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: 8606164
• 负责人: Betsy C. Herold
• 金额: $ 39.41万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8606164
• 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（请参阅说明）：艾滋病毒主要是与承担疾病负担不相称的年轻妇女进行性传播。因此，在没有有效的疫苗的情况下，迫切需要安全有效的预防前预防（PREP）。我们假设最佳策略将结合在多个解剖区室中活跃的有效药物，表现出快速而持续的药代动力学（PK），并且是安全的。理想情况下，应优先考虑持续的递送配方，因为事实证明，遵守日常或依赖于同意的给药很困难。 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.我们已经从IVR中成功地从IVR中传递了TDF和IQP-0528，并将探索替代TFV前药GS7340的阴道传递，因为它比TFV具有比TFV更大的抗病毒活性，并且在淋巴机组织中更好地分布，并且比TDF更稳定。与TFV相比，TDF将成为研究的主要推动者，因为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PTMS中基于储层的IVR TDF递送的令人兴奋的进步。最近的临床试验与口腔和阴道准备的结果相互矛盾，突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可变试验结果。但是，我们建议这些不同的结果也存在生物学基础。我们假设，与荷尔蒙成熟的女性相比，青少年可能有所不同的女性生殖道粘膜环境因性别，荷尔蒙避孕和细菌性阴道病（BV）而改变。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。我们将使用从美国和非洲成人或青少年后的临床样本中，在发起前后的临床样本中，在启动仓库Medroxyprogesterone（DMPA）避孕药之前和之后测试该范式，以及BV成功治疗BV对PK/PD和HIV和HIV HIV和HIV HIV和HIV易于使用新颖的细胞和组织培养模型的影响。我们将评估临床样品对药物渗透性，摄取，代谢和抗病毒活性的影响，并探索有助于观察到的变化的机制。结果将促进最佳配方的识别，并确定预防艾滋病毒的新策略。