Predictive Power of PEth for HIV Prevention in the Long-Acting Era

PROJECT SUMMARY
Unhealthy alcohol use, common among persons with (PWH) and at risk for HIV, is associated with multiple
deleterious effects that increase the risk of HIV transmission. However, identifying individuals with unhealthy
alcohol use in practice remains challenging because self-report consistently underrepresents true alcohol
consumption. An objective measure of alcohol use, with clearly defined associations with clinical outcomes
relevant for HIV prevention and transmission, would eliminate the time and resources dedicated to trying to
subjectively quantify alcohol use, and would instead direct efforts towards swift and effective clinical
interventions. Phosphatidylethanol (PEth) holds tremendous untapped potential as an objective, quantitative
alcohol biomarker that could fill this unmet need. However, PEth has primarily been used in a qualitative and
inconsistent manner which complicates interpretation and hinders actionable interventions. PEth's application
to HIV prevention and treatment is also limited, especially with contemporary HIV pre-exposure prophylaxis
(PrEP) and antiretroviral therapy (ART) with injectable long-acting agents such as cabotegravir (CAB-LA) and
cabotegravir/rilpivirine (CAB/RPV-LA). Delays in PEth concentration results in practice also impedes real-time
interventions. This proposal will address these significant knowledge gaps and is directly responsive to RFA-
AA-21-016. The long-term objective of this work is to advance PEth as an objective and actionable alcohol
biomarker for HIV prevention and treatment. This will be accomplished as follows: Aim 1. Establish the
relationship between PEth concentrations, PrEP adherence, and HIV acquisition among persons at risk
for HIV. Using a seminal PrEP trial, HPTN-083, which compared CAB-LA vs. emtricitabine/tenofovir disoproxil
fumarate (F/TDF) for HIV prevention in men and transgender women who have sex with men, the relationship
between PEth and (1) time to drop-out, (2) time between cabotegravir/placebo injections, (3) intracellular
tenofovir-diphosphate concentrations (an objective PrEP adherence biomarker) and (4) the risk of acquiring
HIV will be established. Aim 2. Determine the ability of PEth to predict the undetectable=untransmissible
(U=U) threshold among PWH with adherence barriers. To prevent HIV transmission and end the epidemic,
suppression of viral replication to <200 copies/mL among PWH is essential. ACTG A5359 is a trial comparing
CAB/RPV-LA vs. oral ART in PWH with a history of non-adherence to ART. A5359 includes a 12-24 week oral
ART induction period with economic incentives (Step 1), followed by randomization to continued oral ART vs.
monthly CAB/RPV-LA injections for 52 weeks (Step 2). The primary objective is to determine the ability of PEth
in Step 1 to predict failure to achieve the U=U threshold in Steps 1 and 2. Aim 3. Develop a point-of-care test
for PEth in whole blood. Using a commercially available miniature mass spectrometer, a point-of-care test
will be developed for PEth. Immediate identification of unhealthy alcohol use will greatly accelerate clinical
interventions and prevent deleterious clinical outcomes in persons at risk for HIV, PWH, and beyond.

Grant Number: 5R01AA030483-04
NIH Institute/Center: NIH
Principal Investigator: Kristina Brooks