A Pilot Study Measuring the Distribution and Permeability of a Vaginal HIV Microbicide Gel Vehicle Using Magnetic Resonance Imaging, Single Photon Emission Computed Tomography/Computed Tomography, and a Radiolabeled Small Molecule

Abstract

Vaginal microbicide gels containing tenofovir have proven effective in HIV prevention, offering the advantage of reduced systemic toxicity. We studied the vaginal distribution and effect on mucosal permeability of a gel vehicle. Six premenopausal women were enrolled. In Phase 1, a spreading gel containing (99m)technetium-DTPA ((99m)Tc) radiolabel and gadolinium contrast for magnetic resonance imaging (MRI) was dosed intravaginally. MRI was obtained at 0.5, 4, and 24 h, and single photon emission computed tomography with conventional computed tomography (SPECT/CT) at 1.5, 5, and 25 h postdosing. Pads and tissues were measured for activity to determine gel loss. In Phase 2, nonoxynol-9 (N-9), containing (99m)Tc-DTPA, was dosed as a permeability control; permeability was measured in blood and urine for both phases. SPECT/CT showed the distribution of spreading gel throughout the vagina with the highest concentration of radiosignal in the fornices and ectocervix; signal intensity diminished over 25 h. MRI showed the greatest signal accumulation in the fornices, most notably 1-4 h postdosing. The median (interquartile range) isotope signal loss from the vagina through 6 h was 29.1% (15.8-39.9%). Mucosal permeability to (99m)Tc-DTPA following spreading gel was negligible, in contrast to N-9, with detectable radiosignal in plasma, peaking at 8 h (5-12). Following spreading gel dosing, 0.004% (0.001-2.04%) of the radiosignal accumulated in urine over 12 h compared to 8.31% (7.07-11.01%) with N-9, (p=0.043). Spreading gel distributed variably throughout the vagina, persisting for 24 h, with signal concentrating in the fornices and ectocervix. The spreading gel had no significant effect on vaginal mucosal permeability.

Hormonal Contraceptives Differentially Suppress TFV and TAF Inhibition of HIV Infection and TFV-DP in Blood and Genital Tract CD4+ T cells

“…Also of relevance is the recent study that bacterial vaginosis-associated bacteria can affect TFV levels and HIV transmission risk 16 . While topical ARV administration offers advantages of higher vaginal drug concentrations and lower systemic toxicity, it is unclear whether protective concentrations of ARVs can be reached in the entire FRT after local ARV administration 17 – 19 . Protection of the entire FRT along with regional lymph nodes is necessary, given the evidence that HIV-target cells are present throughout the FRT 15 , 20 – 23 and studies in non-human primate models showing that infection can occur in all the major anatomical regions of the FRT 21 , 22 .…”

Feasibility of radiolabeled small molecule permeability as a quantitative measure of microbicide candidate toxicity

“…In a separate study of cervicovaginal permeability, we did not use urinary catheters and we still detected a similar magnitude of alteration in mucosal permeability with 4% N-9 which was statistically different from a placebo gel. [18] Therefore, use of the Foley catheter does not appear to be necessary to detect large magnitude changes.…”

Brief Report: Mapping Colorectal Distribution of Cell-Free and Cell-Associated HIV Surrogates Following Simulated Anal Intercourse to Aid Rectal Microbicide Development

“…Our group developed methods to image both HIV surrogates and candidate microbicide products in the lower gastrointestinal tract using single-photon emission computed tomography (SPECT)/computed tomography (CT) and magnetic resonance imaging. [9][10][11] These methods required introduction of novel concentration-distance parameters to provide quantitative measures describing luminal distribution of radiolabel through 3-dimensional tube fitting representing the distal colon. This enabled the efficient quantitative description of distribution and statistical comparison of products and HIV surrogates in the lower gastrointestinal tract.…”