Next Generation Pre-exposure Prophylaxis

描述(由申请人提供)：粘膜接触艾滋病毒是全球绝大多数艾滋病毒-1感染的原因。具体地说，阴道性交是艾滋病毒最常见的传播形式。因此，防止性传播是当务之急。尽管CAPRISA 004试验取得了非常令人鼓舞的结果，但很明显，观察到的保护水平并不理想，还有很大的改进余地。此外，在正在进行的暴露前预防(PrEP)随机临床试验中(单独或联合使用)的化学预防性药物替诺福韦也被广泛用作艾滋病毒感染的一线治疗。在这份提案中，我们结合了默克公司和北卡罗来纳州大学四位杰出研究人员的优势和高度互补的技能，以高度创新的方法解决对下一代PrEP代理开发至关重要的问题。具体地说，1)由默克的Daria Hazuda开发的新的第二代整合酶抑制剂(MK-2048)，其尚未用于治疗或PrEP，并且具有与其他整合酶抑制剂不同的抗药性；2)在UNC，由J.Victor Garcia开发的高度创新的粘膜艾滋病毒体内传播模型，将首次利用无细胞和细胞相关的原发传播/创立者(F/T)病毒在精液存在的情况下进行挑战；3)UNC的Angela Kashuba开发的先进的分析方法，以确定阴道应用的MK-2048的PD/PK，以建立体内保护的相关性；4)UNC的Russ Mumper开发的黏附凝胶制剂和阴道内环，用于优化释放MK-2048，使其能够穿透女性生殖道组织，建立有效的药理屏障。为了实现这些目标，我们提出了以下具体目标：具体目标1)为新一代PrEP药物的开发和体内测试开发基础和临床前框架。具体目的2)开发整合酶抑制剂MK-2048的水基黏附凝胶制剂，用于阴道给药。具体目的3)在人源化BLT小鼠身上进行MK-2048的概念验证安全性和有效性研究。具体目的4)建立药代动力学-药效学(PK-PD)模型，评价MK-2048对人源化BLT小鼠雌性生殖道的保护作用。 与公共卫生有关：尽管使用了抗病毒药物来治疗艾滋病毒/艾滋病，但该流行病仍在继续蔓延。CAPRISA 004试验的最新结果表明，对感染艾滋病毒提供了部分保护，这一方法可用于预防或减缓该流行病的传播。在这项申请中，我们建议开发发现、开发和测试下一代暴露前预防制剂所需的基础设施。

DESCRIPTION (provided by applicant): Mucosal HIV exposures are responsible for the vast majority of HIV-1 infections worldwide. Specifically, vaginal intercourse is the most common form of HIV transmission. Therefore, prevention of sexual transmission is urgently needed. Despite the highly encouraging results from the CAPRISA 004 trial it is clear that the level of protection observed is suboptimal and that there is significant room for further improvement. In addition, Tenofovir, the chemo-prophylactive agent being used (alone or in combination) in ongoing randomized clinical trials of pre-exposure prophylaxis (PrEP) is also being widely used as front line therapy for HIV infection. In this proposal we combine the strengths of four outstanding investigators at Merck and UNC with highly complementary skills to address, using highly innovative approaches, issues of fundamental importance to the development of the next generation of PrEP agents. Specifically, 1) a novel second generation integrase inhibitor (MK-2048) developed by Daria Hazuda at Merck that has not been used for treatment or for PrEP and that has a resistance profile that is different from other integrase inhibitors; 2) at UNC, a highly innovative in vivo model of mucosal HIV transmission developed by J. Victor Garcia that will for the first time utilize cell free and cell associated primary transmitted/founder (F/T) viruses for challenge in the presence of semen; 3) state-of-the-art analytical methods developed by Angela Kashuba at UNC to determine the PD/PK of vaginally applied MK-2048 to establish correlates of in vivo protection; and 4) mucoadhesive gel formulations and intravaginal rings developed by Russ Mumper at UNC for the optimized release of MK-2048 capable of penetrating the tissues of the female reproductive tract to establish an effective pharmacological barrier. In order to attain these goals we propose the following specific aims: Specific Aim 1) To develop the basic and preclinical framework for the development and in vivo testing of new generations of PrEP agents. Specific Aim 2) To develop aqueous-based mucoadhesive gel formulations of the integrase inhibitor MK- 2048 for vaginal administration. Specific Aim 3) To conduct proof-of-concept safety and efficacy studies of MK-2048 in humanized BLT mice. Specific Aim 4) To generate pharmacokinetic-pharmacodynamic (PK-PD) models to assess the protective effect of MK-2048 in the female reproductive tract of humanized BLT mice. PUBLIC HEALTH RELEVANCE: Despite the use of antivirals for the treatment of HIV/AIDS the epidemic continues to spread. Recent results from the CAPRISA 004 trial demonstrating partial protection from HIV acquisition demonstrated that this approach could serve to prevent or slow down the spread of the epidemic. In this application we propose to develop the infrastructure needed to discover, develop and test the next generation of Pre-Exposure Prophylactic agents.