Bridging the Gap: Conference Record [Abstract book, International Conference on AIDS (12th: 1998: Geneva, Switzerland)]

84 Abstracts 12353-12357

12th World AIDS Conference

qd vs. ddl bid alone at week 16 (mean log decrease LH PCR -1.00 vs -0.72
and Roche PCR -0.93 vs -0.70). Ddl qd/hydrea at week 16 was significantly
better than ddl alone qd (mean log decrease LH PCR -1.95 vs -1.00; p =.03
and Roche PCR -1.19 vs -0.93; p = 0.19) and better than ddl bid (decrease LH
PCR -1.95 vs. -0.72 and Roche PCR -1.19 vs -0.70). Ddl bid/hydrea (lower
baseline CD4 count) was not statistically different from ddl bid alone.
Conclusions: Data suggests 1) once daily ddl to be as effective as bid dosing
(possibly more effective) and 2) ddl qd plus hydrea once daily more effective than
ddl alone. The lack of increased benefit of ddl bid with hydrea may be due to
group's later HIV stage (lower baseline CD4). The trend for increased efficacy of
once daily ddl may be due to ghigher intracellular concentrations. Once daily ddl
is well tolerated, without increased side effects, more feasible to schedule into
triple drug regimens, and may be preferable to ddl bid.
S12353Safety and tolerance of abacavir (1592, ABC) alone and in
combination therapy of HIV infection
Seth Hetherington1, H.M. Steel1, S. Lafon', W. Spreen', G. Pearce2. 1Glaxo
Wellcome Inc., 5 Moore Drive, Research Triangle Park, NC, USA; 2Glaxo
Wellcome, Greenford Road, Greenford, England, UK
Background: Abacavir is a nucleoside reverse transcriptase inhibitor (RTI) in
phase III trials for the treatment of HIV infection. A comprehensive understanding
of the safety profile is crucial for optimal use of ABC.
Methods: Data from the following studies will be used to define the safety
profile of ABC: 1) open label multidose phase II studies of patients receiving ABC
alone or with other ART: 2) an open label protocol combining ABC with available
ART; and 3) phase III trials in adults and children.
Results: Among 171 patients who received ABC in phase II trials, the most
common adverse events (AEs) included nausea (44%), headache (35%), asthenia (29%), diarrhea (21%), insomnia (17%), vomiting 13%), abdominal pain
(9%). Most events were mild or moderate in intensity. Only 18 subjects (10%)
discontinued because of AEs, the most common of which were a hypersensitivity
reaction consisting of fever, malaise and usually rash (n = 5); and nausea (n =
5). No other AE resulted in more than a single discontinuation. No changes in
laboratory parameters resulted in study discontinuation. An open label protocol
providing ABC to patients with CD4 count <100/mm3 has enrolled over 1500. To
date, 94 patients discontinued therapy, 56 due to AEs. Reasons for discontinuation included ABC hypersensitivity, malaise, anxiety, and peripheral neuropathy.
Grade 3/4 AEs and lab abnormalities were generally ascribed to concomitant
medications or disease progression. Phase III trials are ongoing and data remains blinded. Across all studies, the most common reason for discontinuation
was ABC hypersensitivity reaction (3%), with onset generally within 4 weeks of
initiating therapy.
Conclusion: These data suggest abacavir can be readily combined with all
other currently marketed antiretroviral agents. The most common reason for discontinuation is a hypersensitivity reaction among 3% of patients. Patients with this
reaction must not be rechallenged with ABC. Grade 3 or 4 laboratory abnormalities were uncommon and usually occurred in combination with other antiretroviral
agents known to cause the event.
12354 Stavudine penetrates the blood-brain barrier
Elmar Straube, B.K. Kuhlmann, M.W. Weimann, R.H. Hoetelman, P. Von
Wussow. Marktst Rasse 27-29, D-30890 Barsinghausen; Nieagnae
Study-Group Germany, Hannover, Germany; 2University of Amsterdam,
Amsterdam, The Netherlands
Objectives: Very limited data about CSF level of various antiretroviral agents are
available.
Methods: 26 patients with HIV infection, who were on combination therapy
with stavudine, underwent lumbar puncture for different neurological reasons.
CD4-count varied from 64 to 803 cells/pl. 75% ranging from 200 to 550 cells/[kl.
HIV RNA copies (Roche Amplicor) were measured in serum and CSF. HIV RNA
were measured between <400 and 337.000/ml in serum, and <400 and 10.000/ml
in CSF. Serum and CSF kinetic of stavudine was obtained.
Results: Maximum level of stavudine in serum was found after 3 hours with a
mean concentration of 349 /g/ml. In contrast, maximal stavudine concentration
in CSF were found between 4 and 7 hours. Mean concentration varied from 87 to
51 pg/ml, respectively. Previous studies have shown that a serum concentration
of 50 pg/ml effectively blocks HIV replication (Bristol-Myers Squibb, data on file).
According to our data this level is reached within one hour after taking 40 mg
stavudine in 50% of the patients studied.
Conclusion: Our data confirm antiretroviral effective concentrations in 85% of
the patients under 2 x 40 mg. Therefore besides ZDV a second antiretroviral
agent is known to penetrate at sufficient quantities into CSF.
12355 Stavudine entry into cerebrospinal fluid of HIV-infected
subjects after single and multiple doses

Kathleen Brady', J. Aldrich2, R. Broston2, R.R. MacGregor2. 1Hospital of the U.
of Penn. 536 Johnson 3400 Spruce St. Philadelphia, PA 19104; 2 University of
Pennsylvania, Philadelphia, PA, USA
Objectives: To establish the cerebrospinal fluid (CSF)-to-plasma ratio of stavudine (d4t) in persons with HIV both at steady state and after a single 40 mg
dose.

Methods: 30 subjects with HIV were recruited to undergo an elective lumbar
puncture (LP). Fifteen subjects were on chronic d4t therapy for clinical reasons.
Trough serum d4t levels were obtained prior to dosing, followed by one hour peak
levels. Patients were randomized to undergo an elective LP either 2, 4 or 6 hours
after dosing. Additional serum levels were drawn immediately prior to the LP.
CSF and serum specimens were frozen at 70~C until drug levels were performed.
CSF was also analyzed for cell counts, protein, and glucose. The results of 15
subjects who received a single dose of d4t are pending and will be reported.
Results: The 15 patients (14 men, 1 woman) on chronic d4t had a median
baseline CD4 count of 348 cells/pL (range 80-738). CSF white blood counts
(WBC) ranged from 1 to 22 cells/mm3 and CSF protein from 31 to 72 mg/dl.
Plasma d4t levels peaked at one hour in all but one patient (mean 2.773 pmol/L,
range.332-4.824 /pmol/L). D4t CSF levels over 2 to 6 hours ranged from.164
to.572 pmol/L with a mean of.260 pmol/L. By robust regression using Huber
weighting, CSF d4t levels increased significantly (p =.0003) over the 2 to 6 hours
(regression coefficient.00042 pLmol/Lmin, Cl.000169-.000678). Time of peak
CSF levels could not be established since levels were still continuing to rise at
6 hours. CSF d4t levels were inversely correlated with pre-LP plasma d4t levels
and weight, but there was no correlation between CSF d4t levels and baseline or
peak serum d4t levels, CSF WBC, CSF protein, baseline CD4, and plasma viral
load.
Conclusions: Stavudine penetrates into the CSF in a slow time-dependent
fashion. Mean CSF stavudine levels equal or exceed the IC50 for HIV (.05-.5
p/mol/L).
12356 Inhibition of lymphoma using ribonucleotide reductase
inhibitors (RRIs) in the murine model of
immunodeficiency disease - MAIDS
Vincent Gallicchio1, C. Mayhew1, H.L. Elford2. 'University of Kentucky, Medical
Center, 121 Washington Avenue, Lexington, KY; 2Molecules for Health,
Richmond, VA, USA
Objectives: To test the efficacy of novel RRIs to inhibit retroviral replication and
development of lymphoma in the murine model of AIDS.
Design: Experimental, in vivo, animal study
Methods: C57BL6 female mice were inoculated i.p. with LP-BM5 MuLV. Noninfected and infected animals were treated with Didox (300 or 460 mg/kg/bw)
or Trimidox (150 or 220 mg/kg/bw) i.p. daily, alone or in combination with ddl
(600 mg/kg/bw), given s.c., beginning 1-day or 1-week post infection. Controls
were virally infected animals not receiving RRIs or ddl. Mice were monitored
for disease progression: survival, splenomegaly, lymphadenopathy, CD4/CD8 ratios, hypergammaglobulinemia, blood toxicity, RT activity, viral gag p12 envelope
glycoprotein expression, and integrated proviral DNA.
Results: RRI infected mice with/without ddl produced increased survival, absence of lymphoma (splenomegaly, lymphadenopathy), reduced RT, gag 12
expression and viral infected PBMCs, marginal blood toxicity, restored CD4/CD8
ratios and reduced integrated proviral DNA. The antiviral effect was enhanced
with ddl; however ddl alone had marginal activity. Drugs were tolerated for >50
weeks.
Conclusions: Results demonstrate RRIs are potent antiviral agents capable
of increasing survival and reducing several parameters of immunodeficiency disease and warrant initiation of clinical trials to examine their antiviral potential in
AIDS.
S12357 An open-label randomized study of Rescriptor" (DLV,
delavirdine mesylate) in triple and quadruple
combinations with zidovudine (ZDV), indinavir (IDV) and
lamivudine (3TC) in HIV-1 infected individuals
Patrick Daly1, S.L. Green2, W.W. Freimuth3, M.A. Conklin3, D.C. Huang3,
L.K. Wathen3. 4012 Cedar Springs Dallas, Texas; Hampton Rd. Medical Spec
PC, Hampton, VA; Pharmacia & Upjohn Inc., Kalamazoo, Ml, USA
Objectives: To compare the safety and efficacy of Rescriptor" (DLV, delavirdine
mesylate) in triple and quadruple combinations with zidovudine (ZDV), indinavir
(IDV) and lamivudine (3TC) in HIV-1 Infected Individuals.
Design: Open-label, randomized
Methods: A clinical study of HIV-1 infected patients with baseline mean CD4
cell counts of 267 cells/mm3 and mean RNA PCR levels of 5.5 log copies/mL
investigated four therapeutic regimens:
DLV (400 mg TID) + ZDV (200 mg TID) + IDV (600 mg q8h)
DLV (400 mg TID) + IDV (600 mg q8h) + 3TC (150 mg BID') 'Dose by body
weight
DLV (400 mg TID) + ZDV (200 mg TID) + IDV (600 mg q8h) + 3TC (150 mg
BID*)
ZDV (200 mg TID) + IDV (800 mg q8h) + 3TC (150 mg BID')
Results: After 4 weeks on therapy, the mean decrease in viral burden was
>3 log in response to DLV+IDV+ZDV. The DLV+IDV+3TC, IDV+ZDV+3TC and
quadruple drug regimen treated groups averaged a >1.6 log diminution in circulat
ing HIV-1 RNA. In the first two months of therapy, these treatment regimens were
well tolerated with no reported incidence of nephrolithiasis. Available updated
data will be presented from this on-going 24 week study.
Conclusions: These results demonstrate that patients on the DLV+IDV+ZDV
therapy achieve a profound early decrease in viral burden which may indicate the
potential for longterm durability of the antiviral response without apparent safety
concerns.