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: 9249465
• 负责人: Meredith R Clark
• 金额: $ 58.28万
• 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 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9249465
• 关键词: AIDS prevention; AIDS/HIV problem; 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; Goals; HIV; HIV Infections; 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; Protocols documentation; Provider; Regimen; Reproductive Health; Research; Safety; Solid; System; Technology; Tenofovir; Testing; Time; Tissues; Topical application; Training; Tube; Uterus; Vagina; Vaginal Gel; Vaginal Ring; Woman; Work; abortion; anti-HIV microbicide; base; cervicovaginal; cost effective; delivery complications; design; efficacy testing; emtricitabine; implantation; improved; in utero; in vivo; innovation; irritation; manufacturing process; microbicide; new technology; nonhuman primate; novel; oral HIV; pandemic disease; pre-exposure prophylaxis; prevent; prophylactic; prototype; public health relevance; reproductive tract; research clinical testing; reversible contraceptive; 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。在全球艾滋病毒/艾滋病流行的同时，非计划怀孕占全世界怀孕总数的近一半，每年导致近10万名产妇因不安全堕胎和妊娠及分娩并发症而死亡。唯一具有概念数据证明的抗HIV杀微生物剂是替诺福韦阴道凝胶，间歇给药， 围产期疗法涉及每日给药方案的HIV预防研究的依从性通常较差。无法证明TFV 1%凝胶的统计学显著疗效 VOICE试验（阴道TFV 1%凝胶每日一次给药）中的不良反应是由于依从性低。不到30%的试验参与者按照方案使用产品。同样，低产品依从性最有可能是在Fem-PrEP试验中无法证明口服富马酸替诺福韦酯（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，该系统释放替诺福韦（TFV）的高效前药富马酸替诺福韦艾拉酚胺（TAF）至少1年。TAF是TFV的一种新的、稳定的、淋巴靶向的前药，作为口服HIV治疗药物正在进行后期临床试验。TAF的效力是TFV的1000倍，并且比前药TDF（Viread（R））更稳定和有效。TAF将与IUS中的铜（Cu）一起持续释放。铜IUS是世界上使用和接受的最成熟和最具成本效益的长效可逆避孕药之一，它也提供非激素的好处。一旦插入IUS，妇女将获得有效、谨慎的保护，并100%坚持，直到经过培训的提供者以简单快速的办公室程序将该系统移除。该项目的主要目标是证明TAF可以从IUS以一定的速率递送，该速率可向局部生殖组织（子宫内膜、宫颈和阴道）提供有效水平的TFV-二磷酸盐（TFV-DP）活性代谢物，并预防女性生殖道中的HIV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。将在家兔模型中评估早期器械原型的安全性和PK。将与开发该模型的疾病控制中心团队合作，在低剂量重复激发非人灵长类动物模型中评估先导IUS的安全性、PK和疗效。拟议工作的成功将为妇女提供一种廉价、谨慎、长效的IUS，这种IUS安全有效，可预防意外/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预防、避孕和妇女整体生殖健康领域的范式转变。