Impact of antimicrobials on penile HIV susceptibility and immunology in uncircumcised men: A randomized phase 1/2 clinical trial

Ronald M. Galiwango, Departments of Medicine and Immunology, University of Toronto, Toronto, ON M5S1A8, Canada.
Brenda Okech, UVRI-IAVI HIV Vaccine Program, Entebbe, Uganda.
Daniel E. Park, Department of Environmental and Occupational Health, Milken Institute School of Public Health, George Washington University, Washington, DC 20052, USA.
Lane Buchanan, Departments of Microbiology and Immunology and Epidemiology and Biostatistics, Schulich School of Medicine and Dentistry, Western University, London, ON N6A3K7, Canada.
Zhongtian Shao, Departments of Microbiology and Immunology and Epidemiology and Biostatistics, Schulich School of Medicine and Dentistry, Western University, London, ON N6A3K7, Canada.
Bernard Bagaya, UVRI-IAVI HIV Vaccine Program, Entebbe, Uganda; Department of Microbiology, Makerere University College of Health Sciences, Kampala, Uganda.
Juliet Mpendo, UVRI-IAVI HIV Vaccine Program, Entebbe, Uganda.
Vineet Joag, Departments of Medicine and Immunology, University of Toronto, Toronto, ON M5S1A8, Canada; Centre for Immunology, University of Minnesota Medical School, Minneapolis, MN 55455, USA.
Sergey Yegorov, Departments of Medicine and Immunology, University of Toronto, Toronto, ON M5S1A8, Canada; McMaster University, Institute for Infectious Disease Research, Guelph, ON L8S4L8, Canada.
Annet Nanvubya, UVRI-IAVI HIV Vaccine Program, Entebbe, Uganda.
Victoria M. Biribawa, UVRI-IAVI HIV Vaccine Program, Entebbe, Uganda.
Teddy Namatovu, UVRI-IAVI HIV Vaccine Program, Entebbe, Uganda.
Charles Kato, UVRI-IAVI HIV Vaccine Program, Entebbe, Uganda.
Barbara Kawoozo, UVRI-IAVI HIV Vaccine Program, Entebbe, Uganda.
Ali Ssetaala, UVRI-IAVI HIV Vaccine Program, Entebbe, Uganda.
Moses Muwanga, Entebbe General Hospital, Entebbe, Uganda.
Maliha Aziz, Department of Environmental and Occupational Health, Milken Institute School of Public Health, George Washington University, Washington, DC 20052, USA.
Tony Pham, Department of Environmental and Occupational Health, Milken Institute School of Public Health, George Washington University, Washington, DC 20052, USA.
Sanja Huibner, Departments of Medicine and Immunology, University of Toronto, Toronto, ON M5S1A8, Canada.
Aaron A. Tobian, Department of Pathology, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA.
Cindy M. Liu, Department of Environmental and Occupational Health, Milken Institute School of Public Health, George Washington University, Washington, DC 20052, USA.
Jessica L. Prodger, Departments of Microbiology and Immunology and Epidemiology and Biostatistics, Schulich School of Medicine and Dentistry, Western University, London, ON N6A3K7, Canada.
Rupert Kaul, Departments of Medicine and Immunology, University of Toronto, Toronto, ON M5S1A8, Canada; Department of Medicine, University Health Network, Toronto, ON M5G2C4, Canada. Electronic address: rupert.kaul@utoronto.ca.

Document Type

Journal Article

Publication Date

8-20-2024

Journal

Cell reports. Medicine

DOI

10.1016/j.xcrm.2024.101705

Keywords

HIV transmission; Uganda; antimicrobials; clinical trial; genital immunology; penile microbiome

Abstract

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 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.

Department

Environmental and Occupational Health

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