Resistance analysis and treatment outcomes in hepatitis C virus genotype 3-infected patients within the Italian network VIRONET-C
Velia Chiara Di Maio
Department of Experimental Medicine, University of Rome Tor Vergata, Rome, Italy
Search for more papers by this authorSilvia Barbaliscia
Department of Experimental Medicine, University of Rome Tor Vergata, Rome, Italy
Search for more papers by this authorElisabetta Teti
Infectious Diseases, University Hospital of Rome Tor Vergata, Rome, Italy
Search for more papers by this authorGianluca Fiorentino
Infectious Diseases, Sant’Andrea Hospital – “La Sapienza”, Rome, Italy
Search for more papers by this authorMartina Milana
Hepatology Unit, University Hospital of Rome Tor Vergata, Rome, Italy
Search for more papers by this authorStefania Paolucci
Molecular Virology Unit, Microbiology and Virology Department, IRCCS Policlinic Foundation San Matteo, Pavia, Italy
Search for more papers by this authorTeresa Pollicino
Department of Internal Medicine, University Hospital of Messina, Messina, Italy
Search for more papers by this authorGiulia Morsica
Division of Infectious Diseases, IRCCS, Ospedale San Raffaele, Milan, Italy
Search for more papers by this authorMario Starace
Laboratory for the identification of prognostic factors of response to the treatment against infectious diseases, University of Campania "L. Vanvitelli", Napoli, Italy
Search for more papers by this authorBianca Bruzzone
Hygiene Unit, IRCCS AOU San Martino-IST, Genoa, Italy
Search for more papers by this authorWilliam Gennari
Microbiology Unit, University Hospital of Modena, Modena, Italy
Search for more papers by this authorValeria Micheli
Clinical Microbiology, Virology and Bioemergencies, ASST Fatebenefratelli Sacco University Hospital, Milan, Italy
Search for more papers by this authorKatia Yu La Rosa
Department of Experimental Medicine, University of Rome Tor Vergata, Rome, Italy
Search for more papers by this authorLuca Foroghi
Infectious Diseases, University Hospital of Rome Tor Vergata, Rome, Italy
Search for more papers by this authorVincenza Calvaruso
Gastroenterology, “P. Giaccone” University Hospital, Palermo, Italy
Search for more papers by this authorIlaria Lenci
Hepatology Unit, University Hospital of Rome Tor Vergata, Rome, Italy
Search for more papers by this authorEnnio Polilli
Infectious Disease Unit, Pescara General Hospital, Pescara, Italy
Search for more papers by this authorSergio Babudieri
Medical, Surgical and Experimental Sciences, University of Sassari, Sassari, Italy
Search for more papers by this authorAlessio Aghemo
Division of Internal Medicine and Hepatology, Humanitas Clinical and Research Center IRCCS, Rozzano, Italy
Search for more papers by this authorGiovanni Raimondo
Department of Internal Medicine, University Hospital of Messina, Messina, Italy
Search for more papers by this authorLoredana Sarmati
Infectious Diseases, University Hospital of Rome Tor Vergata, Rome, Italy
Search for more papers by this authorNicola Coppola
Laboratory for the identification of prognostic factors of response to the treatment against infectious diseases, University of Campania "L. Vanvitelli", Napoli, Italy
Department of Mental Health and Public Medicine, Infectious Diseases Unit, University of Campania “L. Vanvitelli”, Naples, Italy
Search for more papers by this authorCaterina Pasquazzi
Infectious Diseases, Sant’Andrea Hospital – “La Sapienza”, Rome, Italy
Search for more papers by this authorFausto Baldanti
Molecular Virology Unit, Microbiology and Virology Department, IRCCS Policlinic Foundation San Matteo, Pavia, Italy
Search for more papers by this authorGiustino Parruti
Infectious Disease Unit, Pescara General Hospital, Pescara, Italy
Search for more papers by this authorCarlo Federico Perno
IRCCS Children Hospital Bambino Gesù, Rome, Italy
Search for more papers by this authorMario Angelico
Hepatology Unit, University Hospital of Rome Tor Vergata, Rome, Italy
Search for more papers by this authorAntonio Craxì
Gastroenterology, “P. Giaccone” University Hospital, Palermo, Italy
Search for more papers by this authorMassimo Andreoni
Infectious Diseases, University Hospital of Rome Tor Vergata, Rome, Italy
Search for more papers by this authorCorresponding Author
Francesca Ceccherini-Silberstein
Department of Experimental Medicine, University of Rome Tor Vergata, Rome, Italy
Correspondence
Francesca Ceccherini-Silberstein, Department of Experimental Medicine, University of Rome Tor Vergata; Via Montpellier 1, Rome 00133, Italy.
Email: [email protected]
Search for more papers by this authorHCV Virology Italian Resistance Network Group (Vironet C)
†Members are listed in the Appendix section.
Search for more papers by this authorVelia Chiara Di Maio
Department of Experimental Medicine, University of Rome Tor Vergata, Rome, Italy
Search for more papers by this authorSilvia Barbaliscia
Department of Experimental Medicine, University of Rome Tor Vergata, Rome, Italy
Search for more papers by this authorElisabetta Teti
Infectious Diseases, University Hospital of Rome Tor Vergata, Rome, Italy
Search for more papers by this authorGianluca Fiorentino
Infectious Diseases, Sant’Andrea Hospital – “La Sapienza”, Rome, Italy
Search for more papers by this authorMartina Milana
Hepatology Unit, University Hospital of Rome Tor Vergata, Rome, Italy
Search for more papers by this authorStefania Paolucci
Molecular Virology Unit, Microbiology and Virology Department, IRCCS Policlinic Foundation San Matteo, Pavia, Italy
Search for more papers by this authorTeresa Pollicino
Department of Internal Medicine, University Hospital of Messina, Messina, Italy
Search for more papers by this authorGiulia Morsica
Division of Infectious Diseases, IRCCS, Ospedale San Raffaele, Milan, Italy
Search for more papers by this authorMario Starace
Laboratory for the identification of prognostic factors of response to the treatment against infectious diseases, University of Campania "L. Vanvitelli", Napoli, Italy
Search for more papers by this authorBianca Bruzzone
Hygiene Unit, IRCCS AOU San Martino-IST, Genoa, Italy
Search for more papers by this authorWilliam Gennari
Microbiology Unit, University Hospital of Modena, Modena, Italy
Search for more papers by this authorValeria Micheli
Clinical Microbiology, Virology and Bioemergencies, ASST Fatebenefratelli Sacco University Hospital, Milan, Italy
Search for more papers by this authorKatia Yu La Rosa
Department of Experimental Medicine, University of Rome Tor Vergata, Rome, Italy
Search for more papers by this authorLuca Foroghi
Infectious Diseases, University Hospital of Rome Tor Vergata, Rome, Italy
Search for more papers by this authorVincenza Calvaruso
Gastroenterology, “P. Giaccone” University Hospital, Palermo, Italy
Search for more papers by this authorIlaria Lenci
Hepatology Unit, University Hospital of Rome Tor Vergata, Rome, Italy
Search for more papers by this authorEnnio Polilli
Infectious Disease Unit, Pescara General Hospital, Pescara, Italy
Search for more papers by this authorSergio Babudieri
Medical, Surgical and Experimental Sciences, University of Sassari, Sassari, Italy
Search for more papers by this authorAlessio Aghemo
Division of Internal Medicine and Hepatology, Humanitas Clinical and Research Center IRCCS, Rozzano, Italy
Search for more papers by this authorGiovanni Raimondo
Department of Internal Medicine, University Hospital of Messina, Messina, Italy
Search for more papers by this authorLoredana Sarmati
Infectious Diseases, University Hospital of Rome Tor Vergata, Rome, Italy
Search for more papers by this authorNicola Coppola
Laboratory for the identification of prognostic factors of response to the treatment against infectious diseases, University of Campania "L. Vanvitelli", Napoli, Italy
Department of Mental Health and Public Medicine, Infectious Diseases Unit, University of Campania “L. Vanvitelli”, Naples, Italy
Search for more papers by this authorCaterina Pasquazzi
Infectious Diseases, Sant’Andrea Hospital – “La Sapienza”, Rome, Italy
Search for more papers by this authorFausto Baldanti
Molecular Virology Unit, Microbiology and Virology Department, IRCCS Policlinic Foundation San Matteo, Pavia, Italy
Search for more papers by this authorGiustino Parruti
Infectious Disease Unit, Pescara General Hospital, Pescara, Italy
Search for more papers by this authorCarlo Federico Perno
IRCCS Children Hospital Bambino Gesù, Rome, Italy
Search for more papers by this authorMario Angelico
Hepatology Unit, University Hospital of Rome Tor Vergata, Rome, Italy
Search for more papers by this authorAntonio Craxì
Gastroenterology, “P. Giaccone” University Hospital, Palermo, Italy
Search for more papers by this authorMassimo Andreoni
Infectious Diseases, University Hospital of Rome Tor Vergata, Rome, Italy
Search for more papers by this authorCorresponding Author
Francesca Ceccherini-Silberstein
Department of Experimental Medicine, University of Rome Tor Vergata, Rome, Italy
Correspondence
Francesca Ceccherini-Silberstein, Department of Experimental Medicine, University of Rome Tor Vergata; Via Montpellier 1, Rome 00133, Italy.
Email: [email protected]
Search for more papers by this authorHCV Virology Italian Resistance Network Group (Vironet C)
†Members are listed in the Appendix section.
Search for more papers by this authorVC Di Maio and S. Barbaliscia shared first authorship.
Funding information
This work was supported in part by the Italian Ministry of Instruction, University and Research (MIUR) (Bandiera InterOmics Protocollo PB05 1°), the Italian Ministry of Health (RF-2016-02362422), a research grant from Bristol-Myers Squibb (BMS) (Study Protocol AI444-397), a research grant from Investigator-Initiated Studies Program of Merck Sharp & Dohme Corp (IIS 54882), the Fellowship Program/Digital Health Program 2018 of Gilead and by Aviralia and Vironet C Foundations. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. The opinions expressed in this paper are those of the authors and do not necessarily represent those of Merck Sharp & Dohme Corp.
Handling Editor: Luca Valenti
Abstract
Aim
This study aimed to investigate the role of resistance-associated substitutions (RASs) to direct-acting-antivirals (DAAs) in HCV genotype 3 (GT3).
Methods
Within the Italian VIRONET-C network, a total of 539 GT3-infected patients (417 DAA-naïve and 135 DAA-failures, of them, 13 at both baseline and failure) were analysed. Sanger sequencing of NS3/NS5A/NS5B was performed following home-made protocols.
Results
The majority of patients were male (79.4%), 91.4% were injection drug users, 49.3% were cirrhotic and 13.9% were HIV co-infected. Phylogenetic analysis classified sequences as GT3a-b-g-h (98%-0.4%-0.2%-1.2%) respectively.
Overall, 135 patients failed a DAA regimen: sofosbuvir (SOF)/daclatasvir (DCV) or velpatasvir (VEL)±ribavirin (RBV) (N = 91/15) and glecaprevir (G)/pibrentasvir (P) (N = 9). Moreover, 14.8% of patients were treated with suboptimal regimens for GT3: 3D ± RBV (Paritaprevir/r + Ombitasvir+Dasabuvir, N = 15), SOF + Simeprevir (SIM) (N = 1) or SOF/Ledipasvir (LDV) ± RBV (N = 4).
RAS prevalence was 15.8% in DAA-naïve patients. At failure, 81.5% patients showed at least one RAS: 11/25 (44.0%) in NS3, 109/135 (80.7%) in NS5A, 7/111 (6.3%) in NS5B SOF-failures. In NS5A-failures, Y93H RAS was the most prevalent (68.5% vs 5.1% DAA-naïve, P < .001) followed by A30K (12.7% vs 2.8% in DAA-naïve, P < .001). Analysing baseline samples, a higher prevalence of NS5A-RASs was observed before treatment in DAA-failures (5/13, 38.5%) vs DAA-naïves (61/393, 15.5%, P = .04). Regarding 228 DAA-naïve patients with an available outcome, 93.9% achieved a SVR. Interestingly, patients with baseline Y93H and/or A30K had SVR rate of 72.2% vs 95.7% for patients without NS5A-RASs (P = .002).
Conclusions
In this real-life GT3 cohort, the majority of failures harboured resistant variants carrying NS5A-RASs, the most frequent being Y93H. The presence of natural NS5A-RASs before treatment was associated with failure. Further analyses are needed to confirm this observation, particularly for the new current regimens.
CONFLICT OF INTEREST
Francesca Ceccherini-Silberstein: Speaking and/or consulting fees: Abbvie, Gilead, Janssen, Merck/MSD, ViiV Healthcare. All the other authors: None to declare.
Supporting Information
| Filename | Description |
|---|---|
| liv14797-sup-0001-TableS1-S2.docxWord document, 19 KB | Table S1-S2 |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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