Viral Drug Resistance Through 48 Weeks, in a Phase 2b, Randomized, Controlled Trial of the HIV-1 Attachment Inhibitor Prodrug, Fostemsavir

Abstract

Background: Fostemsavir is a prodrug of temsavir, an attachment inhibitor that binds to HIV-1 gp120, blocking viral attachment to host CD4 T-cells. The phase 2b trial AI438011 investigated the safety, efficacy, and dose-response of fostemsavir vs ritonavir-boosted atazanavir (ATV/r) in treatment-experienced, HIV-1-infected subjects.

Methods: Two hundred fifty-one treatment-experienced subjects with baseline (BL) susceptibility to study drugs [temsavir half-maximal inhibitory concentration (IC50) <100 nM, PhenoSense Entry assay] received fostemsavir or ATV/r, each with tenofovir disoproxil fumarate + raltegravir. Subjects meeting resistance-testing criteria were assessed for emergent viral drug resistance. Changes in temsavir IC50 from BL was given a conservative technical cutoff (>3-fold increase).

Results: 66/200 fostemsavir and 14/51 ATV/r subjects had resistance testing performed; 44/66 and 9/14 were successfully tested using the PhenoSense GT assay. No subjects had emergent tenofovir disoproxil fumarate or ATV resistance. Six fostemsavir-treated subjects developed emergent raltegravir resistance. 29/66 fostemsavir-treated subjects had an evaluable phenotype using PhenoSense Entry (which tests for viral susceptibility to temsavir) and 13/29 exhibited >3-fold increase in temsavir IC50 from BL. gp120 population sequencing was successful in 11/13 subjects and 7 had emergent substitutions in gp120 associated with reduced temsavir susceptibility (S375, M426, or M434). However, 5/13 fostemsavir-treated subjects achieved subsequent suppression to <50 copies/mL before the week 48 database lock, regardless of key gp120 substitutions.

Conclusions: Response rates remained similar across study arms regardless of BL nucleoside reverse transcriptase inhibitor, nonnucleoside reverse transcriptase inhibitor, and protease inhibitor resistance-associated mutations. Emergent changes in viral susceptibility occurred more frequently with fostemsavir compared with ATV/r. However, the full impact of temsavir IC50 changes and emergent HIV-1 gp120 substitutions, and thus appropriate clinical cutoffs, requires further study. Fostemsavir is being evaluated in a phase 3 trial in heavily treatment-experienced subjects.

FIGURE 1.

Association of BL substitutions in HIV-1 gp120 at positions S375, M434, M426, and M475, with the number of subjects undergoing resistance testing through week 48 (N = 179). (Left) Susceptibility to temsavir was grouped by BL sequence into subjects without polymorphisms in any of the 4 targeted amino acids (None), subjects with a polymorphism in 1 or more of the 4 targeted amino acids that results in an FC > 3 (includes 4 subjects with 2 polymorphisms; Any FC > 3) and subjects with a polymorphism in 1 of the 4 targeted amino acids that results in a FC < 3; (Any FC ≤ 3). The blue line signifies the number of subjects who met criteria for resistance testing and the orange line signifies the number of subjects who did not meet criteria for resistance testing. Actual numbers with percentages of subjects meeting criteria for resistance testing in each group are shown to the right. Only subjects who had virus with a determinable genotype at gp120 positions 375, 426, 434, and 475 were included in the analysis. (Right) The Any FC > 3 cohort was broken out by individual polymorphisms and blue and orange lines were as before. This analysis includes 17 subjects who had virus with multiple polymorphisms. Ranges of observed temsavir susceptibility in each cohort are noted in both figures.