CONRAD's Preclinical and Clinical Biomarker Activities

Preclinical Updates

Gene Expression Profile of Vaginal Epithelial Cells Exposed to Proinflammatory Agents - Identification of Novel Biomarkers of Mucosal Safety

The gene expression profiles of human vaginal cells exposed to proinflammatory and noninflammatory compounds were analyzed. Profiling revealed a group of genes that is significantly upregulated in human vaginal cells in response to immunoinflammatory stimuli. These genes can serve as biomarkers of genital mucosal inflammation and immune activation.

Clinical Updates

Biomarkers of Compliance and Adherence

Clinical Study of PSA, Yc-DNA and TSPY4

Biomarkers of semen exposure could be used to verify protocol compliance in contraceptive and sexually transmitted infection (STI) prevention trials as well as to determine barrier efficacy. This study aims to gather information on the sensitivity, specificity and residence time of various semen biomarkers including prostate-specific antigen (PSA), the sex determining region of the Y chromosome (Yc-DNA) using two different primers and TSPY4. This information will help inform the selection of biomarkers of exposure for future clinical trials.

Utility of PSA in Female Condom Studies

CONRAD convened a USAID-sponsored meeting in July 2008 to identify a biomarker that could be validated against a biological endpoint, such as pregnancy or an STI, to augment slippage and breakage studies for approval of new female condoms. The goal was to eliminate the need for the currently required contraceptive effectiveness trial.  After exploring the pros and cons of several biological markers, PSA was determined to be the best indicator of female condom performance as it was felt to be stronger evidence than pregnancy or STIs, given the extreme variability in fertility, timing of sex, partner infection, participant compliance and self-reporting of compliance expected in contraceptive and STI prevention studies.

A study of the Program for Appropriate Technology in Health (PATH) Woman’s Condom and the FC2 female condom is comparing slippage, breakage, and other types of failure of the two condoms as well as their ability to prevent vaginal exposure to semen, as indicated by detection of PSA within the vagina. The sensitivity and specificity of reported failures using PSA as the gold standard for the presence of semen will be calculated. The Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) is conducting a concurrent contraceptive efficacy study of the PATH Woman’s Condom. Data from the two studies will be compared.

Support of Xhale Project

An exploratory study tested proprietary technology developed for oral dosing to tag vaginal products and detect the taggants in the breath. After vaginal administration, some of the taggants tested could be detected in the breath, suggesting that a breath test for microbicide gel use if physiologically and technically possible.

Biomarkers of Cervicovaginal Safety

Bacterial Vaginosis and Cervicovaginal Safety

It is hypothesized that bacterial vaginosis (BV), the most common cause of vaginal discharge among women of childbearing age, may significantly alter markers of cervicovaginal safety and increase the risk of HIV transmission. This study enrolled women with bacterial vaginosis and assessed markers of cervicovaginal mucosal safety at three different time points: during acute BV infection and approximately 1 week and 1 month after completing a 7 day course of metronidazole therapy. The study has been completed and data analysis is underway.   

Hormonal Contraception and Cervicovaginal Safety

Hormonal contraceptives, particularly long-lasting methods such as Depo-Provera, are widely used in the developing world, where HIV risk is high. A 2011 study raised concerns that hormonal contraceptives such as oral contraceptives (OCs) and long-lasting injectables might increase a woman’s risk of HIV infection. To help answer questions on hormonal contraceptives and HIV risk, CONRAD is conducting a Phase I study that will assess the effect of Depo-Provera and OCs on markers of vaginal immunity. Participants will use either Depo-Provera or OCs for 3 months and their affects on specific markers of mucosal immunity will be assessed.

Biomarkers of HIV Acquisition

Vaginal Biomarkers and HIV Acquisition

CONRAD researchers are working to identify biomarkers indicating increased susceptibility to HIV acquisition. Using swabs collected from a large study conducted by FHI on the effects of hormonal contraception on HIV acquisition, CONRAD is currently seeking to validate the link between one or more vaginal biomarkers and sexual acquisition of HIV. In a nested case-control study of 3,800 vaginal swabs collected within this prospective trial, we will compare the levels of soluble biomarkers within the vaginas of women who subsequently became infected with HIV compared to women who did not. If successful, this study could validate a vaginal biomarker as a surrogate for increased risk of HIV acquisition.

  

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