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"measurement of t- and b-cells and their subsets in diseases has no clinical meaning." thomas fleming and david demets
"that hiv uses cd4 as its primary receptor, and that cd4+ t-cell numbers decline during aids, are an unfortunate coincidence that have led us astray from understanding the immunopathogenesis of this disease." mario roederer
dear mr. bennett,
1. i think it makes not that much sense to switch from one question to the other! the main question is: is there evidence for "hiv" directly killing t cells? and the answer is no! you couldn't present any single study, either. so the supporters of the hiv hypothesis are in big trouble because more than 160 billion(!) $ are spent for hiv=aids-research that is based on pure speculation as well as ignorance because no single dollar or euro is spent in order to see if other factors than "hiv" might cause aids(-symptoms) or at least might contribute to the development of (well- known) diseases like aids-ks.
2. there may be some hints that "hiv" kills cd4 cells. but there are also studies showing that cd4 cell counts make no sense in the context of aids diagnosis. not only the biggest aids study, the concorde study, called the critical use of cd4 cell counts into question. in this context please allow me to quote from david rasnick's compilation "an abuse of surrogate markers for aids – cd4 cell counts and pcr viral load tests": "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” .
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' .
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/µL, 350/µL, 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...' .
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' . 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' .
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 .
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' .
3. you and all the other people who take the hiv hypothesis for granted (of course, without having any proof for its basic theses) should also not forget that only hiv=aids-research is being financed. so for example, instead of asking "can mr. russell explain the fact that hiv seropositivity (i.e. infection) produces disruption of lymph node architecture?", you should have asked: what have been done in order to study other factors than "hiv" that may explain this? or: does seropositivity always produce disruption of lymph node architecture? if no, how can that be?
4. moreover, i can only repeat myself: the supporters of the hiv hypothesis are not able to make a neutral approach to the issue. saying: "hiv seropositivity (i.e. infection)..." already implies that (1) hiv has been proven, that (2) antibody tests prove hiv, and that (3) positive test results mean that a person is infected by hiv. but none of these claims have been proven.
5. concerning correlation and causation: first, i am "happy" to hear from you that you admit that there is no clear-cut proof for the hiv hypothesis because there is no single study proving the hiv hypothesis. second, you write that "correlation is part of causation". but the problem with that statement is that the correlation of the hiv hypothesis is a very bad one. instead the hiv hypothesis is highly inconsistent. to make it short, please have a look under alexander russell's recent rapid response (here in this rapid response section) "reply to fenton: the outlandish anomalies of the 'hiv' hypothesis" from 24 march 2005. on the other hand, the drug hypothesis saying that aids can be explained by (1) illicit drugs, (2) anti-retroviral and other medical drugs, (3) malnutrition, and/or re-definition of well-known diseases like tbc into aids is very consistent. so relying on correlation as "proof" would mean accepting the drug hypothesis as the hypothesis that needs to be financed urgently!
6. you wrote: "If referring him [= i] to previously outlined posts covering the past year is 'coiling up' then so be it, but i suggest he read the entire list of rapid responses before assuming that anything y say is unsupported. for example a very quick search for hiv mediated cell death revealed the following paper: 'killing of primary cd4+ t cells by non-syncitium inducing macrophage-tropic human immunodeficiency virus type 1' by yu et al, pnas, vol 91 pp 10237-10241, Oct 1994" but: doing a pubmed search for keywords is very easy. but the important question in this case is: was the "hiv-1" that was added to these cells purified, or was it just the supernatant of a culture, or some product of that after filtering and centrifugation? and also: i am not "assuming" that anythiny you say is unsupported, but i just can't see an answer to my simple questions like: where is the study that proves that hiv causes aids? where is the study that proves that hiv kills cd4 cells? so i am not assuming, but i have to state that you don't have a proof for all these theses!
7. you wrote: "the fact that hiv infection precedes a cd4 t cell decline that is not seen in any other human condition is proof enough. it isn't even required that hiv directly kills the t cells, even though it does. smoking after all predisposes people to lung infections, but it doesn't directly introduce the bacterial pathogen... this is why epidemiology is in fact far more than 'just' correlation. you can prove beyond reasonable doubt that a factor is bad or good without having a clue as to why that might be the case." so my questions are: are you saying that hiv infection always precedes a cd4 t cell decline? how do you define an "hiv infection"? what proof do you have that any one hiv test has been validated against purification of the virus?
torsten engelbrecht journalist www.torstenengelbrecht.com
 Goodwin, J. S. (1981) OKT3, OKT4, and all that, Journal of the American Medical Association 246, 947-948
 Roederer, M. (1998) Getting to the HAART of T cell dynamics, Nature Medicine 4, 145-146
 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
 Fleming, T. R., et al. (1996) Surrogate end points in clinical trials: are we being misled?, Annals of Internal Medicine 125, 605-613
 Eleni Papadopulos-Eleopulos et al. (1995) a critical analysis of the HIV-T4-Cell-AIDS-Hypothesis, Genetica 1995: 5-24.
 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
 Fleming, T. R. (1994) Surrogate markers in AIDS and cancer trials, Statistics in Medicine 13, 1423-1435
Competing interests: None declared