2. Academic Validation
  3. Residual phenotypic susceptibility to doravirine in multidrug resistant HIV-1 from subjects enrolled in the PRESTIGIO Registry

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

  • Int J Antimicrob Agents. 2023 Jan 25;106737. doi: 10.1016/j.ijantimicag.2023.106737.
Francesco Saladini 1,  Federica Giammarino 2,  Franco Maggiolo 3,  Micol Ferrara 4,  Giovanni Cenderello 5,  Benedetto M Celesia 6,  Ferdinando Martellotta 7,  Vincenzo Spagnuolo 8,  Giulio M Corbelli 9,  Nicola Gianotti 8,  Maria M Santoro 10,  Stefano Rusconi 11,  Maurizio Zazzi 2,  Antonella Castagna 12,  PRESTIGIO STUDY GROUP
Affiliations

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

Background: Doravirine shows a rather distinct resistance profile within the 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 region were generated from plasma samples at virological failure with documented resistance to PIs, NRTIs, NNRTIs and INSTIs. 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, twenty (91%) were male, median age 55 years (IQR 50-58), time since HIV-1 diagnosis 27 years (23-31), time on ART 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 5 (23%), 4 (18%) and 1 (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 HIVdb algorithm.

Keywords

HIV-1; doravirine; etravirine; in vitro susceptibility; multi-drug resistance; rilpivirine.

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