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+ 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. [Display omitted] •Penile BASIC bacteria are associated with inflammation and increased HIV risk•This trial randomizes men to one of four antimicrobials prior to penile circumcision•Topical metronidazole and oral tinidazole reduce foreskin HIV susceptibility•Topical clindamycin causes the greatest reduction in BASIC species density Within the penile microbiome, BASIC bacteria are linked with tissue inflammation and increased HIV risk. In this randomized trial, Galiwango et al. demonstrate that the four antimicrobials tested have variable effects on penile BASIC density, immunology, and HIV susceptibility. The most consistent effects are mediated by topical metronidazole.