CROI 2017 Abstract e-Book

Abstract eBook

Poster and Themed Discussion Abstracts

439 A LONG-ACTING NANOFORMULATED CABOTEGRAVIR PRODRUG FOR IMPROVED ANTIRETROVIRAL THERAPY Tian Zhou , Benson Edagwa, JoEllyn McMillan, Howard E. Gendelman Univ of Nebraska, Omaha, NE, USA

Background: Significant interest in long-acting parenteral (LAP) antiretroviral drugs (ARVs) has set the bar for future HIV/AIDS care. LAP ARVs can improve treatment adherence and positively affect drug resistance and systemic toxicity patterns. Cabotegravir (CAB), a potent HIV integrase inhibitor, now in phase II clinical trials as a LAP (CAB-LAP), currently demonstrates sustained plasma drug levels in humans up to 52 days after single intramuscular dose. We proposed that CAB-LAP could be modified to further reduce injection volumes and improve pharmacokinetic (PK) profiles. To this end, a nanoformulated prodrug of CAB (called NMCAB) was made to extend the drug half-life and antiretroviral activities and enabled the creation of a long-acting dolutegravir (DTG). Methods: CAB was chemically conjugated to myristoyl chloride, increasing its hydrophobicity. NMCAB was produced by high-pressure homogenization with poloxamer 407. Uptake and retention were tested in human monocyte-derived macrophages (MDM). Antiretroviral activity was evaluated by HIV reverse transcriptase (RT) activity and HIV-1p24 expression. Pharmacokinetics of NMCAB was evaluated in Balb/C mice and compared to parent drug formulations after a single intramuscular injection of 15 or 45 mg/kg. The plasma drug levels were monitored for two months. Results: NMCAB was efficiently taken up by MDMwith sustained slow release of up to 30 days. Notably, the parent drug formulations were eliminated after a single day of treatment. Drug crystals were observed by transmission electron microscopy in NMCAB treated MDM, but not in cells treated with parent drug. NMCAB showed sustained antiretroviral activity in MDM as determined by both RT activity and HIV-1p24 staining for up to 30 days after drug removal. In contrast, parent drug formulations failed to inhibit viral growth one day after drug loading. In in vivo studies, NMCAB showed reduced burst release but was cleared more slowly, resulting in drug levels at later time points being up to 100 times higher than the parent drug formulations (Figure). Replicate results were seen for a created DTG prodrug and will be discussed. Conclusion: Both CAB and DTG prodrugs were successfully synthesized and encapsulated into nanoparticles with clear improvements as a LAP formulation for antiretroviral therapy.

Poster and Themed Discussion Abstracts

440 ANTIVIRAL ACTIVITY OF EFDA AGAINST NRTI-SENSITIVE AND -RESISTANT STRAINS OF HIV-2 Vincent Wu 1 , Robert Smith 1 , Sara Masoum 1 , Dana Raugi 1 , Selly Ba 2 , Moussa Seydi 2 , Jay Grobler 3 , Geoffrey Gottlieb 1 , for the University ofWashington–Dakar HIV-2 Study Group 1 Univ of Washington, Seattle, WA, USA, 2 CHU de Fann, Dakar, Senegal, 3 Merck & Co, West Point, PA, USA Background: EFdA (4´-ethynyl-2-fluoro-2´-deoxyadenosine; MK-8591; Merck & Co.) is an investigational NRTI that blocks HIV-1 replication in culture with 50% effective concentrations (EC50) in the low-nanomolar to picomolar range. EFdA is highly active against HIV-1 and SIV in humanized mice and rhesus macaques, respectively, and a single 10-mg dose of EFdA demonstrated potent antiviral activity for 10 days in a phase 1b proof-of-concept clinical trial. However, studies evaluating the activity of the EFdA against HIV-2 are lacking, and the ability of the drug to inhibit NRTI-resistant mutants of HIV-2 is unknown. Methods: HIV-1 and HIV-2 isolates from antiretroviral-naïve individuals were tested against EFdA in single-cycle infections of MAGIC-5A cells. Site-directed mutants of HIV-2 reverse transcriptase (RT) were generated in a full-length plasmid clone (pROD9) and were evaluated for EFdA resistance in the single-cycle assay. 50% cytotoxic concentrations (CC50) for EFdA were determined using a CellTiter-Glo® luminescence kit. Results: EFdA inhibited HIV-2 infection of MAGIC-5A cells with mean EC50 values (± SD) of 0.58 ± 0.13 nM for 6 group A isolates and 0.55 ± 0.16 nM for 6 group B isolates (range = 0.34–0.83 nM for all 12 HIV-2 strains tested). In contrast, the mean EC50 for 6 HIV-1 isolates, including group M subtype A, B, C and D strains and the group O isolate MVP5180-91, was 2.0 ± 0.43 nM (range = 1.29–2.54 nM; p < 0.0001 for HIV-1 vs. HIV-2, Mann-Whitney test). In spreading infections of CEMss cells, EC50 values for HIV-2 ROD9 and HIV-1 NL4-3 were 38 and 120 pM, respectively. EFdA was fully active against HIV-2 RT mutants K65R and Q151M (EC50 = 0.17 ± 0.04 nM and 0.31 ± 0.05 nM, respectively), whereas the M184V variant was 10-fold resistant to the drug. Similar levels of resistance (12–16-fold) were seen for HIV-2 mutants that harbored M184V plus one or more additional NRTI resistance- associated changes in RT, including a patient-derived clone encoding K65R+N69S+V111I+Q151M+M184V. The CC50 for EFdA in MAGIC-5A cells was >100 nM. Conclusion: EFdA is the most potent inhibitor of HIV-2 replication described to date and is more active against HIV-2 than against HIV-1 in culture. EFdA also inhibits multi-NRTI– resistant HIV-2 mutants with single-cycle EC50 values ≤ 10 nM. These data indicate that EFdA should be evaluated in clinical studies involving HIV-2–infected individuals. 441 WITHDRAWN 442 LONG-TERM SAFETY AND EFFICACY OF CAB AND RPV AS 2-DRUG ORAL MAINTENANCE THERAPY David A. Margolis 1 , Cynthia Brinson 2 , Graham H. Smith 3 , Joseph J. Eron 4 , Gary J. Richmond 5 , Roger P. LeBlanc 6 , Peter E. Williams 7 , William Spreen 1 , Kenneth Sutton 8 , Britt S. Stancil 9 1 ViiV Hlthcare, Rsr Triangle Park, NC, USA, 2 Central Texas Clinical Rsr, Austin, TX, USA, 3 Maple Leaf Med Clinic, Toronto, Ontario, Canada, 4 Univ of North Carolina at Chapel Hill, Chapel Hill, NC, USA, 5 Gary J Richmond MD PA, Ft Lauderdale, FL, USA, 6 Clinique OPUS, Montréal, Québec, Canada, 7 Janssen Rsr and Development, Beerse, Belgium, 8 ViiV Hlthcare, Raleigh, NC, USA, 9 PAREXEL Intl, Durham, NC, USA Background: Cabotegravir (CAB), an HIV INSTI is under development in both oral and long-acting (LA) injectable formulations. LATTE was designed to select a daily oral dose of CAB and to evaluate a two drug ART regimen with rilpivirine (RPV), as suppressive maintenance therapy. Results enabled the LATTE-2 study to evaluate CAB LA + RPV LA dosed once every 1 or 2 months.

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