hospital of Jilin University, Jilin University, Changchun, Jilin, China
| | - Chun-Guang Wang
- Department of Surgery, The Second Hospital of Jilin University, Changchun, Jilin, China
| | - Peng Xiao
- Department of Hepatology, The First Hospital of Jilin University, Jilin University, Changchun, Jilin, China
| | - Yan-Hang Gao
- Department of Hepatology, The First Hospital of Jilin University, Jilin University, Changchun, Jilin, China
- Correspondence to: Yan-Hang Gao, Department of Hepatology, The First Hospital of Jilin University, Jilin University, No. 71, Xinmin Street, Changchun, Jilin 130021, China. Tel: +86-431-81875121, E-mail:
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Gane E, Poordad F, Zadeikis N, Valdes J, Lin CW, Liu W, Asatryan A, Wang S, Stedman C, Greenbloom S, Nguyen T, Elkhashab M, Wörns MA, Tran A, Mulkay JP, Setze C, Yu Y, Pilot-Matias T, Porcalla A, Mensa FJ. Safety and Pharmacokinetics of Glecaprevir/Pibrentasvir in Adults With Chronic Genotype 1-6 Hepatitis C Virus Infections and Compensated Liver Disease. Clin Infect Dis 2020; 69:1657-1664. [PMID: 30923816 PMCID: PMC6821220 DOI: 10.1093/cid/ciz022] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2018] [Accepted: 01/31/2019] [Indexed: 02/06/2023] Open
Abstract
Background Untreated, chronic hepatitis C virus (HCV) infection may lead to progressive liver damage, which can be mitigated by successful treatment. This integrated analysis reports the safety, efficacy, and pharmacokinetics (PK) of the ribavirin-free, direct-acting, antiviral, fixed-dose combination of glecaprevir/pibrentasvir (G/P) in patients with chronic HCV genotype 1–6 infections and compensated liver disease, including patients with chronic kidney disease stages 4 or 5 (CKD 4/5). Methods Data from 9 Phase II and III clinical trials, assessing the efficacy and safety of G/P treatment for 8–16 weeks, were included. The presence of cirrhosis was determined at screening using a liver biopsy, transient elastography, or serum biomarkers. The objectives were to evaluate safety, the rate of sustained virologic response at post-treatment week 12 (SVR12), and steady-state PK by cirrhosis status. Results Among 2369 patients, 308 (13%) were Child-Pugh Class A, including 20 with CKD 4/5. Overall, <1% of patients experienced an adverse event (AE) that led to G/P discontinuation or G/P-related serious AEs (SAEs). The most common AEs were headache and fatigue, occurring at similar frequencies with and without cirrhosis. SAEs were more common in patients with CKD 4/5, but all were unrelated to G/P. There were no cases of drug-induced liver injury or clinically relevant hepatic decompensation. SVR12 rates were 96.4% (297/308) with compensated cirrhosis and 97.5% (2010/2061) without cirrhosis. PK analysis demonstrated a 2.2-fold increase in glecaprevir exposure, but not pibrentasvir exposure, in patients with compensated cirrhosis. Conclusions G/P was safe and efficacious in patients with compensated liver disease, including those with CKD 4/5. Clinical Trials Registration NCT02243280, NCT02243293, NCT02604017, NCT02640482, NCT02640157, NCT02636595, NCT02642432, NCT02651194, and NCT02446717
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Affiliation(s)
| | - Fred Poordad
- The Texas Liver Institute, University of Texas Health Science Center, San Antonio
| | | | | | | | - Wei Liu
- AbbVie Inc., North Chicago, Illinois
| | | | | | | | | | - Tuan Nguyen
- Research and Education, Inc, San Diego, California
| | | | | | - Albert Tran
- University Hospital of Nice, Digestive Centre, France
| | - Jean-Pierre Mulkay
- Hôpital Centre Hospitalier Universitaire Saint-Pierre, Brussels, Belgium
| | | | - Yao Yu
- AbbVie Inc., North Chicago, Illinois
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Yap DYH, Liu KSH, Hsu YC, Wong GLH, Tsai MC, Chen CH, Hsu CS, Hui YT, Li MKK, Liu CH, Kan YM, Yu ML, Yuen MF. Use of glecaprevir/pibrentasvir in patients with chronic hepatitis C virus infection and severe renal impairment. Clin Mol Hepatol 2020; 26:554-561. [PMID: 32854457 PMCID: PMC7641551 DOI: 10.3350/cmh.2020.0058] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2020] [Accepted: 07/02/2020] [Indexed: 02/06/2023] Open
Abstract
Background/Aims Data on treatment efficacy and safety of glecaprevir/pibrentasvir (GLE/PIB) for chronic hepatitis C virus (HCV) infection in Asian patients with severe renal impairment are limited. This study aimed to study the treatment and side effects of GLE/PIB in these patients infected with non-1 genotype (GT) HCV. Methods We prospectively recruited patients with Child’s A cirrhosis and eGFR <30 mL/min/1.73 m2 in Hong Kong and Taiwan during 2017–2018 to receive GLE/PIB treatment. Results Twenty-one patients (GT2, n=7; GT3, n=6; and GT6, n=8) received GLE/PIB for 11.2±1.8 weeks. All except one were treatment-naïve. GLE/PIB was initiated in 16 patients while on dialysis (seven on peritoneal dialysis [PD] and nine on hemodialysis) and in five patients before dialysis. One patient died of PD-related peritonitis during treatment and two were lost to follow up. The SVR12 rate in the remaining 18 patients was 100%. All patients achieved undetectable levels at 4-, 12-, 24- and 48-week after treatment. Patients with deranged alanine aminotransferase showed normalization after 4 weeks and the response was sustained for 48 weeks. No significant adverse event was observed. Conclusions GLE/PIB treatment was associated with high efficacy and tolerability in HCV-infected patients with severe renal impairment.
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Affiliation(s)
- Desmond Y H Yap
- Division of Nephrology, Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China
| | - Kevin S H Liu
- Division of Gastroenterology and Hepatology, Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China
| | - Yu-Chun Hsu
- Division of Gastroenterology, Department of Internal Medicine, Changhua Christian Hospital, Taiwan
| | - Grace L H Wong
- Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Institute of Digestive Disease, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China
| | - Ming-Chang Tsai
- Division of Gastroenterology, Department of Internal Medicine, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Chien-Hung Chen
- Department of Internal Medicine, National Taiwan University Hospital Yunlin Branch, Douliu, Taiwan
| | - Ching-Sheng Hsu
- Liver Diseases Research Centre, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taipei, Taiwan
| | - Yee Tak Hui
- Department of Medicine, Queen Elizabeth Hospital, Hong Kong, China
| | - Michael K K Li
- Department of Medicine and Geriatrics, Tuen Mun Hospital, Hong Kong, China
| | - Chen-Hua Liu
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Yee-Man Kan
- Department of Medicine and Geriatrics, Kwong Wah Hospital, Hong Kong, China
| | - Ming-Lung Yu
- Division of Hepatobiliary, Department of Internal Medicine and Hepatitis Centre, Kaohsiung Medical University Hospital, Kaohshiung Medical University, Kaohsiung, Taiwan
| | - Man-Fung Yuen
- Division of Gastroenterology and Hepatology, Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China
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Takaki S, Imamura M, Yamaguchi S, Fukuhara T, Mori N, Tsuji K, Ohya K, Hayes CN, Aikata H, Chayama K. Real-word efficacy of sofosbuvir, velpatasvir plus ribavirin therapy for chronic hepatitis patients who failed to prior DAA therapy with NS5A-P32 deletion mutated HCV infection. Clin J Gastroenterol 2020; 13:1233-1238. [PMID: 32656649 DOI: 10.1007/s12328-020-01182-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Accepted: 06/23/2020] [Indexed: 12/12/2022]
Abstract
The hepatitis C virus (HCV) NS5A-P32 deletion (P32del) confers potent resistance to NS5A inhibitors. Chronic hepatitis C patients in whom NS5A-P32del variants had emerged during prior direct-acting antiviral (DAA) therapy with an NS5A inhibitor show poor response to DAA retreatment. Here, we report three patients with HCV NS5A-P32del infection who were treated with sofosbuvir, velpatasvir plus ribavirin (SOF/VEL + RBV) in a real-world setting. The patients developed HCV NS5A-P32del, L31F + P32del, or L31V + P32del variants following failure of daclatasvir plus asunaprevir (DCV/ASV) therapy. One of the patients failed to respond to subsequent DCV/ASV and beclabuvir therapy, and the remaining two patients failed to respond to subsequent glecaprevir and pibrentasvir therapy. All three patients completed 24-week SOF/VEL + RBV therapy. Serum HCV RNA became negative at the end of the therapy in all three patients. Two patients with NS5A-P32del and NS5A-L31F + P32del achieved sustained virological response 12 weeks after completion of treatment (SVR12), but HCV relapsed in the remaining NS5A-L13V + P32del patient. Direct sequence analysis detected no additional variants within either the NS5A or NS5B regions at the time of relapse. In conclusion, three patients with prior NS5A-P32del-associated DAA treatment failure received 24 weeks of SOF/VEL + RBV therapy, and two of the patients achieved SVR12.
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Affiliation(s)
- Shintaro Takaki
- Department of Gastroenterology/Liver Center, Hiroshima Red Cross Hospital and Atomic-Bomb Survivors Hospital, Hiroshima, Japan
| | - Michio Imamura
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Science, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan. .,Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan.
| | - Shuji Yamaguchi
- Department of Gastroenterology, Kure Kyosai Hospital, Kure, Japan
| | - Takayuki Fukuhara
- Department of Gastroenterology/Liver Center, Hiroshima Red Cross Hospital and Atomic-Bomb Survivors Hospital, Hiroshima, Japan
| | - Nami Mori
- Department of Gastroenterology/Liver Center, Hiroshima Red Cross Hospital and Atomic-Bomb Survivors Hospital, Hiroshima, Japan
| | - Keiji Tsuji
- Department of Gastroenterology/Liver Center, Hiroshima Red Cross Hospital and Atomic-Bomb Survivors Hospital, Hiroshima, Japan
| | - Kazuki Ohya
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Science, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.,Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan
| | - Clair Nelson Hayes
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Science, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.,Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan
| | - Hiroshi Aikata
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Science, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.,Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan
| | - Kazuaki Chayama
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Science, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.,Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan.,Center for Medical Specialist Graduate Education and Research, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
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Oberoi RK, Zhao W, Rosebraugh M, Mensa F, Wang H, Liu W. A Thorough QT Study of the Combination Glecaprevir + Pibrentasvir on Cardiac Repolarization in Healthy Subjects. Clin Ther 2020; 42:1317-1329. [PMID: 32622784 DOI: 10.1016/j.clinthera.2020.05.009] [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: 01/17/2020] [Revised: 04/10/2020] [Accepted: 05/08/2020] [Indexed: 11/15/2022]
Abstract
PURPOSE Fixed-dose combination glecaprevir (GLE) 300 mg + pibrentasvir (PIB) 120 mg is an orally administered once daily antiviral regimen approved for the treatment of hepatitis C virus (HCV) infection. The objective of this study was to evaluate the potential for cardiac repolarization following GLE + PIB administration in healthy adults. METHODS This placebo- and active-controlled, randomized, single-dose, 4-period, 4-sequence crossover study enrolled 48 healthy subjects. The doses of GLE 400 mg + PIB 120 mg were selected to provide exposures comparable to those with the doses that are therapeutic in the HCV-infected population, GLE 300 mg + PIB 120 mg. The doses of GLE 600 mg + PIB 240 mg were selected to provide supratherapeutic exposures without exceeding the exposures of the GLE + PIB maximal tolerated doses. Moxifloxacin 400 mg (active control/open label) was used for confirming the sensitivity of the ECG assay in detecting QTc prolongation. Time-matched plasma concentrations and triplicate ECGs were obtained on treatment days -1 and 1. The primary end point was time-matched, placebo-corrected, baseline-adjusted Fridericia-corrected QT interval (ΔΔQTcF). Pharmacokinetic-pharmacodynamic analyses characterized the relationship between GLE and PIB plasma concentrations and ΔΔQTcF using a linear regression model and linear mixed-effects model. Findings from categorical analyses of ECG-interval data were also summarized. Tolerability was evaluated through adverse-events monitoring, physical examination including vital sign measurements, ECGs, and laboratory tests. FINDINGS A total of 48 subjects (22 women [46%], 26 men [54%]), were enrolled in the study, and 47 subjects completed all 4 periods. None of the subjects had a change from baseline in QTcF interval of >30 msec or an absolute QTcF interval of >450 msec. Peak ΔΔQTcF values observed at 5 h postdose (Tmax) were 2.9 msec (upper 95% confidence limit, 4.9 msec) with the therapeutic dose and 3.1 msec (upper 95% confidence limit, 5.1 msec) with the supratherapeutic dose, with both upper 95% confidence limits well below the 10-msec threshold. Assay sensitivity was confirmed by peak ΔΔQTcF in the positive control (12.8 ms at 2 h postdose). No statistically significant GLE or PIB concentration-dependent effects on ΔΔQTcF were observed. Headache and skin irritation from ECG electrodes were the most commonly reported AEs. No clinically significant vital sign measurements, ECG findings, or laboratory measurements were observed. There were no patterns of T- and U-wave morphologic abnormalities. IMPLICATIONS The fixed-dose combination regimen of GLE/PIB does not prolong the QTc interval. ClinicalTrials.gov identifier.
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Affiliation(s)
| | | | | | | | | | - Wei Liu
- Clinical Pharmacology and Pharmacometrics, USA.
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Dong Y, Clarke RM, Porter GJ, Betley TA. Efficient C–H Amination Catalysis Using Nickel-Dipyrrin Complexes. J Am Chem Soc 2020; 142:10996-11005. [DOI: 10.1021/jacs.0c02126] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Affiliation(s)
- Yuyang Dong
- Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, Massachusetts 02138, United States
| | - Ryan M. Clarke
- Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, Massachusetts 02138, United States
| | - Gerard J. Porter
- Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, Massachusetts 02138, United States
| | - Theodore A. Betley
- Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, Massachusetts 02138, United States
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40
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Kinoshita A, Koike K, Mizuno Y, Ogata I, Kobayashi Y, Hasegawa K, Shiraishi K, Yoshida H, Nakata R, Yamada N, Yasuda K. Efficacy and safety of glecaprevir/pibrentasvir in patients with hepatitis C virus infection aged ≥75 years. Geriatr Gerontol Int 2020; 20:578-583. [PMID: 32267087 DOI: 10.1111/ggi.13919] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2020] [Revised: 03/05/2020] [Accepted: 03/10/2020] [Indexed: 01/24/2023]
Abstract
AIM Opportunities to treat older patients with hepatitis C virus infection have increased. We investigated the efficacy and safety of glecaprevir/pibrentasvir in patients with HCV infection aged ≥75 years. METHODS We retrospectively evaluated 131 patients with hepatitis C virus infection treated with glecaprevir/pibrentasvir at nine institutions in Japan. The patients were divided into two groups according to their age: the elderly group (n = 43, aged ≥75 years) and younger group (n = 88, aged <75 years). We compared the clinical characteristics, virologic response and adverse events between the two groups. The predictive factors for adverse events were also assessed. RESULTS The presence of cirrhosis (27.9%), a history of hepatocellular carcinoma (23.3%) and comorbidities (88.4%) were more frequently observed in the elderly group than in the younger group. Six (14.0%) patients in the elderly group and 19 (21.6%) in the younger group dropped out before the sustained virologic response 12 assessment. In the intention-to-treat population, 86.0% in the elderly group and 78.4% in the younger group achieved sustained virologic response 12 (P = 0.30). In the modified intention-to-treat population, all patients achieved sustained virologic response 12. A total of 27.5% of patients experienced adverse events. The most frequently observed adverse events was pruritus, and was significantly associated with female sex, the presence of hemodialysis and serum albumin at baseline <4.0 g/dL. CONCLUSION Glecaprevir/pibrentasvir therapy was effective and well tolerated, even in elderly patients with hepatitis C virus infection aged ≥75 years. Geriatr Gerontol Int 2020; ••: ••-••.
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Affiliation(s)
- Akiyoshi Kinoshita
- Division of Gastroenterology and Hepatology, The Jikei University Daisan Hospital, Tokyo, Japan.,Department of Internal Medicine, Sakuragaoka Hospital, Shizuoka, Japan.,Department of Internal Medicine, Johsai Hospital, Tokyo, Japan
| | - Kazuhiko Koike
- Division of Gastroenterology and Hepatology, The Jikei University Daisan Hospital, Tokyo, Japan.,Department of Internal Medicine, Sakuragaoka Hospital, Shizuoka, Japan
| | - Yusuke Mizuno
- Division of Gastroenterology and Hepatology, The Jikei University Daisan Hospital, Tokyo, Japan
| | - Itsuro Ogata
- Division of Gastroenterology and Hepatology, Kawakita General Hospital, Tokyo, Japan
| | | | | | - Koichi Shiraishi
- Division of Gastroenterology, Tokai University Tokyo Hospital, Tokyo, Japan
| | - Hideo Yoshida
- Division of Gastroenterology, Japanese Red Cross Medical Center, Tokyo, Japan
| | - Ryo Nakata
- Division of Gastroenterology, Japanese Red Cross Medical Center, Tokyo, Japan
| | - Norie Yamada
- Division of Gastroenterology, Kiyokawa Hospital, Tokyo, Japan
| | - Kiyomi Yasuda
- Division of Gastroenterology, Kiyokawa Hospital, Tokyo, Japan
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Ombitasvir/paritaprevir/ritonavir & dasabuvir ± ribavirin following protease inhibitors failure - a prospective multi-centre trial. BMC Infect Dis 2020; 20:264. [PMID: 32245397 PMCID: PMC7126165 DOI: 10.1186/s12879-020-4921-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2019] [Accepted: 02/26/2020] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND Hepatitis C virus (HCV) infection is a leading cause of chronic liver disease and hepatocellular carcinoma. Treatment with first generation protease inhibitors (PI) + peg-interferon (pegIFN) and ribavirin (RBV) achieved sustained virologic response (SVR) rates of 65-75% but was associated with multiple side effects. The aim of this study was to evaluate safety and efficacy of Ombitasvir/Paritaprevir/Ritonavir and Dasabuvir (3D) ± RBV in HCV genotype 1 patients that failed previous treatment with first generation PIs. METHODS An investigator-initiated, open-label, multi-centre clinical trial. HCV Genotype 1 patients who were previously null/partial responders or relapsers to telaprevir, boceprevir or simepravir+pegIFN/RBV and met eligibility criteria were included. 3D ± RBV were administrated for 12 or 24 weeks according to label. The primary outcome was antiviral response (SVR12); Secondary outcomes were patient reported outcomes, adverse events and resistance associated variants. RESULTS Thirty-nine patients initiated treatment according to study protocol (59% men, age 54.0 ± 8.7 years, BMI 28.7 ± 4.5 kg/m2). Thirty-seven (94.9%) completed the study. Thirty-five patients had genotype 1b (9 cirrhotics) and 4 had genotype 1a (2 cirrhotics). Intention-to-treat SVR12 was 92.3% and per-protocol SVR12 was 97.3%. The rate of advanced fibrosis (FibroScan® score F3-4) declined from 46.2 to 25.7% (P = 0.045). Abnormal ALT levels declined from 84.6 to 8.6% (P < 0.001). Seven patients (17.9%) experienced serious adverse events (3 Psychiatric admissions, 1 pneumonia, 1 ankle fracture, 2 palpitations), and 12 patients (30.8%) experienced self-reported adverse events, mostly weakness. CONCLUSION 3D ± RBV is safe and effective in achieving SVR among patients with HCV genotype 1 who failed previous first-generation PI treatment. TRIAL REGISTRATION NCT02646111 (submitted to ClinicalTrials.gov, December 28, 2015).
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Mathur P, Kottilil S, Wilson E. Sofosbuvir/velpatasvir/voxilaprevir: a highly effective option for retreatment of hepatitis C in difficult-to-treat patients. Antivir Ther 2020; 24:1-10. [PMID: 30210057 DOI: 10.3851/imp3264] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/02/2018] [Indexed: 02/06/2023]
Abstract
Treatment for hepatitis C has escalated rapidly since the advent of direct-acting antivirals. Although there are highly efficacious, pangenotypic regimens available as standard of care, 5-10% of patients do not achieve virological cure. The recently approved fixed-dose combination of sofosbuvir, velpatasvir and voxilaprevir provides an option for retreatment in patients who have failed prior regimens and have characteristics which make them difficult to treat. This review provides a summary of the evidence for use of Vosevi®, a fixed-dose combination pill for treatment of hepatitis C in treatment-experienced patients.
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Affiliation(s)
- Poonam Mathur
- Division of Clinical Care and Research, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Shyamasundaran Kottilil
- Division of Clinical Care and Research, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Eleanor Wilson
- Division of Clinical Care and Research, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD, USA
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Singh AD, Maitra S, Singh N, Tyagi P, Ashraf A, Kumar R, Shalimar. Systematic review with meta-analysis: impact of baseline resistance-associated substitutions on the efficacy of glecaprevir/pibrentasvir among chronic hepatitis C patients. Aliment Pharmacol Ther 2020; 51:490-504. [PMID: 31943236 DOI: 10.1111/apt.15633] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2019] [Revised: 10/07/2019] [Accepted: 12/20/2019] [Indexed: 12/19/2022]
Abstract
BACKGROUND The effect of baseline resistance-associated substitutions (RAS) on the sustained virologic response at 12 weeks (SVR12) among chronic hepatitis C (CHC) patients receiving the second generation, pan-genotypic glecaprevir/pibrentasvir (G/P) regimen is unclear. AIM To assess the effect of RAS on the SVR12 in CHC patients treated with G/P regimen. METHODS The EMBASE, MEDLINE and Cochrane central register of controlled trials databases were searched for relevant studies published before 1 March 2019. The principal outcome was to compare the SVR12 in CHC patients with and without baseline RAS, particularly in genotype-1, genotype-3 and direct-acting anti-virals (DAAs) failure patients. The outcomes were pooled using a random-effects model and odds ratio (OR) was calculated. The risk of bias was assessed using the Cochrane risk of bias tools for randomised and nonrandomised interventional studies. RESULTS After initially identifying 410 studies, 3302 patients from 17 studies were included. Among 50 cases of virologic failures, 48% had genotype-3 infection, 44% genotype-1 infection and 36% DAA-failure patients. Baseline RAS were present in 44(88%) patients. The most common NS5a and NS3 mutations were Y93H and A166S respectively. The odds of SVR12 were significantly reduced in patients with any baseline RAS (NS3 and/or NS5a) (OR 0.32, 95%C I[0.15, 0.65], I2 = 0%) and NS5a substitutions (OR 0.36, 95%CI [0.18,0.73]). The impact of RAS on SVR12 was significant among genotype-3 patients, but not among genotype-1 or DAA-failure cases. The presence of Y93H and A30K mutations significantly impacted SVR12 rates in genotype-3 patients. CONCLUSION Baseline NS3 or NS5a RAS, especially the NS5a substitutions-A30K, Y93H, decrease the odds of achieving SVR12 in genotype-3 CHC patients.
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Affiliation(s)
- Achintya D Singh
- Department of Internal Medicine, Cleveland Clinic, Cleveland, OH, USA
| | - Souvik Maitra
- Department of Anaesthesia, All India Institute of Medical Sciences, New Delhi, India
| | - Nita Singh
- Department of Gastroenterology, All India Institute of Medical Sciences, New Delhi, India
| | - Payal Tyagi
- Department of Gastroenterology, All India Institute of Medical Sciences, New Delhi, India
| | - Anzar Ashraf
- Department of Gastroenterology, All India Institute of Medical Sciences, New Delhi, India
| | - Ramesh Kumar
- Department of Gastroenterology, All India Institute of Medical Sciences, Patna, India
| | - Shalimar
- Department of Gastroenterology, All India Institute of Medical Sciences, New Delhi, India
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44
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Gupta G, Yakubu I, Bhati CS, Zhang Y, Kang L, Patterson JA, Andrews-Joseph A, Alam A, Ferreira-Gonzalez A, Kumar D, Moinuddin IK, Kamal L, King AL, Levy M, Sharma A, Cotterell A, Reichman TW, Khan A, Kimball P, Stiltner R, Baldecchi M, Brigle N, Gehr T, Sterling RK. Ultra-short duration direct acting antiviral prophylaxis to prevent virus transmission from hepatitis C viremic donors to hepatitis C negative kidney transplant recipients. Am J Transplant 2020; 20:739-751. [PMID: 31652392 DOI: 10.1111/ajt.15664] [Citation(s) in RCA: 65] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2019] [Revised: 10/10/2019] [Accepted: 10/13/2019] [Indexed: 01/25/2023]
Abstract
We conducted an adaptive design single-center pilot trial between October 2017 and November 2018 to determine the safety and efficacy of ultra-short-term perioperative pangenotypic direct acting antiviral (DAA) prophylaxis for deceased hepatitis C virus (HCV)-nucleic acid test (NAT) positive donors to HCV negative kidney recipients (D+/R-). In Group 1, 10 patients received one dose of SOF/VEL (sofusbuvir/velpatasvir) pretransplant and one dose on posttransplant Day 1. In Group 2A (N = 15) and the posttrial validation (Group 2B; N = 25) phase, patients received two additional SOF/VEL doses (total 4) on Days 2 and 3 posttransplant. Development of posttransplant HCV transmission triggered 12-week DAA therapy. For available donor samples (N = 27), median donor viral load was 1.37E + 06 IU/mL (genotype [GT]1a: 70%; GT2: 7%; GT3: 23%). Overall viral transmission rate was 12% (6/50; Group 1:30% [3/10]; Group 2A:13% [2/15]; Group 2B:4% [1/25]). For the 6 viremic patients, 5 (83%) achieved sustained virologic response (3 with first-line DAA therapy; and two after retreatment with second-line DAA). At a median follow-up of 8 months posttransplant, overall patient and allograft survivals were 98%, respectively. The 4-day strategy reduced viral transmission to 7.5% (3/40; 95% confidence interval [CI]: 1.8%-20.5%) and could result in avoidance of prolonged posttransplant DAA therapy for most D+/R - transplants.
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Affiliation(s)
- Gaurav Gupta
- Division of Nephrology, Virginia Commonwealth University School of Medicine, Richmond, Virginia.,Division of Transplantation, Hume-Lee Transplant Center, Virginia Commonwealth University School of Medicine, Richmond, Virginia
| | - Idris Yakubu
- Virginia Commonwealth University School of Pharmacy, Richmond, Virginia
| | - Chandra S Bhati
- Division of Transplantation, Hume-Lee Transplant Center, Virginia Commonwealth University School of Medicine, Richmond, Virginia
| | - Yiran Zhang
- Department of Pharmacotherapy and Outcomes Science, Virginia Commonwealth University School of Pharmacy, Richmond, Virginia
| | - Le Kang
- Department of Biostatistics, Virginia Commonwealth University, Richmond, Virginia
| | - Julie A Patterson
- Department of Pharmacotherapy and Outcomes Science, Virginia Commonwealth University School of Pharmacy, Richmond, Virginia
| | - Ayana Andrews-Joseph
- Division of Transplantation, Hume-Lee Transplant Center, Virginia Commonwealth University School of Medicine, Richmond, Virginia
| | - Anam Alam
- Division of Nephrology, Virginia Commonwealth University School of Medicine, Richmond, Virginia
| | | | - Dhiren Kumar
- Division of Nephrology, Virginia Commonwealth University School of Medicine, Richmond, Virginia
| | - Irfan K Moinuddin
- Division of Nephrology, Virginia Commonwealth University School of Medicine, Richmond, Virginia
| | - Layla Kamal
- Division of Nephrology, Virginia Commonwealth University School of Medicine, Richmond, Virginia
| | - Anne L King
- Division of Nephrology, Virginia Commonwealth University School of Medicine, Richmond, Virginia.,Division of Transplantation, Hume-Lee Transplant Center, Virginia Commonwealth University School of Medicine, Richmond, Virginia
| | - Marlon Levy
- Division of Transplantation, Hume-Lee Transplant Center, Virginia Commonwealth University School of Medicine, Richmond, Virginia
| | - Amit Sharma
- Division of Transplantation, Hume-Lee Transplant Center, Virginia Commonwealth University School of Medicine, Richmond, Virginia
| | - Adrian Cotterell
- Division of Transplantation, Hume-Lee Transplant Center, Virginia Commonwealth University School of Medicine, Richmond, Virginia
| | - Trevor W Reichman
- Division of Transplantation, Hume-Lee Transplant Center, Virginia Commonwealth University School of Medicine, Richmond, Virginia
| | - Aamir Khan
- Division of Transplantation, Hume-Lee Transplant Center, Virginia Commonwealth University School of Medicine, Richmond, Virginia
| | - Pamela Kimball
- Division of Transplantation, Hume-Lee Transplant Center, Virginia Commonwealth University School of Medicine, Richmond, Virginia
| | - Rodney Stiltner
- Virginia Commonwealth University School of Pharmacy, Richmond, Virginia
| | - Mary Baldecchi
- Division of Transplantation, Hume-Lee Transplant Center, Virginia Commonwealth University School of Medicine, Richmond, Virginia
| | - Nathaniel Brigle
- Division of Transplantation, Hume-Lee Transplant Center, Virginia Commonwealth University School of Medicine, Richmond, Virginia
| | - Todd Gehr
- Division of Nephrology, Virginia Commonwealth University School of Medicine, Richmond, Virginia
| | - Richard K Sterling
- Division of Transplantation, Hume-Lee Transplant Center, Virginia Commonwealth University School of Medicine, Richmond, Virginia.,Section of Hepatology, Virginia Commonwealth University School of Medicine, Richmond, Virginia
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45
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Alimohammadi A, Conway B, Yamamoto L. Glecaprevir/pibrentasvir+sofosbuvir: an optimal retreatment strategy in the setting of HCV NS5A resistance. BMJ Case Rep 2020; 13:13/2/e233098. [PMID: 32051160 DOI: 10.1136/bcr-2019-233098] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
Some individuals do not achieve a cure of their hepatitis C virus (HCV) infection due to non-adherence or resistance associated substitutions. Salvage options that are optimised for resistance profiles are essential. We report a 56-year-old Caucasian man with fatigue, depression and confusion in the setting of untreated HCV genotype 3a infection. He received ruzasvir and uprifosbuvir for 12 weeks within a clinical trial. The patient relapsed 4 weeks after the end of treatment and at this time resistance testing showed multiple resistances including a NS5A Y93H mutation. Given that this mutation confers resistance to first line salvage options, sofosbuvir and glecaprevir/pibrentasvir was used for 12 weeks and the patient was cured of HCV infection 12 weeks after the end of treatment. This shows that sofosbuvir and glecaprevir/pibrentasvir is a viable, effective option for second line/salvage therapy of HCV infection in the setting of resistance to NS5A inhibitors with the Y93H mutation.
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Affiliation(s)
- Arshia Alimohammadi
- Vancouver Infectious Diseases Centre, Vancouver, British Columbia, Canada .,Faculty of Medicine, Univertisy of British Columbia, Vancouver, British Columbia, Canada
| | - Brian Conway
- Vancouver Infectious Diseases Centre, Vancouver, British Columbia, Canada
| | - Leo Yamamoto
- Vancouver Infectious Diseases Centre, Vancouver, British Columbia, Canada
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46
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Tani J, Morishita A, Sakamoto T, Takuma K, Nakahara M, Fujita K, Oura K, Tadokoro T, Mimura S, Nomura T, Yoneyama H, Kobara H, Himoto T, Tsutsui A, Senoh T, Nagano T, Ogawa C, Moriya A, Deguchi A, Takaguchi K, Masaki T. Simple scoring system for prediction of hepatocellular carcinoma occurrence after hepatitis C virus eradication by direct-acting antiviral treatment: All Kagawa Liver Disease Group Study. Oncol Lett 2020; 19:2205-2212. [PMID: 32194718 PMCID: PMC7038998 DOI: 10.3892/ol.2020.11341] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2019] [Accepted: 12/12/2019] [Indexed: 02/06/2023] Open
Abstract
Direct acting antivirals (DAA) have recently been developed to treat patients with hepatitis C virus (HCV) infection, and interferon-free DAA treatment has improved the cure rate of patients. However, the occurrence rate of hepatocellular carcinoma (HCC) following HCV eradication remains unknown. Therefore, the present study aimed to identify predictors of HCC occurrence following DAA treatment. Among 1,454 patients infected with HCV, 1,088 patients who achieved sustained virologic response and who had no history of HCC treatment were recruited between September 2014 and November 2018. The incidence of HCC in patients infected with HCV following DAA treatment, and the predictors contributing to HCC occurrence were identified using clinicopathological characteristics and blood test results. During the present study, 26 patients developed HCC. The incidence of HCC was 0.61, 1.88, 2.82 and 3.71% at 6, 12, 18 and 24 months after treatment with DAA, respectively. The results of multivariate analysis identified age [hazard ratio (HR), 1.0729; P=0.0044] and α-fetoprotein (AFP) level after DAA treatment (HR, 1.0486; P=0.0486) as independent factors that may contribute to HCC occurrence following DAA treatment. By using these two factors, a novel scoring system (0-2 points) was established to predict HCC occurrence following HCV eradication by DAA treatment. The incidence of HCC at 2 years was 0.3% in the 0 points group, 6.27% in the 1 point group and 18.37% in the 2 points group. In conclusion, AFP level after DAA treatment and age at DAA administration were identified as independent predictors of HCC occurrence in patients that were treated with DAA. The scoring system that was established in the present study is simple and easy, and using pre-treatment factors may be a convenient tool to predict the risk of HCC occurrence in HCV-free patients following DAA treatment.
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Affiliation(s)
- Joji Tani
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki, Kagawa 761-0793, Japan
| | - Asahiro Morishita
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki, Kagawa 761-0793, Japan
| | - Teppei Sakamoto
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki, Kagawa 761-0793, Japan
| | - Kei Takuma
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki, Kagawa 761-0793, Japan
| | - Mai Nakahara
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki, Kagawa 761-0793, Japan
| | - Koji Fujita
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki, Kagawa 761-0793, Japan
| | - Kyoko Oura
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki, Kagawa 761-0793, Japan
| | - Tomoko Tadokoro
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki, Kagawa 761-0793, Japan
| | - Shima Mimura
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki, Kagawa 761-0793, Japan
| | - Takako Nomura
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki, Kagawa 761-0793, Japan
| | - Hirohito Yoneyama
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki, Kagawa 761-0793, Japan
| | - Hideki Kobara
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki, Kagawa 761-0793, Japan
| | - Takashi Himoto
- Department of Medical Technology, Kagawa Prefectural University of Health Sciences, Takamatsu, Kagawa 761-0123, Japan
| | - Akemi Tsutsui
- Department of Hepatology, Kagawa Prefectural Central Hospital, Takamatsu, Kagawa 760-8557, Japan
| | - Tomonori Senoh
- Department of Hepatology, Kagawa Prefectural Central Hospital, Takamatsu, Kagawa 760-8557, Japan
| | - Takuya Nagano
- Department of Hepatology, Kagawa Prefectural Central Hospital, Takamatsu, Kagawa 760-8557, Japan
| | - Chikara Ogawa
- Department of Gastroenterology and Hepatology, Takamatsu Red Cross Hospital, Takamatsu, Kagawa 760-0017, Japan
| | - Akio Moriya
- Department of Gastroenterology, Mitoyo General Hospital, Kanonji, Kagawa 769-1695, Japan
| | - Akihiro Deguchi
- Department of Gastroenterology, Kagawa Rosai Hospital, Marugame, Kagawa 763-8502, Japan
| | - Kouichi Takaguchi
- Department of Hepatology, Kagawa Prefectural Central Hospital, Takamatsu, Kagawa 760-8557, Japan
| | - Tsutomu Masaki
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki, Kagawa 761-0793, Japan
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Zoratti MJ, Siddiqua A, Morassut RE, Zeraatkar D, Chou R, van Holten J, Xie F, Druyts E. Pangenotypic direct acting antivirals for the treatment of chronic hepatitis C virus infection: A systematic literature review and meta-analysis. EClinicalMedicine 2020; 18:100237. [PMID: 31922124 PMCID: PMC6948236 DOI: 10.1016/j.eclinm.2019.12.007] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2019] [Revised: 12/02/2019] [Accepted: 12/05/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Recent approval and adoption of pangenotypic direct acting antivirals (DAAs) necessitated a revision of the 2015 World Health Organization guidelines for the management of persons with hepatitis C virus (HCV) infection. METHODS We searched MEDLINE, EMBASE, CENTRAL, and relevant conference proceedings to identify randomized and non-randomized trials, as well as prospective observational studies of DAAs. The proportions of persons with events were pooled for sustained virological response at 12 weeks post-treatment (SVR12), discontinuations due to adverse events (DAEs), serious adverse events (SAEs), and all-cause mortality. Analyses were stratified by HCV genotype and antiviral treatment experience, with subgroup analyses based on presence of cirrhosis and HIV-HCV coinfection. FINDINGS The evidence base consisted of 238 publications describing 142 studies. In the overall analysis, which included all persons irrespective of treatment experience or comorbidities, the pooled proportion achieving SVR12 exceeded 0.94 for all pangenotypic regimens across genotypes 1, 2, and 4. Some heterogeneity may have led to lower SVR rates in persons with genotype 3 infection. High SVR12 (>0.90) was observed in persons with genotype 1 infection with cirrhosis, though evidence varied and was limited for genotypes 2-4. Evidence was sparse for persons with HIV-HCV coinfection. All regimens were associated with small proportions of persons with DAEs, SAEs, or all-cause mortality. INTERPRETATION Based on this and other supporting evidence, the WHO issued updated guidelines with a conditional recommendation, based on moderate quality evidence, for the use of pangenotypic DAA regimens for persons with chronic HCV infection aged 18 years and older (July 2018). FUNDING This study was funded by the World Health Organization.
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Affiliation(s)
- Michael J. Zoratti
- Zoratti HEOR Consulting Inc., Oakville, Ontario, Canada
- Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada
| | - Ayesha Siddiqua
- Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada
- Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, Ontario, Canada
| | - Rita E. Morassut
- Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada
| | - Dena Zeraatkar
- Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada
| | - Roger Chou
- Department of Medical Informatics and Clinical Epidemiology, Division of General Internal Medicine and Geriatrics, Oregon Health and Science University, Portland, Oregon, USA
| | - Judith van Holten
- Department of HIV and Global Hepatitis Programme, World Health Organization, Geneva, Switzerland
| | - Feng Xie
- Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada
| | - Eric Druyts
- Pharmalytics Group, Vancouver, British Columbia, Canada
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48
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Rabaan AA, Al-Ahmed SH, Bazzi AM, Alfouzan WA, Alsuliman SA, Aldrazi FA, Haque S. Overview of hepatitis C infection, molecular biology, and new treatment. J Infect Public Health 2019; 13:773-783. [PMID: 31870632 DOI: 10.1016/j.jiph.2019.11.015] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2018] [Revised: 07/08/2019] [Accepted: 11/18/2019] [Indexed: 12/13/2022] Open
Abstract
The World Health Organization estimates that 71 million people worldwide have chronic hepatitis C viral infection. A major challenge is overall lack of public awareness of hepatitis C, particularly among infected people of their infection status. Chronic hepatitis C infection is associated with advanced liver disease, is the main cause of hepatocellular carcinoma and causes many extra-hepatic manifestations. The existence of seven viral genotypes complicates targeting of treatment. Recent years have seen the approval of many direct acting antivirals targeted at hepatitis C virus non-structural proteins. These have revolutionized therapy as they allow achievement of extremely high sustained virologic responses. Of great significance is the development of pan-genotypic drug combinations, including the NS3/4A-NS5A inhibitor combinations sofosbuvir-velpatasvir and glecaprevir-pibrentasvir. However, resistance-associated mutations can result in failure of these treatments in a small number of patients. This, combined with the high costs of treatment, highlights the importance of continued research into effective anti-hepatitis C therapies, for example aimed at viral entry. Recent developments include identification of the potential of low-cost anti-histamines for repurposing as inhibitors of hepatitis C viral entry. In this review we focus on molecular biology of hepatitis C virus, and the new developments in hepatitis C treatment.
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Affiliation(s)
- Ali A Rabaan
- Molecular Diagnostic Laboratory, Johns Hopkins Aramco Healthcare, Dhahran, Saudi Arabia.
| | - Shamsah H Al-Ahmed
- Specialty Paediatric Medicine, Qatif Central Hospital, Qatif, Saudi Arabia
| | - Ali M Bazzi
- Microbiology Laboratory, Johns Hopkins Aramco Healthcare, Dhahran, Saudi Arabia
| | - Wadha A Alfouzan
- Department of Microbiology, Faculty of Medicine, Kuwait University, Safat 13110, Kuwait; Faculty of Medicine, Kuwait University, Dasma 35153, Kuwait
| | - Shahab A Alsuliman
- Internal Medicine and Infectious Disease Department, Dammam Medical Complex, Dammam, Saudi Arabia
| | - Fatimah A Aldrazi
- Infection Control Department, Dammam Medical Complex, Dammam, Saudi Arabia
| | - Shafiul Haque
- Research and Scientific Studies Unit, College of Nursing & Allied Health Sciences, Jazan University, Saudi Arabia
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Bourliere M. Retreatment Options for Patients Who Failed Direct-Acting Antiviral Regimens Containing NS5A Inhibitors: Is Glecaprevir/Pibrentasvir a Valid and Robust Option? Gastroenterology 2019; 157:1473-1475. [PMID: 31606469 DOI: 10.1053/j.gastro.2019.10.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2019] [Accepted: 10/07/2019] [Indexed: 12/24/2022]
Affiliation(s)
- Marc Bourliere
- Department of Hepato-Gastroenterology, Hospital Saint Joseph, Marseille, France.
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50
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Lok AS, Sulkowski MS, Kort JJ, Willner I, Reddy KR, Shiffman ML, Hassan MA, Pearlman BL, Hinestrosa F, Jacobson IM, Morelli G, Peter JA, Vainorius M, Michael LC, Fried MW, Wang GP, Lu W, Larsen L, Nelson DR. Efficacy of Glecaprevir and Pibrentasvir in Patients With Genotype 1 Hepatitis C Virus Infection With Treatment Failure After NS5A Inhibitor Plus Sofosbuvir Therapy. Gastroenterology 2019; 157:1506-1517.e1. [PMID: 31401140 DOI: 10.1053/j.gastro.2019.08.008] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2019] [Revised: 07/30/2019] [Accepted: 08/02/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Treatment options are limited for patients with hepatitis C (HCV) infection with treatment failure after sofosbuvir plus an NS5A inhibitor. There are some data for the efficacy of glecaprevir/pibrentasvir (G/P) in these patients. We performed a randomized trial of the safety and efficacy of 12 and 16 weeks of G/P, with or without ribavirin, in patients with HCV genotype 1 infection with treatment failure after sofosbuvir and an NS5A inhibitor. METHODS We performed a phase 3b, open-label study of patients with chronic HCV genotype 1 infection who received previous treatment with sofosbuvir plus an NS5A inhibitor. Patients without cirrhosis were randomly assigned to groups that received G/P for 12 weeks (n = 78, group A) or 16 weeks (n = 49, group B). Patients with compensated cirrhosis were randomly assigned to groups that received G/P and ribavirin for 12 weeks (n = 21, group C) or G/P for 16 weeks (n = 29, group D). The primary end point was a sustained virologic response 12 weeks after treatment. Samples collected at baseline and at time of treatment failure were sequenced for resistance-associated substitutions in NS3 and NS5A. RESULTS Of the 177 patients in the 4 groups, 81% were men, 79% had HCV genotype 1a infection, and 44% were black. Proportions of patients with sustained virologic response 12 weeks after treatment in groups A, B, C, and D were 90%, 94%, 86%, and 97%, respectively. The treatment failed in 13 (7.3%) patients with HCV genotype 1a infection, 6 (7.9%) in group A, 3 (6.1%) in group B, 3 (6.1%) in group C (6.1%), and 1 (3.4%) in group D. Most patients had baseline resistance-associated substitutions in NS5A. Treatment-emergent resistance-associated substitutions in NS3 and NS5A were observed in 9 and 10 patients with treatment failure, respectively. G/P was well tolerated. Ribavirin increased adverse events but did not increase efficacy. CONCLUSIONS In a randomized study of patients with chronic HCV genotype 1 infection who received previous treatment with sofosbuvir plus an NS5A inhibitor, 16 weeks treatment with G/P produced sustained virologic response 12 weeks after treatment in >90% of patients, including those with compensated cirrhosis. ClinicalTrials.gov, Number: NCT03092375.
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Affiliation(s)
- Anna S Lok
- Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, Michigan.
| | - Mark S Sulkowski
- Divisions of Infectious Diseases and Gastroenterology/Hepatology, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | | | - Ira Willner
- Division of Gastroenterology and Hepatology, Medical University of South Carolina, Charleston, South Carolina
| | - K Rajender Reddy
- Division of Gastroenterology and Hepatology, University of Pennsylvania, Philadelphia, Pennsylvania
| | | | - Mohamed A Hassan
- Division of Gastroenterology, Hepatology, and Nutrition, University of Minnesota, Minneapolis, Minnesota
| | - Brian L Pearlman
- Center for Hepatitis C, Wellstar Health System, Atlanta, Georgia
| | | | - Ira M Jacobson
- Department of Hepatology, New York University Langone Health, New York, New York
| | - Giuseppe Morelli
- Division of Gastroenterology, Hepatology, and Nutrition, University of Florida, Gainesville, Florida
| | - Joy A Peter
- Hepatology Research, University of Florida, Gainesville, Florida
| | - Monika Vainorius
- HCV-TARGET Data Coordinating Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - Larry C Michael
- HCV-TARGET Data Coordinating Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - Michael W Fried
- Division of Gastroenterology and Hepatology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - Gary P Wang
- Division of Infectious Diseases and Global Medicine, University of Florida, Gainesville, Florida
| | | | | | - David R Nelson
- Department of Medicine, University of Florida, Gainesville, Florida
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