Genotypic Profile and Phenotypic Susceptibility to Temsavir in Multidrug Resistant HIV

Fostemsavir, a prodrug of the investigational attachment inhibitor temsavir, is currently under evaluation for treatment-experienced patients with limited treatment options.

In a new study, investigators set out to characterize the genotypic profile and the phenotypic susceptibility to temsavir in samples collected from patients with documented multidrug-resistant HIV-1 who could be candidate for fostemsavir treatment and were enrolled in the Italian PRESTIGIO cohort study.

The findings of the study were presented in a poster presentation session at the Annual Conference on Retroviruses and Opportunistic Infections (CROI 2019) on Wednesday, March 6, 2019.

The investigators sequenced the gp120 region of plasma samples from patients included in the PRESTIGIO cohort, and viral tropism and susceptibility to temsavir were assessed through a “home-made phenotypic assay involving pseudotyped viruses expressing patient derived Env protein.”

Among the 24 patients included in the cohort, 18 participants (75%) were male and the median age was 54 years (range: 52-59). Additionally, the median time since HIV diagnosis was 26 years (range: 24-29), the median time on ART was 25 years (range: 22-26), and 11 participants (46%) had received a previous AIDS diagnosis. The median viral load at first sample collection was 3.87 log10 copies/mL (3.1-5.0) and a median CD4+ cell count of 242 cells/µl (137-387) was documented. At the point of sample collection, 12 participants (50%) were receiving entry inhibitors (MVC and/or T-20).

The investigators note that among 21 of the 24 participants (88%), gp120 sequences belonged to subtype B and temsavir resistance-associated mutations (L116P, A204D, S375M/H/N, M426L, M434I, M475I) were detected in only 3 cases (13%), 2 of which were 426L and 1 of 375N.

Viral tropism was X4 in 8 cases, R5 in 9 cases, and dual-mixed (DM) in 7 cases. Pseudotyped viruses were obtained from 23 of the 24 samples and median IC50 to temsavir 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 [resistance-associated mutations] 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,” write the investigators, also noting that concomitant use of the entry inhibitors did not impact temsavir IC50 values.

Overall, in the study, temsavir resistance-associated mutations were detected in 3 of the 21 samples and the polymorphic resistance-associated mutations M426L was associated with variable reduction of temsavir susceptibility.

“Excluding the viruses harboring M426L, the susceptibility to temsavir was comparable to wild-type strains in all the samples, irrespective of coreceptor usage or exposure to other entry inhibitors,” the investigators conclude.

The study, “Genotypic and Phenotypic Susceptibility to Fostemsavir in Multidrug-Resistant HIV-1,” was presented at CROI 2019 on Wednesday, March 6, 2019 in Seattle, Washington.