AZT Data Lag Hinders Use of AIDS Drug

Last summer, researchers announced preliminary results of a pair of clinical trials that were expected to markedly change the way doctors used the drug AZT in the battle against AIDS.

The first study, in patients with full-blown AIDS, showed that low doses of the drug were just as effective as--but safer and better tolerated than--the 1,200-milligram-a-day dose approved by the Food and Drug Administration.

The second study, in asymptomatic patients infected with the human immunodeficiency virus, showed that low doses of the drug slowed progression to full-blown AIDS. An oversight panel was so impressed with the drug’s life-prolonging potential that the trial was cut short and AZT was offered to subjects who previously had been receiving a worthless placebo.

But neither study has yet been published in a medical journal, the traditional conduit through which word of medical advances is transmitted to doctors in the field. And a promised conference by the National Institute for Allergies and Infectious Diseases to develop recommendations on use of the drug--and speed it to doctors in the field--has yet to materialize.

The lag has left confused doctors reticent to act until they have more concrete data and direct guidance from the government.

The result, some doctors and patient advocacy groups charge, is that thousands of patients around the country are being harmed--either because their doctors are giving them too much AZT or, in the case of patients without symptoms, none at all.

The controversy casts a spotlight on the sluggish pace at which research results are disseminated to physicians in the field, especially in an epidemic like AIDS where the state-of-the-art is changing rapidly. It also raises questions about whether prestigious medical journals--which insist they have waived their rules against pre-publication publicity in the case of public health emergencies like AIDS--have done enough to communicate that policy to scientific investigators.

“It is an outrage,” said Dr. Neil Schram, a Harbor City physician who, as head of the American Assn. of Physicians for Human Rights AIDS Task Force, learned last week of a Southern California patient who had to be hospitalized with AZT-related anemia because his doctor was giving him the higher dose. “Most physicians lack the time and energy to seek out this information. We simply have no good way of communicating rapidly in the medical profession.”

“Clinical trial results are meaningless if they are not translated rapidly into clinical practice so they may improve and prolong the lives of people who are sick,” added the New York chapter of the AIDS Coalition to Unleash Power (ACT UP) in a letter last month to researchers at NIAID and officials of the Food and Drug Administration.

Dr. Bernard Bihari, medical director of New York’s Community Research Initiative, said doctors outside the major centers of the epidemic may not even know about last summer’s findings.

Even in such hard-hit cities as New York, Los Angeles and San Francisco, some well-informed physicians are reluctant to deviate from the FDA-approved dosage guidelines without seeing detailed evidence--even though top federal health officials insist that enough information is currently available for doctors to make rational decisions on the drug’s use.

Though the results of the study in asymptomatic patients were widely interpreted as giving doctors the green light to use AZT, NIAID specifically stated that it was “making no recommendation to physicians regarding clinical practice.” Instead, the agency promised to convene a conference “in the near future” to develop recommendations on use of the drug.

That conference, tentatively scheduled for November, and then December, has yet to take place.

Meanwhile, many doctors are holding off. Some are concerned that insurers won’t pay for a drug that could cost more than $3,000 a year until the FDA broadens its labeling recommendations to include low-dosage recommendations for both symptomatic and asymptomatic individuals. Others are reluctant to give the drug to clinically healthy infected individuals, fearing that the virus may become resistant to the drug--rendering it useless when the patients become sick.

“Many doctors, even AIDS specialists, are perplexed,” Bihari said. “We really want to see the detailed data about different subgroups of patients.”

Dr. Anthony S. Fauci, director of NIAID and the federal government’s top AIDS researcher, blamed the delays on “an accumulation of multiple bureaucratic and trivial reasons.”

“I would have liked to have seen (the conference take place) sooner,” Fauci said in an interview. Now tentatively scheduled for February, the conference “is later than I would have liked it.” But he insisted that “there is enough data available for a doctor to make a rational decision” on whether to institute treatment with AZT and at what dosage.

Some top AIDS practitioners disagree. Dr. Marcus Conant of San Francisco said he is reluctant to “practice medicine by press release” and so he is withholding the drug from some people who NIAID suggests might benefit until he has seen detailed data and can weigh the risk/benefit ratio.

For example, while the August announcements implied that all patients who are HIV positive and have helper T-cell counts of between 200 and 500 per cubic millimeter of blood would benefit from the use of AZT, Conant generally will not initiate therapy if a patient’s T-cell count has been holding steady at, say, 400. Helper T-cells, which are destroyed by HIV, are key sentinels of the immune system; most healthy people have counts of 800 or more.

Conant said that, pending release of the data, he prefers to prescribe the drug only when a patient develops symptoms or when his T-cell count and other tests indicate a declining immune system.

“We have a real dilemma,” acknowledged Dr. Paul Volberding, the UC San Francisco researcher who was the principal investigator in the federally financed study that uncovered the usefulness of AZT in asymptomatic patients. “We want the information to get out as quickly as possible. At the same time, we want the data to be carefully analyzed.”

Volberding said that three months elapsed between the August press release and the time that his group finished their analysis, wrote up their findings and submitted an article to the New England Journal of Medicine in November.

The New England Journal spent another six weeks circulating the manuscript to expert reviewers for critical commentaries, said Dr. Arnold S. Relman, the publication’s editor-in-chief.

“Six weeks is about standard,” Relman said. “Our responsibility is to make sure that the information is as reliable and complete and accurate as possible.” The editors will now review the comments and, if necessary, order revisions in the paper before publication. That will take weeks or even months. They may even reject the paper entirely, forcing further delays in getting the information disseminated.

“We know from long experience that every scientific paper we get has deficiencies and can be improved,” Relman said.

The critics charge that the paper’s authors have been reluctant to present their detailed results pending publication of the article, fearing that the journal might then reject the article.

Volberding, on the other hand, said he is holding back the detailed data from public release because the “checks and balance” provided by the peer-review system will mean the data will be more definitive when it is finally released.

Nevertheless, Relman insisted that “if the information is of urgent concern to the public welfare, we don’t penalize the authors at all” for prepublication publicity.

“We have tried to make it clear: our rules on prepublication publicity do not apply to AIDS or to HIV infection.”

Some critics also blame AZT’s manufacturer, Burroughs Wellcome Co., for delays in submitting the new data to the Food and Drug Administration.

Since AZT was already approved for use in AIDS patients by the agency in 1987, what Burroughs is asking the agency to do now is to relabel the drug--in effect, to officially sanction the drug’s use in patients without symptoms who are infected with HIV. Such an “expanded label” would make it extremely difficult for insurers to avoid paying for the drug.

Kathy Bartlett, a spokeswoman for the company, said all of the data has now been submitted. “I don’t know the specific dates,” she said. “It went in pieces.”

In any case, an FDA advisory committee is slated to meet Jan. 29 to consider expanding the labeling and lowering the approved dosage.

“It is hard to point a finder and say who is at fault,” said Martin Delaney, co-founder of Project Inform, a San Francisco-based clearinghouse on treatment information for HIV. “It is another example of the collective grinding of the bureaucratic gears.”

Delaney urged doctors not to be paralyzed by the lack of detailed information. “Doctors will always be looking at judgment calls,” he said. “That is not going to change by the publication of the data. Waiting for someone else to make a decision for you is a formula for disaster in an epidemic.”