title: A long-acting formulation of the integrase inhibitor raltegravir protects humanized BLT mice from repeated high-dose vaginal HIV challenges.
abstract: Pre-exposure prophylaxis (PrEP) using antiretroviral drugs (ARVs) has been shown to reduce HIV transmission in people at high risk of HIV infection. Adherence to PrEP strongly correlates with the level of HIV protection. Long-acting injectable ARVs provide sustained systemic drug exposures over many weeks and can improve adherence due to infrequent parenteral administration. Here, we evaluated a new long-acting formulation of raltegravir for prevention of vaginal HIV transmission.
  
  
  
  Long-acting raltegravir was administered subcutaneously to BALB/c, NSG (NOD-scid-gamma) and humanized BLT (bone marrow-liver-thymus) mice and rhesus macaques. Raltegravir concentration in peripheral blood and tissue was analysed. Suppression of HIV replication was assessed in infected BLT mice. Two high-dose HIV vaginal challenges were used to evaluate protection from HIV transmission in BLT mice.
  
  
  
  Two weeks after a single subcutaneous injection of long-acting raltegravir in BLT mice (7.5 mg) and rhesus macaques (160 mg), the plasma concentration of raltegravir was comparable to 400 mg orally, twice daily in humans. Serum collected from mice 3 weeks post-administration of long-acting raltegravir efficiently blocked HIV infection of TZM-bl indicator cells in vitro. Administration of long-acting raltegravir suppressed viral RNA in plasma and cervico-vaginal fluids of infected BLT mice, demonstrating penetration of active raltegravir into the female reproductive tract. Using transmitted/founder HIV we observed that BLT mice administered a single subcutaneous dose of long-acting raltegravir were protected from two high-dose HIV vaginal challenges 1 week and 4 weeks after drug administration.
  
  
  
  These preclinical results demonstrated the efficacy of long-acting raltegravir in preventing vaginal HIV transmission.
authors.affiliation: Division of Infectious Diseases, Center for AIDS Research, School of Medicine, University of North Carolina at Chapel Hill, NC, USA.
authors.forename: Martina
authors.initials: M
authors.lastname: Kovarova
authors.affiliation: Division of Infectious Diseases, Center for AIDS Research, School of Medicine, University of North Carolina at Chapel Hill, NC, USA.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Swanson
authors.affiliation: Merck Research Laboratories, Merck & Co., Inc., West Point, PA 19486, USA.
authors.forename: Rosa I
authors.initials: RI
authors.lastname: Sanchez
authors.affiliation: Division of Infectious Diseases, Center for AIDS Research, School of Medicine, University of North Carolina at Chapel Hill, NC, USA.
authors.forename: Caroline E
authors.initials: CE
authors.lastname: Baker
authors.affiliation: Merck Research Laboratories, Merck & Co., Inc., West Point, PA 19486, USA.
authors.forename: Justin
authors.initials: J
authors.lastname: Steve
authors.affiliation: Division of Infectious Diseases, Center for AIDS Research, School of Medicine, University of North Carolina at Chapel Hill, NC, USA.
authors.forename: Rae Ann
authors.initials: RA
authors.lastname: Spagnuolo
authors.affiliation: Merck Research Laboratories, Merck & Co., Inc., West Point, PA 19486, USA.
authors.forename: Bonnie J
authors.initials: BJ
authors.lastname: Howell
authors.affiliation: Merck Research Laboratories, Merck & Co., Inc., West Point, PA 19486, USA.
authors.forename: Daria J
authors.initials: DJ
authors.lastname: Hazuda
authors.affiliation: Division of Infectious Diseases, Center for AIDS Research, School of Medicine, University of North Carolina at Chapel Hill, NC, USA victor_garcia@med.unc.edu.
authors.forename: J Victor
authors.initials: JV
authors.lastname: Garcia
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000008:administration & dosage*; D018890:Chemoprevention / Q000379:methods; D003692:Delayed-Action Preparations / Q000008:administration & dosage*; D018562:Disease Transmission, Infectious / Q000517:prevention & control*; D005260:Female; D015658:HIV Infections / Q000517:prevention & control* / Q000635:transmission; D007279:Injections, Subcutaneous; D008253:Macaca mulatta; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D065129:Pre-Exposure Prophylaxis / Q000379:methods*; D000068898:Raltegravir Potassium / Q000008:administration & dosage*; D016896:Treatment Outcome; D014621:Vagina / Q000821:virology*
chemical_list: D019380:Anti-HIV Agents; D003692:Delayed-Action Preparations; D000068898:Raltegravir Potassium