Impact of Mucosal Immune Enviroment and semen on Prep and PD

粘膜免疫环境和精液对 Prep 和 PD 的影响

• 批准号: 8448474
• 负责人: Betsy C. Herold
• 金额: $ 39.69万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-18 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8448474
• 关键词: AIDS prevention; Adherence; Adolescence; Adolescent; Adult; Affect; African; Algorithms; Anatomy; Antiviral Agents; Bacterial Vaginosis; Behavior; Biological; Biological Response Modifiers; Biopsy; CCR5 gene; Cells; Cervical; Clinic; Clinical; Clinical Research; Clinical Trials; Conflict (Psychology); Contraceptive methods; Data; Dose; Drug Combinations; Drug Formulations; Drug Kinetics; Environment; Enzymes; Epidemic; Epithelial; Equilibrium; Evaluation; Exhibits; Family suidae; Female; Genital system; HIV; HIV Infections; Hormones; Host Defense; Human; Human immunodeficiency virus test; Immune; In Vitro; Individual; Infection; Inflammatory; Instruction; Irrigation; Licensing; Lymphoid Tissue; Macaca; Medroxyprogesterone; Metabolism; Modeling; Oral; Organic Anion Transporters; Outcome; Permeability; Pharmaceutical Preparations; Pharmacodynamics; Play; Predisposition; Prodrugs; Prophylactic treatment; RNA-Directed DNA Polymerase; Resistance; Risk; Role; Safety; Sampling; Seminal fluid; Swab; Tail; Tenofovir; Tenofovir disoproxil fumarate; Testing; Tight Junctions; Tissues; Translating; Vaccines; Vagina; Vaginal Ring; Vaginal delivery procedure; Variant; Viral; Woman; antiretroviral therapy; base; burden of illness; cervicovaginal; cohort; cost; design; drug efficacy; hormonal contraception; inhibitor/antagonist; insight; microbicide; non-nucleoside reverse transcriptase inhibitors; nonhuman primate; novel; novel strategies; pre-clinical; prevent; programs; promoter; rectal; response; sex; tissue/cell culture; uptake; vaginal microbicide; young woman

PROJECT SUMMARY (See Instructions): HIV is primarily sexually transmitted with young women bearing a disproportionate burden of disease. Thus, in the absence of an effective vaccine, there is an urgent need for safe and effective pre-exposure prophylaxis (PrEP). We hypothesize that the optimal strategy will combine potent drugs that are active in multiple anatomic compartments, exhibit rapid and sustained pharmacokinetics (PK), and are safe. Ideally, sustained delivery formulations should be prioritized, as adherence to daily or coitally dependent dosing has proven difficult. Building from these concepts, this Program will focus on intravaginal ring (IVR) delivery of tenofovir (TFV) prodrugs, tenofovir disoproxil fumarate (TDF) or GS7340 in combination with maraviroc (MVC), a licensed CCR5 entry inhibitor, or IQP-0528, a potent non-nucleoside reverse transcriptase and entry inhibitor. We have successfully delivered TDF and IQP-0528 from IVRs in pig-tailed macaques (PTM) and will explore vaginal delivery of the alternative TFV prodrug, GS7340, because it has greater antiviral activity than TFV, better distribution into lymphoid tissues and may be more stable than TDF. TDF will be the primary agent of study because of its greater tissue permeability and potency compared to TFV, excellent safety profile and our exciting progress with reservoir-based IVR TDF delivery in PTMs. The conflicting results of recent clinical trials with oral and vaginal PrEP highlight the difficulties and complexities in translating preclinical data into real world use. Behavior and adherence likely contribute to the variable trial results. However, we propose that there is also a biological basis for these disparate outcomes. We hypothesize that the female genital tract mucosal environment, which may differ in adolescents compared to hormonally mature women, is altered in response to sex, hormonal contraception, and bacterial vaginosis (BV). These changes modulate drug PK and pharmacodynamics (PD), as well as the risk of HIV infection, to shift the balance from protection to infection. We will test this paradigm with clinical samples obtained from U.S. and African adult or adolescent subjects pre- and post-sex, prior to and after initiating depot medroxyprogesterone (DMPA) contraception, and before and after successful treatment of BV for their impact on PK/PD and HIV susceptibility ex vivo using novel cell and tissue culture models. We will evaluate the impact of the clinical samples on drug permeability, uptake, metabolism, and antiviral activity and explore the mechanisms that contribute to observed changes. Results will promote the identification of optimal formulations and identify new strategies for HIV prevention.

项目摘要（参见说明）：艾滋病毒主要通过性传播，年轻女性承受着不成比例的疾病负担。因此，在缺乏有效疫苗的情况下，迫切需要安全有效的暴露前预防（PrEP）。我们假设最佳策略将结合在多个解剖区室中具有活性的强效药物，表现出快速和持续的药代动力学 (PK)，并且是安全的。理想情况下，应优先考虑持续递送制剂，因为事实证明坚持每日或性交依赖性剂量很困难。基于这些概念，该计划将重点关注替诺福韦 (TFV) 前药、富马酸替诺福韦二吡呋酯 (TDF) 或 GS​​7340 与马拉维罗 (MVC)（一种获得许可的 CCR5 进入抑制剂或 IQP-0528）的阴道环 (IVR) 递送，一种有效的非核苷逆转录酶和进入抑制剂。我们已成功在猪尾猕猴 (PTM) 中通过 IVR 递送 TDF 和 IQP-0528，并将探索替代 TFV 前药 GS7340 的阴道递送，因为它比 TFV 具有更强的抗病毒活性，更好地分布到淋巴组织中，并且可能更有效。比 TDF 稳定。 TDF 将成为研究的主要药物，因为与 TFV 相比，它具有更大的组织渗透性和效力、出色的安全性以及我们在 PTM 中基于储库的 IVR TDF 递送方面取得的令人兴奋的进展。最近口服和阴道 PrEP 临床试验的相互矛盾的结果凸显了将临床前数据转化为现实世界使用的困难和复杂性。行为和依从性可能会导致不同的试验结果。然而，我们认为这些不同的结果也有生物学基础。我们假设，与荷尔蒙成熟的女性相比，青少年的女性生殖道粘膜环境可能有所不同，并且会因性、激素避孕和细菌性阴道病（BV）而发生改变。这些变化调节药物 PK 和药效学 (PD) 以及 HIV 感染的风险，从而将平衡从保护转变为感染。我们将使用从美国和非洲成人或青少年受试者在性行为前和性行为后、开始长效甲羟孕酮 (DMPA) 避孕前后以及成功治疗 BV 前后对 PK/ 的影响来测试这一范例。使用新型细胞和组织培养模型进行体外 PD 和 HIV 易感性。我们将评估临床样本对药物渗透性、摄取、代谢和抗病毒活性的影响，并探索导致观察到的变化的机制。结果将促进最佳配方的确定并确定艾滋病毒预防的新策略。