Answering the AIDS Denialists:
CD4 (T-Cell) Counts, and Viral Load

By Bruce Mirken

Courtesy of AIDS Treatment News http://www.aidsnews.org)

The self-styled "AIDS dissidents," groups and individuals advocating the
view that HIV does not cause AIDS, and often urging people with HIV to
reject medical care, have raised their profile in recent months, ratcheting
up their advocacy in the U.S. and attempting to influence the health
policies of foreign governments. Although these forces sometimes accept the
need to treat opportunistic infections, most reject the vast majority of
conventional HIV/AIDS treatment, especially use of drugs to combat HIV. This
article is part of a series in which AIDS TREATMENT NEWS examines key
arguments put forth by the "dissidents"--perhaps more accurately termed
"AIDS denialists," because most deny that AIDS is a genuine epidemic and
many deny that the term "AIDS" even describes a real medical condition.

The AIDS denialist movement is not unified (for example, some groups say
that HIV is a harmless virus, while others say HIV does not exist), so the
summary here of some of their arguments is necessarily only a sketch. More
detailed descriptions can be found in the references listed below.
Answering Denialist Views on CD4 (T-Cell) Tests

One consistent thread running through the denialist literature is the
assertion that AIDS medicine has made a serious mistake by relying on
laboratory markers such as CD4 cell counts, and viral load as measured by
techniques such as polymerase chain reaction (PCR). These markers are
criticized as unreliable at best and a devious effort to hide the failure of
HIV/AIDS science at worst. One recently-formed group, ACT UP Hollywood (not
connected with long-standing ACT UP chapters in New York, Philadelphia and
elsewhere), argues that "all HIV and viral load tests as well as T-cell
counts need to be banned immediately because they are useless indicators of
a person's health."(1)

The arguments against use of CD4 center around two broad issues. One is the
natural variability in CD4 counts, which can be lower than average for
reasons not related to AIDS.(2,3) The other is whether or not CD4 numbers
actually correlate with clinical prognosis. In her book WHAT IF EVERYTHING
YOU THOUGHT YOU KNEW ABOUT AIDS WAS WRONG?, Christine Maggiore, founder of
Los Angeles-based Alive and Well AIDS Alternatives, writes, "A number of
studies found in the biomedical literature show that low T cell counts do
not correlate with compromised immunity, and that normal ranges for T cells
in HIV negative persons can vary from 300 to 2,000."(3) Some denialists cite
the famous Concorde study of early versus deferred use of AZT
monotherapy--in which an AZT-induced boost in CD4 counts did not translate
to improved survival--as proof that, as one writer put it, "there was
absolutely no correlation between CD4 T-cell counts and clinical health."(4)

The denialist argument appears to be built upon a narrow and highly
selective reading of the data. For example one of the sources Maggiore cites
as proof for the above statement that low CD4 counts can occur without HIV,
a Transfusion Safety Study Group report at the 9th International AIDS
Conference, specifically notes that HIV-negative individuals with two or
more CD4 counts below 300 were rare, and that both those with known and
unknown causes of immune suppression "differ from the retrovirus
immunodeficiency pattern" in a number of key parameters, including CD4
percentage and CD4/CD8 ratio.(5)

In other words, transient low CD4 counts seen in other circumstances do not
equal AIDS and bear little resemblance to what is typically seen in
HIV-infected individuals. What the denialists regularly ignore is that while
unusually low CD4 counts can occur for a variety of reasons, numerous large,
long-term cohort studies have demonstrated a distinct pattern associated
with HIV infection: A statistically significant CD4 decline commonly begins
around the time of seroconversion and gradually becomes more severe over
time, eventually leading to increased susceptibility to opportunistic
infections. This has been observed in cohorts of gay men, transfusion
recipients and hemophiliacs. In these cohorts a decline in CD4 count has
been consistently and strongly associated with the development of
AIDS-defining illnesses.(6)

Also neglected in denialist discussions of CD4 is the large body of evidence
associating specific opportunistic infections with lowered CD4 counts. For
example, in the Pulmonary Complications of HIV Study, an 1,182-person
cohort, 79 percent of cases of pneumocystis carinii pneumonia (PCP) occurred
in individuals with CD4 counts below 100 and 95 percent occurred in patients
whose CD4 count was below 200.(7) The Multicenter AIDS Cohort Study (MACS)
has also reported a "greatly increased risk" of PCP when CD4 counts drop
below 200.(8) Numerous other studies have found similar associations between
lowered CD4 counts and increased risk of PCP and other opportunistic
infections.(6,9,10) Such findings formed the basis for long-standing
recommendations regarding opportunistic infection prophylaxis (using drugs
to prevent these infections). Other research relevant to this discussion is
covered in the section on viral load, below.

Regarding the effect of treatment-induced increases in CD4 on clinical
prognosis, the small increases seen in Concorde indeed did not correlate
with improved long-term outcome. But numerous other studies do show a strong
correlation with lowered risk of AIDS-defining opportunistic infections or
death, particularly with larger, HAART-induced CD4 increases. In the
U.S.-government trial ACTG 320 (which compared AZT plus 3TC vs. AZT plus 3TC
plus indinavir [Crixivan(R)]), the indinavir group had a mean CD4 increase
roughly three times that of the AZT/3TC only group, and half as many AIDS-
defining events.(11) In a meta-analysis (combined analysis) of seven (mostly
pre-HAART) antiretroviral studies, researchers found that "having either a
reduction in HIV-1 RNA level or an increase in CD4+ lymphocyte count, or
both, was associated with a delay in clinical disease progression."(12)
Overall, a large body of evidence involving both treated and untreated
patients shows a clear correlation between low or declining CD4 counts and
increased risk of opportunistic infections or death.(13,14)

The denialist view of CD4 counts is used to call into question the 1993
revision of the CDC's AIDS case definition, which added a CD4 count of 200
or lower as an AIDS-defining condition. In Maggiore's words, it "allows
HIV-positives with no symptoms or illness to be diagnosed with AIDS. Since
1993, more than half of all newly diagnosed AIDS cases are counted among
people who are not sick."(3) The mass of evidence showing that HIV-infected
individuals with CD4 counts below 200 are at overwhelmingly increased risk
for life-threatening infections is simply ignored.

And on Viral Load

Maggiore states in her book that "low levels of viral load have not been
correlated with good health, with absence of illness or high T-cell counts,
while high viral loads do not correspond with low T-cells or sickness."(3)
In a recent newspaper column she also complains that viral load tests are
not FDA-approved for diagnosis of HIV infection, and notes, "Viral loads are
found in people who test HIV-negative."(15) Denialist objection to viral
load testing is bolstered by the fact that Kary Mullis, who won a Nobel
prize for developing the basic technique of PCR, is a supporter of their
cause and has questioned the use of his technique to quantify virus.(3)

In a 1996 article published in the denialist journal REAPPRAISING AIDS,
authors Christine Johnson and Paul Philpott demonstrate their scorn for
viral load measurements in the title of their discussion, "Viral Load of
Crap." Focusing on the 1995 Ho and Shaw NATURE papers on viral dynamics,
they write:

"Ho and Shaw's technique looks for HIV RNA, the genetic material found in
the viral core. They assume that since each HIV contains two HIV RNAs, there
must be one HIV for every two HIV RNAs they count. But the large amount of
HIV RNA they report is found only after sending blood samples through
polymerase chain reactions (PCR). PCR is the 'DNA fingerprinting' technology
which takes tiny numbers of genetic molecules (RNA or DNA) and turns them
into huge quantities." What these tests find, they argue, is meaningless:
"Some of these are HIVs that have been neutralized by antibodies, some are
defective HIVs (those that did not form correctly) and some are
free-floating HIV RNA. Though none of these entities has any pathological
capacity, the viral load technique confuses them with whole, infectious
virus, the only kind that has any biological significance."(16)

This essay is typical of the denialist analysis of viral load, illustrating
both its strengths and weaknesses. Like much of the movement's literature,
they discuss only PCR and not the other technologies used to quantify viral
load, mistakenly stating that Ho used PCR when in fact he used bDNA
(branched DNA)--a different process marketed by a different company.(17,18)

Philpott and Johnson effectively lay out the theoretical reasons why
PCR-based viral load tests might produce a misleading result. Indeed,
company researchers and the FDA have acknowledged potential causes of error
and variation in viral load results, and a potential margin of error in
these assays of roughly threefold.(18,19) Thus, when the FDA approved the
Roche Amplicor HIV-1 Monitor (a PCR-based assay), it required the labeling
to indicate that the test can accurately detect a three-fold or greater
change in HIV RNA for patients with a viral load of 1000 copies or greater
and a six-fold or greater change for patients whose viral load is below
1000.(19) (Although Maggiore is correct in saying that the FDA has not
approved PCR for diagnosing HIV infection, she neglects to mention that the
agency did approve it "to assess patient prognosis... or to monitor the
effect of antiviral therapy").

Strikingly, Philpott and Johnson stick entirely to theory and do not address
the key question of whether or not viral load measurements predict the
likelihood of disease progression or death in the real world. A very large
body of evidence indicates they do, some of which was available prior to
their dismissal of the tests as a "Viral Load of Crap." The mass of
confirming data--from ongoing cohort studies as well as antiretroviral
trials--that has accumulated since then is rarely acknowledged in denialist
writings.

Beginning in 1995 John Mellors and colleagues published a series of articles
detailing MACS cohort data showing a strong correlation between baseline
viral load and subsequent disease progression.20,21,22 Using stored blood
samples from patients' early study visits, Mellors examined the rates of
AIDS-defining events and deaths in relation to viral load levels measured
using bDNA. In a 1604-patient sample, only 0.9 percent of those whose
baseline viral load was 500 copies or lower died of AIDS within six years,
while 69.5 percent of those whose viral load was greater than 30,000 copies
died. "Plasma viral load was the single best predictor of outcome," Mellors
wrote, "followed by CD4+ lymphocyte counts [T-cell counts] and neopterin
levels, beta2-microglobulin levels, and thrush or fever. We observed a
strong association between viral load and the subsequent rate of decline in
CD4+ lymphocyte counts."(22)

Similarly strong associations between viral load levels and clinical outcome
have been reported in numerous other cohort studies, including the
1170-patient EuroSIDA cohort(23) and the Multicenter Hemophilia Cohort
Study,(24) among others. In the hemophilia cohort, "each log(10) increase in
baseline viral load was associated with a five-fold increase in risk for
AIDS-related illness during the first six months of follow-up." The
predictive value of viral load was independent of that of CD4 count.

One particularly interesting study looked at viral load in gay men in the
Baltimore MACS cohort and injection drug users in the Baltimore "AIDS Link
to Intravenous Experiences" (ALIVE) cohort. Rather than measuring plasma
HIV-RNA in the usual way, using PCR or bDNA, this study looked at cell-
associated infectious viral load using the quantitative microculture assay.
This method "quantifies the biologically functional and infectious
cell-associated HIV-1 by measuring the amount of HIV infected cells capable
of infecting donor cells from an uninfected person in culture."(25) Looking
at the risk of AIDS-defining infections, non-AIDS-defining bacterial
infections, and death, the researchers found that "higher levels of
infectious viral load were significantly related to increased hazards for
all three outcomes," with little difference between the gay men and the
intravenous drug users. After adjusting for CD4 level and numerous other
factors, viral load was strongly predictive of risk of progression to AIDS.

The association between viral load (measured using bDNA or PCR) and clinical
progression has been seen consistently in HIV treatment trials, including
the meta-analysis of seven studies discussed above,(12) in which "each
10-fold decrease in HIV-1 RNA was associated with a 51 percent reduction in
progression risk." In both the pivotal trial of ritonavir(26) and ACTG
320,(11) patients randomly assigned to the protease inhibitor arm showed
significantly better suppression of viral load and significantly reduced
AIDS-defining events.

After reviewing the available data, including numerous studies not listed
here, the expert panel convened by the Department of Health and Human
Services to determine HIV treatment guidelines recommended using both CD4
and viral load in conjunction with the clinical condition of the patient to
guide therapeutic decision-making. The panel noted, "Multiple analyses in
over 5,000 patients who participated in approximately 18 trials with viral
load monitoring showed a statistically significant dose-response type
association between decreases in plasma viremia and improved clinical
outcome."(27)

Discussion of this data is notably absent even in current denialist
literature. Maggiore's recent column,(15) for example, cites one article
from 1993(28)--very early in the development of these assays--as "studies
showing that viral load test results do not correlate with illness, with
wellness, with T-cell counts or even the finding of virus by co-culture."
This is at best a dubious interpretation of this study, and Maggiore fails
to discuss any of the more recent evidence showing precisely the opposite.
Evidence cited of viral loads found in HIV-negative people turns out to be a
handful of anomalous cases, several of which involve false- negative
antibody tests in people who clearly had AIDS.(29)

Evaluating the Evidence
No lab test or surrogate marker is perfect. All have innate limitations,
natural variation, and a chance of error, and as a result HIV/AIDS
researchers and treatment activists alike have cautioned that physicians
must always remember they are treating patients, not lab values.

The limitations of CD4 and viral load tests, both real and theoretical, have
been exhaustively described by the denialists. But their declarations that
these tests are meaningless are based on a skewed, highly selective reading
of the data that simply omits anything which might contradict their views.
The overwhelming preponderance of evidence strongly indicates that both CD4
and viral load measurements can provide useful and important information
that doctors and patients can use to evaluate progress and make treatment
decisions.

For More Information
Many of the denialist Web sites and books are accessible through the
references below.

Unfortunately, the medical mainstream has usually not bothered to answer
these views--so persons with sincere questions have heard only one side.
This is changing. Meanwhile, the U.S. National Institute of Allergy and
Infectious Diseases has prepared a page of links to publications with
evidence that HIV causes AIDS,
http://www.niaid.nih.gov/spotlight/hiv00/default.htm . Also, see
http://www.aegis.org/topics/aids_debate.html .

References
1.ACT UP Hollywood home page,
http://web.archive.org/web/20010424170317/http://www.outspoken.org/actuphollywoo
d/index.html

2. Strausberg, John. THE AIDS HERETICS. New York Press. March 9, 2000; 13:
10.

3.Maggiore, Christine. WHAT IF EVERYTHING YOU THOUGHT YOU KNEW ABOUT AIDS
WAS WRONG (4th Edition, 2000). American Foundation for AIDS Alternatives,
Studio City, California.

4.Conlan, Mark Gabrish. Interview: John Lauritsen. ZENGER'S. April 1997.

5.Mosley, James. Idiopathic CD4+ Lymphocytopenia: Other Lymphocyte Changes.
IX International Conference on AIDS, Berlin, 1993, abstract #WS-A25-5.

6.Stein, Daniel S, Korvick, Joyce A. and Vermund, Sten H. CD4+ Lymphocyte
Cell Enumeration for Prediction of Clinical Course of Human Immunodeficiency
Virus Disease, a Review. JOURNAL OF INFECTIOUS DISEASES, 1992; 165: 352-363.

7.Stansell, J.D., and others. Predictors of Pneumocystis carinii pneumonia
in HIV-infected persons. Pulmonary Complications of AIDS Study Group.
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE. January 1997;
155:1, 60-66.

8.Phair, J., and others. The risk of Pneumocystis carinii pneumonia among
men infected with human immunodeficiency virus type 1. Multicenter AIDS
Cohort Study Group. NEW ENGLAND JOURNAL OF MEDICINE. January 1990; 322:3,
161-165.

9.Nightingale, SD, and others. Incidence of Mycobacterium
avium-intracellulare complex bacteremia in human immunodeficiency
virus-positive patients. JOURNAL OF INFECTIOUS DISEASES. June 1992; 165: 6,
1082-1085.

10.Spaide, R.F., Gaissinger, A., and Podhorzer, J.R. Risk factors for
cotton-wool spots and for cytomegalovirus retinitis in patients with human
immunodeficiency virus infection OPHTHALMOLOGY. December 1995; 102:12,
1860-1864.

11.Hammer, S., and others. A controlled trial of two nucleoside analogues
plus indinavir in persons with human immunodeficiency virus infection and
CD4 cell counts of 200 per cubic milliliter or less. NEW ENGLAND JOURNAL OF
MEDICINE. 1997; 337: 725-733.

12.Marschner, I. C., and others. Use of Changes in Plasma Levels of Human
Immunodeficiency Virus Type 1 RNA to Assess the Clinical Benefit of
Antiretroviral Therapy. JOURNAL OF INFECTIOUS DISEASES. 1998; 177: 40-47.

13.Smith, D.K., and others. Causes and rates of death among HIV-infected
women 1993-1998: The contribution of illicit drug use and suboptimal HAART
use. 7th Conference on Retroviruses and Opportunistic Infections, San
Francisco, January 30-February 2, 2000, abstract #682.

14.O'Brien, William A., and others. Changes in plasma HIV RNA level and CD4+
lymphocyte counts predict both response to antiretroviral therapy and
therapeutic failure. ANNALS OF INTERNAL MEDICINE. 1997; 126: 939-945.

15.Maggiore, Christine, Questioning AIDS, Q & A. MAGNUS. March/April, 2000.

16.Johnson, Christine and Philpott, Paul. Viral Load of Crap. REAPPRAISING
AIDS. October, 1996.

17.Ho, D.D., and others. Rapid turnover of plasma virions and CD4
lymphocytes in HIV-1 infection. NATURE. January 12, 1995; 373: 123-126.

18.Todd, J. Performance Characteristics for the quantitation of plasma HIV-1
RNA using the branched DNA signal amplification technology. JOURNAL OF
ACQUIRED IMMUNE DEFICIENCY SYNDROMES AND HUMAN RETROVIROLOGY. 1995; 10:
supplement 2, S35-44.

19.Food and Drug Administration, letter to Roche Molecular Systems, March 2,
1999.

20.Mellors, J., and others. Quantitation of HIV-1 RNA in plasma predicts
outcome after seroconversion. ANNALS OF INTERNAL MEDICINE. 1995; 122:
573-579.

21.Mellors, J., and others. Prognosis in HIV-1 infection predicted by the
quantity of virus in plasma. SCIENCE. May 24, 1996; 272: 1167-1170.

22.Mellors, J., and others. Plasma viral load and CD4+ lymphocytes as
prognostic markers in HIV-1 infection. ANNALS OF INTERNAL MEDICINE. 1997;
126: 946-954.

23.Miller, V., and others. Association of viral load, CD4 cell count, and
treatment with clinical progression in HIV patients with very low CD4 cell
counts: The EuroSIDA cohort. 7th Conference on Retroviruses and
Opportunistic Infections, San Francisco, January 30-February 2, 2000,
abstract #454.

24.Engels, E., and others. Plasma HIV-1 viral load in patients with
hemophilia and late-stage HIV disease: A measure of current immune
suppression. ANNALS OF INTERNAL MEDICINE. 1999; 131:256-264.

25.Lyles, C.M., and others. Cell-associated infectious HIV-1 load as a
predictor of clinical progression and survival among HIV-1 infected
injection drug users and homosexual men. EUROPEAN JOURNAL OF EPIDEMIOLOGY.
1999, 15:99-108.

26.Cameron, D.W., and others. Randomized placebo-controlled trial of
ritonavir in advanced HIV-1 disease. THE LANCET. February 21, 1998; 321:
543-549.

27.Panel on Clinical Practices for Treatment of HIV Infection. GUIDELINES
FOR THE USE OF ANTIRETROVIRAL AGENTS IN HIV-INFECTED ADULTS AND ADOLESCENTS.
January 28, 2000. (This document is available at
http://web.archive.org/web/20010424170317/http://www.hivatis.org/ .)

28.Piatak, M, and others. High levels of HIV-1 in plasma during all stages
of infection determined by competitive PCR. SCIENCE. March 1993; 259:
1749-1753.

29.Sullivan, P.S., and others. Persistently negative HIV-1 antibody enzyme
immunoassay results for patients with HIV-1 infection and AIDS: serologic,
clinical and virologic results. Seronegative AIDS Clinical Study Group.
AIDS. January 1999; 12:1, 89-96.

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