Phase I rectally-formulated rectal microbicide

I期直肠配制直肠杀菌剂

基本信息

批准号：
7979337
负责人：
Craig Walter Hendrix
金额：
$ 58.28万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-18 至 2010-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7979337
关键词：
AIDS prevention Address Adverse event Anatomy Anus Appearance Attention Biopsy Characteristics Chemicals Clinical Clinical Research Clinical Trials Design Coitus Columnar Epithelium Couples Development Devices Dose Environment Evolution Failure Future General Population Goals HIV HIV Infections Heterosexuals Histologic Histology Human Volunteers Immunologics Immunology Infection Inflammation Inflammatory Injury Intestines Kinetics Measurement Measures Mechanics Modeling Molecular Mucositis Mucous Membrane Nonoxynol 9 Performance Permeability Phase Predisposition Program Development Rectum Research Ethics Committees Risk Route Safety Sexual Partners Sexual Transmission Simulate Stress Testing Time Study Tissues Toxic effect Trauma Visual Woman base conditioning drug candidate in vivo indexing men men who have sex with men microbicide novel prevent rectal rectal microbicide response response to injury simulation translational study transmission process vaginal microbicide

项目摘要

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.

接受性肛门性交（AI）是异性恋者中的一种常见做法，一般率从5-10％在美国和国外，患有其他艾滋病毒感染风险的女性中，女性的人口高达30-50％。 AI是被认为是与男性发生性关系（MSM）的男性中最常见的艾滋病毒传播途径。由于这种广泛而持续的艾滋病毒风险，正在开发局部HIV直肠菌皮以防止直肠性爱艾滋病毒的传播。总体MDP提案解决了定义开发直肠菌皮的最佳手段，以预防与肛门性交相关的HIV传播（AI）。对直肠微生物的安全性和疗效的评估必须认为，直肠性交本身可能引起粘膜炎症，对测试菌皮的环境进行负面调节，并混淆了评估药物候选药物的安全指标。我们假设AI的机械创伤会随后炎症变化损害粘膜，这既增强了血清神经宿主中HIV感染的风险，又增加了血清阳性宿主中HIV脱落的风险。未能针对这些安全性和功效的这些修饰符进行调整可能会导致（i）错误地将AI毒性归因于杀菌剂，并且（ii）由于AI引起的HIV感染同时增强了HIV感染。为了表征AI对直肠粘膜的免疫炎症后果，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）基于行为相关的条件，通过使用模拟AI，将直肠粘膜可重复地暴露于增加程度的同性压力。在类似设计的试验中比较伙伴夫妇的结果将（2）验证模拟模型的结果，并支持其在未来研究中的使用。为了支持这些研究，我们还将（3）定义对机械（AI）和化学（Nonoxynol-9）创伤的粘膜反应的时间演变，并且（4）（4）定义了新型直肠通透性测量的性能特征。