Journal Article

Mucosal effects of tenofovir 1% gel

Ball, T Blake, Ballweber, Lamar, Burgener, Adam, Friend, David R, Vojtech, Lucia, Hughes, Sean M, Mayer, Kenneth H, Hoesley, Craig, Andrew, Philip, Cranston, Ross D, McElrath, M Juliana, Gottardo, Raphael, Strobl, Johanna, Fourati, Slim, Hladik, Florian, Cameron, Mark J, Johnson, Sherri, Piper, Jeanna, Dai, James Y, McGowan, Ian

2015

Overview

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. Tenofovir is a drug that can stop some viruses—including HIV—from multiplying. It is commonly used in multidrug therapies to control HIV infection. Clinical trials are underway to find out whether using the drug in the form of a gel applied to the vagina or rectum could be an effective way to prevent HIV transmission during sex. Some of the clinical trials carried out so far have produced promising results. However, since the use of gels containing anti-viral drugs is a new strategy for HIV prevention, there are limited data available about the safety of these products. Previous studies have shown that the concentration of tenofovir in the vagina is much higher in individuals using the gel than in those taking the tablet form of the drug. These high concentrations could lead to unexpected effects on the health of the cells exposed to the gel. Here, Hladik, Burgener, Ballweber et al. used a systems biology approach to look at the broad effects of tenofovir gel on tissue from the rectum. Tissue samples taken from the rectums of 15 patients who used tenofovir gel for seven days were compared with tissue samples taken from individuals who used a control gel that did not contain the drug or who did not use any gel. Genes that regulate inflammation were suppressed in the rectal tissue from patients who used tenofovir, as were genes that help these tissues regenerate and produce energy. The tissue from these patients also contained more immune cells, suggesting that their local immune systems were more active. Additionally, Hladik, Burgener, Ballweber et al. observed changes that could potentially lead to the increased growth of cells. Similar differences were also observed in vaginal cells that had been treated with tenofovir in the laboratory. These findings suggest that tenofovir delivered directly to the vagina or rectum may have unintentional local side effects. However, it is important to acknowledge that tenofovir gel has been evaluated in multiple studies that have not observed overt clinical adverse effects. Therefore, the implication of these findings is currently unclear and warrants further study.

• Publisher: eLife Sciences Publications Ltd,eLife Sciences Publications, Ltd
• Subject: Antiretroviral drugs / Biopsy / Cell proliferation / Cell survival / Cellulose / Clinical trials / Disease prevention / Disease transmission / Double-Blind Method / Epithelial cells / Female / Gels / Gene expression / Gene Expression - drug effects / HIV / HIV/AIDS / Human Biology and Medicine / Human immunodeficiency virus / Humans / Infectious diseases / Inflammation / Lymphocytes T / Male / Medical research / microbicides / Microbiology and Infectious Disease / Mitochondria / Mitochondria - drug effects / Mucosa / Mucous Membrane - drug effects / Mucous Membrane - metabolism / Nonoxynol / prevention / Proteomics / Public health / Rectum / Rectum - drug effects / Rectum - metabolism / Reverse Transcriptase Inhibitors - administration & dosage / Reverse Transcriptase Inhibitors - adverse effects / side effect / Tenofovir / Tenofovir - administration & dosage / Tenofovir - adverse effects / Vagina / Vagina - drug effects / Vagina - metabolism