An Etonogestrel/Ethinyl Estradiol/QGriffithsin (ETG/EE/QGRFT) IVR to Prevent Pregnancy and HIV

用于预防怀孕和艾滋病毒的依托孕烯/乙炔雌二醇/QGriffithsin (ETG/EE/QGRFT) IVR

• 批准号: 10394426
• 负责人: Nina R. Derby
• 金额: $ 98.7万
• 依托单位: POPULATION COUNCIL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-06 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10394426
• 关键词: Adherence; Adverse event; Anti-Retroviral Agents; Antiretroviral resistance; Antiviral Agents; Biological Assay; Biological Response Modifiers; Caliber; Collaborations; Colposcopy; Computer Assisted; Contraceptive Agents; Contraceptive Usage; Contraceptive methods; Counseling; Couples; Cross-Over Studies; Development Plans; Dose; Drug Delivery Systems; Drug Kinetics; Estrogens; Ethinyl Estradiol; Etonogestrel; Excision; Fibroins; Formulation; Frequencies; Future; HIV; HIV Infections; HIV drug resistance; HIV resistance; Hemorrhage; High Pressure Liquid Chromatography; High Risk Woman; Human; In Vitro; Infectious Pregnancy Complications; Institutes; Instruction; Interview; Lead; Lectin; Levonorgestrel; Macaca mulatta; Measurement; Measures; Menstruation; Methodology; Pharmacodynamics; Pilot Projects; Placebos; Plasma; Population; Pregnancy; Prevention; Process; Progestins; Questionnaires; Reporting; Research Design; Resistance; Resistance development; Risk; Safety; Science; Self Assessment; Serious Adverse Event; Sex Behavior; Silicones; Silk; Technology; Testing; Text Messaging; Tissues; Vagina; Vaginal Ring; Viremia; Virus Shedding; Woman; Women' s Health; Work; anti-viral efficacy; base; demographics; design; diaries; efficacy study; experimental study; improved; in vivo; innovation; non-drug; novel; parity; preference; prevent; product development; reproductive tract; safety assessment; sex; side effect; simian human immunodeficiency virus; social; technology development; tool; transcriptome; transcriptome sequencing; transmission process; unintended pregnancy; vaginal fluid

An Etonogestrel/Ethinyl Estradiol/QGriffithsin (EEQ) IVR to Prevent Pregnancy and HIV Several multipurpose prevention technologies (MPTs) have been advanced to prevent unintended pregnancy and HIV. The current MPT development pipeline is dominated by antiretroviral (ARV) products with progestin- only contraception using levonorgestrel. The Population Council, in collaboration with Oak Crest Institute of Science (OCIS), proposes to develop a 90d pod-type IVR containing the progestin etonogestrel (ETG), the estrogen ethinyl estradiol (EE), and the anti-HIV lectin QGriffithsin (QGRFT), hereafter referred to as the EEQ IVR, to prevent unintended pregnancy and HIV. This product offers a highly effective contraceptive combination (used in NuvaRing®) with the extremely potent and stable non-ARV anti-HIV lectin QGRFT. The EEQ IVR offers significant advantages over ARV/progestin-only contraceptive products. It could reduce both the emergence of drug-resistant HIV and the concern of potential increased risk of HIV transmission as well as common irregular bleeding complaints associated with use of a progestin-only contraceptive. Aim 1: The proposed product development plan for the EEQ IVR includes innovative formulation work involving pod IVR designs and the use of silk fibroin to achieve QGRFT release for 90d. We will develop a scalable process to manufacture an EEQ IVR. Aim 2: Two lead EEQ IVRs will be tested in safety/pharmacokinetics/pharmacodynamics studies in rhesus macaques (RMs). We intend that the EEQ IVR will be safe, deliver target API doses for 90d in vivo and demonstrate in vitro efficacy against HIV/SHIV AD8. Based on these studies, the lead RM IVR will be selected and advanced to in vivo efficacy studies in RMs. We postulate that the EEQ IVR will be efficacious against SHIV AD8 in vivo and will not drive resistance. Aim 3: We will conduct a pilot study among 24 US couples to compare adherence, preference and acceptability of 3 placebo silicone IVRs of different external diameters (46mm, 56mm and 66mm) to inform the design of the EEQ IVR. Using a 3-way crossover study design, we will identify the external IVR diameter associated with greatest adherence and preference to inform the final EEQ IVR design. The EEQ IVR has the potential to significantly improve women’s health and advance the MPT and drug delivery fields. The EEQ IVR would be the first non-ARV MPT for women at high risk for both unintended pregnancy and HIV acquisition.

用于预防怀孕和艾滋病毒的依托孕烯/乙炔雌二醇/QGriffithsin (EEQ) IVR 多项多用途预防技术 (MPT) 已得到发展，可预防意外怀孕 和艾滋病毒。目前的 MPT 开发管线以含孕激素的抗逆转录病毒 (ARV) 产品为主。 仅使用左炔诺孕酮避孕。人口理事会与 Oak Crest 研究所合作 Science (OCIS) 提议开发一种含有孕激素依托孕烯 (ETG) 的 90 天荚式 IVR， 雌激素乙炔雌二醇 (EE) 和抗 HIV 凝集素 QGriffithsin (QGRFT)，以下简称 EEQ IVR，防止意外怀孕和艾滋病毒。该产品具有高效避孕作用 与极其有效且稳定的非 ARV 抗 HIV 凝集素 QGRFT 的组合（用于 NuvaRing®）。这 EEQ IVR 比仅使用 ARV/孕激素的避孕产品具有显着优势。它可以减少两者 耐药艾滋病毒的出现以及对艾滋病毒传播风险潜在增加的担忧以及 与使用纯孕激素避孕药相关的常见不规则出血症状。目标 1： 拟议的 EEQ IVR 产品开发计划包括涉及 pod IVR 的创新配方工作 设计并利用丝素蛋白实现QGRFT释放90d。我们将开发一个可扩展的流程 制造 EEQ IVR。目标 2：两个领先的 EEQ IVR 将在 恒河猴 (RM) 的安全性/药代动力学/药效学研究。我们希望 EEQ IVR 将是安全的，可在体内提供 90 天的目标 API 剂量，并在体外展示针对 HIV/SHIV AD8 的功效。 根据这些研究，将选择主要的 RM IVR 并将其推进到 RM 的体内功效研究。我们 假设 EEQ IVR 在体内对 SHIV AD8 有效并且不会产生耐药性。目标 3： 我们将对 24 对美国夫妇进行一项试点研究，以比较 3 对夫妇的依从性、偏好和可接受性 不同外径（46 毫米、56 毫米和 66 毫米）的安慰剂硅胶 IVR 为设计提供信息 EEQ IVR。使用 3 路交叉研究设计，我们将确定与以下相关的外部 IVR 直径 最大的坚持和偏好为最终的 EEQ IVR 设计提供信息。 EEQ IVR 有潜力 显着改善女性健康并推动 MPT 和药物输送领域的发展。 EEQ IVR 将是 首个针对意外怀孕和艾滋病毒感染高风险女性的非抗逆转录病毒 MPT。