Phase 2 placebo-controlled randomized trial of LACTIN-V (Lactobacillus crispatus CTV-05) among women at high risk of HIV acquisition in Durban, South Africa

在南非德班感染艾滋病毒高危女性中进行的 LACTIN-V（卷曲乳杆菌 CTV-05）的 2 期安慰剂对照随机试验

• 批准号: 10406532
• 负责人: CRAIG R COHEN
• 金额: $ 6.64万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10406532
• 关键词: 16S ribosomal RNA sequencing; AIDS prevention; Acquired Immunodeficiency Syndrome; Addendum; Adherence; Adverse event; Antibiotics; Atopobium vaginae; Bacteria; Bacterial Vaginosis; Biological Response Modifier Therapy; CCR5 gene; CD4 Positive T Lymphocytes; Cells; Cervical; Communities; Data; Development; Dose; Education; Endocervix; Female; Female genitalia; Genital; Genitalia; Germ-Free; HIV; HIV risk; HLA-DR Antigens; Health; High Risk Woman; Human; Individual; Infection; Inflammation; Intervention; Lactobacillus; Link; Liquid substance; Metagenomics; Methods; Metronidazole; Microbe; Mucous Membrane; Mus; Oral; Phase; Placebos; Population; Prevention; Recurrence; Risk; Safety; Sampling; Severities; Sexually Transmitted Diseases; South Africa; South African; Syndrome; T-Lymphocyte; Technology; Testing; Vagina; Woman; arm; cohort; cytokine; dysbiosis; high risk; microbial community; microbicide; microbiota; parent grant; peer; placebo controlled study; randomized placebo controlled trial; reproductive tract; self-renewal; standard care; vaginal lactobacilli; vaginal microbiome; vaginal microbiota; young woman

ABSTRACT The human vaginal microbiota has long been considered a factor impacting women’s risk for acquiring sexually transmitted infections (STIs) including HIV, but the extent of this contribution and the underlying mechanisms have not been well defined. The FRESH (Females Rising through Education, Support, and Health) cohort consists of HIV-uninfected young South African women in a region where over 60% of 24 year old women are HIV infected. In this population, we demonstrated that women with vaginal microbial communities dominated by Lactobacillus crispatus had a 4-fold lower rate of HIV acquisition, reduced numbers of mucosal CD4+ T cells and lower levels of genital tract proinflammatory cytokines compared with women with communities deficient in Lactobacillus species. This common syndrome of vaginal dysbiosis, characterized by a diverse, non- Lactobacillus dominant microbial community, is known as bacterial vaginosis (BV). Standard treatment with antibiotics leads to a decrease in BV-associated microbes, but re-colonization with Lactobacillus species is often slow, and recurrence of BV is common. Given the apparent protection from infections afforded by a Lactobacillus- dominant vaginal microbiota, an intervention strategy using live biotherapeutic products (LBP) is a logical approach. LACTIN-V, vaginally administered and containining the endogenous L. crispatus CTV-05 strain, has shown excellent tolerability and close to 80% colonization in Phase 1 and 2a studies in the US. We propose a Phase 2 randomized, placebo-controlled trial of LACTIN-V nested within the FRESH cohort. In 60 young South African women with a non-Lactobacillus-dominant microbiota, we plan to assess whether this intervention a) reduces proinflammatory cytokines and HIV target cells in the lower genital tract, b) leads to a persistent Lactobacillus-dominant vaginal microbial community and c) is safe and acceptable in this population of young women at high risk for HIV. The development of female-controlled HIV prevention methods is an urgent priority, but significant challenges remain, such as adherence issues with current approaches and the need for sustainable large scale distribution. The use of a safe LBP is an important paradigm shift in the development of HIV prevention technologies. The FRESH / LACTIN-V project will provide critical data to assess if LACTIN-V could have the potential to offer women a safe, effective, durable, self-renewing, coitally independent, multi- purpose prevention product that promotes vaginal health and provides protection from HIV and potentially other STIs.

摘要 长期以来，人类阴道微生物区系一直被认为是影响女性性行为风险的一个因素 包括艾滋病毒在内的传播感染(STI)，但这种贡献的程度和潜在机制 还没有得到很好的定义。Fresh(通过教育、支持和健康崛起的女性)队列 由未感染艾滋病毒的年轻南非妇女组成，在该地区，超过60%的24岁妇女 感染了艾滋病毒。在这个人群中，我们证明了具有阴道微生物群落的女性受 皱纹乳杆菌的HIV获得率降低了4倍，粘膜CD4+T细胞数量减少， 生殖道促炎细胞因子水平低于社区妇女 乳杆菌菌种。这种常见的阴道生物失调综合征，其特征是多样的、非 乳杆菌为优势微生物群落，称为细菌性阴道病(BV)。标准的治疗方法 抗生素会导致BV相关微生物的减少，但乳杆菌的重新定植往往是 BV的缓慢、复发是常见的。鉴于乳酸菌对感染的明显保护作用- 优势阴道微生物区系，使用活生物治疗产品(LBP)的干预策略是合乎逻辑的 接近。LACTIN-V经阴道给药并含有内源性卷曲乳杆菌CTV-05株，具有 在美国的1期和2a期研究中显示出极好的耐受性和近80%的定殖率。我们提出了一个 在新鲜队列中嵌套的LACTIN-V的第二阶段随机、安慰剂对照试验。在60岁的年轻南方 具有非乳杆菌占优势的微生物群的非洲妇女，我们计划评估这种干预是否是一种) 减少下生殖道中的促炎细胞因子和HIV靶细胞，b)导致持续的 乳杆菌占优势的阴道微生物群落和c)在这一年轻群体中是安全和可接受的。 感染艾滋病毒风险较高的妇女。开发女性控制的艾滋病毒预防方法是当务之急， 但仍然存在重大挑战，例如当前方法的遵守问题，以及需要 可持续的大规模配送。使用安全的LBP是发展中的一个重要的范式转变 艾滋病毒预防技术。Fresh/LACTIN-V项目将提供关键数据，以评估LACTIN-V 有可能为女性提供安全、有效、耐用、自我更新、交友独立、多方面的 目的预防产品，促进阴道健康，提供对艾滋病毒和其他潜在疾病的保护 性传播疾病。