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Cerebrospinal fluid exposure of cenicriviroc in HIV‐positive individuals with cognitive impairment
Author(s) -
Alagaratnam Jasmini,
DillyPenchala Sujan,
Challenger Elizabeth,
Else Laura,
Legg Ken,
Petersen Claire,
Jones Brynmor,
Kulasegaram Ranjababu,
Seyedkazemi Star,
Lefebvre Eric,
Khoo Saye,
Winston Alan
Publication year - 2019
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/bcp.13878
Subject(s) - medicine , cerebrospinal fluid , cart , cognitive impairment , neuroinflammation , neuropsychology , viral load , psychological intervention , biomarker , neurocognitive , immunology , cognition , human immunodeficiency virus (hiv) , psychiatry , inflammation , disease , mechanical engineering , biochemistry , chemistry , engineering
While virologically suppressive combination antiretroviral therapy (cART) has improved the outlook for persons‐with‐HIV (PWH), clinically significant cognitive impairment remains prevalent in otherwise effectively treated PWH. Underlying pathogenesis mechanisms include neuroinflammation, ongoing HIV replication in the central nervous system (CNS), and the contribution of lifestyle factors. At present, no proven interventions exist for the management of cognitive disorders in PWH. Cenicriviroc is a novel inhibitor of C‐C chemokine receptor type 5 (CCR5) and type 2 (CCR2) and is expected to have antiretroviral and anti‐inflammatory activity. Thus, cenicriviroc is a potential intervention for management of cognitive disorders in PWH. We assessed cerebrospinal fluid (CSF) exposure of cenicriviroc following 8 weeks cART intensification with cenicriviroc in PWH with symptomatic cognitive impairment. Cognitively impaired PWH with suppressed plasma HIV RNA on cART were eligible. Our definition of cognitive impairment included the presence of patient‐reported symptoms of cognitive impairment and formal clinical neuropsychological testing confirming cognitive impairment. Exclusion criteria included major depression and current use of CCR5 inhibitors. Paired CSF and plasma sampling were collected for cenicriviroc concentration assessment at baseline and after 8 weeks. Cenicriviroc concentration was determined using reverse phase high‐performance liquid chromatography, interfaced with a mass spectrometer. The EC90 for cenicriviroc 1 is 0.17 ng mL, and the lower limit of quantification (LLOQ) for CSF cenicriviroc concentration (0.24 ng mL) was utilised as the target concentration. Where exposure of cenicriviroc was below the LLOQ, a value 0.24 ng mL was imputed. CSF:serum albumin ratio was used as a surrogate measure of blood‐brain barrier integrity. Patient‐reported outcome measurements (PROMs) including Patient Health Questionnaire–9 item depression scale (PHQ‐9) and computerised cognitive testing (CogstateTM) were assessed. Of seven subjects enrolled, four completed all study procedures. Reasons for early discontinuation included fatigue, headache, depression, and nausea, all possibly related to cenicriviroc. All adverse events occurred within 4 weeks of commencing cenicriviroc, and all three subjects had discontinued cenicriviroc by week 6. Symptoms resolved within 7 days of cenicriviroc discontinuation in all three subjects.