Intravaginal ring eluting tenofovir disoproxil fumarate completely protects macaques from multiple vaginal simian-HIV challenges

James M. Smith, Rachna Rastogi, Ryan S. Teller, Priya Srinivasan, Pedro M.M. Mesquita, Umadevi Nagaraja, Janet M. McNicholl, R. Michael Hendry, Chuong T. Dinh, Amy Martin, Betsy C. Herold, Patrick F. Kiser

Research output: Contribution to journalArticle

75 Scopus citations

Abstract

Topical preexposure prophylaxis interrupts HIV transmission at the site of mucosal exposure. Intermittently dosed vaginal gels containing the HIV-1 reverse transcriptase inhibitor tenofovir protected pigtailed macaques depending on the timing of viral challenge relative to gel application. However, modest or no protection was observed in clinical trials. Intravaginal rings (IVRs) may improve efficacy by providing long-term sustained drug delivery leading to constant mucosal antiretroviral concentrations and enhancing adherence. Although a few IVRs have entered the clinical pipeline, 100% efficacy in a repeated macaque vaginal challenge model has not been achieved. Here we describe a reservoir IVR technology that delivers the tenofovir prodrug tenofovir disoproxil fumarate (TDF) continuously over 28 d. With four monthly ring changes in this repeated challenge model, TDF IVRs generated reproducible and protective drug levels. All TDF IVR-treated macaques (n = 6) remained seronegative and simian-HIV RNA negative after 16 weekly vaginal exposures to 50 tissue culture infectious dose SHIV162p3. In contrast, 11/12 control macaques became infected, with a median of four exposures assuming an eclipse of 7 d from infection to virus RNA detection. Protection was associated with tenofovir levels in vaginal fluid [mean 1.8 × 105 ng/mL (range 1.1 × 104 to 6.6 × 105 ng/mL)] and ex vivo antiviral activity of cervicovaginal lavage samples. These observations support further advancement of TDF IVRs as well as the concept that extended duration drug delivery devices delivering topical antiretrovirals could be effective tools in preventing the sexual transmission of HIV in humans.

Original languageEnglish (US)
Pages (from-to)16145-16150
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number40
DOIs
StatePublished - Oct 1 2013

Keywords

  • Controlled drug delivery
  • Nonhuman primate
  • Pharmacokinetics
  • PrEP

ASJC Scopus subject areas

  • General

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    Smith, J. M., Rastogi, R., Teller, R. S., Srinivasan, P., Mesquita, P. M. M., Nagaraja, U., McNicholl, J. M., Hendry, R. M., Dinh, C. T., Martin, A., Herold, B. C., & Kiser, P. F. (2013). Intravaginal ring eluting tenofovir disoproxil fumarate completely protects macaques from multiple vaginal simian-HIV challenges. Proceedings of the National Academy of Sciences of the United States of America, 110(40), 16145-16150. https://doi.org/10.1073/pnas.1311355110