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

Track B: Clinical Science

Tu.B.21 14- Tu.B.21 18

(62%) received treatment after an AIDS diagnosis and 115 (38%) before AIDS diagnosis.
Product limit estimates of the cumulative mortality rate at 24 months were 32% (~ 3.6) for
late group and 66% (~ 5.7) for the early group (see Figure). Our results rermained
unchanged after controlling for irnitial mono
100 or combination therapy. Although, the AIDS
90 survival curves of the early and late groups
80 were shown to be significantly different (log
10 70 rank p<0.001), there was no difference
Sbetween the two groups in survival from the
5 estimated date of HIV inlection (log rank
0 p=0.239).
S----0- t (n=190) Conclusions:This observational study
10 - *O Early (n=115) demonstrates that initiation of antiretroviral
0 therapy after primary AIDS is associated with
* 1 2 24 36 4 8 6t0 longer AIDS survival. However; time from
Time since primary AIDS (months) HIV-infection to death does not appear to
differ between early and late therapy groups.
c/o Kevin Craib, 608 1081 Burrard Street,Vancouver, BC,V6Z I Y6, Canada Telephone: [phone] Fax: [phone] e-mail: Kevin@~hivnet.ubc.ca
Tu.B.21 14
REBOUND IN ZIDOVUDINE USE AS A RESULT OF LAMIVUDINE AVAILABILITY IN
THE PROVINCE OF BRITISH COLUMBIA
Harris, Marianne, Montaner JSG, Hogg RS,Yip B Gataric N, O'Slhaughnessy MV, Schechter
MT BC Centre for Excellence in HIV/AIDS arid University of British Columrbia,Vancouver,
BC, Canada.
Objective: To assess recent rates of zidovudine (ZDV) prescription in British Columbia
(BC).
Methods: The distribution of antiretroviral drugs in BC is free of clharge to eligible participants through the province-wide HIV/AIDS Treatment Program. In order for physicians to
prescribe ZDV, they must complete a patient enrollment form tlIat also serves as the drug
prescription.This application is accompanied by a CD4 cell count determination Individuals
infected with HIV are eligible to receive ZDV fromr this program if they have at least one
CD4 cell count <0.50 x 109/L (500/pL).There is no other free of charge source of ZDV in
BC. Lamivudine (3TC@) first became available through an open label expanded access program in BC in Feb 94. Data regarding 3TC use in BC was obtained from Glaxo Wellcome
Inc. A non nominal linkage was conducted
between the latter data and the provincial
0a treatment Program using initials and birth.C 5 0 0 dates. Analysis was right censored as of Sept..* 30,95.
t 400 - Results: A total of 848 patients received ZDV
I 3 0 0 - alone fr6 om the program during the study
period. As shown in the figure, a rebound of
2 0 0- ZDV monotherapy use was documented
1 o 0 - since the last quarter of 1994.The shaded
-H bars represent those participants receiving
S 0 - ZDV monotherapy in the provincial Treatment
za Program who were linked to the Glaxo... n...... W ellcome 3TC expanded access program. As
0 " a o 0 a a O of the third quarter of 1995, ZDV use for the
Year-Quarter purpose of combination therapy with 3TC
represented 47% of the ZDV monotherapy
use in BC.
Conclusions: Our data demonstrate that the increase in ZDV monotherapy use during
1995 can be fully attributed to combination therapy use with 3TC obtained through the
expanded access priogram.This rapid increase in the use of ZDV/ 3TC in 1995 was temporally associated with the the release of study data from controlled trials of combination
ZDV/ 3TC therapy
Dr Robert Hogg 608-108 I Burrard Street,Vancouver; B. C.V6Z I Y6 Tel: [phone]
Fax: [phone]
Tu.B.21 IS 5
TRIPLE NUCLEOSIDE ANALOGUE COMBINATIONS AS FIRST OR SECOND LINE
TREATMENT AGAINST HIV- I IN PATIENTS WITH AIDS: PRELIMINARY RESULTS.
Mathez D. I,Winter C.*, _Leibowitch1 I. I Hopital Raymond Poincare, Universit Paris-Ouest,
Garches; * Hopital Intercommnunal de Montreuil.
Objective and strategy:To resort to convergent combinations of 3 nis leoside analogues as
first (treatment naive patients) or second line treatment.
Patients and methods: 5 treatment-naive patients (group I) and 5 AZItfDDC or DDIexperienced patients (group II) received AZT+DDI+3TC (5-8 mg/kg/d each) within 6
weeks of initiation of treatment.Two patients who had failed under AZT+DDC (group III)
received D4T (I mg/kg/d) +DDI+3-TC. Log infectious blood cells /10*7 PBMC, limit of
detection = 0.7(a), atnd log HIV RNA copies/mI plasmas, Amplicor Roche Monito 34 cycles,
limit of detection I(b), were sequentially determined in real time.

Conclusion: Expanded open label tirals with first or second line triple nucleoside analogue
comibinatioiis, based on virological end -points assayed in real time, are warranted to rapidly
assess the general value of these regimens in patients.
Jacques L.LIBO\NITCIH, H6pital Raymond Poincare 92380 Garchres FRANCE
Tu.B.21 16
SAFETY AND TOLERANCE OF A TRIPLE COMBINATION THERAPY WITH AZT, DDI,
AND INTERFERON-a
Bissuel, Francois*, Lteriche K*, Schlienger I*,Irabaud M.A.*", Cotte IL*,TErepo C.'-.;.H6tel
Dieu Itospital; **Medical Research National Health Institute, Lyon, fIrance
Objective: To evaluate the tolerance and safety of a three drug antiretroviral combination
with zidovudine (AZT), didanosine (ddl), and interferon alpha (IFNu).
Methods: An open, uncontrolled, prospective study was conducted in 7 HIV I.infected
patients who received AZT (500 mg/d), ddl (400 mg/d in 6 patients, 200 mg/d in I patient),
and IFN (3 million units 3x/week in 6 patients, I million units 3x/week in I patient). Six
patients had been receiving AZT therapy previously (mean, 28 months).
Results: At entry mean CD4 cell count was 23I ~ 148x106/1. Mean follow -up was 13
rmonths (range, 8 22 rmonths). Only I patient discontinued ddl, because of asialia. Loose
stools were transiently reported in I patient.Transient asthenia in 2 patients was ascribed
to IFNu therapy Biological tolerance was excellent especially concerning hemoglobin, neutrophils, amylase, and aminotransferase serum levels. Five of 7 patients had increased CD4
cell count. At the end of follow-up, CD4 cell count was 347+245x 106/I. Plasma HIV I -RNA
levels (branched DNA, Chiron) did not increase in any of the 7 patients during the study
significantly decreased in 2 patients, and remained negative in 2 other patients.A pol gene
mutation occured at codon 215 in I patient.
Conclusions: These data suggest that long-term triple combination therapy with zidovudine,
didanosine, and IFNa can be given at doses as high as those used in single agent therapy
without occurence of enhanced toxicity Our study provides safety data for future trials that
are needed to assess the beneficial effect of triple antiretroviral therapy on HIV activity clini
cal outcome, and patients quality of life.
F. Bissuel -Infectious and Troprical Unit (PrVilde) - CIfHU Bichat-Claude Bernard - 46 rue
I Henri Hfuchard - 75877 Paris cedex 18- France
Tel: 33- I 4025-7803 Fax: 33--I 40-25-88-60
Tu.B.21 17
PHASE I TOLERANCE AND PHARMOCOKINETICS OF A NEW CASTANOSPERMINE
DERIVATIVE, MDL 28,574A.
Roth, Hellrimut, McPherson M, Hamedani P*n, Herrrmann W M*, Sidarous E, Frampton M,
Maddern J**, Dieterich A*. *PAREXEL International GmbH, Clinical Phiarmacology DivisionBerlin Westend Hospital HI 8, Spandauer Damm 130, FRG 14050 Berlin; *Hoechst Marion
Roussel, Kansas City MO, USA
MDL. 28, 574A (MDL) is a newly developed agent which acts as a hfrost cell a glucosidase I
inhibitor resulting in reduced HIV pathogenicity through reduced infectivity and syncytial
forrmation.
Study Objectives: To determine maximum tolerated dose (M TD), pharmacokinetic and
safety profile of MDL oral solution q.d or b.i.d, doses for 14 days and determine tolerability
of MDL capsules (300 mg b.i.d.) for 8 weeks.
Methods/Results: 61 HIV + Caucasians, without current AIDS defining symptoms, without
antiviral therapy during the preceding 30 days and with mean CD4 counts of 399/mm3
were exposed to 14 days treatment of MDL solution. Plasma pharmacokinetics were determined. Safety laboratory profiles were carried out until three days after termination of
treatment.Vital signs, ECG and adverse events were monitored. ECG parameters and vital
signs were not influenced by any of the applied doses. No clinically relevant and/or drugrelated alteration of laboratory parameters were observed. Adverse events were mainly
gastrointestinal: loose stools, diarrhea and flatulence of grade II toxicity in the first week of
application and were recurrent grade III following 450 mg q.d. MTD of q.d. solution was
assessed at 400 mag. However 240 mg and 300 mg b.i.d. solution had comparable tolerability to the q.d. MTD. An additional 14 patients were enrolled in an 8 week b.i.d. 300 mg capsules treatment in a widely altered design.This treatment was ternrinated prematurely (after
14 days) due to recurrent occurrence of grade III toxicity in transaminase, creatinkinase
(with normal CkMB isoenzyme), and LDH. All laboratory changes were re versible after discontinuatiorn of treatment.
Conclusions: The MTD of MDL. solution is 400mag q.d. An increase of daily intake seems to
be tolerable with a regimen of 300 mg b.i.d. (solution).The limits of tolerability in the capsule formrulation may be due to bioavailability
Hellmut Roth, PAREXEL International GmbH, Clinical Pharmacology Divisiorn-Berlin
Westend Hospital HI 8, Spandauer Damnm 130, FRG 14050 Berlin Tel:[phone] Fax:[phone], email: [email protected]
Tu.B.21 18
SURVIVAL IN PTS WITH CD4 COUNT LESS THAN 50/MMC:ANTIRETROVIRAL
THERAPY AND CLINICAL ASPECTS
1 o Caputo Sersio, Blanc PL., Ble C., Brizzi N., Gabbuti A., larino N., Pierotti., Mazzotta F.
Infectious Disease Unit, S.M. Annunziata Hospital, Antella, Firenze, Italy
Objective: Retrospective study to evaluate survival in HIV pts (pts) with CD4+ count less
than 50/mmc respect antiretroviral and anti-infectious therapies and opportunistic infections
(O.I.) profilaxis.
Methods: From 1/1/94 to /1/96 we obsersed 95 anti H.IV+ pts. 'with CD4+ count less
than <50/mmc. 25 of these didn t have previous CD4 counts.The remaining 70 pts (Male
7 I%, Female 29%, mean age 38,9 years, risk group: IVDA 44%, Omo/bisexual 40%,
Etherosexual I 6%) were having at least one previous CD4+- count more than >50/mmc
and they were enrolled in a retrospective cohort. Of all we have records of antiretroviral
the apy O.. profilaxis, clinical history and days of hospitalization.
Results: The mean survival was 22,24 months (range 6-63), during the observation period
there were 28 deathas (40%). Among main events we observed the following AIDS defining
conditions: CMV (23,6%), MAC (I 3%), Neurotoxoplasmosis (I 1,8%), Cryptococcosis
(I 1,8%). 16 pts before first CD4+ count less < 50/mmc, and 35 after; were treated with
antiretrovial drugs.Table I shows the correlation (univariate analysis) between therapy

(AZT ddl, dcdC, D4T 3TC) and survival (* p=<0.00 I),,2
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Results. Group II III I II III
Week Cellc) RNA(b)
0 ten 2.95 3.25 3.20 4.82 4.63 4.19
I1S[ (n) 1066 (5) 0.60 (5) (2) 1 0.53 (5) -0.46 (4) (2)

I II III
(I-,,91 / PI
140 105 165
1 86 (5) 1 82 (5) (2)

4 Mean 1.38 1.48 2.7 3.35 2.17 2.34 164 178 179
lSD1(n) 05ss5(5) a-0.64(4) (2) t0.59(5) ~1.41(4) ma ~99,5)a 4146(4) (2)
2 Mean 0.77 1.07 0.7 2.14 2.63 1.42 202 227 183
oItt E(n) 1007 (3) 10,61 (4) (I) ~0 80 (4) l.90 (4) ( 1 62 (3) i 169 (4) (1)
24 Mean 0.73 1.27 0.7 2.73 2.58 1.27 240 209 274
Ss S(n) 1007 (4) (2) (2) ~0.73 (4) (2) 2) it105 (4) (2) (2)