What do CD4 counts mean?

The level of CD4 cells in peripheral blood is a prime criterion for diagnosing AIDS (in the United States in particular) and for monitoring antiretroviral treatment. However, these applications of CD4 counts stem from the initial and unhappy coincidence that when “AIDS” appeared around 1980, the counting of immune-system cells was in its infancy. By now it is known that CD4 levels are extremely variable in healthy individuals, and that a variety of physiological conditions other than “HIV” may profoundly influence CD4 counts. There seems to be no fundamental evidential warrant for the manner in which HIV/AIDS diagnosis and treatment rely on CD4 counts. Juliane Sacher among others has pointed out that the levels of CD4 cells in peripheral blood are not a meaningful measure of immune-system status, since these cells move around the body according to where they seem to be needed [Alternative treatments for AIDS, 25 February 2008].

An obvious question: what is the range of CD4 counts in healthy individuals and in a variety of illnesses? (I’m grateful to Tony Lance for alerting me to some of the intriguing sources mentioned in the following).

One of the striking aspects of CD4 counts is how enormously they vary among individuals, including healthy individuals. Here, for example, are data from HIV-negative Senegalese:

C. Mair, S. E. Hawes, H. D. Agne, P. S. Sow, I. N’doye, L. E. Manhart, P. L. Fu, G. S. Gottlieb and N. B. Kiviat. Factors associated with CD4 lymphocyte counts in HIV-negative Senegalese individuals. Clinical and Experimental Immunology 151 (2007) 432-440

In any normal distribution, the standard deviation (s.d. or σ) describes the degree of scatter around the average (or mean) value. Only about 2/3 of a sample are within (±) 1 σ; in other words, about 1/6 are further from the mean on both the higher and the lower sides. In the Table above, among the men with mean CD4 count of 712, σ = 333, about 1 in every 6 men have CD4 counts below 379 or above 1045; and about 2% have counts more than 2σ above and below 712 , that is >1378) and <50. CD4 = 200 is about 1.5σ below the mean, which corresponds to about 6-7% (~1/15) of the sample. In other words, about 1 in every 15 healthy HIV-negative Senegalese men has CD4 counts below the 200 that, in HIV-positive people, is taken to be a sign of AIDS.

Of course, CD4 counts may not follow a normal distribution, especially at upper and lower levels; but since this article reports means and standard deviations without specifying a different distribution, the authors themselves are presuming it is normal. Moreover, a similarly wide range of CD4 counts and an approximation to normal distribution is shown in other data sets as well. For example, healthy North Indians were reported to have a mean CD4 count of 720 with σ = 273 and an actually observed range of 304-1864 among 200 individuals; 10% were below 400, consistent with a normal distribution which would have about 16% below 450 (Ritu Amatya, Madhu Vajpayee, Shweta Kaushik, Sunita Kanswal, R.M. Pandey, and Pradeep Seth. “Lymphocyte immunophenotype reference ranges in healthy Indian adults: implications for management of HIV/AIDS in India”. Clinical Immunology 112 [2004] 290-5). Actual distributions for several African populations, however, show a skewing toward higher CD4 counts, which indeed seems highly plausible a priori — one might expect to see a definite lower bound to CD4 counts in healthy individuals (Williams et al., “HIV infection, antiretroviral therapy, and CD4+ cell count distributions in African populations”, J Inf. Dis. 194 [2006] 1450-8).

Worth particular note is the comment in Amatya et al. that “These low counts could be due to physiological lymphopenia potentially caused by protein energy malnutrition, aging, antigenic polymorphism of the CD4 molecule, prolonged sun exposure, circadian rhythm, and circannual variation [9,10]”. The use of contraceptive pills by women has also been reported to influence CD4 counts (M. K. Maini, R. J. Gilson, N. Chavda, S. Gill, A. Fakoya, E. J. Ross, A. N. Phillips and I. V. Weller. “Reference ranges and sources of variability of CD4 counts in HIV-seronegative women and men”. Genitourin Med 72 [1996) 27-31]. Most of those circumstances do not represent illness. So CD4 counts can be low for a variety of fairly normal, not seriously health-threatening conditions. It follows that reliance on CD4 counts as diagnostic of “HIV disease” increases the danger that some unknown number of “HIV-positive” individuals are being told on the basis of laboratory tests — sometimes SOLELY on the basis of laboratory tests — that they are actually sick even though they feel and actually are healthy; and these people are then at risk of being consigned to toxic “treatment” for this imaginary illness. The risk is greatest if the blood tested for CD4 counts happens to have been drawn in the morning, or in the wrong season of the year, because CD4 counts vary appreciably with both those variables: T. G. Pagleironi et al., “Circannual variation in lymphocyte subsets, revisited”, Transfusion 34 [1994] 512-6; F. Hulstaert et al., “Age-related changes in human blood lymphocyte subpopulations”, Clin. Immunol. Immunopathol. 70 [1994] 152-8. Maini et al. (above) report a 60% variation during the day with lowest counts at 11 am. Yet another report describes a similarly large diurnal variation, from 820 at 8 am to 1320 at 10 pm (Bofill et al., “Laboratory control values for CD4 and CD8 T lymphocytes. Implications for HIV-1 diagnosis”, Clin. Exp. Immunol. 88 [1992] 243-52).

Just as with the tendency to test “HIV-positive”, CD4 counts are influenced by demographic variables: “race, ethnic origin, age group, and gender” (Amatya et al.). Bofill et al. also report a steadily decreasing CD4 count with increasing age. The contrary has been reported, however, by Jiang et al. (“Normal values for CD4 and CD8 lymphocyte subsets in healthy Chinese adults from Shanghai”, Clinical and Diagnostic Laboratory Immunology, 11 [2004] 811-3). The discrepancy may be owing to differing attitudes toward statistical significance: the raw numbers in Jiang et al. do show an increase with age for men and a decrease with age for women but, as with the data of Bofill et al. and all others, the standard deviations are so large, on the order of one third of the mean values, that differences and trends would have to be very considerable if they are to be statistically meaningful.

Again, Jiang et al. report no difference between Chinese men and women, whereas several sources cite women as having higher CD4 counts than men: in Britain (Maini et al.) and in more than dozen other countries in Africa, Asia, and Europe (Mair et al.). Caucasians have higher CD4 counts than Asians or Africans, according to Amatya et al. and Jiang et al., but not according to Maini et al.

All these variations under the influence of several factors would make the diagnostic application of CD4 counts problematic even if “HIV” or “AIDS” had been shown to be the salient influence on CD4 levels. However, just as with the tendency to test “HIV-positive”, CD4 counts may be “low” in a wide range of conditions; perhaps most relevant to HIV/AIDS, in tuberculosis and general trauma, as well as with primary immunodeficiency, early acute phases of such viral infections as influenza, or Dengue fever (Bofill et al.) or recent respiratory infections (Maini et al.).

Not only are CD4 counts dubious for diagnosis or prognosis; just as with the tendency to test “HIV-positive”, CD4 counts generate a number of conundrums if interpreted according to HIV/AIDS theory: the counts are often HIGHER rather than lower in conditions generally regarded as associated with poor health. For example, smokers have higher CD4 counts than non-smokers (Maini et al., Mair et al.) and prostitutes have higher counts than other women (Mair et al.). Another “striking paradox” is in “co-infection” with “HIV” and herpes:
“We observed no effect of HSV-2 status on viral load. However, we did observe that treatment naïve, recently HIV-1 infected adults co-infected with HSV-2+ at the time of HIV-1 acquisition had higher CD4+ T cell counts over time. If verified in other cohorts, this result poses a striking paradox, and its public health implications are not immediately clear” (emphases added; Barbour et al., “HIV-1/HSV-2 co-infected adults in early HIV-1 infection have elevated CD4+ T-Cell counts”, PLoS ONE 2(10) [2007] e1080).

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There seems to be no clear warrant for diagnosing AIDS by means of CD4 counts, which may be why other countries have not followed the US example of taking <200 as a criterion. Similarly, there seems to be no clear warrant for assessing the progress of antiretroviral treatment by means of CD4 counts. Two practical illustrations of that are the fact that CD4 counts do not correlate with (or, changes in are not predicted by)  “viral load” (Rodriguez et al., JAMA, 296 [2006] 1498-1506), and that the NIH Treatment Guidelines distinguish immunologic failure (no increase in CD4 counts) from virologic failure (no decrease in viral load) and from clinical progression (does the patient’s health improve?).

A somewhat related illustration of the failure of HIV/AIDS theory is that “AIDS” patients with Kaposi’s sarcoma may have quite high CD4 counts: see for example Maurer T, Ponte M, Leslie K. “HIV-Associated Kaposi’s Sarcoma with a High CD4 Count and a Low Viral Load”. N Engl J Med 357 (2007) 1352-3; Krown SE, Lee JY, Dittmer DP, AIDS Malignancy Consortium. “More on HIV-Associated Kaposi’s Sarcoma” N Engl J Med 358 (2008) 535-6; D.G. Power, P. J. Mulholland K. J. O’Byrne. “AIDS-related Kaposi’s Sarcoma in a Patient with a Normal CD4 Count”. Clinical Oncology 20 (2008) 97; Stebbing J, Powles T, Bower M. AIDS-associated Kaposi’s sarcoma associated with a low viral load and a high CD4 cell count. AIDS 22 (2008) 551-2. Mani, D., Neil, N., Israel, R., Aboulafia, D. M. “A retrospective analysis of AIDS-associated Kaposi’s Sarcoma in patients with undetectable HIV viral loads and CD4 counts greater than 300 cells/mm3”. J Int Assoc Physicians AIDS Care (Chic Ill) 8 (2009) 279-85.

But then it has also long been known that “AIDS” Kaposi’s sarcoma is not caused by HIV, it’s now attributed to KSHV or HHV-8, which just happened — by the sort of extraordinary coincidence or oddity that is so common in HIV/AIDS matters — just happened to appear at the same time among the same risk groups as “AIDS” and “HIV” did; and then just as mysteriously went a separate path, so that KS declined from about 40% of all “AIDS” case in 1982 to well under 10% from 1987 onwards (Table 30, p. 128 in The Origin, Persistence and Failings of HIV/AIDS Theory).

More sales in the offing for snake oil and Brooklyn Bridges.

More MAINSTREAM ALTERNATIVE treatment for “HIV/AIDS”

“A nutritional formula . . . may help slow CD4 cell decline and reduce immune activation” [Liz Highleyman, reporting on  “Reduced CD4+ T cell decline and immune activation by NR100157, a specific multi-targeted nutritional intervention, in HIV-1 positive adults not on antiretroviral therapy (BITE)” by J. Lange et al., presented at the 49th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, 12-15 September 2009; Abstract H-1230b].
“Pedro Cahn and colleagues with the international BITE study aimed to determine whether a combination nutritional formula could reduce CD4 cells loss in people on ART. The randomized controlled trial was designed to include 800 HIV positive participants in Argentina, Australia, Brazil, Italy, the Netherlands, Thailand, the U.K., and the U.S. Half were randomly assigned to take the nutritional formula, known as NR100157, for 1 year, while the other half received a control product containing the same amount of calories and protein, but without the active ingredients. NR100157 contains several components that individually have demonstrated beneficial effects on immune function in previous studies: Prebiotic oligosaccharides: chains of simple sugars that help maintain healthy flora, or balance of bacteria in the gut; N-acetyl cysteine: a modified amino acid that helps maintain the body’s supply of glutathione, a key antioxidant; Bovine colostrum: nutrient- and antibody-rich fluid produced prior to milk; Omega-3 long-chain polyunsaturated fatty acids: molecules shown to improve the integrity of the gut, which prevents bacteria from leaking out and triggering systemic immune activation; Micronutrients including vitamins and minerals.
The study was stopped early after a planned interim analysis showed significant immunological benefit in the NR100157 arm and no notable safety concerns. . . .
Participants in the NR100157 arm lost significantly fewer CD4 cells per year than those in the control arm (-28 vs -68 cells/mm3, respectively; expected loss for untreated people with HIV 50-70 cells/mm3 annually). There were no significant differences between the 2 arms with regard to CD4 percentage, CD8 cell count, or CD4/CD8 ratio. Plasma viral load remained stable, and similar, in both groups” [emphases added].

Comments:
1. Maintaining healthy gut flora benefits immune function: that’s what Tony Lance discussed in his intestinal dysbiosis hypothesis, including the aspect of gut leakage, systemic immune activation, and potentially testing “HIV-positive” [“What really caused AIDS: Slicing through the Gordian Knot”, 20 February 2008].

2. The “viral load” was stable while CD4 counts varied: in other words, once again, changes in CD4 counts do not correlate with “viral load” [Rodriguez et al., JAMA, 296 (2006) 1498-1506].

3. HIV/AIDS mainstreamers are much more critical of clinical trials of alternative remedies than they are of mainstream endeavors. When mainstreamers publish at “statistical significance” of p<0.05 — wrong once in 20 times —, that’s good; but when an alternative treatment is significant at p=0.03 —  wrong only once in 33 times — that’s cause for HAART enthusiasts and HIV/AIDS believers to be “stunned” that anyone would accept it (“Gut-shielding mix slows CD4 drop in people not taking antiretrovirals”) :
“The data and safety monitoring board (DSMB) recommended stopping BITE early because of a significant difference in CD4 decline between groups and lack of safety concerns. An intention-to-treat analysis at 52 weeks showed a significantly slower annual average CD4-cell drop in the NR100157 group, 28 versus 68 cells/mm(3) with placebo (P = 0.030). . . . In a question-and-answer session after Argentina’s Pedro Cahn presented these findings, Harvard’s Daniel Kuritzkes claimed to be ‘stunned’ that the DSMB would stop the trial of an apparently safe agent when the statistical difference between treatment arms reached only 0.03. He also questioned the investigators’ decision to take the DSMB’s advice. Kuritzkes felt stopping a trial at such a low level of significance leaves open the possibility of bias toward a positive finding” [emphases added].
I suppose Kuritzkes would have been even more astonished that researchers stopped trials of circumcision early on the basis of the usual “95% confidence interval” — i.e., wrong once in 20 times; or that they were ecstatic over the first apparent success of a vaccine trial after many failures, even though one would have expected such an APPARENT success sooner or later at that usual “p<0.05”, “wrong once every 20 times”, criterion.

To be quite clear:
I agree that a single clinical trial is inconclusive, no matter what level of statistical significance may be reached.
I agree that p=0.03 is not in itself a particularly convincing result; still less so, of course, are all the mainstream trials that accept the weaker p<0.05; not to speak of the statistical ignorance that allows researchers at the Centers for Disease Control and Prevention  and elsewhere to confuse correlation with causation and to say such things as “nonsignificantly lower” [“Abuses of statistics in HIV/AIDS research”, 14 September 2009].
My point here is just that alternative treatments are criticized while even worse examples of mainstream contentions are given free passes or even praised.

CD4 counts don’t count — OFFICIAL!

For a very long time, the central belief in HIV/AIDS theory has been that “HIV” kills CD4 cells (albeit by a mechanism that still remains to be identified), thereby wrecking the immune system and allowing opportunistic infections to take over. Measurements of peripheral (in the blood) CD4 cells have been a mainstay in research and treatment. Voices raised to point out the error of this, those of  Heinrich Kremer or Juliane Sacher among others, have been studiously ignored. But now it’s become quite official:

“’In both studies, the volunteers who received IL-2 and antiretrovirals experienced notable, sustained increases in CD4+ T cell counts, as anticipated,’ notes NIAID Director Anthony S. Fauci, M.D. ‘Unfortunately, these increases did not translate into reduced risks of HIV-associated opportunistic diseases or death when compared with the risks in volunteers who were taking only antiretrovirals. Although further analyses may help us better understand these findings, the two studies clearly demonstrated that the use of IL-2 did not improve health outcomes for HIV-infected people.’”

That paragraph is from an official release by the National Institute of Allergy and Infectious Diseases (NIAID), “IL-2 immunotherapy fails to benefit HIV-infected individuals already taking antiretrovirals”

Increased CD4 counts do not translate into better health outcomes
for people on HAART —
even though the aim of HAART is supposed to be lower viral load
that supposedly allows rebounding of CD4 counts.

That could already have been inferred, of course, from the publication by Rodriguez et al., “Predictive value of plasma HIV RNA level on rate of CD4 T-cell decline in untreated HIV infection”, JAMA, 296 [2006] 1498-1506: the predictive value is NIL; viral load doesn’t predict CD4 decline in untreated patients; so why expect that it would do so in  HAART-treated patients? But these IL-2 trials had been running since 1999 and 2000 respectively, so why cut them short just because research has shown them to be superfluous or misguided? Or just because the experts who draw up NIH’s Treatment Guidelines have also been sure for some time that CD4, viral load, and patient health do not correlate with one another, they are independent of one another — that’s why the Treatment Guidelines have to distinguish among “virologic failure” (viral load doesn’t decrease under treatment), “immunologic failure” (CD4 counts don’t increase), and “clinical failure” (operation succeeds, viral load down and CD4 up, patient dies).

Mere facts, though, have never been particularly meaningful in HIV/AIDS research. Anything that clearly contradicts HIV/AIDS theory is not accepted as falsification, instead it’s taken as a mystery to be solved. More from the recent NIAID release:

“These are the findings of two large international clinical trials presented today at the Conference on Retroviruses and Opportunistic Infections (CROI) in Montreal. . . .
IL-2 is produced naturally in the body and plays an important role in regulating CD4+ T cell production and survival. As their CD4+ T cell levels drop, people infected with HIV become more vulnerable to AIDS-related opportunistic diseases and death. Earlier research established that giving synthetic IL-2 plus antiretroviral therapy to people with HIV infection boosts their CD4+ T cell counts more than does antiretroviral therapy alone, but it was unknown whether this boost translated into better health [emphasis added]”.

It’s asserted (highlighted sentence above) as though known with certainty that lower CD4 means worse prognosis; yet

“ESPRIT and SILCAAT were designed to test whether giving IL-2 to HIV-infected individuals already on antiretroviral therapy would keep them healthier longer than HIV-infected individuals taking only antiretrovirals.”

If the highlighted assertion above had been right, then these tests were not needed. If they were needed, then the assertion should not have been made.

These clinical trials themselves appear to have been sound; and they looked at CD4 counts in both ranges of interest — there have been long-standing questions about the optimum CD4 counts at which antiretroviral treatment might best begin:

“Together, the ESPRIT and SILCAAT studies involved more than 5,800 HIV-infected volunteers in 25 countries. Participants were assigned at random to receive either combination antiretroviral therapy alone or combination antiretrovirals plus injections of Proleukin (Novartis Pharmaceuticals, Basel, Switzerland), a synthetic form of IL-2, over several five-day cycles. To evaluate the effects of IL-2 treatment at different stages of HIV infection, the ESPRIT study enrolled people with early-stage infection (CD4+ T cell counts at or above 300 cells per cubic millimeter, or mm3), while the SILCAAT study enrolled volunteers with later-stage HIV infection (CD4+ T cell counts between 50 and 299 cells/ mm3).
It is unclear why increased CD4+ T cell counts did not translate into better health outcomes.”

What’s unclear? Increased CD4 doesn’t produce better prognoses. HIV/AIDS theory is wrong. But of course that’s unthinkable:

“James D. Neaton, . . .  principal investigator of the global clinical trials network that conducted ESPRIT, offers two possible explanations. ‘It could be that the types of CD4+ T cells induced by IL-2 play no role in protecting the HIV-infected patient, and therefore the administration of IL-2 has no benefit,’ says Dr. Neaton. ‘A second possibility is that the CD4+ T cells are at least somewhat functional or that IL-2 has some modest benefit, but that the side effects of IL-2 may neutralize any possible benefit.’
‘. . .although a person’s number of CD4+ T cells is a key measure of success in the treatment of HIV with antiretroviral drugs, we can’t rely on CD4+ T cell counts to predict whether immune-based therapies such as IL-2 will improve the health of HIV-infected individuals,’ concludes Dr. Levy, the principal investigator of SILCAAT.”

If CD4 counts don’t predict what “immune-based” therapies can do . . .
BUT these CD4s are the immune-system cells that have been accepted for a quarter century as the critical ones in HIV/AIDS, the ones that are supposedly killed off by “HIV” — so isn’t EVERY therapy that seeks to increase CD4 an “immune-based” therapy?

If the problem is with the particular TYPE of CD4 cells, these results would be just as damaging to HIV/AIDS theory and practice, since it would mean that faulty or meaningless measures have been used for more than two decades to make life-or-death decisions as to antiretroviral treatment.

Still, the important thing to note is that these trials, though they failed, were actually successful:

“’The purpose of clinical research is to clearly state and accurately test hypotheses with an ultimate goal of improving patient care,’ notes H. Clifford Lane, M.D., director of clinical research at NIAID and a member of the executive committee of ESPRIT. ‘These two clinical trials successfully reached a definitive answer about the utility of IL-2 therapy for treating HIV infection. NIAID thanks the thousands of dedicated volunteers and investigators who made these studies possible. The results will have significant implications for the future development of immune-based therapies for HIV and studies of HIV pathogenesis.’”

But perhaps this was just official spin for public consumption, for at least one other similar trial was abandoned:

“NIAID has discontinued the use of IL-2 in a separate, 20-country clinical trial known as STALWART (which stands for ‘Study of Aldesleukin with and Without Antiretroviral Therapy’).”

I don’t know about SILCAAT, but I do like those acronyms ESPRIT and STALWART. Perhaps NIAID wordsmiths get their inspiration from the Pentagon.