Impact of antimicrobials on penile HIV susceptibility and immunology in uncircumcised men: A randomized phase 1/2 clinical trial
Within the penile microbiome, bacteria associated with seroconversion, immunology, and cells (BASIC species) enhance HIV susceptibility in heterosexual uncircumcised men by inducing foreskin inflammation and HIV target cell recruitment. This phase 1/2 clinical trial randomizes HIV-uninfected Ugandan men (n = 125) to either oral tinidazole, topical metronidazole, topical clindamycin, or topical hydrogen peroxide to define impact on ex vivo foreskin HIV susceptibility, penile immunology, and BASIC species density. Antimicrobials are well tolerated, and 116 (93%) participants complete the protocol. Topical metronidazole and oral tinidazole reduce the inner foreskin tissue density of HIV-susceptible CD4<sup>+</sup> T cells (predefined primary endpoint). Antimicrobials also have varying but substantial effects on reducing prepuce inflammation and BASIC species density, reducing density of foreskin T cell subsets, and increasing foreskin epithelial integrity. Immune alterations correlate strongly with changes in the abundance of BASIC species. Clinical interventions targeting the penile microbiota, particularly topical metronidazole, may reduce HIV susceptibility in uncircumcised men.
Authors
- Lane B Buchanan (ORCID: https://orcid.org/0009-0009-4506-890X)
- Jessica L. Prodger (ORCID: https://orcid.org/0000-0003-0805-4196)
- Cindy Meng-Hsin Liu (ORCID: https://orcid.org/0000-0003-4537-173X)
- Tony Pham (ORCID: https://orcid.org/0000-0001-5654-163X)
- Bernard S. Bagaya (ORCID: https://orcid.org/0000-0002-3847-2615)
- Juliet Mpendo (ORCID: https://orcid.org/0000-0001-8170-9019)
- Vineet Joag (ORCID: https://orcid.org/0000-0002-0723-3347)
- Charles Drago Kato (ORCID: https://orcid.org/0000-0003-3160-6657)
- Ronald Moses Galiwango (ORCID: https://orcid.org/0000-0003-3702-5722)
- Zhongtian Shao
- Sanja Huibner
- Victoria Menya Biribawa (ORCID: https://orcid.org/0009-0000-2115-2693)
- Barbara Kawoozo
- Aaron A.R. Tobian (ORCID: https://orcid.org/0000-0002-0517-3766)
- Moses Muwanga
- Teddy Namatovu
- Ali Ssetaala (ORCID: https://orcid.org/0000-0003-2156-3024)
- Brenda Okech (ORCID: https://orcid.org/0000-0002-1722-5156)
- Annet Nanvubya (ORCID: https://orcid.org/0000-0001-6092-6540)
- Daniel E. Park (ORCID: https://orcid.org/0000-0001-5139-5397)
- Rupert Kaul (ORCID: https://orcid.org/0000-0002-1586-4093)
- Sergey Yegorov (ORCID: https://orcid.org/0000-0002-7136-7921)
- Maliha Aziz (ORCID: https://orcid.org/0000-0002-8347-5487)
Institutions
- Western University (CA)
- Milken Institute (US)
- University Health Network (CA)
- Johns Hopkins University (US)
- University of Toronto (CA)
- George Washington University (US)
- Johns Hopkins Medicine (US)
- Ministry of Agriculture, Animal Industry and Fisheries (UG)
- University of Minnesota Medical Center (US)
- Makerere University (UG)
- Uganda Virus Research Institute (UG)
Publication Details
- Journal
- Cell Reports Medicine
- Published
- 2024-08-29
- DOI
- https://doi.org/10.1016/j.xcrm.2024.101705
- Citations
- 6
- Primary Topic
- Genital Health and Disease
- Type
- article
- Field-Weighted Citation Impact
- 3.44
Funders
- International AIDS Vaccine Initiative
- Canada Research Chairs
- University of Toronto
- National Institutes of Health
- Canadian Institutes of Health Research
- Fogarty International Center