Mucosal integrity and inflammatory markers in the female lower genital tract as potential screening tools for vaginal microbicides

Schreiber, Courtney A.; Fay, C.; Parry, Sam; Elovitz, Michal A.; Zhang, Jian; Shaunik, Alka; Barnhart, Kurt T.

doi:10.1016/j.contraception.2011.02.010

Cited by 9 publications

(8 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Exposure to N9 also altered gene expression of inflammatory mediators in the endometrium. Another study found that intravaginal N9 resulted in reduced endometrial levels of IL8 and IL1β [ 43 ], supporting our findings that N9 perturbs the endometrium although we did not observe altered expression of those specific genes in our study. In cases where the effects could be directly compared between sites (pathway analysis and T-cell phenotypes), the effects of N9 were stronger on the sites closer to the vagina (cervical TZ or endocervix) than those further away (endometrium), consistent with a dose effect.…”

Section: Discussionsupporting

confidence: 90%

Unexpected Inflammatory Effects of Intravaginal Gels (Universal Placebo Gel and Nonoxynol-9) on the Upper Female Reproductive Tract: A Randomized Crossover Study

et al. 2015

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionsupporting

confidence: 90%

Unexpected Inflammatory Effects of Intravaginal Gels (Universal Placebo Gel and Nonoxynol-9) on the Upper Female Reproductive Tract: A Randomized Crossover Study

et al. 2015

View full text Add to dashboard Cite

show abstract

“…Another study of 3-day use of N-9 showed a reduction in SLPI compared with baseline, although a statistical comparison was not performed. 36 Other nonspecific broad-spectrum anti-HIV microbicide candidates including PRO 2000, BufferGel, and Carraguard, which were not effective at preventing HIV infection in clinical trials, also showed decreases in SLPI. [37][38][39] Of note, in a 14-day study of the TFV vaginal gel, no significant effect was seen for a group of soluble mediators, including SLPI, although for statistical reasons a threshold p-value of < 0.01 rather than < 0.05 was used.…”

Section: Vaginal Safety Of Cs Hec Placebo and N-9mentioning

confidence: 99%

Toward Early Safety Alert Endpoints: Exploring Biomarkers Suggestive of Microbicide Failure

Mauck

Lai

Weiner

et al. 2013

AIDS Research and Human Retroviruses

View full text Add to dashboard Cite

TitleToward early safety alert endpoints: exploring biomarkers suggestive of microbicide failure. Several microbicides, including nonoxynol-9 (N-9) and cellulose sulfate (CS), looked promising during early trials but failed in efficacy trials. We aimed to identify Phase I mucosal safety endpoints that might explain that failure. In a blinded, randomized, parallel trial, 60 healthy premenopausal sexually abstinent women applied Universal HEC placebo, 6% CS or 4% N-9 gel twice daily for 13½ days. Endpoints included immune biomarkers in cervicovaginal lavage (CVL) and endocervical cytobrushes, inflammatory infiltrates in vaginal biopsies, epithelial integrity by naked eye, colposcopy, and histology, CVL anti-HIV activity, vaginal microflora, pH, and adverse events. Twenty women enrolled per group. Soluble/cellular markers were similar with CS and placebo, except secretory leukocyte protease inhibitor (SLPI) levels decreased in CVL, and CD3 + and CD45 + cells increased in biopsies after CS use. Increases in interleukin (IL)-8, IL-1, IL-1RA, and myeloperoxidase (MPO) and decreases in SLPI were significant with N-9. CVL anti-HIV activity was significantly higher during CS use compared to N-9 or placebo. CS users tended to have a higher prevalence of intermediate Nugent score, Escherichia coli, and Enterococcus and fewer gram-negative rods. Most Nugent scores diagnostic for bacterial vaginosis were in N-9 users. All cases of histological inflammation or deep epithelial disruption occurred in N-9 users. While the surfactant N-9 showed obvious biochemical and histological signs of inflammation, more subtle changes, including depression of SLPI, tissue influx of CD45 + and CD3 + cells, and subclinical microflora shifts were associated with CS use and may help to explain the clinical failure of nonsurfactant microbicides.

show abstract

“…For example, all three trials of PrEP gels used placebo gels with hydroxyethyl cellulose (HEC); [9,17,37] HEC has been associated with pro-inflammatory vaginal immune markers. [38] Among a sample of women in the CAPRISA 004 study, HIV incidence was associated with pro-inflammatory immune markers in plasma [39] and genital fluid. [40] The VOICE trial -the only RCT offering a comparison between vaginal PrEP and oral placebo -found HIV incidence in both the TFV gel and placebo gel arms (6.0 and 6.8 per 100 PYs, respectively) to be greater than in the oral placebo arm (4.6 per 100 PYs).…”

Section: Results: Evidence Of Failure and Even Harm With Vaginal Gelsmentioning

confidence: 99%

Women’s estimated HIV infections from sex in trials of pre-exposure prophylaxis in Africa: Implications for HIV prevention strategies

Gisselquist

2017

Preprint

View full text Add to dashboard Cite

Introduction: During 2004-15, nine randomized controlled trials (RCT) for HIV prevention tested pre-exposure prophylaxis (PrEP) with oral drugs, vaginal gels, or vaginal rings among more than 17,000 women in Africa.Methods: This study uses information from the nine RCTs to estimate the proportions of HIV from sexual and bloodborne risks, to consider reasons for success or failure with oral PrEP, and to consider risks with vaginal PrEP.Results: Estimating from women's reported frequencies of unprotected coital acts in six RCTs, only a minority of women's infections came from sex. Oral PrEP may have succeeded in at least one trial by reducing infections from both bloodborne and sexual risks. Oral PrEP may have failed in several trials, at least in part, because some women used oral PrEP when they had sexual risks rather than daily as advised. Relatively high incidence with PrEP vaginal gels and rings vs. oral placebo suggests vaginal PrEP had little impact at best and may have been harmful. Discussion: Evidence from this and other studies challenges the common belief most HIV in Africa comes from sex. This challenge has implications for HIV prevention strategies, including: warning about bloodborne risks; and reconsidering PrEP for young women.

show abstract

Mucosal integrity and inflammatory markers in the female lower genital tract as potential screening tools for vaginal microbicides

Cited by 9 publications

References 22 publications

Unexpected Inflammatory Effects of Intravaginal Gels (Universal Placebo Gel and Nonoxynol-9) on the Upper Female Reproductive Tract: A Randomized Crossover Study

Unexpected Inflammatory Effects of Intravaginal Gels (Universal Placebo Gel and Nonoxynol-9) on the Upper Female Reproductive Tract: A Randomized Crossover Study

Toward Early Safety Alert Endpoints: Exploring Biomarkers Suggestive of Microbicide Failure

Women’s estimated HIV infections from sex in trials of pre-exposure prophylaxis in Africa: Implications for HIV prevention strategies

Contact Info

Product

Resources

About