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

摘要 长期以来，人类阴道微生物群一直被认为是影响女性获得性行为风险的一个因素。 包括艾滋病毒在内的传播感染，但这种贡献的程度和潜在的机制 还没有很好的定义。FRESH（女性通过教育、支持和健康崛起）队列 由未感染艾滋病毒的年轻南非妇女组成，该地区超过60%的24岁妇女 感染了艾滋病毒。在这个人群中，我们证明了阴道微生物群落以 卷曲乳杆菌的HIV感染率低4倍，粘膜CD 4 + T细胞数量减少， 与缺乏生殖道促炎细胞因子的社区相比，生殖道促炎细胞因子水平较低 乳杆菌属。这种常见的阴道生态失调综合征，其特征是多样的，非- 乳杆菌属占优势的微生物群落，被称为细菌性阴道病（BV）。标准治疗 抗生素导致BV相关微生物的减少，但乳杆菌属物种的再定殖通常是 慢，BV复发是常见的。因为乳酸杆菌对感染有明显的保护作用- 占主导地位的阴道微生物群，使用活生物制品（LBP）的干预策略是一种合乎逻辑的 approach. LACTIN-V，阴道给药，含有内源性L。crispatus CTV-05菌株，具有 在美国的I期和2a期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 FRESH队列中LACTIN-V的II期随机、安慰剂对照试验。在60个年轻的南 非洲妇女与非乳酸杆菌占主导地位的微生物群，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）导致持续的 乳酸杆菌占主导地位的阴道微生物群落和c）在这一年轻人群中是安全和可接受的 艾滋病毒高危妇女。发展由女性控制的艾滋病毒预防方法是一个紧迫的优先事项， 但仍然存在重大挑战，例如当前方法的遵守问题以及 可持续的大规模分销。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是否 可能有潜力为女性提供一个安全，有效，持久，自我更新，性交独立，多 目的预防产品，促进阴道健康，并提供保护免受艾滋病毒和其他潜在的 性病

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.