The levels and distribution of an anti-HIV microbicide in the genital tract are likely to be critical factors in determining potential efficacy. Up until now, research studies have typically assessed microbicide levels in sexually abstinent women, which neglects to consider the potential impact of sexual activity. A new study in PLoS One looks at whether the physical act of sex and the introduction of semen into the genital tract affects the microbcide candidate 0.5% PRO 2000 gel. The study was conducted and completed before the recent announcement that 0.5% PRO 2000 gel had failed to show efficacy in preventing HIV infection in a large randomized clinical trial.
The results showed that 0.5% PRO 2000 gel levels were significantly lower after sex, and this correlated with a reduced ability of cervicovaginal lavage (CVL) from gel-treated women to inhibit HIV and HSV-2 in vitro. It was noted, however, that lower gel concentrations did not fully explain the reduction in antiretroviral activity; additional experiments revealed that seminal plasma also had an independent effect.
The researchers acknowledge that their study has limitations, including a small sample size and a single-dose approach that may underestimate microbicide levels compared to repeat dosing. Nevertheless, they suggest that “the current paradigm of microbicide development should be modified to include postcoital sampling following single and repeated dosing with both active and placebo products and should be expanded to include both CVL and biopsies to more fully define the pharmacokinetics and pharmacodynamics of lead candidates prior to embarking on large-scale efficacy trials.”
PLoS ONE 5(1): e8781. doi:10.1371/journal.pone.0008781
Marla J. Keller1,2, Pedro M. M. Mesquita3, N. Merna Torres3, Sylvia Cho3, Gail Shust3, Rebecca P. Madan3, Hillel W. Cohen4, Julie Petrie1, Tara Ford1, Lydia Soto-Torres6, Albert T. Profy7, Betsy C. Herold2,3,5*
1 Department of Medicine, Albert Einstein College of Medicine, Bronx, New York, United States of America, 2 Department of Obstetrics and Gynecology and Women's Health, Albert Einstein College of Medicine, Bronx, New York, United States of America, 3 Department of Pediatrics, Albert Einstein College of Medicine, Bronx, New York, United States of America, 4 Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, New York, United States of America, 5 Department of and Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, United States of America, 6 Division of AIDS, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, Maryland, United States of America, 7 Endo Pharmaceuticals, Chadds Ford, Pennsylvania, United States of America
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.
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.
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.
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.