CROI 2024 Abstract eBook

Abstract eBook

Poster Abstracts

P<0.001. A baseline positive UTOXM (vs negative) was associated with: higher homelessness/transient housing rate (52.4% vs 21.4% P=0.028); lower mean income $7,400 vs $31,500, P=0.042; more depression as measured by Mood PHQ8 11.8 vs 6.9, P=0.001 and higher Life Chaos score 14.2 vs 9.0, P=0.001. UTOXM positive 16-week persistence on study was 0.333 (0.182-0.610) vs negative 0.619 (95% CI 0.488-0.785), P=0.0098. Conclusion: Baseline positive UTOXM in PWH starting oral ART predicted highly significant differences in treatment adherence & persistence on study (a surrogate for care retention); and identified a distinct subpopulation in our West Coast US setting with multiple attributes, including life chaos & depression, associated with poor care engagement. Baseline UTOX may be a useful, simple screening tool to identify PWH requiring differentiated care and adherence support on initiation of oral ART, and may be easily employed in mobile testing sites offering quick start care. Preclinical to Human Scaling of Pharmacokinetics for Long-Acting Injectable Antiretrovirals Henry Pertinez 1 , Rajith Rajoli 1 , Andrew Lloyd 1 , Joanne Sharp 1 , Joanne Herriott 1 , Edyta Kijak 1 , Eduardo Gallardo-Toledo 1 , Megan Neary 1 , Helen Cox 1 , Chloe Bramwell 1 , Anthony Valentijn 1 , Usman Arshad 1 , Paul Curley 1 , Charles W. Flexner 2 , Andrew Owen 1 1 University of Liverpool, Liverpool, United Kingdom, 2 The Johns Hopkins University, Baltimore, MD, USA Background: Long-acting injectables (LAIs) have attracted interest for prevention and treatment of infection (including HIV, HCV and tuberculosis), addressing issues with pill burden and adherence. Better methods for scaling preclinical pharmacokinetics (PK) for prediction of human exposure are needed to aid decision making, and accelerate early clinical development through better human dose prediction. Methods: Matching rat and human PK data were sourced from publications or in-house PK studies for 11 marketed intramuscular LAIs. Terminal depot release rates (KA) were determined from analysis of terminal phase, release-dependent, "flip-flop" half-lives. Two approaches for human KA prediction were: 1) Linear regression between human and rat KAs (Fig 1A). 2) Allometric scaling of KA by body size according to formula: KA (human, pred) ≈ KA (rat) x (70 kg/0.3 kg)-0.25 = KA (rat) x 0.255. Qualification was undertaken for cabotegravir and rilpivirine with human LAI PK profiles simulated for comparison with empirical human PK data. For this, human PK disposition was described by a minimal 1-compartment model parameterised with clearance (CL) and steady state volume of distribution (Vss) from published IV PK if available, or via PBPK where absent. This model was deemed sufficient under flip-flop PK due to slow LAI depot release masking multiphasic PK disposition. Depot release input was treated as a simplified 1st order process governed by KA. For qualification, the LAI of interest was removed from the regression used to predict the KA. Given that bioavailability (F) is unknown for novel LAIs and varies for approved LAIs, profiles were simulated assuming 25, 50 and 100% F. Results: A variety of PK profile shapes were evident across LAIs and terminal flip-flop KAs trended faster in rat than human. A good correlation was observed between human and rat KA with all 11 LAIs included (R2 = 0.81, slope coeff. 0.38), and retained with the removal of cabotegravir (R2 = 0.82) or rilpivirine (R2 = 0.81). Reasonable concordance of resulting human PK predictions was observed for cabotegravir (assuming 50% F; Fig.1A) and rilpivirine (assuming 100% F; Fig.1B). Conclusion: This simplified scaling may be useful to predict human terminal release PK from rat studies to inform phase I human dose prediction. More work is needed to predict LAI F, and understand relationships across other species and routes of administration. Final validation of the approach will require a priori application for a novel LAI.

tenofovir diphosphate (TFV-DP) concentrations and self-report (SR)] in people on ART, when initially flagged for reduced adherence. Methods: ART-naïve people from three Cape Town ART clinics had adherence monitored by missed doses (EAM), missed clinic visits or by raised VL. At the time of first flagging by any measure, participants received an adherence support call, and were invited for blood draw for HIV-1 VL and TFV-DP (indicating dosing over 4-8 weeks); urine collected for tenofovir rapid assay (indicating dosing over 3-5 days). SR adherence and EAM data were collected for the prior 30 days. Initial adherence data at the time of first non-adherence are presented here. Results: Between July22 and August23, 116 of 427 (27%) people were flagged for poor ART adherence; 93(80%) by missed doses, 20(17%) by missed visits and 3(3%) by raised viral load. 87 (75%) were women, with mean (±SD) age of 28 (±8) years. Median (IQR) self-reported adherence was 90% (83-97) doses taken in past 30 days; EAM showed reduced adherence across all groups 57% (16-77) doses taken over past 30 days; with suboptimal median (IQR) TFV-DP concentrations: 567 (263-864) fmol/punch (normal range >800fmol/ punch)]. 89(76.7%) had tenofovir in their urine. 35 (30%) of all individuals had VL>50 copies/ml. The median VL was suppressed in all groups by the time of the blood draw. Missed doses and missed visit were flagged sooner: median (IQR) 39 (21-88) and 75(42-117) days than raised viral load: 134(94-194) days. Non-parametric analysis showed no significant associations between flagging method and TFV-DP concentrations, EAM or VL at this early stage of the study. Conclusion: All those flagged for reduced adherence had poor adherence confirmed by objective measures, EAM and TFV-DP concentrations, despite self-reporting near perfect dosing. Positive urine tenofovir reflects reasonable dosing near to the study visit (white-coat dosing). A third of the cohort were viraemic. Poor adherence was noted most rapidly by detection of missed doses and missed visits; allowing time for adherence support before breakthrough viraemia occurs. Baseline Urine Methamphetamine (UTOXM) Predicts ART Adherence and Poor Retention in Care Attributes Sara Browne 1 , Anya Umlauf 1 , Sarah Rojas 2 , Theodoros Katsivas 1 , Florin Vaida 1 , Constance A. Benson 1 1 University of California San Diego, La Jolla, CA, USA, 2 Family Health Centers of San Diego, San Diego, CA, USA Background: The CDC estimates 57% of US persons with HIV (PWH) achieve viral suppression. Early initiation of ART is recommended, but objective baseline tests with predictive ability to distinguish persons at risk of poor ART adherence and engagement in care are lacking. We evaluated the utility of baseline urine toxicology testing for methamphetamine (UTOXM) use in PWH starting oral ART in our West Coast US setting to predict adherence and characteristics associated with poor engagement in care. Methods: PWH initiating ART with ingestible-sensor-enabled antiretroviral technology (IS-ARVs) to observe medication taking for the first 16 weeks of treatment had a baseline UTOXM, with demographics and self-report questionnaires obtained. UTOXM ability to predict IS-ARV-confirmed doses (taking & timing); persistence on study; and baseline demographics and questionnaires were analyzed using mixed-effects logistic regression; Kaplan-Meier curves; and linear models, respectively. No causal analyses were attempted. Results: Sixty-three enrolled participants prescribed IS-ARVs had median age 37 (IQR 30-46) yrs, 82.5% were male, 33.3% White, 34.9% Hispanic, 22.2% African American, 3.2% Asian. UTOXM was negative in 42, positive in 21. Over 6049 observation days evaluated in longitudinal mixed effects logistic regression revealed a negative baseline UTOXM (compared to those who tested positive) was associated with a daily confirmed dose odds ratio (OR) of 3.12 (CI 1.71-5.71), P<0.001 and a regularity of dose timing OR of 5.05 (CL 2.43-10.6),

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