AIDS Treatments 1992/1993: Where Are We Now?

Each new year we write an overview of treatment development, or a list
of treatments to watch in the coming year. This year's overview is
difficult to write. Why? More is happening in AIDS treatment now than
ever before; it is harder than ever to keep up with the news. But
almost all of it is little news, better than nothing, but not centrally
important for saving lives. Examples include FDA approval of yet
another marginal drug; more news on nucleoside trials that could never
produce a decisive improvement; the latest basic-research advance that,
with luck, might be a practical treatment in ten years; more
"alternative" treatments with nothing decisive to offer; another
seminar on how to turn on your immune system; or a new cure-all
proposed (or old one recycled).

What do all of these very different examples have in common? Even when
legitimate and necessary, they also represent the kind of diversionary
activity which occurs when there is no satisfactory way to address a
major problem. When there are no alternatives, such substitute
activities may be better than nothing.

But what is disturbing today is that there are clear, meaningful, and
widely accepted avenues for pursuing potentially major AIDS treatment
advances. But due to mismanagement and disorganization (which stem,
ultimately, from the lack of consistent national political will) they
are not being pursued with even a shadow of the seriousness they
deserve.

The extended example below shows what has happened with what many
scientists consider to be the most promising class of AIDS drug being
developed. As you read it, keep in mind that every drug's story is
different -- and that problems are normal in drug development. The real
issue is not that problems occur, but that there is no effective effort
to fix them. And this issue is not unique to the example below, but is
common to almost every AIDS antiviral ever proposed or tested.

Example: Tat Inhibitors

For years leading AIDS scientists have believed that drugs to inhibit
the "tat" gene of HIV would be perhaps the single most promising
approach to developing better AIDS treatments. This article will not
list the many reasons for the exceptional promise of this class of
drugs (see "Tat Drug Development: Current Status," in AIDS TREATMENT
NEWS #153, June 19, 1992). What most interests us is that almost all
the antivirals now in use or being tested (including AZT, ddI, ddC,
and d4T) can only help to prevent HIV infection of new cells, but have
no effect on the virus in chronically infected cells, leaving a
reservoir which can produce illness in various ways, as well as
creating drug-resistant virus. In contrast, an effective tat inhibitor
would shut down all HIV activity, even in already-infected cells.

Tat inhibitors should be fairly easy to discover, because an efficient
screening test for finding them is readily available. In fact, the
fastest and least expensive approach to developing a tat drug might
well be to screen the thousands of drugs and others substances already
in human use; if a good tat inhibitor is found, then all the safety,
pharmacology, manufacturing, etc. problems will have already been
worked out, and the drug would be ready for use. No one is doing such
screening, however, since there is no commercial incentive.

Instead, the whole pharmaceutical industry (or rather, that small part
of it which has any interest in AIDS) seems to be waiting to see what
happens with the only tat inhibitor drug now in human testing --
code-named Ro-24-7429, being developed by Hoffmann-La Roche. Meanwhile,
governments (and the rest of the AIDS world) wait for industry to
develop tat drugs. In the middle of a major worldwide epidemic, the
most promising approach to treatment development has been abandoned to
a single project with a single drug in a single company. The problem
is that the whole world waits for what might be the wrong tat drug, and
almost certainly is the wrong company.

Ro-24-7429 has been delayed because its complex and unusual
pharmacology required additional studies to learn how to safely
administer it. But the biggest problem has been the lack of commitment
by Roche to the project. First, the company decided to abandon the
drug, calling off an imminent human trial at Johns Hopkins University
by a phone call to the researchers there on April 29, 1991. After AIDS
scientists expressed great concern over the loss of the only tat
inhibitor in development (see "Promising AIDS Drug Looking for a
Sponsor," Science, July 19, 1991, pages 262- 263; also see the Wall
Street Journal, May 30, 1991, page B4), Roche decided to sell
Ro-24-7429 instead of abandoning it. It came within days of selling it
(to Burroughs- Wellcome), but then changed its mind again and decided to
develop the drug itself.

A major problem now seems to be the lack of commitment of enough staff
and resources to this drug within the company. Trials have repeatedly
been delayed, and there is still no data on whether or not the drug
reduces viral load in people, despite the fact that human testing began
well over a year ago.

Within Roche, two people are in charge of the tat inhibitor
development; we do not know if there is any other professional staff on
the project. During a conference call last month, we asked these two
about an earlier attempt to develop a tat drug, which had apparently
failed. At least as far back as 1988, German scientists had proposed
that d- penicillamine, a prescription drug, might be a useful tat
inhibitor; an article published in 1986 described a test of the drug as
an HIV treatment in Germany. A later study, however, (presented in June
1990 at the Sixth International Conference on AIDS in San Francisco)
reported harmful side effects and no evidence of benefit. We wondered
what lessons had been learned from this apparent failure, and how they
were being incorporated into future tat-drug development. But it turned
out that the team developing Ro-24-7429 at Roche did not even know that
d-penicillamine had been proposed or tested as a tat inhibitor, despite
several published papers on the earlier work -- well over a year after
Roche had its own tat inhibitor in people.

This is the project that the whole world has entrusted, for two years,
as the sole human developer of the most promising class of potential
AIDS drugs, the most feasible development path for finding more
effective treatments.

Fortunately the AIDS Clinical Trials Group (ACTG) of the U.S. National
Institute of Allergy and Infectious Diseases (NIAID) began a trial of
Ro-24-7429 in December, 1992. This trial will, for the first time,
measure indicators of viral activity before and after treatment, so
that at last we will know whether or not the drug has biological
activity in people. Our main misgiving now is that Roche has so little
interest in its own drug. What might it know that we don't? And if this
drug should fail, will there be a stampede to reject the whole class of
drugs even if there is no rational reason to do so?

Why would Roche decide not to sell its drug after all, if it had so
little commitment to it? Since we cannot read minds, we can only guess
at possible scenarios. If tat inhibitors are indeed promising but
Ro-24-7429 had problems that would delay or rule out its final
development and marketing, then Roche would stand to lose its valuable
lead in tat drugs if another company entered the field with a better
one. The best way to prevent that would be to avoid releasing the key
data on the drug -- whether it has biological activity in humans --
since other companies would then be likely avoid risk by waiting to see
what happened with Ro-24-7429 before committing themselves to tat drugs
-- giving Roche time to either overcome the problems with Ro-24-7429,
or to find a second-generation drug to replace it.

Another speculation is that if there were anything embarrassing in the
history of the tat drug project, Roche might not have wanted the
evidence to go out its door and beyond its control.

Tat inhibitors appear to be much easier to develop than other classes
of drugs such as protease (proteinase) inhibitors. But the latter have
received much more attention, with several companies competing to
develop them -- probably because protease inhibitors present more
professionally interesting challenges. With tat drugs, enough
fundamental problems have already been solved that what is needed now
is a straightforward, well-managed development effort. But scientists
are attracted to scientific not management problems, and non-scientists
have not understood the drug. And no one has had the national or
international mandate to see that a first-class opportunity was being
wasted, or the authority to do anything about it.

The issue here is not Roche, but the rest of the world. How can the
United States (which does the most biomedical AIDS research), or any
other country, allow its vital interest in better AIDS treatment to
remain so unguarded and unattended?

Comment: Where Do We Go From Here?

We believe that the most important AIDS treatment development in 1992
was the election of Bill Clinton instead of George Bush as U.S.
president. But maybe not for the reasons people think.

At AIDS TREATMENT NEWS we spend considerable time on the phone talking
to people whose primary work is not AIDS -- mainstream reporters and
corporate officials, for example. Already since the election there
seems to be a difference in seriousness, in respect for the issues. The
difference seems to go beyond AIDS, to reflect a national change toward
dealing with public problems, instead of finding clever maneuvers to
excuse an evasion of responsibility.

But the hostile Reagan-Bush administration also provided an excuse for
the AIDS community. With leaders like those, we were free to defend
against the latest attacks as they occurred, without responsibility for
setting our own agenda or for getting results. For example, Bush never
received a consensus demand from the AIDS community for improvements in
treatment research, except for faster access to treatments nearing
approval (which he supported), and for more money (where he was not the
leading obstacle).

Maybe our lack of input made no difference anyway; the White House
overruled the entire AIDS community, as well as the intent of Congress,
on the HIV travel-immigration ban, apparently as a political payoff to
bigots. But in the future, with a potentially responsive government, it
will be disastrous if the AIDS community does not formulate workable
research policies and make them known.

The biggest problem in research is the lack of a consistent national
commitment to save lives. Researchers have not had the support they
need to do what they know is important. So trials have focused on
commercial drugs -- known to be inadequate, but where the money is --
while clear prospects for decisive treatment advances have remained
ignored or grossly under emphasized. And basic research has focused on
high-tech, commercially viable toys with little regard for what could
or could not be used in the foreseeable future.

Covering the News

When reading AIDS TREATMENT NEWSletters in 1993 and beyond, remember
that we have to cover two kinds of news: what happens, and what doesn't
happen. In AIDS treatment development, the latter has been by far the
more important. (The mainstream press need only cover the former,
however, since it is in the entertainment business and not responsible
for conveying information that citizens could use.)

We, too, must spend most of our space on mediocre news -- about the
marginal nucleoside analog, antibiotic, drug combination, or
"alternative" treatment -- because usually that is all there is. And as
the standard of care changes, there may be disruptive ripples through
ongoing clinical trials, which were not designed with the real world in
mind. We will cover the ethical debates, the endless meetings, the
marching in place of hundreds of well-paid professionals going nowhere.
But we should also remember that, with a potentially friendly
government for the first time in the AIDS epidemic, it is more
important than ever before to occasionally step back from the ritual of
the moment to consider what is truly important for saving lives, and
what is not. There is no longer any excuse for a no-win war in AIDS
treatment development. No one can guarantee a date when a better
treatment might be found. But we can insist that the obvious good leads
in front of us be promptly followed up.