Berlin: Concorde Trial Questions Early AZT Use -- Wider Implications

The Concorde trial may be the most influential single
presentation at the Berlin conference -- but not because of
its data, analysis, or contribution to care. Instead,
Concorde is important for prompting rethinking about AIDS,
both for better and for worse.

Background

On April 2, 1993, the medical journal The Lancet published a
one-page letter reporting preliminary analysis of the largest
clinical trial of early treatment with AZT -- the Concorde
trial, conducted in the UK, France, and Ireland. This
analysis questioned the benefit of early use of AZT (in
persons who are asymptomatic and who have no other reason
which would prompt the physician and patient to decide to
begin treatment). In these patients, the study found no long-
term benefit of starting AZT immediately, vs. waiting and
starting later. There was a small short-term benefit of
immediate treatment in delaying disease progression. But
after three years, the two groups were doing about equally
well.

Because AZT did raise T-helper counts, but did not show long-
term benefit in this group of patients, the Concorde
researchers suggested that T-helper counts may not be a
suitable measure for testing new drugs, and that "clinical
endpoints" (death or major disease progression) may need to
be used instead. (Because HIV disease develops slowly, a
policy of requiring clinical endpoints is likely to add
several years development time to each new AIDS drug or drug
combination tested, resulting in the de facto abandonment of
early treatment, and in major delays for all new AIDS drugs.)

After the Lancet letter, U.S. researchers were angry that
they were asked to accept such sweeping conclusions on the
basis of so little information. They could not bring their
professional judgment to bear because data was not available
to them. That was the context in which we published our
critique of the Concorde analysis ("AZT, Early Intervention,
and the Concorde Controversy," AIDS TREATMENT NEWS #173,
April 23, 1993). We argued that the Concorde results might be
explainable within the conventional framework (AZT works in
early disease, T-helper count works as a marker of drug
efficacy), if the physicians started treatment strategically
in the "deferred" treatment group, with the rapid T-helper
boost from AZT heading off clinical endpoints, or at least
postponing them until after the December 31, 1992 data cut-
off for the analysis.

At the Berlin conference, much more Concorde information was
released, especially in the June 8 talk by M. Seligmann (tape
#27; see information below on ordering audio tapes), and by
the trial's statistician, A. Babiker, on June 10, who is not
listed in the program because he replaced Seligmann on that
day (tape #96). Nothing we have heard so far makes us believe
that our critique was erroneous. But it may not be relevant
today, because other issues are now on the table. Before
going on to these, we want to state one concern behind our
critique which should still be kept in mind.

The Concorde trial, after its protocol modification of
October 1989 to allow voluntary switches to AZT for persons
with T-helper counts under 500, did include medical judgment
as an integral part of the "deferred treatment" strategy
being tested. And the Concorde physicians seem to have
provided excellent medical care, with both groups of patients
doing unexpectedly well. But a strategy which worked in the
hands of expert physicians, providing careful monitoring as
part of a major trial, might not be as good in other settings
where it has not been tested, such as in the offices of
inexperienced physicians, or in rushed public clinics. This
should be considered before the strategy is transferred
wholesale to such settings.

Despite this concern, the bottom line from Concorde still
seems to be that if early treatment with AZT did work, it
didn't work very well; otherwise we would have seen more
evidence of benefit in the results. The question now is where
do we go from here.

Uses of Concorde

If Concorde is accepted unthinkingly, it throws away not only
the early treatment we have, but the chance of getting others
in the foreseeable future. That is because statistical proof
using clinical endpoints in early HIV disease requires long,
large trials. Adding the time required to conduct and analyze
the trial itself, the time for recruiting, and the time to
build the required commercial and professional momentum to
get a large trial going, it is likely to take several years
to test each drug or combination. Such trials are not
feasible for many reasons. They would compete with each other
for patients and resources, for example; and when they were
done, the drugs and treatment philosophies they started to
test would likely be obsolete.

The pressure, therefore, is to abandon treatment, writing off
people with HIV, and shift the focus to controlling the
disease only through prevention. This is how mainstream
newspaper editorials are interpreting the Berlin conference
results (and especially the Concorde results). For example, a
June 17 editorial in The New York Times cites the Concorde
results (by saying that AZT "apparently has little or no
effect when given to people who are infected with the virus
but have not yet developed symptoms"); the opening paragraph
concludes that, "There is little choice now but to shift the
emphasis to prevention programs."

We will refer to this editorial again, because buried in it
is a more positive statement which supports another major use
of the Concorde results. And worldwide AIDS prevention is
indeed so critically important today that nothing must be
allowed to detract from it. But the Times editorial and
others like it do illustrate the danger that Concorde will be
used to save money (especially for government agencies like
national health services) by abandoning treatment for people
with HIV.

Despite this danger, U.S. AIDS activists are often welcoming
the Concorde report. They are using it for a different
purpose -- as a focus for a repudiation of third-rate drugs
(AZT, etc.) which have been tested interminably because they
pay the bills, even though it is clear that they are
inherently limited and will never work very well. Meanwhile,
possibilities for more important advances have been neglected
-- the result of sloppy commercialization of science, and of
lack of planning in the public interest.

There have long been movements against AZT. Most of those in
the past have told people not to use it, to reject their
doctor's advice if necessary. Often they have told people to
use something else instead, often something with little
reliable data about its usefulness in HIV, yet still proposed
as the one blanket answer for almost everyone. AIDS TREATMENT
NEWS has seldom covered these movements, because we have been
unwilling to tell people to discard their doctor's advice.

What might be coming out of Concorde is a different kind of
rejection of AZT. It recognizes that this drug has a
legitimate and important place in HIV treatment today, that
it is better than nothing for many people, and that since
there is no single answer for everyone, the decisions about
whether, when, and how to use it should be made individually,
by consultation between patients and their physicians. But at
the same time, it calls for a redirecting of AIDS trials away
from their current focus on third-rate drugs.

The New York Times editorial quoted above also included the
sentence, "Current drugs are a dead end; researchers need
radically new approaches in the search for cures and
vaccines."