Phase I Randomized Safety Study of Twice Daily Dosing of Acidform Vaginal Gel: Candidate Antimicrobial Contraceptive

Marla J Keller,Betsy C Herold,Colleen A Carpenter,Congzhou Liu,Yungtai Lo,David N Fredricks,Mark H Einstein,Rupert Kaul

doi:10.1371/journal.pone.0046901

Abstract

BackgroundAcidform gel, an acid-buffering product that inactivates spermatozoa, may be an effective topical non-hormonal contraceptive. This study was designed to evaluate the safety of vaginal dosing and effects of Acidform on mucosal immune mediators, antimicrobial properties of genital secretions, and vaginal microbiota.MethodsThirty-six sexually abstinent U.S. women were randomized to apply Acidform or hydroxyethylcellulose (HEC) placebo gel twice daily for 14 consecutive days. Safety was assessed by symptoms and pelvic examination. The impact of gel on mucosal immunity was assessed by quantifying cytokines, chemokines, antimicrobial proteins and antimicrobial activity of genital secretions collected by cervicovaginal lavage (CVL) at screening, 2 hours after gel application, and on days 7, 14 and 21. Vaginal microbiota was characterized at enrollment and day 14 using species-specific quantitative PCR assays.ResultsThe median vaginal and cervical pH was significantly lower 2 hours after application of Acidform and was associated with an increase in the bactericidal activity of CVL against E. coli. However, 65% of women who received Acidform had at least one local adverse event compared with 11% who received placebo (p = 0.002). While there was no increase in inflammatory cytokines or chemokines, CVL concentrations of lactoferrin and interleukin-1 receptor antagonist (IL-1ra), an anti-inflammatory protein, were significantly lower following Acidform compared to HEC placebo gel application. There were no significant changes in Lactobacillus crispatus or Lactobacillus jensenii in either group but there was a decrease in Gardnerella vaginalis in the Acidform group (p = 0.08).ConclusionsAcidform gel may augment mucosal defense as evidenced by an increase in bactericidal activity of genital secretions against E. coli and a decrease in Gardnerella vaginalis colonization. However, Acidform was associated with more irritation than placebo and lower levels of antimicrobial (lactoferrin) and anti-inflammatory (IL-1ra) proteins. These findings indicate the need for additional safety studies of this candidate non-hormonal contraceptive.Trial RegistrationClinicalTrials.gov NCT00850837

Highlights

Several epidemiological studies indicate that systemic hormonal contraception, progesterone-containing injectables, may be associated with an increased risk of both HIV acquisition and transmission [1,2,3]
Forty-two of the Adverse event (AE), which occurred among 13 women (11 in the Acidform and 2 in the HEC group), were possibly or probably related to the study products (Table 2)
Eleven of (65%) women who received Acidform had at least 1 AE compared with 2 of (11%) who received HEC placebo gel (p = 0.002)

Summary

Introduction

Several epidemiological studies indicate that systemic hormonal contraception, progesterone-containing injectables, may be associated with an increased risk of both HIV acquisition and transmission [1,2,3]. Following sex, the pH is neutralized to at least 6.0 by semen (pH 7.2–8.2) to promote sperm survival. These observations provided the rationale for developing acid-buffering products as candidate multi-purpose agents that could serve as topical contraceptives and provide protection against acid-sensitive microbes. An acid-buffering product that inactivates spermatozoa, may be an effective topical nonhormonal contraceptive. This study was designed to evaluate the safety of vaginal dosing and effects of Acidform on mucosal immune mediators, antimicrobial properties of genital secretions, and vaginal microbiota

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