Targeting a Retrovirus (1984–1986)
April 24, 1984: A triumphant Margaret Heckler, secretary of health and human services, announced to the expectant reporters assembled at a Washington, D.C., press conference that the cause of AIDS had been found. This report of a virus linked to AIDS ushered in a new wave of debates—about who should receive credit for the discovery of the putative causal agent, which practices were most responsible for its transmission, and whether a retroviral causation was indeed sufficiently proven. But the general acceptance of the retroviral hypothesis of AIDS causation had still other implications that were both immediate and far reaching. Up until that point, medical treatment of people with AIDS had been aimed at controlling, as well as possible, the opportunistic infections and cancers that progressively devastated the bodies of immune-suppressed individuals. These were stopgap measures, at best—not only because many of the opportunistic diseases were difficult to treat, but also because each infection that subsided would generally be replaced by yet another. Lacking an understanding of the fundamental causes of immunosuppression, biomedical science had little hope of reversing the downward course of illness.
The discovery of Luc Montagnier's "LAV," Robert Gallo's "HTLV-III," and Jay Levy's "ARV" instantly changed the scientific agenda for AIDS research. Suddenly it became possible to use a new vocabulary,
one with words like "cure" and "vaccine." Perhaps the most extreme reactions came from politicians with a vested interest in promoting a triumphalist (and nationalist) account of scientific progress. A blood test for the virus would be available in a few months and a vaccine to prevent AIDS would be developed and ready for testing in about two years, announced Secretary Heckler, to the visible discomfort of some of the prominent scientists with her on the podium.
In fact, there were no insurmountable obstacles to the development of the blood test for antibodies to HTLV-III, which was licensed by the Food and Drug Administration (FDA) in just under a year. But those more familiar with the inherent difficulties of vaccine research knew that scientists had succeeded in designing reasonably effective prophylactic vaccines against only a dozen viral illnesses. The most recent such vaccine, against hepatitis B, had taken most of a decade to bring to market. Dr. Anthony Fauci, head of the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH), quickly sought to dispel illusions and dampen inflated expectations. "To be perfectly honest," he told the New York Times a few days after the press conference, "we don't have any idea how long it's going to take to developed a vaccine, if indeed we will be able to develop a vaccine."
A similar degree of uncertainty combined with high hopes surrounded the investigation of treatments for those already suffering from AIDS. The public and the media spoke of "cures," a term which conjured up images of penicillin-like drug that would quickly and efficiently rid the body of the invading microorganism. But unlike the bacteria and fungi that antibiotics treat, viruses—from the common ones, like the cold virus, to the rare and deadly ones, like Ebola—have seldom proven amenable to medical intervention. Viruses insinuate themselves into cellular DNA—the genetic code in the cell's nucleus—transforming infected body cells into factories for the production of more virus. To rid the body of a virus, therefore, requires eliminating every infected body cell without killing uninfected body cells—and scientists in 1984 had little to no idea about how such a task might be accomplished with HTLV-III. Indeed, at the time that the virus was discovered, only three antiviral agents of any kind were licensed for use in the United States, and none of them was entirely effective: amantadine, a drug used against influenza A; vidarabine, which was used against various viral infections of the eye; and acyclovir, a drug used for treating the herpes simplex virus.
The Logic of Treatment
The search for a treatment against an infectious agent can proceed according to a clear theoretical logic or a hit-and-miss pragmatism. At one extreme, researchers may use their knowledge of the pathogen and the disease process to synthesize a novel compound that will target the pathogen or interrupt the pathogenesis (the development of disease). If the newly synthesized drug acts against the infectious agent in vitro and proves to be not too toxic in animal testing, then it can be tried in humans to see if the theoretically predicted effect is observable in practice. At the other extreme, researchers may simply "see what works" by taking existing drugs whose potential efficacy seems plausible (for example, drugs wih known antiviral activity) and adding them to a test tube containing the infectious agent. Such evidence of activity of a drug against a pathogen in vitro is no guarantee, to be sure, that the drug will have any effect on a disease process inside of a living human being or that the human being will be able to tolerate the drug. But it is a good way of screening for promising therapeutic agents.
Since it takes time to synthesize new compounds, and since biomedical researchers knew little about the structure, properties, or life cycle of what would come to be called the human immunodeficiency virus (HIV), hit-and-miss pragmatism was the more likely pathway to quick results. But researchers did possess one crucial fact from the outset that could guide them in the selection of likely agents for testing: they believed they were dealing with a retro virus, composed not of DNA, like most viruses, but RNA. An ordinary DNA virus enters the nucleus of an infected cell and causes the cell to carry out the genetic instructions encoded in the virus's DNA; it transcribes its DNA into RNA, which is then assembled into proteins that form a new virus. But before a retrovirus can integrate itself into the nucleus of an infected cell and replicate, it first has to convert its RNA into DNA—to rewrite its own genetic code "backwards" in a process called reverse transcription. To complete that process, the virus relies on an enzyme it produces, called reverse transcriptase ; this enzyme, in other words, is absolutely essential to the process of viral replication. Inhibit the reverse transcriptase and you inhibit the viral spread: You don't "cure" the patient in the sense of ridding the body of already infected cells and restoring a functioning immune system, but you do—at least in theory—prevent the virus from going on to infect new cells. This
treatment strategy made particular sense if you assumed, as many researchers did, a straightforward model of how HIV caused immune system damage: if AIDS was the long-term result of HIV's direct cytopathic (cell-killing) effects on helper T cells (also called CD4 cells), then stopping the virus in its tracks should prevent the virus from killing more such cells, thereby keeping the immune system from deteriorating further.
It didn't take long for both National Cancer Institute (NCI) scientist and those connected with the Pasteur Institute in France to pursue this promising lead. In October 1984, a group of NCI researchers including Gallo and Samuel Broder, the director of the NCI, published an article in Science describing their in vitro studies with a drug called suramin, which was "known to inhibit the reverse transcriptase of a number of retroviruses." Suramin had been developed by the Bayer Company in Germany more than half a century ago, and, though never licensed in the United States, it had been used extensively in Africa and South America for the treatment of certain parasitic diseases. The NCI researchers found that when suramin was added to HTLV-III in the test tube, the virus became incapable of infecting and killing helper T cells.
Meanwhile, collaborators of Montagnier in France, having made similar assumptions about the logic of treating AIDS, began giving a compound directly to patients—antimoniotungstate, or HPA-23, which was known to incapacitate the reverse transcriptase of certain retroviruses that infect mice. By February 1985, they could offer a brief report in Lancet on a fifteen-day course of treatment with four patients. Comparing the before-and-after assays showed that the drug regimen appeared successful in curtailing the replication of LAV.
But the French researchers also had some words of caution against assuming any easy successes in the fight against AIDS. Even though "infection with LAV seems to be an essential step in the pathogenesis of AIDS," nonetheless a drug that acted against the virus "may not be able to cure the disease." This might be because antiviral therapy came too late, after the virus had already done irreparable damage to the immune system. Or it might be that the pathways from infection to development of AIDS involved more than just direct cell-killing. Perhaps LAV infection instigated "autoimmune mechanisms"—failures of the immune system to distinguish between body cells and invaders, leading the immune system to turn on itself and target other immune cells. In that case, "AIDS could prove to be self-perpetuating even in
the face of inhibition of LAV multiplication." Even if a compound like HPA-23 were eventually proven to be a safe and effective antiviral agent—even if it could be administered to humans in a clinically effective dose, even if its side effects proved tolerable, and even if the initial, promising results could be confirmed in controlled clinical trials with large numbers of patients—it still might not be sufficient to keep AIDS patients alive. "An antiviral won't be the miracle, but it will be absolutely obligatory," Jean Claude Chermann, one of the study coauthors and one of the discoverers of LAV, told Newsweek in April.
That month, more than two thousand researchers from thirty countries converged on Atlanta to attend the first of what would become an annual milestone: the International Conference on AIDS. Researchers in the United States and Europe reported at the conference that testing had begun, or was about to begin, with six drugs in small numbers of patients. These drugs, all of which had been found to have some inhibitory effect on the virus in the test tube, included suramin and HPA-23, as well as ribavirin, an antiviral drug made by a small Southern California pharmaceutical company.
Such studies were just the initial step on the long, uphill path to the marketing of a new drug in the United States. With the passage of the Pure Food and Drug Act in 1906 and the Food, Drug, and Cosmetic Act in 1938, the FDA had been empowered to require that drug manufacturers submit evidence from "adequate tests" showing that a drug was safe, before it could be licensed for sale. Since safety was a relative term, the FDA was expected to assess risk and benefits, which implied making some additional determination of whether the drug was indeed effective. In 1962, in response to public uproar after the drug thalidomide was found to cause birth defects, Congress passed an amendment to the Food, Drug, and Cosmetic Act called the Kefauver-Harris amendment. (Thalidomide had never been licensed in the United States, but some pregnant women participating in studies had received it.) Although the issue with thalidomide was one of safety, the effect of the Kefauver-Harris amendment was to shift the emphasis of drug regulation more heavily in the direction of requiring formal, scientific proof of efficacy.
As Harry Marks has described, by the early 1970s, "with the growth in influence of the National Institutes of Health and the rise of biostatistics as a distinct discipline …, the nature and methods of drug evaluation had achieved a form of scientific and bureaucratic orthodoxy." Usually, the FDA asked for evidence from at least three
"phases" of randomized clinical trials in human subjects performed sequentially: a small Phase I trial to study the drug's toxicity and determine a good dosage for drug absorption; a larger, longer Phase II trial to test the drug's efficacy; and a still larger Phase III trial to bolster the evidence of efficacy in comparison with other treatments for the condition. Each of these studies required planning, recruiting of subjects, careful monitoring, and interpretation and write-up; and the FDA often took its own good time to reach its conclusions, which it made on the basis of recommendations from expert advisory panels. Typically, it might take a drug six or eight years to leap the regulatory hurdles. Critics pointed to the paltry number of drugs that made it to market in the post-Kefauver-Harris environment and argued that U.S. standards were unjustifiably higher than those of other countries. Consumer protectionists responded that U.S. standards were appropriately high, since many countries around the world couldn't afford to perform elaborate drug tests and therefore relied on the FDA to determine what was safe and effective.
Just like medications, any potential vaccine against AIDS would have to pass through extensive testing that included various phases of clinical trials, before the FDA licensed its use. But as reports at the International Conference made clear, even Phase I trials were still a long way off. Researchers had, however, begun identifying "subunits" of the virus that might serve to generate a protective immune response. Using parts of the virus, it was generally assumed, was a safer strategy than using the whole virus: researchers could induce an immune response without having to worry about the risk of accidentally infecting the healthy vaccine recipient. One problem, however, was the recent discovery—Gallo called it "worrisome"—of considerable genetic variation among different strains of the virus. This raised the question of whether any particular subunit could generate protection against every strain. "We have a long way to go before AIDS is preventable or treatable," Dr. Martin Hirsch of Massachusetts General Hospital concluded in reviewing the conference, "but the first steps have been taken, and we are on our way."
The Genesis of Treatment Activism
Observers in gay and lesbian communities had other, more critical perceptions of the International Conference and the depth of the scientific and political commitment to finding treatments for AIDS. Secretary Heckler's statement at the conference regarding
the nation's priorities was widely reported—that AIDS must be stopped "before it spreads to the heterosexual community." Commentators familiar with other scientific conferences observed some distinctive aspects of this one: "The meeting was unusual for the remarkable mixture of participants—doctors and scientists of almost every discipline rubbing elbows with gay activists and media personalities," said the newsletter of the Bay Area Physicians for Human Rights, the gay doctors' group: "The unlikely combinations led to comments about 'strange bedfellows,' but there is no proof of the reality of that phrase."
Moments of levity notwithstanding, this was a threatening time for gay communities. With the availability of the HTLV-III antibody test, many would soon be learning for the first time that they were infected with the virus and faced with an uncertain future. At the same time, as the epidemic became more of a mainstream issue in the United States following reports of actor Rock Hudson's AIDS illness, fears of contagion on the part of the mass public multiplied, leading in many instances to stigmatization of homosexuals, whether healthy or ill. Gay rights and AIDS advocacy organizations feared that those testing positive for viral antibodies would be subject to discrimination, including loss of their jobs, housing, health insurance, and anonymity. In March 1985, the conservative commentator William F. Buckley Jr. proposed, in a notorious New York Times op-ed piece, that "everyone detected with AIDS should be tattooed in the upper forearm to protect common-needle users, and on the buttocks, to prevent the victimization of other homosexuals. …"
The activist response to AIDS by gays and lesbians dated to the earliest days of the epidemic (see chapter I). It rested on the firm base of gay rights activism constructed in the previous decade, with its sex-positive ethic and its suspicious take on medical claims. Now, in response to the new wave of provocations, many who had kept themselves at arm's length from such activism suddenly found themselves drawn into the fray. For a generation of relatively privileged, middle-class gay men, government had been something to restrict, to keep out of their "private" lives. As the boundary between private illness and public health exploded, these same men sought active governmental involvement to fund emergency AIDS research and to protect people with AIDS against discriminatory treatment. However, such assistance was far from the top of the agenda of the Reagan administration, which consistently requested modest funds for AIDS research only to see Congress boost the amounts on its own initiative. Lesbians,
often radicalized by feminism in general and influenced by the feminist health movement of the 1970s in particular, also mobilized in increasing numbers, frequently assuming leadership roles in AIDS struggles.
While the mainstream national gay rights organizations focused on issues of discrimination and budget appropriations, new voices emerged on the horizon. People with AIDS and their supporters discovered in early 1985 that ribavirin, one of the experimental drugs reported to inhibit reverse transcriptase, was available for two dollars a box in the farmacias of Mexico's border towns. Soon a steady stream of couriers were running shipments of ribavirin, along with an unapproved immune-boosting drug called isoprinosine, past U.S. customs and from there to AIDS patients all over the United States.
Elsewhere, wealthy gay men with connections found other pathways to therapies reported to have potential benefit. "There are some Americans in Paris these days who are not so much interested in abstract art or avant-garde literature as they are in saving their own lives," wrote Newsweek in August, a week after Rock Hudson became the most prominent "AIDS exile" to seek treatment with HPA-23. Embarrassed by stories of the "AIDS exiles," the FDA announced that it would permit the administration of HPA-23, along with the other antiviral AIDS drugs that had entered testing, on a "compassionate use" basis—a long-standing FDA mechanism for releasing experimental drugs on a case-by-case basis when requested by physicians for their terminally ill patients, in situations where no standard therapy is available. But the FDA spokesperson struggled to explain that the decision to permit compassionate use was in no way meant to suggest that HPA-23 actually worked . "There is no proven treatment for AIDS yet," he emphasized. "Everyone is assuming that this is a panacea, and there is none." The French, meanwhile, had been forced to discontinue HPA-23 in some patients because of its toxic effects on the blood and the liver.
The availability of drugs in other countries, however, only inclined the new AIDS activists to press for easier access by U.S. patients to a range of experimental compounds. Martin Delaney, at this time a Bay Area business consultant, former seminary student, and current ribavirin "smuggler," emerged as a key voice in these debates. "We don't know for sure how these drugs will work," Delaney told a community forum in the Castro district, the heart of San Francisco's gay community. "But it makes more sense than the next best thing, which is dying without trying anything." In October, Delaney held a press conference
to announce the opening of a new organization, Project Inform, which would conduct studies to determine the benefits of experimental drugs being used in the community, like ribavirin and isoprinosine. "No matter what the medical authorities say, people are using these drugs," Delaney told reporters skeptical of the idea of community-based research. "What we want to do is provide a safe, monitored environment to learn what effects they are having."
Some years back, Delaney himself had participated in an experimental trial of a drug to treat chronic hepatitis. The drug had cured his hepatitis but left him with permanent damage to the nerves in his feet. Delaney considered it a fair bargain; but the drug was thought too toxic, the trial was terminated, and the treatment never approved. It was an experience that would color Delaney's response to the AIDS epidemic. Who should decide what risks a patient can assume—the doctor or the patient?
Rights, Risks, and Ethics
The extensive literature on the ethics of clinical research reflects considerable emphasis on protection of human subjects in biomedical experimentation. This, however, is a rather recent development that has paralleled the rise in importance of the randomized clinical trial both in biomedical fact-making and in regulatory decision making. As historian David Rothman has described, the pivotal moment occurred in 1966 with the New England Journal of Medicine' s publication of a whistle-blowing review article by Henry Beecher, replete with disturbing, recent examples of unethical and potentially harmful experimental research. Beecher catalogued incidents of "investigators who had risked 'the health or the life of their subjects' without informing them of the dangers or obtaining their permission"—for example, withholding penicillin from servicemen with streptococcal infections as part of a study of an alternative therapy. These revelations were followed a few years later by public outrage and congressional hearings in response to news media disclosures about the Tuskegee syphilis study, conducted openly for decades under the auspices of the U.S. Public Health Service, in which hundreds of poor, black sharecroppers were denied existing treatment so that researchers could study the "natural history" of the disease. In 1974 Congress created the National Commission for the Protection of Human Subjects, which issued guidelines on research. In addition, the
NIH began requiring that each research center seeking federal funds for biomedical research on human subjects establish an "institutional review board" to evaluate the ethics of each proposed research "protocol" (the plan for the study).
As Rothman and Harold Edgar have noted, the irony in these protective measures and in the new regulatory regime at the FDA was that they ran counter to the egalitarian and libertarian trends of the 1960s and 1970s in general and to the critique of paternalistic medicine in particular. "Just when patients secured greater autonomy—the right to know a diagnosis, to accept or refuse treatment—the experts at the FDA and review boards controlled the right to regulate new drugs and research protocols." Soon AIDS patients and their advocates began rebelling against what they saw as well-intentioned but deadly paternalism. Activists like Delaney would exert a demand for greater patient autonomy by challenging medical authority from two directions at once. On one hand, they would insist that patients interested in trying experimental drugs should have the right to assume risks rather than endure the benevolent protection of the authorities. On the other hand, they would criticize certain approved and accepted research methods, like trials in which some patients received placebos, characterizing them as unethical for subjecting patients to unfair risks that the patients did not want to assume.
The State of the Art, 1985
As virologist and molecular biologists learned more about the life cycle of the virus, researchers began to speculate about other ways of halting its replication, besides interfering with reverse transcription. NCI researchers analyzed the different points of attack in an article published in September in Cancer Research . First, in order to infect a cell and begin replicating, the outer proteins of the virus (called the "envelope") had to bind to the surface of the cell. Perhaps this binding could be blocked through the use of antibodies; but since most AIDS patients produced antibodies to HTLV-III and became ill nonetheless, it might be that such antibodies were insufficiently protective. Second, after binding to the cell surface, the virus "enters the target cell by an as yet unknown mechanism." If this mechanism could be identified, perhaps entry could be blocked. Third, after reverse trasncription and integration of the viral DNA into the nucleus of the host cell, the virus proceeded to manufacture new viral proteins. The authors noted that this transcription process appeared to be
boosted by a protein, the product of a recently discovered viral gene called tat (for "transactivation"), a gene not found in other known retroviruses. A drug that interfered with this protein might also be an effective antiviral agent. Finally, the new viral proteins were processed and assembled into a fully formed new virus, which was released from the cell by budding. "Our knowledge of these steps is rudimentary at best," the NCI researchers acknowledged, though "interferons have been shown to inhibit the release of other retroviruses. …"
While this was all very nice in theory, the NCI researchers concluded that the best immediate bet remained the reverse transcriptase inhibitors, like suramin. Unfortunately, the early reports on suramin, based on a small Phase I toxicity study by NCI and NIAID, were proving to be mixed at best. The drug did seem to reduce viral replication in vivo as it had in vitro. But "it did not produce clinical or immunological improvement with the regimen used." A larger, Phase II trial would be needed to find out more about the efficacy of the drug. But the concerns about suramin were quickly confirmed a few months into the Phase II study. The drug was far too toxic: it appeared to have caused adrenal failure in several patients and may have hastened some patients' deaths. Later, some treatment activists would claim that the study had been poorly monitored and had subjected its participants to needless risk. The principal investigators, on the other hand, would offer the suramin study both as a cautionary tale and "as an example of how a clinical trial should be conducted": "Trials such as this one … prevent potentially harmful drugs from being distributed to large numbers of patients in the community."
Those skeptical about the viral hypothesis (see part one) interpreted the ongoing difficulties with treatment research as evidence of the inadequacies of the reigning causal models. "If we have agents that effectively inhibit the replication of this virus," said New York physician Dr. Joseph Sonnabend in a New York Native interview in October 1985, "but [those agents] make no impact on the course of this disease, I think it will make apparent, for some people, the actual role of HTLV-III in causing this disease." But research and media attention continued to focus on antiretroviral agents, and in early 1986, NCI researchers found themselves with a potential success on their hands.
"Waiting for the Right Disease"
Samuel Broder, the head of the NCI, had not been putting all his eggs in the suramin basket. In late 1984 he had put out the
word to the big pharmaceutical companies (the ones he considered capable of quickly bringing a drug to market): Send us anything you have on the shelf that might inhibit a retrovirus, and we'll do the assay to see if it halts replication of HTLV-III. Burroughs Wellcome, the North Carolina-based subsidiary of a large British firm called Wellcome PLC, submitted ten compounds, and in February 1985 one of Broder's researchers, Hiroaki Mitsuya, found that one of the compounds was a reverse transcriptase inhibitor with strong antiviral activity: azidothymidine, called 3&0374;-Azido-3&0374;-Deoxythymidine in full or just AZT for short.
AZT had a peculiar history. In the early 1960s, a researcher named Jerome Horwitz at the Michigan Cancer Foundation decided to design a drug that would keep cancer cells from duplicating. With funding from the NCI, and working with such unlikely ingredients as herring sperm, Horwitz and his coworkers synthesized a group of compounds called dideoxythymidines that were designed to look like nucleosides, the building blocks of DNA. In theory, these "nucleoside analogues" would substitute themselves for real nucleosides, thereby interfering with formation of DNA molecules. Without more DNA, the cancer cells would simply stop duplicating. In practice, the treatment was a complete failure. Horwitz gave AZT and the other dideoxythymidines to mice with leukemia, but the drugs showed no effect. "My colleagues and I said that we had a very interesting set of compounds that were waiting for the right disease."
Burroughs Wellcome had tested AZT against animal viruses but had dropped this line of inquiry since it was unrewarding. Now, after getting the good news about AZT from Broder, Burroughs Wellcome filed an "IND" (investigational new drug application) with the FDA. Phase I trials began in July 1985 with nineteen U.S. AIDS patients, under the auspices of the NCI and in collaboration with Duke University. Mitsuya announced the results of the six-week study on the last day of an AIDS conference the following January: AZT kept the virus from replicating in fifteen of the nineteen research subjects, boosting their immune systems (as measured by their T-cell counts) and relieving some of their symptoms. "It's not a dream drug," Mitsuya explained in a television interview, stressing the need for additional testing.
The formal publication of the study in Lancet in March 1986 spelled out more of the details. Researchers recently had discovered that AIDS was frequently accompanied by neurological impairments,
which indicated that the virus was also affecting cells in the brain. An effective therapy, therefore, would have to be capable of crossing a circulatory system defense called the "blood-brain barrier," a feat that many drugs could not accomplish. Fortunately, AZT did appear to cross the blood-brain barrier. In addition, though some subjects had experienced headaches or had developed low white cell counts, the drug could be tolerated relatively well. This was a relief, because AZT "might have been expected to produce intolerable side effects" (in the words of Jean Marx, the reporter for Science who described the trial), given the mechanism of drug action. AZT "fooled" the reverse transcriptase enzyme into using it, in place of the nucleoside it imitated, when transcribing the virus's RNA to DNA. Then, once AZT was added to the growing DNA chain, AZT's structure prevented any additional nucleosides from being added on: reverse transcription simply came to a halt at that point, and the virus stopped replicating. But the problem was that since AZT terminated DNA synthesis, one might logically anticipate that it would have harmful effects on the DNA in healthy cells.
Having shown initial evidence of relative drug safety , the researchers had accomplished the formal objectives of a Phase I trial. But there was nothing to prevent them from reporting the apparent good news about efficacy —the news that attracted media attention. "The results also suggest that at least some immunological reconstitution occurred in most of the patients …, and that a clinical response was obtained in some." However, these findings had to be treated cautiously, since simply being in a trial "may have a strong placebo effect in influencing such factors as appetite and sense of well-being, and it is even possible that improved nutrition may then induce changes in immune function." Only the next step—a so-called "placebo-controlled" Phase II study, conducted in "double-blind" fashion so that neither the subjects nor the researchers would know who was receiving AZT and who was receiving a placebo (a look-alike dummy pill)—could determine whether the observed clinical improvements were truly due to the drug. (This study would be funded by Burroughs Wellcome and conducted at a number of academic centers, including the University of Miami, where it was under the direction of Dr. Margaret Fischl, and the University of California at San Diego, under Dr. Douglas Richman.) The NCI researchers concluded with a summary of the questions that remained to be answered: "We cannot say whether AZT can be tolerated over a long time, whether viral drug resistance will
develop, or ultimately whether AZT will affect disease progression or survival in patients with HTLV-III-induced disease. These are issues which can be resolved only by appropriately controlled long-term studies."