Enfuvirtide cerebrospinal fluid (CSF) pharmacokinetics and potential use in defining CSF HIV-1 origin.
BACKGROUND
Enfuvirtide is a potent inhibitor of systemic HIV-1 replication, but its penetration into the human central nervous system (CNS) has not been analysed. Here, we define cerebrospinal fluid (CSF) enfuvirtide pharmacokinetics and present a case illustrating the use of enfuvirtide as a probe to trace the origins of CSF HIV-1 quasispecies.


METHODS
Enfuvirtide CSF pharmacokinetics were assessed in 18 CSF and plasma sample pairs from four HIV-1-infected individuals. Enfuvirtide levels were measured by liquid chromatography tandem mass spectrometry using known standards and controls that included spiked CSF samples from untreated, HIV-negative individuals. A segment of the gp41 coding region encompassing the heptad repeat HR-1 and HR-2 domains was amplified from selected CSF and plasma samples and independent clones sequenced to assess resistance-associated mutations.


RESULTS
CSF and plasma samples obtained between 2 and 20 h after enfuvirtide injection showed plasma concentrations similar to previous reports (mean 3.687 SD +/- 1.828 mg/ml) with prolonged decay. By contrast, enfuvirtide in all CSF samples was below the assay detection limit of 0.025 mg/ml. In one individual, who developed a transient increase in CSF HIV-1 RNA, seven of seven CSF and plasma clones had identical enfuvirtide resistance-associated V38A mutations, suggesting that the CSF quasispecies derived from that of blood.


CONCLUSIONS
Enfuvirtide penetration into CSF is negligible; thus, in clinical settings, where direct CNS drug exposure is crucial, this drug Is not likely to directly contribute to the local therapeutic effect. Enfuvirtide can be used as a tool to dissect the origin of the CNS virus.
Department of Neurology, University of California, San Francisco, CA, USA. rwprice@sfgh.ucsf.edu
Richard W
RW
Price
Robin
R
Parham
Jing Lu
JL
Kroll
Stephen A
SA
Wring
Brian
B
Baker
Jeff
J
Sailstad
Rebecca
R
Hoh
Teri
T
Liegler
Serena
S
Spudich
Daniel R
DR
Kuritzkes
Steven G
SG
Deeks
D015526:AIDS Dementia Complex / Q000134:cerebrospinal fluid / Q000188:drug therapy* / Q000821:virology; D000328:Adult; D001812:Blood-Brain Barrier / Q000378:metabolism*; D002853:Chromatography, Liquid; D024882:Drug Resistance, Viral / Q000235:genetics*; D000077560:Enfuvirtide; D015700:HIV Envelope Protein gp41 / Q000097:blood / Q000134:cerebrospinal fluid / Q000235:genetics / Q000493:pharmacokinetics* / Q000627:therapeutic use; D023581:HIV Fusion Inhibitors / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics* / Q000627:therapeutic use; D015658:HIV Infections / Q000134:cerebrospinal fluid / Q000188:drug therapy* / Q000821:virology; D015497:HIV-1 / Q000235:genetics*; D006801:Humans; D008137:Longitudinal Studies; D008875:Middle Aged; D009154:Mutation; D010446:Peptide Fragments / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics* / Q000627:therapeutic use; D012367:RNA, Viral / Q000097:blood / Q000134:cerebrospinal fluid; D053719:Tandem Mass Spectrometry
D015700:HIV Envelope Protein gp41; D023581:HIV Fusion Inhibitors; D010446:Peptide Fragments; D012367:RNA, Viral; C514787:gp41 protein, Human immunodeficiency virus 1; D000077560:Enfuvirtide