Fostemsavir (FTR) is a prodrug of the investigational HIV-1 attachment inhibitor temsavir (TMR) currently under evaluation for the treatment of highly experienced patients with limited treatment options. This study aims to characterize the genotypic profile and the phenotypic susceptibility to TMR in a panel of samples collected from patients harboring multi resistant HIV-1 enrolled in the Italian PRESTIGIO cohort and potentially candidate for FTR treatment.
Plasma samples from 24 patients included in the PRESTIGIO cohort were used for the sequencing of gp120 region, while viral tropism and susceptibility to TMR were assessed through a home-made phenotypic assay involving pseudotyped viruses expressing patient derived Env protein. Patient demographics and laboratory data are described as median (Q1-Q3), mean (±SD) or frequency (%).
Among 24 patients, 18 (75%) were male, median age 54 years (52-59), time since HIV-1 diagnosis 26 years (24-29), time on ART 25 years (22-26), 11 (46%) with a previous AIDS diagnosis, a median viral load at first sample collection of 3.87 log10 copies/mL (3.1-5.0) and a median CD4+ cell count of 242 cells/µl (137-387). At the time of sample collection, 12 (50%) were receiving entry inhibitors (MVC and/or T-20). Among 21/24 (88%) gp120 sequences obtained, all belonged to subtype B and TMR RAMs (L116P, A204D, S375M/H/N, M426L, M434I, M475I) were detected in only 3 cases (13%), two 426L and one 375N. Viral tropism was X4, R5, and dual-mixed (DM) in 8, 9 and 7 out of 24 cases, respectively. Pseudotyped viruses were obtained from 23/24 samples and median IC50 to TMR was 0.5 nM (0.3-1.2). The reference wild-type viruses NL4-3 (X4), AD8 (R5) had mean IC50 of 1.1±0.6 nM and 1.3±0.7 nM, respectively, while the two samples harboring RAM 426L (both X4-tropic) had mean IC50 of 6.9±2.9 nM and 1110.6±798.2 nM, resulting in FC values of 6.2 and 1009, respectively. According to viral tropism, median IC50 values were 1.2 nM (0.4-4.2), 0.4 nM (0.3-1.2) and 0.6 nM (0.3-0.8) for X4, R5 and DM viruses, respectively. Concomitant use of MVC or T-20 also did not impact TMR IC50 values.
In this study, TMR RAMs were detected in 3/21 samples and the polymorphic RAM M426L was associated with variable reduction of TMR susceptibility. Except for viruses harboring M426L, the susceptibility to TMR was comparable to wild-type strains in all the samples, irrespective of coreceptor usage or exposure to other entry inhibitors.