TIME: Almanac 1993/TIME Almanac 1993.iso/time/caps/86/86capmed.1

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                è┘╡                                                          September 29, 1986

MEDICINE

A Ray of Hope in the Fight Against AIDS


While not a cure, an experimental drug called AZT prolongs the
life of patients


"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
encouraging 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 capsule
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 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 does. We need to be
restricted to that group and that does 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 inquires (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."

--By Joe Levine.  Reported by Bambang Harymurti/Washington with
other bureaus