title: Toward early safety alert endpoints: exploring biomarkers suggestive of microbicide failure.
abstract: 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.
authors.affiliation: 1 CONRAD , Eastern Virginia Medical School (EVMS), Arlington, Virginia.
authors.forename: Christine K
authors.initials: CK
authors.lastname: Mauck
authors.forename: Jaim Jou
authors.initials: JJ
authors.lastname: Lai
authors.forename: Debra H
authors.initials: DH
authors.lastname: Weiner
authors.forename: Neelima
authors.initials: N
authors.lastname: Chandra
authors.forename: Raina N
authors.initials: RN
authors.lastname: Fichorova
authors.forename: Charlene S
authors.initials: CS
authors.lastname: Dezzutti
authors.forename: Sharon L
authors.initials: SL
authors.lastname: Hillier
authors.forename: David F
authors.initials: DF
authors.lastname: Archer
authors.forename: Mitchell D
authors.initials: MD
authors.lastname: Creinin
authors.forename: Jill L
authors.initials: JL
authors.lastname: Schwartz
authors.forename: Marianne M
authors.initials: MM
authors.lastname: Callahan
authors.forename: Gustavo F
authors.initials: GF
authors.lastname: Doncel
mesh_terms: D000328:Adult; D000890:Anti-Infective Agents / Q000009:adverse effects* / Q000627:therapeutic use*; D015415:Biomarkers / Q000032:analysis*; D002482:Cellulose / Q000009:adverse effects / Q000031:analogs & derivatives / Q000627:therapeutic use; D004311:Double-Blind Method; D005260:Female; D015658:HIV Infections / Q000517:prevention & control*; D006801:Humans; D008875:Middle Aged; D017137:Nonoxynol / Q000009:adverse effects / Q000627:therapeutic use; D010919:Placebos / Q000008:administration & dosage; D017211:Treatment Failure; D014621:Vagina / Q000737:chemistry / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D014627:Vaginitis / Q000139:chemically induced* / Q000473:pathology*; D055815:Young Adult
chemical_list: D000890:Anti-Infective Agents; D015415:Biomarkers; D010919:Placebos; D017137:Nonoxynol; D002482:Cellulose; C020254:cellulose sulfate