Non-adherence to HIV treatment is an important health care problem with subsequent development of drug resistance and disease progression. Doravirine (DOR) is a novel non-nucleoside reverse transcriptase inhibitor (NNRTI) with high activity against both wild-type virus (IC50 5.2ng/ml) and the most prevalent NNRTI-resistant HIV variants. We developed injectable long-acting (LA) formulations of DOR that form an implant after subcutaneous administration, can deliver drug >4 months and can be removed to stop drug delivery. Importantly, DOR delivered in this way efficiently suppresses systemic HIV infection and prevents vaginal HIV transmission.
Extended release of DOR from optimized LA-DOR formulations was assessed in BALB/c mice (n=4 per formulation). Tissue drug levels in selected tissues including lymph nodes, spleen, vagina, cervix, uterus, rectum, ileum, and brain were evaluated 5 weeks post administration. Ability to suppressed established HIV infection in plasma and cervicovaginal secretions (CVS) was assessed in BLT mice infected with transmitted/founder HIV[sub]RHPA[/sub] (n=3). Efficacy to prevent HIV vaginal transmission was evaluated using BLT humanized mice treated with LA-DOR (n= 8) or placebo (n=5). BLT mice were vaginally challenge with HIV[sub]RHPA[/sub] 2, 4 and 6 weeks post LA-DOR administration. Peripheral blood was collected weekly and analyzed for HIV-RNA, CD4 T cells, and drug levels. Twelve weeks post administration (4 weeks after the last challenge), LA-DOR implants were removed to stop drug delivery and viremia was monitored for additional 4 weeks.
Two LA-DOR formulations provided DOR plasma concentrations >10xIC50 for 16 weeks. Median (range) tissue DOR concentrations five-weeks post injection were: vagina 206 ng/g (38.2-229), cervix 271.2 ng/g (42.5-336), uterus 122.3 ng/g (51.6-157), ileum 778.5 ng/g (177-808), rectum 391.4 ng/g (95.2-567), spleen 224.3 ng/g (44.7-351), lymph nodes 281 ng/g (54.4-374), and brain 18.1 (12.9-20.1). LA-DOR suppressed established HIV infection in plasma and CVS in all treated mice. When used for pre-exposure prophylaxis, 4 of 5 controls administered with placebo became infected compared to 1of 8 LA-DOR treated animals. After implant removal, no additional viremia was identified in LA-DOR treated mice.
The LA-DOR formulation can deliver drug for four months after a single subcutaneous injection, penetrate to relevant tissues and efficiently prevent vaginal HIV transmission after multiple HIV challenges.