Toward early safety alert endpoints: Exploring biomarkers suggestive of microbicide failure

Christine K. Mauck, Jaim Jou Lai, Debra H. Weiner, Neelima Chandra, Raina N. Fichorova, Charlene S. Dezzutti, Sharon L. Hillier, David F. Archer, Mitchell D Creinin, Jill L. Schwartz, Marianne M. Callahan, Gustavo F. Doncel

Research output: Contribution to journalArticle

12 Scopus citations


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 13° 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.

Original languageEnglish (US)
Pages (from-to)1475-1486
Number of pages12
JournalAIDS Research and Human Retroviruses
Issue number11
StatePublished - 2013

ASJC Scopus subject areas

  • Immunology
  • Virology
  • Infectious Diseases

Fingerprint Dive into the research topics of 'Toward early safety alert endpoints: Exploring biomarkers suggestive of microbicide failure'. Together they form a unique fingerprint.

  • Cite this

    Mauck, C. K., Lai, J. J., Weiner, D. H., Chandra, N., Fichorova, R. N., Dezzutti, C. S., Hillier, S. L., Archer, D. F., Creinin, M. D., Schwartz, J. L., Callahan, M. M., & Doncel, G. F. (2013). Toward early safety alert endpoints: Exploring biomarkers suggestive of microbicide failure. AIDS Research and Human Retroviruses, 29(11), 1475-1486.