Mucosal effects of tenofovir 1% gel

Abstract

BACKGROUND Tenofovir gel is being evaluated for vaginal and rectal pre-exposure prophylaxis against sexual HIV transmission. Because this is a new prevention strategy targeting large numbers of healthy people, we broadly assessed its effects on the mucosa. METHODS AND FINDINGS 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 taken at baseline, after one application or after seven daily applications (15 subjects/arm). Experiments were repeated using primary vaginal epithelial cells from four healthy women. After seven days of administration, tenofovir 1% gel had broad-ranging biological effects on the rectal mucosa, which were much more pronounced than—but different from—those caused by the detergent nonoxynol-9. Tenofovir profoundly suppressed anti-inflammatory mediators such as interleukin 10; increased T cell densities; caused mitochondrial dysfunction, possibly by blocking PNPT1 expression; and altered regulatory pathways of cell differentiation and survival. Except for leukocyte-derived factors, all these effects were replicated in primary vaginal epithelial cells, which also proliferated significantly faster in tenofovir’s presence. CONCLUSIONS Tenofovir’s suppression of anti-inflammatory activity could diminish its prophylactic efficacy over time. The breadth of mucosal changes, including mitochondrial dysfunction and epithelial proliferation, raises questions about its safety for long-term topical use. These findings suggest that a systems biology evaluation of mucosal effects may be beneficial before advancing to large-scale efficacy trials with topical HIV prevention agents that achieve high, long-lasting local drug concentrations.

Enrichment of herpes simplex virus type 2 (HSV-2) reactive mucosal T cells in the human female genital tract

“…Therapeutic vaccines that have shown activity against FRT HSV-2 shedding and lesions have reached phase II in clinical trials (5) but their effects, if any, on antigen-specific or total T RM are unknown. Antiviral compounds applied directly to the FRT can reduce the risk of HSV-2 acquisition (40), have complex immune signatures (41), and remain under consideration for HIV-1 prevention. Their effect on T RM should be investigated.…”

Repeated rectal application of a hyperosmolar lubricant is associated with microbiota shifts but does not affect PrEP drug concentrations: results from a randomized trial in men who have sex with men

“…While lubricants are typically made with ingredients from the "generally recognized as safe" list and do not contain pharmacologically active ingredients, there is a wide range of variability in the composition and chemical properties of personal lubricants [4]. In particular, water-based lubricants with hyperosmolar properties have been shown to induce epithelial tissue damage and cytotoxicity when applied in a single dose to rectal explants and epithelial cell cultures, or applied intermittently to the rectum of rhesus macaques in vivo [4][5][6][7][8][9]. Inflammation caused by tissue damage alters expression of drug metabolizing enzymes and transporters that can affect the absorption, distribution and clearance of antiretroviral (ARV) drugs [10].…”

Antiretroviral pre-exposure prophylaxis preferences among men who have sex with men in Vietnam: results from a nationwide cross-sectional survey

“…13 Recently, there has been increasing interest in alternative modalities of PrEP delivery, including long-acting injectable PrEP 16 and rectal microbicides, delivered as gels. 17,18 Long-acting injectables are being developed with a once-quarterly injection schedule that has been shown in macaques to maintain suitable drug levels for protection against HIV. 19 Among women, tenofovir 1% gel has been shown to be effective at prevention of vaginal HIV acquisition when inserted pericoitally 17 , although as with oral PrEP, efficacy is highly linked to adherence.…”

“…Although long-acting injectables and rectal microbicides are not yet ready for wide-scale implementation 17,19 , these modalities may offer benefits over a daily oral pill. For example, long acting injectables may have benefits in terms of adherence, by eliminating the need to remember to take a pill everyday.…”