CROI 2024 Abstract eBook

Abstract eBook

Poster Abstracts

948

Bone Mineral Density in Children With HIV-1 Receiving TAF-Based Antiretroviral Therapy N Rakhmanina 1 , Aditya Gaur 2 , Jaime G. Deville 3 , Pope Kosalaraksa 4 , Renate Strehlau 5 , Eva Natukunda 6 , Elizabeth Castaño 7 , Vinicius A. Vieira 8 , Kathryn Kersey 8 , Rory Leisegang 8 , Susanne Crowe 8 , Catherine Gordon 9 1 George Washington University, Washington, DC, USA, 2 St Jude Children's Research Hospital, Memphis, TN, USA, 3 University of California, Los Angeles, CA, USA, 4 Khon Kaen University, Khon Kaen, Thailand, 5 University of the Witwatersrand, Johannesburg, South Africa, 6 Joint Clinical Research Centre, Kampala, Uganda, 7 Hospital del Niño, Panamá City, Panamá, 8 Gilead Sciences, Inc, Foster City, CA, USA, 9 Baylor College of Medicine, Houston, TX, USA Background: Some antiretroviral agents, including tenofovir (TFV), may negatively impact bone health. Tenofovir alafenamide (TAF) results in lower TFV plasma levels than tenofovir disoproxil fumarate, and thus has a better bone safety profile. We examined the medium/long-term treatment effects of TAF based antiretroviral therapies (ARTs) on bone safety in children and adolescents with HIV aged ≥2 y and weighing ≥14 kg. Methods: Data from two open-label, multicohort studies including ART-naïve or -experienced pediatric participants with HIV, treated with emtricitabine/ TAF-containing ARTs, were pooled by age–weight band: Group (G)1: 12–<18 y, ≥35 kg; G2: 6–<12 y, 25–<35 kg; G3: ≥2 y, 14–<25 kg. Bone mineral density (BMD) was assessed using dual-energy X-ray absorptiometry of the spine and total body less head (TBLH) and compared with measurements from individuals without HIV using height–age (HA)–adjusted BMD Z-scores. Results: Overall, 169 participants were treated (G1=78; G2=61; G3=30). For G1, G2 and G3, median ages were 14, 10 and 7 y; 51%, 57% and 63% were female; 72%, 67% and 87% were Black; and 18%, 8% and 3% were Hispanic, respectively. At baseline (BL), the percentage of participants with HIV RNA <50 copies/mL were 35% (G1) and 100% (G2 and G3). Spine and TBLH BMD increased over time (Figure). Spine and TBLH HA-adjusted BMD z-scores also increased from BL, except for a decrease in TBLH HA z-score in female participants in G3. A >4% decrease from BL in spine BMD was observed in 0/44 children in G1 at Week (W) 288, 1/33 in G2 at W240 and 0/25 in G3 at W144. At those timepoints, no participant in any group had a decrease >4% from BL in TBLH BMD. We did not observe any significant correlations between change in HA-adjusted z-score of spine or TBLH BMD at W48 versus TFV maximum plasma concentration or area under the concentration–time curve derived from a noncompartmental analysis over the dosing interval for any of the groups. Conclusion: These medium/long-term BMD data are reassuring regarding bone safety of TAF-containing ARTs in pediatric participants weighing ≥14 kg. Increases in spine and TBLH BMD were consistent with those observed in children and adolescents without HIV, suggesting that TAF-containing ARTs do not compromise the expected bone accrual in pediatric populations.

C trough <0.32mg/L (1 in WB 10-<14kg; 2 in WB 25-<40kg). All children had C trough ≥0.064mg/L. In the 20-<25kg WB, 3TC AUC 0-24h GM was 1.5 times higher in children receiving 50/300mg FCT versus 30/180mg DT; however, the AUC 0-24h GM was not much higher than the AUC 0-24h GM in participants weighing ≥25kg. Conclusion: Preliminary PK results demonstrate that DTG and 3TC concentrations after administration of a DTG/3TC FDC in virologically suppressed children living with HIV are comparable with previous paediatric PK studies of DTG (ODYSSEY) and 3TC (IMPAACT2019). As expected, because of a higher dose/kg in the 20-25kg WB in the FCT group in D3/Penta 21 compared to IMPAACT2019, (300mg v180mg), increased 3TC exposures were observed. Further PK data and safety data are awaited.

947

Pediatric PBPK Scaling Model for a New Long-Acting, 3 HIV Drug Combination in a Single Injection Simone Perazzolo 1 , Zachary R. Stephen 1 , Rachele Delle Fratte 1 , Rachel A. Bender Ignacio 1 , Christine Jonsson 1 , Matthew Hartman 1 , Pablo Belaunzaran Zamudio 2 , Keith W. Crawford 2 , Brett Hanscom 3 , Ann C. Collier 1 , Ann J. Melvin 4 , Rodney J. Ho 1 1 University of Washington, Seattle, WA, USA, 2 National Institute of Allergy and Infectious Diseases, Rockville, MD, USA, 3 Fred Hutchinson Cancer Center, Seattle, WA, USA, 4 Seattle Children's Hospital, Seattle, WA, USA Background: The TLC-ART program successfully engineered lopinavir (LPV), ritonavir (RTV), and tenofovir (TFV) in a single 3-drug long-acting (LA) injectable suspension (TLC-ART 101) that has undergone scale-up, stability and preclinical safety studies. A First-in-Human study (NCT06850728) is ongoing. Leveraging juvenile and adult non-human primate (NHP) data, we developed and validated physiologically based pharmacokinetic models (PBPK) scalable to inform pediatric dosing of TLC-ART 101. Methods: PBPK models have been validated with DcNP and the combined free drugs in adult and juvenile NHPs. We scaled the proposed pediatric doses iteratively and simulated time-courses in each age band to predict safe, detectable, and likely effective drug levels in plasma based on combinatory EC 50 . AUC, terminal half-life, and concentration at 4 weeks after injection were computed. To scale to children, PBPK accounted for liver CYP3A ontogeny, organ volumes and blood flows, GFR maturation, and drug-drug interactions (DDI). Results: The projected dose is presented for each pediatric age-weight band according to the dose- equivalent needed to provide target drug exposure (AUCs) for each of the 3 antiretrovirals (LPV/RTV/TFV) in monthly dosing. The apparent half-life for each drug in TLC-ART 101 ranged from 50-300 hours and was consistent among age groups. The equivalent-dose estimates, based on the weight and metabolic scaling among age groups, were 0.65 to 15.6 mg for LPV, 0.34 to 4.1 mg RTV, and 0.57 to 9.2 mg TFV (~12-24 fold across age bands). Furthermore, possible DDI effects on LPV pharmacokinetics by RTV, which had been observed in NHPs during chronic dosing of TLC-ART 101, were not predicted by the models with the current dosages in humans. Conclusion: We developed a novel PBPK modeling approach that accounts for anatomical, physiological and enzymatic differences between species and age bands, including DDI assessments due to LPV- RTV. This integrated PBPK model may inform dose selection for clinical evaluation of long-acting HIV drug combinations such as TLC-ART 101, thereby accelerating pediatric access to long- acting treatments. To our knowledge, this drug-combination PBPK model is the first to demonstrate adaptability for multiple drugs as synchronized injections, integrating age-specific physiologic parameters. The figure, table, or graphic for this abstract has been removed.

Poster Abstracts

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