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Being Alive
Latest IL-2 Study: Media Hype but Caution Advised
Walt Senterfitt
April 5, 1995
Being Alive 1995 Apr 5: 9

The March 2 issue of the New England Journal of Medicine contained a report by NIH (National Institutes of Health) researchers on the intermittent administration of interleukin-2 (IL-2) intravenously to a small number of HIV-infected patients. The study found that IL-2 significantly boosted CD4 cell counts in some of these patients for more than two years, much longer than typically seen with currently available anti-HIV drugs.

The PR apparatus of NIH went into high gear. The press office of NIAID (National Institute of Allergy and Infectious Disease) where the study was done distributed dozens of copies of canned videotaped interviews with Drs. Clifford Lane and Tony Fauci, arranged more live interviews with the doctors and snowed reporters with a blizzard of paper. Consequently, IL-2 was widely touted across the country as a new wonder drug. The story is in reality more complicated, less dramatic and not new to readers of this and many other AIDS newsletters.

Background IL-2 is a cytokine, one of the hormone-like chemicals produced in one's body to serve as messengers between different cells in the immune system. The cytokines' messages cause more of one kind of immune cell or another to be produced, activated, sensitized to fight a particular microbe and/or shut down when the work is done or the system goes out of balance. IL-2 is produced by T-cells themselves. It can cause various kinds of T-cells, (CD4, CD8 and "natural killer" cells which act against HIV and other microbes directly) and B cells (which act by producing antibodies) to multiply and become sensitized to fight one particular microorganism such as HIV or CMV. Because of its potent abilities in the test tube, natural or genetically-engineered IL-2 has been studied in various forms since 1983 as a potential means of boosting or repairing the immune system. Remember that the reported study is of intravenous (IV) administration of IL-2, not the lower-dose subcutaneous form (given by shallow injection under the skin) being tested in several other clinical trials.

IL-2 has long been recognized as a double-edged sword. By multiplying and activating CD4 cells, it also causes a lot more HIV particles to be produced and released into the bloodstream. Usually, therefore, it is given together with antiretroviral drugs like AZT, ddI or ddC. IL-2 also has the reputation of causing truly nasty side effects (I mean it often makes you sick as a dog) when given in its higher-dose IV forms.

This Study's Design The investigators first studied 23 patients with more than 200 T-cells to find the highest tolerable dose of IL-2. Then they chose 10 patients, also with T-cell counts above 200 (the average count in fact was more than 400) to receive 5-day courses of continuous IV infusions of 18 million IU (international units) of IL-2 a day, with an 8-week rest period between courses. Antiviral agents, most commonly AZT 500 mg/day, were given at the same time. Finally, the researchers gave the same regimen to 15 patients with CD4 counts of 200 or less. Patients could receive Tylenol, Motrin, Demerol, Valium, anti-nausea and/or anti-diarrheal medications for relief of the side effects which resembled the symptoms of a worse-than-you-ever-had flu, including fever. If the side effects were still intolerable, the dose of IL-2 was reduced in increments of 6 million IU per day. Thus, patients in the study actually received between 6 and 18 million IU daily. The regimen was followed for between 7 and 25 months, and patients were observed afterward for up to two years.

Results In 6 of the 10 patients with high CD4 counts, the CD4 count reached a level at least 50% higher than the starting point between one and two months after the first infusion. In two of the patients, the increases were truly dramatic: CD4 counts went from about 800 to nearly 2000, thus causing the group's average increase to be dramatic. Even more striking was the fact that these increases were sustained for up to seven months, and for some patients could be obtained again once they started to fall, by starting IL-2 again.

Toxic effects like high fevers, pain and fluid retention were observed in the majority of the patients.

No consistent changes in viral load were observed, however, as measured by the tools available during most of the study-p24 antigen and HIV viral culture. When the newer assays of viral load became available, frozen plasma of nine patients was tested. Four of these were found to have increases in viral load after each treatment, though these increases were almost always transient. Evaluation of long-term effect on viral load was difficult because the four patients with the most dramatic increa-ses in CD4 had no detectable viral load in the bloodstream to begin with. Among the 15 subjects with low CD4 counts at baseline, three did not continue long enough to be evaluated. Of the remainder, two of the six who started with 100-200 T-cells had CD4 increases of more than 50%. No increases were observed among the six who started with less than 100 T-cells. Furthermore, 10 of the 12 had sustained increases in viral load. Side effects were also a lot more severe in this group.

Reasons to Be Cautious These findings imply that IL-2 is a dangerous drug, especially for those with lower CD4 counts. The increase in viral load, even with concomitant administration of antiviral agents, is scary. It seems very likely on the face of these results that the dangers outweigh potential benefits for those with less than 200 T-cells.

Even for those few who experienced the dramatic rise in CD4 counts, there is no evidence as yet that these rises are associated with practical, clinical benefit. (The study's tiny size and lack of a control group preclude such analysis from its data.) The study involved a very small number of patients, even though these few were intensively studied. It can be quite misleading to generalize from such a small study.

The profile of toxic effects is onerous, though these side effects were in general not life threatening and could be moderated by dose reductions or medications to treat these symptoms.

Finally, the method of administration is burdensome. One must be hooked up to an IV around the clock for five days every two months, and must be in the hospital for monitoring of side effects.

Conclusion This was a small study of a highly experimental form of therapy. The therapy must be regarded so far as very hopeful for some HIV patients and dangerous for many others. It is not the imminently available breakthrough that one might have inferred from the press hype. It does contain some very interesting seeds of possibility, especially in its confirmation of yet another way the immune system might be strengthened or restored in those whose immune systems have not yet been seriously damaged. Hope is always welcome, even essential. But be careful to read the fine print. In this case, it warns of some pretty damn serious dangers.