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

雌孕酮/雌二醇/QGriffithsin(EEQ)IVR用于预防妊娠和HIV 几种多用途预防技术(MPTS)已经被用来预防意外怀孕 和艾滋病病毒。目前的MPT开发流水线主要是含有孕激素的抗逆转录病毒(ARV)产品。 只使用左旋诺孕酮避孕。人口理事会，与橡树冠研究所合作 科学(OCIS)，建议开发一种90d豆荚类型的IVR，其中包含孕酮雌孕酮(ETG)，即 雌激素烯雌二醇(EE)和抗HIV凝集素QGriffithsin(QGRFT)，以下简称EEQ IVR，以防止意外怀孕和艾滋病毒。这个产品是一种高效的避孕药 与极其有效且稳定的非抗逆转录病毒凝集素QGRFT(用于NuvaRing®)的组合。这个 与仅使用抗逆转录病毒/孕激素的避孕产品相比，EEQ IVR具有显著的优势。它可能会减少这两种情况 出现具有抗药性的艾滋病毒以及对艾滋病毒传播风险潜在增加的关切 与仅使用黄体酮避孕药有关的常见不规则出血主诉。目标1： 拟议的EEQ IVR产品开发计划包括涉及吊舱IVR的创新配方工作 设计并使用丝素蛋白实现QGRFT缓释90d。我们将开发一个可扩展的流程来 制造EEQ IVR。目标2：两个领先的EEQ IVR将在 恒河猴(RMS)安全性/药代动力学/药效学研究我们打算将EEQ IVR 将是安全的，在体内提供90d的目标API剂量，并在体外展示对HIV/Shiv AD8的有效性。 在这些研究的基础上，将选择RMIVR的先导，并将其应用于RMS的体内疗效研究。我们 假设EEQ IVR在体内对SHIV AD8有效，不会导致耐药性。目标3： 我们将在24对美国夫妇中进行一项初步研究，比较3对夫妇的忠诚度、偏好和接受度 不同外径(46 mm、56 mm和66 mm)的安慰剂硅胶IVR，以告知设计 EEQ IVR。使用3向交叉研究设计，我们将确定与以下因素相关的外部IVR直径 最大的坚持和偏好，以告知最终的EEQ IVR设计。EEQ IVR有可能 显著改善妇女健康，推进MPT和药物输送领域。EEQ IVR将为 为意外怀孕和感染艾滋病毒的高危妇女提供的第一个非抗逆转录病毒MPT。

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.