title: Durable protection from vaginal simian-human immunodeficiency virus infection in macaques by tenofovir gel and its relationship to drug levels in tissue.
abstract: A vaginal gel containing 1% tenofovir (TFV) was found to be safe and effective in reducing HIV infection in women when used pericoitally. Because of the long intracellular half-life of TFV and high drug exposure in vaginal tissues, we hypothesized that a vaginal gel containing TFV may provide long-lasting protection. Here, we performed delayed-challenge experiments and showed that vaginal 1% TFV gel protected 4/6 macaques against vaginal simian-human immunodeficiency virus (SHIV) exposures occurring 3 days after gel application, demonstrating long-lasting protection. Despite continued gel dosing postinfection, neither breakthrough infection had evidence of drug resistance by ultrasensitive testing of SHIV in plasma and vaginal lavage. Analysis of the active intracellular tenofovir diphosphate (TFV-DP) in vaginal lymphocytes collected 4 h to 3 days after gel dosing persistently showed high TFV-DP levels (median, 1,810 fmol/10(6) cells) between 4 and 24 h that exceed the 95% inhibitory concentration (IC(95)), reflecting rapid accumulation and long persistence. In contrast to those in peripheral blood mononuclear cells (PBMCs) following oral dosing, TFV-DP levels in vaginal lymphocytes decreased approximately 7-fold by 3 days, exhibiting a much higher rate of decay. We observed a strong correlation between intracellular TFV-DP in vaginal lymphocytes, in vitro antiviral activity, and in vivo protection, suggesting that TFV-DP above the in vitro IC(95) in vaginal lymphocytes is a good predictor of high efficacy. Data from this model reveal an extended window of protection by TFV gel that supports coitus-independent use. The identification of protective TFV-DP concentrations in vaginal lymphocytes may facilitate the evaluation of improved delivery methods of topical TFV and inform clinical studies.
authors.affiliation: Laboratory Branch and Quantitative Sciences and Data Management Branch, Division of HIV/AIDS Prevention, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.
authors.forename: Charles
authors.initials: C
authors.lastname: Dobard
authors.forename: Sunita
authors.initials: S
authors.lastname: Sharma
authors.forename: Amy
authors.initials: A
authors.lastname: Martin
authors.forename: Chou-Pong
authors.initials: CP
authors.lastname: Pau
authors.forename: Angela
authors.initials: A
authors.lastname: Holder
authors.forename: Zsuzsanna
authors.initials: Z
authors.lastname: Kuklenyik
authors.forename: Jonathan
authors.initials: J
authors.lastname: Lipscomb
authors.forename: Debra L
authors.initials: DL
authors.lastname: Hanson
authors.forename: James
authors.initials: J
authors.lastname: Smith
authors.forename: Francis J
authors.initials: FJ
authors.lastname: Novembre
authors.forename: J Gerardo
authors.initials: JG
authors.lastname: García-Lerma
authors.forename: Walid
authors.initials: W
authors.lastname: Heneine
mesh_terms: D000225:Adenine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry; D000818:Animals; D019380:Anti-HIV Agents / Q000008:administration & dosage* / Q000737:chemistry; D002478:Cells, Cultured; D004355:Drug Stability; D005260:Female; D015658:HIV Infections / Q000188:drug therapy / Q000276:immunology / Q000517:prevention & control* / Q000821:virology; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006207:Half-Life; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000821:virology; D008137:Longitudinal Studies; D063065:Organophosphonates / Q000008:administration & dosage* / Q000737:chemistry; D016097:Simian Acquired Immunodeficiency Syndrome / Q000188:drug therapy / Q000276:immunology / Q000517:prevention & control / Q000821:virology; D015302:Simian Immunodeficiency Virus / Q000187:drug effects* / Q000502:physiology; D000068698:Tenofovir; D014621:Vagina / Q000187:drug effects* / Q000276:immunology / Q000821:virology; D014622:Vaginal Creams, Foams, and Jellies / Q000008:administration & dosage* / Q000737:chemistry
chemical_list: D019380:Anti-HIV Agents; D063065:Organophosphonates; D014622:Vaginal Creams, Foams, and Jellies; D000068698:Tenofovir; D000225:Adenine
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