[Final Program, International Conference on AIDS (4th: 1988: Stockholm, Sweden), Book 2]

3585 DISTRIBUTION TO CSF AND PHARMACOKINETICS
AFTER IV INFUSION OF FOSCARNET TO PATIENTS
WITH HIV-INFECTION
J SjIvall*, S Bergdahl**, G Movin*, S Ogenstad*,
M Saarimaki*
* Astra Alab AB, Sbdertilje and ** Roslagstulls
Hospital, Stockholm Sweden.
Objective. To investigate the pharmacokinetics and
effects of iv foscarnet.
Methods. Thirteen male patients, with lymphadenopathy
syndrome or AIDS related complex and culture proven
HIV-infection were given a continuous iv infusion of
foscarnet (0.14 to 0.19 mg/kg-1 min-1) during 8 to 21
days. Blood and urine samples were taken during and
after drug administration to monitor foscarnet concentrations. Lumbar puncture was performed during the
infusion in 5 patients.
Results and conclusion. The plasma concentrations
showed large variations both within and between
patients. The disposition of foscarnet could be
explained by a triexponential equation (tl/2 0.40 to
2.52 h, t1/2X2 3.20 to 16.7 h, t x 36 to 196 h.)
Renal clearance accounted for most o the plasma
clearance, the difference probably reflecting the
passage of foscarnet into bone. Up to 20% of the
cumulative dose may have been deposited in bone 7 days
post-infusion. Foscarnet was distributed to the
cerebrospinal fluid in a concentration varying from 13
to 68% of the simultaneous plasma concentration. A
heavily increased diuresis and fluid intake was
recorded in all patients. There appears to be an
association between the degree of malaise, including
symptoms such as nausea, vomiting, fatigue and headache,
and plasma concentrations above 350 pmol 1-1.

35 6 BENEFICIAL EFFECT OF INTERMITTENT INTRA35 6 VENOUS (IV) FOSCARNET (PFA) THERAPY ON
HIV INFECTION IN PATIENTS WITH AIDS.
Mark A Jacobson, S Crowe, J Levy, F Aweeka, J
Gambertoglio, N McManus, J Mills. UCSF and S.F. General
Hospital, San Francisco, CA and AIDS Clinical Trials
Group, NIAID, Bethesda, MD USA
Objective: To determine the activity of PFA, a pyrophosphate analog, in inhibiting HIV replication in vivo.
Methods: 9 patients (pts) with AIDS, treated for
cytomegalovirus retinitis with an induction course of
PFA, 60 mg/kg IV q 8 hours for 14 days, had serum HIV
p24 antigen concentration (Ag) and CD4+ lymphocyte
number /Th) quantified and peripheral blood cultured for
HIV before and at the end of PFA therapy (Rx).
Results: 6 of the 10 pts had detectable p24 Ag in serum
prior to PFA Rx. After 14 days of PFA Rx, serum p24 Ag
concentration in all 6 pts had decreased by 14-89% from
baseline, with a mean reduction of 58% (p=.02, one
sample t text after log transformation). 2 of 8 viremic
pts became HIV culture negative during Rx. 3 pts had
additional serial serum samples obtained while receiving
a maintenance PFA regimen (60 mg/kg, 5 days/week) during
which their p24 Ag levels increased to 54-91% of their
baseline value. All 10 pts had < 50 Th cells/ul at
baseline. After PFA Rx, 8 of the 9 pts had increased
Th, but only one pt increased to > 150. A dose-response
effect was observed in 4 pts who had plasma PFA levels
measured and baseline p24 Ag > 200 pg/ml. For these 4
pts, PFA steady state AUC correlated with the decrease
in serum p24 Ag that occured during PFA Rx (r2=.96,
p=.02). No serious adverse effects of PFA Rx occurred.
Conclusion: Short-term PFA Rx was well-tolerated and
inhibited HIV replication in AIDS pts; further clinical
trials are warranted.

Notes:

3587 TREATMENT WITH FOSCARNET OF PRESUMED CMV
PNEUMONITIS IN PATIENTS WITH AIDS: A DOUBLE
BLIND PLACEBO CONTROLLED STUDY
M Youle*, B Gazzard*, A Chanas**, J Lernstedt***
*St Stephen's Hospital, London, SW10O 9TH
**ASTRA, Edinburgh, ***ASTRA Alab AB Sweden
Objective. As Pneumocystis carinii pneumonia (PCP) is
commonly complicated by cytomegalovirus (CMV), an infection difficult to diagnose rapidly, the value of adding foscarnet to PCP treatment was assessed in a double
blind placebo controlled trial.
Methods. 32 consecutive patients with 'AIDS pneumonia'
were randomly allocated to treatment with foscarnet 230
mg/kg or normal saline plus standard PCP treatment for
14 days. At the time of recruitment blood and alveolar
lavage fluid was tested for CMV by DEAFF.
Result. 4 patients died and 2 withdrew within the first
4 days of therapy (2 on active treatment). Three
patients who clinically deteriorated were treated with
open labelled foscarnet (all died). All 23 patients who
completed 2 weeks of therapy survived to leave hospital.
When analysed on an intention to treat basis there was
no significant difference in deaths or speed of recovery in the active or placebo group. 10 patients had bronchoscopically diagnosed CMV infection (5 on active treatment). The survival of speed of recovery of this group
was no different from those with PCP alone.
Conclusion. The incidence of CMV pneumonitis is not sufficiently high to advocate blind treatment with an anti
CMV drug early in the course of AIDS pneumonia. Although
this small study is liable to a high type II error there
is no support for the concept that concomitant treatment
of potential CMV infection improves the prognosis of PCP.

3588

ANTIVIRAL EFFECT AGAINST HIV IN PATIENTS WITH
AIDS-RELATED COMPLEX GIVEN INTERMITTENT I.V.
FOSCARNET

Susanne Bergdahl*,Anders Sinnerborg**,J Albert"**
J Sj6vall"***, A Larsson"**", M Halvarsson", A AustKettis*, B Jakobsson*,O StrannegArd**
'Rosiagstuil Hospital, **Central Microbiological Lab.,
**National Bacteriological Lab, Stockholm, '**Clinical
Research Astra Alab AB, SSdertAlje, Sweden.
Objective. To determine the in vivo antiviral efficacy of
foscarnet given as intermittent i.v. infusions.
Methods. Study design: Controlled comparative single-cedtre study where the patients were allocated at random to
receive foscarnet or no treatment. Treatment period: 4
weeks with a subsequent follow-up period of 8 weeks.
Patients: Thirty patients with ARC was planned to be included. Foscarnet dose: 50 mg/kg q 8 hrs during 1 h.
Virology: HIV isolations from peripheral mononuclear cells
CSF and plasma, HIV p24 antigen determinations from serum
and CSF. Immunology: T4 lymphocyte counts. Clinical assessments and clinical chemistry and haematology were also in
vestigated as well as overall safety. Foscarnet plasma
levels as well as CSF levels were determined.
Results and conclusions: All 6 of the treated patients
who were HIV antigen positive showed a decrease in HTV
antigen levels during treatment.We have also seen a similar reduction of HIV P24 antigen pretreatment values in
all patients given Foscarnet outside the study. 4 HIV
antigen positive controls had no significant change in
their HIV antigen levels. Temporary clinical improvement
was reported from several patients after treatment.
Completed results of the whole study will be reported.

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