Residual phenotypic susceptibility to doravirine in multidrug-resistant HIV-1 from subjects enrolled in the PRESTIGIO Registry

Francesco Saladini; Federica Giammarino; Franco Maggiolo; Micol Ferrara; Giovanni Cenderello; Benedetto M Celesia; Ferdinando Martellotta; Vincenzo Spagnuolo; Giulio M Corbelli; Nicola Gianotti; Maria M Santoro; Stefano Rusconi; Maurizio Zazzi; Antonella Castagna; PRESTIGIO Study Group

doi:10.1016/j.ijantimicag.2023.106737

Residual phenotypic susceptibility to doravirine in multidrug-resistant HIV-1 from subjects enrolled in the PRESTIGIO Registry

Int J Antimicrob Agents. 2023 Mar;61(3):106737. doi: 10.1016/j.ijantimicag.2023.106737. Epub 2023 Jan 25.

Authors

Affiliations

¹ Department of Medical Biotechnologies, University of Siena, Siena, Italy. Electronic address: saladini6@unisi.it.
² Department of Medical Biotechnologies, University of Siena, Siena, Italy.
³ Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy.
⁴ Unit of Infectious Diseases, Department of Medical Sciences, University of Turin, Turin, Italy.
⁵ Galliera Hospital, Genoa, Italy.
⁶ Garibaldi Hospital, Catania, Italy.
⁷ Centro di riferimento oncologico, Aviano, Italy.
⁸ San Raffaele Scientific Institute, Milan, Italy.
⁹ Plus, Bologna, Italy.
¹⁰ University of Rome Tor Vergata, Rome, Italy.
¹¹ DIBIC Luigi Sacco, University of Milan, Italy.
¹² San Raffaele Scientific Institute, Milan, Italy; San Raffaele Vita-Salute University, Milan, Italy.

PMID: 36708743
DOI: 10.1016/j.ijantimicag.2023.106737

Abstract

Objectives: Doravirine shows a rather distinct resistance profile within the nonnucleoside reverse transcriptase inhibitor (NNRTI) class. This study aimed to evaluate the phenotypic susceptibility to doravirine, rilpivirine and etravirine in a panel of multidrug-resistant (MDR) HIV-1 isolates collected from people living with HIV (PLWH) enrolled in the PRESTIGIO Registry.

Methods: Recombinant viruses expressing PLWH-derived protease, reverse transcriptase coding regions were generated from plasma samples at virological failure with documented resistance to protease inhibitors, nucleoside reverse transcriptase inhibitors, NNRTIs and integrase strand transfer inhibitors. In vitro susceptibility was assessed through a phenotypic assay measuring fold-change values with respect to the reference NL4-3 virus. Genotypic susceptibility was computed by the Stanford HIVdb algorithm 8.9-1.

Results: Plasma samples were collected from 22 PLWH: 20 (91%) were male, median age 55 years (IQR 50-58), time since HIV-1 diagnosis 27 years (23-31) and time on antiretroviral treatment 23 years (22-26). Median doravirine, etravirine and rilpivirine fold-change values were 9.8 (2.9-40.4), 42.9 (3.1-100.0) and 100.0 (17.9-100.0), respectively. According to the fold-change cut-offs, full susceptibility was observed in five (23%), four (18%) and one (5%) cases with doravirine, etravirine and rilpivirine, respectively. Irrespective of the presence of specific doravirine mutations, higher numbers of NNRTI mutations correlated with higher fold-change values for doravirine. By comparing the distribution of fold-change values with the Stanford HIVdb predicted susceptibility, a significant correlation was detected for doravirine and rilpivirine but not etravirine.

Conclusion: Despite extensive cross-resistance among NNRTIs, doravirine can be a valid option in a proportion of PLWH with MDR HIV-1. Doravirine activity appeared to be inferred with fair accuracy by the HIVdb algorithm.

Keywords: Doravirine; Etravirine; HIV-1; In vitro susceptibility; Multidrug resistance; Rilpivirine.

MeSH terms

Anti-HIV Agents* / pharmacology
Anti-HIV Agents* / therapeutic use
Drug Resistance, Viral / genetics
Female
HIV Infections* / drug therapy
HIV-1*
Humans
Male
Middle Aged
Mutation
Reverse Transcriptase Inhibitors / pharmacology
Reverse Transcriptase Inhibitors / therapeutic use
Rilpivirine / therapeutic use

Substances

Anti-HIV Agents
doravirine
Reverse Transcriptase Inhibitors
Rilpivirine
etravirine