Even as excitement grows that new treatments have vastly
improved the outlook for AIDS patients, a cruel irony has
emerged--those who were most conscientious about treating their
disease in the past may have put themselves beyond help from
the promising new discoveries.
Widely heralded new treatments have raised hopes that AIDS,
which has killed an estimated 343,000 Americans, may finally
become a manageable disease, that new drug cocktails built
around protease inhibitors could suppress the virus to the
point of being undetectable. Researcher David Ho was named Time
magazine's "Man of the Year" for his part in its development.
But in the months since protease inhibitors raised worldwide
hopes, some researchers and clinical practitioners report that
many patients--their estimates range from 5% to 30%--will get
little or no benefit from the new treatments.
These patients, who took long courses of AZT and other earlier
antiviral drugs, in effect strengthened the surviving AIDS
virus in their systems, some experts say. In these cases, the
virus spawned mutations that the earlier drugs
missed--mutations that now flourish beyond the reach of current
protease inhibitor therapy.
"The irony is that what we as physicians did a few years ago in
trying to fight the disease has left a number of patients with
fewer options," said Daniel Kuritzkes, an AIDS researcher at
the University of Colorado who is working on the resistance
"We haven't seen the end of the dying," said Michael Gottlieb,
pioneer AIDS physician who gave the disease its name as a UCLA
researcher in 1983, and now heads a clinic in North Hollywood.
"A lot of patients have burned bridges, but of course we didn't
know we were doing that at the time," Gottlieb said. "Some
survive longer than they would have, but they may eventually
become resistant and may very well die of AIDS in the next
couple of years."
"Among the patients I see, I would say that as high as 20% are
in this situation."
Other estimates range from 30% by Andre Pernet--vice president
of research and development for Abbott Laboratories, which
developed a protease inhibitor--to less than 10% by Kuritzkes
and Douglas Richman, a leading researcher at UC San Diego.
The protease inhibitor therapies are still a major advance for
most patients. "Nothing is 100% in this world, except death and
taxes," Richman said. "But this is pretty damn good."
The new treatments rely on a new drug--a protease inhibitor
designed specifically to attack the AIDS virus--taken in
combination with two of the older antivirals. The combination
is commonly known as a protease cocktail.
The drugs must work together. The ultimate effect is greatly
weakened if an older drug is ineffective against the mutated
No formal studies have been conducted to determine how
widespread the resistance problem is, and there is currently no
way to predict with certainty which patients will turn out to
"At first there is a 100% response to the cocktail," said
Pernet. "It's over time that the virus escapes the cocktail.
About six to 12 months after treatment begins, probably as many
as 30% escape it."
This resistance problem began, inadvertently, in 1987 when
clinical trials produced promising evidence that a drug
developed for cancer therapy seemed to stop the progression of
The drug, AZT, became the first AIDS medicine known to work
directly on the virus. Until then, doctors could treat only the
devastating illnesses caused by the virus's crippling of the
immune system--not the virus itself.
Ideally, drugs that target viruses are taken in combination
with other anti-virals. But as AZT was the only drug of its
type available at the time, it was given by itself, called
Initial results were hopeful.
"People talked in those years about the virus becoming
'latent,' " Gottlieb said. "But what we know now is that the
virus is never latent. From the time a person acquires HIV,
this virus is an active infection."
When fully active, HIV replicates at the astonishing rate of 10
billion times a day, Richman said. AZT at least slowed the
rate. But the HIV never stopped reproducing. Worse yet, it
sometimes makes deadly mistakes.
Approximately every millionth replication, according to
Gottlieb, the virus turns out an imperfect copy, a mutation.
"There is no evil purpose for the virus," said Pernet, "it's
just sloppy in its replication. And most of the time, the
mistakes do not matter."
But occasionally, a mutation proves resistant to whatever
antiviral drug the patient is taking, freeing that mutation to
multiply rapidly. The attack on the immune system resumes full
Until the patient's health began to seriously falter--usually
about two years after starting AZT therapy--doctors did not
know the drug had been somehow compromised. Many of these
patients were switched to another drug, ddI, that had in the
meantime been shown to be effective against HIV.
Again, good results were obtained at first, but eventually,
resistance often won out with each new drug.
"The drugs came along one at a time when we did not appreciate
the rapid rate of reproduction, the high frequency of
mutation," said Gottlieb. "It was a resistance accident waiting
There were patients who, for a variety of reasons, did not take
any of the monotherapies--which may have unwittingly put them
in a stronger position today.
Matthew Rosen discovered in December 1989, just before his 27th
birthday, that he was HIV-positive. His physician suggested he
begin taking AZT.
"But I didn't want to take it right then," said Rosen, now 34.
"I had the luxury of not being very sick. I sort of considered
AZT to be a kind of trump card if I did get sick."
Eventually, his doctor insisted. "He said, 'We're in the
arm-twisting stage, nearing the full headlock stage,' " Rosen
Still, Rosen held out and his health remained good. "It was
just dumb luck" he refused, Rosen says now.
By 1990, doctors began experimenting with combination
therapies, first with AZT and ddI, and then AZT with a drug
called ddC. Results were mixed, but somewhat better than
But the next big step in fighting the virus directly did not
come until 1995, when the first clinical trials for a protease
inhibitor were announced.
These new drugs attacked an enzyme called HIV protease, which
is crucial to the virus' ability to replicate. The older drugs
also curbed replication, but at another point in the virus'
life cycle. In a multi-drug treatment, the virus is attacked at
several stages of its reproduction cycle.
In July, scientists announced at an international AIDS
conference that protease inhibitor therapy could drastically
slow the replication of the virus.
The new drug was the breakthrough, but other drugs had to be
included in the therapy to prevent emerging mutations from
multiplying. Therein lay the problem for patients already
resistant to the older drugs.
"For those people, just to add the protease is almost
monotherapy," said Jules Levin, a former Wall Street trader who
founded the National AIDS Treatment Advocacy Project. The
project is well known among medical professionals and patients
for its detailed Internet Web site that includes up-to-date
information on clinical trials and test results.
Levin, HIV-positive for eight years, knows this from personal
"Five years ago I started taking AZT," he said. "About two
years ago, we added 3dc."
AZT and 3dc are two key drugs used in the protease inhibitor
Researchers are working on the resistance problem. Several
trials are now being conducted with combinations that include
two protease inhibitors and only one older drug. Ho, the head
of a New York AIDS research clinic who got the Time award, is
conducting a study that uses four drugs: two protease
inhibitors and two older ones.
Abbott labs has begun testing a protease inhibitor designed to
be five times more powerful than those now available. The hope
is that with all that potency, the new drug will be able to
keep the virus in check by itself.
Glaxo Wellcome is testing a drug that researchers hope will
leave virtually no resistant viruses, even though it works in a
manner similar to AZT.
Levin is on one of the newer regimens--he declined to specify
which--and is cautiously optimistic. "Because of what I know
has happened in the past, I'm trying not to get overconfident,"
"But in the last few months, my test results have been very
The new regimens might come too late for George Prindle, 38,
who exemplifies those who may be trapped by the aftereffects of
"I've seen the whole spectrum of drugs come and go, that's for
sure," said Prindle, at his home in La Habra Heights.
He has been HIV-positive for 11 years, and until he had to stop
working eight years ago, ran the business operations of an
animation company that did work for such firms as Disney and
ABC. His partner in the business, as well as in life, died five
years ago of complications due to AIDS.
Prindle has been on AZT steadily for almost nine years. At
various times, he also has taken courses of ddI and ddC, as
well as other antivirals. These drugs may have helped keep him
alive, but resistant viruses flourished.
He was enrolled in early clinical trials for protease
inhibitors and has already been on several different protease
None worked. Recent tests showed that he had 1.25 million
particles of HIV per cubic centimeter of blood. By comparison,
some patients in whom the new therapies are successful have an
undetectably low virus blood level.
Prindle said he has been told by his doctor that unless a new
therapy is made available soon, he probably has only about six
months to live.
"Well, for the last 11 years they've been telling me I'd be
dying in two years, and I'm still here," he said with a smile.
"Maybe they're wrong this time, too."
For Rosen, who refused the earlier drugs, the outlook is far
more favorable. He finally decided to begin drug therapy.
"This time, I think there is real data to indicate that this
particular drug regimen holds the virus in check," he said.
Just before Christmas, he took his first protease inhibitor
"I'm a little nervous," he said, "but I think the time is
DE ACQUIRED IMMUNE DEFICIENCY SYNDROME; HUMAN IMMUNO DEFICIENCY
VIRUS; AZIDOTHYMIDINE (DRUG); PROTEASE INHIBITORS; MEDICAL
TREATMENTS; MEDICAL RESEARCH
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