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What’s old is becoming new again in the search for potent therapies in treating HIV disease. A well-established treatment for certain types of cancer, therapy with the T-cell growth factor Interleukin-2 (IL-2), is now showing promise as a treatment for HIV. Researchers across the nation have been studying how HIV-infected patients respond when they are given IL-2 in combination with their antiretroviral drug regimen. Some of the investigators’ findings were presented at the 8th Conference on Retroviruses and Opportunistic Infections, held Feb. 4-8 in Chicago.
"IL-2 has been around for a long time, and it’s approved for use in certain types of cancer where it has been shown to have a benefit in controlling tumors," says Ronald Mitsuyasu, MD, a professor of medicine and the director of the University of California - Los Angeles Center for Clinical AIDS Research and Education.
The route to using IL-2 therapeutically for treating cancer and HIV-infected patients is a long and well-worn path. "My lab first discovered the IL-2 molecule and receptor in the late 1970s," says Kendall A. Smith, MD, professor of medicine and immunology at the Weill Medical College of Cornell University in New York City. "We spent a decade or two working on the details of how IL-2 binds to its receptor and what happens subsequently to the cells and immune response," Smith adds.
Now, some 20-plus years after the IL-2 molecule and receptor were first discovered, researchers at Cornell, UCLA, the National Institutes of Health (NIH), and other research centers are close to determining how IL-2 therapy could best be used in treating HIV-infected patients.
NIH investigators first began looking at the possibility of using IL-2 to treat HIV-infected patients during the early 1980s, says H. Clifford Lane, MD, clinical director of the National Institutes of Allergy and Infectious Diseases at NIH in Bethesda, MD. Investigators learned early on that IL-2 had some potency against the AIDS virus, but it was unknown whether the treatment would work in people as well as in the lab.
The first trials in 1983 showed that the crude natural product of IL-2 used in treating AIDS patients had no effect. A year later, researchers gave recombinant IL-2 therapy in doses of a million or more units per day to AIDS patients over a period of eight weeks, Lane says. "The lymphocyte counts would go up over the first week or two, and then they would come back down to baseline," Lane explains. "So the effects looked quite transient."
The studies were repeated in 1986 when AZT became available, and the results were the same. So investigators decided to try something a little different. They began to administer high doses of IL-2 intravenously over a five-day period until about the time the T-cell counts started to climb again, and then they would stop IL-2 for two months. Researchers settled on a protocol that involved administering the IL-2 treatment for five days every eight weeks.
In the beginning of the 1990s, investigators hit the jackpot. They found that patients treated intermittently with IL-2 began to generate more T-cells than they had ever imagined possible. "Giving five days of therapy plus a rest period leads to a positive expansion of the CD4 T-cell count pool," Lane says.
Because investigators had arrived at this protocol through guesswork, they decided to test various other treatment structures to see what worked best. As it turned out, five days over eight weeks was the most effective regimen.
The next step is to prove the treatment has clinical benefit, Smith says. "So what is the clinical benefit of an increase in CD4 cell counts?" he asks. "We need a Phase III clinical end point study." There are two Phase III studies under way in 22 countries that are expected to enroll 5,400 patients total, Smith says.
"Within the entire study, we hope to look at the development of AIDS-surviving illnesses and mortality," Smith says. "We’ll take a large sample of patients, and within that sample we will have enough patients who do show progression to show an effect from IL-2 treatment."
Smith’s research group has been taking an entirely different approach to using IL-2 therapy for HIV-infected patients. The group is studying the administration of IL-2 therapy on a daily basis at about one-tenth of the dose that the NIH team has used. "We found several things when you give IL-2 on a daily basis," Smith says. "First, the natural killer cells increased rapidly over the first couple of months or so, and then they plateaued. Secondly, the CD4 cell count gradually and progressively increased over the course of a year, with an increase of 10 cells per month."
When compared with patients who were treated with highly active antiretroviral therapy (HAART) alone, the patients treated with both IL-2 and HAART had a significantly higher number of CD4 cells.
"At the same time, we found that the CD8 cell count, which was twice the normal count at the time of starting the study, still remained elevated but dropped by 25% from what it was," Smith adds. "People could tolerate IL-2 treatment on a daily basis with no side effects and no systemic side effects, and they could go to work or school and carry on normal activities."
A 1998 trial involved 40 HIV-infected people who had CD4 cell counts of less than 300 cells/ mm3 and who were given a low dose of IL-2 along with HAART for six months, Smith says. The study confirmed data from the earlier research, Smith adds. (See "Benefits of IL-2 therapy in treating HIV disease," in this issue.) "There was a dramatic increase over four months of naive CD4 cell subset," he explains. "The total CD4 cell count was higher than the control, but it had borderline significance."
An offshoot of the therapy was that the IL-2 group had a significant decrease in cholesterol and triglyceride levels, Smith adds. Furthermore, some patients have been receiving IL-2 therapy at the low doses for more than six years, and their CD4 cell counts remain around 1,000 cells/mm3, which is about five times higher than it was when they started IL-2 therapy, Smith says.
Mitsuyasu’s work has built on the NIH research by studying intermittent IL-2 therapy in patients who have more advanced HIV disease, such as those with CD4 cell counts below 400 cells/mm3. "We had questions of whether patients with lower T-cell counts would be able to respond immunologically," Mitsuyasu says. "Also, if you give IL-2 subcutaneous injections, would that be as effective as IL-2 administered intravenously?"
Mitsuyasu and co-investigators began in 1997 to recruit patients who had CD4 cell counts of 50-350 cells/mm3. The patients had not been on protease inhibitor therapy previously but may have been on other antiretrovirals. Patients were randomly assigned to three groups: those given a PI regimen plus IL-2 administered by intravenous infusion; patients given a PI regimen alone; and patients given a PI regimen with IL-2 administered by subcutaneous injection.
"What we found after a year of treatment was that those who got the IL-2 either by subcutaneous injection or intravenous infusion had a markedly higher T-cell count, almost three times higher, than those who were on HAART alone," Mitsuyasu says. "The HAART patients would have a good increase, maybe a 200 T-cell increase, but the IL-2 groups would have a 600-cell increase at the end of the period."
The study was small, involving only 200 patients, so there are limited conclusions that can be drawn from it, Mitsuyasu adds. "What we still don’t know is whether just raising the T-cell count will be of clinical benefit to patients who have more advanced disease, although we suspect from other data that it will be of clinical benefit."
High-dose treatment with IL-2 has some major side effects, including flu-like symptoms, fatigue, fever, and muscle aches, Mitsuyasu says.
Smith says the smaller doses of IL-2 do not have the same problem with side effects as the intermittent, higher-dose IL-2 therapy.
Another drawback to IL-2 therapy is the expense, which is not reimbursed by many insurers. Currently, IL-2 therapy is packaged for cancer patients in vials with the equivalent of 10 doses, costing about $500 per vial, Smith says. "We have an experimental pharmacist who works with our clinical research center and draws up IL-2 in syringes for patients," Smith says. "We send patients home with 14 syringes with which they take a shot every day, and then they throw the syringe away."
Because the use of IL-2 remains experimental and HIV clinicians have no clear protocols for how to administer it, their best strategy would be to refer patients who are interested in IL-2 therapy to some of the ongoing clinical studies, Lane suggests.
For information regarding these studies, contact the NIH at (800) TRIALS-A or on the web at www.espritstudy.org.