Antivirals, Vaccines, Passive Immunotherapy: Talk by Marcus Conant, M. D.

Marcus Conant, M. D., is one of the early discoverers of
AIDS, and now runs one of the largest private HIV practices in
the United States; his San Francisco office also participates in
clinical trials of a number of experimental treatments. For
several years Dr. Conant and his staff have held monthly talks on
AIDS treatments, intended primarily for their patients but also
open to the public without charge. The April 6 meeting was
especially informative; with Dr. Conant's permission we
transcribed parts of it here. [Our own explanatory comments are
in brackets.]

To be added to the mailing list for notification of future
talks, which are usually on the first Monday of each month from 6
to 7 p.m., call Dr. Conant's office at 415/923-1333. For more
information about volunteering for any of the studies described
below, see the note at the end of this article.

International Research

Dr. Conant: "The Germans and the French, unlike the
Americans, have national AIDS meetings each year, as well as the
major international conference; there is a European meeting as
well. In the U. S. there are many meetings, including the AIDS
Clinical Trials Group (ACTG) meetings; there isn't anything like
that in Europe. In Germany, researchers get together once a
year, in a meeting sponsored by the German government, and talk
about what they're doing, including clinical trials. They ended
the conference this year with a panel discussing research
findings and social issues; I was invited to talk about our
treatment guidelines [Dr. Conant's recommendations on when to
start AZT, opportunistic-infection prophylaxis, combination
antivirals, and other treatment]. They had a fairly good
attendance, 700 or 800 people, and they broadcast that panel
throughout Germany.

"I was hoping to bring back some information from that
meeting to say, 'The Germans are doing this, and it really looks
good.' But I didn't see anything that they were doing in Germany
that we weren't doing two years ago. The bottom line is that
what is happening in the leading U. S. AIDS centers probably
still is the cutting edge of what's occurring in AIDS research
around the world. Even in terms of potential treatments like
iscador, which we call "alternative" treatments here, there were
no hard results showing that anything was beneficial.

TP5 (Thymopentin)

"The TP5 study -- this work's been going for years now -- is
up for another review at the end of May. We have some 200
patients in that study; there are another 150 or so around the
country. We hope the drug is going to show benefit stabilizing
T-helper cell levels in the people on TP5 and AZT together -- but
we don't know that until the code is broken [telling which
volunteers are getting TP5 plus AZT, and which are getting
placebo plus AZT]. If the drug looks good, my guess is that
approval could come quickly, because TP5 has been widely used in
Europe now for almost ten years. It's very expensive in Europe,
but is being used not only for AIDS but for herpes, and for other
diseases where an immune modulator might help. With the safety
data from Europe, there should be little trouble getting FDA
approval if the drug is efficacious. For those of you on the
study, after efficacy is shown the sponsor will probably roll
everybody over to open label at least until the drug is available
on the market.

Antivirals: N-Butyl-DNJ Trial

"What we really need in AIDS treatment is another place to
attack the virus. The three drugs we have that are most widely
accepted as effective -- AZT, ddI, and ddC -- block the reverse-
transcriptase step in viral replication. There's some recent
data that AZT, and ddI/ddC, are actually working at different
places on the reverse transcriptase. It is not known yet, but it
is likely that there will be cross resistance between ddI and
ddC; but resistance to AZT is clearly by different mutations than
resistance to ddI.

"We still don't know all the things that AZT and these other
drugs do. One of the major questions that may be answered in the
Amsterdam meeting this year is, "What is AZT doing?" How much of
its effect is in blocking reverse transcriptase, how much is
mediated through stabilizing T-helper counts, and how much of the
effect may be in some other area entirely -- and if so, what else
is this drug doing? Until we have better answers, it is hard to
rationally advise patients -- for example, should they continue
taking AZT after they have started ddI [because the AZT appeared
to be no longer working].

How long have we had AZT? It has been approved for five
years now -- and two years before that, Burroughs-Wellcome was
saying they had a drug they thought was going to work. It took
two years to get it to market, which is a record time; so it's
been seven years without another major AIDS drug. We have the
"son of AZT" in ddI and ddC, based on the same mechanism of
action.

"But clearly we would like to have something that blocked
the virus at some other stage in its life cycle. As in
tuberculosis, combination therapy is best if you combine drugs
that work at different sites.

"We are lucky enough to be running a study of N-butyl-DNJ
[also called butyl-DNJ, or deoxynojirimycin]. This drug blocks
glycosylation of the virus (adding sugars to some of its
proteins) as new virus particles emerge from the cell wall. This
study is exciting because if you look at what is coming for AIDS
treatments, the ones which show great promise, such as the
protease inhibitors and the tat inhibitors, are likely to be
years away from general availability. But N-butyl-DNJ is well
along in trials; the safety data is in. Now if we can
demonstrate that it has efficacy in humans, we could probably get
the FDA to approve this drug fairly quickly. The drug is
exciting not because it will be the greatest AIDS treatment, but
because it could be available in a year or two, so we could block
the virus at two different points in its life cycle.

"We are looking for volunteers for that study. But note
that this trial presents difficulties to volunteers. For
example, on one day you need to lie on a table for five hours and
be bled every hour; sometimes there has been a problem with the
lab, and volunteers have had to go through the whole process
again. Another problem is that the initial formulation of this
drug causes severe diarrhea if you eat carbohydrates, so a
special diet is necessary. The good news is that the company, G.
D. Searle & Co., has developed a new formulation of the drug
which does not cause the diarrhea. So if the drug shows the
efficacy that we expect, then we will move to the second compound
which does not have the same side effects. We cannot use the
second drug now because it does not have all the testing required
for use in the trial; the company wants to know that the drug can
be effective before it spends the money to get the new version
approved.

Volunteers for this study must have T-helper counts between
200 and 500, and no AIDS diagnosis [under the "old" definition of
AIDS, which is still in effect]. They must have taken AZT for at
least 12 weeks. Some people will come off AZT for a short time
while we measure the effect of this drug on the virus. Note that
this is a phase II study; the phase I [dosage and safety] study
has already been done.

Vaccines: gp 120 Trial

"You could also try to block viral entry. One way is to use
a vaccine as a therapeutic, which Jonas Salk proposed in 1987.
With AIDS, when someone is first infected, the viral titers
[blood levels] go up very quickly. Then the immune system
controls the infection; antibodies against several different
viral proteins are created. The person goes for years without
getting sick. Later, when illness does occur, the antibody
titers go down and the viral titers go up.

"Dr. Salk suggested stimulating the antibody level to keep
patients in the latent, asymptomatic stage for much longer. Some
scientists criticized this idea, saying that these people already
had plenty of virus in their bloodstream [to make antibodies
against], so what good would it do to give a vaccine at that
time? But research has shown that you can stimulate HIV-positive
people to make more antibody by giving them vaccines to gp 160,
or to gp 120, or whole viral extract. [gp 160 and gp 120 are
glycoproteins (hence the abbreviation 'gp') made by the virus.
Glycoproteins are made up of amino acids (like ordinary
proteins), but in addition they include sugars.]

"Dr. Robert Redfield [at the Walter Reed Army Institute of
Research] gave HIV-positive volunteers gp 160. Some of them made
antibodies against gp 160, and some did not. In those who did,
the T-helper counts stabilized; in those who did not make
antibodies, the counts declined like those of untreated patients.

"In one trial, a gp 120 vaccine worked even better.
Genentech innoculated a chimpanzee several times with the gp 120
vaccine; then ten times the infectious dose of HIV did not cause
an infection. This also worked on a second chimp. The gp 160
vaccine did not similarly protect chimps. We do not know how
long the immunity will last.

"Genentech is interested in looking at its gp 120 vaccine as
an HIV treatment. They set up a study at San Francisco General
Hospital, the University of California in Los Angeles, and the
Deaconess Hospital in Boston. Last month they also asked us to
be a site. So we are recruiting for this study at the present
time, and expect to be vaccinating people within three weeks with
the gp 120 vaccine. We are looking for 15 volunteers with T-
helper counts over 500; they will be vaccinated seven times in a
year, and have extensive measurements of blood functions. These
volunteers cannot be using recreational drugs, especially
marijuana, and cannot be using AZT; they will be tested from time
to time to assure compliance with study restrictions.

"There are six arms of this study, including a placebo arm,
so there is one chance in six of getting a placebo. Two
different vaccines are being tested. The strain of the AIDS
virus which Gallo isolated was the 3B strain. This turned out to
be common in Europe; but in the U. S., most patients have the MN
strain. Genentech has made a vaccine against both. One group of
volunteers will get the 3B vaccine, another will get MN, and a
third will get low-dose MN. A fourth group will get 3B and MN
simultaneously, another will get them sequentially, and the sixth
group will get the placebo.

"If this study works -- if one or more of the treatments
prove beneficial -- the next step would be to give the vaccine(s)
to patients with lower T-helper counts who are on AZT or ddI as
well.

Passive Immunotherapy

"I'm pleased with how we have been able to put together the
different studies we are doing. We are looking at a new
antiretroviral, N-butyl-DNJ, and we are looking at a new way to
stimulate the immune response. But the next question is, what do
you do for patients who have very low T-helper counts, who will
not have an immune response to the vaccine.

"That is when you try passive immunotherapy [also called
passive hyperimmune therapy], the approach of taking effective
antibodies from healthy HIV-positive people and giving them to
somebody else. We [physicians and medical staff in this office]
have been talking about this for years, but it looks like we will
finally be able to at least start a few patients; and there is
some new data as well.

"Plasma is taken from several patients and pooled to get a
variety of antibodies. Then the plasma is sterilized with a
chemical called beta-propriolactone, which has been used for
years to sterilize vaccines, to kill HIV and any other viruses or
other micro-organisms which may be present. Then the plasma is
infused into people with advanced HIV infection, who can no
longer make their own antibodies against HIV.

"Abraham Karpas in England, who started using this technique
as an AIDS treatment, tried it with ten patients several years
ago and then quit, because at that time he could not contact
enough suitable donors with over 500 T-helper cells in London. A
study was started at the Veterans Hospital in the Bronx, but no
results have been published. There is a small study in Paris.
And a few physicians in private practice in the U. S. are using
this treatment. And recently HemaCare, a company in Southern
California which has been doing a study, released some of its
results [see "Passive Hyperimmune Therapy (Passive
Immunotherapy): New Data Released, California Approval
Possible," AIDS TREATMENT NEWS #148, April 3, 1992].

"Our office is now making preparations to treat some
patients, as well as to apply to the State of California for
approval to do some truly innovative studies. For example,
assume that the gp 120 vaccine is found to work, and boosts the
immune system of HIV-positive people who are vaccinated. Then a
possible study would be to have persons who were successfully
vaccinated donate plasma for passive immunotherapy -- to get
plasma from people with T-helper counts who not only had good
antibodies to start with, but also were vaccinated to increase
their antibodies still further.

"If that works and is safe, a further step would be to
vaccinate HIV-negative volunteers, who would make antibodies and
could then donate plasma for passive immunotherapy. This
approach could help to relieve any possible shortage of HIV-
positive donors. All of this is feasible now.

"The final step, which would require time to develop the
technology, would be to isolate the effective antibody or
antibodies and manufacture them, to provide an unlimited supply.

"The hope is that this research we are doing will lead to
therapies that will give us something which will last from now
until we have better treatments, which I don't think will happen
until 1996 or 1997."

Note: Dr. Conant's office is looking for several special groups
of potential volunteers for ongoing research studies:

(1) People with T-helper counts over 500;

(2) Those who had an opportunistic infection over three years
ago;

(3) Those who have been HIV infected less than two years; and

(4) Anyone who has been on AZT for more than four years.

If you fall into any of those groups and would consider
volunteering, call Dr. Conant's office, 415/923-0555, and leave
your name and number for a return call.