Redesigning Pre-Exposure Prophylaxis

Development of effective prevention strategies is key to controlling the HIV pandemic. Recent work has shown that antiretroviral pre-exposure prophylaxis could play a major role in preventing HIV acquisition (NEJM JW AIDS Clin Care November 23 2010), although this option has been limited by cost and concerns about treatment adherence. Now, researchers (some of them employed by GlaxoSmithKline) have provided evidence that a single injection of GSK1265744 — a novel analogue of the recently approved HIV integrase strand-transfer inhibitor dolutegravir — can provide prolonged protection against intrarectal simian/human immunodeficiency virus (SHIV) infection in macaques.

In initial human studies, an injectable formulation of GSK1265744 had an apparent terminal-phase half-life of 21 to 50 days, and a single 800-mg intramuscular (IM) injection led to sustained mean plasma concentrations >4 times the protein-adjusted level that could block 90% of infections (PAIC₉₀) for 16 weeks. Subsequent studies in macaques showed that two 50-mg/kg IM injections of GSK1265744 administered 4 weeks apart protected eight of eight animals against repeated SHIV challenge (8 weekly intrarectal infusions starting 1 week after the first injection); eight untreated animals became infected after one to seven (median, 2) SHIV infusions. In a follow-up study, 12 macaques were treated with a single 50-mg/kg IM GSK1265744 injection and then challenged weekly with SHIV until infection developed. SHIV infection developed after 6 to 17 virus challenges in these animals, compared with 1 to 7 challenges in four untreated macaques. Analysis revealed that plasma GSK1265744 concentrations >3 times the PAIC₉₀ provided 100% protection against infection.