Postcoital bioavailability and antiviral activity of 0.5% PRO 2000 gel: Implications for future microbicide clinical trials

Marla J. Keller, Pedro M M Mesquita, N. Merna Torres, Sylvia Cho, Gail Shust, Rebecca P. Madan, Hillel W. Cohen, Julie Petrie, Tara Ford, Lydia Soto-Torres, Albert T. Profy, Betsy Herold

Research output: Contribution to journalArticle

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Abstract

Background: The 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. Methods:CVL 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. Results:CVL 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. Conclusions:Postcoital 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.

Original languageEnglish (US)
Article numbere8781
JournalPLoS One
Volume5
Issue number1
DOIs
StatePublished - Jan 22 2010

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Anti-Infective Agents
Therapeutic Irrigation
Biological Availability
Antiviral Agents
bioavailability
clinical trials
anti-infective agents
Gels
Clinical Trials
gels
Human Herpesvirus 2
Human immunodeficiency virus 1
gender
seminal plasma
HIV-1
Semen
pharmacology
luciferase
Cells
Pharmacodynamics

ASJC Scopus subject areas

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

Cite this

Postcoital bioavailability and antiviral activity of 0.5% PRO 2000 gel : Implications for future microbicide clinical trials. / Keller, Marla J.; Mesquita, Pedro M M; Torres, N. Merna; Cho, Sylvia; Shust, Gail; Madan, Rebecca P.; Cohen, Hillel W.; Petrie, Julie; Ford, Tara; Soto-Torres, Lydia; Profy, Albert T.; Herold, Betsy.

In: PLoS One, Vol. 5, No. 1, e8781, 22.01.2010.

Research output: Contribution to journalArticle

Keller, MJ, Mesquita, PMM, Torres, NM, Cho, S, Shust, G, Madan, RP, Cohen, HW, Petrie, J, Ford, T, Soto-Torres, L, Profy, AT & Herold, B 2010, 'Postcoital bioavailability and antiviral activity of 0.5% PRO 2000 gel: Implications for future microbicide clinical trials', PLoS One, vol. 5, no. 1, e8781. https://doi.org/10.1371/journal.pone.0008781
Keller, Marla J. ; Mesquita, Pedro M M ; Torres, N. Merna ; Cho, Sylvia ; Shust, Gail ; Madan, Rebecca P. ; Cohen, Hillel W. ; Petrie, Julie ; Ford, Tara ; Soto-Torres, Lydia ; Profy, Albert T. ; Herold, Betsy. / Postcoital bioavailability and antiviral activity of 0.5% PRO 2000 gel : Implications for future microbicide clinical trials. In: PLoS One. 2010 ; Vol. 5, No. 1.
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abstract = "Background: The 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. Methods:CVL 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. Results:CVL 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. Conclusions:Postcoital 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.",
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AU - Keller, Marla J.

AU - Mesquita, Pedro M M

AU - Torres, N. Merna

AU - Cho, Sylvia

AU - Shust, Gail

AU - Madan, Rebecca P.

AU - Cohen, Hillel W.

AU - Petrie, Julie

AU - Ford, Tara

AU - Soto-Torres, Lydia

AU - Profy, Albert T.

AU - Herold, Betsy

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N2 - Background: The 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. Methods:CVL 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. Results:CVL 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. Conclusions:Postcoital 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.

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