Mucosal effects of tenofovir 1% gel

  1. Florian Hladik  Is a corresponding author
  2. Adam Burgener
  3. Lamar Ballweber
  4. Raphael Gottardo
  5. Lucia Vojtech
  6. Slim Fourati
  7. James Y Dai
  8. Mark J Cameron
  9. Johanna Strobl
  10. Sean M Hughes
  11. Craig Hoesley
  12. Philip Andrew
  13. Sherri Johnson
  14. Jeanna Piper
  15. David R Friend
  16. T Blake Ball
  17. Ross D Cranston
  18. Kenneth H Mayer
  19. M Juliana McElrath
  20. Ian McGowan
  1. University of Washington, United States
  2. University of Manitoba, Canada
  3. Fred Hutchinson Cancer Research Center, United States
  4. Vaccine and Gene Therapy Institute of Florida, United States
  5. Univeristy of Washington, United States
  6. University of Alabama, United States
  7. FHI 360, United States
  8. National Institutes of Health, United States
  9. Eastern Virginia Medical School, United States
  10. University of Pittsburgh School of Medicine, United States
  11. Beth Israel Deaconess Hospital, Harvard Medical School, United States
  12. Univeristy of Pittsburgh School of Medicine, United States

Abstract

Tenofovir gel is being evaluated for vaginal and rectal pre-exposure prophylaxis against HIV transmission. Because this is a new prevention strategy, we broadly assessed its effects on the mucosa. In MTN-007, a phase-1, randomized, double-blinded rectal microbicide trial, we used systems genomics/proteomics to determine the effect of tenofovir 1% gel, nonoxynol-9 2% gel, placebo gel or no treatment on rectal biopsies (15 subjects/arm). We also treated primary vaginal epithelial cells from four healthy women with tenofovir in vitro. After seven days of administration, tenofovir 1% gel had broad-ranging effects on the rectal mucosa, which were more pronounced than, but different from, those of the detergent nonoxynol-9. Tenofovir suppressed anti-inflammatory mediators, increased T cell densities, caused mitochondrial dysfunction, altered regulatory pathways of cell differentiation and survival, and stimulated epithelial cell proliferation. The breadth of mucosal changes induced by tenofovir indicates that its safety over longer-term topical use should be carefully monitored.

Article and author information

Author details

  1. Florian Hladik

    Department of Obstetrics and Gynecology, University of Washington, Seattle, United States
    For correspondence
    fhladik@fhcrc.org
    Competing interests
    The authors declare that no competing interests exist.
  2. Adam Burgener

    Department of Medical Microbiology, University of Manitoba, Winnipeg, Canada
    Competing interests
    The authors declare that no competing interests exist.
  3. Lamar Ballweber

    Vaccine and Infectious Diseases Division, Fred Hutchinson Cancer Research Center, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Raphael Gottardo

    Department of Biostatistics, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Lucia Vojtech

    Department of Obstetrics and Gynecology, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Slim Fourati

    Vaccine and Gene Therapy Institute of Florida, Port Saint Lucie, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. James Y Dai

    Department of Biostatistics, Univeristy of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Mark J Cameron

    Vaccine and Gene Therapy Institute of Florida, Port Saint Lucie, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Johanna Strobl

    Vaccine and Infectious Diseases Division, Fred Hutchinson Cancer Research Center, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Sean M Hughes

    Department of Obstetrics and Gynecology, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Craig Hoesley

    Department of Medicine, University of Alabama, Birmingham, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Philip Andrew

    FHI 360, Durham, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. Sherri Johnson

    FHI 360, Durham, United States
    Competing interests
    The authors declare that no competing interests exist.
  14. Jeanna Piper

    Division of AIDS, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.
  15. David R Friend

    CONRAD, Eastern Virginia Medical School, Arlington, United States
    Competing interests
    The authors declare that no competing interests exist.
  16. T Blake Ball

    Department of Medical Microbiology, University of Manitoba, Winnipeg, Canada
    Competing interests
    The authors declare that no competing interests exist.
  17. Ross D Cranston

    University of Pittsburgh School of Medicine, Pittsburgh, United States
    Competing interests
    The authors declare that no competing interests exist.
  18. Kenneth H Mayer

    Fenway Health, Beth Israel Deaconess Hospital, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  19. M Juliana McElrath

    Department of Medicine, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  20. Ian McGowan

    Univeristy of Pittsburgh School of Medicine, Pittsburgh, United States
    Competing interests
    The authors declare that no competing interests exist.

Reviewing Editor

  1. Sema Sgaier, Bill & Melinda Gates Foundation, India

Ethics

Human subjects: MTN-007 (ClinicalTrials.gov registration NCT01232803) was a phase 1, double blind, placebo-controlled trial in which participants were randomized to receive rectal reduced glycerin tenofovir 1%, nonoxynol-9 (N-9) 2% or hydroxyethylcellulose (HEC) gels, or no-treatment (1:1:1:1), at three clinical research sites (Pittsburgh, PA; Birmingham, AL; and Boston, MA). The study protocol was approved by IRBs at all three sites. All participants gave written informed consent. The study details, and general safety and acceptability data, have been published elsewhere (McGowan I et al. [2013] A phase 1 randomized, double blind, placebo controlled rectal safety and acceptability study of tenofovir 1% gel [MTN-007]. PLoS ONE 8: e60147). CONSORT checklist, CONSORT flow chart and MTN-007 IRB approval were submitted with the prior paper, and are attached again here.

Version history

  1. Received: August 27, 2014
  2. Accepted: February 2, 2015
  3. Accepted Manuscript published: February 3, 2015 (version 1)
  4. Version of Record published: February 27, 2015 (version 2)

Copyright

This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

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  1. Florian Hladik
  2. Adam Burgener
  3. Lamar Ballweber
  4. Raphael Gottardo
  5. Lucia Vojtech
  6. Slim Fourati
  7. James Y Dai
  8. Mark J Cameron
  9. Johanna Strobl
  10. Sean M Hughes
  11. Craig Hoesley
  12. Philip Andrew
  13. Sherri Johnson
  14. Jeanna Piper
  15. David R Friend
  16. T Blake Ball
  17. Ross D Cranston
  18. Kenneth H Mayer
  19. M Juliana McElrath
  20. Ian McGowan
(2015)
Mucosal effects of tenofovir 1% gel
eLife 4:e04525.
https://doi.org/10.7554/eLife.04525

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https://doi.org/10.7554/eLife.04525

Further reading

  1. What are the side effects when Tenofovir gel is used as a prophylactic against HIV?