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
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.
Leave a Reply