Exploratory human trials of rectal microbicides

该提案将解决与逆转录酶（RT）发展相关的关键问题 抗逆转录病毒直肠杀微生物剂拟议的研究将使用RT抑制剂UC-781作为候选直肠杀微生物剂。 杀微生物剂和Biosyn Inc.，将成为该项目的私营部门领导者。 本提案的第一个目的是确定RT直肠给药的最佳临床前安全性评估。 杀微生物剂与必要的新药申请（IND）研究，然后是艾滋病毒研究 血清阴性受试者，随后在HIV血清阳性受试者中进行评价。尽管本项目中提议的研究侧重于RT类杀微生物剂，但预计本提案中开发的方法学方法可用于评价其他类杀微生物剂的安全性和初步疗效。目标1有四个具体目标：（1）进行必要的临床前动物研究，提交IND，允许涉及直肠给药UC-781凝胶的人体研究，（2）确定广泛的免疫学、分子学和组织病理学参数在评估潜在杀微生物剂毒性时的灵敏度和特异性，（3）评价肠外植体/感染系统作为产生直肠杀微生物剂在抗HIV感染中的效力的早期离体/体外证据的手段;（4）表征肛门性交活动对UC-781凝胶的分布和生物利用度的影响。 本研究的第二个目的是描述UC-781凝胶直肠给药的病毒学后遗症， HIV-1感染者。更具体地说，将进行研究以确定直肠给予UC-781凝胶后血浆、粘膜和直肠分泌物HIV-1病毒载量的动力学变化。此外，将对基线和治疗后粘膜和血浆病毒分离株进行基因分型，以确定UC-781凝胶暴露是否与病毒突变演变相关，以及这些变化是否仅限于直肠粘膜隔室或可在血浆隔室中检出。这些研究的完成将提供必要的数据，以优化未来的直肠杀微生物剂Phasel试验，提供艾滋病毒阳性受试者对RT杀微生物剂的病毒学反应的具体信息，并补充在U-19赠款项目1中开始的直肠杀微生物剂药物开发的临床前/发现阶段。

This proposal will address the critical issues pertinent to the development of reverse transcriptase (RT) antiretroviral rectal microbicides The proposed studies will use the RT inhibitor UC-781 as a candidate rectal microbicide and Biosyn Inc., will be the private sector leader of the project. The first aim of this proposal will be to define the optimal preclinical safety assessment of an RT rectal microbicide with the necessary Investigational New Drug Application (IND) studies, followed by studies in HIV seronegative subjects with subsequent evaluation in HIV seropositive subjects. Although the studies proposed in this project focus on the RT class of microbicide it is anticipated that the methodological approaches developed in this proposal could be used to evaluate other classes of microbicide for safety and preliminary efficacy. There are four specific goals in Aim 1: (1) To conduct the necessary preclinical animal studies, to file an IND, to allow human studies involving rectal administration of UC-781 gel, (2) To determine the sensitivity and specificity of a broad range of immunological, molecular and histopathological parameters in assessing potential microbicide toxicity, (3) To evaluate the intestinal explant / infection system as a means of generating early ex vivo/in vitro evidence of rectal microbicide efficacy in resisting HIV infection, and (4) To characterize the effect of anal coital activity on the distribution and bioavailabilty of UC-781 gel. The second aim of the study is to characterize the virological sequelae of rectal administration of UC-781 gel in subjects with HIV-1 infection. More specifically, studies will be conducted to determine the kinetic changes in plasma, mucosal, and rectal secretion HIV-1 viral load after rectal administration ofUC-781 gel. In addition, baseline and post treatment mucosal and plasma viral isolates will be genotyped to determine whether exposure to UC-781 gel is associated with evolution of viral mutations and whether these changes are restricted to the rectal mucosal compartment or can be detected in the plasma compartment. Completion of these studies will provide the necessary data to optimize the future conduct of rectal microbicide Phasel trials, provide specific information on the virological responses to RT microbicides in HIV positive subjects, and compliment the preclinical/discovery phase of rectal microbicide drug development begun in Project 1 of this U-19 Grant.