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Objectives: Cabotegravir + rilpivirine (CAB + RPV) dosed monthly or every 2 months is the first complete long‐acting (LA) regimen recommended by treatment guidelines for the maintenance of HIV‐1 virological suppression. This post hoc analysis summarizes outcomes for Asian participants through week 96. Methods: Data from Asian participants naive to CAB + RPV randomized to receive dosing every 4 weeks (Q4W) or every 8 weeks (Q8W) in the FLAIR (NCT02938520) and ATLAS‐2M (NCT03299049) phase 3/3b studies were pooled. The proportion of participants with plasma HIV‐1 RNA ≥50 and <50 copies/mL (per FDA Snapshot algorithm), incidence of confirmed virological failure (CVF; two consecutive HIV‐1 RNA ≥200 copies/mL), pharmacokinetics, safety, and tolerability through week 96 were assessed. Results: Overall, 41 Asian participants received CAB + RPV (Q8W, n = 17; Q4W, n = 24). At week 96, 83% (n = 34/41) of participants maintained HIV‐1 RNA <50 copies/mL, none had HIV‐1 RNA ≥50 copies/mL, and 17% (n = 7/41) had no virological data. No Asian participant met the CVF criterion. Drug‐related adverse events occurred in 44% (n = 18/41) of participants; none were Grade ≥3. All injection site reactions were Grade 1 or 2; median duration was 2 days and most resolved within 7 days (90%, n = 390/435). CAB and RPV trough concentrations remained well above their respective protein‐adjusted 90% inhibitory concentrations (CAB, 0.166 μg/mL; RPV, 12 ng/mL) through week 96. Conclusions: CAB + RPV LA demonstrated high efficacy, with no participants having CVF, and an acceptable safety profile in Asian participants through week 96. These data support CAB + RPV LA as a complete regimen for the maintenance of HIV‐1 virological suppression in Asian individuals. [ABSTRACT FROM AUTHOR]

Background: Cabotegravir is an HIV integrase inhibitor in clinical development with both oral and long-acting (LA) injectable formulations. Cabotegravir is primarily metabolized by uridine 5'-diphospho-glucuronosyltransferase (UGT) 1A1, a known polymorphic enzyme with functional variants that can affect drug metabolism and exposure.Objectives: To investigate the pharmacogenetic effects of the reduced-function alleles UGT1A1*6, UGT1A1*28 and/or UGT1A1*37 on steady-state pharmacokinetics (PK) and safety of oral cabotegravir (30 mg/day) and intramuscular cabotegravir LA (400 mg every 4 weeks or 600 mg every 8 weeks).Methods: Plasma cabotegravir PK was assessed in 346 UGT-genotyped participants with and without UGT1A1 functional variants across six studies (four Phase I and two Phase II) of oral cabotegravir, including 215 HIV-infected participants who received oral cabotegravir followed by cabotegravir LA. Changes from baseline in total bilirubin and ALT were assessed in one study (LATTE; NCT01641809).Results: Statistically significant (P < 0.05) associations were observed between UGT1A1 genotype and plasma cabotegravir PK parameters, with 28%-50% increases following oral cabotegravir [plasma cabotegravir concentration at the end of the dosing interval (Ctau), 1.50-fold; AUCtau, 1.41-fold; and Cmax, 1.28-fold] and 16%-24% increases following cabotegravir LA administration (48 week Ctau, 1.24-fold; AUCtau, 1.16-fold; and Cmax, 1.18-fold) among those with low-versus-normal genetically predicted UGT1A1 activity. A statistically significant (P < 10-5) association between predicted UGT1A1 activity and maximum change in total bilirubin was also observed (2.45-fold asymptomatic increase for low versus normal) without a corresponding change in ALT.Conclusions: This modest increase in oral and parenteral cabotegravir exposure associated with a reduced function of UGT1A1 is not considered clinically relevant based on accumulated safety data; no dose adjustment is required. [ABSTRACT FROM AUTHOR]

Background: Long-acting (LA) formulations of cabotegravir, an HIV integrase inhibitor, and rilpivirine, an NNRTI, are in development as monthly or 2 monthly intramuscular (IM) injections for maintenance of virological suppression.Objectives: To evaluate cabotegravir and rilpivirine CSF distribution and HIV-1 RNA suppression in plasma and CSF in HIV-infected adults participating in a substudy of the Phase 2b LATTE-2 study (NCT02120352).Methods: Eighteen participants receiving cabotegravir LA 400 mg + rilpivirine LA 600 mg IM [every 4 weeks (Q4W), n = 3] or cabotegravir LA 600 mg + rilpivirine LA 900 mg IM [every 8 weeks (Q8W), n = 15] with plasma HIV-1 RNA <50 copies/mL enrolled. Paired steady-state CSF and plasma concentrations were evaluable in 16 participants obtained 7 (±3) days after an injection visit. HIV-1 RNA in CSF and plasma were assessed contemporaneously using commercial assays.Results: Median total CSF concentrations in Q4W and Q8W groups, respectively, were 0.011 μg/mL and 0.013 μg/mL for cabotegravir (0.30% and 0.34% of the paired plasma concentrations) and 1.84 ng/mL and 1.67 ng/mL for rilpivirine (1.07% and 1.32% of paired plasma concentrations). Cabotegravir and rilpivirine total CSF concentrations exceeded their respective in vitro EC50 for WT HIV-1 (0.10 ng/mL and 0.27 ng/mL, respectively). All 16 participants had HIV-1 RNA <50 copies/mL in plasma and CSF, and 15 of 16 participants had HIV-1 RNA <2 copies/mL in CSF.Conclusions: A dual regimen of cabotegravir LA and rilpivirine LA achieved therapeutic concentrations in the CSF resulting in effective virological control in CSF. [ABSTRACT FROM AUTHOR]

Cabotegravir is an integrase inhibitor in clinical development for the treatment and prevention of HIV infection using oral tablets for short‐term, lead‐in use before subsequent administration of a long‐acting injectable formulation. This phase 1, single‐center, randomized, 2 × 2 crossover study evaluated the effect of a high‐fat meal on the pharmacokinetics (PK) of oral cabotegravir. Healthy adults received oral cabotegravir 30 mg as a single dose on 2 separate occasions, either after fasting or following a high‐fat meal (∼53% fat, ∼870 kcal). Safety evaluations and serial PK samples were collected, and a mixed‐effects model was used to determine within‐participant treatment comparison of noncompartmental PK parameters. Twenty‐four patients were enrolled and had a mean body mass index of 25.6 kg/m2; 67% were male. Compared with the fasting state, coadministration of cabotegravir with a high‐fat meal increased plasma cabotegravir area under the concentration‐time curve and maximal drug concentration, each by 14%. The slight 14% to 17% increase in exposure associated with a high‐fat, high‐calorie meal was not considered clinically significant. No grade 3/4 adverse events (AEs), drug‐related AEs, or AEs leading to discontinuation were reported. [ABSTRACT FROM AUTHOR]

S/GSK1349572 is an unboosted, once-daily integrase inhibitor with a novel resistance profile. As standard of care for patients infected with HIV is combination therapy, the potential interaction between S/GSK1349572 and ritonavir-boosted protease inhibitors was evaluated. In an open-label, repeat-dose, 2-period, 2-sequence crossover study in healthy participants, S/GSK1349572 was administered at 30 mg once daily for 5 days, followed by randomization to lopinavir/ritonavir 400/100 mg twice daily or darunavir/ritonavir 600/100 mg twice daily coad-ministered with S/GSK1349572 30 mg once daily for 14 days. There was no washout between periods. Serial pharmacokinetic (PK) samples and safety assessments were obtained throughout the study. Thirty of 31 participants completed the study (15 participants per group). Treatment comparisons of steady-state S/GSK1349572 PK parameters demonstrated that coadministration of lopinavir/ritonavir had no significant effect on steady-state PK of S/GSK1349572. Coadministration of darunavir/ritonavir resulted in a nonclinically significant reduction in steady-state plasma S/GSK1349572 exposures. Plasma S/GSK1349572 AUC(0-τ ), Cmax, and Cτdecreased by 22%, 11%, and 38%, respectively, on average. S/GSK1349572 was well tolerated with no serious adverse events (AEs) or withdrawals due to drug-related AEs. The most frequent drug-related AEs were diarrhea, dizziness, and headache. No dosage adjustment for S/ GSK1349572 is required when used with lopinavir/ritonavir or darunavir/ritonavir. [ABSTRACT FROM PUBLISHER]