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 长期以来，人类阴道菌群一直被认为是影响妇女获得性行为的风险的因素 传播感染（ETI）在内，包括艾滋病毒，但这种贡献的程度和潜在的机制 尚未得到很好的定义。新鲜（通过教育，支持和健康升起的女性）队列 由艾滋病毒未感染的年轻南非妇女组成，在这个24岁妇女中有60％以上 艾滋病毒感染。在这个人群中，我们证明了具有阴道微生物群落的妇女由 乳酸乳杆菌的艾滋病毒获取率降低了4倍，粘膜CD4+ T细胞数量减少了 与社区不足的女性相比 乳杆菌。这种阴道营养不良的常见综合征，其特征是潜水员，非 - 乳杆菌主要的微生物群落被称为阴道细菌（BV）。标准治疗 抗生素导致BV相关的微生物降低，但与乳杆菌的重殖通常是 慢速，BV的复发很常见。鉴于明显的保护免受乳酸杆菌的感染的保护 主要的阴道微生物群，一种使用实时生物治疗产品（LBP）的干预策略是逻辑 方法。乳蛋白v，阴道施用并包含内源性乳杆菌CTV-05菌株 在美国，在第1阶段和2A研究中显示出极好的耐受性和接近80％的定殖。我们提出了一个 第2阶段的乳蛋白V的随机安慰剂对照试验嵌套在新鲜人群中。在60岁的南方 非洲妇女患有非乳突杆菌的微生物群，我们计划评估这种干预措施是否a） 降低下生殖道中的促炎细胞因子和HIV靶细胞，b）导致持续 乳酸杆菌的阴道微生物群落和c）在这一年轻人中是安全且可以接受的 艾滋病毒高风险的妇女。女性控制的艾滋病毒预防方法的发展是紧迫的优先事项， 但是仍然存在重大挑战，例如与当前方法的依从性问题以及需要 可持续的大规模分布。安全LBP的使用是开发的重要范式转变 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是否 可能有可能为妇女提供安全，有效，耐用，自我更新，独立，多重的 促进阴道健康并提供艾滋病毒及其他潜在其他潜在保护的预防产品 性传播疾病。