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Frericks N, Klöhn M, Lange F, Pottkämper L, Carpentier A, Steinmann E. Host-targeting antivirals for chronic viral infections of the liver. Antiviral Res 2025; 234:106062. [PMID: 39716667 DOI: 10.1016/j.antiviral.2024.106062] [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: 11/29/2024] [Revised: 12/18/2024] [Accepted: 12/19/2024] [Indexed: 12/25/2024]
Abstract
Infection with one or several of the five known hepatitis viruses is a leading cause of liver disease and poses a high risk of developing hepatocellular carcinoma upon chronic infection. Chronicity is primarily caused by hepatitis B virus (HBV) and hepatitis C virus (HCV) and poses a significant health burden worldwide. Co-infection of chronic HBV infected patients with hepatitis D virus (HDV) is less common but is marked as the most severe form of chronic viral hepatitis. Hepatitis A virus (HAV) and hepatitis E virus (HEV) primarily cause self-limiting acute hepatitis. However, studies have also reported chronic progression of HEV disease in immunocompromised patients. While considerable progress has been made in the treatment of HCV and HBV through the development of direct-acting antivirals (DAAs), challenges including drug resistance, incomplete viral suppression resulting in failure to achieve clearance and the lack of effective treatment options for HDV and HEV remain. Host-targeting antivirals (HTAs) have emerged as a promising alternative approach to DAAs and aim to disrupt virus-host interactions by modulating host cell pathways that are hijacked during the viral replication cycle. The aim of this review is to provide a comprehensive overview about the major milestones in research and development of HTAs for chronic HBV/HDV and HCV infections. It also summarizes the current state of knowledge on promising host-targeting therapeutic options against HEV infection.
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Affiliation(s)
- Nicola Frericks
- Department of Molecular and Medical Virology, Ruhr University Bochum, Bochum, Germany
| | - Mara Klöhn
- Department of Molecular and Medical Virology, Ruhr University Bochum, Bochum, Germany
| | - Frauke Lange
- Institute for Experimental Virology, TWINCORE Centre for Experimental and Clinical Infection Research, a joint venture between Hannover Medical School (MHH) and Helmholtz Centre for Infection Research (HZI), Hannover, Germany
| | - Lilli Pottkämper
- Department of Molecular and Medical Virology, Ruhr University Bochum, Bochum, Germany
| | - Arnaud Carpentier
- Institute for Experimental Virology, TWINCORE Centre for Experimental and Clinical Infection Research, a joint venture between Hannover Medical School (MHH) and Helmholtz Centre for Infection Research (HZI), Hannover, Germany
| | - Eike Steinmann
- Department of Molecular and Medical Virology, Ruhr University Bochum, Bochum, Germany; German Centre for Infection Research (DZIF), External Partner Site, Bochum, Germany.
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Xavier JB, Schmillevitch J, Emori C, Uehara S, Nunes EJ, Ferraz ML. EARLY NONINVASIVE EVALUATION OF LIVER FIBROSIS AFTER HEPATITIS C TREATMENT: THE IMPACT OF INFLAMMATION. ARQUIVOS DE GASTROENTEROLOGIA 2024; 61:e24043. [PMID: 39776122 DOI: 10.1590/s0004-2803.24612024-043] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/17/2024] [Accepted: 10/29/2024] [Indexed: 01/11/2025]
Abstract
BACKGROUND Liver biopsy (LB) is still the gold standard method for assessing hepatic fibrosis (HF), associated diseases, and liver inflammation. Nowadays, noninvasive techniques such as Acoustic radiation force impulse (ARFI) elastography have been introduced instead of liver biopsy. However, there are controversies about the time it should be performed after treatment for hepatitis C virus (HCV). OBJECTIVE To evaluate hepatic fibrosis using ARFI technology before and after successive treatments for chronic HCV. METHODS We prospectively included 50 adult patients with chronic HCV (genotype 1). Patients were first submitted to triple therapy with first-generation protease inhibitors (boceprevir and telaprevir) at the hepatitis division of the Gastroenterology Department of the Federal University of São Paulo. The non-responders underwent re-treatment with interferon-free direct-acting antiviral agents (DDAs - sofosbuvir associated with daclatasvir or simeprevir). Assessment of hepatic stiffness by ARFI was performed before and after the first treatment and before and after the re-treatment with DDAs. RESULTS ARFI values decreased significantly after treatments. In patients on first-generation protease inhibitor therapy and achieving sustained virological response (SVR), ARFI decreased from 2.41±0.58 pre-treatment to 2.02+/-0.58 (P<0.042) post-treatment. In patients who did not reach SVR, that is, non-responders, a significant reduction was similarly observed (2.39±0.63 to 2.03±0.54; P<0.001 before and after treatment, respectively). Before starting the re-treatment, non-responders had elevated ARFI values again, dropping after SVR following re-treatment (from 2.46±0.57 to 1.45±0.68, P<0.004). Laboratory parameters such as AST and ALT were directly correlated to ARFI elastography. CONCLUSION The evaluation of hepatic elastography by the ARFI method before and after (6 - 9 months) successive treatment of hepatitis C in responders and non-responders led to the conclusion that the reduction of elastography parameters seems to be related to a decrease in hepatic inflammation rather than a reduction in fibrosis per se.
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Affiliation(s)
| | - Joel Schmillevitch
- Faculdade de Ciências Médicas da Santa Casa de São Paulo, São Paulo, SP, Brasil
| | - Christini Emori
- Instituto de Infectologia Emílio Ribas, São Paulo, SP, Brasil
| | - Silvia Uehara
- Universidade Federal de Mato Grosso do Sul, Hospital Universitário Maria Aparecida Pedrossian, Campo Grande, MS, Brasil
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Mahmoud YH, Eysa B, Ahmed EMS, Abdelaziz H, Zayed AM, Baki AA, Hosny A, Hassany M. Effect of treatment of chronic hepatitis c virus patients with direct-acting anti-retroviral drugs on semen and hormonal parameters. Clin Exp Reprod Med 2024; 51:309-313. [PMID: 38853129 PMCID: PMC11617913 DOI: 10.5653/cerm.2023.06772] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2023] [Revised: 01/30/2024] [Accepted: 02/22/2024] [Indexed: 06/11/2024] Open
Abstract
OBJECTIVE Hepatitis C virus (HCV) infection is known to influence the seminal and hormonal parameters of infected men. This study was performed to assess the effects of HCV clearance using direct-acting antiviral (DAA) agents on semen and hormonal parameters. METHODS A total of 50 patients with chronic HCV were enrolled, and conventional semen analysis was performed according to World Health Organization guidelines. Basal levels of total testosterone, free testosterone (FT), follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2), prolactin, and sex hormone-binding globulin (SHBG) were assessed before and 3 months after treatment with DAAs. RESULTS Following DAA treatment, statistically significant increases were observed in sperm motility and the proportion of grade A sperm. Additionally, the percentage of abnormal forms was significantly decreased after treatment (p=0.000). However, no significant differences were observed in semen volume, concentration, or total sperm count. Sex hormone analysis of patients after DAA treatment revealed significant increases in FT, LH, and FSH levels, along with significant decreases in SHBG, prolactin, and E2 levels. CONCLUSION Following HCV clearance, we noted an improvement in sperm motility and an increase in the percentage of sperm with normal morphology. Treatment with DAAs was also associated with increased levels of FT and LH, along with decreased levels of SHBG, prolactin, and E2.
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Affiliation(s)
- Yosra H. Mahmoud
- Department of Clinical Pathology, Gastrointerology and Infectious Diseases, National Hepatology and Tropical Medicine Research Institute, Cairo, Egypt
| | - Basem Eysa
- Department of Hepatology, Gastrointerology and Infectious Diseases, National Hepatology and Tropical Medicine Research Institute, Cairo, Egypt
| | - Eman Mohamed Salah Ahmed
- Department of Dermatology, Andrology, Sexual Medicine and STDS, Faculty of Medicine, Helwan University, Helwan, Egypt
| | - Heba Abdelaziz
- Public Health Department, National Hepatology and Tropical Medicine Research Institute, Cairo, Egypt
| | - Ashgan Mohamed Zayed
- Department of Medical Microbiology, Faculty of Medicine, Port-Said University, Port Said, Egypt
| | - Amin Abdel Baki
- Department of Hepatology, Gastrointerology and Infectious Diseases, National Hepatology and Tropical Medicine Research Institute, Cairo, Egypt
| | - Ahmed Hosny
- Department of Dermatology, Andrology, Sexual Medicine and STDS, Faculty of Medicine, Helwan University, Helwan, Egypt
| | - Mohamed Hassany
- Tropical Medicine Department, National Hepatology and Tropical Medicine Research Institute, Cairo, Egypt
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Sinclair S, Shearen S, Ghobrial Y, Trad G, Abdul Basit S, Shih D, Ryan JK. Review of the Effects of Antiviral Therapy on Hepatitis B/C-Related Mortality and the Regression of Fibrosis. Viruses 2024; 16:1531. [PMID: 39459866 PMCID: PMC11512229 DOI: 10.3390/v16101531] [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: 08/16/2024] [Revised: 09/19/2024] [Accepted: 09/23/2024] [Indexed: 10/28/2024] Open
Abstract
Hepatitis B and Hepatitis C are viral causes of Hepatitis that lead to significant worldwide mortality and morbidity through the sequelae of fibrosis and hepatocellular carcinoma. In this review, we have summarized recent studies that have examined the effects of antiviral therapy on the regression of fibrosis and the reduction in mortalities associated with the viruses. Antiviral therapy significantly decreases mortality and induces the regression of fibrosis.
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Affiliation(s)
| | | | | | | | | | | | - John K. Ryan
- Comprehensive Digestive Institute of Nevada, Las Vegas, NV 89148, USA (S.A.B.); (D.S.)
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Ali RA, Awadalla EA, Amin YA, Fouad SS, Ahmed MAEB, Hassan MH, Abdel-Kahaar E, Abdel-Aziz RH. The deleterious effects of sofosbuvir and ribavirin (antiviral drugs against hepatitis C virus) on different body systems in male albino rats regarding reproductive, hematological, biochemical, hepatic, and renal profiles and histopathological changes. Sci Rep 2024; 14:5682. [PMID: 38453980 PMCID: PMC10920821 DOI: 10.1038/s41598-024-55950-5] [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: 10/18/2023] [Accepted: 02/29/2024] [Indexed: 03/09/2024] Open
Abstract
Sofosbuvir is one of the crucial drugs used in the treatment of chronic hepatitis C virus (HCV) in adults and children with compensated liver disease, including cirrhosis. It may be used alone or with other drugs. Ribavirin is an antiviral medication used to treat HCV infection. It is not effective when used alone and must be used in combination with other medications, such as sofosbuvir. This study pertains to a comprehensive assessment of the deleterious effects of sofosbuvir (an antiviral drug against chronic HCV) or sofosbuvir combined with ribavirin (an antiviral drug against RNA and DNA viruses) on several biological activities of the body, including hematological, hormonal, biochemical, histological, and immunohistochemical examinations during a long-standing period on male healthy rats. In addition, fertility assessments were performed, including sperm collections and semen parameter investigations. This study was conducted on 21 male rats divided into three equal groups. Group I (control group) received distilled water; group II (sofosbuvir group) received sofosbuvir (4 mg/kg); and group III (sofosbuvir + ribavirin) received sofosbuvir (4 mg/kg) plus ribavirin (30 ml/kg). All groups received the specific drug for six months. Blood and tissue samples were collected for hematological, hormonal, biochemical, histological, and immunohistochemical examinations. In addition, sperm collection and assessments of semen parameters were performed. Results revealed that sofosbuvir causes a highly significant decrease in the mean of most hematological, immunological, hormonal, and biochemical parameters, except for a few numbers of parameters such as neutrophils, monocytes, basophils, cortisol, GOT, and lipase, which exhibit a significant increase. The same occurred in the sofosbuvir + ribavirin group, but at much higher levels, as most hematological, immunological, hormonal, and biochemical parameters exhibit a highly significant decrease except for monocytes, triglyceride, and lipase, which exhibit a significant increase. When compared to the sofosbuvir group alone, the sofosbuvir + ribavirin group demonstrated a highly significant decline in the mean of most hematological, immunological, hormonal, and biochemical parameters except lymphocytes and triglycerides, which exhibit a substantial increase. For the reproductive parameters, both groups exhibit a significant decrease in the total sperm motility percentage. Finally, it can be concluded that sofosbuvir causes acute pancreatitis and combined immunodeficiency. Ribavirin is associated with hormonal deficiency, which indicates the occurrence of hypopituitarism. Moreover, sofosbuvir and ribavirin synergistically affect myelosuppression and cause iron-deficiency anemia. However, sofosbuvir, or its combination with ribavirin, is associated with a reduced risk of hepatocellular carcinoma. Besides, adding ribavirin to be combined with sofosbuvir improved the immunodeficiency caused by sofosbuvir; this confirms that using ribavirin with sofosbuvir reduces the side effects of both alone.
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Affiliation(s)
- Rana A Ali
- Zoology Department, Faculty of Science, South Valley University, Qena, Egypt
| | | | - Yahia A Amin
- Department of Theriogenology, Faculty of Veterinary Medicine, Aswan University, Aswan, Egypt.
| | - Samer S Fouad
- Qena University Hospital, South Valley University, Qena, Egypt
| | | | - Mohammed H Hassan
- Department of Medical Biochemistry, Faculty of Medicine, South Valley University, Qena, Egypt
| | - Emaad Abdel-Kahaar
- Department of Medical Pharmacology, Faculty of Medicine, South Valley University, Qena, Egypt
- Institute of Clinical Pharmacology, Medical Faculty Mannheim, Ruprecht-Karls-University, Heidelberg, Germany
| | - Rehab H Abdel-Aziz
- Department of Medical Physiology, Faculty of Medicine, South Valley University, Qena, Egypt
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Samuel S, Abulawi A, Malik R. Hepatitis C and Nonalcoholic Steatohepatitis in the 21st Century: Impact on Liver Disease and Liver Transplantation. GASTROENTEROLOGY INSIGHTS 2023; 14:249-270. [DOI: 10.3390/gastroent14030018] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/03/2025] Open
Abstract
Hepatitis C infection is a leading etiology of hepatic dysfunction and a major indication for liver transplantation due to the development of fibrosis, cirrhosis, and hepatocellular carcinoma. Nonalcoholic fatty liver disease (NAFLD) and, specifically, its subtype nonalcoholic steatohepatitis (NASH) is a rising cause of liver disease. It is predicted to surpass hepatitis C as a leading indication for transplant. The introduction of direct-acting antivirals (DAAs) decreased the prevalence of chronic hepatitis C infections, but the obesity epidemic and metabolic syndrome have increased the prevalence of NASH. Weight loss and dietary modifications are recommended NASH therapies, but unlike for hepatitis C, federally approved agents are lacking and currently under investigation. Clinical trials face many barriers in NASH treatment because of the difficulty of diagnosis and a lack of standardized and accurate clinical and histologic responses. Mortality and morbidity in NASH are heightened because of the presence of multiple comorbidities including cardiovascular disease, diabetes, and renal dysfunction. A liver transplant may be indicated, but a thorough screening of candidates, including a comprehensive cardiovascular assessment, is essential to ensuring successful outcomes pre- and post-transplant. Therapeutic agents for NASH are warranted before it becomes a significant and leading cause of morbidity and mortality worldwide.
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Affiliation(s)
- Sonia Samuel
- Division of Gastroenterology & Hepatology, Albany Medical Center, 47 New Scotland Ave, Albany, NY 12208, USA
| | - Ahmad Abulawi
- Division of Gastroenterology & Hepatology, Albany Medical Center, 47 New Scotland Ave, Albany, NY 12208, USA
| | - Raza Malik
- Division of Gastroenterology & Hepatology, Albany Medical Center, 47 New Scotland Ave, Albany, NY 12208, USA
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Brzdęk M, Zarębska-Michaluk D, Invernizzi F, Cilla M, Dobrowolska K, Flisiak R. Decade of optimizing therapy with direct-acting antiviral drugs and the changing profile of patients with chronic hepatitis C. World J Gastroenterol 2023; 29:949-966. [PMID: 36844142 PMCID: PMC9950869 DOI: 10.3748/wjg.v29.i6.949] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Revised: 11/22/2022] [Accepted: 01/09/2023] [Indexed: 02/10/2023] Open
Abstract
Chronic infection with the hepatitis C virus (HCV) remains a major health problem affecting approximately 58 million people worldwide. In the era of interferon (IFN)-based regimens, patients particularly infected with genotypes 1 and 4 achieved a low response rate. The implementation of direct-acting antivirals changed the landscape of HCV treatment. The increase in effectiveness provided us with the hope of eliminating HCV as a significant public threat by 2030. In the following years, there was an observed improvement in the treatment of HCV with genotype-specific regimens and highly effective pangenotypic options that are the most recent stage of the revolution. The optimization of therapy was accompanied by changes in the patient profile from the beginning of the IFN-free era over time. Patients treated with antiviral therapies were younger in successive periods, less burdened with comorbidities and comedications, more frequently treatment-naïve and had less advanced liver disease. Before the IFN-free era, specific subpopulations such as patients with HCV/HIV coinfection, those with a history of previous treatment, patients with renal impairment or with cirrhosis had lower chances for a virologic response. Currently, these populations should no longer be considered difficult to treat. Despite the high effectiveness of HCV therapy, there is a small percentage of patients with treatment failure. However, they can be effectively retreated with pangenotypic rescue regimens.
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Affiliation(s)
- Michał Brzdęk
- Collegium Medicum, Jan Kochanowski University, Kielce 25-516, Poland
| | | | - Federica Invernizzi
- Center for Liver Disease, Division of Internal Medicine and Hepatology, IRCCS Ospedale San Raffaele, Milan 20-132, Italy
| | - Marta Cilla
- Center for Liver Disease, Division of Internal Medicine and Hepatology, IRCCS Ospedale San Raffaele, Milan 20-132, Italy
| | | | - Robert Flisiak
- Department of Infectious Diseases and Hepatology, Medical University of Białystok, Białystok 15-540, Poland
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Abstract
Covalent drugs have been used to treat diseases for more than a century, but tools that facilitate the rational design of covalent drugs have emerged more recently. The purposeful addition of reactive functional groups to existing ligands can enable potent and selective inhibition of target proteins, as demonstrated by the covalent epidermal growth factor receptor (EGFR) and Bruton's tyrosine kinase (BTK) inhibitors used to treat various cancers. Moreover, the identification of covalent ligands through 'electrophile-first' approaches has also led to the discovery of covalent drugs, such as covalent inhibitors for KRAS(G12C) and SARS-CoV-2 main protease. In particular, the discovery of KRAS(G12C) inhibitors validates the use of covalent screening technologies, which have become more powerful and widespread over the past decade. Chemoproteomics platforms have emerged to complement covalent ligand screening and assist in ligand discovery, selectivity profiling and target identification. This Review showcases covalent drug discovery milestones with emphasis on the lessons learned from these programmes and how an evolving toolbox of covalent drug discovery techniques facilitates success in this field.
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Affiliation(s)
- Lydia Boike
- Department of Chemistry, University of California, Berkeley, Berkeley, CA, USA
- Novartis-Berkeley Center for Proteomics and Chemistry Technologies, Berkeley, CA, USA
- Innovative Genomics Institute, Berkeley, CA, USA
| | - Nathaniel J Henning
- Department of Chemistry, University of California, Berkeley, Berkeley, CA, USA
- Novartis-Berkeley Center for Proteomics and Chemistry Technologies, Berkeley, CA, USA
- Innovative Genomics Institute, Berkeley, CA, USA
| | - Daniel K Nomura
- Department of Chemistry, University of California, Berkeley, Berkeley, CA, USA.
- Novartis-Berkeley Center for Proteomics and Chemistry Technologies, Berkeley, CA, USA.
- Innovative Genomics Institute, Berkeley, CA, USA.
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Zhang H, Zhang XQ, Huang LS, Fang X, Khan M, Xu Y, An J, Schooley RT, Huang Z. Synergistic inhibition of hepatitis C virus infection by a novel microtubule inhibitor in combination with daclatasvir. Biochem Biophys Rep 2022; 30:101283. [PMID: 35647321 PMCID: PMC9136107 DOI: 10.1016/j.bbrep.2022.101283] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2022] [Revised: 05/15/2022] [Accepted: 05/16/2022] [Indexed: 11/23/2022] Open
Abstract
Even though substantial progress has been made in the treatment of hepatitis C virus (HCV) infection, viral resistance and relapse still occur in some patients and additional therapeutic approaches may ultimately be needed should viral resistance become more prevalent. Microtubules play important roles in several HCV life cycle events, including cell attachment, entry, cellular transportation, morphogenesis and progeny secretion steps. Therefore, it was hypothesized that microtubular inhibition might be a novel approach for the treatment of HCV infection. Here, the inhibitory effects of our recently developed microtubule inhibitors were studied in the HCV replicon luciferase reporter system and the infectious system. In addition, the combination responses of microtubule inhibitors with daclatasvir, which is a clinically used HCV NS5A inhibitor, were also evaluated. Our results indicated that microtubule targeting had activity against HCV replication and showed synergistic effect with a current clinical drug.
Microtubule inhibition affects HCV replication. Compound 9f displays time and concentration dependent inhibitory activities against HCV production. Combination of compound 9f with Daclatasvir shows modest synergistic effects against HCV replication.
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Affiliation(s)
- Huijun Zhang
- Division of Infectious Diseases and Global Public Health, Department of Medicine, School of Medicine, University of California at San Diego, La Jolla, 92093, California, USA
- School of Life and Health Sciences, The Chinese University of Hong Kong, Shenzhen, 518172, China
- School of Life Sciences, Tsinghua University, Beijing, 100084, China
| | - Xing-Quan Zhang
- Division of Infectious Diseases and Global Public Health, Department of Medicine, School of Medicine, University of California at San Diego, La Jolla, 92093, California, USA
| | - Lina S. Huang
- Division of Infectious Diseases and Global Public Health, Department of Medicine, School of Medicine, University of California at San Diego, La Jolla, 92093, California, USA
| | - Xiong Fang
- School of Life Sciences, Tsinghua University, Beijing, 100084, China
| | - Mohsin Khan
- Division of Infectious Diseases and Global Public Health, Department of Medicine, School of Medicine, University of California at San Diego, La Jolla, 92093, California, USA
| | - Yan Xu
- School of Life and Health Sciences, The Chinese University of Hong Kong, Shenzhen, 518172, China
| | - Jing An
- Division of Infectious Diseases and Global Public Health, Department of Medicine, School of Medicine, University of California at San Diego, La Jolla, 92093, California, USA
- Corresponding author.
| | - Robert T. Schooley
- Division of Infectious Diseases and Global Public Health, Department of Medicine, School of Medicine, University of California at San Diego, La Jolla, 92093, California, USA
- Corresponding author.
| | - Ziwei Huang
- Division of Infectious Diseases and Global Public Health, Department of Medicine, School of Medicine, University of California at San Diego, La Jolla, 92093, California, USA
- Corresponding author.
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Direct-Acting Antiviral Agents for Hepatitis C Virus Infection-From Drug Discovery to Successful Implementation in Clinical Practice. Viruses 2022; 14:v14061325. [PMID: 35746796 PMCID: PMC9231290 DOI: 10.3390/v14061325] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2022] [Revised: 06/13/2022] [Accepted: 06/15/2022] [Indexed: 12/13/2022] Open
Abstract
Today, hepatitis C virus infection affects up to 1.5 million people per year and is responsible for 29 thousand deaths per year. In the 1970s, the clinical observation of unclear, transfusion-related cases of hepatitis ignited scientific curiosity, and after years of intensive, basic research, the hepatitis C virus was discovered and described as the causative agent for these cases of unclear hepatitis in 1989. Even before the description of the hepatitis C virus, clinicians had started treating infected individuals with interferon. However, intense side effects and limited antiviral efficacy have been major challenges, shaping the aim for the development of more suitable and specific treatments. Before direct-acting antiviral agents could be developed, a detailed understanding of viral properties was necessary. In the years after the discovery of the new virus, several research groups had been working on the hepatitis C virus biology and finally revealed the replication cycle. This knowledge was the basis for the later development of specific antiviral drugs referred to as direct-acting antiviral agents. In 2011, roughly 22 years after the discovery of the hepatitis C virus, the first two drugs became available and paved the way for a revolution in hepatitis C therapy. Today, the treatment of chronic hepatitis C virus infection does not rely on interferon anymore, and the treatment response rate is above 90% in most cases, including those with unsuccessful pretreatments. Regardless of the clinical and scientific success story, some challenges remain until the HCV elimination goals announced by the World Health Organization are met.
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Abstract
In the 1970s, an unknown virus was suspected for documented cases of transfusion-associated hepatitis, a phenomenon called non-A, non-B hepatitis. In 1989, the infectious transmissible agent was identified and named hepatitis C virus (HCV) and, soon enough, the first diagnostic HCV antibody test was developed, which led to a dramatic decrease in new infections. Today, HCV infection remains a global health burden and a major cause of liver cirrhosis, hepatocellular carcinoma and liver transplantation. However, tremendous advances have been made over the decades, and HCV became the first curable, chronic viral infection. The introduction of direct antiviral agents revolutionized antiviral treatment, leading to viral eradication in more than 98% of all patients infected with HCV. This Perspective discusses the history of HCV research, which reads like a role model for successful translational research: starting from a clinical observation, specific therapeutic agents were developed, which finally were implemented in national and global elimination programmes.
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Affiliation(s)
- Michael P. Manns
- grid.10423.340000 0000 9529 9877Hannover Medical School, Hannover, Germany
| | - Benjamin Maasoumy
- grid.10423.340000 0000 9529 9877Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
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Chemello L, Cavalletto L, Ferrari S, Monaco S. Impact of direct acting antivirals (DAA) on neurologic disorders in chronic hepatitis C. Minerva Gastroenterol (Torino) 2021; 67:234-243. [PMID: 34672486 DOI: 10.23736/s2724-5985.21.02865-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
INTRODUCTION Neurologic and neuropsychiatric manifestations sometimes provide the first evidence of an unknown HCV infection. These conditions develop with a variable ranging of morbidity, including: "brain fog," fatigue, subtle cognitive and attention impairment, but also with more severe complications or acute presentation, like encephalomyelitis, encephalopathy, stroke and peripheral nerves involvement. EVIDENCE ACQUISITION We performed a systematic literature search on PubMed, Cochrane Library and Web of Science databases for articles only in English language, that assessed the relationship between "DAA treatment and neurologic disorders" and after the attainment of SVR in full reports of cases that received the DAA schedule from January 2015 to December 2019. The following terms were used: "chronic Hepatitis C," "HCV," "DAA," "direct-acting antiviral," "SVR," "sustained virologic response," peripheral neuropathy" and "neurologic diseases or disorders." EVIDENCE SYNTHESIS HCV infection does not only involve the liver, causing cirrhosis and hepatocellular carcinoma (HCC), but also induces extrahepatic manifestations (EHM), mainly due to a complex immune disease, that damage small and medium vessels, called "mixed cryoglobulinemic vasculitis" (MCV). This kind of mechanism generates most of the HCV-induced neurological damages. Since 2015, the availability of direct-acting antiviral (DAA) oral molecules interfering with HCV replication has completely revolutionized therapeutic options and the target population, which now includes patients aged 12 to 80 years and with advanced liver disease. Relevant was the highlighted DAA effectiveness by achievement of a sustained virologic response (SVR) in about 95% of cases, showing a great tolerability. CONCLUSIONS This favorable effect has arisen in a wide category of patients infected by HCV, including subjects with cirrhosis and complications and/or with EHM, who showed a significant improvement of their symptoms and the disease regression. In this concise review, we examine the clinical outcomes after the introduction of the DAA for the treatment of chronic hepatitis C (CHC), focusing on the neurologic disorders and concluding that there is a strong amelioration of neurologic conditions in several cases, particularly, after attaining the viral eradication with a favorable course in most treated cases.
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Affiliation(s)
- Liliana Chemello
- Unit of Internal Medicine and Hepatology, Department of Medicine (DIMED), Clinica Medica 5, University Hospital of Padua, Padua, Italy -
| | - Luisa Cavalletto
- Unit of Internal Medicine and Hepatology, Department of Medicine (DIMED), Clinica Medica 5, University Hospital of Padua, Padua, Italy
| | - Sergio Ferrari
- Unit of Neurology, Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Verona, Italy
| | - Salvatore Monaco
- Unit of Neurology, Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Verona, Italy
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Ma H, Miller C, Wong N. Don't Let the Tornado Get You! The Effects of Agency Assignment and Self-Construal on Responses to Tornado Preparedness Messages. HEALTH COMMUNICATION 2021; 36:703-713. [PMID: 31931623 DOI: 10.1080/10410236.2020.1712038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/10/2023]
Abstract
This experiment explores the effects of agency assignment and self-construal on responses to tornado preparedness messages. Participants (N = 276) were randomly assigned to one of four conditions crossing agency assignment and self-construal. Results found threat agency associated with greater perceived susceptibility and tornado threat, whereas self-construal was primarily associated with perceived threat severity, such that those primed with interdependent self-construal showed marginally increased perceptions of tornado severity relative to those primed with independent self-construal. Self-construal did not appear to moderate the effects of agency assignment on attitudes or behavioral intentions. Results are discussed in light of potential psychological reactance, suggesting human agency assignment should be used cautiously, since it may pose an increased threat to perceived freedoms in certain instances. Moreover, combining human agency and independent self-construal may trigger negative cognitions directed toward the message and/or its source. It is concluded that cautious, strategic use of agency assignment can improve message acceptance and facilitate adaptive, preparedness actions.
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Affiliation(s)
- Haijing Ma
- Department of Communication, University of Oklahoma
| | | | - Norman Wong
- Department of Communication, University of Oklahoma
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14
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Kumar R, Kumar V, Lee KW. A computational drug repurposing approach in identifying the cephalosporin antibiotic and anti-hepatitis C drug derivatives for COVID-19 treatment. Comput Biol Med 2021; 130:104186. [PMID: 33360831 PMCID: PMC7748973 DOI: 10.1016/j.compbiomed.2020.104186] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Revised: 12/14/2020] [Accepted: 12/15/2020] [Indexed: 12/16/2022]
Abstract
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused over 1.4 million deaths worldwide. Repurposing existing drugs offers the fastest opportunity to identify new indications for existing drugs as a stable solution against coronavirus disease 2019 (COVID-19). The SARS-CoV-2 main protease (Mpro) is a critical target for designing potent antiviral agents against COVID-19. In this study, we identify potential inhibitors against COVID-19, using an amalgam of virtual screening, molecular dynamics (MD) simulations, and binding-free energy approaches from the Korea Chemical Bank drug repurposing (KCB-DR) database. The database screening of KCB-DR resulted in 149 binders. The dynamics of protein-drug complex formation for the seven top scoring drugs were investigated through MD simulations. Six drugs showed stable binding with active site of SARS-CoV-2 Mpro indicated by steady RMSD of protein backbone atoms and potential energy profiles. Furthermore, binding free energy calculations suggested the community-acquired bacterial pneumonia drug ceftaroline fosamil and the hepatitis C virus (HCV) protease inhibitor telaprevir are potent inhibitors against Mpro. Molecular dynamics and interaction analysis revealed that ceftaroline fosamil and telaprevir form hydrogen bonds with important active site residues such as Thr24, Thr25, His41, Thr45, Gly143, Ser144, Cys145, and Glu166 that is supported by crystallographic information of known inhibitors. Telaprevir has potential side effects, but its derivatives have good pharmacokinetic properties and are suggested to bind Mpro. We suggest the telaprevir derivatives and ceftaroline fosamil bind tightly with SARS-CoV-2 Mpro and should be validated through preclinical testing.
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Affiliation(s)
- Raj Kumar
- Department of Biotechnology and Bioinformatics, Jaypee University of Information Technology, Waknaghat, Solan, Himachal Pradesh, 173 234, India.
| | - Vikas Kumar
- Division of Life Science, Department of Bio & Medical Big Data (BK21 Four Program), Plant Molecular Biology and Biotechnology Research Center (PMBBRC), Research Institute of Natural Science (RINS), Gyeongsang National University (GNU), 501 Jinju-daero, Jinju, 52828, Republic of Korea
| | - Keun Woo Lee
- Division of Life Science, Department of Bio & Medical Big Data (BK21 Four Program), Plant Molecular Biology and Biotechnology Research Center (PMBBRC), Research Institute of Natural Science (RINS), Gyeongsang National University (GNU), 501 Jinju-daero, Jinju, 52828, Republic of Korea.
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15
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Falade-Nwulia O, Sulkowski MS. Hepatitis C Virus Treatment: Simplifying the Simple and Optimizing the Difficult. J Infect Dis 2020; 222:S745-S757. [PMID: 33245350 PMCID: PMC8171802 DOI: 10.1093/infdis/jiaa534] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
The availability of safe, efficacious, oral direct-acting antivirals (DAAs) have ushered in a new era of hepatitis C treatment with potential to eliminate hepatitis C as a public health threat. To achieve population-level effectiveness of these oral DAAs, hepatitis C treatment by a wide range of providers in different settings will be essential to increase the number of persons treated. We provide a clinical review of hepatitis C treatment with a focus on practical tools for management of hepatitis C in majority of currently infected individuals who can be easily cured and optimization of treatment for those in whom treatment may not be as simple.
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Affiliation(s)
| | - Mark S Sulkowski
- Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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16
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Li X, Han J, Lee HW, Yoon YS, Jin Y, Khadka DB, Yang S, Kim M, Cho WJ. SAR study of bisamides as cyclophilin a inhibitors for the development of host-targeting therapy for hepatitis C virus infection. Bioorg Med Chem 2020; 28:115679. [PMID: 32912430 DOI: 10.1016/j.bmc.2020.115679] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Revised: 07/23/2020] [Accepted: 07/26/2020] [Indexed: 12/12/2022]
Abstract
The therapy of chronic hepatitis C virus infections has significantly improved with the development of direct-acting antivirals (DAAs), which contain NS3/4A protease, NS5A, and NS5B polymerase inhibitors. However, mutations in specific residues in these viral target genes are associated with resistance to the DAAs. Especially inhibitors of NS3/4A protease and NS5A, such as grazoprevir and velpatasvir, have a low barrier to resistant mutations. As a result, the mutations influence the virological outcomes after DAA treatment. CypA inhibitors, as host-targeted agents, act on host factors to inhibit HCV replication, exhibiting a high resistance barrier and pan-genotype activities against HCV. Therefore, they can be developed into alternative, more effective anti-HCV agents. However, CypA inhibitors are natural products and analogs. Based on previous studies, bisamide derivatives were designed and synthesized to develop a novel class of CypA inhibitors. Bisamide derivative 7c is a promising compound with potent anti-HCV activity at subtoxic concentrations. Surface plasmon resonance experiments revealed that 7c directly binds to CypA. All these studies indicated that the derivative 7c is a potent CypA inhibitor, which can be used as a host-targeted agent in combination with other antiviral agents for anti-HCV treatment.
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Affiliation(s)
- Xiaoli Li
- College of Pharmacy, Chonnam National University, Gwangju 61186, Republic of Korea
| | - Jinhe Han
- College of Pharmacy, Chonnam National University, Gwangju 61186, Republic of Korea
| | - Hye Won Lee
- Infectious Disease Research Center, Korea Research Institute of Chemical Technology (KRICT), Daejeon 34114, Republic of Korea
| | - Yi-Seul Yoon
- Infectious Disease Research Center, Korea Research Institute of Chemical Technology (KRICT), Daejeon 34114, Republic of Korea
| | - Yifeng Jin
- College of Pharmacy, Chonnam National University, Gwangju 61186, Republic of Korea
| | - Daulat B Khadka
- College of Pharmacy, Chonnam National University, Gwangju 61186, Republic of Korea
| | - Suhui Yang
- College of Pharmacy, Chonnam National University, Gwangju 61186, Republic of Korea
| | - Meehyein Kim
- Infectious Disease Research Center, Korea Research Institute of Chemical Technology (KRICT), Daejeon 34114, Republic of Korea; Graduate School of New Drug Discovery and Development, Chungnam National University, Daejeon 34134, Republic of Korea.
| | - Won-Jea Cho
- College of Pharmacy, Chonnam National University, Gwangju 61186, Republic of Korea.
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17
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Sherif ZA, Nouraie M, Begum R, Afsari A, Shokrani B, Lee E, Laiyemo AO, Brim H, Ashktorab H. Factors influencing treatment outcome in hepatitis C virus minority patients at an inner-city hospital: A STROBE-complaint article. Medicine (Baltimore) 2020; 99:e19505. [PMID: 32243366 PMCID: PMC7220685 DOI: 10.1097/md.0000000000019505] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2019] [Revised: 01/10/2020] [Accepted: 02/11/2020] [Indexed: 12/20/2022] Open
Abstract
Chronic hepatitis C virus (HCV) infection disproportionately affects African-Americans (AAs) and is a major contributor to liver failure and mortality. Genetic factors may not be the only cause in outcome disparity. We retrospectively investigated whether genetic host factors, viral genotypes, and treatment compliance in AA patients impacted the efficacy and the sustained virological response (SVR) rate of the interferon (IFN)-based treatment regimen. The medical chart review included 76 African-American patients (age ranging from 26 to 76) with varying levels of hepatitis condition. Fifty-seven (75%) of them had a clinically verifiable HCV infection and were followed by a hepatologist for 2 years at Howard University Hospital in Washington, DC. Both comprehensive metabolic profile and complete blood count analyses were performed. Among the 57 patients whose viral and IL28B genotypes were determined, sixty-eight percent (68%) were infected with viral genotype 1 and 71% harbored the CT allele of the IL28B gene. Among the 12 patients who completed treatment with IFN-based dual or triple therapy, 58% had achieved SVR 12 weeks following completion of treatment; 33% had a partial response with under 6000 viral count after 16 weeks of treatment; and there was one patient with viral genotype 1a and CT allele who did not respond to the medications. The results of this study prove that the PEG IFN-based regimen was effective in treating HCV-infected AA patients despite the current availability of new direct-acting antivirals. The major obstacles contributing to a low reduction in HCV infection and outcome in the AA community were avoidance or lack of treatment or compliance; contraindications, medication side effects, non-adherence, and payer eligibility restrictions.
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Affiliation(s)
- Zaki A. Sherif
- Department of Biochemistry and Molecular Biology, College of Medicine, Howard University
| | | | - Rehana Begum
- Department of Medicine, Howard University Hospital
- Division of Gastroenterology, Howard University Hospital
| | - Ali Afsari
- Cancer Center, Howard University Hospital
- Department of Pathology, Howard University Hospital
| | | | - Edward Lee
- Department of Pathology, Howard University Hospital
- Department of Pathology, College of Medicine, Howard University, Washington, DC, USA
| | - Adeyinka O. Laiyemo
- Department of Medicine, Howard University Hospital
- Division of Gastroenterology, Howard University Hospital
| | - Hassan Brim
- Cancer Center, Howard University Hospital
- Department of Pathology, College of Medicine, Howard University, Washington, DC, USA
| | - Hassan Ashktorab
- Department of Medicine, Howard University Hospital
- Cancer Center, Howard University Hospital
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18
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Hu K, Zhu Z, Mathahs MM, Tran H, Bommer J, Testa CA, Schmidt WN. Metalloprotoporphyrin Inhibition of HCV NS3-4A Protease: Structure-Activity Relationships. DRUG DESIGN DEVELOPMENT AND THERAPY 2020; 14:757-771. [PMID: 32158194 PMCID: PMC7048954 DOI: 10.2147/dddt.s201089] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/10/2019] [Accepted: 11/07/2019] [Indexed: 12/14/2022]
Abstract
Background Antiviral actions of tetrapyrroles have been described in a number of systems. Our goal was to evaluate antagonism of the HCV NS3-4A protease by a variety of common porphyrins and characterize structure-activity relationships that may be useful for future drug design of HCV and related Flaviviruses. Methods Using fluorometric assays, common metalloprotoporphyrins (MPP) all inhibited NS3-4A protease with IC50 values in low micromolar ranges [CoPP (1.4 µM) < ZnPP = MnPP = SnPP < CuPP < FePP (6.5 µM) = protoporphyrin]. Results Lineweaver-Burk plots confirmed that MPP: NS3 inhibition was basically competitive. All tested MPPs inhibited HCV genotype 1A, 1B, 2A and 3A recombinant proteases with the same fidelity suggesting wide antagonistic capabilities. However, when the MPPs were tested in cellular incubations with HCV replicons only Zn, Fe and free-base protoporphyrin showed comparable EC50 and IC50 values suggesting that there may be critical differences in MPP uptake and intracellular availability. Meso, deutero, and isohematoporphyrin derivatives, with or without metal substitution, all showed less anti-protease and antiviral activities as compared to protoporphyrins, suggesting that the planar, vinyl side chains are important for protease active site binding. MPPs were also active against three common protease mutants (T54A, A156T, and V36M) with equivalent or better IC50 values as compared to wild type enzyme. Conclusion These findings document the versatility of MPPs as antiviral agents with an expanded sensitivity for HCV genotypes and resistance to some common viral mutations. The results also suggest that further study of MPP structure and function will be useful for the development of new antiviral agents.
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Affiliation(s)
- Katherine Hu
- Department of Internal Medicine and Research Service, Veterans Affairs Medical Center, Iowa City, IA 52246, USA.,Department of Internal Medicine of the Roy G. And Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
| | - Zhaowen Zhu
- Department of Internal Medicine and Research Service, Veterans Affairs Medical Center, Iowa City, IA 52246, USA.,Department of Internal Medicine of the Roy G. And Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
| | - Meleah M Mathahs
- Department of Internal Medicine and Research Service, Veterans Affairs Medical Center, Iowa City, IA 52246, USA.,Department of Internal Medicine of the Roy G. And Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
| | - Huy Tran
- Department of Internal Medicine and Research Service, Veterans Affairs Medical Center, Iowa City, IA 52246, USA.,Department of Internal Medicine of the Roy G. And Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
| | - Jerry Bommer
- Frontier Scientific, Logan, UT 84321, USA.,Echelon Biosciences Inc, Salt Lake City, UT 84108, USA
| | | | - Warren N Schmidt
- Department of Internal Medicine and Research Service, Veterans Affairs Medical Center, Iowa City, IA 52246, USA.,Department of Internal Medicine of the Roy G. And Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
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19
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Rodrigues JPV, Cazarim MDS, Chachá SGF, Martinelli ADLC, Pereira LRL. Cost-effectiveness analysis is a mandatory strategy for health systems: evidence from a study involving therapies for hepatitis C. CAD SAUDE PUBLICA 2020; 36:e00036619. [PMID: 32022174 DOI: 10.1590/0102-311x00036619] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2019] [Accepted: 08/02/2019] [Indexed: 11/22/2022] Open
Abstract
Cost-effectiveness analysis is essential in health decision making. Several countries use it as synthesis of evidence to incorporate health technologies. The protease inhibitors (PI) boceprevir (BOC) and telaprevir (TVR) are indicated for chronic hepatitis C treatment and were incorporated in guidelines worldwide. Pre-marketing clinical trials showed higher sustained virological response rates in relation to previous therapies, but the incorporation of PIs generated a significant financial impact. The aim of this study was to discuss the relevance of cost-effectiveness analysis through a study that involved the inclusion of PIs in a clinical protocol. The analysis was part of a real-life study that included patients infected with hepatitis C virus genotype 1 treated in a tertiary university hospital in Brazil. Triple therapies (TT) with ribavirin (RBV), peginterferon α-2a (Peg-INF α-2a) and BOC or TVR were compared to dual therapy with RBV and Peg-INF α-2a. Sensitivity analysis of the cost-effectiveness ratio indicated an 88.2% chance of TTs presenting a higher cost per cure. The incremental cost-effectiveness ratios (ICER) exceeded the Brazilian gross domestic product (GDP) per capita by three times in all proposed scenarios. The sensitivity of ICER showed an 88.4% chance of TT not being cost-effective. The impact of PI incorporation was negative and the conduct about this could have been different if a previous cost-effectiveness analysis had been conducted.
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Affiliation(s)
- João Paulo Vilela Rodrigues
- Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, Brasil.,Faculdade de Ciências Farmacêuticas, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brasil
| | - Maurílio de Souza Cazarim
- Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, Brasil
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20
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Costa VD, Delvaux N, Brandão-Mello CE, Nunes EP, de Sousa PSF, de Souza Rodrigues LLLX, Lampe E, do Amaral Mello FC. Prevalence of baseline NS3 resistance-associated substitutions (RASs) on treatment with protease inhibitors in patients infected with HCV genotype 1. Clin Res Hepatol Gastroenterol 2019; 43:700-706. [PMID: 30880098 DOI: 10.1016/j.clinre.2019.02.009] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2018] [Revised: 02/01/2019] [Accepted: 02/11/2019] [Indexed: 02/04/2023]
Abstract
BACKGROUND AND AIMS Treatment for hepatitis C has evolved significantly with the licensing of direct-acting antiviral drugs (DAAs). However, one of the limiting factors of the effectiveness of antiviral therapy with protease inhibitors (PIs) is the emergence of resistance caused by point mutations. The aim of this study was to determine the prevalence of resistance-associated substitutions (RASs) in HCV NS3 gene in patients infected with genotype 1 before therapy with simeprevir. METHODS A total of 73 serum samples from 15 treatment-experienced patients with boceprevir/telaprevir and 58 DAA-naïve patients were collected before therapy with DAAs simeprevir, daclatasvir and/or sofosbuvir. Presence of baseline resistance-associated substitutions (RAS) in the serine protease domain of HCV NS3 was analyzed by nucleotide sequencing followed by amino acid deduction. RESULTS Overall RAS prevalence in this study was 13.7% (10/73). RAS prevalence for HCV subtype 1b was 17.4% (4/23) while for HCV subtype 1a was 12% (6/50). Primary mutations V36M/L and R155K were observed only in HCV subtype 1a, whereas T54S and Q80K were identified only in HCV subtype 1b. RAS V36M, which is related to reduction of susceptibility to second-generation PIs, was the most frequent in the study (6.9%; 5/73). CONCLUSIONS Our results indicated that Brazilian isolates of HCV present a distinct pattern of RAS depending on the infecting viral subtype. In contrast to data from other countries, RAS Q80K prevalence in Brazil is low in HCV subtype 1a. This study improves the knowledge of genetic barrier for resistance to PIs involving RASs in chronically infected patients and its possible impact on an unsuccessful treatment outcome, information that might be crucial to upcoming decisions of incorporation of new DAAs in Brazilian guidelines of antiviral therapy against HCV infection.
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Affiliation(s)
- Vanessa Duarte Costa
- Laboratório de Hepatites Virais, Instituto Oswaldo Cruz, FIOCRUZ, avenida Brasil, 4365 - Manguinhos, 21040-900, Rio de Janeiro, RJ, Brazil.
| | - Nathália Delvaux
- Laboratório de Hepatites Virais, Instituto Oswaldo Cruz, FIOCRUZ, avenida Brasil, 4365 - Manguinhos, 21040-900, Rio de Janeiro, RJ, Brazil
| | - Carlos Eduardo Brandão-Mello
- Hospital Universitário Gaffrée & Guinle, UNIRIO, R. Mariz e Barros, 775 - Maracanã, 20270-001, Rio de Janeiro, RJ, Brazil
| | - Estevão Portela Nunes
- Instituto Nacional de Infectologia Evandro Chagas, INI/FIOCRUZ, avenida Brasil, 4365 - Manguinhos, 21040-360, Rio de Janeiro, RJ, Brazil
| | - Paulo Sérgio Fonseca de Sousa
- Laboratório de Hepatites Virais, Instituto Oswaldo Cruz, FIOCRUZ, avenida Brasil, 4365 - Manguinhos, 21040-900, Rio de Janeiro, RJ, Brazil
| | | | - Elisabeth Lampe
- Laboratório de Hepatites Virais, Instituto Oswaldo Cruz, FIOCRUZ, avenida Brasil, 4365 - Manguinhos, 21040-900, Rio de Janeiro, RJ, Brazil
| | - Francisco Campello do Amaral Mello
- Laboratório de Hepatites Virais, Instituto Oswaldo Cruz, FIOCRUZ, avenida Brasil, 4365 - Manguinhos, 21040-900, Rio de Janeiro, RJ, Brazil
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21
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Leahy J, Thom H, Jansen JP, Gray E, O'Leary A, White A, Walsh C. Incorporating single-arm evidence into a network meta-analysis using aggregate level matching: Assessing the impact. Stat Med 2019; 38:2505-2523. [PMID: 30895655 DOI: 10.1002/sim.8139] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2017] [Revised: 11/27/2018] [Accepted: 02/14/2019] [Indexed: 01/21/2023]
Abstract
Increasingly, single-armed evidence is included in health technology assessment submissions when companies are seeking reimbursement for new drugs. While it is recognized that randomized controlled trials provide a higher standard of evidence, these are not available for many new agents that have been granted licenses in recent years. Therefore, it is important to examine whether alternative strategies for assessing this evidence may be used. In this work, we examine approaches to incorporating single-armed evidence formally in the evaluation process. We consider matching aggregate level covariates to comparator arms or trials and including this evidence in a network meta-analysis. We consider two methods of matching: (i) we include the chosen matched arm in the data set itself as a comparator for the single-arm trial; (ii) we use the baseline odds of an event in a chosen matched trial to use as a plug-in estimator for the single-arm trial. We illustrate that the synthesis of evidence resulting from such a setup is sensitive to the between-study variability, formulation of the prior for the between-design effect, weight given to the single-arm evidence, and extent of the bias in single-armed evidence. We provide a flowchart for the process involved in such a synthesis and highlight additional sensitivity analyses that should be carried out. This work was motivated by a hepatitis C data set, where many agents have only been examined in single-arm studies. We present the results of our methods applied to this data set.
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Affiliation(s)
- Joy Leahy
- School of Computer Science and Statistics, Trinity College Dublin, The University of Dublin, Dublin, Ireland
- National Centre for Pharmacoeconomics, St. James's Hospital, Dublin, Ireland
| | - Howard Thom
- Bristol Medical School: Population Health Sciences, University of Bristol, Bristol, UK
| | - Jeroen P Jansen
- Department of Health Research and Policy Epidemiology, Stanford University School of Medicine, Stanford, California
| | - Emma Gray
- School of Medicine, Trinity College Dublin, The University of Dublin, Dublin, Ireland
| | - Aisling O'Leary
- National Centre for Pharmacoeconomics, St. James's Hospital, Dublin, Ireland
| | - Arthur White
- School of Computer Science and Statistics, Trinity College Dublin, The University of Dublin, Dublin, Ireland
- National Centre for Pharmacoeconomics, St. James's Hospital, Dublin, Ireland
| | - Cathal Walsh
- National Centre for Pharmacoeconomics, St. James's Hospital, Dublin, Ireland
- Department of Mathematics and Statistics, Health Research Institute and MACSI, University of Limerick, Limerick, Ireland
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22
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Caroleo B, Caroleo MC, Cimellaro A, Colangelo L, Perticone M, Di Mizio G, De Sarro G, Gallelli L. Glecaprevir/Pibrentasvir Induced Cholestatic Jaundice in a HCV Patient with Renal Failure. A Case Presentation. Curr Drug Saf 2019; 14:67-71. [PMID: 30444202 DOI: 10.2174/1574886313666181116100452] [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: 07/23/2018] [Revised: 10/25/2018] [Accepted: 11/12/2018] [Indexed: 12/26/2022]
Abstract
BACKGROUND Direct-acting Antivirals (DAA) are currently used in the treatment of chronic HCV infection. In patients with renal failure Glecaprevir/Pibrentasvir (genotype 1-6) is recommended for its safety and efficacy. CASE PRESENTATION Although these pharmacological characteristics, an adverse drug reaction (ADR) has been reported during Glecaprevir/Pibrentasvir treatment, such as the development of cholestatic jaundice in an elderly patient with chronic HCV (genotype 2) infection. At examination, patient was jaundiced associated with intense pruritus. RESULTS Ultrasound and laboratory biochemical tests excluded a liver failure (e.g. liver cancer, and liver lithiasis) or pancreatic cancer while Naranjo probability scale (score 6) suggested an association between cholestatic jaundice and Glecaprevir/Pibrentasvir administration. About 1 month after drug discontinuation, an improvement has been documented in both jaundice and pruritus, with a normalization in bilirubin levels (total bilirubin: 0.96 mg/dL), HCV-RNA was undetected also. It is worth mentioning that although we reported the development of cholestatic jaundice upon treatment with Glecaprevir/Pibrentasvir we recorded a clinical efficacy (HCV-RNA <15 IU/L) after 4 weeks from the beginning of the treatment, with a complete remission of clinical symptoms until 7 months after drug discontinuation. CONCLUSION These data support the clinical efficacy of Glecaprevir/Pibrentasvir association in elderly patients, despite the sub-optimal period of treatment.
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Affiliation(s)
- Benedetto Caroleo
- Department of Medical and Surgical Science, Elderly Operative Unit, Mater Domini Hospital, University of Catanzaro, Catanzaro, Italy
| | - Maria Cristina Caroleo
- Department of Pharmacy Health and Nutritional Sciences, University of Calabria, Rende (CS), Calabria, Italy
| | - Antonio Cimellaro
- Department of Medical and Surgical Science, Elderly Operative Unit, Mater Domini Hospital, University of Catanzaro, Catanzaro, Italy
| | - Lidia Colangelo
- Department of Medical and Surgical Science, Elderly Operative Unit, Mater Domini Hospital, University of Catanzaro, Catanzaro, Italy
| | - Maria Perticone
- Department of Medical and Surgical Science, Elderly Operative Unit, Mater Domini Hospital, University of Catanzaro, Catanzaro, Italy
| | - Giulio Di Mizio
- Department of Law and Economic Science, University Magna Graecia of Catanzaro, Catanzaro, Italy
| | - Giovambattista De Sarro
- Department of Health Sciences, Clinical Pharmacology and Pharmacovigilance Unit, Mater Domini Hospital, University of Catanzaro, Catanzaro, Italy
| | - Luca Gallelli
- Department of Health Sciences, Clinical Pharmacology and Pharmacovigilance Unit, Mater Domini Hospital, University of Catanzaro, Catanzaro, Italy
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23
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Casey JL, Feld JJ, MacParland SA. Restoration of HCV-Specific Immune Responses with Antiviral Therapy: A Case for DAA Treatment in Acute HCV Infection. Cells 2019; 8:cells8040317. [PMID: 30959825 PMCID: PMC6523849 DOI: 10.3390/cells8040317] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2019] [Revised: 03/26/2019] [Accepted: 03/30/2019] [Indexed: 12/11/2022] Open
Abstract
Worldwide, 71 million individuals are chronically infected with Hepatitis C Virus (HCV). Chronic HCV infection can lead to potentially fatal outcomes including liver cirrhosis and hepatocellular carcinoma. HCV-specific immune responses play a major role in viral control and may explain why approximately 20% of infections are spontaneously cleared before the establishment of chronicity. Chronic infection, associated with prolonged antigen exposure, leads to immune exhaustion of HCV-specific T cells. These exhausted T cells are unable to control the viral infection. Before the introduction of direct acting antivirals (DAAs), interferon (IFN)-based therapies demonstrated successful clearance of viral infection in approximately 50% of treated patients. New effective and well-tolerated DAAs lead to a sustained virological response (SVR) in more than 95% of patients regardless of viral genotype. Researchers have investigated whether treatment, and the subsequent elimination of HCV antigen, can reverse this HCV-induced exhausted phenotype. Here we review literature exploring the restoration of HCV-specific immune responses following antiviral therapy, both IFN and DAA-based regimens. IFN treatment during acute HCV infection results in greater immune restoration than IFN treatment of chronically infected patients. Immune restoration data following DAA treatment in chronically HCV infected patients shows varied results but suggests that DAA treatment may lead to partial restoration that could be improved with earlier administration. Future research should investigate immune restoration following DAA therapies administered during acute HCV infection.
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Affiliation(s)
- Julia L Casey
- Institute of Medical Science, University of Toronto, Toronto, ON M5S 1A8, Canada.
| | - Jordan J Feld
- Institute of Medical Science, University of Toronto, Toronto, ON M5S 1A8, Canada.
- Toronto General Hospital Research Institute, University Health Network, Toronto, ON M5G 2C4, Canada.
| | - Sonya A MacParland
- Toronto General Hospital Research Institute, University Health Network, Toronto, ON M5G 2C4, Canada.
- Departments of Laboratory Medicine & Pathobiology and Immunology, University of Toronto, Toronto, ON M5S 1A1, Canada.
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Gómez ME, Gentile EA, Martini MF, Cuestas ML, Mathet VL, Moltrasio GY, Moglioni AG. Synthesis of New Indanyl Nucleoside Analogues and their Biological Evaluation on Hepatitis C Virus (HCV) Replicon. Molecules 2019; 24:molecules24050990. [PMID: 30862130 PMCID: PMC6429379 DOI: 10.3390/molecules24050990] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2019] [Revised: 02/28/2019] [Accepted: 03/02/2019] [Indexed: 11/16/2022] Open
Abstract
Here, we report a convenient synthetic procedure for the preparation of four novel indanyl carbanucleoside derivatives in the racemic form. The action of these compounds against hepatitis C virus was evaluated in vitro using the replicon cell line, Huh7.5 SG. Contrary to our expectations, all these compounds did not inhibit, but rather promoted HCV genotype 1b (HCVg1b) replication. Similar effects have been reported for morphine in the replicon cell lines, Huh7 and Huh8. Several biological experiments and computational studies were performed to elucidate the effect of these compounds on HCVg1b replication. Based on all the experiments performed, we propose that the increase in HCVg1b replication could be mediated, at least in part, by a similar mechanism to that of morphine on the enhancement of this replication. The presence of opioid receptors in Huh7.5 SG cells was indirectly determined for the first time in this work.
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Affiliation(s)
- Matías E Gómez
- Cátedra de Química Medicinal, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Ciudad Autónoma de Buenos Aires C1113AAD, Argentina.
| | - Emiliano A Gentile
- Instituto de Investigaciones en Microbiología y Parasitología Médica, CONICET-Universidad de Buenos Aires, Ciudad Autónoma de Buenos Aires C1121ABF, Argentina.
| | - M Florencia Martini
- Cátedra de Química Medicinal, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Ciudad Autónoma de Buenos Aires C1113AAD, Argentina.
- Instituto de la Química y Metabolismo del Fármaco, CONICET-Universidad de Buenos Aires, Ciudad Autónoma de Buenos Aires C1113AAD, Argentina.
| | - María L Cuestas
- Instituto de Investigaciones en Microbiología y Parasitología Médica, CONICET-Universidad de Buenos Aires, Ciudad Autónoma de Buenos Aires C1121ABF, Argentina.
| | - Verónica L Mathet
- Instituto de Investigaciones en Microbiología y Parasitología Médica, CONICET-Universidad de Buenos Aires, Ciudad Autónoma de Buenos Aires C1121ABF, Argentina.
| | - Graciela Y Moltrasio
- Cátedra de Química Orgánica II, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Ciudad Autónoma de Buenos Aires C1113AAD, Argentina.
| | - Albertina G Moglioni
- Cátedra de Química Medicinal, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Ciudad Autónoma de Buenos Aires C1113AAD, Argentina.
- Instituto de la Química y Metabolismo del Fármaco, CONICET-Universidad de Buenos Aires, Ciudad Autónoma de Buenos Aires C1113AAD, Argentina.
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25
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Rasche A, Sander AL, Corman VM, Drexler JF. Evolutionary biology of human hepatitis viruses. J Hepatol 2019; 70:501-520. [PMID: 30472320 PMCID: PMC7114834 DOI: 10.1016/j.jhep.2018.11.010] [Citation(s) in RCA: 50] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2018] [Revised: 11/09/2018] [Accepted: 11/10/2018] [Indexed: 02/06/2023]
Abstract
Hepatitis viruses are major threats to human health. During the last decade, highly diverse viruses related to human hepatitis viruses were found in animals other than primates. Herein, we describe both surprising conservation and striking differences of the unique biological properties and infection patterns of human hepatitis viruses and their animal homologues, including transmission routes, liver tropism, oncogenesis, chronicity, pathogenesis and envelopment. We discuss the potential for translation of newly discovered hepatitis viruses into preclinical animal models for drug testing, studies on pathogenesis and vaccine development. Finally, we re-evaluate the evolutionary origins of human hepatitis viruses and discuss the past and present zoonotic potential of their animal homologues.
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Affiliation(s)
- Andrea Rasche
- Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute of Virology, 10117 Berlin, Germany,German Center for Infection Research (DZIF), Germany
| | - Anna-Lena Sander
- Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute of Virology, 10117 Berlin, Germany
| | - Victor Max Corman
- Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute of Virology, 10117 Berlin, Germany,German Center for Infection Research (DZIF), Germany
| | - Jan Felix Drexler
- Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute of Virology, 10117 Berlin, Germany; German Center for Infection Research (DZIF), Germany.
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26
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Tolentino B, Singh RR, Misra S, Dieterich DT, Sarpel D. An update on the management of hepatitis C virus and human immunodeficiency virus co-infection. Future Virol 2019. [DOI: 10.2217/fvl-2018-0116] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
An estimated 2.3 million people globally are co-infected with HIV and HCV. Liver disease is now a leading cause of non-AIDS-related mortality among HIV-infected patients. The development of direct-acting antiviral agents has revolutionized the treatment of HIV/HCV co-infection with sustained virologic response response rates above 95% in most patient populations. This article provides an update on the management of acute and chronic HCV in patients co-infected with HIV including a section on drug–drug interactions.
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Affiliation(s)
- Bryan Tolentino
- Department of Medicine, Division of Infectious Disease, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Ritu R Singh
- Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Suresh Misra
- Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Douglas T Dieterich
- Department of Medicine, Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Dost Sarpel
- Department of Medicine, Division of Infectious Disease, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
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27
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Jain MK, Thamer M, Therapondos G, Shiffman ML, Kshirsagar O, Clark C, Wong RJ. Has Access to Hepatitis C Virus Therapy Changed for Patients With Mental Health or Substance Use Disorders in the Direct-Acting-Antiviral Period? Hepatology 2019; 69:51-63. [PMID: 30019478 DOI: 10.1002/hep.30171] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2017] [Accepted: 07/05/2018] [Indexed: 12/20/2022]
Abstract
Direct-acting antivirals (DAA) for hepatitis C virus (HCV) became available in 2014, but the role of mental health or substance use disorders (MH/SUD) on access to treatment is unknown. The objective of this study was to examine the extent and predictors of HCV treatment in the pre-DAA and post-DAA periods in four large, diverse health care settings in the United States. We conducted a retrospective analysis of 29,544 adults with chronic HCV who did or did not receive treatment from January 1, 2011, to February 28, 2017. Kaplan-Meier curve was used to examine cumulative risk for receiving HCV treatment stratified by MH/SUD. Predictors of HCV treatment in the pre-DAA (January 1, 2011, to December 31, 2013) and post-DAA (January 1, 2014, to February 28, 2017) cohorts were analyzed using multivariate generalized estimating equations and a modified Poisson model. Overall, 21.7% (2,879/13,240) of those with chronic HCV post-DAA were treated compared with 3.5% (574/16,304) in the pre-DAA period. Compared with non-Hispanic whites, Hispanic whites (adjusted odds ratio [AOR] 0.36; 95% confidence interval [CI], 0.25, 0.52) were less likely to be treated in the post-DAA period. Those with concurrent nonalcoholic fatty liver disease (AOR 1.39; 95% CI, 1.05, 1.83), cirrhosis (AOR 2.00; 95% CI, 1.74, 2.31), and liver transplant (AOR 2.72; 95% CI, 1.87, 3.94) were more likely to be treated post-DAA. Those with MH/SUD were less likely to be treated both before (AOR 0.46; 95% CI, 0.36, 0.60) and after (AOR 0.63; 95% CI, 0.55, 0.71) DAA therapy was available. Overall, the cumulative risk for receiving HCV treatment from 2011 to 2017 among those with versus without MH/SUD was 13.6% versus 21.6%, respectively (P < 0.001). Conclusion: The volume of patients treated for HCV has increased in the post-DAA period, especially among those with liver-related comorbidities, but disparities in access to treatment continue among those with MH/SUD.
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Affiliation(s)
- Mamta K Jain
- Division of Infectious Diseases, University of Texas Southwestern Medical Center, Dallas, TX.,Parkland Health and Hospital System, Dallas, TX
| | - Mae Thamer
- Medical Technology and Practice Patterns Institute, Bethesda, MD
| | - George Therapondos
- Multi-Organ Transplant Institute, Ochsner Health System, New Orleans, LA
| | | | - Onkar Kshirsagar
- Medical Technology and Practice Patterns Institute, Bethesda, MD
| | | | - Robert J Wong
- Division of Gastroenterology & Hepatology, Alameda Health System - Highland Hospital, Oakland, CA
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28
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Alqahtani SA, Sulkowski MS. The Role of Interferon for the Treatment of Chronic Hepatitis C Virus Infection. TOPICS IN MEDICINAL CHEMISTRY 2019:97-113. [DOI: 10.1007/7355_2018_59] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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29
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Detection of anti-protease inhibitors resistance mutations in HCV strains infecting treatment-naïve chronic patients from Romania. REV ROMANA MED LAB 2018. [DOI: 10.2478/rrlm-2018-0029] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
Abstract
Background: Severe complications of chronic hepatitis C – i.e. cirrhosis and hepatocellular carcinoma – are important causes of morbidity and mortality worldwide. Despite the overwhelming rates of sustained virologic response achieved after therapy with different combinations of direct-acting antiviral drugs (DAAs), treatment failure is still recorded, and is due to the mutations harboured by hepatitis C virus (HCV) resistance associated variants (RAVs) selected during therapy. Baseline RAVs testing was found significant for guiding treatment in the cases of treatment failure and, sometimes, in naïve patients.
Methods: Romanian chronic hepatitis C patients unexposed to DAAs and infected with subtype 1b HCV were studied. Serum samples were used for Sanger population sequencing of a fragment containing NS3 viral protease, known to harbour resistance mutation against protease inhibitors (PIs).
Results: Catalytic triad and zinc-binding site in the studied sequences were conserved. Low-intermediate resistance mutations to first generation PIs were detected either alone or in conjunction with resistance substitutions associated with second generation PIs. Cross-resistance and reduced susceptibility to certain DAAs were observed.
Discussion: This study focused on HCV patients infected with subtype 1b strains, the most prevalent in Romania. The rate of RAVs found in this work is consistent with the results reported by similar studies from other countries. Noticeably, numerous polymorphisms of unknown significance to DAAs resistance, but reflecting the high genetic variability of HCV, were found in the studied sequences. Testing for RAVs can be a useful method for guiding treatment in a cost-efficient manner in developing countries where access to DAAs is limited.
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30
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Tamborini Permunian E, Gervaso L, Gerdes V, Moja L, Guasti L, Squizzato A. Direct-acting antiviral drugs for chronic hepatitis C and risk of major vascular events: a systematic review. Intern Emerg Med 2018; 13:775-790. [PMID: 29611106 DOI: 10.1007/s11739-018-1828-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2017] [Accepted: 03/08/2018] [Indexed: 12/23/2022]
Abstract
Direct-acting antiviral drugs (DAAs) were recently approved for treating hepatitis C virus-related chronic hepatitis. As advanced chronic liver disease may predispose patients to thrombotic events, it is still uncertain whether DAAs may influence the actual risk of major arterial and venous thrombotic events. We performed a systematic review to assess the incidence of major vascular events in patients receiving DAAs for HCV chronic hepatitis during phase-III randomized controlled trials (RCTs). Two reviewers identified studies through Pubmed database until October 2015. Reporting and incidence of any vascular events were compared with reporting and incidence of major bleeding, anemia (a prespecified safety outcome) and headache (a common non-prespecified safety outcome). 33 RCTs, encompassing 14,764 patients, were included. Only 13 (39%) and 4 (12%) RCTs provide data on any arterial or venous events, respectively. Occurrence of anemia and headache is reported in all studies. Crude unweighted rate of major arterial events is 0.16% (95% CI 0.10-0.24) of the total included population and 0.47% in those 13 RCTs reporting data. Crude unweighted rate of major venous events is 0.03% of the total included population (95% CI 0.01-0.08) and 0.22% in those four RCTs reporting data. Crude unweighted rate of major bleeding is 0.07% (95% CI 0.03-0.1). Incidence of thrombotic events in HCV patients receiving DAAs may be low, but an incorrect estimation cannot be excluded.
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Affiliation(s)
- Eleonora Tamborini Permunian
- Department of Medicine and Surgery, Research Centre on Thromboembolic Disorders and Antithrombotic Therapies, University of Insubria, Varese, Italy
| | - Lorenzo Gervaso
- Oncology Unit, IRCCS Fondazione Salvatore Maugeri, University of Pavia, Pavia, Italy
| | - Victor Gerdes
- Department of Internal Medicine, MC Slotervaart, Amsterdam, The Netherlands
| | - Lorenzo Moja
- Unit of Clinical Epidemiology, I.R.C.C.S. Orthopedic Institute Galeazzi, Milan, Italy
| | - Luigina Guasti
- Department of Medicine and Surgery, Research Centre on Thromboembolic Disorders and Antithrombotic Therapies, University of Insubria, Varese, Italy.
- U.O. Medicina Interna 1, ASST Settelaghi, Viale Borri, 57, 21100, Varese, Italy.
| | - Alessandro Squizzato
- Department of Medicine and Surgery, Research Centre on Thromboembolic Disorders and Antithrombotic Therapies, University of Insubria, Varese, Italy
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31
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Tummers M, van Hoorn R, Levering C, Booth A, van der Wilt GJ, Kievit W. Optimal search strategies for identifying moderators and predictors of treatment effects in PubMed. Health Info Libr J 2018; 36:318-340. [PMID: 30006959 DOI: 10.1111/hir.12230] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2017] [Accepted: 06/07/2018] [Indexed: 11/28/2022]
Abstract
BACKGROUND Treatment effects differ across patients. To guide selection of treatments for patients, it is essential to acknowledge these differences and identify moderators or predictors. Our aim was to generate optimal search strategies (commonly known as filters) for PubMed to retrieve papers identifying moderators and predictors of treatment effects. METHODS Six journals were hand-searched for articles on moderators or predictors. Selected articles were randomly allocated to a development and validation set. Search terms were extracted from the development set and tested for their performance. Search filters were created from combinations of these terms and tested in the validation set. RESULTS Of 4407 articles, 198 were considered to be relevant. The most sensitive filter in the development set '("Epidemiologic Methods" [MeSH] OR assign* OR control*[tiab] OR trial*[tiab]) AND therapy*[sh]' yielded in the validation set a sensitivity of 89% [88%-90%] and a specificity of 80% [79%-82%]. CONCLUSIONS The search filters created in this study can help to efficiently retrieve evidence on moderators and predictors of treatment effect. Testing of the filters in multiple domains should reveal robustness across disciplines. These filters can facilitate the retrieval of evidence on moderators and predictors of treatment effects, helping the implementation of stratified or personalised health care.
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Affiliation(s)
- Marcia Tummers
- Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Ralph van Hoorn
- Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Charlotte Levering
- Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Andrew Booth
- School of Health and Related Research (ScHARR), Health Economics and Decision Science (HEDS), University of Sheffield Regent Court, Sheffield, UK
| | - Gert Jan van der Wilt
- Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Wietske Kievit
- Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
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32
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Gomes LO, Teixeira MR, Rosa JAD, Feltrin AA, Rodrigues JPV, Vecchi MD, Carneiro JMM, Noblat LDACB, Chachá SGF, Martinelli ADLC, Pereira LRL, Silveira MPT, Blatt CR, Farias MR. Hepatitis C in Brazil: lessons learned with boceprevir and telaprevir. Rev Inst Med Trop Sao Paulo 2018; 60:e29. [PMID: 29972466 PMCID: PMC6029893 DOI: 10.1590/s1678-9946201860029] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2018] [Accepted: 03/28/2018] [Indexed: 01/09/2023] Open
Abstract
In 2012, the first-generation protease inhibitors telaprevir (TVR) and boceprevir (BOC) were introduced in the Brazilian health system for treatment of chronic hepatitis C, after their approval by the National Committee for Health Technology Incorporation (CONITEC). However, these medicines were discontinued in 2015. The short period of use in therapy and their high cost require a discussion about the consequences for patients and for the health system of the early incorporation of new therapies. The article presents a qualitative analysis of the incorporation process of both medications in Brazil and the results of a multicenter study that included patients treated with BOC or TVR between January 2011 and December 2015 in five Brazilian cities. The study included 855 patients (BOC: n=247) and (TVR: n=608). The document analysis showed that CONITEC's decision to incorporate BOC and TVR was based on results of phase III clinical trials that compared sustained virologic response (SVR) rates of patients treated with BOC and TVR with rates of those that received placebo. However, these studies included a low percentage of cirrhotic patients. The SVR rates observed in this multicenter study were worse than clinical trials pointed out (BOC: 45.6%; TVR: 51.8%), but similar to those achieved with previously adopted therapies. The discontinuation rate due to adverse events was (BOC: 15.4%; TVR: 12.7%). Based on these unsatisfactory results, the study brings a discussion that goes beyond the therapy outcomes, exploring the incorporation of these high-cost medicines and the related decision-making process, contributing to future decisions in medicine policies and in the treatment of chronic hepatitis C.
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Affiliation(s)
- Lenyta Oliveira Gomes
- Departamento de Ciências Farmacêuticas, Centro de Ciências da Saúde, Universidade Federal de Santa Catarina, Florianópolis, Santa Catarina, Brazil
| | - Marina Rodrigues Teixeira
- Departamento de Ciências Farmacêuticas, Centro de Ciências da Saúde, Universidade Federal de Santa Catarina, Florianópolis, Santa Catarina, Brazil
| | - Júnior André da Rosa
- Departamento de Ciências Farmacêuticas, Centro de Ciências da Saúde, Universidade Federal de Santa Catarina, Florianópolis, Santa Catarina, Brazil
| | | | - João Paulo V Rodrigues
- Departamento de Ciências Farmacêuticas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, São Paulo, Brazil
| | - Mariane D'Avila Vecchi
- Faculdade de Medicina, Universidade Federal de Pelotas, Pelotas, Rio Grande do Sul, Brazil
| | | | | | - Silvana Gama F Chachá
- Departamento de Medicina, Universidade Federal de São Carlos, São Carlos, São Paulo, Brazil
| | - Ana de Lourdes C Martinelli
- Departamento de Clínica Médica, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, São Paulo, Brazil
| | - Leonardo Regis L Pereira
- Departamento de Ciências Farmacêuticas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, São Paulo, Brazil
| | - Marysabel Pinto T Silveira
- Departamento de Fisiologia e Farmacologia, Instituto de Biologia, Universidade Federal de Pelotas, Pelotas, Rio Grande do Sul, Brazil
| | - Carine Raquel Blatt
- Departamento de Farmacociências, Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre, Rio Grande do Sul, Brazil
| | - Mareni Rocha Farias
- Departamento de Ciências Farmacêuticas, Centro de Ciências da Saúde, Universidade Federal de Santa Catarina, Florianópolis, Santa Catarina, Brazil
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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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Aberegg SK, Hersh AM, Samore MH. Do non-inferiority trials of reduced intensity therapies show reduced effects? A descriptive analysis. BMJ Open 2018; 8:e019494. [PMID: 29500210 PMCID: PMC5855198 DOI: 10.1136/bmjopen-2017-019494] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
OBJECTIVES To identify non-inferiority trials within a cohort where the experimental therapy is the same as the active control comparator but at a reduced intensity and determine if these non-inferiority trials of reduced intensity therapies have less favourable results than other non-inferiority trials in the cohort. Such a finding would provide suggestive evidence of biocreep in these trials. DESIGN This metaresearch study used a cohort of non-inferiority trials published in the five highest impact general medical journals during a 5-year period. Data relating to the characteristics and results of the trials were abstracted. PRIMARY OUTCOME MEASURES Proportions of trials with a declaration of superiority, non-inferiority and point estimates favouring the experimental therapy and mean absolute risk differences for trials with outcomes expressed as a proportion. RESULTS Our search yielded 163 trials reporting 182 non-inferiority comparisons; 36 comparisons from 31 trials were between the same therapy at reduced and full intensity. Compared with trials not evaluating reduced intensity therapies, fewer comparisons of reduced intensity therapies demonstrated a favourable result (non-inferiority or superiority) (58.3%vs82.2%; P=0.002) and fewer demonstrated superiority (2.8%vs18.5%; P=0.019). Likewise, point estimates for reduced intensity therapies more often favoured active control than those for other trials (77.8%vs39.7%; P<0.001) as did mean absolute risk differences (+2.5% vs -0.7%; P=0.018). CONCLUSIONS Non-inferiority trials comparing a therapy at reduced intensity to the same therapy at full intensity showed reduced effects compared with other non-inferiority trials. This suggests these trials may have a high rate of type 1 errors and biocreep, with significant implications for the design and interpretation of future non-inferiority trials.
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Affiliation(s)
| | - Andrew M Hersh
- The University of Utah, Salt Lake City, Utah, USA
- Brooke Army Medical Center, San Antonio, Texas, USA
| | - Matthew H Samore
- The University of Utah, Salt Lake City, Utah, USA
- Epidemiology, Veterans Affairs Salt Lake City Health Care System, Salt Lake City, Utah, USA
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35
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Kjellin M, Wesslén T, Löfblad E, Lennerstrand J, Lannergård A. The effect of the first-generation HCV-protease inhibitors boceprevir and telaprevir and the relation to baseline NS3 resistance mutations in genotype 1: experience from a small Swedish cohort. Ups J Med Sci 2018; 123. [PMID: 29536805 PMCID: PMC5901468 DOI: 10.1080/03009734.2018.1441928] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND The clinical experience with protease-inhibitor (PI) triple regimen appears disappointing regarding effect, side effects, high work load, and costs. This real-world study evaluates baseline and emerging resistance-associated substitutions (RASs) and their significance for treatment outcome. METHOD Thirty-six genotype 1a/b patients treated according to Swedish recommendations during 2011-2013 with triple therapy including pegylated interferon and ribavirin in combination with a protease-inhibitor, either boceprevir (BOC) or telaprevir (TVR), were retrospectively evaluated. Frozen serum samples from the patients were tested for resistance with pan-genotypic population sequencing. RESULTS Overall, 56% (20/36) of the patients achieved sustained viral response (SVR). The SVR was comparable between BOC (64%; 9/14) and TVR (50%; 11/22) (p = 0.07), and the IL28B type non-CC (48%; 12/25) and CC (46%; 6/13) (p = 0.77). The SVR was higher in patients without cirrhosis (89.5%; 17/19) (p < 0.0005), in treatment-naïve patients (70%; 14/20) (p = 0.02), and those with low viral load (<800,000 IU/mL) (66.7%; 8/12) (p < 0.0002), compared to those with cirrhosis (17.6%; 3/17), treatment-experienced (37.5%; 6/16), and high viral load (>800,000 IU/mL) (50%; 12/24). CONCLUSION PI triple regimes were highly effective in treatment-naïve patients without cirrhosis, but in this real-world cohort an inferior effect was evident in cirrhotic and treatment-experienced patients. Although tested on a limited sample, the baseline resistance testing seems to have no impact on prediction of therapy outcome. The reason could be that the baseline RASs T54S and V55A have relatively low resistance towards BOC and TVR. Emerging RASs, mainly R155K, with known high resistance to BOC and TVR were frequently found in non-responders.
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Affiliation(s)
- Midori Kjellin
- Section of Clinical Microbiology, Department of Medical Sciences, Uppsala University Hospital, Sweden
| | - Terése Wesslén
- Section of Infectious Diseases, Department of Medical Sciences, Uppsala University Hospital, Sweden
| | - Erik Löfblad
- Section of Infectious Diseases, Department of Medical Sciences, Uppsala University Hospital, Sweden
| | - Johan Lennerstrand
- Section of Clinical Microbiology, Department of Medical Sciences, Uppsala University Hospital, Sweden
| | - Anders Lannergård
- Section of Infectious Diseases, Department of Medical Sciences, Uppsala University Hospital, Sweden
- CONTACT Anders Lannergård Department of Medical Sciences, Section of Infectious Diseases, Uppsala University, S 751 85 Uppsala, Sweden
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36
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Ferenci P. Editorial: are additional tests needed to predict sustained virologic response in hepatitis C treated with interferon-free direct-acting antiviral combinations? Aliment Pharmacol Ther 2018; 47:848-849. [PMID: 29446143 DOI: 10.1111/apt.14508] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Affiliation(s)
- P Ferenci
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
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37
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Sherman KE, Shah VH. Viral Hepatitis: Knowledge and Treatments for Hepatitis B and C Virus and Associated Transplantation and Neoplasia. Gastroenterology 2018; 154:453-456. [PMID: 29154778 DOI: 10.1053/j.gastro.2017.10.047] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2017] [Revised: 10/31/2017] [Accepted: 10/31/2017] [Indexed: 12/02/2022]
Affiliation(s)
- Kenneth E Sherman
- Division of Digestive Diseases, University of Cincinnati College of Medicine, Cincinnati, Ohio.
| | - Vijay H Shah
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.
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38
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Maughan A, Ogbuagu O. Pegylated interferon alpha 2a for the treatment of hepatitis C virus infection. Expert Opin Drug Metab Toxicol 2018; 14:219-227. [PMID: 29271660 DOI: 10.1080/17425255.2018.1421173] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Treatments for hepatitis C virus (HCV) infection have advanced rapidly in the last decade. Pegylated interferon alpha 2a (PEG-IFN alpha 2a) alone, in combination with ribavirin and with or without direct acting antivirals (DAAs) is modestly effective in the treatment of chronic HCV infection. Areas covered: The review describes the chemistry, pharmacokinetic and pharmacodynamic properties, clinical efficacy, safety and drug-drug interaction profiles of PEG-IFN alpha 2a. Expert opinion: Despite the availability of DAAs and its formidable toxicity profile, PEG-IFN alpha 2a retains a role for the treatment of acute HCV and chronic HCV infection in resource limited settings and for end-stage renal disease patients and others who cannot access DAAs or are DAA-ineligible. Knowledge of pharmacogenetic profiles which favor successful treatment outcomes with IFN-based therapies may allow for selection of best candidates for the regimen.
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Affiliation(s)
- Ashly Maughan
- a Yale AIDS Program, Section of Infectious Diseases , Yale University School of Medicine , New Haven , CT , USA
| | - Onyema Ogbuagu
- a Yale AIDS Program, Section of Infectious Diseases , Yale University School of Medicine , New Haven , CT , USA
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Yang N, Sun C, Zhang L, Liu J, Song F. Identification and Analysis of Novel Inhibitors against NS3 Helicase and NS5B RNA-Dependent RNA Polymerase from Hepatitis C Virus 1b (Con1). Front Microbiol 2017; 8:2153. [PMID: 29209282 PMCID: PMC5701637 DOI: 10.3389/fmicb.2017.02153] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2017] [Accepted: 10/20/2017] [Indexed: 01/22/2023] Open
Abstract
Hepatitis C virus (HCV) leads to severe liver diseases, including liver fibrosis, cirrhosis and hepatocellular carcinoma. Non-structural protein 3 helicase (NS3h) and non-structural protein 5B RNA-dependent RNA polymerase (NS5B) are involved in the replication of HCV RNA genome, and have been proved to be excellent targets for discovery of direct-acting antivirals. In this study, two high-throughput screening systems, fluorescence polarization (FP)-based ssDNA binding assay and fluorescence intensity (FI)-based dsRNA formation assay, were constructed to identify candidate NS3h and NS5B inhibitors, respectively. A library of approximately 800 small molecules and crude extracts, derived from marine microorganisms or purchased from the National Compound Resource Center, China, were screened, with three hits selected for further study. Natural compound No.3A5, isolated from marine fungi, inhibited NS3h activity with an IC50 value of 2.8 μM. We further demonstrated that compound No.3A5 inhibited the abilities of NS3h to bind ssDNA in electrophoretic mobility shift assay and to hydrolyze ATP. The NS3h-inhibitory activity of compound No.3A5 was reversible in our dilution assay, which indicated there was no stable NS3h-No.3A5 complex formed. Additionally, compound No.3A5 exhibited no binding selectivity on NS3h or single strand binding protein of Escherichia coli. In NS5B assays, commercial compounds No.39 and No.94 previously reported as kinase inhibitors were found to disrupt dsRNA formation, and their IC50 values were 62.9 and 18.8 μM, respectively. These results highlight how identifying new uses for existing drugs is an effective method for discovering novel HCV inhibitors. To our knowledge, all inhibitors reported in this study were originally discovered with HCV anti-non-structural protein activities in vitro.
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Affiliation(s)
- Na Yang
- Key Laboratory of Experimental Marine Biology, Institute of Oceanology, Chinese Academy of Sciences, Qingdao, China.,Laboratory for Marine Biology and Biotechnology, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China
| | - Chaomin Sun
- Key Laboratory of Experimental Marine Biology, Institute of Oceanology, Chinese Academy of Sciences, Qingdao, China.,Laboratory for Marine Biology and Biotechnology, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China
| | - Lixin Zhang
- Laboratory for Marine Biology and Biotechnology, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China.,State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, China
| | - Jianguo Liu
- Key Laboratory of Experimental Marine Biology, Institute of Oceanology, Chinese Academy of Sciences, Qingdao, China.,Laboratory for Marine Biology and Biotechnology, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China
| | - Fuhang Song
- Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China
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40
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Hepatitis C cross-genotype immunity and implications for vaccine development. Sci Rep 2017; 7:12326. [PMID: 28951612 PMCID: PMC5615075 DOI: 10.1038/s41598-017-10190-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2017] [Accepted: 08/02/2017] [Indexed: 01/03/2023] Open
Abstract
While about a quarter of individuals clear their primary hepatitis C (HCV) infections spontaneously, clearance (spontaneous or treatment-induced) does not confer sterilizing immunity against a future infection. Since successful treatment does not prevent future infections either, an effective vaccine is highly desirable in preventing HCV (re)infection. However, development of an effective vaccine has been complicated by the diversity of HCV genotypes, and complexities in HCV immunological responses. Smaller studies on humans and chimpanzees reported seemingly opposing results regarding cross-neutralizing antibodies. We report a lack of cross-genotype immunity in the largest cohort of people to date. In the adjusted Cox proportional hazards model, reinfection with a heterologous HCV genotype (adjusted Hazard Ratio [aHR]: 0.45, 95% CI: 0.25–0.84) was associated with a 55% lower likelihood of re-clearance. Among those who cleared their first infection spontaneously, the likelihood of re-clearance was 49% lower (aHR: 0.51, 95% CI: 0.27–0.94) when reinfected with a heterologous HCV genotype. These findings indicate that immunity against a particular HCV genotype does not offer expanded immunity to protect against subsequent infections with a different HCV genotype. A prophylactic HCV vaccine boosted with multiple HCV genotype may offer a broader and more effective protection.
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Goel A, Bhadauria DS, Kaul A, Prasad N, Gupta A, Sharma RK, Rai P, Aggarwal R. Safety and effectiveness of response-guided therapy using pegylated interferon and ribavirin for chronic hepatitis C virus infection in patients on maintenance dialysis. Nephrology (Carlton) 2017; 22:706-711. [PMID: 27286895 DOI: 10.1111/nep.12833] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2016] [Revised: 05/18/2016] [Accepted: 06/01/2016] [Indexed: 12/17/2022]
Affiliation(s)
- Amit Goel
- Department of Gastroenterology; Sanjay Gandhi Postgraduate Institute of Medical Sciences; Lucknow India
| | | | - Anupma Kaul
- Department of Nephrology; Sanjay Gandhi Postgraduate Institute of Medical Sciences; Lucknow India
| | - Narayan Prasad
- Department of Nephrology; Sanjay Gandhi Postgraduate Institute of Medical Sciences; Lucknow India
| | - Amit Gupta
- Department of Nephrology; Sanjay Gandhi Postgraduate Institute of Medical Sciences; Lucknow India
| | - Raj Kumar Sharma
- Department of Nephrology; Sanjay Gandhi Postgraduate Institute of Medical Sciences; Lucknow India
| | - Praveer Rai
- Department of Gastroenterology; Sanjay Gandhi Postgraduate Institute of Medical Sciences; Lucknow India
| | - Rakesh Aggarwal
- Department of Gastroenterology; Sanjay Gandhi Postgraduate Institute of Medical Sciences; Lucknow India
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Kah J, Volz T, Lütgehetmann M, Groth A, Lohse AW, Tiegs G, Sass G, Dandri M. Haem oxygenase-1 polymorphisms can affect HCV replication and treatment responses with different efficacy in humanized mice. Liver Int 2017; 37:1128-1137. [PMID: 27992676 DOI: 10.1111/liv.13347] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2016] [Accepted: 11/22/2016] [Indexed: 12/31/2022]
Abstract
BACKGROUND & AIMS Enhancement of host anti-oxidant enzymes, such as haemoxygenase-1, may attenuate virus-mediated hepatocyte injury, while the induction of HO-1 by cobalt-protoporphyrin-IX (CoPP) administration, as the application of its haem degradation product biliverdin (BV), was shown to hinder HCV replication in vitro. In addition, (GT)n -repeats length in the polymorphic region of the HO-1 promoter may affect HO-1 expression and responsiveness to infection and disease severity. Aim of this study was to investigate the antiviral and hepatoprotective effects of CoPP-mediated HO-1 induction, alone or in combination with interferon alpha (peg-IFNα), in HCV-infected mice harbouring hepatocytes from donors with different HO-1-promoter polymorphisms. METHODS Upon establishment of HCV infection, CoPP, BV and peg-IFNα were given alone or in combination. Viraemia changes and intrahepatic human gene expression were determined by qRT-PCR and immunohistochemistry. RESULTS CoPP administration increased human HO-1 expression and significantly reduced viraemia, although changes correlated with promoter length (Δ0.5log and Δ2log reduction with medium- and short-polymorphism respectively). Polymorphisms did not influence BV-mediated antiviral effects (Δ1log). Notably, HO-1 induction attenuated basal HCV-driven enhancement of interferon genes and pro-inflammatory cytokines, both in cells with short- or medium-polymorphisms. Moreover, simultaneous administration of CoPP and peg-IFNα reduced viraemia even stronger (median 3log), whereas 1log viraemia reduction was determined in mice receiving peg-IFNα monotherapy. CONCLUSIONS Although the protective function of HO-1 could be elicited in vivo with both host polymorphisms, the strength of HO-1 induction and suppression of HCV occurred in a polymorphism-dependent manner, indicating that host-genetic determinants may affect disease progression and infection outcome.
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Affiliation(s)
- Janine Kah
- I. Department of Medicine, Center for Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.,Institute of Experimental Immunology and Hepatology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Tassilo Volz
- I. Department of Medicine, Center for Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Marc Lütgehetmann
- I. Department of Medicine, Center for Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.,Institute of Microbiology, Virology and Hygiene, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Anne Groth
- I. Department of Medicine, Center for Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Ansgar W Lohse
- I. Department of Medicine, Center for Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.,German Center for Infection Research, Hamburg-Lübeck-Borstel Partner Site, Hamburg, Germany
| | - Gisa Tiegs
- Institute of Experimental Immunology and Hepatology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Gabriele Sass
- Institute of Experimental Immunology and Hepatology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Maura Dandri
- I. Department of Medicine, Center for Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.,German Center for Infection Research, Hamburg-Lübeck-Borstel Partner Site, Hamburg, Germany
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43
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Gray E, O'Leary A, Bergin C, Cannon M, Courtney G, Crosbie O, De Gascun CF, Fanning LJ, Feeney E, Houlihan DD, Kelleher B, Lambert JS, Lee J, Mallon P, McConkey S, McCormick A, McKiernan S, McNally C, Murray F, Sheehan G, Stewart S, Walsh C, Norris S. Effectiveness of interferon-free therapy for the treatment of HCV-patients with compensated cirrhosis treated through the Irish early access program. Expert Rev Gastroenterol Hepatol 2017; 11:593-601. [PMID: 28276815 DOI: 10.1080/17474124.2017.1292850] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND We investigated the real-world effectiveness of interferon-free regimens for the treatment of patients with compensated cirrhosis infected with hepatitis C virus (HCV). METHOD Using the Irish national HCV treatment registry, the effectiveness and safety of interferon-free regimens for HCV-infected patients treated between April 2015 and August 2016, was determined. RESULTS A SVR12 was achieved in 86% of subjects treated with sofosbuvir/ledipasvir ± ribavirin (SOF/LDV±RBV), 93% treated with paritaprevir, ombitasvir and ritonavir combined with dasabuvir ± ribavirin (3D±RBV) and 89% treated with sofosbuvir/daclatasvir ± ribavirin (SOF/DCV±RBV). The discontinuation rate was 5% and the on-treatment mortality rate was 1%. CONCLUSION The availability of interferon-free regimens represents a significant breakthrough for the treatment of HCV infection. Treatments options, with high SVR12 rates, are now available for patients with compensated cirrhosis who were unsuitable for treatment with interferon-based regimens. Data obtained from studies conducted in real world practice provide robust information fundamental for input into future economic evaluations for agents used for the treatment of HCV infection.
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Affiliation(s)
- E Gray
- a School of Medicine, Trinity College Dublin , Dublin , Ireland
| | - A O'Leary
- b National Centre for Pharmacoeconomics, St. James' Hospital , Dublin , Ireland.,c School of Pharmacy, Royal College of Surgeons of Ireland , Dublin , Ireland
| | - C Bergin
- a School of Medicine, Trinity College Dublin , Dublin , Ireland.,e St James' Hospital , Dublin , Ireland
| | - M Cannon
- f Beaumont Hospital , Dublin , Ireland
| | - G Courtney
- g St. Luke's Hospital , Kilkenny , Ireland
| | - O Crosbie
- h Cork University Hospital , Cork , Ireland
| | - C F De Gascun
- i National Virus Reference Laboratory , University College Dublin , Dublin , Ireland
| | - L J Fanning
- j Molecular Virology Diagnostic & Research Laboratory, Department of Medicine , University College Cork , Cork , Ireland
| | - E Feeney
- k St. Vincent's University Hospital , Dublin , Ireland
| | - D D Houlihan
- k St. Vincent's University Hospital , Dublin , Ireland
| | - B Kelleher
- d Mater Misericordiae University Hospital , Dublin , Ireland
| | - J S Lambert
- d Mater Misericordiae University Hospital , Dublin , Ireland.,n School of Medicine , University College Dublin , Dublin , Ireland
| | - J Lee
- l University College Hospital , Galway , Ireland
| | - Pwg Mallon
- d Mater Misericordiae University Hospital , Dublin , Ireland.,n School of Medicine , University College Dublin , Dublin , Ireland
| | | | - A McCormick
- k St. Vincent's University Hospital , Dublin , Ireland
| | | | - C McNally
- f Beaumont Hospital , Dublin , Ireland
| | - F Murray
- f Beaumont Hospital , Dublin , Ireland
| | - G Sheehan
- d Mater Misericordiae University Hospital , Dublin , Ireland
| | - S Stewart
- d Mater Misericordiae University Hospital , Dublin , Ireland
| | - C Walsh
- m University of Limerick , Limerick , Ireland
| | - S Norris
- a School of Medicine, Trinity College Dublin , Dublin , Ireland.,e St James' Hospital , Dublin , Ireland
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Gray E, Pasta DJ, Norris S, O'Leary A. Effectiveness of triple therapy with direct-acting antivirals for hepatitis C genotype 1 infection: application of propensity score matching in a national HCV treatment registry. BMC Health Serv Res 2017; 17:288. [PMID: 28424064 PMCID: PMC5395881 DOI: 10.1186/s12913-017-2188-1] [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: 08/26/2016] [Accepted: 03/24/2017] [Indexed: 11/18/2022] Open
Abstract
Background Observational studies are used to measure the effectiveness of an intervention in non-experimental, real world scenarios at the population level and are recognised as an important component of the evidence pyramid. Such data can be accrued through prospective cohort studies and a patient registry is a proven method for this type of study. The national hepatitis C (HCV) registry was established in Ireland in 2012 with the aim of monitoring the clinical and economic outcomes from new, high cost regimens for the treatment of HCV infection. A sustained virological response (SVR) 24 weeks following completion of therapy with interferon-containing regimens is considered a cure. Non-randomisation in these studies can result in confounding or selection bias. Propensity score (PS) matching is one of a number of statistical tools that can be used to mitigate the effects of confounding in observational studies. Methods We analysed the data of 309 patients who underwent triple therapy treatment with telaprevir (TPV) in combination with pegylated-interferon and ribavirin (PR) or boceprevir (BOC)/PR between June 2012 and December 2014. The decision to initiate treatment and the selection of the treatment regimen was at the discretion of the physician. To adjust for confounding, three approaches to propensity score matching were assessed Adjusted sustained-virological response rates (SVR), odds ratios, p-values and 95% confidence intervals were calculated from the three PS matched dataset. Results Prior to matching, the unadjusted sustained virological response rates 24 weeks after treatment complete (SVR24) were 74% (n = 158/215) and 61% (n = 57/94) for telaprevir/PR and boceprevir/PR, respectively. After matching, adjusted SVR24 rates were between 73–74% and 60–61% for telaprevir/PR and boceprevir/PR, respectively. Conclusion Efficacy rates were comparable with those reported in pivotal clinical trials and real world studies. After adjusting for confounding, we conclude that there was no difference in treatment effect after PS matching. The small sample size limits the conclusions that can be made about the effect of PS matching. Propensity score adjustment remains a tool that can be applied to future analysis, however, we suggest, where possible, using a larger sample size in order to reduce the uncertainty around the outcomes. Electronic supplementary material The online version of this article (doi:10.1186/s12913-017-2188-1) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Emma Gray
- School of Medicine, Trinity College Dublin, Dublin, Ireland.
| | | | - Suzanne Norris
- School of Medicine, Trinity College Dublin, Dublin, Ireland.,Department of Hepatology, St James' Hospital, Dublin, Ireland
| | - Aisling O'Leary
- National Centre for Pharmacoeconomics, St. James' Hospital, Dublin, Ireland.,School of Pharmacy, Royal College of Surgeons of Ireland, Dublin, Ireland
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45
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Vermehren J, Stelzl E, Maasoumy B, Michel-Treil V, Berkowski C, Marins EG, Paxinos EE, Marino E, Wedemeyer H, Sarrazin C, Kessler HH. Multicenter Comparison Study of both Analytical and Clinical Performance across Four Roche Hepatitis C Virus RNA Assays Utilizing Different Platforms. J Clin Microbiol 2017; 55:1131-1139. [PMID: 28122870 PMCID: PMC5377840 DOI: 10.1128/jcm.02193-16] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2016] [Accepted: 01/02/2017] [Indexed: 02/07/2023] Open
Abstract
The efficacy of antiviral treatment for chronic hepatitis C virus (HCV) infection is determined by measuring HCV RNA at specific time points throughout therapy using highly sensitive and accurate HCV RNA assays. This study compared the performances of two recently developed real-time PCR HCV RNA assays, cobas HCV for use on the cobas 6800/8800 systems (cobas 6800/8800 HCV) and cobas HCV for use on the cobas 4800 system (cobas 4800 HCV), with those of two established assays, the Cobas AmpliPrep/Cobas TaqMan HCV quantitative test, version 2 (CAP/CTM v2) and the Cobas TaqMan HCV test, version 2 for use with the High Pure system (HPS/CTM v2). The limits of detection (LODs) and linearity at lower concentrations (5 to 1000 IU/ml) were assessed for cobas 6800/8800 HCV and cobas 4800 HCV using WHO standard traceable panels representing HCV genotypes (GT) 1 to 4. Pairwise assay comparisons were also performed using 245 clinical samples representing HCV GT 1 to GT 4. Results from cobas 6800/8800 HCV and cobas 4800 HCV were linear at low HCV RNA concentrations (<0.3 log10 IU/ml difference between expected and observed results) with LODs of 8.2 IU/ml and 11.7 IU/ml, respectively, for GT 1. The new assays showed excellent agreement with results from CAP/CTM v2 and HPS/CTM v2 in samples with quantifiable viral loads. The concordances using the 6 million IU/ml cutoff were high among all four assays (90 to 94%). In conclusion, the cobas 6800/8800 HCV and cobas 4800 HCV tests are sensitive and linear and correlate well with the established Roche assays used in clinical practice.
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Affiliation(s)
- Johannes Vermehren
- Medizinische Klinik 1, Universitätsklinikum Frankfurt, Frankfurt, Germany
| | - Evelyn Stelzl
- Institut für Hygiene, Mikrobiologie und Umweltmedizin, Medizinische Universität Graz, Graz, Austria
| | - Benjamin Maasoumy
- Klinik für Gastroenterologie, Hepatologie und Endokrinologie, Medizinische Hochschule Hannover, Hannover, Germany
| | | | - Caterina Berkowski
- Medizinische Klinik 1, Universitätsklinikum Frankfurt, Frankfurt, Germany
| | - Ed G Marins
- Roche Molecular Systems, Pleasanton, California, USA
| | | | | | - Heiner Wedemeyer
- Klinik für Gastroenterologie, Hepatologie und Endokrinologie, Medizinische Hochschule Hannover, Hannover, Germany
| | - Christoph Sarrazin
- Medizinische Klinik 1, Universitätsklinikum Frankfurt, Frankfurt, Germany
| | - Harald H Kessler
- Institut für Hygiene, Mikrobiologie und Umweltmedizin, Medizinische Universität Graz, Graz, Austria
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Alqahtani S, Ozaras R, Isakov V, Wyles D, Ferenci P, Feld JJ, Calinas F, Gschwantler M, Gane E, Crawford D, Jacobson IM, Dumas EO, King M, Sulkowski M. Time to viral suppression is not related to achievement of SVR12 in HCV GT1-infected patients treated with ombitasvir/paritaprevir/ritonavir and dasabuvir with or without ribavirin. J Viral Hepat 2017; 24:280-286. [PMID: 27935166 DOI: 10.1111/jvh.12641] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2016] [Accepted: 09/27/2016] [Indexed: 01/01/2023]
Abstract
High rates of sustained virologic response at post-treatment week 12 (SVR12) were achieved in six phase 3 trials of ombitasvir (OBV, an NS5A inhibitor), paritaprevir (an NS3/4A protease inhibitor) co-dosed with ritonavir (PTV/r) + dasabuvir (DSV, an NS5B RNA polymerase inhibitor) (ie, 3D regimen) with or without ribavirin (RBV) in adults with chronic genotype (GT) 1 hepatitis C virus (HCV) infection. We assessed whether time to first HCV RNA value below the lower limit of quantification in patients with and without cirrhosis was associated with achievement of SVR12. Data were analysed from GT1-infected patients enrolled in six phase 3 studies of 3D ± RBV. Patients who experienced non-virologic failure were excluded from analysis. HCV RNA was determined using the Roche COBAS TaqMan RT-PCR assay (lower limit of quantification, LLOQ =25 IU/mL). SVR12 was analysed by week of first HCV RNA suppression, defined as HCV RNA <LLOQ. The analysis included a total of 2027 patients. Cumulative proportions of subjects with initial HCV RNA suppression <LLOQ at weeks 1, 2, 4 and 6 were 31%, 81%, 99% and 100%, respectively. SVR12 was achieved by 98%, 97%, 98% and 92% of patients with initial suppression at Weeks 1, 2, 4 and 6, respectively (P=.42, trend test). Across six phase 3 trials of 3D ± RBV, most patients achieved viral suppression by week 2. Time to viral suppression was not associated with subsequent achievement of SVR12, suggesting that on-treatment virologic monitoring may not be necessary with this regimen.
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Affiliation(s)
- S Alqahtani
- Johns Hopkins University, Baltimore, MD, USA
| | - R Ozaras
- Cerrahpasa Medical School, Istanbul, Turkey
| | - V Isakov
- Institute of Nutrition, Moscow, Russia
| | - D Wyles
- University of Colorado School of Medicine, Denver, CO, USA
| | - P Ferenci
- Universitaetsklinik fuer Innere Medizin III, Vienna, Austria
| | - J J Feld
- University of Toronto, Toronto, ON, Canada
| | - F Calinas
- Central Lisbon Hospital Centre, Lisbon, Portugal
| | | | - E Gane
- Auckland City Hospital, Auckland, New Zealand
| | - D Crawford
- School of Medicine, The University of Queensland, Brisbane, QLD, Australia
| | | | | | - M King
- AbbVie Inc., North Chicago, IL, USA
| | - M Sulkowski
- Johns Hopkins University, Baltimore, MD, USA
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Mangia A, Foster GR, Berg CP, Curescu M, Ledinghen VD, Habersetzer F, Manolakopoulos S, Negri E, Papatheodoridis G, Ahlers S, Castillo M, Bakalos G, Mauss S. Efficacy and safety profile of boceprevir- or telaprevir-based triple therapy or dual peginterferon alfa-2a or alfa-2b plus ribavirin therapy in chronic hepatitis C: the real-world PegBase observational study. Ann Gastroenterol 2017; 30:327-343. [PMID: 28469364 PMCID: PMC5411384 DOI: 10.20524/aog.2017.0136] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2016] [Accepted: 02/19/2017] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND The aim of the study was to determine the efficacy and safety of triple therapy with a first-generation protease inhibitor (PI; boceprevir, telaprevir) plus peginterferon alfa-2a or -2b plus ribavirin, and dual therapy (peginterferon alfa-2a or -2b plus ribavirin) in patients with chronic hepatitis C (CHC) in routine clinical practice. METHODS PegBase was an international, prospective, observational study in which 4441 patients with CHC were enrolled in 27 countries. This analysis focuses on results in 4100 treatment-naïve and previously treated patients treated with PI-based triple therapy or dual therapy, according to the discretion of the investigator and local standards of practice. The primary efficacy outcome was sustained virological response after 12-week follow up (SVR12). RESULTS SVR12 rates in treatment-naïve genotype (G) 1 patients were 56.6% and 62.9% for recipients of boceprevir plus peginterferon alfa-2a/ribavirin and boceprevir plus peginterferon alfa-2b/ribavirin, respectively, and 65.3% and 58.6% for recipients of telaprevir plus peginterferon alfa-2a/ribavirin and telaprevir plus peginterferon alfa-2b/ribavirin, respectively. In previously treated patients assigned to these four regimens, SVR12 rates were 43.6%, 48.3%, 60.3% and 56.1%, respectively. Among treatment-naïve patients assigned to peginterferon alfa-2a/ribavirin and peginterferon alfa-2b/ribavirin, respectively, SVR12 rates were 49.2% and 41.9% in G1 patients, 75.7% and 83.3% in G2 patients, 65.9% and 65.9% in G3 patients, and 49.7%, and 51.1% in G4 patients. The safety and tolerability of dual and triple therapy were consistent with previous reports. CONCLUSION The efficacy and safety of first-generation PI-based triple-therapy and dual-therapy regimens in this real-world cohort were broadly comparable to those of previous studies.
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Affiliation(s)
- Alessandra Mangia
- Liver Unit, IRCCS Hospital "Casa Sollievo della Sofferenza", San Giovanni Rotondo, Italy
| | - Graham R Foster
- Institute of Cellular and Molecular Sciences, Queen Mary University of London, London, UK
| | - Christoph P Berg
- Department of Internal Medicine, Medizinische Universitätsklinik Tübingen, Tübingen, Germany
| | - Manuela Curescu
- Clinic of Infectious Diseases, University of Medicine and Pharmacy Timişoara, Timişoara, Romania
| | | | - François Habersetzer
- Unité Hépatologie, Pôle Hépato-digestif, Hôpitaux Universitaires de Strasbourg, Inserm 1110, Université de Strasbourg, Strasbourg, France
| | | | - Elisa Negri
- UO Malattie Infettive ed Epatologia, Azienda Ospedaliero - Universitaria di Parma, Parma, Italy
| | | | | | | | | | - Stefan Mauss
- Center for HIV and Hepatogastroenterology, Düsseldorf, Germany
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McGowan DC, Khamlichi MD, De Groot A, Pauwels F, Delouvroy F, Van Emelen K, Simmen K, Raboisson P. Synthesis and evaluation of novel HCV replication inhibitors. Mol Divers 2017; 21:475-481. [PMID: 28293834 DOI: 10.1007/s11030-017-9733-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2016] [Accepted: 02/20/2017] [Indexed: 12/15/2022]
Abstract
Direct acting antiviral agents to cure hepatitis C virus (HCV) infection has emerged as the gold standard therapy. Along with protease inhibitors, nucleoside polymerase inhibitors and non-nucleoside polymerase inhibitors, the inhibition of NS5a has proved to be an effective way to treat HCV patients. Here we report on novel HCV NS5a inhibitors which were synthesized and evaluated in the HCV replicon assay. A series of inhibitors were formed by a cycloaddition reaction in parallel to establish new leads and explore the effects of unsymmetrical cap substitution. This led to the identification of several triazoles with picomolar potency in vitro against hepatitis C virus.
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Affiliation(s)
- David C McGowan
- Janssen Infectious Diseases BVBA, Turnhoutseweg 30, 2340, Beerse, Belgium.
| | - Mourad D Khamlichi
- Villapharma Research, Parque Tecnológico de Fuente Álamo, Ctra. El Estrecho-Lobosillo, Km. 2,5- Av. Azul, 30320, Fuente Álamo de Murcia, Murcia, Spain
| | - Alex De Groot
- Janssen Infectious Diseases BVBA, Turnhoutseweg 30, 2340, Beerse, Belgium
| | - Frederik Pauwels
- Janssen Infectious Diseases BVBA, Turnhoutseweg 30, 2340, Beerse, Belgium
| | - Frédéric Delouvroy
- Janssen Infectious Diseases BVBA, Turnhoutseweg 30, 2340, Beerse, Belgium
| | - Kristof Van Emelen
- Janssen Infectious Diseases BVBA, Turnhoutseweg 30, 2340, Beerse, Belgium
| | - Kenneth Simmen
- Janssen Infectious Diseases BVBA, Turnhoutseweg 30, 2340, Beerse, Belgium
| | - Pierre Raboisson
- Janssen Infectious Diseases BVBA, Turnhoutseweg 30, 2340, Beerse, Belgium
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Ponziani FR, Mangiola F, Binda C, Zocco MA, Siciliano M, Grieco A, Rapaccini GL, Pompili M, Gasbarrini A. Future of liver disease in the era of direct acting antivirals for the treatment of hepatitis C. World J Hepatol 2017; 9:352-367. [PMID: 28321272 PMCID: PMC5340991 DOI: 10.4254/wjh.v9.i7.352] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2016] [Revised: 10/26/2016] [Accepted: 12/01/2016] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) infection has been a global health problem for decades, due to the high number of infected people and to the lack of effective and well-tolerated therapies. In the last 3 years, the approval of new direct acting antivirals characterized by high rates of virological clearance and excellent tolerability has dramatically improved HCV infection curability, especially for patients with advanced liver disease and for liver transplant recipients. Long-term data about the impact of the new direct acting antivirals on liver fibrosis and liver disease-related outcomes are not yet available, due to their recent introduction. However, previously published data deriving from the use of pegylated-interferon and ribavirin lead to hypothesizing that we are going to observe, in the future, a reduction in mortality and in the incidence of hepatocellular carcinoma, as well as a regression of fibrosis for people previously affected by hepatitis C. In the liver transplant setting, clinical improvement has already been described after treatment with the new direct acting antivirals, which has often led to patients delisting. In the future, this may hopefully reduce the gap between liver organ request and availability, probably expanding liver transplant indications to other clinical conditions. Therefore, these new drugs are going to change the natural history of HCV-related liver disease and the epidemiology of HCV infection worldwide. However, the global consequences will depend on treatment accessibility and on the number of countries that could afford the use of the new direct acting antivirals.
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Affiliation(s)
- Francesca Romana Ponziani
- Francesca Romana Ponziani, Francesca Mangiola, Cecilia Binda, Maria Assunta Zocco, Massimo Siciliano, Antonio Grieco, Maurizio Pompili, Antonio Gasbarrini, Internal Medicine, Gastroenterology and Hepatology, Catholic University Sacred Heart of Rome, Agostino Gemelli Hospital, 00168 Rome, Italy
| | - Francesca Mangiola
- Francesca Romana Ponziani, Francesca Mangiola, Cecilia Binda, Maria Assunta Zocco, Massimo Siciliano, Antonio Grieco, Maurizio Pompili, Antonio Gasbarrini, Internal Medicine, Gastroenterology and Hepatology, Catholic University Sacred Heart of Rome, Agostino Gemelli Hospital, 00168 Rome, Italy
| | - Cecilia Binda
- Francesca Romana Ponziani, Francesca Mangiola, Cecilia Binda, Maria Assunta Zocco, Massimo Siciliano, Antonio Grieco, Maurizio Pompili, Antonio Gasbarrini, Internal Medicine, Gastroenterology and Hepatology, Catholic University Sacred Heart of Rome, Agostino Gemelli Hospital, 00168 Rome, Italy
| | - Maria Assunta Zocco
- Francesca Romana Ponziani, Francesca Mangiola, Cecilia Binda, Maria Assunta Zocco, Massimo Siciliano, Antonio Grieco, Maurizio Pompili, Antonio Gasbarrini, Internal Medicine, Gastroenterology and Hepatology, Catholic University Sacred Heart of Rome, Agostino Gemelli Hospital, 00168 Rome, Italy
| | - Massimo Siciliano
- Francesca Romana Ponziani, Francesca Mangiola, Cecilia Binda, Maria Assunta Zocco, Massimo Siciliano, Antonio Grieco, Maurizio Pompili, Antonio Gasbarrini, Internal Medicine, Gastroenterology and Hepatology, Catholic University Sacred Heart of Rome, Agostino Gemelli Hospital, 00168 Rome, Italy
| | - Antonio Grieco
- Francesca Romana Ponziani, Francesca Mangiola, Cecilia Binda, Maria Assunta Zocco, Massimo Siciliano, Antonio Grieco, Maurizio Pompili, Antonio Gasbarrini, Internal Medicine, Gastroenterology and Hepatology, Catholic University Sacred Heart of Rome, Agostino Gemelli Hospital, 00168 Rome, Italy
| | - Gian Lodovico Rapaccini
- Francesca Romana Ponziani, Francesca Mangiola, Cecilia Binda, Maria Assunta Zocco, Massimo Siciliano, Antonio Grieco, Maurizio Pompili, Antonio Gasbarrini, Internal Medicine, Gastroenterology and Hepatology, Catholic University Sacred Heart of Rome, Agostino Gemelli Hospital, 00168 Rome, Italy
| | - Maurizio Pompili
- Francesca Romana Ponziani, Francesca Mangiola, Cecilia Binda, Maria Assunta Zocco, Massimo Siciliano, Antonio Grieco, Maurizio Pompili, Antonio Gasbarrini, Internal Medicine, Gastroenterology and Hepatology, Catholic University Sacred Heart of Rome, Agostino Gemelli Hospital, 00168 Rome, Italy
| | - Antonio Gasbarrini
- Francesca Romana Ponziani, Francesca Mangiola, Cecilia Binda, Maria Assunta Zocco, Massimo Siciliano, Antonio Grieco, Maurizio Pompili, Antonio Gasbarrini, Internal Medicine, Gastroenterology and Hepatology, Catholic University Sacred Heart of Rome, Agostino Gemelli Hospital, 00168 Rome, Italy
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Islam N, Krajden M, Shoveller J, Gustafson P, Gilbert M, Buxton JA, Wong J, Tyndall MW, Janjua NZ. Incidence, risk factors, and prevention of hepatitis C reinfection: a population-based cohort study. Lancet Gastroenterol Hepatol 2017; 2:200-210. [DOI: 10.1016/s2468-1253(16)30182-0] [Citation(s) in RCA: 91] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2016] [Revised: 11/17/2016] [Accepted: 11/17/2016] [Indexed: 02/06/2023]
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