CROI 2024 Abstract eBook

Abstract eBook

Poster Abstracts

Methods: A solid drug nanoparticle (SDN) formulation of BIC was manufactured using emulsion-templated freeze-drying (ETFD) prior to formation of a solid format using vacuum compression moulding (VCM). Resulting BIC formulations were injected (16.8mg BIC per animal) subcutaneously with a 12-gauge needle into the scapular region of male Sprague Dawley rats (n = 4, 250-300g). Plasma samples were collected from the lateral tail vein for 13-weeks post injection. BIC concentrations were quantified in plasma using validated LC-MS/MS and the injection site was terminally harvested for histopathological analysis. Results: ETFD yielded solids consisting of 70% BIC by weight, with subsequent dispersion in water yielding BIC particles with hydrodynamic diameters (Dz) between 700-850 nm, as determined by dynamic light scattering. Plasma BIC concentrations exceeded the human oral steady-state C trough within 3 hours of administration and remained above this level for 42 days (T max = 2 days; AUC 0-tlast = 22427 μg.h/mL). No behavioural issues were encountered, animals gained weight throughout and no visible injection-site reactions were evident. Conclusion: Preclinical data for a novel BIC solid injectable demonstrated sustained therapeutic concentrations in rats for 42 days. Further work is required to understand dose linearity and proportionality, assess removability, and estimate doses and durations likely to be achievable in humans.

(11200/13291) with <50 copies/ml, p<0.0001. By ART-regimens, detectable LLV (50-999copies/ml) was 13.9% (1540/11054) with DTG-containing versus 14.1% (551/3916) with other ART-regimens, p=0.81.By age, detectable LLV was 13.8% among adults versus 16.9% children/adolescents, p=0.01. Most importantly, the trend overtime of detectable LLV between 50-200 copies/ml increased significantly from 65.2% (534/819) in 2020, 70.7% (678/958) in 2021 and 72.2% (227/314) in 2022, p=0.001. Conclusion: Even though VS rate appears encouraging, there is a significant increasing proportion of patients with detectable LLV in this DTG-era. Of note, LLV with 50-200 copies appears highly predominant, suggesting a revision of threshold for VS at a maximum of 200 copies/ml in resource-limited settings like Cameroon. Increased Viral Suppression With Adherence Counseling Incorporating a Point-of-Care Urine TFV Test Leonard T Bikinesi 1 , Matthew A. Spinelli 2 , Ntombizodwa M. Nyoni 3 , Jesaya Hifindwako 4 , Assegid Mengistu 1 , Jacques Kamangu 1 , Gram Mutandi 5 , Daniella Mouton 4 , Fekir Negussie 3 , Rachel S. Beard 5 , Monica Gandhi 2 , Steven Y. Hong 5 1 Ministry of Health and Social Services, Windhoek, Namibia, 2 University of California San Francisco, San Francisco, CA, USA, 3 UCSF Institute for Global Health Sciences – Namibia, Windhoek, Namibia, 4 Namibia Institute of Pathology, Windhoek, Namibia, 5 US Centers for Disease Control and Prevention Windhoek, Windhoek, Namibia Background: Innovative approaches are needed to achieve the third UNAIDS 95-95-95 target, to increase and sustain virologic suppression (VS) in patients on ART, specifically co-formulated tenofovir (TFV)-lamivudine-dolutegravir (DTG) or TLD. Virologic failure in patients on TLD is likely due to non-adherence because of DTG's high resistance barrier. Identifying non-adherence to TLD with a point-of-care (POC) metric and tailored counseling on the test may help patients achieve viral suppression (VS). We integrated a low-cost, POC urine test to detect TFV into standard WHO-recommended enhanced adherence counseling (EAC) to improve VS in adults with non-VS on TLD in Namibia. Methods: Patients on TLD with viral load (VL) >1000 copies/mL after completing ≥1 round of EAC were enrolled from 42 clinics across Namibia. At each monthly ART pick-up, participants completed the POC urine test and received EAC informed by test results. After 3 months (round 1), participants received a viral load (VL) test. If VS was not achieved, up to 3 additional rounds of POC urine testing with EAC was provided, with an HIV drug resistance test sent at month(M) 9. Acceptability of the urine assay was assessed via surveys administered to participants and providers. Results: Of 211 participants enrolled (median age 33 years, interquartile range 22-46, 61% female), 195 reached M3 and received a follow-up VL, with 169 (87%) achieving VS within M3 and 182 (93%) by M9. Moreover, in those who achieved VS, positive TFV in urine increased from 81% at baseline to 96% at M9 compared to a change from 31% to 41% among unsuppressed individuals. Drug resistance testing was performed in 5 remaining participants with high VL at M9. All 5 had variable urine TFV results over visits and one had DTG resistance (N155H and R263K mutations). Overall, 84% of participants and 89% of interviewed providers agreed/strongly agreed that the urine test improved EAC. Conclusion: Nearly 90% of patients on TLD with VL >1000 copies/mL achieved VS within 3 months (93% at M9) following EAC that incorporated a urine-based POC TFV test, compared to 33% of individuals receiving 1-3 rounds of standard WHO-recommended EAC. Encouraging results of this pre-post intervention support rigorous testing in a future randomized clinical trial. Given the cost of VL and resistance testing in lower-and middle-income countries, this POC urine test has great potential to help achieve the third 95-95-95 target in a low-cost, scalable manner. Preclinical Pharmacokinetics of a Novel Long-Acting Bictegravir Solid Injectable in Rats Usman Arshad , Joanne Sharp, Megan Neary, Joanne Herriott, Edyta Kijak, Eduardo Gallardo-Toledo, Paul Curley, Helen Cox, Eleanor Barlow, James J. Hobson, Andrew B. Dwyer, Jonathan Massam, Steve Rannard, Andrew Owen University of Liverpool, Liverpool, United Kingdom Background: Bictegravir (BIC), is an integrase strand transfer inhibitor, effective for HIV treatment when combined with emtricitabine and tenofovir alafenamide. Another integrase inhibitor, cabotegravir, has been demonstrated to be effective in pre-exposure prophylaxis as a single agent and is available as a long-acting (LA) injectable medicine. This work describes preclinical pharmacology of a novel BIC LA solid injectable.

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Poster Abstracts

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Shape-Shifting Tail Decay Is the Pharmacokinetic Profile of an Ultra-Long Acting Bictegravir Prodrug Mohammad Ullah Nayan 1 , Ivana Massud 2 , Srijanee Das 1 , Brady Sillman 1 , Brandon Hanson 1 , Arpan Acharya 1 , Tiancheng Edwards 2 , Richard Haaland 2 , Siddappa N. Byrareddy 1 , Gerardo Garcia-Lerma 2 , Walid Heneine 2 , Charles W. Dobard 2 , Howard E. Gendelman 1 , Benson Edagwa 1 1 University of Nebraska Medical Center, Omaha, NE, USA, 2 Centers for Disease Control and Prevention, Atlanta, GA, USA Background: The advantages of long-acting (LA) antiretroviral therapy (ART) for regimen adherence and sustained viral suppression are unquestioned. However, the requirement for bi-monthly clinic visits, injection site reactions, large dosing volumes, and long pharmacokinetic (PK) tail pose notable challenges to widespread LA ART use. Consequently, there is an immediate need for ultra-LA (ULA) ART capable of synchronizing dosing intervals with established six-month clinic visits. We report the PK and biodistribution profiles of two lead bictegravir (BIC) prodrug formulations in two animal species, in pursuit of a ULA BIC prodrug formulation with a short PK tail. Methods: Dimeric (MXBIC) and monomeric (M2BIC) BIC prodrugs were synthesized by esterification reactions and converted into aqueous surfactant stabilized solid drug nanosuspensions by high-pressure homogenization. Formulation stability, particle size, homogeneity, and surface charge were assessed. PK profiles, biodistribution, and terminal phase PK tails were evaluated in Sprague Dawley (SD) rats and rhesus macaques (RM) after intramuscular (IM) injection dosing. Results: Dimeric BIC prodrug formulations (NMXBIC formulations 1 and 2) demonstrated plasma BIC levels above the protein-adjusted 95% inhibitory concentration (PA-IC 95 ) for > 6 months in SD rats after a single 45 mg BIC.eq./ kg IM injection. Increasing the formulation concentration of NMXBIC by 1.5 fold (NMXBIC formulation 2) and subsequent reduction of injection volume boosted plasma BIC levels, but doubling the dose for formulation 2 in SD rats did not lead to a proportional increase in plasma BIC levels. Specifically, BIC levels following NMXBIC formulation 2 dosing were sustained at levels ≥ 14x PA-IC 95 for 6 months. In RM, a single IM injection of NMXBIC (100mg. BIC eq./kg) sustained plasma BIC levels at ≥ 4x PA-IC 95 for more than 6 months. Notably, regardless of the dose and species, plasma BIC levels after NMXBIC treatment exhibited

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CROI 2024 186