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. 2025 Jul:239:106157.
doi: 10.1016/j.antiviral.2025.106157. Epub 2025 Apr 18.

Combined doravirine and islatravir cooperate to inhibit NRTI and NNRTI resistant HIV-1 in vitro

Federica Giammarino  1 , Chiara Paletti  2 , Niccolò Bartolini  2 , Lia Fiaschi  2 , Camilla Biba  2 , Ilenia Varasi  2 , Emanuele Focà  3 , Roberto Gulminetti  4 , Micol Ferrara  5 , Laura Comi  6 , Ilaria Vicenti  2 , Antonella Castagna  7 , Maurizio Zazzi  2 , Francesco Saladini  8 ; PRESTIGIO Study Group
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Combined doravirine and islatravir cooperate to inhibit NRTI and NNRTI resistant HIV-1 in vitro

Federica Giammarino et al. Antiviral Res. 2025 Jul.

Abstract

Doravirine and islatravir have shown promising activity against multidrug resistant HIV-1. In this study we aimed to evaluate the in vitro susceptibility to doravirine and islatravir as well as their combinatorial activity in a panel of 38 recombinant viruses harboring multiple NRTI and NNRTI mutations. One additional recombinant virus had the M184V mutation alone. According to the IC50 fold-change (FC) values calculated with respect to the NL4-3 wild-type strain, full susceptibility to doravirine was detected in 15/39 (38.5 %) samples, while high-level resistance was mainly associated with specific doravirine resistance mutations. Decreased susceptibility to islatravir was associated with the presence of the M184V/I mutation and increasing numbers of TAMs and NRTI resistance mutations. According to ZIP model of the SynergyFinder Plus tool, the combination of doravirine and islatravir showed additive activity in 37/40 (92.5 %) viruses (including the NL4-3 strain), while synergy and antagonism in one and two cases, respectively. The combination sensitivity score calculated by SynergyFinder Plus indicated a cooperative effect between doravirine and islatravir higher than that observed for the reference NL4-3 strain in 22 (56 %) recombinant viruses. The Multi-dimensional Synergy of Combinations (MuSyC) tool predicted synergy and antagonism in 25 (62.5 %, including NL4-3 virus) and 15 (37.5 %) cases, respectively. MuSyC scores showed a negative correlation with doravirine FC values, number of NRTI mutations and presence of M184V/I, but not with islatravir FC values. Doravirine and islatravir may cooperatively inhibit NRTI and NNRTI resistant viruses despite complex mutational profiles, however the accumulation of resistance mutations may reduce the combinatorial activity.

Keywords: Combinatorial activity; Doravirine; HIV-1; Islatravir; Multidrug resistance.

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Conflict of interest statement

Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Francesco Saladini received speaker's honoraria from ViiV Healthcare. Emanuele Focà received speakers' honoraria, research grants and payments for advisory board from Gilead Sciences, MSD, Viiv Healthcare and Astrazeneca. Laura Comi received speaker's honoraria from ViiV Healthcare and Gilead Sciences and payments for advisory board from MSD. Antonella Castagna received personal fees for advisory boards, speaker panels and educational materials from Gilead Sciences, ViiV Healthcare, Janssen-Cilag, MSD and Theratechnlogies. Maurizio Zazzi received grants for his institution from MSD and personal fees from MSD, ViiV Healthcare and Gilead Sciences. All other authors have no conflicts of interest to declare.

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