Department of Immunology, University of Toronto, St. George Campus Medical Sciences Building #6356 1 King's College Circle, Toronto, ON, M5S 1A8, Canada.
Department of Medicine, University of Toronto, Toronto, ON, Canada.
Trials. 2019 Jul 19;20(1):443. doi: 10.1186/s13063-019-3545-7.
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). 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/DESIGN: This 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.
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.
ClinicalTrials.gov, NCT03412071 . Retrospectively registered on 26 January 2018.
在未行包皮环切术的异性恋男性中，包皮是 HIV 感染的主要部位，但许多流行地区的男性不愿意行阴茎包皮环切术（PC）。观察性研究表明，促炎厌氧菌在未行包皮环切术的阴茎中富集，这些细菌可能通过增加包皮炎症细胞因子和募集 HIV 易感 CD4 靶细胞来增加 HIV 易感性。本试验将研究全身和局部抗菌药物对离体包皮 HIV 易感性的影响。
方法/设计：这是一项随机、开放性临床试验，将招募 125 名要求行自愿性 PC 的 HIV 阴性乌干达男性，将他们随机分为五组（每组 25 人）。对照组将立即行 PC，而四组干预组将延迟 1 个月行 PC，并在这期间分别给予口服替硝唑、阴茎局部甲硝唑、局部克林霉素或局部过氧化氢。在 PC 时，使用 A 型、R5 嗜性 HIV 假病毒测定法（主要终点），定量测定这些干预措施对离体包皮来源 CD4 T 细胞中 HIV 进入的影响；次要终点包括抗菌药物对参与者阴茎的免疫参数和微生物群以及其女性性伴侣（如果适用）阴道微生物群的影响，通过多重酶联免疫吸附试验和 16S rRNA 测序进行评估。
目前迫切需要开发可接受、简单且有效的方法，来预防不愿行 PC 的男性感染 HIV。本试验将深入了解包皮微生物群在 HIV 易感性中的因果作用，以及简单的以微生物群为重点的临床干预措施的影响。这可能为未来使用低成本、非手术干预措施来降低未行包皮环切术的异性恋男性 HIV 风险的临床试验铺平道路。
ClinicalTrials.gov，NCT03412071。于 2018 年 1 月 26 日进行了回顾性注册。
