Abstract
BackgroundSeveral active ingredients proposed as vaginal microbicides have been shown paradoxically to increase susceptibility to infection in mouse genital herpes (HSV-2) vaginal susceptibility models and in clinical trials. In addition, "inactive ingredients" (or excipients) used in topical products to formulate and deliver the active ingredient might also cause epithelial toxicities that increase viral susceptibility. However, excipients have not previously been tested in susceptibility models.MethodsExcipients commonly used in topical products were formulated in a non-toxic vehicle (the "HEC universal placebo"), or other formulations as specified. Twelve hours after exposure to the excipient or a control treatment, mice were challenged with a vaginal dose of HSV-2, and three days later were assessed for infection by vaginal lavage culture to assess susceptibility.ResultsThe following excipients markedly increased susceptibility to HSV-2 after a single exposure: 5% glycerol monolaurate (GML) formulated in K-Y® Warming Jelly, 5% GML as a colloidal suspension in phosphate buffered saline, K-Y Warming Jelly alone, and both of its humectant/solvent ingredients (neat propylene glycol and neat PEG-8). For excipients formulated in the HEC vehicle, 30% glycerin significantly increased susceptibility, and a trend toward increased HSV-2 susceptibility was observed after 10% glycerin, and 0.1% disodium EDTA, but not after 0.0186% disodium EDTA. The following excipients did not increase susceptibility: 10% propylene glycol, 0.18%, methylparaben plus 0.02% propylparaben, and 1% benzyl alcohol.ConclusionsAs reported with other surfactants, the surfactant/emulsifier GML markedly increased susceptibility to HSV-2. Glycerin at 30% significantly increased susceptibility, and, undiluted propylene glycol and PEG-8 greatly increased susceptibility.
Highlights
Several active ingredients proposed as vaginal microbicides have been shown paradoxically to increase susceptibility to infection in mouse genital herpes (HSV-2) vaginal susceptibility models and in clinical trials
We found that a single exposures to the candidate microbicides nonoxynol-9 and C31G caused a marked increase in susceptibility to HSV-2, concordant with the increased susceptibility to HIV with nonoxynol-9 observed in a Phase III clinical microbicide trial [2], and a trend toward increased transmission in a Phase III trial of C31G [3]
Using an inoculum of 1 ID50, we found that 5% glycerol monolaurate (GML) formulated in K-Y Warming Jelly (KYWJ), caused a 10-fold increase in susceptibility to HSV-2, somewhat greater than the increase observed after KYWJ vehicle alone
Summary
Several active ingredients proposed as vaginal microbicides have been shown paradoxically to increase susceptibility to infection in mouse genital herpes (HSV-2) vaginal susceptibility models and in clinical trials. The rate of heterosexual male to female HIV transmission reported in a comprehensive review averaged about 1 in 1250 acts; even during the highly infectious stage immediately after HIV acquisition in the male partner the rate averaged less than 1 in 100 acts [5]. In both the SIV macaque and the FIV macaque models, 10,000 times more virus was required for infection via vaginal challenge than via parenteral challenge [6,7]. It follows that a topical microbicide that compromises this normally potent cervicovaginal barrier could substantially increase susceptibility to HIV or other pathogens
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