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

项目总结 在全球范围内，超过50%的艾滋病毒感染者是女性，每年约50%的怀孕是计划外怀孕。 因此，迫切需要推广妇女控制的多用途预防技术方法。 (MPTS)和可以与性行为脱节的交付策略。注射用制剂很好 男女均可耐受，避孕有效，患者可接受性高， 合规性1-4。最近引入系统PrEP领域的创新是长效(LA)配方 抗逆转录病毒药物(ARV)以纳米制剂的形式在数周内稳定释放药物，并在 预防的动物模型5-7，人类模型8-10。目前，有两种不同的LA配方 考虑用于预防艾滋病毒：LA形式的利培韦林(RPV/TMC278)和LA形式的卡波替加韦 (CAB/GSK744)9，11-12。这些LA抗逆转录病毒药物的注射需要使用口服卡波替格韦或 利培韦林以满足目前的安全考虑，因为一旦注射这些药物，几个月内都可以检测到水平 而且这种药物不能被移除，也不能加速清除。尽管艾滋病毒PrEP取得了这些进展， 目前还没有开发中的LA可注射MPT制剂，主要是因为目前的限制 使用纳米颗粒悬浮液的LA注射制剂，其中两种药物不能组合成 单次注射。在此R01拨款中，并基于我们现有的数据，我们建议对以下项目进行全面评估 一种第一线注射的MPT，提供持久和持续的预防艾滋病毒传播的保护，高效 避孕，提高用户依从性，以及在发生意外不良事件时移除的能力 或在考虑停止LA HIV PrEP和/或避孕时。我们将通过以下方式实现这一目标 利用辅料开发液体MPT制剂，该辅料在皮下形成可生物降解的储存库 注射(原位成型植入物(ISFI))。我们建议对这种新型药物传递进行综合评价。 使用高度相关的猴/人类免疫缺陷病毒(SHIV)猕猴模型作为 一个非常宝贵的临床前工具，用来评估ISFI针对SIV收购的有效性。这一尖端技术 将使用综合方法来评估我们提出的调查是否 持续预防艾滋病毒感染和怀孕可以使用独特的和高度的 创新的超长效独立MPT ISFI配方。

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.