This is a pre-copyedited, author-produced PDF of an article
accepted for publication in AIDS Research and Human
Retroviruses following peer review. The version of record
2016 May;32(5):409-11. doi: 10.1089/aid.2015.0337. is
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Elvitegravir/cobicistat/tenofovir/emtricitabine Penetration in the Cerebrospinal Fluid of Three HIV-positive Patients.
Calcagno A, Simiele M, Motta I, Mornese Pinna S, Bertucci R, A. D’Avolio, G.Di Perri, Bonora S Unit of Infectious Diseases, Department of Medical Sciences, University of Torino, Torino, Italy.
Running Head: CSF Elvitegravir/cobicistat Type of article: Letter to the Editor
Key words: elvitegravir, cobicistat, tenofovir, emtricitabine, cerebrospinal fluid, central ervous
system, pharmacokinetics, HIV.
Word count: 794 Figures: 1
Corresponding Author:
Andrea Calcagno
Unit of Infectious Diseases
Ospedale Amedeo di Savoia, ASLTO2 C.so Svizzera 164
10149 Torino, Italy +390114393884
Highly active antiretroviral treatment is extremely effective in controlling viral replication and in improving immune system function in HIV-positive patients; however in some organs low-level
replication persists and it has recently been associated with insufficient tissue drug penetration.1
Cerebrospinal fluid (CSF) HIV RNA, an acceptable proxy of central nervous system (CNS) replication, is usually undetectable in effectively treated individuals; nevertheless CSF escape has been reported in approximately 10% of asymptomatic patients and to be the cause of severe
neurological symptoms in a few cases.2,3 Higher degrees of antiretroviral drugs’ CSF penetration
(either as concentration effectiveness scores or directly measured) have been associated with lower compartmental viral loads.4,5 Elvitegravir/cobicistat/tenofovir/emtricitabine is a single tablet
regimen that showed good efficacy and tolerability: no data are available on elvitegravir and
cobicistat CSF concentrations and a prospective study is currently ongoing.6,7 Despite a high protein
binding (98-99%) elvitegravir is a small and lipophilic molecule (molecular weight 442 Da and LogP 4.5) thus suggesting a good passage into the CSF. Elvitegravir is a p-glycoprotein substrate that is inhibited by cobicistat; however the effect on blood brain barrier transporters (such as OATP1A2) has been poorly characterized.
We describe three HIV-positive patients on elvitegravir/cobicistat/tenofovir/emtricitabine that received lumbar punctures for persistent headache in the absence of other neurological complaints (and with normal brain CT scans). After obtaining written informed consent (allowing the procedure, drug measurement and potential anonymous data publication) cerebrospinal fluid was withdrawn using atraumatic needles. Recent adherent was reported to be above 90% of prescribed doses and the last dose was administered under direct observation. Beside biochemical and virological exams CSF was tested for albumin levels; antiretroviral plasma and CSF concentrations (on samples collected less than 15 minutes apart) were measured by validated UPLC-MS/MS methods [with lower limits of quantification of 11.7 ng/mL (plasma) and 0.125 ng/mL (CSF)].
Patient A was middle-aged female with body mass index (BMI) of 27.5 Kg/m2; her CD4 cell count
and plasma HIV RNA were 441 cells/uL and <20 copies/mL. Patient B was a male in his forties (BMI of 26.4 Kg/m2) with a previous diagnosis of disseminated cryptococcosis without meningeal involvement; his CD4 cell count and plasma HIV RNA were 46 cells/uL and <20 copies/mL. In these two subjects the onset of headache was unrelated to the introduction of elvitegravir/cobicistat/tenofovir/emtricitabine.
Patient C was a young male in his thirties (BMI of 22.2 Kg/m2) with a previous diagnosis of cytomegalovirus retinitis; two months after starting elvitegravir/cobicistat/tenofovir/emtricitabine plus atazanavir (300 mg once daily) he complained of persistent headache. His CD4 cell count and plasma HIV RNA were 75 cells/uL and 395 copies/mL. All subjects had a normal renal function with estimated creatinine clearances of 112.1, 86.3 and 103.2 mL/min.
CSF samples were negative for causes of encephalitis, contained no cells and showed normal protein levels; CSF serum albumin ratios were within age-corrected range representing normal blood brain barriers. CSF HIV RNA was 56, <20 and 71 copies/mL, respectively.
Plasma and CSF concentrations (in ng/ml) as well as CSF-to-plasma ratios are summed up in Fig.1. In patients C atazanavir plasma and CSF concentrations were 692 and 36 ng/mL; CSF to plasma ratio was 0.05. Tenofovir and emtricitabine CSF to plasma ratios were respectively 0 (0-0.07) and 0.51 (0.37-0.76); in 2 out of 3 samples CSF tenofovir was not detectable.
In this case series we describe elvitegravir and cobicistat CSF concentrations. Elvitegravir levels ranged from 2.4 ng/mL to 11.7 ng/mL (14-24 hours after drug intake) with one trough sample
below in vitro non protein-adjusted 50% effective concentration (3.9 ng/mL).8 Elvitegravir CSF
concentrations were 0.3% (0.4-0.8) of plasma levels. Patient C higher elvitegravir Ctrough may be due to the concomitant administration of atazanavir: yet this did not influence elvitegravir CSF exposure, that was comparable to patient B. Cobicistat exposure in the CSF was highly variable
with concentrations ranging from 2 to 31% of plasma ones. We cannot extend these observations to other subjects nor judge the pharmacodynamic of elvitegravir in the central nervous system given the inter-patient variability and the differences between plasma and CSF pharmacokinetic profiles. CSF HIV RNA was either well controlled or lower than plasma level in 2 out of 3 patients and detectable at very low level in the third one (56 copies/mL). Pooled data from tenofovir/emtricitabine /elvitegravir/cobicistat treated patients suggested that the drugs distribute into the central nervous system because several participants (11-12%) reported somnolence,
headache, dizziness, insomnia or abnormal dreams.7,8 Raltegravir and dolutegravir (the two other
commercially available integrase inhibitors) were associated with CSF levels above 50% inhibitory concentrations in the majority of patients but with a significant inter-patient variability. 9-10
In conclusion, to the best of our knowledge these are the first data concerning the penetration of elvitegravir/cobicistat in the CSF: prospective studies are currently ongoing to establish the appropriateness of compartmental exposure.
Conflicts of interest
A. Calcagno has received grants, travel grants and speaker’s honoraria from Abbvie, Bristol-Myers Squibb (BMS), Gilead, Merck Sharp & Dohme (MSD), Janssen-Cilag, Viiv. S. Bonora. has received grants, travel grants and consultancy fees from Abbott, Boehringer-Inghelheim, BMS, Gilead- Sciences, GSK, MSD, Pfizer and Janssen-Cilag. G. Di Perri has received grants, travel grants and consultancy fees from Abbott, Boehringer-Inghelheim, BMS, Gilead- Sciences, GSK, MSD, Pfizer, Roche and Tibotec (Johnson & Johnson). Other authors have no potential conflict of interest to declare
Funding
References
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Time (hours) Elvitegravir Cobicistat plasma (ng/mL) CSF (ng/mL) ratio plasma (ng/mL) CSF (ng/mL) ratio Patient A 14 1389 11.7 0.0084 344 8.4 0.0244 Patient B 24 676 2.4 0.0035 38 5.8 0.1526 Patient C 24 1197 4.8 0.0040 23 7.3 0.3174
Fig.1 Elvitegravir concentrations in plasma (circles) and cerebrospinal fluid (triangles) and cobicistat concentrations (table underneath). The graph is semi-logaritmic. “CSF”, cerebrospinal
