Abstracts Vol. 1 [International Conference on AIDS (11th: 1996: Vancouver, Canada)]

Mo.B.1140- Mo.B. 1144

Monday, July 8, 1996

and those with counts 51- I 300 cells/mm3. Study participants are being followed for up to six
months, with HIV- I RNA PCR viral load and clinical assessments conducted it weeks 2, 4,
8, 12, 16 and 24.
Results: Of the active patients participating in this virologic substudy for wh om data were
available, 82% of the study population was white; 98% male; 99% reported prior use of antiretroviral therapies (AZT (9 1%), 3TC (78%), d4T (49%), ddC (4 I%), ddl (v 1%), other protease inhibitors (1 %)): and 47% reported a previous opportunistic infection. Fewer than 1%
of the participants were antiretroviral naive. Median baseline CD4 cell counts and plasma
HIV RNA copy number for study participants stratified by entry CD4 cell counts ( 50
cells/mm3 and > 50 cells/mm3) were 15 cells with 86,240 copies and 192 cells with 19,400
copies, respectively
Conclusion: Participants in this compassionate treatment program for saquinavir had
advanced HIV disease, extensive prior treatment with a variety of antiretroviral therapies,
low CD4 cell counts and moderately high viral load. Analyses of the effect on plasma HIV
RNA of adding saquinavir to existing nucleoside analogue regimens and the correlation with
CD4 cell counts and clinical outcome will be presented.
Ramon A. (Gabriel) Torrems, 412 Sixth Avenue, Ste. 401, New York, NYTel. [phone]
Facs. [phone] e-mail: gabrieltop~gAOL.com
Mo.B.I 140
SINGLE-DOSE AND STEADY-STATE PHARMACOKINETICS OF ESCALATING
REGIMENS OF 1592U89 WITH AND WITHOUT ZIDOVUDINE
McDowell,rames A, Symonds VVT, LaFon SW 1592U89 Clinical Trial Group, Glaxo
Wellcome, Inc., Research Triangle Park, NC, USA
Objective:To determine the single dose and steady-state pharmacokinetics (PK) of escalating regimens of I1592U89, a new purine-based nucleoside analog with significant in vitro antiHIV activity and to evaluate possible effects of concomitant zidovudine (ZDV) capsules
upon the PK of I 592U89.
Methods: 1592U89 was administered as monotherapy for four weeks followed by eight
weeks of a placebo-controlled ZDV combination phase. Four 1592U89 dose cohorts of
200 mg, 400 mg and 600 mg thrice daily (TID) and 300 mg twice daily (BID) were combined with ZDV/placebo dose regimens of 200 mgTID or 300 mg BID.Twenty HIV positive
patients were enrolled into each cohort with 10 receiving ZDV placebo. PK profiles, 13 to
15 samples, were obtained on three occasions: the first dose, at the end of Week 4, and
during Week I 2. CSF samples at I1.5 hours postdose were obtained from a subset of the
patients. Plasma and CSF samples were assayed by a validated HPLC method.
Results: Enrollment is complete for two cohorts and 14 patients are currently enrolled in
the third cohort Not all completed patient profiles have been assayed for each profile period. PK parameter means (CVs) are based on preliminary plasma and CSF 1592U89 sample
assays.The mean of 4 CSF: plasma 1592U89 concentration ratios was 17.9%.

Mo.B. I 142
LOW DOSE AZT IN COMBINATION WITH DDC IN HIV+ PATIENTS (PTS) WITH
HEMATOLOGICAL INTOLERANCE (HI) OR FAILURE TO AZT (FA). FINAL REPORT
Lupo. Sergi-. Bortoirz'i R. aborda M. Fernandez E, Kneitschel R, Santarelli MT Faculty of
Medicine, Universit,/ of Rosario, Argentina.
Objective: the primary oblective is to evaluate tolerance and toxicity associated with low
dose of AZT ir cornbirnation with ddC in pts previously treated with AZT with HI and FA.
The secondary objective is to assess the efficacy of this association.
Methods: final analysis included 51I pts, 34/17 male/female median age 29 years (range 20 -53), treated with AZT (1I00 mg/tid) + ddC (0.75 mg/tid). Risk behavior was: IVDU 26
(5 1%), heterosexual I 5 (29%), homosexual/bisexual I 0 (20%). In HI were enrolled 2 1 pts
and in FA 30 pts, with a median previous AZT (500 mg/day) therapy of I I months (range
I -34). Initial stage (WHO Staging System): I = 13 (25%), 2 = 7 (I13%), 3 = 10 (19%), 4 =
21 (41%).
Results: median treatment duration was 1I4 months (mo), 10 pts progressed to stage 4
(PCP 3, MYC 2, OEC 2.TOXO I, CMV I, MAl I). Five pts were excluded due to toxicity
(peripheral neurophaty 3 (6%), esophageal ulcer I (2%), pancreatitis I (2%)), 1! pts died
during treastment. Estimated overall SV is 72% at 20 mo. Median hemoglobin, neutrophils
and CD4 at baseline and during treatment were:

Baseline 3 mo
Hemoglobin (g%) HI 9.2 9.7
FA 12.7 13.0
Neutrophils (I000/mm3) HI 1.9 1.4
FA 1.7 2.2
CD4 (cell/ml) HI 189 130
FA 190 224

6 mo
9.9
13.0
1.5
2.1
152
259

9 mo
10.8
1.0
1.2
2.0
91
185

12 mo
11.1
12.3
2.0
1.9
61
I30

15 0
I 5 O
10.5
12.5
2.2
2.0
98
147

18 mo
11.0
12.6 I
1.3,
2.1
81 4
181 0,0.

Conclusions: low dose AZT in combination with ddC was well tolerated in this group of
HIV + pts with HI or FA, who had been previously treated with AZT alone. No pts were
excluded due to hematological toxicity Clinical and immunological response may be considered successfully for this group of pts.
S. Lupo, Rodriguez 1215, (2000) Rosario, Santa Fe, Argentina Telephone: (54) (4 I) 248045
Fax: (54) (4 I) 248045

G
0

Cohort
200 mg
TID
400 mg
TID

Preliminary PK Parameter Means (CV)
Profile AUC Cmax Tmax
Period (hr*pg/mL) (pg/mL) (hours)
First Dose 2.62 (31%) 1.48 (33%) 1.04 (44%)
4th Week 4.19 (36%) 2.15 (25%) 0.90 (49%)
12th Week 3.53 (28%) 1.75 (22%) 1.04 (53%)
First Dose 7.55 (4 1%) 3.08 (28%) 0.83 (21%)
4th Week 7.05 (33%) 3.29 (29%) 0.94 (39%)

Half-Life
(hours)
0.99 (16%)
1.23 (24%)
1.13_ (5%)
1.33 (21%)
1.25 (22%)

Conclusions: The Cmax and AUC values within the 200 mgTID cohort are relative y constant with similar variance.These values show dose proportional increases in the 400 mg
TID cohort. Mean half-life was from I to 1.3 hours. No ZDV effects were apparent.
James A McDowell, Glaxo Wellcome, Inc., 3030 Cornwallis Road, Research Triangle Park,
NC, 27709 Tel: [phone], Fax: [phone], email: limmcdowellus.wfl.com
Mo.B. I 141
ACYCLOVIR IN COMBINATION WITH ZIDOVUDINE DOES NOT PROLONG
SURVIVAL IN ADVANCED HIV DISEASE
Ertbelding, Emily I., Moore RD, Chaisson RE. Johns Hopkins University School of Medicine,
Baltimore, Maryland, USA
Objective: To evaluate the association between combination acyclovir (ACV) and zidovudine (ZDV) use and survival in a cohort of HIV-infected patients receiving care at an urban
HIV clinic.
Methods: We measured survival in a cohort of HIV-infected patients who had CD4 cell
counts of 500 per cubic millimeter or less and who enrolled for care at a single urban HIV
clinic between December 1988 and April 1995 (median follow-up= 2.35 years).We compared survival rates in users of ACV ZDV, and ACV/ZDV in combination to survival rates o
those using neither drug.We used Cox proportional hazards analysis to identify factors
associated with prolonged survival.
Results: Among the 1408 patients enrolled in the cohort, there were no significant differences in overall survival between ACV users and non-users. After adjustment for CD4 cell
count and the use of other antiretroviral agents, ACV use alone was associated with a relative hazard (RH) of death of 0.988 (p=0.945; 95% confidence interval [CI] 0.701, 1.342):
ZDV use alone with a RH of 0.312 (p < 0.001; 95% CI 0.248, 0.392): and combination use
of ACV and ZDV associated with a RH of 1.387 (p=0.212; 95% CI 0.830, 2.316).
Conclusions: The use of ACV in combination with ZDV is not associated with prolonged
survival in this cohort of HIV-infected patients.
E.J. Erbelding. Ross 1159,720 Rutland Ave, Baltimore, MD, USA Phone [phone];
Fax [phone]: eerbelditwelchlink.welch.jhu.edu

Mo.B. 143
ANTI-HIV ACTIVITY AFTER 24 WEEK OF THE DIDANOSINE AND HYDROXYUREA
COMBINATION IN HIV-I INFECTED PATIENTS WITH CD4+ MEAN VALUE BELOW
200/MM3
Ruiz, Lidia*, Clotet B**, Cabrera C*, Ib nez A*, Puig T*, Sirera G**. *Retrovirology
Laboratory IRSI-Caixa; **HIV Unit, Hospital Universitari Germans Trias y Pujol, Badalona,
Barcelona, Spain
Hydroxyurea (HU) has shown to potentiate the anti-HIV- I effect of didanosine (ddl) in
vitro.We report 24 weeks follow-up of the anti-HIV activity of the ddl+HU combination
administered to patients with CD4 mean value below 200/mrm3.
Our first objective was to assess the anti-HIV activity through variations in viral load and in
CD4+ cell count. Also, we evaluated the potential side-effects of this drug combination in
advanced HIV I positive patients.
Seventeen HIV-I seropositive patients with 145 CD4+/mm3 mean value at baseline (range:
1 -430/mm3) received ddl+HU for 24 weeks: 200 mg of ddl/12h and 500mg of HU/ I2h.
Eleven patients were naive for ddl and 6 had already received this treatment (>3 months).
Over the 24 week-period, the ddl+HU combination was associated with a mean decrease
in HIV- I RNA levels of 1.44 log l0. In 7 of these patients (4 1%) the decrease was greater
than 1.5 log10.The mean increase in absolute CD4+ count was 60 cells/mm3 at week 24.
Additionally, we studied the syncytium inducing (SI) capacity as baseline and at the end of the
study, to evaluate if there were differences in treatment efficacy with respect to the NSI/SI
phenotype.The decrease in viral load in patients with SI phenotype was not significant.
The tolerance was good although grade I1-11 alopecia appeared in 3 patients with very low
CD4 cell count (<50/mm3). Also there were no significant variations in biological parameters associated with renal, hepatic, and pancreatic functions. Hydroxyurea associated to ddl
is a promising combination that deserves a controlled trial to confirm its efficacy
L Ruiz., Retrovirology Lab IRSI-Caixa. HOSPITAL UNIVERSITARI GERMANS TRIAS I PUJOL.
089 I 6 Badalona. SPAIN TEL. 34-3-465 I 2 00 EXT 426 or 430 FAX. [phone]
Mo.B.I 144
CRIXIVAN: SUMMARY OF 24-WEEK EXPERIENCE WITH CRIXIVAN AT 2.4G/D IN
PHASE II TRIALS.
Chodakewitz, Jeffrey A, Leavitt R, Massari F, Hildebrand C, Arcuri K. Gilde L, Nessly M,
Meibohm A, Ghosh K, Radkowski R, Getson A. Rockhold F. Merck Research Laboratories,
West Point, PA, USA
Objectives: To integrate information regarding the efficacy and safety of CRIXIVANTM
(indinavir sulfate, CXN), an oral HIV protease inhibitor, as assessed in multiple phase II
clinical trials.
Methods: Information from 3 different phase II clinical trials in which CXN therapy was initiated at the phase III dose (2.4 g/day) is summarized.Two studies randomized nucleoside
analog (NA)-naive patients (pts) to CXN monotherapy NA therapy (ZDV or ZDV/ddl) or
combination therapy (CXN + NA).The third study evaluated CXN alone at > 2.4 g/d.
Results: Pts evaluated: 67 - CXN at 2.4 g/d, 53 - CXN+NA, 47 - ZDV or ZDV/ddl.
Efficacy: CXN was associated with consistent changes in both CD4 counts and vRrA.
After 24 weeks, median CD4 increase with CXN alone ranged from 26 - 80 cells/erim3
with 36 - 65% having CD4 counts at least 50 cells above pretreatment baseline. Median
maximal declines in vRNA with monotherapy ranged from -2.0 to -2.3 log lO copies/mL. At
Week 24, 9 - 40% of pts receiving monotherapy had vRNA below assay detection (200
copies/mL). Combination therapy with CXN + NA generally demonstrated somewhat
greater declines in vRNA with similar increases in CD4 counts. The proportion of pts with
vRNA below assay detection tended to be greater among pts 'eceiving combination therapy Differences between monotherapy and combination therapy were not statistically significant. Safety - CXN was generally well tolerated both alone and in combination with NAs.

79