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Wedemeyer H, Leus M, Battersby TR, Glenn J, Gordien E, Kamili S, Kapoor H, Kessler HH, Lenz O, Lütgehetmann M, Mixson-Hayden T, Simon CO, Thomson M, Westman G, Miller V, Terrault N, Lampertico P. HDV RNA assays: Performance characteristics, clinical utility, and challenges. Hepatology 2025; 81:637-650. [PMID: 37640384 PMCID: PMC11289715 DOI: 10.1097/hep.0000000000000584] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2023] [Accepted: 06/15/2023] [Indexed: 08/31/2023]
Abstract
Coinfection with HBV and HDV results in hepatitis D, the most severe form of chronic viral hepatitis, frequently leading to liver decompensation and HCC. Pegylated interferon alpha, the only treatment option for chronic hepatitis D for many years, has limited efficacy. New treatments are in advanced clinical development, with one recent approval. Diagnosis and antiviral treatment response monitoring are based on detection and quantification of HDV RNA. However, the development of reliable HDV RNA assays is challenged by viral heterogeneity (at least 8 different genotypes and several subgenotypes), intrahost viral diversity, rapid viral evolution, and distinct secondary structure features of HDV RNA. Different RNA extraction methodologies, primer/probe design for nucleic acid tests, lack of automation, and overall dearth of standardization across testing laboratories contribute to substantial variability in performance characteristics of research-based and commercial HDV RNA assays. A World Health Organization (WHO) standard for HDV RNA, available for about 10 years, has been used by many laboratories to determine the limit of detection of their assays and facilitates comparisons of RNA levels across study centers. Here we review challenges for robust pan genotype HDV RNA quantification, discuss particular clinical needs and the importance of reliable HDV RNA quantification in the context of drug development and patient monitoring. We summarize distinct technical features and performance characteristics of available HDV RNA assays. Finally, we provide considerations for the use of HDV RNA assays in the context of drug development and patient monitoring.
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Affiliation(s)
- Heiner Wedemeyer
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
- Excellence Cluster RESIST, Hannover Medical School, Hannover, Germany
- D-SOLVE: EU-funded Network on Individualized Management of Hepatitis D
- German Center for Infection Research (DZIF), Partner Site Hannover-Braunschweig, Braunschweig, Germany
| | - Mitchell Leus
- Forum for Collaborative Research, School of Public Health, University of California, Berkeley, Washington DC Campus, Washington, District of Columbia, USA
| | | | - Jeffrey Glenn
- Departments of Medicine (Division of Gastroenterology and Hepatology) and Microbiology & Immunology, Stanford University School of Medicine, Stanford, California, USA
| | - Emmanuel Gordien
- Laboratoire de microbiologie clinique, Centre National de Référence pour les virus des hépatites B, C et Delta, Hôpital Avicenne Assistance Publique – Hôpitaux de Paris, Bobigny, France
| | - Saleem Kamili
- Division of Viral Hepatitis, Centers for Disease Control and Prevention, Atlanta, Georgia, USA
| | - Hema Kapoor
- Ex Quest Diagnostics, HK Healthcare Consultant LLC, Secaucus, New Jersey, USA
| | - Harald H. Kessler
- Diagnostic and Research Center for Molecular Biomedicine, Medical University of Graz, Graz, Austria
| | - Oliver Lenz
- Clinical Microbiology and Immunology, Janssen Pharmaceutica NV, Beerse, Belgium
| | - Marc Lütgehetmann
- Institute for Microbiology, Virology and Hygiene, University Medical Center Hamburg Eppendorf (UKE), Hamburg, Germany
- German Center for Infection Research (DZIF), Partner Site Hamburg, Lübeck, Kiel, Germany
| | - Tonya Mixson-Hayden
- Division of Viral Hepatitis, Centers for Disease Control and Prevention, Atlanta, Georgia, USA
| | - Christian O. Simon
- Clinical Development and Medical Affairs, Roche Diagnostics Solutions, Rotkreuz, Switzerland
| | - Michael Thomson
- Division of Antivirals, US Food and Drug Administration, Silver Spring, Maryland, USA
| | - Gabriel Westman
- Swedish Medical Products Agency, Uppsala, Sweden
- Department of Medical Sciences, Uppsala University, Uppsala, Sweden
| | - Veronica Miller
- Forum for Collaborative Research, School of Public Health, University of California, Berkeley, Washington DC Campus, Washington, District of Columbia, USA
| | - Norah Terrault
- Division of Gastrointestinal and Liver Diseases, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
| | - Pietro Lampertico
- Division of Gastroenterology and Hepatology, Foundation IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
- Department of Pathophysiology and Transplantation, CRC “A. M. and A. Migliavacca” Center for Liver Disease, University of Milan, Milan, Italy
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Zhuang W, Camacho L, Silva CS, Thomson M, Snyder K. A robust biostatistical method leverages informative but uncertainly determined qPCR data for biomarker detection, early diagnosis, and treatment. PLoS One 2022; 17:e0263070. [PMID: 35100319 PMCID: PMC8803186 DOI: 10.1371/journal.pone.0263070] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Accepted: 01/11/2022] [Indexed: 11/19/2022] Open
Abstract
As a common medium-throughput technique, qPCR (quantitative real-time polymerase chain reaction) is widely used to measure levels of nucleic acids. In addition to accurate and complete data, experimenters have unavoidably observed some incomplete and uncertainly determined qPCR data because of intrinsically low overall amounts of biological materials, such as nucleic acids present in biofluids. When there are samples with uncertainly determined qPCR data, some investigators apply the statistical complete-case method by excluding the subset of samples with uncertainly determined data from analysis (CO), while others simply choose not to analyze (CNA) these datasets altogether. To include as many observations as possible in analysis for interesting differential changes between groups, some investigators set incomplete observations equal to the maximum quality qPCR cycle (MC), such as 32 and 40. Although straightforward, these methods may decrease the sample size, skew the data distribution, and compromise statistical power and research reproducibility across replicate qPCR studies. To overcome the shortcomings of the existing, commonly-used qPCR data analysis methods and to join the efforts in advancing statistical analysis in rigorous preclinical research, we propose a robust nonparametric statistical cycle-to-threshold method (CTOT) to analyze incomplete qPCR data for two-group comparisons. CTOT incorporates important characteristics of qPCR data and time-to-event statistical methodology, resulting in a novel analytical method for qPCR data that is built around good quality data from all subjects, certainly determined or not. Considering the benchmark full data (BFD), we compared the abilities of CTOT, CO, MC, and CNA statistical methods to detect interesting differential changes between groups with informative but uncertainly determined qPCR data. Our simulations and applications show that CTOT improves the power of detecting and confirming differential changes in many situations over the three commonly used methods without excess type I errors. The robust nonparametric statistical method of CTOT helps leverage qPCR technology and increase the power to detect differential changes that may assist decision making with respect to biomarker detection and early diagnosis, with the goal of improving the management of patient healthcare.
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Affiliation(s)
- Wei Zhuang
- Division of Bioinformatics and Biostatistics, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, Arkansas, United States of America
| | - Luísa Camacho
- Division of Biochemical Toxicology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, Arkansas, United States of America
| | - Camila S. Silva
- Division of Biochemical Toxicology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, Arkansas, United States of America
| | - Michael Thomson
- Office of New Drugs, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, United States of America
| | - Kevin Snyder
- Office of New Drugs, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, United States of America
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Sarrazin C, Zimmermann T, Berg T, Hinrichsen H, Mauss S, Wedemeyer H, Zeuzem S. Prophylaxe, Diagnostik und Therapie der Hepatitis-C-Virus(HCV)-Infektion. ZEITSCHRIFT FUR GASTROENTEROLOGIE 2020; 58:1110-1131. [PMID: 33197953 DOI: 10.1055/a-1226-0241] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Affiliation(s)
- C Sarrazin
- Medizinische Klinik II Gastroenterologie, Hepatologie, Infektiologie, Diabetologie, St. Josefs-Hospital, Wiesbaden, Deutschland.,Medizinische Klinik I Gastroenterologie, Hepatologie, Pneumologie, Endokrinologie, Universitätsklinikum Frankfurt, Frankfurt, Deutschland
| | - T Zimmermann
- Medizinische Klinik II, Klinikum Worms, Worms, Deutschland.,Medizinische Klinik und Poliklinik, Gastroenterologie und Hepatologie, Universitätsmedizin Mainz, Mainz, Deutschland
| | - T Berg
- Klinik und Poliklinik für Gastroenterologie und Rheumatologie, Universitätsklinikum Leipzig, Leipzig, Deutschland
| | | | - S Mauss
- MVZ, Düsseldorf, Deutschland
| | - H Wedemeyer
- Klinik für Gastroenterologie, Hepatologie und Endokrinologie, Medizinische Hochschule Hannover, Hannover, Deutschland
| | - S Zeuzem
- Medizinische Klinik I Gastroenterologie, Hepatologie, Pneumologie, Endokrinologie, Universitätsklinikum Frankfurt, Frankfurt, Deutschland
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Paolucci S, Novazzi F, Piralla A, Maserati R, Gulminetti R, Novati S, Barbarini G, Sacchi P, Fratini A, Bellotti L, Baldanti F. Viral dynamics among HCV infected patients with different genotypes treated with genotypic specific or pan-genotypic direct-acting antiviral agent combinations. Infect Drug Resist 2019; 12:1975-1984. [PMID: 31372005 PMCID: PMC6627173 DOI: 10.2147/idr.s205282] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2019] [Accepted: 03/25/2019] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND New hepatitis C virus (HCV) therapies have improved efficacy, allowed pangenotypic applications, increased barriers to drug resistance and shortened therapy duration. METHODS Patients infected with different HCV genotypes were divided into two groups: group 1 included 169 patients receiving genotypic specific regimens (GSR), while group 2 included 186 patients receiving pan-genotypic regimens (PGR). Patient's HCV RNA was quantified and sequenced. RESULTS Comparable sustained viral response (SVR) rates were observed in both GSR and PGR treated patients. Nevertheless, even if not significant, a greater proportion of non-detectable levels (NDL) of HCV RNA was observed in patients treated with PGR as compared with GSR. Overall, among patients in the GSR and PGR groups with residual viremia, 124/169 (73.4%) and 125/186 (67.2%) at four weeks, and 66/169 (39.1%) and 58/186 (31.2%) at eight weeks, achieved SVR. No difference was observed in the clinical outcome comparing patients in the GSR and PGR groups according to genotype. While, comparing patients between the two groups, the proportion of patients with NDL HCV RNA at four and eight weeks was higher in patients infected with genotype 1b treated with PGR (p=0.0015). A significantly higher number of patients infected with 1b had RASs at baseline (p=0.0001). In addition, the proportion of patients with treatment failure was higher in patients with RASs at baseline compared with those without (p=0.012). Overall, 2.5% patients failed to achieve SVR after DAA treatment. CONCLUSION A sharp HCV RNA decrease was observed in patients treated with both GSR and PGR. However, even if comparable, a slightly greater number of patients treated with PGR achieved NDL HCV RNA as compared with GSR. A significant difference was observed in patients with baseline RASs, both in relation to treatment failure and genotype. In conclusion, the use of new DAA combinations helps patients achieve a more rapid virologic response.
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Affiliation(s)
- Stefania Paolucci
- Molecular Virology Unit, Microbiology and Virology Department, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Policlinico, San Matteo, Pavia, Italy
| | - Federica Novazzi
- Molecular Virology Unit, Microbiology and Virology Department, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Policlinico, San Matteo, Pavia, Italy
| | - Antonio Piralla
- Molecular Virology Unit, Microbiology and Virology Department, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Policlinico, San Matteo, Pavia, Italy
| | - Renato Maserati
- Institute of Infectious Diseases, University of Pavia, Pavia, Italy
| | | | - Stefano Novati
- Institute of Infectious Diseases, University of Pavia, Pavia, Italy
| | - Giorgio Barbarini
- Division of Infectious and Tropical Diseases, Fondazione IRCCS Policlinico, San Matteo, Pavia, Italy
| | - Paolo Sacchi
- Division of Infectious and Tropical Diseases, Fondazione IRCCS Policlinico, San Matteo, Pavia, Italy
| | - Alice Fratini
- Molecular Virology Unit, Microbiology and Virology Department, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Policlinico, San Matteo, Pavia, Italy
| | - Laura Bellotti
- Molecular Virology Unit, Microbiology and Virology Department, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Policlinico, San Matteo, Pavia, Italy
| | - Fausto Baldanti
- Molecular Virology Unit, Microbiology and Virology Department, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Policlinico, San Matteo, Pavia, Italy
- Department of Clinical, Surgical, Diagnostic and Pediatric Sciences, University of Pavia, Pavia, Italy
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Effects of microvirin monomers and oligomers on hepatitis C virus. Biosci Rep 2017; 37:BSR20170015. [PMID: 28507200 PMCID: PMC6434159 DOI: 10.1042/bsr20170015] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2016] [Revised: 05/02/2017] [Accepted: 05/10/2017] [Indexed: 12/25/2022] Open
Abstract
Microvirin (MVN) is a carbohydrate-binding protein which shows high specificity for high-mannose type N-glycan structures. In the present study, we tried to identify whether MVN could bind to high-mannose containing hepatitis C virus (HCV) envelope glycoproteins, which are heavily decorated high-mannose glycans. In addition, recombinantly expressed MVN oligomers in di-, tri- and tetrameric form were evaluated for their viral inhibition. MVN oligomers bound more efficiently to HCV virions, and displayed in comparison with the MVN monomer a higher neutralization potency against HCV infection. The antiviral effect was furthermore affected by the peptide linker sequence connecting the MVN monomers. The results indicate that MVN oligomers such as trimers and tetramers may be used as future neutralization agents against HCV infections.
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Pierce VM, Eversley JS, Tran TK, Rosenberg ES. Differences between quantification of genotype 3 hepatitis C virus RNA by Versions 1.0 and 2.0 of the COBAS AmpliPrep/COBAS TaqMan HCV Test. Clin Chem Lab Med 2017; 55:956-961. [DOI: 10.1515/cclm-2016-0799] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2016] [Accepted: 11/01/2016] [Indexed: 11/15/2022]
Abstract
AbstractBackground:Differences between the designs of hepatitis C virus (HCV) viral load assays can result in genotype-related variability in RNA quantification. We tested paired aliquots of plasma specimens from HCV-infected individuals using two versions (v1.0 and v2.0) of the Roche COBAS AmpliPrep/COBAS TaqMan HCV Test (CAP/CTM HCV) and noted variability between results for a subset of specimens; we then sought to determine whether discrepant results were more prevalent among specific HCV genotypes.Methods:Archived and prospectively-collected plasma samples from 114 unique patients were tested using CAP/CTM HCV v1.0 and v2.0. The HCV genotype result for each patient was determined by retrospectively reviewing laboratory records.Results:All (46/46) specimens with quantifiable viral loads from patients with genotype 1 or 2 infection had CAP/CTM HCV v1.0 and v2.0 results that were within 0.5 logConclusions:In patients infected with HCV genotype 3, sequential CAP/CTM HCV viral load results should be compared with caution and interpreted in the context of the specific assay version used.
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Maasoumy B, Vermehren J. Diagnostics in hepatitis C: The end of response-guided therapy? J Hepatol 2016; 65:S67-S81. [PMID: 27641989 DOI: 10.1016/j.jhep.2016.07.023] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2016] [Revised: 07/20/2016] [Accepted: 07/21/2016] [Indexed: 02/07/2023]
Abstract
On-treatment hepatitis C virus (HCV) RNA has been used to predict response to interferon (IFN)-based therapy. The concept of response-guided treatment (RGT) was established to determine optimal treatment duration and to early identify patients not responding to futile therapies. RGT helped to improve sustained virologic response (SVR) rates and lower the rates of adverse effects. RGT was of particular importance for telaprevir- and boceprevir-based triple therapies. RGT strategies are dependent on highly sensitive and reproducible HCV RNA quantification. However, different HCV RNA assays are used in routine clinical practice and these differ significantly in their performance characteristics. The development of IFN-free therapies has fundamentally changed the role of on-treatment HCV RNA for SVR prediction. Given the high efficacy and excellent tolerability of IFN-free regimens, the interest in treatment individualization has decreased. However, shorter treatment durations may still be desirable, particularly with respect to the high costs of current IFN-free direct-acting antiviral agents (DAAs). Moreover, some difficult-to-treat patients remain, e.g., those infected with HCV genotype 3 in whom the current standard of care may not always be sufficient to achieve SVR, especially in treatment-experienced patients with cirrhosis. Here, a RGT extension may be feasible. However, current data on the predictive value of on-treatment HCV RNA are limited and have shown conflicting results. As more potent DAAs become available, the role of response prediction may diminish further. Currently, shorter treatment duration is only based on baseline HCV RNA whereas no RGT strategy is recommended for any of the approved DAA regimens available.
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Affiliation(s)
- Benjamin Maasoumy
- Medizinische Hochschule Hannover, Klinik für Gastroenterologie, Hepatologie und Endokrinologie, Hannover, Germany
| | - Johannes Vermehren
- Universitätsklinikum Frankfurt, Medizinische Klinik 1, Frankfurt am Main, Germany.
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Omata M, Kanda T, Wei L, Yu ML, Chuang WL, Ibrahim A, Lesmana CRA, Sollano J, Kumar M, Jindal A, Sharma BC, Hamid SS, Dokmeci AK, Al-Mahtab M, McCaughan GW, Wasim J, Crawford DHG, Kao JH, Yokosuka O, Lau GKK, Sarin SK. APASL consensus statements and recommendations for hepatitis C prevention, epidemiology, and laboratory testing. Hepatol Int 2016; 10:681-701. [PMID: 27229718 PMCID: PMC5003900 DOI: 10.1007/s12072-016-9736-3] [Citation(s) in RCA: 66] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2016] [Accepted: 04/20/2016] [Indexed: 02/06/2023]
Abstract
The Asian Pacific Association for the Study of the Liver (APASL) convened an international working party on "APASL consensus statements and recommendations for management of hepatitis C" in March 2015 to revise the "APASL consensus statements and management algorithms for hepatitis C virus infection" (Hepatol Int 6:409-435, 2012). The working party consisted of expert hepatologists from the Asian-Pacific region gathered at the Istanbul Congress Center, Istanbul, Turkey on 13 March 2015. New data were presented, discussed, and debated during the course of drafting a revision. Participants of the consensus meeting assessed the quality of the cited studies. The finalized recommendations for hepatitis C prevention, epidemiology, and laboratory testing are presented in this review.
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Affiliation(s)
- Masao Omata
- Yamanashi Prefectural Central Hospital, 1-1-1 Fujimi, Kofu-shi, Yamanashi, 400-8506, Japan.
- The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.
| | - Tatsuo Kanda
- Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Lai Wei
- Peking University People's Hospital, Peking University Hepatology Institute, Beijing, China
| | - Ming-Lung Yu
- Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan
| | - Wang-Long Chuang
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Alaaeldin Ibrahim
- GI/Liver Division, Department of Internal Medicine, University of Benha, Banha, Egypt
| | | | - Jose Sollano
- University Santo Tomas Hospital, Manila, Philippines
| | - Manoj Kumar
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Ankur Jindal
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | | | - Saeed S Hamid
- Department of Medicine, Aga Khan University and Hospital, Stadium Road, Karachi, 74800, Pakistan
| | - A Kadir Dokmeci
- Department of Gastroenterology, Ankara University School of Medicine, Ankara, Turkey
| | - Mamun Al-Mahtab
- Department of Hepatology, Bangabandhu Sheikh Mujib Medical University, Dhaka, 1000, Bangladesh
| | - Geofferey W McCaughan
- Royal Prince Alfred Hospital, Centenary Institute, University of Sydney, Sydney, Australia
| | - Jafri Wasim
- Department of Medicine, Aga Khan University and Hospital, Stadium Road, Karachi, 74800, Pakistan
| | - Darrell H G Crawford
- University of Queensland, School of Medicine, Woolloongabba, QLD, 4102, Australia
| | - Jia-Horng Kao
- National Taiwan University College of Medicine and National Taiwan University Hospital, Taipei, Taiwan
| | - Osamu Yokosuka
- Graduate School of Medicine, Chiba University, Chiba, Japan
| | - George K K Lau
- The Institute of Translational Hepatology, Beijing 302 Hospital, Beijing, China
| | - Shiv Kumar Sarin
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
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Garbuglia AR, Visco-Comandini U, Lionetti R, Lapa D, Castiglione F, D’Offizi G, Taibi C, Montalbano M, Capobianchi MR, Paci P. Ultrasensitive HCV RNA Quantification in Antiviral Triple Therapy: New Insight on Viral Clearance Dynamics and Treatment Outcome Predictors. PLoS One 2016; 11:e0158989. [PMID: 27560794 PMCID: PMC4999094 DOI: 10.1371/journal.pone.0158989] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2016] [Accepted: 06/25/2016] [Indexed: 02/06/2023] Open
Abstract
OBJECTIVES Identifying the predictive factors of Sustained Virological Response (SVR) represents an important challenge in new interferon-based DAA therapies. Here, we analyzed the kinetics of antiviral response associated with a triple drug regimen, and the association between negative residual viral load at different time points during treatment. METHODS Twenty-three HCV genotype 1 (GT 1a n = 11; GT1b n = 12) infected patients were included in the study. Linear Discriminant Analysis (LDA) was used to establish possible association between HCV RNA values at days 1 and 4 from start of therapy and SVR. Principal component analysis (PCA) was applied to analyze the correlation between HCV RNA slope and SVR. A ultrasensitive (US) method was established to measure the residual HCV viral load in those samples which resulted "detected <12IU/ml" or undetectable with ABBOTT standard assay, and was retrospectively used on samples collected at different time points to establish its predictive power for SVR. RESULTS According to LDA, there was no association between SVR and viral kinetics neither at time points earlier than 1 week (days 1 and 4) after therapy initiation nor later. The slopes were not relevant for classifying patients as SVR or no-SVR. No significant differences were observed in the median HCV RNA values at T0 among SVR and no-SVR patients. HCV RNA values with US protocol (LOD 1.2 IU/ml) after 1 month of therapy were considered; the area under the ROC curve was 0.70. Overall, PPV and NPV of undetectable HCV RNA with the US method for SVR was 100% and 46.7%, respectively; sensitivity and specificity were 38.4% and 100% respectively. CONCLUSION HCV RNA "not detected" by the US method after 1 month of treatment is predictive of SVR in first generation Protease inhibitor (PI)-based triple therapy. The US method could have clinical utility for advanced monitoring of virological response in new interferon based DAA combination regimens.
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Affiliation(s)
- Anna Rosa Garbuglia
- Laboratory of Virology, “Lazzaro Spallanzani” National Institute for Infectious Diseases, IRCCS, Rome, Italy
- * E-mail:
| | - Ubaldo Visco-Comandini
- Clinical Department, “Lazzaro Spallanzani” National Institute for Infectious Diseases, IRCCS, Rome, Italy
| | - Raffaella Lionetti
- Clinical Department, “Lazzaro Spallanzani” National Institute for Infectious Diseases, IRCCS, Rome, Italy
| | - Daniele Lapa
- Laboratory of Virology, “Lazzaro Spallanzani” National Institute for Infectious Diseases, IRCCS, Rome, Italy
| | | | - Gianpiero D’Offizi
- Clinical Department, “Lazzaro Spallanzani” National Institute for Infectious Diseases, IRCCS, Rome, Italy
| | - Chiara Taibi
- Clinical Department, “Lazzaro Spallanzani” National Institute for Infectious Diseases, IRCCS, Rome, Italy
| | - Marzia Montalbano
- Clinical Department, “Lazzaro Spallanzani” National Institute for Infectious Diseases, IRCCS, Rome, Italy
| | - Maria Rosaria Capobianchi
- Laboratory of Virology, “Lazzaro Spallanzani” National Institute for Infectious Diseases, IRCCS, Rome, Italy
| | - Paola Paci
- Istituto di Analisi dei Sistemi ed Informatica “Antonio Ruberti” (IASI)—CNR, Rome, Italy
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10
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Su PY, Yen HH, Hsu YC, Wu SS, Kor CT, Su WW. Rapid virological response assessment by Abbott RealTime hepatitis C virus assay for predicting sustained virological responses in patients with hepatitis C virus genotype 1 treated with pegylated-interferon and ribavirin. Kaohsiung J Med Sci 2016; 32:381-6. [PMID: 27450028 DOI: 10.1016/j.kjms.2016.06.002] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2015] [Revised: 05/28/2016] [Accepted: 05/30/2016] [Indexed: 01/28/2023] Open
Abstract
The lower limits of virus detection of hepatitis C virus (HCV) RNA detection assays are continuously improving. We aimed to assess the utility of more precise definition of 4(th) week viral load [rapid virological response (RVR)] in predicting sustained virological response (SVR) in HCV genotype 1 patients treated with pegylated-interferon (PEG-IFN) and ribavirin. Clinical data of treatment-naïve HCV genotype 1 patients were retrospectively collected from 2009 to 2014. Patients were grouped according to 4(th) week viral load as follows: undetectable (n = 90) and detectable but not quantifiable (< 12 IU/mL, n = 27). All patients received PEG-IFNα-2a or -2b and ribavirin for 24 weeks. Serum HCV RNA levels were measured by Abbott RealTime (ART; Abbott Molecular, Abbott Park, IL, USA) HCV assay. SVR was 95.5% and 63% in the undetectable group and < 12 IU/mL group of 4(th) week viral load, respectively. The between-group difference in SVR was significant (p < 0.001). We determined 4(th) week viral load was independently associated with SVR (odds ratio = 19.28; p = 0.002) and a good predictor of SVR [area under the curve (AUC) = 0.775; p = 0.001]. ART HCV assays had a stronger SVR predictive value in HCV genotype 1 patients, indicating that only the undetectable group of 4(th) week viral load patients measured by ART HCV assay should be considered for shorter treatment time (24 weeks) with PEG-IFN and ribavirin.
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Affiliation(s)
- Pei-Yuan Su
- Department of Gastroenterology, Changhua Christian Hospital, Changhua, Taiwan, ROC
| | - Hsu-Heng Yen
- Department of Gastroenterology, Changhua Christian Hospital, Changhua, Taiwan, ROC
| | - Yu-Chun Hsu
- Department of Gastroenterology, Changhua Christian Hospital, Changhua, Taiwan, ROC
| | - Shun-Sheng Wu
- Department of Gastroenterology, Changhua Christian Hospital, Changhua, Taiwan, ROC
| | - Chew-Teng Kor
- Internal Medicine Research Center, Changhua Christian Hospital, Changhua, Taiwan, ROC
| | - Wei-Wen Su
- Department of Gastroenterology, Changhua Christian Hospital, Changhua, Taiwan, ROC; School of Medicine, Chung Shan Medical University, Taichung, Taiwan, ROC.
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11
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Molecular Detection and Characterization of Hepatitis C Virus. Mol Microbiol 2016. [DOI: 10.1128/9781555819071.ch31] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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12
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Impact of HCV kinetics on treatment outcome differs by the type of real-time HCV assay in NS3/4A protease inhibitor-based triple therapy. Antiviral Res 2015; 126:35-42. [PMID: 26692214 DOI: 10.1016/j.antiviral.2015.12.001] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2015] [Revised: 11/27/2015] [Accepted: 12/07/2015] [Indexed: 12/21/2022]
Abstract
Repeated measurement of the HCV RNA level is essential for properly monitoring treatment efficacy. The aim of this study was to determine the utility of two HCV real-time assays in the evaluation of the impact of hepatitis C virus (HCV) kinetics on the outcome of triple therapy with NS3/4A protease inhibitors (PIs), telaprevir or simeprevir. This study consisted of 171 Japanese patients infected with HCV genotype 1. All 3266 serum samples taken during and post treatment were tested with both the COBAS AmpliPrep/COBAS TaqMan (CAP/CTM) HCV Test v2.0 and the Abbott RealTime (ART) HCV Test. Of the 2597 samples undetectable (lower limit of detection [<LOD]) for HCV RNA by the CAP/CTM assay from the on and post treatment, 400 (15.4%) (369 detectable/less than the lower limitation of quantification [<LLOQ] and 31 quantifiable) were detectable by the ART assay. HCV RNA < LOD within the first four weeks by ART was associated with sustained virological response (SVR) for the difficult-to-treat group that included patients with advanced fibrosis or prior partial/null response. In contrast, for the non-difficult-to-treat group, almost all of the late responders by ART achieved SVR, unlike by CAP/CTM. Despite HCV RNA being once < LOD by ART, 33.1% patients experienced the reappearance of residual HCV RNA (detectable/<LLOQ) during treatment. This event in the first 12 weeks (with PI-treatment period) was not related to treatment failure, however, relapse was observed in all patients with a reappearance of residual HCV RNA after 12 weeks (without PI-treatment period). The superior ability to detect low-level HCV RNA by ART could be useful for predicting SVR by difficult-to-treat patients in the early period and relapse in the late period.
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13
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Forns X, Gordon SC, Zuckerman E, Lawitz E, Calleja JL, Hofer H, Gilbert C, Palcza J, Howe AYM, DiNubile MJ, Robertson MN, Wahl J, Barr E, Buti M. Grazoprevir and elbasvir plus ribavirin for chronic HCV genotype-1 infection after failure of combination therapy containing a direct-acting antiviral agent. J Hepatol 2015; 63:564-72. [PMID: 25895428 DOI: 10.1016/j.jhep.2015.04.009] [Citation(s) in RCA: 123] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2015] [Revised: 03/31/2015] [Accepted: 04/16/2015] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS The Phase-2 C-SALVAGE study evaluated an investigational interferon-free combination of grazoprevir (a NS3/4A protease inhibitor) and elbasvir (a NS5A inhibitor) with ribavirin for patients with chronic HCV genotype-1 infection who had failed licensed DAA-containing therapy. METHODS C-SALVAGE was an open-label study of grazoprevir 100 mg and elbasvir 50 mg QD with weight-based ribavirin BID for 12 weeks in cirrhotic and non-cirrhotic patients with chronic HCV genotype-1 infection who had not attained SVR after ⩾4 weeks of peginterferon and ribavirin plus either boceprevir, telaprevir, or simeprevir. Exclusion criteria included decompensated liver disease, hepatocellular carcinoma, and HIV or HBV co-infection. The primary efficacy outcome was SVR12 defined as a HCV RNA level below the assay limit of quantification 12 weeks after the end of treatment. RESULTS Of the 79 patients treated with ⩾1 dose of study drug, 66 (84%) patients had a history of virologic failure on a regimen containing a NS3/4A protease inhibitor; 12 of the other 13 patients discontinued prior treatment because of adverse experiences. At entry, 34 (43.6%) of 78 evaluable patients harbored NS3 RAVs. SVR12 rates were 76/79 (96.2%) overall, including 28/30 (93.3%) patients with genotype 1a infection, 63/66 (95.5%) patients with prior virologic failure, 43/43 (100%) patients without baseline RAVs, 31/34 (91.2%) patients with baseline NS3 RAVs, 6/8 (75.0%) patients with baseline NS5A RAVs, 4/6 (66.7%) patients with both baseline NS3 and RAVs, and 32/34 (94.1%) cirrhotic patients. None of the five reported serious adverse events were considered drug-related. CONCLUSIONS Grazoprevir and elbasvir plus ribavirin for 12 weeks provides a promising new treatment option for patients after failure of triple therapy containing an earlier-generation protease inhibitor.
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Affiliation(s)
- Xavier Forns
- Liver Unit, Hospital Clinic, IDIBAPS and CIBEREHD, Barcelona, Spain.
| | | | | | - Eric Lawitz
- The Texas Liver Institute, University of Texas Health Science Center, San Antonio, TX, USA
| | - Jose L Calleja
- Servicio de Gastroenterología y Hepatología, Hospital Universitario Puerta de Hierro, Universidad Autonoma de Madrid, Madrid, Spain
| | - Harald Hofer
- Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria
| | | | | | | | | | | | | | - Eliav Barr
- Merck and Co., Inc., Kenilworth, NJ, USA
| | - Maria Buti
- Hospital Universitario Valle Hebron and Ciberehd, Barcelona, Spain
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14
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Grüner N, Viazov S, Korn K, Knöll A, Trippler M, Schlaak JF, Gerken G, Roggendorf M, Ross RS. Performance characteristics of the VERSANT hepatitis C virus RNA 1.0 (kPCR) assay. Int J Med Microbiol 2015; 305:627-35. [PMID: 26384868 DOI: 10.1016/j.ijmm.2015.08.012] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
HCV RNA assays are of central importance for virological diagnostics and for clinical planning and monitoring of an antiviral combination treatment of chronic HCV infections. The objective of the pre-market evaluation of the VERSANT HCV RNA 1.0 Assay (kPCR) was to collect analytical performance data for this new method of HCV RNA quantification and to compare them with the high standards that exist in this context. The assay exhibited a specificity of 100%. The mean intra- and inter-assay imprecision was 14.1% and 14.6%, respectively. The detection limit was determined to be 16IU/ml (95% confidence interval: 11.9-30.6IU/ml) and consequently corresponded to the manufacturer's claims (i.e. 15IU/ml). The test exhibited linearity for all HCV genotypes in a broad range from 15 to 10(8)IU HCV RNA/ml. Hence, the kPCR assay in general is well suitable for HCV RNA determinations in clinical practice. However, in a methodological comparison, a considerable under-quantification of the concentrations of HCV genotype 2 and 3 isolates was detected. Provided that the assay's manufacturer will quickly remedy this shortcoming, the VERSANT HCV RNA 1.0 (kPCR) can be called a completely reliable technique for HCV RNA quantification in routine virological diagnostics.
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Affiliation(s)
- Nico Grüner
- Institute of Virology, National Reference Centre for Hepatitis C, Essen University Hospital, University of Duisburg-Essen, Hufelandstr., D-45122 Essen, Germany
| | - S Viazov
- Institute of Virology, National Reference Centre for Hepatitis C, Essen University Hospital, University of Duisburg-Essen, Hufelandstr., D-45122 Essen, Germany
| | - K Korn
- Institute of Clinical and Molecular Virology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Schlossgarten 4, D-91054 Erlangen, Germany
| | - A Knöll
- Institute of Clinical and Molecular Virology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Schlossgarten 4, D-91054 Erlangen, Germany
| | - M Trippler
- Department of Gastroenterology and Hepatology, Essen University Hospital, University of Duisburg-Essen, Hufelandstr., D-45122 Essen, Germany
| | - J F Schlaak
- Department of Gastroenterology and Hepatology, Essen University Hospital, University of Duisburg-Essen, Hufelandstr., D-45122 Essen, Germany
| | - G Gerken
- Department of Gastroenterology and Hepatology, Essen University Hospital, University of Duisburg-Essen, Hufelandstr., D-45122 Essen, Germany
| | - M Roggendorf
- Institute of Virology, National Reference Centre for Hepatitis C, Essen University Hospital, University of Duisburg-Essen, Hufelandstr., D-45122 Essen, Germany
| | - R Stefan Ross
- Institute of Virology, National Reference Centre for Hepatitis C, Essen University Hospital, University of Duisburg-Essen, Hufelandstr., D-45122 Essen, Germany.
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15
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Strassl R, Rutter K, Stättermayer AF, Beinhardt S, Kammer M, Hofer H, Ferenci P, Popow-Kraupp T. Real-Time PCR Assays for the Quantification of HCV RNA: Concordance, Discrepancies and Implications for Response Guided Therapy. PLoS One 2015; 10:e0135963. [PMID: 26274922 PMCID: PMC4537232 DOI: 10.1371/journal.pone.0135963] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2015] [Accepted: 07/29/2015] [Indexed: 01/22/2023] Open
Abstract
BACKGROUND AND AIMS Monitoring of chronic Hepatitis C (CHC) treatment relies on HCV RNA quantification by means of real-time PCR methods. Assay specific analytical sensitivities may impact therapy management. METHODS Comparative analysis between three commercial assays (Roche COBAS AmpliPrep/COBAS TaqMan Version 1 (CAP/CTM Ver. 1), Version 2 (CAP/CTM Ver. 2) and the Abbott RealTime HCV (ART) assay) was performed on 247 available samples taken at key decision time points during antiviral therapy of 105 genotype 1 patients (triple therapy: n = 70; dual therapy: n = 35). RESULTS Overall concordance of HCV RNA measurements was high between the two Roche systems (89%; n = 220/247) but lower between the Roche assays and the ART (CAP/CTM Ver. 1 vs ART: 77.3%; n = 191/247 and CAP/CTM v.2 vs ART: 80.1%; n = 198/247). Most discrepancies were noted in week 4/8 samples with residual viremia ( CONCLUSION An abbreviated course of treatment can safely be applied in patients with residual viremia (
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Affiliation(s)
- Robert Strassl
- Department of Laboratory Medicine, Division of Clinical Virology, Medical University of Vienna, Vienna, Austria
| | - Karoline Rutter
- Department of Internal Medicine III, Division of Gastroenterology & Hepatology, Medical University of Vienna, Vienna, Vienna, Austria
| | - Albert Friedrich Stättermayer
- Department of Internal Medicine III, Division of Gastroenterology & Hepatology, Medical University of Vienna, Vienna, Vienna, Austria
| | - Sandra Beinhardt
- Department of Internal Medicine III, Division of Gastroenterology & Hepatology, Medical University of Vienna, Vienna, Vienna, Austria
| | - Michael Kammer
- Center for Medical Statistics, Informatics, and Intelligent Systems (CeMSIIS), Medical University of Vienna, Vienna, Austria
| | - Harald Hofer
- Department of Internal Medicine III, Division of Gastroenterology & Hepatology, Medical University of Vienna, Vienna, Vienna, Austria
| | - Peter Ferenci
- Department of Internal Medicine III, Division of Gastroenterology & Hepatology, Medical University of Vienna, Vienna, Vienna, Austria
| | - Theresia Popow-Kraupp
- Department of Laboratory Medicine, Division of Clinical Virology, Medical University of Vienna, Vienna, Austria
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16
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Sarrazin C, Dierynck I, Cloherty G, Ghys A, Janssen K, Luo D, Witek J, Buti M, Picchio G, De Meyer S. An OPTIMIZE study retrospective analysis for management of telaprevir-treated hepatitis C virus (HCV)-infected patients by use of the Abbott RealTime HCV RNA assay. J Clin Microbiol 2015; 53:1264-9. [PMID: 25653396 PMCID: PMC4365219 DOI: 10.1128/jcm.03030-14] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2014] [Accepted: 01/28/2015] [Indexed: 12/17/2022] Open
Abstract
Protease inhibitor (PI)-based response-guided triple therapies for hepatitis C virus (HCV) infection are still widely used. Noncirrhotic treatment-naive and prior relapser patients receiving telaprevir-based treatment are eligible for shorter, 24-week total therapy if HCV RNA is undetectable at both weeks 4 and 12. In this study, the concordance in HCV RNA assessments between the Roche High Pure System/Cobas TaqMan and Abbott RealTime HCV RNA assays and the impacts of different HCV RNA cutoffs on treatment outcome were evaluated. A total of 2,629 samples from 663 HCV genotype 1 patients receiving telaprevir/pegylated interferon/ribavirin in OPTIMIZE were analyzed using the High Pure System and reanalyzed using Abbott RealTime (limits of detection, 15.1 IU/ml versus 8.3 IU/ml; limits of quantification, 25 IU/ml versus 12 IU/ml, respectively). Overall, good concordance was observed between the assays. Using undetectable HCV RNA at week 4, 34% of the patients would be eligible for shorter treatment duration with Abbott RealTime versus 72% with the High Pure System. However, using <12 IU/ml for Abbott RealTime, a similar proportion (74%) would be eligible. Of the patients receiving 24-week total therapy, 87% achieved a sustained virologic response with undetectable HCV RNA by the High Pure System or <12 IU/ml by Abbott RealTime; however, 92% of the patients with undetectable HCV RNA by Abbott RealTime achieved a sustained virologic response. Using undetectable HCV RNA as the cutoff, the more sensitive Abbott RealTime assay would identify fewer patients eligible for shorter treatment than the High Pure System. Our data confirm the <12-IU/ml cutoff, as previously established in other studies of the Abbott RealTime assay, to determine eligibility for shortened PI-based HCV treatment. (The study was registered with ClinicalTrials.gov under registration no. NCT01241760.).
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Affiliation(s)
| | | | | | - Anne Ghys
- Janssen Infectious Diseases BVBA, Beerse, Belgium
| | | | - Donghan Luo
- Janssen Research and Development, LLC, Titusville, New Jersey, USA
| | - James Witek
- Janssen Research and Development, LLC, Titusville, New Jersey, USA
| | - Maria Buti
- Hospital Valle Hebron and Ciberehd del Institute Carlos III, Barcelona, Spain
| | - Gaston Picchio
- Janssen Research and Development, LLC, Titusville, New Jersey, USA
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17
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Kessler HH, Cobb BR, Wedemeyer H, Maasoumy B, Michel-Treil V, Ceccherini-Nelli L, Bremer B, Hübner M, Helander A, Khiri H, Heilek G, Simon CO, Luk K, Aslam S, Halfon P. Evaluation of the COBAS(®) AmpliPrep/COBAS(®) TaqMan(®) HCV Test, v2.0 and comparison to assays used in routine clinical practice in an international multicenter clinical trial: The ExPECT study. J Clin Virol 2015; 67:67-72. [PMID: 25959162 DOI: 10.1016/j.jcv.2015.03.023] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2014] [Revised: 03/25/2015] [Accepted: 03/28/2015] [Indexed: 12/31/2022]
Abstract
BACKGROUND The COBAS(®) AmpliPrep(®)/COBAS(®) TaqMan(®) HCV Test, v2.0 (CAP/CTM2) is used for HCV RNA viral load monitoring. OBJECTIVES The performance of the CAP/CTM2 was compared to other widely used tests, including a manual version of the assay (the COBAS(®) TaqMan(®) HCV Test, v2.0 for use with the High Pure System, HPS/CTM2) predominantly used during phase III clinical trials for the new direct acting antiviral therapies. STUDY DESIGN Low HCV RNA level comparisons were performed across tests (Abbott Realtime HCV Test, ART; COBAS(®) AmpliPrep(®)/COBAS(®) TaqMan(®) HCV Test, v1.0, CAP/CTM1; CAP/CTM2; and HPS/CTM2) using dilutions of the 2nd HCV WHO International Standard. Additionally, the clinical performance of the CAP/CTM2 was evaluated with 421 leftover HCV RNA-positive routine clinical samples. RESULTS All quantifiable WHO dilutions were within ±0.3log10IU/mL of the expected results across tests and the analytical sensitivity resulted in a limit of detection of 12IU/mL (95% confidence interval, 10, 15). When clinical samples were tested the results for 87% (367 of 421) of all sample comparisons were within ±0.5log10IU/mL. When low viral load results (25-3500IU/mL) were compared, values obtained by the ART assay were significantly lower (p<0.0001) than those obtained with the CAP/CTM2. CONCLUSIONS The new CAP/CTM2 showed good accuracy with comparable sensitivity to comparator assays. The new kit is well-suited for use in the routine diagnostic laboratory, especially for accurate monitoring of patients receiving triple therapy or interferone-free regimens.
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Affiliation(s)
- Harald H Kessler
- Molecular Diagnostics Laboratory, IHMEM, Medical University of Graz, Graz, Austria.
| | - Bryan R Cobb
- Roche Molecular Systems, Inc., Pleasanton, CA, USA
| | - Heiner Wedemeyer
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Benjamin Maasoumy
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | | | | | - Birgit Bremer
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Margit Hübner
- Molecular Diagnostics Laboratory, IHMEM, Medical University of Graz, Graz, Austria
| | | | - Hacene Khiri
- Laboratoire ALPHABIO, Hôpital Europeen, Marseille, France
| | | | | | - Kevin Luk
- Roche Molecular Systems, Inc., Pleasanton, CA, USA
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18
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Sarrazin C, Wedemeyer H, Cloherty G, Cohen DE, Chevaliez S, Herman C, Bernstein B, Pawlotsky JM. Importance of very early HCV RNA kinetics for prediction of treatment outcome of highly effective all oral direct acting antiviral combination therapy. J Virol Methods 2015; 214:29-32. [PMID: 25528998 DOI: 10.1016/j.jviromet.2014.11.027] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2014] [Revised: 11/17/2014] [Accepted: 11/25/2014] [Indexed: 01/08/2023]
Abstract
Interferon-free combination therapies lead to rapid suppression of HCV RNA early during treatment. The potential to predict virologic response and failure as well as to guide treatment duration with measurement of HCV RNA very early during treatment by highly sensitive assays is not well known. In 11 IL28B CC (rs12979860) patients infected with HCV genotype 1, who received DAA combination therapy with the NS3 protease inhibitor ABT-450/r together with the non-nucleoside NS5B polymerase inhibitor ABT-072 and ribavirin for 12 weeks, HCV RNA was assessed frequently by the RealTime HCV (ART) and the High-Pure-System/Cobas TaqMan (HPS) assays during and after treatment. Overall, at 33 of 131 time points during treatment residual HCV RNA was detectable by ART but undetectable by HPS while the converse was observed in only two samples. Of the two patients who experienced virologic relapse, one patient had residual viremia at week 6 of treatment by ART only while the other patient never had undetectable HCV RNA by the ART assay. However, residual viremia was also observed by ART as late as therapy weeks 9, 10 and 12 in patients with subsequent sustained virologic response. In patients with sustained response no viremia was observed at multiple time points during post-treatment follow up by either assay. The higher sensitivity of the ART in comparison to the HPS assay may be associated with more frequent detection of residual viremia during highly effective, interferon-free combination therapies. However, the significance of this finding in predicting virologic failure appears to be limited.
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Affiliation(s)
- Christoph Sarrazin
- Goethe University Hospital, Medizinische Klinik 1, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany
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19
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Maasoumy B, Hunyady B, Calvaruso V, Makara M, Vermehren J, Haragh A, Susser S, Bremer B, Cloherty G, Manns MP, Craxì A, Wedemeyer H, Sarrazin C. Performance of two HCV RNA assays during protease inhibitor-based triple therapy in patients with advanced liver fibrosis and cirrhosis. PLoS One 2014; 9:e110857. [PMID: 25389779 PMCID: PMC4229112 DOI: 10.1371/journal.pone.0110857] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2014] [Accepted: 09/19/2014] [Indexed: 12/15/2022] Open
Abstract
Introduction On-treatment HCV RNA measurements are crucial for the prediction of a sustained virological response (SVR) and to determine treatment futility during protease inhibitor-based triple therapies. In patients with advanced liver disease an accurate risk/benefit calculation based on reliable HCV RNA results can reduce the number of adverse events. However, the different available HCV RNA assays vary in their diagnostic performance. Aim To investigate the clinical relevance of concordant and discordant results of two HCV RNA assays during triple therapy with boceprevir and telaprevir in patients with advanced liver fibrosis/cirrhosis. Methods We collected on-treatment samples of 191 patients with advanced liver fibrosis/cirrhosis treated at four European centers for testing with the Abbott RealTime (ART) and COBAS AmpliPrep/COBAS TaqMan HCV v2.0 (CTM) assays. Results Discordant test results for HCV RNA detectability were observed in 23% at week 4, 17% at week 8/12 and 9% at week 24 on-treatment. The ART detected HCV RNA in 41% of week 4 samples tested negative by the CTM. However, the positive predictive value of an undetectable week 4 result for SVR was similar for both assays (80% and 82%). Discordance was also found for application of stopping rules. In 27% of patients who met stopping rules by CTM the ART measured levels below the respective cut-offs of 100 and 1000 IU/ml, respectively, which would have resulted in treatment continuation. In contrast, in nine patients with negative HCV RNA by CTM at week 24 treatment would have been discontinued due to detectable residual HCV RNA by the ART assay. Importantly, only 4 of these patients failed to achieve SVR. Conclusion Application of stopping rules determined in approval studies by one assay to other HCV RNA assays in clinical practice may lead to over and undertreatment in a significant number of patients undergoing protease inhibitor-based triple therapy.
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Affiliation(s)
- Benjamin Maasoumy
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hanover, Germany
| | - Bela Hunyady
- Somogy County Kaposi Mor Teaching Hospital, Kaposvar, Hungary
- University of Pecs, Pecs, Hungary
| | - Vincenza Calvaruso
- Section of Gastroenterology, Di.Bi.M.I.S., University of Palermo, Palermo, Italy
| | - Mihály Makara
- Outpatient Clinic, Saint Laszlo Hospital, Budapest, Hungary
| | - Johannes Vermehren
- Department of Medicine 1, JW Goethe-University Hospital, Frankfurt am Main, Germany
| | - Attila Haragh
- Somogy County Kaposi Mor Teaching Hospital, Kaposvar, Hungary
| | - Simone Susser
- Department of Medicine 1, JW Goethe-University Hospital, Frankfurt am Main, Germany
| | - Birgit Bremer
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hanover, Germany
| | - Gavin Cloherty
- Abbott Molecular, Des Plaines, Illinois, United States of America
| | - Michael P. Manns
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hanover, Germany
| | - Antonio Craxì
- Section of Gastroenterology, Di.Bi.M.I.S., University of Palermo, Palermo, Italy
| | - Heiner Wedemeyer
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hanover, Germany
| | - Christoph Sarrazin
- Department of Medicine 1, JW Goethe-University Hospital, Frankfurt am Main, Germany
- * E-mail:
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20
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Long-term follow-up of patients receiving boceprevir for treatment of chronic hepatitis C. Antiviral Res 2014; 113:71-8. [PMID: 25446895 DOI: 10.1016/j.antiviral.2014.10.010] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2014] [Revised: 10/03/2014] [Accepted: 10/16/2014] [Indexed: 11/24/2022]
Abstract
The durability of sustained virologic response (SVR) following boceprevir-based therapy in patients with hepatitis C virus (HCV) infection has not been reported. Furthermore, in patients receiving protease inhibitor-based therapies, development of resistance can contribute to treatment failure. The aim of the present study was to follow the clinical progression of patients treated with boceprevir after treatment in phase 2/3 clinical trials. This was a 3-year, long-term follow-up analysis of patients enrolled in boceprevir phase 2/3 studies. No treatment was administered during follow-up. Patients with SVR were assessed for durability of viral eradication. Non-SVR patients with on-treatment resistance-associated variants (RAVs) were assessed for longevity of RAVs. A total of 1148 patients (SVR, n=696; virologic failure, n=452) were enrolled in this follow-up analysis. The median duration of follow-up was approximately 3.4 years (range of 0.0-4.1 years). Overall, 3 of 696 patients with SVR had detectable HCV RNA during the follow-up period (relapse rate of 0.4% or 1.3 relapses/1000 person-years). The majority of patients who developed RAVs during the initial treatment study (228/314, 73%) reverted to wild-type (WT) within 3 years (RAVs persisted in 27% of patients). The median time for all RAVs to become undetectable was 1.11 years (95% confidence interval 1.05-1.20 years). V36M, T54A, A156S, I/V170A and V36M+R155K appeared to have a faster rate of return to WT (median times to return to WT of ⩽0.9 years); whereas, T54S, R155K, V55A and T54S+R155K had a slower rate of return to WT (median times to return to WT of approximately 1.1 years). Return to WT appeared slightly faster in patients with G1b RAVs compared to those with G1a RAVs, and in patients with previous non-response or relapse versus breakthrough or incomplete virologic response. SVR was durable in most patients treated with boceprevir. Furthermore, most RAVs present at the time of virologic failure reverted to WT over time. Time to return to WT was associated with the phenotype of RAV, presumably a reflection of the fitness of the mutant virus, suggesting that HCV RAVs are not permanently archived, but are replaced in the viral population by WT virus.
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21
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Cobb B, Heilek G, Vilchez RA. Molecular diagnostics in the management of chronic hepatitis C: key considerations in the era of new antiviral therapies. BMC Infect Dis 2014; 14 Suppl 5:S8. [PMID: 25236936 PMCID: PMC4160902 DOI: 10.1186/1471-2334-14-s5-s8] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Molecular tests that detect and/or quantify HCV RNA are important in the diagnosis and management of patients with chronic hepatitis C (CHC) undergoing anti-viral therapy. The primary goal of anti-HCV therapy is to achieve a sustained virologic response (SVR) defined as "undetectable" Hepatitis C Virus (HCV) RNA in the serum or plasma at 12 to 24 weeks following the end of treatment.
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Affiliation(s)
- Bryan Cobb
- Roche Molecular Systems Inc., Pleasanton, California, USA
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22
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Ansaldi F, Orsi A, Sticchi L, Bruzzone B, Icardi G. Hepatitis C virus in the new era: Perspectives in epidemiology, prevention, diagnostics and predictors of response to therapy. World J Gastroenterol 2014; 20:9633-9652. [PMID: 25110404 PMCID: PMC4123355 DOI: 10.3748/wjg.v20.i29.9633] [Citation(s) in RCA: 110] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2013] [Revised: 04/18/2014] [Accepted: 05/19/2014] [Indexed: 02/06/2023] Open
Abstract
Despite the great successes achieved in the fields of virology and diagnostics, several difficulties affect improvements in hepatitis C virus (HCV) infection control and eradication in the new era. New HCV infections still occur, especially in some of the poorest regions of the world, where HCV is endemic and long-term sequelae have a growing economic and health burden. An HCV vaccine is still no available, despite years of researches and discoveries about the natural history of infection and host-virus interactions: several HCV vaccine candidates have been developed in the last years, targeting different HCV antigens or using alternative delivery systems, but viral variability and adaption ability constitute major challenges for vaccine development. Many new antiviral drugs for HCV therapy are in preclinical or early clinical development, but different limitations affect treatment validity. Treatment predictors are important tools, as they provide some guidance for the management of therapy in patients with chronic HCV infection: in particular, the role of host genomics in HCV infection outcomes in the new era of direct-acting antivirals may evolve for new therapeutic targets, representing a chance for modulated and personalized treatment management, when also very potent therapies will be available. In the present review we discuss the most recent data about HCV epidemiology, the new perspectives for the prevention of HCV infection and the most recent evidence regarding HCV diagnosis, therapy and predictors of response to it.
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Cloherty G, Cohen D, Sarrazin C, Wedemeyer H, Chevaliez S, Herman C, Bernstein B, Pawlotsky JM. HCV RNA assay sensitivity impacts the management of patients treated with direct-acting antivirals. Antivir Ther 2014; 20:177-83. [PMID: 24941124 DOI: 10.3851/imp2810] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/27/2014] [Indexed: 10/25/2022]
Abstract
BACKGROUND Application of response-guided therapy (RGT) rules to the treatment of HCV infection with pegylated interferon-α2a and ribavirin, and direct-acting antivirals (DAAs) such as the NS3/4A protease inhibitors (PIs) boceprevir and telaprevir, relies on the determination of viral genotype and on-treatment HCV RNA level. Currently there are few data available regarding the clinical impact of the analytical differences that exist between different HCV RNA quantification assays on treatment decisions such as those involved in RGT. METHODS We sought to ascertain the concordance between two HCV RNA quantification assays, the Roche/High-Pure-System COBAS(®) TaqMan (CTM) version 2 and Abbott RealTime HCV (ART), and to understand the impact of different assay characteristics on treatment decisions. We evaluated 1,336 specimens collected from 74 patients enrolled in the Phase II CHAMPION-2 study of the investigational DAAs ABT-450 (an acylsulfonamide NS3/4A PI), ABT-072 and ABT-333 (both non-nucleoside NS5B polymerase inhibitors). RESULTS HCV RNA level results were highly correlated, but CTM values were higher than those from ART by an average of 0.46 log IU/ml. Use of ART HCV RNA level results led to a higher positive predictive value of week 4 viral load for the achievement of a sustained virological response 24 weeks after the end of treatment (100% versus 87% using the lower limit of detection as the threshold). CONCLUSIONS This study suggests that HCV viral load assay performance characteristics need to be taken into consideration when managing HCV patients with RGT. Further studies are required to determine whether a consensus HCV RNA level threshold can be established or whether HCV viral load assays with greater sensitivity can increase cure rates with RGT.
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Bakulin I, Pasechnikov V, Varlamicheva A, Sannikova I. NS3 protease inhibitors for treatment of chronic hepatitis C: Efficacy and safety. World J Hepatol 2014; 6:326-339. [PMID: 24868326 PMCID: PMC4033290 DOI: 10.4254/wjh.v6.i5.326] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2013] [Accepted: 04/11/2014] [Indexed: 02/06/2023] Open
Abstract
A new treatment paradigm for hepatitis C is that the treatment must include an existing direct-acting antiviral agent, namely, a protease inhibitor (PI) combined with PEGylated interferon-α and ribavirin. The currently marketed PIs and PIs in clinical trials have different mechanisms of action. The development of new PIs aims for an improved safety profile and higher effectiveness. This article reviews NS3/4A protease inhibitors, focusing on major criteria such as their effectiveness and safety. Specific attention is paid to dosing regimens and adverse event profiles of PIs administered in clinical settings.
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Schønning K. Comparison of the QIAGEN artus HCV QS-RGQ test with the Roche COBAS Ampliprep/COBAS TaqMan HCV test v2.0 for the quantification of HCV-RNA in plasma samples. J Clin Virol 2014; 60:323-7. [PMID: 24894603 DOI: 10.1016/j.jcv.2014.05.002] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2014] [Revised: 04/24/2014] [Accepted: 05/01/2014] [Indexed: 12/16/2022]
Abstract
BACKGROUND Quantification of Hepatitis C Virus (HCV)-RNA is important for the clinical management of patients undergoing antiviral therapy. OBJECTIVES To compare the quantification of clinical plasma samples by the Roche COBAS AmpliPrep/COBAS TaqMan HCV test v2.0 and the artus HCV QS-RGQ test. STUDY DESIGN HCV-RNA viral load in 155 plasma samples from HCV-seropositive individuals was determined using the COBAS test and retrospectively with the artus. Furthermore, a dilution series of an Acrometrix standard was tested with both tests in replicates of five to assess differences in limit of detection and precision. RESULTS Two clinical samples showed inhibition using the artus test and were excluded from analysis. Of the clinical samples, 20 tested negative in both tests, 7 tested positive in the COBAS test and negative in the artus test, and 126 samples were quantified by both tests. The mean overall difference between tests (artus-COBAS) was 0.27 log IU/mL. The mean difference of quantification varied little across genotype 1a, 1b, 2b and 3a (range: +0.15 to +0.35 log IU/mL). Both tests were precise (%CV at 1000 IU/mL 1.1 and 1.8 for the COBAS and artus test, respectively). CONCLUSIONS The limit of detection appeared lower in the COBAS test than the artus test when analyzed from a limited number of replicates. Both tests were precise with the artus test quantifying higher than the COBAS test on average. It is therefore recommended to monitor individual patients with the same test throughout treatment.
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Affiliation(s)
- Kristian Schønning
- Department of Clinical Microbiology, 445, Copenhagen University Hospital, Hvidovre, Kettegård Alle 30, DK-2650 Hvidovre, Denmark.
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Butcher A, Aslam S, Hemyari P, Cowen U, Heilek G. HCV RNA detection in HCV antibody-positive patients with the COBAS AmpliPrep/COBAS TaqMan HCV test, v2.0 in comparison with FDA-approved nucleic acid tests. J Clin Virol 2014; 60:336-40. [PMID: 24881014 DOI: 10.1016/j.jcv.2014.04.018] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2013] [Revised: 04/16/2014] [Accepted: 04/23/2014] [Indexed: 12/12/2022]
Abstract
BACKGROUND Analysis of hepatitis C virus (HCV) RNA levels is critical for assessing the efficacy of antiviral therapy and the achievement of a sustained virologic response. OBJECTIVE AND STUDY DESIGN This study evaluated the clinical performance of the COBAS AmpliPrep/COBAS TaqMan HCV quantitative test, version 2.0 (TAQMAN v2.0) with the COBAS AmpliPrep/COBAS TaqMan HCV quantitative test, version 1.0 (TAQMAN v1.0), the VERSANT HCV qualitative assay (VERSANT), and the COBAS AMPLICOR HCV test, v2.0 (AMPLICOR) qualitative test for the detection of HCV RNA in serum or EDTA plasma from patients who are or have been infected with HCV and carry HCV antibodies. RESULTS A total of 277 participants were evaluable for the percent agreement analysis of the TAQMAN v2.0 with the VERSANT and with the AMPLICOR. The overall percent agreement between the TAQMAN v2.0 and the VERSANT or the AMPLICOR was 99.3% (95% CI: 97.4%, 99.8%) or 98.9% (95% CI: 96.9%, 99.6%), respectively. The overall percent agreement between the TAQMAN v2.0 and the TAQMAN v1.0 when 267 of the original samples were assessed was 98.9% (95% CI=96.7%, 99.6%). CONCLUSION The TAQMAN v2.0 demonstrated high correlation with the previously approved HCV RNA quantitative and qualitative tests.
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Affiliation(s)
- Ann Butcher
- Roche Molecular Systems, Inc., 4300 Hacienda Drive, Pleasanton, CA 94588, United States
| | - Shagufta Aslam
- Roche Molecular Systems, Inc., 4300 Hacienda Drive, Pleasanton, CA 94588, United States
| | - Pari Hemyari
- Roche Molecular Systems, Inc., 4300 Hacienda Drive, Pleasanton, CA 94588, United States
| | - Ula Cowen
- Roche Molecular Systems, Inc., 4300 Hacienda Drive, Pleasanton, CA 94588, United States
| | - Gabrielle Heilek
- Roche Molecular Systems, Inc., 4300 Hacienda Drive, Pleasanton, CA 94588, United States.
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Vermehren J, Aghemo A, Falconer K, Susser S, Lunghi G, Zeuzem S, Colombo M, Weiland O, Sarrazin C. Clinical significance of residual viremia detected by two real-time PCR assays for response-guided therapy of HCV genotype 1 infection. J Hepatol 2014; 60:913-9. [PMID: 24424305 DOI: 10.1016/j.jhep.2014.01.002] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2013] [Revised: 12/27/2013] [Accepted: 01/06/2014] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS The duration of current standard dual and protease inhibitor-based triple therapies for chronic hepatitis C is determined by assessment of early viral kinetics. Little is known about differences between HCV RNA assays for the use in response guided therapy. METHODS HCV RNA was assessed by two widely used real-time PCR-based assays, Cobas Ampliprep/Cobas TaqMan (CAP), and Real-Time HCV (ART) in 903 samples of hepatitis C genotype 1 patients treated with dual (n=169) or telaprevir-based triple therapy (n=164) in three European countries. RESULTS Overall, CAP and ART were in excellent agreement for the determination of HCV-RNA concentrations (mean difference 0.21 log10 IU/ml). For treatment-naïve patients treated with peginterferon-alfa and ribavirin a lower rate of undetectable HCV-RNA at week 4 (RVR) was observed for ART (9%) vs. CAP (16%). Although 11/27 (41%) of patients with shortened treatment (24weeks) had detectable HCV-RNA <12IU/ml by ART at week 4 none of these patients experienced virologic relapse after treatment cessation. In patients who received triple therapy, 67% and 37% had undetectable HCV-RNA at week 4 by CAP and ART, respectively. However, 18/31 (58%) eligible patients for shortened treatment based on CAP had detectable HCV-RNA by ART at week 4. Again, relapse was not observed in these patients. CONCLUSIONS Lower rates of undetectable HCV-RNA at week 4 were observed with ART compared to CAP in patients treated with dual and triple therapies. For ART, detectable <12IU/ml HCV-RNA levels at week 4 may be sufficient as part of the criteria used for selecting patients who receive a shortened treatment regimen.
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Affiliation(s)
- Johannes Vermehren
- Medizinische Klinik 1, Universitätsklinikum Frankfurt, Frankfurt am Main, Germany
| | - Alessio Aghemo
- 1st Division of Gastroenterology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy
| | - Karolin Falconer
- Division of Infectious Diseases, Department of Medicine, Karolinska University Hospital Huddinge, Stockholm, Sweden
| | - Simone Susser
- Medizinische Klinik 1, Universitätsklinikum Frankfurt, Frankfurt am Main, Germany
| | - Giovanna Lunghi
- Laboratory of Clinical Chemistry and Microbiology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy
| | - Stefan Zeuzem
- Medizinische Klinik 1, Universitätsklinikum Frankfurt, Frankfurt am Main, Germany
| | - Massimo Colombo
- 1st Division of Gastroenterology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy
| | - Ola Weiland
- Division of Infectious Diseases, Department of Medicine, Karolinska University Hospital Huddinge, Stockholm, Sweden
| | - Christoph Sarrazin
- Medizinische Klinik 1, Universitätsklinikum Frankfurt, Frankfurt am Main, Germany.
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Saludes V, González V, Planas R, Matas L, Ausina V, Martró E. Tools for the diagnosis of hepatitis C virus infection and hepatic fibrosis staging. World J Gastroenterol 2014; 20:3431-3442. [PMID: 24707126 PMCID: PMC3974510 DOI: 10.3748/wjg.v20.i13.3431] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2013] [Revised: 12/05/2013] [Accepted: 03/06/2014] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) infection represents a major public health issue. Hepatitis C can be cured by therapy, but many infected individuals are unaware of their status. Effective HCV screening, fast diagnosis and characterization, and hepatic fibrosis staging are highly relevant for controlling transmission, treating infected patients and, consequently, avoiding end-stage liver disease. Exposure to HCV can be determined with high sensitivity and specificity with currently available third generation serology assays. Additionally, the use of point-of-care tests can increase HCV screening opportunities. However, active HCV infection must be confirmed by direct diagnosis methods. Additionally, HCV genotyping is required prior to starting any treatment. Increasingly, high-volume clinical laboratories use different types of automated platforms, which have simplified sample processing, reduced hands-on-time, minimized contamination risks and human error and ensured full traceability of results. Significant advances have also been made in the field of fibrosis stage assessment with the development of non-invasive methods, such as imaging techniques and serum-based tests. However, no single test is currently available that is able to completely replace liver biopsy. This review focuses on approved commercial tools used to diagnose HCV infection and the recommended hepatic fibrosis staging tests.
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Elsharkawy AM. Commentary: detection of low level viraemia in telaprevir-based triple therapy for hepatitis C virus. Aliment Pharmacol Ther 2014; 39:543-4. [PMID: 24494842 DOI: 10.1111/apt.12610] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2013] [Accepted: 12/17/2013] [Indexed: 12/25/2022]
Affiliation(s)
- A M Elsharkawy
- Liver Unit, University Hospitals Birmingham, Birmingham, UK.
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30
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Maasoumy B, Wedemeyer H. Commentary: detection of low level viraemia in telaprevir-based triple therapy for hepatitis C virus - authors' reply. Aliment Pharmacol Ther 2014; 39:544-5. [PMID: 24494844 DOI: 10.1111/apt.12642] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2014] [Accepted: 01/10/2014] [Indexed: 12/08/2022]
Affiliation(s)
- B Maasoumy
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
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31
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Fevery B, Susser S, Lenz O, Cloherty G, Perner D, Picchio G, Sarrazin C. HCV RNA quantification with different assays: implications for protease-inhibitor-based response-guided therapy. Antivir Ther 2014; 19:559-67. [PMID: 24584086 DOI: 10.3851/imp2760] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/12/2013] [Indexed: 10/25/2022]
Abstract
BACKGROUND Response-guided therapy (RGT) for HCV treatment, whereby therapy duration is shortened according to on-treatment virological response, requires patient HCV RNA concentrations below the lower limit of quantification (LLOQ) or limit of detection (LOD) of the viral load assay at weeks 4 and 12. Concordance of two assays and impact on treatment decisions were investigated. METHODS Plasma samples (n=1,411; baseline to week 12) from HCV genotype-1-infected patients (n=290) receiving simeprevir (TMC435) plus pegylated interferon-α2a/ribavirin in the PILLAR study (NCT00882908) were analysed using Roche High-Pure-System/COBAS(®) TaqMan(®) v2.0 assay (HPS; LLOQ 25 IU/ml and LOD 15 IU/ml; Roche Diagnostics, Indianapolis, IN, USA) and reanalysed using Abbott realtime assay (ART; LLOQ and LOD 12 IU/ml; Abbott Molecular Inc., Des Plaines, IL, USA). RESULTS Overall, 217/766 (28.3%) samples from different time points with HCV RNA undetectable by HPS had HCV RNA detectable by ART. Conversely, 35/584 (6.0%) samples undetectable by ART were detectable by HPS. For both assays, most discrepant samples (96-100%) had HCV RNA<25 IU/ml. At week 4, 75.5% of samples were undetectable by HPS, whereas 49.4% were undetectable by ART, resulting in different RGT assessment in 26.1% (P<0.0001). At week 12, 95.4% and 91.9% of samples were undetectable with HPS and ART, respectively. CONCLUSIONS Lower rates of undetectable HCV RNA with ART at week 4 suggest that if RGT criteria are determined with ART, the proportion of patients qualifying for shorter treatment duration may be significantly lower (26%). Therefore, different RGT criteria may be necessary for ART to maximize numbers benefiting from shortened treatment. Further testing and validation are required.
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Affiliation(s)
- Bart Fevery
- Janssen Infectious Disease BVBA, Beerse, Belgium
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Maasoumy B, Cobb B, Bremer B, Luk K, Halfon P, Aslam S, Manns MP, Cornberg M, Wedemeyer H. Detection of low HCV viraemia by repeated HCV RNA testing predicts treatment failure to triple therapy with telaprevir. Aliment Pharmacol Ther 2014; 39:85-92. [PMID: 24206524 DOI: 10.1111/apt.12544] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2013] [Revised: 09/12/2013] [Accepted: 10/12/2013] [Indexed: 01/07/2023]
Abstract
BACKGROUND Early on-treatment virological response is one of the most important predictors for sustained virological response (SVR) to treatment of chronic hepatitis C virus (HCV) genotype 1 infection with triple therapy including HCV protease inhibitors (PI). Treatment duration (24 vs. 48 weeks) is based on HCV RNA results at weeks 4 and 12 of PI therapy when HCV RNA must be 'undetectable' to allow shorter therapy. AIM To analyse the reliability of HCV RNA measurements at key decision time points (weeks 4 and 12) and the predictive value of concordant or discordant assay results for SVR. METHODS Weeks 4 and 12 samples of patients receiving telaprevir-containing triple therapy were initially tested with the AmpliPrep/COBAS-TaqMan_HCV-Test-v1.0 (limit of detection; LOD = 15IU/mL) and retested with the AmpliPrep/COBAS-TaqMan_HCV-Test-v2.0 (LOD = 15IU/mL) and the High_Pure/COBAS-TaqMan_HCV-Test-v2.0 (LOD = 20IU/mL). RESULTS Concordance among the three test results in classifying samples as HCV RNA 'undetectable' or 'detectable' was only 55% at week 4, but 85% at week 12. Retesting of 'undetectable' week 4 samples with the respective other assays revealed positive HCV RNA results in 32-50%. In 30%, HCV RNA was 'undetectable' by all three tests at week 4 and all of these patients achieved SVR. In contrast, treatment failure occurred in 62% of patients with at least one 'detectable' result, including cases with one or two other 'undetectable' tests at week 4. CONCLUSIONS A single 'undetectable' HCV RNA result at week 4 is not always associated with achieving SVR. Repeated testing in difficult-to-treat patients may identify those at risk for treatment failure.
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Affiliation(s)
- B Maasoumy
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
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Rosenberg WM, Tanwar S, Trembling P. Complexities of HCV management in the new era of direct-acting antiviral agents. QJM 2014; 107:17-9. [PMID: 24065837 DOI: 10.1093/qjmed/hct181] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
The availability of the direct-acting antiviral agents (DAAs) boceprevir and telaprevir provides improved treatment outcomes for many patients infected with hepatitis C virus (HCV) genotype 1. However, HCV infection must first be identified before a decision on treatment can be made and currently many patients remain unaware that they have the virus. Given the lack of prompt diagnosis, disease severity should be determined as a baseline reference for treatment, and novel non-invasive techniques for evaluating fibrosis are now available. For patients receiving a DAA regimen, response-guided therapy based on the detection, absence or level of HCV RNA at specified time points is required to achieve an optimal treatment outcome. Knowledge of the test used to measure HCV RNA and its analytical sensitivity, as well as how to interpret the results correctly, are therefore required to administer therapy appropriately. Furthermore, effective treatment management includes appropriate handling of side effects. This increased complexity associated with DAA regimens has resulted in confusion over many aspects of care, including treatment monitoring, viral load result interpretation and the optimal duration of therapy. These issues are discussed here in addition to the benefits of referring patients infected with HCV to a specialist centre.
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Affiliation(s)
- W M Rosenberg
- MA, MBBS, DPhil, FRCP, UCL Institute for Liver & Digestive Health, Division of Medicine, University College London, Royal Free Campus, Rowland Hill Street, Hampstead, London NW3 2PF, UK.
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Fierer DS, Dieterich DT, Mullen MP, Branch AD, Uriel AJ, Carriero DC, van Seggelen WO, Hijdra RM, Cassagnol DG. Telaprevir in the treatment of acute hepatitis C virus infection in HIV-infected men. Clin Infect Dis 2013; 58:873-9. [PMID: 24336914 DOI: 10.1093/cid/cit799] [Citation(s) in RCA: 57] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023] Open
Abstract
BACKGROUND There is an international epidemic of hepatitis C virus (HCV) infection among human immunodeficiency virus (HIV)-infected men who have sex with men. Sustained virologic response (SVR) rates with pegylated interferon and ribavirin treatment are higher in these men during acute HCV than during chronic HCV, but treatment is still lengthy and SVR rates are suboptimal. METHODS We performed a pilot study of combination therapy with telaprevir, pegylated interferon, and ribavirin in acute genotype 1 HCV infection in HIV-infected men. Men who were treated prior to the availability of, or ineligible for, telaprevir were the comparator group. The primary endpoint was SVR12, defined as an HCV viral load <5 IU/mL at least 12 weeks after completing treatment. RESULTS In the telaprevir group, 84% (16/19) of men achieved SVR12 vs 63% (30/48) in the comparator group. Among men with SVR, median time to undetectable viral load was week 2 in the telaprevir group vs week 4 in the comparator group, and 94% vs 53% had undetectable viral loads at week 4. Most patients (81%) who achieved SVR in the telaprevir group received ≤12 weeks of treatment and there were no relapses after treatment. The overall safety profile was similar to that known for telaprevir-based regimens. CONCLUSIONS Incorporating telaprevir into treatment of acute genotype 1 HCV in HIV-infected men halved the treatment duration and increased the SVR rate. Larger studies should be done to confirm these findings. Clinicians should be alert to detect acute HCV infection of HIV-infected men to take advantage of this effective therapy and decrease further transmission in this epidemic.
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Stewart JR, Boehm AB, Dubinsky EA, Fong TT, Goodwin KD, Griffith JF, Noble RT, Shanks OC, Vijayavel K, Weisberg SB. Recommendations following a multi-laboratory comparison of microbial source tracking methods. WATER RESEARCH 2013; 47:6829-6838. [PMID: 23891204 DOI: 10.1016/j.watres.2013.04.063] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/01/2012] [Revised: 04/07/2013] [Accepted: 04/24/2013] [Indexed: 06/02/2023]
Abstract
Microbial source tracking (MST) methods were evaluated in the Source Identification Protocol Project (SIPP), in which 27 laboratories compared methods to identify host sources of fecal pollution from blinded water samples containing either one or two different fecal types collected from California. This paper details lessons learned from the SIPP study and makes recommendations to further advance the field of MST. Overall, results from the SIPP study demonstrated that methods are available that can correctly identify whether particular host sources including humans, cows and birds have contributed to contamination in a body of water. However, differences between laboratory protocols and data processing affected results and complicated interpretation of MST method performance in some cases. This was an issue particularly for samples that tested positive (non-zero Ct values) but below the limits of quantification or detection of a PCR assay. Although false positives were observed, such samples in the SIPP study often contained the fecal pollution source that was being targeted, i.e., the samples were true positives. Given these results, and the fact that MST often requires detection of targets present in low concentrations, we propose that such samples be reported and identified in a unique category to facilitate data analysis and method comparisons. Important data can be lost when such samples are simply reported as positive or negative. Actionable thresholds were not derived in the SIPP study due to limitations that included geographic scope, age of samples, and difficulties interpreting low concentrations of target in environmental samples. Nevertheless, the results of the study support the use of MST for water management, especially to prioritize impaired waters in need of remediation. Future integration of MST data into quantitative microbial risk assessments and other models could allow managers to more efficiently protect public health based on site conditions.
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Affiliation(s)
- Jill R Stewart
- Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, University of North Carolina, 1301 Michael Hooker Research Center, 135 Dauer Drive, Campus Box #7431, Chapel Hill, NC 27599, USA.
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Peng HK, Chen WC, Lin YT, Tseng CK, Yang SY, Tzeng CC, Lee JC, Yang SC. Anti-hepatitis C virus RdRp activity and replication of novel anilinobenzothiazole derivatives. Antiviral Res 2013; 100:269-75. [DOI: 10.1016/j.antiviral.2013.08.009] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2013] [Revised: 07/29/2013] [Accepted: 08/05/2013] [Indexed: 12/12/2022]
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Abstract
GOALS To describe current hepatitis C virus (HCV) treatment practices in the United States and identify physician characteristics associated with the use of first generation direct-acting antivirals (DAAs). BACKGROUND HCV treatment practice patterns have not been assessed after the introduction of DAA, which are now considered standard of care for most HCV genotype 1 patients. STUDY We sampled nationally representative physicians treating HCV patients with DAAs through a web-based survey. Stepwise multivariate logistic regression was performed to identify physician characteristics associated with the use of DAAs in 4 clinical vignettes (early stage fibrosis, prior null response, human immunodeficiency virus (HIV) co-infection, and post-liver transplantation). RESULTS Of 1658 deliverable emails, 337 (20.3%) clinicians responded. Fifty percent of providers recommended DAA therapy for treatment-naive patients with early stage fibrosis, whereas 49% of providers would await new therapies. For prior null responders with significant fibrosis, 74% would attempt retreatment using DAAs and 26% would await new therapies. Off-label use of DAAs was recommended by 69% of providers for patients with HIV infection and 48% of providers for post-liver transplant patients. Academic affiliation was significantly associated with higher rates of off-label use in both HIV and post-liver transplant patients. CONCLUSIONS Despite more potent and less toxic therapies on the horizon, many physicians recommended DAAs in treatment-naive patients with early stage fibrosis. Providers also frequently recommended DAAs for off-label uses, such as treating post-liver transplant patients and those coinfected with HIV.
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Abstract
The introduction of telaprevir and boceprevir in the treatment of chronically HCV genotype 1 infected patients has led to substantially improved sustained virologic response rates and shorter treatment duration for a growing group of patients. Management and monitoring of patients receiving protease inhibitor-based triple therapy is of major importance and has become more complicated. Close monitoring of HCV RNA levels for patients on protease inhibitor-based therapy to identify subjects who are eligible for shortening of treatment duration, are virological non-responders or are in danger of experiencing a viral breakthrough is strongly recommended. Several virological tools including qualitative and quantitative HCV RNA assays for detection and quantification of HCV RNA are commercially available. We review these methods and their implications for HCV therapy as well as current sustained virologic response definition, stopping rules and recommendations for protease inhibitor-based treatment durations.
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Affiliation(s)
- Kai-Henrik Peiffer
- Klinikum der J. W. Goethe-Universität, Medizinische Klinik 1, Theodor-Stern-Kai 7, Frankfurt am Main, Germany
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Evaluation of the Roche COBAS AmpliPrep/COBAS TaqMan HCV Test. Diagn Microbiol Infect Dis 2013; 77:25-30. [DOI: 10.1016/j.diagmicrobio.2013.05.012] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2013] [Revised: 05/13/2013] [Accepted: 05/17/2013] [Indexed: 11/20/2022]
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Acero Fernández D, Ferri Iglesias MJ, López Nuñez C, Louvrie Freire R, Aldeguer Manté X. [To consider negative viral loads below the limit of quantification can lead to errors in the diagnosis and treatment of hepatitis C virus infection]. GASTROENTEROLOGIA Y HEPATOLOGIA 2013; 36:443-9. [PMID: 23849764 DOI: 10.1016/j.gastrohep.2013.04.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/10/2013] [Revised: 04/19/2013] [Accepted: 04/23/2013] [Indexed: 10/26/2022]
Abstract
INTRODUCTION For years many clinical laboratories have routinely classified undetectable and unquantifiable levels of hepatitis C virus RNA (HCV-RNA) determined by RT-PCR as below limit of quantification (BLOQ). This practice might result in erroneous clinical decisions. AIM To assess the frequency and clinical relevance of assuming that samples that are BLOQ are negative. MATERIAL AND METHOD We performed a retrospective analysis of RNA determinations performed between 2009 and 2011 (Cobas/Taqman, lower LOQ: 15 IU/ml). We distinguished between samples classified as «undetectable» and those classified as «<1.50E+01IU/mL» (BLOQ). RESULTS We analyzed 2.432 HCV-RNA measurements in 1.371 patients. RNA was BLOQ in 26 samples (1.07%) from 23 patients (1.68%). BLOQ results were highly prevalent among patients receiving Peg-Riba: 23 of 216 samples (10.6%) from 20 of 88 patients receiving treatment (22.7%). The clinical impact of BLOQ RNA samples was as follows: a) 2 patients initially considered to have negative results subsequently showed quantifiable RNA; b) 8 of 9 patients (88.9%) with BLOQ RNA at week 4 of treatment later showed sustained viral response; c) 3 patients with BLOQ RNA at weeks 12 and 48 of treatment relapsed; d) 4 patients with BLOQ RNA at week 24 and/or later had partial or breakthrough treatment responses, and e) in 5 patients the impact were null or could not be ascertained. CONCLUSIONS This study suggests that BLOQ HCV-RNA indicates viremia and that equating a BLOQ result with a negative result can lead to treatment errors. BLOQ results are highly prevalent in on-treatment patients. The results of HCV-RNA quantification should be classified clearly, distinguishing between undetectable levels and levels that are BLOQ.
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Affiliation(s)
- Doroteo Acero Fernández
- Servicio de Aparato Digestivo, Hospital Universitario de Girona Doctor Josep Trueta, España.
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Chen J, Florian J, Carter W, Fleischer RD, Hammerstrom TS, Jadhav PR, Zeng W, Murray J, Birnkrant D. Earlier sustained virologic response end points for regulatory approval and dose selection of hepatitis C therapies. Gastroenterology 2013; 144:1450-1455.e2. [PMID: 23470616 DOI: 10.1053/j.gastro.2013.02.039] [Citation(s) in RCA: 132] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2012] [Revised: 02/14/2013] [Accepted: 02/27/2013] [Indexed: 01/22/2023]
Abstract
BACKGROUND & AIMS Trials of therapies for chronic hepatitis C have used detection of hepatitis C virus (HCV) at week 24 of follow-up (sustained virologic response [SVR] 24) as a primary end point. However, there is increasing evidence that most patients who have an SVR at earlier time points (such as SVR12) maintain it until week 24. Use of earlier time points for key regulatory decisions (SVR12) and dose selection (SVR4) could facilitate HCV drug development. METHODS We assessed data from 15 phase II and III trials, 3 pediatric studies, and 5 drug-development programs to determine the concordance between SVR24 and SVR12 or SVR4. Data were analyzed from groups of subjects who received various combinations and regimens with interferon, pegylated-interferon, ribavirin, and direct-acting antivirals. RESULTS The positive predictive value (PPV) of SVR12 was 98% and the negative predictive value (NPV) was 99% for SVR24 among subjects with genotype 1 HCV infection. A similar level of concordance was observed for subjects with HCV genotype 2 or 3 infections, as well as in pediatric studies. About 2% of subjects who achieved an SVR12 subsequently relapsed by week 24 (did not achieve an SVR24). Furthermore, the treatment effect size (difference between treatment and active control arms) was similar for subjects with SVR12 and SVR24. The PPV of SVR4 was 91% and the NPV was 98% for SVR24 in subjects with genotype 1 HCV infection. CONCLUSIONS SVR12 and SVR24 measurements were concordant in a large population of subjects with HCV infection who participated in clinical trials with various treatment regimens and durations. SVR12 is suitable as a primary end point for regulatory approval. SVR4 might be used to guide dose and treatment strategies in trials.
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Affiliation(s)
- Jianmeng Chen
- Division of Pharmacometrics, Office of Clinical Pharmacology, Center of Drug Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland 20993-0002, USA
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Cobb B, Pockros PJ, Vilchez RA, Vierling JM. HCV RNA viral load assessments in the era of direct-acting antivirals. Am J Gastroenterol 2013; 108:471-5. [PMID: 23552304 DOI: 10.1038/ajg.2012.248] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Recent regulatory approvals of the NS3/4A protease inhibitors boceprevir and telaprevir launched a new therapeutic era for hepatitis C virus (HCV) genotype 1 infection. Decisions to shorten, extend, or stop treatment with these direct-acting antiviral (DAA) regimens require accurate quantification of serum HCV RNA levels. To effectively use DAA therapies, clinicians must understand performance characteristics of HCV RNA real-time PCR assays and the clinical significance of HCV RNA that is detectable below the lower limit of quantification. This review summarizes terms used to report HCV RNA viral load results, explains the analytical performance of the PCR assay used in the clinical trials of boceprevir and telaprevir, and compares currently available commercial assays.
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Affiliation(s)
- Bryan Cobb
- Roche Molecular Systems Inc., Pleasanton, CA, USA
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43
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Abstract
The advent of triple therapy (TT) with first-generation protease inhibitors boceprevir (BOC) and telaprevir (TVR) in addition to pegylated interferon and ribavirin (PEG-IFN/RBV) has resulted in a significant improvement in the sustained virological response (SVR) rate and potentially in life years gained compared to dual therapy (DT), when treating naïve or treatment-experienced patients with genotype 1 (G1) chronic hepatitis C (CHC). This benefit is partly offset by the increased complexity of treatment, and the increased costs and risks of therapy, making it necessary to optimize the indications for TT. Naïve patients with mild fibrosis and the IL28B CC polymorphism and/or with a rapid virological response (RVR) to DT can still benefit from DT, while TT is preferable in all others. Phase 3 trials have clearly shown that a 1 log(10) decrease in HCVRNA after 4 weeks of DT associated with a favourable IL28B genotype and a low stage of fibrosis, and a pattern of previous response to DT in treatment-experienced patients are the strongest predictors of an SVR to TT. Moreover, an extended rapid virological response (eRVR) is associated with an SVR rate >90%, so that the overall duration of treatment can be shortened in a high proportion of patients. Further efforts to optimize the current TT regimens both by increasing efficacy and improving tolerance are still needed. Most important, in the future, treatment can probably be personalized based on data from post-marketing surveillance of TT providing information about patient groups that were underrepresented in phase 3 studies such as those with cirrhosis.
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Affiliation(s)
- Salvatore Petta
- Sezione di Gastroenterologia, Di.Bi.M.I.S., University of Palermo, Palermo, Italy.
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44
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Abstract
In the direct-acting antiviral (DAA) era of hepatitis C virus (HCV) therapy, health care providers must be knowledgeable about genotype and subtype of HCV infection and interpretation of quantitative HCV viral assays to monitor treatment responses. They may also choose to assess interleukin 28B genotypes or resistance-associated variants after ineffective DAA therapy. DAA therapies require understanding of performance characteristics of quantitative HCV RNA assays and the definitions of terms used to report results. Only quantitative HCV RNA assays with a limit of detection of 10 to 15 IU/mL are appropriate for managing patients on DAA therapy.
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Affiliation(s)
- John M Vierling
- Department of Medicine, Liver Center, Baylor College of Medicine, Houston, TX 77030, USA.
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Martel-Laferrière V, Dieterich DT. Update on combinations of DAAs with and without pegylated-interferon and ribavirin: triple and quadruple therapy more than doubles SVR. Clin Liver Dis 2013. [PMID: 23177285 DOI: 10.1016/j.cld.2012.09.001] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Monotherapy is an ineffective way to treat hepatitis C and it leads to rapid development of resistance. An increasing number of drugs are currently being developed for the treatment of hepatitis C. This allows combination strategies that can overcome the development of resistance and improve sustained virologic response rates. This article focuses on the 2 main strategies in development: quadruple combination therapies, including pegylated-interferon and triple/quadruple pegylated-interferon free combination therapies. If the first combinations are leading to extremely high sustained virologic responses, the second ones offer hope that the era of pegylated-interferon will end soon.
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Affiliation(s)
- Valérie Martel-Laferrière
- Division of Liver Diseases, Department of Medicine, Mount Sinai School of Medicine, New York, NY 10029, USA.
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Lontok E, Mani N, Harrington PR, Miller V. Closing in on the target: sustained virologic response in hepatitis C virus genotype 1 infection response-guided therapy. Clin Infect Dis 2013; 56:1466-70. [PMID: 23362287 DOI: 10.1093/cid/cit025] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Retrospective analyses of the boceprevir and telaprevir phase 3 trial data demonstrate the clinical relevance of detected but not quantifiable hepatitis C virus (HCV) genotype 1 RNA during treatment. These analyses illustrate the importance of using precise and standard terminology in reporting low-level HCV RNA results for consistent data collection across clinical trials, and to ensure optimal virologic response-guided treatment decision making in clinical practice. In the context of currently available quantitative HCV RNA assays, we clarify that unquantifiable HCV RNA should be classified as target detected or target not detected, as both have been shown to reflect clinically different qualitative HCV RNA levels during treatment. Additionally, use of terms such as "undetectable" or "below limit of detection" should be avoided as such terms are imprecise, not consistently defined, and often misinterpreted.
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Affiliation(s)
- Erik Lontok
- Forum for Collaborative HIV Research, University of California, Berkeley, Washington, DC 20036, USA.
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Second-generation Cobas AmpliPrep/Cobas TaqMan HCV quantitative test for viral load monitoring: a novel dual-probe assay design. J Clin Microbiol 2012; 51:571-7. [PMID: 23241371 DOI: 10.1128/jcm.01784-12] [Citation(s) in RCA: 59] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Hepatitis C virus (HCV) RNA viral load (VL) monitoring is a well-established diagnostic tool for the management of chronic hepatitis C patients. HCV RNA VL results are used to make treatment decisions with the goal of therapy to achieve an undetectable VL result. Therefore, a sensitive assay with high specificity in detecting and accurately quantifying HCV RNA across genotypes is critical. Additionally, a lower sample volume requirement is desirable for the laboratory and the patient. This study evaluated the performance characteristics of a second-generation real-time PCR assay, the Cobas AmpliPrep/Cobas TaqMan HCV quantitative test, version 2.0 (CAP/CTM HCV test, v2.0), designed with a novel dual-probe approach and an optimized automated extraction and amplification procedure. The new assay demonstrated a limit of detection and lower limit of quantification of 15 IU/ml across all HCV genotypes and was linear from 15 to 100,000,000 IU/ml with high accuracy (<0.2-log(10) difference) and precision (standard deviation of 0.04 to 0.22 log(10)). A specificity of 100% was demonstrated with 600 HCV-seronegative specimens without cross-reactivity or interference. Correlation to the Cobas AmpliPrep/Cobas TaqMan HCV test (version 1) was good (n = 412 genotype 1 to 6 samples, R(2) = 0.88; R(2) = 0.94 without 105 genotype 4 samples). Paired plasma and serum samples showed similar performance (n = 25, R(2) = 0.99). The sample input volume was reduced from 1 to 0.65 ml in the second version. The CAP/CTM HCV test, v2.0, demonstrated excellent performance and sensitivity across all HCV genotypes with a smaller sample volume. The new HCV RNA VL assay has performance characteristics that make it suitable for use with currently available direct-acting antiviral agents.
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Wedemeyer H, Jensen DM, Godofsky E, Mani N, Pawlotsky JM, Miller V. Recommendations for standardized nomenclature and definitions of viral response in trials of hepatitis C virus investigational agents. Hepatology 2012; 56:2398-403. [PMID: 22707382 DOI: 10.1002/hep.25888] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2012] [Accepted: 05/26/2012] [Indexed: 12/29/2022]
Abstract
Outdated virological response terms used at key trial timepoints in clinical trials with first-generation direct-acting antivirals plus pegylated interferon and ribavirin have failed to keep pace with hepatitis C virus (HCV) drug development. A more intuitive and flexible nomenclature capable of adapting to continuing advances in HCV drug development is needed. Assistance in standardization of the field was provided by members of the Hepatitis C Virus Drug Development Advisory Group, a project of the Forum for Collaborative HIV Research with participation from the American Association for the Study of Liver Diseases, European Association for the of the liver, and the Infectious Diseases Society of America. Our proposed descriptive, virological response nomenclature for key decision points in trials (with and without lead-in treatment) is based on an assay-specified lower limit of quantitation cutoff. This allows responses to be categorized as either quantifiable or unquantifiable HCV RNA, with unquantifiable responses further divided based on whether target HCV RNA was detected or not detected. The unified reporting recommendations will facilitate interpretation of results across clinical trials and validation of new response-guided timepoints. As time-critical treatment parameters are shortened in HCV trials, the proposed nomenclature will greatly simplify and facilitate future adaptations of virological response terms. Our proposed nomenclature will also be helpful in developing treatment guidelines for use in clinical practice.
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Petta S, Craxì A. Therapeutic algorithms for chronic hepatitis C in the DAA era during the current economic crisis: whom to treat? How to treat? When to treat? BMC Infect Dis 2012; 12 Suppl 2:S3. [PMID: 23173606 PMCID: PMC3495629 DOI: 10.1186/1471-2334-12-s2-s3] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
The advent of triple therapy (TT) with first-generation protease inhibitors boceprevir (BOC) and telaprevir (TVR) in addition to pegylated interferon and ribavirin resulted in a significant gain in terms of sustained virological response (SVR) when treating naive or previous treated patients with genotype 1 (G1) chronic hepatitis C (CHC). This gain is partly balanced by the increased complexity of treatment and by the raised costs and risks of therapy, making necessary to optimize the indication to TT.Specifically, the identification of patient needing to TT over DT, the choice of the more correct therapeutic approach according to baseline and on treatment SVR predictors, and the timing of antiviral treatment, appear key issues to evaluate when considering TVR or BOC-based therapies.Along this line, further efforts aimed to optimize the current TT regimens are still needed, especially in under-represented groups of patients in phase 3 studies such as those with cirrhosis, where post-marketing data are giving interesting evidences.
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Affiliation(s)
- Salvatore Petta
- Sezione di Gastroenterologia, Di.Bi.M.I.S., University of Palermo, Italy
| | - Antonio Craxì
- Sezione di Gastroenterologia, Di.Bi.M.I.S., University of Palermo, Italy
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Boceprevir: a protease inhibitor for the treatment of hepatitis C. Clin Ther 2012; 34:2021-38. [PMID: 22975763 DOI: 10.1016/j.clinthera.2012.08.009] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2012] [Accepted: 08/17/2012] [Indexed: 02/07/2023]
Abstract
BACKGROUND Boceprevir is a protease inhibitor indicated for the treatment of chronic hepatitis C virus (HCV) genotype 1 infection in combination with peginterferon and ribavirin for treatment-naive patients and those who previously failed to improve with interferon and ribavirin treatment. OBJECTIVE This article provides an overview of the mechanism of action, pharmacologic and pharmacokinetic properties, clinical efficacy, and tolerability of boceprevir. METHODS Relevant information was identified through a search of PubMed (1990-July 2012), EMBASE (1990-July 2012), International Pharmaceutical Abstracts (1970-July 2012), and Google Scholar using the key words boceprevir, SCH 503034, non-structural protein 3 (NS3) serine protease inhibitor, and direct-acting antiviral agent (DAA). Additional information was obtained from the US Food and Drug Administration's Web site, review of the reference lists of identified articles, and posters and abstracts from scientific meetings. RESULTS Clinical efficacy of boceprevir was assessed in 2 Phase III trials, Serine Protease Inhibitor Therapy-2 (SPRINT-2) for treatment-naive patients and Retreatment with HCV Serine Protease Inhibitor Boceprevir and PegIntron/Rebetol 2 (RESPOND-2) for treatment-experienced patients. In SPRINT-2, patients were randomized to receive peginterferon + ribavirin (PR) or peginterferon + ribavirin + boceprevir (PRB); duration of boceprevir therapy varied from 24, 32, to 44 weeks on the basis of HCV RNA results. The primary endpoint was achievement of sustained virologic response (SVR; lower limit of detection, 9.3 IU/mL). The addition of boceprevir was shown to be superior, with overall SVR rates ranging from 63% to 66% compared with 38% with PR (P < 0.001). Results of SVR in SPRINT-2 were also reorganized to monitor SVRs in black and non-black patients. Treatment-experienced patients were assessed in RESPOND-2; however, null responders were excluded. Patients were again randomized to PR or PRB; duration of boceprevir therapy varied from 32 to 44 weeks on the basis of HCV RNA results. SVR was significantly higher in patients receiving boceprevir (59%-66% vs 21% with PR; P < 0.001). This benefit was seen in both previous nonresponders (SVR, 40%-52% vs 7% with PR), as well as previous relapsers (SVR, 69%-75% vs 29% with PR). Importantly, SVR could be attained with a shortened course of therapy in almost one half of all treated patients in SPRINT-2 (44%) and RESPOND-2 (46%). CONCLUSIONS Boceprevir was well tolerated in clinical trials and a welcomed addition to our HCV armamentarium.
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