Phase I rectally-formulated rectal microbicide

接受性肛交(AI)是异性恋者中的一种常见做法，其发生率一般在5%-10%之间 在美国和国外，有其他艾滋病毒感染风险的妇女中，妇女比例高达30%-50%。AI是 被认为是男男性行为者(MSM)中最常见的艾滋病毒传播途径。由于这种广泛和持续的艾滋病毒风险，正在开发局部艾滋病毒直肠杀菌剂来防止直肠性行为。 艾滋病毒的传播。总的MDP提案涉及需要确定开发直肠杀菌剂的最佳手段，以防止与肛交(AI)相关的艾滋病毒传播。对直肠杀微生物剂的安全性和有效性的评估必须考虑到，直肠性交本身可能会引起粘膜炎症，对测试杀菌剂的环境产生负面影响，并混淆了评估候选药物的安全指数。我们假设AI的机械创伤损害了粘膜，并伴随着随后的炎症变化，这些变化既增加了血清阴性宿主中艾滋病毒感染的风险，又增加了血清阳性宿主中艾滋病毒的脱落。如果不对这些安全性和有效性的修饰物进行调整，可能会导致(I)错误地将AI毒性归因于杀菌剂，以及(Ii)由于AI同时增强艾滋病毒感染而未能证明有效性。为了表征AI对直肠黏膜的免疫炎症后果，我们建议在临床研究中模拟AI。在不断升级的剂量-反应研究中，我们将(1)基于行为相关条件，通过使用模拟人工智能，重复地将直肠粘膜暴露于不断增加的性行为应激程度。在类似设计的试验中比较伴侣伴侣的结果将(2)验证模拟模型的结果，并支持它在未来的研究中使用。为了支持这些研究，我们还将(3)定义机械创伤(AI)和化学创伤(Nonoxnol-9)对粘膜反应的时间演变，以及(4)定义新的直肠通透性测量的性能特征。

Receptive anal intercourse (AI) is a common practice among heterosexuals with rates from 5-10% in the general population of women up to 30-50% among women with other risk for HIV infection, both in the US and abroad. AI is considered to be the most common route of HIV transmission in men who have sex with men (MSM). Because of this broad and continuing HIV risk, topical HIV rectal microbicides are being developed to prevent rectal sexual transmission of HIV. The overall MDP proposal addresses the need to define the optimal means of developing rectal microbicides for the prevention of HIV transmission associated with anal intercourse (AI). Assessments of safety and efficacy for rectal microbicides must consider that rectal intercourse itself may induce mucosal inflammation, negatively conditioning the environment in which the microbicides will be tested as well as confounding the safety indices by which a drug candidate would be evaluated. We hypothesize that the mechanical trauma of AI damages the mucosa with subsequent inflammatory changes which both enhance the risk for HIV infection in the seronegative host and increase HIV shedding in the seropositive host. Failure to adjust for these modifiers of safety and efficacy may result in both (i) falsely attributing AI toxicity to the microbicide and (ii) failing to demonstrate efficacy because of simultaneous enhancement of HIV infection due to AI. To characterize the immuno-inflammatory consequences of AI on the rectal mucosa, we propose to simulate AI in clinical studies. In escalating dose-response studies, we will (1) reproducibly expose the rectal mucosa to increasing degrees of coital stress through the use of simulated AI, based on behaviorally relevant conditions. Comparing results from partnered couples in a similarly designed trial will (2) validate the results from the simulated model, and support its use in future studies. To support these studies, we will also (3) define the temporal evolution of the mucosal response to mechanical (AI) and chemical (Nonoxynol-9) trauma and (4) define performance characteristics of novel rectal permeability measurements.