Ultra-Long-Acting Polymeric Injectable Multi-Purpose Prevention Technology for Contraception and HIV Prevention

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PROJECT SUMMARY Globally, over 50% of those infected with HIV are women, and annually, ~50% of all pregnancies are unplanned. Therefore, there is a critical need to promote female-controlled methods of multipurpose prevention technologies (MPTs) and delivery strategies that can be disassociated from the sex act. Injectable formulations are well tolerated by men and women, are efficacious for contraception, and have high patient acceptability and compliance1-4. Innovations recently introduced into the field of systemic PrEP are long-acting (LA) formulations of antiretrovirals (ARVs) that stably release drugs over many weeks as nano-formulations and have activity in animal models of prevention5-7 and in humans8-10. Currently, there are two different LA formulations being considered for HIV prevention: a LA form of rilpivirine (RPV/TMC278) and a LA form of cabotegavir (CAB/GSK744)9, 11-12. Injections of these LA ARVs requires a 4-week ‘lead-in’ regimen using oral cabotegravir or rilpivirine to fulfil current safety considerations as once injected these agents have detectable levels for months and the drug cannot be removed or have its clearance accelerated. Despite these advances in HIV PrEP, currently there are no LA injectable MPT formulations in development mainly because of limitations of current LA injectable formulations utilizing nanoparticle suspensions whereby two drugs cannot be combined into a single injection. In this R01 grant and building on our existing data, we propose a comprehensive evaluation of a first-in-line injectable MPT that offers durable and sustained protection from HIV transmission, high efficacy of contraception, increased user compliance, and the ability to be removed in case of unanticipated adverse events or when considering discontinuation from the LA HIV PrEP and/or contraception. We will achieve this goal by developing a liquid MPT formulation utilizing excipients that form a biodegradable depot after subcutaneous injection (in-situ forming implant (ISFI)). We propose a comprehensive evaluation of this novel drug delivery approach using a highly relevant macaque model of mucosal simian/human immunodeficiency virus (SHIV) as an invaluable preclinical tool to assess the efficacy of the ISFI against SHIV acquisition. This cutting-edge combined approach will be utilized to evaluate the scientific premise of our proposal to investigate whether sustained protection against HIV acquisition and pregnancy can be achieved using a unique and highly innovative ultra-long-acting coitally-independent MPT ISFI formulation.