A platform for monitoring the efficacy and optimal dosing of long-acting ART

项目概要/摘要 迅速出现的用于治疗和预防的长效抗逆转录病毒疗法（ART）模式 是基于一个尺寸适合所有的剂量策略，尽管这些是我们在现实世界中的第一次经验， 患者管理的挑战是常见的。为了解决这个问题，我们提出了一种新的药理学方法。 在现实世界中的长效ART监测平台。我们的目标是开发和验证在家里的自我- 采集和床旁（POC）检测定量卡替拉韦/利匹韦林（CAB/RPV）浓度， 支持患者管理，并告知长效ART和PrEP的最佳使用， 该平台将广泛实施，并能够适应下一个在线长效艾滋病毒疗法， 发展 CAB/RPV浓度在严格对照试验中具有影响力，即使在1%的病毒学水平下， 突破率在1，039名参与者中，CAB/RPV浓度在单一剂量下变化超过10倍。 4-注射后一周时间点。在观察到的13个艾滋病毒突破中，没有一个发生在浓度为 两种药物均高于中位数，无论存在其他风险因素-包括存档 耐药突变另一方面，一些患者达到了CAB/RPV浓度 远高于预期水平，并且可以轻松地将给药延长至Q8 W以上，但这种可能性并不存在。 充分调查。在实践中，CAB/RPV浓度比严格控制的浓度变化更大。 因为现实世界的患者错过了预约，更换了提供者，离开/重新进入护理。此外，本发明还 注射与注射之间的人内变异性未知。为了解决这些差距和需求，我们建议 具体目标如下：目标1。家庭自行采集和POC检测。充分发挥两国 初步数据使用在家里自我收集和POC测试通过微型质谱仪，我们将 使用来自30名接受Q4 W或Q8 W治疗的HIV（PWH）感染者的样本，开发并优化合适的检测方法 长效可注射CAB/RPV。将使用FDA生物分析指南对试验进行验证。目标2.分类 真实世界纵向队列中的CAB/RPV浓度。通过纵向采血， PWH接受Q4 W或Q8 W长效注射CAB/RPV，我们计划将药物浓度分为低， 预期和高类别，并定义特定的药代动力学（PK）参数，包括 人与人之间的差异目标3。建立个性化给药间隔的药代动力学策略。 我们将确定理想的药物浓度检测策略，以确定患者特异性PK，反过来， 达到目标浓度的最佳给药频率。我们设想了一个易于使用的界面， 将输入药物浓度以计算个性化给药。此应用程序是及时和提供 创新，以跟上快速出现的长效时代。

Project Summary/Abstract The rapidly emerging modalities of long-acting antiretroviral therapy (ART) for treatment and prevention are based on a one-size-fits-all dosing strategy despite these being our first experiences in real-world settings, where patient management challenges are common. To address this issue, we propose a novel pharmacologic monitoring platform for long-acting ART in real-world settings. We aim to develop and validate at-home self- collections and point-of-care (POC) testing for quantitative cabotegravir/rilpivirine (CAB/RPV) concentrations to support patient management and inform optimal use of long-acting ART and PrEP, with the vision that this platform will be widely implementable and able to accommodate next in line long-acting HIV therapies in development. CAB/RPV concentrations were influential in tightly controlled trials, even with a 1% virologic breakthrough rate. Among 1,039 participants, CAB/RPV concentrations varied by more than 10-fold at a single 4-week post-injection time point. Of 13 observed HIV breakthroughs, none occurred when concentrations of both drugs were above the median, no matter what other risk factors were present –including archived resistance mutations. On the other end of the spectrum, some patients achieved CAB/RPV concentrations well-above expected levels and could comfortably extend dosing beyond Q8W, but this possibility was not adequately investigated. In practice, CAB/RPV concentrations will be more variable than in tightly controlled trials because real-world patients miss appointments, change providers, and leave/reenter care. Additionally, within-person variability from injection-to-injection is unknown. To address these gaps and needs, we propose the following specific aims: Aim 1. Validate at-home self-collections and POC testing. Building on our preliminary data using at-home self-collections and POC testing via miniature mass spectrometry, we will develop and optimize suitable assays using samples from 30 persons with HIV (PWH) receiving Q4W or Q8W long-acting injectable CAB/RPV. Assays will be validated using FDA bioanalytical guidance. Aim 2. Classify CAB/RPV concentrations in a real-world longitudinal cohort. Through longitudinal blood collections in 50 PWH receiving Q4W or Q8W long-acting injectable CAB/RPV, we plan to classify drug concentrations into low, expected, and high categories and define specific pharmacokinetic (PK) parameters, including within- and between-person variability. Aim 3. Establish pharmacokinetic strategies for personalized dose intervals. We will identify the ideal drug concentration testing strategy to determine patient-specific PK, and in turn, the optimal dose frequency to achieve goal concentrations. We envision an easy-to-use interface where clinicians will input drug concentrations to calculate personalized dosing. This application is timely and provides innovations to keep pace with the rapidly emerging long-acting era.