CROI 2024 Abstract eBook

Abstract eBook

Poster Abstracts

DTG levels (4000-6500 ng/mL) in pregnant dams. However, five-fold lower DTG levels were observed in embryo brain following NDTG injections. For daily oral DTG, average concentrations of 196 ng/g were recorded compared to 34 ng/g and 45 ng/g for single or two IM injections of NDTG, respectively. MRI scanning of live dams was performed to acquire T1 maps of the embryo brain to assess oxidative stress. Significantly lower T1 values were noted in daily oral DTG treated mice, whereas comparative T1 values were noted between control and NDTG-treated mice, indicating prevention of DTG-induced oxidative stress when delivered as NDTG. Proteomic profiling of embryo brain tissues demonstrated reductions in oxidative stress, mitochondrial impairments, and amelioration of impaired neurogenesis and synaptogenesis in NDTG-treated group. Conclusion: This work suggests that long-acting drug delivery can prevent DTG-linked neurodevelopmental deficits by limiting drug exposure to the embryo brain. The figure, table, or graphic for this abstract has been removed. A New Measure of ART Activity in CSF and Association With Persistence and Cognitive Function Sean N Avedissian 1 , Caitlyn McCarthy 2 , Ronald J. Bosch 2 , Ying Mu 1 , Serena Spudich 3 , Leah H. Rubin 4 , Lee Winchester 1 , Timothy Mykris 1 , Jonathan A. Weinhold 1 , Joshua C. Cyktor 5 , Joseph J. Eron 6 , John W. Mellors 5 , Rajesh T. Gandhi 7 , Deborah K. McMahon 5 , Courtney V. Fletcher 1 1 University of Nebraska Medical Center, Omaha, NE, USA, 2 Harvard TH Chan School of Public Health, Boston, MA, USA, 3 Yale University, New Haven, CT, USA, 4 The Johns Hopkins Hospital, Baltimore, MD, USA, 5 University of Pittsburgh, Pittsburgh, PA, USA, 6 University of North Carolina at Chapel Hill, Chapel Hill, NC, USA, 7 Massachusetts General Hospital, Boston, MA, USA Background: ACTG A5321, a prospective study of HIV-1 reservoirs among persons with HIV on antiretroviral therapy (ART), previously showed detection of HIV DNA in cells from cerebrospinal fluid (CSF) was associated with poorer global cognitive function. We conducted a cross-sectional analysis of antiretroviral (ARV) pharmacokinetics (PK) in CSF and investigated relationships among a novel measure of ART regimen activity and HIV persistence in CSF and cognitive function. Methods: Participants were on ART for a median of 8.1 years with sustained plasma HIV suppression at time of lumbar puncture (LP). CSF ARV concentrations, cell-associated HIV DNA and inflammatory biomarkers were measured; a neuropsychological test battery (outcome=global deficit score, GDS) was administered just prior to or at LP. ARV levels were quantified by LC/ MS/MS. Population PK modeling was used to estimate CSF drug exposure. CSF inhibitory quotients (IQ) were calculated for each ARV in a regimen as ratio of predicted CSF trough to literature values for in vitro HIV inhibitory concentration (i.e., IC 50 , IC 90 ). The geometric mean of CSF IQs of all drugs in each participant's ARV regimen was calculated (ART-IQ-GeoM). Statistical analyses evaluated associations among the ART-IQ-GeoM and CSF HIV DNA, biomarkers and GDS. Results: CSF ARV levels were measured in 44 chronic-treated participants on TDF/FTC-based ART: 43 (98%) male sex at birth; 36 (97% of 37) male gender; 33 (75%) white non-Hispanic, 6 (14%) black non-Hispanic; median age, 49 yrs; median CD4 count, 642 cells/µL; 43 (98%) with plasma HIV RNA <40 copies/ mL. Third drugs in ARV regimens were: EFV (n=17), ATV/r (8), RAL (8), EVG/c (5), DRV/r (4) and DTG (2). The median (Q1, Q3) ART-IQ-GeoM was higher in those with undetectable vs detectable CSF HIV DNA 0.9 (0.5, 1.6) vs 0.5 (0.3, 0.9), p=0.027 (Figure). A rank-based analysis gave similar findings. Higher ART-IQ GeoM was associated with lower GDS (i.e., better global cognitive function, Spearman: -0.30, p=0.05). There was no association between CSF inflammatory biomarkers and ART-IQ-GeoM. Conclusion:\ The ART IQ metric is a new approach to assess ART regimen activity. Higher ART-IQ-GeoM was associated with a lack of detection of CSF HIV DNA and better global cognitive function. These findings suggest ART regimen activity affects HIV persistence in CSF. This tool provides a basis for further investigations of relationships between regimen activity and biomarkers of HIV persistence in the CSF and other viral reservoirs.

and early NPAEs in adults failing efavirenz-based antiretroviral therapy and switching to a dolutegravir-based regimen. Methods: We conducted a pharmacogenetic sub-study of participants enrolled into the ARTIST clinical trial, who were switched from tenofovir emtricitabine-efavirenz to tenofovir-lamivudine-dolutegravir and randomised to supplementary dolutegravir 50 mg dose or placebo for the first 2 weeks. Primary outcome was change in sleep quality from baseline to week 2. NPAEs were assessed by questionnaires and neuropsychological testing before and after the switch. Plasma dolutegravir trough concentrations were collected at week 2. We genotyped polymorphisms relevant to efavirenz disposition [CYP2B6 (rs3745274 G → T, rs28399499 T → C and rs4803419 C → T), and CYP2A6 rs28399433 A → C], dolutegravir disposition (UGT1A1 rs887829 C → T), and dolutegravir toxicity (SLC22A2 rs316019 C → A). Multivariate logistic regression analyses were used to determine associations between genetic polymorphisms and early NPAEs. Results: 128 participants were evaluable for genetic analyses. The median age was 38 years (IQR 32–45), 68% female, median duration on ART was 85 months (IQR 50–119), and median baseline HIV-1 RNA was 4.0 log 10 copies/ mL (IQR 3.5–4.7). Insomnia events occurred in 17 (13%) participants. There were no statistically significant associations between genetic polymorphisms and worsening sleep quality. UGT1A1 rs887829 homozygous TT genotype was associated with higher dolutegravir exposure [β = 0.841 (95% CI -0.030 to 1.711), P = 0.058]. CYP2B6 slow efavirenz metaboliser genotype was associated with lower dolutegravir exposure in both arms, but this was only statistically significant in the supplementary dolutegravir arm [β = -1.457 (95% CI -2.467 to -0.447), P = 0.006; Figure 1]. Conclusion: Among participants who switched from efavirenz to dolutegravir, early insomnia events were common, but these were not associated with known functional polymorphisms. CYP2B6 slow metaboliser genotype was associated with lower dolutegravir exposure, reflecting prolonged efavirenz induction effect. Long-Acting Dolutegravir Formulation Reduces Fetal Drug Exposure Emma G Foster 1 , Brady Sillman 1 , Yutong Liu 1 , Micah Summerlin 1 , Vikas Kumar 1 , Balasrinivasa R. Sajja 1 , Adam R. Cassidy 2 , Benson Edagwa 1 , Howard E. Gendelman 1 , Aditya N. Bade 1 1 University of Nebraska Medical Center, Omaha, NE, USA, 2 Mayo Clinic, Rochester, MN, USA Background: Dolutegravir (DTG) is a preferred first-line antiretroviral for the treatment of people living with human immunodeficiency virus type one (PLWHIV). Fifteen million PLWHIV world-wide are expected to be treated with DTG regimen by 2025. This includes pregnant women, who remain a significant infected population. Widespread DTG usage is linked to its high potency, barrier to resistance, and cost-effectiveness. Despite such benefits, potential risks of DTG-linked fetal neurodevelopmental toxicity remain a concern. To this end, novel formulation strategies are timely to maximize DTG's therapeutic potentials while limiting adverse events during pregnancy. Thus, we posit that injectable long-acting (LA) nanoformulated DTG (NDTG) could provide improved safety by reducing fetal drug exposures compared to orally administered drug. Methods: Pregnant C3H/HeJ mice were treated with daily oral DTG at a human equivalent dosage (5 mg/kg). These were compared against pregnant mice injected with intramuscular (IM) NDTG given at 45 or 25 mg/kg at one or two doses, respectively. Treatment began at gestation day (GD) 0.5. DTG levels were measured in plasma of dams and in whole brain tissues of embryos at GD 17.5 using mass spectrometry. Magnetic resonance imaging (MRI) and non-targeted proteomic tests were performed on embryo brains at GD 17.5 to cross-validate pathobiological pathways. Results: Single (45 mg/kg) or two (25 mg/kg) IM injections of NDTG, or daily oral DTG administration (5 mg/kg) achieved equivalent therapeutic plasma

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