AIDS; WORDS FROM THE FRONT
By Tom Bethell
Spin Nov. 1994

At gay 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.

Since 1983, 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."

Haverkos's 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 used poppers.

Nitrites - 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.

No reports 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.

Hank Wilson, 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."

Analyzing the 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."

Surrounded 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.

Second, there 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.

Conant, clinical 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.

"The primary 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.

Finally, Haverkos 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."

Unfortunately 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.

In retrospect, 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.

The second 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.)

As Duesberg 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.

Despite this 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.

Butyl nitrites 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").

"The use 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."

Wilson's boyfriend, 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 of nitrites.

Wilson's group 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."

Gebbie, who 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."

When Haverkos 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."

Jaffe, who 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."

Haverkos believes 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."

About 5,000 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. *