Use of next-generation sequencing on HIV-1 DNA to assess archived resistance in highly treatment-experienced people with multidrug-resistant HIV under virological control: data from the PRESTIGIO Registry
Author:
Armenia Daniele1, Spagnuolo Vincenzo2ORCID, Bellocchi Maria C3, Galli Laura2, Duca Leonardo3, Marchegiani Greta3, Clemente Tommaso24ORCID, Carioti Luca3, Lolatto Riccardo2, Calza Leonardo5, Celesia Benedetto M6, Cascio Antonio7, Francisci Daniela8, Saracino Annalisa9, Torti Carlo1011, Zazzi Maurizio12, Castagna Antonella24, Santoro Maria M3ORCID, , Castagna Antonella, Spagnuolo Vincenzo, Galli Laura, Maggiolo Franco, Calza Leonardo, Focà Emanuele, Lagi Filippo, Cenderello Giovanni, Di Biagio Antonio, Marchetti Giulia, Rusconi Stefano, Cervo Adriana, Gagliardini Roberta, Bonora Stefano, Cattelan Anna Maria, Zazzi Maurizio, Santoro Maria Mercedes, Zazzi Maurizio, Santoro Maria Mercedes, Galli Andrea, Saladini Francesco, Armenia Daniele, Carini Elisabetta, Bagaglio Sabrina, Galli Laura, Lolatto Riccardo, Diotallevi Sara, Tavio Marcello, Paggi Alessandra Mataloni, Vichi Francesca, Bellucci Alessio, Mirabelli Elisa, Saracino Annalisa, Balena Flavia, Maggiolo Franco, Comi Laura, Valenti Daniela, Suardi Claudia, Calza Leonardo, Malerba Federica, Castelli Francesco, Focà Emanuele, Minisci Davide, Pennati Francesca, Celotti Anna, Brognoli Francesca, Menzaghi Barbara, Farinazzo Maddalena, Cacopardo Bruno, Celesia Benedetto Maurizio, Raddusa Michele Salvatore Paternò, Giarratana Carmen, Torti Carlo, Fusco Paolo, Bruno Gabriele, Pan Angelo, Brambilla Paola, Fornabaio Chiara, Bartoloni Alessandro, Giachè Susanna, Corsi Paola, Kiros Seble Tekle, Lagi Filippo, Ducci Filippo, Santantonio Teresa, Caputo Sergio Lo, Ferrara Sergio, Narducci Marianna, Pontali Emanuele, Feasi Marcello, Sarà Antonio, Bassetti Matteo, Di Biagio Antonio, Blanchi Sabrina, Castagna Antonella, Spagnuolo Vincenzo, Carini Elisabetta, Bagaglio Sabrina, Galli Laura, Lolatto Riccardo, Galli Andrea, Clemente Tommaso, Borjesson Rebecka Papaioannu, Diotallevi Sara, Antinori Spinello, Formenti Tiziana, Giacomelli Andrea, Marchetti Giulia, Gazzola Lidia, De Flaviis Federica, Puoti Massimo, Moioli Cristina, D’Amico Federico, Mussini Cristina, Cervo Adriana, Enrica Roncaglia, Giulia Nardini, Beghetto Barbara, Manzillo Elio, Lanzardo Amedeo, Cattelan Anna Maria, Mazzitelli Maria, Cascio Antonio, Trizzino Marcello, Fronti Elisa, Laccabue Diletta, Gulminetti Roberto, Zuccarini Andrea, Francisci Daniela, Schiaroli Elisabetta, De Socio Giuseppe, Garlassi Elisa, Corsini Romina, Gagliardini Roberta, Fusto Marisa, Sarmati Loredana, Malagnino Vincenzo, Lamonica Silvia, Di Giambenedetto Simona, Mulas Tiziana, Cenderello Giovanni, Pincino Rachele, Tumbarello Mario, Fabbiani Massimiliano, Panza Francesca, Rancan Ilaria, Di Perri Giovanni, Bonora Stefano, Ferrara Micol, Fantino Silvia, Malena Marina, Fiscon Marta
Affiliation:
1. Departmental Faculty, Saint Camillus International University of Health Sciences , Rome , Italy 2. Clinic of Infectious Diseases, Istituto Scientifico San Raffaele , Milan , Italy 3. Department of Experimental Medicine, University of Rome ‘Tor Vergata’ , Rome , Italy 4. Faculty of Medicine and Surgery, Vita-Salute San Raffaele University , Milan , Italy 5. Department of Medical and Surgical Sciences, Unit of Infectious Diseases, Policlinico Sant’Orsola-Malpighi , Bologna , Italy 6. Unit of Infectious Diseases, Garibaldi Hospital , Catania , Italy 7. Infectious and Tropical Diseases Unit—Department of Health Promotion, Maternal and Infant Care, Internal Medicine and Medical Specialties, University of Palermo , Palermo , Italy 8. Clinic of Infectious Diseases, Department of Medicine and Surgery, University of Perugia , Perugia , Italy 9. Clinic of Infectious Diseases, University of Bari , Bari , Italy 10. Dipartimento di Scienze di Mediche e Chirurgiche, Fondazione Policlinico Universitario "A. Gemelli" IRCCS , Rome , Italy 11. Dipartimento di Sicurezza e Bioetica, Università Cattolica del Sacro Cuore , Rome , Italy 12. Department of Medical Biotechnologies, University of Siena , Siena , Italy
Abstract
Abstract
Background
To clarify whether next-generation sequencing (NGS) can be useful for resistance assessment in virologically suppressed highly treatment-experienced (HTE) individuals with MDR HIV.
Methods
Ninety-one participants from the PRESTIGIO Registry were included. NGS was performed on HIV-DNA at 1%, 5% and 20% cut-offs; major drug resistance mutations (DRMs) were evaluated and compared with those detected in historical plasma genotypic resistance testing (h-GRT). APOBEC editing was also characterized.
Results
Participants had a complex and long treatment history [median 23 (IQR 21–25) years of ART exposure) and had been virologically suppressed since a median of 3 (IQR 2–5) years. Among all major DRMs detected by HIV-DNA NGS and/or h-GRT, 30% were exclusively found through NGS. The highest detection rate of historical major DRMs was reached with NGS set at 1%, but unusual substitutions and extensive APOBEC hypermutations suggest technical issues and poor clinical relevance in the 1%–5% interval. At NGS set at 5%, 67.2% of historical major DRMs were detected. The number of major DRMs detected exclusively by DNA-NGS as minority variants (frequency 5%–20%) was significantly higher in individuals who later experienced virological rebound compared with those who maintained virological control [median 2 (IQR 1–3) versus 1 (0–2), P = 0.030] and positively correlated with viraemia levels at rebound (rho = 0.474, P = 0.030).
Conclusions
In non-viraemic people with an MDR virus, HIV-1 DNA NGS set at 5% is an acceptable technical cut-off that might help to reveal mutations with a potential clinical relevance. Moreover, the number of minority resistance mutations additionally detected by NGS might be associated with loss of virological control.
Funder
Gilead Sciences ViiV Healthcare Theratechnologies Merck Sharp & Dohme
Publisher
Oxford University Press (OUP)
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