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1
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Zhang H, Quadeer AA, McKay MR. Direct-acting antiviral resistance of Hepatitis C virus is promoted by epistasis. Nat Commun 2023; 14:7457. [PMID: 37978179 PMCID: PMC10656532 DOI: 10.1038/s41467-023-42550-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Accepted: 10/13/2023] [Indexed: 11/19/2023] Open
Abstract
Direct-acting antiviral agents (DAAs) provide efficacious therapeutic treatments for chronic Hepatitis C virus (HCV) infection. However, emergence of drug resistance mutations (DRMs) can greatly affect treatment outcomes and impede virological cure. While multiple DRMs have been observed for all currently used DAAs, the evolutionary determinants of such mutations are not currently well understood. Here, by considering DAAs targeting the nonstructural 3 (NS3) protein of HCV, we present results suggesting that epistasis plays an important role in the evolution of DRMs. Employing a sequence-based fitness landscape model whose predictions correlate highly with experimental data, we identify specific DRMs that are associated with strong epistatic interactions, and these are found to be enriched in multiple NS3-specific DAAs. Evolutionary modelling further supports that the identified DRMs involve compensatory mutational interactions that facilitate relatively easy escape from drug-induced selection pressures. Our results indicate that accounting for epistasis is important for designing future HCV NS3-targeting DAAs.
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Affiliation(s)
- Hang Zhang
- Department of Electronic and Computer Engineering, The Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong SAR, China
| | - Ahmed Abdul Quadeer
- Department of Electronic and Computer Engineering, The Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong SAR, China.
| | - Matthew R McKay
- Department of Electrical and Electronic Engineering, University of Melbourne, Melbourne, VIC, Australia.
- Department of Microbiology and Immunology, University of Melbourne, at The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia.
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2
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Medina C, García AH, Crespo FI, Toro FI, Mayora SJ, De Sanctis JB. A Synopsis of Hepatitis C Virus Treatments and Future Perspectives. Curr Issues Mol Biol 2023; 45:8255-8276. [PMID: 37886964 PMCID: PMC10605161 DOI: 10.3390/cimb45100521] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2023] [Revised: 10/10/2023] [Accepted: 10/10/2023] [Indexed: 10/28/2023] Open
Abstract
Hepatitis C virus (HCV) infection is a worldwide public health problem. Chronic infection with HCV can lead to liver cirrhosis or cancer. Although some immune-competent individuals can clear the virus, others develop chronic HCV disease due to viral mutations or an impaired immune response. IFNs type I and III and the signal transduction induced by them are essential for a proper antiviral effect. Research on the viral cycle and immune escape mechanisms has formed the basis of therapeutic strategies to achieve a sustained virological response (SVR). The first therapies were based on IFNα; then, IFNα plus ribavirin (IFN-RBV); and then, pegylated-IFNα-RBV (PEGIFNα-RIV) to improve cytokine pharmacokinetics. However, the maximum SVR was 60%, and several significant side effects were observed, decreasing patients' treatment adherence. The development of direct-acting antivirals (DAAs) significantly enhanced the SVR (>90%), and the compounds were able to inhibit HCV replication without significant side effects, even in paediatric populations. The management of coinfected HBV-HCV and HCV-HIV patients has also improved based on DAA and PEG-IFNα-RBV (HBV-HCV). CD4 cells are crucial for an effective antiviral response. The IFNλ3, IL28B, TNF-α, IL-10, TLR-3, and TLR-9 gene polymorphisms are involved in viral clearance, therapeutic responses, and hepatic pathologies. Future research should focus on searching for strategies to circumvent resistance-associated substitution (RAS) to DAAs, develop new therapeutic schemes for different medical conditions, including organ transplant, and develop vaccines for long-lasting cellular and humoral responses with cross-protection against different HCV genotypes. The goal is to minimise the probability of HCV infection, HCV chronicity and hepatic carcinoma.
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Affiliation(s)
- Christian Medina
- Institute of Immunology Dr. Nicolás E. Bianco C., Faculty of Medicine, Universidad Central de Venezuela, Caracas 1040, Venezuela; (C.M.); (F.I.C.); (F.I.T.); (S.J.M.)
| | - Alexis Hipólito García
- Institute of Immunology Dr. Nicolás E. Bianco C., Faculty of Medicine, Universidad Central de Venezuela, Caracas 1040, Venezuela; (C.M.); (F.I.C.); (F.I.T.); (S.J.M.)
| | - Francis Isamarg Crespo
- Institute of Immunology Dr. Nicolás E. Bianco C., Faculty of Medicine, Universidad Central de Venezuela, Caracas 1040, Venezuela; (C.M.); (F.I.C.); (F.I.T.); (S.J.M.)
| | - Félix Isidro Toro
- Institute of Immunology Dr. Nicolás E. Bianco C., Faculty of Medicine, Universidad Central de Venezuela, Caracas 1040, Venezuela; (C.M.); (F.I.C.); (F.I.T.); (S.J.M.)
| | - Soriuska José Mayora
- Institute of Immunology Dr. Nicolás E. Bianco C., Faculty of Medicine, Universidad Central de Venezuela, Caracas 1040, Venezuela; (C.M.); (F.I.C.); (F.I.T.); (S.J.M.)
| | - Juan Bautista De Sanctis
- Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, 779 00 Olomouc, Czech Republic
- The Czech Advanced Technology and Research Institute (Catrin), Palacky University, 779 00 Olomouc, Czech Republic
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3
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Obradovic B, Roberts O, Owen A, Milosevic I, Milic N, Ranin J, Dragovic G. Expression of CYP2B6 Enzyme in Human Liver Tissue of HIV and HCV Patients. MEDICINA (KAUNAS, LITHUANIA) 2023; 59:1207. [PMID: 37512019 PMCID: PMC10385124 DOI: 10.3390/medicina59071207] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/19/2023] [Revised: 06/15/2023] [Accepted: 06/21/2023] [Indexed: 07/30/2023]
Abstract
Background and Objectives: Hepatitis C virus (HCV) and human immunodeficiency virus (HIV) infections present significant public health challenges worldwide. The management of these infections is complicated by the need for antiviral and antiretroviral therapies, which are influenced by drug metabolism mediated by metabolic enzymes and transporters. This study focuses on the gene expression of CYP2B6, CYP3A4, and ABCB1 transporters in patients with HIV, HCV, and HIV/HCV co-infection, aiming to assess their potential association with the choice of therapy, patohistological and clinical parameters of liver damage such as the stage of liver fibrosis, serum levels of ALT and AST, as well as the grade of liver inflammation and other available biochemical parameters. Materials and Methods: The study included 54 patients who underwent liver biopsy, divided into HIV-infected, HCV-infected, and co-infected groups. The mRNA levels of CYP2B6, CYP3A4, and ABCB1 was quantified and compared between the groups, along with the analysis of liver fibrosis and inflammation levels. Results: The results indicated a significant increase in CYP2B6 mRNA levels in co-infected patients, a significant association with the presence of HIV infection with an increase in CYP3A4 mRNA levels. A trend towards downregulation of ABCB1 expression was observed in patients using lamivudine. Conclusions: This study provides insight into gene expression of CYP2B6 CYP3A4, and ABCB1 in HIV, HCV, and HIV/HCV co-infected patients. The absence of correlation with liver damage, inflammation, and specific treatment interventions emphasises the need for additional research to elucidate the complex interplay between gene expression, viral co-infection, liver pathology, and therapeutic responses in these particular patients population.
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Affiliation(s)
- Bozana Obradovic
- University of Belgrade, Faculty of Medicine, Department of Pharmacology, Clinical Pharmacology and Toxicology, 11000 Belgrade, Serbia
| | - Owain Roberts
- University of Buckingham Medical School, Faculty of Medicine and Health Sciences, University of Buckingham, Buckingham MK18 1EG, UK
| | - Andrew Owen
- Centre of Excellence in Long-Acting Therapeutics (CELT), Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool L69 3BX, UK
| | - Ivana Milosevic
- Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia
- Clinic of Infectious and Tropical Diseases, Clinical Centre of Serbia, 11000 Belgrade, Serbia
| | - Natasa Milic
- University of Belgrade, Faculty of Medicine, Department of Medical Statistics & Informatics, 11000 Belgrade, Serbia
| | - Jovan Ranin
- Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia
- Clinic of Infectious and Tropical Diseases, Clinical Centre of Serbia, 11000 Belgrade, Serbia
| | - Gordana Dragovic
- University of Belgrade, Faculty of Medicine, Department of Pharmacology, Clinical Pharmacology and Toxicology, 11000 Belgrade, Serbia
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4
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Leiva RA, Bergersen BM, Finbråten AK, Sandvei PK, Simonsen Ø, Rosseland CM, Hagen K, Young L, Roberts RS, Mikkelsen Y, Singh R, Lagging M, Dalgard O. High real-world effectiveness of 12-week elbasvir/grazoprevir without resistance testing in the treatment of patients with HCV genotype 1a infection in Norway. Scand J Gastroenterol 2023; 58:264-268. [PMID: 36063075 DOI: 10.1080/00365521.2022.2118555] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
BACKGROUND AND AIMS The recommended treatment duration of hepatitis C virus (HCV) genotype 1a (GT1a) infection with elbasvir/grazoprevir (EBR/GZR) in the presence of a high baseline viral load and resistance associated substitutions (RAS) is 16 weeks with ribavirin added. The objective of this study was to evaluate the real-world effectiveness of 12 weeks of EBR/GZR without ribavirin and regardless of baseline viral load and RAS testing. METHOD This retrospective, observational cohort study was performed at five Norwegian hospitals that did not systematically utilize RAS testing. All adult patients with chronic HCV GT1a and compensated liver disease who had received 12 weeks of EBR/GZR without ribavirin and baseline RAS testing, were included. The primary endpoint was sustained virologic response at week 12 (SVR12), or if not available, at week 4 (SVR4). RESULTS We included 433 patients and attained SVR data on 388. The mean age was 45.7 years (22-73 years). 67.2% were male. HIV co-infection was present in 3.8% (16/424) and cirrhosis in 4% (17/424). The viral load was >800 000 IU/mL in 55.0% (235/427) of patients. Overall SVR was achieved in 97.2% (377/388). SVR was achieved in 98.3% (169/172) of those with viral load ≤800 000 IU/mL and in 96.2% (202/210) of those with viral load >800 000 IU/mL. CONCLUSION We observed high SVR rates among patients with HCV GT1a infection treated with EBR/GZR for 12 weeks without ribavirin, with no regard to baseline viral load and no RAS testing.
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Affiliation(s)
- Rafael A Leiva
- Department of Infectious Diseases, Haukeland University Hospital, Bergen, Norway
| | - Bente M Bergersen
- Department of Infectious Diseases, Oslo University Hospital, Ullevål, Norway
| | - Ane-Kristine Finbråten
- Department of Infectious Diseases, Oslo University Hospital, Ullevål, Norway.,Unger-Vetlesen Institute, Lovisenberg Diaconal Hospital, Oslo, Norway
| | | | - Øystein Simonsen
- Department of Infectious Diseases, Østfold Hospital, Kalnes, Norway
| | | | | | | | | | | | | | - Martin Lagging
- Department of Infectious Diseases/Virology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.,Department of Clinical Microbiology, Region Västra Götaland, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Olav Dalgard
- Department of Infectious Diseases, Akershus University Hospital, Lørenskog, Norway.,Institute for Clinical Medicine, University of Oslo, Oslo, Norway
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5
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Brzdęk M, Zarębska-Michaluk D, Invernizzi F, Cilla M, Dobrowolska K, Flisiak R. Decade of optimizing therapy with direct-acting antiviral drugs and the changing profile of patients with chronic hepatitis C. World J Gastroenterol 2023; 29:949-966. [PMID: 36844142 PMCID: PMC9950869 DOI: 10.3748/wjg.v29.i6.949] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Revised: 11/22/2022] [Accepted: 01/09/2023] [Indexed: 02/10/2023] Open
Abstract
Chronic infection with the hepatitis C virus (HCV) remains a major health problem affecting approximately 58 million people worldwide. In the era of interferon (IFN)-based regimens, patients particularly infected with genotypes 1 and 4 achieved a low response rate. The implementation of direct-acting antivirals changed the landscape of HCV treatment. The increase in effectiveness provided us with the hope of eliminating HCV as a significant public threat by 2030. In the following years, there was an observed improvement in the treatment of HCV with genotype-specific regimens and highly effective pangenotypic options that are the most recent stage of the revolution. The optimization of therapy was accompanied by changes in the patient profile from the beginning of the IFN-free era over time. Patients treated with antiviral therapies were younger in successive periods, less burdened with comorbidities and comedications, more frequently treatment-naïve and had less advanced liver disease. Before the IFN-free era, specific subpopulations such as patients with HCV/HIV coinfection, those with a history of previous treatment, patients with renal impairment or with cirrhosis had lower chances for a virologic response. Currently, these populations should no longer be considered difficult to treat. Despite the high effectiveness of HCV therapy, there is a small percentage of patients with treatment failure. However, they can be effectively retreated with pangenotypic rescue regimens.
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Affiliation(s)
- Michał Brzdęk
- Collegium Medicum, Jan Kochanowski University, Kielce 25-516, Poland
| | | | - Federica Invernizzi
- Center for Liver Disease, Division of Internal Medicine and Hepatology, IRCCS Ospedale San Raffaele, Milan 20-132, Italy
| | - Marta Cilla
- Center for Liver Disease, Division of Internal Medicine and Hepatology, IRCCS Ospedale San Raffaele, Milan 20-132, Italy
| | | | - Robert Flisiak
- Department of Infectious Diseases and Hepatology, Medical University of Białystok, Białystok 15-540, Poland
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Zarębska-Michaluk D, Brzdęk M, Jaroszewicz J, Tudrujek-Zdunek M, Lorenc B, Klapaczyński J, Mazur W, Kazek A, Sitko M, Berak H, Janocha-Litwin J, Dybowska D, Supronowicz Ł, Krygier R, Citko J, Piekarska A, Flisiak R. Best therapy for the easiest to treat hepatitis C virus genotype 1b-infected patients. World J Gastroenterol 2022; 28:6380-6396. [PMID: 36533109 PMCID: PMC9753050 DOI: 10.3748/wjg.v28.i45.6380] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Revised: 10/01/2022] [Accepted: 11/19/2022] [Indexed: 12/02/2022] Open
Abstract
BACKGROUND The revolution in treatment of patients with chronic hepatitis C virus (HCV) infection dates back to the introduction of direct-acting antivirals (DAAs). The increase in efficacy was most pronounced in patients infected with genotype (GT) 1b, as this was the most poorly responsive population to treatment during the interferon era.
AIM To identify the most effective interferon-free therapy for GT1b-infected patients and to determine positive and negative predictors of virological response.
METHODS This real-world retrospective analysis included patients chronically infected with GT1b HCV whose data were obtained from the multicenter observational EpiTer-2 database. Treatment effectiveness was evaluated for each therapeutic regimen as the percentage of sustained virological responses (SVR). Assessment of the safety was based on the evaluation of the course of therapy, the occurrence of adverse events including serious ones, deaths during treatment and in the post 12-wk follow-up period.
RESULTS The studied population consisted of 11385 patients with a mean age of 53 ± 14.8 years and a female predominance (53.4%). The majority of them were treatment-naïve (74.6%) and patients with cirrhosis accounted for 24.3%. Of the DAA regimens used, 76.9% were GT-specific with ombitasvir/paritaprevir/ritonavir + dasabuvir ± ribavirin being the most used option (32.4%). A total of 10903 patients responded to treatment resulting in a 98.1% in the per-protocol analysis after excluding 273 patients without SVR data. The effectiveness of all regimens exceeded 90% and the highest SVR of 98.9% was achieved in patients treated with a combination of glecaprevir/pibrentasvir. Logistic regression analyses showed that the virologic response was independently associated with female sex [odds ratio (OR) = 1.67], absence of decompensated cirrhosis at baseline (OR = 2.42) and higher baseline platelets (OR = 1.004 per 1000/μL increase), while the presence of human immunodeficiency virus (HIV) coinfection significantly decreased the odds of response (OR = 0.39). About 95%-100% of patients completed therapy irrespective of the drug regimen. At least one adverse effect occurred in 10.9%-36.3% and most of them were mild. No treatment related deaths have been reported.
CONCLUSION We documented very high effectiveness and a good safety profile across all DAA regimens. Positive predictors of SVR were female sex, absence of decompensated cirrhosis at baseline and higher platelet count while HIV coinfection reduced the effectiveness.
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Affiliation(s)
| | - Michał Brzdęk
- Department of Infectious Diseases, Jan Kochanowski University, Kielce 25-317, Poland
| | - Jerzy Jaroszewicz
- Department of Infectious Diseases and Hepatology, Medical University of Silesia, Katowice 40-055, Poland
| | | | - Beata Lorenc
- Pomeranian Center of Infectious Diseases, Medical University Gdańsk, Gdańsk 80-214, Poland
| | - Jakub Klapaczyński
- Department of Internal Medicine and Hepatology, Central Clinical Hospital of the Ministry of Internal Affairs and Administration, Warszawa 00-241, Poland
| | - Włodzimierz Mazur
- Clinical Department of Infectious Diseases, Medical University of Silesia, Chorzów 41-500, Poland
| | | | - Marek Sitko
- Department of Infectious and Tropical Diseases, Jagiellonian University, Kraków 31-088, Poland
| | - Hanna Berak
- Hospital for Infectious Diseases, Hospital for Infectious Diseases, Warszawa 02-091, Poland
| | - Justyna Janocha-Litwin
- Department of Infectious Diseases and Hepatology, Medical University Wrocław, Wrocław 50-367, Poland
| | - Dorota Dybowska
- Department of Infectious Diseases and Hepatology, Faculty of Medicine, Nicolaus Copernicus University, Bydgoszcz 85-030, Poland
| | - Łukasz Supronowicz
- Department of Infectious Diseases and Hepatology, Medical University of Białystok, Białystok 15-089, Poland
| | - Rafał Krygier
- Infectious Diseases and Hepatology Outpatient Clinic, Gemini NZOZ, Żychlin 62-571, Poland
| | - Jolanta Citko
- Medical Practice of Infections, Regional Hospital, Olsztyn 10-561, Poland
| | - Anna Piekarska
- Department of Infectious Diseases and Hepatology, Medical University Łódź, Łódź 90-419, Poland
| | - Robert Flisiak
- Department of Infectious Diseases and Hepatology, Medical University of Białystok, Białystok 15-089, Poland
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Meshram RJ, Kathwate GH, Gacche RN. Progress, evolving therapeutic/diagnostic approaches, and challenges in the management of hepatitis C virus infections. Arch Virol 2022; 167:717-736. [PMID: 35089390 PMCID: PMC8795940 DOI: 10.1007/s00705-022-05375-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2021] [Accepted: 12/02/2021] [Indexed: 12/11/2022]
Abstract
Hepatitis C virus (HCV) infections are emerging as one of the foremost challenges in healthcare owing to its chronicity and the virus's quasispecies nature. Worldwide, over 170 million people are chronically infected with HCV, with an annual mortality of over 500,000 people across the world. The emerging pathophysiological evidence links HCV infections to a risk of developing liver diseases such as cirrhosis and hepatocellular carcinoma. Despite the great strides that have been made towards understanding the pathophysiology of disease progression, the tailored treatments of HCV infection remain to be established. The present review provides an update of the literature pertaining to evolving therapeutic approaches and prophylactic measures for the effective management of HCV infections. An extensive discussion of established and experimental immune prophylactic measures also sheds light on current developments in the design of vaccination strategies against HCV infection. We have also attempted to address the application of nanotechnology in formulating effective therapeutic interventions against HCV. Pointing out the limitations of the existing diagnostic methods and therapeutic approaches against HCV might inspire the design and development of novel, efficient, reliable, and cost-effective diagnostic technologies as well as novel therapeutic and immune prophylactic interventions for the effective management of HCV.
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Affiliation(s)
| | | | - Rajesh Nivarti Gacche
- Department of Biotechnology, Savitribai Phule Pune University, Pune, MS, 411007, India.
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Zhang W, Li S, Liu H, Zhang Y, Xie H, Peng D, Peng H, Ou Z, Peng Z, Dong W, An D. Development of the Enabling Route for a Novel HCV NS3/4A Inhibitor, Furaprevir. Org Process Res Dev 2022. [DOI: 10.1021/acs.oprd.1c00315] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Affiliation(s)
- Weihong Zhang
- State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University, Changsha 410082, P. R. China
| | - Shixi Li
- The State Key Laboratory of Anti-Infective Drug Development (NO. 2015DQ780357), Sunshine Lake Pharma Co. Ltd., Dongguan 523871, P. R. China
| | - Haiwang Liu
- The State Key Laboratory of Anti-Infective Drug Development (NO. 2015DQ780357), Sunshine Lake Pharma Co. Ltd., Dongguan 523871, P. R. China
| | - Yingjun Zhang
- The State Key Laboratory of Anti-Infective Drug Development (NO. 2015DQ780357), Sunshine Lake Pharma Co. Ltd., Dongguan 523871, P. R. China
- Dongguan HEC TaiGen Biopharmaceuticals Co. Ltd., Dongguan 523000, P. R. China
| | - Hongpeng Xie
- The State Key Laboratory of Anti-Infective Drug Development (NO. 2015DQ780357), Sunshine Lake Pharma Co. Ltd., Dongguan 523871, P. R. China
| | - Dahua Peng
- The State Key Laboratory of Anti-Infective Drug Development (NO. 2015DQ780357), Sunshine Lake Pharma Co. Ltd., Dongguan 523871, P. R. China
| | - Hongtao Peng
- The State Key Laboratory of Anti-Infective Drug Development (NO. 2015DQ780357), Sunshine Lake Pharma Co. Ltd., Dongguan 523871, P. R. China
| | - Zijian Ou
- The State Key Laboratory of Anti-Infective Drug Development (NO. 2015DQ780357), Sunshine Lake Pharma Co. Ltd., Dongguan 523871, P. R. China
| | - Zhihong Peng
- State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University, Changsha 410082, P. R. China
| | - Wanrong Dong
- State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University, Changsha 410082, P. R. China
| | - Delie An
- State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University, Changsha 410082, P. R. China
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9
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Pabjan P, Brzdęk M, Chrapek M, Dziedzic K, Dobrowolska K, Paluch K, Garbat A, Błoniarczyk P, Reczko K, Stępień P, Zarębska-Michaluk D. Are There Still Difficult-to-Treat Patients with Chronic Hepatitis C in the Era of Direct-Acting Antivirals? Viruses 2022; 14:96. [PMID: 35062302 PMCID: PMC8779728 DOI: 10.3390/v14010096] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2021] [Revised: 12/29/2021] [Accepted: 01/04/2022] [Indexed: 12/17/2022] Open
Abstract
Difficult-to-treat populations with chronic hepatitis C (CHC), in the era of interferon treatment, included patients with liver cirrhosis, kidney impairment, treatment-experienced individuals, and those coinfected with the human immunodeficiency virus. The current study aimed to determine whether, in the era of direct-acting antivirals (DAA), there are still patients that are difficult-to-treat. The study included all consecutive patients chronically infected with hepatitis C virus (HCV) who started interferon-free therapy between July 2015 and December 2020 in the Department of Infectious Diseases in Kielce. The analyzed real-world population consisted of 963 patients, and most of them were infected with genotype 1 (87.6%) with the predominance of subtype 1b and were treatment-naïve (78.8%). Liver cirrhosis was determined in 207 individuals (21.5%), of whom 82.6% were compensated. The overall sustained virologic response, after exclusion of non-virologic failures, was achieved in 98.4%. The univariable analysis demonstrated the significantly lower response rates in males, patients with liver cirrhosis, decompensation of hepatic function at baseline, documented esophageal varices, concomitant diabetes, body mass index ≥25, and previous ineffective antiviral treatment. Despite an overall very high effectiveness, some unfavorable factors, including male gender, genotype 3 infection, liver cirrhosis, and treatment experience, significantly reduce the chances for a virologic response were identified.
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Affiliation(s)
- Paweł Pabjan
- Department of Infectious Diseases, Voivodship Hospital, Jan Kochanowski University, 25-317 Kielce, Poland; (P.P.); (K.P.); (A.G.); (P.B.); (K.R.); (P.S.)
| | - Michał Brzdęk
- Collegium Medicum, Jan Kochanowski University, 25-369 Kielce, Poland; (M.B.); (K.D.); (K.D.)
| | - Magdalena Chrapek
- Faculty of Natural Sciences, Jan Kochanowski University, 25-369 Kielce, Poland;
| | - Kacper Dziedzic
- Collegium Medicum, Jan Kochanowski University, 25-369 Kielce, Poland; (M.B.); (K.D.); (K.D.)
| | - Krystyna Dobrowolska
- Collegium Medicum, Jan Kochanowski University, 25-369 Kielce, Poland; (M.B.); (K.D.); (K.D.)
| | - Katarzyna Paluch
- Department of Infectious Diseases, Voivodship Hospital, Jan Kochanowski University, 25-317 Kielce, Poland; (P.P.); (K.P.); (A.G.); (P.B.); (K.R.); (P.S.)
| | - Anna Garbat
- Department of Infectious Diseases, Voivodship Hospital, Jan Kochanowski University, 25-317 Kielce, Poland; (P.P.); (K.P.); (A.G.); (P.B.); (K.R.); (P.S.)
| | - Piotr Błoniarczyk
- Department of Infectious Diseases, Voivodship Hospital, Jan Kochanowski University, 25-317 Kielce, Poland; (P.P.); (K.P.); (A.G.); (P.B.); (K.R.); (P.S.)
| | - Katarzyna Reczko
- Department of Infectious Diseases, Voivodship Hospital, Jan Kochanowski University, 25-317 Kielce, Poland; (P.P.); (K.P.); (A.G.); (P.B.); (K.R.); (P.S.)
| | - Piotr Stępień
- Department of Infectious Diseases, Voivodship Hospital, Jan Kochanowski University, 25-317 Kielce, Poland; (P.P.); (K.P.); (A.G.); (P.B.); (K.R.); (P.S.)
| | - Dorota Zarębska-Michaluk
- Department of Infectious Diseases, Voivodship Hospital, Jan Kochanowski University, 25-317 Kielce, Poland; (P.P.); (K.P.); (A.G.); (P.B.); (K.R.); (P.S.)
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10
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Hung HY, Chen CY, Liao YH. A Retrospective Cohort Study: Safety and Effectiveness of Elbasvir/Grazoprevir ± Ribavirin Compared With Ombitasvir/Paritaprevir/Ritonavir/Dasabuvir ± Ribavirin in Patients With Chronic Hepatitis C Genotype 1 Infection. Front Pharmacol 2021; 12:640317. [PMID: 34566631 PMCID: PMC8458878 DOI: 10.3389/fphar.2021.640317] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Accepted: 08/05/2021] [Indexed: 11/13/2022] Open
Abstract
Background: The direct-acting antiviral (DAA) agents are widely used to treat hepatitis C virus (HCV) genotype (GT) 1 infection, while it may cause severe liver damage. The objectives of the study were to evaluate the incidence of drug-induced liver injury (DILI), sustained virologic response at post-treatment week 12 (SVR12), and recurrence rates in HCV GT 1 infection. Methods: This was a retrospective cohort study that included patients diagnosed with HCV GT 1 infection, who had received intervention and treatment with elbasvir/grazoprevir (EBR/GZR) ± ribavirin (RBV) versus ombitasvir/paritaprevir/ritonavir (OBV/PTV/r) + dasabuvir ± RBV (as control group) for 12 or 24 weeks at a regional hospital in southern Taiwan between April 2016 and August 2018. The primary outcome of the study was to compare the incidence rate ratio (IRR) of DILI via Poisson regression, and the secondary outcome was to evaluate the effectiveness of two treatment regimens expressed as a percentage. Results: The study included 149 patients in the control group and 105 patients in the intervention group of which 99.33 and 98.1% patients, respectively, achieved SVR12. In the control group, one patient experienced relapse, whereas in the intervention group, two patients relapsed. Furthermore, in the control group, a total of nine patients developed DILI as determined during follow-up care. Of these patients, three were 55-84 years old. In the intervention group, six patients developed DILI. The IRR of DILI caused by EBR/GZR treatment was 2.84 times higher than that caused by the OBV/PTV/r treatment regimen. Conclusion: There was no significant difference between the studied DAA regimens regarding the incidence of DILI and effectiveness during the treatment. DILI occurrence during therapy did not affect the cure rate of medication. The present study results can provide reference data for drug selection among patients with HCV. Trial registration: The study was approved by DMF-CYCH (CYCH IRB No: 2018067).
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Affiliation(s)
- Hsuan-Yu Hung
- Department of Pharmacy, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi, Taiwan
| | - Chung-Yu Chen
- Master Program in Clinical Pharmacy, School of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan.,Department of Pharmacy, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.,Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Yi-Hsiang Liao
- Chinese Medical Department, Park One International Hospital, Kaohsiung, Taiwan
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11
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Ahmed M, Mansey AE, Wahsh EA, Gomaa AA, Rabea HM. Efficacy and Safety of Ombitasvir plus Paritaprevir, Ritonavir and Ribavirin in Non-cirrhotic Treatment-naïve and Treatment-experienced Egyptians with Chronic HCV Genotype-4 Infection. Curr Med Sci 2021; 41:581-586. [PMID: 34047942 DOI: 10.1007/s11596-021-2363-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2019] [Accepted: 12/11/2020] [Indexed: 01/11/2023]
Abstract
Hepatitis C virus genotype 4 (HCV-GT4) is a risk factor for cirrhosis, hepatocellular carcinoma and liver failure. A combination of three new direct-acting antivirals ombitasvir, paritaprevir, and ritonavir has been recommended for treatment of HCV-GT4 infection. The current study was aimed to assess the efficacy and safety of this combination plus ribavirin in non-cirrhotic, treatment-naïve and -experienced Egyptians with HCV-GT4 infection in a real-world setting. A total of 255 Egyptians with HCV-GT4 infection were enrolled, including 82 treatment-experienced and 173 treatment-naïve patients. All of them completed 12-week treatment protocol of ombitasvir, paritaprevir and ritonavir as an oral dose combination with ribavirin. Virological response (VR) was measured, as well as the biochemical parameters related to treatment efficacy and adverse events at baseline and after treatment, at 4 (VR4) and 12 (VR12) weeks post-treatment. The results showed that the VR4 rates were 98.8% in both groups, and VR12 rates were 97.7% and 96.3% in treatment-naïve and -experienced patients, respectively, with no significant differences found between the groups concerning VR4 (P=0.9) and VR12 (P=0.3). The most common adverse events were headache and fatigue, which were significantly more common (P=0.001 and 0.003, respectively) in treatment-experienced than in treatment-naïve group. The quadruple regimen was well-tolerated, and the reported adverse events were generally mild to moderate. This real-world setting study confirms that the combination of ombitasvir, paritaprevir, ritonavir, and ribavirin is highly effective in the treatment of HCV- GT4 infection with a good safety and tolerability profile.
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Affiliation(s)
- Manar Ahmed
- Department of Clinical Pharmacy, Faculty of Pharmacy, Beni Suef University, Beni Suef, 62521, Egypt
| | - Azza E Mansey
- Department of Clinical Pharmacy, Faculty of Pharmacy, Menoufia University, Al Menoufia, 32511, Egypt
| | - Engy A Wahsh
- Department of Clinical Pharmacy, Faculty of Pharmacy, October 6 university, Giza, 12573, Egypt.
| | - Ahmed A Gomaa
- Department of Tropical Medicine, Faculty of Medicine, Fayoum University, Fayoum, 63511, Egypt
| | - Hoda M Rabea
- Department of Clinical Pharmacy, Faculty of Pharmacy, Beni Suef University, Beni Suef, 62521, Egypt
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12
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Onorato L, Pisaturo M, Starace M, Minichini C, Di Fraia A, Astorri R, Coppola N. Virological Factors Associated with Failure to the Latest Generation of Direct Acting Agents (DAA) and Re-Treatment Strategy: A Narrative Review. Viruses 2021; 13:432. [PMID: 33800289 PMCID: PMC8000640 DOI: 10.3390/v13030432] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Revised: 03/02/2021] [Accepted: 03/04/2021] [Indexed: 12/12/2022] Open
Abstract
The availability of all oral direct acting antiviral agents (DAAs) has revolutionized the management of HCV infections in recent years, allowing to achieve a sustained virological response (SVR) in more than 95% of cases, irrespective of hepatitis C Virus (HCV) genotype or staging of liver disease. Although rare, the failure to the latest-generation regimens (grazoprevir/elbasvir, sofosbuvir/velpatasvir, pibrentasvir/glecaprevir) represents a serious clinical problem, since the data available in the literature on the virological characteristics and management of these patients are few. The aim of the present narrative review was to provide an overview of the impact of baseline RASs in patients treated with the latest-generation DAAs and to analyze the efficacy of the available retreatment strategies in those who have failed these regimens.
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Affiliation(s)
| | | | | | | | | | | | - Nicola Coppola
- Department of Mental Health and Public Medicine, Section of Infectious Diseases, University of Campania L. Vanvitelli, 80138 Naples, Italy; (L.O.); (M.P.); (M.S.); (C.M.); (A.D.F.); (R.A.)
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13
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Due OT, Thakkinstian A, Thavorncharoensap M, Sobhonslidsuk A, Wu O, Phuong NK, Chaikledkaew U. Cost-Utility Analysis of Direct-Acting Antivirals for Treatment of Chronic Hepatitis C Genotype 1 and 6 in Vietnam. VALUE IN HEALTH : THE JOURNAL OF THE INTERNATIONAL SOCIETY FOR PHARMACOECONOMICS AND OUTCOMES RESEARCH 2020; 23:1180-1190. [PMID: 32940236 PMCID: PMC7491253 DOI: 10.1016/j.jval.2020.03.018] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/02/2019] [Revised: 02/05/2020] [Accepted: 03/23/2020] [Indexed: 05/12/2023]
Abstract
OBJECTIVE Very few cost-utility analyses have either evaluated direct-acting antivirals (DAAs) on hepatitis C virus (HCV) genotype 6 patients or undertaken societal perspective. Recently, DAAs have been introduced into the Vietnamese health insurance drug list for chronic hepatitis C (CHC) treatment without empirical cost-effectiveness evidence. This study was conducted to generate these data on DAAs among CHC patients with genotypes 1 and 6 in Vietnam. METHODS A hybrid decision-tree and Markov model was employed to compare costs and quality-adjusted life-years (QALYs) of available DAAs, including (1) sofosbuvir/ledipasvir, (2) sofosbuvir/velpatasvir, and (3) sofosbuvir plus daclatasvir, with pegylated-interferon plus ribavirin (PR). Primary data collection was conducted in Vietnam to identify costs and utility values. Incremental cost-effectiveness ratios were estimated from societal and payer perspectives. Uncertainty and scenario analyses and value of information analyses were performed. RESULTS All DAAs were cost-saving as compared with PR in CHC patients with genotypes 1 and 6 in Vietnam, and sofosbuvir/velpatasvir was the most cost-saving regimen, from both societal and payer perspectives. From the societal perspective, DAAs were associated with the increment of quality-adjusted life-years by 1.33 to 1.35 and decrement of costs by $6519 to $7246. Uncertainty and scenario analyses confirmed the robustness of base-case results, whereas the value of information analyses suggested the need for further research on relative treatment efficacies among DAA regimens. CONCLUSIONS Allocating resources for DAA treatment for HCV genotype 1 and 6 is surely a rewarding public health investment in Vietnam. It is recommended that the government rapidly scale up treatment and enable financial accessibility for HCV patients.
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Affiliation(s)
- Ong The Due
- Mahidol University Health Technology Assessment (MUHTA) Graduate Program, Mahidol University, Bangkok, Thailand; Health Strategy and Policy Institute, Ministry of Health, Hanoi, Vietnam
| | - Ammarin Thakkinstian
- Mahidol University Health Technology Assessment (MUHTA) Graduate Program, Mahidol University, Bangkok, Thailand; Department of Clinical Epidemiology and Biostatistics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Montarat Thavorncharoensap
- Mahidol University Health Technology Assessment (MUHTA) Graduate Program, Mahidol University, Bangkok, Thailand; Social and Administrative Pharmacy Division, Department of Pharmacy, Faculty of Pharmacy, Mahidol University, Bangkok, Thailand
| | - Abhasnee Sobhonslidsuk
- Division of Gastroenterology and Hepatology, Department of Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Olivia Wu
- Health Economics and Health Technology Assessment (HEHTA), Institute of Health and Wellbeing, University of Glasgow, Glasgow, United Kingdom
| | | | - Usa Chaikledkaew
- Mahidol University Health Technology Assessment (MUHTA) Graduate Program, Mahidol University, Bangkok, Thailand; Social and Administrative Pharmacy Division, Department of Pharmacy, Faculty of Pharmacy, Mahidol University, Bangkok, Thailand.
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14
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Keikha M, Eslami M, Yousefi B, Ali-Hassanzadeh M, Kamali A, Yousefi M, Karbalaei M. HCV genotypes and their determinative role in hepatitis C treatment. Virusdisease 2020; 31:235-240. [PMID: 32904762 PMCID: PMC7459022 DOI: 10.1007/s13337-020-00592-0] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2019] [Accepted: 04/24/2020] [Indexed: 02/05/2023] Open
Abstract
Nowadays, exposure to infectious diseases caused by pathogenic viruses has become one of the major human concerns in health fields. In the meantime, hepatitis viruses are associated with health problems, especially in liver tissue. So far, several types of these viruses have been known including: HAV, HBV, HCV, HDV, HEV, and HGV. Nevertheless, it seems that hepatitis C is the major viral infection among all of the hepatitis infections. The cirrhosis and hepatocellular carcinoma are known as the most important pathological complications of this virus, from which seven genotypes have been identified. However, among these genotypes, the incidence rate of genotypes 1 and 3 is more than others. In this review, we have investigated the relationship between all HCV genotypes and therapeutic responses against them. Regarding heterogeneity between hepatitis C genotypes, it is not possible to access an effective vaccine against this virus, and treatment is the only applicable strategy. Response to treatment is different among genotypes, and it has resulted that each genotype has a specific therapeutic regimen of itself. Therefore, it seems that determination of hepatitis C genotype, as a key tool, is essential in controlling therapeutic regimen, improving local control programs and eventually producing an effective vaccine.
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Affiliation(s)
- Masoud Keikha
- Department of Microbiology and Virology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Majid Eslami
- Cancer Research Center, Semnan University of Medical Sciences, Semnan, Iran
| | - Bahman Yousefi
- Department of Immunology, Semnan University of Medical Sciences, Semnan, Iran
| | - Mohammad Ali-Hassanzadeh
- Department of Immunology, School of Medicine, Jiroft University of Medical Sciences, Jiroft, Iran
| | - Ali Kamali
- Department of Internal Medicine, School of Medicine, Jiroft University of Medical Sciences, Jiroft, Iran
| | - Masoud Yousefi
- Department of Microbiology and Virology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mohsen Karbalaei
- Department of Microbiology and Virology, School of Medicine, Jiroft University of Medical Sciences, Jiroft, Iran
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15
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Zarębska-Michaluk D, Jaroszewicz J, Buczyńska I, Simon K, Lorenc B, Tudrujek-Zdunek M, Tomasiewicz K, Sitko M, Garlicki A, Janczewska E, Dybowska D, Halota W, Pawłowska M, Pabjan P, Mazur W, Czauż-Andrzejuk A, Berak H, Horban A, Socha Ł, Klapaczyński J, Piekarska A, Blaszkowska M, Belica-Wdowik T, Dobracka B, Tronina O, Deroń Z, Białkowska-Warzecha J, Laurans Ł, Flisiak R. Real-world experience with Grazoprevir/Elbasvir in the treatment of previously "difficult to treat" patients infected with hepatitis C virus genotype 1 and 4. J Gastroenterol Hepatol 2020; 35:1238-1246. [PMID: 31734959 DOI: 10.1111/jgh.14936] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2019] [Revised: 11/04/2019] [Accepted: 11/13/2019] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND AIM Grazoprevir/elbasvir (GZR/EBR) was approved for the treatment of chronic hepatitis C virus (HCV) genotype 1 and 4 infected patients with or without compensated liver cirrhosis. The aim of this study was to assess GZR/EBR regimen in the real-world experience, particularly in previously "difficult-to-treat" patients with chronic kidney diseases, human immunodeficiency virus-coinfected, cirrhotics, and treatment-experienced. METHODS The analysis included patients treated with GZR/EBR selected from 10 152 individuals from the EpiTer-2 database, large national real-world study evaluating antiviral treatment in 22 Polish hepatology centers between 2015 and 2018. Data were completed retrospectively and submitted online. RESULTS A total of 1615 patients who started GZR/EBR therapy in 2017 and 2018 with a female predominance (54%) and median age of 54 years were analyzed. The majority were infected with GT1b (89%) and treatment naïve (81%). Liver cirrhosis was diagnosed in 19%, and 70% of patients had comorbidities, of which chronic renal disease was present in 7% and HIV-coinfection in 4%. Overall, a sustained virologic response (SVR) was achieved by 95% according to intent-to-treat (ITT) and 98% after exclusion of lost to follow up (modified ITT). No differences were found in cure rate between all included patients and subpopulations previously considered as difficult-to-treat. Majority of patients completed the treatment course as scheduled, adverse events were mostly mild and did not lead to therapy discontinuation. CONCLUSIONS GZR/EBR treatment carried-out in patients infected with HCV genotype 1 and 4 demonstrated good tolerability and an excellent SVR rate with no effectiveness reduction in so called difficult-to-treat populations.
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Affiliation(s)
| | - Jerzy Jaroszewicz
- Department of Infectious Diseases and Hepatology, Medical University of Silesia, Katowice, Poland
| | - Iwona Buczyńska
- Department of Infectious Diseases and Hepatology, Medical University Wrocła, Wrocław, Poland
| | - Krzysztof Simon
- Department of Infectious Diseases and Hepatology, Medical University Wrocła, Wrocław, Poland
| | - Beata Lorenc
- Pomeranian Center of Infectious Diseases, Medical University Gdańsk, Gdańsk, Poland
| | | | | | - Marek Sitko
- Department of Infectious and Tropical Diseases, Jagiellonian University, Kraków, Poland
| | - Aleksander Garlicki
- Department of Infectious and Tropical Diseases, Jagiellonian University, Kraków, Poland
| | - Ewa Janczewska
- Department of Basic Medical Sciences, ID Clinic, Hepatology Outpatient Department, School of Public Health in Bytom, Medical University of Silesia, Bytom, Poland
| | - Dorota Dybowska
- Department of Infectious Diseases and Hepatology, Ludwik Rydygier Collegium Medicum in Bydgoszcz Faculty of Medicine, Nicolaus Copernicus University, Toruń, Poland
| | - Waldemar Halota
- Department of Infectious Diseases and Hepatology, Ludwik Rydygier Collegium Medicum in Bydgoszcz Faculty of Medicine, Nicolaus Copernicus University, Toruń, Poland
| | - Małgorzata Pawłowska
- Department of Infectious Diseases and Hepatology, Ludwik Rydygier Collegium Medicum in Bydgoszcz Faculty of Medicine, Nicolaus Copernicus University, Toruń, Poland
| | - Paweł Pabjan
- Department of Infectious Diseases, Jan Kochanowski University, Kielce, Poland
| | - Włodzimierz Mazur
- Clinical Department of Infectious Diseases, Medical University of Silesia, Katowice, Poland
| | - Agnieszka Czauż-Andrzejuk
- Department of Infectious Diseases and Hepatology, Medical University of Białystok, Białystok, Poland
| | - Hanna Berak
- Hospital for Infectious Diseases in Warsaw, Warsaw, Poland
| | - Andrzej Horban
- Hospital for Infectious Diseases in Warsaw, Warsaw, Poland
| | - Łukasz Socha
- Department of Infectious Diseases, Hepatology and Liver Transplantation, Pomeranian Medical University, Szczecin, Poland
| | - Jakub Klapaczyński
- Department of Internal Medicine and Hepatology, Central Clinical Hospital of the Ministry of Internal Affairs and Administration, Warsaw, Poland
| | - Anna Piekarska
- Department of Infectious Diseases and Hepatology, Medical University of Łódź, Łódź, Poland
| | - Maria Blaszkowska
- Department of Infectious Diseases and Hepatology, Medical University of Silesia, Katowice, Poland
| | - Teresa Belica-Wdowik
- Regional Center for Diagnosis and Treatment of Viral Hepatitis and Hepatology, Kraków, Poland
| | | | - Olga Tronina
- Department of Transplantation Medicine, Nephrology, and Internal Diseases, Medical University of Warsaw, Warszawa, Poland
| | - Zbigniew Deroń
- Ward of Infectious Diseases and Hepatology, Biegański Regional Specialist Hospital, Łódź, Poland
| | | | - Łukasz Laurans
- Department of Infectious Diseases, Hepatology and Liver Transplantation, Pomeranian Medical University, Szczecin, Poland.,Multidisciplinary Regional Hospital, Gorzów Wielkopolski, Poland
| | - Robert Flisiak
- Department of Infectious Diseases and Hepatology, Medical University of Białystok, Białystok, Poland
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16
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Abdel-Daim MM. Editorial: the road to elimination of viral hepatitis-another promising real-world experience. Aliment Pharmacol Ther 2020; 52:405-406. [PMID: 32592247 DOI: 10.1111/apt.15837] [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: 12/09/2022]
Abstract
LINKED CONTENTThis article is linked to Drysdale et al paper. To view this article, visit https://doi.org/10.1111/apt.15609.
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Affiliation(s)
- Mohamed M Abdel-Daim
- Department of Zoology, College of Science, King Saud University, Riyadh, Saudi Arabia
- Pharmacology Department, Faculty of Veterinary Medicine, Suez Canal University, Ismailia, Egypt
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17
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Drysdale K, Ntuli Y, Bestwick J, Gelson W, Agarwal K, Forton D, Mutimer D, Elsharkawy AM, Townley C, Mahomed F, Foster GR. English hepatitis C registry data show high response rates to directly acting anti-virals, even if treatment is not completed. Aliment Pharmacol Ther 2020; 52:168-181. [PMID: 32441382 DOI: 10.1111/apt.15780] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2019] [Revised: 10/31/2019] [Accepted: 04/17/2020] [Indexed: 12/11/2022]
Abstract
BACKGROUND In England, choice of hepatitis C therapy is determined by national contracts that change with time, facilitating comparisons between different regimens. England has a diverse population with hepatitis C including large proportions of uncommon viral genotypes. AIM To evaluate efficacy of directly acting anti-viral treatments for hepatitis C in England using real-world data from the national treatment registry. METHODS Sustained virological response (SVR) rates 12 weeks after treatment completion for patients treated between 2014 and August 2018 who attended for SVR tests were analysed in univariate subgroups using Chi-squared tests. Multivariate models were constructed with clinically relevant variables to determine predictors of SVR and evaluate the impact of treatment regimens. RESULTS SVR data were available on 14,603 treated patients. The overall SVR rate was 95.59% [95% CI 95.25%-95.91%]. Multivariable regression modelling in patients with genotype 1 infection showed that the odds of SVR with elbasvir/grazoprevir were higher than for those treated with sofosbuvir/ledipasvir (OR 1.891, 95% CI 1.072-3.336, P = 0.028). For genotype 3, we found no significant difference between any of the treatment regimens. Patients who completed at least one third of the planned treatment duration achieved SVR rates in excess of 80%. CONCLUSIONS All of the currently licensed hepatitis C direct-acting anti-viral regimens had similar efficacy (>95%) in an unselected population. Noncompletion of planned treatment duration still resulted in over 80% SVR rates provided that more than one third of treatment was completed.
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Affiliation(s)
- Kathryn Drysdale
- Barts Liver Centre, Blizard Institute, Queen Mary University of London, London, UK.,Barts Health NHS Trust, London, UK
| | - Yevedzo Ntuli
- Barts Liver Centre, Blizard Institute, Queen Mary University of London, London, UK.,Institute of Liver Studies, King's College Hospital, London, UK
| | - Jonathan Bestwick
- Wolfson Institute of Preventive Medicine, Queen Mary University of London, London, UK
| | | | - Kosh Agarwal
- Institute of Liver Studies, King's College Hospital, London, UK
| | | | - David Mutimer
- NIHR Birmingham Biomedical Research Centre, University Hospitals Birmingham NHS Foundation Trust and University of Birmingham, Birmingham, UK
| | - Ahmed M Elsharkawy
- NIHR Birmingham Biomedical Research Centre, University Hospitals Birmingham NHS Foundation Trust and University of Birmingham, Birmingham, UK
| | - Ceri Townley
- Specialised Services National Support team, NHS England, Southampton, UK
| | - Faizel Mahomed
- NHS Arden and Greater East Midlands Commissioning Support Unit, Leicester, UK
| | - Graham R Foster
- Barts Liver Centre, Blizard Institute, Queen Mary University of London, London, UK.,Barts Health NHS Trust, London, UK
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18
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Manca F, Robinson E, Dillon JF, Boyd KA. Eradicating hepatitis C: Are novel screening strategies for people who inject drugs cost-effective? THE INTERNATIONAL JOURNAL OF DRUG POLICY 2020; 82:102811. [PMID: 32585583 DOI: 10.1016/j.drugpo.2020.102811] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Revised: 05/20/2020] [Accepted: 05/25/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND In developed countries, people who inject drugs (PWID) have a high prevalence of hepatitis C virus (HCV), yet they are often under-diagnosed. The World Health Organization has set 2030 as a target year for HCV elimination. To meet this target, improving screening in convenient community settings in order to reach infected undiagnosed individuals is a priority. This study assesses the cost-effectiveness of alternative novel strategies for diagnosing HCV infection in PWID. METHODS A cost-effectiveness analysis was undertaken to compare HCV screening at needle exchange centres, substance misuse services and at community pharmacies, with the standard practice of detection during general practitioners' consultations. A decision tree model was developed to assess the incremental cost per positive diagnosis, and a Markov model explored the net monetary benefit (NMB) and the cost per Quality Adjusted Life Years (QALYs) gained over a lifetime horizon. RESULTS Needle exchange services provided a 7.45-fold increase in detecting positive individuals and an incremental cost of £12,336 per QALY gained against current practice (NMB £163,827), making this the most cost-effective strategy over a lifetime horizon. Screening at substance misuse services and pharmacies was cost-effective only at a £30,000/QALY threshold. With a 24% discount to HCV treatment list prices, all three screening strategies become cost-effective at £20,000/QALY. CONCLUSIONS Targeting PWID populations with screening at needle exchange services is a highly cost-effective strategy for reaching undiagnosed HCV patients. When applying realistic discounts to list prices of drug treatments, all three strategies were highly cost-effective from a UK NHS perspective. All of these strategies have the potential to make a cost-effective contribution to the eradication of HCV by 2030.
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Affiliation(s)
- Francesco Manca
- Health Economics and Health Technology Assessment (HEHTA), Institute of Health and Wellbeing, University of Glasgow, 1 Lilybank Gardens, Glasgow G12 8RZ, UK.
| | - Emma Robinson
- School of Medicine, University of Dundee, Ninewells hospital and Medical school, DD1 9SY Dundee, UK.
| | - John F Dillon
- School of Medicine, University of Dundee, Ninewells hospital and Medical school, DD1 9SY Dundee, UK.
| | - Kathleen Anne Boyd
- Health Economics and Health Technology Assessment (HEHTA), Institute of Health and Wellbeing, University of Glasgow, 1 Lilybank Gardens, Glasgow G12 8RZ, UK.
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19
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Rabaan AA, Al-Ahmed SH, Bazzi AM, Alfouzan WA, Alsuliman SA, Aldrazi FA, Haque S. Overview of hepatitis C infection, molecular biology, and new treatment. J Infect Public Health 2019; 13:773-783. [PMID: 31870632 DOI: 10.1016/j.jiph.2019.11.015] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2018] [Revised: 07/08/2019] [Accepted: 11/18/2019] [Indexed: 12/13/2022] Open
Abstract
The World Health Organization estimates that 71 million people worldwide have chronic hepatitis C viral infection. A major challenge is overall lack of public awareness of hepatitis C, particularly among infected people of their infection status. Chronic hepatitis C infection is associated with advanced liver disease, is the main cause of hepatocellular carcinoma and causes many extra-hepatic manifestations. The existence of seven viral genotypes complicates targeting of treatment. Recent years have seen the approval of many direct acting antivirals targeted at hepatitis C virus non-structural proteins. These have revolutionized therapy as they allow achievement of extremely high sustained virologic responses. Of great significance is the development of pan-genotypic drug combinations, including the NS3/4A-NS5A inhibitor combinations sofosbuvir-velpatasvir and glecaprevir-pibrentasvir. However, resistance-associated mutations can result in failure of these treatments in a small number of patients. This, combined with the high costs of treatment, highlights the importance of continued research into effective anti-hepatitis C therapies, for example aimed at viral entry. Recent developments include identification of the potential of low-cost anti-histamines for repurposing as inhibitors of hepatitis C viral entry. In this review we focus on molecular biology of hepatitis C virus, and the new developments in hepatitis C treatment.
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Affiliation(s)
- Ali A Rabaan
- Molecular Diagnostic Laboratory, Johns Hopkins Aramco Healthcare, Dhahran, Saudi Arabia.
| | - Shamsah H Al-Ahmed
- Specialty Paediatric Medicine, Qatif Central Hospital, Qatif, Saudi Arabia
| | - Ali M Bazzi
- Microbiology Laboratory, Johns Hopkins Aramco Healthcare, Dhahran, Saudi Arabia
| | - Wadha A Alfouzan
- Department of Microbiology, Faculty of Medicine, Kuwait University, Safat 13110, Kuwait; Faculty of Medicine, Kuwait University, Dasma 35153, Kuwait
| | - Shahab A Alsuliman
- Internal Medicine and Infectious Disease Department, Dammam Medical Complex, Dammam, Saudi Arabia
| | - Fatimah A Aldrazi
- Infection Control Department, Dammam Medical Complex, Dammam, Saudi Arabia
| | - Shafiul Haque
- Research and Scientific Studies Unit, College of Nursing & Allied Health Sciences, Jazan University, Saudi Arabia
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20
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Zarębska-Michaluk D. Viral hepatitis C treatment shortening - what is the limit? Clin Exp Hepatol 2019; 5:265-270. [PMID: 31893236 PMCID: PMC6935848 DOI: 10.5114/ceh.2019.88085] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2019] [Accepted: 08/20/2019] [Indexed: 12/24/2022] Open
Abstract
Successful antiviral treatment for hepatitis C virus (HCV) infection is crucial to prevent progression of the disease and its most serious complications. Therapy options have changed over the years with improvement of treatment efficacy, safety and simplification. They evolved from interferon and ribavirin combination administered for 24-72 weeks through interferon (IFN)-based triple therapies with 24-48 weeks duration to the all-oral, well-tolerated direct-acting antiviral regimens lasting for 8-16 weeks and with almost 100% cure rates. The benefits of shorter treatment duration are cost reduction, access to therapy for more patients, and lower risk of adverse events and nonadherence. This review summarizes data on treatment options, focusing on the recommended durations of different regimens depending on HCV genotype, severity of liver disease and history of previous therapy. According to currently available data, shortening treatment below 8 weeks does not provide additional benefits, although the further simplification of therapy is still a subject of study.
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21
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Zhu X, Wang M, Liu M, Yu X, Huang P. Efficacy and safety of direct-acting antivirals for treatment-naive patients with genotype 1 hepatitis C virus infection. Per Med 2019; 16:421-429. [PMID: 31591934 DOI: 10.2217/pme-2018-0121] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
This systematic review was performed on the basis of Preferred Reporting Items for Systematic Reviews and Meta-analyses and Cochrane recommendations to compare sustained virological response (SVR12) and the serious adverse events in patients treated by directing-acting antivirals. We conducted a literature search in PubMed/Medline, EBSCO, Embase and the Cochrane Library until 2018. A consistency model was used to get the relative effect of odds ratio among regimens and the possibility for the efficacy and safety of 13 regimen, and we divided these regimens into DUAL or TRIO regimens to conduct integrated data analysis. The results demonstrated that dual or triple directing-acting antiviral-combined regimens had higher SVR12 rates, Daclatasvir plus Asunaprevir may be a good choice for genotype 1 patients, and regimens without Ribavirin and interferon are safer.
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Affiliation(s)
- Xiaobo Zhu
- Department of Pharmacy, People's Hospital of Danyang, Danyang 212300, China
| | - Mingqi Wang
- Department of Epidemiology, Xu Zhou Medical University, Xuzhou 221000, China
| | - Mei Liu
- Department of Epidemiology, Nanjing Medical University, Nanjing 211166, China
| | - Xinghao Yu
- Department of Epidemiology, Xu Zhou Medical University, Xuzhou 221000, China
| | - Peng Huang
- Department of Epidemiology, Nanjing Medical University, Nanjing 211166, China.,Key Laboratory of Infectious Diseases, Nanjing Medical University, Nanjing 211166, China
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22
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Montasser MF, Zaky S, Salaheldin M, Johar D, Abushouk AI, El-Raey F, Al-Husseini M, Mohammed EG. Fib-4 Predicts Early Hematological Adverse Events Induced by Interferon-Based Triple Therapy in Chronic Hepatitis C Virus Patients. J Interferon Cytokine Res 2019; 39:85-94. [PMID: 30657408 DOI: 10.1089/jir.2018.0131] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Interferon-alpha (IFN-α)-based therapy is associated with several hematological adverse events in hepatitis C virus (HCV)-infected patients with advanced fibrosis. We performed this study to evaluate the association between Fibrosis-4 (Fib-4) index and hematological adverse events in patients with chronic HCV infection, undergoing IFN-α-based triple therapy. We included 120 HCV-infected patients, receiving triple therapy: weekly PegIFN-α, daily ribavirin (1,000-1,200 mg), and daily sofosbuvir (400 mg) for 12 weeks. We compared Fib-4 scores for patients who developed hematological adverse events at weeks 4 (w4) and w12 of treatment and w12 post-treatment versus those who did not. Treatment with the aforementioned triple regimen was associated with a sustained virological response (SVR)-12 rate of 93.9%. We found no significant associations (P > 0.05) between SVR12 rate and the degree of fibrosis or the risk of hematological adverse events. The Fib-4 score could predict patients who developed hematological adverse events (anemia, leukopenia, and neutropenia) in the first month of treatment, but not in later stages. A Fib-4 cutoff value of 3.59 had high specificity for anemia, leukopenia, and neutropenia (85.1%, 87.2%, and 88.2%, respectively), but had low sensitivity for detecting the 3 events. In conclusion, the Fib-4 score may predict early hematological adverse effects in HCV-infected patients on IFN-based triple therapy.
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Affiliation(s)
- Mohamed F Montasser
- 1 Tropical Medicine Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Samy Zaky
- 2 Tropical Medicine Department, Faculty of Medicine, Al-Azhar University, Cairo, Egypt
| | - Mohamed Salaheldin
- 1 Tropical Medicine Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Dina Johar
- 3 Physiology and Pathophysiology Department, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Canada
| | | | - Fathiya El-Raey
- 4 Tropical Medicine Department, Faculty of Medicine, Al-Azhar University, Damietta, Egypt
| | - Muneer Al-Husseini
- 1 Tropical Medicine Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt
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23
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Chen P, Ma A, Liu Q. Cost-Effectiveness of Elbasvir/Grazoprevir Versus Daclatasvir Plus Asunaprevir in Patients with Chronic Hepatitis C Virus Genotype 1b Infection in China. Clin Drug Investig 2018; 38:1031-1039. [PMID: 30194584 DOI: 10.1007/s40261-018-0702-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND AND OBJECTIVE New direct-acting antivirals (DAAs) have high efficacy and tolerability in the treatment of hepatitis C virus (HCV) infection. The objective of this study was to assess the cost-effectiveness of elbasvir/grazoprevir (EBR/GZR) versus daclatasvir plus asunaprevir (DCV + ASV) in Chinese patients with chronic HCV genotype (GT) 1b infection stratified by cirrhosis status and treatment history. METHODS A cohort state-transition model was constructed to simulate the course of chronic HCV infection in patients stratified by cirrhosis status and treatment history. The model projected lifetime outcomes and costs in terms of HCV treatment, laboratory tests, clinical procedures, and hospitalizations. Mean age of the study cohort at baseline was 45 years, based on published sources. Sustained virologic response (SVR) rates were derived from clinical trials. Healthcare resource utilization and health utilities were extracted or estimated from published studies in Chinese populations. The stability of the base-case analysis was validated by deterministic and probabilistic sensitivity analyses. RESULTS In each subpopulation of Chinese patients, treatment with EBR/GZR dominated treatment with DCV + ASV, with lower costs and higher quality-adjusted life-years (QALYs). Sensitivity analysis demonstrated that EBR/GZR was the cost-effective option compared to DCV + ASV in 77.4-97.4% or 94.1-100% of model simulations in Chinese treatment-naïve or treatment-experienced patients, respectively, as the cost-effectiveness threshold changed from zero to US$24,150/QALY (three times GDP per capita in China). CONCLUSIONS Treatment with EBR/GZR was the cost-effective option for patients with chronic HCV GT1b infection in China, regardless of cirrhosis status or treatment history.
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Affiliation(s)
- Pingyu Chen
- School of International Pharmaceutical Business, China Pharmaceutical University, No. 639 Longmian Road, Jiangning District, Nanjing, 211198, People's Republic of China
| | - Aixia Ma
- School of International Pharmaceutical Business, China Pharmaceutical University, No. 639 Longmian Road, Jiangning District, Nanjing, 211198, People's Republic of China.
| | - Qiang Liu
- School of International Pharmaceutical Business, China Pharmaceutical University, No. 639 Longmian Road, Jiangning District, Nanjing, 211198, People's Republic of China
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24
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Ahmed M. Era of direct acting anti-viral agents for the treatment of hepatitis C. World J Hepatol 2018; 10:670-684. [PMID: 30386460 PMCID: PMC6206157 DOI: 10.4254/wjh.v10.i10.670] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2018] [Revised: 05/15/2018] [Accepted: 05/23/2018] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C infection is universal and the most common indication of liver transplantation in the United States. The period of less effective interferon therapy with intolerable side effects has gone. Now we have stepped into the era of direct acting anti-viral agents (DAAs) against hepatitis C virus. Treatment of hepatitis C is now extremely effective, tolerable and requires a short duration of intake of oral agents. Less monitoring is required with the current therapy and drug-drug interactions are less than the previous regimen. The current treatment options of chronic hepatitis C with various DAAs are discussed in this article.
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Affiliation(s)
- Monjur Ahmed
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Thomas Jefferson University, Philadelphia, PA 19107, United States.
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25
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Lahser F, Galloway A, Hwang P, Palcza J, Brunhofer J, Wahl J, Robertson M, Barr E, Black T, Asante-Appiah E, Haber B. Interim analysis of a 3-year follow-up study of NS5A and NS3 resistance-associated substitutions after treatment with grazoprevir-containing regimens in participants with chronic HCV infection. Antivir Ther 2018; 23:593-603. [PMID: 30038064 DOI: 10.3851/imp3253] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/21/2018] [Indexed: 10/28/2022]
Abstract
BACKGROUND In HCV-infected people who fail to achieve sustained virological response after receiving a direct-acting antiviral regimen, virological failure is almost always accompanied by the presence of resistance-associated substitutions (RASs) in the target protein(s). The aim of this long-term observational study was to evaluate the persistence of NS3/4A and NS5A RASs in participants with genotype (GT) 1 infection who relapsed following treatment with a grazoprevir-containing treatment regimen. METHODS RASs were evaluated at baseline (that is, pre-dose on day 1 of the original treatment), at the time of virological failure, and up to follow-up week 96. A total of 58 participants were included. RESULTS In participants treated with elbasvir/grazoprevir ± ribavirin, observed baseline NS3 RASs included 56F, 80K/L, 122N and 170V/I, and observed treatment-emergent NS3 RASs included 36M, 56F/H, 122G, 132I, 156G/I/L/P/T, 168A/E/G/V/Y and 170T. Observed baseline NS5A RASs included 28M/T/V, 30H/R, 31M/V and 93H/N, and treatment-emergent NS5A RASs included 28A/G/S/T, 30H/R, 31M/V and 93H/N/S. Baseline NS3 and NS5A RASs present at time of failure tended to persist during follow-up, and most were detectable for more than 2 years following virological failure. Treatment-emergent NS5A RASs present at time of failure also tended to persist for more than 2 years following virological failure (93%). By contrast, >80% of treatment-emergent NS3 RASs detected at failure had been supplanted by wild type by week 36. CONCLUSIONS Treatment-emergent NS5A RASs can persist for extended periods of time. Retreatment strategies should take account of the presence of these RASs.
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Affiliation(s)
- Frederick Lahser
- Department of Infectious Diseases, Merck & Co., Inc. Kenilworth, NJ, USA
| | - Angela Galloway
- Department of Infectious Diseases, Merck & Co., Inc. Kenilworth, NJ, USA
| | - Peggy Hwang
- Department of Infectious Diseases, Merck & Co., Inc. Kenilworth, NJ, USA
| | - John Palcza
- Department of Infectious Diseases, Merck & Co., Inc. Kenilworth, NJ, USA
| | - Joann Brunhofer
- Department of Infectious Diseases, Merck & Co., Inc. Kenilworth, NJ, USA
| | - Janice Wahl
- Department of Infectious Diseases, Merck & Co., Inc. Kenilworth, NJ, USA
| | - Michael Robertson
- Department of Infectious Diseases, Merck & Co., Inc. Kenilworth, NJ, USA
| | - Eliav Barr
- Department of Infectious Diseases, Merck & Co., Inc. Kenilworth, NJ, USA
| | - Todd Black
- Department of Infectious Diseases, Merck & Co., Inc. Kenilworth, NJ, USA
| | | | - Barbara Haber
- Department of Infectious Diseases, Merck & Co., Inc. Kenilworth, NJ, USA
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