title: The long-acting integrase inhibitor GSK744 protects macaques from repeated intravaginal SHIV challenge.
abstract: Daily preexposure prophylaxis (PrEP) with Truvada is a proven HIV prevention strategy; however, its effectiveness is limited by low adherence. Antiretroviral drug formulations that require infrequent dosing may increase adherence and thus PrEP effectiveness. We investigated whether monthly injections of a long-acting formulation of the HIV integrase inhibitor GSK1265744 (GSK744 LA) prevented simian/human immunodeficiency virus (SHIV) infection by vaginal challenge in macaques. Female pigtail macaques (n = 12) were exposed to intravaginal inoculations of SHIV twice a week for up to 11 weeks. Half of the animals received a GSK744 LA injection every 4 weeks, and half received placebo. GSK744 LA, at plasma concentrations achievable with quarterly injections in humans, protected all six macaques from infection. Placebo controls were all infected after a median of 4 (range, 2 to 20) vaginal challenges with SHIV. Efficacy was related to high and sustained vaginal and plasma drug concentrations that remained above the protein-adjusted 90% inhibitory concentration during the dosing cycles. These data support advancement of GSK744 LA as a potential PrEP candidate for women.
authors.affiliation: Laboratory Branch, Division of HIV/AIDS Prevention, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention, Atlanta, GA 30329, USA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Radzio
authors.affiliation: GlaxoSmithKline, Research Triangle Park, NC 27709, USA.
authors.forename: William
authors.initials: W
authors.lastname: Spreen
authors.affiliation: GlaxoSmithKline, Research Triangle Park, NC 27709, USA.
authors.forename: Yun Lan
authors.initials: YL
authors.lastname: Yueh
authors.affiliation: Laboratory Branch, Division of HIV/AIDS Prevention, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention, Atlanta, GA 30329, USA.
authors.forename: James
authors.initials: J
authors.lastname: Mitchell
authors.affiliation: Laboratory Branch, Division of HIV/AIDS Prevention, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention, Atlanta, GA 30329, USA.
authors.forename: Leecresia
authors.initials: L
authors.lastname: Jenkins
authors.affiliation: Laboratory Branch, Division of HIV/AIDS Prevention, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention, Atlanta, GA 30329, USA. ggarcia-lerma@cdc.gov.
authors.forename: J Gerardo
authors.initials: JG
authors.lastname: García-Lerma
authors.affiliation: Laboratory Branch, Division of HIV/AIDS Prevention, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention, Atlanta, GA 30329, USA.
authors.forename: Walid
authors.initials: W
authors.lastname: Heneine
mesh_terms: D000282:Administration, Intravaginal; D000818:Animals; D044966:Anti-Retroviral Agents / Q000627:therapeutic use*; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000627:therapeutic use; D004338:Drug Combinations; D004353:Drug Evaluation, Preclinical; D000069480:Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination; D005260:Female; D016219:Immunotherapy, Adoptive; D020128:Inhibitory Concentration 50; D019429:Integrase Inhibitors / Q000627:therapeutic use*; D008251:Macaca; D009943:Organophosphorus Compounds / Q000627:therapeutic use; D011728:Pyridones / Q000627:therapeutic use*; D016097:Simian Acquired Immunodeficiency Syndrome / Q000517:prevention & control* / Q000821:virology; D015302:Simian Immunodeficiency Virus / Q000187:drug effects*; D014621:Vagina / Q000821:virology; D054659:Diketopiperazines
chemical_list: D044966:Anti-Retroviral Agents; D003841:Deoxycytidine; D004338:Drug Combinations; D000069480:Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination; D019429:Integrase Inhibitors; D009943:Organophosphorus Compounds; D011728:Pyridones; C584914:cabotegravir; D054659:Diketopiperazines