Ultra-long-acting Biodegradable and Tunable Polymeric Solid Implant for HIV Treatment Maintenance

项目总结 尽管自40年前艾滋病开始流行以来，艾滋病治疗取得了巨大进展，2020年~3800万人 全球人民都感染了艾滋病毒，每年约有150万人新感染艾滋病毒1。 联合抗逆转录病毒疗法(CART)有效地将艾滋病毒复制抑制到几乎检测不到的水平 在大多数感染艾滋病毒的患者中，并显著减少艾滋病的发病率。然而今天，据估计， 73%的艾滋病毒携带者可以使用购物车，导致约1000万人无法获得治疗。 因此，当务之急是增加获得CART的机会，并实施提高依从性和有效性的疗法。 新的药物组合已将有效控制所需的药片数量减少到每天一片 艾滋病毒极大地方便了治疗。然而，与其他慢性病一样，坚持每日服药 由于结构、行为和社会障碍2-5，对许多艾滋病毒携带者来说仍然是一个挑战。非- 坚持治疗有重大后果，包括出现抗药性和 潜在的治疗效果丧失6-8。因此，正在探索替代方法，以减少 每日给药的负担，包括长效注射、口服和植入性产品9-15。这个 我们计划所基于的基本假设是消除或减少 个人坚持可以提高艾滋病毒治疗和预防战略的有效性。在本R01中 在我们现有数据的基础上，我们建议对一种可生物降解和高度 可调聚合物固体植入物(PSI)，可提供持久和持续的艾滋病毒抑制，增加用户 依从性，以及在发生意想不到的不良事件或过敏反应时移除的能力。我们会 通过使用一种新的工程工艺来开发超长效可生物降解的PSI来实现这一目标 生产小尺寸植入物(1-4厘米长)，药物含量高(高达85wt%)。我们提出了一个全面的 对这种新的药物传递方法的评估使用模拟努力来验证体外工具来指导 配方开发和高度相关的RT-SHV猕猴感染模型是一个无价的 用于评估PSI维持病毒抑制效果的临床前工具。这一尖端技术结合了 我们将使用一种方法来评估我们建议在老鼠和猕猴身上进行研究的科学前提 独特且高度创新的超长效PSI技术的安全性和有效性。

PROJECT SUMMARY Despite enormous strides made in HIV treatment since the epidemic began 40 years ago, in 2020 ~38 million people globally were living which HIV, and ~1.5 million people are newly infected with HIV every year1. Combination antiretroviral therapy (cART) effectively suppresses HIV replication to virtually undetectable levels in most HIV infected patients and dramatically reduces the incidence of AIDS. Today however, an estimated 73% of people living with HIV have access to cART leaving ~10 million people without access to treatment.1 It is therefore imperative to increase access to cART and implement therapies that improve adherence and efficacy. New drug combinations have reduced to one per day the number of pills needed to be taken to effectively control HIV greatly facilitating treatment. However, as with other chronic conditions, adherence to daily medications remains a challenge for many individuals living with HIV due to structural, behavioral, and social barriers2-5. Non- adherence to treatment has significant consequences including the emergence of drug-resistance and the potential loss of therapeutic effectiveness6-8. As such, alternative approaches are being explored to decrease the burden of daily pill administration, including long-acting injectable, oral, and implantable products9-15. The fundamental hypothesis on which our program is based is that eliminating or reducing the impact of individual adherence could increase the efficacy of HIV treatment and prevention strategies. In this R01 grant and building on our existing data, we propose a comprehensive evaluation of a biodegradable and highly tunable polymeric solid implant (PSI) that offers durable and sustained HIV viral suppression, increased user compliance, and the ability to be removed in case of unanticipated adverse events or allergic reaction. We will achieve this goal by developing an ultra-long-acting biodegradable PSI using a novel engineering process to generate small size implants (1-4 cm long) with high drug content (up to 85 wt%). We propose a comprehensive evaluation of this novel drug delivery approach using modeling efforts to validate an in vitro tool to guide formulation development and a highly relevant macaque model of infection with RT-SHIV as an invaluable preclinical tool to assess the efficacy of the PSI to maintain virus suppression. This cutting-edge combined approach will be utilized to evaluate the scientific premise of our proposal in mice and macaques to investigate the safety and efficacy of a unique and highly innovative ultra-long-acting PSI technology.