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

用于维持艾滋病毒治疗的超长效可生物降解和可调聚合物固体植入物

基本信息

批准号：
10759149
负责人：
Soumya Rahima Benhabbour
金额：
$ 73.39万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-10 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10759149
关键词：
Acquired Immunodeficiency Syndrome Address Adherence Adult Adverse event Allergic Reaction Animals Anti-Retroviral Agents Antiretroviral drug resistance Behavioral Characteristics Chronic Communities Data Development Dose Drug Delivery Systems Drug Kinetics Drug resistance Engineering Epidemic Evaluation FDA approved Failure Fatigue Formulation Fostering Goals Grant HIV HIV Infections HIV Seropositivity HIV-1 Health Benefit Health Services Accessibility Health protection Implant Implantable Infusion Pumps In Vitro Inbred BALB C Mice Incidence Individual Infection Injectable Injections Lead Macaca Macaca mulatta Maintenance Measures Medical Modeling Mus Oral Patients Performance Persons Pharmaceutical Preparations Plasma Polymers Prevention strategy Privacy Process Property Public Health Regimen Research Personnel Safety Solid Suspensions System Tail Technology Testing Therapeutic Tissues Toxic effect Treatment Protocols User Compliance Viral Viral Load result Viremia Virus allergic response antiretroviral therapy biodegradable polymer chemical property chronic infection controlled release cost effective design drug release kinetics efficacy evaluation implant design improved in vivo innovation manufacture manufacturing process nanoparticle nonhuman primate novel novel drug combination novel therapeutics pharmacologic pharmacometrics pill pre-clinical pre-exposure prophylaxis programs simian human immunodeficiency virus social social stigma therapeutic effectiveness tool transmission process treatment duration treatment strategy virtual

项目摘要

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.

项目概要尽管自 40 年前艾滋病毒流行开始以来，艾滋病毒治疗取得了巨大进步，但到 2020 年，约 3800 万人全球范围内都有艾滋病毒感染者，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 HIV 复制抑制至几乎不可检测的水平在大多数艾滋病毒感染者中，艾滋病的发病率显着降低。然而今天，估计 73% 的艾滋病毒感染者可以获得 cART 治疗，导致约 1000 万人无法获得治疗。1 因此，必须增加 cART 的获取并实施提高依从性和疗效的疗法。新的药物组合已将有效控制所需服用的药片数量减少到每天一颗 HIV极大地促进了治疗。然而，与其他慢性病一样，坚持每日用药由于结构、行为和社会障碍，对于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，包括耐药性的出现和治疗效果的潜在损失6-8。因此，正在探索替代方法来减少每日服用药物的负担，包括长效注射剂、口服剂和植入剂产品9-15。这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策略的功效。在这个R01 并根据我们现有的数据，我们提出了对可生物降解和高度可调谐聚合物固体植入物 (PSI) 可提供持久且持续的 HIV 病毒抑制，增加使用者依从性，以及在发生意外不良事件或过敏反应时移除的能力。我们将通过使用新颖的工程工艺开发超长效可生物降解 PSI 来实现这一目标生成具有高药物含量（高达 85 wt%）的小尺寸植入物（1-4 厘米长）。我们提出一个全面的使用建模工作来验证体外工具来评估这种新型药物输送方法制剂开发和高度相关的 RT-SHIV 感染猕猴模型是非常有价值的评估 PSI 维持病毒抑制功效的临床前工具。这种前沿的结合该方法将用于评估我们在小鼠和猕猴中进行研究的建议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。