CROI 2020 Abstract eBook

Abstract eBook

Poster Abstracts

Results: Among the 12 children enrolled, the median age was 38 months (range 26 to 50 months), 75%were female, the median CD4 cell count was 1211 cells/mm 3 and CD4%was 34%. All children were receiving lopinavir/ritonavir, zidovudine, lamivudine (and one was also on abacavir). All but one infusion occurred on schedule and to completion, and infusions were well tolerated. No infusion reactions occurred, and no grade 3 or 4 events were related to either bNAb. For VRC01LS, median (range) first dose peak concentrations (C max ) and Day 84 trough concentrations (C84D) were 726 (559-799) mcg/mL and 157 (126-201) mcg/mL respectively, both about half of predicted values based on PK in uninfected adults (Figure 1A). For 10-1074, median (range) first dose C max and C84D concentrations were 1633 (1174-1999) mcg/mL and 258 (122-467) mcg/mL respectively, both somewhat greater than predicted values from HIV-infected adults on suppressive ART (Figure 1B). Conclusion: Intravenous VRC01LS and 10-1074 were safe and well tolerated among HIV+ children receiving ART.Pediatric PK of these two bNAbs differed from PK in adults. For VRC01LS, an increased maintenance dose of at least 15mg/kg may be needed to achieve concentrations similar to adults when dosed monthly. For 10-1074, predicted adult concentrations were slightly exceeded with 30mg/kg monthly.

CAB was > 0.166μg/mL (protein adjusted (PA)-IC 90 ) in 30/30 subjects at the 1-month LTFU visit, and ranged between 0.034 to 0.152μg/mL (< PA-IC 90 ) in 8 subjects and was nonquantifiable (12 ng/mL (PA-IC 90 ) in all subjects (29/29); at 12-month LTFU visit, plasma RPV was >LLOQ (1ng/mL) in all subjects (23/23), ranging up to 63.8 ng/mL and >PA-IC 90 in 11/23. Adverse events were uncommonly reported, and no patients met CVF criteria during LTFU on alternative ART, which included dolutegravir and elvitegravir integrase inhibitor based regimens, darunavir protease inhibitor based regimens, and RPV non-nucleoside reverse transcriptase based regimens. Conclusion: The CAB and RPV plasma concentrations observed during LTFU are consistent with the apparent absorption-rate limited t 1/2 for each LA formulation. Both CAB and RPV have a low drug interaction potential as perpetrators. Alternative ART selection after discontinuing CAB LA + RPV LA may include CYP3A and/or UGT1A1 inducers or inhibitors, without efficacy or safety concerns despite potential for transient increases in CAB and RPV concentrations by inhibitors.

Poster Abstracts

467 WITHDRAWN 468 MK-8504 AND MK-8583 (TENOFOVIR PRODRUGS) SINGLE-DOSE PK AND ANTIVIRAL ACTIVITY IN HIV Randolph P. Matthews 1 , Sarah J. Hsieh 1 , Jesse C. Nussbaum 1 , Guido H. Jajamovich 1 , Tian Zhao 1 , Diana Selverian 1 , Michaelanne Wasenius 1 , Liesbeth Haspeslagh 2 , Caroline Cilissen 2 , Dirk Schuermann 3 , Sylvie Rottey 4 , Marta Boffito 5 , Deanne J. Rudd 1 , S. Aubrey Stoch 1 , Marian Iwamoto 1 1 Merck & Co, Inc, Kenilworth, NJ, USA, 2 MSD Belgium, Brussels, Belgium, 3 Charité Universitätsmedizin, Berlin, Germany, 4 Ghent University, Ghent, Belgium, 5 Chelsea and Westminster Hospital, London, UK Background: There is a need for Human Immunodeficiency Virus (HIV-1) treatments with improved safety profiles and increased ease of administration. MK-8504 and MK-8583 are nucleoside reverse transcriptase inhibitors (NRTIs) that are novel tenofovir (TFV) prodrugs, with a potential for weekly dosing due to the long t 1/2 of the active diphosphate (TFV-DP). Single-dose pharmacokinetics (PK) and antivirologic activity of these compounds were assessed in two Phase 1 programs. Methods: Single doses of 2-240 mg MK-8504 were tested in healthy adults, and single doses up to 240 mg were tested in ART-naïve persons living with HIV (PLWH). Single doses of MK-8583 2-150 mg were tested in healthy adults, and a single dose of 100 mg was tested in ART-naïve PLWH. Plasma and peripheral blood mononuclear cells (PBMCs) were collected up to 10 days after dosing for PK and viral load (VL). Results: Oral MK-8504 and MK-8583 were rapidly absorbed (T max ~ 0.5 hour); MK-8583 was rapidly eliminated from plasma (t 1/2 0.2-0.4 hours), while MK-8504 had slower elimination (t 1/2 6-8 hours). As expected, plasma TFV concentrations were generally similar, with a median T max of 1-4 hours after both MK-8504 and MK-8583 administration, and a t 1/2 of 20-38 hours for MK-8504 and 19-30 hours for MK-8583. The levels of TFV-DP in PBMCs exhibited a median T max of 4-24 hr for both compounds, with a t 1/2 of 48-115 hours for MK-8504 and 65-192 hours for MK-8504. The PK in PLWH and healthy participants were similar. Despite PBMC TFV-DP concentrations consistently above the efficacious trough concentration for marketed TFV prodrugs (100 nM), HIV-1 VL reduction was suboptimal for both compounds. The mean VL reduction at 7 days was 0.6 log 10 copies/mL for MK-8583 and 0.9 log 10 copies/mL at the top dose of MK-8504, and several participants failed to achieve consistent VL reduction. There was

466 CABOTEGRAVIR AND RILPIVIRINE PK FOLLOWING LONG-ACTING HIV TREATMENT DISCONTINUATION Susan Ford 1 , Herta Crauwels 2 , Kelong Han 3 , Stefaan Rossenu 2 , Feifan Zhang 3 , Jenny O. Huang 4 , David A. Margolis 5 , Kenneth Sutton 5 , Krischan J. Hudson 5 , Peter E. Williams 2 , William Spreen 5 , Parul Patel 5 1 GlaxoSmithKline, Research Triangle Park, NC, USA, 2 Janssen, Beerse, Belgium, 3 GlaxoSmithKline, Collegeville, PA, USA, 4 GlaxoSmithKline, Mississauga, Canada, 5 ViiV Healthcare, Research Triangle Park, NC, USA Background: Long-acting (LA) regimens of cabotegravir (CAB) + rilpivirine (RPV) given monthly and every 2-months are in development for maintenance of HIV suppression. Both products exhibit absorption-rate limited PK following intramuscular (IM) administration, with apparent half-life (t 1/2 ) estimates of 5.6 -11 weeks (CAB) and 28 weeks (RPV). Following LA treatment discontinua- tion, CAB and RPV may remain measurable in plasma for a year or longer. Available long-term follow up (LTFU) pharmacokinetic (PK) data from discontinued subjects in Phase 2b/3 studies (LATTE-2/ATLAS) are presented. Methods: HIV-infected subjects who received CAB LA + RPV LA every 4 (Q4W, n=33) or every 8 weeks (Q8W, n=5) and withdrew for any reason were required to switch to alternative antiretroviral therapy (ART) and enter LTFU (1 year), with PK sampling at 1, 3, 6, 9 and 12 months after final injections. Plasma CAB and RPV concentrations were determined by validated LC-MS/MS assays. RPV concentrations in subjects receiving oral RPV in LTFU were excluded from the results (n=6). Results: Figure 1 represents CAB and RPV plasma concentrations for subjects entering LTFU after having been on CAB LA+RPV LA from 4 to 72 weeks. Plasma

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