CROI 2025 Abstract eBook

Abstract eBook

Poster Abstracts

703

WITHDRAWN

705

Creating an Ultralong-Acting Dolutegravir Prodrug Homodimer Bhoomika Gowda 1 , Suyash Deodhar 1 , Nam Le 1 , Samiksha S. Raut 1 , Brandon Hanson 1 , Brady Sillman 1 , Brian Kearney 2 , Alborz Yazdi 2 , Howard Gendelman 1 , Benson Edagwa 1 1 University of Nebraska Medical Center, Omaha, NE, USA, 2 Exavir Therapeutics, Inc, San Francisco, CA, USA Background: Dolutegravir (DTG) is a widely used effective integrase strand transfer inhibitor with a high barrier to resistance. It is a recommended first-line treatment regimen for HIV-1-infected adults and children. However, DTG’s impact is limited by its daily dose requirements and suboptimal adherence. Long-acting formulations would improve optimal usage and reduce the emergence of drug resistance. To these ends, we focused on developing ultra-long-acting (ULA) prodrugs. One was a DTG monomeric ester prodrug formulation (NM2DTG). NM2DTG safely extended the drug’s apparent half-life [Nat. Commun., 3226 (2022)]. To further improve NM2DTG’s pharmacokinetic (PK) profile, DTG prodrug homodimers were synthesized and screened. An ULA DTG injectable dimer prodrug formulation (NM7DTG) was then identified, with the potential for or beyond a four-month dosing interval. Methods: A library of DTG homodimers was synthesized and nanoformulated by high-pressure homogenization. Parent DTG formulations (NDTG) were prepared in parallel and used as a control. Cellular uptake and retention, antiretroviral efficacy, and cytotoxicity were evaluated in primary human monocyte-derived macrophages (MDM). The PK profile of a single intramuscular injection (IM) of 50 mg DTG equivalents/kg was then tested in Sprague Dawley (SD) rats. Results: The DTG homodimers demonstrated distinct physicochemical properties compared to the native drug. NM7DTG formulations showed increased intracellular drug uptake, retention, and antiretroviral activities. NDTG demonstrated a suboptimal PK profile at four months, with plasma DTG levels declining rapidly below 4x the PA-IC 90 at four weeks. In contrast, NM7DTG sustained therapeutic drug levels throughout this observation period and was tolerated well. Conclusions: A single IM injection of a novel homodimeric NM7DTG formulation sustains plasma DTG levels above 4x PA-IC 90 for > four months. Loading more DTG molecules per prodrug unit mass in NM7DTG could also reduce drug injection volumes.

704

Evaluating Efficacy of Crushed Bictegravir/Emtricitabine/Tenofovir Alafenamide Administered via Tube Joshua T. Mercure 1 , Kayla Bey 1 , Eric Gillett 2 , Jeffrey C. Pearson 2 , Suzanne McCluskey 1 , Alex Rock 1 1 Massachusetts General Hospital, Boston, MA, USA, 2 Brigham and Women's Hospital, Boston, MA, USA Background: Bictegravir/emtricitabine/tenofovir alafenamide (B/F/ TAF) is a single-tablet regimen (STR) with no recommendations from the manufacturer regarding crushing or dissolving tablets for adult use. However, oral ingestion may be impractical for hospitalized individuals requiring enteral feeding. Despite some healthcare institutions administering B/F/TAF in crushed or dissolved form in such cases, there is limited clinical evidence regarding the efficacy of this approach. Methods: Electronic health records from Massachusetts General Hospital and Brigham and Women’s Hospital were reviewed from December 2016 to December 2023 to evaluate the virologic outcomes of people living with HIV who received crushed or dissolved B/F/TAF administered via enteral tube for at least 7 days during inpatient hospitalization. The primary end point was continued or achieved viral suppression (<200 copies/mL) after administration of crushed or dissolved B/F/TAF within a 12 month follow up period. Secondary endpoints included the development of antiretroviral resistance and change in antiretroviral therapy (ART). Results: From the initial cohort of 54 patients, 22 were excluded for having less than 7 days of B/F/TAF via tube and 13 were excluded for not having a follow-up viral load available within 12 months. A total of 19 patients (84%M) were included in the study and received crushed or dissolved B/F/TAF for a median of 19 days (IQR = 7.5, 64). The need for tube administration was characterized as intubation in 74% (n = 14) of the study cohort. Of the 19 patients for which a follow-up viral load was available, 89% (n = 17) were found to be undetectable. A total of 8 patients had a detectable viral load at the time of admission, and 6 of them showed an undetectable viral load within a year of receiving B/F/TAF via tube. Both patients with a detectable viral load at baseline showed a 2.8 and 3.3 log reduction in viral load at follow-up. Conclusions: The ability of B/F/TAF to garner or maintain viral suppression when given via tube was demonstrated in our study population. Although this study is limited by its retrospective nature and lack of therapeutic drug monitoring the absence of emergent resistance or virologic failure following crushed B/F/TAF remains reassuring and suggests that providing the STR via tube while patients are NPO is a reasonable alternative to changing ART altogether.

Poster Abstracts

706

Development of a 2-Drug Long-Acting Removable Formulation for HIV Suppression Martina Kovarova 1 , Sarah Wessel 1 , Rae Ann Spagnuolo 1 , Nurjahan Begum 1 , Lijun Ling 2 , Diana Battaglia 2 , Katie Mollan 1 , Amanda Schauer 1 , Jose Victor Garcia Martinez 2 , Manse Kim 2 1 University of North Carolina at Chapel Hill, Chapel Hill, NC, USA, 2 University of Alabama at Birmingham, Birmingham, AL, USA Background: Non-adherence to HIV treatment increases the risk of viral rebound and the development of drug resistance. Long-acting formulations have shown improved compliance compared with conventional regimens requiring frequent dosing, leading to better outcomes and treatment continuation. Here, an in situ forming implant system (ISFI) was used to develop a long-acting (LA) formulation that can co-deliver two drugs post administration of a single formulation. These ISFI formulations are injectable and solidified to implants after subcutaneous injection. If there is a risk of adverse effects from the implant, the implant can be safely removed to stop drug delivery. Methods: First, an injectable LA formulation of the non-nucleoside reverse transcriptase inhibitor doravirine (DOR-ISFI) was developed. The second drug,

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