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: 10617632
• 负责人: CRAIG R COHEN
• 金额: $ 4.88万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-12 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10617632
• 关键词: 16S ribosomal RNA sequencing; AIDS prevention; Acquired Immunodeficiency Syndrome; Addendum; Adherence; Adverse event; Africa South of the Sahara; 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; Grant; 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; Participant; 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; peer; phase II trial; placebo controlled study; prevent; 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.

抽象的 人类阴道微生物群长期以来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 FRESH（通过教育、支持和健康而崛起的女性）群体尚未得到明确定义。 由未感染艾滋病毒的南非年轻女性组成，该地区 60% 以上的 24 岁女性感染艾滋病毒 在这个感染艾滋病毒的人群中，我们证明了阴道微生物群落占主导地位的女性。 卷曲乳杆菌的 HIV 感染率降低 4 倍，粘膜 CD4+ T 细胞数量减少，并且 与缺乏生殖道促炎细胞因子的社区的女性相比，生殖道促炎细胞因子水平较低 这种常见的阴道菌群失调综合征，其特点是存在多种非乳酸菌。 乳酸菌占主导地位的微生物群落，被称为细菌性阴道病（BV）的标准治疗。 抗生素导致 BV 相关微生物减少，但乳酸菌物种的重新定殖通常是 鉴于乳酸菌对感染具有明显的保护作用，细菌性阴道病的复发很常见。 阴道微生物群，使用活生物治疗产品（LBP）的干预主导策略是合乎逻辑的 LACTIN-V 经阴道给药，含有内源性卷曲乳杆菌 CTV-05 菌株。 在美国的 1 期和 2a 期研究中显示出优异的耐受性和接近 80% 的定植率。 LACTIN-V 的 2 期随机、安慰剂对照试验在 FRESH 队列中进行，受试者为 60 名南方年轻人。 对于微生物群非乳杆菌为主的非洲女性，我们计划评估这种干预是否a) 减少下生殖道中的促炎细胞因子和 HIV 靶细胞，b) 导致持久 以乳杆菌为主的阴道微生物群落 c) 在该年轻人群体中是安全且可接受的 艾滋病毒高危妇女 制定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 可持续的大规模分布的使用是发展中的一个重要的范式转变。 HIV 预防技术。FRESH / LACTIN-V 项目将提供关键数据来评估 LACTIN-V 是否有效。 可能有潜力为妇女提供安全、有效、持久、自我更新、性独立、多方面的机会 目的预防产品，可促进阴道健康并提供针对艾滋病毒和其他潜在疾病的保护 性传播感染。