A Ray of Hope in the Fight Against Aids

By Joe Levine

"This is not a cure. We don't want to overpromise to the thousands of people who have AIDS." Robert Windom, of the Department of Health and Human Services, chose his words carefully as he faced the press in Washington last ! week, determined not to raise any false hopes. Despite Windom's caution, the dramatic news he reported was bound to be en couraging to AIDS victims around the world: early results of clinical tests with an experimental drug called azidothymidine (AZT) had shown that it slowed the attack of the AIDS virus and seemed to prolong the lives of many of its victims.

The results were so remarkable, Windom said, that tests in a dozen medical centers were being halted so that control groups of AIDS sufferers -- who had been receiving only placebos, or dummy drugs -- could immediately begin treatment with AZT. Furthermore, Windom has petitioned the Food and Drug Administration for speedy approval to distribute the drug to thousands of other AIDS victims, but only those who have also suffered from Pneumocystis carinii pneumonia (PCP), a rare form of pneumonia that frequently afflicts AIDS patients. David Barry, vice president for research at Burroughs Wellcome, the pharmaceutical firm that produces the drug, stressed to reporters that AZT was "not a cure for AIDS but rather a treatment." Over the next few months, he said, "we will be continuing a very intensive research program to answer critical questions about the drug."

Across the country, nonetheless, the announcement set off a flurry of excitement and controversy. AIDS hot lines and doctors' offices were flooded with calls, community leaders warned about undue optimism, and doctors debated the ethical and medical issues raised by the early cancellation of the AZT study.

That study, designed by Burroughs Wellcome Co. in collaboration with medical specialists and AIDS experts, began in February and was scheduled to end in December; it involved 282 subjects. Some were victims of AIDS who during the previous four months had also suffered their first bout of PCP. The remaining subjects had ARC (AIDS-related complex); although they were infected with the AIDS virus, their symptoms were not as severe as those of full-blown AIDS. Each patient took a capsule every four hours. For slightly more than half the group, those capsules contained AZT. For the control group, the capsules contained a placebo, a harmless, inactive substance. The tests were "double blind" to ensure that results would be interpreted objectively; neither the doctors administering the tests nor the AIDS victims knew who was getting the real drug. That information was known only to a few Burroughs Wellcome officials, who monitored the results flowing in from the participating centers.

From the start, the company and an independent review board had agreed that if AZT proved to be toxic, the patients would immediately be taken off the drug and the test halted. But if AZT turned out to be clearly beneficial, it would immediately be offered to those patients who had been receiving only the placebo -- which would in effect also terminate the study. But everyone, including Dannie King, Burroughs Wellcome's AZT project director, was reasonably confident that the study would run its full course. Said King before the results were known: "It's going to have to be one extraordinary effect to stop that trial."

The effect was indeed extraordinary. By mid-September there had been 16 deaths among the 137 patients receiving the placebo and only one among the 145 taking AZT. Those being given the drug developed fewer AIDS-associated infections, gained weight and showed growing numbers of helper T cells (the immune-system cells attacked by the AIDS virus) in their bloodstream. The independent review board of AIDS experts, set up by a division of the National Institutes of Health in February, promptly recommended that the study be halted and the drug given to the placebo patients.

AZT was first synthesized in 1964 by Jerome Horwitz of the Michigan Cancer Foundation as a possible anticancer drug. But it proved ineffective against tumors and was largely forgotten until 1984, after Robert Gallo of the National Cancer Institute (NCI) and Luc Montagnier of the Pasteur Institute in Paris independently isolated the AIDS virus.

Some viruses consist of a segment of double-stranded DNA surrounded by a protein skin. When they invade a cell, the DNA takes over the cell's genetic machinery and orders it to produce copies of the virus, which escape to infect other cells. The victim cell is often killed in the process. But the AIDS virus is a so-called retrovirus and contains single-stranded RNA. Alone, RNA lacks the ability to conquer cells, but retroviruses carry an enzyme called reverse transcriptase. When the AIDS virus invades an immune-system T cell, the enzyme enables the viral RNA to convert to DNA, take over the cell's machinery, produce copies of itself and disable the cell.

Scientists at Burroughs Wellcome suspected that the long-unused AZT might be what was needed to stop the AIDS virus. They discovered that when the drug enters a human cell, it is converted by a human enzyme into a "false sugar" ) that resembles, but is not identical to, the sugar used by the AIDS virus' reverse transcriptase to help build a DNA strand. If the AIDS enzyme mistakenly adds a false sugar molecule to the DNA chain, DNA synthesis is halted. So, they reasoned, further reproduction of the virus would be stopped.

At the request of Burroughs Wellcome, Samuel Broder and his colleagues at NCI and other institutions tested AZT in late 1984 and early 1985 on AIDS- infected human cells in the test tube and found that it seemed to interfere with viral reproduction. Subsequently, they began testing the drug on 19 AIDS and ARC victims, and early this year reported in the British journal Lancet that the subjects had shown remarkable improvement. There was, however, at least one troublesome side effect: a reduction in their blood-cell counts. It was as a result of this early work that Burroughs Wellcome requested and was given FDA approval for the larger study that began in February.

When word of the early success with AZT began circulating in the medical community, it set off a debate over further AIDS testing. If the drug seemed to slow the progress of the disease, some researchers asked, was it ethical to conduct tests in which half the patients got placebos and thus had no chance to benefit from the treatment? Albert Jonsen, a professor of ethics at the University of California, San Francisco, concedes that the placebo question is "an agonizing problem," but he insists that placebos are the only way to find out "whether there is an effect that is attributable to the drug and not to chance."

Harmon Smith, a professor of theology at Duke's divinity school and a professor of family medicine at the university's medical school, strongly supports the use of placebos -- especially when early results, no matter how heartening, are inconclusive. "The scientific and clinical value of a trial may well depend on a placebo being tested simultaneously with an experimental drug," he says. Still, shouldn't researchers make exceptions in cases of AIDS, an always fatal disease? "It may sound harsh and unfeeling," Smith says, "but I think the answer is no. The decision can't be directed by any feelings toward the subject population."

But for many doctors, the new, dramatic results left little room for debate. "If the data are so compelling," says Dr. Jerome Groopman, AZT project director at New England Deaconess Hospital, "I don't think you can justify doing any more placebo trials."

! Last week's announcement raised other questions about ethics. The expected quick approval by the FDA to allow the drug treatment for any AIDS victim who has also had PCP will exclude half the 11,000 AIDS victims still alive in the U.S. Says Holly Smith of the San Francisco AIDS Foundation: "For the person who does not qualify, it provides no ray of hope. In fact, it may increase levels of frustration, and stress and frustration can create negative medical effects." But the study established the effects of AZT only on those AIDS patients who had had PCP. The drug could act differently on those with other symptoms. Says Dr. Margaret Fischl, who led testing of AZT at the University of Miami Medical School: "We tested a specific group at a specific dose. We need to be restricted to that group and that dose until we get more experience." Anthony Fauci of the NIH estimates that Burroughs Wellcome now has enough AZT to supply about 2,500 patients. But the company is expected to increase production of the drug by the time the FDA approves its wider use. Says Fauci: "It's conceivable that AZT might be available in the market by next January."

There will be plenty of customers. Last week, a few hours after a nationwide toll-free hot line for AZT inquiries (800-843-9388) was established at NIH, operators averaged more than 100 calls an hour. The phones were also ringing at AIDS crisis centers across the country. "People want a validation," said Michele Reis, director of educational services at the Howard Brown Memorial Clinic in Chicago. "They want to know, 'How do we get it?' " Reported Msgr. Fred Tondalo, executive director of Center One in Fort Lauderdale, an AIDS community group: "We got a lot of mothers calling, asking if it was true that they had found some miracle drug." Those familiar with past disappointments were more realistic. "This gives people who have the disease another option, albeit just a prolongation of the inevitable," said Robert Kunst, director of the Miami-based lobbying group Cure AIDS Now. "I just hope this is not a repeat of what the French pulled off last year when they tooted their own horns saying they had found a cure."

The evidence presented last week suggested this is not the case. But at week's end AIDS researchers were stressing that the study was terminated too soon to learn if the drug prolongs life for more than just a few months or if it has any serious long-term side effects. And they were confident that AZT is not the ultimate weapon against AIDS, that other, more effective drugs will come along. "This is not the end of the story," says Jerome Groopman. "It's exciting to have a drug that appears to benefit patients with AIDS, but there's a lot more work that has to be done."

With reporting by Bambang Harymurti/Washington, with other bureaus