Pharmacokinetics and antiviral activity of cabotegravir and rilpivirine in cerebrospinal fluid following long-acting injectable administration in HIV-infected adults

Scott L Letendre, Anthony Mills, Debbie Hagins, Susan Swindells, Franco Felizarta, Jerome Devente, Christopher Bettacchi, Yu Lou, Susan Ford, Kenneth Sutton, Jafar Sadik Shaik, Herta Crauwels, Ronald D'Amico, Parul Patel, Scott L Letendre, Anthony Mills, Debbie Hagins, Susan Swindells, Franco Felizarta, Jerome Devente, Christopher Bettacchi, Yu Lou, Susan Ford, Kenneth Sutton, Jafar Sadik Shaik, Herta Crauwels, Ronald D'Amico, Parul Patel

Abstract

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.

© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy.

Figures

Figure 1.
Figure 1.
LATTE-2 Phase 2b study design and CSF substudy schedule. aSubjects who withdrew after at least one IM dose entered the long-term follow-up period (not shown). bSubjects could elect to enter Q4W and Q8W LA extension phase beyond Week 96. cLumbar puncture was carried out 1 week post-injection ± 3 days. ABC/3TC, abacavir/lamivudine; CAB, cabotegravir; PO, orally; Q4W, every 4 weeks; Q8W, every 8 weeks; RPV, rilpivirine.

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