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

Mo.B.1323 - Mo.B.1328

Monday, July 8, 1996

Age (mos.)

Enter Clin Class A
Enter Clin Class B
Enter Clin Class C
Enter Immun Stage 2
Enter Immun Stage 3
Death

6 12
56% 74%
33% 55%
I2% 21%
26% 34%
10% 14%
1% 5%

18
82%
64%
26%
43%
20%
6%

24
84%
70%
34%
50%
22%
10%

Conclusions: Over half of infants on our cohort reached moderate or severe clinical stages
or death by I 2 mos. of age. Progression to Clinical Stage B was the best predictor of subsequent progression to AIDS Stage.The majority of infants followed the CDC Class proposed
course of disease progression.
Clemente Diaz, MD University of Puerto Rico, Medical Sciences Campus WITS Project PO
Box 365067, San Juan, Puerto Rico, USA 00936-5067 Phone: [phone]
Fax: [phone] E-mail: diaz clemente(ifstrforg
Mo.B. 1323
MORTALITY IN BACTERAEMIC HIV-INFECTED AFRICAN CHILDREN
Mason, PR, Nathoo K, Mhlanga S, Gwanzura L. University of Zimbabwe Medical School
Objective: To examine mortality in HIV infected children admitted to hospital in Harare,
Zimbabwe with with acute non-focal signs of infection.
Methods: Our definition of HIV was positive serology plus either age > 17 months, or positive p24 antigenemia or clinical evidence. Blood cultures were taken from all children and
post mortem lung biopsies were taken from a sub-sample of HIV infected children and
examined for Pneurnocysts crinii.
Results: Three hundred and nine children were included, most diagnosed with pneumonia,
septicaemia and/or meningitis. 168 (54%) seropositive children met criteria of HIV infection.
Bacteremia was detected in 67 (40%) HIV and 28 (20%) non-HIV children (OR=2.68;
p<0.00 I). Prevalent organisms were staphylococci, pneumococci and enterobacteria. Fifty
two (17%) children died. Mortality was associated with HIV infection in children up to 6
months of age (28% vs. 12% non-HIV:; OR= 2.81; p<0.05). Mortality in HIV infected bacterernmic children was 30% vs I a% non-HIV infected bacteremic children (OR=3.55,
p<0.05).There was no s ignficant difference in mortality between HIV infected children with
Gram + ve (29%) or Gram ve (32%) organisms, whether HIV infected or not. Examination
of post mortem lung tissue indicated P crini in 10/20 samples.
Conclusions: There is high risk of acute bacteremia and associated mortality in HIV infected
children in Zimbabwe. Approaches to early management must take account of both well
recognised pathogens and organisms usually considered to be of low virulence.
PR.Mason. P 0 Box A 78 Avondale, Harare, Zimbabwe Tel: 263-4-79 I 631
Fax [phone] email pmasonchealthnet.zw
Mo.B. 1324
PLASMA PHARMACOKINETICS OF 3'-AMINO-3'-DEOXYTHYMIDINE,A CYTOTOXIC
METABOLITE OF ZIDOVUDINE.
Hoetelmans, Richard MW*, Meenhorst PL*, Mulder JW*, Burger DM**, Koks CHW*,
Beijnen JH*. * Slotervaart Hospital, AmsterdamThe Netherlands; * University Hospital
Nijmegen,The Netherlands.
Objective: The pharmacokinetic parameters of 3'-amino 3 -deoxythymidine (AMT), a cytotoxic metabolite of zidovudine, have not been fully investigated yet due to low concentrations of AMT in plasma. We have determined the plasma pharmacokinetics of AMT in HIV
+ patients with a highly sensitive HPLC assay
Methods: After an overnight fast, patients ingested 250 mg of zidovudine.Twelve blood
samples were collected during 6 hours. Plasma concentrations of AMT were determined
with a validated HPLC assay using fluorescence detection after derivatization with fluorescamine. Plasma concentration time data were analyzed by non-compartmental methods.
The following pharmacokinetic parameters were determined: elimination half-life (t ), area
under the plasma concentration-time curve extrapolated to infinity (AUC), maximum concentration (Cmax), time to Cmax (Tmax) and mean residence time (MRT).
Results: Ten patients (9 male, I female) were included in the protocol. Means and standard
deviations (s.d.) of pharmacokinetic parameters are:

py she would have required a zidovudine dose of approximately I 800 mg/day to achieve
and maintain this concentration.The second woman weighed 128 kg and was in her 9th
month of pregnancy She would have required a zidovudine dose of approximately 1000
mg/day to maintain the average Css of 0.7 pM. Results are summarized in Table I
Conclusion: These data suggest extreme variability in the pharmacokinetic disposition of
zidovudine in obese pregnant HIV-infected women. Individual monitoring of zidovudine disposition in this population may enhance the efficacy of this medication as a means to
reducing vertical transmission.
K Schwebde, HIV Programs, Suite I 25, St. Paul-Ramsey Medical center, 640 Jackson Street,
St. Paul, Minnesota, 55 10 I USA.Tel: 6 I 2 22 I- I 280:; Fax: 6 I 2-221-861 6
Mo.B. 1326
SAFETY,TOLERABILITY AND PHARMACOKINETICS (PK) OF HBY-097 IN
ASYMPTOMATIC AND MILDLY SYMPTOMATIC HIV POSITIVE PATIENTS
Shah, A.*, Kumor, K.*, Sullivan, J.*, Amand, R.*, Cole, 5.*, Agarwal,V*, Krol, G.*, Huguenel, E.*,
Suarez, JR.**, Heller, AH.*. *Bayer Corp.,West Haven, CT a HMRI, Sommerville, NJ. USA
Objective: This study was designed to characterize the safety, tolerability and PK of oral
HBY-097 (a non-nucleoside reverse transcriptase inhibitor being developed by Hoechst
Marion Roussel and Bayer) following doses of I 25, 250, 375, 500 and 750 mg tid for 7 days
and 14 days (750 mg dose only) in asymptomatic and mildly symptomatic HIV positive subjects with CD4 counts between 200 and 500 cells/mm3.
Method: Each dose step was planned to include 9 subjects (6 on active drug and 3 on
placebo). Subjects received I dose on Day I and continued on a tid dose regimen from
Days 2-6 (Days 2-13 for the 14-day treatment) with a single dose on the final day of treatment. Blood and urine samples were collected for PK analysis and for clinical laboratory
evaluation at appropriate intervals over the course of the study HBY-097 and its M2 and
M3 metabolites were measured in serum samples using an HPLC assay In the 14 day study
plasma for HIV-RNA quantitation was collected at baseline, Days I14 and 21.
Results: HBY-097 was safe and reasonably well tolerated with no consistent dose-related
adverse event or laboratory abnormalities.Two subjects in the 750 mg tid x 14 day treat
ment group discontinued study medication due to a generalized maculopapular rash which
emerged on Day 10. HBYO097 was rapidly absorbed following PO doses.The considerable
overlap in Cmax and AUC values between the dose levels indicated high interindividual
variability. Following the 250, 500 and 750 mg doses, trough concentrations ranged from
206- 720 pg/L, 364- i 226 pg/L and 46 -2 I16 pg/L, respectively. Based on the IC90 range of
clinical isolates, and the high protein binding (>95%), it was predicted that these trough
concentrations would be clinically relevant. M2 concentrations are approximately 2 fold
higher than those of the parent compound.Two of 3 subjects who completed 750 mg tid x
I 4 days treatment showed greater than one log reduction in the viral load after I 4 days of
treatment; the third subject had very low viral load at baseline whi ch reached 0 after 14
days of treatment.The data indicate that HBY-097 is reasonably well tolerated and exhibits
promising antiviral properties.
Anita Shah, PhD, Bayer Corporation, 400 Morgan Lane, West Haven, CT 06516 I
Tel, #: 203/937 2837; Fax #: [phone]
Mo.B. 1327
'EFFECT OF HIV INFECTION ON ALPHA -ACID GLYCOPROTEIN (AAG)
CONCENTRATIONS
Goodwin, S Diane, Renehan CJ, Schooley RT Pieper JA. Schools of Pharmacy and Medicine,
University of Colorado Health Sciences Center, Denver, CO, USA
Objective: Serum protein binding of drugs plays an important role in drug disposition, pharmacologic effect, and toxicity Elevated concentrations of the serum protein AAG have been
observed in chronic inflammatory diseases. Recent data indicate that binding of the protease
inhibitors to AAG inhibits the cellular uptake and in vitro activity of these compounds and
may have clinical implications for their antiretroviral activityThe purpose of this study was to
evaluate the effect of HIV infection and stage of infection on serum AAG concentrations.
Methods: Serum AAG concentrations were measured (via nephelometry) in 3 groups of
medically stable HIV- infected patients and a group of healthy volunteers: group A (HIV -positive, asymptomatic, CD4 count > 500/mm3; n=- 10); group B (HIV positive, mild-moderate
symptoms, CD4 count 200-499/mm3; n= I 5); group C (HIV-positive. AIDS, CD4 count
<200/mm3: n-= 15), group D (healthy volunteers; n- 5).The study was approved by the
University of Colorado Human Subjects Committee. AAG concentrations in the four
groups were compared by ANOVA, with the Tukey Kramer multiple comparisons test.
Correlation of CD4 count with AAG concentration was evaluated using orthogonal regression. Level of significance was defined as p<0.05.
Results: Serum AAG concentrations (mg/dL) in groups A, B, C, and D were 51.2+ 14.52,
63. I 3~ I 2.43, 70.67~ I17.66, and 53.27+9.62, respectively AAG concentrations in group C
were significantly higher than those observed in both groups A and D (p<0.01). Mean CD4
counts (cells/mm3) in groups A, B, and C were 7 16.95+176.72, 332.80+86.70, and
83.47+70.70, respectively. AAG concentrations showed a weak correlation with CD4
counts (r 0.4 137, p<0.01 ), with less than 20% of the variance in AAG concentratons due
to CD4 rcasnts.
Conclusion: Serum AAG concentrations are significantly elevated in patents with advanced
DIV infection, as compared with patients at errrinr stages of disaae Ths ebser vatren nay
have implications for pharmacokinetics and pharmacodynamics of drugs highly bound to
AAG, such as the protease inhibitors.
S. Diane Goodwin, Care Management Division, Glaxo Wellcome Inc., 5 Moore Drive,
Research Triangle Park, NC 27713 USA Telephone: [phone]; Fax: [phone]
Mo.B. 1328
THE SAFETY AND PHARMACOKINETICS OF LAMIVUDINE (3TC) IN PATIENTS
WITH RENAL IMPAIRMENT, INCLUDING THOSE ON HAEMODIALYSIS
MA Johnson, GJ Yuen, MJ Daniel, R Plumb, J Moss, *Prof GA Verpooten, *A Jurgens,
*D Van Caesbroeck, *PJ Arnouts, *Prof M De Broe. Clinical Pharmacology Division,
Glaxo Wellcome plc, Greenford, UK and *Department of Nephrology, University Hospital,
Antwerp, Belgium.
The effect of renal impairment on the pharmacokinetics of lamivudine (GRI09714X)
administered orally to non-HBV or HIV infected healthy subjects and renally-impaired

t l/2(hr) AUC (hr*ng/mL) Cmax (ng/mL)
mean 4.4 31.2 5.9
s.d. I 6.8 1.8

Tmax (hr)
0.7
0.7

Conclusions: In general, concentrations of AMT after ingestion of 250 mg zidovudine are
below 10 ng/mL.This is considerably lower than reported by Stagg et al. (Clin Pharmacol
Ther 1992;51:668-76). Peak concentrations of AMT are observed I hour after oral administration. AMT is slower eliminated from plasma than zidovudine with a half life of approximately 4.4 hours.
R.M.W. Hoetelmans, Sloatervaart Hospital, Department af Pharmacy, Lo uwesweg 6, 1066 EC
AMSTERDAM,The Netherlands.Tel. [phone], Fax [phone] Email aprhtcslz.nl
Mo.B. 1325
DISPOSITION OF ZIDOVUDINE IN TWO OBESE PREGNANT WOMEN WITH
HUMAN IMMUNODEFICIENCY VIRUS TYPE I (HIV-I) INFECTION
Schwebke K, I Acosta ERI Henry K, I Fletcher CV.2 I St. Paul-Ramsey Medical Center St.
Paul; University of Minnesota, Minneapolis, MN, USA
Objectives: It has recently been demonstrated that zidovudine can reduce vertical transmission of human immunodeficiency virus (HIV) by approximately two-thirds.The purpose of
this case series was to describe zidovudine pharmacokinetics in two obese pregnant HIVinfected women.
Methods: Zidovudine concentrations were determined in two obese pregnant HIV-infected
women after oral administration. Concentration-time data were analyzed using Bayesian
estimation and a two-component, time-delay model.
Results: The first woman weighed 142.5 kg and was in her 8th month of pregnancy when
zidovudine concentration (Css) of 0.7 pM (the population average), to be the goal of thera