The Development of a Rectal Enema As Microbicide (DREAM) Program addresses the critical need to develop a highly effective, safe, and acceptable microbicide enema with the promise of greater adherence as a more behaviorally-transparent alternative for the prevention of rectal HIV infection. The overall goal of the program is to develop a single dose rectal enema to deliver a tenofovir (TFV) prodrug capable of providing one week of protection. This strategy builds upon proven high levels of efficacy of TFV-based pre-exposure prophylaxis (PrEP) in adherent persons and directly targets the greatest weakness of PrEP regimens - prophylactic failure due to poor adherence. Given the common practice of rectal douching with an enema prior to receptive anal sex, we have selected a dosing strategy which requires little or no behavioral change compared to other oral and topical approaches. Topical delivery also significantly reduces systemic exposure compared to oral and injectable approaches. We propose pharmacokinetic enhancements to increase TFV bioavailability and provide sustained release. Three TFV prodrugs with far greater tissue and cellular uptake than TFV itself - TFV disoproxil fumarate, TFV alafenamide fumarate (TAF, formerly GS7340), and CMX157 - have been selected for study. Integrated with 3 other projects and 3 cores in the DREAM Program, Project 1 involves a series of clinical studies to achieve the following specific aims:
Aim 1 : Determine the combination of TFV dose and enema tonicity best able to achieve our colon tissue target drug concentrations.
Aim 2 : Compare TFV enema dosing before and after to recommend dose timing and the impact of semen on tissue drug concentrations.
Aim 3 : Evaluate the use of biomarkers for both enema dosing and sexual activity to provide objective evidence of adherence to protocol prescribed dosing.
Aim 4 : Provide clinical samples (plasma, PBMC, colon tissue/cells, rectal fluid) to support method development and assay validation in Project 2, Project 3, and Core C.

Public Health Relevance

A safe, effective HIV pre-exposure prophylaxis strategy with high levels of adherence is urgently needed to protect men and women at highest risk of HIV infection from anal sex. We propose development of a TFV enema to take advantage of common enema use associated with anal sex and the proven efficacy of TFV. This project optimizes the TFV enema formulation to inform more advanced clinical studies.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program--Cooperative Agreements (U19)
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Special Emphasis Panel (ZAI1-BP-A (M2))
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Johns Hopkins University
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Hoang, Thuy; Date, Abhijit A; Ortiz, Jairo Ortiz et al. (2018) Development of rectal enema as microbicide (DREAM): Preclinical progressive selection of a tenofovir prodrug enema. Eur J Pharm Biopharm :
Hummert, Pamela; Parsons, Teresa L; Ensign, Laura M et al. (2018) Validation and implementation of liquid chromatographic-mass spectrometric (LC-MS) methods for the quantification of tenofovir prodrugs. J Pharm Biomed Anal 152:248-256
Carballo-Dieguez, Alex; Giguere, Rebecca; Lentz, Cody et al. (2018) Rectal Douching Practices Associated with Anal Intercourse: Implications for the Development of a Behaviorally Congruent HIV-Prevention Rectal Microbicide Douche. AIDS Behav :
Xiao, Peng; Gumber, Sanjeev; Marzinke, Mark A et al. (2018) Hypo-osmolar Formulation of Tenofovir (TFV) Enema Promotes Uptake and Metabolism of TFV in Tissues, Leading to Prevention of SHIV/SIV Infection. Antimicrob Agents Chemother 62:
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Seneviratne, Herana Kamal; Hendrix, Craig W; Fuchs, Edward J et al. (2018) MALDI Mass Spectrometry Imaging Reveals Heterogeneous Distribution of Tenofovir and Tenofovir Diphosphate in Colorectal Tissue of Subjects Receiving a Tenofovir-Containing Enema. J Pharmacol Exp Ther 367:40-48
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