PI Perspective #17
December 1995 View PDF En
español
Four New Concepts for Combating HIV Infection …
and Why They Won’t Be Tried Anytime Soon
The new generation of antiviral drugs and the widespread availability
of the PCR tests for measuring viral load have opened new pathways
in the treatment of HIV disease. While protease inhibitors look
very promising, HIV-infected people may benefit as much from new
insights about the nature of the disease provided by the drugs and
diagnostic tests. We now have a far better understanding of how
quickly the virus replicates, where it is reproduced, and how it
responds to treatment. This is suggesting new strategies that go
beyond mere viral suppression. AIDS research is on the threshold
of approaches in which the process—the way we use the drugs—may
be at least as important as the products themselves.
In theory this may allow us to reach new thresholds of effectiveness
in combating HIV infection. The critical question now is whether
anyone will exercise the leadership and foresight necessary to do
the needed work. Since these new approaches focus on strategies
and processes rather than products, the usual cast of sponsors is
unlikely to show much interest.
Concept #1: Strategic use of antiviral combinations.
The almost universal practice of medicine today is product oriented.
Doctors and patients alike tend to think in product terms: use (or
don’t use) AZT; switch from AZT to ddI, etc. Once a person
begins taking a drug, conventional practice keeps the person on
it until there is evidence of failure or intolerance. If people
stay on a drug long enough, it is almost certain that their virus
will become resistant to it.
One way to delay or avoid the problems of resistance and toxicity
is to assume from the beginning that it will be necessary to change
therapy on a routine basis. A new generation of “strategy”
trials will soon begin testing various ways to do this. In this
approach, study volunteers (or individuals acting with their doctors)
will begin therapy using an agreed upon first step, probably a well
understood combination such as AZT + 3TC. If a drug or combination
doesn’t result in a significant reduction in HIV levels within
a month, it probably never will. Thus, physicians can reach a decision
point within 30 days to either continue the therapy or switch to
something else. Afterwards, viral load (PCR) and CD4+ cell testing
will give additional guidance about what to do next. There are at
least three possible long-term strategies:
A. Change to a different drug or combination
on a timed basis,
such as every six months. In this approach, the “signal-to-switch”
is based on data from previous trials showing how quickly resistance
develops, on average, to this drug or combination. One likely limitation
of this approach is that the “average” time to resistance
may not apply to every individual situation. Thus some people using
this approach might stay on a therapy longer than they should, while
others may abandon it too quickly, shortening the duration of benefit
they might have received. However, even with these risks, this approach
seems likely to work better than simply waiting for people to fail
on the drug.
B. Change to a different drug or combination
when the viral load increases significantly. This approach
relies upon viral load testing (PCR) to give the “signal to
switch” therapies. Many scientists favor this approach since
the viral load test is the most direct measure of viral activity
generally available. In this sense, viral load is not a “surrogate”
marker but a direct measure of an antiviral drug’s effect
on its intended target.
One possible weakness of this shows up with protease
inhibitor drugs. Recent studies have demonstrated that these drugs
appear to provide sustained improvements in CD4+ cells even after
PCR testing shows that viral load has begun to increase. It is not
clear whether this says something about the limitations of PCR testing,
or whether virus produced after using a protease inhibitor is somehow
weakened and less likely to cause damage to the immune system. Whatever
the answer, this approach seems to offer the most precise way to
determine the value of a therapy used for suppressing virus levels.
Additional studies already underway will help answer the question.
C. Change to a different drug or combination
when CD4+ cell levels begin to fall significantly, but before clinical
changes occur.
While CD4+ tests are only one measure of the health of the immune
system, they correlate well with clinical symptoms and the risk
of opportunistic infections. The main risk of using this approach,
however, is that it may not give the “signal-to-switch”
until after the damage is done and a significant and perhaps irretrievable
loss of CD4+ cells has occurred.
It is not clear which “switching” strategy will produce
the best clinical and survival benefits. Any of them are likely
to be superior to remaining on a drug or combination until clinical
signs of failure become evident. Any of them will diminish the risk
of developing long-term, cumulative side effects from the individual
drugs or combinations. A likely fourth strategy will simply be to
take all 3 points into consideration and make a reasonable judgment
call about when to switch therapies.
Using any of these strategies will require careful monitoring and
access to a wide array of drugs. Fortunately, this is finally becoming
possible. There are now four approved antivirals (AZT, ddI, ddC,
d4T,3TC), and one available drug targeted at cellular activity (hydroxyurea).
Several important drugs are waiting just offstage for approval over
the next several months, including nevirapine, delavirdine, and
three protease inhibitors (saquinavir, indinavir sulfate, and ritonavir).
Practical considerations:
Unfortunately, physicians and their patients are largely on their
own when trying to figure out how best to employ such strategies.
The goal of studying these approaches will be to determine standards
of care, not to meet FDA licensing requirements. Consequently, drug
manufacturers have little interest in paying for them. The responsibility
for this type of testing falls to the federal government’s
AIDS research establishment. But at the moment, the federal program
is reducing the amount of funding devoted to clinical trials, so
prospects there look bleak. At a time when there is a rapidly growing
backlog of critically needed clinical trials which can only be done
by the federal government, there is less money being allocated to
fund them.
Concept #2: Activate the dormantly infected compartments
of the immune system.
No matter how good antiviral drugs become, it seems unrealistic
to hope that it will be possible to use them for a person’s
entire normal lifespan. Even the best therapies may still encounter
problems with long-term toxicity, tolerance, and resistance. An
ideal solution to HIV infection, like any other disease, would be
to end the battle between virus and the immune system conclusively.
This is not necessarily an unreachable goal. Short of reaching that
goal, it might at least be possible to greatly reduce the total
body burden of HIV in hopes of adding many years to life expectancy.
The key question might be determining the best time and way to use
the available drugs to make the greatest possible impact.
Today’s best combinations are, in some people, doing an excellent
job shutting down virus reproduction in the “fast-acting”
compartment of the immune system. This compartment is made up of
activated, infected cells which are rapidly producing virus and
which are quickly dying and being replaced by new cells. Recent
data from the Aaron Diamond Research Center and the University of
Alabama demonstrate that most of the infected cells producing new
virus are newly formed every 48 hours. It is precisely because this
compartment is so highly active that it makes a good target for
antiviral drugs (and for the immune system itself).
New studies show that even when drugs stop virus production from
this compartment, a trickle of virus production continues from elsewhere.
Scientists believe it is coming from the “slow-acting compartments,”
probably including follicular dendritic cells, macrophages and monocytes,
and infected but inactive CD4+ cells (latently infected cells).
In contrast to the fast-acting cells, these produce a small amount
of virus but the cells live long, slow lives. This makes them very
difficult to deal with, either by a drug or by the immune system.
The problem of these cells is insidious. Well before all of these
cells finally become active and visible targets, a drug has usually
been in use for so long that the virus from the fast-acting compartments
is starting to become resistant. Thus, the first target is getting
out of control again before the second target becomes accessible.
One proposal is to try to simultaneously activate all or most of
the slow-acting infected cells while fighting back intensely with
antivirals, supportive therapies, and the immune system itself.
Once activated, cells become visible targets for the immune system
while the drugs should be capable of coping with any new virus they
attempt to produce. In theory, this might make it possible to “burn
out” the HIV infection much as the body does other acute infections.
Failing this lofty goal, the strategy might at least “set
the clock back” by several years by greatly reducing the level
of underlying, slow-acting infected cells. Overall, this approach
would seek to turn HIV infection from a slow, chronic infection
into an acute infectious state. The strategy would invite an all
out war between HIV infection and the immune system. Many people
experience a period of acute infection very early in the course
of the disease, before HIV becomes a slow, chronic infection. Even
then, the body almost, but not quite, wins the battle, greatly suppressing
the virus for many years to come. Rerunning that battle with the
help of antiviral therapies and supportive measures might rid the
body of the infection once and forever or at least greatly curb
its spread.
This process-oriented approach would best be tested in a hospital
setting to assure safety. Researchers would first treat the patient
to maximize suppression of HIV with the most potent available combination
of antiviral drugs, possibly one or more protease inhibitors and
one or more RT inhibitor drugs (AZT, ddI, ddC, d4T, 3TC, nevirapine
and delavirdine). Since the duration of the process would be brief,
it might be feasible to use the drugs at higher than normal doses.
Hospital admission would occur at the peak of viral suppression.
The patient would be monitored daily for all signs of HIV activity
as well as general health. At the chosen moment, physicians would
systemically administer one or more of several agents known to activate
dormant and slow-acting cells. As with interleukin-2 therapy, there
would likely be a brief increase in viral load which should be contained
by the antivirals. Supportive therapies could be used to suppress
harmful cytokine release and oxidative stress.
No one knows how long this scenario should continue or whether
it would need to be repeated. Only a few days of activation might
be required, since most or all the infected cells should quickly
die and be replaced within a matter of days. The immune system itself
should quickly target and destroy any cells which begin to express
HIV. This strategy might either eliminate virtually all infected
cells and free virus, or cause a dramatic, lasting reduction in
the threshold levels of virus produced in the body.
When first proposed in 1990, many scientists rejected this strategy
out of fear that the available antivirals would not control viral
replication during the procedure. With protease inhibitors, more
effective combinations, and extremely powerful but short-lived single
agents like nevirapine, this is no longer the case. Today, we have
better tools and the knowledge to experiment in this fashion. The
key will be initiating the activation scenario while the patient
is still sensitive to the drugs. The biggest unknown is how much
damage will be incurred in the battle, and this question troubles
many scientists. Others, however, argue that the total body burden
of HIV, on a relative scale, is still fairly small compared to some
other diseases from which the body recovers.
Practical Considerations:
The main obstacles to testing an “activation strategy”
are politics and money. Since the experiment is not about any particular
product or drug, it will not find a ready commercial sponsor. Government
or academia must take the initiative, though neither is quick to
take on high-risk / high-gain clinical experiments. However, there
is little magic about this approach. Any competent hospital and
research team could develop and implement the necessary protocol.
Concept #3: Fight drug resistance by creating a steadier
level of drug activity.
One possible factor in the rapid development of resistance to antiviral
drugs is that their effective potency may vary widely over the course
of the day. To be truly effective, a drug needs to be present in
the blood stream at a certain level. If the level goes too high,
the risk of toxicity grows; if the level falls too low, even briefly,
inadequate suppression of virus occurs. Drugs levels in the blood
rise to high peaks shortly after a drug is taken but fall to troughs
before it is time to take the next dose. Recent studies have shown
the large of amounts of new virus are literally made every few hours,
so it is likely that the rate of viral production fluctuates each
day as a person cycles through a daily dosing regimen. The trough
level between doses may provide an ideal opportunity for the development
of resistant virus since it permits replication in the presence
of inadequate levels of a drug. This unfortunate balance of drug
vs. virus occurs every few hours in between daily dosing.
There are several possible ways to correct this problem. One might
be readily available to individual patients, at least those using
two and three drug combinations. Someone taking three drugs might
stagger the doses rather than taking all three drugs together. This
might provide a steadier level of virus suppression than a fixed
dosing regimen. Exactly how this should be done is unclear and will
likely vary depending on the combination. Some elements of a combination
might still be best taken together because of a desired synergistic
interaction, such as AZT + 3TC or ddI plus hydroxyurea. But if a
third or fourth drug is added to this scenario, a greater benefit
might be achieved by taking it in between the doses of the other
two drugs.
Practical Considerations:
Relatively simple laboratory or animal studies could quickly test
this approach. Some of the necessary data might already exist in
the pharmacokinetic profiles of the drugs. If such data were promising,
it would then be necessary to conduct small human studies. A positive
outcome could lead either to changing the instructions to patients
on how to use existing drugs in combination, or to the development
of time-release formulations designed to produce steadier blood
levels of the drugs throughout the day. This would be a relatively
simple task for the pharmaceutical industry.
Concept #4: Shift the reservoir of infected cells out
of the lymph system and into the blood stream.
Researchers seem to agree that a key component sustaining chronic
HIV infection is the presence of reserves of virally infected cells
and free virus trapped in the lymph nodes and other lymphoid tissues.
Over time, the chronic infection seems to overwhelm the lymph nodes
and the tissue is critically damaged. Conventional wisdom holds
that it’s a good thing all that virus is tied up in the lymph
nodes since that keeps it from spreading elsewhere. A contrary view
argues that this chronic entrapment of cells in the lymph system
might be one of the reasons the immune system fails to cope the
infection. And most people would agree that the eventual resulting
destruction of the lymph system by chronic infection is not a good
thing. As CD4+ cells are brought into use by the body, they circulate
through the lymph system and may become infected while there. A
further problem is that there is some evidence that our current
drugs are not as effective in fighting viral reproduction in the
lymph system as they are in the blood stream (though this is far
from certain). Finally, there is great concern that the eventual
breakdown of the lymph system due to long-term HIV infection render
the system useless.
What if there were a way to drive all those infected cells out
of the lymph system and into the blood steam? What if the infection
could be kept out of the lymph system before it destroys it? While
it might temporarily increase the virus levels in the blood, in
theory it might also render the infected cells and entrapped virus
more vulnerable to existing therapies. And giving the lymph system
a rest, even if a temporary one, might permit the system to heal
itself rather than proceed to its inevitable destruction.
In 1992, researchers at the National Cancer Institute proposed
to rid the lymph system of virus by destroying the lymph nodes altogether,
using a process called “total nodal irradiation.” No
human experiment was ever done for fear of the many unknowns that
might result, even though this approach is sometimes used in cancer
treatment. It might be possible to achieve the same goal without
destroying anything and without the dangers inherent in radiation
treatment. Researchers at one university have been testing this
controversial theory for nearly two years in an animal model. A
potent well known toxin (pertussis toxin) was applied in a minuscule
dose (100 micrograms) to a monkey in an advanced stage of SIV-infection,
the equivalent of human AIDS. The pertussis toxin is known to generate
an immunologic “shock” to the lymph system, causing
it to restructure itself to deal with the toxin and block entry
to the lymph system by other infectious agents—perhaps a defensive
trick the body learned somewhere in the course of evolution. Even
without the use of antiviral drugs, this apparently resulted dramatic,
lasting drop in viral load in the first animal tested, as well as
a substantial weight gain and return to normal clinical condition.
Later experiments, not yet published, have repeated the process
in five additional animals who were compared to five controls (similar
but untreated monkeys). This time, the treated animals were given
lower dose injections of the toxin every two months but still no
antiviral drugs. None suffered any detectable side effects. Four
of the five control animals were dead after 8 months, while four
of the five treated animals were alive with improved clinical condition.
The one treated animal which died did so in the earliest weeks of
the study, suggesting that it was perhaps too ill at baseline to
benefit from treatment.
Practical Considerations:
There is no clear sponsor or drug manufacturer who wants to try
developing a dangerous toxin as a medicine. The scientists involved
are applying for Investigational New Drug status for the toxin which
will permit human testing, but getting approval will take up to
year. Many scientists and physicians will be wary of giving a toxin
to immune-suppressed people. But the animal studies show no signs
of harm and it is the clinical data, not the theories, which count
most.
Other researchers point out that there may be several other possible
ways to break up the clustering of infected cells and virus in the
lymph nodes. If so, all the better. They should all be tested.
Commentary
While promising, these are not the only strategies or process-oriented
approaches worth attention. Others, like a long-standing and important
proposal to suppress some aspects of immune function, have remained
untested for half a decade or more. Like other new approaches, these
strategies carry some risk with their potential benefit. No one
can guarantee that they will not harm a volunteer or that they will
produce better results than conventional therapy. We know the risks
and benefits of current therapy, and both are limited. To make the
next major advances against HIV infection, research may have to
step outside the boundaries of conventional thinking and product-oriented
research. All of these approaches are based on reasonable, if not
fully understood, scientific concepts and it’s fairly certain
that the experiments could be done with FDA approval. With a little
more determination, researchers could bring these and many similar
experiments into human clinical testing within a matter of months.
The greatest obstacle faced by all these strategies is that they
come at a time when the NIH Office of AIDS Research—not the
Congress—is reducing the dollars spent on clinical research.
Many clinical research sites around the country are preparing to
shut their doors. The AIDS research budget planning process is operating
on assumptions about the balance of basic vs. clinical science that
are now two years out of date. The only thing that can change this
is the volume of the outcry from people with AIDS and their supporters.
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