Bridging the gap between preclinical and clinical microbicide trials: Blind evaluation of candidate gels in murine models of efficacy and safety

Theodore J. Segarra, Esra Fakioglu, Natalia V. Cheshenko, Sarah S. Wilson, Pedro M M Mesquita, Gustavo F. Doncel, Betsy Herold

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

Background: Despite significant protection in preclinical studies, cellulose sulfate (CS) failed to protect women against HIV-1/2 and was associated with a trend toward increased HIV-1 acquisition in one of the clinical trials. These results highlight the need for preclinical tests more predictive of clinical outcomes. The objective of this study was to test coded vaginal gels, including CS, in murine models of safety and efficacy to determine the models' utility for evaluating future products. Methods: Four coded formulations, including 6% CS, 2% PRO 2000 and two placebo gels, were administered intravaginally to medroxyprogesterone-treated mice and their ability to prevent genital herpes (efficacy) or to alter the susceptibility to low dose HSV challenge (safety) was determined. Nonoyxnol-9 served as a positive toxicity control. Results: CS and PRO 2000 significantly protected mice from genital herpes following infection with a laboratory or clinical isolate of HSV-2 introduced in buffer (p<0.001). However, protection was reduced when virus was introduced in seminal plasma. Moreover, mice were significantly more susceptible to infection with low doses of HSV-2 when challenged 12 h after the 7th daily dose of CS or nonoxynol-9 (p<0.05). The increased susceptibility was associated with alterations in epithelial architecture. Conclusions: CS prevented genital herpes when present at the time of viral challenge, but increased the rate of infection when gel was applied daily for 7 days with a vaginal wash prior to viral inoculation. The findings presumably reflect altered epithelial architecture, which may have contributed to the trend towards increased HIV observed clinically.

Original languageEnglish (US)
Article numbere27675
JournalPLoS One
Volume6
Issue number11
DOIs
StatePublished - Nov 11 2011

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Anti-Infective Agents
sulfates
cellulose
anti-infective agents
animal models
Gels
Clinical Trials
gels
Safety
Herpes Genitalis
genitalia
Human Herpesvirus 2
Human immunodeficiency virus 1
HIV-1
mice
dosage
Infection
Nonoxynol
Medroxyprogesterone
Foams and Jellies Vaginal Creams

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Bridging the gap between preclinical and clinical microbicide trials : Blind evaluation of candidate gels in murine models of efficacy and safety. / Segarra, Theodore J.; Fakioglu, Esra; Cheshenko, Natalia V.; Wilson, Sarah S.; Mesquita, Pedro M M; Doncel, Gustavo F.; Herold, Betsy.

In: PLoS One, Vol. 6, No. 11, e27675, 11.11.2011.

Research output: Contribution to journalArticle

Segarra, Theodore J. ; Fakioglu, Esra ; Cheshenko, Natalia V. ; Wilson, Sarah S. ; Mesquita, Pedro M M ; Doncel, Gustavo F. ; Herold, Betsy. / Bridging the gap between preclinical and clinical microbicide trials : Blind evaluation of candidate gels in murine models of efficacy and safety. In: PLoS One. 2011 ; Vol. 6, No. 11.
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