title: Postexposure protection of macaques from vaginal SHIV infection by topical integrase inhibitors.
abstract: Coitally delivered microbicide gels containing antiretroviral drugs are important for HIV prevention. However, to date, microbicides have contained entry or reverse transcriptase inhibitors that block early steps in virus infection and thus need to be given as a preexposure dose that interferes with sexual practices and may limit compliance. Integrase inhibitors block late steps after virus infection and therefore are more suitable for post-coital dosing. We first determined the kinetics of strand transfer in vitro and confirmed that integration begins about 6 hours after infection. We then used a repeat-challenge macaque model to assess efficacy of vaginal gels containing integrase strand transfer inhibitors when applied before or after simian/human immunodeficiency virus (SHIV) challenge. We showed that gel containing the strand transfer inhibitor L-870812 protected two of three macaques when applied 30 min before SHIV challenge. We next evaluated the efficacy of 1% raltegravir gel and demonstrated its ability to protect macaques when applied 3 hours after SHIV exposure (five of six protected; P < 0.05, Fisher's exact test). Breakthrough infections showed no evidence of drug resistance in plasma or vaginal secretions despite continued gel dosing after infection. We documented rapid vaginal absorption reflecting a short pharmacological lag time and noted that vaginal, but not plasma, virus load was substantially reduced in the breakthrough infection after raltegravir gel treatment. We provide a proof of concept that topically applied integrase inhibitors protect against vaginal SHIV infection when administered shortly before or 3 hours after virus exposure.
authors.affiliation: Laboratory Branch, Division of HIV/AIDS Prevention, Centers for Disease Control and Prevention, Atlanta, GA 30333, USA.
authors.forename: Charles
authors.initials: C
authors.lastname: Dobard
authors.forename: Sunita
authors.initials: S
authors.lastname: Sharma
authors.forename: Urvi M
authors.initials: UM
authors.lastname: Parikh
authors.forename: Rolieria
authors.initials: R
authors.lastname: West
authors.forename: Andrew
authors.initials: A
authors.lastname: Taylor
authors.forename: Amy
authors.initials: A
authors.lastname: Martin
authors.forename: Chou-Pong
authors.initials: CP
authors.lastname: Pau
authors.forename: Debra L
authors.initials: DL
authors.lastname: Hanson
authors.forename: Jonathan
authors.initials: J
authors.lastname: Lipscomb
authors.forename: James
authors.initials: J
authors.lastname: Smith
authors.forename: Francis
authors.initials: F
authors.lastname: Novembre
authors.forename: Daria
authors.initials: D
authors.lastname: Hazuda
authors.forename: J Gerardo
authors.initials: JG
authors.lastname: Garcia-Lerma
authors.forename: Walid
authors.initials: W
authors.lastname: Heneine
mesh_terms: D000282:Administration, Intravaginal; D000287:Administration, Topical; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology / Q000627:therapeutic use; D001826:Body Fluids; D004305:Dose-Response Relationship, Drug; D024882:Drug Resistance, Viral / Q000187:drug effects; D005260:Female; D005782:Gels; D019429:Integrase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D007700:Kinetics; D008251:Macaca / Q000097:blood / Q000821:virology*; D056990:Post-Exposure Prophylaxis; D011374:Progesterone / Q000097:blood; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D016097:Simian Acquired Immunodeficiency Syndrome / Q000097:blood / Q000188:drug therapy* / Q000517:prevention & control* / Q000821:virology; D015302:Simian Immunodeficiency Virus / Q000187:drug effects / Q000502:physiology*; D013997:Time Factors; D014621:Vagina / Q000187:drug effects / Q000473:pathology / Q000821:virology*; D019562:Viral Load / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D005782:Gels; D019429:Integrase Inhibitors; D018894:Reverse Transcriptase Inhibitors; D011374:Progesterone