Abstract Body

Background: Pre-exposure prophylaxis (PrEP) with long-acting antiretroviral drugs has the potential to overcome the challenges of adherence associated with daily PrEP. The HIV integrase inhibitor GSK1265744 has been formulated as a long-acting injectable nanosuspension (GSK744 LA) and is an attractive candidate for PrEP. We used a pigtail macaque model to investigate systemic and vaginal GSK744 LA pharmacokinetics (PK) and evaluate efficacy against vaginal SHIV infection. This model assesses PrEP under physiologic conditions because pigtails have menstrual cycles similar to women, do not require the use of depo Provera to ensure vaginal infection, and can be infected with lower and more physiologic virus doses. Methodology: Drug PK was evaluated in plasma and vaginal secretions from 6 macaques receiving two intramuscular (IM) injections of GSK744 LA (50mg/kg) administered 4 weeks apart. The prophylactic efficacy of GSK744 LA was investigated in macaques repeatedly challenged with SHIV. Macaques received GSK744 LA (n = 6) or placebo (n = 6) IM every 4 weeks (total of 3 injections), and were concurrently exposed twice a week to low (50 TCID50) doses of SHIV162P3. Infection was monitored by serology and PCR amplification of SHIV RNA and proviral DNA. Results: Peak plasma drug concentrations (Cmax = 3,753 ng/ml; range = 2,488-9,903) were within the range reported in humans receiving 400 mg IM, with levels remaining above the protein adjusted IC90 (166 ng/ml) for a median of 49 days (range = 28->63) after the last dose. Peak GSK744 concentrations in vaginal secretions (911 ng/ml; range = 427-1,877) were lower than in plasma. Area under the curve values over 28 days were also lower in vaginal secretions (11,511 ng*day/ml; range = 3,956-14,011) relative to plasma (70,333 ng*day/ml; range = 40,265-169,341). All 6 macaques receiving GSK744 LA remained seronegative and viral RNA and DNA negative during the 22 SHIV challenges and 12 weeks after the last GSK744 LA injection. In contrast, all 6 controls were SHIV RNA positive after a median of 4 (range = 2-20) exposures (p<0.001). Conclusions: We show that single, monthly injections of GSK744 LA that reproduce the human dose fully protect macaques against repeated vaginal SHIV exposures. The high protection seen despite lower vaginal drug concentrations suggest a contribution of mucosal and systemic GSK744 to the observed protection. These data support advancement of GSK744 LA as a PrEP candidate for women.