Abstract
BackgroundThe foreskin is the main site of HIV acquisition in a heterosexual uncircumcised man, but many men in endemic countries are reluctant to undergo penile circumcision (PC). Observational studies suggest that proinflammatory anaerobic bacteria are enriched on the uncircumcised penis, where they may enhance HIV susceptibility through increased foreskin inflammatory cytokines and the recruitment of HIV-susceptible CD4+ target cells. This trial will examine the impact of systemic and topical antimicrobials on ex vivo foreskin HIV susceptibility.Methods/designThis randomized, open-label clinical trial will randomize 125 HIV-negative Ugandan men requesting voluntary PC to one of five arms (n = 25 each). The control group will receive immediate PC, while the four intervention groups will defer PC for 1 month and be provided in the interim with either oral tinidazole, penile topical metronidazole, topical clindamycin, or topical hydrogen peroxide. The impact of these interventions on HIV entry into foreskin-derived CD4+ T cells will be quantified ex vivo at the time of PC using a clade A, R5 tropic HIV pseudovirus assay (primary endpoint); secondary endpoints include the impact of antimicrobials on immune parameters and the microbiota of the participant’s penis and of the vagina of their female partner (if applicable), assessed by multiplex enzyme-linked immunosorbent assay and 16S rRNA sequencing.DiscussionThere is a critical need to develop acceptable, simple, and effective means of HIV prevention in men unwilling to undergo PC. This trial will provide insight into the causative role of the foreskin microbiota on HIV susceptibility, and the impact of simple microbiota-focused clinical interventions. This may pave the way for future clinical trials using low-cost, nonsurgical intervention(s) to reduce HIV risk in uncircumcised heterosexual men.Trial registrationClinicalTrials.gov, NCT03412071. Retrospectively registered on 26 January 2018.
Highlights
The foreskin is the main site of HIV acquisition in a heterosexual uncircumcised man, but many men in endemic countries are reluctant to undergo penile circumcision (PC)
There is a critical need to develop acceptable, simple, and effective means of HIV prevention in men unwilling to undergo PC. This trial will provide insight into the causative role of the foreskin microbiota on HIV susceptibility, and the impact of simple microbiota-focused clinical interventions. This may pave the way for future clinical trials using low-cost, nonsurgical intervention(s) to reduce HIV risk in uncircumcised heterosexual men
Foreskin tissues are enriched for highly HIV-susceptible CD4+ T cell subsets, including T helper 17 (Th17) cells and CD4+ T cells expressing the HIV coreceptor CCR5 [11], and these highly susceptible CD4+ T cell subsets were reduced in the foreskins of HIV-exposed but seronegative men [12]
Summary
The steep decline in global HIV incidence observed in the 1990s and early 2000s has recently plateaued [34], indicating a critical need to refocus HIV prevention efforts and develop community-appropriate prevention tools. Based on recent studies linking the foreskin microbiota with local penile inflammation, increased HIV target cell density, and enhanced HIV acquisition risk, this clinical study will assess the impact of commonly used antibacterial agents on foreskin HIV susceptibility, immunology, and microbiota in Ugandan men. While the penile microbiota may be a central determinant of HIV risk, it is not known whether and/or in what way common antimicrobials will alter the composition of the foreskin microbiota It is an important point of principle to demonstrate that such changes, once induced, can alter local tissue immunology and HIV susceptibility. This randomized, open-label clinical trial aims to establish the impact of four widely available, cheap, and well-tolerated antimicrobials on foreskin immunology, HIV susceptibility, and microbiota.
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