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Inzaule S, Easterbrook P, Latona A, Ford NP, Irving W, Matthews PC, Vitoria M, Duncombe C, Giron A, McCluskey S, Lesi O, Tchamgoue S, Halford R, Adda D, Thomson E, Dusheiko G, Jordan MR. Prevalence of Drug Resistance Associated Substitutions in Persons With Chronic Hepatitis C Infection and Virological Failure Following Initial or Re-treatment With Pan-genotypic Direct-Acting Antivirals: A Systematic Review and Meta-analysis. Clin Infect Dis 2024; 79:1437-1446. [PMID: 39361017 PMCID: PMC11650865 DOI: 10.1093/cid/ciae431] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2023] [Indexed: 10/05/2024] Open
Abstract
BACKGROUND The advent of short-course, curative treatment with direct-acting antivirals (DAA) has given promise for the global elimination of hepatitis C virus (HCV) infections by 2030. Virological failure occurs in 2%-12% of persons receiving curative DAA treatment and may be presaged by pre-existing polymorphisms or result from selection of drug resistant variants during therapy. METHODS We conducted a systematic review to assess the prevalence of HCV resistance associated substitutions (RAS) among individuals with chronic hepatitis C infection who had virological failure following initial or re-treatment with pan-genotypic DAA regimens. We included 34 and 22 studies assessing RAS in people with virological failure published between January 2014 and July 2023. Pooled RAS prevalence was estimated using random-effects meta-analysis. RESULTS The pooled prevalence of RAS in people with virological failure following initial DAA treatment was 78.0% (95% confidence interval [CI]: 62.0-92.0) for sofosbuvir/velpatasvir, 81.0% (95% CI: 67.0-93.0) for sofosbuvir/daclatasvir, and 79.0% (95% CI: 70.0-87.0) for glecaprevir/pibrentasvir, with a high prevalence of resistance to the NS5A inhibitors. Among those with virological failure following re-treatment regimens, RAS were present in 93.0% (95% CI: 83.0-99.0) for sofosbuvir/velpatasvir/voxilepravir and in 100% (95% CI: 92.0-100) for glecaprevir/pibrentasvir, with resistance driven by RAS to NS5A inhibitors. DISCUSSION At least 1 RAS is present in a high proportion of the few individuals with virological failure following initial or re-treatment with pan-genotypic DAA regimens. There is a need for ongoing surveillance for DAA-associated resistance, to assess risk factors for their development and clinical impact to inform best practice strategies for re-treatment.
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Affiliation(s)
- Seth Inzaule
- Amsterdam Institute for Global Health and Development, and Department of Global Health, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Philippa Easterbrook
- HIV, Hepatitis and Sexually Transmitted Infection Department, World Health Organization, Geneva, Switzerland
| | - Ashley Latona
- Division of Geographic Medicine and Infectious Diseases,Tufts University School of Medicine, Boston, Massachusetts, USA
| | - Nathan P Ford
- HIV, Hepatitis and Sexually Transmitted Infection Department, World Health Organization, Geneva, Switzerland
| | - William Irving
- School of Life Sciences, Division of Microbiology and Infectious Diseases, The University of Nottingham, Nottingham, United Kingdom
| | | | - Marco Vitoria
- HIV, Hepatitis and Sexually Transmitted Infection Department, World Health Organization, Geneva, Switzerland
| | - Chris Duncombe
- International Association of Providers of AIDS Care, Washington, DC, USA
| | - Amalia Giron
- Independent Consultant, Guatemala city, Guatemala
| | - Suzanne McCluskey
- Division of Infectious Diseases, Havard Medical School, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Olufunmilayo Lesi
- HIV, Hepatitis and Sexually Transmitted Infection Department, World Health Organization, Geneva, Switzerland
| | - Serge Tchamgoue
- Faculty of Medicine and Pharmaceutical Sciences, University of Douala, Douala, Cameroon
| | | | | | - Emma Thomson
- Medical Research Council-University of Glasgow Centre for Virus Research, Glasgow, United Kingdom
| | - Geoff Dusheiko
- Institute for Global Health, University College London, London, United Kingdom
| | - Michael R Jordan
- Division of Geographic Medicine and Infectious Diseases,Tufts University School of Medicine, Boston, Massachusetts, USA
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Dietz J, Graf C, Berg CP, Port K, Deterding K, Buggisch P, Peiffer KH, Vermehren J, Dultz G, Geier A, Reiter FP, Bruns T, Schattenberg JM, Durmashkina E, Gustot T, Moreno C, Trauth J, Discher T, Fischer J, Berg T, Kremer AE, Müllhaupt B, Zeuzem S, Sarrazin C. Rare HCV subtypes and retreatment outcomes in a cohort of European DAA-experienced patients. JHEP Rep 2024; 6:101072. [PMID: 39006503 PMCID: PMC11246049 DOI: 10.1016/j.jhepr.2024.101072] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2023] [Revised: 03/15/2024] [Accepted: 03/18/2024] [Indexed: 07/16/2024] Open
Abstract
Background and Aims Data on the prevalence and characteristics of so-called rare HCV genotypes (GTs) in larger cohorts is limited. This study investigates the frequency of rare GT and resistance-associated substitutions and the efficacy of retreatment in a European cohort. Methods A total of 129 patients with rare GT1-6 were included from the European resistance database. NS3, NS5A, and NS5B were sequenced and clinical parameters and retreatment efficacies were collected retrospectively. Results Overall 1.5% (69/4,656) of direct-acting antiviral (DAA)-naive and 4.4% (60/1,376) of DAA-failure patients were infected with rare GT. Although rare GTs were almost equally distributed throughout GT1-6 in DAA-naive patients, we detected mainly rare GT4 (47%, 28/60 GT4; of these n = 17, subtype 4r) and GT3 (25%, 15/60 GT3, of these n = 8, subtype 3b) among DAA-failures. A total of 62% (37/60) of DAA failures had not responded to first-generation regimes and the majority was infected with rare GT4 (57%, 21/37). In contrast, among patients with failure to pangenotypic DAA regimens (38%, 23/60), infections with rare GT3 were overrepresented (57%, 13/23). Although NS5A RASs were uncommon in rare GT2, GT5a, and GT6, we observed combined RASs in rare GT1, GT3, and GT4 at positions 28, 30, 31, which can be considered as inherent. DAA failures with completed follow-up of retreatment, achieved a high SVR rate (94%, 45/48 modified intention-to-treat analysis; 92%, 45/49 intention-to-treat). Three patients with GT4f, 4r, or 3b, respectively, had virological treatment failure. Conclusions In this European cohort, rare HCV GT were uncommon. Accumulation of specific rare GT in DAA-failure patients suggests reduced antiviral activities of DAA regimens. The limited global availability of pangenotypic regimens for first line therapy as well as multiple targeted regimens for retreatment could result in HCV elimination targets being delayed. Impact and implications Data on the prevalence and characteristics of rare HCV genotypes (GT) in larger cohorts are still scarce. This study found low rates of rare HCV GTs among European HCV-infected patients. In direct-acting antiviral (DAA)-failure patients, rare GT3 subtypes accumulated after pangenotypic DAA treatment and rare GT4 after first generation DAA failure and viral resistance was detected at NS5A positions 28, 30, and 31. The limited global availability of pangenotypic DAA regimens for first line therapy as well as multiple targeted regimens for retreatment could result in HCV elimination targets being delayed.
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Affiliation(s)
- Julia Dietz
- Medical Clinic 1, Department of Medicine, Goethe University, Frankfurt, Germany
- German Center for Infection Research (DZIF), External Partner Site Frankfurt, Germany
| | - Christiana Graf
- Medical Clinic 1, Department of Medicine, Goethe University, Frankfurt, Germany
- German Center for Infection Research (DZIF), External Partner Site Frankfurt, Germany
- Department of Internal Medicine II, University Hospital Munich, Munich, Germany
| | - Christoph P. Berg
- Department of Internal Medicine I, University of Tübingen, Tübingen, Germany
| | - Kerstin Port
- Department of Gastroenterology, Hepatology and Endocrinology, Medizinische Hochschule Hannover, Hannover, Germany
| | - Katja Deterding
- Department of Gastroenterology, Hepatology and Endocrinology, Medizinische Hochschule Hannover, Hannover, Germany
| | - Peter Buggisch
- Institute for Interdisciplinary Medicine IFI, Hamburg, Germany
| | - Kai-Henrik Peiffer
- Medical Clinic 1, Department of Medicine, Goethe University, Frankfurt, Germany
- Department of Internal Medicine B, University of Münster, Münster, Germany
| | - Johannes Vermehren
- Medical Clinic 1, Department of Medicine, Goethe University, Frankfurt, Germany
| | - Georg Dultz
- Medical Clinic 1, Department of Medicine, Goethe University, Frankfurt, Germany
| | - Andreas Geier
- Division of Hepatology, Department of Medicine II, University Hospital Würzburg, Würzburg, Germany
| | - Florian P. Reiter
- Division of Hepatology, Department of Medicine II, University Hospital Würzburg, Würzburg, Germany
| | - Tony Bruns
- Department of Medicine III, University Hospital Aachen, Aachen, Germany
| | - Jörn M. Schattenberg
- Department of Internal Medicine II, Saarland University Medical Center Homburg, Homburg, Germany
- Saarland University, Saarbrücken, Germany
| | | | - Thierry Gustot
- Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, CUB Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium
| | - Christophe Moreno
- Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, CUB Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium
| | - Janina Trauth
- Department of Internal Medicine II, Section of Infectious Diseases, Justus-Liebig-University Giessen, Giessen, Germany
- German Lung Center (DZL), Giessen, Germany
| | - Thomas Discher
- Department of Internal Medicine II, Section of Infectious Diseases, Justus-Liebig-University Giessen, Giessen, Germany
- German Lung Center (DZL), Giessen, Germany
| | - Janett Fischer
- Section of Hepatology, Department of Gastroenterology and Rheumatology, University Hospital Leipzig, Leipzig, Germany
| | - Thomas Berg
- Section of Hepatology, Department of Gastroenterology and Rheumatology, University Hospital Leipzig, Leipzig, Germany
| | - Andreas E. Kremer
- Swiss Hepato-Pancreato-Biliary Center and Department of Gastroenterology and Hepatology, University Hospital Zürich, University of Zürich, Zürich, Switzerland
| | - Beat Müllhaupt
- Swiss Hepato-Pancreato-Biliary Center and Department of Gastroenterology and Hepatology, University Hospital Zürich, University of Zürich, Zürich, Switzerland
| | - Stefan Zeuzem
- Medical Clinic 1, Department of Medicine, Goethe University, Frankfurt, Germany
- German Center for Infection Research (DZIF), External Partner Site Frankfurt, Germany
| | - Christoph Sarrazin
- Medical Clinic 1, Department of Medicine, Goethe University, Frankfurt, Germany
- German Center for Infection Research (DZIF), External Partner Site Frankfurt, Germany
- Medizinische Klinik 2, St. Josefs-Hospital, Wiesbaden, Germany
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3
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Brzdęk M, Zarębska-Michaluk D, Rzymski P, Lorenc B, Kazek A, Tudrujek-Zdunek M, Janocha-Litwin J, Mazur W, Dybowska D, Berak H, Parfieniuk-Kowerda A, Klapaczyński J, Sitko M, Sobala-Szczygieł B, Piekarska A, Flisiak R. Changes in characteristics of patients with hepatitis C virus-related cirrhosis from the beginning of the interferon-free era. World J Gastroenterol 2023; 29:2015-2033. [PMID: 37155527 PMCID: PMC10122793 DOI: 10.3748/wjg.v29.i13.2015] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2022] [Revised: 01/16/2023] [Accepted: 03/20/2023] [Indexed: 04/06/2023] Open
Abstract
BACKGROUND Nearly 290000 patients with chronic hepatitis C die annually from the most severe complications of the disease. One of them is liver cirrhosis, which occurs in about 20% of patients chronically infected with the hepatitis C virus (HCV). Direct-acting antivirals (DAAs), which replaced interferon (IFN)-based regimens, significantly improved the prognosis of this group of patients, increasing HCV eradication rates and tolerability of therapy. Our study is the first to assess changes in patient profile, effectiveness, and safety in the HCV-infected cirrhotic population in the IFN-free era.
AIM To document changes in patient characteristics and treatment regimens along with their effectiveness and safety profile over the years.
METHODS The studied patients were selected from 14801 chronically HCV-infected individuals who started IFN-free therapy between July 2015 and December 2021 in 22 Polish hepatology centers. The retrospective analysis was conducted in real-world clinical practice based on the EpiTer-2 multicenter database. The measure of treatment effectiveness was the percentage of sustained virologic response (SVR) calculated after excluding patients lost to follow-up. Safety data collected during therapy and the 12-wk post-treatment period included information on adverse events, including serious ones, deaths, and treatment course.
RESULTS The studied population (n = 3577) was balanced in terms of gender in 2015-2017, while the following years showed the dominance of men. The decline in the median age from 60 in 2015-2016 to 57 years in 2021 was accompanied by a decrease in the percentage of patients with comorbidities and comedications. Treatment-experienced patients dominated in 2015-2016, while treatment-naive individuals gained an advantage in 2017 and reached 93.2% in 2021. Genotype (GT)-specific options were more prevalent in treatment in 2015-2018 and were supplanted by pangenotypic combinations in subsequent years. The effectiveness of the therapy was comparable regardless of the period analyzed, and patients achieved an overall response rate of 95%, with an SVR range of 72.9%-100% for the different therapeutic regimens. Male gender, GT3 infection, and prior treatment failure were identified as independent negative predictors of therapeutic success.
CONCLUSION We have documented changes in the profile of HCV-infected cirrhotic patients over the years of accessibility to changing DAA regimens, confirming the high effectiveness of IFN-free therapy in all analyzed periods.
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Affiliation(s)
- Michał Brzdęk
- Department of Infectious Diseases, Jan Kochanowski University, Kielce 25-317, Poland
| | | | - Piotr Rzymski
- Department of Environmental Medicine, Poznan University of Medical Sciences, Poznań 60-806, Poland
- Integrated Science Association, Universal Scientific Education and Research Network, Poznań 60-806, Poland
| | - Beata Lorenc
- Pomeranian Center of Infectious Diseases, Medical University Gdańsk, Gdańsk 80-214, Poland
| | | | | | - Justyna Janocha-Litwin
- Department of Infectious Diseases and Hepatology, Medical University Wrocław, Wrocław 50-367, Poland
| | - Włodzimierz Mazur
- Clinical Department of Infectious Diseases, Clinical University of Silesia in Katowice, Chorzów 41-500, Poland
| | - Dorota Dybowska
- Department of Infectious Diseases and Hepatology, Faculty of Medicine, Nicolaus Copernicus University, Bydgoszcz 85-030, Poland
| | - Hanna Berak
- Daily Department, Hospital for Infectious Diseases in Warsaw, Warszawa 01-201, Poland
| | - Anna Parfieniuk-Kowerda
- Department of Infectious Diseases and Hepatology, Medical University of Białystok, Białystok 15-089, Poland
| | - Jakub Klapaczyński
- Department of Internal Medicine and Hepatology, Central Clinical Hospital of the Ministry of Internal Affairs and Administration, Warszawa 00-241, Poland
| | - Marek Sitko
- Department of Infectious and Tropical Diseases, Jagiellonian University, Kraków 31-088, Poland
| | - Barbara Sobala-Szczygieł
- Department of Infectious Diseases, Medical University of Silesia in Katowice, Bytom 41-902, Poland
| | - Anna Piekarska
- Department of Infectious Diseases and Hepatology, Medical University of Łódź, Łódź 90-419, Poland
| | - Robert Flisiak
- Department of Infectious Diseases and Hepatology, Medical University of Białystok, Białystok 15-089, Poland
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4
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Dietz J, Müllhaupt B, Buggisch P, Graf C, Peiffer KH, Matschenz K, Schattenberg JM, Antoni C, Mauss S, Niederau C, Discher T, Trauth J, Dultz G, Schulze Zur Wiesch J, Piecha F, Klinker H, Müller T, Berg T, Neumann-Haefelin C, Berg CP, Zeuzem S, Sarrazin C. Long-term persistence of HCV resistance-associated substitutions after DAA treatment failure. J Hepatol 2023; 78:57-66. [PMID: 36031158 DOI: 10.1016/j.jhep.2022.08.016] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Revised: 07/29/2022] [Accepted: 08/15/2022] [Indexed: 02/01/2023]
Abstract
BACKGROUND & AIMS Data on the long-term persistence of HCV resistance-associated substitutions (RASs) after treatment with direct-acting antivirals (DAAs) are limited. This study evaluated the persistence of NS3, NS5A, and NS5B RASs for up to 5 years after the end of treatment (EOT). METHODS We included samples from 678 individuals with an HCV genotype (GT) 1 or 3 infection and virologic DAA treatment failure collected in the European Resistance Database. NS3, NS5A, and NS5B were sequenced, and clinical parameters were evaluated. RESULTS A total of 242 individuals with HCV GT1a (36%), 237 with GT1b (35%), and 199 (29%) with GT3 and a DAA failure were included. After protease inhibitor failure, the frequencies of NS3 RASs were 40-90% after the EOT. NS3 RASs disappeared rapidly in GT1b and GT3 after follow-up month 3 but were stable (≥60%) in GT1a owing to Q80K. The SOF-resistant NS5B RAS S282T was only found in individuals with GT3a. Non-nucleoside NS5B RASs were frequent in GT1 (56-80%) and decreased to 30% in GT1a but persisted in GT1b. NS5A RASs were very common in all GTs after NS5A inhibitor failure (88-95%), and even after follow-up month 24, their frequency was 65% and higher. However, RASs in GT1b had a stable course, whereas RASs in GT1a and GT3 declined slightly after follow-up month 24 (GT1a, 68%; GT1b, 95%; and GT3, 65%), mainly because of the slow decline of high-level resistant Y93H. CONCLUSIONS We found that low-to medium-level RASs persisted, whereas high-level resistant RASs disappeared over time. Different patterns of RAS persistence according to HCV subtype could have implications for retreatment with first-generation DAAs and for global HCV elimination goals. IMPACT AND IMPLICATIONS There are little data on the long-term persistence of HCV resistance-associated substitutions (RASs) after DAA treatment failure, and RASs could have an impact on the efficacy of a rescue treatment. Especially in countries with limited availability of VOX/VEL/SOF or G/P/SOF, different patterns of RAS persistence could have implications for retreatment with first-generation DAAs and for global HCV elimination goals. The different patterns of RAS persistence identified in this study can be used to derive general rules regarding the persistence of RASs after DAA failure that could be applied by physicians in less developed countries to plan individualized HCV retreatment.
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Affiliation(s)
- Julia Dietz
- Department of Internal Medicine 1, University Hospital, Goethe University, Frankfurt, Germany; German Center for Infection Research (DZIF), External Partner Site Frankfurt, Frankfurt, Germany
| | - Beat Müllhaupt
- Swiss Hepato-Pancreato-Biliary Center and Department of Gastroenterology and Hepatology, University Hospital Zürich, Zürich, Switzerland
| | - Peter Buggisch
- Institute for Interdisciplinary Medicine IFI, Hamburg, Germany
| | - Christiana Graf
- Department of Internal Medicine 1, University Hospital, Goethe University, Frankfurt, Germany; German Center for Infection Research (DZIF), External Partner Site Frankfurt, Frankfurt, Germany
| | - Kai-Henrik Peiffer
- Department of Internal Medicine 1, University Hospital, Goethe University, Frankfurt, Germany; German Center for Infection Research (DZIF), External Partner Site Frankfurt, Frankfurt, Germany
| | | | - Jörn M Schattenberg
- Department of Internal Medicine I, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany
| | - Christoph Antoni
- Department of Medicine II, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
| | - Stefan Mauss
- Center for HIV and Hepatogastroenterology, Düsseldorf, Germany
| | | | - Thomas Discher
- Department of Internal Medicine II, Section of Infectious Diseases, Justus-Liebig-University Giessen, Giessen, Germany, member of the German Lung Center (DZL)
| | - Janina Trauth
- Department of Internal Medicine II, Section of Infectious Diseases, Justus-Liebig-University Giessen, Giessen, Germany, member of the German Lung Center (DZL)
| | - Georg Dultz
- Department of Internal Medicine 1, University Hospital, Goethe University, Frankfurt, Germany; German Center for Infection Research (DZIF), External Partner Site Frankfurt, Frankfurt, Germany
| | - Julian Schulze Zur Wiesch
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; German Center for Infection Research (DZIF), Partner Site Hamburg-Lübeck-Borstel-Riems, Hamburg, Germany
| | - Felix Piecha
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; German Center for Infection Research (DZIF), Partner Site Hamburg-Lübeck-Borstel-Riems, Hamburg, Germany
| | - Hartwig Klinker
- Department of Internal Medicine II, Division of Infectious Diseases, University Hospital Würzburg, Germany
| | - Tobias Müller
- Department of Hepatology and Gastroenterology, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Thomas Berg
- Section of Hepatology, Department of Gastroenterology and Rheumatology, University Hospital Leipzig, Leipzig, Germany
| | - Christoph Neumann-Haefelin
- Department of Medicine II, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Christoph P Berg
- Department of Internal Medicine I, University of Tübingen, Tübingen, Germany
| | - Stefan Zeuzem
- Department of Internal Medicine 1, University Hospital, Goethe University, Frankfurt, Germany; German Center for Infection Research (DZIF), External Partner Site Frankfurt, Frankfurt, Germany
| | - Christoph Sarrazin
- Department of Internal Medicine 1, University Hospital, Goethe University, Frankfurt, Germany; German Center for Infection Research (DZIF), External Partner Site Frankfurt, Frankfurt, Germany; Medizinische Klinik 2, St. Josefs-Hospital, Wiesbaden, Germany.
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5
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Howe AY, Rodrigo C, Cunningham E, Douglas MW, Dietz J, Grebely J, Popping S, Sfalcin JA, Parczewski M, Sarrazin C, de Salazar A, Fuentes A, Sayan M, Quer J, Kjellin M, Kileng H, Mor O, Lennerstrand J, Fourati S, di Maio VC, Chulanov V, Pawlotsky JM, Harrigan PR, Ceccherini-Silberstein F, Garcia F, Martinello M, Matthews G, Fernando FF, Esteban JI, Müllhaupt B, Wiesch JSZ, Buggisch P, Neumann-Haefelin C, Berg T, Berg CP, Schattenberg JM, Moreno C, Stauber R, Lloyd A, Dore G, Applegate T, Ignacio J, Garcia-Cehic D, Gregori J, Rodriguez-Frias F, Rando A, Angelico M, Andreoni M, Babudieri S, Bertoli A, Cento V, Coppola N, Craxì A, Paolucci S, Parruti G, Pasquazzi C, Perno CF, Teti E, Vironet C, Lannergård A, Duberg AS, Aleman S, Gutteberg T, Soulier A, Gourgeon A, Chevaliez S, Pol S, Carrat F, Salmon D, Kaiser R, Knopes E, Gomes P, de Kneght R, Rijnders B, Poljak M, Lunar M, Usubillaga R, Seguin C, Tay E, Wilson C, Wang DS, George J, Kok J, Pérez AB, Chueca N, García-Deltoro M, Martínez-Sapiña AM, Lara-Pérez MM, García-Bujalance S, Aldámiz-Echevarría T, Vera-Méndez FJ, Pineda JA, Casado M, Pascasio JM, Salmerón J, Alados-Arboledas JC, Poyato A, Téllez F, Rivero-Juárez A, Merino D, et alHowe AY, Rodrigo C, Cunningham E, Douglas MW, Dietz J, Grebely J, Popping S, Sfalcin JA, Parczewski M, Sarrazin C, de Salazar A, Fuentes A, Sayan M, Quer J, Kjellin M, Kileng H, Mor O, Lennerstrand J, Fourati S, di Maio VC, Chulanov V, Pawlotsky JM, Harrigan PR, Ceccherini-Silberstein F, Garcia F, Martinello M, Matthews G, Fernando FF, Esteban JI, Müllhaupt B, Wiesch JSZ, Buggisch P, Neumann-Haefelin C, Berg T, Berg CP, Schattenberg JM, Moreno C, Stauber R, Lloyd A, Dore G, Applegate T, Ignacio J, Garcia-Cehic D, Gregori J, Rodriguez-Frias F, Rando A, Angelico M, Andreoni M, Babudieri S, Bertoli A, Cento V, Coppola N, Craxì A, Paolucci S, Parruti G, Pasquazzi C, Perno CF, Teti E, Vironet C, Lannergård A, Duberg AS, Aleman S, Gutteberg T, Soulier A, Gourgeon A, Chevaliez S, Pol S, Carrat F, Salmon D, Kaiser R, Knopes E, Gomes P, de Kneght R, Rijnders B, Poljak M, Lunar M, Usubillaga R, Seguin C, Tay E, Wilson C, Wang DS, George J, Kok J, Pérez AB, Chueca N, García-Deltoro M, Martínez-Sapiña AM, Lara-Pérez MM, García-Bujalance S, Aldámiz-Echevarría T, Vera-Méndez FJ, Pineda JA, Casado M, Pascasio JM, Salmerón J, Alados-Arboledas JC, Poyato A, Téllez F, Rivero-Juárez A, Merino D, Vivancos-Gallego MJ, Rosales-Zábal JM, Ocete MD, Simón MÁ, Rincón P, Reus S, De la Iglesia A, García-Arata I, Jiménez M, Jiménez F, Hernández-Quero J, Galera C, Balghata MO, Primo J, Masiá M, Espinosa N, Delgado M, von-Wichmann MÁ, Collado A, Santos J, Mínguez C, Díaz-Flores F, Fernández E, Bernal E, De Juan J, Antón JJ, Vélez M, Aguilera A, Navarro D, Arenas JI, Fernández C, Espinosa MD, Ríos MJ, Alonso R, Hidalgo C, Hernández R, Téllez MJ, Rodríguez FJ, Antequera P, Delgado C, Martín P, Crespo J, Becerril B, Pérez O, García-Herola A, Montero J, Freyre C, Grau C, Cabezas J, Jimenez M, Rodriguez MAM, Quilez C, Pardo MR, Muñoz-Medina L, Figueruela B. Characteristics of hepatitis C virus resistance in an international cohort after a decade of direct-acting antivirals. JHEP Rep 2022; 4:100462. [PMID: 35434589 PMCID: PMC9010635 DOI: 10.1016/j.jhepr.2022.100462] [Show More Authors] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Accepted: 02/05/2022] [Indexed: 10/24/2022] Open
Abstract
BACKGROUND & AIMS Direct-acting antiviral (DAA) regimens provide a cure in >95% of patients with chronic HCV infection. However, in some patients in whom therapy fails, resistance-associated substitutions (RASs) can develop, limiting retreatment options and risking onward resistant virus transmission. In this study, we evaluated RAS prevalence and distribution, including novel NS5A RASs and clinical factors associated with RAS selection, among patients who experienced DAA treatment failure. METHODS SHARED is an international consortium of clinicians and scientists studying HCV drug resistance. HCV sequence linked metadata from 3,355 patients were collected from 22 countries. NS3, NS5A, and NS5B RASs in virologic failures, including novel NS5A substitutions, were examined. Associations of clinical and demographic characteristics with RAS selection were investigated. RESULTS The frequency of RASs increased from its natural prevalence following DAA exposure: 37% to 60% in NS3, 29% to 80% in NS5A, 15% to 22% in NS5B for sofosbuvir, and 24% to 37% in NS5B for dasabuvir. Among 730 virologic failures, most were treated with first-generation DAAs, 94% had drug resistance in ≥1 DAA class: 31% single-class resistance, 42% dual-class resistance (predominantly against protease and NS5A inhibitors), and 21% triple-class resistance. Distinct patterns containing ≥2 highly resistant RASs were common. New potential NS5A RASs and adaptive changes were identified in genotypes 1a, 3, and 4. Following DAA failure, RAS selection was more frequent in older people with cirrhosis and those infected with genotypes 1b and 4. CONCLUSIONS Drug resistance in HCV is frequent after DAA treatment failure. Previously unrecognized substitutions continue to emerge and remain uncharacterized. LAY SUMMARY Although direct-acting antiviral medications effectively cure hepatitis C in most patients, sometimes treatment selects for resistant viruses, causing antiviral drugs to be either ineffective or only partially effective. Multidrug resistance is common in patients for whom DAA treatment fails. Older patients and patients with advanced liver diseases are more likely to select drug-resistant viruses. Collective efforts from international communities and governments are needed to develop an optimal approach to managing drug resistance and preventing the transmission of resistant viruses.
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Key Words
- DAA
- DAA, direct-acting antiviral
- DCV, daclatasvir
- DSV, dasabuvir
- GT, genotype
- HCV
- LDV, ledipasvir
- NI, nucleoside
- NNI, non-nucleoside
- NS5A
- NS5AI, NS5A replication complex inhibitor
- OR, odds ratio
- PI, NS3 protease inhibitor
- PIB, pibrentasvir
- RAS
- RASs, resistance-associated substitutions
- SHARED, The Surveillance of Hepatitis C Antiviral Resistance, Epidemiology and methoDologies
- SOF, sofosbuvir
- SVR, sustained virologic response
- VEL, velpatasvir
- aOR, adjusted odds ratio
- sFC, substitution frequency change
- virologic failure
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Pabjan P, Brzdęk M, Chrapek M, Dziedzic K, Dobrowolska K, Paluch K, Garbat A, Błoniarczyk P, Reczko K, Stępień P, Zarębska-Michaluk D. Are There Still Difficult-to-Treat Patients with Chronic Hepatitis C in the Era of Direct-Acting Antivirals? Viruses 2022; 14:96. [PMID: 35062302 PMCID: PMC8779728 DOI: 10.3390/v14010096] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2021] [Revised: 12/29/2021] [Accepted: 01/04/2022] [Indexed: 12/17/2022] Open
Abstract
Difficult-to-treat populations with chronic hepatitis C (CHC), in the era of interferon treatment, included patients with liver cirrhosis, kidney impairment, treatment-experienced individuals, and those coinfected with the human immunodeficiency virus. The current study aimed to determine whether, in the era of direct-acting antivirals (DAA), there are still patients that are difficult-to-treat. The study included all consecutive patients chronically infected with hepatitis C virus (HCV) who started interferon-free therapy between July 2015 and December 2020 in the Department of Infectious Diseases in Kielce. The analyzed real-world population consisted of 963 patients, and most of them were infected with genotype 1 (87.6%) with the predominance of subtype 1b and were treatment-naïve (78.8%). Liver cirrhosis was determined in 207 individuals (21.5%), of whom 82.6% were compensated. The overall sustained virologic response, after exclusion of non-virologic failures, was achieved in 98.4%. The univariable analysis demonstrated the significantly lower response rates in males, patients with liver cirrhosis, decompensation of hepatic function at baseline, documented esophageal varices, concomitant diabetes, body mass index ≥25, and previous ineffective antiviral treatment. Despite an overall very high effectiveness, some unfavorable factors, including male gender, genotype 3 infection, liver cirrhosis, and treatment experience, significantly reduce the chances for a virologic response were identified.
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Affiliation(s)
- Paweł Pabjan
- Department of Infectious Diseases, Voivodship Hospital, Jan Kochanowski University, 25-317 Kielce, Poland; (P.P.); (K.P.); (A.G.); (P.B.); (K.R.); (P.S.)
| | - Michał Brzdęk
- Collegium Medicum, Jan Kochanowski University, 25-369 Kielce, Poland; (M.B.); (K.D.); (K.D.)
| | - Magdalena Chrapek
- Faculty of Natural Sciences, Jan Kochanowski University, 25-369 Kielce, Poland;
| | - Kacper Dziedzic
- Collegium Medicum, Jan Kochanowski University, 25-369 Kielce, Poland; (M.B.); (K.D.); (K.D.)
| | - Krystyna Dobrowolska
- Collegium Medicum, Jan Kochanowski University, 25-369 Kielce, Poland; (M.B.); (K.D.); (K.D.)
| | - Katarzyna Paluch
- Department of Infectious Diseases, Voivodship Hospital, Jan Kochanowski University, 25-317 Kielce, Poland; (P.P.); (K.P.); (A.G.); (P.B.); (K.R.); (P.S.)
| | - Anna Garbat
- Department of Infectious Diseases, Voivodship Hospital, Jan Kochanowski University, 25-317 Kielce, Poland; (P.P.); (K.P.); (A.G.); (P.B.); (K.R.); (P.S.)
| | - Piotr Błoniarczyk
- Department of Infectious Diseases, Voivodship Hospital, Jan Kochanowski University, 25-317 Kielce, Poland; (P.P.); (K.P.); (A.G.); (P.B.); (K.R.); (P.S.)
| | - Katarzyna Reczko
- Department of Infectious Diseases, Voivodship Hospital, Jan Kochanowski University, 25-317 Kielce, Poland; (P.P.); (K.P.); (A.G.); (P.B.); (K.R.); (P.S.)
| | - Piotr Stępień
- Department of Infectious Diseases, Voivodship Hospital, Jan Kochanowski University, 25-317 Kielce, Poland; (P.P.); (K.P.); (A.G.); (P.B.); (K.R.); (P.S.)
| | - Dorota Zarębska-Michaluk
- Department of Infectious Diseases, Voivodship Hospital, Jan Kochanowski University, 25-317 Kielce, Poland; (P.P.); (K.P.); (A.G.); (P.B.); (K.R.); (P.S.)
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Sarrazin C. Treatment failure with DAA therapy: Importance of resistance. J Hepatol 2021; 74:1472-1482. [PMID: 33716089 DOI: 10.1016/j.jhep.2021.03.004] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Revised: 02/24/2021] [Accepted: 03/01/2021] [Indexed: 12/14/2022]
Abstract
Viral resistance is a major reason for virological failure in patients being treated with direct-acting antivirals (DAAs) for chronic HCV infection. However, the importance of viral resistance mainly depends on the DAA regimen and HCV genotype. For first-line therapy with glecaprevir/pibrentasvir (G/P) or velpatasvir/sofosbuvir (VEL/SOF) no general baseline resistance analysis is required because of the high antiviral activity and high barrier to resistance. If available, resistance testing may help to optimise therapy in certain subgroups of patients with HCV genotype 3 and other rare HCV geno/subtypes. Voxilaprevir/velpatasvir/sofosbuvir (VOX/VEL/SOF) is the first choice for the second-line treatment of patients following a previous DAA failure, with rates of viral eradication above 90% irrespective of the presence of resistance-associated substitutions (RASs). However, in resource-limited settings, only first-generation DAAs may be available for second-line therapy. Here, RASs selected during initial antiviral therapy should be considered if testing is available and rescue treatment should include a switch to a regimen with a new DAA class to optimise treatment response. Patients with HCV genotype 3 are overrepresented in the group who experience DAA treatment failure. Limited data are available for third-line therapies, but promising results have been achieved with G/P plus SOF or VOX/VEL/SOF with or without ribavirin for 12 to 24 weeks; these regimens should be administered irrespective of a patient's RAS profile.
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Affiliation(s)
- Christoph Sarrazin
- St. Josefs-Hospital, Beethovenstr. 20, 65189 Wiesbaden, Germany; Goethe-University Hospital, Medizinische Klinik 1, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany.
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Sarrazin C, Zimmermann T, Berg T, Hinrichsen H, Mauss S, Wedemeyer H, Zeuzem S. [Not Available]. 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] [MESH Headings] [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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9
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Piecha F, Gänßler JM, Ozga AK, Wehmeyer MH, Dietz J, Kluwe J, Laschtowitz A, von Felden J, Sterneck M, Jordan S, Pischke S, Lohse AW, Schulze zur Wiesch J. Treatment and re-treatment results of HCV patients in the DAA era. PLoS One 2020; 15:e0232773. [PMID: 32369527 PMCID: PMC7200014 DOI: 10.1371/journal.pone.0232773] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2019] [Accepted: 04/21/2020] [Indexed: 12/14/2022] Open
Abstract
Background Re-treatment in patients with a chronic hepatitis C virus (HCV) infection and a previous failure to direct-acting antiviral (DAA) treatment remains a challenge. Therefore, we investigated the success rate of treatment and re-treatment regimens used at our center from October 2011 to March 2018. Methods A retrospective analysis of DAA-based HCV therapies of 1096 patients was conducted. Factors associated with a virological relapse were identified by univariable and multivariable logistic regression, treatment success of the re-treatment regimens was evaluated by an analysis of sustained virological response (SVR) rates in patients with a documented follow-up 12 weeks after the end of treatment. Results Of 1096 patients treated with DAA-based regimens, 91 patients (8%) were lost to follow-up, 892 of the remaining 1005 patients (89%) achieved an SVR12. Most patients (65/113, 58%) who experienced a virological relapse received an interferon-based DAA regimen. SVR rates were comparable in special cohorts like liver transplant recipients (53/61, 87%) and people with a human immunodeficiency virus (HIV) coinfection (41/45, 91%). On multivariable analysis, interferon-based DAA therapy was associated with treatment failure (odds ratio 0.111, 95%-confidence interval 0.054–0.218) among others. One hundred seventeen patients with multiple DAA treatment courses were identified, of which 97 patients (83%) experienced a single relapse, but further relapses after two (18/117, 15%) or even three (2/117, 2%) treatment courses were also observed. Eighty-two of 96 (85%) re-treatment attempts with all-oral DAA regimens were successful after an initial treatment failure. Conclusion Overall, DAA re-treatments were highly effective in this real-world cohort and only a minority of patients failed more than two treatment courses. Switching to–or addition of–a new drug class seem to be valid options for the re-treatment of patients especially after failure of an interferon-based regimen.
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Affiliation(s)
- Felix Piecha
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- German Center for Infection Research (DZIF), Partner Site Hamburg-Lübeck-Borstel-Riems, Hamburg, Germany
- * E-mail:
| | - Jan-Michael Gänßler
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Ann-Kathrin Ozga
- Center for Experimental Medicine, Institute of Medical Biometry and Epidemiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Malte H. Wehmeyer
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Julia Dietz
- Department of Internal Medicine 1, University Hospital Frankfurt, Frankfurt, Germany
- German Center for Infection Research (DZIF), External Partner Site Frankfurt, Frankfurt, Germany
| | - Johannes Kluwe
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Alena Laschtowitz
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Johann von Felden
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Martina Sterneck
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Sabine Jordan
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Sven Pischke
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Ansgar W. Lohse
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- German Center for Infection Research (DZIF), Partner Site Hamburg-Lübeck-Borstel-Riems, Hamburg, Germany
| | - Julian Schulze zur Wiesch
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- German Center for Infection Research (DZIF), Partner Site Hamburg-Lübeck-Borstel-Riems, Hamburg, Germany
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