Testing … testing …

By Celia Farber
Journalist and AIDS commentator

Original Publication
SPIN magazine, New York, Spring 1994.

Rumblings of discontent among people diagnosed HIV positive have meant an increasing reluctance to submit to the stress of T-cell counting now that we are beginning to realize how meaningless the practice is. Celia Farber, journalist and AIDS commentator writes about how T-cell counting affects the lives of HIV-positive people

A homeless man sitting on the sidewalk, holds up a cardboard sign, on he has scrawled: "Help me. I have AIDS. I only have 190 T-cells." At an AIDS support-group meeting, the discussion revolves around T-cells, as it so often does. People with HIV cling to their T-cell counts like a score-card for survival - the higher the count, the longer you have to live. Supposedly. One person after another details his or her T-cell odyssey, reciting a dizzying spectrum of numbers. "'My last count was 267 but the one before that was 340 so they've actually gone down," says one an, "but the funny thing is, I feel better than ever." Another man, looking conspicuously healthy, raises his hand and announces defiantly "I only have one T-cell left. But it's a damn good one!" The room erupts in laughter; a kind of comic relief in the face of a medical absurdity-a room full of ordinary people grasping at mysterious immunological jargon.

"People have been terrorised by these T-cell counts," says Michael Ellner, a New York City AIDS counsellor with some very unorthodox views on AIDS, and the president of this support group, HEAL (Health Education AIDS Liaison). "I tell people to ignore them. We have no idea what they mean, so why should people get so frantic about them?" Most people working in the field of AIDS would disagree vehemently with Ellner. Ever since AIDS was first recognised as a Syndrome in 1981, counting the CD4 lymphocytes, or so-called T-4 cells (measured in cells per cubic millimetre), has played a pivotal role in AIDS, not just in charting the disease's progression, but also in determining everything from drug research to treatment guidelines, to the very definition of AIDS - who has it and who doesn't. This followed the observation, made in the early years of the epidemic, that people with AIDS seemed to get sicker as their CD4 cells diminished. With HIV itself being so mysterious - hiding in cells, killing cells by all kinds of unknown mechanisms, mutating wildly - the CD4 cell, solid and quantifiable, became an alternative point of fixation instead.

You could see it, watch it, measure it, and the hope was, high-tech drugs could replenish it and cure the disease. But now researchers are beginning to question the absolute link between CD4 counts and AIDS. And even the most expert immunologists confess they are mystified by the CD4 cell's exact role in the human immune sys-tem. Research has shown that certain people have stayed healthy for years with very low counts. Some people who are not even HIV-positive have shown low T-cell counts - low enough to parallel AIDS. And the final straw came at last year's International Conference on AIDS in Berlin, when the results for the Concorde study were revealed. The study, which looked at the long-term use of AZT in HIV-positive but asymptomatic people, concluded that although AZT was able to raise the level of T-cells, those with higher T-cells were no healthier for it. By the close of the conference, almost a decade after it was elevated to the pinnacle of immunological influence, the value of T-cell counts was shaken, amid promises that a new and better marker would replace it.

Paradoxically, the Centers for Disease Control (CDC) revised its AIDS definition as of January 1993 to include the CD4 count. According to the old definition, a person didn't have AIDS until his or her first AIDS-defining ill-ness. But by the new definition, anybody who is HIV-positive and has a CD4 count below 200 has AIDS, regardless of symptoms. A spokesperson from the CDC National AIDS hot line, referring to the surgeon general's report, explains the CDC's logic in changing the definition. Thanks to antiviral drugs and other therapies, people were going longer without developing infections. So the definition was broadened in an attempt to include all people whose health was threatened because their T-cell count had dropped to a certain level, even if they had no infections. When pressed why the figure was precisely 200, CDC spokesperson Tom Skinner said it reflected the consensus of several medical associations.

The U.S. Public Health Service still recommends that CD4 cells be monitored every three to six months in all HIV-positive people, and many doctors still feel they are both a good marker for declining health and offer parame-ters for treatment choices. But many people who are HIV-positive are beginning to turn away from the CD4 count as an all-important indicator. "Personally, I'm not doing it anymore," says one HIV-positive woman at the HEAL meeting when the talk turns to T-cell counts. "I'm not being scared to death by a number anymore." "You get bombarded," a man cries in a voice tinged with despera-tion. "Low T-cells, you're gonna die - That's still in me. I have to catch myself I say, How do I feel? Great - then I forget it. But other people with this T-cell business, they just go crazy. And they'll do anything, and take anything, because of it." The discussion in this room is a microcosm of the real confusion that looms, though is rarely admitted, over all AIDS research. What do T-cell counts really mean? What makes them go up and down? Why don't people feel better or worse when the count changes, if they're such a good predictor for sickness? One man raises his hand. "I asked my doctor, is there a correlation between high T-cells, low T-cells, sickness, health? He says they really don't know."

The reason the T-4 cell came to play such a central role in AIDS can be traced to the earliest observations made about the syndrome. In 1981, researchers were startled to find that the first AIDS patients, had almost no T-4 cells. Later, when HIV was discovered, and it was found that HIV infected precisely these cells, it was concluded that AIDS was basically a disease of T-4 deficiency, caused by HIV. But today, researchers have radically revised that view, has on the observation first made as early as 1987 by HIV sceptic Dr. Peter Duesberg that HIV does not kill enough cells to account for the depletion. Instead, researchers are exploring the possibility that various "indirect cell-killing, mechanisms" are involved and proposing that AIDS may be not a problem of immune suppression but of an immune system gone haywire, possibly even attacking itself.

The immune system is believed to protect the body against disease by a complex interaction between several kinds of white cells, which attack anything they perceive as foreign entering the body. A distinction is made between two arms of the immune system, the B-cell arm and the T-cell arm. While B-lymphocytes identify invaders, starting the process of their destruction by cre-ating antibodies, the T-lymphocytes attach themselves to invaders and destroy them. The T-lymphocytes are said to be the front line defence of the immune system. There are two T-cell types that are routinely measured in AIDS-"T-helpers" (T-4s) and T-suppressors (T-8s), and these are normally found in a ratio of about two to one. In the blood of AIDS patients, instead of having two helpers to one suppressor, the ratio is reversed. This was soon seized upon, and designated as the hallmark of the disease. But while elevated T-8 cells were once considered bad news, today the theory itself has reversed, as researchers find many long-term survivors with high T-8 levels. "I don't understand how that notion came into being, that high T-8s were bad," says Dr. Pamela Jo Harris at the AIDS Clinical Research Center in Washington, D.C. "From the very beginning we observed that people with high T-8s did very well." Today researchers speculate that the T-8 cells may be doing the job of the missing T-4 cells. What few people realise, amid the barrage of AIDS and T-cell jargon, is that research is still relatively new. Back when these observations were made in the mid-'80s, the techniques for enumerating T-lymphocyte populations were just being developed. "It was a marriage of convenience between something that was being studied and an epidemic that evolved alongside it," explains Harris. "We were just beginning to understand T-cells so we tried to match them up with the disease. And in some ways that did people a disservice because it deflected people from looking at other things."

"I do think that, generally, there is a correlation between a decline in CD4s and a decline in health, but that is not always the case," says Dr Joseph Sonnabend, a veteran New York City AIDS doctor. "There are many abnormalities in the bloodwork of a person with AIDS - not just the CD4 count, virtually all the lymphocyte sub-sets are off base. There are people with normal CD4 counts who still have these abnormalities, who even have high CD4 counts and still get PCP [pneumocystis carinii pneumonia], for example. And the opposite is also true, that there are those with very low counts who have remained relatively healthy. The problem here is the same problem as elsewhere in AIDS research, that we've been operating on these very simple models of disease, based on assumptions that were made about things that couldn't be known when they were made."

Dr. Gene Shearer, a National Institutes of Health immunologist on the cutting edge of AIDS research, agrees. "You can't account for all the immunological problems in AIDS by just counting up the numbers of cells that have disappeared." But Sonnabend defends the practice of monitoring T-cells: "It does tell you something," he says, "and it does give guidance in terms of prophylaxis against PCP most importantly, which used to be the leading killer of people with AIDS." This is perhaps the crux of the issue, the reason given by doctors and AIDS organisations alike for getting one's T-cells tested: If they are found to be low, certain preventative measures should be taken. A fervent campaign has been organised around this concept, known as "early intervention." The idea is that if you are HIV-positive and your T-cells are steadily declining, certain drugs may act as a stopgap. In 1989, the government recommended therapy with powerful, toxic AIDS drugs such as AZT for a count of 500 or lower. Current government guidelines state that anybody with a T-cell count under 200 should take anti-PCP drugs permanently. Critics have pointed out however, that many people have lived for years with T-4 counts well below 200 and have not developed PCP, and that some people who have taken the prophylaxis drugs, which are often quite toxic, have gotten the disease anyway. "The 200 cut off point really screws over a lot of people who have just over 200 CD4 cells and are quite sick," says Harris, referring to the new CDC definition of AIDS, "and conversely, it makes people who have less than 200 feel they're dying, when they may have ten or more years of health in front of them. I think we've made the mistake of attributing everything under the sun to CD4 levels, basically because we had a paucity of information," says Harris.

"In my practice, I've seen a lot of people who have been at less than 50 T-cells for years, who are doing fine. It is true, generally speaking, that you're more at risk for an opportunistic infection if your T-cells are less than 200, but that's only one of an awful lot of variables, most of which we have not identified. A drop in T-cells by itself is no reason to panic. Nor is a rise in T-cells a reason to be overjoyed. I think people in the community have a better perspective on this than some of the academics do." Immunologist and author Dr. Ed Golub concurs. When AIDS came along there had been a religious belief that you need helper function and that CD4 cells give that helper function, that the immune system is at a hair-trig-ger and that if you take away a little bit of function you're going to take away that increment of immunity. Well, not necessarily. The immune system is incredibly complex and although we've examined the parts, we real-ly have no idea how the parts fit together in the body. We got it wrong - the immune system doesn't protect. And one of the arguments that I have used is that you can remove 90 percent of the CD4 cells and people are still okay; so they must be there for some other reason, but the obvious question is: If they're falling, what else is going wrong?"

Dr. Haynes Sheppard, AIDS researcher and California State Department of Health Services immunologist, points out the normal CD4 count in the uninfected popu-lation can in fact vary widely - from as low as 300 to as high as 2,000. 'What you usually hear is that normal is 1,000," says Sheppard. But 1,000 is the median of the normal distribution of the CD4 count that has a curve that starts at 400 and goes out to 2,000." He continues, "What's important and what has always been a marker of immune progression is the rate at which the CD4 cells are lost. Someone who loses half his or her original count in a year is progressing much faster than someone who loses 10 percent." But, I ask him, is the person who starts with 500 "more immune suppressed" than the person who started with 1,000? "Well, that's something we're beginning to look at, whether normal people prior to HIV infection, if their normal CD4 count is toward the lower end of the distribution, do they then end up progressing to AIDS more rapidly? I can't give you an answer because we really haven't looked at the data that way yet. My laboratory manager is a perfect example," says Sheppard. "HIV- negative, perfectly normal 50-year-old male. We measure his counts as a normal control and he is almost always around 400. And if he got HIV-infected tomorrow, he'd be a candidate for AZT therapy, prior to any progres-sion whatsoever."

In 1992, discoveries of cases of so-called idiopathic CD4 lymphocytopenia (ICL), in which people became severely immune suppressed and even died, though they were not infected with HIV, made researchers look more closely at the T-cell ratios of HIV-negative people. The ICL cases served as a reminder that severe immune suppression can occur independent of HIV and that HIV-positive peo-ple are not the only ones with low T-4 cell counts. Dr. Robert Root-Bernstein devotes several chapters to non-HIV-related causes of T-cell depletion in his book Rethinking AIDS (Free Press). He scoured the medical literature and found T-cell ratios identical to those of AIDS patients in many categories of cancer patient transplant patients, long-term IV drug users, children with genetically inherited immune deficiencies, people suffering from malnourishment, blood transfusion recipients, people who had just undergone surgery or anaesthesia to name but a few. T-cell depletion has also been correlated with anxiety and depression which are obviously factors in people given an AIDS diagnosis.

Dr. James Mosley of the Transfusion Safety Study Group presented a paper at the International Conference on AIDS in 1993 exploring the CD4 counts of HIV-negative Americans. After testing over 2,000 blood samples collected in 1985 to track HIV infec-tions related to blood transfusions, Mosley found some healthy people had counts as low as 200 and proposed that a CD4 count as low as 300 should fall within the parameters of a "normal" count. Mosley told SPIN, "No one had particularly looked at uninfected persons in the lower range of normal. We observed these over a period of up to six years and they had no health problems that could be related to an immune deficiency. Everyone assumes that a low CD4 count necessarily means immune deficiency. It does not." Studies have shown that CD4 counts can differ based on gender, age, race, and even time of day.

One estimate has it that a CD4 count can fluctuate as much as 35 to 74 percent in a single day. One study demonstrated that T-cells decline with age. Children have much higher T-cell counts than adults and infants born to HIV-positive mothers have died even though their T-cells are over 1,000. Another recent study showed CD4 counts are markedly higher in women than in men and higher in smokers than in non-smokers. Even though individuals tend to hold their breath over every last T-cell, the laboratories that count them are far less precise. One study pre-sented at the International Conference on AIDS in 1993 looked at the variations between CD4 counts from the same blood, different laboratories. Nine out of twenty-four patients studied had such different counts from the various labs that the results would lead to different treatment recommendations. Three out of those nine met the revised CDC/AIDS defini-tion according to some lab results, but did not have AIDS according to others. A recent study in the Journal of the American Medical Association describes a group of HIV-positive people in Brazil who had very high CD4 counts-over 1,000-and still died of AIDS. They were all co-infected with another virus, HTLV-1 which causes a proliferation of CD4 cells. Throughout the study, their counts remained high - as high as 1,000 - and their health declined. The authors concluded that "for this group, the higher mean CD4 lymphocyte count does not appear to offer immunologic benefit."

Denny, 36, has been HIV-positive, with declining T--cells and virtually no symptoms, for at least ten years. His story illustrates the confusion and emotional roller coaster most people in the world of AIDS diag-nostics face. "I tested positive to the antibody in 1985. Around the beginning of 1991 I started having a lot of throat infections and tonsillitis. So I got my T-cells tested. They were at 532. Four months later, they were 304; then two months later, 428." Denny's T-cells continued to decline, but after a tonsillectomy, he remains symptom-free. Today, he has 59 T-cells. 'The funny thing is," he says, "the only time I've been sick, back when I was having all those throat infec-tions, my T-cells were 496. In between I have not had any serious illness. Certainly not any opportunistic infections. My T-8 cells, on the other hand, have been up as high as 2,500. It used to be that if your T8s got high they thought that was really bad, but now they're saying it's good." Meanwhile, Denny continues to defy the prevailing beliefs about low T-4 cells and AIDS. "Because of all this media hype about T-cells," he says, "I do have some concerns but I don't think they're as important as people think they are, but I wouldn't mind having them a little higher, just to be on the safe side."