Virological outcomes, resistance profile and viral evolution of lenacapavir-based regimens in heavily treatment-experienced people: data from the PRESTIGIO Registry.
11 affiliations
- 1Department of Experimental Medicine, University of Rome 'Tor Vergata', Via Montpellier 1, Rome 00133, Italy.
- 2Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy.
- 3Department of Medical Biotechnologies, University of Siena, Siena, Italy.
- 4Infectious Disease Clinic, University of Modena and Reggio Emilia, AOU Policlinico di Modena, Modena, Italy.
- 5Infectious Diseases Unit, San Martino Hospital Genoa, University of Genoa, Genoa, Italy.
- 6Infectious Diseases Unit, Azienda Scaligera di Verona, Verona, Italy.
- 7Department of Clinical and Experimental Sciences, University of Brescia-ASST Spedali Civili, Brescia, Italy.
- 8Clinical and Research Infectious Diseases Department, National Institute for Infectious Diseases Lazzaro Spallanzani IRCCS, Rome, Italy.
- 9S.C. Malattie Infettive, ASST Ovest Milanese, Legnano General Hospital, Legnano, Italy.
- 10Department of Biomedical and Clinical Sciences, Università Degli Studi di Milano, Milan, Italy.
- 11Infectious Diseases Unit, Vita-Salute San Raffaele University, Milan, Italy.
Abstract
Background
Lenacapavir (LEN) is a first-in-class, long-acting HIV-1 capsid inhibitor, approved for the treatment of heavily treatment-experienced (HTE) people with HIV (PWH) with multidrug resistance (MDR). To date, few data are available on resistance profiles in real life.Methods
Paired plasma and PBMC samples from nine HTE PWH with MDR enrolled in the PRESTIGIO Registry receiving LEN in combination with an optimized background regimen were collected before (baseline) and during LEN treatment. Next-generation sequencing was performed using in-house protocols. LEN susceptibility was assessed by single-cycle assay. Intra-patient viral evolution was evaluated through quasispecies distance analysis.Results
At baseline, no major LEN resistance-associated mutations were detected; the accessory capsid polymorphism T107A was identified as a minority variant (5.9%) in one case, with phenotypic assays confirming full LEN susceptibility (mean fold-change: 1.2). Participants received LEN for a median [IQR] of 19.8 [18.5-23.2] months. Two individuals started LEN with undetectable viremia and maintained suppression. The other seven participants were viremic; six achieved viral suppression, with one experiencing a blip. One low-adherent participant exhibited persistent viremia with Q67K and K70H as the majority variants in both plasma (98.5%; 97.8%) and PBMCs (75.7%; 75.6%), conferring a 2081-fold reduction in LEN susceptibility. Intra-host variability in the capsid and pol regions remained low over time and across compartments.Conclusions
In this case series of HTE PWH with MDR, LEN was highly associated with maintenance or achievement of virological suppression and limited virus evolution, with only one participant remaining viremic and showing a majority highly LEN-resistant variant.
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BibTeX
@article{santoro2026virological,
title = {{Virological outcomes, resistance profile and viral evolution of lenacapavir-based regimens in heavily treatment-experienced people: data from the PRESTIGIO Registry.}},
author = {Maria Mercedes Santoro and Daniele Spalletta and Vincenzo Spagnuolo and Chiara Paletti and Greta Marchegiani and Maria Concetta Bellocchi and Riccardo Lolatto and Luca Carioti and Adriana Cervo and Antonio Di Biagio and Marta Fiscon and Emanuele Focà and Roberta Gagliardini and Stefano Rusconi and Maurizio Zazzi and Antonella Castagna and Francesco Saladini and Francesca Ceccherini-Silberstein and PRESTIGIO Registry and the},
journal = {The Journal of antimicrobial chemotherapy},
year = {2026},
month = oct,
doi = {10.1093/jac/dkag335},
url = {https://europepmc.org/article/MED/42948967},
note = {CC BY},
}
RIS
TY - JOUR
TI - Virological outcomes, resistance profile and viral evolution of lenacapavir-based regimens in heavily treatment-experienced people: data from the PRESTIGIO Registry.
AU - Maria Mercedes Santoro
AU - Daniele Spalletta
AU - Vincenzo Spagnuolo
AU - Chiara Paletti
AU - Greta Marchegiani
AU - Maria Concetta Bellocchi
AU - Riccardo Lolatto
AU - Luca Carioti
AU - Adriana Cervo
AU - Antonio Di Biagio
AU - Marta Fiscon
AU - Emanuele Focà
AU - Roberta Gagliardini
AU - Stefano Rusconi
AU - Maurizio Zazzi
AU - Antonella Castagna
AU - Francesco Saladini
AU - Francesca Ceccherini-Silberstein
AU - PRESTIGIO Registry
AU - the
PY - 2026
DA - 2026/10/01
JO - The Journal of antimicrobial chemotherapy
DO - 10.1093/jac/dkag335
UR - https://europepmc.org/article/MED/42948967
AB - Background Lenacapavir (LEN) is a first-in-class, long-acting HIV-1 capsid inhibitor, approved for the treatment of heavily treatment-experienced (HTE) people with HIV (PWH) with multidrug resistance (MDR). To date, few data are available on resistance profiles in real life.Methods Paired plasma and PBMC samples from nine HTE PWH with MDR enrolled in the PRESTIGIO Registry receiving LEN in combination with an optimized background regimen were collected before (baseline) and during LEN treatment. Next-generation sequencing was performed using in-house protocols. LEN susceptibility was assessed by single-cycle assay. Intra-patient viral evolution was evaluated through quasispecies distance analysis.Results At baseline, no major LEN resistance-associated mutations were detected; the accessory capsid polymorphism T107A was identified as a minority variant (5.9%) in one case, with phenotypic assays confirming full LEN susceptibility (mean fold-change: 1.2). Participants received LEN for a median [IQR] of 19.8 [18.5-23.2] months. Two individuals started LEN with undetectable viremia and maintained suppression. The other seven participants were viremic; six achieved viral suppression, with one experiencing a blip. One low-adherent participant exhibited persistent viremia with Q67K and K70H as the majority variants in both plasma (98.5%; 97.8%) and PBMCs (75.7%; 75.6%), conferring a 2081-fold reduction in LEN susceptibility. Intra-host variability in the capsid and pol regions remained low over time and across compartments.Conclusions In this case series of HTE PWH with MDR, LEN was highly associated with maintenance or achievement of virological suppression and limited virus evolution, with only one participant remaining viremic and showing a majority highly LEN-resistant variant.
SN - 0305-7453
SN - 1460-2091
ER -