Postcoital Bioavailability and Antiviral Activity of 0.5% PRO 2000 Gel: Implications for Future Microbicide Clinical Trials

Abstract

BackgroundThe pharmacokinetics and pharmacodynamics of vaginal microbicides are typically assessed among sexually abstinent women. However, the physical act of sex may modulate gel distribution, and preclinical studies demonstrate seminal plasma interferes with the antiviral activity of several microbicides. This study compared the biological activity and concentration of PRO 2000 in cervicovaginal lavage (CVL) collected in the absence or following coitus.MethodsCVL samples were collected from ten heterosexual couples at baseline, after sex, after a single dose of 0.5% PRO 2000 gel and sex, and after gel application without sex. The impact of CVL on HIV-1 infection of TZM-bl cells and HSV-2 infection of CaSki cells was monitored by luciferase and plaque assay, respectively. PRO 2000 concentrations were measured by fluorescence.ResultsCVL collected after PRO 2000 application significantly inhibited HIV-1 and HSV-2 (p = 0.01). However, the antiviral activity was reduced following sex and no significant protective effect was observed in postcoital CVL obtained in the presence compared to the absence of PRO 2000 for HIV (p = 0.45) or HSV-2 (p = 0.56). Less PRO 2000 was recovered in postcoital CVL, which, in conjunction with interference by seminal plasma, may have contributed to lower antiviral activity.ConclusionsPostcoital responses to PRO 2000 differ from precoital measures and the results obtained may provide insights into the clinical trial findings in which there was no significant protection against HIV-1 or HSV-2. Postcoital studies should be incorporated into clinical studies before embarking on large-scale efficacy trials.

Pharmacokinetics and Safety Assessment of Anti-HIV Dapivirine Vaginal Microbicide Rings with Multiple Dosing

“…CVL from participants exposed to placebo vaginal rings inhibited HIV-infection by a mean of 18% when used neat, but the activity was lost when samples were diluted 1:10 ( Figure 3). This low level of activity was attributed to some innate inhibition in vaginal lavage fluid, an effect that has been documented previously [22,27,28]. In contrast, samples from participants treated with rings containing dapivirine inhibited HIVinfection by a mean of 89% when used neat, and retained 71% inhibitory activity when diluted 10-fold (Figure 3).…”

“…A CVL was performed by rinsing the cervical os and posterior vaginal wall with 10 mL of sterile saline [22,23]. The fluid was collected in a labeled 15 mL conical polypropylene tube.…”

Efficacy of HIV antiviral polyanionic carbosilane dendrimer G2-S16 in the presence of semen

“…The differences in results obtained between SPL7013 and G2-S16 dendrimers could be because SPL7013 is a PLLdendrimer with 32 anionic naphthalene sulfonate groups in the periphery, and it has been shown that semen components or the alkaline pH of semen decreases the anti-HIV activity of polyanions by neutralizing their negative charge 24,[30][31][32][33] or by competitive binding to the viral envelope. 34 These data provide conceivable explanations as to why semen abrogates the antiviral activity of polyanions.…”

UC781 Microbicide Gel Retains Anti-HIV Activity in Cervicovaginal Lavage Fluids Collected following Twice-Daily Vaginal Application

“…It is also possible that semen may inhibit UC781 antiviral activity in vivo as has been suggested for other microbicide candidates, although previous in vitro studies indicate that UC781 is unaffected by seminal plasma (15,18). Additionally, UC781 bioavailability may be reduced during coitus as recently reported by Keller et al for PRO2000, potentially rendering UC781 microbicide gel less effective against HIV infection (16). Through the use of multiple tests incorporating seminal plasma, coitus, and ex vivo assays, future safety and preclinical trials will be able to generate important results regarding the potential efficacy of microbicide candidates prior to extensive clinical efficacy trials.…”

“…The preclinical testing outcomes for all of these products suggested that they might significantly reduce sexual transmission of HIV when used appropriately in a clinical trial. However, a recent report using ex vivo testing of PRO2000 claimed that this product may lose some of its anti-infective activity after vaginal application and sexual intercourse (16). Except for PRO2000, it is not known whether exposure of microbicide gels to female genital secretions in vivo lowers their anti-HIV activity and may have contributed to the disappointing outcomes in some clinical efficacy trials.…”