AIDS AND POPPERS
By Tom Bethell
AIDS; Virus or Drug Induced?
Once a week, Dr. Harry Haverkos puts on the white uniform of the Public Health Service, and goes to work at the National Institute on Drug Abuse in Rockville, Maryland. It is one of over 40 divisions comprising the National Institutes of Health. Dr. Haverkos, 43, is the director of the Office of AIDS at NIDA, and although he is a cautious man, not given to dramatic statements, he is persistent, and for over ten years he has been pursuing a line of inquiry about AIDS that has received remarkably little attention considering its potential importance.
Since 1983, when he was working at the Centers for Disease Control in Atlanta (CDC), and began analyzing the early data on AIDS, he has been intrigued by the possible role of a widely abused drug called poppers. A nitritebased inhalant, it just may be a missing key to the endless medical puzzle called AIDS. In particular, Haverkos believes that the drug 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,' he said. 'There has to be something else' (Haverkos, 1994).
Haverkos's career with the Public Health Service was launched just as AIDS was discovered. A Notre Dame graduate, he attended the Medical College of Ohio in Toledo, and did his intern residency at Akron City Hospital. Then, in July, 1981, he joined the CDC in Atlanta. Something new and strange was happening in the homosexual communities on both the East and West Coasts. Young homosexuals, apparently in good health, were coming down with previously rare diseases. One month earlier, five case of Pneumocystis carinii pneumonia had been reported by Dr. Michael Gottlieb in Los Angeles (CDC, 1981a).
'The patients did not know each other and had no known common contacts or knowledge of sexual partners who had had similar diseases', Dr. Gottlieb reported. 'The 5 did not have comparable histories of sexually transmitted disease... Two of the 5 reported having frequent homosexual contacts with various partners. All 5 reported using inhalant drugs...'.
One month later, on July 3, 1981, there was a second report in the CDC's Morbidity and Mortality Weekly Report (CDC, 1981b). By now there were 15 cases of pneumocystis, and 26 cases of Kaposi's sarcoma were added to the list. The report pointed out that KS was normally very rare, found among elderly men and usually manifesting a 'chronic clinical course'. In these new cases the 'fulminant clinical course' seemed quite different. 'The occurrence of this number of KS cases during a 30month period among young homosexual men is considered highly unusual', the report added. This time there was no mention of drug use.
On the same day, however, there was an article by Lawrence K. Altman in the New York Times (Altman, 1981). Headlined 'Rare Cancer Seen in 41 Homosexuals', this was probably the first article to appear in the national press about the condition that would later be called AIDS. The 41 cases had been found in New York and California. 'The cause of the outbreak is unknown, and there is as yet no evidence of contagion', Altman wrote. As before, none of the patients knew one another, and Dr. James Curran, at that point a 'spokesman' for the CDC, was reported as saying that 'the best evidence against contagion is that no cases have been reported to date outside the homosexual community or in women'.
Dr. Alvin FriedmanKien of New York University Medical Center, who had reported many of these cases, told Altman that among nine of the 'victims' (a word that would later be abolished from AIDS reporting), he had found 'severe defects in their immunological systems', with their T and Bcell lymphocytes evidently malfunctioning. Most of these cases involved men who had had 'multiple and frequent sexual encounters with different partners', sometimes 'as many as ten sexual encounters each night up to four times a week'. And Altman added this little detail: 'Many' of these men 'reported that they had used drugs, such as amyl nitrite...'. Six weeks later, another report in MMWR once again failed to say anything about drug use (CDC, 1981c).
At the CDC, Dr. James Curran was put in charge of setting up a task force to investigate this new medical phenomenon, which early on was named GRID (Gayrelated Immune Deficiency). On his second day on the job, Harry Haverkos was signed up it may have helped that he and Curran had both gone to Notre Dame. The newly formed group was called the Kaposi's Sarcoma and Opportunistic Infections Task Force, and it included a dozen or so members. One of the first points to emerge was that virtually all the men in the initial cluster of cases they investigated had been frequent users of the nitrite inhalants called 'poppers'.
Nitrites have a respectable medical pedigree. In 1867, amyl nitrite was used to relieve angina pains in heart patients (Brunton, 1867). A volatile liquid, it came in a meshcovered glass ampule which could be broken, or 'popped', and held to the nose. When the fumes were inhaled, the pain subsided. Nitrites expand arteries, and they do so by permitting muscles to relax (Nickerson, 1975). No reports of KS or immune problems surfaced in those heart patients, but then the inhalant was used only rarely, and during the patients' later years. There are amyl, butyl, alkyl and isopropryl nitrites, but it is always the nitrite part that is important.
Earlywarning signs about the recreational use of nitrites began to appear in the medical literature in the 1970s. Dr. Guy Everett of the Chicago Medical School noted in 1972 that amyl nitrite 'is widely used by men, who most commonly sniff an inhaler or break a 'popper' shortly before orgasm'. The purpose seemed to be 'a sense of prolonged orgasm and increased sense of excitement', he wrote. Some said that poppers gave them a headache or aching eyes, however, and 'these are certainly warning signs of possible serious side effects' (Everett, 1972). Dr. David Smith, the founder and medical director of the HaightAshbury Free Medical Clinic, added that although poppers were gaining popularity outside 'the drug culture or the deviant subculture', there seemed to be 'less use or interest by either heterosexual or lesbian women' (Smith, 1972).
The American Journal of Psychiatry warned in 1978 that 'popping and snorting volatile nitrites' was a 'current fad for getting high'. But research raised the question whether 'repeated use of these products could increase the risk of developing cancer'. The problem was that 'inhaled nitrites could interact freely with endogenous trivalent nitrogen compounds to produce nitrosamines', some of which 'are known to be carcinogenic (Sigell, 1978). The following year the same journal noted that nitriteuse had proliferated among homosexuals. Their use was 'strongly related to a number of unconventional, deviant sexual practices', which were not named (Goode & Troiden, 1979). Reviewing the physiological effects of nitrites on the eve of the epidemic, Thomas Haley of the FDA warned once again that if a certain metabolism occurred, nitrites would produce nitrosamines, 'which are potent carcinogens' (Haley, 1980).
The CDC Task Force set forth in 1981 in search of the epidemic. In The Band Played On, Randy Shilts detailed their exploits in San Francisco:
'Dr. Harold Jaffe [of the CDC] looked nervously toward the barroom door. Even with a stiffsummer breeze, the air was redolent with something thickly acrid, like a strange mixture of battery acid and vegetable shortening. The Ambush looked as seedy as Jaffe had heard, the kind of place where you feet stick to the floor. It was also the source of the poppers about which the gay men in San Francisco couldn't rave enough. The Ambush's own brand of poppers, sold directly in an upstairs leather shop, didn't give you headaches, patients told Jaffe ... [But] Jaffe didn't believe he would find the solution in poppers ... Amyl nitrite had been around for a century without killing anybody' (Shilts, 1987).
Most AIDS reporters have been less candid than Randy Shilts, but he nonetheless remained silent about the real attraction of poppers. In fact, it has rarely appeared in print. 'He avoided the issue', said Hank Wilson, a gay activist in San Francisco, who founded the Committee to Monitor Poppers in 1981. 'The great breaker of the taboos had his own taboo on this issue'. Mr. Wilson himself, who manages a singleroom occupancy hotel in San Francisco, was candid about poppers. 'They relax your sphincter muscle, okay?' he said. 'If you're having casual sex, in a park or a bathroom or in a tearoom, wherever, and it's quick, it's casual? You don't generally have as much foreplay, you're more orgasmic oriented, as opposed to pleasuring someone. You see what I'm saying. Poppers facilitate quick anal intercourse' (Wilson, 1993).
The same claim was published in Medical Aspects of Human Sexuality, in 1975. Poppers were by the mid 1970s being widely used by gay men, the journal reported, because they enabled 'the passive partner in anal intercourse to relax the anal musculature and thereby facilitate the introduction of the penis' (Labataille, 1975).
Virtually all the early homosexual patients later diagnosed with AIDS had used poppers. 'Amyl nitrite was used at least once by all the patients with Kaposi's sarcoma (in their study)', Michael Marmor et al. reported in The Lancet in 1982, 'and further passive exposure at homosexual discotheques was reported by many' (Marmor et al., 1982). Analysing the data from three early CDC studies, Dr. Haverkos and coworkers found that out of 87 patients with Kaposi's, pneumocystis or both, all but three had used poppers (Haverkos et al., 1985). He had interviewed one of those three himself, in a New York hospital. 'He had pneumocystis, was short of breath, and was eager to get back upstairs to his room', Haverkos recalled. 'He simply answered 'no' to questions and skipped whole sections of the interview' (Haverkos, 1994). Questions about nitriteuse came at the end of the form. It is quite likely, in fact, that all 87 of the men had used poppers.
Surrounded by stacks of papers and medical journals in his cramped office, Haverkos gives several reasons for suspecting that nitrites are the cause of Kaposi's. The statistical connection between the two is impressive. Repeated use of poppers, and the incidence of KS, have been overwhelmingly confined to gay men. 'About 96% of Kaposi's cases occur in gay men, as opposed to 65% of all AIDS cases', he said. Twice as many whites as blacks use poppers and twice as many get Kaposi's. After warnings about nitrites spread through the gay community in the mid 1980s, both the use of poppers and the incidence of Kaposi's declined.
The unwritten rule of public health seems to be that infectious disease must always trump toxicology, even when the epidemiological indicators of infectious disease are missing. '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', Haverkos said. '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'.
When asked what changes in AIDS research and reporting he would like to see, he made a simple request. About 5000 new cases of Kaposi's are reported every year, but we still don't know how many of these people used nitrites. Why not? The forms that clinicians fill out to this day lack questions about nitrite use. They ask about sexual orientation, about intravenous drug use and other categories traditionally linked to AIDS. But nothing about poppers. 'I almost had a question about nitrites put on the CDC surveillance form back in 1984', Haverkos said. 'But they had to weed it, make it a little shorter, and that was one of the questions that they took off'.
No cases of KS have been reported among bloodtransfusion recipients where the donor himself later developed the cancer. This suggests that HIV alone is insufficient to cause the disease, and that whatever does cause KS is not readily transmitted through blood. In addition, a number of HIVfree cases of KS have been reported by two doctors, Alvin FriedmanKien in New York and Marcus Conant in San Francisco (FriedmanKien et al., 1990; Perlman, 1993).
Dr. Conant, Clinical Professor of Dermatology at the University of California, San Francisco, told the San Francisco Chronicle that he had found half a dozen nonHIV 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'. Dr. Conant rejects the nitrite theory of KS as well, although he admitted that he has made 'no formal study' on the use of nitrites by his own KS patients (Conant, 1994).
Kaposi's is a bloodvessel tumor, and nitrites act on blood vessels. 'The lesions are most common on the face, nose and chest', Haverkos said. 'If you're inhaling vapors, that is where you will encounter the highest concentrations'. Dr. Sidney Mirvish of the University of Nebraska Medical Center has demonstrated that isobutyl nitrite vapor is mutagenic in the Ames test, and that inhaled vapor is eleven times more dangerous than nitrite in liquid form (Mirvish et al., 1993).
'The primary action of nitrites is cell intoxication', said Dr. Peter Duesberg, a cell biologist at the University of California, Berkeley. 'Nitrites reach into the bone marrow and interfere with the creation of new blood cells, including Tcells. They kill enzymes, and they mutate DNA' (Duesberg, 1994a). Duesberg believes that nitrite use alone is sufficient to explain most of the early AIDS cases among gay men, where either immune suppression or KS was found.
'Put all those points together', Dr. Haverkos said, '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 added, 'the CDC and the NIH then published two big studies in which they didn't find an association between nitrites and KS'. Perhaps the most important was the Multicenter AIDS Cohort Study. Between 1984 and 1985, about 5000 gay men in four cities participated. Those who developed AIDS were compared with HIVpositive controls who did not, and nitrite users did not seem to be concentrated in the AIDS group. The authors, however, noted the limitations of their own research. 'We did not attempt to quantify nitrite usage... It is thus possible that we missed or obscured a meaningful association' (Polk et al. 1987).
Patients were asked how frequently they had 'used poppers during sex in the past two years', Haverkos points out, and by the time subjects were asked the question, many gay men had become wary of poppers through pointofsale warnings in gay bars and porn shops. These had had their deterrent effect. Statistics from the San Francisco Health Department show a dramatic drop in the use of poppers between 1982 and 1988 (Wilson, 1994a). Therefore, by the time subjects in the MAC study were interviewed, it is likely than many were no longer using poppers, or had given them up two years earlier. The yes/no, ever/never questions that have also been used in other epidemiological studies have consistently failed even to try to quantify lifetime use of nitrites.
In retrospect, it seems possible that government medicine was not terribly interested in finding a toxicological or behavioral cause of AIDS. The virologists were on the case very quickly. The first three reports in MMWR all include 'editorial notes' mentioning cytomegalovirus, and such comments as: 'activation of oncogenic virus during periods of immunosuppression may result in the development of KS' (CDC, 1981b). James Curran of the CDC considered the possibility that a 'bad batch of the inhalants could have triggered the immune problems'. That would explain why sickness seemed to be limited to three cities. 'Contaminated vials' therefore might be the answer. But, Randy Shilts reported, Curran never really gave credence to the nitrite theory. After all, 'some five million doses of nitrite inhalants were sold in American in 1980 alone' (Shilts, 1987).
Mary Guinan, another Task Force member, thought that 'somebody who gets a rush from heroin isn't going to toy around with something as lightweight as disco inhalants', an odd remark in view of their known widespread use by homosexuals at that time (ibid). Harold Jaffe of the CDC 'didn't believe he would find the solution in poppers', Shilts reported. 'If the puzzle was that simple, somebody would have solved it by now' (ibid). In fact, amyl nitrite 'had been around for a century without killing anybody'.
In Sentinel for Health, a history of the CDC published in 1992, Elizabeth Etheridge describes the visit of Jaffe and Guinan to San Francisco in 1981, where they took blood samples from patients and controls, the latter drawn from the practices of private physicians, friends (but not sexual partners) of patients, and homosexuals selected from VD clinics. Etheridge's reporting, based on an interview with Harold Jaffe, continued as follows:
'When the task was done and the data from all the cities were analyzed, there was little doubt it was a sexually transmitted disease. The lifestyles of the patients and the controls were quite different, the patients being much more sexually active, much more likely to have sex with people they did not know. Reports from the lab showed that cases had much lower Tlymphocyte counts than controls. While many of the patients were routine users of amyl nitrites or 'poppers', no one in the KSOI Task Force believed that the disease was a toxicological problem' (Etheridge, 1992).
Haverkos was on the Task Force, and he still does believe just that. Today Harold Jaffe is the director of the division of HIV/AIDS at the Centers for Disease Control and Prevention. He has relented a little, but not much. 'The observation we're trying to explain is: Why is it that among all persons with HIV infection, KS is so common among gay men?' he said in an interview. 'And we don't know the answer to that. There are a number of theories. 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' (Jaffe, 1994).
Haverkos replied that these cases are extremely rare, and he says that there has been no followup to determine if misdiagnosis occurred. 'I don't think you can dismiss nitrites because of a few underevaluated studies', he said (Haverkos, 1994).
'The difficulty is this', Dr. Jaffe added. 'Nitrite use among gay men also tends to be associated with other behaviors. Men with a heavy use of nitrite inhalants often also are highly sexually active, and have other sexually transmitted diseases. So it's very hard in doing studies to be able to separate out all these behaviors that are highly associated'.
Nonetheless, it seems remarkable that professional disease sleuths should have found it so hard to believe that a carcinogen, reported as a new fad among homosexual men in the 1970s, might be the cause of a new cancer that emerged in the 1980s and emerged among the very people who had been inhaling it.
An indicator of the CDC's evident desire to subordinate toxicity to infection in searching for a cause came in 1983. In that year, even 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. 'Current research favors the theory that AIDS is caused by an infective agent, possibly a member of the retrovirus group', the pamphlet explained (U.S. Public Health Service, 1983).
The second most important experiment enabling the CDC to 'rule out' poppers was a study done on mice, conducted in 198283 by Daniel Lewis and Dennis Lynch of the National Institute of Occupational Safety and Health (a subdivision of the Centers for Disease Control). Mice were exposed to various concentrations of isobutyl nitrite for up to 18 weeks, and the effect on their immune systems was measured. A sharply lower white blood cell count was observed in male mice (down to nearly one third the level of controls), but the overall conclusion of the study was that 'at the levels tested, isobutyl nitrite had no significant detrimental effect on the immune system of mice' (Haverkos & Dougherty, 1988).
In May, 1994, however, the National Institutes of Health sponsored a 'technical review' of nitrite inhalants at a public meeting in Gaithersburg, Maryland. Among the speakers was Daniel Lewis. In conducting the experiment, he explained, nitrite dosage had been kept low, approximating the background exposure levels encountered by humans working in a poppers factor. In a detailed report on the meeting, the writer John Lauritsen noted: 'Lewis explained that in determining the dose, they had to adjust it below the level at which they were 'losing' the mice'. It is possible that the mice they 'lost' had in fact succumbed to immunotoxicity exactly what the study claimed not to have found (Lauritsen, 1994a). When asked how he accounted for the discrepancy between the findings of this study, and others definitely showing immunesystem impairment (Ortiz & Rivera, 1988), Lewis responded: 'dosage and length of exposure'. Nitrites 'should be considered a hazardous substance', he added (Lauritsen, 1994b).
What about the testing of nitrites on human subjects? Eighteen male volunteers were tested for a few days by Elizabeth Dax and William Adler at the Addiction Research Center in the late 1980s. After the last inhalation, blood was drawn for the immune profile; and then again after one, four and seven days had passed. Modest depression of Tlymphocyte counts and natural killer cells were observed, with a rebound to baseline levels taking place several days after the last inhalation (Dax, 1991). Lee Soderberg of the University of Arkansas also made a presentation at the Gaithersburg session. His experiments, with mice subjected to a stronger nitrite dose, definitely showed immunesystem impairment, especially a reduction of macrophage activity. Here, too, immune functions seemed to recover after about a week (Soderberg & garnet, 1991).
During a question period, Dr. Duesberg, who was an observer although not a speaker at the session, raised this issue of reversibility. Among homosexuals, he pointed out, nitrite use had often gone on for years. What is needed, he suggested, are longerterm studies. But Soderberg said that his team had 'no data on more chronic exposure' (Lauritsen, 1994a).
Duesberg said later that those who had so carefully investigated smoking and lung cancer would not have been content to give subjects a few cartons of Marlboros, and having found that they caused no ill effects, proclaim cigarettes to be safe. 'With drugs, the dose is the poison', he said (Duesberg, 1994a). And the dose accumulates. The apparent failure to appreciate this point is the answer to Jaffe's and Curran's earlier belief that nitrites could hardly be the cause of disease, because nitriteuse was already so widespread by 1981. The key point is that nitriteuse as a fad or habit in the gay community had apparently been going on for about ten years by the time Kaposi's emerged. And that may well be the time it takes for the critical doselevel to build up.
Duesberg has proposed to correct the research lacuna by exposing mice to nitrites for longer periods, and then seeing what happens. Will they develop pneumocystis or something resembling Kaposi's? In August, 1993, while he was working on a grant application to fund such an experiment (together with an experienced animal researcher from the University of California, Davis), Duesberg discussed the situation with
Daniel Koshland, who at the time was both the editor of Science magazine and, like Duesberg, a member of the Department of Molecular and Cell Biology at U.C. Berkeley. Duesberg told Koshland about the widespread use of poppers among homosexuals, the toxicity of nitrites, and the need for further animal experimentation. Koshland had heard very little about al1 of this potentially crucial background to the AIDS controversy (Duesberg, 1994a). The upshot was that he supported Duesberg's grant proposal. His letter of support was submitted along with the grant application to the National Institute on Drug Abuse. In it he wrote:
'As an observer, I have in the past been critical of Duesberg for not suggesting experiments to resolve this controversy. However, he has now answered my call with a proposal to test the role of nitrite inhalants as a cofactor in AIDS. Certainly this idea seems intuitively to have merit, as nitrites have long been known for their potent mutagenic and carcinogenic effects. He plans to extend some unfinished work by other laboratories in the mid1980s on mice ...' (Koshland, 1993).
Despite this endorsement from the editor of the leading science journal in the country, the proposal was turned down by the National Institute on Drug Abuse. The agency cited Duesberg's lack of 'preliminary experiments' in the field, and his failure to give a full hearing to opposing views. He resubmitted an amended proposal in August 1994, again supported by an endorsement from Daniel Koshland. But this too was turned down, in a letter dated November 30,1994. 'No further consideration be given to this application', the accompanying note read (Duesberg, 1994b).
Butyl nitrites were officially banned by the Anti Drug Abuse Act of 1988 (Public Law 100690), but manufacturers responded by selling chemical variants as 'room odorizers' and marketing them under such names as 'Rush', 'Ram', and 'Locker Room'. Then, in the 1990 Omnibus Crime Control Act, mainly in response to the concerns of Rep. Mel Levine of California, 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 daze!' ad copy in a gay magazine trumpeted), carburetor cleaner ('The good stuff') and leather stripper ('Not an overpriced 'headache in a bottle' like those other brands') (Wilson. 1994b).
'The use of poppers is increasing across the board in the big cities', the antipoppers activist Hank Wilson claimed, in an interview in the summer of 1994. 'It's in the air in the San Francisco clubs. I personally stopped going to the sex clubs about 18 months ago because the air got so bad' (Wilson, 1994c).
Wilson's boyfriend, who always used poppers with sex and had KS, died last year of AIDS. Wilson himself was diagnosed with AIDS in 1987, but looks to be in good health (he steers clear of AZT). Institutional memory in the gay community is short, Wilson said, 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 pointofsale warnings were mandated in California, but have since lapsed.
Wilson was furious that James Curran, now in a position of real power as the chief of AIDS research at the CDC, had not issued a community alert. Wilson cited a number of recent studies, including a 1994 report published in the Journal of the American Medical Association (Lemp et al., 1994), showing incontrovertibly that popper use is a risk factor for unsafe sex. (A call by this reporter to Curran's office at the CDC was referred to the press office. Tom Skinner of that of office said: 'It's my understanding that the use of nitrites is associated with unsafe sex. But to say that it's directly the cause of unsafe sex, there is no scientific proof of that'). (CDC, 1994).
Wilson's group is affiliated with ACT UP/Golden Gate, and by the end of 1993 a few of its members began to take action. Ernest Harding of Los Angeles wrote to Kristine Gebbie's office complaining about a letter from the Consumer Product Safety Commission, reassuring one of the poppers manufacturers that their nitrite configuration was not covered by the law and was therefore legal. At the same time, Shane Que Hee, an associate professor of Environmental Health Sciences at UCLA, who has written a textbook on biological monitoring with a chapter devoted to volatile nitrites, wrote to Rep. Henry Waxman (DCalif) recommending that 'the immunosuppressive properties of these drugs should be researched completely before they are sold publicly' (Hee, 1993).
The professor also wrote to the Consumer Product Safety Commission in Washington, urging that it withdraw approval of nitrite inhalants. He received a reply from the Office of Compliance and Enforcement saying that the commission had no such authority. 'The nitrite ban enacted by Congress is not all inclusive', Michael Bogumill wrote, 'as it is limited to consumer products containing volatile alkyl nitrites, which, according to chemical experts, does not necessarily include all volatile organic nitrites' (Bogumill, 1994). Therefore the commission could do nothing. Nitrites continue to be sold, in compliance with the letter but not the spirit of the law.
In the correspondence with Gebbie, Ernest Harding added that the alcohol congener in poppers is not the relevant issue. 'It is the nitrite component that is dangerous, and on this basis we cannot permit the sale of any such product, whether it be disguised as a room odorizer, videohead cleaner, or any other obfuscation'. Gebbie responded by asking NIH if something couldn't be done, and in response the 'technical review' of nitrite inhalants was held in Gaithersburg in May.
One session was titled, 'Do Nitrites Act as a CoFactor in Kaposi's Sarcoma?' The best known speaker was the National Cancer Institute's Robert Gallo, codiscoverer of HIV. What he said was noteworthy. Although HIV was surely a 'catalytic factor' in Kaposi's, he said, 'there must be something else involved'. Then he added:
'I don't know if I made this point clear, but I think that everybody here knows we never found HIV DNA in 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' (Lauritsen, 1994a).
In response to a question from Dr. Haverkos, who said that not a single case of KS had been reported among blood recipients where the donor had KS, Gallo allowed: 'The nitrites could be the primary factor'. Also worth noting is a comment of Anthony Fauci, at the time chief of AIDS research at NIH. In a San Francisco Chronicle article questioning the link between HIV and Kaposi's, Fauci was quoted as saying: 'I would not be totally surprised if we found out that KS is caused by a combination of things. Maybe by an agent that is at this point unrecognized' (Perlman, 1993).
Let us briefly review: In 1981, the CDC found that gay men were coming down with unusual diseases, among them a rare cancer, Kaposi's sarcoma. It turned out that with very rare exceptions, all these men had been inhaling a volatile substance of known mutagenic and carcinogenic potential, for the purpose of getting 'high' and facilitating anal intercourse. Despite the best regulatory efforts of Congress, this substance is still sold legally. Meanwhile in 1984, in the course of an election campaign, we were told that the cause of AIDS had been discovered. The virus HIV was the culprit. Ten years later, we were told by the codiscoverer of the virus that nitrite inhalants 'could be the primary factor' in KS, which, Dr. Fauci thought at the end of 1993, might be caused 'by an agent that at this point is unrecognized'. By mid 1994, then, it was clear from the mouths of the government's leading researchers that they still did not understand AIDS.
That August, Haverkos attended the 10th Inter national AIDS Conference in Yokohama. He wasn't wellknown enough to give a speech, but he was given space to displayed the 'poster' that he and the CDC's Peter Drotman had put together. It analyses 12 epidemiological studies that have been used to examine the role of nitrites and other potential cofactors in the development of Kaposi's, and it shows that these questionnaires had failed to quantitate nitrite use.
'Went okay', Haverkos said later, in his usual lowkey manner. Nothing earthshattering. A few people came by and talked. A reporter from a Canadian newspaper interviewed him. 'I've been figuring this story was going to break since, oh, about 1985', he said with a laugh.
Then, near the end of 1994, there was an unexpected development in the story. In midDecember, a husband and wife team at Columbia University held a press conference declaring that they had found traces of what may be a newly detected virus in tissue taken from deceased AIDS patients with Kaposi's. The scientists, Yuan Chang and Patrick S. Moore, used a new technique (representational difference analysis) to help identify molecular fragments from genes of the apparent virus. The DNA sequences were homologous to, but distinct from protein genes of the herpes virus. They were found in 90% of KStissue from patients who had died with AIDSrelated KS, in 15% of nonKS tissue from AIDS patients, and not at all in nonKS tissue from people without AIDS.
With accompanying news media fanfare, their findings were reported in Science magazine (Chang et al., 1994). Earlier that year, Moore had attended Haverkos's nitrite review session as a silent observer. Before joining his wife at Columbia, he had worked for the Centers for Disease Control and Prevention in Colorado, and for New York City's public health servlce.
Moore and Chang duly emphasized the preliminary nature of their findings. They had neither isolated the virus, nor determined its complete structure, nor proved that it was the cause of Kaposi's sarcoma. 'There's a long step between finding DNA sequences and having a virus', said Dr. George Miller, a Yale University expert in herpes viruses (Altman, 1994). Nonetheless, Dr. Harold Jaffe of CDC told Jon Cohen for an accompanying article in Science that 'it's a tremendously exciting result ... At this point we can't say that it's the etiologic agent, but I think it's a very good candidate'.
The opinion of Dr. Gallo was sought. The new paper was 'really good work', he said, but he still had 'major questions' (Cohen, 1994). These dealt with the claim that the putative virus is found rarely or not at all outside the population of gay men. (This would make it unique among herpes viruses, which are found in a large proportion of the general population.) Cohen's Science article was headlined: 'Is a New Virus the Cause of KS?'
Almost in passing, the main Science paper noted that investigators had long suspected that AIDSrelated Kaposi's might be infectious, and that over the years suspected causal agents had included: cytomegalovirus, hepatitis B virus, human herpes virus 6, HIV, and Mycoplasma penetrans. 'Extensive investigations, however, have not demonstrated an etiologic association between any of these agents and AIDSKS', Chang, Moore et al. added. Thus, it seemed, HIV was quietly dropped from the list of the possible causes of Kaposi's.
Lawrence K. Altman, who attended the press conference, came through with a frontpage story in the New York Times (Altman, 1994). Headlined 'Apparent Virus May Be a Cause of Fatal Cancer in AIDS Patients', it made no mention of HIV at all. A simultaneous report by Lisa M. Krieger in the San Francisco Examiner ('AIDSrelated cancer linked to herpes virus') began as follows:
'New research suggests that Kaposi's sarcoma, a potentially deadly disease long thought to be caused by HIV, is instead caused by a type of sexually transmitted herpes virus that preys on people with AIDS' (Krieger, 1994).
Four days later, a second story by Altman was published in the New York Times (Altman, 1994b). Since its initial article in July, 1981, the paper had remained loyal to the infectiousagent theory of Kaposi's and said very little about nitrite use. In this second article, however, Altman raised a number of interesting questions. If the new 'virus' causes Kaposi's, for example, 'why did it appear at the same time as HIV?' Why two new viruses at once? And 'does the Kaposi's sarcoma virus suppress the immune system independently of the AIDS virus?' He further asked: 'Why has the percentage of AIDS patients with Kaposi's sarcoma declined in the United States over the last ten years?' (Nitrite use, of course, has likewise declined.) Altman still seemed to be skirting the key question: What role, if any, was reserved for HIV in the development of Kaposi's?
When I spoke to Dr. Harry Haverkos in midDecember, he still had not seen the article in Science, but he had discussed the news with former colleagues at the Centers for Disease Control in Atlanta. If the new discovery held up, he said, and the etiologic agent for KS had indeed been found, HIV would probably still be regarded as a cofactor predisposing the patient to KS by weakening the immune system. He used the analogy of tuberculosis. About ten million people in the U.S. are infected with TB, he said, but only about one million will develop active disease in their lifetime. Various factors (coalminers' disease, for example) may weaken the TBinfected patient sufficiently to allow the dormant bacillus to become active.
Haverkos stressed, however, that the Columbia University team still had a way to go. Just as earlier sexually transmitted agents for KS had not survived closer examination, so this new (presumed) virus might not either. Meanwhile, he admitted, his nitrite hypothesis had been dealt a setback, if only because researchers would not take it seriously 'until they have sorted out this new factor.' Which could take time. In the mid1980s, he recalled, he was about to embark on a study of nitrites with the military, when just at that moment the Armed Forces Institute of Pathology, on the campus of Walter Reed Hospital in Bethesda, came forth with the hypothesis that mycoplasmas were a cofactor for KS. This theory didn't survive scrutiny, but 'by the time they sorted it out, the impetus to do the study I had proposed had withered away, and the people at the Institute who were interested in it had been transferred somewhere else.'
Still, he said, there was a positive side to the new development. 'It does suggest that there must indeed be a cofactor for KS.' Back in 1984, when the cause of AIDS was announced at a press conference held by the HHS Secretary Margaret Heckler, it was assumed that the then culprit, HIV, was the necessary and sufficient cause of a syndrome that prominently included
Kaposi's sarcoma. Ten years later, the unwary reader might not have noticed that a certain threeletter acronym was totally absent from the press release distributed at the Moore and Chang news conference at Columbia University. HIV had quietly disappeared from the picture. *
Tom Bethell is Washington correspondent of the American Spectator. He wrote this article while he was a Media Fellow at the Hoover Institution, Stanford University. An abbreviated version of this article was published in Spin, November, 1994.
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