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 cenicriviroc1 is 0.17 ng mL−1, and the lower limit of quantification (LLOQ) for CSF cenicriviroc concentration (0.24 ng mL−1) was utilised as the target concentration. Where exposure of cenicriviroc was below the LLOQ, a value 0.24 ng mL−1 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)2 and computerised cognitive testing (Cogstate™) 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.
No changes in PROMs or cognitive scores were evident over the study period.
At week 8, peak plasma cenicriviroc concentrations were detectable in all four subjects and detectable in the CSF in two subjects and below the LLOQ in two (Table 1). Mean CSF:plasma cenicriviroc concentration ratio was no more than 0.18% (95% CI of the upper estimate, 0.09%‐0.28%). CSF:serum albumin ratios were higher in those with detectable CSF cenicriviroc exposure (Table 1).
Table 1.
Individual subject blood and cerebrospinal fluid parameters at week 8
| Subject 1 | Subject 2 | Subject 3 | Subject 4 | |
|---|---|---|---|---|
| Cenicriviroc concentration | ||||
| CSF, ng mL−1 | 0.82 | 0.40 | 0.24 (<LLOQ) | 0.24 (<LLOQ) |
| Plasma, ng mL−1 | 718.6 | 211.0 | 411.9 | 70.5 |
| CSF: plasma cenicriviroc concentration ratio (%) | 0.11 | 0.19 | 0.06 | 0.34 |
| Albumin concentration | ||||
| CSF, mg L−1 | 1070 | 453 | 374 | 202 |
| Serum, g L−1 | 38 | 42 | 40 | 40 |
| CSF: serum albumin ratio | 28.2 | 10.8 | 9.4 | 5.1 |
| Antiretroviral therapy | abacavir, lamivudine, raltegravir | lamivudine, atazanavir, ritonavir | tenofovir DF, emtricitabine, dolutegravir | tenofovir DF, emtricitabine, raltegravir |
| Cenicriviroc dose | 150 mg | 50 mg | 150 mg | 150 mg |
Abbreviations: CSF, cerebrospinal fluid; tenofovir DF, tenofovir disoproxil fumarate; LLOQ, lower limit of quantification.
This is the first report to describe the CSF exposure of cenicriviroc. Strengths of our study include the assessment of pharmacokinetic parameters in the target population (PWH with cognitive disorders), and witnessed dosing prior to CSF examination.
The major limitation of our study is the small sample size, which restricts the interpretation of pharmacodynamic observations. Small improvements in cognitive function have been reported with cenicriviroc therapy in PWH.3
Our rationale for not including individuals on maraviroc was to ensure that any pharmacodynamic effects seen were not due to effects of another CCR5‐inhibitor. Given that many PWH with cognitive disorders were receiving maraviroc in our clinical setting, this criterion hampered our ability to reach our target recruitment of 10 subjects. Due to funding restrictions, it was necessary to stop recruitment after six months.
The high dropout rate seen in our cohort may be related to PWH with clinically significant cognitive disorders being more susceptible to adverse events, especially CNS adverse events. Our findings differ from larger studies assessing cenicriviroc in PWH, where adverse event rates were low and tolerability was high.4 Blood‐brain‐barrier disruption is well described in PWH and in PWH with cognitive disorders.5 The elevated CSF:serum albumin ratio is evidence of such disruption in participants in our study. CSF cenicriviroc exposure may be lower in other cohorts where there is less blood‐brain‐barrier disruption.
Based on our preliminary data, CSF cenicriviroc exposure was close to the EC90. While our study demonstrated that cenicriviroc exposure is detectable in the CSF, whether this is sufficient exposure for antiretroviral and anti‐inflammatory activity within the CNS needs to be determined, given that drug penetration into brain tissue was not measured.
COMPETING INTERESTS
J.A. has received honoraria from MSD and Gilead Sciences. S.K. has received grants for research and the Liverpool HIV drug interactions website from Gilead, ViiV, Janssen, and Merck. A.W. has received honoraria or research grants on behalf of Imperial College London or been a consultant or investigator in clinical trials sponsored by Bristol‐Myers Squibb, Gilead Sciences, GlaxoSmithKline, Janssen‐Cilag, Roche, and ViiV Healthcare. The other authors have no competing interests to declare.
ACKNOWLEDGEMENTS
We would like to thank the following groups and individuals for their contributions (listed alphabetically): Dr Laurent Fischer, Allergan plc, South San Francisco, USA. Albert Busza, Clinical Imaging Facility (CIF), Imperial College London (UK). David Back, Department of HIV Pharmacology, University of Liverpool (UK). Nadia Naous, Severine Ray, and Rosy Weston, Department of Research Pharmacy, Imperial College Healthcare NHS Trust (UK). Scott Mullaney, Imperial College HIV Clinical Trials Unit, St. Mary's Campus (UK).
Alagaratnam J, Dilly‐Penchala S, Challenger E, et al. Cerebrospinal fluid exposure of cenicriviroc in HIV‐positive individuals with cognitive impairment. Br J Clin Pharmacol. 2019;85:1039–1040. 10.1111/bcp.13878
Contributor Information
Jasmini Alagaratnam, Email: j.alagaratnam@imperial.ac.uk.
Alan Winston, Email: a.winston@imperial.ac.uk.
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