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: 10372975
• 负责人: CRAIG R COHEN
• 金额: $ 82.75万
• 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/10372975
• 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.

摘要