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.

最近引入系统准备领域的创新是长效的 （LA）抗逆转录病毒的公式在数周内稳定释放药物 作为基于纳米晶体的形成或静脉内环。这些方法 提供主要好处，包括：（a）减轻患者合规性差的能力 每天进行全身准备剂量； （b）降低HIV的潜力 预防前线HIV治疗药物； （c）他们的能力 在不需要伴侣的知识或同意的情况下谨慎使用。 此外，使用了类似的优势来使用LA 艾滋病毒治疗的公式。我们的合作努力的长期目标 在DR之间。加西亚，本布布尔，瓦尔和科瓦洛瓦将开发交付 可以提供耐用且持续病毒的LA治疗和准备系统 在提供灵活性的同时，抑制和/或保护艾滋病毒传播 选择主动成分，高效率的HIV抑制和增加的用户 遵守。 动物模型对于预防HIV的体内评估至关重要 方法。在开发中取得了重大进展， 实施非人类灵长类动物（NHP）和人性化小鼠 SIV/HIV感染的模型，用于评估局部微生物的系统性 暴露前预防和HIV治疗。虽然这两个系统已经 证明可以洞悉艾滋病毒收购过程和有效性 在不同的干预措施中，使用人性化小鼠的一个值得注意的优势是 能够使用高度相关的传播/创始人人类病毒和人类 在人类精液存在下，被感染的细胞进行挑战实验。在这个 考虑到骨髓/肝脏/胸腺（或BLT）小鼠已被广泛使用 评估新型预防方法和艾滋病毒治疗的效率 感染。使用时人，NHP和BLT小鼠之间的一致结果 相同的药物和相同的挑战途径（即直肠与阴道）确认 该模型对艾滋病毒临床前效率评估的适用性 预防和治疗干预措施如以下具体目的： 特定目的1）开发和表征新颖，安全有效的聚合物 - 基于艾滋病毒治疗和 预防。 特定目的2：在体内评估超长作用EFDA ISFI的效率 防止艾滋病毒传播的公式。 特定目的3：在体内评估超长组合的效率 作用抗逆转录病毒配方，以控制体内HIV复制。