Abstract
Intravaginal anti-HIV microbicides could provide women with a self-controlled means for HIV prevention, but results from clinical trials have been largely disappointing. We postulated that unrecognized effects of intravaginal gels on the upper female reproductive tract might contribute to the lower-than-expected efficacy of HIV microbicides. Our objective was to study the effects of intravaginal gels on the immune microenvironment of the cervix and uterus. In this randomized crossover study, 27 healthy female volunteers used a nightly application of intravaginal nonoxynol-9 (N9) gel as a “failed” microbicide or the universal placebo gel (UPG) as a “safe” gel (intervention cycles), or nothing (control cycle) from the end of menses to the mid-luteal phase. At a specific time-point following ovulation, all participants underwent sample collection for measurements of T-cell phenotypes, gene expression, and cytokine/chemokine protein concentrations from 3 anatomic sites above the vagina: the cervical transformation zone, the endocervix and the endometrium. We used hierarchical statistical models to estimate mean (95% CI) intervention effects, for N9 and UPG relative to control. Exposure to N9 gel and UPG generated a common “harm signal” that included transcriptional up-regulation of inflammatory genes chemokine (C-C motif) ligand 20 (macrophage inflammatory factor-3alpha) and interleukin 8 in the cervix, decreased protein concentrations of secretory leukocyte protease inhibitor, and transcriptional up-regulation of inflammatory mediators glycodelin-A and osteopontin in the endometrium. These results need to be replicated with a larger sample, but underscore the need to consider the effects of microbicide agents and gel excipients on the upper female reproductive tract in studies of vaginal microbicides.
Highlights
Vaginal microbicides are topical antimicrobials that block, kill, or inactivate HIV and/or other sexually transmitted pathogens when placed in the vagina prior to exposure
We studied the in vivo effects of 2 agents: N9 and universal placebo gel (UPG), compared to a no-treatment control, measuring biological effects on 3 anatomic sites above the vagina: the cervical transformation zone (TZ), the endocervix and the endometrium
This study was designed to explore the in vivo effects of the intravaginal products N9 and UPG on the upper FRT
Summary
Vaginal microbicides are topical antimicrobials that block, kill, or inactivate HIV and/or other sexually transmitted pathogens when placed in the vagina prior to exposure. 3.5% N9 in a carbomer gel increased HIV transmission compared to carbomer gel alone in a high-risk population of women [3] This was attributed in part to findings that N9 increased risk of sexually transmitted infections and genital ulcers, presumably providing a portal for HIV access to target Tcells [4,5,6]. Subsequent investigations revealed that N9 injures epithelial cell membranes, resulting in the release of pro-inflammatory cytokines, recruitment of inflammatory mediators and efflux of macrophages in the vagina [7]. These findings prompted an increased focus on the safety of candidate microbicides with measurements of vaginal epithelial integrity and inflammatory infiltrates [8]
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