Abstract Body

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 (t1/2) estimates of 5.6 -11 weeks (CAB) and 28 weeks (RPV). Following LA treatment discontinuation, 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.

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).

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 CAB was > 0.166μg/mL (protein adjusted (PA)-IC90) in 30/30 subjects at the 1-month LTFU visit, and ranged between 0.034 to 0.152μg/mL (< PA-IC90) in 8 subjects and was nonquantifiable (<lower limit of quantification (LLOQ, 0.025μg/mL)) in 17 subjects at the 12-month LTFU visit.  At the 1-month LTFU visit, plasma RPV was >12 ng/mL (PA-IC90) 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-IC90 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.

The CAB and RPV plasma concentrations observed during LTFU are consistent with the apparent absorption-rate limited t1/2 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.