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

IF 11.7 1区医学 Q1 CELL BIOLOGY

Cell Reports Medicine Pub Date : 2024-08-20 DOI:10.1016/j.xcrm.2024.101705

Ronald M Galiwango, Brenda Okech, Daniel E Park, Lane Buchanan, Zhongtian Shao, Bernard Bagaya, Juliet Mpendo, Vineet Joag, Sergey Yegorov, Annet Nanvubya, Victoria M Biribawa, Teddy Namatovu, Charles Kato, Barbara Kawoozo, Ali Ssetaala, Moses Muwanga, Maliha Aziz, Tony Pham, Sanja Huibner, Aaron A R Tobian, Cindy M Liu, Jessica L Prodger, Rupert Kaul

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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.

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抗菌药物对未行包皮环切术男性阴茎 HIV 易感性和免疫学的影响：1/2期随机临床试验。

在阴茎微生物组中，与血清转换、免疫学和细胞相关的细菌（BASIC 菌种）通过诱导包皮炎症和 HIV 靶细胞招募，提高了未接受包皮环切术的异性恋男性对 HIV 的易感性。这项 1 / 2 期临床试验对未感染 HIV 的乌干达男性（n = 125）随机进行口服替硝唑、外用甲硝唑、外用克林霉素或外用过氧化氢治疗，以确定对体内外包皮 HIV 易感性、阴茎免疫学和 BASIC 细胞密度的影响。抗菌药的耐受性良好，116 人（93%）完成了治疗方案。外用甲硝唑和口服替硝唑可降低包皮内组织中易感染艾滋病病毒的 CD4+ T 细胞密度（预定的主要终点）。抗菌药物对减少包皮炎症和 BASIC 菌种密度、降低包皮 T 细胞亚群密度和增加包皮上皮完整性也有不同但实质性的作用。免疫改变与 BASIC 物种丰度的变化密切相关。针对阴茎微生物群的临床干预措施，尤其是外用甲硝唑，可能会降低未行包皮环切术男性对艾滋病毒的易感性。

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来源期刊

Cell Reports Medicine Biochemistry, Genetics and Molecular Biology-Biochemistry, Genetics and Molecular Biology (all)

CiteScore

15.00

自引率

1.40%

发文量

231

审稿时长

40 days

期刊介绍： Cell Reports Medicine is an esteemed open-access journal by Cell Press that publishes groundbreaking research in translational and clinical biomedical sciences, influencing human health and medicine. Our journal ensures wide visibility and accessibility, reaching scientists and clinicians across various medical disciplines. We publish original research that spans from intriguing human biology concepts to all aspects of clinical work. We encourage submissions that introduce innovative ideas, forging new paths in clinical research and practice. We also welcome studies that provide vital information, enhancing our understanding of current standards of care in diagnosis, treatment, and prognosis. This encompasses translational studies, clinical trials (including long-term follow-ups), genomics, biomarker discovery, and technological advancements that contribute to diagnostics, treatment, and healthcare. Additionally, studies based on vertebrate model organisms are within the scope of the journal, as long as they directly relate to human health and disease.

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