- Dr David Rasnick on Surrogate Markers
- Posted by PaulKing
Dr David Rasnick on Surrogate Markers
It should come as a shock, no doubt, to learn that if three laboratory
tests somehow disappeared or were outlawed (HIV antibody test, CD4 cell
count, PCR viral load test), then AIDS, as commonly understood, would
formally vanish from the USA and Europe. The three laboratory tests in
question are called surrogate markers because they stand in for either
AIDS itself or for its supposed cause, HIV. According to the current
definition of AIDS, no matter how sick an American or European is with
AIDS-defining diseases, he or she cannot be classified as an AIDS case if
antibodies to HIV are not present. In other words, for an American or
European doctor to diagnose pneumonia, TB, dementia, cervical cancer, etc.
as AIDS it is necessary to obtain laboratory test results that satisfy the
definition of AIDS. Since the HIV- antibody test has been discussed in
depth already, I will limit my remarks to CD4 cell counts and viral load.
At the beginning of the AIDS epidemic, it was already recognized as
probably a mistake to use CD4 as a marker of AIDS or even a measure of
therapeutic effectiveness. In 1981, James Goodwin, MD, wrote what he
called "a diatribe against the measurement of T-cell subsets in human
diseases" [1]. His "diatribe" began: "It's starting again. ...The T- and
B-cell measures--having run through the sick, the elderly, the young, the
pregnant, the bereaved--had finally run out of diseases. Each condition
was the subject of many reports; so that now, to give but one example, we
can conclude with some assurance that T-cell numbers are up, down, or
unchanged in old folks. And it's starting all over again, this time with
T-cell subsets."
"What will they find?" he asked. "Sometimes the suppressor cell markers
will be up and helper cells down; sometimes the suppressor cells will be
down and the helper cells up; sometimes they'll be unchanged--and various
combinations of the aforementioned. ...My strongest argument is this:
Measurement of T and B cells and their subsets in diseases has no clinical
meaning."
"Nonimmunologists have naturally assumed that any subject occupying so
much journal space must be relevant in some way--a logical but incorrect
assumption. ...And while the identification of T- cell subsets in mouse
and man represents a major breakthrough in the understanding of
immunoregulation, the enumeration of these subsets in myriad diseases
largely represents a waste of time".
As recently as 1998, Mario Roederer of Stanford University confirmed
Goodwin's assessment that an obsession with T-cell subsets in AIDS
patients has been a mistake: "[T]he facts (1) that HIV uses CD4 as its
primary receptor, and (2) that CD4+ T cell numbers decline during AIDS,
are an unfortunate coincidence that have led us astray from understanding
the immunopathogenesis of this disease" [2].
Prior to Roederer's remarks, the use of the CD4 (T-cell counts) as a
surrogate marker of disease progression was also criticized by the authors
of the Concorde Study, the largest clinical trial evaluating the use of
AZT: The authors concluded that:
"The small but highly significant and persistent difference in CD4 count
between the groups was not translated into a significant clinical benefit.
Thus, analyses of the time until certain concentrations of CD4 were
reached (eg, 200/_L, 350/_L, or 50% of baseline) revealed significantly
shorter times in the Def[erred] group. Had such analyses been regarded as
fundamental, the trial might have been stopped early with a false-positive
result. This discrepancy in the differences between Imm[ediate] and Def
groups in terms of changes of CD4 count and of long-term clinical response
casts doubt on the uncritical use of CD4 counts as 'surrogate endpoints'
in trials..." [3].
Thomas Fleming and David DeMets have stated that, "The use of surrogate
end points has probably been more intensely discussed in the design and
analysis of clinical trials of HIV infection and AIDS than in any other
area" [4]. However, "Predictions having an accuracy of approximately 50%,
such as the accuracy seen with the CD4 count in the HIV setting, are as
uninformative as a toss of a coin." With regards to clinical trials and
FDA approval of anti-HIV drugs, Fleming and DeMets have warned that,
"Surrogate end points are rarely, if ever, adequate substitutes for the
definitive clinical outcome in phase 3 trials" [4].
Indeed, a summary result from a 1993 state-of-the-art conference had
previously concluded that the effect of treatment on the most popular
surrogate, CD4 cell count, did not accurately predict the effect of
treatment on the clinical outcomes, that is, progression to AIDS or time
to death [5]. Nevertheless, with the exception of the early AZT clinical
trials, all subsequent anti-HIV drug trials and FDA approvals have relied
exclusively on the measurements of these surrogate markers and not on the
real clinical outcomes, such as morbidity and mortality, that matter to
most people.
A year later, Fleming stated that, "It is very apparent one cannot simply
consider establishment of statistically significant treatment effects on
CD4 cell counts to be a valid surrogate for either of the two clinical
endpoints. When the progression to AIDS/death endpoint was positive, the
CD4 endpoint appropriately was significantly positive in 7 of 8 trials;
unfortunately however, the CD4 endpoint was significantly positive in 6 of
8 trials in which the progression to AIDS/death endpoint was negative. The
relationship of CD4 effects and survival is even more unsatisfactory. The
CD4 endpoint was significantly positive in only 2 of 4 trials in which the
survival endpoint was positive; yet it was significantly positive in 6 of
7 trials in which the survival endpoint was negative. In three other
trials, survival trends were observed which were in the opposite direction
of significant treatment effects on CD4" [6].
The well-recognized problems with CD4 counts eventually led to its being
replaced by the PCR viral-load test as the primary surrogate marker to be
used in anti-HIV drug clinical trials. But, the "viral load" test has its
share of problems. To start with, Roche's "AMPLICOR HIV-1 MONITOR Test is
not intended to be used as a screening test for HIV or as a diagnostic
test to confirm the presence of HIV infection" (Roche Diagnostic Systems
AMPLICOR HIV-1 MONITOR Test package insert, PMA No. BP950005/4).
To save space, below is a list of some of the problems with the viral load
test that were published in the scientific, medical literature:
False positive or false negative? It depends on the answer you want.
Apparently, absence of antibodies to HIV trumps a high viral load result.
Schwartz D. H. et al., "Extensive evaluation of a seronegative participant
in an HIV-1 vaccine trial as a result of false-positive PCR" (1997) The
Lancet 350: 256-259:
An individual tested positive by PCR, but was antibody negative.
Therefore, the patient's viral load of 100,000 copies of RNA per ml was
called false-positive. It took $5000 worth of PCR testing in several labs
to get the "right" answer: negative.
----------------------
Christine Defer et al., "Multicentre quality control of polymerase chain
reaction [viral load] for detection of HIV DNA" (1992) AIDS 6: 659-663:
"False-positive and false-negative results were observed in all
laboratories (concordance with serology ranged from 40 to 100%)."
----------------------
Michael P. Busch et al., "Poor sensitivity, specificity, and
reproducibility of detection of HIV-1 DNA in serum by polymerase chain
reaction" (1992) Journal of Acquired Immune Deficiency 5: 872-877:
"The results indicate that current techniques for detecting cell-free
HIV-1 DNA in serum lack adequate sensitivity, specificity, and
reproducibility for widespread clinical applications."
"In any event, the levels of viral (and cellular) DNA in serum appear to
be so low that reproducible detection, even with use of PCR, is not
currently possible."
----------------------
Josiah D. Rich et al., "Misdiagnosis of HIV infection by HIV-1 plasma
viral load testing: a case series" (1999) Annals of Internal Medicine 130:
37-39:
"The availability of sensitive assays for plasma HIV viral load and the
trend toward earlier and more aggressive treatment of HIV infection has
led to the inappropriate use of these assays as primary tools for the
diagnosis of acute HIV infection."
"Physicians should exercise caution when using the plasma viral load
assays to detect primary HIV infection..."
"Plasma viral load tests for HIV-1 were neither developed nor evaluated
for the diagnosis of HIV infection..."
------------------------
M. Piatak et al., "High levels of HIV-1 in plasma during all stages of
infection determined by competitive PCR" (1993) Science 259: 1749-1754:
"Plasma virus levels determined by QC-PCR correlated with, but exceeded by
an average of 60,000-fold, virus titers measured by endpoint dilution
culture."
In fact, 53% of the viral load positive patients had no culturable HIV.
"For HIV-1 propagated in vitro, total virions have been reported to exceed
culturable infectious units by factors of 10,000 to 10,000,000, ratios
similar to those we observed in plasma."
------------------------
Haynes W. Sheppard et al., "Viral burden and HIV disease" (1993) Nature
364: 291:
"...the high level of plasma virus observed by Piatak et al. [reference
above] was about 99.9 per cent non-culturable, suggesting that it was
either neutralized or defective. Therefore, rather than supporting a
cytopathic model, this observation actually may help explain the
relatively slow dissemination of the infected cell burden and thus the
relative ineffectiveness of therapy with nucleoside analogues which target
this process.
"...we question the longitudinal conclusions some of these investigators
have drawn from cross-sectional data. The results presented are equally
consistent with the conclusion that higher viraemia is a consequence of,
rather than the proximate cause of, defective immune responses."
------------------------
Simply put: the AIDS surrogate markers are being abused. These surrogate
markers are causing a great deal of harm by labeling people with myriad
diseases and conditions--even healthy people who only have antibodies to
HIV--as having incurable AIDS, which is said to be invariably fatal. The
surrogate markers are also being used to obtain FDA approval of clinically
ineffective AIDS chemotherapies that are highly toxic and even lethal if
taken long enough.
David Rasnick
References
1. Goodwin, J. S. (1981) OKT3, OKT4, and all that, Journal of the American
Medical Association 246, 947-948
2. Roederer, M. (1998) Getting to the HAART of T cell dynamics, Nature
Medicine 4, 145-146
3. Seligmann, M., et al. (1994) Concorde: MRC/ANRS randomised double-blind
controlled trial of immediate and deferred zidovudine in symptom-free HIV
infection, Lancet 343, 871-881
4. Fleming, T. R., et al. (1996) Surrogate end points in clinical trials:
are we being misled?, Annals of Internal Medicine 125, 605- 613
5. Sande, M. A., et al. (1993) National Institute of Allergy and
Infectious Diseases state-of-the-art Panel on Anti-retroviral therapy for
adult HIV-infected patients, Journal of the American Medical Association
270, 2583-2589
6. Fleming, T. R. (1994) Surrogate markers in AIDS and cancer trials,
Statistics in Medicine 13, 1423-1435 </
- Posted by Gary Stein
"PaulKing" <aimulti@aimultimedia.com> wrote in message
news:2a6830e6da5a9f281d0e70a1c1d36cf1@localhost.ta lkabouthealthnetwork.com...
prior to the advent of either test so in that way these test were used to
diagnosis AIDS prior to the patients experiencing one of the earlier defined
marker OI's.
Secondly and much more important both CD4 counts and Viral load numbers can
be used to very accurately predicated a patients disease progression and
these predication are highly consistent when compared in one patient between
both markers and across vast numbers of patients comparing patient to
patient. How doe Rasnick explain this fact, well sadly he simply ignores it
and carries on with his arguments as if no retrospective studies of tens of
thousands of AIDS patients had proved beyond any doubt the accuracy of both
CD4 counts and Viral load numbers in predicting disease progression in AIDS
patients.
This fact is also never acknowledged on any dissident website nor do they
have any logical way to explain away this data set that unequivocally
destroys there arguments against the usefulness of CD4 and Viral load
testing. These retrospective studies prove with out any chance for argument
that both tests are measuring something that very very accurately predicates
disease progression in HIV and AIDS patients so even if you don't believe in
HIV's existence you still can not argue that these test are not useful in
managing the health of patients. Something the denialist don't want you to
know, because it is a fact that they have no ammunition to use against.
Gary Stein
- Posted by PaulKing
Dr David Rasnick on Surrogate Markers
It should come as a shock, no doubt, to learn that if three laboratory
tests somehow disappeared or were outlawed (HIV antibody test, CD4 cell
count, PCR viral load test), then AIDS, as commonly understood, would
formally vanish from the USA and Europe. The three laboratory tests in
question are called surrogate markers because they stand in for either
AIDS itself or for its supposed cause, HIV. According to the current
definition of AIDS, no matter how sick an American or European is with
AIDS-defining diseases, he or she cannot be classified as an AIDS case if
antibodies to HIV are not present. In other words, for an American or
European doctor to diagnose pneumonia, TB, dementia, cervical cancer, etc.
as AIDS it is necessary to obtain laboratory test results that satisfy the
definition of AIDS. Since the HIV- antibody test has been discussed in
depth already, I will limit my remarks to CD4 cell counts and viral load.
At the beginning of the AIDS epidemic, it was already recognized as
probably a mistake to use CD4 as a marker of AIDS or even a measure of
therapeutic effectiveness. In 1981, James Goodwin, MD, wrote what he
called "a diatribe against the measurement of T-cell subsets in human
diseases" [1]. His "diatribe" began: "It's starting again. ...The T- and
B-cell measures--having run through the sick, the elderly, the young, the
pregnant, the bereaved--had finally run out of diseases. Each condition
was the subject of many reports; so that now, to give but one example, we
can conclude with some assurance that T-cell numbers are up, down, or
unchanged in old folks. And it's starting all over again, this time with
T-cell subsets."
"What will they find?" he asked. "Sometimes the suppressor cell markers
will be up and helper cells down; sometimes the suppressor cells will be
down and the helper cells up; sometimes they'll be unchanged--and various
combinations of the aforementioned. ...My strongest argument is this:
Measurement of T and B cells and their subsets in diseases has no clinical
meaning."
"Nonimmunologists have naturally assumed that any subject occupying so
much journal space must be relevant in some way--a logical but incorrect
assumption. ...And while the identification of T- cell subsets in mouse
and man represents a major breakthrough in the understanding of
immunoregulation, the enumeration of these subsets in myriad diseases
largely represents a waste of time".
As recently as 1998, Mario Roederer of Stanford University confirmed
Goodwin's assessment that an obsession with T-cell subsets in AIDS
patients has been a mistake: "[T]he facts (1) that HIV uses CD4 as its
primary receptor, and (2) that CD4+ T cell numbers decline during AIDS,
are an unfortunate coincidence that have led us astray from understanding
the immunopathogenesis of this disease" [2].
Prior to Roederer's remarks, the use of the CD4 (T-cell counts) as a
surrogate marker of disease progression was also criticized by the authors
of the Concorde Study, the largest clinical trial evaluating the use of
AZT: The authors concluded that:
"The small but highly significant and persistent difference in CD4 count
between the groups was not translated into a significant clinical benefit.
Thus, analyses of the time until certain concentrations of CD4 were
reached (eg, 200/_L, 350/_L, or 50% of baseline) revealed significantly
shorter times in the Def[erred] group. Had such analyses been regarded as
fundamental, the trial might have been stopped early with a false-positive
result. This discrepancy in the differences between Imm[ediate] and Def
groups in terms of changes of CD4 count and of long-term clinical response
casts doubt on the uncritical use of CD4 counts as 'surrogate endpoints'
in trials..." [3].
Thomas Fleming and David DeMets have stated that, "The use of surrogate
end points has probably been more intensely discussed in the design and
analysis of clinical trials of HIV infection and AIDS than in any other
area" [4]. However, "Predictions having an accuracy of approximately 50%,
such as the accuracy seen with the CD4 count in the HIV setting, are as
uninformative as a toss of a coin." With regards to clinical trials and
FDA approval of anti-HIV drugs, Fleming and DeMets have warned that,
"Surrogate end points are rarely, if ever, adequate substitutes for the
definitive clinical outcome in phase 3 trials" [4].
Indeed, a summary result from a 1993 state-of-the-art conference had
previously concluded that the effect of treatment on the most popular
surrogate, CD4 cell count, did not accurately predict the effect of
treatment on the clinical outcomes, that is, progression to AIDS or time
to death [5]. Nevertheless, with the exception of the early AZT clinical
trials, all subsequent anti-HIV drug trials and FDA approvals have relied
exclusively on the measurements of these surrogate markers and not on the
real clinical outcomes, such as morbidity and mortality, that matter to
most people.
A year later, Fleming stated that, "It is very apparent one cannot simply
consider establishment of statistically significant treatment effects on
CD4 cell counts to be a valid surrogate for either of the two clinical
endpoints. When the progression to AIDS/death endpoint was positive, the
CD4 endpoint appropriately was significantly positive in 7 of 8 trials;
unfortunately however, the CD4 endpoint was significantly positive in 6 of
8 trials in which the progression to AIDS/death endpoint was negative. The
relationship of CD4 effects and survival is even more unsatisfactory. The
CD4 endpoint was significantly positive in only 2 of 4 trials in which the
survival endpoint was positive; yet it was significantly positive in 6 of
7 trials in which the survival endpoint was negative. In three other
trials, survival trends were observed which were in the opposite direction
of significant treatment effects on CD4" [6].
The well-recognized problems with CD4 counts eventually led to its being
replaced by the PCR viral-load test as the primary surrogate marker to be
used in anti-HIV drug clinical trials. But, the "viral load" test has its
share of problems. To start with, Roche's "AMPLICOR HIV-1 MONITOR Test is
not intended to be used as a screening test for HIV or as a diagnostic
test to confirm the presence of HIV infection" (Roche Diagnostic Systems
AMPLICOR HIV-1 MONITOR Test package insert, PMA No. BP950005/4).
To save space, below is a list of some of the problems with the viral load
test that were published in the scientific, medical literature:
False positive or false negative? It depends on the answer you want.
Apparently, absence of antibodies to HIV trumps a high viral load result.
Schwartz D. H. et al., "Extensive evaluation of a seronegative participant
in an HIV-1 vaccine trial as a result of false-positive PCR" (1997) The
Lancet 350: 256-259:
An individual tested positive by PCR, but was antibody negative.
Therefore, the patient's viral load of 100,000 copies of RNA per ml was
called false-positive. It took $5000 worth of PCR testing in several labs
to get the "right" answer: negative.
----------------------
Christine Defer et al., "Multicentre quality control of polymerase chain
reaction [viral load] for detection of HIV DNA" (1992) AIDS 6: 659-663:
"False-positive and false-negative results were observed in all
laboratories (concordance with serology ranged from 40 to 100%)."
----------------------
Michael P. Busch et al., "Poor sensitivity, specificity, and
reproducibility of detection of HIV-1 DNA in serum by polymerase chain
reaction" (1992) Journal of Acquired Immune Deficiency 5: 872-877:
"The results indicate that current techniques for detecting cell-free
HIV-1 DNA in serum lack adequate sensitivity, specificity, and
reproducibility for widespread clinical applications."
"In any event, the levels of viral (and cellular) DNA in serum appear to
be so low that reproducible detection, even with use of PCR, is not
currently possible."
----------------------
Josiah D. Rich et al., "Misdiagnosis of HIV infection by HIV-1 plasma
viral load testing: a case series" (1999) Annals of Internal Medicine 130:
37-39:
"The availability of sensitive assays for plasma HIV viral load and the
trend toward earlier and more aggressive treatment of HIV infection has
led to the inappropriate use of these assays as primary tools for the
diagnosis of acute HIV infection."
"Physicians should exercise caution when using the plasma viral load
assays to detect primary HIV infection..."
"Plasma viral load tests for HIV-1 were neither developed nor evaluated
for the diagnosis of HIV infection..."
------------------------
M. Piatak et al., "High levels of HIV-1 in plasma during all stages of
infection determined by competitive PCR" (1993) Science 259: 1749-1754:
"Plasma virus levels determined by QC-PCR correlated with, but exceeded by
an average of 60,000-fold, virus titers measured by endpoint dilution
culture."
In fact, 53% of the viral load positive patients had no culturable HIV.
"For HIV-1 propagated in vitro, total virions have been reported to exceed
culturable infectious units by factors of 10,000 to 10,000,000, ratios
similar to those we observed in plasma."
------------------------
Haynes W. Sheppard et al., "Viral burden and HIV disease" (1993) Nature
364: 291:
"...the high level of plasma virus observed by Piatak et al. [reference
above] was about 99.9 per cent non-culturable, suggesting that it was
either neutralized or defective. Therefore, rather than supporting a
cytopathic model, this observation actually may help explain the
relatively slow dissemination of the infected cell burden and thus the
relative ineffectiveness of therapy with nucleoside analogues which target
this process.
"...we question the longitudinal conclusions some of these investigators
have drawn from cross-sectional data. The results presented are equally
consistent with the conclusion that higher viraemia is a consequence of,
rather than the proximate cause of, defective immune responses."
------------------------
Simply put: the AIDS surrogate markers are being abused. These surrogate
markers are causing a great deal of harm by labeling people with myriad
diseases and conditions--even healthy people who only have antibodies to
HIV--as having incurable AIDS, which is said to be invariably fatal. The
surrogate markers are also being used to obtain FDA approval of clinically
ineffective AIDS chemotherapies that are highly toxic and even lethal if
taken long enough.
David Rasnick
References
1. Goodwin, J. S. (1981) OKT3, OKT4, and all that, Journal of the American
Medical Association 246, 947-948
2. Roederer, M. (1998) Getting to the HAART of T cell dynamics, Nature
Medicine 4, 145-146
3. Seligmann, M., et al. (1994) Concorde: MRC/ANRS randomised double-blind
controlled trial of immediate and deferred zidovudine in symptom-free HIV
infection, Lancet 343, 871-881
4. Fleming, T. R., et al. (1996) Surrogate end points in clinical trials:
are we being misled?, Annals of Internal Medicine 125, 605- 613
5. Sande, M. A., et al. (1993) National Institute of Allergy and
Infectious Diseases state-of-the-art Panel on Anti-retroviral therapy for
adult HIV-infected patients, Journal of the American Medical Association
270, 2583-2589
6. Fleming, T. R. (1994) Surrogate markers in AIDS and cancer trials,
Statistics in Medicine 13, 1423-1435 </OBJECT></LAYER>
- Posted by PaulKing
Dr David Rasnick on Surrogate Markers
It should come as a shock, no doubt, to learn that if three laboratory
tests somehow disappeared or were outlawed (HIV antibody test, CD4 cell
count, PCR viral load test), then AIDS, as commonly understood, would
formally vanish from the USA and Europe. The three laboratory tests in
question are called surrogate markers because they stand in for either
AIDS itself or for its supposed cause, HIV. According to the current
definition of AIDS, no matter how sick an American or European is with
AIDS-defining diseases, he or she cannot be classified as an AIDS case if
antibodies to HIV are not present. In other words, for an American or
European doctor to diagnose pneumonia, TB, dementia, cervical cancer, etc.
as AIDS it is necessary to obtain laboratory test results that satisfy the
definition of AIDS. Since the HIV- antibody test has been discussed in
depth already, I will limit my remarks to CD4 cell counts and viral load.
At the beginning of the AIDS epidemic, it was already recognized as
probably a mistake to use CD4 as a marker of AIDS or even a measure of
therapeutic effectiveness. In 1981, James Goodwin, MD, wrote what he
called "a diatribe against the measurement of T-cell subsets in human
diseases" [1]. His "diatribe" began: "It's starting again. ...The T- and
B-cell measures--having run through the sick, the elderly, the young, the
pregnant, the bereaved--had finally run out of diseases. Each condition
was the subject of many reports; so that now, to give but one example, we
can conclude with some assurance that T-cell numbers are up, down, or
unchanged in old folks. And it's starting all over again, this time with
T-cell subsets."
"What will they find?" he asked. "Sometimes the suppressor cell markers
will be up and helper cells down; sometimes the suppressor cells will be
down and the helper cells up; sometimes they'll be unchanged--and various
combinations of the aforementioned. ...My strongest argument is this:
Measurement of T and B cells and their subsets in diseases has no clinical
meaning."
"Nonimmunologists have naturally assumed that any subject occupying so
much journal space must be relevant in some way--a logical but incorrect
assumption. ...And while the identification of T- cell subsets in mouse
and man represents a major breakthrough in the understanding of
immunoregulation, the enumeration of these subsets in myriad diseases
largely represents a waste of time".
As recently as 1998, Mario Roederer of Stanford University confirmed
Goodwin's assessment that an obsession with T-cell subsets in AIDS
patients has been a mistake: "[T]he facts (1) that HIV uses CD4 as its
primary receptor, and (2) that CD4+ T cell numbers decline during AIDS,
are an unfortunate coincidence that have led us astray from understanding
the immunopathogenesis of this disease" [2].
Prior to Roederer's remarks, the use of the CD4 (T-cell counts) as a
surrogate marker of disease progression was also criticized by the authors
of the Concorde Study, the largest clinical trial evaluating the use of
AZT: The authors concluded that:
"The small but highly significant and persistent difference in CD4 count
between the groups was not translated into a significant clinical benefit.
Thus, analyses of the time until certain concentrations of CD4 were
reached (eg, 200/_L, 350/_L, or 50% of baseline) revealed significantly
shorter times in the Def[erred] group. Had such analyses been regarded as
fundamental, the trial might have been stopped early with a false-positive
result. This discrepancy in the differences between Imm[ediate] and Def
groups in terms of changes of CD4 count and of long-term clinical response
casts doubt on the uncritical use of CD4 counts as 'surrogate endpoints'
in trials..." [3].
Thomas Fleming and David DeMets have stated that, "The use of surrogate
end points has probably been more intensely discussed in the design and
analysis of clinical trials of HIV infection and AIDS than in any other
area" [4]. However, "Predictions having an accuracy of approximately 50%,
such as the accuracy seen with the CD4 count in the HIV setting, are as
uninformative as a toss of a coin." With regards to clinical trials and
FDA approval of anti-HIV drugs, Fleming and DeMets have warned that,
"Surrogate end points are rarely, if ever, adequate substitutes for the
definitive clinical outcome in phase 3 trials" [4].
Indeed, a summary result from a 1993 state-of-the-art conference had
previously concluded that the effect of treatment on the most popular
surrogate, CD4 cell count, did not accurately predict the effect of
treatment on the clinical outcomes, that is, progression to AIDS or time
to death [5]. Nevertheless, with the exception of the early AZT clinical
trials, all subsequent anti-HIV drug trials and FDA approvals have relied
exclusively on the measurements of these surrogate markers and not on the
real clinical outcomes, such as morbidity and mortality, that matter to
most people.
A year later, Fleming stated that, "It is very apparent one cannot simply
consider establishment of statistically significant treatment effects on
CD4 cell counts to be a valid surrogate for either of the two clinical
endpoints. When the progression to AIDS/death endpoint was positive, the
CD4 endpoint appropriately was significantly positive in 7 of 8 trials;
unfortunately however, the CD4 endpoint was significantly positive in 6 of
8 trials in which the progression to AIDS/death endpoint was negative. The
relationship of CD4 effects and survival is even more unsatisfactory. The
CD4 endpoint was significantly positive in only 2 of 4 trials in which the
survival endpoint was positive; yet it was significantly positive in 6 of
7 trials in which the survival endpoint was negative. In three other
trials, survival trends were observed which were in the opposite direction
of significant treatment effects on CD4" [6].
The well-recognized problems with CD4 counts eventually led to its being
replaced by the PCR viral-load test as the primary surrogate marker to be
used in anti-HIV drug clinical trials. But, the "viral load" test has its
share of problems. To start with, Roche's "AMPLICOR HIV-1 MONITOR Test is
not intended to be used as a screening test for HIV or as a diagnostic
test to confirm the presence of HIV infection" (Roche Diagnostic Systems
AMPLICOR HIV-1 MONITOR Test package insert, PMA No. BP950005/4).
To save space, below is a list of some of the problems with the viral load
test that were published in the scientific, medical literature:
False positive or false negative? It depends on the answer you want.
Apparently, absence of antibodies to HIV trumps a high viral load result.
Schwartz D. H. et al., "Extensive evaluation of a seronegative participant
in an HIV-1 vaccine trial as a result of false-positive PCR" (1997) The
Lancet 350: 256-259:
An individual tested positive by PCR, but was antibody negative.
Therefore, the patient's viral load of 100,000 copies of RNA per ml was
called false-positive. It took $5000 worth of PCR testing in several labs
to get the "right" answer: negative.
----------------------
Christine Defer et al., "Multicentre quality control of polymerase chain
reaction [viral load] for detection of HIV DNA" (1992) AIDS 6: 659-663:
"False-positive and false-negative results were observed in all
laboratories (concordance with serology ranged from 40 to 100%)."
----------------------
Michael P. Busch et al., "Poor sensitivity, specificity, and
reproducibility of detection of HIV-1 DNA in serum by polymerase chain
reaction" (1992) Journal of Acquired Immune Deficiency 5: 872-877:
"The results indicate that current techniques for detecting cell-free
HIV-1 DNA in serum lack adequate sensitivity, specificity, and
reproducibility for widespread clinical applications."
"In any event, the levels of viral (and cellular) DNA in serum appear to
be so low that reproducible detection, even with use of PCR, is not
currently possible."
----------------------
Josiah D. Rich et al., "Misdiagnosis of HIV infection by HIV-1 plasma
viral load testing: a case series" (1999) Annals of Internal Medicine 130:
37-39:
"The availability of sensitive assays for plasma HIV viral load and the
trend toward earlier and more aggressive treatment of HIV infection has
led to the inappropriate use of these assays as primary tools for the
diagnosis of acute HIV infection."
"Physicians should exercise caution when using the plasma viral load
assays to detect primary HIV infection..."
"Plasma viral load tests for HIV-1 were neither developed nor evaluated
for the diagnosis of HIV infection..."
------------------------
M. Piatak et al., "High levels of HIV-1 in plasma during all stages of
infection determined by competitive PCR" (1993) Science 259: 1749-1754:
"Plasma virus levels determined by QC-PCR correlated with, but exceeded by
an average of 60,000-fold, virus titers measured by endpoint dilution
culture."
In fact, 53% of the viral load positive patients had no culturable HIV.
"For HIV-1 propagated in vitro, total virions have been reported to exceed
culturable infectious units by factors of 10,000 to 10,000,000, ratios
similar to those we observed in plasma."
------------------------
Haynes W. Sheppard et al., "Viral burden and HIV disease" (1993) Nature
364: 291:
"...the high level of plasma virus observed by Piatak et al. [reference
above] was about 99.9 per cent non-culturable, suggesting that it was
either neutralized or defective. Therefore, rather than supporting a
cytopathic model, this observation actually may help explain the
relatively slow dissemination of the infected cell burden and thus the
relative ineffectiveness of therapy with nucleoside analogues which target
this process.
"...we question the longitudinal conclusions some of these investigators
have drawn from cross-sectional data. The results presented are equally
consistent with the conclusion that higher viraemia is a consequence of,
rather than the proximate cause of, defective immune responses."
------------------------
Simply put: the AIDS surrogate markers are being abused. These surrogate
markers are causing a great deal of harm by labeling people with myriad
diseases and conditions--even healthy people who only have antibodies to
HIV--as having incurable AIDS, which is said to be invariably fatal. The
surrogate markers are also being used to obtain FDA approval of clinically
ineffective AIDS chemotherapies that are highly toxic and even lethal if
taken long enough.
David Rasnick
References
1. Goodwin, J. S. (1981) OKT3, OKT4, and all that, Journal of the American
Medical Association 246, 947-948
2. Roederer, M. (1998) Getting to the HAART of T cell dynamics, Nature
Medicine 4, 145-146
3. Seligmann, M., et al. (1994) Concorde: MRC/ANRS randomised double-blind
controlled trial of immediate and deferred zidovudine in symptom-free HIV
infection, Lancet 343, 871-881
4. Fleming, T. R., et al. (1996) Surrogate end points in clinical trials:
are we being misled?, Annals of Internal Medicine 125, 605- 613
5. Sande, M. A., et al. (1993) National Institute of Allergy and
Infectious Diseases state-of-the-art Panel on Anti-retroviral therapy for
adult HIV-infected patients, Journal of the American Medical Association
270, 2583-2589
6. Fleming, T. R. (1994) Surrogate markers in AIDS and cancer trials,
Statistics in Medicine 13, 1423-1435 </
