Long-acting injectable multipurpose prevention technology for prevention of HIV and unplanned pregnancy.

Only condoms are proven to protect against both HIV and unplanned pregnancy, however, poor user acceptability and lack of partner cooperation impede effectiveness. We developed an injectable ultra-long-acting, biodegradable, and removable in-situ forming implant (ISFI) as multipurpose prevention technology (MPT). MPT ISFIs co-formulated an antiretroviral (dolutegravir (DTG)) or cabotegravir (CAB)), and a hormonal contraceptive (etonogestrel (ENG) or medroxyprogesterone acetate (MPA)). All formulations were well-tolerated in mice with no signs of chronic local or systemic inflammation. Plasma CAB and DTG concentrations were above 4× PA-IC90 for 90 days with zero-order and diffusion-controlled absorption, respectively, and no differences when co-formulated with either hormone. Plasma ENG and MPA concentrations were quantifiable for 90 days. Complete removal of CAB/MPA ISFIs resulted in MPA concentrations falling below the limit of quantification after 24 h post-removal, but incomplete CAB elimination from plasma. Collectively, we demonstrated the ability to co-formulate antiretrovirals with contraceptives in an ISFI that is well-tolerated with sustained plasma concentrations up to 90 days.

Ultra-long-acting in-situ forming implants with cabotegravir protect female macaques against rectal SHIV infection.

Ultra-long-acting delivery platforms for HIV pre-exposure prophylaxis (PrEP) may increase adherence and maximize public health benefit. We report on an injectable, biodegradable, and removable in-situ forming implant (ISFI) that is administered subcutaneously and can release the integrase inhibitor cabotegravir (CAB) above protective benchmarks for more than 6 months. CAB ISFIs are well-tolerated in female mice and female macaques showing no signs of toxicity or chronic inflammation. In macaques, median plasma CAB concentrations exceed established PrEP protection benchmarks within 3 weeks and confer complete protection against repeated rectal SHIV challenges. Implant removal via a small incision in 2 macaques at week 12 results in a 7- to 48-fold decrease in plasma CAB levels within 72 hours. Modeling to translate CAB ISFI dosing suggests that a 3 mL injection would exceed protective benchmarks in humans for over 5 months post administration. Our results support the clinical advancement of CAB ISFIs for ultra-long-acting PrEP in humans.