Background: Surrogate markers of HIV-1 pre-exposure prophylaxis and microbicide efficacy are needed. One potential surrogate is the antiviral activity in cervicovaginal lavage (CVL) after exposure to candidate products. We measured CVL antiviral activity in women using oral or vaginal tenofovir-based pre-exposure prophylaxis and correlated activity with drug and immune mediator levels.
Methods: Inhibitory activity against HIV-1 and herpes simplex virus (HSV)-2 and concentrations of interleukin (IL)-1β, IL-6, IL-8, interferon-γ, induced protein 10 (IP-10), macrophage inflammatory protein (MIP)-1α, MIP-3a, lactoferrin, secretory leukocyte protease inhibitor, and defensins were measured in CVL obtained from 60 women at baseline and after 6 weeks of a randomized sequence of oral and topical tenofovir. CVL tenofovir concentrations were measured by mass spectrometry.
Results: The number of women with CVL anti-HIV activity ≥90% increased significantly from 5.0% at baseline to 89.1% after daily use of 1% tenofovir gel (relative risk = 17.85, P < 0.001), but there was no increase after daily oral tenofovir. The CVL anti-HIV activity correlated with drug levels (Spearman correlation coefficient 0.64 after tenofovir gel; P < 0.001) but not with the concentrations of mucosal immune mediators. No increase in CVL anti-HSV activity was observed after either drug regimen, an observation consistent with the higher concentrations of tenofovir needed to inhibit HSV-2 infection. The CVL anti-HSV activity correlated with lactoferrin, defensins, IP-10, IL-8, and detectable levels of MIP-1α but not with drug levels.
Conclusions: CVL may provide a surrogate for local but not systemic drug efficacy and a tool to better understand mucosal factors that modulate antiviral activity in genital tract secretions.
*Departments of Pediatrics and Microbiology-Immunology, Albert Einstein College of Medicine, Yeshiva University, New York, NY;
†University of Pittsburgh, Pittsburgh, PA;
‡Magee-Womens Research Institute, Pittsburgh, PA;
§University of Washington, Seattle, WA;
‖Fred Hutchinson Cancer Research Center, Seattle, WA; and
¶Johns Hopkins University, Baltimore, MD.
Correspondence to: Betsy C. Herold, MD, Albert Einstein College of Medicine, Yeshiva University, 1300 Morris Park Avenue, Forchheimer 702, New York, NY 10461 (e-mail: email@example.com).
Supported by the Microbicide Trials Network, which is funded by the National Institute of Allergy and Infectious Diseases (UM1 AI068633 and UM1 AI068615), the National Institute of Child Health and Development, and the National Institute of Mental Health, and by U19AI076980 (BCH) and R01AI065309 (BCH).
Presented in part at the Microbicides 2012 Conference, April 16, 2012, Sydney, Australia.
The authors have no conflicts of interest to disclose.
The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health.
Received September 20, 2013
Accepted January 02, 2014