Novel long-acting microbicide and contraceptive intrauterine system

新型长效杀菌剂及避孕宫内节育系统

• 批准号: 8711938
• 负责人: DAVID R FRIEND
• 金额: $ 60.78万
• 依托单位: EASTERN VIRGINIA MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-04 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8711938
• 关键词: Accounting; Acquired Immunodeficiency Syndrome; Address; Adherence; Africa South of the Sahara; Animal Model; Animals; Anti-Retroviral Agents; Benchmarking; Biological Markers; Blood; Cells; Centers for Disease Control and Prevention (U.S.); Cervix Uteri; Cessation of life; Collaborations; Computer Simulation; Contraceptive Agents; Contraceptive Usage; Contraceptive methods; Copper; Coupled; Data; Development; Devices; Diphosphates; Dose; Drug Kinetics; Effectiveness; Endometrium; Engineering; Evaluation; Female; Fumarates; Gel; Genital system; Gilead brand of tenofovir disoproxil fumarate; Goals; HIV; High Prevalence; Implant; In Vitro; Incidence; Infection; Infectious Pregnancy Complications; Inflammation; Intrauterine Devices; Ions; Lead; Levonorgestrel; Liquid substance; Lymphatic; Lymphocyte; Lymphoid; Macaca; Macaca nemestrina; Mechanics; Modeling; Oral; Oryctolagus cuniculus; Participant; Pharmaceutical Preparations; Pharmacodynamics; Polymers; Population; Pregnancy; Pregnancy Complications; Prevention; Procedures; Prodrugs; Prophylactic treatment; Protocols documentation; Provider; Regimen; Reproductive Health; Research; Safety; Shapes; Solid; Staging; System; Technology; Tenofovir; Tenofovir disoproxil fumarate; Testing; Time; Tissues; Training; Tube; Unplanned pregnancy; Uterus; Vagina; Vaginal Gel; Vaginal Ring; Virus Diseases; Woman; Work; abortion; base; cervicovaginal; contraceptive microbicide; cost effective; design; efficacy testing; emtricitabine; implantation; improved; in utero; in vivo; innovation; irritation; manufacturing process; microbicide; new technology; nonhuman primate; novel; pandemic disease; prevent; prophylactic; prototype; public health relevance; reproductive; research clinical testing; screening; simian human immunodeficiency virus; success; transmission process; unintended pregnancy

DESCRIPTION (provided by applicant): Globally, approximately 34 million people are infected with human immunodeficiency virus (HIV), and sub- Saharan Africa is the region with the highest prevalence of infections. The incidence rate remains stubbornly high at 2.5 million new infections each year. In parallel with the global HIV/AIDS pandemic, unplanned pregnancies account for nearly half of all pregnancies worldwide and lead to almost 100,000 maternal deaths per year as a result of unsafe abortions and complications of pregnancy and delivery. The only anti-HIV microbicide with proof of concept data is tenofovir vaginal gel, dosed in an intermittent, pericoital regimen. Adherence in HIV prevention studies involving daily dosing regimens has generally been poor. The inability to demonstrate statistically significant efficacy for TFV 1% gel in the VOICE trial (once daily dosing with vaginal TFV 1% gel) was due to low adherence. Less than 30% of trial participants used the product per protocol. Similarly, low product adherence was most likely responsible for the inability to demonstrate effectiveness of oral tenofovir disoproxil fumarate (TDF)/emtricitabine in the Fem-PrEP trial. We propose to address these problems by developing an innovative intrauterine system (IUS) releasing a highly potent prodrug of tenofovir (TFV), tenofovir alafenamide fumarate (TAF) for a minimum of 1 year. TAF is a new, stable, lymphoid-targeting prodrug of TFV, which is undergoing late-stage clinical testing as an oral HIV treatment. TAF is 1000 times more potent than TFV and more stable and potent than the prodrug TDF (Viread(R)). TAF will be released continuously in combination with copper (Cu) from the IUS. Cu IUSs are one of the most well-established and cost-effective long-acting reversible contraceptives used and accepted around the world, which also provide non-hormonal benefits. Once an IUS is inserted, women have effective, discreet protection with 100% adherence, until the system is removed by a trained provider in a simple and fast office procedure. The main goal of this project is to demonstrate that TAF can be delivered from an IUS at a rate that provides effective levels of TFV-diphosphate (TFV-DP), the active metabolite, to local genital tissues (endometrium, cervix and vagina) and prevents HIV infection in the female reproductive tract. Benchmarks for pharmacokinetics (PK) (e.g., TFV-DP concentrations in vaginal lymphocytes) will be based on existing in vivo data. Safety and PK of early device prototypes will be assessed in the rabbit model. Safety, PK and efficacy of a lead IUS will be assessed in the low-dose repeat challenge nonhuman primate model in collaboration with the Centers for Disease Control team who developed this model. Success of the proposed work will provide women with access to an inexpensive, discreet, long-acting IUS that is safe and effective to prevent unintended/mistimed pregnancy and HIV infection, and will lead to a paradigm shift in the fields of HIV pre-exposure prophylaxis, contraception, and women's overall reproductive health.

描述（由申请人提供）：全球约有 3400 万人感染人类免疫缺陷病毒 (HIV)，撒哈拉以南非洲是感染率最高的地区。发病率仍然居高不下，每年有 250 万新感染者。在艾滋病毒/艾滋病全球流行的同时，意外怀孕占全世界怀孕总数的近一半，每年导致近 100,000 名孕产妇因不安全堕胎以及妊娠和分娩并发症而死亡。唯一具有概念验证数据的抗 HIV 杀菌剂是替诺福韦阴道凝胶，间歇给药， 性交周围方案。涉及每日给药方案的艾滋病毒预防研究的依从性普遍较差。无法证明 TFV 1% 凝胶具有统计显着功效 在 VOICE 试验中（每天一次使用阴道 TFV 1% 凝胶给药）的原因是依从性低。不到 30% 的试验参与者按照方案使用了该产品。同样，产品依从性低很可能是导致 Fem-PrEP 试验中无法证明口服富马酸替诺福韦二吡呋酯 (TDF)/恩曲他滨有效性的原因。我们建议通过开发一种创新的宫内系统 (IUS) 来解决这些问题，该系统释放一种高效的替诺福韦 (TFV) 前药，富马酸替诺福韦艾拉酚胺 (TAF)，持续时间至少 1 年。 TAF 是 TFV 的一种新型、稳定、靶向淋巴的前药，作为口服 HIV 治疗药物正在进行后期临床测试。 TAF 的效力比 TFV 强 1000 倍，并且比前药 TDF (Viread(R)) 更稳定、更有效。 TAF 将与 IUS 中的铜 (Cu) 结合持续释放。 Cu IUS 是世界各地使用和接受的最成熟、最具成本效益的长效可逆避孕药之一，它还提供非激素益处。一旦插入 IUS，女性就会得到有效、谨慎的保护，并且 100% 遵守，直到经过培训的提供者通过简单而快速的办公室程序移除该系统。该项目的主要目标是证明 TAF 可以从 IUS 中以一定的速度输送到局部生殖组织（子宫内膜、子宫颈和阴道），从而提供有效水平的 TFV-二磷酸 (TFV-DP)（活性代谢物）。预防女性生殖道中的艾滋病毒感染。药代动力学 (PK) 基准（例如阴道淋巴细胞中的 TFV-DP 浓度）将基于现有的体内数据。早期设备原型的安全性和 PK 将在兔子模型中进行评估。将与开发该模型的疾病控制中心团队合作，在低剂量重复挑战非人类灵长类动物模型中评估主要 IUS 的安全性、PK 和有效性。拟议工作的成功将为妇女提供一种廉价、谨慎、长效的 IUS，它安全有效地预防意外/不合时宜的怀孕和艾滋病毒感染，并将导致艾滋病毒暴露前领域的范式转变预防、避孕和妇女的整体生殖健康。