P15.26 LB
Background: In the absence of a vaccine against HIV infection topically applied pre-exposure prophylaxis with microbicides represents one of the promising options for protection in women who have no choice in their partners' use of condoms. When delivered at the point of entry microbicides work to deliver localised concentrations of drugs that have the potential to block the earliest stages of infection and prevent transmission. The effectiveness of microbicides as a preventative strategy has been demonstrated in humans and non-human primates. The use of formulated combinations of antiretroviral drugs as microbicides has been promoted as a means to check viral escape and provide broad protection. Moreover it has been suggested that a number of antiretroviral drugs may be capable of interacting with cellular mechanisms that serve to boost drug activity at mucosal sites.
Methods: As part of an EU funded project we investigated the possibility of developing optimized microbicide formulations for vaginal and rectal delivery. We examined the advantages of double and triple combination approaches to the inhibition of virus entry and transmission in cells derived from human cervical tissue explants, peripheral blood mononuclear cells and dendritic cells.
Results: In the models tested we obtained evidence supporting the use of two reverse transcriptase inhibitors (Tenofovir and TMC-120) and a protease inhibitor (Darunavir) in combination to inhibit infection and transmission of HIV-1. This effect was demonstrated in a fold reduction in the IC50 values of the drugs in combination when compared with single drugs. We then showed the effect of the drugs on the ATP activity of the membrane bound cellular transporter p-glycoprotein.
Conclusions: Our results highlight the potential to boost intracellular concentrations and the antiviral effect of the drugs by modulating the activity of cell transporter molecules. Subsequent experiments will seek to examine this outcome in human cellular and mucosal tissue explant models.
