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Review
. 2014:383:117-36.
doi: 10.1007/82_2013_325.

Rectal microbicide development

Ian McGowan  1 , Charlene Dezzutti
Affiliations
Review

Rectal microbicide development

Ian McGowan et al. Curr Top Microbiol Immunol. 2014.

Abstract

The last few years have seen important progress in demonstrating the efficacy of oral pre-exposure prophylaxis, vaginal microbicides, and treatment as prevention as effective strategies for reducing the risk of acquiring or transmitting HIV infection. There has also been significant progress in the development of rectal microbicides. Preclinical non-human primate studies have demonstrated that antiretroviral microbicides can provide significant protection from rectal challenge with SIV or SHIV. Recent Phase 1 rectal microbicide studies have characterized the safety, acceptability, compartmental pharmacokinetics (PK), and pharmacodynamics (PD) of both UC781 and tenofovir gels. The tenofovir gel formulation used in vaginal studies was not well tolerated in the rectum and newer rectal-specific formulations have been developed and evaluated in Phase 1 studies. The PK/PD data generated in these Phase 1 studies may reduce the risk of advancing ineffective candidate rectal microbicides into late stage development. Tenofovir gel is currently poised to move into Phase 2 evaluation and it is possible that a Phase 2B/3 effectiveness study with this product could be initiated in the next 2-3 years.

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Figures

Fig. 1
Fig. 1
A detailed view of the colon. The colon is lined with a single layer of epithelium, covered by mucus that separates the luminal contents from the underlying lamina propria. The lamina propria is a rich source of immune cells that includes dendritic cells (purple), T cells (blue), plasma cells (pink), and tissue macrophage (tan). Virus (red) can reach the lamina propria through micro tears, transcytosis through the epithelium, or by binding to epithelial cells or dendritic cells. Recent data suggest cell-free virus reaches immune targets to infect the resident immune cells (T cells in blue/red)
Fig. 2
Fig. 2
Colorectal biopsies were collected before (V2) and 30 min after (V3) a single rectal dose of UC781 gel. The biopsies were challenged ex vivo with 104 TCID50 of HIV-1BaL (Fletcher et al. 2006) and explant supernatant was collected for HIV-1 p24 quantification every 3–4 days following infection (Anton et al. 2011). The pharmacodynamic response was calculated as the difference between V2 and V3 Day 14 cumulative HIV-1 p24 levels
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