Abstract Book Vol. 2 [International Conference on AIDS (14th: 2002: Barcelona, Spain)]

424 Abstracts ThPeB7360-ThPeB7363

XIV International AIDS Conference

TNF alpha and ILl0 in the HIV seropositive and seronegative groups. In the combined group, IFN gamma and TNF alpha were significantly higher in stage 2 disease than in stage 1 disease. There was no significant correlation between the
cytokine levels and CD4 counts in the CSF
Conclusions: This study suggests that the immune response to TBM is similar
in both HIV seropositive and HIV seronegative patients. Although the number of
patients in the two groups was small (type 1 statistical error), the known similar
clinical response to treatment supports our findings.
Presenting author: Ahmed Bhigjee, Dept of Neurology, Wentworth Hospital,
Private Bag, Jacobs 4026, South Africa, Tel.: [phone], Fax: [phone], E-mail: [email protected]
ThPeB7360 Cerebrospinal fluid (CSF) HIV-RNA supressed by
Saquinavir and Nelfinavir in combination with 2
Nucleoside Analogues
M. Gisslen', L. Hagberg', B. Svennerholm2, F. Bernadotte3, U. Nillroth3.
'Goteborg University/Dpt. ofInfectious Diseases, Dpt ofInfectious Diseases,
Sah/grenska University Hospital/Ostra, SE-41685 Goteborg, Sweden; 2Goteborg
University/Dpt. of Virology, Goteborg, Sweden; 3Roche AB, Stockholm, Sweden
Background: Highly active anti-retroviral therapy (HAART) effectively decreases
HIV-RNA in plasma in the majority of HIV-infected individuals. Unfortunately, the
regimens sometimes fail and drug resistances emerge. One critical factor might
be virus replication in tissue compartments difficult to reach by drugs. The aim of
this study was to investigate if saquinavir-sgc in combination with nelfinavir has a
positive effect on the HIV-RNA viral suppression in the CSF.
Methods: An open-label, single arm, single center, 48 week study. HIV-1 infected
anti-retroviral naive patients received treatment with nelfinavir 1250 mg BID and
saquinavir-sgc 1200 mg BID in combination with 2 nucleoside analogues (NRTIs).
CSF samples were drawn at screening, week 12 and 48 and plasma samples additionally at week 2, 4, 8, 24, and 36 for the assessment of HIV-RNA viral load,
Roche ultrasensitive assay.
Results: 8 patients were enrolled: mean age, 41 years; 75 % blacks: 50 % men.
At base-line the median HIV-RNA was 16 000 copies/ml in CSF (range 157-254
000) and 114 450 copies/ml in plasma (range 7100-383 000). The number of patients with HIV-RNA below the limits of 50 and 400 copies/ml in CSF and plasma
are shown in the table. Efficacy was assessed by Intention To Treat analysis (ITT).
HIV RNA sample Baseline Week 12 Week 24 Week 48
CSF <50 copies/mIl 0/8 (0%) 6/8 (75%) N.A. 5/8 (62%)
Plasma <50 copies/ml 0/8 (0%) 5/8 (62%) 3/8 (38%) 5/8 (62%)
CSF <400 copies/ml 1/8(12%) 8/8(100%) N.A. 6/8 (75%)
Plasma <400 copies/mIl 0/8 (0%) 8/8 (100%) 5/8 (62%) 6/8 (75%)
The median CD4-cell count increased from 200 (range 20-310) to 370 and 330
cells/liL, at week 24 and 48, respectively One patient was withdrawn from the
study at week 24 due to treatment failure. A second patient stopped taking all
study medication at week 36 and had a viral rebound at week 48. All other patients managed to take the considerable large number of tablets throughout the
study The treatment was generally well tolerated.
Conclusions: Nelfinavir in combination with saquinavir and 2 NRTIs are effective
in reducing viral load in CSF and plasma. PK analysis is ongoing.
Presenting author: Magnus Gisslen, Dpt of Infectious Diseases, Sahigrenska
University Hospital/Ostra, SE-41685 Goteborg, Sweden, Tel.: [phone],
Fax: [phone], E-mail: magnus.gisslen @ infect.gu.se
ThPeB7361 Significance of a positive Epstein-Barr virus PCR in
the cerebrospinal fluid in the absence of brain
lesions consistent with primary central nervous
system lymphoma
M.B. Ristig', D. Clifford2, W. Seyfried3, W.G. Powderly', G.A. Storch4.
' Washington University School of Medicine, Department of Internal Medicine,
Division of Infectious Diseases, St. Louis, MD, United States; 2 Washington
University School of Medicine, Department of Neurology St. Louis, Missour,
United States; 3 ahigo University School of Medicine, AIDS Clinical Trials
Unit, St. Louis, Missouri, United States; Washington University School of
Medicine, Department of Pediatrics, St. Louis, Missouri, United States
Background: Primary central nervous system lymphoma (PCNSL) is strongly
associated with Epstein-Barr virus (EBV). Less is known about EBV-related CNS
disease in HIV+ subjects without mass lesions. EBV-DNA is frequently detected
by PCR in the cerebrospinal fluid (CSF) and its significance is uncertain. The
purpose of this study was to determine clinical significance of EBV-DNA in the
absence of lesions in the brain consistent with lymphoma.
Methods: Retrospective longitudinal study of patients who had an EBV PCR in
the CSF between 1994 to 2001 at a single clinical site. A multiplex PCR was used

to detect EBV plus toxoplasma DNA. PCNSL was defined as focal brain lesions
(FBL) with a positive brain biopsy or EBV PCR, negative toxoplasma serology
or clinical failure of toxoplasma therapy. Patients with FBL caused by PCNSL at
baseline were excluded. All EBV+ individuals were matched with EBV negative
cases. Survival analysis was performed.
Results: 75 of 332 CSFs were EBV-DNA positive. 52 (69%) of 75 originated from
HIV+ subjects and follow up data was available from 47 cases. 13/47 (28%) had

PCNSL or NHL brain lesions; all died. The remaining 34 EBV+, HIV+ patients
were followed for a median of 28 months. At baseline, the median CD4 cell count
was 69 cell/mm3, and median plasma HIV-RNA was 69,289 copies/ml. Two subjects developed clinically apparent PCNSL 1 to 26 month of follow up. None of
the individuals with a negative PCR developed PCNSL after a median follow up
of 24 months.
Conclusion: In HIV+ individuals EBV-DNA in the CSF in the absence of FBL
consistent with brain lymphoma is associated with a 6% risk (95% CI 0 %-20%, p
0.17) of subsequent development of FBL and PCNSL over an approximate 2 year
period. There was no significant difference in survival between EBV (+) and EBV
(-) individuals, but the study is underpowered to detect a difference.
Presenting author: Maria Bibiana Ristig, Washington University School of
Medicine, AIDS Clinical Trials Unit, 4511 Forestpark Ave.Suite 304, St.Louis,
Mo.63108, United States, Tel.: [phone], Fax: [phone], E-mail:
[email protected]
ThPeB7362 Population pharmacokinetics of hydroxyurea in
cerebrospinal fluid and plasma of HIV-1-infected
adults
J.J. McNabb, S. Swindells, C. Cobos, E. Lien, K. Manouilov, PR Gwilt. University
of Nebraska Medical Center, Omaha, NE, United States
Background: Hydroxyurea (HU) is a ribonucleotide reductase inhibitor that potentiates the activity of antiretroviral nucleosides. An affordable compound with
minimal drug interactions, HU may have utility in resource-poor settings. HU is
also a small molecule with potential to penetrate the central nervous system
(CNS). This study investigated the cerebrospinal fluid (CSF) penetration of HU
in HIV-infected patients. ARV drug penetration into the CNS is highly variable and
may be important in treating and/or preventing neurological complications of HIV1 disease. Very limited data in both animals and HIV-negative humans suggest
that penetration of HU into CSF is approximately 25% of plasma levels.
Methods: HIV-1-infected adult participants (n=12) were given a single dose of
oral hydroxyurea at 800 mg, 1000 mg, or 1200 mg. CSF samples were obtained
simultaneously with plasma samples at intervals over 8 hours. HU concentrations
were determined by a validated HPLC assay. CSF and plasma HU concentrations
were simultaneously modeled with NONMEM using a linear one compartment
model with first order elimination.
Results: The mean PK parameters were: absorption rate constant at 2.24 1/hr,
volume of distribution 48.0 L, half-life 2.13 hours, clearance 15.6 L/hr, clearance
into CSF 3.59 L/hr and clearance out of CSF 17.7 L/hr. Mean plasma concentrations ranged from a peak of 0.17 - 0.33 mM to a trough of 0.2 - 0.7 mM. The model
predicts an approximately 20% HU penetrance into CSF. At 5 hours post-dose,
CSF concentrations were continuing to increase relative to declining plasma concentrations. CSF concentrations ranged from 0.01 to 0.04 mM.
Conclusions: CSF penetrance of HU in HIV-1-infected subjects is approximately
20%. Entry of HU into the CSF is slow relative to its exit, with sustained concentrations in the CSF post-dose. HU concentrations in plasma and CSF are similar
to concentrations required to inhibit HIV-1 in vitro.
Presenting author: JoCarol McNabb, 986045 Nebraska Medical Center, Omaha, NE 681098-6045, United States, Tel.: [phone], Fax: [phone],
E-mail: [email protected]
ThPeB7363 High rate of neuropsychological impairment in
patients with advanced HIV-infection despite
long-term HAART
L.A.J. Cysiquel, B.J. Brew2, P. Maruff3. '1University of New South Wales/St.
Vincent's Clinical School, Darlinghurst Sydney NSW Australia; 2 University of
New South Wales, St. Vincents Hospital, Sydney, Australia; 3La Trobe
University, School of Psychological Sciences, Melbourne, Australia
Background: Several studies have demonstrated that Highly Active Antiretroviral
Therapy (HAART) significantly improves cognitive function in HIV-infection. However, the durability remains unknown. Also there (AAN criern that the pattern
of cognitive deficit may be changing.
Methods: Fiffy-two patients on HAART for five years, with advanced HIV-infection
(Stage C3, 1993 CDC Classification) were examined with a comprehensive neuropsychological battery assessing eight cognitive domains plus depression, anxiety and stress.
Results: The mean (SD) nadir CD4 cell count was 65.07 p. I (60.07) and current CD4 cell count was 294.7 p. I (222.5). The mean (SD) plasma HIV RNA was
61360.8 cpy/mI (140912.6). Patients were not significantly depressed, anxious or
stressed. Using the American Academy of Neurology (AAN) criteria, we found that
76.9% (40) subjects were neuropsychologically impaired and 23.1% (12) unimpaired. When patients with previous brain HIV involvement (clinically resolved on
HAART) were excluded the prevalence of impairment remained comparable. The
prevalence of cognitive impairment tended to decrease, with no significant statisti
cal difference, when patients with undetectable HIV RNA were included, 64% (16)
impaired and 31% (9) unimpaired. The pattern of impairment remains consistent
with the previous reports with a predominance of deficits in fine-motor coordination, attention, speed processing and memory and mental flexibility. However,
further analysis revealed that some areas of functioning usually less affected in
HIV-infection such as long-term memory retention are also becoming significantly
affected.