A long-acting integrase inhibitor protects female macaques from repeated high-dose intravaginal SHIV challenge

• Published in: Science translational medicine 2015-01, Vol.7 (270), p.270ra4-270ra4
• Main Authors: Andrews, Chasity D, Yueh, Yun Lan, Spreen, William R, St Bernard, Leslie, Boente-Carrera, Mar, Rodriguez, Kristina, Gettie, Agegnehu, Russell-Lodrigue, Kasi, Blanchard, James, Ford, Susan, Mohri, Hiroshi, Cheng-Mayer, Cecilia, Hong, Zhi, Ho, David D, Markowitz, Martin
• Format: Article
• Language: English
• Subjects: Administration, Intravaginal; Animals; Anti-Retroviral Agents - pharmacokinetics; Anti-Retroviral Agents - therapeutic use; Female; Genome, Viral; Integrase Inhibitors - pharmacokinetics; Integrase Inhibitors - therapeutic use; Likelihood Functions; Macaca; Medroxyprogesterone Acetate - chemistry; Molecular Sequence Data; Mutation; Pyridones - chemistry; Simian Acquired Immunodeficiency Syndrome - prevention & control; Simian Acquired Immunodeficiency Syndrome - virology; Simian Immunodeficiency Virus - drug effects; Vagina - virology; Viral Load
• ISSN: 1946-6234; 1946-6242
• DOI: 10.1126/scitranslmed.3010298

Long-acting GSK1265744 (GSK744 LA) is a strand transfer inhibitor of the HIV/SIV (simian immunodeficiency virus) integrase and was shown to be an effective preexposure prophylaxis (PrEP) agent in a low-dose intrarectal SHIV (simian-human immunodeficiency virus) rhesus macaque challenge model. We examined the pharmacokinetics and efficacy of GSK744 LA as PrEP against repeat high-dose intravaginal SHIV challenge in female rhesus macaques treated with Depo-Provera (depot medroxyprogesterone acetate), which promotes viral transmission vaginally. When Depo-Provera-treated female rhesus macaques were dosed with GSK744 LA (50 mg/kg) monthly, systemic and tissue drug concentrations were lower than previously observed in male rhesus macaques. GSK744 concentrations were fivefold lower on average in cervical tissues than in rectal tissues. Eight female rhesus macaques were treated with GSK744 LA at week 0, and four female rhesus macaques served as controls. All animals received a high-dose challenge of SHIV162P3 at week 1. No infection was detected in GSK744 LA-treated rhesus macaques, whereas viremia was detected 1 to 2 weeks after SHIV challenge in all control animals. The GSK744 LA-treated rhesus macaques were given a second administration of drug at week 4 and further challenged at weeks 5 and 7. GSK744 LA treatment protected six of eight female rhesus macaques against three high-dose SHIV challenges, whereas all control animals became infected after the first challenge (P = 0.0003, log-rank test). These results support further clinical development of GSK744 LA for PrEP.