title: Intermittent prophylaxis with oral truvada protects macaques from rectal SHIV infection.
abstract: HIV continues to spread globally, mainly through sexual contact. Despite advances in treatment and care, preventing transmission with vaccines or microbicides has proven difficult. A promising strategy to avoid transmission is prophylactic treatment with antiretroviral drugs before exposure to HIV. Clinical trials evaluating the efficacy of daily treatment with the reverse transcriptase inhibitors tenofovir disoproxil fumarate (TDF) or Truvada (TDF plus emtricitabine) are under way. We hypothesized that intermittent prophylactic treatment with long-acting antiviral drugs would be as effective as daily dosing in blocking the earliest stages of viral replication and preventing mucosal transmission. We tested this hypothesis by intermittently giving prophylactic Truvada to macaque monkeys and then exposing them rectally to simian-human immunodeficiency virus (SHIV) once a week for 14 weeks. A simple regimen with an oral dose of Truvada given 1, 3, or 7 days before exposure followed by a second dose 2 hours after exposure was as protective as daily drug administration, possibly because of the long intracellular persistence of the drugs. In addition, a two-dose regimen initiated 2 hours before or after virus exposure was effective, and full protection was obtained by doubling the Truvada concentration in both doses. We saw no protection if the first dose was delayed until 24 hours after exposure, underscoring the importance of blocking initial replication in the mucosa. Our results show that intermittent prophylactic treatment with an antiviral drug can be highly effective in preventing SHIV infection, with a wide window of protection. They strengthen the possibility of developing feasible, cost-effective strategies to prevent HIV transmission in humans.
authors.affiliation: Division of HIV/AIDS Prevention, National Center for HIV, Hepatitis, STD, and Prevention, Centers for Disease Control and Prevention, 1600 Clifton Road, Atlanta, GA 30329, USA. GGarcia-Lerma@cdc.gov
authors.forename: J Gerardo
authors.initials: JG
authors.lastname: García-Lerma
authors.forename: Mian-er
authors.initials: ME
authors.lastname: Cong
authors.forename: James
authors.initials: J
authors.lastname: Mitchell
authors.forename: Ae S
authors.initials: AS
authors.lastname: Youngpairoj
authors.forename: Qi
authors.initials: Q
authors.lastname: Zheng
authors.forename: Silvina
authors.initials: S
authors.lastname: Masciotra
authors.forename: Amy
authors.initials: A
authors.lastname: Martin
authors.forename: Zsuzsanna
authors.initials: Z
authors.lastname: Kuklenyik
authors.forename: Angela
authors.initials: A
authors.lastname: Holder
authors.forename: Jonathan
authors.initials: J
authors.lastname: Lipscomb
authors.forename: Chou-Pong
authors.initials: CP
authors.lastname: Pau
authors.forename: John R
authors.initials: JR
authors.lastname: Barr
authors.forename: Debra L
authors.initials: DL
authors.lastname: Hanson
authors.forename: Ron
authors.initials: R
authors.lastname: Otten
authors.forename: Lynn
authors.initials: L
authors.lastname: Paxton
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Folks
authors.forename: Walid
authors.initials: W
authors.lastname: Heneine
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D000284:Administration, Oral; D000818:Animals; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D004338:Drug Combinations; D000069480:Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination; D007700:Kinetics; D007963:Leukocytes, Mononuclear / Q000821:virology; D008251:Macaca / Q000821:virology*; D063065:Organophosphonates / Q000493:pharmacokinetics*; D009943:Organophosphorus Compounds / Q000493:pharmacokinetics*; D016016:Proportional Hazards Models; D012007:Rectum / Q000821:virology*; D012107:Research Design; D016097:Simian Acquired Immunodeficiency Syndrome / Q000517:prevention & control*; D015302:Simian Immunodeficiency Virus / Q000378:metabolism*; D000068698:Tenofovir; D013997:Time Factors; D016896:Treatment Outcome; D019562:Viral Load
chemical_list: D004338:Drug Combinations; D000069480:Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination; D063065:Organophosphonates; D009943:Organophosphorus Compounds; D003841:Deoxycytidine; D000068698:Tenofovir; D000225:Adenine