FROM THE FRONT
By Tom Bethell
Spin Nov. 1994
clubs across the country, the air is heavy with the acrid smell
of poppers, a drug from the '70s known for its quick high. Tom Bethell
finds a lone crusader at the National Institutes of Health who thinks
poppers may solve one of the oldest mysteries of AIDS.
Once a week,
Dr. Harry Haverkos puts on the white uniform of the Public Health
Services and goes to work as the director of the AIDS office at
the National Institute on Drug Abuse (NIDA), one of the 40 departments
comprising the Maryland-based National Institutes of Health (NIH).
Haverkos, 43, is a cautious man, not given to dramatic statements,
but he is also persistent, and for over ten years he has mounted
a quiet, one-man crusade.
when, he began analyzing the early data on AIDS, he has been intrigued
by a widely abused drug called poppers and its possible role in
AIDS. He believes these nitrite-based inhalants may be the mysterious
cause of Kaposi's sarcoma (KS), the rare form of cancer, that, at
the outset of the epidemic, almost defined AIDS. "It's clear
that HIV alone can't explain Kaposi's," says Haverkos. "There
has to be something else."
career in public health began just as AIDS was discovered. In July
1981, he had joined the Centers for Disease Control (CDC) in Atlanta.
That year, young gay men in Los Angeles, San Francisco, and New
York were reportedly coming down with previously rare illnesses,
among them Pneumocystis carinii pneumonia (PCP) and KS. In the past,
KS had almost affected elderly men and was benign. The new version
was potentially fatal.
Dr. James Curran,
then head of the CDC's Venereal Disease Prevention Service and now
associated director for HIV/AIDS, set up an investigating committee
- the Kaposi's Sarcoma and Opportunistic Infections task force (KSOI)
- and immediately signed Haverkos up. From their first field interviews,
the KSOI members suspected that nitrites were involved in this strange
new syndrome, since many of the men in the initial cases had frequently
amyl, butyl, and Isopropyl - have a respectable medical pedigree.
In 1867, amyl nitrite was first used to relieve angina pains in
heart patients. A volatile liquid, it came in a mesh-covered glass
ampule that could be broken or "popped" and held to the
nose. When the fumes were inhaled, the pain subsided. Nitrates expand
arteries by permitting muscles to relax.
of KS or immune problems surfaced in those heart patients, but the
inhalant was used only rarely and during the patients' later years.
Even so, there were early warning signs about the recreational use
of nitrites in the medical literature beginning in the 1970s. Dr
Guy Everett of the Chicago Medical School noted in Medical Aspects
of Human Sexuality that amyl nitrite was "widely used by men,
who most commonly sniff an inhaler or break a 'popper' shortly before
orgasm." In 1975, the same journal explicitly described the
function; They enable "the passive partner in anal intercourse
to relax the anal musculature." Three years later, the American
Journal of Psychiatry warned that new research "raises the
issue of whether repeated use of these products could increase the
risk of developing cancer." This last point was underscored
when, on the eve of the AIDS epidemic, a researcher at the Food
and Drug Administration warned that if a certain metabolization
occurred, nitrites would produce potent carcinogens.
a gay activist in San Francisco who founded the Committee to Monitor
Poppers in 1981, is candid about why poppers are so prevalent. "If
you're having casual sex, in a park or bathroom, wherever, you don't
have as much foreplay, you're more orgasmic-orientated. Poppers
facilitate quick anal intercourse."
data from three early CDC studies, Haverkos and other researchers
found that out of 87 patients with KS, PCP, or both, all but three
admitted to using poppers. But the governments officials did not
seem interested in a toxicological cause of AIDS. Curran thought
there might be a "bad batch" of contaminated poppers out
there - the "brown acid" of nitrites. Another KSOI member,
Harold Jaffe, insisted, "If the puzzle was that simple, somebody
would have solved it by now."
by stacks of medical journals in his cramped office, Haverkos gives
four main reasons why he links KS with nitrite use. First, there
is the statistical connection: Repeated use of poppers and incidence
of KS have been confined to gay men. "About 96 percent of Kaposi's
cases occur in gay men, who make up 65 percent of all AIDS cases,"
he says. Twice as many whites as blacks use poppers - and twice
as many get KS. After warnings about nitrites spread through the
gay community in the mid-'80s, both the use of poppers and the incidence
of KS declined.
is the lack of a firm HIV connection to KS. No cases of KS have
been reported among blood-transfusion recipients where the blood
donor him-self later developed the cancer. This suggests that HIV
alone is not sufficient to cause the disease, and that whatever
does cause KS is not readily transmitted through blood. In addition,
a number of HIV-free cases of KS have been reported by two doctors,
Alvin Friedman-Kien in New York and Marcus Conant in San Francisco.
professor of dermatology at the University of California, San Francisco,
told the San Francisco Chronicle in 1993 that he had found six non-HIV
cases of KS in the Bay area, that "dozens more" have been
found elsewhere in the country, and that the evidence is "overwhelming
that [KS] is not caused by HIV." Conant rejects the nitrite
theory as well, although he admits he has made "no formal study"
on the use of the drug by his KS patients.
The third reason
Haverkos suspects a nitrite connection to KS is that the disease
is caused by an abnormal growth of blood vessels, and nitrite act
on blood vessels. Dr. Sidney Mirvish of the University of Nebraska
Medical Center has found that isobutyl nitrite vapor causes cell
mutation and that inhaled vapor is 11 times more dangerous than
nitrite in its liquid form.
action of nitrites is cell intoxication," says Dr. Peter Duesberg,
a molecular biologist at the University of California, Berkeley.
"They reach into the bone marrow and interfere with the creation
of new blood cells, including T-cells. They kill enzymes, and they
mutate DNA." Duesberg believes nitrite use alone is sufficient
to explain most of the early AIDS cases, where immune suppression
and a rare cancer were found.
says, "The KS lesions are most common in the face, nose, and
chest. If you're inhaling vapors, that is where you will have the
highest concentrations." Put those points together, he says,
and "you don't have to be a rocket scientist to see that there
is some logic to the hypothesis."
for the hypothesis, he adds, "the CDC and the NIH published
two big studies where they didn't find an association between nitrites
and KS." The most important of these was the Multicenter AIDS
Cohort Study. Between 1984 and 1985, about 5,000 gay men in various
cities participated; those who developed AIDS were compared with
HIV-positive controls who did not. However, the authors noted the
limitations of their research: "We did not attempt to quantify
[nitrite] usage... It is thus possible that we have missed or obscured
a meaningful association." As Haverkos points out, by the time
those in the study were asked if they had "used nitrites during
sex in the past two years," many gay men had become wary of
poppers through point-of-sale warnings in gay bars and porn shops.
Statistics from the San Francisco Health Department show a dramatic
drop in the use of poppers between 1982 and 1988.
it seems incredible that professional disease sleuths would find
it so hard to believe that a carcinogen, reported as a new fad among
gay men in the early 1970s, might be the cause of a cancer that
emerged in the 1980s - and emerged among the very people who had
been inhaling it. But in 1983, before HIV was identified as "the
virus that causes AIDS," the Public Health Service put out
a brochure, "What Gay and Bisexual Men Should Know About AIDS,"
specifically claiming that nitrite inhalants had been "ruled
out" as a cause of AIDS.
large study that the NIH refers to when dismissing the role of nitrites
was conducted in 1988. The researchers found that while the white
blood cell count of treated male mice went down to one third of
those in untreated controls, nitrites "had no significant detrimental
effect on the immune system of mice." Haverkos believes the
dosage was too low and the duration of the experiment too short
to approximate the condition of habitual users of poppers. (In fact,
one of the scientists involved in the study has since explained
that the dosage was kept low because at higher levels of nitrites,
they had "lost" the mice.)
like to say about drugs, "The dose is the poison." And
as with cigarettes, the dose accumulates. In 1993, Duesberg proposed
a new study using mice. He discussed the idea with Daniel Koshland,
editor of Science magazine and a fellow member of the department
of Molecular and Cell Biology at Berkeley. Although Koshland had
been critical of Duesberg in the past, he wrote a letter to NIDA
supporting his colleague's proposal.
endorsement from the editor of the nation's leading science journal,
the NIH refused to offer funding, citing Duesberg's lack of "preliminary
experiments" in the field and his failure to give full hearing
to opposing views; the NIH also complained that the longer proposed
test periods corresponded with the natural lifespan of mice. Duesberg
is resubmitting an amended proposal.
were officially banned in the U.S. In 1988, but manufacturers responded
by selling chemical variants as room odorizers marketed under such
names as "Rush" and "Locker Room." Finally,
in the 1990 Omnibus Crime Act, Congress outlawed the manufacture
and sale of all alkyl nitrites. Once again the chemistry was reconfigured,
and by 1992 nitrites were back on the market, sold as video head
cleaner, polish remover ("Just like the old days!" ad
copy in a gay magazine trumpets), carburetor cleaner ("The
good stuff"), and leather stripper ("Not an overpriced
'headache in the bottle' like those other brands").
of poppers is increasing across the board in the big cities,"
activist Hank Wilson claims. "I personally stopped going to
the sex clubs in San Francisco about 18 months ago because the air
got so bad."
who always used poppers with sex had KS, died last year of AIDS.
Institutional memory in the gay community is short, Wilson says,
and there is concern that young men who have come to the big city
in the 1990s will think of poppers as "the new toy." They
know little of the battles that were fought a decade ago, when point-of-sale
warnings were mandated in California, but have since lapsed.
Wilson is furious
that James Curran, now in a position of real power at the CDC, has
not issued a community alert. Wilson cites a number of recent studies,
including a 1994 report published in the Journal of American Medical
Association, showing incontrovertibly that poppers use is a risk
factor for unsafe sex. He also points out that a 1988 NIDA study
of 18 HIV-negative gay men showed that poppers caused immune-system
impairment. But the study was not cross-indexed and so did not show
in the AIDS indices used by doctors until quite recently. Doctors
therefore have had little reason to warn patients about the dangers
is affiliated with ACT UP?Golden Gate, and by the end of 1993, a
few members of that organization were complaining to Kristine Gebble's
AIDS office at the White House. They were particularly upset about
a letter from the Consumer Product Safety Commission in Washington,
reassuring one of the poppers manufactures that the reconfigured
chemical formula is within the law. A member of Wilson's group pointed
out to Gebble that "it is the nitrite components that is dangerous,
and on this basis we cannot permit the sales of any such product,
whether it be disguised as a room odorizer, video head cleaner,
or any other obfuscation."
has since been replaced as "AIDS czar," responded by asking
the NIH if something couldn't be done. In May this year, a "technical
review" of nitrite inhalants was organized by Haverkos in Galtherburg,
Maryland. One session was titled "Do nitrites act as a cofactor
in Kaposi's sarcoma?" and the best known invited speaker was
the National Cancer Institute's Dr. Robert Gallo, the co-discoverer
of HIV. What he said was noteworthy. Although Gallo felt HIV was
surely a "catalytic factor" in KS, he said, "There
must be something else involved."
pointed out that not a single case of KS has been reported among
blood recipients where the donor had the disease, Gallo conceded:
"The nitrites could be the primary factor."
spoke at the conference now seems more open to the nitrite theory
than he did in the early days of the epidemic. "It's at least
possible that nitrites might play a role in Kaposi's developing
in gay men. But I don't think they could be the entire explanation,
because Kaposi's does occur in other HIV-infected persons who do
not use nitrites."
the government's unofficial position today is that HIV may not be
involved in KS, but whatever is, is transmitted sexually; the unwritten
rule of public health seems to be that infectious disease always
trumps toxicology. Haverkos argues: "If somebody could find
me five white women with Kaposi's who did not use nitrites, between
the ages of 18 and 45, sexually linked to a man with Kaposi's -
just five couples - that would take me back. But we're 13 years
into this epidemic, and I have not seen such cases reported. If
this was a sexually transmitted agent, there ought to be a handful
of women like that."
new cases of AIDS-related KS are reported every year, but researchers
don't know how many of them involve nitrites. Why not? The forms
that clinicians fill out still lack questions about nitrite use.
Instead, they ask about sexual orientation, intravenous drug use,
and the other categories traditionally linked to AIDS. "I almost
had a question about nitrites put on the CDC surveillance form back
in 1984," Haverkos says, "but they had to weed it, make
it a little shorter, and that was one of the questions they took
off." Undaunted, Haverkos says he'll keep up his crusade until
the medical community starts asking the right questions. *