This proposal addresses the need to develop a rational, cost effective, and scientifically robust approach to the development of topical rectal microbicides from preclinical to exploratory studies in humans. The individual projects explore distinct, but overlapping areas of microbicide research that, cumulatively, will define the future of rectal microbicide development. The key premise that underpins the proposal is that receptive anal intercourse (RAI) is a common activity, playing a significant role in the transmission of HIV infection. Heterosexual RAI is common, with rates of 5-10% in US women and is considered to be the most common route of HIV transmission in men who have sex with men. Failure to acknowledge the role that RAI plays in the global AIDS pandemic is likely to limit the success of intervention strategies and compromise attempts to develop safe and effective vaginal microbicides. This MDP Project application is a U19, a collaborative effort with NIH and private sectors, to initiate coordinated, multidisciplinary research involving many of the world's experts in disciplines related to rectal microbicide development. We have focused our efforts on one class of microbicides, the reverse-transcriptase (RT) inhibitors (PMPA, UC-781, and TMC-120), two of which are in clinical trials as vaginal microbicide form. We have the support of three corporate sponsors (Biosyn, Inc., Gilead Sciences, and Tibotec-Virco) to initiate these efforts. The """"""""preclinical"""""""" phase includes cell line, intestinal explant and macaque studies of microbicide safety and efficacy (Project by McGowan) which will progress microbicides into exploratory human trials designed to optimize microbicide safety evaluation, provide initial ex vivo/in vitro efficacy data, and information about distribution and bioavailability of RT microbicides (Project by Corner). The goal, over 5 years, will be to assess, what are the most cost effective and predictive assays for use in future microbicide development. Projects by Gorbach will target the role of RAI on mucosal function, the behavioral correlates of RAI, and acceptability studies of candidate formulations. Failure to adjust for these modifiers of safety and efficacy may result in (1) falsely attributing RAI toxicity to the microbicide and (2) failing to demonstrate efficacy because of simultaneous enhancement of HIV transmission due to RAI. The information derived from these studies will be critical for RT development, but will also provide a rational basis for the development of other classes of rectal microbicides.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
1U19AI060614-01
Application #
6804854
Study Section
Special Emphasis Panel (ZRG1-AARR-A (51))
Program Officer
Black, Roberta J
Project Start
2004-08-15
Project End
2009-07-31
Budget Start
2004-08-15
Budget End
2005-07-31
Support Year
1
Fiscal Year
2004
Total Cost
$2,429,940
Indirect Cost
Name
University of California Los Angeles
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Chiu, Wai Kan; Brand, Rhonda M; Camp, Danielle et al. (2017) The Safety of Multiple Flexible Sigmoidoscopies with Mucosal Biopsies in Healthy Clinical Trial Participants. AIDS Res Hum Retroviruses 33:820-826
Leyva, Francisco; Fuchs, Edward J; Bakshi, Rahul et al. (2015) Simultaneous Evaluation of Safety, Acceptability, Pericoital Kinetics, and Ex Vivo Pharmacodynamics Comparing Four Rectal Microbicide Vehicle Candidates. AIDS Res Hum Retroviruses 31:1089-97
Preza, Gloria Cuevas; Yang, Otto O; Elliott, Julie et al. (2015) T lymphocyte density and distribution in human colorectal mucosa, and inefficiency of current cell isolation protocols. PLoS One 10:e0122723
Yang, Otto O; Ibarrondo, F Javier; Price, Charles et al. (2014) Differential blood and mucosal immune responses against an HIV-1 vaccine administered via inguinal or deltoid injection. PLoS One 9:e88621
Yang, Kuo-Hsiung; Hendrix, Craig; Bumpus, Namandje et al. (2014) A multi-compartment single and multiple dose pharmacokinetic comparison of rectally applied tenofovir 1% gel and oral tenofovir disoproxil fumarate. PLoS One 9:e106196
Richardson-Harman, Nicola; Hendrix, Craig W; Bumpus, Namandjé N et al. (2014) Correlation between compartmental tenofovir concentrations and an ex vivo rectal biopsy model of tissue infectibility in the RMP-02/MTN-006 phase 1 study. PLoS One 9:e111507
Gorbach, Pamina M; Pines, Heather; Javanbakht, Marjan et al. (2014) Order of orifices: sequence of condom use and ejaculation by orifice during anal intercourse among women: implications for HIV transmission. J Acquir Immune Defic Syndr 67:424-9
Pines, Heather A; Gorbach, Pamina M; Weiss, Robert E et al. (2013) Acceptability of potential rectal microbicide delivery systems for HIV prevention: a randomized crossover trial. AIDS Behav 17:1002-15
Leyva, Francisco J; Bakshi, Rahul P; Fuchs, Edward J et al. (2013) Isoosmolar enemas demonstrate preferential gastrointestinal distribution, safety, and acceptability compared with hyperosmolar and hypoosmolar enemas as a potential delivery vehicle for rectal microbicides. AIDS Res Hum Retroviruses 29:1487-95
Gorbach, Pamina M; Weiss, Robert E; Fuchs, Edward et al. (2012) The slippery slope: lubricant use and rectal sexually transmitted infections: a newly identified risk. Sex Transm Dis 39:59-64

Showing the most recent 10 out of 35 publications