Enfuvirtide Cerebrospinal Fluid (CSF) Pharmacokinetics and Potential Use in Defining CSF HIV-1 Origin

Antivir Ther. 2008;13(3):369-74.


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.

Publication types

  • Case Reports
  • Research Support, N.I.H., Extramural

MeSH terms

  • AIDS Dementia Complex / cerebrospinal fluid
  • AIDS Dementia Complex / drug therapy*
  • AIDS Dementia Complex / virology
  • Adult
  • Blood-Brain Barrier / metabolism*
  • Chromatography, Liquid
  • Drug Resistance, Viral / genetics*
  • Enfuvirtide
  • HIV Envelope Protein gp41 / blood
  • HIV Envelope Protein gp41 / cerebrospinal fluid
  • HIV Envelope Protein gp41 / genetics
  • HIV Envelope Protein gp41 / pharmacokinetics*
  • HIV Envelope Protein gp41 / therapeutic use
  • HIV Fusion Inhibitors / blood
  • HIV Fusion Inhibitors / cerebrospinal fluid
  • HIV Fusion Inhibitors / pharmacokinetics*
  • HIV Fusion Inhibitors / therapeutic use
  • HIV Infections / cerebrospinal fluid
  • HIV Infections / drug therapy*
  • HIV Infections / virology
  • HIV-1 / genetics*
  • Humans
  • Longitudinal Studies
  • Middle Aged
  • Mutation
  • Peptide Fragments / blood
  • Peptide Fragments / cerebrospinal fluid
  • Peptide Fragments / pharmacokinetics*
  • Peptide Fragments / therapeutic use
  • RNA, Viral / blood
  • RNA, Viral / cerebrospinal fluid
  • Tandem Mass Spectrometry


  • HIV Envelope Protein gp41
  • HIV Fusion Inhibitors
  • Peptide Fragments
  • RNA, Viral
  • gp41 protein, Human immunodeficiency virus 1
  • Enfuvirtide