Antiviral Strategies

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'/ Antiviral Strategies
Discussion Paper
the patient to the risk of toxicity and create the opportunity to
develop viral resistance, without adding any measurable clinical
benefit? Or, on the other hand, might using a powerful combination early on make it possible to suppress the disease for the longest possible period or even permanently? These questions remain
unanswered.
There are many opinions but very little hard data. Plenty of data
show that most HIV-infected people will live longer with therapy,
even if there is no precise way to determine when to start. There
are other data, however, that indicate that a small subset of HIVinfected people (less than 5%) fare very well for long periods (more
than 15 years) without therapy. Some researchers argue that intervening with therapy could, theoretically, upset this balance in
such people. But, it may be equally valid to test therapy in such
people to see whether, with a little more help, the body might be
able to rid itself permanently of any risk of symptomatic disease.
But for now, both views are equally valid and in need of research.
Not all people have access to the same treatment options and different people respond differently to individual drugs. The options
include existing approved drugs and combinations, experimental
drugs accessed through clinical trials and expanded access programs, and other unapproved drugs. Even though all studies which
have compared two vs. three drug combinations have concluded
that people fare better on the triple combinations, not everyone
has access to three drugs. Still others can't tolerate three drugs,
or can't find three drugs they haven't used up before.
One thing is certain: How these drugs are used is critical. Developing an effective treatment strategy requires taking what is known
from clinical studies and, what we know about how HIV causes
immune destruction (pathogenesis), and combining it with expert opinion. Several factors should be considered:
( Successful long-term use of therapies is more important
than short-term gains. It is possible to get short-term benefits at the cost of wasting potential long-term benefits.
4 People who are being treated for the first time have the
greatest number of options and generally have the best
possible response to therapy. It is critical to think of the
long-term picture when choosing options. A strategy should
provide long-term benefits from the chosen therapies while
preserving options for future use. An example of an ineffective strategy would be to begin therapy using single drugs or
modest combinations that merely reduce, but do not fully
suppress, viral replication. Such a strategy does little more
than waste the drugs being used by employing them in a way
that leads to rapid development of viral resistance.

Reducing viral load as low as possible, preferably below
the level of detection with the current tests, should be
the goal of anti-HIV therapy. Drugs and combinations which
have a larger, more consistent and longer-lasting effect in
reducing viral loads and increasing CD4+ cell counts are likely
to produce longer-lasting clinical and survival benefits. People
with HIV RNA levels below the limit of detection have a significantly longer lasting response than people with detectable viral loads. When therapy fails to reduce viral load below
the limit of detection, it is usually a sign that the therapy will
fail over the next several months. Today, most available viral
load tests measure reliably down to 400 or 500 copies of virus. Any number below this is considered "undetectable."
However, new tests (not yet widely available) will soon make
it possible to measure as low as 20 copies of virus. Studies
have already shown that people who reach "undetectable" levels on this new test will have a longer lasting effect from
therapy than those only reach the limit of detection on the
older tests. It will take a longer period of time to reduce viral
levels below the limit of detection with these new tests.
4 The question of whether everyone should be treated immediately has not yet been fully answered. Theoretically,
the sooner HIV replication is reduced or stopped, the better.
But this goal must be measured against possible side effects
of long-term therapy, long-term interference with quality of
life and the risk of using options prematurely. An individual's
ability to take the medications correctly also has an impact
(see "Quality of Life Issues" below). Both the 'very aggressive' and the 'less aggressive' approaches can be supported as
matters of reasonable personal choice. For now, neither has
been proven right for all situations.
Lessons from treating tuberculosis show that it is important to change or add two new therapies at the same
time. This will help combat viral resistance to the drugs. Just
adding a protease inhibitor on top of an existing therapy regimen that is not suppressing HIV RNA to below the limit of
detection is unlikely to produce the dramatic results seen in
the clinical studies. The best results in clinical studies have
always come when two or more new drugs are started at the
same time. It might be possible to achieve the necessary degree of viral suppression in some situations by changing only
one drug when viral load is low (below 5,000 copies HIV RNA).
However, in other instances, far less consistent results have
been shown than changing two drugs simultaneously.
( The use of treatment that is only partially effective speeds
the development of viral resistance. If a treatment reduces
viral load but still permits a measurable level of viral activity,
the virus that is still present is capable of mutating and developing resistance to that treatment. When a 3-drug combi
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