The Failure of Viral Load Tests
JAMA Study Shakes AIDS Science, Angers HIV Advocates
A nationwide team of orthodox AIDS researchers led by doctors Benigno
Rodriguez and Michael Lederman of Case Western Reserve University in
Cleveland are disputing the value of viral load testsa standard used since
1996 to assess health, predict progression to disease, and grant
approval to new AIDS drugsafter their study of 2,800 HIV positives
concluded
viral load measures failed in more than 90% of cases to predict or
explain immune status.
Published in the September 27, 2006 issue of the Journal of the
American Medical Association (JAMA), the findings by Rodriguez et al shake
the
foundation of the past decade of AIDS science to its core, inciting
skepticism and anger among many HIV adherents.
Belief in viral load spread quickly following the 1996 publication of a
paper in the journal Science authored by Dr John Mellors and colleagues
at the University of Pittsburgh. Mellor et al claimed that numbers
produced by the viral load test could accurately predict progression to
disease in HIV positives. Soon, use of this new technology extended far
beyond conclusions drawn by the study and its approval by the FDA as a
prognostic tool.
Claiming viral load numbers corresponded to actual amounts of
infectious virus, scientists used the test as a glib response to
unanswered
questions about how HIV could cause AIDS (Its the virus, stupid!).
Pharmaceutical companies jumped on the bandwagon, using changes in viral
load
numbers in place of actual health or survival benefits to gain FDA
approval of highly toxic protease inhibitors, a primary ingredient of
todays
HAART. Treatment advocates began using viral load to encourage healthy
HIV positives with unhealthy numbers to hit early and hard with the
newly approved drugs, while AIDS doctors throughout the world started
using viral load for everything from diagnosing illness to confirming HIV
infection.
The new uses for viral load emerged and gained popular acceptance
despite the fact that, according to manufacturers literature, the viral
load
test is not intended to be used as a screening test for HIV or as a
diagnostic to confirm the presence of HIV infection.
In a September 29th news article regarding the Rodriguez study, Mellors
announced he doesn't agree with the paper at all, insisting that viral
load is the most powerful predictor of time to AIDS and death." Some
AIDS rethinkers note that in defending his opinion, Mellors describes
viral load as powerful, an adjective frequently found in the headlines of
AIDS drug ads--drugs approved for use based on their ability to affect
viral load numbers rather than to produce clinical health benefits or
increase survival.
While Mellors and others protest or down play the significance of the
JAMA article, Rodriguez's group stands by its conclusion that viral load
is only able to predict progression to disease in 4% to 6% of
HIV-positives studied, challenging much of the basis for current AIDS
science
and treatment policy.
For further information see: Cohen J. Study says HIV blood levels don't
predict immune decline. Science 313(5795):1868, 2006; Rodriquez B,
Sethi AK, Cheruvu VK, et al. Predictive value of plasma HIV RNA level on
rate of CD4 T-cell decline in untreated HIV infection. JAMA
296(12):1498-506, 2006
On Sun, 03 Dec 2006 06:19:46 -0500, "tsip29" <nnormen@hotmail.com>
wrote:
the researchers themselves ...
http://www.aidstruth.org/rodriguez-lederman.php
What our work means
By Benigno Rodriguez M.D. M.Sc. and Michael M. Lederman M.D.
Case Western Reserve University
Center for AIDS Research
Working with a large group of collaborators from across the nation, we
recently published the results of a multicenter study designed to
explore the role of the plasma HIV RNA level (also known as viral
load) as a predictor of the rate of CD4 cell loss in individual
HIV-infected persons. This publication, entitled "Predictive value of
plasma HIV RNA level on rate of CD4 T cell decline in untreated HIV
infection" (Rodriguez et al, JAMA 296:1498-1506, 2006), has generated
extensive and sometimes impassionate discussion about the significance
of HIV viremia and its role in HIV infection and disease progression,
both among scientists and the general public. Positive as we believe
cross-examination of scientific findings to be, we have learned with
growing concern about interpretations of the work that are not only
inaccurate, but misleading and potentially dangerous to HIV-infected
persons everywhere. Thus, we are writing here to clarify the
significance of this work, its implications for the role of HIV viral
load measurement in clinical practice, and its meaning to persons
living with HIV/AIDS.
Briefly, we used complex statistical modeling to calculate the
estimated speed at which HIV-infected persons not receiving treatment
for HIV would lose their CD4 cells over time, and then asked a simple
question: based on a single measurement of those persons' viral loads,
how well can one account for the variation in the rate of CD4 cell
loss from one person to the next? To the surprise of many, the answer
is "very poorly" - to the tune of only 4-6%. Most disturbing among all
the interpretations of this finding, this has been taken by some to
mean that our data raise doubts about HIV being the cause of AIDS;
some have gone as far as to affirm that our results prove that it is
not. As this is the most damaging of all the interpretations of our
work, we will address it first.
There is absolutely no doubt that HIV is the cause of AIDS; far from
challenging the veracity of this statement, our work further confirms
it. This is easily appreciated from our initial analysis of the data,
which shows that on average, individuals with higher viral loads tend
to lose CD4 cells more rapidly that those with lower viral loads.
There is no contradiction between this finding and our main message,
because the overall trend among a group of subjects cannot be directly
translated into a prediction of what will happen to a single
individual within that group. Importantly, this finding replicates,
rather than disputes, the substance of the seminal paper by Mellors et
al (Ann Internal Med 1997; 126: 946-954), which demonstrated this
almost 10 years ago. Thus, using our work to claim that those previous
conclusions are invalid reveals either a combination of sloppy
thinking, sloppy reading or malicious intent. We choose to believe
that it is the first two.
What, then, are the implications of our work for understanding the
biology of HIV infection? Twenty-five years after AIDS was first
recognized, we have made enormous scientific and medical progress in
learning about this disease and how to treat it, but great uncertainty
still remains about how HIV infection causes the progressive immune
deficiency that results in AIDS. For the past few years, a group of
scientists (the Cleveland Immunopathogenesis Consortium), has been
meeting regularly to join efforts to identify the mechanisms of
HIV-induced immune deficiency; the work discussed herein is a product
of this collaboration. Our results imply that although HIV infection
drives the progressive immune deficiency of AIDS (as evidenced by the
response to successful treatment with anti-HIV medicines, which
decrease the viral load, increase CD4 cell numbers, and prevent or
help resolve opportunistic infections, reflecting an improvement in
immune function), there must be other intervening elements that cause
progressive CD4 cell losses in HIV infection.
An oft-cited analogy posits that the clinical course of HIV infection
can be thought of as a train approaching a broken bridge: the CD4 cell
count is the distance that separates the train from certain doom,
whereas the viral load is the speed at which the train is traveling
towards that point. Expanding on this image, we propose that the
train's fuel, rather than a single material, can be thought of as a
mixture of combustibles, of which the number of viral particles in the
blood (i.e., the viral load) is but one of the components. As the
relative contribution of each component to the mixture changes, so
does the efficiency of combustion and hence the power of the engine
and the speed of the train. From this follows that were the train to
run out of fuel, it would cease to move. This sine qua non in the
equation is the presence of HIV in the system: no HIV, no AIDS. Thus,
in two persons with the same amount of HIV in the blood, the
efficiency of combustion and hence the speed of the train (rate of CD4
decline) may vary; that is precisely what our work shows. For the
HIV-infected patient, this means that it is very difficult to predict
what the pace of his or her CD4 cell decline will be just based upon
measurement of the amount of HIV in blood. For this reason, more
recent treatment guidelines have placed less emphasis on using HIV
levels in blood to determine when to start treatment. Once antiviral
treatment is started, however, it is critical to monitor the HIV
levels in blood, because these levels remain the best indicator of the
success of the treatment and the likelihood that its benefits will be
sustained over time.
The next obvious question is, "What are the other elements in the fuel
mixture that are driving the engine?" In the mid 1990's the late
Janice Giorgi and others proposed that immune activation was a key
element in driving the pace at which HIV disease progressed. Since
then, many groups, including our own consortium, have been thinking
along those very same lines as evidence that immune activation is an
important element in driving CD4 T cell losses in chronic HIV
infection accumulates. In chronic HIV infection, a variety of immune
cells display telltale molecules that indicate that they have been
activated, and as Dr. Giorgi pointed out years ago, the level of
expression of these markers predicts the rate of HIV disease
progression better than do blood levels of HIV. Equally important, a
number of studies have shown the turnover of immune cells (that is,
the process of division and death of these cells) is greatly
accelerated in HIV infection, including cells that are not a primary
target for HIV infection. The reason for this accelerated turnover is
the subject of heated debate (The Push:Pull debate). Proponents of the
pull theory believe that as HIV destroys immune cells, more cells are
produced in order to make up for the losses, i.e., new cells are being
pulled into division and expansion. Those who subscribe to the push
model think that disorderly immune activation resulting from HIV
infection pushes immune cells inappropriately into incomplete cell
division and death. If you haven't guessed yet, we sit more with the
pushers than with the pullers. So to our view, the key important
question to ask now is how does HIV infection result in the systemic
immune activation that drives CD4 T cell losses? We think that this
will soon be illuminated. Stay tuned.
In summary then:
1. HIV is the cause of AIDS
2. In large groups of HIV infected persons who are not receiving antiretroviral therapy, those with higher levels of HIV in blood tend on average to lose CD4 cells from circulation faster than do those with lower levels of HIV in blood. But…
3. Levels of HIV in blood explain only a small portion of the variability in the rate at which CD4 T cells are lost. Therefore:
1. For any one HIV infected person not receiving antiretroviral therapies it is difficult to predict the rate at which CD4 T cells will be lost.
2. Expanded efforts to identify the other elements that drive CD4 cell losses in chronic HIV infection are needed.
