title: Pharmacodynamic Activity of Dapivirine and Maraviroc Single Entity and Combination Topical Gels for HIV-1 Prevention.
abstract: OBJECTIVE
  Dapivirine (DPV), a non-nucleoside reverse transcriptase inhibitor, and maraviroc (MVC), a CCR5 antagonist, were formulated into aqueous gels designed to prevent mucosal HIV transmission.
  
  
  METHODS
  0.05% DPV, 0.1% MVC, 0.05% DPV/0.1% MVC and placebo gels were evaluated for pH, viscosity, osmolality, and in vitro release. In vitro assays and mucosal tissues were used to evaluate anti-HIV activity. Viability (Lactobacilli only) and epithelial integrity in cell lines and mucosal tissues defined safety.
  
  
  RESULTS
  The gels were acidic and viscous. DPV gel had an osmolality of 893 mOsm/kg while the other gels had an osmolality of <100 mOsm/kg. MVC release was similar from the single and combination gels (~5 μg/cm(2)/min(1/2)), while DPV release was 10-fold less from the single as compared to the combination gel (0.4331 μg/cm(2)/min(1/2)). Titrations of the gels showed 10-fold more drug was needed to protect ectocervical than colonic tissue. The combination gel showed ~10- and 100-fold improved activity as compared to DPV and MVC gel, respectively. All gels were safe.
  
  
  CONCLUSIONS
  The DPV/MVC gel showed a benefit blocking HIV infection of mucosal tissue compared to the single entity gels. Combination products with drugs affecting unique steps in the viral replication cycle would be advantageous for HIV prevention.
authors.affiliation: University of Pittsburgh, 204 Craft Avenue, Pittsburgh, Pennsylvania, 15213, USA. cdezzutti@mwri.magee.edu.|Magee-Womens Research Institute, Pittsburgh, Pennsylvania, USA. cdezzutti@mwri.magee.edu.
authors.forename: Charlene S
authors.initials: CS
authors.lastname: Dezzutti
authors.affiliation: Magee-Womens Research Institute, Pittsburgh, Pennsylvania, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Yandura
authors.affiliation: Magee-Womens Research Institute, Pittsburgh, Pennsylvania, USA.
authors.forename: Lin
authors.initials: L
authors.lastname: Wang
authors.affiliation: University of Pittsburgh, 204 Craft Avenue, Pittsburgh, Pennsylvania, 15213, USA.|Magee-Womens Research Institute, Pittsburgh, Pennsylvania, USA.
authors.forename: Bernard
authors.initials: B
authors.lastname: Moncla
authors.affiliation: Statistical Center for HIV/AIDS Research and Prevention, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Teeple
authors.affiliation: International Partnership for Microbicides, Silver Springs, Maryland, USA.
authors.forename: Brid
authors.initials: B
authors.lastname: Devlin
authors.affiliation: International Partnership for Microbicides, Silver Springs, Maryland, USA.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Nuttall
authors.affiliation: Statistical Center for HIV/AIDS Research and Prevention, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
authors.forename: Elizabeth R
authors.initials: ER
authors.lastname: Brown
authors.affiliation: University of Pittsburgh, 204 Craft Avenue, Pittsburgh, Pennsylvania, 15213, USA.|Magee-Womens Research Institute, Pittsburgh, Pennsylvania, USA.
authors.forename: Lisa C
authors.initials: LC
authors.lastname: Rohan
mesh_terms: D000287:Administration, Topical; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D002584:Cervix Uteri / Q000378:metabolism / Q000821:virology; D003106:Colon / Q000378:metabolism / Q000821:virology; D003510:Cyclohexanes / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D004338:Drug Combinations; D065546:Drug Liberation; D005260:Female; D005782:Gels; D023581:HIV Fusion Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D015658:HIV Infections / Q000517:prevention & control* / Q000635:transmission; D054303:HIV Reverse Transcriptase / Q000008:administration & dosage / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D066298:In Vitro Techniques; D000077592:Maraviroc; D009092:Mucous Membrane / Q000378:metabolism / Q000821:virology; D011743:Pyrimidines / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D012007:Rectum / Q000378:metabolism / Q000821:virology; D012212:Rheology; D014230:Triazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*
chemical_list: D019380:Anti-HIV Agents; D003510:Cyclohexanes; D004338:Drug Combinations; D005782:Gels; D023581:HIV Fusion Inhibitors; D011743:Pyrimidines; D014230:Triazoles; D054303:HIV Reverse Transcriptase; D000077592:Maraviroc; C481671:Dapivirine
keywords: Antiretroviral drugs; Drug combinations; HIV prevention; Pre-exposure prophylaxis; Rectal microbicides