ViiV Healthcare and Janssen R&D.

Drug-drug interactions between antiretroviral medications and rifampin complicate the treatment of HIV and tuberculosis coinfection. This study evaluated the effect of rifampin on the pharmacokinetics of oral cabotegravir, an integrase strand transfer inhibitor being investigated for long-acting treatment and prevention of HIV-1 infection. This was a phase I, single-center, open-label, fixed-sequence crossover study in healthy adults. The objective was to evaluate the effect of steady-state rifampin on the single-dose plasma pharmacokinetics of cabotegravir. Subjects received a single oral dose of cabotegravir (30 mg) on day 1 followed by plasma sampling on days 1 to 8. Treatment with once-daily oral rifampin (600 mg) occurred on days 8 to 28. Subjects received a second dose of 30 mg cabotegravir on day 21 followed by pharmacokinetic sampling on days 21 to 28. Fifteen subjects were enrolled and completed the study. Rifampin decreased the cabotegravir area under the concentration-time curve from 0 h to infinity and the half-life by 59% and 57%, respectively, whereas oral clearance was increased 2.4-fold. The maximum concentration of cabotegravir in plasma was unaffected by coadministration with rifampin. All adverse events were mild in severity, with chromaturia attributed to rifampin observed in all subjects. Rifampin induction of cabotegravir metabolism resulted in increased cabotegravir oral clearance and significantly decreased cabotegravir exposures. Rifampin is expected to increase cabotegravir clearance following long-acting injectable administration. Concomitant administration of rifampin with oral and long-acting formulations of cabotegravir is not recommended currently without further study. (This study has been registered at ClinicalTrials.gov under registration no. NCT02411435.)

Background In the LATTE-2 phase IIb study, long-acting (LA) injectable cabotegravir + rilpivirine dosed every 8 weeks (Q8W) or 4 weeks (Q4W) demonstrated comparable efficacy with daily oral antiretroviral therapy (ART) through 96 weeks in ART-naive adults with HIV-1. Here we report efficacy, tolerability, and safety of cabotegravir + rilpivirine LA over ~5 years. Methods After 20 weeks of oral cabotegravir + abacavir/lamivudine, participants were randomized to cabotegravir + rilpivirine LA Q8W or Q4W or continue oral ART through the 96-week maintenance period. In the extension period through Week 256, participants continued their current LA regimen (randomized Q8W/Q4W groups) or switched from oral ART to Q8W or Q4W LA therapy (extension-switch groups). Endpoints assessed included proportion of participants with HIV-1 RNA <50 copies/mL (Snapshot algorithm) and adverse events (AEs). Results At Week 256, 186 (81%) of 230 participants in randomized Q8W/Q4W groups and 41 (93%) of 44 participants in extension-switch groups had HIV-1 RNA <50 copies/mL. No protocol-defined virologic failures occurred after Week 48. Injection-site reactions infrequently resulted in discontinuation (4 [2%] and 1 [2%] participants in randomized Q8W/Q4W and extension-switch groups, respectively). Three participants in randomized Q8W/Q4W groups experienced drug-related serious AEs, including 1 fatal serious AE (Q4W group); none occurred in extension-switch groups. Of 25 participants with AEs leading to withdrawal, 20 were in the randomized Q4W group; no AE leading to withdrawal occurred in >1 participant. Conclusions Cabotegravir + rilpivirine LA exhibited long-term efficacy and tolerability, demonstrating its durability as maintenance therapy for HIV-1 infection (ClinicalTrials.gov, NCT02120352).

Objectives: Long-acting formulations of cabotegravir (CAB) and rilpivirine (RPV) have demonstrated efficacy in Phase 3 studies. POLAR (NCT03639311) assessed antiviral activity and safety of CAB+RPV long-acting administered every 2 months (Q2M) in adults living with HIV-1 who previously received daily oral CAB+RPV in LATTE (NCT01641809). Design: A Phase 2b, multicenter, open-label, rollover study. Methods: LATTE participants with plasma HIV-1 RNA less than 50 copies/ml who completed at least 300 weeks on study were eligible. Participants elected to switch to either CAB+RPV long-acting Q2M or daily oral dolutegravir/RPV for maintenance of virologic suppression. The primary endpoint was the proportion of participants with HIV-1 RNA greater than or equal to 50 copies/ml at Month 12 (M12) per the Food and Drug Administration Snapshot algorithm. The incidence of confirmed virologic failure (CVF, two consecutive HIV-1 RNA measurements greater than or equal to 200 copies/ml), as well as safety, laboratory, and patient-reported outcomes (HIV Treatment Satisfaction and preference questionnaires) were also assessed. Results: Of 97 participants enrolled, 90 chose to receive CAB+RPV long-acting and seven chose dolutegravir/RPV. At M12, no participant had HIV-1 RNA greater than or equal to 50 copies/ml or met the CVF criterion in either treatment group. No new safety signals were identified. Total treatment satisfaction was high at Baseline and remained stable through M12 across both treatment groups. Overall, 88% ( n = 77/88) of long-acting arm participants preferred CAB+RPV long-acting to oral CAB+RPV. Conclusion: CAB+RPV long-acting maintained virologic suppression in participants who had previously received daily oral CAB+RPV for at least 5 years in LATTE, with a favorable safety profile. Most participants preferred CAB+RPV long-acting to their prior oral CAB+RPV regimen at M12.

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.