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

项目摘要 尽管自40年前艾滋病开始流行以来，艾滋病毒治疗取得了巨大进展，但到2020年， 全球约有100万人感染艾滋病毒，每年约有150万人新感染艾滋病毒1。 联合抗逆转录病毒治疗（cART）有效地抑制艾滋病毒复制到几乎检测不到的水平 在大多数艾滋病病毒感染者中，大大降低了艾滋病的发病率。然而，据估计， 73%的艾滋病毒感染者可以获得cART，约有1000万人无法获得治疗。 因此，必须增加获得cART的机会，并实施改善依从性和疗效的疗法。 新的药物组合已经减少到每天一个药丸的数量需要采取有效控制 艾滋病极大地促进了治疗。然而，与其他慢性疾病一样，坚持每日用药 由于结构性、行为性和社会性障碍，对许多艾滋病毒感染者来说仍然是一个挑战2 -5。非 坚持治疗会产生重大后果，包括出现耐药性， 潜在的治疗效果丧失6 -8。因此，正在探索其他方法，以减少 每日服用药丸的负担，包括长效注射、口服和植入产品9 -15。的 我们的计划所依据的基本假设是，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效力。在此R 01 赠款和建设我们现有的数据，我们提出了一个全面的评估，生物降解和高度 可调聚合物固体植入物（PSI），提供持久和持续的HIV病毒抑制，增加用户 顺应性，以及在发生意外不良事件或过敏反应时移除的能力。我们将 实现这一目标，通过开发一种超长效生物降解PSI使用一种新的工程过程， 产生具有高药物含量（高达85wt%）的小尺寸植入物（1- 4cm长）。我们提出一个全面的 评价这种新的药物输送方法，使用建模工作，以验证体外工具，以指导 制剂开发和高度相关的猕猴模型感染RT-SHIV作为一个宝贵的 临床前工具，以评估PSI维持病毒抑制的功效。这种尖端技术结合了 方法将被用来评估我们的建议在小鼠和猕猴调查的科学前提 安全性和有效性的一个独特的和高度创新的超长效PSI技术。

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.