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Miles,
I'll try (it's 7 pages):
January 19, 1997
Drug Combinations Are Changing the
Outlook for AIDS
In This Article:
The Potential: Trying to Keep Up With Innovations
The Challenge: Restoration to Normality?
The Regimen: Cutting It Down to a Few Pills
The Outlook: Conflicting Views on Declaring Cure
By LAWRENCE K. ALTMAN
n the last year, the widespread use of combinations of new and
older drugs has changed the face of AIDS, promising to transform
a fatal infection to a manageable chronic disease.
There are several different combinations, many of which include the
new protease inhibitor drugs. All can drive the amount of HIV, the
AIDS virus, below the levels of detection in the blood for up to 18
months, which is as long as testing has been done.
With such therapy, some individuals have come off their death beds
and many who were less seriously ill are leading more normal lives.
"The good news is that there are a bunch more smiling faces in my
clinic today than were there a year or two ago," said Dr. Julio
Montaner, an AIDS expert in Vancouver, British Columbia.
But for an unknown number of other people, the drugs are failing. For
them, combination therapy is another in a long list of bitter
disappointments in AIDS.
In the wake of the initial flush of success, many important problems
and questions have emerged. Among those cited in interviews with 20
experts were:
-- Has publicity about the initial wave of success created unrealistic
expectations about a therapy for which long-term effectiveness and
safety are unknown?
-- Is the therapy failing in many people because they took the wrong
combinations, before doctors fully understood how the drugs should
be prescribed?
-- Can an AIDS-damaged immune system ever be restored to
normal?
-- Are health officials doing enough to monitor strains of HIV that have
become resistant to new therapies?
These are among the problems and questions that 21,000 experts will
discuss at a five-day scientific meeting on AIDS in Washington starting
on Wednesday, along with perhaps the biggest question in the minds of
everyone with AIDS: Can the disease be cured?
Although no one knows exactly how many people use combination
therapies, it is estimated that among the roughly 750,000 people
infected with the human immunodeficiency virus, tens of thousands of
people in the United States are using the new therapies. And there is
no question that many doctors' practices have changed dramatically.
Dr. Jeffrey Greene said that in the 13 years he has been an AIDS
doctor in New York, he has made house calls about twice a month on
dying patients who were too sick to come to his office. "I have not
made a house call in six months," Greene said. "It's pretty incredible."
At Case Western Reserve University Hospitals of Cleveland, Dr.
Michael Lederman said that on average about eight of the 650 patients
in the hospitals' AIDS clinics died each month over the last three years.
But the number of the hospitals' AIDS deaths has fallen in recent
months, and in December, for the first time, there were none.
Dr. Chris Tsoukas, an AIDS expert at McGill University in Montreal,
said the new therapies had contributed to about a 50 percent decline in
the daily number of AIDS patients at several hospitals in Canada.
Tsoukas said that his group cared for about 1,000 people infected
with HIV, and that each day in recent years eight to 16 of them were
in the hospital. But Tsoukas added, "For the first time in the 14 years
that I have been practicing, we have had not had more than three
patients in the hospital in a single month."
Clearly the era of treating HIV with a single drug is over, and the new
combinations appear to be the most potent therapy developed in the
16-year battle against acquired immune deficiency syndrome, experts
said.
But too little time has passed for anyone to know whether the drugs
will lose their effectiveness and after what period, and some experts
are concerned that the gains have been oversold as victory against the
disease.
"A triumphant attitude has emerged that makes it sound like we are on
the verge of solving this whole thing," said Dr. Ronald Bayer, a
professor at the Columbia University School of Public Health in New
York.
Bayer, who has been interviewing doctors who have treated AIDS
from the beginning, for an oral history project, said: "The thing that is
amazing is how so many have forgotten that we have seen moments of
what appeared to be great promise quickly turn to disappointment."
One example is AZT, which, though effective, is not the cure that some
people had hoped it would be. Another is a genetically engineered
product known as recombinant CD-4, which failed to have any benefit
in clinical trials.
A number of patients have not been helped by combination therapies,
although again, no clear numbers are available. But one reason for
some of the failures has become clear. Some doctors had been tacking
on a protease inhibitor to whatever else a patient was taking. That
practice appears not to work in many cases.
Many experts now say that at least two new drugs should be used for
initial anti-HIV treatment or when a switch is made from a failing drug
regimen. And the drugs must be started simultaneously to avoid drug
resistance.
"Doctors really did not appreciate that point" when protease drugs first
became available a year ago, said Dr. Roy Gulick, an expert at New
York University. Thus, he and other doctors said, many patients were
started on a drug regimen that will ultimately fail for a large number of
them.
Guidelines published in The Journal of the American Medical
Association in July suggest using at least two new drugs, and
practitioners have been learning this independently through experience
and in discussions with one another. But the Food and Drug
Administration has approved the use of a protease inhibitor alone.
The reality, experts said, is that no one knows what proportion of
those who are taking the drug combinations are benefiting from them
or failing to do so. Practitioners generally do not track such information
the way researchers did in the clinical studies that first showed the
benefits of the combination therapies.
"The hype around this is unfair," said Dr. Ian Weller, an expert at
University College and Middlesex School of Medicine in London. "We
should be cautiously optimistic, but we have taken three paces forward
when we should have taken one in terms of what messages we are
giving to the community. The downside is that many patients are setting
their sights too high."
The Potential
Trying to Keep Up With Innovations
he Food and Drug Administration has approved the marketing
of three new protease drugs since December 1995 under its
plan to accelerate development of AIDS drugs, bringing to nine the
total number of drugs approved for combating the disease. The
agency's approval of protease inhibitors was based partly on a few
short studies that had involved small numbers of patients.
If the drugs are stopped, the virus bounces back. Based on current
knowledge, the drugs must be taken for a lifetime.
Doctors say that they are just beginning to learn how to use the drugs
most effectively. The FDA is investigating a suspected new
complication from protease inhibitors -- spontaneous bleeding among
hemophiliacs.
Gulick, the New York University expert who helped lead one of the
major combination studies, said, "Things are changing almost faster
than we can get the word out to people."
So much so that Dr. Victoria Sharp said that her team of AIDS
doctors at Beth Israel Medical Center in New York had added an
extra set of weekly conferences devoted to keeping abreast of new
developments in protease drug combination therapy and discussing
how to use them in managing difficult cases.
To help clarify therapy options, the National Institutes of Health have
appointed two panels to develop new guidelines and update old ones
for treating HIV infection. Their reports are scheduled to be issued
later this year.
One of the important aspects of combination therapy is measurement.
The effectiveness of the therapy would be largely unknown without
new tests to measure the amount of HIV, the so-called viral load, in
the blood.
Such monitoring is now considered crucial in guiding therapy. A patient
can continue the same regimen as long as viral load is low. A significant
rise in viral load can signal the need to change therapy.
But some private and state health insurance plans do not pay for
viral-load tests that may need to be done several times a year, each at
a cost of $100 or more. Doctors said that when they could not use
viral load to direct treatment, patients were not receiving optimal care.
The total cost of combination therapy can be as much as $15,000 a
year, and the amount paid by insurance varies with policies.
And with more drugs available to combat HIV and the many
opportunistic infections that can occur as complications of AIDS, the
number of potential combinations increases substantially and the
number of studies that can be done far exceeds the ability to pay for
them.
"If you talk to investigators around the country you will hear that many
have studies that are just languishing," particularly the long-term ones,
said Dr. Donald Abrams of San Francisco General Hospital, "and I am
not sure we are currently learning how to best use them."
Dr. Fred Valentine, an AIDS expert at New York University who
headed the FDA's advisory panel on HIV drugs, said that the apparent
success of combination therapy confronted scientists, drug companies
and health officials with a major problem: How can enough patients be
recruited for the studies that are needed or planned to develop the
simpler regimens and better therapies that are still needed?
The Challenge
Restoration to Normality?
major question that has not been answered is whether a ravaged
immune system can be restored to normal functioning. Some
evidence of change in the immune system has been observed, but not a
reversal of the damage done by the AIDS virus.
Soon after combination therapy begins, two things usually happen.
One is that the amount of AIDS virus in the blood drops. The other is
that the number of special immune cells in the blood, known as CD-4
cells, rises and then reaches a plateau at less than a normal level.
Until the viral load measures were introduced, the CD-4 count was the
main laboratory test used to follow an individual's course and to guide
therapy.
"The CD-4 tells you where you are in a disease and the viral load tells
you where you are going in the disease," said Dr. Anthony Fauci, who
heads the National Institute of Allergy and Infectious Diseases.
"If your CD-4 count is a normal 1,000, even if your virus level is high,
right now you are in good shape," Fauci said. "But if your virus level is
high, you are going in the wrong direction. If your CD-4 count is low,
say 50, even if your viral level has been brought down to undetectable,
you are at an advanced stage of disease."
If the immune system of an AIDS patient is back functioning fully, it
might be possible to reduce drugs to prevent pneumocystis pneumonia
and other infections that thrive in people whose immune systems are
damaged. No one knows how high an individual's CD-4 count would
need to rise to make it practical to stop preventive drugs. In fact, it
may never be possible.
Research by Dr. Clifford Lane at Fauci's institute suggests that when
an AIDS patient's CD-4 count drops, certain types, or clones, of
CD-4 cells are lost.
These are the ones that may allow the immune system of such a patient
to respond to the specific infectious agents that cause opportunistic
infections in AIDS. Then, when the CD-4 count rises after an
individual starts combination therapy, the overall number of CD-4 cells
increases.
"You have more of the same clones," Fauci said, "but if you have lost
certain clones, that loss may be permanent and the individual may not
respond to opportunistic infections as a healthy person would."
The observation that the CD-4 count does not fully return to normal
suggests that the new therapies do not completely reverse the damage
the immune system incurs from long-standing HIV infection. And that
leaves researchers with a new challenge: to find new ways to try to
restore the immune system to normal. Tests are under way to
determine whether IL-2, a substance that the body normally uses to
allow CD-4 cells to multiply, will work.
The Regimen
Cutting It Down to a Few Pills
ombination therapy regimens are arguably the most demanding
of any in medicine. An individual must swallow dozens of pills a
day, and the number can exceed 60 for those who need additional
drugs to combat opportunistic infections. Some combinations include
two drugs, others three.
Depending on the drugs in the combination, the regimen requires a
person to take some drugs on an empty stomach and others with food.
Additionally, some drugs must be refrigerated. Also, some protease
inhibitors can drastically alter the potency of other drugs, causing
serious unwanted effects.
So a major goal is to develop new drugs or reformulate existing ones
so that a pill could last a day or contain more than one drug.
Until simpler regimens are developed, combination therapy can fail for
many reasons. Among them are failure to adhere to the schedule,
inability to fully absorb the drugs because of AIDS-related intestinal
upsets, and strains of the virus that are resistant to drugs.
HIV resistance to AZT was a common problem in the past. About 15
percent of new AIDS cases on the East and West coasts of the United
States are caused by HIV strains resistant to AZT.
Experts say that the possibility that strains of HIV will emerge that are
resistant to combination therapies is a frightening one. In theory, a
combination of two or more drugs deals the virus such a blow that
HIV cannot multiply and resistance does not have a chance to evolve.
But the theory depends on all the drugs being taken as prescribed.
But people generally dislike taking pills regularly and many fail to finish
something as simple as a recommended course of antibiotics for
common infections. In AIDS, skipping just a few doses can be fatal
because it can allow drug-resistant strains of HIV to take over.
"Even when patients feel well and have responded to therapy
beautifully," said Valentine, the NYU expert, "the schedule of taking
drugs several times a day reminds them that they have a lethal illness,
and that is tough to take."
No one knows what proportion of new HIV infections are the results
of strains already resistant to protease inhibitors and how often
resistance occurs among those taking the combinations. The reason is
that such monitoring is not done on a systematic basis even by
research-oriented AIDS groups.
"Not a lot of work is going on in looking at people who recently
became infected and trying to identify what proportion are resistant to
drug X or Y," said Dr. Sten Vermund, who heads the department of
epidemiology at the University of Alabama in Birmingham. "We are
waiting for some leadership on this arena."
Dr. Lawrence Corey of the University of Washington in Seattle said
health officials are lagging in creating programs to monitor drug
resistance for HIV and other viruses. But such viral surveillance
systems are about 50 times more costly than those for bacteria, Corey
said.
The Centers for Disease Control and Prevention in Atlanta are
planning a pilot national survey of HIV resistance similar to programs
they conduct for drug-resistant bacteria, said Dr. Harold Jaffe, an
official of the federal agency.
Development of resistance to drugs does not make the virus more
virulent but increases the difficulty of treating HIV. So a deep concern
is that individuals who develop protease-resistant strains will transmit
them to others. If this happens often enough, the resistant strains could
create a significant public-health problem.
Because of the costs of combination therapy and the likelihood that
resistant strains will develop among people who do not adhere to the
demanding schedules, many experts have discussed whether doctors
should withhold such therapy from those individuals they judge to be
potential non-compliers.
Bayer, who has been holding meetings to discuss the problem at
Columbia, said, "The issue is of major concern and one with which we
are hardly grappling."
The Outlook
Conflicting Views on Declaring Cure
he ultimate success of combination therapy would be to cure
AIDS, a concept that has been so far from conventional thinking
that few experts have bothered to come up with such a definition. Thus
there is widespread confusion about what to call a cure.
Proof would require a process of several steps starting with treating an
infected individual. After blood tests showed no evidence of HIV
multiplication and no evidence of the virus's genetic material hiding in
cells for a period of time, then the individual would have to agree to
stop therapy and undergo frequent testing to determine if the virus
returned.
There could be reappearance after therapy is stopped, if HIV finds a
sanctuary, for example in the brain or semen.
One reason for skepticism about curing AIDS is that the virus
integrates itself into the machinery of normal cells.
Dr. David Ho, the head of the Aaron Diamond AIDS Research
Center in New York, has developed a mathematical model that
assumes that the life span of the cells that HIV infects is up to three
years. If those cells die and no HIV is left in the body, then Ho
theorizes that the cells that replace the old ones should be uninfected.
Thus, a cure.
But some assumptions in Ho's model have been challenged at recent
meetings and their accuracy can be determined only by testing the
theory in people. Ho's team has said it eventually intends to do this by
asking infected people participating in a small study to stop the drug
after HIV has remained undetected for a period.
The possibility of a cure is also being tested in a federally financed
national trial that will take several years to complete. Participants will
agree to drop one drug from a three-drug combination in step-ladder
fashion after HIV has remained undetectable for a lengthy period and
then go through testing to determine whether the virus-free state
persists.
Even if the combinations do not cure AIDS but their knockout punch
lasts many years, present and future combination therapy would qualify
as a major medical advance and point the way to new therapies for
other diseases.
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