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Román López CG, Triana González S, Cano Díaz AL, Lopez DDF, Mata Marín JA, Gaytán Martínez JE. Effectiveness of Direct Antiviral Agents in People with HCV-Monoinfection Compared to HCV/HIV Coinfection in a Real Life Setting. Viruses 2024; 16:1724. [PMID: 39599839 PMCID: PMC11599026 DOI: 10.3390/v16111724] [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: 09/01/2024] [Revised: 10/14/2024] [Accepted: 10/26/2024] [Indexed: 11/29/2024] Open
Abstract
Direct-acting antivirals (DAA) are effective in patients with hepatitis C virus (HCV) infection, but there is little information about real-world effectiveness in people living with human immunodeficiency virus (PLH). The aim of this study was to determinate the effectiveness of DAA to achieve sustained virologic response at week 12 post-treatment (SVR12) in PLH with HCV coinfection and in people with HCV-monoinfection. We conducted a prospective cohort. The full analysis set (FAS) included all subjects enrolled in the study; the modified analysis set (MAS) excluded cases with missing data to evaluate SVR12. A total of 278 people were included, 130 (46.7%) with HCV/HIV-coinfection and 148 (53.2%) with HCV-monoinfection. In the HCV/HIV-coinfection group, 82 (63%) received GLE/PIB for 8 weeks, 45 (34.6%) received SOF/VEL for 12 weeks, and 3 (2.3%) were treated with SOF/VEL + RBV for 12 weeks. In the HCV-monoinfection group, 62 (41.8%) received GLE/PIB for 8 weeks, 28 (18.9%) received SOF/VEL for 12 weeks, and 58 (39.1%) participants were treated with SOF/VEL + RBV for 12 weeks. In the FAS analysis, SVR12 was 81.6% in the HCV/HIV-coinfection group and 86.4% in the HCV-monoinfection group (p = 0.128). In the MAS analysis, both groups achieved 100% of SVR12. In this cohort, the effectiveness of DAA to achieve SVR12 was similar between HCV/HIV-coinfection and HCV-monoinfection cases, regardless of advanced liver disease with no differences between treatment regimens.
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Affiliation(s)
- Cristina Guadalupe Román López
- Internal Medicine Department, Hospital Regional No. 1 “Ignacio García Tellez”, Instituto Mexicano del Seguro Social, Mérida 97150, Yucatán, Mexico;
| | - Salma Triana González
- Infectious Diseases Department, Hospital de Infectologia “La Raza” National Medical Center, Instituto Mexicano del Seguro Social, Mexico City 02990, Mexico; (S.T.G.); (A.L.C.D.); (D.D.F.L.); (J.E.G.M.)
| | - Ana Luz Cano Díaz
- Infectious Diseases Department, Hospital de Infectologia “La Raza” National Medical Center, Instituto Mexicano del Seguro Social, Mexico City 02990, Mexico; (S.T.G.); (A.L.C.D.); (D.D.F.L.); (J.E.G.M.)
| | - Dulce Daniela Flores Lopez
- Infectious Diseases Department, Hospital de Infectologia “La Raza” National Medical Center, Instituto Mexicano del Seguro Social, Mexico City 02990, Mexico; (S.T.G.); (A.L.C.D.); (D.D.F.L.); (J.E.G.M.)
| | - José Antonio Mata Marín
- Infectious Diseases Department, Hospital de Infectologia “La Raza” National Medical Center, Instituto Mexicano del Seguro Social, Mexico City 02990, Mexico; (S.T.G.); (A.L.C.D.); (D.D.F.L.); (J.E.G.M.)
| | - Jesús Enrique Gaytán Martínez
- Infectious Diseases Department, Hospital de Infectologia “La Raza” National Medical Center, Instituto Mexicano del Seguro Social, Mexico City 02990, Mexico; (S.T.G.); (A.L.C.D.); (D.D.F.L.); (J.E.G.M.)
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Samantaray M, Pattabiraman R, Murthy TPK, Ramaswamy A, Murahari M, Krishna S, Kumar SB. Structure-based virtual screening of natural compounds against wild and mutant (R1155K, A1156T and D1168A) NS3-4A protease of Hepatitis C virus. J Biomol Struct Dyn 2024; 42:8505-8522. [PMID: 37646701 DOI: 10.1080/07391102.2023.2246583] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Accepted: 08/04/2023] [Indexed: 09/01/2023]
Abstract
NS3-4A, a serine protease, is a primary target for drug development against Hepatitis C Virus (HCV). However, the effectiveness of potent next-generation protease inhibitors is limited by the emergence of mutations and resulting drug resistance. To address this, in this study a structure-based drug design approach is employed to screen a large library of 7320 natural compounds against both wild-type and mutant variants of NS3-4A protease. Telaprevir, a widely used protease inhibitor, was recruited as the control drug. The top 10 compounds with favorable binding affinities underwent drug-likeness evaluation. Based on ADMET studies, complexes of NP_024762 and NP_006776 were selected for molecular dynamic simulations. Principal component analysis (PCA) was employed to explore the conformational space and protein dynamics of the protein-ligand complex using a Free Energy Landscape (FEL) approach. The cosine values obtained from FEL analysis ranged from 0 to 1, and eigenvectors with cosine values below 0.2 were chosen for further analysis. To forecast binding free energies and evaluate energy contributions per residue, the MM-PBSA method was employed. The results highlighted the crucial role of amino acids in the catalytic domain for the binding of the protease with phytochemicals. Stable associations between the top compounds and the target protease were confirmed by the formation of hydrogen bonds in the binding pocket involving residues: His1057, Gly1137, Ser1139, and Ala1157. These findings suggest the potential of these compounds for further validation through biological evaluation.Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
- Mahesh Samantaray
- Department of Bioinformatics, Pondicherry University, Pondicherry, India
| | - Ramya Pattabiraman
- Department of Biotechnology, M S Ramaiah Institute of Technology, Bengaluru, Karnataka, India
| | - T P Krishna Murthy
- Department of Biotechnology, M S Ramaiah Institute of Technology, Bengaluru, Karnataka, India
| | - Amutha Ramaswamy
- Department of Bioinformatics, Pondicherry University, Pondicherry, India
| | - Manikanta Murahari
- Department of Pharmacy, Koneru Lakshmaiah Education Foundation, Vaddeswaram, AP, India
| | - Swati Krishna
- Department of Biotechnology, M S Ramaiah Institute of Technology, Bengaluru, Karnataka, India
| | - S Birendra Kumar
- Department of Biotechnology, M S Ramaiah Institute of Technology, Bengaluru, Karnataka, India
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Kamal S, Shahzad A, Rehman K, Tariq K, Akash MSH, Imran M, Assiri MA. Therapeutic Intervention of Serine Protease Inhibitors against Hepatitis C Virus. Curr Med Chem 2024; 31:2052-2072. [PMID: 37855348 DOI: 10.2174/0109298673234823230921090431] [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: 11/16/2022] [Revised: 05/12/2023] [Accepted: 05/23/2023] [Indexed: 10/20/2023]
Abstract
Hepatitis C virus (HCV) is a globally prevalent and hazardous disorder that is responsible for inducing several persistent and potentially fatal liver diseases. Current treatment strategies offer limited efficacy, often accompanied by severe and debilitating adverse effects. Consequently, there is an urgent and compelling need to develop novel therapeutic interventions that can provide maximum efficacy in combating HCV while minimizing the burden of adverse effects on patients. One promising target against HCV is the NS3-4A serine protease, a complex composed of two HCV-encoded proteins. This non-covalent heterodimer is crucial in the viral life cycle and has become a primary focus for therapeutic interventions. Although peginterferon, combined with ribavirin, is commonly employed for HCV treatment, its efficacy is hampered by significant adverse effects that can profoundly impact patients' quality of life. In recent years, the development of direct-acting antiviral agents (DAAs) has emerged as a breakthrough in HCV therapy. These agents exhibit remarkable potency against the virus and have demonstrated fewer adverse effects when combined with other DAAs. However, it is important to note that there is a potential for developing resistance to DAAs due to alterations in the amino acid position of the NS3-4A protease. This emphasizes the need for ongoing research to identify strategies that can minimize the emergence of resistance and ensure long-term effectiveness. While the combination of DAAs holds promise for HCV treatment, it is crucial to consider the possibility of drug-drug interactions. These interactions may occur when different DAAs are used concurrently, potentially compromising their therapeutic efficacy. Therefore, carefully evaluating and monitoring potential drug interactions are vital to optimize treatment outcomes. In the pursuit of novel therapeutic interventions for HCV, the field of computational biology and bioinformatics has emerged as a valuable tool. These advanced technologies and methodologies enable the development and design of new drugs and therapeutic agents that exhibit maximum efficacy, reduced risk of resistance, and minimal adverse effects. By leveraging computational approaches, researchers can efficiently screen and optimize potential candidates, accelerating the discovery and development of highly effective treatments for HCV, treatments.
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Affiliation(s)
- Shagufta Kamal
- Department of Biochemistry, Government College University, Faisalabad, Pakistan
| | - Asif Shahzad
- Department of Biochemistry, Government College University, Faisalabad, Pakistan
| | - Kanwal Rehman
- Department of Pharmacy, The Women University, Multan, Pakistan
| | - Komal Tariq
- Department of Biochemistry, Government College University, Faisalabad, Pakistan
| | | | - Muhammad Imran
- Research center for Advanced Materials Science (RCAMS), King Khalid University, Abha, Saudi Arabia
- Department of Chemistry, Faculty of Science, King Khalid University, Abha, Saudi Arabia
| | - Mohammed Ali Assiri
- Research center for Advanced Materials Science (RCAMS), King Khalid University, Abha, Saudi Arabia
- Department of Chemistry, Faculty of Science, King Khalid University, Abha, Saudi Arabia
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Coyle CR, Desjardins MR, Curriero FC, Rudolph J, Astemborski J, Falade-Nwulia O, Kirk GD, Thomas DL, Mehta SH, Genberg BL. Geographic variation in HCV treatment penetration among people who inject drugs in Baltimore, MD. J Viral Hepat 2023; 30:810-818. [PMID: 37382024 PMCID: PMC10527489 DOI: 10.1111/jvh.13864] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2023] [Revised: 06/06/2023] [Accepted: 06/09/2023] [Indexed: 06/30/2023]
Abstract
We evaluated geographic heterogeneity in hepatitis C virus (HCV) treatment penetration among people who inject drug (PWID) across Baltimore, MD since the advent of direct-acting antivirals (DAAs) using space-time clusters of HCV viraemia. Using data from a community-based cohort of PWID, the AIDS Linked to the IntraVenous Experience (ALIVE) study, we identified space-time clusters with higher-than-expected rates of HCV viraemia between 2015 and 2019 using scan statistics. We used Poisson regression to identify covariates associated with HCV viraemia and used the regression-fitted values to detect adjusted space-time clusters of HCV viraemia in Baltimore city. Overall, in the cohort, HCV viraemia fell from 77% in 2015 to 64%, 49%, 39% and 36% from 2016 to 2019. In Baltimore city, the percentage of census tracts where prevalence of HCV viraemia was ≥85% dropped from 57% to 34%, 25%, 22% and 10% from 2015 to 2019. We identified two clusters of higher-than-expected HCV viraemia in the unadjusted analysis that lasted from 2015 to 2017 in East and West Baltimore and one adjusted cluster of HCV viraemia in West Baltimore from 2015 to 2016. Neither differences in age, sex, race, HIV status, nor neighbourhood deprivation were able to explain the significant space-time clusters. However, residing in a cluster with higher-than-expected viraemia was associated with age, sex, educational attainment and higher levels of neighbourhood deprivation. Nearly 4 years after DAAs became available, HCV treatment has penetrated all PWID communities across Baltimore city. While nearly all census tracts experienced improvements, change was more gradual in areas with higher levels of poverty.
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Affiliation(s)
- Catelyn R. Coyle
- Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States of America
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States of America
- Merck & Co. Inc., Rahway, NJ
| | - Michael R. Desjardins
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States of America
- Spatial Science for Public Health Center, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States of America
| | - Frank C. Curriero
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States of America
- Spatial Science for Public Health Center, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States of America
- Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States of America
| | - Jacqueline Rudolph
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States of America
| | - Jacquie Astemborski
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States of America
| | - Oluwaseun Falade-Nwulia
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States of America
| | - Gregory D. Kirk
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States of America
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States of America
| | - David L. Thomas
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States of America
| | - Shruti H. Mehta
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States of America
| | - Becky L. Genberg
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States of America
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Izhari MA. Molecular Mechanisms of Resistance to Direct-Acting Antiviral (DAA) Drugs for the Treatment of Hepatitis C Virus Infections. Diagnostics (Basel) 2023; 13:3102. [PMID: 37835845 PMCID: PMC10572573 DOI: 10.3390/diagnostics13193102] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2023] [Revised: 09/23/2023] [Accepted: 09/28/2023] [Indexed: 10/15/2023] Open
Abstract
Hepatitis C virus (HCV) is a hepatotropic virus that affects millions of human lives worldwide. Direct-acting antiviral (DAA) regimens are the most effective HCV treatment option. However, amino acid substitution-dependent resistance to DAAs has been a major challenge. This study aimed to determine the increasing risk of DAA resistance due to substitutions in DAA target non-structural proteins (NS3/4A, NS5A, and NS5B). Using a Sequence Retrieval System (SRS) at the virus pathogen resource (ViPR/BV-BRC), n = 32763 target protein sequences were retrieved and analyzed for resistance-associated amino acid substitutions (RAASs) by the Sequence Feature Variant Type (SFVT) antiviral-resistance assessment modeling tool. Reference target protein sequences with 100% identity were retried from UniProt following NCBI BLAST. The types and locations of RAASs were identified and visualized by AlphaFold and PyMol. Linux-r-base/R-studio was used for the data presentation. Multi-drug-resistant variants of NS3/4A in genotype 1 (n = 9) and genotype 5 (n = 5) along with DAA-specific NS3/4A, NS5A, and NS5B variants were identified pan-genotypically. A total of 27 variants (RAASs) of all the targets were identified. Fourteen genotype 1-specific substitutions: V1196A, V1158I, D1194A/T/G, R1181K, T1080S, Q1106R, V1062A, S1148G, A1182V, Y2065N, M2000T, and L2003V were identified. The most frequent substitutions were V1062L and L2003M, followed by Q2002H. L2003V, Q2002H, M2000T, Y2065N, and NL2003M of NS5A and L2003M of NS5B conferred resistance to daclatasvir. S2702T NS5B was the sofosbuvir-resistant variant. D1194A NS3/4A was triple DAA (simeprevir, faldaprevir, and asunaprevir) resistant. The double-drug resistant variants R1181K (faldaprevir and asunaprevir), A1182V and Q1106K/R (faldaprevir and simeprevir), T1080S (faldaprevir and telaprevir), and single drug-resistant variants V1062L (telaprevir), D1194E/T (simeprevir), D1194G (asunaprevir), S1148A/G (simeprevir), and Q1106L (Boceprevir) of NS3/4A were determined. The molecular phenomenon of DAA resistance is paramount in the development of HCV drug candidates. RAASs in NS3, NS5A, and NS5B reduce the susceptibility to DAAs; therefore, continuous RAAS-dependent resistance profiling in HCV is recommended to minimize the probability of DAA therapeutic failure.
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Affiliation(s)
- Mohammad Asrar Izhari
- Department of Laboratory Medicine, Faculty of Applied Medical Sciences, Al-Baha University, Al-Baha 65522, Saudi Arabia
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Shaikh A, Goli K, Lee TH, Rich NE, Benhammou JN, Keeling S, Kim D, Ahmed A, Goss J, Rana A, Singal AG, Kanwal F, Cholankeril G. Reduction in Racial and Ethnic Disparity in Survival Following Liver Transplant for Hepatocellular Carcinoma in the Direct-acting Antiviral Era. Clin Gastroenterol Hepatol 2023; 21:2288-2297.e4. [PMID: 36521738 PMCID: PMC10686256 DOI: 10.1016/j.cgh.2022.11.038] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Revised: 11/24/2022] [Accepted: 11/30/2022] [Indexed: 01/07/2023]
Abstract
BACKGROUND & AIMS Black patients with hepatocellular cancer (HCC), often attributed to hepatitis C virus (HCV) infection, have suboptimal survival following liver transplant (LT). We evaluated the impact of direct-acting antiviral (DAA) availability on racial and ethnic disparities in wait list burden post-LT survival for candidates with HCC. METHODS Using the United Network for Organ Sharing registry, we identified patients with HCC who were listed and/or underwent LT from 2009 to 2020. Based on date of LT, patients were categorized into 2 era-based cohorts: the pre-DAA era (LT between 2009 and 2011) and DAA era (LT between 2015 and 2017, with follow-up through 2020). Kaplan-Meier and Cox proportional hazards analyses were used to compare post-LT survival, stratified by era and race and ethnicity. RESULTS Annual wait list additions for HCV-related HCC decreased significantly in White and Hispanic patients during the DAA era, with no change (P = .14) in Black patients. Black patients had lower 3-year survival than White patients in the pre-DAA era (70.6% vs 80.1%, respectively; P < .001) but comparable survival in the DAA era (82.1% vs 85.5%, respectively; P = .16). 0n multivariable analysis, Black patients in the pre-DAA era had a 53% higher risk (adjusted hazard ratio [HR], 1.53; 95% confidence interval [CI], 1.28-1.84), for mortality than White patients, but mortality was comparable in the DAA era (adjusted HR, 1.23; 95% CI, 0.99-1.52). In a stratified analysis in Black patients, HCV-related HCC carried more than a 2-fold higher risk of mortality in the pre-DAA era (adjusted HR, 2.86; 95% CI, 1.50-5.43), which was reduced in the DAA era (adjusted HR, 1.34; 95% CI, 0.78-2.30). CONCLUSIONS With the availability of DAA therapy, racial disparities in post-LT survival have improved.
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Affiliation(s)
- Anjiya Shaikh
- Department of Medicine, University of Connecticut School of Medicine, Farmington, Connecticut
| | - Karthik Goli
- Department of Student Affairs, Baylor College of Medicine, Houston, Texas
| | - Tzu-Hao Lee
- Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, Texas; Hepatology Program, Division of Abdominal Transplantation, Michael E DeBakey Department of General Surgery, Baylor College of Medicine, Houston, Texas
| | - Nicole E Rich
- Division of Digestive and Liver Diseases, UT Southwestern Medical Center, Dallas, Texas
| | - Jihane N Benhammou
- The Vatche and Tamar Manoukian Division of Digestive Diseases, University of California at Los Angeles, Los Angeles, California
| | - Stephanie Keeling
- Department of Student Affairs, Baylor College of Medicine, Houston, Texas
| | - Donghee Kim
- Division of Gastroenterology and Hepatology, Department of Medicine, Stanford, California
| | - Aijaz Ahmed
- Division of Gastroenterology and Hepatology, Department of Medicine, Stanford, California
| | - John Goss
- Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, Texas
| | - Abbas Rana
- Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, Texas
| | - Amit G Singal
- Division of Digestive and Liver Diseases, UT Southwestern Medical Center, Dallas, Texas
| | - Fasiha Kanwal
- Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, Texas; Center for Innovations in Quality, Effectiveness and Safety, Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas
| | - George Cholankeril
- Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, Texas; Hepatology Program, Division of Abdominal Transplantation, Michael E DeBakey Department of General Surgery, Baylor College of Medicine, Houston, Texas.
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Nascimento YDA, Silva LD, Ramalho de Oliveira D. The Lived Experience of Patients Utilizing Second-Generation Direct-Acting Antiviral for Treatment of Chronic Hepatitis C Virus Infection: A Phenomenological Analysis. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2022; 19:12540. [PMID: 36231842 PMCID: PMC9566709 DOI: 10.3390/ijerph191912540] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Revised: 09/28/2022] [Accepted: 09/29/2022] [Indexed: 06/16/2023]
Abstract
Hepatitis C is a global public health problem, and the aim of this study was to understand the experiences of patients with hepatitis C using second-generation antivirals. In-depth interviews were conducted with ten outpatients, cognitively capable of reporting their experience, followed up at a university clinic. Field diaries kept during the interviews were also used. The researchers carried out a thematic analysis to identify the ways in which individuals experienced their medication; then, these ways were reorganized to encompass the essential structures of the experience. The patients experienced the use of DAAs as providing resolution and it was permeated by: the experience of time-stagnant time, waiting for medication and the cure; the experience of spaces, understood as necessary and imposed spaces; the experience of relationships with others, personified by the support provided by healthcare professionals; the experience of sexuality, when patients developed several coping strategies to deal with the challenges imposed by the treatment. To conclude, increasing the knowledge about the patients' experiences can contribute to improve the healthcare model for hepatitis C, since several patients have severe hepatic impairment, and the eradication of the virus is only one of the stages of patients' treatments.
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Affiliation(s)
- Yone de Almeida Nascimento
- College of Pharmacy, Center for Pharmaceutical Care Studies, Universidade Federal de Minas Gerais, Belo Horizonte 31270-901, MG, Brazil
| | - Luciana Diniz Silva
- College of Medicine, Universidade Federal de Minas Gerais, Belo Horizonte 31270-901, MG, Brazil
| | - Djenane Ramalho de Oliveira
- College of Pharmacy, Center for Pharmaceutical Care Studies, Universidade Federal de Minas Gerais, Belo Horizonte 31270-901, MG, Brazil
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Giampaoli O, Sciubba F, Biliotti E, Spagnoli M, Calvani R, Tomassini A, Capuani G, Miccheli A, Taliani G. Precision Medicine: Determination of Ribavirin Urinary Metabolites in Relation to Drug Adverse Effects in HCV Patients. Int J Mol Sci 2022; 23:ijms231710043. [PMID: 36077436 PMCID: PMC9456413 DOI: 10.3390/ijms231710043] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2022] [Revised: 08/26/2022] [Accepted: 08/31/2022] [Indexed: 11/25/2022] Open
Abstract
The most commonly used antiviral treatment against hepatitis C virus is a combination of direct-acting antivirals (DAAs) and ribavirin (RBV), which leads to a shortened duration of therapy and a sustained virologic response until 98%. Nonetheless, several dose-related side effects of RBV could limit its applications. This study aims to measure the urinary concentration of RBV and its main metabolites in order to evaluate the drug metabolism ability of HCV patients and to evaluate the adverse effects, such as anemia, with respect to RBV metabolite levels. RBV and its proactive and inactive metabolites were identified and quantified in the urine of 17 HCV males with severe liver fibrosis using proton nuclear magnetic resonance (1H-NMR) at the fourth week (TW4) and at the twelfth week of treatment (EOT). Four prodrug urinary metabolites, including RBV, were identified and three of them were quantified. At both the TW4 and EOT stages, six HCV patients were found to maintain high concentrations of RBV, while another six patients maintained a high level of RBV proactive metabolites, likely due to nucleosidase activity. Furthermore, a negative correlation between the reduction in hemoglobin (Hb) and proactive forms was observed, according to RBV-triphosphate accumulation causing the hemolysis. These findings represent a proof of concept regarding tailoring the drug dose in relation to the specific metabolic ability of the individual, as expected by the precision medicine approach.
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Affiliation(s)
- Ottavia Giampaoli
- NMR-Based Metabolomics Laboratory (NMLab), Sapienza University of Rome, 00185 Rome, Italy
- Department of Environmental Biology, Sapienza University of Rome, 00185 Rome, Italy
| | - Fabio Sciubba
- NMR-Based Metabolomics Laboratory (NMLab), Sapienza University of Rome, 00185 Rome, Italy
- Department of Environmental Biology, Sapienza University of Rome, 00185 Rome, Italy
| | - Elisa Biliotti
- Department of Clinical Medicine, Policlinico Umberto I, Sapienza University of Rome, 00161 Rome, Italy
| | - Mariangela Spagnoli
- Department of Occupational Medicine, Epidemiology and Hygiene, INAIL, Monte Porzio Catone, 00078 Rome, Italy
| | - Riccardo Calvani
- Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy
| | - Alberta Tomassini
- NMR-Based Metabolomics Laboratory (NMLab), Sapienza University of Rome, 00185 Rome, Italy
- Department of Chemistry, Sapienza University of Rome, 00185 Rome, Italy
| | - Giorgio Capuani
- NMR-Based Metabolomics Laboratory (NMLab), Sapienza University of Rome, 00185 Rome, Italy
- Department of Chemistry, Sapienza University of Rome, 00185 Rome, Italy
| | - Alfredo Miccheli
- NMR-Based Metabolomics Laboratory (NMLab), Sapienza University of Rome, 00185 Rome, Italy
- Department of Environmental Biology, Sapienza University of Rome, 00185 Rome, Italy
- Correspondence:
| | - Gloria Taliani
- Department of Clinical Medicine, Policlinico Umberto I, Sapienza University of Rome, 00161 Rome, Italy
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Majid A, Khan S, Siraj S, Haleem S, ul Haq N, Ullah R, Ali EA, Mustafa A, Hussain H, Sohaib M. Emergence of resistance against direct acting antivirals in chronic HCV patients: A real-world study. Saudi J Biol Sci 2022; 29:2613-2619. [PMID: 35531150 PMCID: PMC9072881 DOI: 10.1016/j.sjbs.2021.12.044] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Revised: 12/02/2021] [Accepted: 12/19/2021] [Indexed: 01/09/2023] Open
Abstract
Interferon/Ribavirin therapy has been replaced by Direct Acting Antivirals (DAAs) due to emergence of Resistance Associated Variants (RAVs) and decrease Sustain Virologic Response (SVR). Current study investigated treatment response of Sofosbuvir and Ribavirin in chronic HCV patients. Total 256 HCV patients with genotype 1a, 2 and 3a received sofosbuvir/ribavirin according to international standards. HCV RNA presence in serum was used as marker for end treatment response (ETR) and sustain virologic response after 24 weeks of treatment (SVR24) in each case. Response to treatment with SOF + RBV was found statistically significant among different HCV genotypes (GT) as out of 47 HCV GT1 patients 42(89.36%) resulted into good ETR but 4(9.52%) of these relapsed and 5(10.63%) led into virologic failure. 5(100%) HCV GT2 patients resulted into SVR24 whereas, out of 204 HCV GT3 patients 194(95.69%) achieved good ETR however, 8(4.12%) of these relapsed and 10(4.90%) resulted in to virologic failure. Efficacy of therapy was found non-significant in treatment naïve and treatment experienced patients as in this study out of 145 treatment naïve patients 139(95.86%) achieved good ETR where 4(2.87%) relapsed while 6(4.13%) led into virologic break through on the other hand among 111 treatment experienced patients 102(91.89%) resulted into good ETR but 8(7.84%) relapsed whereas 9(8.10%) lead into virologic failure. Current study also propose that various liver and spleen complications/liver cirrhosis are related to response of HCV patients to SOF + RBV therapy whereas, variables like old age, gender is not compromising treatment response to DAAs therapy. Various mild side effects encountered by patients during treatment were fatigue, insomnia, headache, nausea, burning body, diarrhea, cough. Overall, this study reported 89.45% efficacy of SOF + RBV regime in chronic HCV Pakistani patients. Current study suggests hunting for possible reasons of resistance so that SOF + RBV therapy may not share the same fortune as previous therapies in near future.
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Affiliation(s)
- Abdul Majid
- Department of Zoology, Kohat University of Science and Technology, Kohat, Pakistan
| | | | - Sami Siraj
- Institute of Basic Medical Sciences, Khyber Medical University, Pakistan
| | - Sumbal Haleem
- Department of Zoology, Kohat University of Science and Technology, Kohat, Pakistan
| | - Najib ul Haq
- Peshawar Medical College, Riphah International University, Pakistan
| | - Riaz Ullah
- Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
| | - Essam A. Ali
- Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
| | - Adeela Mustafa
- Community Medicine Department, Khyber Medical College Peshawar, Pakistan
| | - Hidayat Hussain
- Department of Bioorganic Chemistry, Leibniz Institute of Plant Biochemistry, Weinberg 3, D-06120 Halle (Salle), Germany
| | - Muhammad Sohaib
- Department of Soil Science, College of Food and Agricultural Sciences, King Saud University, 12 Riyadh 11451, Saudi Arabia
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10
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Aydın NN, Köksal İ. An Evaluation of Chronic Hepatitis C Patients’ Responses to Direct-Acting Antivirals According to Transient Elastography and Serum Biomarkers. Egypt J Immunol 2022. [DOI: 10.4274/vhd.galenos.2022.2021-8-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
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11
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Oe N, Takeda H, Eso Y, Takai A, Marusawa H. Clinical and Molecular Basis of Hepatocellular Carcinoma after Hepatitis C Virus Eradication. Pathogens 2022; 11:pathogens11040430. [PMID: 35456105 PMCID: PMC9028726 DOI: 10.3390/pathogens11040430] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Revised: 03/28/2022] [Accepted: 03/30/2022] [Indexed: 12/11/2022] Open
Abstract
Hepatocellular carcinoma (HCC) arises in the background of chronic liver diseases, including hepatitis and liver cirrhosis caused by hepatitis C virus (HCV) infection. It is well known that HCV eradication using antiviral drugs can efficiently inhibit hepatocarcinogenesis. Recent advances in and development of direct-acting antiviral (DAA) drugs has revolutionized the treatment of HCV infection, and the vast majority of HCV patients can achieve HCV eradication using DAAs. However, mounting evidence clearly indicates that HCC inevitably occurs in a subset of patients after successful viral eradication using DAA therapy. Cancer is a genetic disease, and the accumulation of genetic and epigenetic aberrations may cause hepatocarcinogenesis in chronically damaged liver, even after virus elimination. In this review, we highlight HCC development after HCV eradication and discuss the current understanding of the molecular mechanisms of tumorigenesis after virus elimination, focusing on the genetic and epigenetic background of chronically damaged liver tissues.
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Affiliation(s)
- Natsumi Oe
- Department of Gastroenterology, Red Cross Osaka Hospital, Osaka 5438555, Japan;
| | - Haruhiko Takeda
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto 6068501, Japan; (H.T.); (Y.E.); (A.T.)
| | - Yuji Eso
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto 6068501, Japan; (H.T.); (Y.E.); (A.T.)
| | - Atsushi Takai
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto 6068501, Japan; (H.T.); (Y.E.); (A.T.)
| | - Hiroyuki Marusawa
- Department of Gastroenterology, Red Cross Osaka Hospital, Osaka 5438555, Japan;
- Correspondence: ; Tel.: +81-6-6774-5111; Fax: +81-6-6774-5131
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12
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Pellicelli A, Giannelli V, Zoli V, Regine G, Cortese A, Ettorre GM, Carmenini E, Pellicelli V, Rigacci L. Resolution of primary hepatic marginal zone lymphoma in a hepatitis C virus-infected patient treated with a direct-acting antiviral. Oxf Med Case Reports 2021; 2021:omab022. [PMID: 34055359 PMCID: PMC8143661 DOI: 10.1093/omcr/omab022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2020] [Revised: 02/05/2021] [Accepted: 02/18/2021] [Indexed: 11/24/2022] Open
Abstract
The favorable impact of antiviral therapy on low-grade hepatitis C virus (HCV)-related non-Hodgkin lymphoma manifesting as marginal zone lymphoma (MZL) has been reported in some clinical studies. However, primary HCV-related marginal zone lymphomas (MZLs) confined to the liver have not been described in the literature nor have the resolution of liver lymphoma through anti-HCV eradication treatment. The authors report a genotype 1b HCV-positive patient with chronic hepatitis who exhibited lesions involving both hepatic lobes resembling hepatocellular carcinoma. Liver biopsy revealed an MZL of the liver. Antiviral treatment using sofosbuvir associated with simeprevir as unique treatment was started and resulted in complete haematological response. In HCV-related MZL isolated to the liver, antiviral treatment has led to the eradication of viral infection and a complete haematological response. Antiviral therapy should be considered as a first-line treatment for HCV-related primary MZLs of the liver.
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Affiliation(s)
- Adriano Pellicelli
- Liver Unit, Department of Liver Transplant, Azienda Ospedaliera San Camillo Forlanini, Rome, Italy
| | - Valerio Giannelli
- Liver Unit, Department of Liver Transplant, Azienda Ospedaliera San Camillo Forlanini, Rome, Italy
| | - Valerio Zoli
- Hematology Unit, Azienda Ospedaliera San Camillo Forlanini, Rome, Italy
| | - Giovanni Regine
- Department of Radiology, Azienda Ospedaliera San Camillo Forlanini, Rome, Italy
| | - Andrea Cortese
- Department of Radiology, Azienda Ospedaliera San Camillo Forlanini, Rome, Italy
| | - Giuseppe M Ettorre
- Division of General Surgery and Liver Transplantation, Azienda Ospedaliera San Camillo Forlanini, Rome, Italy
| | - Enrico Carmenini
- Liver Unit, Department of Liver Transplant, Azienda Ospedaliera San Camillo Forlanini, Rome, Italy
| | - Valeria Pellicelli
- Internal Medicine, Azienda Ospedaliera Sant'Andrea Università degli Studi "La Sapienza", Rome, Italy
| | - Luigi Rigacci
- Hematology Unit, Azienda Ospedaliera San Camillo Forlanini, Rome, Italy
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13
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ACG Clinical Guideline: Diagnosis and Management of Idiosyncratic Drug-Induced Liver Injury. Am J Gastroenterol 2021; 116:878-898. [PMID: 33929376 DOI: 10.14309/ajg.0000000000001259] [Citation(s) in RCA: 192] [Impact Index Per Article: 48.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2020] [Accepted: 01/25/2021] [Indexed: 12/11/2022]
Abstract
Idiosyncratic drug-induced liver injury (DILI) is common in gastroenterology and hepatology practices, and it can have multiple presentations, ranging from asymptomatic elevations in liver biochemistries to hepatocellular or cholestatic jaundice, liver failure, or chronic hepatitis. Antimicrobials, herbal and dietary supplements, and anticancer therapeutics (e.g., tyrosine kinase inhibitors or immune-checkpoint inhibitors) are the most common classes of agents to cause DILI in the Western world. DILI is a diagnosis of exclusion, and thus, careful assessment for other etiologies of liver disease should be undertaken before establishing a diagnosis of DILI. Model for end-stage liver disease score and comorbidity burden are important determinants of mortality in patients presenting with suspected DILI. DILI carries a mortality rate up to 10% when hepatocellular jaundice is present. Patients with DILI who develop progressive jaundice with or without coagulopathy should be referred to a tertiary care center for specialized care, including consideration for potential liver transplantation. The role of systemic corticosteroids is controversial, but they may be administered when a liver injury event cannot be distinguished between autoimmune hepatitis or DILI or when a DILI event presents with prominent autoimmune hepatitis features.
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14
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Mostafa MA, Kamal O, Yassin A, Nagi MA, Ahmed OA, Ahmed HA. The diagnostic value of normalized ADC using spleen as reference organ in assessment liver fibrosis. THE EGYPTIAN JOURNAL OF RADIOLOGY AND NUCLEAR MEDICINE 2020. [DOI: 10.1186/s43055-020-00212-3] [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
To investigate the value of liver ADC normalization using spleen as a reference organ in liver fibrosis assessment compared to Fibroscan.
A total of 60 participants were included, 30 HCV positive patients and 30 in control group. We calculated mean spleen apparent diffusion coefficient (ADC), liver mean ADC, and normalized liver ADC (defined as the ratio of liver ADC to spleen ADC) which were compared between cirrhotic patients and the control group. Data was analyzed, and ROC was used to evaluate the performance of nADC.
Results
No significant difference between spleen ADC values of patient and control groups or in-between different fibrosis stages. A negative correlation between liver ADC and nADC values with increasing fibrosis stages. We also found that the mean liver ADC and nADC value in patients with hepatic fibrosis were significantly lower than that of control group (1.53 × 10−3 mm2/s vs 1.65 × 10−3 mm2/s). After analysis with ROC, nADC shows higher diagnostic performance compared to liver ADC. nADC area under the curve (AUC) was 0.878 for detection of stage ≥ F2 with sensitivity and specificity of 87% and 80% respectively while ADC AUC was 0.548 with sensitivity and specificity of 62% and 72% respectively (p = 0.021); ≥ F3 AUC of nADC was 0.891 with sensitivity and specificity of 88.7% and 80% respectively while ADC AUC is 0.603 with sensitivity and specificity of 72% and 72% respectively (p = 0.023), and F4 stage nADC AUC was 0.879 for with sensitivity and specificity of 90% and 80% respectively, while ADC AUC was 0.648 with sensitivity and specificity of 80% and 72% respectively (p = 0.054).
Conclusion
Normalized liver ADC using the spleen as reference organs increases the diagnostic performance of MR in evaluation liver fibrosis compared to ADC alone.
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15
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Mostafa AM, Saafan HA, Al-Tawashi AS, Kasem MH, Alaa AM, Eltobgy MM, Moubarak AS, Gharib MM, Awwad MA, Omar HM, El-Derany MO. Interleukin-17 haplotyping predicts hepatocellular carcinoma in sofosbuvir, pegylated interferon-alpha-2a & ribavirin treated chronic hepatitis C patients. Virus Res 2020; 292:198226. [PMID: 33171166 DOI: 10.1016/j.virusres.2020.198226] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2020] [Revised: 09/22/2020] [Accepted: 11/04/2020] [Indexed: 02/07/2023]
Abstract
Suspect has been directed towards some direct acting antivirals (DAAs) due to their reported association with hepatocellular carcinoma (HCC) development in chronic hepatitis C (CHC) patients. The mechanisms behind HCC development, following CHC treatment, were not well understood and may be linked to genetic variabilities in different patients which affect several cytokine productions involved in angiogenesis and inflammation. Of these variabilities, is the genetic polymorphisms in the interleukin-17 (IL-17) A receptor gene. Being an important pleiotropic cytokine, this study aimed to investigate the association between haplotypes in IL-17A receptor rs2275913 and rs3819024 and development of HCC in CHC patients treated with either triple therapy (sofosbuvir (SOF), pegylated interferon-alpha-2a (Peg-IFNα-2a) & ribavirin(RBV)) or with dual therapy (Peg-IFNα-2a&RBV). A cohort of 100 CHC patients was recruited in this study. Samples were tested for single nucleotide polymorphism (SNPs) in IL-17A receptor (rs2275913 and rs3819024) using TaqMan Genotyping assay. Our results showed that the presence of G-G haplotype in IL-17A (rs2275913& rs3819024) is inversely associated with HCC development in patients receiving triple therapy. While, high serum AFP levels are directly associated with HCC development in patients receiving triple therapy. However, in patients receiving dual therapy, HCC development was only associated with high serum alpha fetoprotein (AFP) levels and was not correlated to any specific allele in our studied SNPs. Such results highlight the importance of IL17A receptor gene haplotyping in the prediction of HCC development in patients receiving triple therapy. These results will aid in performing tailored, personalized strategy for CHC treatment.
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Affiliation(s)
- Ahmed M Mostafa
- Biochemistry Department, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt
| | - Hesham A Saafan
- Pharmaceutical Chemistry Department, Faculty of Pharmacy, Badr University, Cairo, Egypt
| | - Ahmed S Al-Tawashi
- Drug Design Program, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt
| | - Muhannad H Kasem
- Drug Design Program, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt
| | - Ahmed M Alaa
- Drug Design Program, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt
| | - Mahmoud M Eltobgy
- Drug Design Program, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt
| | - Ahmed S Moubarak
- Drug Design Program, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt
| | - Manar M Gharib
- Drug Design Program, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt
| | - Mohamed A Awwad
- Drug Design Program, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt
| | - Hazem M Omar
- Radiology Department, Faculty of Medicine, Menoufia University, Menoufia, Egypt
| | - Marwa O El-Derany
- Biochemistry Department, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt.
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16
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Chopra D, Bhandari B. Sofosbuvir: Really Meets the Unmet Needs for Hepatitis C Treatment? Infect Disord Drug Targets 2020; 20:2-15. [PMID: 30113002 DOI: 10.2174/1871526518666180816101124] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2018] [Revised: 07/31/2018] [Accepted: 08/07/2018] [Indexed: 02/06/2023]
Abstract
Chronic hepatitis C remains a major public health concern with a prevalence of more than 1% worldwide. Of late, with the discovery of newer drugs, chronic HCV treatment has touched new dimensions. The treatment has progressed from Interferons to Pegylated interferon (Peg IFN) based therapy, with or without ribavirin to treatment with orally active Direct Acting Antivirals (DAA) with Peg IFN and ribavirin and eventually to various combinations of DAA, without IFN. Introduction of newer DAAs has transfigured the treatment of chronic HCV. Chronic HCV patients with advanced liver disease, psychiatric condition, anemia or autoimmune diseases, not eligible for Peg IFN based therapy have a ray of hope now. Amongst all DAAs, nucleoside inhibitors have been the most promising agent. Thus the present review focuses on Sofosbuvir, one of the most effective nucleoside inhibitors; in terms of potency, resistance profile, activity against all genotypes of HCV and adverse effects. FDA approved Sofobuvir for clinical use in 2013. Chemically, it is 2'-deoxy-2'-α-fluoro-β-Cmethyluridine- 5'-triphosphate; a phosphoramidate prodrug that is activated by enzyme present in human liver. It is a highly potent inhibitor of HCV NS5B polymerase. Efficacy of the Sofosbuvir has been established in various phase 2 and phase 3 clinical trials like PROTON, ELECTRON, FUSION, POSITRON etc. Sofosbuvir has a good safety profile with few mild to moderate adverse effects. Evidence reveals that sofosbuvir has substantial impact on the treatment of HCV.
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Affiliation(s)
- Deepti Chopra
- Department of Pharmacology and Physiology, Government Institute of Medical Sciences, Greater Noida, U.P, India
| | - Bharti Bhandari
- Department of Pharmacology and Physiology, Government Institute of Medical Sciences, Greater Noida, U.P, India
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17
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Rao H, Yang X, Tan Y, Ning Q, Yang D, Wang J, Yang Y, Zheng S, Yang D, Hou J, Xie Q, Zhao C, Zhang L, Mao X, Sun T, Bai L, Zhang F, Jin J, Zhao Y, Wang M, Xie W, Ma Y, Quan J, Yan X, An P, Lin F, Jia J, Hu X, Gong Z, Wu J, Chen Y, Jia Z, Lin M, Wang G, Zhu Y, Zhang Y, Xie H, Luo L, Ren Q, Huang R, Wei L. Efficacy and Safety of All-oral Emitasvir and Sofosbuvir in Patients with Genotype 1b HCV Infections without Cirrhosis. J Clin Transl Hepatol 2020; 8:255-261. [PMID: 33083247 PMCID: PMC7562795 DOI: 10.14218/jcth.2020.00031] [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: 04/13/2020] [Revised: 07/05/2020] [Accepted: 08/12/2020] [Indexed: 02/05/2023] Open
Abstract
Background and Aims: Emitasvir is a new type of hepatitis C virus (HCV) nonstructural protein 5A (NS5A) inhibitor, and the data of phase 2 trial has shown emitasvir-sofosbuvir to have good safety and tolerance. We conducted this phase 3 trial to further verify the efficacy and safety. Methods: We evaluated the antiviral activity and safety of a 12-week regimen of emitasvir phosphate (100 mg) combined with sofosbuvir (400 mg) once daily in non-cirrhotic patients with genotype 1 HCV infection. The primary endpoint was a sustained virological response at 12 weeks (SVR12) after the end of treatment. Results: Of the 362 patients enrolled in the trial, 39.8% were male, 99.2% had HCV genotype 1b, 0.8% had genotype 1a and 79.8% were treatment-naïve. The average age was 47.2 years. All patients completed the treatment and follow-up. All 3 patients with genotype 1a achieved SVR. Two genotype 1b treatment-naïve patients experienced virologic relapse. The rate of SVR12 was 99.7% (358/359), and SVR24 was 99.4% (357/359) in genotype 1b. Overall, 36.2% had resistance-associated substitutions (RASs) in NS5A and 98.3% had RASs in NS5B at baseline. The RASs at baseline had no effect on the rates of response. Serious adverse events were reported in 16 patients and were not related to emitasvir-sofosbuvir. Most adverse events did not require therapy. Conclusions: The 12 weeks of treatment with emitasvir-sofosbuvir was a highly efficient and safe treatment for a wide range of patients with HCV genotype 1b infection without cirrhosis, who had not been treated or who had been treated with interferon-based regimen previously.
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Affiliation(s)
- Huiying Rao
- Peking University People’s Hospital, Peking University Hepatology Institute, National Clinical Research Center for Infectious Disease, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing International Cooperation Base for Science and Technology on NAFLD Diagnosis, Beijing, China
| | - Xingxiang Yang
- Department of Infectious Diseases, Sichuan Provincial People’s Hospital, Chengdu, Sichuan, China
| | - Youwen Tan
- Department of Hepatology, The Third People’s Hospital of Zhenjiang, Zhenjiang, Jiangsu, China
| | - Qin Ning
- Department of Infectious Diseases, Tongji Hospital, Tongji Medical College Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Daokun Yang
- Department of Infectious Diseases, The First Affiliated Hospital of Xinxiang Medical College, Xinxiang, Henan, China
| | - Jiefei Wang
- Shanghai Public Health Clinical Center, Shanghai, China
| | - Yongfeng Yang
- Department of Hepatology, The Second Hospital of Nanjing, Nanjing, Jiangsu, China
| | - Sujun Zheng
- Center of Artificial liver, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Dongliang Yang
- Department of Infectious Disease, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Jinlin Hou
- Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Qing Xie
- Department of Infectious Diseases, Ruijin Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Caiyan Zhao
- Department of Infectious Diseases, The Third Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Lunli Zhang
- Department of Infectious Diseases, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Xiaorong Mao
- Department of Infectious Diseases, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Tong Sun
- Department of Infectious Diseases, Wuxi Fifth People’s Hospital, Wuxi, Jiangsu, China
| | - Lang Bai
- Infectious Diseases Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Fuchun Zhang
- Department of Hepatology, Guangzhou Eighth People’s Hospital, Guangzhou, Guangdong, China
| | - Jinglan Jin
- Department of Hepato-Biliary-Pancreatic Diseases, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Yingren Zhao
- Department of Infectious Diseases, Xi’an Jiaotong University First Affiliated Hospital, Xi’an, Shaanxi, China
| | - Maorong Wang
- Department of Infectious Diseases, DiBaYi Hospital of the Chinese People’s Liberation Army, Nanjing, Jiangsu, China
| | - Wen Xie
- Hepatology Center, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Yingjie Ma
- Department of Infectious Diseases, Zhengzhou People’s Hospital, Zhengzhou, Henan, China
| | - Jun Quan
- Department of Infectious Diseases, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Xuebing Yan
- Department of Infectious Diseases, Xuzhou Medical College Affiliated Hospital, Xuzhou, Jiangsu, China
| | - Ping An
- Department of Infectious Diseases, Shenyang Sixth People’s Hospital, Shenyang, Liaoning, China
| | - Feng Lin
- Department of Infectious Diseases, Hainan General Hospital, Haikou, Hainan, China
| | - Jidong Jia
- Hepatology Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Xiaoxuan Hu
- Department of Infectious Diseases, Hunan Provincial People’s Hospital, Changsha, Hunan, China
| | - Zuojiong Gong
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Jie Wu
- Department of Infectious Diseases, Wuhan central hospital, Wuhan, Hubei, China
| | - Yongping Chen
- Department of Infectious Diseases, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Zhansheng Jia
- Department of Infectious Diseases, Tangdu Hospital, The Fourth Military Medical University of the People’s Liberation Army, Xi’an, Shaanxi, China
| | - Minghua Lin
- Department of Hepatology, Meng Chao Hepatobiliary Hospital, Fujian Medical University, Fuzhou, Fujian, China
| | - Guiqiang Wang
- Department of Infectious Diseases, Peking University First Hospital, Beijing, China
| | - Yueyong Zhu
- Department of Infectious Diseases, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian, China
| | - Yingjun Zhang
- State Key Laboratory of Anti-Infective Drug Development (NO.2015DQ780357), Sunshine Lake Pharma Co., Ltd, Dongguan, Guangdong, China
| | - Hongming Xie
- State Key Laboratory of Anti-Infective Drug Development (NO.2015DQ780357), Sunshine Lake Pharma Co., Ltd, Dongguan, Guangdong, China
| | - Lin Luo
- State Key Laboratory of Anti-Infective Drug Development (NO.2015DQ780357), Sunshine Lake Pharma Co., Ltd, Dongguan, Guangdong, China
| | - Qingyun Ren
- State Key Laboratory of Anti-Infective Drug Development (NO.2015DQ780357), Sunshine Lake Pharma Co., Ltd, Dongguan, Guangdong, China
| | - Rui Huang
- Peking University People’s Hospital, Peking University Hepatology Institute, National Clinical Research Center for Infectious Disease, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing International Cooperation Base for Science and Technology on NAFLD Diagnosis, Beijing, China
| | - Lai Wei
- Hepatopancreatobiliary Center, Beijing Tsinghua Changgung Hospital, Tsinghua University, Beijing, China
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18
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Ghanem SE, Elsabaawy M, Shebl N, Abdelsameea E, Othman W, El-Bassal FI, Elgedawy GA, Elsabaawy DM, Helal ML. Value of IFNL3 genetic polymorphism in the prediction of HCV treatment response to direct-acting antiviral drugs versus interferon therapy. Expert Rev Anti Infect Ther 2020; 18:947-954. [PMID: 32419526 DOI: 10.1080/14787210.2020.1771180] [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: 02/16/2020] [Accepted: 05/15/2020] [Indexed: 10/24/2022]
Abstract
Background: Despite the outstanding results of direct-acting antiviral therapies (DAAs) of Hepatitis C infection (HCV), non-responders had to be more defined. Aim: assess the outcome of DAAs in linkage with Interferon lambda 3 (IFNL3) in HCV patients. Methods: This case-control-study was conducted on 495 chronic-HCV (genotype-4a), previously treated Egyptians by either DAAs (responders 195, 120 relapsers) or interferon/ribavirin (IFN/RBV) (140 responders, 60 relapsers), and 98 healthy controls. IFNL3 distribution, clinical and laboratory data were assessed. Results: CT was the most predominant genotype in Egyptians (51%). All genotypes were sensitive to DAAs mainly CT genotype (60%), even TT genotype (resistant to IFN/RBV 40%) had 29.2% sensitivity. CT genotype was predominant in sofosbuvir/Daclatasvir responders (67.6%) (OR = 0.66), while non-CT prevailed in relapsers (56.7%). TT genotype may respond to SOF/Ledi better than other regimens (66.7%). In IFN/RBV relapsers; CT genotype was commoner (50%) than others, while CC genotype predominated in responders (54.3%). The c allele was the commonest in responders to IFN/RBV (71.4%), while the T allele was resistant to treatment (65% in relapsers). Addition of RBV to SOF/DCV reported higher resistance with CT genotype (42.2%-50%) and TT genotype (17.8%-27.8%). Conclusion: This study recommended IFNL3 genotyping to be a prerequisite before stratifying treatment for HCV-4a Egyptians.
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Affiliation(s)
- Samar E Ghanem
- Department of Clinical Biochemistry and Molecular Diagnostics, National Liver Institute, Menoufia University , Shebin El‑Kom, Egypt
| | - Maha Elsabaawy
- Depatment of Hepatology and Gastroenterology, National Liver Institute, Menoufia University , Shebin El‑Kom, Egypt
| | - Nashwa Shebl
- Depatment of Hepatology and Gastroenterology, National Liver Institute, Menoufia University , Shebin El‑Kom, Egypt
| | - Eman Abdelsameea
- Depatment of Hepatology and Gastroenterology, National Liver Institute, Menoufia University , Shebin El‑Kom, Egypt
| | - Warda Othman
- Depatment of Hepatology and Gastroenterology, National Liver Institute, Menoufia University , Shebin El‑Kom, Egypt
| | - Fathia I El-Bassal
- Clinical Pathology Department, Faculty of Medicine, Menoufia University , Shebin El‑Kom, Egypt
| | - Gamalat A Elgedawy
- Department of Clinical Biochemistry and Molecular Diagnostics, National Liver Institute, Menoufia University , Shebin El‑Kom, Egypt
| | - Dalia M Elsabaawy
- Department of Clinical Pharmacy, Faculty of Pharmacy, Menoufia University , Shebin El‑Kom, Egypt
| | - Marwa L Helal
- Department of Clinical Biochemistry and Molecular Diagnostics, National Liver Institute, Menoufia University , Shebin El‑Kom, Egypt
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Moradi M, Mozafari F, Hosseini S, Rafiee R, Ghasemi F. A concise review on impacts of microRNAs in biology and medicine of hepatitis C virus. GENE REPORTS 2020. [DOI: 10.1016/j.genrep.2020.100761] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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20
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Huang P, Wang CH, Zhuo LY, Xia XS, Yang S, Zhang JW, Fan HZ, Wu JJ, Yu R, Yue M, Zhang Y. Polymorphisms rs763110 in FASL is linked to hepatitis C virus infection among high-risk populations. Br J Biomed Sci 2020; 77:112-117. [PMID: 32209020 DOI: 10.1080/09674845.2020.1747182] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2019] [Accepted: 03/20/2020] [Indexed: 12/14/2022]
Abstract
BACKGROUND The Fas cell surface death receptor (FAS) and Fas ligand (FASL) can participate in the apoptosis of immune cells and target cells infected with a virus through the FAS-FASL signalling pathway. The decoy receptor 3 (DCR3) can competitively inhibit the binding of FAS to FASL. Our aim is to investigate the effect of single nucleotide polymorphisms (SNPs) in FAS, FASL and DCR3 on hepatitis C virus (HCV) infection. METHODS Four SNPs (rs763110 in FASL, rs1324551 and rs2234767 in FAS and rs2257440 in DCR3) were genotyped in 1495 controls free of HCV, 522 individuals with spontaneous HCV clearance and 732 patients with hepatitis C virus infection. The RegulomeDB database and RNAfold web servers were used to explore potential biological functions of SNPs. RESULTS FASL rs763110 was associated with susceptibility to HCV infection, and not to CHC. The odds ratio (95% confidence interval) of HCV infection in high-risk populations carrying FASL rs763110-TT was 1.82 (1.36-2.51, P < 0.001) compared to that of CC genotypes and 1.93 (1.43-2.60, P < 0.001) higher than that of CC + CT genotypes. Based on computer simulation, FASL rs763110-T may affect the transcription of mRNA by affecting the binding of a transcription factor, leading to structural changes in mRNA. CONCLUSION The genetic variant in FASL is linked with HCV infection, but not to spontaneous HCV clearance.
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Affiliation(s)
- P Huang
- Department of Epidemiology and Biostatistics, Key Laboratory of Infectious Diseases, Nanjing Medical University , Nanjing, China
- Institute of Epidemiology and Microbiology, Eastern Theater Command Centers for Disease Control and Prevention , Nanjing, China
| | - C H Wang
- Institute of Epidemiology and Microbiology, Eastern Theater Command Centers for Disease Control and Prevention , Nanjing, China
| | - L Y Zhuo
- Department of Epidemiology and Biostatistics, Key Laboratory of Infectious Diseases, Nanjing Medical University , Nanjing, China
| | - X S Xia
- College of Life Science and Technology, Kunming University of Science and Technology , Kunming, China
| | - S Yang
- Department of Biostatistics, School of Public Health, Nanjing Medical University , Nanjing, China
| | - J W Zhang
- Department of Anesthesiology, Affiliated Drum-Tower Hospital of Medical College of Nanjing University , Jiangsu, China
| | - H Z Fan
- Department of Information, The First Affiliated Hospital of Nanjing Medical University , Nanjing, China
| | - J J Wu
- Department of Epidemiology and Biostatistics, Key Laboratory of Infectious Diseases, Nanjing Medical University , Nanjing, China
| | - R Yu
- Department of Epidemiology and Biostatistics, Key Laboratory of Infectious Diseases, Nanjing Medical University , Nanjing, China
| | - M Yue
- Department of Infectious Diseases, The First Affiliated Hospital of Nanjing Medical University , Nanjing, China
- State Key Laboratory of Virology, School of Basic Medical Sciences, Wuhan University , Wuhan, China
| | - Y Zhang
- Department of Epidemiology and Biostatistics, Key Laboratory of Infectious Diseases, Nanjing Medical University , Nanjing, China
- Institute of Epidemiology and Microbiology, Eastern Theater Command Centers for Disease Control and Prevention , Nanjing, China
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21
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Mattingly TJ, Love BL. Changes in Cost-Effectiveness for Chronic Hepatitis C Virus Pharmacotherapy: The Case for Continuous Cost-Effectiveness Analyses. J Manag Care Spec Pharm 2020; 26:879-886. [PMID: 32584675 PMCID: PMC10391261 DOI: 10.18553/jmcp.2020.26.7.879] [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: 11/05/2022]
Abstract
BACKGROUND Cost-effectiveness evaluations for hepatitis C virus (HCV) treatments have been published frequently, but new products with significant cost and effectiveness differences make these analyses obsolete. How valuable are economic models for a fixed time period in a dynamic market? OBJECTIVE To estimate the cost-effectiveness of the best available HCV treatment at different points in time, using the same comparator to demonstrate how rapid innovation in a disease area influences economic outcomes. METHODS A Markov model was used to calculate the cost-effectiveness of treatment in 2010, 2012, 2014, 2016, and 2018 compared with a standard comparator (no treatment) from the payer perspective. Expected drug costs and treatment effectiveness estimates for sustained virologic response (SVR) were calculated using recommended regimens for each of the 6 HCV genotypes at each time point and distribution of genotypes in the United States. Patients entered the model with different stages of fibrosis. Utility estimates for each health state were used to calculate quality-adjusted life-years (QALYs) earned at each cycle. Incremental cost-effectiveness ratios were reported for each year to compare the "treatment versus no treatment" decision at that time. RESULTS No HCV treatment resulted in a gain of 11.54 QALYs over a 20-year time horizon at a cost of $42,938. Costs for treated groups were $69,075, $123,267, $125,431, $86,782, and $56,470 for the 2010, 2012, 2014, 2016, and 2018 scenarios, respectively. QALYs gained for treated groups were 12.90, 12.97, 13.34, 13.39, and 13.46 for the 2010, 2012, 2014, 2016, and 2018 scenarios, respectively. The incremental cost-effectiveness ratios in each year compared with no treatment were $19,218 per QALY, $56,104 per QALY, $45,829 per QALY, $23,699 per QALY, and $7,048 per QALY. CONCLUSIONS Treatment effectiveness for HCV has increased steadily, while treatment costs increased substantially from 2010-2014 before decreasing to its lowest point in 2018. Thus, the dynamic nature of innovation creates the need for iterative cost-effectiveness analyses. DISCLOSURES No outside funding supported this study. Mattingly reports unrelated consulting from the National Health Council, Bristol Myers Squibb, G&W Laboratories, Allergy and Asthma Foundation of American, and the Massachusetts Health Policy Commission. Love reports an unrelated research grant from the American Cancer Society.
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Affiliation(s)
- T. Joseph Mattingly
- Department of Pharmaceutical Health Services Research, University of Maryland School of Pharmacy, Baltimore
| | - Bryan L. Love
- Department of Clinical Pharmacy and Outcomes Sciences, University of South Carolina College of Pharmacy, Columbia
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22
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McKnight AH, Townsend ML, Hashem MG, Naggie S, Park LP, Britt RB. Standard Versus Extended Duration Direct-Acting Antiviral Therapy in Hepatitis C Patients With Slow Response to Treatment. Ann Pharmacother 2020; 54:1057-1064. [PMID: 32406244 DOI: 10.1177/1060028020921166] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Response-guided hepatitis C therapy was standard with interferon-based regimens but is not used for direct-acting antivirals (DAAs). Week 4 viral kinetics may predict sustained virological response (SVR) with DAAs, but it is unclear whether extending therapy in slow responders affects outcomes. OBJECTIVES The primary objective was to compare SVR rates between traditional and extended duration groups. Secondary objectives were to compare SVR rates among subgroups and to determine factors associated with SVR. METHODS This institutional review board-approved, retrospective, single-center study identified patients with chronic hepatitis C virus (HCV) infection with detectable week 4 HCV RNA who were treated with DAAs. Patients were excluded for early discontinuation, treatment regimen not recommended first-line, or missing HCV RNA labs. Patients were stratified into traditional and extended duration groups. The primary end point was SVR. Secondary end points included factors associated with SVR and rationale for extension of therapy duration. RESULTS A total of 363 patients were included; 58 (16%) received extended therapy. Patients were primarily genotype 1a (70%) and treatment naïve (80%). More than half had advanced fibrosis or cirrhosis. SVR12 rates were 100% in the extended duration group and 96.7% in the traditional duration group (P = 0.37). There were no associations with SVR and prespecified patient-specific factors. Sample size was limited. CONCLUSION AND RELEVANCE Based on these findings, a recommendation for extension of therapy cannot be made for patients with detectable HCV RNA at week 4 of treatment at this time. Cost analyses may help guide recommendations to re-treat rare failures versus extend therapy in all slow responders.
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Affiliation(s)
| | | | | | - Susanna Naggie
- Durham Veterans Affairs Health Care System, Durham, NC, USA.,Department of Medicine, Infectious Diseases Division, Duke University Hospital, Durham, NC, USA.,Duke University School of Medicine, Durham, NC, USA
| | - Lawrence P Park
- Durham Veterans Affairs Health Care System, Durham, NC, USA.,Department of Medicine, Infectious Diseases Division, Duke University Hospital, Durham, NC, USA.,Duke Global Health Institute, Durham, NC, USA
| | - Rachel B Britt
- Durham Veterans Affairs Health Care System, Durham, NC, USA
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23
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Bhatia M, Gupta E. Emerging resistance to directly-acting antiviral therapy in treatment of chronic Hepatitis C infection-A brief review of literature. J Family Med Prim Care 2020; 9:531-538. [PMID: 32318377 PMCID: PMC7113931 DOI: 10.4103/jfmpc.jfmpc_943_19] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2019] [Revised: 12/16/2019] [Accepted: 12/24/2019] [Indexed: 12/13/2022] Open
Abstract
Hepatitis caused by Hepatitis C virus (HCV) is a major cause of chronic liver disease. HCV is transmitted by injection drug use, blood transfusion, hemodialysis, organ transplantation and less frequently sexual intercourse. It has been recognized as a global health problem because of the progression to cirrhosis and hepatocellular carcinoma. Globally, about 170 million people are infected with HCV. Since the discovery of this virus in 1989, the clinical management of chronic hepatitis C infection has undergone a paradigm shift from alpha interferon to direct-acting antiviral (DAA) therapy. However, resistance to many of these antiviral agents has been reported increasingly from all over the globe. This review article focuses on the emerging HCV resistance to DAAs and the relevance of in vitro DAA resistance testing in clinical practice.
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Affiliation(s)
- Mohit Bhatia
- Department of Microbiology, All India Institute of Medical Sciences, Rishikesh, Uttarakhand, India
| | - Ekta Gupta
- Department of Virology, Institute of Liver and Biliary Sciences, New Delhi, India
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24
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Li X, Li J, Feng Y, Cai H, Li YP, Peng T. Long-chain fatty acyl-coenzyme A suppresses hepatitis C virus infection by targeting virion-bound lipoproteins. Antiviral Res 2020; 177:104734. [PMID: 32057770 DOI: 10.1016/j.antiviral.2020.104734] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2019] [Revised: 12/18/2019] [Accepted: 02/03/2020] [Indexed: 12/12/2022]
Abstract
Hepatitis C virus (HCV) is a leading cause of chronic hepatitis and end-stage liver diseases. Mature HCV virions are bound by host-derived lipoproteins. Lack of an HCV vaccine warrants a major role of antiviral treatment in the global elimination of hepatitis C. Although direct-acting antivirals (DAAs) are replacing the interferon-based treatment and have dramatically improved the cure rate, the presence of viral variants resistant to DAAs, HCV genotype/subtype-specific efficacy, and high cost of DAAs argue novel and affordable regimens. In this study, we identified the antiviral effects of long-chain fatty acyl-coenzyme A (LCFA-CoA) against the infections of HCV genotypes 1-6 through targeting mature HCV-bound lipoproteins, suggesting novel mechanism(s) of antiviral different from those used by host-targeting agents or DAAs. We found that the antiviral activity of LCFA-CoA relied on the long-chain saturated fatty acid and the CoA group, and was enhanced when combined with pegylated-interferon or DAAs. Importantly, we demonstrated that LCFA-CoA efficiently inhibited the infection of HCV variants carrying DAA-resistant mutations. The mechanistic study revealed that LCFA-CoA specifically abolished the attachment and binding steps and also inhibited the cell-to-cell viral transmission. LCFA-CoA targeted mature HCV-bound lipoproteins, but not apolipoproteins B or E. In addition, LCFA-CoA could also inhibit the infection of the dengue virus. Our findings suggest that LCFA-CoA could potentially serve as a supplement HCV therapy, particularly for the DAA-resistant HCV variants. Taken together, LCFA-CoA may be further developed to be a novel class of antivirals with mechanism(s), different from host-targeting agents or DAAs, of targeting the components associated with mature HCV virions.
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Affiliation(s)
- Xinlei Li
- State Key Laboratory of Respiratory Disease, Sino-French Hoffmann Institute, Guangzhou Medical University, Guangzhou, China
| | - Jinqian Li
- Institute of Human Virology, Zhongshan School of Medicine, Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education, Sun Yat-sen University, Guangzhou, 510080, China
| | - Yetong Feng
- Institute of Human Virology, Zhongshan School of Medicine, Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education, Sun Yat-sen University, Guangzhou, 510080, China
| | - Hua Cai
- State Key Laboratory of Respiratory Disease, Sino-French Hoffmann Institute, Guangzhou Medical University, Guangzhou, China
| | - Yi-Ping Li
- Institute of Human Virology, Zhongshan School of Medicine, Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education, Sun Yat-sen University, Guangzhou, 510080, China.
| | - Tao Peng
- State Key Laboratory of Respiratory Disease, Sino-French Hoffmann Institute, Guangzhou Medical University, Guangzhou, China.
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25
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The Evaluation of Medication Adherence in Patients Infected With HCV Receiving Protease Inhibitors: A Pilot Study. Gastroenterol Nurs 2019; 42:259-268. [PMID: 31145250 DOI: 10.1097/sga.0000000000000386] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
Adherence to treatment is essential for hepatitis C cure. Studies show the complexity of the treatment due to side effects, many pills, and rigor in the schedules. The aim of this study was to evaluate the adherence to treatment with protease inhibitor in patients with hepatitis C. It is a longitudinal, observational, prospective pilot study with patients with hepatitis C genotype 1. Bimonthly consultations and biweekly calls for 20 weeks were performed. Evaluation methods for adherence were Measure of Adherence to Treatment score, patient report, count pills, and sustained virological response. Twenty-two patients were enrolled. Mean age was 54.0 ± 8.72 years; 50% were men, educational level was 7.9 ± 3.89 years for the study, and intake of pills was 2.2 ± 1.60 per day. Adverse events reported were fatigue (90.9%), muscular pain (72.7%), and nausea (68.2%). In total, 71.4% of patients took 100% of medications and were classified as having a high degree of adherence to treatment. The sustained virological response was not significant in relation to the high or low adherence degree. Measure of Adherence to Treatment score is a good instrument to measure adherence to protease inhibitor treatment. The adherence of patients undergoing long-term and complex treatments improves when the multidisciplinary team follows up every 7-15 days. The patient's access to the team through additional phone calls or medical/nursing appointment is essential to improve adherence.
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26
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Xu X, Feng B, Guan Y, Zheng S, Sheng J, Yang X, Ma Y, Huang Y, Kang Y, Wen X, Li J, Tan Y, He Q, Xie Q, Wang M, An P, Gong G, Liu H, Ning Q, Hua R, Ning B, Xie W, Zhang J, Huang W, Yang Y, Lin M, Zhao Y, Yu Y, Jia J, Yang D, Chen L, Ye Y, Nan Y, Gong Z, Zhang Q, Hu P, Wang F, Li Y, Li D, Jia Z, Hou J, Chen C, Wu JJ, Wei L. Efficacy and Safety of All-oral, 12-week Ravidasvir Plus Ritonavir-boosted Danoprevir and Ribavirin in Treatment-naïve Noncirrhotic HCV Genotype 1 Patients: Results from a Phase 2/3 Clinical Trial in China. J Clin Transl Hepatol 2019; 7:213-220. [PMID: 31608212 PMCID: PMC6783683 DOI: 10.14218/jcth.2019.00033] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2019] [Revised: 09/12/2019] [Accepted: 09/15/2019] [Indexed: 02/05/2023] Open
Abstract
Background and Aims: Ravidasvir (RDV) is a new generation pangenotypic hepatitis C virus (HCV) NS5A inhibitor, with high barrier to baseline resistance-associated species. This is the first phase 2/3 study conducted in Mainland China confirming the efficacy and safety of RDV + ritonavir-boosted danoprevir + ribavirin for 12 weeks in treatment-naïve noncirrhotic patients with genotype 1 infection in a large population. Methods: In this multicenter, randomized, double-blinded, placebo-controlled phase 2/3 trial (NCT03362814), we enrolled 424 treatment-naïve, noncirrhotic adult HCV genotype 1 patients. All patients were randomized at 3:1 ratio to receive a combination of RDV 200mg once daily plus ritonavir-boosted danoprevir 100mg/100mg twice daily and oral ribavirin 1000/1200mg/day (body weight <75/≥75 kg) (n = 318) or placebo (n = 106) for 12 weeks. The primary end-point was the rate of sustained virologic response 12 weeks after the end of treatment, and the safety was evaluated and compared between treatment and placebo groups. Results: The overall rate of sustained virological response at 12 weeks after treatment is 99% (306/309, 95%, CI: 97%-100%) under per protocol set analysis. All patients harboring baseline NS5A resistance-associated species in the treatment group (76/76, per protocol set) achieved sustained virological response at 12 weeks after treatment. No treatment-related serious adverse events were reported. Laboratory abnormalities showed mild or moderate severity (grade 1 and grade 2) in liver function tests. Conclusions: In treatment-naïve, noncirrhotic HCV Chinese patients infected with HCV genotype 1, all-oral regimen of RDV + ritonavir-boosted danoprevir + ribavirin for 12 weeks was highly efficacious, safe, and well tolerated.
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Affiliation(s)
- Xiaoyuan Xu
- Peking University First Hospital, Beijing, China
| | - Bo Feng
- Peking University People’s Hospital, Beijing, China
| | - Yujuan Guan
- Guangzhou Eighth People’s Hospital, Guangzhou, China
| | - Sujun Zheng
- Beijing YouAn Hospital, Capital Medical University, Beijing, China
| | - Jifang Sheng
- The First Affiliated Hospital of Medical School of Zhejiang University, Hangzhou, China
| | | | - Yuanji Ma
- West China Hospital, Sichuan University, Chengdu, China
| | - Yan Huang
- Xiangya Hospital, Central South University, Changsha, China
| | - Yi Kang
- Henan Provincial People’s Hospital, Zhengzhou, China
| | | | - Jun Li
- Jiangsu Province Hospital, Nanjing, China
| | - Youwen Tan
- Zhenjiang No.3 People’s Hospital, Zhenjiang, China
| | - Qing He
- The Third People’s Hospital of Shenzhen, Shenzhen, China
| | - Qing Xie
- Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Maorong Wang
- People’s Liberation Army Bayi Hospital, Nanjing, China
| | - Ping An
- Shenyang Sixth People’s Hospital, Shenyang, China
| | - Guozhong Gong
- The 2nd Xiangya Hospital of Central South University, Changsha, China
| | - Huimin Liu
- Xixi Hospital of Hangzhou, Hangzhou, China
| | - Qin Ning
- Tongji Medical College of Huazhong University of Science & Technology, Wuhan, China
| | - Rui Hua
- The First Hospital of Jilin University, Changchun, China
| | - Bo Ning
- Baoji Center Hospital, Baoji, China
| | - Wen Xie
- Beijing Ditan Hospital, Beijing, China
| | - Jiming Zhang
- Huashan Hospital Affiliated to Fudan University, Shanghai, China
| | - Wenxiang Huang
- Chongqing Medical University No.1 Affiliated Hospital, Chongqing, China
| | | | - Minghua Lin
- Fujian Fuzhou Municipal Infectious Disease Hospital, Fuzhou, China
| | - Yingren Zhao
- No.1 Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Yanhong Yu
- The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Jidong Jia
- Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | | | - Liang Chen
- Shanghai Public Health Clinical Center, Shanghai, China
| | - Yinong Ye
- Foshan No.1 People’s Hospital, Foshan, China
| | - Yuemin Nan
- The Third Hospital of Hebei Medical University, Shijiazhuang, China
| | | | - Quan Zhang
- The Affiliated Hospital of Guizhou Medical University, Guiyang, China
| | - Peng Hu
- The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | | | - Yongguo Li
- The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Dongliang Li
- Fuzhou General Hospital of Nanjing Military Command, Fuzhou, China
| | - Zhansheng Jia
- Tang Du Hospital, Fourth military Medical University, Xi’an, China
| | - Jinlin Hou
- Nanfang Hospital, Nanfang Medical University, Guangzhou, China
| | - Chengwei Chen
- The 85 branch of the Chinese People’s Liberation Army Hospital, Shanghai, China
| | - Jinzi J. Wu
- Ascletis BioScience Co., Ltd. Hangzhou, China
| | - Lai Wei
- Tsinghua Changgeng Hospital, Beijing, China
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El-Shabrawi M, Hassanin F. Paediatric hepatitis C virus infection and its treatment: Present, past, and future. Arab J Gastroenterol 2019; 20:163-174. [PMID: 31585703 DOI: 10.1016/j.ajg.2019.09.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2019] [Revised: 06/01/2019] [Accepted: 09/15/2019] [Indexed: 01/08/2023]
Abstract
Hepatitis C virus (HCV) infection is a major cause of chronic liver disease in the world. It is a challenging medico-social problem in the paediatric population. High HCV infection rates are reported in low and middle incomes countries. From the health economic point of view treatment of hepatitis C virus (HCV) with subsequent virus eradication is very effective as it eliminates the long-term sequelae of untreated or maltreated HCV. In this review we summarize the updates and highlight the historical approach of treatment of chronic HCV infection in children in the new era of directly acting antiviral (DAA) agents.
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Hsu W, Peng C, Su W, Lai H, Lin C, Chuang P, Chen S, Chen H, Wang H, Huang G. Treatment with direct‐acting antiviral agents is associated with increased platelet count in patients with chronic hepatitis C. ADVANCES IN DIGESTIVE MEDICINE 2019. [DOI: 10.1002/aid2.13124] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Affiliation(s)
- Wei‐Fan Hsu
- Division of Hepatogastroenterology, Department of Internal MedicineChina Medical University Hospital Taichung Taiwan
| | - Cheng‐Yuan Peng
- Division of Hepatogastroenterology, Department of Internal MedicineChina Medical University Hospital Taichung Taiwan
- School of MedicineChina Medical University Taichung Taiwan
| | - Wen‐Pang Su
- Division of Hepatogastroenterology, Department of Internal MedicineChina Medical University Hospital Taichung Taiwan
| | - Hsueh‐Chou Lai
- Division of Hepatogastroenterology, Department of Internal MedicineChina Medical University Hospital Taichung Taiwan
- School of Chinese MedicineChina Medical University Taichung Taiwan
| | - Chia‐Hsin Lin
- Division of Hepatogastroenterology, Department of Internal MedicineChina Medical University Hospital Taichung Taiwan
| | - Po‐Heng Chuang
- Division of Hepatogastroenterology, Department of Internal MedicineChina Medical University Hospital Taichung Taiwan
| | - Sheng‐Hung Chen
- Division of Hepatogastroenterology, Department of Internal MedicineChina Medical University Hospital Taichung Taiwan
- School of MedicineChina Medical University Taichung Taiwan
| | - Hung‐Yao Chen
- Division of Hepatogastroenterology, Department of Internal MedicineChina Medical University Hospital Taichung Taiwan
| | - Hung‐Wei Wang
- Division of Hepatogastroenterology, Department of Internal MedicineChina Medical University Hospital Taichung Taiwan
| | - Guan‐Tarn Huang
- Division of Hepatogastroenterology, Department of Internal MedicineChina Medical University Hospital Taichung Taiwan
- School of MedicineChina Medical University Taichung Taiwan
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29
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Tam E, Borgia S, Yoshida EM, Cooper C, Ford JA, Vachon ML, Sherman M, Halsey-Brandt J. Real-world health care utilization in treatment of HCV: Results from the Canadian SIMPLE observational trial. CANADIAN LIVER JOURNAL 2019; 2:91-107. [DOI: 10.3138/canlivj.2018-0024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2018] [Accepted: 12/13/2018] [Indexed: 11/20/2022]
Abstract
Background: As hepatitis C virus (HCV) treatment continues to evolve, there is an ongoing need to understand and optimize real-world disease management. The primary objective of the SIMPLE study was to describe the real-life management of genotype 1 (G1) HCV in Canada treated with boceprevir + pegylated interferon and ribavirin therapy. Methods: This was an observational, prospective cohort, multicentre, non-interventional study of patients with G1 HCV. A single cohort of adult patients were to be managed as per standard of care (SoC) and treated with 4 weeks of PegRBV dual therapy, followed by boceprevir + PegRBV for 24–44 weeks, with 24-weeks follow-up. Treatment compliance, health care resource utilization (HCRU), HCV viral load, and hematological adverse event (AE) data were collected. Results: This study enrolled 159 patients. All investigators were well educated on the Canadian consensus guidelines for HCV management but only a minority of patients were treated according to treatment guidelines. Viral response was achieved by >50% of patients by week 8 of therapy and in 50%–60% of tested patients during follow-up. An average of 17.9 HCRU visits were reported during the study period. The most commonly used resources were nursing visits for routine follow-up. Conclusions: Results from this real-world study suggest that most patients were not treated according to the product monograph. Further studies are required to determine how oral treatments fit into this paradigm and how these findings extrapolate to the current treatment model. This study can serve as a benchmark for future real-world treatment including heath care utilization analyses.
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Affiliation(s)
- Edward Tam
- LAIR Centre, Vancouver, British Columbia
| | | | | | | | - Jo-Ann Ford
- Vancouver General Hospital, Vancouver, British Columbia
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Zullig LL, Bhatia HL, Gellad ZF, Eatherly M, Henderson R, Bosworth HB. Adoption of direct-acting antiviral medications for hepatitis C: a retrospective observational study. BMC Health Serv Res 2019; 19:521. [PMID: 31345218 PMCID: PMC6657375 DOI: 10.1186/s12913-019-4349-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2018] [Accepted: 07/16/2019] [Indexed: 01/27/2023] Open
Abstract
BACKGROUND Approximately 3.5 million Americans are infected with the hepatitis C virus (HCV). Although many patients with HCV are asymptomatic, HCV is the leading cause of infection-related death in the U.S. With advances in curative medication therapy for HCV, many of these deaths are preventable. Access to innovative therapies may be unevenly distributed. Our objective was to describe medication prescribers' adoption of innovative HCV pharmacotherapy across prescriber, geographical location, and time. METHODS This is a retrospective, secondary data analysis among a national cohort of patients prescribed direct-acting antiviral HCV medications with curative intent. We assessed prescriptions by time, geographic location, and provider type. RESULTS The peak of the adoption rate occurred within 45 days; nearly one-sixth of all prescribers had already prescribed one of the new drugs. Geographical regions (Midwest, South, and West all p ≥ 0.05) nor gender (p = 0.455) of a prescriber impacted adoption. Similarly, patient income did not influence the likelihood of a prescriber to adopt the new drugs earlier (p = 0.175). Gastroenterologists or hepatologists were more likely earlier adopters compared to primary care physicians (p = 0.01). CONCLUSIONS Because of the relative advantage of newer therapies, we anticipated that there would be an initial surge as early adopters prescribed the new medications and use would dwindle over time as the initial HCV cohort was cured. The data demonstrate that our hypothesis is essentially supported. There is a reduction in prescriptions at approximately 5 months post-approval and treatment is typically required for 3 months. There has been a surge in clinicians' adoption of innovative HCV treatments. As patients are cured of their infection, we anticipate a decreased need for chronic management of HCV. TRIAL REGISTRATION Not applicable.
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Affiliation(s)
- Leah L Zullig
- Center of Innovation to Accelerate Discovery and Practice Transformation (ADAPT), Durham Veterans Affairs Health Care Center, 411 West Chapel Hill Street, Suite 600, Durham, NC, 27701, USA.,Department of Population Health Sciences, Duke University Medical Center, Durham, NC, USA
| | | | - Ziad F Gellad
- Center of Innovation to Accelerate Discovery and Practice Transformation (ADAPT), Durham Veterans Affairs Health Care Center, 411 West Chapel Hill Street, Suite 600, Durham, NC, 27701, USA.,Division of Gastroenterology, Duke University Medical Center, Durham, NC, USA
| | | | | | - Hayden B Bosworth
- Center of Innovation to Accelerate Discovery and Practice Transformation (ADAPT), Durham Veterans Affairs Health Care Center, 411 West Chapel Hill Street, Suite 600, Durham, NC, 27701, USA. .,Department of Population Health Sciences, Duke University Medical Center, Durham, NC, USA. .,Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC, USA.
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Todorovska B, Joksimovic N, Caloska-Ivanova V, Dimitrova-Genadieva M, Trajkovska M, Curakova E, Kiprijanovska S, Zafirova-Ivanovska B, Serafimoski V. Factors That Influence the Virological Response in Patients with Chronic Hepatitis C Treated with Pegylated Interferon and Ribavirin. ACTA ACUST UNITED AC 2019; 38:25-33. [PMID: 28593897 DOI: 10.1515/prilozi-2017-0003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
INTRODUCTION The success of the antiviral treatment in patients with chronic hepatitis C depends on the factors related to the virus and the host. The aim of the study is the analysis of the antiviral therapy which is a combination of pegylated interferon and ribavirin, considering various factors that will identify the predictors of the sustained virological response. MATERIAL AND METHODS This retrospective study included 226 patients, divided in two groups. Patients with sustained virological response and patients without sustained virological response were compared in terms of the following factors: genotype, viral load, gender, age, inflammatory and fibrotic changes in the liver, metabolic abnormalities, obesity and fatty liver. RESULTS The rate of the sustained virological response is 83.6%, more frequently in patients with genotype 3, with evidenced statistical significance (90.54%). The factors that significantly contribute to sustained virological response are related to the age (p = 0.0001), genotype (p = 0.002), mode of transmission (p = 0.005), inflammatory changes in the liver (p = 0.028), body mass index (p = 0.022) and insulin resistance (p = 0.039). The high rate of sustained virological response is related to the younger age of the patients which indirectly means short Hepatitis C Virus infection duration, absence of advanced liver disease and lack of significant co-morbid conditions. Single confirmed independent predictors of sustained virological response are the age (OR 0.928, p = 0.0001) and genotype (OR 3.134, p = 0.005). CONCLUSIONS Factors that are related to the virological response are the age, genotype, mode of transmission, inflammatory changes in the liver, body mass index and insulin resistance, but still, independent predictors of sustained virologic response are the age and the genotype.
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Affiliation(s)
- Beti Todorovska
- University Clinic of Gastroenterohepatology, Faculty of Medicine, University "Ss. Cyril and Methodius", Skopje
| | - Nenad Joksimovic
- University Clinic of Gastroenterohepatology, Faculty of Medicine, University "Ss. Cyril and Methodius", Skopje
| | - Viktorija Caloska-Ivanova
- University Clinic of Gastroenterohepatology, Faculty of Medicine, University "Ss. Cyril and Methodius", Skopje
| | | | - Meri Trajkovska
- University Clinic of Gastroenterohepatology, Faculty of Medicine, University "Ss. Cyril and Methodius", Skopje
| | - Elena Curakova
- University Clinic of Gastroenterohepatology, Faculty of Medicine, University "Ss. Cyril and Methodius", Skopje
| | - Sanja Kiprijanovska
- Research Center for Genetic Engineering and Biotechnology "Georgi D. Efremov", Macedonian Academy of Sciences and Arts, Skopje
| | - Beti Zafirova-Ivanovska
- Institute of Epidemiology and Biostatistics, Faculty of Medicine, University "Ss. Cyril and Methodius", Skopje
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Raja R, Baral S, Dixit NM. Interferon at the cellular, individual, and population level in hepatitis C virus infection: Its role in the interferon-free treatment era. Immunol Rev 2019; 285:55-71. [PMID: 30129199 DOI: 10.1111/imr.12689] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
The advent of powerful direct-acting antiviral agents (DAAs) has revolutionized the treatment of hepatitis C. DAAs cure nearly all patients with short duration, oral treatments. Significant efforts are now underway to optimize DAA-based treatments. We discuss the potential role of interferon in this optimization. Clinical studies present compelling evidence that DAAs perform better in treatment-naive individuals than in individuals who previously failed treatment with interferon, a surprising correlation because interferon and DAAs are thought to act independently. Recent mathematical models explore a mechanistic hypothesis underlying this correlation. The hypothesis invokes the action of interferon at the cellular, individual, and population levels. Strong interferon responses prevent the productive infection of cells, reduce viral replication, and impede the development of resistance to DAAs in infected individuals and improve cure rates elicited by DAAs in treated populations. The models develop descriptions of these processes, integrate them into a comprehensive framework, and capture clinical data quantitatively, providing a successful test of the hypothesis. Individuals with strong endogenous interferon responses thus present a promising subpopulation for reducing DAA treatment durations. This review discusses the conceptual advances made by the models, highlights the new insights they unravel, and examines their applicability to optimize DAA-based treatments.
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Affiliation(s)
- Rubesh Raja
- Department of Chemical Engineering, Indian Institute of Science, Bangalore, India
| | - Subhasish Baral
- Department of Chemical Engineering, Indian Institute of Science, Bangalore, India
| | - Narendra M Dixit
- Department of Chemical Engineering, Indian Institute of Science, Bangalore, India.,Centre for Biosystems Science and Engineering, Indian Institute of Science, Bangalore, India
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33
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Hsu WF, Lai HC, Su WP, Lin CH, Chuang PH, Chen SH, Chen HY, Wang HW, Huang GT, Peng CY. Rapid decline of noninvasive fibrosis index values in patients with hepatitis C receiving treatment with direct-acting antiviral agents. BMC Gastroenterol 2019; 19:63. [PMID: 31029101 PMCID: PMC6486982 DOI: 10.1186/s12876-019-0973-5] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2018] [Accepted: 03/31/2019] [Indexed: 12/23/2022] Open
Abstract
Background Studies on temporal changes in noninvasive fibrosis indices and liver stiffness measurement (LSM) in patients with chronic hepatitis C (CHC) treated with direct-acting antiviral agents (DAAs) are limited. Methods We retrospectively enrolled consecutive patients with CHC who had received DAAs. Results In total, we recruited 395 consecutive patients, of which 388 (98.2%) achieved a sustained virologic response (SVR) at 12 weeks after therapy. In patients who received DAA therapy and achieved SVR 12 weeks after therapy (n = 388), the median aspartate aminotransferase/platelet ratio index (APRI) value decreased from 1.19 (0.62–2.44) at baseline to 0.50 (0.32–0.95), 0.51 (0.31–0.92), 0.48 (0.31–0.88), and 0.52 (0.33–0.92) at week 2, week 4, end of therapy, and PW12, respectively (all P < 0.001). The median FIB-4 value decreased from 2.88 (1.56–5.60) at baseline to 2.10 (1.30–3.65), 2.15 (1.30–3.65), 2.11 (1.37–3.76), and 2.22 (1.45–3.82) at week 2, week 4, end of therapy, and PW12, respectively (all P < 0.001). The median alanine aminotransferase level significantly decreased from week 2 until PW12 (all P < 0.001). The platelet count significantly increased from 2 weeks after DAA therapy initiation until PW12 (all P < 0.001); however, the magnitude of changes in the platelet count was low. In patients with paired LSMs obtained using acoustic radiation force impulse elastography at baseline and PW12 (n = 199), the median LSM decreased from 1.78 (1.25–2.30) m/s at baseline to 1.38 (1.14–1.88) m/s at PW12 (P < 0.001). Conclusions Noninvasive fibrosis indices, namely APRI and FIB-4, exhibited a rapid and sustained decline from week 2 until PW12 in patients with CHC who achieved SVR to DAA therapy. The rapid decline in APRI and FIB-4 values might mainly result from improvement in necroinflammation. Electronic supplementary material The online version of this article (10.1186/s12876-019-0973-5) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Wei-Fan Hsu
- Division of Hepatogastroenterology, Department of Internal Medicine, China Medical University Hospital, No. 2, Yuh-Der Road, 40447, Taichung, Taiwan.,Graduate Institute of Biomedical Science, China Medical University, 40442, Taichung, Taiwan
| | - Hsueh-Chou Lai
- Division of Hepatogastroenterology, Department of Internal Medicine, China Medical University Hospital, No. 2, Yuh-Der Road, 40447, Taichung, Taiwan.,School of Chinese Medicine, China Medical University, 40442, Taichung, Taiwan
| | - Wen-Pang Su
- Division of Hepatogastroenterology, Department of Internal Medicine, China Medical University Hospital, No. 2, Yuh-Der Road, 40447, Taichung, Taiwan.
| | - Chia-Hsin Lin
- Division of Hepatogastroenterology, Department of Internal Medicine, China Medical University Hospital, No. 2, Yuh-Der Road, 40447, Taichung, Taiwan
| | - Po-Heng Chuang
- Division of Hepatogastroenterology, Department of Internal Medicine, China Medical University Hospital, No. 2, Yuh-Der Road, 40447, Taichung, Taiwan
| | - Sheng-Hung Chen
- Division of Hepatogastroenterology, Department of Internal Medicine, China Medical University Hospital, No. 2, Yuh-Der Road, 40447, Taichung, Taiwan.,Graduate Institute of Biomedical Science, China Medical University, 40442, Taichung, Taiwan.,School of Medicine, China Medical University, 40442, Taichung, Taiwan
| | - Hung-Yao Chen
- Division of Hepatogastroenterology, Department of Internal Medicine, China Medical University Hospital, No. 2, Yuh-Der Road, 40447, Taichung, Taiwan
| | - Hung-Wei Wang
- Division of Hepatogastroenterology, Department of Internal Medicine, China Medical University Hospital, No. 2, Yuh-Der Road, 40447, Taichung, Taiwan
| | - Guan-Tarn Huang
- Division of Hepatogastroenterology, Department of Internal Medicine, China Medical University Hospital, No. 2, Yuh-Der Road, 40447, Taichung, Taiwan.,School of Medicine, China Medical University, 40442, Taichung, Taiwan
| | - Cheng-Yuan Peng
- Division of Hepatogastroenterology, Department of Internal Medicine, China Medical University Hospital, No. 2, Yuh-Der Road, 40447, Taichung, Taiwan. .,School of Medicine, China Medical University, 40442, Taichung, Taiwan.
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El-Shabrawi MH, Kamal NM, Mogahed EA, Elhusseini MA, Aljabri MF. Perinatal transmission of hepatitis C virus: an update. Arch Med Sci 2019; 16:1360-1369. [PMID: 33224335 PMCID: PMC7667440 DOI: 10.5114/aoms.2019.83644] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2018] [Accepted: 09/02/2018] [Indexed: 12/17/2022] Open
Abstract
Infection with hepatitis C virus (HCV) is a major health problem worldwide. A large proportion of perinatal HCV infections are silent and may present later in adulthood with long-term complications. HCV has no effective immune prophylaxis and hence appropriate follow-up of all infants born to HCV-infected mothers is necessary. Universal antenatal screening for HCV is largely debatable. Intrauterine and partum transmission of HCV are both possible and higher rates are associated with a high maternal serum viral load (> 106 copies per milliliter), concomitant HIV infection, prolonged or difficult delivery, and invasive fetal monitoring during delivery. Infection during pregnancy and infancy needs to be investigated more in order to design management strategies for perinatal transmission of HCV most effectively. The recently approved new-generation, oral, direct-acting antiviral drugs may open a new era in HCV therapy for pregnant women and infected infants if proved to be safe during conception and infancy.
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Affiliation(s)
| | - Naglaa M. Kamal
- Department of Pediatrics and Pediatric Hepatology, Faculty of Medicine, Cairo University, Egypt
| | - Engy A. Mogahed
- Department of Pediatrics and Pediatric Hepatology, Faculty of Medicine, Cairo University, Egypt
| | - Mona A. Elhusseini
- Department of Obstetrics and Gynecology, Red Crescent Hospital, Cairo, Egypt
| | - Mohamed F. Aljabri
- Department of Pediatrics and Pediatric Neurology, Alhada Armed Forces Hospital, Taif, Saudi Arabia
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Effect of sofosbuvir and daclatasvir on lipid profile, glycemic control and quality of life index in chronic hepatitis C, genotype 3 patients. Indian J Gastroenterol 2019; 38:39-43. [PMID: 30710219 DOI: 10.1007/s12664-019-00935-w] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2018] [Accepted: 01/06/2019] [Indexed: 02/04/2023]
Abstract
OBJECTIVES The management of hepatitis C has progressed from interferon-based therapy to oral direct acting antiviral therapy. Deranged lipid levels (total cholesterol, triglyceride) after treatment with interferon-based therapy are well known. There is a paucity of data on changes in lipid profile, glycemic parameters and alteration in quality of life with the newer regimen. This study was designed to assess the changes in lipid profile, glycemic parameters, quality of life in chronic hepatitis C patients with genotype 3 after treatment with sofosbuvir and daclatasvir. METHODS The study was a single-centre, prospective study, conducted at tertiary care hospital from January 2017 to December 2017. Fifty patients, who received sofosbuvir (400 mg) and daclatasvir (60 mg) orally once daily for a period of 12 weeks for chronic hepatitis C and genotype 3, were recruited. RESULTS Total cholesterol levels (166.9 ± 23.8 to 192.4 ± 34.5 mg/dL, p-value < 0.0001) and low-density cholesterol (LDL) levels (100.9 ± 22.8 to 121.6 ± 37.2, p-value < 0.0001) were elevated after the treatment. A significant decrease in median levels of glycated hemoglobin (HbA1c) was observed (5.57% to 5.41%, p-value < 0.002). Quality of life markedly improved in all domains, i.e. physical, physiological, environmental, and social relationships according to an abbreviated form of World Health Organization quality of life assessment named WHOQOL-BREF questionnaire. Treatment was found to be effective with sustained virological response (SVR) achieved in 94% patients. CONCLUSIONS Our study reports a substantial increment in total cholesterol, and low-density lipoprotein with sofosbuvir and daclatasvir treatment though it achieved SVR in 94% of patients and improved their quality of life.
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Abstract
The first clinical application of magnetic resonance elastography (MRE) was in the evaluation of chronic liver disease (CLD) for detection and staging of liver fibrosis. In the past 10 years, MRE has been incorporated seamlessly into a standard magnetic resonance imaging (MRI) liver protocol worldwide. Liver MRE is a robust technique for evaluation of liver stiffness and is currently the most accurate noninvasive imaging technology for evaluation of liver fibrosis. Newer MRE sequences including spin-echo MRE and 3 dimensional MRE have helped in reducing the technical limitations of clinical liver MRE that is performed with 2D gradient recalled echo (GRE) MRE. Advances in MRE technology have led to understanding of newer mechanical parameters such as dispersion, attenuation, and viscoelasticity that may be useful in evaluating pathological processes in CLD and may prove useful in their management.This review article will describe the changes in CLD that cause an increase in stiffness followed by principle and technique of liver MRE. In the later part of the review, we will briefly discuss the advances in liver MRE.
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37
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Depression among adults with chronic hepatitis C on antiviral treatment in Port-Said, Egypt. J Public Health (Oxf) 2018. [DOI: 10.1007/s10389-018-0907-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/17/2022] Open
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38
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Deming R, Ford MM, Moore MS, Lim S, Perumalswami P, Weiss J, Wyatt B, Shukla S, Litwin A, Reynoso S, Laraque F. Evaluation of a hepatitis C clinical care coordination programme's effect on treatment initiation and cure: A surveillance-based propensity score matching approach. J Viral Hepat 2018; 25:1236-1243. [PMID: 29757491 DOI: 10.1111/jvh.12929] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2018] [Accepted: 04/25/2018] [Indexed: 12/13/2022]
Abstract
Hepatitis C (HCV) is a viral infection that if left untreated can severely damage the liver. Project INSPIRE was a 3 year HCV care coordination programme in New York City (NYC) that aimed to address barriers to treatment initiation and cure by providing patients with supportive services and health promotion. We examined whether enrolment in Project INSPIRE was associated with differences in HCV treatment and cure compared with a demographically similar group not enrolled in the programme. INSPIRE participants in 2015 were matched with a cohort of HCV-infected persons identified in the NYC surveillance registry, using full optimal matching on propensity scores and stratified by INSPIRE enrolment status. Conditional logistic regression was used to assess group differences in the two treatment outcomes. Two follow-up sensitivity analyses using individual pair-matched sets and the full unadjusted cohort were also conducted. Treatment was initiated by 72% (790/1130) of INSPIRE participants and 36% (11 960/32 819) of study-eligible controls. Among initiators, 65% (514/790) of INSPIRE participants compared with 47% (5641/11 960) of controls achieved cure. In the matched analysis, enrolment in INSPIRE increased the odds of treatment initiation (OR: 5.25, 95% CI: 4.47-6.17) and cure (OR: 2.52, 95% CI: 2.00-3.16). Results from the sensitivity analyses showed agreement with the results from the full optimal match. Participation in the HCV care coordination programme significantly increased the probability of treatment initiation and cure, demonstrating that care coordination for HCV-infected individuals improves treatment outcomes.
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Affiliation(s)
- R Deming
- New York City Department of Health and Mental Hygiene, Long Island City, NY, USA
| | - M M Ford
- New York City Department of Health and Mental Hygiene, Long Island City, NY, USA
| | - M S Moore
- New York City Department of Health and Mental Hygiene, Long Island City, NY, USA
| | - S Lim
- New York City Department of Health and Mental Hygiene, Long Island City, NY, USA
| | - P Perumalswami
- Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - J Weiss
- Division of General Internal Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - B Wyatt
- Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - S Shukla
- Montefiore Medical Center, Bronx, NY, USA
| | - A Litwin
- Montefiore Medical Center, Bronx, NY, USA
| | - S Reynoso
- Montefiore Medical Center, Bronx, NY, USA
| | - F Laraque
- New York City Department of Health and Mental Hygiene, Long Island City, NY, USA
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Matthew AN, Leidner F, Newton A, Petropoulos CJ, Huang W, Ali A, KurtYilmaz N, Schiffer CA. Molecular Mechanism of Resistance in a Clinically Significant Double-Mutant Variant of HCV NS3/4A Protease. Structure 2018; 26:1360-1372.e5. [PMID: 30146168 DOI: 10.1016/j.str.2018.07.004] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2018] [Revised: 07/01/2018] [Accepted: 07/21/2018] [Indexed: 12/22/2022]
Abstract
Despite significant progress in hepatitis C virus (HCV) protease inhibitor (PI) drug design, resistance remains a problem causing treatment failure. Double-substitution variants, notably Y56H/D168A, have emerged in patients who fail therapy with a PI-containing regimen. The resistance conferred by Asp168 substitutions has been well characterized and avoided in newer inhibitors. However, an additional mutation at Tyr56 confers resistance to even the most robust inhibitors. Here, we elucidate the molecular mechanisms of resistance for the Y56H/D168A variant against grazoprevir (and four analogs), paritaprevir, and danoprevir through inhibition assays, co-crystal structures, and molecular dynamics simulations. The PIs' susceptibility to Y56H/D168A varies, with those stacking on the catalytic His57 losing the most potency. For such inhibitors, the Y56H substitution disrupts favorable stacking interactions with the neighboring catalytic His57. This indirect mechanism of resistance threatens to cause multi-PI failure as all HCV PIs in clinical development rely on interactions with the catalytic triad.
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Affiliation(s)
- Ashley N Matthew
- Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA 01605, USA
| | - Florian Leidner
- Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA 01605, USA
| | - Alicia Newton
- Monogram Biosciences, South San Francisco, CA 94080, USA
| | | | - Wei Huang
- Monogram Biosciences, South San Francisco, CA 94080, USA
| | - Akbar Ali
- Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA 01605, USA
| | - Nese KurtYilmaz
- Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA 01605, USA
| | - Celia A Schiffer
- Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
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Liver Transplantation in Hepatitis C-Infected Patients: Experience From a South American Transplant Center. Transplant Proc 2018; 50:493-498. [PMID: 29579834 DOI: 10.1016/j.transproceed.2017.11.046] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2017] [Accepted: 11/11/2017] [Indexed: 12/16/2022]
Abstract
BACKGROUND Around 2.4% of the world's population is infected with hepatitis C virus (HCV), and it is the most common cause of liver transplantation (LT) in the world. Latin America (LA), with nearly 9% of the world population, has had a continuous increase in the number of LTs per year. Yet, due to the lack of mandatory data collection and a well-developed health-care system, access to transplantation is limited in most LA countries. We report the first LA experience of HCV-infected LT patients. METHODS We performed a retrospective cohort study by reviewing the medical histories of all HCV-infected LT patients between 1996 and 2016 who acquired HCV before their LT, at the Fundación Valle del Lilí, Cali, Colombia. RESULTS Between January 1996 and December 2015, a total of 770 LTs were performed, of which 75 had a cirrhotic liver due to HCV infection. With a median follow-up time of 24.4 months (interquartile range [IQR] 4.7-61.2 months), patient survival was 44.9% and 66.9% for the time periods 1996-2006 and 2007-2015, respectively. Hepatocellular carcinoma (HCC) was present in 30.6% of the patients, and overall postoperative complications had an incidence of 80%. CONCLUSIONS This is the first report of LT in HCV-infected patients in Colombia and in LA. Our results are comparable to those of other transplant centers worldwide with regard to postoperative complications and patient survival. Patients with LT in the 1996-2006 time frame had higher morbidity and mortality. Studies including larger numbers of patients are needed to determine the reason for this finding.
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Saab S, Le L, Saggi S, Sundaram V, Tong MJ. Toward the elimination of hepatitis C in the United States. Hepatology 2018; 67:2449-2459. [PMID: 29181853 DOI: 10.1002/hep.29685] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2017] [Revised: 11/13/2017] [Accepted: 11/20/2017] [Indexed: 12/12/2022]
Abstract
The emergence of effective direct-acting antiviral (DAA) agents has reignited discussion over the potential for hepatitis C elimination in the United States. Eliminating hepatitis C will require a critical examination of technical feasibility, economic considerations, and social/political attention. Tremendous advancement has been made with the availability of sensitive diagnostic tests and highly effective DAAs capable of achieving sustained viral response (SVR) in more than 95% of patients. Eliminating hepatitis C also requires escalating existing surveillance networks to monitor for new epidemics. All preventive interventions such as clean syringe and needle exchange programs, safe injection sites, opioid substitution therapies, and mental health services need to be expanded. Although costs of DAAs have raised budget concerns for hepatitis C elimination, studies have shown that eliminating hepatitis C will produce a savings of up to 6.5 billion USD annually along with other intangible benefits such as increased work productivity and quality of life. Economic models and meta-analyses strongly suggest universal hepatitis C screening for all adults rather than just for birth cohort and high-risk populations. Social and political factors are at least as important as technical feasibility and economic considerations. Due to lack of promotion and public awareness, HCV elimination efforts continue to receive inadequate funding. Social stigma continues to impede meaningful policy changes. Eliminating hepatitis C is an attainable public health goal that will require intense collaboration and sustained public support. (Hepatology 2018;67:2449-2459).
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Affiliation(s)
- Sammy Saab
- Department of Surgery, University of California Los Angeles, Los Angeles, CA
| | - Long Le
- Department of Medicine, University of California Los Angeles, Los Angeles, CA
| | - Satvir Saggi
- Olive View Medical Center, University of California Los Angeles, Los Angeles, CA
| | - Vinay Sundaram
- Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA
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Vasanthakumar A, Davis JW, Abunimeh M, Söderholm J, Zha J, Dumas EO, Cohen DE, Waring JF, Lagging M. Reduced ITPase activity and favorable IL28B genetic variant protect against ribavirin-induced anemia in interferon-free regimens. PLoS One 2018; 13:e0198296. [PMID: 29851985 PMCID: PMC5979032 DOI: 10.1371/journal.pone.0198296] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2018] [Accepted: 05/16/2018] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND Genetic variants of inosine triphosphatase (ITPA) that confer reduced ITPase activity are associated with protection against ribavirin(RBV)-induced hemolytic anemia in peginterferon(IFN)/RBV-based treatment of hepatitis C virus (HCV). Patients with reduced ITPase activity showed improved treatment efficacy when treated with IFN/RBV. In addition, a genetic polymorphism near the IL28B gene is associated with an improved response to IFN/RBV treatment. RBV has been an important component of IFN-containing regimens, and is currently recommended in combination with several IFN-free regimens for treatment of harder to cure HCV infections. AIM To evaluate whether genetic variations that reduce ITPase activity impact RBV-induced anemia in IFN-free/RBV regimens. METHODS In this study, genetic analyses were conducted in the PEARL-IV trial to investigate the effect of activity-reducing ITPA variants as well as IL28B polymorphism on anemia, platelet (PLT) counts, and virologic response in HCV genotype1a-infected patients treated with the direct-acting antiviral (DAA) regimen of ombitasvir/paritaprevir/ritonavir and dasabuvir±RBV. RESULTS Reduction in ITPase activity and homozygosity for the IL28Brs12979860 CC genotype protected against RBV-induced anemia. In patients receiving RBV, reduced ITPase activity was associated with reduced plasma RBV concentration and higher PLT counts. ITPase activity had no impact on response to DAA treatment, viral kinetics, or baseline IP-10 levels. CONCLUSIONS Our study demonstrates that genetics of ITPA and IL28B may help identify patients protected from RBV-induced anemia when treated with IFN-free regimens. Our work demonstrates for the first time that IL28B genetics may also have an impact on RBV-induced anemia. This may be of particular significance in patients with difficult-to-cure HCV infections, such as patients with decompensated cirrhosis where RBV-containing regimens likely will continue to be recommended.
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Affiliation(s)
| | - Justin W. Davis
- AbbVie Inc., North Chicago, Illinois, United States of America
| | - Manal Abunimeh
- AbbVie Inc., North Chicago, Illinois, United States of America
| | - Jonas Söderholm
- AbbVie Inc., North Chicago, Illinois, United States of America
| | - Jiuhong Zha
- AbbVie Inc., North Chicago, Illinois, United States of America
| | - Emily O. Dumas
- AbbVie Inc., North Chicago, Illinois, United States of America
| | - Daniel E. Cohen
- AbbVie Inc., North Chicago, Illinois, United States of America
| | | | - Martin Lagging
- Department of Infectious Diseases/Virology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Göteborg, Sweden
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Chachá SGF, Rodrigues JPV, Araújo RC, Pereira LRL, Villanova MG, Souza FF, Santana RDC, Martinelli ADLC. First-wave protease inhibitors for hepatitis C genotype 1 treatment: a real-life experience in Brazilian patients. Rev Soc Bras Med Trop 2018; 51:146-154. [PMID: 29768546 DOI: 10.1590/0037-8682-0153-2017] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2017] [Accepted: 03/28/2018] [Indexed: 02/07/2023] Open
Abstract
INTRODUCTION Licensed for chronic hepatitis C treatment in 2011, the protease inhibitors (PIs) telaprevir (TVR) and boceprevir (BOC), which have high sustained viral responses (SVR), ushered a new era characterized by the development of direct-action drugs against the hepatitis C virus (HCV). The aim of this study was to analyze the effectiveness and safety of BOC and TVR administered with pegylated interferon and ribavirin and to share the experience of a Brazilian reference center. METHODS A retrospective descriptive study was conducted in patients with HCV genotype 1 infection who started treatment between July 2013 and December 2015. Data were collected using a computerized system. RESULTS A total of 115 subjects were included, of which 58 (50.4 %) had liver cirrhosis and 103 (89.6 %) used TVR. The overall SVR rate was 61.7 % (62.1 % for TVR and 58.3 % for BOC). The presence of cirrhosis was associated with a lower SVR rate, whereas patients who relapsed after prior therapy had a greater chance of showing SVR than did non-responders. The incidence of adverse drug reactions (ADRs) was high. Almost all patients (~100 %) presented with hematologic events. Furthermore, treatment had to be discontinued in 15 subjects (13 %) due to severe ADRs. CONCLUSIONS In conclusion, the SVR rates in our study were lower than those reported in pre-marketing studies but were comparable to real-life data. ADRs, particularly hematological ADRs, were more common compared to those in previous studies and resulted in a high rate of treatment discontinuity.
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Affiliation(s)
- Silvana Gama Florencio Chachá
- Departamento de Medicina, Universidade Federal de São Carlos, São Carlos, SP, Brasil.,Divisão de Gastroenterologia, Departamento de Clínica Médica, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brasil
| | - João Paulo Vilela Rodrigues
- Centro de Pesquisa em Assistência Farmacêutica e Farmácia Clínica, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brasil
| | - Roberta Chaves Araújo
- Divisão de Gastroenterologia, Departamento de Clínica Médica, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brasil
| | - Leonardo Régis Leira Pereira
- Centro de Pesquisa em Assistência Farmacêutica e Farmácia Clínica, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brasil
| | - Márcia Guimarães Villanova
- Divisão de Gastroenterologia, Departamento de Clínica Médica, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brasil
| | - Fernanda Fernandes Souza
- Divisão de Gastroenterologia, Departamento de Clínica Médica, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brasil
| | - Rodrigo de Carvalho Santana
- Divisão de Moléstias Infecciosas, Departamento de Clínica Médica, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brasil
| | - Ana de Lourdes Candolo Martinelli
- Divisão de Gastroenterologia, Departamento de Clínica Médica, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brasil
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Hartati S, Aoki C, Hanafi M, Angelina M, Soedarmono P, Hotta H. Antiviral effect of <em>Archidendron pauciflorum</em> leaves extract to hepatitis C virus: An <em>in vitro</em> study in JFH-1 strain. MEDICAL JOURNAL OF INDONESIA 2018. [DOI: 10.13181/mji.v27i1.2189] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/16/2022] Open
Abstract
Background: Hepatitis C virus (HCV) is a leading cause of chronic liver diseases. Drug resistance to the regimen is also increasing. Hence, there is a need for new anti-HCV agents that are less toxic and more efficacious. The aim of this study is to evaluate the possibility of A. pauciflorum extracts can be a antiviral drug.Methods: Huh-7it cells were infected with the HCV genotype 2a strain JFH-I in the presence of methanol extracts of Archidenron pauciflorum. The methanol extract further partition used n-hexane, ethyl acetate, n-butanol, and water showed in which butanol extracts exerted the strongest IC50 (6.3 g/ml). Further, the butanol fraction was fractionated and yielded into 13 fractions.Results: The methanol extract of the leaves of A. pauciflorum exhibited concentration dependent inhibition against the JFH1 strain of HCV genotype 2a with an IC50 is 72.5 μg/ml. The butanol fraction exhibited the highest anti-HCV activity with an IC50 is 6.3 μg/ml. The butanol fraction was fractionated which yielded 13 fractions. Fractions 5 and 13 exhibited high anti-HCV activities with IC50 is 5.0 μg/ml and 8.5 μg/ml and a time-of-addition study demonstrated that fraction 5 inhibited viral infection at the post-entry step, whereas fraction 13 primarily inhibited the viral entry step.Conclusion: The extract A. pauciflorum can be used as a herbal-based antiviral drug.
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Kumar A, Rajput MK, Paliwal D, Yadav A, Chhabra R, Singh S. Genotyping & diagnostic methods for hepatitis C virus: A need of low-resource countries. Indian J Med Res 2018; 147:445-455. [PMID: 30082568 PMCID: PMC6094507 DOI: 10.4103/ijmr.ijmr_1850_16] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2016] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) infection is a blood borne and transfusion-transmitted infection (TTI). It has emerged as one of the major health challenges worldwide. In India, around 12-18 million peoples are infected with HCV, but in terms of prevalence percentage, its looks moderate due to large population. The burden of the HCV infection increases due to lack of foolproof screening of blood and blood products before transfusion. The qualified screening and quantification of HCV play an important role in diagnosis and treatment of HCV-related diseases. If identified early, HCV infection can be managed and treated by recently available antiviral therapies with fewer side effects. However, its identification at chronic phase makes its treatment very challenging and sometimes ineffective. The drugs therapy for HCV infection treatment is also dependent on its genotype. Different genotypes of HCV differ from each other at genomic level. The RNA viruses (such as HCV) are evolving perpetually due to interaction and integration among people from different regions and countries which lead to varying therapeutic response in HCV-infected patients in different geographical regions. Therefore, proper diagnosis for infecting virus and then exact determination of genotype become important for targeted treatment. This review summarizes the general information on HCV, and methods used for its diagnosis and genotyping.
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Affiliation(s)
- Anoop Kumar
- National Institute of Biologicals, Noida, India
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Imprialos KP, Stavropoulos K, Doumas M, Skalkou A, Zografou I, Athyros VG. The potential role of statins in treating liver disease. Expert Rev Gastroenterol Hepatol 2018; 12:331-339. [PMID: 29431526 DOI: 10.1080/17474124.2018.1439379] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Statins are commonly use for the management of dyslipidemia, worldwide. Various studies have demonstrated that statins offer significant reduction in the risk of cardiovascular morbidity and mortality. However, this class of drugs has been implicated in potential liver toxicity, thus has been considered as a 'forbidden-drug' in patients with increased liver enzymes. Areas covered: Studies have shown that statins might offer clinical benefits in the setting of viral hepatitis, progression of cirrhosis, and hepatocellular carcinoma. More importantly, this class of drugs was shown to ameliorate liver histological (in both imaging and biopsy studies) and functional alterations in patients with non-alcoholic fatty liver disease or non-alcoholic steatohepatitis. In addition, two large survival studies have demonstrated reduction in the risk for cardiovascular events with statin use in patients with elevated transaminase levels at baseline. Expert commentary: These benefits were of greater extent compared with patients with normal liver function tests at baseline. However, current international guidelines seem to neglect these findings and are not including statins in the management algorithm of patients with non-alcoholic fatty liver disease or steatohepatitis. Future randomized studies providing biopsy-proven benefits will establish the use of statins in the prevention of cardiovascular events and therapeutic algorithm of these patients.
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Affiliation(s)
- Konstantinos P Imprialos
- a Second Propedeutic Department of Internal Medicine , Aristotle University of Thessaloniki , Thessaloniki , Greece
| | - Konstantinos Stavropoulos
- a Second Propedeutic Department of Internal Medicine , Aristotle University of Thessaloniki , Thessaloniki , Greece
| | - Michael Doumas
- b Veterans Affairs Medical Center , George Washington University , Washington , DC , USA
| | - Anastasia Skalkou
- a Second Propedeutic Department of Internal Medicine , Aristotle University of Thessaloniki , Thessaloniki , Greece
| | - Ioanna Zografou
- a Second Propedeutic Department of Internal Medicine , Aristotle University of Thessaloniki , Thessaloniki , Greece
| | - Vasilios G Athyros
- a Second Propedeutic Department of Internal Medicine , Aristotle University of Thessaloniki , Thessaloniki , Greece
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Zaman B, Hassan W. Development of Stability Indicating HPLC–UV Method for Determination of Daclatasvir and Characterization of Forced Degradation Products. Chromatographia 2018. [DOI: 10.1007/s10337-018-3503-7] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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Gutwerk A, Wex T, Stein K, Langner C, Canbay A, Malfertheiner P, Link A. Helicobacter Pylori Serology in Relation to Hepatitis C Virus Infection and IL28B Single Nucleotide Polymorphism. J Clin Med 2018; 7:44. [PMID: 29510558 PMCID: PMC5867570 DOI: 10.3390/jcm7030044] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2017] [Revised: 03/01/2018] [Accepted: 03/02/2018] [Indexed: 12/18/2022] Open
Abstract
The aim of the study was to evaluate the serological rate of Helicobacter pylori (H. pylori) infection in patients with chronic hepatitis C virus (HCV) infection and determine any correlations with liver damage and IL28B single-nucleotide polymorphism (SNP). One hundred eighty-nine patients with chronic HCV infection were included in the study, and H. pylori status was defined based on anti-H. pylori-IgG or anti-CagA-IgG antibodies using enzyme-linked immunosorbent assay (ELISA). Liver damage was assessed using histology or transient elastography. IL28B C/T polymorphism (rs12979860) was evaluated in circulating blood cells using a PCR-based restriction fragment length polymorphism assay. Overall H. pylori serology was positive in 38.1% of our HCV-infected subjects. Among those, the anti-CagA-IgG positivity rate was 43.1% and was within the range of previously described populations of the same region. Highest prevalence of H. pylori was found in patients between 31 and 40 years compared to other age subgroups. The seropositivity rate was higher in the non-cirrhotic group than the cirrhotic one (45.4% vs. 20.0%, p < 0.05). No difference was found in IL28B genotype between H. pylori-positive and -negative cohorts. However, we observed a trend for the lower anti-CagA-IgG expression level in relation to the IL28B T-allele. Our results do not support an association between HCV and H. pylori infection. Whether IL28B SNP has a functional role in modulation of serological response to H. pylori CagA needs further investigation.
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Affiliation(s)
- Alexander Gutwerk
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Magdeburg, Leipziger Str. 44, 39120 Magdeburg, Germany.
| | - Thomas Wex
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Magdeburg, Leipziger Str. 44, 39120 Magdeburg, Germany.
- Medical Laboratories for Clinical Chemistry, Microbiology and Infectious Diseases, Department of Molecular Genetics, 39124 Magdeburg, Germany.
| | - Kerstin Stein
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Magdeburg, Leipziger Str. 44, 39120 Magdeburg, Germany.
| | - Cosima Langner
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Magdeburg, Leipziger Str. 44, 39120 Magdeburg, Germany.
| | - Ali Canbay
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Magdeburg, Leipziger Str. 44, 39120 Magdeburg, Germany.
| | - Peter Malfertheiner
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Magdeburg, Leipziger Str. 44, 39120 Magdeburg, Germany.
| | - Alexander Link
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Magdeburg, Leipziger Str. 44, 39120 Magdeburg, Germany.
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Shear-wave elastography for the assessment of liver fibrosis in liver transplant recipients treated for hepatitis C virus recurrence. Eur J Gastroenterol Hepatol 2018; 30:27-32. [PMID: 29049126 DOI: 10.1097/meg.0000000000001003] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
OBJECTIVES Direct-acting antiviral agents have revolutionized hepatitis C therapy, and are also found to be effective in the liver transplant setting. The extent of liver fibrosis influences patient management and is used to monitor therapeutic effects. Shear-wave elastography (SWE) is a relatively new imaging-based method that has not yet been studied extensively in liver transplant patients. Our aim was to study the effect of direct-acting antivirals in heaptitis C recurrence on liver stiffness determined by SWE. PATIENTS AND METHODS A total of 23 liver transplant patients with hepatitis C recurrence were enrolled in this prospective study. The patients underwent 24 weeks of ombitasvir/paritaprevir/ritonavir+dasabuvir±ribavirin combination therapy. Elastographic examinations, serological tests and laboratory tests were performed, and serum biomarkers of liver fibrosis were calculated the day before treatment (baseline) and at the end of the treatment. RESULTS All our patients became hepatitis C virus RNA negative by the end of the treatment. Median liver stiffness values decreased significantly after treatment compared with baseline (8.72±3.77 vs. 7.19±2.4 kPa; P<0.001). Among the studied laboratory values, a significant decrease was observed in the levels of alanine aminotransferase, aspartate aminotransferase and γ-glutamyltransferase, whereas international normalized ratio levels increased. Serum biomarkers, namely aspartate aminotransferase-to-platelet ratio index and Fibrosis-4, decreased significantly after treatment compared with baseline. CONCLUSION In the present study, SWE was succesfully used to monitor the beneficial therapeutic effects of direct-acting antivirals in hepatitis C recurrence following liver transplantation. We believe that SWE is a useful noninvasive diagnostic tool in the follow-up of hepatitis C treatment in liver transplant patients.
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Nolte FS. Molecular Microbiology. PRINCIPLES AND APPLICATIONS OF MOLECULAR DIAGNOSTICS 2018. [PMCID: PMC7150357 DOI: 10.1016/b978-0-12-816061-9.00005-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Background Nucleic acid (NA) amplification techniques are now commonly used to diagnose and manage patients with infectious diseases. The growth in the number of Food and Drug Administration–approved test kits and analyte-specific reagents has facilitated the use of this technology in clinical laboratories. Technological advances in NA amplification techniques, automation, NA sequencing, and multiplex analysis have reinvigorated the field and created new opportunities for growth. Simple, sample-in, answer-out molecular test systems are now widely available that can be deployed in a variety of laboratory and clinical settings. Molecular microbiology remains the leading area in molecular pathology in terms of both the numbers of tests performed and clinical relevance. NA-based tests have reduced the dependency of the clinical microbiology laboratory on more traditional antigen detection and culture methods and created new opportunities for the laboratory to impact patient care. Content This chapter reviews NA testing as it applies to specific pathogens or infectious disease syndromes, with a focus on those diseases for which NA testing is now considered the standard of care and highlights the unique challenges and opportunities that these tests present for clinical laboratories.
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