Mucosal effects of tenofovir 1% gel

Abstract

Tenofovir gel is being evaluated for vaginal and rectal pre-exposure prophylaxis against HIV transmission. Because this is a new prevention strategy, we broadly assessed its effects on the mucosa. In MTN-007, a phase-1, randomized, double-blinded rectal microbicide trial, we used systems genomics/proteomics to determine the effect of tenofovir 1% gel, nonoxynol-9 2% gel, placebo gel or no treatment on rectal biopsies (15 subjects/arm). We also treated primary vaginal epithelial cells from four healthy women with tenofovir in vitro. After seven days of administration, tenofovir 1% gel had broad-ranging effects on the rectal mucosa, which were more pronounced than, but different from, those of the detergent nonoxynol-9. Tenofovir suppressed anti-inflammatory mediators, increased T cell densities, caused mitochondrial dysfunction, altered regulatory pathways of cell differentiation and survival, and stimulated epithelial cell proliferation. The breadth of mucosal changes induced by tenofovir indicates that its safety over longer-term topical use should be carefully monitored.Clinical trial registration: NCT01232803.DOI: http://dx.doi.org/10.7554/eLife.04525.001

Tenofovir Inhibits Wound Healing of Epithelial Cells and Fibroblasts from the Upper and Lower Human Female Reproductive Tract

“…In particular, CCL20 is chemoattractant for Th17 cells, high susceptible targets for HIV infection4041. Our results and those of others42 suggest that TFV creates a proinflammatory environment leading to the recruitment of HIV target cells at the wound site. If these findings are confirmed in vivo , then it implies that TFV creates an opportunity for HIV to infect at mucosal surfaces by both delaying wound healing and through chemotactic attraction of immune cells susceptible to HIV infection.…”

Microbicide vaginal rings: Technological challenges and clinical development

“…In 2006, Gilead Sciences granted a co-exclusive, royalty-free license to CONRAD and the IPM to develop TFV vaginal formulations for use by women in developing countries to prevent HIV infection. Since then, a large number of journal papers have been published describing either TFV or TDF formulated for vaginal application, including gels [128][129][130][131][132][133][134][135][136][137][138][139][140][141][142][143][144], tablets [145][146][147], nanoparticles [148][149][150] and VRs [43,[61][62][63]68,83,[86][87][88][89]91,151,152].…”

Treatment with commonly used antiretroviral drugs induces a type I/III interferon signature in the gut in the absence of HIV infection

“…Proliferation-related gene sets were conflicting in the rectum (two sets up in one study and down in the other). In a prior study of rectal tenofovir 1% gel, we noted induction of pro-proliferative pathways on both the transcriptomic and proteomic level 7 (Figure 4), suggesting that the drugs have a proliferation-inducing effect especially on these cells. Based on co-expression of glycoprotein 2, they may be M cells, which are highly active immunological sentinels of the intestinal mucosa [15][16][17] .…”

“…This is surprising, given that the GI tract harbors the largest HIV burden on and off ART 5 and is a major source of immune dysfunction in PLWH 2 . Moreover, two trials of tenofovir application directly to the female genital tract or the rectum as topical PrEP demonstrated a pro-inflammatory effect on the mucosa 6,7 . Analogous to these studies of topical PrEP, oral PrEP offers a unique opportunity to define the immunological effects of tenofovir-emtricitabine without interference by HIV infection, HIV-associated comorbidities or the additional drugs PLWH must take.…”