Evidence of a source of HIV type 1 within the central nervous system by ultraintensive sampling of cerebrospinal fluid and plasma.
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.
Haas
D W
DW
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
Clough
L A
LA
Johnson
B W
BW
Harris
V L
VL
Spearman
P
P
Wilkinson
G R
GR
Fletcher
C V
CV
Fiscus
S
S
Raffanti
S
S
Donlon
R
R
McKinsey
J
J
Nicotera
J
J
Schmidt
D
D
Shoup
R E
RE
Kates
R E
RE
Lloyd
R M
RM
Larder
B
B
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
D019380:Anti-HIV Agents; D017320:HIV Protease Inhibitors; D012367:RNA, Viral; D018894:Reverse Transcriptase Inhibitors; D019259:Lamivudine; D018119:Stavudine; D019888:Nelfinavir