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 ARTexposure) 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 cutoff 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.
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 / Armenia, D.; Spagnuolo, V.; Bellocchi, M. C.; Galli, L.; Duca, L.; Marchegiani, G.; Clemente, T.; Carioti, L.; Lolatto, R.; Calza, L.; Celesia, B. M.; Cascio, A.; Francisci, D.; Saracino, A.; Torti, C.; Zazzi, M.; Castagna, A.; Santoro, M. M.; Castagna, A.; Spagnuolo, V.; Galli, L.; Maggiolo, F.; Calza, L.; Foca, E.; Lagi, F.; Cenderello, G.; Biagio, A. D.; Marchetti, G.; Rusconi, S.; Cervo, A.; Gagliardini, R.; Bonora, S.; Cattelan, A. M.; Galli, A.; Saladini, F.; Armenia, D.; Carini, E.; Bagaglio, S.; Galli, L.; Lolatto, R.; Diotallevi, S.; Tavio, M.; Paggi, A. M.; Vichi, F.; Bellucci, A.; Mirabelli, E.; Saracino, A.; Balena, F.; Maggiolo, F.; Comi, L.; Valenti, D.; Suardi, C.; Calza, L.; Malerba, F.; Castelli, F.; Foca, E.; Minisci, D.; Pennati, F.; Celotti, A.; Brognoli, F.; Menzaghi, B.; Farinazzo, M.; Cacopardo, B.; Celesia, B. M.; Raddusa, M. S. P.; Giarratana, C.; Fusco, P.; Bruno, G.; Pan, A.; Brambilla, P.; Fornabaio, C.; Bartoloni, A.; Giache, S.; Corsi, P.; Kiros, S. T.; Lagi, F.; Ducci, F.; Santantonio, T.; Caputo, S. L.; Ferrara, S.; Narducci, M.; Pontali, E.; Feasi, M.; Sara, A.; Bassetti, M.; Biagio, A. D.; Blanchi, S.; Castagna, A.; Spagnuolo, V.; Carini, E.; Bagaglio, S.; Galli, L.; Lolatto, R.; Galli, A.; Clemente, T.; Borjesson, R. P.; Antinori, S.; Formenti, T.; Giacomelli, A.; Marchetti, G.; Gazzola, L.; Flaviis, F. D.; Puoti, M.; Moioli, C.; D'Amico, F.; Mussini, C.; Cervo, A.; Enrica, R.; Giulia, N.; Beghetto, B.; Manzillo, E.; Lanzardo, A.; Cattelan, A. M.; Mazzitelli, M.; Cascio, A.; Trizzino, M.; Fronti, E.; Laccabue, D.; Gulminetti, R.; Zuccarini, A.; Francisci, D.; Schiaroli, E.; Socio, G. D.; Garlassi, E.; Corsini, R.; Gagliardini, R.; Fusto, M.; Sarmati, L.; Malagnino, V.; Lamonica, S.; Giambenedetto, S. D.; Mulas, T.; Cenderello, G.; Pincino, R.; Tumbarello, M.; Fabbiani, M.; Panza, F.; Rancan, I.; Perri, G. D.; Bonora, S.; Ferrara, M.; Fantino, S.; Malena, M.; Fiscon, M.. - In: JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY. - ISSN 0305-7453. - 79:9(2024), pp. 2354-2363. [10.1093/jac/dkae236]
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
Spagnuolo V.;Clemente T.;Castagna A.;Castagna A.;Spagnuolo V.;Galli A.;Bagaglio S.;Castagna A.;Spagnuolo V.;Bagaglio S.;Galli A.;Clemente T.;Borjesson R. P.;D'Amico F.;Ferrara M.;
2024-01-01
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 ARTexposure) 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 cutoff 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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
