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TOTAL AND UNBOUND DORAVIRINE CONCENTRATIONS AND VIRAL SUPPRESSION IN CSF OF HIV+ PTS
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CROI 2021 March 6-10 Reported by Jules Levin
Juan M . Tiraboschi1, Sofia Scevola1, Sujan D. Penchala2, Laura Else2, Paula Prieto1, María Saumoy1, Jordi Niubo1, Benito Garcia-Vidal1, Saye Khoo2, Daniel Podzamczer1
1Bellvitge University Hospital, Barcelona, Spain, 2University of Liverpool, Liverpool, UK
Background: Doravirine (DOR) is a new HIV-1 non-nucleoside reverse transcriptase inhibitor (NNRTI) that has demonstrated a good efficacy and safety profile in clinical trials. Initial pharmacokinetic studies demonstrated a time to maximal concentration of 1-5 h, not extensive binding to plasma proteins (76%) and poor solubility in water. In animal models the tissue distribution was assessed using 14C-labelled DOR. Low levels of radioactivity were observed in the brain suggesting that DOR does not readily cross the blood-brain-barrier. We determined DOR levels in cerebrospinal fluid (CSF) as well as HIV viral load in this compartment in HIV-1 virologically suppressed patients.
Methods: This is a single-arm, open-label, single-center study. After an initial assessment, 15 participants switched from stable ART to Emtricitabine/ Tenofovir alafenamide (FTC/TAF) plus DOR 100 mg OD orally. At week 4, blood and CSF samples were collected 24 h post dose, when DOR concentrations are expected to be lowest. Total DOR concentrations in plasma and CSF were determined using a validated LC-MS method. Unbound DOR concentrations were determined using Rapid Equilibrium Dialysis. HIV RNA was measured in plasma and CSF by RT-PCR (LLQ 20 copies/mL).
Results: A total of 14 plasma and 15 CSF samples were collected. Median age was 47 years (27-65), 86% were male. At baseline, median CD4 cell count and HIV viral load in plasma were 773 cells/uL (372 - 1744) and <20 copies/ml respectively. Most patients switched from InSTI based regimens [Bictegravir (5); Dolutegravir (4) and Elvitegravir (3)]. At week 4, only one patient had detectable viral load in CSF (32 copies/ml) while undetectable in blood plasma. The DOR unbound fraction in plasma and CSF were 12.8% and 76.1% respectively. DOR total CSF/total plasma ratio was 0.13. DOR total CSF/unbound plasma was 0.99, suggesting that DOR crosses the blood brain barrier primarily via passive diffusion (Table 1).
Conclusion: Total and unbound trough DORA concentrations in CSF exceeded the EC50 value against WT virus (5.1 ng/mL) by 11.4 and 8.7-fold respectively, suggesting that DOR given in combination with FTC/TAF may contribute to inhibit viral replication in this compartment.
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