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

最近引入系统性PrEP领域的创新是长期有效的 (A)能在数周内稳定释放药物的抗逆转录病毒制剂 无论是以纳米晶体为基础的配方还是阴道内环。这些方法 提供的主要好处包括：(A)能够缓解患者依从性差的情况 每日全身注射PrEP；(B)减少对艾滋病毒的依赖的可能性 预防第一线的艾滋病毒治疗药物；以及(C)它们有能力 在某种程度上谨慎地使用，而不需要合作伙伴的知情或同意。 此外，对于LA的使用也考虑了类似的优点 用于艾滋病毒治疗的配方。我们这次合作的长期目标是 加西亚、本哈博、瓦尔和科瓦罗娃博士之间的合作是开发一种分娩 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，同时在 有效成分的选择、高效的抑制HIV和增加使用量 合规性。 动物模型是体内评价艾滋病毒预防的关键 接近了。发展和改革取得重大进展。 非人灵长类(NHP)和人源化小鼠的实现 用于评价局部杀微生物剂的SIV/HIV感染模型 暴露前预防和艾滋病毒治疗。尽管这两个系统都已经 显示了对艾滋病毒感染过程的洞察力和有效性 在不同的干预措施中，使用人源化小鼠的一个显著优势是 能够使用高度相关的传播/创建者人类病毒和人类 在人类精液存在的情况下进行挑战实验的感染细胞。在这 在这方面，骨髓/肝脏/胸腺(或BLT)小鼠已被广泛用于 评价新的艾滋病毒预防方法和治疗方法的效果 感染。在人、NHP和BLT小鼠之间使用时的结果一致 相同的药物和相同的挑战途径(即直肠和阴道)证实 该模型在HIV临床前疗效评价中的适用性 下列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- 基于超长效原位成型植入物(ISFI)用于HIV治疗和 预防。 特定目标2：超长效EFdA ISFI的体内疗效评估 预防艾滋病毒传播的配方。 具体目标3：体内评估超长时间联合给药的疗效 代理抗逆转录病毒制剂，以控制艾滋病毒在体内的复制。

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.