A randomized trial to assess anti-HIV activity in female genital tract secretions and soluble mucosal immunity following application of 1% tenofovir gel

Marla J. Keller, Rebecca P. Madan, N. Merna Torres, Melissa J. Fazzari, Sylvia Cho, Sabah Kalyoussef, Gail Shust, Pedro M M Mesquita, Nicolette Louissaint, Jianmeng Chen, Hillel W. Cohen, Erin C. Diament, Anna C. Lee, Lydia Soto-Torres, Craig W. Hendrix, Betsy Herold

Research output: Contribution to journalArticle

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Abstract

Background: 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. Methods: 30 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. Results: A 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. Conclusions: Tenofovir 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.

Original languageEnglish (US)
Article numbere16475
JournalPLoS One
Volume6
Issue number1
DOIs
StatePublished - 2011

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Tenofovir
mucosal immunity
Mucosal Immunity
Therapeutic Irrigation
female genitalia
Gels
gels
HIV
secretion
Pharmacodynamics
pharmacology
anti-infective agents
Anti-Infective Agents
placebos
biomarkers
Biomarkers
Placebos
semen
Semen
luciferase

ASJC Scopus subject areas

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

Cite this

A randomized trial to assess anti-HIV activity in female genital tract secretions and soluble mucosal immunity following application of 1% tenofovir gel. / Keller, Marla J.; Madan, Rebecca P.; Merna Torres, N.; Fazzari, Melissa J.; Cho, Sylvia; Kalyoussef, Sabah; Shust, Gail; Mesquita, Pedro M M; Louissaint, Nicolette; Chen, Jianmeng; Cohen, Hillel W.; Diament, Erin C.; Lee, Anna C.; Soto-Torres, Lydia; Hendrix, Craig W.; Herold, Betsy.

In: PLoS One, Vol. 6, No. 1, e16475, 2011.

Research output: Contribution to journalArticle

Keller, MJ, Madan, RP, Merna Torres, N, Fazzari, MJ, Cho, S, Kalyoussef, S, Shust, G, Mesquita, PMM, Louissaint, N, Chen, J, Cohen, HW, Diament, EC, Lee, AC, Soto-Torres, L, Hendrix, CW & Herold, B 2011, 'A randomized trial to assess anti-HIV activity in female genital tract secretions and soluble mucosal immunity following application of 1% tenofovir gel', PLoS One, vol. 6, no. 1, e16475. https://doi.org/10.1371/journal.pone.0016475
Keller, Marla J. ; Madan, Rebecca P. ; Merna Torres, N. ; Fazzari, Melissa J. ; Cho, Sylvia ; Kalyoussef, Sabah ; Shust, Gail ; Mesquita, Pedro M M ; Louissaint, Nicolette ; Chen, Jianmeng ; Cohen, Hillel W. ; Diament, Erin C. ; Lee, Anna C. ; Soto-Torres, Lydia ; Hendrix, Craig W. ; Herold, Betsy. / A randomized trial to assess anti-HIV activity in female genital tract secretions and soluble mucosal immunity following application of 1% tenofovir gel. In: PLoS One. 2011 ; Vol. 6, No. 1.
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abstract = "Background: 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. Methods: 30 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. Results: A 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. Conclusions: Tenofovir 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.",
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AU - Keller, Marla J.

AU - Madan, Rebecca P.

AU - Merna Torres, N.

AU - Fazzari, Melissa J.

AU - Cho, Sylvia

AU - Kalyoussef, Sabah

AU - Shust, Gail

AU - Mesquita, Pedro M M

AU - Louissaint, Nicolette

AU - Chen, Jianmeng

AU - Cohen, Hillel W.

AU - Diament, Erin C.

AU - Lee, Anna C.

AU - Soto-Torres, Lydia

AU - Hendrix, Craig W.

AU - Herold, Betsy

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N2 - Background: 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. Methods: 30 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. Results: A 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. Conclusions: Tenofovir 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.

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