title: Evidence of a source of HIV type 1 within the central nervous system by ultraintensive sampling of cerebrospinal fluid and plasma.
abstract: Defining the source of HIV-1 RNA in cerebrospinal fluid (CSF) will facilitate studies of treatment efficacy in the brain. Four antiretroviral drug-naive adults underwent two 48-hr ultraintensive CSF sampling procedures, once at baseline and again beginning on day 4 after initiating three-drug therapy with stavudine, lamivudine, and nelfinavir. At baseline, constant CSF HIV-1 RNA concentrations were maintained by daily entry of at least 10(4) to 10(6) HIV-1 RNA copies into CSF. Change from baseline to day 5 ranged from -0.38 to -1.18 log(10) HIV-1 RNA copies/ml in CSF, and from -0.80 to -1.33 log(10) HIV-1 RNA copies/ml in plasma, with no correlation between CSF and plasma changes. There was no evidence of genotypic or phenotypic viral resistance in either CSF or plasma. With regard to pharmacokinetics, mean CSF-to-plasma area-under-the-curve (AUC) ratios were 38.9% for stavudine and 15.3% for lamivudine. Nelfinavir and its active M8 metabolite could not be accurately quantified in CSF, although plasma M8 peak level and AUC(0-8hr) correlated with CSF HIV-1 RNA decline. This study supports the utility of ultraintensive CSF sampling for studying HIV-1 pathogenesis and therapy in the CNS, and provides strong evidence that HIV-1 RNA in CSF arises, at least in part, from a source other than plasma.
authors.affiliation: Division of Infectious Diseases, Department of Medicine and Department of Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee 37212, USA. david.w.haas@vanderbilt.edu
authors.forename: D W
authors.initials: DW
authors.lastname: Haas
authors.forename: L A
authors.initials: LA
authors.lastname: Clough
authors.forename: B W
authors.initials: BW
authors.lastname: Johnson
authors.forename: V L
authors.initials: VL
authors.lastname: Harris
authors.forename: P
authors.initials: P
authors.lastname: Spearman
authors.forename: G R
authors.initials: GR
authors.lastname: Wilkinson
authors.forename: C V
authors.initials: CV
authors.lastname: Fletcher
authors.forename: S
authors.initials: S
authors.lastname: Fiscus
authors.forename: S
authors.initials: S
authors.lastname: Raffanti
authors.forename: R
authors.initials: R
authors.lastname: Donlon
authors.forename: J
authors.initials: J
authors.lastname: McKinsey
authors.forename: J
authors.initials: J
authors.lastname: Nicotera
authors.forename: D
authors.initials: D
authors.lastname: Schmidt
authors.forename: R E
authors.initials: RE
authors.lastname: Shoup
authors.forename: R E
authors.initials: RE
authors.lastname: Kates
authors.forename: R M
authors.initials: RM
authors.lastname: Lloyd
authors.forename: B
authors.initials: B
authors.lastname: Larder
mesh_terms: D000328:Adult; D019380:Anti-HIV Agents / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics; D002490:Central Nervous System / Q000821:virology*; D004352:Drug Resistance, Microbial; D014644:Genetic Variation; D015658:HIV Infections / Q000097:blood / Q000134:cerebrospinal fluid / Q000188:drug therapy / Q000821:virology*; D017320:HIV Protease Inhibitors / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D019259:Lamivudine / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics; D019888:Nelfinavir / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics; D012367:RNA, Viral / Q000134:cerebrospinal fluid*; D018894:Reverse Transcriptase Inhibitors / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics; D018119:Stavudine / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics; D013997:Time Factors
chemical_list: D019380:Anti-HIV Agents; D017320:HIV Protease Inhibitors; D012367:RNA, Viral; D018894:Reverse Transcriptase Inhibitors; D019259:Lamivudine; D018119:Stavudine; D019888:Nelfinavir