EATN: European AIDS Treatment News

DRUGS IN DEVELOPMENT
EFAVIRENZ,
SUSTIVA~, DMP-266

W hat do we currently know
about efavirenz (also
What do we currently know
known as DMP-266), the
non-nucleoside reverse
transcriptase inhibitor (NNRTI) developed
by DuPont Pharma Laboratories? We
know the basics - it is an antiretroviral
with a definite action on HIV (and by itself
very little); the currently available figures
concerning this molecule are still limited.
It is therefore difficult to identify precisely
what kind of place efavirenz may have in
the current therapeutic arsenal.
The clinical development of efavirenz
(the commercial name of which will be
Sustiva~) began in March 1996. At first
sight, this molecule presents an attractive
profile, for its pharmacokinetic and
pharmacological properties: it has a long
half-life, from 40 to 52 hours, which
allows it to be taken only once a day.
Within the current context of
multitherapies, this is a clear advantage.
Moreover, there is no interaction between
efavirenz and food, which means it can
be taken indifferently during or between
meals. Lastly, the capsules, each with a
dose of 200 mg, need no specific
conservation precaution.
As concerns interactions, efavirenz is
principally metabolised by the liver; it is
an inducer of activity of the CYP3A4
isozyme of the P450 cytochrome, which
means that it raises the activity of the
latter. Interaction problems are therefore
probable between efavirenz and other
medicines metabolised by the same
isozyme. In the same way, inhibitors of
CYP3A4 risk lowering the metabolisation
of efavirenz and so raising the plasmatic
concentrations. On the other hand, the
inducers of CYP3A4 may increase the
metabolisation of efavirenz and reduce
the plasmatic concentrations. There are
not yet any available figures evaluating
such interactions in vivo. In vitro_, it
seems that efavirenz lowers the
concentrations of indinavir and
clarythromycin, and raises that of
nelfinavir. The concentrations of
saquinavir rise or fall according to the
dose of efavirenz administered. However,
these interaction studies in vitro have
been carried out with different dosages
from those used today. In any case, the
association of efavirenz and the following
molecules is counter-prescribed:

rifampicin, terfenadine, astemizole,
cisapride, triazolam and midazolam. It
would also be important to have the
clinical information on interactions with
the complete range of antiretrovirals
which may be associated with efavirenz
so as to avoid the combinations which
cause problems of this type.
For the moment, only the results of
two trials are available. The first, 003,
evaluated different dosage plans of the
association of efavirenz and indinavir (1).
This trial included no less than 8 cohorts
of patients. At the moment, results are
available for the first four (2).
The results of the trial confirmed the
antiretroviral activity of efavirenz. (see
table). In another cohort of the same
study, after 12 weeks, the pareticipants
could add d4T to their regimen. Of
course, today we know that it is better to
start a new combination rather than add
to one that is failing... In any case, the
double combo efavirenz/indinavir had a
significant anti-HIV activity, similar to
what might be expected from a triple
combination, and that lasts (at least out
to 48 weeks) (3). The next study, 005,
was a dose ranging study in combination
with AZT/3TC. Reduction in viral loads in
the four groups were: 200 mg 93%, 400
mg 85%, 600 mg 88%, AZT/3TC alone
39%. The CD4 rises were also all very
similar between the three doses.
This study showed that a triple combo
without a PI could bring the majority of
participants to below detection. Efavirenz
is relatively well tolerated, with nausea
(20%), rash (19%), dizziness (17%),

headache (16%), diahrrea (13%) and
asthenia (12%) the most reported. The
sensation of vertigo seems to come 1 or 2
hours after dosing, and usually goes away
within the first two weeks. Anyone who
has this sensation is advised to take the
medicine before going to bed, or splitting
the dose, half in the morning, half in the
evening (it's indicated to take it all at
once, a big plus for compliance, but they
counsel you to do it BID if you feel dizzy).
It has a similar resistance profile to the
other NNRTI's, notably V106A, V1081,
Y181C and Y188C. The two associated
with a strong resistance are K103N and
L100L. According to the company, the
dosage of 600 would be the most likely
to prevent said resistances.This remains to
be seen in vivo.
In conclusion, for its once-a-day
dosing, as well as for its toxicity and
resistance profiles, it seems interesting,
although with the limited data on hand,
it's very difficult to say. It's available right
now in clinical tests and expanded use
(named patient) basis throughout Europe.
(1) The association efavirenz and indinavir
seems to have been a priority because of a large
stakehold by MSD. Nevertheless, a notable
decrease of the concentrations of indinavir have
been observed in association with efavirenz; but
no guideline has been recommended when
indinavir and efavirenz are associated in the
framework of a three-way therapy.
(2) Reported first at ICAAC Toronto, 30.9.97,
later at ECCAT Hamburg, 14.10.97.
(3) The dosing of Efavirenz went form 200 to
600 mg/day in week 36 of this study.
FRANK FONTENAY, FRANCE

STUDY 003, VIROLOGICAL AND IMMUNOLOGICAL RESULTS AT 12, 24 AND 48 WEEKS

EFAVIRENZIINDINAVIR

INDINAVIR

NUMBER OF PATIENTS
BASELINE HIV RNA LOG 10
BASELINE CD4/MM3
MEAN DECREASE HIV RNA AT W24
MEAN DECREASE HIV RNA AT W48
% PATIENTS HIV RNA <400 AT W 12
% PATIENTS HIV RNA <400 AT W24
0/ PATIENTS HIV RNA < 400 AT W4
MEAN INCREASE CD4/MM3 AT W24
MEAN INCREASE CD4/MM3 AT W48

59
5,09 (~0,44)
283 (~119)
-2,72
-2,36
74
94
889
+199
+240

42
5,02 (~0,69)
284 (~119)
1167
-1 66?
50
74
77
+108
+153

<0,05
_.<.0,0.5..
<0,05
<0,05
< 0,05
<0,05
<0,05

24 WINTER 1997/98