Next generation ultra-long acting antiretroviral formulations for HIV treatment and prevention

用于治疗和预防艾滋病毒的下一代超长效抗逆转录病毒制剂

• 批准号: 10877335
• 负责人: J. Victor Garcia-Martinez
• 金额: $ 36.05万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-24 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10877335
• 关键词: Next; generation; ultra; long; acting

Innovations recently introduced into the field of systemic PrEP are long-acting (LA) formulations of antiretrovirals that stably release drugs over many weeks either as nanocrystal-based-formulations or intravaginal rings. These approaches offer major benefits including: (a) the ability to mitigate poor patient compliance with daily systemic PrEP dosing; (b) the potential for a reduced reliance of HIV prevention on the front-line HIV therapeutic drugs; and (c) their ability to be utilized somewhat discreetly without requiring a partner’s knowledge or consent. In addition, similar advantages have been considered for the use of LA formulations for HIV therapy. Our long-term goal of this collaborative effort between Drs. Garcia, Benhabbour, Wahl and Kovarova is to develop a delivery systems for LA therapy and PrEP that can offer durable and sustained viral suppression and/or protection from HIV transmission while providing flexibility in the choice of active ingredient, high efficacy of HIV inhibition and increased user compliance. Animal models are essential for the in vivo evaluation of HIV prevention approaches. Significant progress has been made in the development and implementation of both non-human primate (NHP) and humanized mouse models of SIV/HIV infection for the evaluation of topical microbicides, systemic pre-exposure prophylaxis and HIV treatment. Although both systems have been shown to provide insight into the process of HIV acquisition and the effectiveness of different interventions, one notable advantage of using humanized mice is the ability to use highly relevant transmitted/founder human viruses and human infected cells for challenge experiments in the presence of human semen. In this regard, bone marrow/liver/thymus (or BLT) mice have become widely utilized to evaluate the efficacy of novel prevention approaches and treatment to HIV infection. Concordant results between humans, NHP and BLT mice when using the same drug and the same route of challenge (i.e. rectal vs. vaginal) confirm the suitability of this model for the pre-clinical efficacy evaluation of HIV prevention and therapy interventions as proposed in the following Specific Aims: Specific Aim 1) To develop and characterize novel, safe and effective polymer- based ultra-long acting in-situ forming implants (ISFI) for HIV treatment and prevention. Specific Aim 2: In vivo assessment of the efficacy of ultra-long acting EFdA ISFI formulation to prevent HIV transmission. Specific Aim 3: In vivo assessment of the efficacy of a combination ultra-long- acting antiretroviral formulation to control HIV replication in vivo.

最近引入系统性PrEP领域的创新是长效的 (LA)在多周内稳定释放药物的抗逆转录病毒制剂 或者作为基于纳米胶囊的制剂或者阴道环。这些方法 提供的主要益处包括：（a）能够减轻患者依从性差 每日全身性PrEP给药;（B）降低对HIV依赖的可能性 预防艾滋病毒的前线治疗药物;以及（c）他们是否有能力 在不需要伴侣的知情或同意的情况下谨慎地使用。 此外，对于LA的使用也考虑了类似的优点 用于HIV治疗的制剂。我们这项合作努力的长期目标 加西亚、本哈布、瓦尔和科瓦洛娃医生的合作是 用于LA治疗和PrEP的系统，可以提供持久和持续的病毒 抑制和/或防止艾滋病毒传播，同时提供灵活性， 活性成分的选择，抑制艾滋病病毒的高功效和增加用户 合规 动物模型对于体内评价HIV预防是必不可少的 接近。在发展方面取得重大进展， 非人灵长类动物（NHP）和人源化小鼠实施 用于评价局部杀微生物剂的SIV/HIV感染模型，全身 暴露前预防和艾滋病毒治疗。虽然这两个系统都 显示出对艾滋病毒感染过程和有效性的深入了解， 在不同的干预措施中，使用人源化小鼠的一个显著优点是 能够使用高度相关的传播/创始人人类病毒和人类 感染的细胞在人类精液的存在下进行挑战实验。在这 在这方面，骨髓/肝脏/胸腺（或BLT）小鼠已被广泛用于 评估新的艾滋病毒预防和治疗方法的有效性 感染当使用时，人类、NHP和BLT小鼠之间的结果一致 相同的药物和相同的激发途径（即直肠与阴道）证实了 该模型用于HIV临床前疗效评价的适用性 以下具体目标中提出的预防和治疗干预措施： 具体目标1）开发和表征新型、安全和有效的聚合物- 用于HIV治疗的基于超长效原位成型植入物（ISFI）， 预防 具体目的2：超长效EFdA ISFI的疗效的体内评估 预防艾滋病毒传播。 具体目标3：联合超长- 抗逆转录病毒制剂，以控制体内HIV复制。