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

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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.