Characterization of UC781-Tenofovir Combination Gel Products for HIV-1 Infection Prevention in an Ex Vivo Ectocervical Model

Abstract

dHIV continues to be a problem worldwide. Topical vaginal microbicides represent one option being evaluated to stop the spread of HIV. With drug candidates that have a specific action against HIV now being studied, it is important that, when appropriate and based on the mechanism of action, the drug permeates the tissue so that it can be delivered to specific targets which reside there. Novel formulations of the nucleotide reverse transcriptase inhibitor tenofovir (TFV) and the nonnucleoside reverse transcriptase inhibitor UC781 have been developed and evaluated here. Gels with three distinct rheological properties were prepared. The three gels released both UC781 and TFV under in vitro conditions at concentrations equal to or above the reported 50% effective concentrations (EC 50 s). The drug concentrations in ectocervical tissues were well in excess of the reported EC 50 s. The gels maintain ectocervical viability and prevent infection of ectocervical explants after a HIV-1 challenge. This study successfully demonstrates the feasibility of using this novel combination of antiretroviral agents in an aqueous gel as an HIV infection preventative.

Pharmacology of Antiretrovirals in the Female Genital Tract for HIV Prevention

“…Because this approach typically uses surgical discard or cadaver tissue rather than biopsies, the amount of tissue is typically not a limiting factor, which allows the examination of several doses from the same donor, lending itself to the possibility for dose‐response curves and establishment of IC50s. The explant model has shown several PrEP candidates have preventive capacity in female genital tract including tenofovir, dapivirine, rilpivirine, and maraviroc as protective in blocking HIV infection in female genital tract …”

On-demand microbicide products: design matters

“…The delivery of more than one active molecule may further increase the complexity of the product development, especially those drugs that display different physicochemical properties. Previously, the combination of water-soluble TFV and hydrophobic UC 781 has been reported as a gel formulation [70]. Similarly, TFV and DPV were incorporated efficiently in a film formulation [73].…”

“…Dosing amount and restrictions on dosage size could be a limitation for film dosage forms. A wide array of physicochemically diverse ARV drugs have been incorporated into films namely TFV [73, 70], DPV [17, 73, 108], EfdA [109], efavirenz [110], RC-101 [77], VRC01 anti-HIV mAb [111], and si-RNA and nanoparticles [112]. …”

HIV pre-exposure prophylaxis trials: the road to success

“…One additional tool that may assist in bridging the findings from animal models into human studies is the human tissue explant model. In this model, human mucosal tissue from rectal or genital tract compartments is collected and maintained in an ex-vivo culture system [52–54]. This model allows for mucosal tissue biopsies to be removed from antiretroviral-dosed healthy volunteers and infected with a laboratory strain of HIV ex-vivo to determine whether clinically relevant drug exposure prevents HIV infection.…”