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To Start or not to Start?
by James Learned
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The question of when it’s
best to begin antiretroviral therapy may be as controversial
and frustrating as any of the many HIV treatment questions
to which we have no clear answers. The US Department of Health
and Human Services (DHHS) HIV treatment guidelines were revised
in February, and the biggest change in the guidelines addresses
this question.
Since their first appearance
in 1997, the guidelines have been relatively aggressive in
their recommendations about when people with no symptoms should
consider starting treatment. They’ve recommended that treatment
be considered once CD4 counts fall below 500 or viral load
[the amount of HIV in the blood] rise above 20,000 copies/mL
by PCR [Amplicor], the most commonly used test. The newly
revised guidelines lean more toward delaying therapy in people
without symptoms—they now recommend considering therapy if
CD4s fall below 350 or viral load rises above 55,000. Many
people living with HIV and their healthcare providers have
been delaying treatment despite the guidelines’ previous recommendations,
but this is still a big change.
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When combination therapy first
went into widespread use in 1996, people increasingly needed
help figuring out how to best use the drugs. The DHHS guidelines,
often simply referred to as the federal treatment guidelines,
were created to offer people a roadmap to help them navigate
their way through their options. Developed by a group of researchers,
physicians and community members, the guidelines can help
in the process of determining if and when to start therapy,
what drugs to start with, when to stop or switch, and how
best to use available diagnostic tests. They reflect our current
understanding of HIV progression and treatment and are periodically
revised as ongoing research increases our understanding of
HIV.
Clearly, current anti-HIV
drugs can’t rid the body of HIV. Even when viral load is undetectable,
HIV is still reproducing at low levels. The realization that
treatment with current drugs will probably be lifelong is
the impetus behind the change in the guidelines. The change
also reflects an appreciation of long-term drug side effects,
the recognition that these drugs require a difficult level
of adherence, and the likely development of drug-resistant
virus while on lifelong therapy. If we had drugs that completely
suppressed HIV, caused no short or long-term side effects,
and were easy to take, everyone would start them soon after
infection. But that’s unfortunately not the case.
As much as we’d like a clear
answer about when to start treatment, the debate continues.
In the rush to get to the tables and charts, it can be easy
to overlook the guidelines’ thoughtful discussion of some
of the benefits and risks of starting treatment later rather
than earlier. Possible benefits of delaying treatment include
better quality of life, no drug-related side effects, putting
off the development of drug-resistant virus, and having more
drug options later on, when you might need them more. On the
other hand, the risks of delaying treatment include the possibility
that your immune system might have suffered irreversible damage
and it might be harder to achieve an undetectable viral load
[below the level able to be measured by your test].
But starting treatment early
requires a consideration of risks and benefits, too. The stronger
your immune system is when you start, the easier it is to
achieve and maintain an undetectable viral load—and drug resistance
is less likely to develop when your viral load is undetectable.
Earlier treatment might also delay or even prevent damage
to the immune system. Conversely, possible risks of starting
treatment early include a reduced quality of life due to short
and long-term side effects, the development of drug resistance
if viral load doesn’t stay undetectable, and limited treatment
options in the future.
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The information we have to
help us answer the question of when to start comes from retrospective
studies based on patients’ medical records, rather than from
prospective studies designed specifically to answer the question.
Such a prospective trial is extremely difficult to design.
It would have to run for years and enroll thousands of people.
And a trial that started now would, at best, answer the question
of when to start therapy in 2001, with the treatments available
in 2001. By the time the trial ended years from now, new,
hopefully better drugs and strategies would be available and
our understanding of HIV disease would be more complete.
At the 8th Conference on
Retroviruses and Opportunistic Infections (CROI) in February,
there were many reports on retrospective studies that looked
at the relationship between disease progression and CD4 counts
and/or viral load levels of people when they first started
combination therapy. A retrospective study from Johns Hopkins
University looked at what happened to 1,014 patients who began
two- or three-drug combinations after July 1, 1999. There
was a strong correlation between disease progression and starting
therapy with CD4 counts below 200. The higher rate of disease
progression in these patients may be at least partly explained
by observations made by the Johns Hopkins group (and other
studies) that people are less likely to achieve undetectable
viral load if they start treatment with a CD4 count below
200. Progression rates in people who started therapy with
CD4 counts between 200 and 350 didn’t differ substantially
from those who started when their CD4s were above 350. Interestingly,
pre-treatment viral load levels, independent of CD4 count,
didn’t predict clinical outcome. The study looked at pre-treatment
viral loads less than or greater than 20,000, 100,000, and
200,000, and found no differences in disease progression between
the groups.
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A study from the Centers for
Disease Control and Prevention (CDC) looked at more than 5,100
people who started two- or three-drug combinations in 1994
or later. The risk of death was significantly higher for people
who started treatment when their CD4s were below 200 compared
to those who started treatment when their CD4s were above
200. The study showed a trend for better clinical outcomes
in people who started treatment with CD4 counts between 200
and 350, but the difference wasn’t statistically significant.
And people who started treatment with CD4 counts above 350
showed no clear benefit.
These and other studies show
pretty convincingly that people who begin therapy before their
CD4s dip below 200 do better clinically. So is it best to
consider treatment before you reach that point? Probably.
But what’s the cutoff? Somewhere between 200 and 350, perhaps.
But even then, there are so many factors to consider. Is someone
whose CD4 count has dropped from 700 to 300 in a year in the
same situation as someone whose CD4s have remained steady
at 300 for five years? Clearly not. This is where the individual
flexibility called for within the text of the guidelines comes
into play.
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As people living with HIV
and their healthcare providers make complicated treatment
decisions—including the decision about when to start therapy—the
federal guidelines can be enormously helpful. But the guidelines
have limitations, and it’s important that we recognize those
limitations. They are guidelines, a tool.
They include recommendations,
suggestions, information and discussion. They are not a “one-size-fits-all”
formula for treatment, nor are they intended to be.
The data we have on HIV disease
progression are based on what seems to happen to groups of
people—populations, not individuals. These data and the real-life
experience of people living with HIV support the revision
to the guidelines, that therapy be considered by people without
symptoms when the CD4 count is below 350 (rather than 500
as previously recommended), or the viral load is above 55,000
(rather than 20,000). But if there’s one thing we’ve learned
over the last twenty years, it’s that HIV disease varies widely
from person to person. The percentages and probabilities don’t
necessarily apply to you, your very particular situation,
and the many factors that contribute to who you are—a unique
individual.
James Learned is CRIA’s Director
of Treatment Education Initiative at the Community Research
on AIDS (CRIA) in New York and Editor of
CRIA Update.
Copyright © 2001—CRIA Update.
Vol. 10 No. 2 Spring 2001. Reproduced with permission. Visit
www.criany.org.
For a free copy of the guidelines, call 1-800-448-0440, visit
www.hivatis.org
or write ATIS, P.O. Box 6303, Rockville, MD 20849-6303. Available
in Spanish.
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