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
  • 1. Department of Medical Biotechnologies, University of Siena, Siena, Italy. Electronic address: [email protected].
  • 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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