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

Abstract

Disruption of the epithelium in the female reproductive tract (FRT) is hypothesized to increase HIV infection risk by interfering with barrier protection and facilitating HIV-target cell recruitment. Here we determined whether Tenofovir (TFV), used vaginally in HIV prevention trials, and Tenofovir alafenamide (TAF), an improved prodrug of TFV, interfere with wound healing in the human FRT. TFV treatment of primary epithelial cells and fibroblasts from the endometrium (EM), endocervix (CX) and ectocervix (ECX) significantly delayed wound closure. Reestablishment of tight junctions was compromised in EM and CX epithelial cells even after wound closure occurred. In contrast, TAF had no inhibitory effect on wound closure or tight junction formation following injury. TAF accumulated inside genital epithelial cells as TFV-DP, the active drug form. At elevated levels of TAF treatment to match TFV intracellular TFV-DP concentrations, both equally impaired barrier function, while wound closure was more sensitive to TFV. Furthermore, TFV but not TAF increased elafin and MIP3a secretion following injury, molecules known to be chemotactic for HIV-target cells. Our results highlight the need of evaluating antiretroviral effects on genital wound healing in future clinical trials. A possible link between delayed wound healing and increased risk of HIV acquisition deserves further investigation.

A Subcutaneous Implant of Tenofovir Alafenamide Fumarate Causes Local Inflammation and Tissue Necrosis in Rabbits and Macaques

“…(42)). Previous tissue culture based on TFV has observed inhibition of wound healing in models using epithelial cells and fibroblasts isolated from the upper and lower human female reproductive tract (43). A phase 1 clinical trial of a TDF intravaginal ring was stopped early due to the development of Grade 1 vaginal ulceration near the ring after 32 days of use (44).…”

“…A phase 1 clinical trial of a TDF intravaginal ring was stopped early due to the development of Grade 1 vaginal ulceration near the ring after 32 days of use (44). Rodriguez-Garcia et al observed significant inhibition of wound closure with one mg/mL (3277 μM) TFV and with concentrations of TAF higher than eight μM (43). Our results are, therefore consistent with previous observations of TFV’s interference with wound healing, but the exact molecular mechanisms that cause the observed local toxicity of these implants is unknown.…”

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

“…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 .…”

“…Despite the advantages that TAF offers for HIV treatment, it is not currently approved for Pre-Exposure Prophylaxis (PrEP) 28 . However, its ability to protect against mucosal HIV infection and determination of genital tissue concentrations are being investigated 20 , 29 , 30 .…”

A strategic action framework for multipurpose prevention technologies combining contraceptive hormones and antiretroviral drugs to prevent pregnancy and HIV

“…For example, additional epidemiological, basic science and clinical research is needed to determine more conclusively the role of selected HCs other than DMPA with respect to risk of acquiring HIV in women and will impact the entire HIV prevention field beyond MPT development. Phase I safety studies with new MPT products could be designed to address issues such as the potential impact of progestins and estrogen on vaginal microbiome composition and vaginal, cervical and endometrial tissues, and the role of microscopic mucosal injury during intercourse which could facilitate the risk of HIV and STI acquisition [44,45]. Further work should also be performed to identify concrete biomarkers for HIV acquisition risk that can be measured in earlier-stage clinical trials.…”