HIV RNA -- Time to Wake Up and Save Lives

Accurate tests for the level of HIV RNA in blood plasma --
which shows the number of HIV virions present in the blood --
are now commercially available to physicians, and have been
available for research use for some time. The greatest need
now is to use these tests in many small, rapid trials, to
learn how to better use the drugs we already have, and others
which could readily be made available. We need to try many
strategies to reduce the viral load as much as possible, and
keep it down. We need to individualize these strategies for
individual patients, because it is clear that existing,
available drugs and combinations of drugs can work very well
for some people but not at all for others. We need to quickly
learn who is benefiting, and test other options for those who
are not.

Many researchers agree with this kind of strategy. But the
mainstream is not yet ready to move. Instead, it wants to
first do other trials to prove beyond a doubt that HIV RNA
testing is useful for testing drugs. These trials will take
years -- if they can be conducted at all.

Yet it is already clear that HIV RNA is a much better measure
of the virus in the bloodstream than any other test we have.
It is also becoming clear that this viral load in the blood
reflects viral reproduction in the lymph nodes and elsewhere.
Reducing the level of virus in the blood does NOT mean that
it has been removed from the lymph nodes or other tissues;
but usually it does mean that the virus throughout the body
has become, at least temporarily, less active.

We need to learn how to use combinations of drugs and other
treatments to keep HIV inactive indefinitely. It will
probably be hard to do this. But we now have tests that open
doors to creativity by researchers, physicians, and patients,
because they can tell rapidly and reliably whether a
treatment is working for a patient to reduce the virus -- and
how long it is working. When it stops working, new approaches
can be tried. As experience develops and knowledge is
exchanged -- in research settings, and also in physicians'
offices -- we will learn what strategies are most likely to
work, and how to deliver better care to patients in all
stages of HIV disease.

Examples: Approved Antiretrovirals

What drugs should be tested in this way? One good place to
start is with the drugs already approved by the FDA as
antiretrovirals -- AZT, d4T, ddI, ddC -- and combinations of
those drugs. First, establish a baseline value of HIV RNA for
an individual patient, while the patient is on a stable
treatment regimen. If that value is low, and the patient is
otherwise doing well, the decision might be to leave well
enough alone -- but to watch the test in the future. If the
value is high, then switch to (or add) other regimens which
make sense for that patient; within about two weeks the test
will show whether the new regimen is working to reduce the
virus. If it is not, other options can be tried.

What is "low" and what is "high"? This is still being
learned, but a rule of thumb is that anything under 10,000
copies of RNA per milliliter of plasma is fairly low, and
anything over 100,000 copies is fairly high. [Note that some
testing companies report the number of copies for other than
one milliliter of plasma; in this case the number on the lab
report needs to be multiplied by 20, or by some other factor,
to get the number per milliliter.] Some researchers believe
that it may be good enough to keep the HIV RNA under some
threshold amount, probably somewhere between 10,000 and
100,000; others suspect that it may be important to keep the
value as low as possible. At this time no one knows for sure.

Example: Acyclovir

Besides the four approved antiretrovirals, many other
treatments can be tested this way. For example, two major
trials and one epidemiological study have unexpectedly
suggested that acyclovir may substantially improve survival
of persons with advanced HIV disease. But none of these
studies was planned in advance to test that possibility, and
none has given definitive answers, so this issue remains
controversial. There are at least four unpublished studies
with additional information; but it is clear that at least
three of the four, and perhaps all of them, will not give
definitive answers either.

Acyclovir does NOT inhibit HIV directly; but it might help
indirectly by inhibiting certain herpes viruses, which are
believed to make HIV more active. If so, this indirect
benefit might be indicated by a decrease in HIV RNA. If such
a decrease is seen -- and a small, rapid trial would be
enough to find out -- then physicians might be more confident
about using acyclovir for improving survival of people with
AIDS, and targeting the treatment to those most likely to
benefit.

Small trials measuring viral load could help to answer
questions which are unlikely to be answered in any other way.
(1) Is AZT necessary to get this possible benefit from the
acyclovir? No one knows, since the previous trials which
suggested this benefit all used AZT in addition. (2) If
acyclovir is found to (indirectly) lower HIV in late-stage
disease, would it also help in earlier stage HIV infection?
None of the previous studies have shown such a benefit. But
they would probably not have found it even if it was there,
because people with early infection either were not included
in the studies, or would not have had time to get sick during
the period that the studies were run. (3) Which patients
benefit? Only those who have been infected with herpes (which
includes much of the general U.S. population, including a
large majority of gay men)? Only (or mainly) those who have
active herpes outbreaks? Or could those who have never been
infected also benefit, perhaps because the acyclovir
suppressed unknown viruses which might activate HIV?

Definitive answers to these questions would require trials
with hundreds of people, lasting for years. Obviously such
trials will never be run. But it would be easy to find out if
the amount of virus in the blood goes down after the
treatment is started. And this information -- which would
strongly suggest that the treatment is beneficial, although
it would not prove that -- would be useful for physicians and
patients making treatment decisions.

Example: "Alternative" Treatments

Dozens of herbs, nutritional supplements, and other
treatments without commercial or government sponsors have
come into substantial use by persons with HIV. Some -- for
example, certain herbs used in traditional medicine as anti-
infectives -- have shown anti-HIV activity in laboratory
tests. But conventional drug development, which costs an
average of over $100,000,000 per new drug approved, will
never be done for them.

It is quite possible that some "alternative" treatments do in
fact reduce viral load in people. They could then be tested
in combination trials with approved antivirals, protease
inhibitors, or other treatments, to help design better
antiviral regimens. But others, which are being taken in the
hope of an antiviral effect, will be found to have none.
Persons who are using those treatments clearly need to know
this information.

Recently a small underground trial tested the combination of
Ro 24-7429 (the abandoned Hoffmann-La Roche tat inhibitor)
plus pentoxifylline, a prescription drug, using blood tests
to detect changes in viral load. Laboratory experiments had
suggested that the two drugs might work very well together.
But in people, the combination was found to be completely
ineffective as an antiviral. Viral load went up, sometimes
greatly, in four of the five patients; in the fifth, the
viral load was down at four weeks, but the decrease was so
small that it was well within the error of the test. This
result has not previously been published; AIDS TREATMENT NEWS
is seeking more information and preparing a more complete
report.

There is no evidence of any benefit from Ro 24-7429; this
small trial answered the one remaining question, of whether
the combination with pentoxifylline would have antiviral
activity. If modern viral testing had been available when Ro
24-7429 was first tried in people, several years of wasted
effort could have been avoided.

The Obstacles Today

Testing for HIV RNA is now being incorporated in most new
trials of antiretrovirals -- not to prove that the drugs
work, but to help in understanding their action. We agree
this is appropriate. What, then, is the issue?

The central issue is not about technology, but about
professional, commercial, and political will. The small,
exploratory trials of available drugs are not being done
today for the same reasons they have not been done in the
past. These reasons include lack of commercial incentive,
excessive influence of industry over professional and
governmental agendas, and pervasive neglect of treatment and
research by the leadership of AIDS organizations. This is why
the trials we need are not being done -- despite the new
technology which would make them faster, cheaper, and more
reliable then ever before.

Perhaps the basic problem in AIDS research is that the
interest we share in saving lives does not translate into the
institutional arrangements necessary for doing so.