Perspective: Information, Inspiration and Advocacy for People Living with HIV/AIDS

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Considering all these things, it's actually
surprising that the drugs have worked as
well as they have in so many people. Almost any AIDS hospital or practice in the
country can confirm that the drugs have
reduced death and disease rates dramatically.
When people report high "failure" rates in
the context of such overwhelming evidence
of success, it suggests that we need to take
a very careful look at what is meant by
"failure." Typically, "failure" in recent studies simply means that a person using the
drug either was unable to achieve "undetectable" levels of virus, or saw a return to
"detectable" levels after initial success in
making it "undetectable." This is a very
narrow and technical definition of "failure,"
especially when it is accompanied by record
low rates of new opportunistic infections
and deaths. Failure is being defined solely
as some degree of change in a laboratory
marker, making no distinction between
someone whose viral load reached 500 copies HIV RNA and someone whose viral load
has soared to 5 million. It also doesn't tell
us if a person who failed one therapy was
able to go on to some other therapy that
brought viral replication back under control. It also doesn't tell how many of the
people in the studies had their best chances
for successful long-term therapy wasted by
early use of the original version of saquinavir. Use of this drug has now been clearly
implicated as a cause of early failure on the
drug itself and on subsequent, more potent
protease inhibitors. In one study, prior use
of the original version of saquinavir was
identified as a primary predictor of failure
for people using indinavir.
More importantly, it's not clear what the
clinical consequence is of seeing a return to
measurable viral load. Evidence suggests
that a rise in the HIV RNA level is not
accompanied by an immediate return of
symptoms or a loss of the improvement
experienced in measures of immunity. It just
means that the viral load has moved above
a certain arbitrary threshold. Even though
keeping viral levels "undetectable" is associated with the largest and longest lasting
benefits from treatment, drugs and combinations which caused significant reductions
in viral load (without achieving the goal of
"undetectable") were still associated with
improved clinical condition and longer survival time.
We also don't know how much of the reported "failure" is due to relentless, natural progression toward resistance, versus
how much it is being hastened by non-adherence to the prescribed regimens. Without such data, it's impossible to determine

how applicable the reported "failure" rates
are to people who are highly adherent.
Clinical data suggest that people who can
carefully adhere to "the program" have a
much higher (though still not perfect) success rate.
Despite these uncertainties, we do know the
answer to some questions about treatment
failure and resistance. Most relevant are
data from presentations at the Resistance
meeting in the summer of 1997, in St. Petersburg, Florida. A key study there showed
that when people achieved "undetectable"
levels of virus on the new ultra-sensitive
assays (measuring down to 50 or 20 copies
of virus), they are very likely to have a long
and successful run on their treatment regimen, probably measured in years. In contrast, those who never reached "undetectable" or, surprisingly, those who only
reached "undetectable" on the older, standard viral load tests (measuring only down
to 500 copies of virus), were likely to experience "drug failure" (rising viral load)
within 6 to 12 months. The ability to reach
"undetectable" status on either version of
the test was greatly affected by the individual's viral load prior to initiating
therapy. If it was low to begin with, it was
easy to keep it undetectable for long periods. The higher it was at the start, the
tougher it was to reach "undetectable."
What to Do?
What does this mean to people struggling
to make wise decisions about the use of
these new drugs? Here are a few questions
people find themselves facing, and a few
possible answers:
I'm doing OK for now, but am I doomed to
see my drugs fail? How soon?
No currently available HIV treatment
regimen is likely to last for a full normal
lifetime and none has been shown to
"eradicate" the virus. Until we can completely suppress viral replication, drug
resistance is likely to contribute to treatment failure over time. How long it can
be fully suppressed is uncertain. When
people achieve undetectable levels on the.
new ultra-sensitive viral load tests, the -
durability of response is greatly enhanced
and seems to produce a result beyond the.
initial expectations of most scientists. -
When the new therapies work and reach -
their goal, they seem to work remark-.
ably well. If this is your experience, the.
message is clear: as long as you're following the general "rules" about 3-drug -
combination therapy, just keep doing what.
you're doing. If you're one of the lucky *
few who at least temporarily achieve "un
detectable" viral load on a 2-drug regimen, you might want to consider adding
a third potent drug before your viral load
starts to rise again. Since the new ultrasensitive tests seem to be important for
predicting durability of treatment effect,
their availability must be hastened. Until
that test becomes widely available, people
can take some comfort in recent research
that suggests that when people persist a
year or longer at the "undetectable" level
on the standard test, it's quite likely they
are also "undetectable" on the ultra-sensitive test. Your own adherence to your
regimen will likely remain the most critical variable affecting the durability of
your treatment.
What's going to happen when the drugs
fail?
We don't know clinically when viral load
returns to measurable levels, how quickly
the immune system might be compromised again. We do know that it does
not signal immediate decline to clinical
illness or death. The rates of return to
clinical illness and new opportunistic infections are nowhere near as high as the
reported rates of "treatment failure."
There is plenty of evidence that even temporary success in suppressing viral load
can lead to significant levels of immune
restoration. The longer suppression of
virus is maintained, the larger the improvement seems to be. It may be that
clinical and immunologic decline simply
lags behind the return of viral load by
several months, but even if this is the case,
it gives a cushion of time while awaiting
new and better therapies.
Some virologists also believe that the
highly mutated form of virus that evolves
to resist the drugs is in many ways not as
"fit" or destructive as the original "wild
type" virus that most people started with.
The virus has to pay a price, perhaps a
high price, for accumulating all those
mutations it needs to become resistant to
the drugs. Collectively, those mutations
may make fundamental changes in the
virus and its capabilities. It may still be
capable of replicating, but it may be diminished in other ways, such as its ability to damage the immune system. At
worst, things would only be back to
where they were before the advent of the
protease inhibitors, with new drugs on
the way.
When these drugs fail, will anything help?
Yes, there is hope that other things may
help, but we need to be especially realistic on this point. Few people will have a

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PI PERSPECTIVE NUIVIBER 23 NOVEIVBER 1 997