Cerebrospinal fluid HIV-1 RNA, intrathecal immunoactivation, and drug concentrations after treatment with a combination of saquinavir, nelfinavir, and two nucleoside analogues: the M61022 study.
BACKGROUND
The way various antiretroviral drugs and drug combinations affect HIV-1 infection in the central nervous system is still largely unknown. The aim of this study was to determine the cerebrospinal fluid (CSF) steady-state concentrations of saquinavir and nelfinavir in relation to plasma concentrations, and to study their effect in combination with two nucleoside reverse transcriptase inhibitors (NRTIs) on CSF viral loads, intrathecal immunoactivation, and blood-brain barrier integrity.


METHODS
Paired CSF and plasma samples from 8 antiretroviral-naïve HIV-1 infected patients starting combination therapy with saquinavir, nelfinavir, and two nucleoside analogues were collected prior to treatment, and again after approximately 12 and 48 weeks of antiretroviral therapy. Additional plasma samples were taken at weeks 2, 4, 8, 24, and 36. The concentrations of protease inhibitors were analysed, as were levels of HIV-1 RNA, CD4+ T-cell count, beta2-microglobulin, neopterin, albumin ratio, IgG index, and monocytic cell count.


RESULTS
None of the patients in the study presented with HIV-1 RNA < 50 copies/mL in CSF or plasma prior to treatment, compared to 5/7 at the end of the study. Signs of cell-mediated intrathecal immunoactivation, measured by neopterin and beta2-microglobulin, decreased significantly in both CSF and serum, although only 1/7 reached normal CSF neopterin levels after 48 weeks of treatment. There was no significant reduction of albumin ratio, IgG index or CSF monocytic cell count. Saquinavir median (range) concentrations were < 2.5 (< 2.5-96.0) nM unbound in plasma, and < 2.5 (< 2.5-9.0) nM total in CSF. Nelfinavir median (range) concentrations were 10.0 (< 2.0-31.0) nM unbound in plasma, and < 2.0 (< 2.0-23.0) nM total in CSF. Saquinavir and nelfinavir were detectable in 7/15 and 9/15 CSF samples, respectively.


CONCLUSIONS
Saquinavir and nelfinavir, in combination with two NRTIs, decrease the CSF viral load and, to a lesser extent, intrathecal immunoactivation. We found reasonably high CSF concentrations of nelfinavir, but suboptimal concentrations of saquinavir.
Department of Infectious Diseases, The Sahlgrenska Academy, Göteborg University, Göteborg, Sweden. aylin.yilmaz@infect.gu.se
Aylin
A
Yilmaz
Dietmar
D
Fuchs
Lars
L
Hagberg
Ulrika
U
Nillroth
Lars
L
Ståhle
Jan-Olof
JO
Svensson
Magnus
M
Gisslén
D000328:Adult; D019380:Anti-HIV Agents / Q000097:blood / Q000134:cerebrospinal fluid / Q000627:therapeutic use*; D018791:CD4 Lymphocyte Count; D004359:Drug Therapy, Combination; D005260:Female; D015658:HIV Infections / Q000188:drug therapy*; D015497:HIV-1 / Q000378:metabolism*; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood / Q000134:cerebrospinal fluid; D008297:Male; D008875:Middle Aged; D019888:Nelfinavir / Q000097:blood / Q000134:cerebrospinal fluid / Q000627:therapeutic use*; D019798:Neopterin / Q000134:cerebrospinal fluid; D012367:RNA, Viral / Q000097:blood / Q000134:cerebrospinal fluid*; D019258:Saquinavir / Q000097:blood / Q000134:cerebrospinal fluid / Q000627:therapeutic use*; D001613:beta 2-Microglobulin / Q000097:blood / Q000134:cerebrospinal fluid
D019380:Anti-HIV Agents; D007074:Immunoglobulin G; D012367:RNA, Viral; D001613:beta 2-Microglobulin; D019798:Neopterin; D019888:Nelfinavir; D019258:Saquinavir