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

Track B: Clinical Science

Tu.B.2125 - Tu.B.2129

lead to the selection of virus with reduced sensitivity to other proteinase inhibitors, in particular MK-639, the unique pattern of resistance mutations seen in the viral proteinase of
saquinavir resistant strains suggests little potential for such cross resistance. Analysis of genotypic changes in the proteinase gene of saquinavir resistant laboratory strains of HIV (generated by in vitro passage in the presence of increasing concentrations of the drug) has shown
that resistance is due primarily to mutations at positions 48 (G toV) and 90 (L to M).Virus
with these mutations shows an 83 fold reduction in sensitivity to saquinavir when compared
to wild type virus (VVT IC50 3nM, mutant IC50 250nM) but only a 3.75 fold change in
sensitivity to MK-639 (VVT IC50 - 40nm, mutant IC50 150nM).
In phase 1/I11 trials of saquinavir (VI 3330 in Italy, O 13328 in the UK and NV I 4255 in the
USA) phenotypic changes in sensitivity to the drug were infrequent (<25% of patients after
48 weeks treatment) and genotypic changes occurred consistently only at G48V and L9OM,
even after up to 3 years of treatment.The L90M mutation predominated and appeared to
have a much less pronounced effect on sensitivity to saquinavir than the double mutant
which was rare (2/85 patients).
A number of clinical isolates showing mutations at L90M and/or G48V have been analysed
with respect to sensitivity to both saquinavir and MK-639.These isolates showed increases
in IC50 (compared to pre-treatment virus from the same patient) of up to 50 fold for
saquinavir and <4 fold for MK-639.Virus isolated from one patient after 40 weeks of therapy (600mg tid saquinavir) showed a 44 fold decrease in sensitivity to saquinavir along with
mutations at positions 48 and 90 of the viral proteinase (patient PBMC and plasma).This
virus isolate showed only a <4 fold change (not significant) in sensitivity to MK-639.
These preliminary results indicate that saquinavir treatment will not induce significant cross
resistance to MK-639. Further analysis of the efficacy of various proteinase inhibitors (MK639,ABT-538,VX-478) against viruses isolated from patients after long term treatment with
saquinavir is in progress.
J Charles Craig, Roche Products Ltd, 40 Broadwater Road, Welwyn Garden City Herts AL7
3AY, UK
Tu.B.2125
THE EFFECT OF ZIDOVUDINE DOSE ON THE FORMATION OF INTRACELLULAR
PHOSPHORYLATED METABOLITES
Patrick Hoggardi, Sara Gibbons1, Edmund Wilkins2, Gareth Veal I, Michael Barry1, Saye
Khoo, David Back 1. I. Department of Pharmacology & Therapeutics, University of
Liverpool, PO Box 147, LIVERPOOL, UK, L69 3BX 2. Department of Infectious Diseases &
Tropical Medicine, North Manchester General Hospital, MANCHESTER, UK, M8 5RB.
Background. Zidovudine (ZDV) requires intracellular phosphorylation to ZDV-triphosphate
prior to the inhibition of HIV replication.The effect of ZDV dose on the formation of intracellular phosphorylated metabolites may help define the optimum daily dose of ZDV, which
is still unknown.
Methods.The plasma and intracellular phosphorylated metabolite concentrations of ZDV
were determined over a 12 h period following oral administration of ZDV 100 mg and
ZDV 300 mg to 10 HIV seropositive patients at steady state during two dosing regimens i.e.
100 mg t.d.s. (300 mg/day) and 300 mg b.d. (600 mg/day).The intracellular ZDV phosphates, ZDV-monophosphate (ZDV-MP), ZDV-diphosphate (ZDV-DP) and ZDV-triphosphate (ZDV-TP) were measured in peripheral blood mononuclear cells using a combination
of high performance liquid chromatography (HPLC) and radioimmunoassay.
Results.There was a greater than three fold increase in maximum plasma concentration
(Cmax) following ZDV 300 mg when compared with ZDV 100 mg (2.69 ~ 0.5 1 versus
0.77 ~ 0.14 pM; mean ~ s.d.).The area under the concentration time curve (AUC0 -12h)
was also significantly increased (5.68 ~ 0.95 versus 2.14 ~ 0.57 pmol.L- I1.h) following ZDV
300 mg dose. For total intracellular ZDV phosphate metabolites the AUC0 I 2h was doubled (7.64 ~ 3.67 versus 3.71 ~ 1.83 pmoles. 106cells-I.h) in patients taking 300 mg compared with 100 mg.The AUC0 -12h for ZDV-MP was significantly increased at the higher
dose (6.47 ~ 3.14 versus 2.77 ~ 1.70 pmoles. 106cells-T.h) whereas the active moiety ZDVTP was not significantly different (0.42 ~ 0.42 versus 0.61 ~ 0.81I pmoles. 106cells- I.h) following ZDV 100 mg and 300 mg.
Conclusions. Administration of ZDV 100 mg orally produces similar concentrations of the
active metabolite, ZDV-TR and significantly less of the potentially toxic metabolite, ZDV-MP
when compared with ZDV 300 mg orallyThis finding supports clinical data indicating the
efficacy of low dose (300 mg/day) ZDV.The measurement of ZDV intracellular phosphorylated metabolites represents a significant advance in our understanding of the clinical pharmacology of the drug.
Patrick Hoggard, Department of Pharmacology & Therapeutics, University of Liverpool, PO
Box 147, LIVERPOOL, UK, L69 3BX.Tel: [phone]
Tu.B.2126
IMPACT OF LAMIVUDINE AND ZIDOVUDINE THERAPY ON QUALITY OF LIFE
(QOL)
Scott-Lennox. lane*, McLaughlin-Miley CJ*t, Mauskopf, JA*. * Glaxo Wellcome Inc.,
Research Triangle Park NC t University of South Carolina, Columbia, SC
Objective: Improving a patient's present and/or future QOL should be a primary goal of
anti-retroviral (AR) therapyThis study examined: I) how much change observed in patients'
self-reported QOL is explained by change in surrogate markers and AR therapy; and 2)
whether QOL changes in patients with lower CD4 cell counts (ie, 200 cells/mm3) at
baseline are similar to those in patients with higher CD4 cell counts at baseline.
Methods: HIV-infected patients (N=252) with CD4 counts of 100-300 cells/mm3 and >6
months prior AR therapy were randomly assigned to receive zalcitabine 0.75 mg tid plus
zidovudine 200 mg tid (ddC+ZDV), lamivudine I50 mg plus ZDV (LAM I50+ZDV), or
LAM 300 mg plus ZDV (LAM300+ZDV). At baseline and at weeks I 6, 32, 52, and study
end, CD4 cell counts and PCR-RNA values were measured and patients completed the
Medical Outcomes Study Health Status Questionnaire for HIV (MOS-HIV). Ordinary leastsquares regression analysis of the intent-to-treat population was used to estimate the relationship between treatments and changes in QOL scores (from baseline to week 32) and
between changes in QOL scores and changes in CD4 and RNA values (from baseline to
week 32).
Results: LAM I50+ZDV compared with ddC+ZDV was associated with more favorable
changes in QOL scores for 10 out of I I MOS-HIV scales; however, this was statistically

significant only for the physical function scale. CD4 cell count increases and RNA decreases
were not associated significantly with changes in QOL scores. Patients with lower CD4 cell
counts compared with those with higher counts at baseline experienced less favorable
changes in all quality of life scores by week 32, but this effect was statistically significant only
for the cognitive and social functioning scales.
Conclusions: Treatment with LAM I150+ZDV compared with ddC+ZDV had a more favorable QOL outcome in the dimension of physical function. Patients with CD4 counts greater
than 200 cells/mm3 at baseline were more likely to experience positive changes in their
QOL (cognitive and social functioning) with combination anti-retroviral therapyThere was
no evidence of a relationship between changes in surrogate markers and changes in QOL.
Jane Scott-Lennox, Ph.D., Glaxo Wellcome Inc, Five Moore Dr Research Triangle Park, NC
27709.Telephone: [phone] Fax: [phone], Email: [email protected]
Tu.B.2127
DYNAMIC MULTIDRUG THERAPIES FOR HIV:A SYSTEMATIC APPROACH
Wein, Lawrence M.*, Zenios, S.*, Nowak, M.**. *M.I.T, Cambridge, MA, USA; **University
of Oxford, Oxford, UK
Objective: To derive dynamic multidrug therapeutic strategies, where the combination of
agents received by an individual changes over time in response to the disease progression.
Methods: Formulate and analyze a mathematical control problem, which tracks the dynamics of uninfected and infected CD4+ cells and free virus, and allows the virus to mutate into
various strains.The controller observes the individual's current status and chooses among a
set of reverse transcriptase and protease inhibitors in a dynamic fashion in order to minimize the total viral load over a finite time horizon. Use computer simulation to compare
derived dynamic strategy to traditional static therapies.
Results: A simple mathematical expression is derived that dictates the drug combination
that should be used at each point in time. For an illustrative two-virus, two-drug example,
the dynamic multidrug therapy outperforms its static counterparts: the total viral load is
reduced, the uninfected CD4 count is increased, and the emergence of drug resistant
strains is delayed.These benefits are achieved by frequently changing therapies over time in
response to and in anticipation of the emergence of drug-resistant strains. In addition, the
dynamic policy attempts to maintain the more fit virus strains at a relatively low level, while
perhaps allowing the less fit strains to partially establish themselves.
Conclusions: The model and analysis provide a systematic way of developing dynamic multidrug strategies. Numerical results suggest that such therapies have the potential to significantly outperform the static protocols that are currently in use.
Lawrence M.Wein, Sloan School of Management, Rm. E53-343, M.I.T., Cambridge, MA
02139 USA, Ph: 617-253-6697, Fx: 617-258-7579, email: I [email protected]
Tu.B.2128
AN OBSERVATIONAL STUDY OF VERTICAL TRANSMISSION WHEN THE MOTHER
BUT NOT THE INFANT RECEIVED ORAL ZIDOVUDINE
Ann I. Melvin, Frenkel LM, Cowles MK, Shapiro DE, Watts DH, McCellan C, Mohan K,
Burchett S, Bryson YJ, O'Sullivan MJ, Landers D. the Pediatric AIDS Clinical Trials Group
Objective: To examine the rate of vertical transmission from HIV- I infected women who
were treated with zidovudine (ZDV) during their pregnancies, but whose infants were not
treated with ZDV.
Methods: Data firom all HIV-I infected pregnant women followed prospectively prior to
February 1994 at 5 university HIV clinics who were prescribed ZDV during pregnancy
were included in this studyThe following variables were analyzed: effect of intravenous
ZDV; number of weeks of ZDV during pregnancy; continuity of ZDV usage; maternal
demographics, length of gestation, type of delivery and CD4 values.
Results: One hundred and eighty-eight women and 190 infants (two pairs of twins) were
included in the study.Treatment practices and demographics varied between sites. Overall
20% of the women had CD4 counts close to delivery of <200. Seventy-three percent of
the infants were delivered vaginally with 12.2% born at <37 weeks gestation.The women
took ZDV for a mean duration of 14.2 weeks during gestation with 15.6% receiving intravenous ZDV during labor.Those receiving intravenous ZDV during labor received a mean
of 493 mg over a mean of 8. I hours. None of the infants were treated with ZDV after
birth. HIV- I infection status is unknown for II of the infants.Among the remaining motherinfant pairs there were 22 infected infants, a vertical transmission rate of I12.4% (CI 8.0 -18.2%).Variation in transmission rates between sites could have occurred by chance (by
DerSimonian and Laird's and Fishers exact tests). Except for a trend towards decreased
transmission among women who received intravenous ZDV during labor and increased
transmission among women with CD4 counts <200, no clinical or treatment variables were
associated with the rate of vertical transmission.
Conclusions: The results of this observational study suggest that the use of ZDV in pregnancy apart form the treatment of the infant after birth can lower the vertical transmission
rate of HIV- I when compared to untreated women observed in other studies (26% in
ACTG 076). Further studies are indicated to determine the role of neonatal ZDV treatment of HIV- I exposed infants.
Ann J. Melvin; Dept. Pediatrics, Div. Infect. Dis., Univ of Washington; 4800 Sand Point Way
NE; CH-32; Seattle, WA 98 105 (206) 526-2 II 6 [phone] email: [email protected]
Tu.B.2 129
A RANDOMIZED PHASE II DOSE RANGE-FINDING STUDY OF THE HIV PROTEASE
INHIBITOR VIRACEPTTM AS MONOTHERAPY IN HIV POSITIVE PATIENTS
Conant, Marcus*, Markowitz, M.**, Hurley A.**, Ho, D.**, Peterkin, J.***, Chapman, S.***
*Conant Medical Group, San Francisco, CA; **Aaron Diamond AIDS Research Centet NY
and ***Agouron Pharmaceuticals, IncLa Jolla, CA
Objective: To optimize the dose and regimen of the HIV protease inhibitoVIRACEPT, for
controlled Phase II/Ill trials.
Methods: After a two-week antiretroviral therapy wash-out period, 30 HIV positive patients
with CD4 cell counts > 200 cells/mm3 and quantitative HIV RNA titers of 20,000
copies/ml were randomized to receive 500 mg tid, 750 mg tid and 1000 mg tid (1000 mg
1500 mg, and 3000 mg/day) ofVIRACEPT for 28 days (10 patients per arm).The primary
endpoints were changed from baseline in CD4 cell counts and quantitative plasma HIV
RNA titers.

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