Abstract
BackgroundPreclinical and early phase clinical microbicide studies have not consistently predicted the outcome of efficacy trials. To address this gap, candidate biomarkers of microbicide pharmacodynamics and safety were evaluated in a double-blind, placebo-controlled trial of tenofovir gel, the first microbicide to demonstrate significant protection against HIV acquisition.Methods30 women were randomized to apply a single daily dose of tenofovir or placebo gel for 14 consecutive days. Anti-HIV activity was measured in cervicovaginal lavage (CVL) on Days 0, 3, 7, 14 and 21 by luciferase assay as a surrogate marker of pharmacodynamics. Endogenous activity against E. coli and HSV-2 and concentrations of immune mediators were quantified in CVL as candidate biomarkers of safety. Tenofovir levels were measured in CVL and blood.ResultsA significant increase in anti-HIV activity was detected in CVL from women who applied tenofovir gel compared to their endogenous anti-HIV activity in genital tract secretions on Day 0 and compared to activity in CVL from women in the placebo group. The activity correlated significantly with CVL concentration of tenofovir (r = 0.6, p<0.001) and fit a sigmoid Emax pharmacodynamic model. Anti-HIV activity in CVL from women who applied tenofovir persisted when virus was introduced in semen, whereas endogenous anti-HIV activity decreased. Tenofovir did not trigger an inflammatory response or induce sustained loss in endogenous antimicrobial activity or immune mediators.ConclusionsTenofovir gel had no deleterious impact on soluble mucosal immunity. The increased anti-HIV activity in CVL, which persisted in the presence of semen and correlated with tenofovir concentration, is consistent with the efficacy observed in a recent clinical trial. These results promote quantified CVL anti-HIV activity as a surrogate of tissue pharmacodynamics and as a potential biomarker of adherence to product. This simple, feasible and inexpensive bioassay may promote the development of models more predictive of microbicide efficacy.Trial RegistrationClinicalTrials.gov NCT00594373
Highlights
The lack of biomarkers of efficacy and safety continues to impede development of microbicides for the prevention of HIV
We found that 14 daily applications of 0.5% PRO 2000 gel did not result in any significant inflammatory response or loss in endogenous antimicrobial activity of genital tract secretions [2]
While sufficient biologically active drug to inhibit HIV and HSV-2 infection was retained in cervicovaginal lavage (CVL) collected following gel application [1,4], the antiviral activity was markedly reduced when virus was introduced in seminal plasma, reflecting interference by seminal proteins with the antiviral activity of PRO 2000 [3]
Summary
Initial in vitro studies of PRO 2000 gel suggested promising activity against HIV-1 and HSV-2, but the microbicide failed to provide significant protection against infection in large-scale efficacy studies. While sufficient biologically active drug to inhibit HIV and HSV-2 infection was retained in cervicovaginal lavage (CVL) collected following gel application [1,4], the antiviral activity was markedly reduced when virus was introduced in seminal plasma, reflecting interference by seminal proteins with the antiviral activity of PRO 2000 [3]. Preclinical and early phase clinical microbicide studies have not consistently predicted the outcome of efficacy trials. To address this gap, candidate biomarkers of microbicide pharmacodynamics and safety were evaluated in a doubleblind, placebo-controlled trial of tenofovir gel, the first microbicide to demonstrate significant protection against HIV acquisition
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