HIV-1 reverse transcriptase sequence in plasma and cerebrospinal fluid of patients with AIDS dementia complex treated with Abacavir.
OBJECTIVE
To assess HIV-1 RNA levels and the relationship between HIV-1 reverse transcriptase (RT) genotype from plasma and cerebrospinal fluid (CSF) during treatment with abacavir (Ziagen, ABC) or placebo in combination with stable background therapy (SBG) in subjects with AIDS dementia complex (ADC) (study CNA3001).


METHODS
One-hundred and five HIV-1 infected adults with ADC were randomized to receive either ABC (600 mg twice daily) or ABC-matched placebo (twice daily) in addition to SBG for 12 weeks.


METHODS
Plasma and CSF were collected for population sequencing at baseline and week 12 (CSF optional). Sequences were analyzed for mutations associated with resistance to nucleoside reverse transcriptase inhibitors (NRTI).


RESULTS
Sixty out of sixty-seven subjects with baseline plasma HIV-RT sequence data harbored virus with > or = 1 NRTI-associated mutations; 50 out of 67 had the M184V mutation. At week 12, more subjects in the ABC group had plasma HIV-1 RNA < or = 400 copies/ml than the SBG group (46% versus 13%, P = 0.002). Non-response to ABC was associated with multiple baseline zidovudine (ZDV)/stavudine (d4T)-associated mutations. Baseline RT mutation patterns differed in 14 out of 21 (67%) paired samples from plasma and CSF. Four subjects experienced > 1 log10 copies/ml reductions in CSF HIV-1 RNA, two in the absence of reductions in plasma HIV-1 RNA and two with undetectable plasma HIV-1 RNA at baseline.


CONCLUSIONS
Substantial decreases in plasma and CSF HIV-1 RNA following addition of ABC were not precluded by baseline HIV-1 NRTI-associated mutations, including the M184V mutation, but non-responders commonly harbored multiple ZDV/d4T-associated mutations. HIV-1 RNA responses and RT genotype appear to be discordant between CSF and plasma in some subjects.
Lanier
E R
ER
Glaxo Wellcome, Research Triangle Park, North Carolina 27709, USA.
Sturge
G
G
McClernon
D
D
Brown
S
S
Halman
M
M
Sacktor
N
N
McArthur
J
J
Atkinson
J H
JH
Clifford
D
D
Price
R W
RW
Simpson
D
D
Torres
G
G
Catalan
J
J
Marder
K
K
Power
C
C
Hall
C
C
Romero
C
C
Brew
B
B
D015526:AIDS Dementia Complex / Q000188:drug therapy* / Q000201:enzymology; D000293:Adolescent; D000328:Adult; D000368:Aged; D019380:Anti-HIV Agents / Q000627:therapeutic use*; D004252:DNA Mutational Analysis; D015224:Dideoxynucleosides / Q000627:therapeutic use*; D004311:Double-Blind Method; D005838:Genotype; D054303:HIV Reverse Transcriptase / Q000097:blood / Q000134:cerebrospinal fluid / Q000235:genetics*; D015497:HIV-1 / Q000235:genetics*; D006801:Humans; D008875:Middle Aged; D012367:RNA, Viral / Q000097:blood / Q000134:cerebrospinal fluid; D018894:Reverse Transcriptase Inhibitors / Q000627:therapeutic use*; D000099227:Abacavir
D019380:Anti-HIV Agents; D015224:Dideoxynucleosides; D054303:HIV Reverse Transcriptase; D012367:RNA, Viral; D018894:Reverse Transcriptase Inhibitors; D000099227:Abacavir