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

54 Abstracts 12213-12216

12th World AIDS Conference

Methods: 60 ART naive patients (HIV-1 RNA < 30,000 c/mL (vRNA), CD4
> 100 cells/mm3), were originally randomized to 3 doses of ABC BID, for 24
weeks (CNAB2002). Patients who either completed 24 weeks of ABC therapy, or
met switch criteria based upon vRNA, CD4+ cell counts, or occurrence of AIDS
defining events, had the option to switch to open-label ABC (300 mg BID) plus
3TC/ZDV. Response on open-label ABC was assessed by quantitative vRNA and
CD4 counts, analysed based on a baseline, reset when patients began open-label
ABC. Safety was assessed by changes in laboratory results and adverse event
reporting.
Results: 55 patients entered open label (OL). Results indicate that treatment
regimens containing abacavir, provide a substantial, additional, antiviral and
immunologic benefit, after prior therapy with abacavir alone.
OL Wk 4 OL Wk 16 OL Wk 48 OL Wk 72
Median additional decrease: -1.8 -1.9 -2.3 xx
VL log10 (Min, Max) (-0.5, -2.4) (-1,-2.7 (-1.7,-3.1) xx
Median additional increase: 45 51 110 xx
CD4/mm3 (Min, Max) (-15,130) (15,163) (27,179) xx
% <400 copies/mL 68 55 60 xx
% <50 copies/mL 26 40 42 xx
46/55 patients remained on ABC/3TC/ZDV; 1 on ABC therapy alone; 7 added
PIs to ABC/3TC/ZDV, and 1 substituted D4T for ZDV. Three patients were lost
to follow-up during open-label. All ABC regimens are well tolerated. The most
common AEs reported were nausea/vomiting, malaise, fatigue and headache. No
cases of hypersensitivity occurred during the open-label phase of this study.
Conclusion: For antiretroviral naive patients receiving abacavir in combination with 3TC/ZDV, the extent and long term durability of viral suppression and
immunologic response, together with the good safety profile, indicates that, triple
nucleoside therapy containing abacavir, may be an alternative to protease inhibitor
containing regimens.
12213 Early and sustained changes in lymphoctye
sub-populations during abacavir (ABC) and PI therapy
Dennis Kelleher1, Michael Lederman2, J. Mellors3, D. Haas4, E. Cooney5,
J. Horton6, J. Stanford7, R. Haubrich8. 1Glaxo Wellcome 5 More Drive RTP
NC27613 Antiviral CLinical Research; 2Case Western Research University,
Cleveland OH; 3University of Pittsburgh/VAMC, Pittsburgh PA; 4 Vanderbilt
University, Nashville TN; 5Yale University, New Haven CT; 6Carolinas Medical
Center, Charlotte NC; 7Kansas City AIDS Research Consortium, Kansas City
MO; 8UCSD Treatment Center, San Diego CA, USA
Background: Therapy for 16 weeks combining ABC with one of five different PI
induced changes in selected T-Lymphoctye populations across the five treatment
arms indicative of immune recovery. We extended the analysis to present effects
by treatment arm.
Methods: In study CNAA2004, 78 antiretroviral naive patients (median CD4
cell count of 349) began therapy with abacavir (300 mg q12h) combined with
one of five different PI (indinavir, ritonavir, nelfinavir, 141W94 [amprenavir, USAN
approved], and saquinavir.sgc) at the standard dosing. T-lymphocyte sub-populations, selected for relevance to possible immune recovery, were quantified by
4-color flow cytometry.
Preliminary Results: 16 Week Median Change from Baseline - Absolute (ABS)
and % where appropriate
Treatment CD4+ CD8+ Naive ABS CD4 Memory CD4+28+ CD38+ HLA DR+
1592+ (N) ABS ABS CD62L+45RA+ ABS % %
CD4+ CD45B@g5RA- CD4+ CD8+
141W94 (13) +100 -240 +35 +24 +74 +9.5 -15.2 -32.2
Indinavir (13) +239 +25 +53 +24 +152 +5.8 -8.8 -24.9
Ritonavir (12) +45 +34 +31 +15 +48 +6.5 -8.1 -17.9
Saquinavir (14) +173 +30 +27 +24 +126 +6.6 -5.8 -18.0
Nelfinavir (12) +142 -88 +7 +20 +113 +5.0 -18.5 -27.6
Conclusions: Treatment of antiretroviral naive subjects with abacavir and PI
results in early and substantial improvements in the lymphoctye abnormalities
associated with HIV infection. Increased numbers of naive CD4+ and CD8+ cells
and increased numbers of CD28+CD4+ cells may predict recovery of immune
potential and immune function, respectively.
[12214 A second generation non-nucleoside reverse
transcriptase inhibitor (S-1153) for the treatment of HIV
infection: A phase I study
Bruce J. Dezube1, Mark S. Jacobs2, G. Leoung2, T. Fujiwara4, J.A. Proper1,
B. Anderson'2, J. Carpenter1, T.A. Dahl3. 1Beth Israel Deaconess Medical
Center, 330 Brookline Ave, Boston, MA; 2HIV Care, Saint Francis Memorial
Hospital, San Francisco, CA; 3 Lexigen Pharmaceuticals, Lexington, MA, USA;
4Shionogi & Co., Osaka, Japan

Background: S-1153 is a novel NNRTI which has a 10-fold greater in-vitro activity
against HIV-1 than nevirapine and delavirdine. Resistance of HIV-1 to S-1153 is
seen only after double or triple mutations, as opposed to the one mutation for the
current FDA approved NNRTI's.
Methods: A Phase I dose escalation PK/safety study was conducted with
S-1153 administered over 7 dose levels-1.7, 3.3, 5.0, 6.7, and 8.3 mg/kg t.i.d, and

10.0 and 12.5 mg/kg b.i.d. Patients received study drug for 14 days (first 4 dose
levels) or for 28 days (last three dose levels). S-1153 drug levels were evaluated
with and without food at some of the levels. Entry CD4+ cell counts were 50-500
cells/ml. Concomitant antiretroviral therapy, other than protease inhibitor or other
NNRTI's, was permitted but not required, provided it was stable for >4 weeks
prior to study entry.
Results: 54 patients received S-1153. Bioavailability was high, and drug levels
were not significantly affected by food. All patients completed dosing without any
evidence of S-1153 related Grade 3 or 4 toxicity. The study drug related adverse
events were mild nausea and metallic taste. These side effects were ameliorated by taking S-1153 with food. No rashes have been observed. Target S-1153
blood levels were maintained at 8 and 12 hours dosing intervals. In patients who
received S-1153 for 28 days (N = 25), all but two had received >6 month of
NRTIs, four had failed PIs and ten were taking NRTIs while on study. Only one
patient had an undetectable viral load <200 copies/ml (Amplicor HIV-1 PCR)
on entry, 11 patients had >10,000 copies/mI. In these 11 patients, the average
decrease in viral load was >1.74 log10, (range 0.74-2.6) Viral load levels became
undetectable in 12 of 25 patients while receiving S-1153. The average rise in
CD4+ cells was 122 cells/ml in these 25 patients.
Conclusions: S-1153 administered either twice or thrice daily is well-tolerated,
achieves therapeutic plasma levels, and demonstrates potent antiviral activity
even in antiretroviral experienced patients.
12215 1 Early intervention with maximally suppressive
antiretroviral therapy lowers CD8 counts toward the
normal range
Alan L. Landay', M. Agnoli2, M. Czerniewski2, J. Spritzler3, J. Pottage2. 11653
West Congress PKWY, 1577 Jelke, Chicago, IL 60612; 2Rush Medical College,
Chicago, IL; 3Harvard School of Public Health Chicago IL, USA
Background: The utilization of potent antiviral therapies capable of reducing HIV
plasma RNA to undetectable levels has resulted in significant changes in the
immune response. This study was undertaken to evaluate immune restoration in
early HIV disease (CD4 > 500 cells/ul).
Methods: We evaluated 24 antiretroviral naive patients receiving a combination
of indinavir, zidovudine, lamivudine, at baseline, 4, 12 and 24 weeks post therapy.
Three color immunophenotyping of CD4 and CD8 subsets utilizing antibodies
identifying activation (HLADR/CD38), and maturation (CD45RA/CD62L) markers
was performed. In vitro lymphoproliferative assays were carried out.
Results: Viral load was below quantification (<400 copies/ml) in 80% of patients by week 4 and 100% of the evaluable patients at 24 weeks had viral RNA <
400 copies/ml. Median CD4 counts increased from baseline values of 562 cells/ul
to 598 cell/ul at wk 4 (ns) while CD8 cells fell from 723 cells/ul to 634 cells/ul at
wk 4 (p =.005) and to 483 cells/ul by week 24 (p =.01). CD8 subset analysis
demonstrated a significant (p =.002) reduction in activation antigen (HLADR+
CD38+ median 37% at baseline) expression at 4 weeks (30%) with further (p =.02) reduction at 24 weeks (28%). Significant (p =.002) increases in percent naive
cells (CD45RA+ CD62L+ median 18% at baseline) were seen at week 4 (25%)
with no further increases at 24 weeks (23%). Expression of activation antigens on
CD4 cells (median 7% at baseline) was significantly (p =.009) reduced at week
4 (median 5.5%) without further changes at 24 weeks. Naive CD4 cells were not
significantly changed at week 24 which paralleled a lack of enhanced recall or
HIV antigen responses.
Conclusion: Institution of highly active antiretroviral therapy in early HIV infection most significatly affects CD8 cells. The ability to normalize CD8 cell counts
may allow for reconstitution of host immune effector mechanisms known to be
lost early in HIV infection.
12216 Preliminary clinical safety and pharmacokinetics profile
of (+)-calanolide A - a naturally occurring NNRTI
Ze-Qi Xu1, T. Creagh2, J. Giltner3, J. Ruckle4, P. Frank3, D. Tolbert5,
M.T. Flavin3. 112305 South New Ave., Suite O, Lemont, IL; 2Clinica/ &
Epidemiology Consultants, Atlanta, GA; 3Sarawak MediChem Research,
Lemont, IL; 4Northwest Kinetics, Tacoma, WA; 5QTEC, Vernon Hills, IL, USA
Background: (+)-Calanolide A (CA) is a novel non-nucleoside reverse transcriptase inhibitor (NNRTI) with potent in vitro activity against HIV-1 and unique
pharmacokinetic properties. The compound was originally isolated from a natural
source and has been synthesized for preclinical and clinical development. Animal
studies have indicated that CA readily crosses the blood-brain barrier, may be
preferentially distributed in the lymphatic system, and appears to have a unique
resistance profile in vitro. A study has been performed to evaluate the safety and
pharmacokinetics of single escalating dose and a multiple dose regimen of CA in
healthy normal subjects.
Methods: In a Phase IA single escalating dose study, a total of 47 HIV-negative
subjects were administered CA orally in doses ranging from 200 to 800 mg in
200 mg increments. Safety evaluations included CBC/diff., chemistry, PT, PTT,
urinalysis, ECG, and physical exams. Subjects remained in the clinic for the first

24 or 48 hours after dosing and were also seen at I and 2 weeks post-dosing.
Blood samples were drawn for pharmacokinetics up to 24 hours or 48 hours
post-dosing, and plasma levels were analyzed by HPLC.
Results: All adverse events were generally mild and transient, except for one
Grade 4 lipase elevation which was completely asymptomatic. The most common
adverse events in these studies were dizziness, taste perversion, headache,
eructation, nausea, and dyspepsia. Two episodes of rash, a common toxicity for