1995 Outlook: Research Strategy

As 1995 begins, we have more opportunities for progress
toward major improvement in AIDS/HIV treatments than ever
before. And we have clear, feasible paths to follow -- of
safe, rapid, low-cost, high-quality treatment trials in
people, to get solid preliminary information on how certain
potential treatments work in practice. Researchers now have
better tools to run these trials than in the past -- and some
of the new tools, especially tests for plasma HIV RNA, are
also available to individual physicians and patients.

Also, we are hearing more cases of unexpected improvement in
people with HIV or AIDS -- sometimes beyond what would be
thought possible. The most dramatic examples are usually from
clinical trials of experimental treatments such as protease
inhibitors. But there are others who are lucky enough to do
quite well with approved treatments or treatment combinations
which happen to work for them. And some do well with
"alternative" treatments, or their own combinations of
approved, experimental, and/or alternative approaches. We
have long believed that the best strategy available is to try
many different treatments, keeping the ones that seem to work
for oneself, and discarding the ones that seem not to work.

Strategy, Part I: Small, Rapid Screening Trials

These success stories are not the answer, however. They do
not work for everyone, and usually there is no way to predict
who will benefit. Also, no one knows how long the successes
will last -- although often they seem to work for years, with
no evidence of failure in sight.

These success stories, instead, should be seen as treatment
leads, entry points for further research. For each lead,
physicians and scientists should use their best judgment to
try to define a class of patients who might reproducibly
benefit. The next step is to run a small, rapid "proof of
principle" trial -- usually in only a few patients, perhaps
ten to 20 -- looking for consistent changes in measurable
indicators of improvement. There might or might not be a
control group in this trial.

What would happen then? Most of the proposed treatments
tested this way, perhaps 80 or 90 percent, would probably be
found not to work. But there are dozens of good-quality leads
waiting for such a test, and a number of them would come out
with strong support. These would then have the
social/political momentum needed to move rapidly into further
research.

This proposal for many short, rapid screening trials is not
controversial, but is generally accepted as something that
can and should be done. The cost and other resource
requirements would be modest. The problem today is finding
the political and institutional will to make the research
happen.

Strategy, Part II: A New Way to Prove Clinical Benefit

The next step after the screening trials is more
controversial. Those short trials will look for a measurable,
reproducible improvement, usually in blood work. But what
then? Change in a blood test may not prove that the treatment
actually benefits patients. Usually we need other kinds of
trials to show this.

Here we face a serious problem. The prevailing thinking so
far has focused on a kind of clinical-benefit trial design
which will take hundreds of patients for each drug studied,
and take years to produce conclusive answers. This kind of
trial randomly assigns the treatment being tested to some
patients, while others are assigned to standard treatment
instead. Then both groups are observed to see which one gets
sick faster. It takes a long time because AIDS progresses
slowly; even if the new treatment being tested were a
complete, instant cure, the trial might still take years,
because it would have to wait for a statistically significant
number of those on the standard treatment to get sick or die.
And even aside from the time required to run the study
itself, it usually takes years to politic for, finance,
design, organize, and recruit for such a large trial (in
addition to the time to analyze the data, distribute the
results, and get them into standard medical practice). Even
aside from the problem of making people wait for years to get
better treatments, it is clear that there will not be enough
patients available, let alone enough money or trained
researchers, to test more than a few of the treatments which
are likely to pass the small screening trials.

There is a better approach. The treatments which pass the
small screening trials in all probability do benefit patients
-- the difficulty is in finding a feasible way to prove that
conclusively. What we suggest is combining a number of
treatments which work well in the screening trials, until the
cumulative benefit of all of them is great enough to be
clearly visible -- not only in delaying illness, which takes
a long time to see, but also in getting sick people well,
which usually happens much more quickly. When patients
regularly get out of bed and go back about their lives, when
those who were disabled can work again, when chronic
infections disappear with no further need for antibiotics or
other specific treatments, then the value of the AIDS/HIV
treatment will be unambiguous. Statistical proof could be
rapidly obtained, through small, rapid trials (much like the
screening trials) which compare immediate vs. delayed therapy
-- for example, randomly assigning volunteers to either start
the treatment now, or to start it in six weeks. Long-term
followup would of course be included, to make sure that the
benefits last, and to watch for long-term side effects.

This research strategy offers definitive proof of clinical
benefit in small, rapid, inexpensive trials -- instead of the
huge years-long trials that are usually believed necessary to
prove clinical benefit. It may not prove the benefit of each
individual treatment -- only of a certain, partly-arbitrary
combination. But the information available today suggests
that this strategy could quickly provide relief and save
lives; those who want more refined information could pursue
it later.

This approach to proving clinical benefit, unfortunately, is
not yet part of the ongoing conversation on how to improve
AIDS research. We have never heard it discussed or proposed
anywhere. Hopefully our readers will help to get this idea
onto the table, to be considered professionally and accepted
or rejected on its merits. None of the alternatives offers an
acceptable outcome.

This proposal for proving clinical benefit turns the small,
rapid screening trial into part of a complete strategy for
going from where we are now to where we need to be to save
lives. Let's further develop and improve this strategy, and
use it as an organizing tool to get the research done.

Strategy, Part III: New Mechanisms of Action

A third potential research strategy would seek to develop
treatments which control HIV through new, previously-unknown
mechanisms of action.

This could be done through intensive research into what might
be called mystery treatments -- accidental or lucky
discoveries of drugs or other treatments which seem to be
helping in some way, but which have no known mechanism of
action. Mystery treatments may include prescription drugs
(one possible example is sulfasalazine), certain nutrients
(see "Some Vitamins Associated with Decrease Risk of AIDS and
Death," AIDS TREATMENT NEWS #214, January 6, 1995), or other
approaches such as exercise. The goal is not so much to
develop these treatments themselves, as to discover how they
might work. If a new mechanism of action is found, then a
whole new approach to AIDS treatment would become possible.

The key is to direct more research attention and resources
into investigations of mystery treatments, which could lead
to potentially major advances in understanding and treating
HIV disease. This is the opposite of what happens now, which
is that potential treatments without a known mechanism of
action are largely ignored.

How does one begin to study a possible treatment with no
known mechanism of action? One way is to look for consistent
changes in any of the virological, immunological, and other
tests which are available. Any repeatable, predictable
treatment effect could serve as a lead or clue. And of course
this research would be done in collaboration with
specialists, usually outside the AIDS field, with expertise
in the treatment being studied; they can help to identify and
evaluate research leads.

Political Strategy: Organizing National Will

AIDS research and AIDS prevention have always suffered from a
lack of full national commitment to AIDS. Today this problem
is becoming more critical than ever before. As it affects
research, it takes many forms:

* AIDS research has long overemphasized large, high-tech,
complex, and product-oriented projects, because those are the
ones people get paid to do, the ones that build a politically
powerful constituency (lobby). Corporate research is almost
always oriented toward proprietary products; in theory,
government and foundation research should fill in the gaps by
doing necessary work which companies will not do -- including
basic research, and also including the small trials that we
suggested above, for those treatment leads which are not
products that corporations will study. But due to conflict of
interest, revolving-door employment, and increasing reliance
by academic institutions on entrepreneurial funding, non-
corporate institutions have not adequately set their own
agendas. As a result, academic, government, and foundation
researchers have tended to study the same drugs and
approaches that corporations already are studying, or should
be.

Part of the problem is the ever-increasing difficulty of
making anything happen in clinical research (due to ever-
growing costs and regulatory requirements, as well as
increasing scarcity of funds). This creates a conservative
bias, by making it hard to get any trial off the ground
unless it has a large, pre-existing constituency. Since new
ideas almost never come into being with a large constituency,
they almost always suffer great delays while the necessary
professional/commercial/regulatory momentum develops.

In other circumstances, it would be possible to correct these
structural defects. But due to the widespread attitudes
around AIDS, the nation has not found the will to do so.

* The recent elections have created new and serious problems.
Many members of Congress seem to be interested in
representing only one group of people -- white, heterosexual
men with good incomes -- and have little interest in anyone
else's concerns. (A more accurate statement would be that
they represent the frustrations of certain voters, and the
interests of multinational big business.) Since relatively
few such people have AIDS, money may be taken from AIDS for
tax reduction, military spending, and other rewards for those
who financed the recent political campaigns.

* Recently we spoke with two business reporters not connected
with AIDS, and found a well-developed ideology of fatalism
tailor-made to justify not bothering with AIDS research. One
compared AIDS research to a swamp, in that the farther you go
in, the deeper you get, without end. The other compared AIDS
to the common cold -- more serious, he acknowledged, but
similar in that despite ongoing progress, we do not expect to
ever see a time when people do not get colds (or, by obvious
analogy, a time when people do not die of AIDS).

These images did not come from their personal experience, but
from somewhere else. This ideology does not reflect anyone's
experience, but appears to have been constructed for a
purpose -- to justify abandoning people with AIDS or HIV.

* Other national-will problems are closer to home. AIDS
service organizations have never shown much interest in
research -- and neither has organized medicine. And public-
policy experts, in Washington and elsewhere, seldom
understand science and technology issues, or have any serious
interest in them.

* Also close to home is the lack of popular mobilization on
AIDS. Most people affected by HIV do nothing, ever, to help
the cause of AIDS research. One major reason is that
organizers have not created effective channels for them to
use in doing so. In most locations, the only options, the
only ways to interact with the issue, are to send a check to
a distant national organization -- or possibly to sit through
many hours of high-tension, ego-battle meetings, before the
new person is allowed to actually do anything which
contributes. Many people want to meet with friends and
neighbors to write and call Congress to support AIDS funding
-- perhaps the most important thing they could be doing now
-- but nobody has organized to give them the information they
need.

The public motivation certainly does exist; as we pointed out
in the last issue of AIDS TREATMENT NEWS, at least 50 million
people in the U.S. alone have a relative, friend, or
acquaintance whom they know has AIDS or HIV. What must be
done is to establish a social movement so that these millions
of people can make their voices heard, instead of remaining
silent as is almost always the case today.

In summary, we now have excellent opportunities for progress
in treating AIDS. But they are not being exploited
effectively. Solutions have been identified; it is up to us
to organize and insist that they be implemented.