OA22.02
Background: Dapivirine (DPV), a non-nucleoside reverse transcriptase inhibitor, and maraviroc (MVC), a CCR5 antagonist, were formulated into aqueous gels to prevent mucosal HIV transmission. We hypothesize the combination gel will have more potency against HIV infection of mucosal tissue as compared to either single drug gel.
Methods: Dilutions of 0.05% DPV, 0.1% MVC, and 0.05% DPV/0.1% MVC gels were evaluated on polarized ectocervical and colonic mucosal explant cultures exposed to HIV-1BaL. After an overnight culture, the explants were washed and medium replenished in the basolateral compartment. Every 3 to 4 days, supernatant was collected and replenished for up to 21 days. HIV-1 replication was monitored in culture supernatant by p24 ELISA.
Results: Dilutions of the gels for ectocervical tissue began at 1:20 for DPV concentrations of ∼75900 nM and MVC concentrations of ∼97500 nM, while dilutions for colonic tissue began at 1:2000; a 100-fold more dilute than what was used for the ectocervical tissue. For ectocervical tissue, 7590 nM of DPV resulted in complete tissue protection while 97500 nM of MVC was partially protective (6 of 8 explants showed no HIV replication). The combination gel at 7590 nM of DPV/9750 nM of MVC completely protected the tissue, while 759 nM of DPV/975 nM of MVC was partially protective (6 of 8 explants showed no HIV replication). For colonic explants, DPV gel diluted to 759 nM completely protected the tissue, higher dilutions showed no protection. MVC gel diluted to 975 nM showed no substantial protection of the colonic tissue. The combination gel diluted to 759 nM of DPV/975 nM of MVC completely protected the colonic tissue while the 10-fold higher dilution was partially protective (6 of 8 explants showed no HIV replication).
Conclusions: Combining both drugs in a single formulation demonstrated modest synergy. Collectively, these data provide a rationale for further testing of these products as dual compartment microbicides.
