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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.
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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%).”
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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.”
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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…”
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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.”
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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.”
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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
Comment by David Rasnick - November 8, 2007 at 6:33 am