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.

项目概要（见说明）：艾滋病毒主要通过性传播，年轻妇女承担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，最佳策略将结合联合收割机有效的药物，在多个解剖室的活性，表现出快速和持续的药代动力学（PK），是安全的。理想情况下，应优先考虑持续给药制剂，因为坚持每日或性交依赖性给药已被证明是困难的。基于这些概念，该计划将重点关注替诺福韦（TFV）前药、富马酸替诺福韦酯（TDF）或GS 7340与马拉韦罗（MVC）（一种获得许可的CCR 5进入抑制剂）或IQP-0528（一种强效非核苷逆转录酶和进入抑制剂）的阴道环（IVR）给药。我们已经成功地将TDF和IQP-0528从猪尾猕猴（PTM）的IVRs中递送，并将探索替代TFV前药GS 7340的阴道递送，因为它具有比TFV更大的抗病毒活性，更好地分布到淋巴组织中，并且可能比TDF更稳定。TDF将成为研究的主要药物，因为与TFV相比，TDF具有更大的组织渗透性和效力，具有出色的安全性，并且我们在PTM中基于TDF的IVR TDF递送方面取得了令人兴奋的进展。最近口服和阴道PrEP临床试验的相互矛盾的结果突出了将临床前数据转化为真实的世界使用的困难和复杂性。行为和依从性可能会导致可变的试验结果。然而，我们认为这些不同的结果也有生物学基础。我们假设，女性生殖道粘膜环境，这可能是不同的青少年相比，尿道成熟的妇女，改变性，激素避孕，细菌性阴道病（BV）。这些变化调节药物PK和药效学（PD）以及HIV感染的风险，将平衡从保护转移到感染。我们将使用新型细胞和组织培养模型，使用从美国和非洲成人或青少年受试者中获得的临床样本（在性生活前后、开始长效甲羟孕酮（DMPA）避孕之前和之后、以及成功治疗BV之前和之后）测试这种模式对PK/PD和HIV易感性的影响。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。研究结果将促进确定最佳配方，并确定预防艾滋病毒的新战略。