OA22.01
Background: Our previous studies demonstrate the protective concentration of tenofovir diphosphate (TFVdp) in vaginal explants is >10-fold higher than in TZM-bl cells. Here we investigate maraviroc's (MVC) efficacy in cells and vaginal explants, and determine the explant's prediction potential of a dose-challenge study from biopsies of volunteers given an oral dose of MVC+tenofovir disoproxil fumurate (TDF).
Methods: TZM-bl cells (n=3) and vaginal explants (n=5 donors) were incubated 24h in MVC 0.01-500ug/mL prior to challenge with HIV-1 JR-CSF. Combination MVC+tenofovir (TFV) was also used in cells to define the effects of drugs combined. Compared to undosed controls, efficacy was assessed using a luciferase reporter assay in cells, and spliced RNA 24-72h post-inoculation in explants. A dose-challenge study was performed in 6 HIV-, pre-menopausal women administered a single 600mg MVC+600mg TDF dose. 24h post-dose, 4 vaginal+cervical biopsies were collected for viral challenge and evaluated for infection in the same manner as explant tissue. HIV protection was defined as spliced RNA within one standard deviation of background.
Results: In vaginal explants, MVC protective efficacy waned after 24h. Within 24h, MVC EC50 was 9.7ug/mL, which was >1000-fold higher than the EC50 in TZM-bl cells (0.006 ug/mL). Additivity of MVC+TFV was confirmed for HIV protection. The TZM-bl model and the explant model predicted 100% and 16% efficacy, respectively, 24h after a 600mg MVC+TDF dose. In the healthy volunteers, protection was observed in 50% (3/6) of vaginal biposies and 67% (4/6) of cervical biopsies, with 50% (3/6) of women having complete protection against HIV challenge.
Conclusions: Similar to TFVdp, cell models overestimated the efficacy of MVC in vaginal explants. Data from TZM-bl cell monolayers over predicted, and tissue explants under predicted, efficacy in a healthy volunteer dose-challenge study. Tissue concentrations at 24h after single high-dose of MVC+TDF were moderately protective against HIV infection.
