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

项目摘要/摘要 用于治疗和预防的长效抗逆转录病毒疗法(ART)的迅速崛起 是基于一刀切的剂量策略，尽管这是我们在现实世界中的第一次经验， 在那里，患者管理挑战是常见的。为了解决这个问题，我们提出了一种新的药理学方法 现实世界中长效艺术的监控平台。我们的目标是开发和验证在家自助式 收集和护理点(POC)检测定量卡波替格韦/利培韦林(CAB/RPV)浓度以 支持患者管理并告知长效ART和PrEP的最佳使用，以期实现这一点 平台将可广泛实施，并能够适应下一批长效艾滋病毒疗法 发展。 CAB/RPV浓度在严格控制的试验中有影响，即使有1%的病毒学 突破率。在1,039名参与者中，CAB/RPV浓度一次变化超过10倍 注射后4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 这两种药物都高于中位数，无论存在什么其他风险因素--包括存档 抗药性突变。另一方面，一些患者达到了CAB/RPV浓度 远高于预期水平，可以轻松地将剂量延长到Q8W以外，但这种可能性并非如此 经过充分调查。在实践中，CAB/RPV浓度将比严格控制下的浓度变化更大 试验，因为现实世界的患者错过了预约，更换了提供者，并离开/重新进入护理。另外， 从注射到注射的人内变异性是未知的。为了解决这些差距和需求，我们建议 具体目标如下：目标1.验证居家自我收集和POC测试。建立在我们的 使用家庭自助收集的初步数据和通过微型质谱仪进行的POC测试，我们将 使用30名接受Q4W或Q8W治疗的HIV(PWH)患者的样本，开发和优化合适的检测方法 长效可注射CAB/RPV。检测将根据FDA的生物分析指南进行验证。目标2.分类 真实世界纵向队列中的CAB/RPV浓度。通过50个月的纵向采血 在接受Q4W或Q8W长效注射剂CAB/RPV时，我们计划将药物浓度分为低、 预期的和较高的类别，并定义特定的药代动力学(PK)参数，包括-和 人与人之间的可变性。目的3.建立个体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测试策略来确定患者特定的PK，进而， 达到目标浓度的最佳剂量频率。我们设想了一个易于使用的界面，临床医生 将输入药物浓度以计算个性化剂量。此应用程序是及时的，并提供了 创新以跟上快速崛起的长效时代的步伐。

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.