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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."