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Hasan M, Parvez MSA, Azim KF, Imran MAS, Raihan T, Gulshan A, Muhit S, Akhand RN, Ahmed SSU, Uddin MB. Main protease inhibitors and drug surface hotspots for the treatment of COVID-19: A drug repurposing and molecular docking approach. Biomed Pharmacother 2021; 140:111742. [PMID: 34052565 PMCID: PMC8130501 DOI: 10.1016/j.biopha.2021.111742] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Revised: 05/07/2021] [Accepted: 05/13/2021] [Indexed: 12/14/2022] Open
Abstract
Here, drug repurposing and molecular docking were employed to screen approved MPP inhibitors and their derivatives to suggest a specific therapeutic agent for the treatment of COVID-19. The approved MPP inhibitors against HIV and HCV were prioritized, while RNA dependent RNA Polymerase (RdRp) inhibitor remdesivir including Favipiravir, alpha-ketoamide were studied as control groups. The target drug surface hotspot was also investigated through the molecular docking technique. Molecular dynamics was performed to determine the binding stability of docked complexes. Absorption, distribution, metabolism, and excretion analysis was conducted to understand the pharmacokinetics and drug-likeness of the screened MPP inhibitors. The results of the study revealed that Paritaprevir (-10.9 kcal/mol) and its analog (CID 131982844) (-16.3 kcal/mol) showed better binding affinity than the approved MPP inhibitors compared in this study, including remdesivir, Favipiravir, and alpha-ketoamide. A comparative study among the screened putative MPP inhibitors revealed that the amino acids T25, T26, H41, M49, L141, N142, G143, C145, H164, M165, E166, D187, R188, and Q189 are at potentially critical positions for being surface hotspots in the MPP of SARS-CoV-2. The top 5 predicted drugs (Paritaprevir, Glecaprevir, Nelfinavir, and Lopinavir) and the topmost analog showed conformational stability in the active site of the SARS-CoV-2 MP protein. The study also suggested that Paritaprevir and its analog (CID 131982844) might be effective against SARS-CoV-2. The current findings are limited to in silico analysis and lack in vivo efficacy testing; thus, we strongly recommend a quick assessment of Paritaprevir and its analog (CID 131982844) in a clinical trial.
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Affiliation(s)
- Mahmudul Hasan
- Department of Pharmaceuticals and Industrial Biotechnology, Sylhet Agricultural University, Sylhet 3100, Bangladesh
| | - Md Sorwer Alam Parvez
- Department of Genetic Engineering and Biotechnology, Shahjalal University of Science and Technology, Sylhet 3114, Bangladesh
| | - Kazi Faizul Azim
- Department of Microbial Biotechnology, Sylhet Agricultural University, Sylhet 3100, Bangladesh
| | - Md Abdus Shukur Imran
- Department of Pharmaceuticals and Industrial Biotechnology, Sylhet Agricultural University, Sylhet 3100, Bangladesh
| | - Topu Raihan
- Department of Genetic Engineering and Biotechnology, Shahjalal University of Science and Technology, Sylhet 3114, Bangladesh
| | - Airin Gulshan
- Faculty of Biotechnology and Genetic Engineering, Sylhet Agricultural University, Sylhet 3100, Bangladesh
| | - Samuel Muhit
- Department of Epidemiology and Public Health, Sylhet Agricultural University, Sylhet 3100, Bangladesh
| | - Rubaiat Nazneen Akhand
- Department of Biochemistry and Chemistry, Sylhet Agricultural University, Sylhet 3100, Bangladesh
| | - Syed Sayeem Uddin Ahmed
- Department of Epidemiology and Public Health, Sylhet Agricultural University, Sylhet 3100, Bangladesh.
| | - Md Bashir Uddin
- Department of Medicine, Sylhet Agricultural University, Sylhet 3100, Bangladesh.
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A Novel Small Molecule Inhibits Hepatitis C Virus Propagation in Cell Culture. Microbiol Spectr 2021; 9:e0043921. [PMID: 34319169 PMCID: PMC8552720 DOI: 10.1128/spectrum.00439-21] [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] [Indexed: 12/02/2022] Open
Abstract
Hepatitis C virus (HCV) can cause acute and chronic infection that is associated with considerable liver-related morbidity and mortality. In recent years, there has been a shift in the treatment paradigm with the discovery and approval of agents that target specific proteins vital for viral replication. We employed a cell culture-adapted strain of HCV and human hepatoma-derived cells lines to test the effects of our novel small-molecule compound (AO13) on HCV. Virus inhibition was tested by analyzing RNA replication, protein expression, and virus production in virus-infected cells treated with AO13. Treatment with AO13 inhibited virus spread in cell culture and showed a 100-fold reduction in the levels of infectious virus production. AO13 significantly reduced the level of viral RNA contained within cell culture fluids and reduced the cellular levels of HCV core protein, suggesting that the compound might act on a late step in the viral life cycle. Finally, we observed that AO13 did not affect the release of infectious virus from infected cells. Docking studies and molecular dynamics analyses suggested that AO13 might target the NS5B RNA polymerase, however, real-time RT-PCR analyses of cellular levels of HCV RNA showed only an ∼2-fold reduction in viral RNA levels in the presence of AO13. Taken together, this study revealed that AO13 showed consistent, but low-level antiviral effect against HCV, although the mechanism of action remains unclear. IMPORTANCE The discovery of curative antiviral drugs for a chronic disease such as HCV infection has encouraged drug discovery in the context of other viruses for which no curative drugs currently exist. Since we currently face a novel virus that has caused a pandemic, the need for new antiviral agents is more apparent than ever. We describe here a novel compound that shows a modest antiviral effect against HCV that could serve as a lead compound for future drug development against other important viruses such as SARS-CoV-2.
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Abutaleb A, Sherman KE. A changing paradigm: management and treatment of the HCV/HIV-co-infected patient. Hepatol Int 2018; 12:500-509. [PMID: 30238230 PMCID: PMC6471674 DOI: 10.1007/s12072-018-9896-4] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2018] [Accepted: 09/06/2018] [Indexed: 12/15/2022]
Abstract
Hepatitis C virus (HCV) treatment in HIV/HCV co-infected individuals has renewed relevance given the ongoing opioid crisis and rise of new HIV and HCV infections associated with injection drug use. Patients co-infected with HIV and HCV demonstrate increased rates of hepatic fibrosis, progression to liver failure, and liver-related mortality. HIV co-infection does not impact outcomes of current HCV treatments, and patients should be treated the same as HCV mono-infected persons, though attention to drug:drug interactions is required. In this review, we discuss the mechanisms mediating injury to the liver in HIV mono-infection and HIV/HCV co-infection, and present the landmark trials of HCV treatment in HIV-infected individuals.
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Affiliation(s)
- Ameer Abutaleb
- Division of Clinical Care and Research, Institute of Human Virology, University of Maryland, Baltimore, MD, USA
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Maryland, Baltimore, MD, USA
| | - Kenneth E Sherman
- Division of Digestive Diseases, University of Cincinnati College of Medicine, Cincinnati, OH, 45267, USA.
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Chung RT, Ghany MG, Kim AY, Marks KM, Naggie S, Vargas HE, Aronsohn AI, Bhattacharya D, Broder T, Falade-Nwulia OO, Fontana RJ, Gordon SC, Heller T, Holmberg SD, Jhaveri R, Jonas MM, Kiser JJ, Linas BP, Lo Re V, Morgan TR, Nahass RG, Peters MG, Reddy KR, Reynolds A, Scott JD, Searson G, Swan T, Terrault NA, Trooskin SB, Wong JB, Workowski KA. Hepatitis C Guidance 2018 Update: AASLD-IDSA Recommendations for Testing, Managing, and Treating Hepatitis C Virus Infection. Clin Infect Dis 2018; 67:1477-1492. [PMID: 30215672 PMCID: PMC7190892 DOI: 10.1093/cid/ciy585] [Citation(s) in RCA: 475] [Impact Index Per Article: 67.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2017] [Accepted: 07/14/2018] [Indexed: 11/13/2022] Open
Abstract
Recognizing the importance of timely guidance regarding the rapidly evolving field of hepatitis C management, the American Association for the Study of Liver Diseases (AASLD) and the Infectious Diseases Society of America (IDSA) developed a web-based process for the expeditious formulation and dissemination of evidence-based recommendations. Launched in 2014, the hepatitis C virus (HCV) guidance website undergoes periodic updates as necessitated by availability of new therapeutic agents and/or research data. A major update was released electronically in September 2017, prompted primarily by approval of new direct-acting antiviral agents and expansion of the guidance's scope. This update summarizes the latest release of the HCV guidance and focuses on new or amended recommendations since the previous September 2015 print publication. The recommendations herein were developed by volunteer hepatology and infectious disease experts representing AASLD and IDSA and have been peer reviewed and approved by each society's governing board.
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Suda G, Ogawa K, Morikawa K, Sakamoto N. Treatment of hepatitis C in special populations. J Gastroenterol 2018; 53:591-605. [PMID: 29299684 PMCID: PMC5910474 DOI: 10.1007/s00535-017-1427-x] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2017] [Accepted: 12/19/2017] [Indexed: 02/08/2023]
Abstract
Hepatitis C virus (HCV) infection is one of the primary causes of liver cirrhosis and hepatocellular carcinoma. In hemodialysis patients, the rate of HCV infection is high and is moreover associated with a poor prognosis. In liver transplantation patients with HCV infection, recurrent HCV infection is universal, and re-infected HCV causes rapid progression of liver fibrosis and graft loss. Additionally, in patients with HCV and human immunodeficiency virus (HIV) co-infection, liver fibrosis progresses rapidly. Thus, there is an acute need for prompt treatment of HCV infection in these special populations (i.e., hemodialysis, liver transplantation, HIV co-infection). However, until recently, the standard anti-HCV treatment involved the use of interferon-based therapy. In these special populations, interferon-based therapies could not achieve a high rate of sustained viral response and moreover were associated with a higher rate of adverse events. With the development of novel direct-acting antivirals (DAAs), the landscape of anti-HCV therapy for special populations has changed dramatically. Indeed, in special populations treated with interferon-free DAAs, the sustained viral response rate was above 90%, with a lower incidence and severity of adverse events.
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Affiliation(s)
- Goki Suda
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, North 15, West 7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan.
| | - Koji Ogawa
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, North 15, West 7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan
| | - Kenichi Morikawa
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, North 15, West 7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan
| | - Naoya Sakamoto
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, North 15, West 7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan
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Sikavi C, Chen PH, Lee AD, Saab EG, Choi G, Saab S. Hepatitis C and human immunodeficiency virus coinfection in the era of direct-acting antiviral agents: No longer a difficult-to-treat population. Hepatology 2018; 67:847-857. [PMID: 29108121 DOI: 10.1002/hep.29642] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2017] [Revised: 09/26/2017] [Accepted: 11/02/2017] [Indexed: 12/11/2022]
Abstract
UNLABELLED The treatment of chronic hepatitis C (HCV) in human immunodeficiency virus 1 (HIV)-infected individuals has been historically marked by low sustained virologic response (SVR) rates in comparison to those without HIV infection, resulting in the Food and Drug Administration labeling those coinfected as a "special population with an unmet medical need." We systematically reviewed the treatment of chronic HCV infection in those infected with HIV. We propose that with the advent of direct-acting antiviral (DAA) agents, patients coinfected with HCV and HIV have similar SVR rates as HCV-monoinfected persons and that DAAs address an unmet medical need in this population. A review was performed using Medical Subject Heading terms within the PubMed, EMBASE, and Cochrane Library databases to search for studies dated between January 2004 and July 2017. Keywords used in the study included "hepatitis C," "HIV," "coinfection," and "direct-acting antiviral." SVR rates for those with HCV and HIV coinfection treated with interferon-based therapies were substantially lower that SVR rates of HCV-monoinfected individuals. The advent of DAA agents has resulted in similar SVR rates between monoinfected and coinfected individuals, with SVR >93%. These medications have been demonstrated to have improved safety, efficacy, and tolerability in comparison to interferon-based regimens. CONCLUSION The designation of a "special population" for those with coinfection requires reconsideration; DAA therapies have resulted in similarly high rates of SVR for HCV infection in those with and without HIV infection; despite these improvements, however, clinicians must be cognizant of negative predictors of SVR and barriers to treatment that may be more common in the coinfected population. (Hepatology 2018;67:847-857).
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Affiliation(s)
- Cameron Sikavi
- Department of Medicine at Harbor, University of California at Los Angeles Medical Center, Torrance, CA
| | - Phillip H Chen
- Department of Surgery, University of California at Los Angeles, Los Angeles, CA
| | - Alex D Lee
- Department of Surgery, University of California at Los Angeles, Los Angeles, CA
| | - Elena G Saab
- Department of Surgery, University of California at Los Angeles, Los Angeles, CA
| | - Gina Choi
- Department of Surgery, University of California at Los Angeles, Los Angeles, CA.,Department of Medicine, University of California at Los Angeles, Los Angeles, CA
| | - Sammy Saab
- Department of Surgery, University of California at Los Angeles, Los Angeles, CA.,Department of Medicine, University of California at Los Angeles, Los Angeles, CA
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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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Naggie S, Muir AJ. Oral Combination Therapies for Hepatitis C Virus Infection: Successes, Challenges, and Unmet Needs. Annu Rev Med 2017; 68:345-358. [PMID: 27686017 DOI: 10.1146/annurev-med-052915-015720] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
The current standard of care for the treatment of hepatitis C virus (HCV) consists of interferon-free direct-acting antiviral (DAA) regimens, including combinations of DAAs and fixed-dose combination pills. DAAs for HCV are likely to be heralded as one of medicine's greatest advancements. Viral eradication rates are pushing 100% for many HCV-infected populations, including patients with HIV/HCV coinfection, decompensated cirrhosis, liver and kidney transplants, and end-stage liver disease. We highlight the greatest successes of combination DAA therapies, discuss the ongoing challenges, and identify the remaining patient subgroups with unmet medical needs.
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Affiliation(s)
- Susanna Naggie
- Duke University School of Medicine and Duke Clinical Research Institute, Durham, North Carolina 27715;
| | - Andrew J Muir
- Duke University School of Medicine and Duke Clinical Research Institute, Durham, North Carolina 27715;
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Abstract
Human immunodeficiency virus (HIV) and hepatitis C virus (HCV) infections affect millions of persons around the globe and cause profound morbidity and mortality. A major intersection exists between these two epidemics, with HCV infection being more common in persons with HIV than in the general population, largely due to shared routes of transmission. HCV co-infection increases risk for liver- and non-liver-related morbidity and mortality, making HCV treatment a priority in HIV co-infected persons, but the treatment of HCV in co-infected patients has been daunting for multiple reasons. Until recently, HCV treatment has frequently been deferred due to the low rates of cure, significant adverse effects, burdensome duration of therapy and drug-drug interactions with HIV antiretroviral medications. Untreated HCV has resulted in significant health consequences for the millions of those infected and has led to multiple downstream impacts on our healthcare systems around the world. The development of a remarkable number of new HCV direct-acting agents (DAAs) that are significantly more efficacious and tolerable than the previous interferon-based regimens has transformed this important field of medicine, with the potential to dramatically reduce the burden of infection and improve health outcomes in this population. This review will summarize the epidemiology and clinical impact of HIV/HCV co-infection and current approaches to the treatment of HCV in HIV/HCV co-infected patients.
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Affiliation(s)
- Jake A. Scott
- Division of Infectious Diseases and Geographic Medicine, Department of Medicine, Stanford University School of Medicine, Palo Alto, CA, USA
| | - Kara W. Chew
- Division of Infectious Diseases, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
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10
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Bagwell A, Chastain CA. Hepatitis C Treatment in HIV Coinfection: Approaches, Challenges, and Future Opportunities. CURRENT TREATMENT OPTIONS IN INFECTIOUS DISEASES 2016. [DOI: 10.1007/s40506-016-0097-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
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11
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Hull M, Shafran S, Wong A, Tseng A, Giguère P, Barrett L, Haider S, Conway B, Klein M, Cooper C. CIHR Canadian HIV Trials Network Coinfection and Concurrent Diseases Core Research Group: 2016 Updated Canadian HIV/Hepatitis C Adult Guidelines for Management and Treatment. THE CANADIAN JOURNAL OF INFECTIOUS DISEASES & MEDICAL MICROBIOLOGY = JOURNAL CANADIEN DES MALADIES INFECTIEUSES ET DE LA MICROBIOLOGIE MEDICALE 2016; 2016:4385643. [PMID: 27471521 PMCID: PMC4947683 DOI: 10.1155/2016/4385643] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 09/25/2015] [Accepted: 12/15/2015] [Indexed: 12/13/2022]
Abstract
Background. Hepatitis C virus (HCV) coinfection occurs in 20-30% of Canadians living with HIV and is responsible for a heavy burden of morbidity and mortality. Purpose. To update national standards for management of HCV-HIV coinfected adults in the Canadian context with evolving evidence for and accessibility of effective and tolerable DAA therapies. The document addresses patient workup and treatment preparation, antiviral recommendations overall and in specific populations, and drug-drug interactions. Methods. A standing working group with HIV-HCV expertise was convened by The Canadian Institute of Health Research HIV Trials Network to review recently published HCV antiviral data and update Canadian HIV-HCV Coinfection Guidelines. Results. The gap in sustained virologic response between HCV monoinfection and HIV-HCV coinfection has been eliminated with newer HCV antiviral regimens. All coinfected individuals should be assessed for interferon-free, Direct Acting Antiviral HCV therapy. Regimens vary in content, duration, and success based largely on genotype. Reimbursement restrictions forcing the use of pegylated interferon is not acceptable if optimal patient care is to be provided. Discussion. Recommendations may not supersede individual clinical judgement. Treatment advances published since December 2015 are not considered in this document.
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Affiliation(s)
- Mark Hull
- British Columbia Centre for Excellence in HIV/AIDS, University of British Columbia, Vancouver, BC, Canada V6T 1Z4
| | | | - Alex Wong
- Regina Qu'Appelle Health Region, Regina, SK, Canada S4P 1E2
| | - Alice Tseng
- Toronto General Hospital, Toronto, ON, Canada M5G 2C4
| | | | - Lisa Barrett
- Dalhousie University, Halifax, NS, Canada B3H 4R2
| | | | - Brian Conway
- Vancouver Infectious Diseases Centre, Vancouver, BC, Canada V6Z 2C7
| | | | - Curtis Cooper
- The Ottawa Hospital, General Campus, G12, 501 Smyth Road, Ottawa, ON, Canada K1H 8L6
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Rockstroh JK, Hardy WD. Current treatment options for hepatitis C patients co-infected with HIV. Expert Rev Gastroenterol Hepatol 2016; 10:689-95. [PMID: 26799571 DOI: 10.1586/17474124.2016.1145545] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
With the availability of all-oral, direct acting antivirals (DAAs), hepatitis C virus (HCV) therapy has been revolutionized for HIV/HCV co-infected patients. Indeed HCV cure rates are now no longer different between HCV mono and HIV/HCV co-infected persons and are both greater than 95%. Therefore, current treatment guidelines no longer separate these two groups. Indications for HCV treatment and choice of DAA combination are now the same for all HCV patients. In HIV/HCV co-infection however, drug interactions between HIV and HCV agents need be checked prior to starting HCV therapy. Finally, the higher risk of hepatic decompensation in HIV/HCV co-infected patients, including those receiving successful antiretroviral therapy, continues to make these patients a high priority group for receiving access to modern DAA combination therapy.
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Affiliation(s)
- Jürgen Kurt Rockstroh
- a Department of Medicine I , Bonn University Hospital , Bonn , Germany.,b German Centre for Infection Research (DZIF) , Partner Site Bonn-Cologne , Bonn , Germany
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Wang LS, D'Souza LS, Jacobson IM. Hepatitis C-A clinical review. J Med Virol 2016; 88:1844-55. [PMID: 27097298 DOI: 10.1002/jmv.24554] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/10/2016] [Indexed: 12/18/2022]
Abstract
With an estimated prevalence of about 170 million people worldwide, chronic hepatitis C is an important cause of chronic liver disease associated with a substantial risk of cirrhosis and hepatocellular carcinoma. The recent past has borne witness to remarkable advancements in the treatment of chronic hepatitis C with the development of novel, effective, and well tolerated medications that have resulted in paradigm shifts in treatment approaches and may potentially affect the natural history of the disease. We provide a clinical review of current concepts and future developments in the management of chronic hepatitis C to aid in the understanding and individualization of chronic hepatitis C treatment. J. Med. Virol. 88:1844-1855, 2016. © 2016 Wiley Periodicals, Inc.
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Affiliation(s)
- Lan S Wang
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Texas Health Science Center at Houston, Houston, Texas
| | - Lionel S D'Souza
- Division of Digestive Diseases, Department of Medicine, Mount Sinai Beth Israel Medical Center, New York, New York
| | - Ira M Jacobson
- Division of Digestive Diseases, Department of Medicine, Mount Sinai Beth Israel Medical Center, New York, New York
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Current guidelines and prioritizing treatment of hepatitis C virus in HIV-infected patients. Curr Opin HIV AIDS 2016; 10:323-9. [PMID: 26248119 DOI: 10.1097/coh.0000000000000178] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
PURPOSE OF REVIEW Coinfection with hepatitis C virus (HCV) and HIV is a significant public health problem worldwide. The broad spectrum antivirals interferon-alpha (IFN) and ribavirin (RBV) have lower sustained virologic response rates in HIV-HCV coinfection compared with HCV monoinfection, with significant associated toxicities and prolonged treatment courses. The recent availability of direct acting antivirals (DAA) has transformed the treatment of HCV, with the opportunity of cure available for most patients with much more tolerable regimens. These regimens are now being studied in HIV-HCV coinfection. RECENT FINDINGS DAA-based regimens for HIV-HCV coinfection have shown excellent efficacy, with cure rates similar to HCV monoinfection. Either in combination with IFN and RBV, or in 'IFN-free' regimens, cure rates of over 90% are the goal for all HIV-HCV-infected individuals. Data are excellent in genotype 1 infection, but further data on genotype 2-6 are required. These regimens have been shown to be cost-effective in HCV monoinfection, and are likely to be cost-effective in HIV-HCV coinfection. Nonetheless they remain expensive. Recent guidelines have identified coinfected patients as a group for prioritization for treatment, regardless of fibrosis stage. Earlier treatment of those likely to transmit HCV is also recommended. SUMMARY With the use of DAA, HCV infection in HIV should be curable for most patients, and HIV-infected patients should be prioritized for treatment. The optimal treatment regimens for some genotypes have yet to be determined. The significant cost of DAA-containing regimens is likely to significantly impair their widespread use for the short to medium term, even in well resourced settings, and those with more advanced liver disease are likely to access them first.
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Direct-acting antiviral-based therapy for chronic hepatitis C virus in HIV-infected patients. Curr Opin HIV AIDS 2016; 10:337-47. [PMID: 26248121 DOI: 10.1097/coh.0000000000000182] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
PURPOSE OF REVIEW The aim of this review was to detail the current therapies and treatments for chronic hepatitis C virus in coinfected patients, focusing on HCV antiviral agents currently used in practice today or scheduled to enter the open market soon. RECENT FINDINGS Several direct-acting antiviral (DAA) combinations show high sustained virologic response (SVR) rates in HIV/HCV-coinfected patients, which are often close to those observed in HCV-monoinfected patients. Most recommendations regarding treatment stem from trials with coinfected patients. However, data are lacking for some aspects of HCV-treatment in coinfection, so extrapolations must be made from data obtained predominately from monoinfected patients. SUMMARY HIV/HCV-coinfected patients, who, not too long ago, had inferior outcomes in capturing SVR, now enjoy similar fates as the monoinfected patients. They should thus be prioritized for treatment, since HCV and liver disease have become major causes of morbidity and mortality in this population. However, potential drug-drug interactions between antiretroviral agents and DAAs have to be systematically anticipated before initiating HCV therapy.
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Directly acting antivirals for hepatitis C virus arrive in HIV/hepatitis C virus co-infected patients: from 'mind the gap' to 'where's the gap?'. AIDS 2016; 30:975-89. [PMID: 26836785 DOI: 10.1097/qad.0000000000001042] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
In patients living with HIV infection with hepatitis C (HCV) is common. HIV/HCV co-infection results in more rapid liver fibrosis progression than HCV alone and end-stage liver disease is a major cause of morbidity and mortality in co-infected patients. Historically, treatment outcomes with interferon based therapy in this group have been poor but with the advent of directly acting antiviral (DAA) drugs for HCV, rates of cure have improved dramatically. This article reviews recent evidence on the treatment of HCV in co-infected patients including the efficacy of new regimens and information on drug-drug interactions between DAAs and antiretroviral therapy. We also discuss the relationship between the pathogenesis of HIV and HCV infections, the treatment of acute hepatitis C and the current debate regarding the cost-effectiveness and affordability of DAAs.
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17
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Reau N, Fried MW, Nelson DR, Brown RS, Everson GT, Gordon SC, Jacobson IM, Lim JK, Pockros PJ, Reddy KR, Sherman KE. HCV Council--critical appraisal of data: recommendations for clinical practice in a rapidly evolving therapeutic landscape. Liver Int 2016; 36:488-502. [PMID: 26509462 PMCID: PMC5063106 DOI: 10.1111/liv.12993] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2015] [Accepted: 10/21/2015] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS HCV Council 2014, like its predecessor HCV Council 2011, assembled leading clinicians and researchers in the field of hepatitis C to critically evaluate current data regarding best practices for managing patients with chronic hepatitis C virus (HCV). METHODS Clinical practice statements were developed that reflect the areas of potential controversy with high clinical impact. Faculty members were responsible for reviewing the literature to support or reject these statements. After a review and comprehensive discussion of the data, the HCV Council faculty voted on the nature of the evidence and the level of support for each statement. RESULTS The results of the detailed analysis with expert opinion are summarized in this article. CONCLUSION Numerous questions regarding optimal management of certain populations and clinical scenarios remain unanswered. The discussion in the article provides a summary of evidenced-based expert opinion that may help guide clinicians as additional information is developed.
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Affiliation(s)
- Nancy Reau
- Rush University Medical CenterChicagoILUSA
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18
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Maruyama A, Hussaini T, Partovi N, Erb SR, Azalgara VM, Zalunardo N, Pick N, Hull M, Yoshida EM. Successful Treatment of Hepatitis C with Simeprevir, Sofosbuvir, and Ribavirin in an HIV Coinfected Liver Transplant Patient with Advanced Chronic Kidney Disease. THE CANADIAN JOURNAL OF INFECTIOUS DISEASES & MEDICAL MICROBIOLOGY = JOURNAL CANADIEN DES MALADIES INFECTIEUSES ET DE LA MICROBIOLOGIE MEDICALE 2016; 2016:8372835. [PMID: 27366182 PMCID: PMC4904549 DOI: 10.1155/2016/8372835] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/11/2015] [Accepted: 08/10/2015] [Indexed: 06/06/2023]
Abstract
Although major advances have occurred in treating patients with hepatitis C virus (HCV) with the development of new direct-acting antivirals (DAAs), treatment of liver transplant recipients with HCV, human immunodeficiency virus (HIV) coinfection, and renal disease is challenging due to the lack of efficacy and safety data in this population. We report a case of successful HCV therapy in a postliver transplant HIV coinfected patient, with stage 4 chronic kidney disease, using an all-oral regimen of simeprevir, sofosbuvir, and ribavirin. The 51-year-old male achieved SVR24, and no specific HIV-related or transplant-related adverse events were documented during the treatment period. The new DAAs show promise for HIV coinfected patients and those with severe to end-stage renal disease (ESRD); however, robust clinical trials or large cohort studies will need to be conducted to confirm the efficacy and safety of these newer agents in this setting.
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Affiliation(s)
- Anna Maruyama
- Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, Canada
| | - Trana Hussaini
- Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, Canada
| | - Nilufar Partovi
- Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, Canada
| | - Siegfried R. Erb
- Division of Gastroenterology, University of British Columbia, Vancouver, BC, Canada
| | | | - Nadia Zalunardo
- Division of Nephrology, University of British Columbia, Vancouver, BC, Canada
| | - Neora Pick
- Division of AIDS, University of British Columbia, Vancouver, BC, Canada
| | - Mark Hull
- Division of AIDS, University of British Columbia, Vancouver, BC, Canada
| | - Eric M. Yoshida
- Division of Gastroenterology, University of British Columbia, Vancouver, BC, Canada
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19
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Diatta T, Chavade D, Degos F, d'Andon A, Guillevin L. [Hepatitis C infection: Therapeutic strategies]. Presse Med 2016; 45:495-508. [PMID: 27006245 DOI: 10.1016/j.lpm.2016.02.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2016] [Revised: 02/19/2016] [Accepted: 02/22/2016] [Indexed: 10/22/2022] Open
Abstract
The development of new direct acting antivirals has significantly modified strategies to treat chronic hepatitis C. Treatments were previously made of an interferon-based combination. This article aims to review the direct acting antivirals clinical data and to discuss the new regimens for the management of chronic hepatitis C. Direct acting antivirals combinations - with or without ribavirin - are the new chronic hepatitis C standard treatment regimen. These combinations often result in sustained viral response rate (>90%, including in patients with uncomplicated cirrhosis) after a 12-week treatment for most patients. The innovation could represent a new era for patients with unmet medical need (especially ineligible or non-responders to interferon and/or ribavirin patients). Further investigations are required to confirm the efficacy in specific population (complicated cirrhosis, pre- or post-transplantation, chronic renal failure, comorbidities, etc.) where clinical data are still limited. Other treatments are currently being developed and might lead to new perspectives, especially in terms of treatment duration or therapeutic simplification.
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Affiliation(s)
- Thierno Diatta
- Haute Autorité de santé, service évaluation du médicament, 5, avenue du Stade-de-France, 93218 Saint-Denis La Plaine cedex, France.
| | - Delphine Chavade
- Haute Autorité de santé, service évaluation du médicament, 5, avenue du Stade-de-France, 93218 Saint-Denis La Plaine cedex, France
| | - Françoise Degos
- Haute Autorité de santé, service évaluation du médicament, 5, avenue du Stade-de-France, 93218 Saint-Denis La Plaine cedex, France
| | - Anne d'Andon
- Haute Autorité de santé, service évaluation du médicament, 5, avenue du Stade-de-France, 93218 Saint-Denis La Plaine cedex, France
| | - Loïc Guillevin
- Haute Autorité de santé, service évaluation du médicament, 5, avenue du Stade-de-France, 93218 Saint-Denis La Plaine cedex, France
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20
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Scherer ML, Sammons C, Nelson B, Hammer SM, Verna E. Anti-Hepatitis Virus Agents. CLINICAL VIROLOGY 2016:239-270. [DOI: 10.1128/9781555819439.ch13] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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21
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Bednasz CJ, Sawyer JR, Martinez A, Rose PG, Sithole SS, Hamilton HR, Kaufman FS, Venuto CS, Ma Q, Talal A, Morse GD. Recent advances in management of the HIV/HCV coinfected patient. Future Virol 2016; 10:981-997. [PMID: 26877758 PMCID: PMC4751983 DOI: 10.2217/fvl.15.64] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Chronic hepatitis C virus (HCV) is a global epidemic, affecting approximately 150 million individuals throughout the world. The implications of HCV infection have been magnified in those who are infected with both HCV and the HIV as liver disease progression, liver failure and liver-related death are increased, particularly in those without well-controlled HIV disease. The development of direct-acting antiviral agents for HCV that allow shorter treatment periods with increased efficacy and decreased adverse events have greatly changed the outlook for HCV-infected individuals. With these advancements, growing treatment options for the coinfected population have also come. This review will address pharmacotherapy issues in the HIV/HCV coinfected population.
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Affiliation(s)
- Cindy J Bednasz
- School of Pharmacy & Pharmaceutical Sciences,
University at Buffalo, 285 Kapoor Hall, Buffalo, New York 14214, USA
- New York State Center of Excellence in Bioinformatics
& Life Sciences, University at Bufalo, 701 Ellicott Street, Buffalo, New
York 14203, USA
| | - Joshua R Sawyer
- School of Pharmacy & Pharmaceutical Sciences,
University at Buffalo, 285 Kapoor Hall, Buffalo, New York 14214, USA
| | - Anthony Martinez
- Buffalo General Medical Center, University at Buffalo,
Room. 617F, B Building, Buffalo, New York 14203, USA
- Hepatology, Division of Gastroenterology, Hepatology
& Nutrition, Erie County Medical Center, 462 Grider Street, Buffalo, New
York 14215, USA
| | - Patrick G Rose
- School of Pharmacy & Pharmaceutical Sciences,
University at Buffalo, 285 Kapoor Hall, Buffalo, New York 14214, USA
| | - Samantha S Sithole
- Translational Pharmacology Research Core, niversity at
Buffalo, 701 Ellicott Street, Buffalo, New York 14203, USA
| | - Holly R Hamilton
- New York State Center of Excellence in Bioinformatics
& Life Sciences, University at Bufalo, 701 Ellicott Street, Buffalo, New
York 14203, USA
- Immunodeficiency Services Clinic, Erie County Medical
Center, 462 Grider Street, Buffalo, New York 14215, USA
| | - Farzia S Kaufman
- Translational Pharmacology Research Core, NYS Center of
Excellence in Bioinformatics & Life Sciences, University at Buffalo, 701
Ellicott Street, Buffalo, New York 14203–1101, USA
| | - Charles S Venuto
- Center for Human Experimental Therapeutics, University of
Rochester Medical Center, 265 Crittenden Blvd. CU 420694, Rochester, New York
14642–0694, USA
| | - Qing Ma
- School of Pharmacy & Pharmaceutical Sciences, New
York State Center of Excellence in Bioinformatics & Life Sciences,
University at Buffalo, 701 Ellicott Street, Buffalo, New York 14203, USA
| | - Andrew Talal
- UBMD Center for Clinical Care & Research in Liver
Disease, 875 Ellicott Street, Suite 6090, Buffalo, New York 14203, USA
- Division of Gastroenterology, Hepatology and Nutrition,
Clinical & Translational Research Center, 875 Ellicott Street, Suite 6090,
Buffalo, New York 14203, USA
| | - Gene D Morse
- Pharmacy Practice (Medicine and Pediatrics), School of
Pharmacy and Pharmaceutical Sciences, University at Buffalo, 285 Kapoor Hall,
Buffalo, New York 14214, USA
- New York State Center of Excellence in Bioinformatics and
Life Sciences, University at Buffalo, 701 Ellicott Street, Buffalo, New York 14203,
USA
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22
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Pillai AA, Wedd J, Norvell JP, Parekh S, Cheng N, Young N, Spivey JR, Ford R. Simeprevir and Sofosbuvir (SMV-SOF) for 12 Weeks for the Treatment of Chronic Hepatitis C Genotype 1 Infection: A Real World (Transplant) Hepatology Practice Experience. Am J Gastroenterol 2016; 111:250-60. [PMID: 26832650 DOI: 10.1038/ajg.2015.422] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2015] [Accepted: 12/04/2015] [Indexed: 12/11/2022]
Abstract
OBJECTIVES The combination of simeprevir (SMV) and sofosbuvir (SOF) was found to be well-tolerated with high sustained virologic response (SVR) rates in patients with genotype 1 chronic hepatitis C in clinical trials. Previous experience with hepatitis C virus (HCV) therapy has shown that patient tolerability and treatment efficacy described in controlled clinical trials did not necessarily mirror the "real world" experience. The goal of this study was to define SVR rates in a "real world" analysis and to explore predictors of treatment response with SMV and SOF. METHODS This is a retrospective study examining the "real world" treatment of 170 patients with chronic HCV genotype 1 using the combination of SMV and SOF with or without ribavirin (RBV) for a fixed 12-week duration irrespective of prior interferon therapy, transplant status or fibrosis stage. Differences between SVR cohorts were analyzed by both intention-to-treat (ITT) and per protocol. RESULTS The vast majority of patients were genotype 1a, 77% were cirrhotic in the non-LT group, and 35% of the entire cohort was African-American. Combination treatment with SMV and SOF in genotype 1 chronic HCV patients achieved an overall SVR rate at 12 weeks after completion of therapy (SVR12) of 78% by ITT and 86% by per protocol (84% in non-liver transplant (LT) patients and 89% in post-LT recipients). The presence of hepatocellular carcinoma was found to be a significant negative predictor of SVR12, whereas an undetectable week eight VL was a significant positive predictor of SVR in the entire cohort. CONCLUSIONS Our data confirm excellent SVR outcomes with favorable safety and tolerability profiles in patients who carry many traditional high-risk features for non-response, including post-LT recipients and patients with advanced liver disease.
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Affiliation(s)
- Anjana A Pillai
- Emory University Hospital, Section of Hepatology, Division of Digestive Diseases and The Emory Transplant Center, Atlanta, Georgia, USA
| | - Joel Wedd
- Emory University Hospital, Section of Hepatology, Division of Digestive Diseases and The Emory Transplant Center, Atlanta, Georgia, USA
| | - J P Norvell
- Emory University Hospital, Section of Hepatology, Division of Digestive Diseases and The Emory Transplant Center, Atlanta, Georgia, USA
| | - Samir Parekh
- Emory University Hospital, Section of Hepatology, Division of Digestive Diseases and The Emory Transplant Center, Atlanta, Georgia, USA
| | - Nicole Cheng
- Emory University Hospital, Section of Hepatology, Division of Digestive Diseases and The Emory Transplant Center, Atlanta, Georgia, USA
| | - Nikita Young
- Emory University Hospital, Section of Hepatology, Division of Digestive Diseases and The Emory Transplant Center, Atlanta, Georgia, USA
| | - James R Spivey
- Emory University Hospital, Section of Hepatology, Division of Digestive Diseases and The Emory Transplant Center, Atlanta, Georgia, USA
| | - Ryan Ford
- Emory University Hospital, Section of Hepatology, Division of Digestive Diseases and The Emory Transplant Center, Atlanta, Georgia, USA
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23
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Andersohn F, Claes AK, Kulp W, Mahlich J, Rockstroh JK. Simeprevir with pegylated interferon alfa 2a plus ribavirin for treatment of hepatitis C virus genotype 1 in patients with HIV: a meta-analysis and historical comparison. BMC Infect Dis 2016; 16:10. [PMID: 26753774 PMCID: PMC4709957 DOI: 10.1186/s12879-015-1311-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2014] [Accepted: 12/07/2015] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND About one third of patients infected with human immunodeficiency virus (HIV) also have chronic hepatitis due to hepatitis C virus (HCV). HCV therapy with simeprevir, pegylated interferon alfa (PegIFNα) and ribavirin (RBV) have been shown to be superior to PegIFNα + RBV alone in non-HIV patients, but no randomized trials in patients with HCV genotype 1 (HCV-1)/HIV coinfection are available. METHODS This was a historical comparison of study C212 (simeprevir + PegIFNα-2a + RBV in patients with HCV-1/HIV coinfection) with studies in which HCV-1/HIV coinfected patients were treated with PegIFNα-2a + RBV alone. A systematic literature search was performed to identify eligible studies. Efficacy and safety results of PegIFNα-2a + RBV studies were combined in random- and fixed-effects inverse-variance weighted meta-analyses of proportions using the Freeman-Tukey double arcsin transformation method, and compared with the results of study C212. RESULTS The literature search revealed a total of 2392 records, with 206 articles selected for full-text review. Finally, 11 relevant articles reporting on 12 relevant study groups were included. Results on sustained virologic response 24 weeks after end of treatment (SVR24) were available from all 12 study groups. Pooled SVR24 for PegIFNα-2a + RBV from the random-effects meta-analysis was 28.2% (95% CI 23.8% to 32.9%). The comparison between study C212 (SVR24 = 72.6%; 95% CI 63.1% to 80.9%) revealed substantial superiority of simeprevir + PegIFNα-2a + RBV compared to PegIFNα-2a + RBV alone, with an absolute risk difference of 45% (95% CI 34 to 55). This finding was robust in a sensitivity analysis that only included historical studies with a planned treatment duration of at least 48 weeks and the same RBV dose as in study C212. No increases in the frequency of important adverse event categories including anemia were identified, but these analyses were limited by the low number of studies. CONCLUSION This historical comparison provides first systematic evidence for the superiority of simeprevir + PegIFNα-2a + RBV compared to PegIFNα-2a + RBV in patients with HCV-1/HIV coinfection. Given the limitations of the historical comparison for safety endpoints, additional data on the comparative safety of simeprevir in patients with HCV-1/HIV coinfection would be desirable. TRIAL REGISTRATION Identifier for study TMC435-TiDP16-C212 (ClinicalTrials.gov): NCT01479868.
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Affiliation(s)
- Frank Andersohn
- Charité - University Medicine Berlin; Institute for Social Medicine, Epidemiology and Health Economics, 10098, Berlin, Germany.
- Frank Andersohn Consulting & Research Services, Mandelstr. 16, 10409, Berlin, Germany.
| | | | - Werner Kulp
- Xcenda GmbH, Lange Laube 31, 30159, Hannover, Germany.
| | - Jörg Mahlich
- Janssen K.K., Tokyo, Japan.
- University of Düsseldorf; Düsseldorf Institute of Competition Economics (DICE), Universitätsstraße 1, 40225, Düsseldorf, Germany.
| | - Jürgen Kurt Rockstroh
- Department of Medicine I, University Hospital Bonn, Sigmund-Freud-Str. 25, 53105, Bonn, Germany.
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24
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Saeed S, Strumpf EC, Walmsley SL, Rollet-Kurhajec K, Pick N, Martel-Laferrière V, Hull M, Gill MJ, Cox J, Cooper C, Klein MB, Cohen J, Conway B, Cooper C, Côté P, Cox J, Gill J, Haider S, Harris M, Haase D, Hull M, Montaner J, Moodie E, Pick N, Rachlis A, Rouleau D, Sandre R, Tyndall JM, Vachon ML, Walmsley S, Wong D. How Generalizable Are the Results From Trials of Direct Antiviral Agents to People Coinfected With HIV/HCV in the Real World? Clin Infect Dis 2016; 62:919-926. [PMID: 26743093 PMCID: PMC4787608 DOI: 10.1093/cid/civ1222] [Citation(s) in RCA: 63] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2015] [Accepted: 11/18/2015] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Direct-acting antivirals (DAAs) against hepatitis C virus (HCV) have been described as revolutionary. However, it remains uncertain how effective these drugs will be for individuals coinfected with human immunodeficiency virus (HIV)-HCV. Bridging this gap between efficacy and effectiveness requires a focus on the generalizability of clinical trials. METHODS Generalizability of DAA trials was assessed by applying the eligibility criteria from 5 efficacy trials: NCT01479868, PHOTON-1 (NCT01667731), TURQUOISE-I (NCT01939197), ION-4 (NCT02073656), and ALLY-2 (NCT02032888) that evaluated simeprevir; sofosbuvir; ombitasvir, paritaprevir/ritonavir/dasabuvir; sofosbuvir/ledipasvir; and daclatasvir/sofosbuvir, respectively, to the Canadian Coinfection Cohort, representing approximately 23% of the total coinfected population in care in Canada. RESULTS Of 874 active participants, 70% had chronic HCV, of whom 410, 26, 94, and 11 had genotypes 1, 2, 3, and 4, respectively. After applying trial eligibility criteria, only 5.9% (24/410) would have been eligible for enrollment in the simeprevir trial, 9.8% (52/530) in PHOTON-1, 6.3% (26/410) in TURQUOISE-I, and 8.1% (34/421) in ION-4. The ALLY-2 study was more inclusive; 43% (233/541) of the cohort would have been eligible. The most exclusive eligibility criteria across all trials with the exception of ALLY-2 were restriction to specific antiretroviral therapies (63%-79%) and active illicit drug use (53%-55%). CONCLUSIONS DAA trial results may have limited generalizability, since the majority of coinfected individuals were not eligible to participate. Exclusions appeared to be related to improving treatment outcomes by not including those at higher risk of poor adherence and reinfection--individuals for whom real-world data are urgently needed.
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Affiliation(s)
- Sahar Saeed
- Department of Medicine, Division of Infectious Diseases/Chronic Viral Illness Service, McGill University Health Centre.,Department of Epidemiology & Biostatistics
| | - Erin C Strumpf
- Department of Epidemiology & Biostatistics.,Department of Economics, McGill University, Montreal, Quebec
| | - Sharon L Walmsley
- Division of Infectious Diseases, Toronto Hospital, University Health Network, Ontario.,Canadian Institutes of Health Research, Canadian HIV Trials Network
| | - Kathleen Rollet-Kurhajec
- Department of Medicine, Division of Infectious Diseases/Chronic Viral Illness Service, McGill University Health Centre
| | - Neora Pick
- Division of Infectious Diseases, Oak Tree Clinic, BC Women's Hospital, Vancouver, British Columbia
| | | | - Mark Hull
- Department of Infectious Disease, Centre for Excellence in HIV/AIDS, St. Paul's Hospital, Vancouver, British Columbia
| | | | - Joseph Cox
- Department of Epidemiology & Biostatistics.,Public Health Department, Montreal Health and Social Services Agency, Quebec
| | - Curtis Cooper
- Department of Medicine, University of Ottawa, Ontario, Canada
| | - Marina B Klein
- Department of Medicine, Division of Infectious Diseases/Chronic Viral Illness Service, McGill University Health Centre.,Canadian Institutes of Health Research, Canadian HIV Trials Network
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25
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Qing J, Luo R, Wang Y, Nong J, Wu M, Shao Y, Tang R, Yu X, Yin Z, Sun Y. Resistance analysis and characterization of NITD008 as an adenosine analog inhibitor against hepatitis C virus. Antiviral Res 2015; 126:43-54. [PMID: 26724382 DOI: 10.1016/j.antiviral.2015.12.010] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2015] [Revised: 12/19/2015] [Accepted: 12/22/2015] [Indexed: 12/18/2022]
Abstract
Hepatitis disease caused by hepatitis C virus (HCV) is a severe threat to global public health, affecting approximately 3% of the world's population. Sofosbuvir (PSI-7977), a uridine nucleotide analog inhibitor targeting the HCV NS5B polymerase, was approved by FDA at the end of 2013 and represents a key step towards a new era in the management of HCV infection. Previous study identified NITD008, an adenosine nucleoside analog, as the specific inhibitor against dengue virus and showed good antiviral effect on other flaviviruses or enteroviruses. In this report, we systematically analyzed the anti-HCV profile of NITD008, which was discovered to effectively suppress the replication of different strains of HCV in human hepatoma cells with a low nanomolar activity. On genotype 2a virus, or 2a, 1a, and 1b replicon cells, EC50 values were 8.7 nM, 93.3 nM, 60.0 nM and 67.2 nM, and selective index values were >2298.9, >214.4, >333.3, >298.5 respectively. We demonstrated that resistance to NITD008 was conferred by mutation in NS5B (S282T) in the HCV infectious virus genotype 2a (JFH-1). Then, we compared the resistant profiles of NITD008 and PSI-7977, and found that the folds change of EC50 of NITD008 to full replicon cells containing mutation S282T was much bigger than PSI-7977(folds 76.50 vs. 4.52). Analysis of NITD008 cross-resistance against previously reported NS5B drug-selected mutations showed that the resistance pattern of NITD008 was not completely similar to PSI-7977, and meanwhile, S282T resistant mutation to NITD008 emerge more easily in cell culture than PSI-7977. Interestingly, NITD008 displayed significant synergistic effects with the NS5B polymerase inhibitor PSI-7977, however, only additive effects with alpha interferon (IFNα-2b), ribavirin, and an NS3 protease inhibitor. These results verify that NITD008 is an effective analog inhibitor against hepatitis C virus and a good research tool as a supplement to other types of nucleoside analogs.
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Affiliation(s)
- Jie Qing
- Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China.
| | - Rui Luo
- Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China
| | - Yaxin Wang
- Center of Basic Molecular Science, Department of Chemistry, Tsinghua University, Beijing 100084, China
| | - Junxiu Nong
- Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China
| | - Ming Wu
- Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China
| | - Yan Shao
- Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China
| | - Ruoyi Tang
- Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China
| | - Xi Yu
- Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China
| | - Zheng Yin
- Center of Basic Molecular Science, Department of Chemistry, Tsinghua University, Beijing 100084, China.
| | - Yuna Sun
- National Laboratory of Macromolecules, Institute of Biophysics, Chinese Academy of Science, Beijing 100101, China.
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26
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Mandorfer M, Steiner S, Schwabl P, Payer BA, Aichelburg MC, Grabmeier-Pfistershammer K, Trauner M, Reiberger T, Peck-Radosavljevic M. Treatment intensification with boceprevir in HIV-positive patients with acute HCV-genotype 1 infection at high risk for treatment failure. Wien Klin Wochenschr 2015; 128:414-20. [PMID: 26659706 DOI: 10.1007/s00508-015-0912-6] [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: 07/06/2015] [Accepted: 11/19/2015] [Indexed: 12/25/2022]
Abstract
BACKGROUND According to current guidelines, the universal use of direct-acting antiviral agents in HIV-positive patients with acute hepatitis C (AHC) is not recommended. We aimed to evaluate the concept of treatment intensification with boceprevir (BOC) in HIV-positive patients with HCV-genotype 1 AHC (HIV/AHC-GT1) at high risk for failure to pegylated interferon/ribavirin therapy (PEGIFN/RBV). METHODS Nineteen consecutive HIV-positive patients with HIV/AHC-GT1 who underwent antiviral therapy were studied retrospectively. Patients were treated with PEGIFN/RBV for 24 or 48 weeks, depending on rapid virologic response (RVR; undetectable HCV-RNA at treatment week [W] 4). Patients without complete early virologic response (cEVR; undetectable HCV-RNA at W 12) were offered treatment intensification with BOC at W 12, resulting in 36 weeks of BOC/PEGIFN/RBV triple therapy (total treatment duration: 48 weeks). RESULTS Thirty-seven percent (7/19) of patients had an RVR and 74 % (14/19) of patients had a cEVR. BOC was used in four out of five patients who did not achieve cEVR and one patient elected to proceed with PEGIFN/RBV. Sustained virologic response (SVR; undetectable HCV-RNA 24 weeks after the end of treatment) rates were 100 % (14/14) among patients with cEVR treated with PEGIFN/RBV and 75 % (3/4) among patients without cEVR receiving BOC add-on. The patient without cEVR who preferred to continue with PEGIFN/RBV did not achieve SVR. Thus, the overall SVR rate was 89 % (17/19) in intention to treat analysis. CONCLUSIONS BOC add-on in selected HIV/AHC-GT1 resulted in a high overall SVR rate. If 2nd generation direct-acting antiviral agents (DAAs) are not available, treatment intensification with BOC can be considered in HIV/AHC-GT1 at high risk for failure to PEGIFN/RBV.
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Affiliation(s)
- Mattias Mandorfer
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.,Vienna HIV & Liver Study Group, Vienna, Austria
| | - Sebastian Steiner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.,Vienna HIV & Liver Study Group, Vienna, Austria
| | - Philipp Schwabl
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.,Vienna HIV & Liver Study Group, Vienna, Austria
| | - Berit A Payer
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.,Vienna HIV & Liver Study Group, Vienna, Austria
| | - Maximilian C Aichelburg
- Division of Immunology, Allergy and Infectious Diseases, Department of Dermatology, Medical University of Vienna, Vienna, Austria.,Vienna HIV & Liver Study Group, Vienna, Austria
| | - Katharina Grabmeier-Pfistershammer
- Division of Immunology, Allergy and Infectious Diseases, Department of Dermatology, Medical University of Vienna, Vienna, Austria.,Vienna HIV & Liver Study Group, Vienna, Austria
| | - Michael Trauner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria
| | - Thomas Reiberger
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.,Vienna HIV & Liver Study Group, Vienna, Austria
| | - Markus Peck-Radosavljevic
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria. .,Vienna HIV & Liver Study Group, Vienna, Austria.
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A Conserved Inhibitory Mechanism of a Lycorine Derivative against Enterovirus and Hepatitis C Virus. Antimicrob Agents Chemother 2015; 60:913-24. [PMID: 26596952 DOI: 10.1128/aac.02274-15] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2015] [Accepted: 11/19/2015] [Indexed: 02/06/2023] Open
Abstract
Enterovirus 71 (EV71) (Picornaviridae family) and hepatitis C virus (HCV) (Flaviviridae family) are the causative agents of human hand, foot, and mouth disease (HFMD) and hepatitis C, resulting in a severe pandemic involving millions of infections in the Asia-Pacific region and worldwide. The great impact of EV71 and HCV on public health highlights the need to further our understanding of the biology of these two viruses and develop effective therapeutic antivirals. Here, we evaluated a total of 32 lycorine derivatives and demonstrated that 1-acetyllycorine suppressed the proliferation of multiple strains of EV71 in various cells. The results of the drug resistance analysis revealed that 1-acetyllycorine targeted a phenylalanine (F76) in EV71 2A protease (2A(pro)) to stabilize the conformation of a unique zinc finger. Most interestingly, the zinc binding site in EV71 2A(pro) is the exclusive homolog of HCV NS3 among all viruses. Further analysis revealed that 1-acetyllycorine also inhibits HCV with high efficacy, and the mutation on R118 in HCV NS3, which corresponds to F76 in EV71 2A(pro), confers the resistance of HCV to 1-acetyllycorine. These results revealed a conserved mechanism of 1-acetyllycorine against EV71 and HCV through targeting viral proteases. We also documented the significant synergistic anti-EV71 and anti-HCV effects of 1-acetyllycorine with reported inhibitors, supporting potential combination therapy for the treatment of EV71 and HCV infections.
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Sanford M. Simeprevir: a review of its use in patients with chronic hepatitis C virus infection. Drugs 2015; 75:183-96. [PMID: 25559421 DOI: 10.1007/s40265-014-0341-2] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Simeprevir (Olysio™; Galexos™; Sovriad®) is an orally-administered NS3/4A protease inhibitor for use in combined drug regimens against chronic hepatitis C virus (HCV) infection. This article reviews studies relevant to the EU simeprevir label. In proof-of-concept studies, simeprevir had potent antiviral activity against all HCV genotypes, except genotype 3. In trials in patients with chronic HCV genotype 1 infection, week-12 sustained virological response (SVR12) rates in treatment-naïve patients and prior relapsers were significantly higher with simeprevir plus peginterferon-α/ribavirin (PR) [79-89 %] than with placebo plus PR (36-62 %). In prior partial/null responders, the SVR12 rate with simeprevir plus PR (54 %) was noninferior to that with telaprevir plus PR (55 %). Simeprevir plus PR was also efficacious in patients with HCV genotype 1/HIV-1 co-infection. In prior null responders without severe liver fibrosis (cohort 1) and treatment-naïve patients with severe liver fibrosis (cohort 2) treated with simeprevir plus sofosbuvir, the SVR12 rate for the two cohorts combined was 92 %. In patients with chronic HCV genotype 4 infection, the SVR12 rates with simeprevir plus PR were 83, 87 and 40 % in treatment-naïve patients, prior relapsers and prior null responders, respectively. Grade 3-4 adverse event, serious adverse event and treatment withdrawal rates with simeprevir plus PR were similar to those with placebo plus PR. Skin rashes with simeprevir were mostly mild or moderate; serious photosensitivity reactions occur, but are rare. Simeprevir is efficacious and generally well tolerated in patients with chronic HCV genotypes 1 and 4 infection. Studies of simeprevir in interferon-free regimens and in other subpopulations with HCV infections will be of interest.
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Affiliation(s)
- Mark Sanford
- Springer, Private Bag 65901, Mairangi Bay, 0754, Auckland, New Zealand,
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Abstract
Hepatitis C virus (HCV) coinfection is prevalent in patients with human immunodeficiency virus (HIV) and has an accelerated disease course. Direct-acting antiviral (DAA) therapies that do not require interferon increase response rates to levels identical to those seen in HCV monoinfection. However, drug-drug interaction between antiretrovirals and HCV medication is the major consideration in deciding on the appropriate HCV therapeutic approach in patients with HIV. This article summarizes the currently available data with HCV DAAs in patients with HIV, and focuses on predicting and managing drug interaction to facilitate successful DAA-based HCV therapy in those with HIV.
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Lo Re V, Kallan MJ, Tate JP, Lim JK, Goetz MB, Klein MB, Rimland D, Rodriguez-Barradas MC, Butt AA, Gibert CL, Brown ST, Park LS, Dubrow R, Reddy KR, Kostman JR, Justice AC, Localio AR. Predicting Risk of End-Stage Liver Disease in Antiretroviral-Treated Human Immunodeficiency Virus/Hepatitis C Virus-Coinfected Patients. Open Forum Infect Dis 2015; 2:ofv109. [PMID: 26284259 PMCID: PMC4536329 DOI: 10.1093/ofid/ofv109] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2015] [Accepted: 07/05/2015] [Indexed: 12/15/2022] Open
Abstract
Background. End-stage liver disease (ESLD) is an important cause of morbidity among human immunodeficiency virus (HIV)/hepatitis C virus (HCV)-coinfected patients. Quantifying the risk of this outcome over time could help determine which coinfected patients should be targeted for risk factor modification and HCV treatment. We evaluated demographic, clinical, and laboratory variables to predict risk of ESLD in HIV/HCV-coinfected patients receiving antiretroviral therapy (ART). Methods. We conducted a retrospective cohort study among 6016 HIV/HCV-coinfected patients who received ART within the Veterans Health Administration between 1997 and 2010. The main outcome was incident ESLD, defined by hepatic decompensation, hepatocellular carcinoma, or liver-related death. Cox regression was used to develop prognostic models based on baseline demographic, clinical, and laboratory variables, including FIB-4 and aspartate aminotransferase-to-platelet ratio index, previously validated markers of hepatic fibrosis. Model performance was assessed by discrimination and decision curve analysis. Results. Among 6016 HIV/HCV patients, 532 (8.8%) developed ESLD over a median of 6.6 years. A model comprising FIB-4 and race had modest discrimination for ESLD (c-statistic, 0.73) and higher net benefit than alternative strategies of treating no or all coinfected patients at relevant risk thresholds. For FIB-4 >3.25, ESLD risk ranged from 7.9% at 1 year to 26.0% at 5 years among non-blacks and from 2.4% at 1 year to 14.0% at 5 years among blacks. Conclusions. Race and FIB-4 provided important predictive information on ESLD risk among HIV/HCV patients. Estimating risk of ESLD using these variables could help direct HCV treatment decisions among HIV/HCV-coinfected patients.
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Affiliation(s)
- Vincent Lo Re
- Departments ofMedicine
- Biostatistics and Epidemiology and Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine, University of Pennsylvania, Philadelphia
- Medical Service, Philadelphia VA Medical Center, Pennsylvania
| | - Michael J. Kallan
- Biostatistics and Epidemiology and Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine, University of Pennsylvania, Philadelphia
| | - Janet P. Tate
- VA Connecticut Healthcare System, West Haven
- Yale University School of Medicine, New Haven, Connecticut
| | - Joseph K. Lim
- VA Connecticut Healthcare System, West Haven
- Yale University School of Medicine, New Haven, Connecticut
| | - Matthew Bidwell Goetz
- VA Greater Los Angeles Healthcare System and David Geffen School of Medicine at UCLA, California
| | - Marina B. Klein
- Chronic Viral Illness Service, McGill University Health Centre, Montreal, Canada
| | - David Rimland
- Atlanta VA Medical Center and Emory University School of Medicine, Georgia
| | - Maria C. Rodriguez-Barradas
- Infectious Diseases Section, Michael E. DeBakey VA Medical Center and Department of Medicine, Baylor College of Medicine, Houston, Texas
| | - Adeel A. Butt
- VA Pittsburgh Healthcare System, Pennsylvania
- Hamad Healthcare Quality Institute, Doha, Qatar
- Hamad Medical Corporation, Doha, Qatar
| | - Cynthia L. Gibert
- Washington DC VA Medical Center, George Washington University Medical Center, Washington, District of Columbia
| | - Sheldon T. Brown
- James J. Peters VA Medical Center and Mt. Sinai School of Medicine, New York, New York
| | - Lesley S. Park
- Yale University School of Medicine, New Haven, Connecticut
- Yale School of Public Health, New Haven, Connecticut
| | - Robert Dubrow
- Yale University School of Medicine, New Haven, Connecticut
- Yale School of Public Health, New Haven, Connecticut
| | | | | | - Amy C. Justice
- VA Connecticut Healthcare System, West Haven
- Yale University School of Medicine, New Haven, Connecticut
| | - A. Russell Localio
- Biostatistics and Epidemiology and Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine, University of Pennsylvania, Philadelphia
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Shuldiner SR, Gong L, Muir AJ, Altman RB, Klein TE. PharmGKB summary: peginterferon-α pathway. Pharmacogenet Genomics 2015; 25:465-74. [PMID: 26111151 PMCID: PMC4757589 DOI: 10.1097/fpc.0000000000000158] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Affiliation(s)
| | - Li Gong
- Department of Genetics, Stanford University, Stanford, California
| | - Andrew J. Muir
- Duke Clinical Research Institute, Duke University, Durham, North Carolina, USA
| | - Russ B. Altman
- Department of Genetics, Stanford University, Stanford, California
- Department of Bioengineering, Stanford University, Stanford, California
| | - Teri E. Klein
- Department of Genetics, Stanford University, Stanford, California
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Ermis F, Senocak Tasci E. New treatment strategies for hepatitis C infection. World J Hepatol 2015; 7:2100-2109. [PMID: 26301052 PMCID: PMC4539403 DOI: 10.4254/wjh.v7.i17.2100] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2015] [Revised: 06/04/2015] [Accepted: 07/18/2015] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C infection can lead to cirrhosis and hepatocellular carcinoma and it is an important cause of mortality and morbidity. Achieving a sustained virological response has been the major aim for decades. Interferon treatment was the primarily developed therapy against the infection. Addition of the guanosine analog ribavirin to stop viral RNA synthesis increased the response rates as well as the adverse effects of the treatment. The increasing demands for alternative regimens led to the development of direct-acting antivirals (DAAs). The approval of sofosbuvir and simeprevir signaled a new era of antiviral treatment for hepatitis C infection. Although the majority of studies have been performed with DAAs in combination with interferon and resulted in a decrease in treatment duration and increase in response rates, the response rates achieved with interferon-free regimens provided hope for patients ineligible for therapy with interferon. Most DAA studies are in phase II leading to phase III. In the near future more DAAs are expected to be approved. The main disadvantage of the therapy remains the cost of the drugs. Here, we focus on new treatment strategies for hepatitis C infection as well as agents targeting hepatitis C virus replication that are in clinical development.
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Affiliation(s)
- Fatih Ermis
- Fatih Ermis, Department of Gastroenterology, Duzce University Faculty of Medicine, 81620 Duzce, Turkey
| | - Elif Senocak Tasci
- Fatih Ermis, Department of Gastroenterology, Duzce University Faculty of Medicine, 81620 Duzce, Turkey
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Shafran SD. HIV Coinfected Have Similar SVR Rates as HCV Monoinfected With DAAs: It's Time to End Segregation and Integrate HIV Patients Into HCV Trials. Clin Infect Dis 2015; 61:1127-34. [DOI: 10.1093/cid/civ438] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2015] [Accepted: 05/21/2015] [Indexed: 12/19/2022] Open
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Abstract
Since the approval of the first direct-acting antiviral agents (DAAs), treatment for hepatitis C virus (HCV) has undergone significant transformation. A new milestone in the treatment of HCV, the approval of the first interferon-free regimens, could be achieved by the end of 2013. For patients with HCV who have absolute or relative contraindications to pegylated-interferon or have failed the currently available treatments, the arrival of new regimens will have a major impact on long-term outcomes. The combinations of DAAs in trials are numerous, and many have demonstrated sustained virologic response rates higher than 90 %. These improvements have also been observed in previous null responders and patients who failed telaprevir- or boceprevir-based regimens. Some specific subpopulations may not be perfectly served by interferon-free regimens, such as patients with genotypes 1a or 3 or cirrhosis, whereas others, such as HIV-infected patients or transplant patients, will definitively benefit from regimens with a lower burden of side effects. This paper reviews the interferon-free regimens currently in phase II or III for which sustained virologic response data are available and discusses the successes and potential pitfalls of these regimens.
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Piroth L, Paniez H, Taburet AM, Vincent C, Rosenthal E, Lacombe K, Billaud E, Rey D, Zucman D, Bailly F, Bronowicki JP, Simony M, Diallo A, Izopet J, Aboulker JP, Meyer L, Molina JM. High Cure Rate With 24 Weeks of Daclatasvir-Based Quadruple Therapy in Treatment-Experienced, Null-Responder Patients With HIV/Hepatitis C Virus Genotype 1/4 Coinfection: The ANRS HC30 QUADRIH Study. Clin Infect Dis 2015; 61:817-25. [PMID: 25977266 DOI: 10.1093/cid/civ381] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2015] [Accepted: 04/05/2015] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND Few direct anti-hepatitis C virus (HCV) agents have been studied in difficult-to-treat null responder and cirrhotic human immunodeficiency virus (HIV)-coinfected patients. Daclatasvir and asunaprevir combined with pegylated interferon/ribavirin (peg-IFN/RBV) have shown promising results in HCV-monoinfected patients. METHODS An open-label, single-arm, phase 2 study was conducted in HIV/HCV genotype 1/4-coinfected patients who were null responders to prior peg-IFN/RBV standard therapy and on a raltegravir-based regimen with HIV RNA <400 copies/mL. They received a 4-week lead-in phase with peg-IFN/RBV, followed by 24 weeks of asunaprevir (100 mg twice daily), daclatasvir (60 mg once daily), and peg-IFN/RBV. The primary endpoint was sustained virologic response 12 weeks after the end of treatment (SVR12) using intent-to-treat analysis. RESULTS Seventy-five patients were included, of whom 27 (36%) had cirrhosis. The median baseline CD4 count was 748 (interquartile range, 481-930) cells/µL. The global SVR12 rate was 96.0% (95% confidence interval [CI], 88.8%-99.2%; n = 72/75), 92.6% (95% CI, 75.7%-99.1%; n = 25/27) in cirrhotic patients, 94.6% (95% CI, 81.8%-99.3%; n = 35/37) in genotype 1 patients, and 97.4% (95% CI, 86.2%-99.9%; n = 37/38) in genotype 4 patients. Six patients (8%) stopped HCV therapy prematurely: 2 due to HCV breakthrough, 4 to adverse events (1 lung cancer, 3 infections). One patient with cirrhosis (with baseline platelet count <150 000 platelets/µL and albuminemia <35 g/L) died from multiorgan failure. Overall, 36 serious adverse events occurred in 21 (28%) patients. No HIV breakthrough was observed. CONCLUSIONS In HIV/HCV genotype 1/4-coinfected null responders, a 24-week regimen combining daclatasvir, asunaprevir, and peg-IFN/RBV was associated with a very high cure rate. The safety profile was acceptable, even though cirrhotic patients with low albuminemia and platelets should be monitored closely. This combination is a new option in this difficult-to-treat population. CLINICAL TRIALS REGISTRATION NCT01725542.
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Affiliation(s)
- Lionel Piroth
- Infectious Diseases Department, Centre Hospitalo-Universitaire, and Unité Mixte de Recherche (UMR)1347, Université de Bourgogne, Dijon
| | - Hubert Paniez
- Institut National de la Santé et de la Recherche Médicale (INSERM) SC10-US019, Villejuif
| | - Anne Marie Taburet
- Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Bicêtre, Hôpitaux Universitaires Paris Sud, Clinical Pharmacy
| | - Corine Vincent
- Institut National de la Santé et de la Recherche Médicale (INSERM) SC10-US019, Villejuif
| | - Eric Rosenthal
- Service de Médecine Interne, Hôpital de l'Archet, and Université de Nice-Sophia Antipolis
| | - Karine Lacombe
- Sorbonne Universités, Université Pierre et Marie CURIE (UPMC) Paris 06, INSERM UMR_S 1136, Institut Pierre Louis d'Epidémiologie et de Santé Publique, and Service de maladies infectieuses, Hôpital Saint-Antoine, AP-HP
| | - Eric Billaud
- Infectious Diseases Department, Centre Hospitalo-Universitaire, Nantes
| | - David Rey
- Le Trait d'Union, Hôpitaux Universitaires, Strasbourg
| | - David Zucman
- Infectious Diseases Department, Hôpital Foch, Suresnes
| | - François Bailly
- Department of Hepatology, Hôpital de la Croix-Rousse, Hospices Civils de Lyon
| | - Jean-Pierre Bronowicki
- INSERM U954, Centre Hospitalier Universitaire de Nancy, Université de Lorraine, Vandoeuvre les Nancy
| | - Mélanie Simony
- Agence Nationale de Recherche sur le Sida et les Hépatites Virales, France REcherche Nord & sud Sida-hiv Hépatites, Paris
| | - Alpha Diallo
- Agence Nationale de Recherche sur le Sida et les Hépatites Virales, France REcherche Nord & sud Sida-hiv Hépatites, Paris
| | - Jacques Izopet
- Department of Virology, INSERM U1043 IFR-BMT, and Université Paul Sabatier, Toulouse
| | - Jean-Pierre Aboulker
- Institut National de la Santé et de la Recherche Médicale (INSERM) SC10-US019, Villejuif
| | - Laurence Meyer
- Institut National de la Santé et de la Recherche Médicale (INSERM) SC10-US019, Villejuif
| | - Jean-Michel Molina
- Infectious Diseases Department, Hôpital Saint-Louis-AP-HP, and Université Paris Diderot, Sorbonne Paris Cité, France
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Greenberg KI, Perazella MA, Atta MG. HIV and HCV Medications in End-Stage Renal Disease. Semin Dial 2015; 28:397-403. [PMID: 25845407 DOI: 10.1111/sdi.12367] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Human immunodeficiency virus (HIV) infection and hepatitis C virus (HCV) infection affect populations worldwide. With the availability of over 35 Food and Drug Administration approved medications for treatment of HIV, the morbidity and mortality associated with HIV has greatly improved. On the other hand, treatment options for HCV have been limited until very recently. While the use of protease inhibitors (such as boceprevir and telaprevir) has become standard of care for treatment of hepatitis C in the general population, data for individuals with impaired kidney function, particularly those on dialysis, are extremely limited. Use of medications in dialysis patients can be challenging given the dose adjustments that must be made for renally cleared molecules, and potentially increased impact of adverse effects such as anemia. Recommendations for dosing of marketed therapies for HIV and HCV are reviewed.
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Affiliation(s)
- Keiko I Greenberg
- Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Mark A Perazella
- Section of Nephrology, Department of Medicine, Yale University School of Medicine, New Haven, Connecticut
| | - Mohamed G Atta
- Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland
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Jafari A, Khalili H, Izadpanah M, Dashti-Khavidaki S. Safely treating hepatitis C in patients with HIV or hepatitis B virus coinfection. Expert Opin Drug Saf 2015; 14:713-31. [PMID: 25813487 DOI: 10.1517/14740338.2015.1019461] [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] [Indexed: 12/29/2022]
Abstract
INTRODUCTION There are several clinical trials and prospective studies which support the use of direct-acting antiviral agents (DAAs) in hepatitis C virus (HCV)-coinfected patients. In this review, the safety of DAAs in HCV patients coinfected with hepatitis B virus (HBV) or HIV has been evaluated. AREAS COVERED All available prospective studies, clinical trials and congress abstracts in the English language that assessed the safety and efficacy of DAAs in HCV coinfections have been considered. EXPERT OPINION The newer DAAs in the treatment of HCV/HIV-coinfected patients resolved major limitations of the first-generation protease inhibitors including complex dosing, poor tolerability and interactions with antiretroviral drugs. There are not yet enough data regarding the safety and efficacy of DAAs in some coinfected patients with comorbidities, nor for pregnant, lactating or pediatric patients. Evaluating the safety and efficacy of these agents in these subgroups with HCV coinfection is recommended for future studies. The role of new direct-acting antiviral-based therapy for the treatment of patients with HCV/HBV coinfection remains to be evaluated.
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Affiliation(s)
- Atefeh Jafari
- Tehran University of Medical Sciences, Department of Clinical Pharmacy, Faculty of Pharmacy , Tehran , Iran
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Osinusi A, Townsend K, Kohli A, Nelson A, Seamon C, Meissner EG, Bon D, Silk R, Gross C, Price A, Sajadi M, Sidharthan S, Sims Z, Herrmann E, Hogan J, Teferi G, Talwani R, Proschan M, Jenkins V, Kleiner DE, Wood BJ, Subramanian GM, Pang PS, McHutchison JG, Polis MA, Fauci AS, Masur H, Kottilil S. Virologic response following combined ledipasvir and sofosbuvir administration in patients with HCV genotype 1 and HIV co-infection. JAMA 2015; 313:1232-9. [PMID: 25706232 PMCID: PMC7780246 DOI: 10.1001/jama.2015.1373] [Citation(s) in RCA: 169] [Impact Index Per Article: 16.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
IMPORTANCE There is an unmet need for interferon- and ribavirin-free treatment for chronic hepatitis C virus (HCV) infection in patients co-infected with human immunodeficiency virus (HIV). OBJECTIVE To evaluate the rates of sustained virologic response (SVR) and adverse events in previously untreated patients with HCV genotype 1 and HIV co-infection following a 12-week treatment of the fixed-dose combination of ledipasvir and sofosbuvir. DESIGN, SETTING, AND PARTICIPANTS Open-label, single-center, phase 2b pilot study of previously untreated, noncirrhotic patients with HCV genotype 1 and HIV co-infection conducted at the Clinical Research Center of the National Institutes of Health, Bethesda, Maryland, from June 2013 to September 2014. Patients included those receiving antiretroviral therapy with HIV RNA values of 50 copies/mL or fewer and a CD4 T-lymphocyte count of 100 cells/mL or greater or patients with untreated HIV infection with a CD4 T-lymphocyte count of 500 cells/mL or greater. Serial measurements of safety parameters, virologic and host immune correlates, and adherence were performed. INTERVENTIONS Fifty patients with HCV genotype 1 never before treated for HCV were prescribed a fixed-dose combination of ledipasvir (90 mg) and sofosbuvir (400 mg) once daily for 12 weeks. MAIN OUTCOMES AND MEASURES The primary study outcome was the proportion of patients with sustained viral response (plasma HCV RNA level <12 IU/mL) 12 weeks after end of treatment. RESULTS Forty-nine of 50 participants (98% [95% CI, 89% to 100%]) achieved SVR 12 weeks after end of treatment, whereas 1 patient experienced relapse at week 4 following treatment. In the patient with relapse, deep sequencing revealed a resistance associated mutation in the NS5A region conferring resistance to NS5A inhibitors, such as ledipasvir. The most common adverse events were nasal congestion (16% of patients) and myalgia (14%). There were no discontinuations or serious adverse events attributable to study drug. CONCLUSIONS AND RELEVANCE In this open-label, uncontrolled, pilot study enrolling patients co-infected with HCV genotype 1 and HIV, administration of an oral combination of ledipasvir and sofosbuvir for 12 weeks was associated with high rates of SVR after treatment completion. Larger studies that also include patients with cirrhosis and lower CD4 T-cell counts are required to understand if the results of this study generalize to all patients co-infected with HCV and HIV. TRIAL REGISTRATION clinicaltrials.gov Identifier:NCT01878799.
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Affiliation(s)
- Anu Osinusi
- Division of Infectious Diseases, Institute of Human Virology, University of Maryland, Baltimore2Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland3Gilead Sciences Inc, F
| | - Kerry Townsend
- Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland
| | - Anita Kohli
- Critical Care Medicine Department, NIH Clinical Center, National Institutes of Health, Bethesda, Maryland5Clinical Research Directorate/Clinical Monitoring Research Program, Leidos Biomedical Research, Inc (formerly SAIC-Frederick, Inc), Frederick Nationa
| | - Amy Nelson
- Division of Infectious Diseases, Institute of Human Virology, University of Maryland, Baltimore2Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland
| | - Cassie Seamon
- Critical Care Medicine Department, NIH Clinical Center, National Institutes of Health, Bethesda, Maryland
| | - Eric G Meissner
- Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland6Department of Microbiology and Immunology, Medical University of South Carolina College of Medicine, Charleston
| | - Dimitra Bon
- Institute of Biostatistics and Mathematical Modeling, Johann Wolfgang Goethe University, Frankfurt, Germany
| | - Rachel Silk
- Division of Infectious Diseases, Institute of Human Virology, University of Maryland, Baltimore5Clinical Research Directorate/Clinical Monitoring Research Program, Leidos Biomedical Research, Inc (formerly SAIC-Frederick, Inc), Frederick National Laborato
| | - Chloe Gross
- Division of Infectious Diseases, Institute of Human Virology, University of Maryland, Baltimore5Clinical Research Directorate/Clinical Monitoring Research Program, Leidos Biomedical Research, Inc (formerly SAIC-Frederick, Inc), Frederick National Laborato
| | - Angie Price
- Division of Infectious Diseases, Institute of Human Virology, University of Maryland, Baltimore5Clinical Research Directorate/Clinical Monitoring Research Program, Leidos Biomedical Research, Inc (formerly SAIC-Frederick, Inc), Frederick National Laborato
| | - Mohammad Sajadi
- Division of Infectious Diseases, Institute of Human Virology, University of Maryland, Baltimore
| | - Sreetha Sidharthan
- Critical Care Medicine Department, NIH Clinical Center, National Institutes of Health, Bethesda, Maryland
| | - Zayani Sims
- Critical Care Medicine Department, NIH Clinical Center, National Institutes of Health, Bethesda, Maryland
| | - Eva Herrmann
- Institute of Biostatistics and Mathematical Modeling, Johann Wolfgang Goethe University, Frankfurt, Germany
| | | | | | - Rohit Talwani
- Division of Infectious Diseases, Institute of Human Virology, University of Maryland, Baltimore
| | - Michael Proschan
- Biostatistics Research Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland
| | | | - David E Kleiner
- Department of Pathology, National Cancer Institute, Rockville, Maryland
| | - Brad J Wood
- Center for Interventional Oncology, Radiology and Imaging Sciences, NIH Clinical Center and National Cancer Institute, Bethesda, Maryland
| | | | | | | | - Michael A Polis
- Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland
| | - Anthony S Fauci
- Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland
| | - Henry Masur
- Critical Care Medicine Department, NIH Clinical Center, National Institutes of Health, Bethesda, Maryland
| | - Shyam Kottilil
- Division of Infectious Diseases, Institute of Human Virology, University of Maryland, Baltimore2Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland
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Affiliation(s)
| | - Arthur Y Kim
- Division of Infectious Diseases, Massachusetts General Hospital and Department of Medicine, Harvard Medical School, Boston, MA 02114, USA.
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Coppola N, Martini S, Pisaturo M, Sagnelli C, Filippini P, Sagnelli E. Treatment of chronic hepatitis C in patients with HIV/HCV coinfection. World J Virol 2015; 4:1-12. [PMID: 25674512 PMCID: PMC4308522 DOI: 10.5501/wjv.v4.i1.1] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2014] [Revised: 09/30/2014] [Accepted: 10/27/2014] [Indexed: 02/05/2023] Open
Abstract
Hepatitis C virus (HCV) infection is one of the most frequent causes of comorbidity and mortality in the human immunodeficiency virus (HIV) population, and liver-related mortality is now the second highest cause of death in HIV-positive patients, so HCV infection should be countered with adequate antiviral therapy. In 2011 began the era of directly acting antivirals (DAAs) and the HCV NS3/4A protease inhibitors telaprevir and boceprevir were approved to treat HCV-genotype-1 infection, each one in combination with pegylated interferon alfa (Peg-IFN) + ribavirin (RBV). The addition of the first generation DAAs, strongly improved the efficacy of antiviral therapy in patients with HCV-genotype 1, both for the HCV-monoinfected and HIV/HCV coinfected, and the poor response to Peg-IFN + RBV in HCV/HIV coinfection was enhanced. These treatments showed higher rates of sustained virological response than Peg-IFN + RBV but reduced tolerability and adherence due to the high pill burden and the several pharmacokinetic interactions between HCV NS3/4A protease inhibitors and antiretroviral drugs. Then in 2013 a new wave of DAAs arrived, characterized by high efficacy, good tolerability, a low pill burden and shortened treatment duration. The second and third generation DAAs also comprised IFN-free regimens, which in small recent trials on HIV-positive patients have shown comforting preliminary results in terms of efficacy, tolerability and adherence.
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Barrio Gascón CD, Buti M. The potential role of simeprevir for the treatment of hepatitis C. Future Virol 2015. [DOI: 10.2217/fvl.14.108] [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
ABSTRACT Simeprevir is an HCV NS3/4A protease inhibitor with antiviral activity against HCV genotypes 1, 2, 4, 5 and 6. Simeprevir (SMV) has been approved for the treatment of genotype 1 and 4 patients in combination with PEGylated interferon (PEG-IFN) and ribavirin (RBV) or other direct antiviral agents. SMV plus PEG-IFN/RBV for 12 weeks in naive patients and prior relapsers with chronic hepatitis C genotype 1 or 4, followed by 12 additional weeks of PEG-IFN/RBV has yielded high efficacy rates. In IFN-free therapy, SMV combined with other antiviral drugs such as sofosbuvir achieved highly sustained virologic response rates in treatment-naive and experienced patients with HCV genotype 1 infection. SMV is generally well tolerated. SMV represents an important advance in the treatment of hepatitis C.
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Affiliation(s)
- Cristina del Barrio Gascón
- Liver Unit, Hospital Universitario de la Vall d'Hebron and Ciberehd del Instituto Carlos III, Barcelona, Spain
| | - Maria Buti
- Liver Unit, Hospital Universitario de la Vall d'Hebron and Ciberehd del Instituto Carlos III, Barcelona, Spain
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CIHR Canadian HIV Trials Network Co-Infection and Concurrent Diseases Core: Updated Canadian guidelines for the treatment of hepatitis C infection in HIV-hepatitis C coinfected adults. CANADIAN JOURNAL OF INFECTIOUS DISEASES & MEDICAL MICROBIOLOGY 2015; 25:311-20. [PMID: 25587293 PMCID: PMC4277159 DOI: 10.1155/2014/251989] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Treatment of HIV-hepatitis C virus (HCV)-coinfected individuals is considerably more complex than the treatment of monoinfected individuals, due to several factors including interactions among medications and accelerated progression of liver disease. Since the first Canadian guidelines for the treatment of HIV-HCV coinfected patients were published in the Winter 2013 issue of the Journal, several new medications that show considerable promise for the treatment of HCV have become available in Canada. Thus, the authors provide an update to the 2013 guidelines and include updated recommendations for treatment that incorporate these new medications. BACKGROUND: Hepatitis C virus (HCV) coinfection occurs in 20% to 30% of Canadians living with HIV and is responsible for a heavy burden of morbidity and mortality. Management of HIV-HCV coinfection is more complex due to the accelerated progression of liver disease, the timing and nature of antiretroviral and HCV therapy, mental health and addictions management, socioeconomic obstacles and drug-drug interactions between new HCV direct-acting antiviral therapies and antiretroviral regimens. OBJECTIVE: To update national standards for the management of HCV-HIV coinfected adults in the Canadian context. METHODS: A standing working group with specific clinical expertise in HIV-HCV coinfection was convened by The Canadian Institute of Health Research HIV Trials Network to review recently published data regarding HCV antiviral treatments and to update the Canadian HIV-HCV coinfection guidelines. RESULTS: Recent data suggest that the gap in sustained virological response rates between HCV monoinfection and HIV-HCV coinfection has been eliminated with newer HCV antiviral regimens. All HIV-HCV coinfected individuals should be assessed for HCV therapy. First-line treatment for genotypes 1 through 6 includes pegylated interferon and weight-based ribavirin dosing plus the nucleotide sofosbuvir for 12 weeks. Sofosbuvir in combination with the protease inhibitor simeprevir is another first-line consideration for genotype 1 infection. Sofosbuvir with ribavirin for 12 weeks (genotype 2) and 24 weeks (genotype 3) is also recommended as first-line treatment. DISCUSSION: Recommendations may not supersede individual clinical judgement.
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Younossi ZM, Stepanova M, Sulkowski M, Naggie S, Puoti M, Orkin C, Hunt SL. Sofosbuvir and Ribavirin for Treatment of Chronic Hepatitis C in Patients Coinfected With Hepatitis C Virus and HIV: The Impact on Patient-Reported Outcomes. J Infect Dis 2015; 212:367-77. [PMID: 25583164 DOI: 10.1093/infdis/jiv005] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2014] [Accepted: 11/28/2014] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Sofosbuvir-containing regimens have been approved for treatment of hepatitis C virus (HCV) infection in human immunodeficiency virus (HIV)-infected patients. We assessed the effect of treatment with sofosbuvir and ribavirin on patient-reported outcomes (PROs) in individuals with HIV/HCV coinfection. METHODS HIV/HCV-coinfected patients were treated for 12 or 24 weeks with sofosbuvir and ribavirin. Matched HCV-monoinfected controls were also evaluated. All subjects completed standard PRO questionnaires before, during, and after treatment. RESULTS Included were 497 participants from the PHOTON-1 and PHOTON-2 clinical trials. At baseline, more impairment in PRO scores was noted in HIV/HCV-coinfected patients, compared with HCV-monoinfected patients. During treatment, moderate decrements in PRO scores (change, up to -6.8% on a 0%-100% scale; P = .0053) were experienced regardless of treatment duration and were similar to those for HCV-monoinfected patients (all P > .05). In 413 HIV/HCV-coinfected patients with a virologic response sustained for 12 weeks after treatment cessation, most PRO scores improved (change, up to +7.6%; P < .0001), similar to findings for HCV-monoinfected patients. In multivariate analysis, in addition to clinico-demographic predictors, coinfection with HIV was associated with PRO impairment at baseline (beta, up to -7.6%; P < .002) but not with treatment-emergent changes in PRO scores (all P > .05). CONCLUSIONS Patients with HIV/HCV coinfection tolerate interferon-free sofosbuvir-based anti-HCV regimens well and, despite the presence of some baseline impairment, have treatment-emergent changes in PRO scores that are similar to those of patients with HCV monoinfection. CLINICAL TRIALS REGISTRATION NCT01667731 (PHOTON-1), NCT01783678 (PHOTON-2), NCT01604850 (FUSION), and NCT01682720 (VALENCE).
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Affiliation(s)
- Zobair M Younossi
- Center for Liver Diseases, Department of Medicine, Inova Fairfax Hospital Betty and Guy Beatty Center for Integrated Research, Inova Health System, Falls Church, Virginia
| | - Maria Stepanova
- Center for Liver Diseases, Department of Medicine, Inova Fairfax Hospital Betty and Guy Beatty Center for Integrated Research, Inova Health System, Falls Church, Virginia Center for Outcomes Research in Liver Diseases, Washington, D.C
| | | | | | - Massimo Puoti
- Division of Infectious Diseases, AO Ospedale Niguarda Ca' Granda, Milan, Italy
| | - Chloe Orkin
- Barts Health NHS Trust, London, United Kingdom
| | - Sharon L Hunt
- Center for Liver Diseases, Department of Medicine, Inova Fairfax Hospital Betty and Guy Beatty Center for Integrated Research, Inova Health System, Falls Church, Virginia
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Hirashima N, Iwase H, Shimada M, Imamura J, Sugiura W, Yokomaku Y, Watanabe T. An Hepatitis C Virus (HCV)/HIV Co-Infected Patient who Developed Severe Hepatitis during Chronic HCV Infection: Sustained Viral Response with Simeprevir Plus Peginterferon-Alpha and Ribavirin. Intern Med 2015; 54:2173-7. [PMID: 26328642 DOI: 10.2169/internalmedicine.54.4344] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
We herein describe the case of a 42-year-old man who developed severe hepatitis caused by hepatitis C virus (HCV) infection at 14 years after the start of human immunodeficiency virus (HIV) treatment. Surprisingly, the levels of alanine aminotransferase (ALT) fluctuated, reaching a peak higher than 1,000 IU/L during chronic HCV infection, and the hepatic histology showed advanced liver fibrosis at 3 years after the primary HCV infection. He was treated with simeprevir, peginterferon-alpha, and ribavirin with a sustained viral response. We conclude that HCV/HIV co-infected patients need to commence anti-HCV therapy when the levels of ALT fluctuate severely under successful HIV control.
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Affiliation(s)
- Noboru Hirashima
- Department of Gastroenterology, National Hospital Organization Nagoya Medical Center, Japan
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Joseph D, Rose P, Strelkowa N, Schultz A, Garcia J, Elgadi M, Huang F. Effect of faldaprevir on raltegravir pharmacokinetics in healthy volunteers. J Clin Pharmacol 2014; 55:384-91. [PMID: 25352040 DOI: 10.1002/jcph.418] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2014] [Accepted: 10/20/2014] [Indexed: 12/21/2022]
Abstract
Faldaprevir is a potent hepatitis C virus (HCV) NS3/4A protease inhibitor and an inhibitor of UDP-glucuronosyltransferase-1A1 (UGT1A1), which is involved in raltegravir clearance. Raltegravir, an HIV integrase inhibitor, may be used in combination with HCV treatment in HCV/HIV co-infected patients. In this open-label, 2-period, fixed-sequence study, 24 healthy volunteers (12 males) received faldaprevir 240 mg and raltegravir 400 mg in 2 treatment schedules (A and B) separated by a washout phase of ≥7 days: (A) twice-daily raltegravir (Days 1-3), once-daily raltegravir (Day 4); (B) twice-daily raltegravir and twice-daily faldaprevir (loading dose, Day 1), twice-daily raltegravir and once-daily faldaprevir (Days 2-5), once-daily raltegravir and once-daily faldaprevir (Day 6). Pharmacokinetics and safety were assessed over 132 hours post-dosing. Compared with raltegravir alone, co-administration with faldaprevir led to 2.7-fold and 2.5-fold increases in raltegravir geometric mean AUC(τ,ss) and C(max,ss), respectively, and a similar increase in raltegravir glucuronide metabolite exposure. No serious adverse events (AEs) were reported and no subject discontinued due to AEs. Faldaprevir and raltegravir co-administration was well tolerated and resulted in a moderate increase in raltegravir exposure.
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Affiliation(s)
- David Joseph
- Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, USA
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Saab S, Gordon SC, Park H, Sulkowski M, Ahmed A, Younossi Z. Cost-effectiveness analysis of sofosbuvir plus peginterferon/ribavirin in the treatment of chronic hepatitis C virus genotype 1 infection. Aliment Pharmacol Ther 2014; 40:657-75. [PMID: 25065960 DOI: 10.1111/apt.12871] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2014] [Revised: 04/15/2014] [Accepted: 06/20/2014] [Indexed: 12/17/2022]
Abstract
BACKGROUND Sofosbuvir, an oral NS5B nucleotide polymerase inhibitor, is indicated for the treatment of patients infected with hepatitis C virus (HCV). AIM To evaluate the long-term health economic outcomes of sofosbuvir + pegylated interferon alfa/ribavirin (pegIFN/RBV) compared with current treatments in patients infected with HCV genotype 1 in the US. METHODS A decision-analytic Markov model was developed to estimate health outcomes, number needed to treat and short-term and long-term economic outcomes, including incremental cost-effectiveness ratios and cost per sustained virological response (SVR), for several sofosbuvir-comparator regimen pairings for a cohort of 10 000 patients. It considered three patient cohorts: treatment-naïve, treatment-experienced and treatment-naïve human immunodeficiency virus (HIV) co-infected. Subgroup analyses were conducted for treatment-naïve patients with and without cirrhosis. RESULTS Reductions in the incidence of new cases of liver-disease complications with sofosbuvir + pegIFN/RBV compared with pegIFN/RBV, boceprevir + pegIFN/RBV, telaprevir + pegIFN/RBV and simeprevir + pegIFN/RBV were 64-82%, 50-68%, 43-58% and 33-56%, respectively. Sofosbuvir + pegIFN/RBV was typically associated with the lowest 1-year cost per SVR. When considering the lifetime incremental cost per quality-adjusted life-year gained, sofosbuvir + pegIFN/RBV was the most cost-effective treatment option assessed. Sofosbuvir + pegIFN/RBV generally dominated (less costly and more effective than) boceprevir + pegIFN/RBV, telaprevir + pegIFN/RBV and simeprevir + pegIFN/RBV. CONCLUSION Sofosbuvir + pegIFN/RBV yields more favourable future health and economic outcomes than current treatment regimens for patients across all levels of treatment experience and cirrhosis stage, as well as for individuals with or without HIV co-infection.
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Affiliation(s)
- S Saab
- Department of Medicine, University of California, Los Angeles, CA, USA
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Corchado S, López-Cortés LF, Rivero-Juárez A, Torres-Cornejo A, Rivero A, Márquez-Coello M, Girón-González JA. Liver fibrosis, host genetic and hepatitis C virus related parameters as predictive factors of response to therapy against hepatitis C virus in HIV/HCV coinfected patients. PLoS One 2014; 9:e101760. [PMID: 25013899 PMCID: PMC4094489 DOI: 10.1371/journal.pone.0101760] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2014] [Accepted: 06/11/2014] [Indexed: 02/08/2023] Open
Abstract
OBJECTIVE To establish the role of liver fibrosis as a predictive tool of response to pegylated interferon alpha (Peg-IFN) and ribavirin (RBV) treatment in human immunodeficiency (HIV)/hepatitis C virus (HCV) coinfected patients, in addition to recognized predictive factors (HCV load, HCV genotype, IL-28B polymorphism). PATIENTS AND METHODS A sample of 267 HIV/HCV coinfected patients was treated with Peg-IFN and RBV. Predictive factors of rapid (RVR) and sustained (SVR) virological response were analyzed. Independent variables were age, sex, IL28B, -238 TNF-α and -592 IL-10 polymorphisms, HCV genotype, HCV-RNA levels, significant fibrosis or cirrhosis and CD4+ T cell count. RESULTS Patients infected by HCV genotype 1 (n = 187) showed RVR and SVR in 12% and 39% of cases, respectively. The parameters associated with RVR were IL28B genotype CC and plasma HCV-RNA levels <600,000 IU/ml. Advanced liver fibrosis was negatively associated with SVR in patients without RVR. A SVR was obtained in 42% of subjects with HCV genotype 4, and the independent factors associated with SVR were IL28B genotype CC and an HCV-RNA <600,000 IU/ml. A SVR was obtained in 66% of patients with HCV genotypes 2/3; in this case, the independent parameter associated with SVR was the absence of significant liver fibrosis. TNF-α and IL-10 polymorphisms were not associated with SVR, although a significantly higher percentage of -238 TNF-α genotype GG was detected in patients with significant liver fibrosis. CONCLUSIONS In HIV/HCV coinfected patients with HCV genotypes 1 or 4, RVR, mainly influenced by genotype IL28B and HCV-RNA levels, reliably predicted SVR after 4 weeks of therapy with Peg-IFN plus RBV. In patients infected by HCV genotype 3, an elevated relapse rate compromised the influence of RVR on SVR. Relapses were related to the presence of advanced liver fibrosis. Liver cirrhosis was associated with a -238 TNF-α polymorphism in these patients.
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Affiliation(s)
- Sara Corchado
- Unidad de Enfermedades Infecciosas, Hospital Universitario Puerta del Mar, Cádiz, Spain
| | - Luis F. López-Cortés
- Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío/Centro Superior de Investigaciones Científicas/Universidad de Sevilla, Sevilla, Spain
| | - Antonio Rivero-Juárez
- Maimonides Institute for Research in Biomedicine of Cordoba/Reina Sofia University Hospital, Córdoba, Spain
| | - Almudena Torres-Cornejo
- Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío/Centro Superior de Investigaciones Científicas/Universidad de Sevilla, Sevilla, Spain
| | - Antonio Rivero
- Maimonides Institute for Research in Biomedicine of Cordoba/Reina Sofia University Hospital, Córdoba, Spain
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Braun DL, Rauch A, Durisch N, Eberhard N, Anagnostopoulos A, Ledergerber B, Metzner KJ, Böni J, Weber R, Fehr J. Efficacy of lead-in silibinin and subsequent triple therapy in difficult-to-treat HIV/hepatitis C virus-coinfected patients. HIV Med 2014; 15:625-30. [PMID: 24894776 DOI: 10.1111/hiv.12166] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/08/2014] [Indexed: 11/28/2022]
Abstract
OBJECTIVES The efficacy of current hepatitis C virus (HCV) triple therapy, including a protease inhibitor, is limited in HIV/HCV-coinfected patients with advanced liver fibrosis and nonresponse to previous peginterferon-ribavirin. These patients have a low chance (only 30%) of achieving a sustained virological response (SVR) during triple therapy and cannot wait for next-generation anti-HCV drugs. In a pilot study, we investigated the efficacy of a lead-in therapy with silibinin before triple therapy in difficult-to-treat patients. METHODS Inclusion criteria were HIV/HCV coinfection with advanced liver fibrosis and documented failure of previous peginterferon-ribavirin treatment. Intervention was lead-in therapy with intravenous silibinin 20 mg/kg/day for 14 days. Subsequently, peginterferon-ribavirin combined with telaprevir was initiated for 12 weeks, followed by peginterferon-ribavirin dual therapy until week 48 after initiation of triple therapy. The outcome measurements were HCV RNA after silibinin lead-in, at weeks 2, 4 and 12 of triple therapy, and SVR at week 24 after the end of treatment. RESULTS We examined six HIV/HCV-coinfected patients (four infected with genotype 1a). All had fibrosis grade METAVIR ≥F3 and were on fully suppressive antiretroviral therapy. Mean HCV RNA decline after silibinin therapy was 2.6 log10 IU/mL (range 2-3 log10 IU/mL). Five of the six patients were virologically suppressed at weeks 2 and 4, and all six at week 12 of triple therapy. One experienced a viral breakthrough thereafter. Four of five patients (80%) showed an SVR 24. One patient had an SVR 12 but has not yet reached week 24. CONCLUSIONS A lead-in with silibinin before triple therapy is highly effective and increases the probability of HCV treatment success in difficult-to-treat HIV/HCV-coinfected patients with advanced liver fibrosis and previous failure of peginterferon-ribavirin.
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Affiliation(s)
- D L Braun
- Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
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