Tenofovir Douche as HIV Preexposure Prophylaxis for Receptive Anal Intercourse: Safety, Acceptability, Pharmacokinetics, and Pharmacodynamics (DREAM 01).

Rebecca Giguere, Hans M L Spiegel, Namandje N Bumpus, Amer Al-Khouja, Christina Bagia, Cindy Jacobson, Julie Elliott, Jared Engstrom, Aaron Seigel, Madhuri Manohar, Teresa Parsons, Stacey Edick, Rhonda Brand, Ken Ho, Lisa C Rohan, Alex Carballo-Dieguez, Ethel D Weld, Lin Wang, Mark A Marzinke, Ian McGowan, Peter Anton, Douglas J Hartman, Craig W Hendrix, Edward J Fuchs, Rahul P Bakshi

Journal: The Journal of infectious diseases 2024;229(4):1131-1140

PMID: 38019657

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Abstract

BACKGROUND

Despite highly effective HIV preexposure prophylaxis (PrEP) options, no options provide on-demand, nonsystemic, behaviorally congruent PrEP that many desire. A tenofovir-medicated rectal douche before receptive anal intercourse may provide this option.

METHODS

Three tenofovir rectal douches-220 mg iso-osmolar product A, 660 mg iso-osmolar product B, and 660 mg hypo-osmolar product C-were studied in 21 HIV-negative men who have sex with men. We sampled blood and colorectal tissue to assess safety, acceptability, pharmacokinetics, and pharmacodynamics.

RESULTS

The douches had high acceptability without toxicity. Median plasma tenofovir peak concentrations for all products were several-fold below trough concentrations associated with oral tenofovir disoproxil fumarate (TDF). Median colon tissue mucosal mononuclear cell (MMC) tenofovir-diphosphate concentrations exceeded target concentrations from 1 hour through 3 to 7 days after dosing. For 6-7 days after a single product C dose, MMC tenofovir-diphosphate exceeded concentrations expected with steady-state oral TDF 300 mg on-demand 2-1-1 dosing. Compared to predrug baseline, HIV replication after ex vivo colon tissue HIV challenge demonstrated a concentration-response relationship with 1.9 log10 maximal effect.

CONCLUSIONS

All 3 tenofovir douches achieved tissue tenofovir-diphosphate concentrations and colorectal antiviral effect exceeding oral TDF and with lower systemic tenofovir. Tenofovir douches may provide a single-dose, on-demand, behaviorally congruent PrEP option, and warrant continued development. Clinical Trials Registration . NCT02750540.

Address: Division of Clinical Pharmacology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.; Division of Infectious Diseases, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.; Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.; Orion Biotechnology, Ottawa, Ontario, Canada.; Division of Gastroenterology, Department of Medicine, University of California Los Angeles, Los Angeles, California, USA.; Division of Clinical Pharmacology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.; Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.; HIV Center for Clinical and Behavioral Studies, Columbia University and NewYork State Psychiatric Institute, New York, New York, USA.; Magee Womens Research Institute, Pittsburgh, Pennsylvania, USA.; Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.; Magee Womens Research Institute, Pittsburgh, Pennsylvania, USA.; Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.; Division of Clinical Pharmacology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.; Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.; Kelly Government Solutions, Contractor to Division of AIDS, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland, USA.; Division of Clinical Pharmacology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.; Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.; Division of Clinical Pharmacology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.; Division of Infectious Diseases, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.; Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

DOI: 10.1093/infdis/jiad535

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MeSH Terms: Humans, Male, Adenine, Anti-HIV Agents, Colorectal Neoplasms, Diphosphates, Emtricitabine, HIV Infections, Homosexuality, Male, Organophosphates, Pre-Exposure Prophylaxis, Sexual and Gender Minorities, Tenofovir