title: Prevention of rectal SHIV transmission in macaques by daily or intermittent prophylaxis with emtricitabine and tenofovir.
abstract: BACKGROUND
  In the absence of an effective vaccine, HIV continues to spread globally, emphasizing the need for novel strategies to limit its transmission. Pre-exposure prophylaxis (PrEP) with antiretroviral drugs could prove to be an effective intervention strategy if highly efficacious and cost-effective PrEP modalities are identified. We evaluated daily and intermittent PrEP regimens of increasing antiviral activity in a macaque model that closely resembles human transmission.
  
  
  RESULTS
  We used a repeat-exposure macaque model with 14 weekly rectal virus challenges. Three drug treatments were given once daily, each to a different group of six rhesus macaques. Group 1 was treated subcutaneously with a human-equivalent dose of emtricitabine (FTC), group 2 received orally the human-equivalent dosing of both FTC and tenofovir-disoproxil fumarate (TDF), and group 3 received subcutaneously a similar dosing of FTC and a higher dose of tenofovir. A fourth group of six rhesus macaques (group 4) received intermittently a PrEP regimen similar to group 3 only 2 h before and 24 h after each weekly virus challenge. Results were compared to 18 control macaques that did not receive any drug treatment. The risk of infection in macaques treated in groups 1 and 2 was 3.8- and 7.8-fold lower than in untreated macaques (p = 0.02 and p = 0.008, respectively). All six macaques in group 3 were protected. Breakthrough infections had blunted acute viremias; drug resistance was seen in two of six animals. All six animals in group 4 that received intermittent PrEP were protected.
  
  
  CONCLUSIONS
  This model suggests that single drugs for daily PrEP can be protective but a combination of antiretroviral drugs may be required to increase the level of protection. Short but potent intermittent PrEP can provide protection comparable to that of daily PrEP in this SHIV/macaque model. These findings support PrEP trials for HIV prevention in humans and identify promising PrEP modalities.
authors.affiliation: Division of HIV/AIDS Prevention, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention, Atlanta, Georgia, USA. GGarcia-Lerma@cdc.gov
authors.forename: J Gerardo
authors.initials: JG
authors.lastname: García-Lerma
authors.forename: Ron A
authors.initials: RA
authors.lastname: Otten
authors.forename: Shoukat H
authors.initials: SH
authors.lastname: Qari
authors.forename: Eddie
authors.initials: E
authors.lastname: Jackson
authors.forename: Mian-Er
authors.initials: ME
authors.lastname: Cong
authors.forename: Silvina
authors.initials: S
authors.lastname: Masciotra
authors.forename: Wei
authors.initials: W
authors.lastname: Luo
authors.forename: Caryn
authors.initials: C
authors.lastname: Kim
authors.forename: Debra R
authors.initials: DR
authors.lastname: Adams
authors.forename: Michael
authors.initials: M
authors.lastname: Monsour
authors.forename: Jonathan
authors.initials: J
authors.lastname: Lipscomb
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Johnson
authors.forename: David
authors.initials: D
authors.lastname: Delinsky
authors.forename: Raymond F
authors.initials: RF
authors.lastname: Schinazi
authors.forename: Robert
authors.initials: R
authors.lastname: Janssen
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Folks
authors.forename: Walid
authors.initials: W
authors.lastname: Heneine
mesh_terms: D000225:Adenine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood; D000818:Animals; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood; D004334:Drug Administration Schedule; D000068679:Emtricitabine; D008251:Macaca; D008253:Macaca mulatta; D063065:Organophosphonates / Q000008:administration & dosage* / Q000097:blood; D012007:Rectum / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D016097:Simian Acquired Immunodeficiency Syndrome / Q000097:blood / Q000517:prevention & control* / Q000635:transmission*; D015302:Simian Immunodeficiency Virus / Q000187:drug effects* / Q000378:metabolism; D000068698:Tenofovir
chemical_list: D063065:Organophosphonates; D003841:Deoxycytidine; D000068698:Tenofovir; D000068679:Emtricitabine; D000225:Adenine