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Mechanisms and Consequences of Genetic Variation in Hepatitis C Virus (HCV). Curr Top Microbiol Immunol 2023; 439:237-264. [PMID: 36592248 DOI: 10.1007/978-3-031-15640-3_7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
Chronic infection with hepatitis C virus (HCV) is an important contributor to the global incidence of liver diseases, including liver cirrhosis and hepatocellular carcinoma. Although common for single-stranded RNA viruses, HCV displays a remarkable high level of genetic diversity, produced primarily by the error-prone viral polymerase and host immune pressure. The high genetic heterogeneity of HCV has led to the evolution of several distinct genotypes and subtypes, with important consequences for pathogenesis, and clinical outcomes. Genetic variability constitutes an evasion mechanism against immune suppression, allowing the virus to evolve epitope escape mutants that avoid immune recognition. Thus, heterogeneity and variability of the HCV genome represent a great hindrance for the development of vaccines against HCV. In addition, the high genetic plasticity of HCV allows the virus to rapidly develop antiviral resistance mutations, leading to treatment failure and potentially representing a major hindrance for the cure of chronic HCV patients. In this chapter, we will present the central role that genetic diversity has in the viral life cycle and epidemiology of HCV. Incorporation errors and recombination, both the result of HCV polymerase activity, represent the main mechanisms of HCV evolution. The molecular details of both mechanisms have been only partially clarified and will be presented in the following sections. Finally, we will discuss the major consequences of HCV genetic diversity, namely its capacity to rapidly evolve antiviral and immunological escape variants that represent an important limitation for clearance of acute HCV, for treatment of chronic hepatitis C and for broadly protective vaccines.
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Nada A, Sabry A, Elabd NS, Abdu Allah AM, Elnaidany N, Abbasy M. B-type natriuretic peptide (BNP) in HCV-positive Egyptian patients: the impact of HCV eradication on plasma BNP levels. EGYPTIAN LIVER JOURNAL 2021. [DOI: 10.1186/s43066-021-00133-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Abstract
Background
Chronic hepatitis C virus (HCV) infection represents a major health-related burden in Egypt. HCV is considered as a major cardiovascular risk factor. BNP (B-type natriuretic peptide) has been determined as a credible diagnostic and prognostic cardiac biomarker. We aimed to assess plasma BNP in HCV-positive Egyptian patients prior and after HCV eradication by direct-acting antiviral agents (DAAs) therapy. Eighty-nine chronic HCV-positive patients were enrolled in our prospective research. They were provided with DAAs therapy in the form of sofosbuvir and daclatasvir without or with ribavirin for 12 weeks. History, clinical evaluation, and laboratory assessment: CBC, liver and kidney function tests, viral markers (HCVAb, HBVsAg, and HIVAb) by ELISA, HCV RNA by real-time PCR, and BNP by ELISA were assessed. FIB-4 and aspartate aminotransferase-to-platelet ratio index (APRI) scores were ranked.
Results
Plasma BNP displayed a non-significant (p = 0.124) increase of its serum mean values in post eradication of HCV than its baseline values. Baseline BNP exhibited a significant positive correlation with FIB4 (r = 0.411, P < 0.001) and APRI score (r = 0.418, p < 0.001) with a considerably negative correlation with platelets (r = − 0.274, p = 0.009), in addition to higher pretreatment BNP values in cirrhotic than in non-cirrhotic patients (p < 0.001), while non-significant relations were found regarding sex, BMI, and drug regimen (with or without ribavirin) (p = 0.950, 0.845, and 0.738, respectively). Additionally, plasma BNP values considerably decreased post-treatment in patients presented with higher baseline BNP values and more advanced liver disease (higher FIB4, APRI, and the presence of liver cirrhosis).
Conclusion
Our findings propose on the one side, the necessity of cardiac monitoring during chronic HCV infection and, on the other, the valuable impacts of HCV eradication on HCV-associated cardiac morbidities.
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Gross LZF, Sacerdoti M, Piiper A, Zeuzem S, Leroux AE, Biondi RM. ACE2, the Receptor that Enables Infection by SARS-CoV-2: Biochemistry, Structure, Allostery and Evaluation of the Potential Development of ACE2 Modulators. ChemMedChem 2020; 15:1682-1690. [PMID: 32663362 PMCID: PMC7405163 DOI: 10.1002/cmdc.202000368] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Revised: 07/13/2020] [Indexed: 01/07/2023]
Abstract
Angiotensin converting enzyme 2 (ACE2) is the human receptor that interacts with the spike protein of coronaviruses, including the one that produced the 2020 coronavirus pandemic (COVID-19). Thus, ACE2 is a potential target for drugs that disrupt the interaction of human cells with SARS-CoV-2 to abolish infection. There is also interest in drugs that inhibit or activate ACE2, that is, for cardiovascular disorders or colitis. Compounds binding at alternative sites could allosterically affect the interaction with the spike protein. Herein, we review biochemical, chemical biology, and structural information on ACE2, including the recent cryoEM structures of full-length ACE2. We conclude that ACE2 is very dynamic and that allosteric drugs could be developed to target ACE2. At the time of the 2020 pandemic, we suggest that available ACE2 inhibitors or activators in advanced development should be tested for their ability to allosterically displace the interaction between ACE2 and the spike protein.
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Affiliation(s)
- Lissy Z. F. Gross
- Chemical Biology of Regulatory MechanismsIBioBA-CONICET-Partner Institute of the Max Planck SocietyGodoy Cruz 2390Buenos AiresArgentina
| | - Mariana Sacerdoti
- Chemical Biology of Regulatory MechanismsIBioBA-CONICET-Partner Institute of the Max Planck SocietyGodoy Cruz 2390Buenos AiresArgentina
| | - Albrecht Piiper
- Internal Medicine IFrankfurt University HospitalTheodor-Stern-Kai 7Frankfurt am MainGermany
| | - Stefan Zeuzem
- Internal Medicine IFrankfurt University HospitalTheodor-Stern-Kai 7Frankfurt am MainGermany
| | - Alejandro E. Leroux
- Chemical Biology of Regulatory MechanismsIBioBA-CONICET-Partner Institute of the Max Planck SocietyGodoy Cruz 2390Buenos AiresArgentina
| | - Ricardo M. Biondi
- Chemical Biology of Regulatory MechanismsIBioBA-CONICET-Partner Institute of the Max Planck SocietyGodoy Cruz 2390Buenos AiresArgentina
- Internal Medicine IFrankfurt University HospitalTheodor-Stern-Kai 7Frankfurt am MainGermany
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Enhanced Efficacy of Direct-Acting Antivirals in Hepatitis C Patients by Coadministration of Black Cumin and Ascorbate as Antioxidant Adjuvants. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2020; 2020:7087921. [PMID: 32566096 PMCID: PMC7290872 DOI: 10.1155/2020/7087921] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/19/2020] [Revised: 04/11/2020] [Accepted: 05/08/2020] [Indexed: 12/29/2022]
Abstract
The widespread adaptation of a new generation of direct-acting antiviral agents (DAAs) unveils a superlative effect in the eradication of the hepatitis C virus (HCV). However, this therapy has been reported to exhibit vigorous side effects that pose a risk in fleet recovery. This study was conducted to investigate the efficacy of DAAs: sofosbuvir (SOF) and ribavirin (RBV), along with black cumin (BLC) and ascorbate (ASC), as adjuvants on hematological parameters; oxidative stress markers such as total antioxidant status (TAS), superoxide dismutase (SOD), reduced (GSH) and oxidized (GSSG) glutathione (GSH), gamma-glutamyl transferase (GGT), and malondialdehyde (MDA); liver function markers such as aspartate transaminase (AST), alanine aminotransferase (ALT), bilirubin, and alkaline phosphatase (ALP); and viral load with determined genotypes. HCV-infected patients (n = 30) were randomly divided into two equal groups: control group (n = 15) and treatment group (n = 15). The control group was subjected only to SOF and RBV (400 mg each/day). Synergistically, the treatment group was administered with adjuvant therapy of BLC (250 mg/day) and ASC (1000 mg/day) along with DAAs (400 mg each/day) for 8 weeks. All selected patients were subjected to sampling at pre- and posttreatment stages for the assessment of defined parameters. The data revealed that the BLC/ASC adjuvant therapy boosted the efficacy of DAAs by reducing the elevated levels of liver markers such as AST, ALT, ALP, and bilirubin in the treatment group compared with those in the control group (P > 0.05). The adjuvant therapy synchronously showed an ameliorating effect on hematological parameters. The SOF/RBV with adjuvant therapy also demonstrated an increasing effect in the activity of SOD, TAS, and GSH and a decreasing effect for GSSG, GGT, and malondialdehyde (MDA; P > 0.05) followed by curtailing a RT-PCR-quantified viral load. Our findings provide evidence that systemic administration of BLC/ASC efficiently alleviates hematological, serological, and antioxidant markers as well as the viral load in hepatitis C patients. This highlights a potentially novel role of BLC and ASC in palliating hepatitis C.
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Lim JK, Liapakis AM, Shiffman ML, Lok AS, Zeuzem S, Terrault NA, Park JS, Landis CS, Hassan M, Gallant J, Kuo A, Pockros PJ, Vainorius M, Akushevich L, Michael L, Fried MW, Nelson DR, Ben-Ari Z. Safety and Effectiveness of Ledipasvir and Sofosbuvir, With or Without Ribavirin, in Treatment-Experienced Patients With Genotype 1 Hepatitis C Virus Infection and Cirrhosis. Clin Gastroenterol Hepatol 2018; 16:1811-1819.e4. [PMID: 29306043 PMCID: PMC6034985 DOI: 10.1016/j.cgh.2017.12.037] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2017] [Revised: 11/30/2017] [Accepted: 12/22/2017] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS We aimed to evaluate the safety and effectiveness of 12 or 24 weeks treatment with ledipasvir and sofosbuvir, with or without ribavirin, in treatment-experienced patients with hepatitis C virus (HCV) genotype 1 infection and cirrhosis in routine clinical practice. Patients were followed in a multi-center, prospective, observational cohort study (HCV-TARGET). METHODS We collected data from 667 treatment-experienced adults with chronic genotype 1 HCV infection who began treatment with ledipasvir and sofosbuvir, with or without ribavirin, from 2011 through September 15, 2016, according to the regional standards of care, at academic (n = 39) and community (n = 18) centers in the United States, Canada, Germany, and Israel. Information was collected from medical records and abstracted into a unique centralized data core. Independent monitors systematically reviewed data entries for completeness and accuracy. Demographic, clinical, adverse event, and virologic data were collected every 12 weeks during treatment and during the follow-up period. The primary efficacy endpoint was sustained virologic response, defined as a level of HCV RNA below the lower limit of quantification or undetectable at a minimum 64 days after the end of treatment (SVR12). The per-protocol population (n = 610) was restricted to patients who completed 12 or 24 weeks of treatment (±2 weeks) and had final virologic outcomes available. RESULTS The per-protocol analysis revealed that 579 patients (93.8%) achieved an SVR12, including 50/51 patients who received ledipasvir and sofosbuvir for 12 weeks (98%), 384/408 patients who received ledipasvir and sofosbuvir for 24 weeks (94.1%), 68/70 patients who received ledipasvir and sofosbuvir with ribavirin for 12 weeks (97.1%), and 57/60 patients who received ledipasvir and sofosbuvir with ribavirin for 24 weeks (95%). On multivariate analysis, neither treatment duration nor the addition of ribavirin was associated with SVR12. Compensated cirrhosis (odds ratio [OR] compared to decompensated cirrhosis, 2.41; 95% CI, 1.16-5.02), albumin ≥ 3.5 g/dL (OR, 3.15; 95% CI 1.46-6.80), or total bilirubin ≤ 1.2 mg/dL (OR 3.34; 95% CI, 1.59-7.00) were associated with SVR12. CONCLUSIONS In an analysis of safety and effectiveness data from the HCV-TARGET study, we found treatment with ledipasvir and sofosbuvir, with or without ribavirin, to be effective and well tolerated by treatment-experienced patients with genotype 1 HCV infection and compensated cirrhosis. There were no significant differences in rate of SVR12 among patients treated with ledipasvir and sofosbuvir for 12 or 24 weeks, with or without ribavirin. Patients with decompensated cirrhosis appear to benefit from the addition of ribavirin or extension of ledipasvir and sofosbuvir treatment to 24 weeks. ClinicalTrials.gov no: NCT10474811.
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Affiliation(s)
- Joseph K Lim
- Yale University School of Medicine, New Haven, Connecticut.
| | | | | | - Anna S Lok
- University of Michigan, Ann Arbor, Michigan
| | - Stefan Zeuzem
- J. W. Goethe University Hospital, Frankfurt, Germany
| | - Norah A Terrault
- University of California-San Francisco, San Francisco, California
| | | | | | | | | | | | | | | | | | - Larry Michael
- University of North Carolina, Chapel Hill, North Carolina
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Randolph JT, Krueger AC, Donner PL, Pratt JK, Liu D, Motter CE, Rockway TW, Tufano MD, Wagner R, Lim HB, Beyer JM, Mondal R, Panchal NS, Colletti L, Liu Y, Koev G, Kati WM, Hernandez LE, Beno DWA, Longenecker KL, Stewart KD, Dumas EO, Molla A, Maring CJ. Synthesis and Biological Characterization of Aryl Uracil Inhibitors of Hepatitis C Virus NS5B Polymerase: Discovery of ABT-072, a trans-Stilbene Analog with Good Oral Bioavailability. J Med Chem 2018; 61:1153-1163. [PMID: 29342358 DOI: 10.1021/acs.jmedchem.7b01630] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
ABT-072 is a non-nucleoside HCV NS5B polymerase inhibitor that was discovered as part of a program to identify new direct-acting antivirals (DAAs) for the treatment of HCV infection. This compound was identified during a medicinal chemistry effort to improve on an original lead, inhibitor 1, which we described in a previous publication. Replacement of the amide linkage in 1 with a trans-olefin resulted in improved compound permeability and solubility and provided much better pharmacokinetic properties in preclinical species. Replacement of the dihydrouracil in 1 with an N-linked uracil provided better potency in the genotype 1 replicon assay. Results from phase 1 clinical studies supported once-daily oral dosing with ABT-072 in HCV infected patients. A phase 2 clinical study that combined ABT-072 with the HCV protease inhibitor ABT-450 provided a sustained virologic response at 24 weeks after dosing (SVR24) in 10 of 11 patients who received treatment.
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Affiliation(s)
- John T Randolph
- Research and Development, AbbVie Inc. , North Chicago, Illinois 60064, United States
| | - A Chris Krueger
- Research and Development, AbbVie Inc. , North Chicago, Illinois 60064, United States
| | - Pamela L Donner
- Research and Development, AbbVie Inc. , North Chicago, Illinois 60064, United States
| | - John K Pratt
- Research and Development, AbbVie Inc. , North Chicago, Illinois 60064, United States
| | - Dachun Liu
- Research and Development, AbbVie Inc. , North Chicago, Illinois 60064, United States
| | - Christopher E Motter
- Research and Development, AbbVie Inc. , North Chicago, Illinois 60064, United States
| | - Todd W Rockway
- Research and Development, AbbVie Inc. , North Chicago, Illinois 60064, United States
| | - Michael D Tufano
- Research and Development, AbbVie Inc. , North Chicago, Illinois 60064, United States
| | - Rolf Wagner
- Research and Development, AbbVie Inc. , North Chicago, Illinois 60064, United States
| | - Hock B Lim
- Research and Development, AbbVie Inc. , North Chicago, Illinois 60064, United States
| | - Jill M Beyer
- Research and Development, AbbVie Inc. , North Chicago, Illinois 60064, United States
| | - Rubina Mondal
- Research and Development, AbbVie Inc. , North Chicago, Illinois 60064, United States
| | - Neeta S Panchal
- Research and Development, AbbVie Inc. , North Chicago, Illinois 60064, United States
| | - Lynn Colletti
- Research and Development, AbbVie Inc. , North Chicago, Illinois 60064, United States
| | - Yaya Liu
- Research and Development, AbbVie Inc. , North Chicago, Illinois 60064, United States
| | - Gennadiy Koev
- Research and Development, AbbVie Inc. , North Chicago, Illinois 60064, United States
| | - Warren M Kati
- Research and Development, AbbVie Inc. , North Chicago, Illinois 60064, United States
| | - Lisa E Hernandez
- Research and Development, AbbVie Inc. , North Chicago, Illinois 60064, United States
| | - David W A Beno
- Research and Development, AbbVie Inc. , North Chicago, Illinois 60064, United States
| | - Kenton L Longenecker
- Research and Development, AbbVie Inc. , North Chicago, Illinois 60064, United States
| | - Kent D Stewart
- Research and Development, AbbVie Inc. , North Chicago, Illinois 60064, United States
| | - Emily O Dumas
- Research and Development, AbbVie Inc. , North Chicago, Illinois 60064, United States
| | - Akhteruzzaman Molla
- Research and Development, AbbVie Inc. , North Chicago, Illinois 60064, United States
| | - Clarence J Maring
- Research and Development, AbbVie Inc. , North Chicago, Illinois 60064, United States
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Welzel TM, Nelson DR, Morelli G, Di Bisceglie A, Reddy RK, Kuo A, Lim JK, Darling J, Pockros P, Galati JS, Frazier LM, Alqahtani S, Sulkowski MS, Vainorius M, Akushevich L, Fried MW, Zeuzem S. Effectiveness and safety of sofosbuvir plus ribavirin for the treatment of HCV genotype 2 infection: results of the real-world, clinical practice HCV-TARGET study. Gut 2017; 66:1844-1852. [PMID: 27418632 PMCID: PMC5595101 DOI: 10.1136/gutjnl-2016-311609] [Citation(s) in RCA: 63] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2016] [Revised: 06/01/2016] [Accepted: 06/04/2016] [Indexed: 12/12/2022]
Abstract
OBJECTIVE Due to a high efficacy in clinical trials, sofosbuvir (SOF) and ribavirin (RBV) for 12 or 16 weeks is recommended for treatment of patients with HCV genotype (GT) 2 infection. We investigated safety and effectiveness of these regimens for GT2 in HCV-TARGET participants. DESIGN HCV-TARGET, an international, prospective observational study evaluates clinical practice data on novel antiviral therapies at 44 academic and 17 community medical centres in North America and Europe. Clinical data were centrally abstracted from medical records. Selection of treatment regimen and duration was the investigator's choice. The primary efficacy outcome was sustained virological response 12 weeks after therapy (SVR12). RESULTS Between December 2013 and April 2015, 321 patients completed 12 weeks (n=283) or 16 weeks (n=38) of treatment with SOF and RBV. Prior treatment experience and cirrhosis was more frequent among patients in the 16-week regimen compared with 12 weeks (52.6% vs 27.6% and 63.2% vs 21.9%, respectively). Overall, SVR12 was 88.2%. The SVR12 in patients without cirrhosis was 91.0% and 92.9% for 12 or 16 weeks of therapy, respectively. In patients with cirrhosis treated for 12 or 16 weeks, SVR12 was 79.0% and 83%. In the multivariate analysis, liver cirrhosis, lower serum albumin and RBV dose at baseline were significantly associated with SVR12. Common adverse events (AEs) included fatigue, anaemia, nausea, headache, insomnia, rash and flu-like symptoms. Discontinuation due to AEs occurred in 2.8%. CONCLUSIONS In this clinical practice setting, SOF and RBV was safe and effective for treatment of patients with HCV GT2 infection. TRIAL REGISTRATION NUMBER NCT01474811.
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Affiliation(s)
- Tania M Welzel
- JW Goethe University Hospital, Frankfurt am Main, Germany
| | | | | | | | | | - Alexander Kuo
- University of California, San Diego, San Diego, California, USA
| | - Joseph K Lim
- Yale University of School of Medicine, New Haven, Connecticut, USA
| | - Jama Darling
- University of North Carolina, Chapel Hill, North Carolina, USA
| | | | | | | | | | | | | | - Lucy Akushevich
- University of North Carolina, Chapel Hill, North Carolina, USA
| | - Michael W Fried
- University of North Carolina, Chapel Hill, North Carolina, USA
| | - Stefan Zeuzem
- JW Goethe University Hospital, Frankfurt am Main, Germany
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D'Ambrosio R, Degasperi E, Colombo M, Aghemo A. Direct-acting antivirals: the endgame for hepatitis C? Curr Opin Virol 2017; 24:31-37. [PMID: 28419938 DOI: 10.1016/j.coviro.2017.03.017] [Citation(s) in RCA: 71] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2017] [Accepted: 03/30/2017] [Indexed: 12/13/2022]
Abstract
Directly-acting antivirals (DAA) have finally allowed all patients to be potentially cured from chronic hepatitis C (HCV) infection. All-oral, Interferon (IFN)-free regimens are based upon the combination of molecules targeting different sites of the HCV replication process. Three classes of DAA exist: protease inhibitors (anti-NS3/4A), RNA-dependent polymerase inhibitors (anti-NS5B) and anti-NS5A inhibitors, which are characterized by different antiviral potency and barrier to resistance and therefore are usually combined in different treatment schedules. Treatment regimens are still largely dependent on HCV genotype and stage of liver disease, with duration ranging between 12 weeks and 24 weeks, while overall treatment efficacy has climbed to nearly 95% in most patient groups, including historically difficult-to-treat categories (HCV genotype 1, advanced liver disease). The elimination of IFN has allowed safe and efficacious treatment of patients formerly contraindicated to antiviral therapy, such as decompensated cirrhosis and solid organ transplant recipients. Availability of potent and safe antiviral drugs combined with improvement of worldwide access to treatment could finally lead to HCV elimination in the next decades.
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Affiliation(s)
- Roberta D'Ambrosio
- Division of Gastroenterology and Hepatology, IRCCS Ca' Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy
| | - Elisabetta Degasperi
- Division of Gastroenterology and Hepatology, IRCCS Ca' Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy
| | - Massimo Colombo
- Humanitas Clinical and Research Center, Humanitas Research Hospital, Rozzano, Italy
| | - Alessio Aghemo
- Division of Gastroenterology and Hepatology, IRCCS Ca' Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy.
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Yang YM, Choi EJ. Efficacy and safety outcomes of sofosbuvir-based treatment regimens for hepatitis C virus-infected patients with or without cirrhosis from phase III clinical trials. Ther Clin Risk Manag 2017; 13:477-497. [PMID: 28442915 PMCID: PMC5395279 DOI: 10.2147/tcrm.s134818] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Background With the appearance of oral direct-acting antivirals (DAAs), the field of hepatitis C virus (HCV) treatment has been dramatically changed. This evolution makes possible for all oral treatments to be available for the treatment of HCV-infected patients. The aims of this review were to report the efficacy and safety of sofosbuvir (SOF)-based regimens for the treatment of patients with chronic HCV infection and to provide our clinical perspectives on these regimens. Methods A literature search of clinical studies published in PubMed and posted on ClinicalTrials.gov website was performed to identify studies evaluating the efficacy or safety of SOF-containing treatment regimens. Results A total of 23 clinical trials were examined in the review. The evaluated SOF-based regimens are as follows: SOF/daclatasvir (DCV) ± ribavirin (RBV), SOF/ledipasvir (LDV) ± RBV, SOF/simeprevir (SMV), SOF/velpatasvir (VEL) ± RBV, and SOF/RBV ± peginterferon (peg-IFN). These SOF-based regimens were at least effective and safe for HCV-infected patients with or without cirrhosis. The SOF/VEL ± RBV regimen, a pan-genotypic DAA regimen, was effective for the treatment of patients with HCV genotype 1, 2, 3, 4, 5, or 6 infection. The 24-week SOF/RBV regimen was as effective as the 12-week SOF/RBV/peg-IFN regimen. Patients with HCV genotype 3 infection could have benefits from the use of the 24-week SOF/RBV regimen. For cirrhotic patients with HCV genotype 3 infection, the 12-week SOF/RBV/peg-IFN regimen could be considered as an alternative treatment option when access to SOF-based regimens with other DAAs is limited. In the included studies, significant adverse events due to SOF-based regimens were not reported. Conclusion The clinical trials suggest that SOF-based treatment regimens for HCV-infected patients with or without cirrhosis can be at least effective and safe patient-convenient medications. However, it is necessary to monitor HCV-infected patients, since rare adverse events, drug–drug interactions, and drug–disease interactions can occur in real clinical settings.
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Affiliation(s)
- Young-Mo Yang
- Department of Pharmacy, College of Pharmacy, Chosun University, Gwangju, South Korea
| | - Eun Joo Choi
- Department of Pharmacy, College of Pharmacy, Chosun University, Gwangju, South Korea
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Current therapy for chronic hepatitis C: The role of direct-acting antivirals. Antiviral Res 2017; 142:83-122. [PMID: 28238877 PMCID: PMC7172984 DOI: 10.1016/j.antiviral.2017.02.014] [Citation(s) in RCA: 126] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2016] [Revised: 02/07/2017] [Accepted: 02/22/2017] [Indexed: 12/12/2022]
Abstract
One of the most exciting developments in antiviral research has been the discovery of the direct-acting antivirals (DAAs) that effectively cure chronic hepatitis C virus (HCV) infections. Based on more than 100 clinical trials and real-world studies, we provide a comprehensive overview of FDA-approved therapies and newly discovered anti-HCV agents with a special focus on drug efficacy, mechanisms of action, and safety. We show that HCV drug development has advanced in multiple aspects: (i) interferon-based regimens were replaced by interferon-free regimens; (ii) genotype-specific drugs evolved to drugs for all HCV genotypes; (iii) therapies based upon multiple pills per day were simplified to a single pill per day; (iv) drug potency increased from moderate (∼60%) to high (>90%) levels of sustained virologic responses; (v) treatment durations were shortened from 48 to 12 or 8 weeks; and (vi) therapies could be administered orally regardless of prior treatment history and cirrhotic status. However, despite these remarkable achievements made in HCV drug discovery, challenges remain in the management of difficult-to-treat patients.
HCV genotype-specific drugs evolve to pan-genotypic drugs. Drug potency increases from moderate (∼60%) to high (>90%) levels of sustained virologic response. Treatment durations are shortened from a 48-week to 12-week or 8-week period. HCV therapies based upon multiple pills per day are simplified to a single pill per day. HCV therapies are administered orally regardless of prior treatment history and cirrhotic status.
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11
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Ivanenkov YA, Aladinskiy VA, Bushkov NA, Ayginin AA, Majouga AG, Ivachtchenko AV. Small-molecule inhibitors of hepatitis C virus (HCV) non-structural protein 5A (NS5A): a patent review (2010-2015). Expert Opin Ther Pat 2017; 27:401-414. [PMID: 27967269 DOI: 10.1080/13543776.2017.1272573] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
INTRODUCTION Non-structural 5A (NS5A) protein has achieved a considerable attention as an attractive target for the treatment of hepatitis C (HCV). A number of novel NS5A inhibitors have been reported to date. Several drugs having favorable ADME properties and mild side effects were launched into the pharmaceutical market. For instance, daclatasvir was launched in 2014, elbasvir is currently undergoing registration, ledipasvir was launched in 2014 as a fixed-dose combination with sofosbuvir (NS5B inhibitor). Areas covered: Thomson integrity database and SciFinder database were used as a valuable source to collect the patents on small-molecule NS5A inhibitors. All the structures were ranked by the date of priority. Patent holder and antiviral activity for each scaffold claimed were summarized and presented in a convenient manner. A particular focus was placed on the best-in-class bis-pyrrolidine-containing NS5A inhibitors. Expert opinion: Several first generation NS5A inhibitors have recently progressed into advanced clinical trials and showed superior efficacy in reducing viral load in infected subjects. Therapy schemes of using these agents in combination with other established antiviral drugs with complementary mechanisms of action can address the emergence of resistance and poor therapeutic outcome frequently attributed to antiviral drugs.
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Affiliation(s)
- Yan A Ivanenkov
- a Department of Biological and Medical Physics , Moscow Institute of Physics and Technology (State University) , Dolgoprudny City , Moscow Region , Russia.,b Department of Computational and Medicinal Chemistry , ChemDiv , San Diego , CA , USA.,c Chemistry Department , Moscow State University , Moscow , Russia
| | - Vladimir A Aladinskiy
- a Department of Biological and Medical Physics , Moscow Institute of Physics and Technology (State University) , Dolgoprudny City , Moscow Region , Russia
| | - Nikolay A Bushkov
- a Department of Biological and Medical Physics , Moscow Institute of Physics and Technology (State University) , Dolgoprudny City , Moscow Region , Russia
| | - Andrey A Ayginin
- a Department of Biological and Medical Physics , Moscow Institute of Physics and Technology (State University) , Dolgoprudny City , Moscow Region , Russia
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12
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Yang R, Yang X, Xiu B, Rao H, Fei R, Guan W, Liu Y, Wang Q, Feng X, Zhang H, Wei L. Hepatitis C Virus Genotype Analyses in Chronic Hepatitis C Patients and Individuals With Spontaneous Virus Clearance Using a Newly Developed Serotyping Assay. J Clin Lab Anal 2017; 31:e22014. [PMID: 27292225 PMCID: PMC6817036 DOI: 10.1002/jcla.22014] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2016] [Accepted: 05/18/2016] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND We developed a novel HCV serotyping assay and detected the genotypes in chronic hepatitis C (CHC) patients and individuals with spontaneous viral clearance (SVC). METHODS Nine hundred and ninety-seven patients were enrolled in a previous study; their samples were genotyped originally using the molecular assays. Among them, 190 patients achieved sustained virological response; the post-treatment samples were also serotyped. Moreover, 326 samples from follow-up cohorts were serotyped, among whom 66 were from SVC individuals, and 260 from CHC patients. RESULTS Nine hundred and fifty-eight out of 997 samples were available for serotyping, among which 29 samples generated indeterminate serotyping results. The consistency between the genotyping and serotyping assays was 91.50% (850/929). The specificity and sensitivity were 98.45% and 88.77% for genotype 1, 96.42% and 93.97% for genotype 2, and 94.15% and 80.52% for non-genotype 1 or 2. However, only 41 of 60 genotype-6 samples were correctly serotyped. Little difference was found in the 190 paired serotyping results. No difference existed in the genotype distribution between the SVC and CHC groups (P = 0.08). CONCLUSIONS The assay provides an accurate alternative for determining HCV genotypes, whereas it is not recommended for detecting genotype 6. Furthermore, it facilitates identifying the genotypes in SVC individuals. HCV genotype has little impact on SVC.
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Affiliation(s)
- Ruifeng Yang
- Peking University People's HospitalPeking University Hepatology InstituteBeijing Key Laboratory of Hepatitis C and Immunotherapy for Liver DiseasesBeijingChina
| | - Xiqin Yang
- Institute of Basic Medicine ScienceAcademy of Military Medical SciencesBeijingChina
| | - Bingshui Xiu
- Institute of Basic Medicine ScienceAcademy of Military Medical SciencesBeijingChina
| | - Huiying Rao
- Peking University People's HospitalPeking University Hepatology InstituteBeijing Key Laboratory of Hepatitis C and Immunotherapy for Liver DiseasesBeijingChina
| | - Ran Fei
- Peking University People's HospitalPeking University Hepatology InstituteBeijing Key Laboratory of Hepatitis C and Immunotherapy for Liver DiseasesBeijingChina
| | - Wenli Guan
- Peking University People's HospitalPeking University Hepatology InstituteBeijing Key Laboratory of Hepatitis C and Immunotherapy for Liver DiseasesBeijingChina
| | - Yan Liu
- Peking University People's HospitalPeking University Hepatology InstituteBeijing Key Laboratory of Hepatitis C and Immunotherapy for Liver DiseasesBeijingChina
| | - Qian Wang
- Peking University People's HospitalPeking University Hepatology InstituteBeijing Key Laboratory of Hepatitis C and Immunotherapy for Liver DiseasesBeijingChina
| | - Xiaoyan Feng
- Institute of Basic Medicine ScienceAcademy of Military Medical SciencesBeijingChina
| | - Heqiu Zhang
- Institute of Basic Medicine ScienceAcademy of Military Medical SciencesBeijingChina
| | - Lai Wei
- Peking University People's HospitalPeking University Hepatology InstituteBeijing Key Laboratory of Hepatitis C and Immunotherapy for Liver DiseasesBeijingChina
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13
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Weiler N, Zeuzem S, Welker MW. Concise review: Interferon-free treatment of hepatitis C virus-associated cirrhosis and liver graft infection. World J Gastroenterol 2016; 22:9044-9056. [PMID: 27895394 PMCID: PMC5107588 DOI: 10.3748/wjg.v22.i41.9044] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2016] [Revised: 08/09/2016] [Accepted: 10/19/2016] [Indexed: 02/06/2023] Open
Abstract
Chronic hepatitis C is a major reason for development of cirrhosis and hepatocellular carcinoma and a leading cause for liver transplantation. The development of direct-acting antiviral agents lead to (pegylated) interferon-alfa free antiviral therapy regimens with a remarkable increase in sustained virologic response (SVR) rates and opened therapeutic options for patients with advanced cirrhosis and liver graft recipients. This concise review gives an overview about most current prospective trials and cohort analyses for treatment of patients with liver cirrhosis and liver graft recipients. In patients with compensated cirrhosis Child-Pugh-Turcotte (CTP) class A, all approved agents are safe and SVR rates do not significantly differ from patients without cirrhosis in general. In patients with decompensated cirrhosis CTP class B or C, daclastasvir, ledipasvir, velpatasvir, and sofosbuvir are approved, and SVR rates higher than 90% can be achieved. Especially for patients with a model of end stage liver disease score higher than 15 and therefore eligible for liver transplantation, data is scarce. Reported SVR rates in patients with cirrhosis CTP class C are lower compared to patients with a less severe liver disease. In liver transplant recipients with a maximum of CTP class A, SVR rates are comparable to patients without LT. Patients with decompensated graft cirrhosis should be treated on an individual basis.
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14
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Liu F, Shimakami T, Murai K, Shirasaki T, Funaki M, Honda M, Murakami S, Yi M, Tang H, Kaneko S. Efficient Suppression of Hepatitis C Virus Replication by Combination Treatment with miR-122 Antagonism and Direct-acting Antivirals in Cell Culture Systems. Sci Rep 2016; 6:30939. [PMID: 27484655 PMCID: PMC4971519 DOI: 10.1038/srep30939] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2016] [Accepted: 07/11/2016] [Indexed: 02/05/2023] Open
Abstract
Direct-acting antivirals (DAAs) against Hepatitis C virus (HCV) show effective antiviral activity with few side effects. However, the selection of DAA-resistance mutants is a growing problem that needs to be resolved. In contrast, miR-122 antagonism shows extensive antiviral effects among all HCV genotypes and a high barrier to drug resistance. In the present study, we evaluated three DAAs (simeprevir, daclatasvir, and sofosbuvir) in combination with anti-miR-122 treatment against HCV genotype 1a in cell cultures. We found that combination treatments with anti-miR-122 and a DAA had additive or synergistic antiviral effects. The EC50 values of simeprevir in simeprevir-resistant mutants were significantly decreased by combining simeprevir with anti-miR-122. A similar reduction in EC50 in daclatasvir-resistant mutants was achieved by combining daclatasvir with anti-miR-122. Combination treatment in HCV-replicating cells with DAA and anti-miR-122 sharply reduced HCV RNA amounts. Conversely, DAA single treatment with simeprevir or daclatasvir reduced HCV RNA levels initially, but the levels later rebounded. DAA-resistant mutants were less frequently observed in combination treatments than in DAA single treatments. In summary, the addition of miR-122 antagonism to DAA single treatments had additive or synergistic antiviral effects and helped to efficiently suppress HCV replication and the emergence of DAA-resistant mutants.
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Affiliation(s)
- Fanwei Liu
- Department of Gastroenterology, Kanazawa University Hospital, Kanazawa, Ishikawa 920-8641, Japan
| | - Tetsuro Shimakami
- Department of Gastroenterology, Kanazawa University Hospital, Kanazawa, Ishikawa 920-8641, Japan
| | - Kazuhisa Murai
- Department of Gastroenterology, Kanazawa University Hospital, Kanazawa, Ishikawa 920-8641, Japan
| | - Takayoshi Shirasaki
- Department of Gastroenterology, Kanazawa University Hospital, Kanazawa, Ishikawa 920-8641, Japan
| | - Masaya Funaki
- Department of Gastroenterology, Kanazawa University Hospital, Kanazawa, Ishikawa 920-8641, Japan
| | - Masao Honda
- Department of Gastroenterology, Kanazawa University Hospital, Kanazawa, Ishikawa 920-8641, Japan
| | - Seishi Murakami
- Department of Gastroenterology, Kanazawa University Hospital, Kanazawa, Ishikawa 920-8641, Japan
| | - Minkyung Yi
- Department of Microbiology and Immunology, University of Texas Medical Branch at Galveston, Galveston, TX 77555-0144, USA
| | - Hong Tang
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Shuichi Kaneko
- Department of Gastroenterology, Kanazawa University Hospital, Kanazawa, Ishikawa 920-8641, Japan
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15
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Alavian SM, Hajarizadeh B, Bagheri Lankarani K, Sharafi H, Ebrahimi Daryani N, Merat S, Mohraz M, Mardani M, Fattahi MR, Poustchi H, Nikbin M, Nabavi M, Adibi P, Ziaee M, Behnava B, Rezaee-Zavareh MS, Colombo M, Massoumi H, Bizri AR, Eghtesad B, Amiri M, Namvar A, Hesamizadeh K, Malekzadeh R. Recommendations for the Clinical Management of Hepatitis C in Iran: A Consensus-Based National Guideline. HEPATITIS MONTHLY 2016; 16:e40959. [PMID: 27799966 PMCID: PMC5075356 DOI: 10.5812/hepatmon.guideline] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/31/2016] [Accepted: 07/31/2016] [Indexed: 02/07/2023]
Abstract
CONTEXT Hepatitis C virus (HCV) infection is a major public health issue worldwide, including Iran. The new direct-acting antiviral agents (DAAs) with high efficacy have changed the landscape of HCV treatment. This guideline provides updated recommendations for clinical management of HCV infection in Iran. EVIDENCE ACQUISITION The recommendations of this guideline are based on international and national scientific evidences and consensus-based expert opinion. Scientific evidences were collected through a systematic review of studies that evaluated efficacy and safety of DAA regimens, using PubMed, Scopus and Web of Science. Expert opinion was based on the consensus of Iran Hepatitis Scientific Board (IHSB) in the 3rd national consensus on management of Hepatitis C in Iran, held on 22nd of July 2016. RESULTS Pegylated Interferon alpha (PegIFN), Ribavirin (RBV), Sofosbuvir (SOF), Ledipasvir (LDV) and Daclatasvir (DCV) are currently available in Iran. Pre-treatment assessments include HCV RNA level, HCV genotype and resistance testing, assessment of liver fibrosis, and underlying diseases. In HCV genotype 1 and 4, DCV/SOF and LDV/SOF are recommended. In HCV genotype 2, SOF plus RBV and in HCV genotype 3, DCV/SOF is recommended. Additional care for underlying diseases should be considered. CONCLUSIONS Affordable new HCV treatment regimens are available in Iran, providing an opportunity for HCV elimination. Recommendations provided in this current national guideline can facilitate evidence-based management of HCV infection.
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Affiliation(s)
- Seyed Moayed Alavian
- Baqiyatallah Research Center for Gastroenterology and Liver Diseases (BRCGL), Baqiyatallah University of Medical Sciences, Tehran, IR Iran
- Middle East Liver Diseases (MELD) Center, Tehran, IR Iran
| | - Behzad Hajarizadeh
- Viral Hepatitis Clinical Research Program, The Kirby Institute, The University of New South Wales (UNSW Australia), Sydney, Australia
| | | | - Heidar Sharafi
- Baqiyatallah Research Center for Gastroenterology and Liver Diseases (BRCGL), Baqiyatallah University of Medical Sciences, Tehran, IR Iran
- Middle East Liver Diseases (MELD) Center, Tehran, IR Iran
| | | | - Shahin Merat
- Liver and Pancreatobiliary Diseases Research Center, Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, IR Iran
| | - Minoo Mohraz
- Iranian Research Center for HIV/AIDS (IRCHA), Tehran University of Medical Sciences, Tehran, IR Iran
| | - Masoud Mardani
- Infectious Diseases and Tropical Medicine Research Center, Shahid Beheshti University of Medical Sciences, Tehran, IR Iran
| | - Mohamad Reza Fattahi
- Gastroenterohepatology Research Center, Shiraz University of Medical Sciences, Shiraz, IR Iran
| | - Hossein Poustchi
- Liver and Pancreatobiliary Diseases Research Center, Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, IR Iran
| | - Mehri Nikbin
- Middle East Liver Diseases (MELD) Center, Tehran, IR Iran
| | - Mahmood Nabavi
- Department of Infectious Diseases and Tropical Medicine, Shahid Beheshti University of Medical Sciences, Tehran, IR Iran
| | - Peyman Adibi
- Department of Gastroenterology and Hepatology, Isfahan University of Medical Sciences, Isfahan, IR Iran
| | - Masood Ziaee
- Hepatitis Research Center, Birjand University of Medical Sciences, Birjand, IR Iran
| | - Bita Behnava
- Baqiyatallah Research Center for Gastroenterology and Liver Diseases (BRCGL), Baqiyatallah University of Medical Sciences, Tehran, IR Iran
- Middle East Liver Diseases (MELD) Center, Tehran, IR Iran
| | - Mohammad Saeid Rezaee-Zavareh
- Baqiyatallah Research Center for Gastroenterology and Liver Diseases (BRCGL), Baqiyatallah University of Medical Sciences, Tehran, IR Iran
- Middle East Liver Diseases (MELD) Center, Tehran, IR Iran
- Student’s Research Committee, Baqiyatallah University of Medical Sciences, Tehran, IR Iran
| | - Massimo Colombo
- Department of Medicine, Gastroenterology Division 1, AM and A Migliavacca Center for the Study of Liver Disease, Ca’ Granda Ospedale Maggiore Policlinico, University of Milan, Italy
| | - Hatef Massoumi
- New York Associates in Gastroenterology, Bronx, New York, USA
| | - Abdul Rahman Bizri
- Division of Infectious Diseases, Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon
| | | | - Majid Amiri
- Gastroenterology and Hepatology Department, Gouin Hospital, Clichy, France
| | - Ali Namvar
- Department of Hepatitis and AIDS, Pasteur Institute of Iran, Tehran, IR Iran
| | - Khashayar Hesamizadeh
- Baqiyatallah Research Center for Gastroenterology and Liver Diseases (BRCGL), Baqiyatallah University of Medical Sciences, Tehran, IR Iran
- Middle East Liver Diseases (MELD) Center, Tehran, IR Iran
| | - Reza Malekzadeh
- Liver and Pancreatobiliary Diseases Research Center, Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, IR Iran
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16
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Majumdar A, Kitson MT, Roberts SK. Systematic review: current concepts and challenges for the direct-acting antiviral era in hepatitis C cirrhosis. Aliment Pharmacol Ther 2016; 43:1276-92. [PMID: 27087015 DOI: 10.1111/apt.13633] [Citation(s) in RCA: 122] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2015] [Revised: 10/06/2015] [Accepted: 03/29/2016] [Indexed: 12/12/2022]
Abstract
BACKGROUND The burden of HCV cirrhosis is high and projected to increase significantly over the next decade. While interferon therapy is problematic in HCV cirrhosis, the era of direct-acting anti-viral (DAA) therapy provides effective treatment for patients with cirrhosis. AIM To systematically review the results of DAA therapy to date in patients with HCV cirrhosis, and highlight the ongoing challenges for DAA therapy in this population. METHODS A structured Medline search was conducted to obtain phase II and III HCV trials in patients with cirrhosis. Citations from review articles were cross-referenced and conference abstracts from EASL and AASLD liver meetings for the preceding 3 years were reviewed manually. Keywords used included hepatitis C, cirrhosis and the DAA's: sofosbuvir, ledipasvir, velpatasvir, grazoprevir, elbasvir, daclatasvir, beclabuvir, asunaprevir, simeprevir, paritaprevir, ombitasvir and dasabuvir. RESULTS Successful direct-acting anti-viral treatment is now possible in patients with HCV-related cirrhosis including those with liver decompensation with several regimens now offering sustained virological response (SVR) of 90-95%. Overall success rates in GT1 cirrhosis are excellent while GT3-infected patients with cirrhosis remain hard to cure. The pangenotypic combination of sofosbuvir and velpatasvir holds promise for GT3 cirrhosis achieving SVR of ~90%. CONCLUSIONS Potent DAA therapies provide much needed, safe and highly effective treatment options for persons with HCV cirrhosis including those previously deemed unsuitable for treatment. Combination therapy with two or more classes of drug is essential to achieve high efficacy and minimise viral resistance, with the role of ribavirin still under evaluation. However, several challenges remain including the hard-to-cure groups of GT3 cirrhosis and direct-acting anti-viral failures, and managing drug-drug interactions.
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Affiliation(s)
- A Majumdar
- Department of Gastroenterology, Alfred Hospital, Melbourne, Vic., Australia.,UCL Institute for Liver and Digestive Health and Sheila Sherlock Liver Centre Royal Free Hospital, London, UK
| | - M T Kitson
- Department of Gastroenterology, Alfred Hospital, Melbourne, Vic., Australia
| | - S K Roberts
- Department of Gastroenterology, Alfred Hospital, Melbourne, Vic., Australia
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17
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Liver transplantation for hepatobiliary malignancies: a new era of "Transplant Oncology" has begun. Surg Today 2016; 47:403-415. [PMID: 27130463 DOI: 10.1007/s00595-016-1337-1] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2015] [Accepted: 04/06/2016] [Indexed: 01/10/2023]
Abstract
The indications of liver transplantation for hepatobiliary malignancies have been carefully expanded in a stepwise fashion, despite the fundamental limitations in oncological, immunological, and technical aspects. A new era of "Transplant Oncology," the fusion of transplant surgery and surgical oncology, has begun, and we stand at the dawn of a paradigm shift in multidisciplinary cancer treatment. For hepatocellular carcinoma, new strategies have been undertaken to select recipients based on biological and dynamic markers instead of conventional morphological and static parameters, opening the doors for a more deliberate expansion of the Milan criteria and locoregional therapies before liver transplantation. Neoadjuvant chemoradiation therapy followed by liver transplantation for unresectable perihilar cholangiocarcinoma developed by the Mayo Clinic provided excellent outcomes in a US multicenter study; however, the surgical indications are not necessarily universal and await international validation. Similarly, an aggressive multidisciplinary approach has been applied for other tumors, including intrahepatic cholangiocarcinoma, hepatoblastoma, liver metastases from colorectal and neuroendocrine primary and gastrointestinal stromal tumors as well as rare tumors, such as hepatic undifferentiated embryonal sarcoma and infantile choriocarcinoma. In conclusion, liver transplantation is an important option for hepatobiliary malignancies; however, prospective studies are urgently needed to ensure the appropriate patient selection, organ allocation and living donation policies, and administration of antineoplastic immunosuppression.
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18
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Atsukawa M, Tsubota A, Shimada N, Yoshizawa K, Abe H, Asano T, Ohkubo Y, Araki M, Ikegami T, Okubo T, Kondo C, Osada Y, Nakatsuka K, Chuganji Y, Matsuzaki Y, Iwakiri K, Aizawa Y. Effect of native vitamin D3 supplementation on refractory chronic hepatitis C patients in simeprevir with pegylated interferon/ribavirin. Hepatol Res 2016; 46:450-458. [PMID: 26289410 DOI: 10.1111/hepr.12575] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2015] [Revised: 08/11/2015] [Accepted: 08/11/2015] [Indexed: 02/08/2023]
Abstract
AIM Protease inhibitors with pegylated interferon (PEG IFN)/ribavirin improve a sustained virological response (SVR) rate to approximately 90% in chronic hepatitis C genotype 1b patients with IL28B rs8099917 genotype TT, but yield only approximately 50% in those with the unfavorable non-TT. Among such treatment-refractory patients, serum vitamin D levels could influence the SVR rate. This randomized controlled trial was conducted to assess the effect of native vitamin D supplementation in simeprevir with PEG IFN/ribavirin for 1b patients with non-TT. METHODS Patients were randomly assigned to receive simeprevir (100 mg/day) for 12 weeks plus PEG IFN/ribavirin for 24 weeks (control group, n = 58), or vitamin D (2000 IU/day) for 16 weeks including a lead-in phase plus PEG IFN/ribavirin for 24 weeks (vitamin D group, n = 57). The primary end-point was sustainably undetectable viremia 24 weeks after the end of treatment (SVR). RESULTS SVR rates were 37.9% in the control group and 70.2% in the vitamin D group. In subgroup analysis, SVR rates of prior null responders were 11.8% and 54.5%, respectively. SVR rates for advanced fibrosis were 28.6% and 65.4%. SVR rates for patients with vitamin D3 deficiency at the baseline were 25.0% in the control group and 66.7% in the vitamin D group. Overall, the SVR rate was significantly higher in patients with high serum 25(OH)D3 levels at the beginning of combination therapy than in those with low serum 25(OH)D3 levels. CONCLUSION Native vitamin D3 supplementation improved SVR rates in simeprevir with PEG IFN/ribavirin for chronic hepatitis C genotype 1b patients with refractory factors.
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Affiliation(s)
- Masanori Atsukawa
- Department of Internal Medicine, Division of Gastroenterology, Nippon Medical School Chiba Hokusoh Hospital, Inzai
| | - Akihito Tsubota
- Core Research Facilities for Basic Science, Research Center for Medical Sciences, Jikei University School of Medicine, Tokyo
| | | | | | - Hiroshi Abe
- Jikei University School of Medicine Katsushika Medical Center
| | - Toru Asano
- Tokyo Metropolitan Bokutoh Hospital, Tokyo
| | | | | | | | - Tomomi Okubo
- Department of Internal Medicine, Division of Gastroenterology, Nippon Medical School Chiba Hokusoh Hospital, Inzai
| | - Chisa Kondo
- Department of Internal Medicine, Division of Gastroenterology, Nippon Medical School Chiba Hokusoh Hospital, Inzai
| | | | | | | | | | | | - Yoshio Aizawa
- Jikei University School of Medicine Katsushika Medical Center
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19
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Treatment of hepatitis C in patients with cirrhosis: remaining challenges for direct-acting antiviral therapy. Drugs 2016; 75:823-34. [PMID: 25943281 DOI: 10.1007/s40265-015-0401-2] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Chronic hepatitis C virus (HCV) infection is a major global health concern, resulting in significant morbidity and mortality. Treatment using interferon-based therapy in patients with HCV-related cirrhosis has been problematic due to toxicity and poor tolerability. Furthermore, interferon therapy is contraindicated in those with advanced cirrhosis or clinical decompensation, who are arguably the group most in need of viral eradication. The arrival of the direct-acting antiviral (DAA) era has resulted in the development of well-tolerated and highly effective interferon-free drug regimens that promise to dramatically change the therapeutic landscape for those with advanced HCV-related liver disease, including patients with clinical decompensation or pre-liver transplantation. Many successful DAA combinations have emerged; however, a number of challenges remain including the establishment of the optimal treatment duration, the ideal combination of drug classes and determining the role of ribavirin. Moreover, the identification of treatment-experienced patients with genotype 3 HCV cirrhosis as a difficult-to-treat subgroup is a significant impediment to overcome, as are those who have failed prior DAA therapy. Despite these barriers, the ongoing prolific development of safe and effective DAA combinations indicates the future is optimistic for the ultimate goal of HCV eradication.
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20
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Chacko KR, Gaglio PJ. Meet the Classes of Directly Acting Antiviral Agents: Strengths and Weaknesses. Clin Liver Dis 2015; 19:605-17, v. [PMID: 26466650 DOI: 10.1016/j.cld.2015.06.002] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
This article discusses direct-acting antiviral agents that target hepatitis C virus replication, their mechanism of action, strengths, and weaknesses. In addition, varying strategies using combinations of these agents are discussed.
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Affiliation(s)
- Kristina R Chacko
- Division of Hepatology, Department of Medicine, Montefiore Einstein Liver Center, Montefiore Medical Center, Albert Einstein College of Medicine, 111 East 210 Street Rosenthal 2 Red Zone, Bronx, NY 10467, USA
| | - Paul J Gaglio
- Division of Hepatology, Department of Medicine, Montefiore Einstein Liver Center, Montefiore Medical Center, Albert Einstein College of Medicine, 111 East 210 Street Rosenthal 2 Red Zone, Bronx, NY 10467, USA.
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21
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Ermis F, Senocak Tasci E. New treatment strategies for hepatitis C infection. World J Hepatol 2015; 7:2100-2109. [PMID: 26301052 PMCID: PMC4539403 DOI: 10.4254/wjh.v7.i17.2100] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2015] [Revised: 06/04/2015] [Accepted: 07/18/2015] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C infection can lead to cirrhosis and hepatocellular carcinoma and it is an important cause of mortality and morbidity. Achieving a sustained virological response has been the major aim for decades. Interferon treatment was the primarily developed therapy against the infection. Addition of the guanosine analog ribavirin to stop viral RNA synthesis increased the response rates as well as the adverse effects of the treatment. The increasing demands for alternative regimens led to the development of direct-acting antivirals (DAAs). The approval of sofosbuvir and simeprevir signaled a new era of antiviral treatment for hepatitis C infection. Although the majority of studies have been performed with DAAs in combination with interferon and resulted in a decrease in treatment duration and increase in response rates, the response rates achieved with interferon-free regimens provided hope for patients ineligible for therapy with interferon. Most DAA studies are in phase II leading to phase III. In the near future more DAAs are expected to be approved. The main disadvantage of the therapy remains the cost of the drugs. Here, we focus on new treatment strategies for hepatitis C infection as well as agents targeting hepatitis C virus replication that are in clinical development.
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Affiliation(s)
- Fatih Ermis
- Fatih Ermis, Department of Gastroenterology, Duzce University Faculty of Medicine, 81620 Duzce, Turkey
| | - Elif Senocak Tasci
- Fatih Ermis, Department of Gastroenterology, Duzce University Faculty of Medicine, 81620 Duzce, Turkey
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