Pharmacokinetics of long‐acting cabotegravir and rilpivirine in virologically suppressed adolescents living with HIV‐1 in Sub‐Saharan Africa: Data from the LATA trial

15 Introduction: Adolescents living with HIV face unique challenges in maintaining virological suppression, with adherence to daily oral antiretroviral therapy (ART) being a major barrier. Long-acting injectable (LA) ART with cabotegravir (CAB) and rilpivirine (RPV), administered once every 8 weeks (Q8W), has shown promising efficacy and acceptability in adults and adolescents, but limited data are available for adolescents in African settings. The LATA trial (NCT05154747) is evaluating Q8W LA CAB/RPV (600/900 mg) vs. once daily oral lamivudine/tenofovir disoproxil fumarate/dolutegravir in virologically suppressed (HIV-1 RNA < 50c/mL) adolescents aged 12 to <20 years in Sub-Saharan Africa. Here, we present pharmacokinetic (PK) data from a nested sub-study in the CAB/RPV trial arm to assess drug exposure at the end of year 1 of LA CAB/RPV in adolescents living with HIV-1 in Africa. Methods: We aimed for ≥20 evaluable PK curves, with a male/female ratio of ~1:1. Participants received loading doses of LA CAB/RPV (600/900 mg) at Weeks 4 and 8 post-randomization, followed by maintenance dosing Q8W. An optional 4-week Oral Lead-In (OLI) with CAB/RPV was available between randomisation and Week 4. Participants who did not opt for the OLI continued their current oral ART during that period. Five blood samples, protected from light and processed and frozen at −80°C within recommended 3 h of blood draw (achieved for 138/140 [99%] samples), were taken around the second maintenance dose (week 24) at t = 0 (pre-injection), 3 days (±1 day), 7 days (±2 days), 28 days (±7 days) and 56 days (±7 days, pre-week 32 injection). CAB and RPV concentrations were measured using a validated UPLC–MS/MS method. PK parameters (AUC0-56d, Cmax and Ctrough) for CAB and RPV were calculated using non-compartmental PK analysis. The numbers of adolescents with CAB and RPV Ctrough below 4x PA-IC90 and Q1 (the lower quartile of drug concentrations observed in adult patients) are summarized. AUC0-56d and Ctrough levels are compared to adult phase III data from the LATTE-2 and ATLAS-2M trials and to data from the MOCHA trial in adolescents (cohort 2). Results: Twenty-eight adolescents from Uganda, Zimbabwe and South Africa were included (13/15 female/male). A total of 16 (57%) had received a 4-week CAB/RPV OLI. At week 24 visit, median (range) age was 17.4 (12.7–20.4) years, BMI 21.0 (14.0–28.9) kg/m2. For CAB, the AUC0-56d, Cmax and Ctrough geometric mean (GM) (%CV) were 4887 (30) h*mg/L, 5.35 (42) mg/L and 2.19 (47) mg/L respectively. For RPV, AUC0-56d, Cmax and Ctrough, GM (%CV) were 150.12 (29) h*mg/L, 0.194 (33) mg/L and 0.078 (28) mg/L respectively. Three adolescents (11%) had a CAB Ctrough below 1.12 mg/L (Q1 threshold) and one (4%) below 0.66 mg/L (4x PA-IC90), at 0.63 mg/L. All adolescents had RPV Ctrough values above both 0.032 mg/L (Q1 threshold) and 0.048 mg/L (4x PA-IC90). CAB and RPV exposures were comparable to values reported previously in adults and adolescents. Conclusion: LA CAB/RPV therapy in this African adolescent cohort resulted in drug exposures consistent with earlier adult and adolescent populations. The 96-week primary analysis will provide data on the efficacy of CAB/RPV LA injectables in African adolescents.