Subject: AIDS Treatment News #329
From: "John S. James" <[email-masked]>
Date: Wed, 20 Oct 1999 13:06:22 -0700

AIDS Treatment News Issue #329, October 15, 1999
   phone 800-TREAT-1-2, or 415-255-0588

CONTENTS:

IL-2 Low Dose and Treatment Interruption: Interview with 
Kendall A. Smith, M.D.

Retroviruses Conference: Community Press Registration 
Deadline November 12

Women and HIV/AIDS Conference: Tape, Web Reports Available

FDA Advisory Meetings: Adefovir, Nov. 1; Resistance Testing 
Nov. 2-3

***** IL-2 Low Dose and Treatment Interruption: Interview 
with Kendall A. Smith, M.D.

by John S. James

Stopping antiretroviral treatment, even after long periods of 
suppression of HIV to below detectable levels, usually 
results in high levels of virus returning rapidly--although 
there have been a few exceptions, like the famous "Berlin 
patient," who stopped antiretrovirals and had very little HIV 
return, apparently because the immune system had become able 
to keep the virus under control.

At the recent large medical conference in San Francisco 
(ICAAC, the 39th Interscience Conference on Antimicrobial 
Agents and Chemotherapy), there was great interest in a small 
study which reported partial success in all nine volunteers 
who stopped antiretrovirals under certain conditions(1). HIV 
did return and reach high levels, but then was partly 
controlled by the immune system, without the patient 
restarting antiretrovirals. And unlike the Berlin patient, 
these volunteers were not recently infected.

This result surprised everyone, including the researchers who 
did the study. Although it is widely agreed that this 
protocol is not ready for general use, the research is an 
important step toward treatments which could enable the body 
to control the virus, reducing or possibly eliminating 
dependence on antiretroviral drugs for some patients, or 
improving the results of antiretroviral therapy.

This study was presented by Kendall A. Smith, M.D., whose 
laboratory first identified the IL-2 molecule and the IL-2 
receptor in the late 1970s and early 1980s. We asked Dr. 
Smith to explain the new study to our readers.

* * *

AIDS TREATMENT NEWS: You used a much lower dose of IL-2 than 
the two big international studies which are about to start 
(the Esprit trial funded by NIAID, the U.S. National 
Institute of Allergy and Infectious diseases, which will 
enroll 4,000 people--and the SILCAAT trial by Chiron 
Corporation, to enroll 1,400). Also, patients in your study 
gave themselves a subcutaneous injection every day--instead 
of the NIAID schedule of high dose for only five days of 
every two months. What dose did you use, and why did you 
choose the low dose and every-day schedule?

Dr. Smith: Our dose was equivalent to about 2,000,000 units 
per day of the Chiron IL-2 preparation, for an averaged-sized 
adult, given by a single subcutaneous injection every day. At 
the NIH (the U.S. National Institutes of Health), the dose is 
15,000,000 units per day--about seven and a half times 
larger. [Note: Dr. Smith's abstract published at ICAAC lists 
a dose of 250,000 units of Amgen's IL-2, which is not on the 
market in the U.S. The Amgen preparation is more potent, so 
more Chiron IL-2 units are necessary for an equivalent 
effect.]

ATN: To what extent do people have IL-2 side effects at the 
low dose?

Dr. Smith: We adjust the dose so that there are no systemic 
side effects, no fevers or flu-like symptoms; if people do 
get these effects, we reduce the dose. Then the only side 
effect is local inflammation at the site of injection-- which 
is bothersome, but has not been limiting; people have not 
discontinued their treatment because of the local 
inflammation.

ATN: What is the theory behind the low dose, and why it can 
be effective without the side effects?

Dr. Smith: IL-2 is a natural hormone produced by the body; it 
is one of the most critical hormones for the immune system. 
Studies in mice have found that if they lack IL-2, they have 
a severely compromised immune system.

The theory behind the low dose is based upon the IL-2 
receptor. After we discovered the IL-2 receptor in 1981, we 
spent more than 10 years trying to understand the 
relationship between IL-2 binding to its receptor and IL-2 
promotion of T cell growth. Then, within the past 5 years, in 
human volunteers we have studied carefully the IL-2 doses 
required to achieve the IL-2 concentrations sufficient to 
fully saturate the IL-2 receptors and to promote a maximal 
response from the T cells.

IL-2 interacts with lymphocytes which express IL-2 receptors 
on their cell surface. T cells express IL-2 receptors that 
have a very high affinity for IL-2, which means that you 
don't need much IL-2 to bind to them, because they hold onto 
it very well. Therefore low doses will produce low 
concentrations which are still enough to bind to the IL-2 
receptors on activated T cells. 

Another cell involved is the natural killer (NK) cell. About 
90% of the natural killer cells lack one of the components of 
the IL-2 receptor, which lowers their affinity about a 
hundred fold. Therefore they are only affected if you use 
higher doses; then you can bind to the IL-2 receptor on all 
these NK cells. That causes toxicity, because there are about 
a billion circulating NK cells; if IL-2 binds to the 
receptors on all these cells, they become activated and make 
their own cytokines.

And the cytokines they make are the so-called pro-
inflammatory cytokines; the prototypic one, and the worst 
source of side effects, is tumor necrosis factor. This 
excessive TNF causes the constitutional symptoms--fever, 
fatigue, and the so-called capillary leak syndrome--that are 
associated with high-dose IL-2. These are due to secondary 
cytokines released by NK cells, and TNF is the major one.

So the thing to do is to keep your doses low enough so that 
you bind to the high-affinity receptors on T cells, but avoid 
activating most of the natural killer cells. Also, our data 
indicate that constant low doses of IL-2 are better than 
intermittent high doses of IL-2, in that the low, continuous 
IL-2 concentrations prevent loss of cells due to apoptosis 
(programmed cell death).

ATN: In your study, when did patients give themselves the 
daily injection? And does the medication need to be 
refrigerated?

Dr. Smith: You can take the IL-2 whenever you want to; most 
of our patients have been taking it in the evening, before 
going to bed. It should be refrigerated, so they need access 
to a refrigerator.

ATN: What patients qualified for your study?

Dr. Smith: They had to have a CD4 count between 200 and 500, 
and be on successful antiretroviral treatment, with a viral 
load remaining less than 400. Then in our study, they 
continued their HAART treatment, and also received low-dose 
IL-2, for periods ranging from 3 months to one year. Then 
they could choose to enter the treatment-interruption part of 
the study, where they would stop HAART but continue the IL-2.

The purpose of the first part [the treatment with IL-2 plus 
HAART] was to see if we could use low-dose IL-2 to accelerate 
the recovery of CD4 T cells and other lymphocytes. We found 
that we could do that. During our studies, a group of 
patients essentially came back to normal in certain 
immunological parameters; and they had had undetectable virus 
for some time, because of the effectiveness of the HAART.

The second question was, is it possible to discontinue the 
HAART, and continue the IL-2, to augment and help the immune 
system, so that the immune system can help control any 
residual HIV in the body?

Here we were asking a different question than was asked by 
Tony Fauci's group, and David Ho's, and others--who were 
trying to use high doses of IL-2 to actually activate virus 
while continuing HAART, to purge latent HIV from the system. 
I became discouraged with that approach about a year and a 
half ago, simply because of the numbers; the estimate is that 
there are at least one to ten million HIV-infected cells, 
even when there is no detectable virus in the plasma. Ten 
million does not sound like very much, but it means you need 
a seven log decrease in order to get rid of the very last 
cell. In other diseases, like cancer and other infections 
where we have such data, that has basically been impossible.

Also, there are other virus infections that, once you become 
infected, you never rid the body of the very last virus; 
instead, the remaining virus goes into a dormant or latent 
state. This is common in viral infections of the herpes 
family; examples are chicken pox, herpes simplex, and CMV. 
When you become infected, a normal immune system can suppress 
the replicating virus; you don't need any drugs. However, the 
body does not eradicate the very last virus; rather, it keeps 
the residual virus dormant. If a patient is later 
immunocompromised, either through drugs, or AIDS, or 
something else that might happen to them, then those viruses 
that had been kept dormant are no longer controlled, and they 
come back again.

The immune system is quite effective in keeping some viruses 
dormant. Therefore it might be possible to help it do the 
same thing with HIV as it already does with CMV.

ATN: When you gave IL-2 plus HAART for a year, did the CD4 
count return to normal in all the patients, or only some?

Dr. Smith: It was a matter of time; some people took longer 
than others. But in a year or two of continuous HAART and IL-
2, you can get almost all of these individuals [starting with 
CD4 counts of at least 200, in this trial] back into the 
normal range of circulating CD4 cells.

Then the key question is whether they have specific immunity 
to HIV itself after their CD4 counts have returned to normal. 
The most important test to demonstrate specific immunity is 
to discontinue the antiretroviral drugs, and see if the 
immune system can either keep the virus dormant, or control 
its resurgence if it comes back.

So far we have only 9 individuals who have tried 
discontinuing the HAART, but continuing the IL-2. We found 
that in all these individuals the virus came back, in an 
average time of about two and a half to three weeks, and then 
it increased rapidly for two weeks, to a peak level. But 
during the next two weeks, the viral load fell precipitously, 
and arrived at a level approximately 10% of the peak. Our 
mean peak viral load was about 350,000 copies, which 
decreased to a mean of about 26,000--more than an order of 
magnitude (10-fold) decrease, which happened without any 
antiretrovirals. Apparently the body responded to the virus 
and brought the levels down.

CD8 Cells and IL-2

Dr. Smith: How does the body do this? When we studied the 
immune system, we found that at the same time the virus is 
coming back and increasing, there was an increase in the 
level of the killer T cells, the CD8-positive T cells [which 
are different from the natural killer (NK) cells mentioned 
earlier]. It is well known in immunology that these CD8 
killer cells are the ones that fight off viral infections. 
And over the last several years, animal studies have shown 
very well that when you inject a virus, these CD8 T cells 
multiply very rapidly.

Two things make the cells multiply. One is the presence of 
the virus itself; the T cells recognize the virus. And when 
they recognize it, they express IL-2 receptors, and the CD4 T 
cells make IL-2, and then IL-2 is the agent that causes the 
CD8 T cells to multiply.

So the rapid expansion of CD8 T cells in our patients was 
mediated, I think, by the same kind of two-fold mechanism-- 
the cells recognizing the virus, and then responding to the 
IL-2 we were administering.

ATN: Is IL-2 known to be lower than normal in people with 
AIDS?

Dr. Smith: We don't yet have all the data on that. But there 
have been reports that the answer is yes, that there is a 
relative, but not absolute, deficiency of IL-2 producing 
capacity in HIV infection. We also have our own data, where 
we studied 50 HIV-positive individuals and compared them to 
uninfected, and we found evidence for a selective deficiency 
of IL-2 production.

I think that even healthy people, if confronted with a 
systemic infection, have difficulty making enough IL-2 fast 
enough to be able to handle that infection rapidly. So the 
therapeutic administration makes up for any deficiency of IL-
2 in persons with HIV, but also goes beyond that and corrects 
any deficiency that might be present normally.

ATN: And the CD8 levels stayed up?

Dr. Smith: That's a second part of it. In experimental 
animals, when the virus comes down and you no longer have it 
stimulating the T cells, then the CD8-positive T-cell count 
also comes down. The striking thing about our data is that 
the CD8 count did not come down, it stayed up. From animal 
tests, we now know that it comes down because there is not 
enough IL-2 to sustain the population; these CD8 cells then 
die due to apoptosis [programmed cell death]. The therapeutic 
administration of IL-2 seems to prevent that.

So IL-2 first expands the number of CD8 cells, but then it 
also keeps them alive and functioning, so they can more 
effectively react against any residual virus-infected cells. 

ATN: Did these 9 patients end up with a stable viral load 
lower than they started with, before any treatment?

Dr. Smith: We have data on their viral loads before they 
started on HAART [from their medical records, since these 
patients started antiretroviral treatment before the IL-2 
study began], and the level was lower after the treatment 
than before they started. The mean viral load before HAART 
was about 70,000 copies; afterwards it is about 25,000. This 
change was statistically significant. However, I think that 
we now need to do a prospective trial to answer the question 
as to whether our approach will lead to a lower viral set-
point. That was not really the aim of this initial study, but 
our data provide hope that additional stimulation of the 
immune system may ultimately control viral replication 
altogether, just as it does in the herpes virus family.

ATN: How long have these 9 patients been off antiretrovirals?

Dr. Smith: Each patient consulted with his or her physician 
to decide whether to restart HAART treatment. So far 5 have 
done so. The other 4 are still off HAART, but receiving IL-2. 
So far the maximum time off HAART is 9 months.

ATN: What was the biggest surprise of this study?

Dr. Smith: We expected the HIV viral load to rise when 
antiretrovirals were discontinued, but we did not expect to 
then see it fall more than 10 fold without any antiretroviral 
therapy. Everyone though the viral load would go up and then 
reach a plateau [a steady level]. But from the literature on 
animal studies, we should not have been surprised, we should 
have anticipated this fall.

We expected the rise and plateau based on anecdotal reports 
in the past few years, of people stopping their HAART and the 
virus coming back again. But those patients were not followed 
as frequently and as carefully as our volunteers. People may 
have missed the viral load peak altogether. We did viral 
loads twice a week, and CD4 and CD8 counts once a week. If we 
had not done those twice weekly viral loads, we would have 
missed the peaks in some of the individuals--it could go up 
and down so fast that we could have missed it if we had only 
measured viral loads weekly. So it could look like patients 
plateaued, just because the researchers missed the peak.

ATN: Did the virus return more slowly with your volunteers 
than reported by others?

Dr. Smith: A report from Barcelona earlier this summer on ten 
patients treated for two years with HAART, without IL-2, 
noted that all ten had viral load return within two or three 
days after antiretrovirals were discontinued. And Tony Fauci 
and Rick Davey from his lab reported on 18 patients at the 
recent ICAAC meeting that had received HAART and had 
extremely low levels of virus, but in 17 of the 18 the viral 
load came back in about 10 days when treatment was 
discontinued, vs. our average time of 19 days.

Seventeen of these 18 went up to a high level and then 
plateaued. They did have one patient that looked like all 9 
of ours--where the viral load went up and then came back down 
again.

ATN: I remember the joking reference at ICAAC to "the 
Bethesda patient" [from the well-known "Berlin patient" who 
discontinued antiretroviral therapy and was able keep the 
virus under control].

Are the big IL-2 trials coming up--one funded by NIAID and 
the other by Chiron Corporation--set up to address the 
information you have learned?

Dr. Smith: They are not. They have been working with a 
different hypothesis than we have, with a very different 
dosing regimen; it's like trying to compare apples and 
oranges.

ATN: My understanding is that the big NIAID trial is to see 
if those increases in T cells provide clinical benefit [in 
patients starting with a CD4 count of at least 300]--and the 
Chiron trial will study somewhat more advanced patients [CD4 
T-cell counts between 50 and 300, but viral load under 10,000 
copies]?

Dr. Smith: Yes, and the Chiron study is using a somewhat 
lower dose, about 10 million units a day instead of 15 
million. All these people will get toxicity--which is the 
reason you can only give the treatment for five days, 
particularly with individuals who are trying to work and 
carry on a normal life.

The purpose of their experiments is to try to accelerate the 
repair of the immune system with IL-2. I believe IL-2 will do 
that, but that you don't have to subject people to the 
toxicity. You can lower the dose almost 10 fold and give it 
every day, instead of giving higher doses every two months.

Each of those studies could include a low-dose IL-2 arm, if 
they want to. Then there would be a comparison of the immune 
recovery, but without the toxicity.

ATN: Are there data on whether or not any CD8 count increase 
on the intermittent schedule will be lost in the seven weeks 
off IL-2?

Dr. Smith: The high dose, intermittent regimen causes first a 
decrease in all circulating lymphocyte subsets, including CD4 
and CD8 T cells, NK cells, B cells, and monocytes, during the 
5 day treatment interval. Later, there is a rebound when the 
IL-2 therapy is stopped, and all of the cells increase to 
about 10-fold the pre-therapy levels. Subsequently, over the 
next 7 weeks, there is a gradual decline of all of these 
cells to pre-therapy levels. So it is not clear whether there 
is simply a redistribution of cells from the circulation to 
the tissues during the treatment interval, then back again 
into the circulation after the treatment is stopped.

ATN: What was the role of your laboratory in the discovery of 
IL-2?

Dr. Smith: My laboratory discovered the IL-2 molecule, in the 
late 1970s--this was one of three phases of the discovery of 
IL-2.

First, the activity of IL-2 as a T cell growth promoter was 
discovered in 1976 by Doris Morgan working with Frank 
Ruscetti in Robert Gallo's lab at the U.S. National Cancer 
Institute. They found that something released from growing 
lymphocytes would make other lymphocytes grow--but they did 
not know what was responsible for the activity. This group 
did not follow up on their findings because they were 
interested in leukemia and retroviruses. 

Later, we picked up this work and purified and characterized 
the active molecule, IL-2, in a series of experiments in the 
late '70s and early '80s.

Still later, Tadatsugu Taniguchi and others in Japan cloned 
the gene for IL-2, making it possible to use genetic 
engineering to manufacture it in large enough quantities that 
it could be used in treating patients.

ATN: And your new research isn't the end of the story, but a 
step along the road?

Dr. Smith: Exactly, it is just a beginning. However, I think 
that we now have seen a light to illuminate our way.

For More Information

A literature review of IL-2 therapy for restoration of 
immunity, by Dr. Smith and others, is scheduled for 
publication in THE AIDS READER, November 1999(2). A detailed 
technical background paper on IL-2 will soon be available 
online(3); also see clinical papers on the use of the low 
dose in therapy(4,5).

References

1. Jacobson EL, Emert R, Giordano M, Kovacs E, Mumneh N, Sohn 
T, Warren D, and Smith KA. Restoration of immunity after HIV 
infection. 39th Annual Interscience Conference on 
Antimicrobial Agents and Chemotherapy, San Francisco, 
September 1999 [abstract #1828].

2. Smith KA, Jacobson EL, Emert R and others. Restoration of 
Immunity with Interleukin-2 Therapy. THE AIDS READER (in 
press).

3. Smith, Kendall A. Interleukin 2 (IL-2). Cytokine Database 
(in press).

4. Jacobson, EL, Pilaro, F, & Smith, KA, Rational interleukin 
therapy for HIV positive individuals: Daily low doses enhance 
immune function without toxicity. PROCEEDINGS OF THE NATIONAL 
ACADEMY OF SCIENCES (USA). 1996; volume 93, pages 10405-
10410.

5. Smith, KA, Rational interleukin 2 therapy. CANCER JOURNAL. 
1997; volume 3, pages S137-S140.

***** Retroviruses Conference: Community Press Registration 
Deadline November 12

The annual Retroviruses conference--the most important AIDS 
medical science conference in the U.S.--always fills up early 
and turns many people away. "Community press" (meaning AIDS 
newsletters and similar publications) is one of the few ways 
for those who are not researchers or physicians to attend 
(there may be a limited number of scholarships, which also 
get people in the door). You cannot attend this conference 
just by paying a fee, no matter how early you register.

The next Retroviruses conference begins January 30, 2000, in 
San Francisco, but community press must register by November 
12 at the latest (this registration is first come first 
served, and may close early). If you want to go, it is 
important to register now.

The following email was sent to previous community press 
registrants on September 20:

"The 7th Conference on Retroviruses and Opportunistic 
Infections will be held January 30-February 2, 2000 at the 
San Francisco Marriott. The deadline for community press 
registration is November 12th (there will be no on-site 
registration).

"To be accredited, journalists should submit:

"1) A letter from their editor (or a copy of the 
publication's masthead with reporter's name listed)

"2) a sample of one recent bylined article, preferably from 
the last Retrovirus Conference

"3) letter of assignment (for freelance writers only)

"These materials should be submitted to the Office of the 
Retrovirus Conference Secretariat (115 S. Saint Asaph St., 
Alexandria, VA 22314; phone: 703-535-6862; fax: 703-535-
6899).

"All applications will be handled on a first-come, first-
served basis.

"Within two weeks of receipt of press application and after 
press credentials have been approved , a confirmation letter 
and housing information will be sent.

"Special blocks of hotel rooms have been reserved for media 
at the hotels in the official block. Press confirmation 
letters will be accompanied by a press housing form. Members 
of the media will not be able to register or obtain housing 
until accredited. Housing opens for accredited journalists on 
November 30th.

"For further information, please visit our website at 
www.retroconference.org. Thank you."

***** Women and HIV/AIDS Conference: Tape, Web Reports 
Available

The 1999 National Conference on Women and HIV/AIDS took place 
October 9-12 in Los Angeles. A recording of a one-hour panel 
discussion just after the conference, with three HIV 
physicians and one treatment advocate, is available by 
calling toll-free 888-207-2647, code 1146. This overview 
includes many practical questions and answers.

Additional information is on the Web at:
http://www.hivandhepatitis.com
under Internet Conference Reports. Or see
http://www.womenandhiv99.com
which is the official site for this conference.

***** FDA Advisory Meetings: Adefovir, Nov. 1; Resistance 
Testing Nov. 2-3

Two meetings of the FDA Antiviral Drugs Advisory Committee 
will take place in early November, in Gaithersburg, Maryland, 
near Washington DC. (Public transportation is available; take 
the Metro to the Shady Grove stop--the end of the Red Line--
and call the hotel or take a taxi to the Gaithersburg Holiday 
Inn.) These meetings are open to the public, with one hour of 
each meeting scheduled for public testimony.

FDA advisory committee meetings are usually the place where 
it is possible to learn the most about new drugs or tests. 
The adefovir meeting will probably determine whether Gilead 
Sciences' drug adefovir dipivoxil will be approved (the FDA 
is not required to follow an advisory committee 
recommendation, but almost always does). Community sentiment 
has been mixed on this drug, due to the difficult balance of 
risks and benefits; we are seeing some support for approval 
but with a narrow indication.

Note that the other meeting, on genotypic and phenotypic 
resistance testing, will focus on their use in antiretroviral 
drug development, but will also look at evidence supporting 
clinical use.

Here is an October 12 FDA announcement of these meetings:

"November 1999 Meetings ANTIVIRAL DRUGS ADVISORY COMMITTEE

"On November 1, 1999, from 8:30 a.m. to 5 p.m. the committee 
will discuss new drug application (NDA) 20-993, adefovir 
dipivoxil (Gilead Sciences Incorporated), for the treatment 
of HIV (human immunodeficiency virus) infection. The meeting 
will be held in The Ballrooms at the Gaithersburg Holiday 
Inn, 2 Montgomery Village Avenue, Gaithersburg, Maryland. If 
you need accommodations or directions to the hotel, the 
Holiday Inn can be reached directly at 301-948-8900. The open 
public hearing portion of the meeting will be scheduled 
between approximately 1 p.m. and 2 p.m. Interested persons 
may present data, information or views, orally or in writing, 
pertinent to the issues under discussion by the committee 
(see below for more information on presentations).

"On November 2 and 3, 1999, from 8:30 a.m. to 5 p.m., the 
meeting will be dedicated to presentations and committee 
discussions to address issues related to testing for 
development of resistant Human Immunodeficiency Virus (HIV-
1), with an emphasis on its potential role in antiretroviral 
drug development. The primary objectives of these 
deliberations are to obtain advisory committee 
recommendations on the amount and type of resistance data 
needed to support both preclinical and clinical development 
of antiretroviral drugs and antiretroviral product labeling. 
This two-day meeting will explore the following scientific 
issues: performance characteristics of genotypic and 
phenotypic assays; definitions of antiviral drug resistance; 
relationships between the development of mutations or reduced 
susceptibility and treatment outcome; and available evidence 
supporting the clinical utility of testing for the 
development of antiviral drug resistance. The open public 
hearing is scheduled for November 3, 1999, from 1 - 2:00 p.m. 
Those wishing to make a formal presentation during the open 
public hearing at either of these meetings should notify 
Rhonda Stover or John Schupp, Center for Drug Evaluation and 
Research, HFD-21, Food and Drug Administration, 5600 Fishers 
Lane, Rockville, Maryland 20857, 301-827-7001. Please submit 
a brief statement of the general nature of the evidence or 
arguments to be presented, along with the names and 
affiliation of proposed speakers, and an indication of the 
approximate time requested for the presentation. Time 
allotted for each presentation may be limited depending on 
the number of requests received. 

"For up-to-date information about these meetings, or other 
meetings of the Antiviral Drugs Advisory Committee, please 
call the FDA Advisory Committee Information Line at 1-800-
741-8138 (301-443-0572 in the Washington, D.C. area) and 
enter code no. 12531."

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