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For: Dietz J, Spengler U, Müllhaupt B, Schulze Zur Wiesch J, Piecha F, Mauss S, Seegers B, Hinrichsen H, Antoni C, Wietzke-Braun P, Peiffer KH, Berger A, Matschenz K, Buggisch P, Backhus J, Zizer E, Boettler T, Neumann-Haefelin C, Semela D, Stauber R, Berg T, Berg C, Zeuzem S, Vermehren J, Sarrazin C, Giostra E, Berning M, Hampe J, De Gottardi A, Rauch A, Semmo N, Discher T, Trauth J, Fischer J, Gress M, Günther R, Heinzow H, Schmidt J, Herrmann A, Stallmach A, Hilgard G, Deterding K, Lange C, Ciesek S, Wedemeyer H, Hoffmann D, Klinker H, Schulze P, Kocheise F, Müller-Schilling M, Kodal A, Kremer A, Ganslmayer M, Siebler J, Lammert F, Rissland J, Löbermann M, Götze T, Canbay A, Lohse A, von Felden J, Jordan S, Maieron A, Moradpour D, Chave JP, Moreno C, Müller T, Muche M, Epple HJ, Port K, von Hahn T, Cornberg M, Manns M, Reinhardt L, Ellenrieder V, Rockstroh J, Schattenberg J, Sprinzl M, Galle P, Roeb E, Steckstor M, Schmiegel W, Brockmeyer N, Seufferlein T, Stremmel W, Strey B, Thimme R, Teufel A, Vogelmann R, Ebert M, Tomasiewicz K, Trautwein C, Tacke F, Koenen T, Weber T, Zachoval R, Mayerle J, Raziorrouh B, Angeli W, Beckebaum S, Doberauer C, Durmashkina E, Hackelsberger A, Erhardt A, Garrido-Lüneburg A, Gattringer H, Genné D, Gschwantler M, Gundling F, Hametner S, Schöfl R, Hartmann C, Heyer T, Hirschi C, Jussios A, Kanzler S, Kordecki N, Kraus M, Kullig U, Wollschläger S, Magenta L, Beretta-Piccoli BT, Menges M, Mohr L, Muehlenberg K, Niederau C, Paulweber B, Petrides A, Pinkernell M, Piso R, Rambach W, Reiser M, Riecken B, Rieke A, Roth J, Schelling M, Schlee P, Schneider A, Scholz D, Schott E, Schuchmann M, Schulten-Baumer U, Seelhoff A, Stich A, Stickel F, Ungemach J, Walter E, Weber A, Winzer T, Abels W, Adler M, Audebert F, Baermann C, Bästlein E, Barth R, Barthel K, Becker W, Behrends J, Benninger J, Berger F, Berzow D, Beyer T, Bierbaum M, Blaukat O, Bodtländer A, Böhm G, Börner N, Bohr U, Bokemeyer B, Bruch H, Bucholz D, Burkhard O, Busch N, Chirca C, Delker R, Diedrich J, Frank M, Diehl M, Dienethal A, Dietel P, Dikopoulos N, Dreck M, Dreher F, Drude L, Ende K, Ehrle U, Baumgartl K, Emke F, Glosemeyer R, Felten G, Hüppe D, Fischer J, Fischer U, Frederking D, Frick B, Friese G, Gantke B, Geyer P, Schwind H, Glas M, Glaunsinger T, Goebel F, Göbel U, Görlitz B, Graf R, Gruber H, Härter G, Herder M, Heuchel T, Heuer S, Höffl KH, Hörster H, Sonne JU, Hofmann W, Holst F, Hunstiger M, Hurst A, Jägel-Guedes E, John C, Jung M, Kallinowski B, Kapzan B, Kerzel W, Khaykin P, Klarhof M, Klüppelberg U, Klugewitz K, Knapp B, Knevels U, Kochsiek T, Körfer A, Köster A, Kuhn M, Langekamp A, Künzig B, Link R, Littman M, Löhr H, Lutz T, Knecht G, Lutz U, Mainz D, Mahle I, Maurer P, Mayer C, Meister V, Möller H, Heyne R, Moritzen D, Mroß M, Mundlos M, Naumann U, Nehls O, Ningel K, Oelmann A, Olejnik H, Gadow K, Pascher E, Petersen J, Philipp A, Pichler M, Polzien F, Raddant R, Riedel M, Rietzler S, Rössle M, Rufle W, Rump A, Schewe C, Hoffmann C, Schleehauf D, Schmidt K, Schmidt W, Schmidt-Heinevetter G, Schmidtler-von Fabris J, Schnaitmann E, Schneider L, Schober A, Niehaus-Hahn S, Schwenzer J, Seidel T, Seitel G, Sick C, Simon K, Stähler D, Stenschke F, Steffens H, Stein K, Steinmüller M, Sternfeld T, Strey B, Svensson K, Tacke W, Teuber G, Teubner K, Thieringer J, Tomesch A, Trappe U, Ullrich J, Urban G, Usadel S, von Lucadou A, Weinberger F, Werheid-Dobers M, Werner P, Winter T, Zehnter E, Zipf A. Efficacy of Retreatment After Failed Direct-acting Antiviral Therapy in Patients With HCV Genotype 1-3 Infections. Clin Gastroenterol Hepatol 2021;19:195-198.e2. [PMID: 31706062 DOI: 10.1016/j.cgh.2019.10.051] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [What about the content of this article? (0)] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2019] [Revised: 09/19/2019] [Accepted: 10/25/2019] [Indexed: 02/07/2023]

For:	Dietz J, Spengler U, Müllhaupt B, Schulze Zur Wiesch J, Piecha F, Mauss S, Seegers B, Hinrichsen H, Antoni C, Wietzke-Braun P, Peiffer KH, Berger A, Matschenz K, Buggisch P, Backhus J, Zizer E, Boettler T, Neumann-Haefelin C, Semela D, Stauber R, Berg T, Berg C, Zeuzem S, Vermehren J, Sarrazin C, Giostra E, Berning M, Hampe J, De Gottardi A, Rauch A, Semmo N, Discher T, Trauth J, Fischer J, Gress M, Günther R, Heinzow H, Schmidt J, Herrmann A, Stallmach A, Hilgard G, Deterding K, Lange C, Ciesek S, Wedemeyer H, Hoffmann D, Klinker H, Schulze P, Kocheise F, Müller-Schilling M, Kodal A, Kremer A, Ganslmayer M, Siebler J, Lammert F, Rissland J, Löbermann M, Götze T, Canbay A, Lohse A, von Felden J, Jordan S, Maieron A, Moradpour D, Chave JP, Moreno C, Müller T, Muche M, Epple HJ, Port K, von Hahn T, Cornberg M, Manns M, Reinhardt L, Ellenrieder V, Rockstroh J, Schattenberg J, Sprinzl M, Galle P, Roeb E, Steckstor M, Schmiegel W, Brockmeyer N, Seufferlein T, Stremmel W, Strey B, Thimme R, Teufel A, Vogelmann R, Ebert M, Tomasiewicz K, Trautwein C, Tacke F, Koenen T, Weber T, Zachoval R, Mayerle J, Raziorrouh B, Angeli W, Beckebaum S, Doberauer C, Durmashkina E, Hackelsberger A, Erhardt A, Garrido-Lüneburg A, Gattringer H, Genné D, Gschwantler M, Gundling F, Hametner S, Schöfl R, Hartmann C, Heyer T, Hirschi C, Jussios A, Kanzler S, Kordecki N, Kraus M, Kullig U, Wollschläger S, Magenta L, Beretta-Piccoli BT, Menges M, Mohr L, Muehlenberg K, Niederau C, Paulweber B, Petrides A, Pinkernell M, Piso R, Rambach W, Reiser M, Riecken B, Rieke A, Roth J, Schelling M, Schlee P, Schneider A, Scholz D, Schott E, Schuchmann M, Schulten-Baumer U, Seelhoff A, Stich A, Stickel F, Ungemach J, Walter E, Weber A, Winzer T, Abels W, Adler M, Audebert F, Baermann C, Bästlein E, Barth R, Barthel K, Becker W, Behrends J, Benninger J, Berger F, Berzow D, Beyer T, Bierbaum M, Blaukat O, Bodtländer A, Böhm G, Börner N, Bohr U, Bokemeyer B, Bruch H, Bucholz D, Burkhard O, Busch N, Chirca C, Delker R, Diedrich J, Frank M, Diehl M, Dienethal A, Dietel P, Dikopoulos N, Dreck M, Dreher F, Drude L, Ende K, Ehrle U, Baumgartl K, Emke F, Glosemeyer R, Felten G, Hüppe D, Fischer J, Fischer U, Frederking D, Frick B, Friese G, Gantke B, Geyer P, Schwind H, Glas M, Glaunsinger T, Goebel F, Göbel U, Görlitz B, Graf R, Gruber H, Härter G, Herder M, Heuchel T, Heuer S, Höffl KH, Hörster H, Sonne JU, Hofmann W, Holst F, Hunstiger M, Hurst A, Jägel-Guedes E, John C, Jung M, Kallinowski B, Kapzan B, Kerzel W, Khaykin P, Klarhof M, Klüppelberg U, Klugewitz K, Knapp B, Knevels U, Kochsiek T, Körfer A, Köster A, Kuhn M, Langekamp A, Künzig B, Link R, Littman M, Löhr H, Lutz T, Knecht G, Lutz U, Mainz D, Mahle I, Maurer P, Mayer C, Meister V, Möller H, Heyne R, Moritzen D, Mroß M, Mundlos M, Naumann U, Nehls O, Ningel K, Oelmann A, Olejnik H, Gadow K, Pascher E, Petersen J, Philipp A, Pichler M, Polzien F, Raddant R, Riedel M, Rietzler S, Rössle M, Rufle W, Rump A, Schewe C, Hoffmann C, Schleehauf D, Schmidt K, Schmidt W, Schmidt-Heinevetter G, Schmidtler-von Fabris J, Schnaitmann E, Schneider L, Schober A, Niehaus-Hahn S, Schwenzer J, Seidel T, Seitel G, Sick C, Simon K, Stähler D, Stenschke F, Steffens H, Stein K, Steinmüller M, Sternfeld T, Strey B, Svensson K, Tacke W, Teuber G, Teubner K, Thieringer J, Tomesch A, Trappe U, Ullrich J, Urban G, Usadel S, von Lucadou A, Weinberger F, Werheid-Dobers M, Werner P, Winter T, Zehnter E, Zipf A. Efficacy of Retreatment After Failed Direct-acting Antiviral Therapy in Patients With HCV Genotype 1-3 Infections. Clin Gastroenterol Hepatol 2021;19:195-198.e2. [PMID: 31706062 DOI: 10.1016/j.cgh.2019.10.051] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [What about the content of this article? (0)] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2019] [Revised: 09/19/2019] [Accepted: 10/25/2019] [Indexed: 02/07/2023]

Number

Cited by Other Article(s)

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
Philippa C Matthews The Francis Crick Institute, London, 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
Rachel Halford World Hepatitis Alliance, Geneva, Switzerland
Danjuma Adda World Hepatitis Alliance, Geneva, Switzerland
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
Elena Durmashkina Medizinische Klinik 2, St. Josefs-Hospital, Wiesbaden, 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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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
Dorota Zarębska-Michaluk 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
Adam Kazek ID Clinic, Mysłowice 41-400, Poland
Magdalena Tudrujek-Zdunek Department of Infectious Diseases, Medical University of Lublin, Lublin 20-059, 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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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
Katrin Matschenz Institute for Interdisciplinary Medicine IFI, Hamburg, 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
Claus Niederau Katholische Kliniken Oberhausen, Oberhausen, 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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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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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

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]

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]

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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