Inter‐ and intraindividual variability of long‐acting cabotegravir/rilpivirine pharmacokinetics after 1 year of continuous use

16 Background: Low plasma concentrations of long-acting cabotegravir/rilpivirine (LA CAB/RPV) are associated with increased risk of virologic failure. However, real world data from the Swiss cohort found that trough LA CAB/RPV concentrations demonstrate high interindividual variability (coefficient of variation [CV]: CAB 31%, RPV 35%) and intraindividual variability (CV: CAB 52%, RPV 29%) during the first 12 months of use. We sought to characterize the variability in trough plasma concentrations of CAB and RPV in people with HIV (PWH) receiving LA CAB/RPV after 1 year of continuous use. Methods: We conducted a prospective pharmacokinetic study in virologically suppressed PWH who had received >12 months of continuous LA CAB/RPV (600 mg/900 mg) given intramuscularly every 2 months. All doses were administered by the same four nurses. Plasma samples were collected pre-injection at 3 consecutive visits, and CAB/RPV concentrations were quantified via LC–MS/MS. The primary outcomes were interindividual and intraindividual CAB and RPV trough concentration variability reported as percentage CV, Fleiss Kappa, and intraclass correlation coefficient (ICC). The secondary outcome was proportion of participants with CAB or RPV concentrations below 4x PA-IC90 (CAB = 664 ng/mL; RPV = 48 ng/mL). We performed descriptive statistics (median; interquartile range [IQR] or range) for participant demographics and outcomes. Results: Overall, 141 trough samples were obtained from 47 participants receiving LA CAB/RPV for 65 weeks (IQR 56, 82) at entry. Most participants were male (83%) and White (74%) with a median age of 45 years (IQR 33, 59) and body mass index of 28.2 kg/m2 (IQR 26, 33). Geometric mean CAB and RPV concentrations were 1447.7 ng/mL (range 104.4–4191 ng/mL) and 76.8 ng/mL (range 22.16–232.2 ng/mL), respectively. Interindividual CV for CAB was 47.3% (IQR 46.2, 48.9) and 47.2% (IQR 45.5, 48.7) for RPV. CAB and RPV Fleiss Kappa was −0.008 and −0.007, respectively, indicating poor interindividual agreement. Intraindividual CV for CAB was 24.6% (IQR 15.4, 38.5%) and 27.5% (IQR 19, 41.8%) for RPV. ICC was 0.81 and 0.72 for CAB and RPV, respectively, indicating good intraindividual agreement for CAB and moderate intraindividual agreement for RPV. There were 20 (14%) RPV and 10 (7%) CAB concentrations below 4x PA-IC90. Thirty-nine (83%) participants remained virologically suppressed throughout the follow-up period. Of the 8 (17%) participants with detectable viremia, 10 HIV RNA measurements were >20 copies/mL (range 23–75 copies/mL). Only one participant had CAB <4x PA-IC90, but none had RPV < 4x PA-IC90. All eight participants subsequently re-suppressed (HIV-RNA < 20 copies/mL) while remaining on LA CAB/RPV. Conclusions: After 1 year of continuous use, interindividual and intraindividual variability persists for CAB and RPV. In our cohort, interindividual variability for CAB and RPV was higher compared to previously reported data during the initial 12 months of use. Additionally, intraindividual variability for CAB was lower, while RPV variability was similar to prior data during the first 12 months of use. There were more RPV concentrations below 4x PA-IC90 than CAB; however, all participants remained virologically controlled on LA CAB/RPV.