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NIDA Meeting Calls For Research Into
The Poppers-Kaposi's Sarcoma Connection
By John Lauritsen
New York Native 13 June 1994
Gaithersburg, Maryland, 24 May 1994.
The National Institute on Drug Abuse (NIDA) sponsored a high-level
meeting, "Technical Review: Nitrite Inhalants", held outside
Washington, DC on the 23rd and 24th of May,
1994. The toxicologists, AIDS researchers, and others present reached
a consensus urging research into the connection between the nitrite
inhalants (or "poppers") and Kaposi's sarcoma (KS). The
meeting was organized by Harry Haverkos of NIDA, who has been writing
since 1985 about the health hazards of the nitrite inhalants.(1)
Robert Gallo, as unofficial voice of the AIDS Establishment, disclosed
important revisions in the AIDS-paradigm. It is now necessary to
consider co-factors. No longer is HIV believed to cause KS by itself;
at most it may aggravate KS after it has been caused by something
else. No longer is HIV believed to kill T-cells; whatever damage
it allegedly does, it does indirectly. Speaking informally, Gallo
discussed the latest thinking on the nature and causes of KS.
The meeting had implications that went beyond the issue of the
nitrites, important as that may be. It indicated a willingness,
on the part of the Public Health Service, to re-think the basic
premises of the AIDS model that has prevailed since 1984. It is
high time, for the HIV-AIDS hypothesis has been a total failure,
both in terms of public health benefits and in terms of making accurate
predictions.
Molecular biologist Peter Duesberg, the foremost critic of the
HIV-AIDS hypothesis, attended the meeting as an invited observer.
He has designed experiments, and is waiting for funding, to examine
the effects of long-term nitrites exposure in animals. From attacks
on Duesberg in the popular and quasi-scientific press, one might
have expected him to be treated as a pariah. This was not at all
the case: the other scientists were friendly, and listened to him
with respect when he discussed points of retrovirology, on which
he is one of the world's leading experts. A reconciliation took
place between Robert Gallo and Peter Duesberg; the two are on friendly
terms again, for the first time since 1987, when the first interview
with Duesberg appeared in the New York Native.(2)
For the rest of this article, I'll give some background information
on poppers, followed by a chronological account of the NIDA meeting
and my own conclusions.
Background: Poppers and their toxicities
As a prescription drug, amyl nitrite was used by elderly people
for emergency relief of attacks of angina pectoris (heart
pain). Historically, the use of the nitrite inhalants (amyl nitrite,
butyl nitrite, isobutyl nitrite, etc.) for recreational purposes
has been limited almost entirely to gay men. The first reports of
recreational use date from the early 1960s, after the amyl nitrite
prescription requirement was eliminated by the FDA. The drug appeared
to intensify and prolong the sensation of orgasm. It facilitated
anal intercourse, by relaxing the smooth sphincter muscles and deadening
the sense of pain.(3)
The FDA re-instated the prescription requirement in 1969. In 1970
a new industry stepped into the breach, marketing little bottles
containing mixtures of butyl and isobutyl nitrite. By 1974 the poppers
craze was in full swing. Ads for them appeared in all gay publications.
At gay discotheques men could be seen, shuffling around in a daze,
holding poppers bottles under their nose. The miasma of nitrite
fumes was taken for granted at gay gathering places: bars, baths,
leather clubs. Some gay men were never without their little bottle,
from which they snorted fumes around the clock. Two separate studies
in the 70s found gay men who were no longer able to perform sexually
without the use of poppers.(4)
The toxicities of the volatile nitrites were well known before
the advent of AIDS. In 1980 Thomas Haley, one of America's leading
toxicologists, published a two-page summary of nitrite toxicities,
with 115 references listed. Here are a few of the highlights:
The toxic effects of amyl nitrite inhalation include rapid flushing
of the face, pulsation in the head, cyanosis, confusion, vertigo,
motor unrest, weakness, yellow vision, hypotension, soft thready
pulse, and fainting. Accidental prolonged inhalation of amyl nitrite
has resulted in death from respiratory failure.... Fatalities have
occurred in workers exposed to organic nitrates after strenuous
exercise 1 to 2 days after cessation of exposure. Nitrite causes
a loss of tone of the vascular bed and pooling and trapping of blood
in the veins of the lower extremities, resulting in marked arteriolar
constriction and the induction of anoxemia in vital tissues, causing
death.... The formation of methemoglobin by aliphatic nitrite interferes
with oxyhemoglobin, causing anoxia of vital organs.... The use of
volatile nitrites to enhance sexual performance and pleasure can
result in syncope and death by cardiovascular collapse.(5)
Also in 1980 appeared the first of several studies to demonstrate
that the volatile nitrites are powerfully mutagenic.(6) (That is,
they cause cells to mutate, they cause damage to the chromosomes.)
This is cause for concern, as almost all known carcinogens are also
mutagens.
Subsequent studies, both in vitro and in vivo, have
shown that poppers damage the immune system. They cause two kinds
of anemia: Heinz body hemolytic anemia and methemoglobinemia. They
damage the lungs. They have the potential to cause cancer by producing
deadly N-nitroso compounds in interaction with many common drugs
and chemicals, including antihistamines, artificial sweeteners,
and pain killers.(7)
When the first cases of AIDS were identified in 1981, or the predecessor
cases of GRID (Gay Related Immune Deficiency), poppers were high
on the list of etiological suspects. Here, after all, was a drug
used heavily and almost exclusively by the group of people getting
sick. Nevertheless, despite compelling epidemiological and toxicological
evidence, the Centers for Disease Control (CDC) hastened to exonerate
poppers. They did so for two reasons, both of which were spurious.
First, the CDC found AIDS patients who had never used poppers;
therefore, argued the CDC, poppers could not be the cause. The CDC's
assumption was that "AIDS" constituted a single, coherent
disease entity with a single cause. Second, the CDC conducted
a brief mice study in 1982-1983, and claimed to find "no evidence
of immunotoxicity". These results are contradicted by several
other studies, which did find that the inhalation of nitrite
fumes causes immune suppression in mice. The reasons for the negative
findings of the CDC mice study were explained at the Gaithersburg
meeting by one of the investigators, Daniel Lewis, about which more
below.
The Epidemiology of Nitrite Use
After a welcome by Richard A. Millstein, Deputy Director of NIDA,
Harry Haverkos opened the meeting on Monday, May 23 with a brief
overview of the volatile nitrites, their use and regulation. He
then turned the session over to Zili Sloboda of NIDA, who moderated
the morning session devoted to epidemiology. She stressed the "importance
of prevention messages".
Andrea Kopstein of NIDA discussed the ambiguities involved in such
phrases as "inhalant abuse". The inhalants are diverse
substances that happen to be defined by the route of intake. The
lack of clarity as to what constitutes an "inhalant" causes
confusion in responses to questions in surveys. She presented studies
of lifetime use of nitrites among sex and ethnic groups, which showed
that use of amyl and butyl nitrite among U.S. males decreased after
1986, though inhalant use remained just as high.
Lisa Jacobson, of the Johns Hopkins School of Hygiene and Public
Health, presented data from the much used and abused MACS study,
a cohort of gay male volunteers. Those men who were "sero-prevalent"
(that is, HIV-antibody-positive on entry into the study) had much
higher poppers use. Among all groups in the study, the use of poppers
declined.
Kenneth Mayer, a physician living in the Boston area, was among
the first to sound the warning about poppers to gay men.(8) He discussed
surveys, which found that the use of poppers is a risk factor for
becoming HIV-antibody-positive. But what does that mean? He mentioned
two possibilities: being HIV-antibody-positive might be a marker
for other health risks, or it might be a marker for illness. He
posed the basic question: which is more hazardous, unsafe sex or
drug use?
The highlight of the morning session was "Advertising Trends",
presented by Hank Wilson, a San Francisco activist who in 1981 founded
the Committee to Monitor Poppers.(9) He began by saying that, with
regard to poppers, gay men had been uninformed, misinformed, partially
informed, and confused. He then showed stunning color slides of
several dozen poppers ads, from the early 70s through the late 80s.
This must rank among the most brilliant advertising campaigns in
history. Within only a few years hundreds of thousands of men were
persuaded that poppers were an integral part of their own "gay
identity". The ads conveyed the message that nothing could
be butcher or sexier than to inhale noxious chemical fumes. Bulging
muscles were linked to a drug that is indisputably hazardous to
the health.
Beginning in the early 70s ads for poppers appeared in all of the
gay press-ads for special inhalers-an ad for a brand named "Discorama",
specifically targeted at disco dancers. One ad gave an 800 number,
with the message, "We'll pay you to try..." (The free
trial tactic has also been used on the street by dealers of heroin,
crack, and other such commodities). An ad for the poppers brand
RUSH focussed on the phrase, "Better Living Through Chemistry"-and
no irony was intended.
However, warnings about the dangers of poppers began to appear
in both the gay and the mainstream press, and for the decade of
the 80s, these messages competed with disinformation from the poppers
industry and their allies. Wilson showed the front page of a December
1981 issue of the New York Native, with a banner headline,
"Do poppers cause cancer?". This message got across even
to people who just glanced at it on the newsstand. A Pittsburgh
paper. OUT, repeated the same heading. The City of San Francisco
required than a warning notice be placed at all points of sale for
poppers. The June 4-17 1984 issue of the New York Native
carried an article, "Poppers" The Writing On The Wall".
On 19 July 1985 the Seattle Gay News published a boxed warning
on poppers. And in 1985 poppers were banned from the most popular
disco in San Francisco. The mainstream press in San Francisco also
began to carry the message that poppers were dangerous.
But the poppers industry had its own resources. A 1983 pamphlet
published by the CDC, "What gay and bisexual men should know
about AIDS", claimed that there was no relationship between
AIDS and poppers, on the basis of a single mice study (to be discussed
below). In effect, the government gave the green light on poppers
use. The CDC's mice study was cited in a press release sent out
by Joseph F. Miller, President of Great Lakes Products, the world's
largest manufacturer of poppers. Miller's press release, run by
most of the gay press, claimed that "Jim" Curran of CDC's
AIDS Branch had given him a guided tour of the CDC and assured him
there was no relationship between poppers and AIDS. When Curran
responded with a letter saying that he had been misinterpreted,
and that poppers may play a role as cofactor in some of the illnesses
in the syndrome, his letter was ignored by the gay papers who had
run the press release from Miller. Great Lakes Products followed
through with a series of ads in the Advocate, entitled "Blueprint
For Health", which gave the impression that poppers, like vitamins,
fresh air, exercise and sunshine, were an ingredient in the healthy
lifestyle.
In 1987 a San Diego gay paper began running full-page ads for poppers.
The Windy City Times in Chicago ran full-page ads, as well
as articles attacking the critics of poppers. Heartland,
a mid-west gay paper owned by Great Lakes Products, ran ads and
articles defending their product. The San Francisco Sentinel
ran an ad that warned of an impending ban on poppers ban, and urged
its readers to "STOCK UP!". In 1992, three years after
poppers had been outlawed by act of Congress, a stand at a gay street
fair in Chicago offered iced tea for $1 and poppers for $5. In 1992
the manufacturer of RUSH sent out a mail order ad to "preferred
customers".
Hank Wilson concluded his presentation by making the point:
Poppers are easy and cheap to make, they are highly profitable,
and there is a demand for them. Therefore, they will always be available.
For this reason, education is essential.
Do Nitrites Lead to Increased Risky Sexual Behavior and HIV
Transmission?
The afternoon session of 23 May began by considering the relationship
between use of poppers and becoming HIV-antibody-positive. Whether
this matters depends on whether or not HIV is the cause of "AIDS".
Since I don't believe that HIV is even pathogenic, and consider
the survey research (a.k.a. "epidemiology") performed
by academics, physicians, and members of the Public Health Service
to be far below professional standards, I took a rather dim view
of this session.
In broad strokes-the speakers indicated that those who were HIV-antibody-positive
were more likely to have more sex and to use all drugs more heavily.
Ken Mayer presented Boston data indicating a very high Odds Risk
(OR) of seroconversion for those who always used poppers when they
had passive anal intercourse. He pointed out that this was biologically
plausible, inasmuch as poppers relaxed the smooth sphincter muscle,
dilated the blood vessels, and deadened the sense of pain (thus
increasing the risk of anal trauma).
In the discussion period I put two questions to Mayer: 1) "What
is the basis for determining 'HIV infection'? The antibody tests?",
and 2) "Is there really evidence that these people had a viral
infection, and if so, was the virus sufficiently biochemically active
as to cause illness?" He replied that the ELISA and the Western
Blot antibody tests were used, and that they were sometimes followed
up by viral culture. This question is important, as an article in
Bio/Technology last year demonstrated that the antibody tests
are unvalidated and extremely unreliable-that many HIV-antibody-positive
people have never been infected by the virus itself, which in any
event is virtually never biochemically active to a degree that would
enable it to cause illness.(10)
Jay Philip Paul, an AIDS prevention specialist in San Francisco,
discussed the complexities of classifying events as "risky"
or "safe". There are many confounding effects among sexual
behavior, drug use, and other likely health risks. He emphasized
that one could never conduct a controlled study (survey) to answer
the question of causality.
Do Nitrites Suppress the Immune System?
The second afternoon session on 23 May dealt with in vivo
toxicological studies, two involving mice and one involving human
subjects.
First was Daniel Lewis of the National Institute for Occupational
Safety and Health. He was one of those who conducted the 1982-93
CDC mice study that was the basis of the MMWR news item (9
September 1983), which claimed to find "no evidence of immunotoxic
reactions". In that study the doses were extremely low, approximating
levels to be encountered as background exposure (used as "room
odorizer", workers in a poppers factory) rather than those
encountered when using poppers as a drug (i.e., inhaling directly
from the bottle).
Lewis explained that, in determining the dose, they had to adjust
it below the level where they were "losing" the mice-
however, the supplier of the mice later disclosed that the mice
were suffering from a low-grade infection. This means that the deaths
of the exposed mice may well have been due to immunotoxicity-exactly
what the study conclusions claimed not to find-rather than to the
acute toxicity of the nitrite fumes. The end result was that the
dose was far too low to be meaningful.
The study was not blinded, as the mice inhaling IBN vapors developed
a "yellowish tinge". Although there were no significant
changes in body weight, there were reduced liver and thymus weights,
and an increase in spleen weights. 100% of the exposed mice developed
methemoglobinemia. The white cell count went down sharply.
In the question period I stated that other mice studies had found
that nitrite inhalation caused immune suppression in mice. How did
Lewis explain the discrepancy between his findings and the others?
His answer was short and sweet: "Dosage and length of exposure".
The second mice study was presented by Lee Soderberg, of the University
of Arkansas. His mice inhaled 900 ppm nitrite fumes for 45 minutes
daily for 14 days, then were allowed to rest for 1-3 days. Then
tests were performed. They found that there were decreases in both
body and spleen weight, the cells in the spleen and in the blood
were reduced, the response to conA was reduced (-28%), the T-dependent
cells were very sharply reduced, accessory cell function was affected
(there was reduced ability to support proliferation of normal T-cells),
the macrophage functions were greatly reduced (especially tumoricidal
activity). The recovery of immune functions generally took about
a week; however it took longer for macrophage cytotoxicity to recover
(about 2 weeks).
Soderberg and his colleagues reached the conclusion that exposure
of mice to nitrites via inhalation impaired:
- T-dependent antibody responses
- T-mediated cytotoxicity
- macrophage tumoricidal activity
In the question period Peter Duesberg raised the issue of reversibility:
What about something that goes on for years? Analogies here would
be the length of exposure required to achieve a causal relationship
between cigarettes and lung cancer, or between alcohol and cirrhosis.
Soderberg replied that his team had "no data on more chronic
exposure".
The third speaker was William Adler of the National Institutes
of Health. His study was of 8 human volunteers, HIV-antibody-negative
males, who inhaled poppers three times per day for one week, and
then intermittently for another week and a half. Baseline immunological
test batteries were run before, during, and after exposure. The
investigators found that the main change was in natural killer (NK)
cell activity, which dropped very sharply. They reached the conclusion:
"The results showed that exposure to amyl nitrite can induce
changes in immune function even after short exposure to moderate
doses."
Do Nitrites Act as a Cofactor in Kaposi's Sarcoma?
The second day of the meeting, 24 May 1994, addressed the key question:
Do poppers play a role in causing KS? The first speaker was Harry
Haverkos, who began by showing a slide indicating that there appear
to be four kinds of KS:
1. Classic KS, occurring among older men, indolent.
2. African KS: 25-40 age group, first indolent then fatal in 5-8
years.
3. Iatrogenic KS (e.g., renal transplant): indolent or fulminant.
4. Epidemic or AIDS KS: gay white males, fulminant, survival 1-3
years.
And he posed the question: "Are these all the same?"
Haverkos cited the cases of HIV-negative cases of gay men with
KS (16 in the practice of one physician alone). He reviewed the
epidemiological data, which were inconsistent. Four studies found
a strong and dose-related relationship between the use of nitrites
and the development of KS-however, other studies did not.
He cited a recent study which found that the volatile nitrites
are even more powerfully mutagenic than had previously been thought.
Iso-butyl nitrite vapors were 11 times as mutagenic as iso-butyl
nitrite in solution.(11)
Haverkos presented a slide: REASONS TO CONSIDER NITRITE INHALANTS
A COFACTOR IN THE PATHOGENESIS OF KAPOSI'S SARCOMA (KS) IN AIDS:
- Four epidemiologic studies have demonstrated a strong association.
- Decline in proportion of cases among gay men parallels decline
in nitrite inhalant abuse among gay men.
- Distribution of KS lesions correlates with areas of nitrite vapor
exposure (nose, face, chest) in many cases.
- Plausible mechanisms of action have been proposed:
- Formation of cholesterol nitrite (carcinogen)
- Immune suppression.
- Only hypothesis promoted that fits *all* 4 aspects of national
surveillance data.
He followed this with another slide: WHY AIDS-RELATED KAPOSI'S SARCOMA
(KS) IS NOT EXPLAINED BY A SEXUALLY TRANSMITTED AGENT:
- Very little KS reported outside gay male population.
- Among gay men, KS is associated with white race and high socioeconomic
status.
- KS in women with AIDS no more likely among sexual partners of
bisexual men that sexual partners of heterosexual drug abusers.
- No one can find the infectious agent.
In conclusion Haverkos presented a series of recommendations:
- All clinicians/researchers should take a drug history, including
inhalants, from patients with Kaposi's sarcoma.
- A multisite study of KS cofactors is needed (similar to what
was done for Reye's syndrome).
- Women and heterosexual men with KS should be thoroughly evaluated
to identify potential cofactors.
- Animal models should be explored.
- A comparative analysis of nitrite use and KS rates should be
conducted whenever such data are available, e.g., MACS sites.
The next speaker was Harold Jaffe of the CDC, who said that he would
take a "con position" for the purpose of the meeting,
even though he was open to the possibility that the nitrites might
play some role in causing or aggravating KS. He argued that the
KS co-factor is likely to be a transmissible agent, since one study
had found an association between KS and rimming. The risk for KS
is highest among those who lead a particular kind of sexual lifestyle,
characterized not only by nitrites use, but also by multiple, anonymous
sexual partners.
In the question period I made the point that the nitrites obviously
could not be the sole cause of one or all of the forms of KS. The
question is whether they play a causal role in some or most of the
cases of epidemic (AIDS) KS. Their biochemical properties are consistent
with such a role. In contrast, nothing can be said about a microbe
which has yet to be discovered.
Following Jaffe's presentation, Haroutune Armenian of the Johns
Hopkins School of Hygiene and Public Health presented a re-analysis
of data from the MACS study. He found a stronger association between
rimming and KS than between poppers and KS. The use of marijuana
and hashish were found to be high risk factors for KS. Not only
did he not find a dose-related correlation between poppers use and
KS, he they found exactly the opposite: a strong, statistically
significant negative correlation. In other words, the more poppers
you use, the less likely you are to develop KS. Obviously this violates
common sense, and contradicts other studies, which found a strong
positive correlation. The most likely explanation is that
Armenian's data are wrong. It should be noted that Armenian merely
re-analyzed data that had been collected by others, in a study designed
by others.
Robert Gallo Revises the Paradigm
The final speaker on the question of whether poppers play a role
in causing KS was Robert Gallo of the National Cancer Institute,
who is still regarded by many as America's foremost AIDS expert.
He began by saying that he wanted to open up basic questions, and
had no fixed opinion regarding co-factors for KS- whether chemical,
viral, or a combination. Though not in agreement with all that Harry
Haverkos had said, for example the donor recipient or localization
arguments, he was willing to be persuaded.
To my knowledge, this was the first time for Gallo or any other
top "AIDS expert" to admit publicly that HIV was not the
primary cause of KS. He said: "We believe that HIV in KS is
an enormous catalytic factor, but there must be something else involved."
He continued:
Do you believe that all Kaposi's is one and the same disease? I
don't. Why should we say they are, any more than all leukemias are
the same? Leukemias don't all have the same pathogenesis. Even T-cell
leukemias don't all have the same pathogenesis. So why should we
say a benign disease of old men in East Europe of Mediterranean
or Jewish stock have the same disease as a sudden disease in younger
people that is far more aggressive? And do we believe that the iatrogenic
renal transplant Kaposi's associated with therapies and immune suppression
is the same disease? I'd at least leave open the possibility that
these are quite distinct, even pathogenetically. I know there's
a great desire to link the African with the modern or epidemic form
of KS, and I can understand that, because they're both aggressive.
But they may not be. Therefore, what one tells you may not be good
for the other.... And when you go to the iatrogenic renal transplant
KS, you have to argue that it's a ubiquitous transmitted agent,
because all of the people that have it in their kidneys weren't
involved in rimming.
Gallo then went on to revise the most basic premise of the AIDS
construct: the assumption that an underlying condition of "immune
deficiency" is responsible for causing, indirectly, the various
AIDS-indicator diseases. He said:
There's a common belief that it's immune suppression that is involved.
Our data would argue the opposite-that it's immune stimulation.
You can have Kaposi's in the absence of immune suppression. I don't
think there's any evidence that in the older classic Kaposi's sarcoma-among
older men-that there's immune suppression. There's not good evidence
that there's immune suppression in the African form. And when you
speak of the immune suppression of the iatrogenic Kaposi's, you
have to keep in mind that there's also immune stimulation.
And he posed a few additional questions:
Ask yourselves, who here has evidence that Kaposi's is a true malignancy?
Is it only polyclonal hyperplasia that can harm and even kill? Or
does it really evolve into a true cancer? And if so, how often?
There's an enormous increase of Kaposi's in HIV-infected gay men.
What's the role of HIV?
Gallo then proceeded to present a summary of findings from his
laboratory regarding KS:
The first thing I can tell you is that we've been able to regularly
culture from Kaposi's tumors what pathologists say is a tumor cell.
We asked: What is the role of HIV in all this? And we found that
inflammatory cytokines ... were the very likely initiatory events
in creating this cell. We said, "Oh, the role of HIV is likely
to be in increasing these inflammatory cytokines." But we have
learned-this should be of interest to everybody that isn't completely
married to HIV-that the inflammatory cytokines are reportedly increased
in gay men even without HIV infection. Inflammatory cytokines are
usually promoted by immune activation, not by immune suppression.
So here was a paradox.... So the inflammatory cytokines may be increased
by HIV, but I wish I knew what else was increasing them before a
gay man was ever infected with HIV. Maybe it's nitric oxide, maybe
it's a sexually transmitted virus, maybe it's all of them, maybe
it has to do with rimming because it's immune stimulation with non-specific
infections.... I don't want to out-Duesberg Duesberg, but those
are what our observations on pathogenesis are.
Now what I can tell you new-and it hasn't been published-is that
we have finally demonstrated that at least sometimes Kaposi's can
become a true malignancy. That is, from a late-stage patient, we
have immortalized tetraploid cell lines with marker chromosomes,
a truly malignant cell that metastasizes within a nude mouse, killing
the animal rapidly.... Now comes the difficult question: That cell
looks just like the other cells I've been talking about, except
it's malignant. It looks like it's derived from them. It is there
all the time, but I can't tell, because it's not morphologically
distinguishable, as the tumor cell is in Hodgkins disease. Remember,
Hodgkins disease is a hodgepodge, like Kaposi's. The tumor cell
is a rare cell, but you can see it, because it's got a distinct
morphology. This doesn't. Maybe it's there all the time, and Kaposi's
a malignancy from the beginning. I don't know. The alternative is
that Kaposi's is a benign hyperplasia that gets worse in time, and
that in some people will evolve into a clonal malignancy.
I don't want to get into the semantics. I believe that HIV obviously
plays a role in this disease. I think the epidemiology is not debatable.
But I think that there is more going on. I don't know what that
"more going on" is. For me it's whatever is accounting
for the increase in inflammatory cytokines.
I don't know if I made this point clear, but I think that everybody
here knows-we never found HIV DNA in the tumor cells of KS. So this
is not directly transforming. And in fact we've never found HIV
DNA in T-cells, although we've only looked at a few. So in other
words we've never seen the role of HIV as a transforming virus in
any way. The role of HIV has to be indirect.
During the question period Harry Haverkos responded to Gallo's
earlier criticisms. When looking at national data, we do see a decline
of KS among US gay men. On the localization phenomenon: the product,
nitrites, is in the lungs and the blood vessels; it is where the
lesions occur, whereas HIV is not there. We do not see the expected
donor-recipient connection-there is not a single reported case of
KS among blood recipients where the donor had KS.
Gallo then admitted: "The nitrites could be the primary
factor. What if the nitrites had the ability, interacting with endothelial
cells, to produce to produce a tremendous amount of 'X', of inflammatory
cytokines?"
Peter Duesberg raised the point that HIV couldn't always play a
role in KS, to which Gallo replied:
No, Peter, the other forms could be the classical KS that always
existed. That's the point. You see, you want to make them all the
same. Let's realize that those may be the classical KS that always
existed. KS always existed, probably through all of human evolution.
It was described in the 1800s. But HIV makes something that was
rare become something like this. That happens in a lot of human
diseases. We don't know what causes classical KS at all, or African
KS. They may be the same disease; they may be different. I think
they're different. But even if we have no knowledge of what the
etiologic agents are, when I study pathogenesis of HIV-KS, I come
to the importance of inflammatory cytokines, endothelial cells,
and the TAT protein. I used to think all the time, HIV is also producing
the increase in inflammatory cytokines, but it's only in the past
few months that I've learned that in gay men, there's an increase
in these same inflammatory cytokines before HIV infection. Why?
I don't know.
Someone then asked, "What are the inflammatory cytokines?"
Gallo replied: "The inflammatory cytokines are IL1 [interleukin
1], TNF [tumor necrosis factor], and gamma interferon. In gay men,
the inflammatory cytokines are increased before HIV infection."
In response to a question about AIDS-related dementia he replied:
"The mechanism of dementia in HIV-infected people is totally
unknown."
Glen Hopkins, an activist from Los Angeles, raised the question
of high dose, long-term exposure. Poppers, after all, do promote
mutagenesis. To this Gallo replied: "That's the most important
thing, mutagenesis. Also perhaps nitric oxide."
General Discussion
The final, general discussion, was moderated by Paul Stolley of
the University of Maryland School of Medicine. Robert Gallo started
to leave, got to the door, hesitated, then came back and sat next
to Peter Duesberg. Within a few minutes he had his arm around him,
and stayed there for the duration of the final session.
When discussion focussed on what research ought to be done, Gallo
spoke strongly in favor of an animal model, and said that Duesberg's
research ought to be funded.
There was general agreement that the toxicology and epidemiology
of nitrites use ought to be rigorously investigated.
My own conclusions, which I expressed inadequately at the meeting,
are as follows:
1) The nitrites-KS hypothesis has to be framed carefully. Obviously
the nitrites cannot be the cause of all cases of KS, or even of
all cases of "epidemic" or "AIDS KS", as not
all such
cases have used them. The hypothesis would have to be something
like this: The volatile nitrites play a role, as either primary
cause or co-factor, in the etiology of "epidemic" or "AIDS
KS".
2) Animal research should be conducted, using high dose and long-term
exposure. Ideally, the animals should be those closest to humans,
though cost factors may rule this out.
3) New survey (or epidemiological) research should be conducted
to obtain in-depth information on drug usage and other health risks
of those who have been diagnosed as having "AIDS". The
research should be up to professional survey research standards
in terms of study design, sampling, questionnaire design, analysis,
etc.
The toxicities of the nitrites are well established, and have been
since at least 1980. As Hank Wilson argued on Monday, poppers will
always be available-therefore it is important to educate gay men
and the youth of America as to the physical consequences of using
them.
Conclusion
In light of the statements made by Gallo, it is hard not to think
of the tens of thousands of gay men with KS who have died, and of
the treatments they received. If HIV is not the cause of KS, then
how appropriate were the nucleoside analogue drugs, like AZT and
ddI, whose theoretical basis is the HIV-AIDS hypothesis? Similarly,
if KS is really not a malignancy, how appropriate were chemotherapy
drugs based on the assumption that KS is a malignancy? Did
these men die from KS, or from the treatments they were given?
It may be hoped that this meeting is a signal of greater willingness
on the part of the AIDS Establishment to re-consider the basic AIDS
paradigm. Kaposi's sarcoma as an AIDS phenomenon remains a puzzle,
and no hypothesis so far put forward seems fully adequate to explain
it. It could be that KS comprises diverse conditions with diverse
causes. Having said that, however, the nitrites-KS hypothesis is
very much alive, more than a decade after its precipitous rejection
by the CDC. *
References
1. Harry Haverkos et al., "Disease manifestation
among homosexual men with acquired immunodeficiency syndrome: A
possible role of nitrites in Kaposi's sarcoma, *Sexually Transmitted
Diseases*, October-December 1985. Harry Haverkos and John Dougherty,
editors; *Health Hazards of Nitrite Inhalants*, NIDA Research Monograph
83, 1988.
2. John Lauritsen, "Saying No To HIV: An Interview
With Prof. Peter Duesberg, Who Says, 'I Would Not Worry About Being
Antibody Positive'", *New York Native*, Issue 220, 6 July 1987.
3. For an excellent overview of poppers and their
toxicities, read "Nitrite Inhalants: Historical Perspective",
by Guy R. Newell et al., in NIDA Monograph 83 (cited above). See
also Chapter X: "Poppers: The End of an Era" in John Lauritsen,
*The AIDS War*, New York 1993.
4. Ronald W. Wood, "The Acute Toxicity of Nitrite
Inhalants", in NIDA Research Monograph 83 (cited above).
5. Thomas H. Haley, "Review of the Physiological
Effects of Amyl, Butyl, and Isobutyl Nitrites", *Clinical Toxicology*,
pp. 317-329, 1980.
6. I. Quinto, "The Mutagenicity of Alkylnitrites
in the Salmonella Test" (translation from the Italian), *Bolletino
Societa Italiana Biologia Sperimentale*, 56:816-820, 1980.
7. These points are covered in various chapters in
NIDA Research Monograph 83 (cited above).
8. Kenneth Mayer and James D'Eramo, "Poppers:
A Storm Warning", *Christopher Street*, Issue 78.
9. I have collaborated with Hank Wilson since 1983.
In 1986 we published a little book, *Death Rush: Poppers & AIDS*,
which included an annotated bibliography. Unfortunately it is now
out-of-print.
10. Eleni Papadopulos-Eleopulos et al., "Is
a Western Blot Proof of HIV Infection?", *Bio/Technology*,
June 1993, pp. 691-707.
11. Sidney Mirvish et al., "Mutagenicity of
Iso-Butyl Nitrite Vapor in Ames Test and Some Relevant Chemical
Properties, Including the Reaction of Iso-Butyl Nitrite with Phosphate",
*Environmental and Molecular Mutagenesis*, 1993;21:247-252.
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