T H E   N I H    C A T A L Y S T SEPTEMBER   -   OCTOBER   1 9 9 7 



The following account of IL-2 therapy trials in HIV-infected people marks the debut of our promised occasional feature on "hot new clinical trials" at NIH and is based on published material and interviews with two of the principal investigators, H. Clifford Lane, NIAID clinical director, and Joseph Kovacs, a senior investigator in the Critical Care Medicine Department at the NIH Clinical Center.

IL-2 Immune Boost
In HIV-Infected Patients
To Be Tested in Thousands Worldwide

by Janet Yee and Fran Pollner

The most conspicuous excitement lately in the HIV-AIDS arena has been generated by the clinical success of protease inhibitors, which, used in combination with other antiretroviral agents, have yielded stunning results in decimating viral burden in HIV-infected individuals.

But attacking the virus directly is but one part of a two-fisted strategy in dealing with the ravages of HIV infection. The partner of antiviral therapy in the battle against AIDS is immune system reconstitution, the focus of an NIH team of investigators that has been conducting clinical trials of a recombinant version of interleukin-2 (IL-2), an endogenous immune system stimulator. This cytokine would be used in conjunction with any antiretroviral regimen deemed appropriate for any given patient and, unlike the therapeutic agents whose action is HIV-directed, is unperturbed by the virus' capacity for mutation and resistance.

Begun in earnest in 1991 with open studies involving handfuls of patients, IL-2 research has progressed to the point where plans are being finalized for a Phase III clinical trial that will inevolve nearly 4,000 HIV-infected people in about a dozen countries..

According to H. Clifford Lane, NIAID clinical director and a principal investigator, the protocol for the randomized, controlled trial was completed this summer and recruitment will likely begin early next year.

Eventually, more than 3,700 HIV-infected individuals from the United States, Canada, Argentina, South Africa, Thailand, Australia, the United Kingdom, Spain, Italy, The Netherlands, Belgium, and Germany (and possibly Switzerland and France) will be enrolled.

The goal of the study is to determine whether the increases in CD4+ T cells induced by IL-2 seen in preliminary studies translate to fewer AIDS-related complications and improved survival for HIV-infected patients. All patients will be on antiretroviral therapy, with half randomly assigned to a group that will also receive IL-2. Patients will adhere to protocol for two years, with follow-up monitoring of CD4 counts, viral burden, and incidence and severity of opportunistic infections continuing for another four years.

Patients assigned to the IL-2 treatment arm will self-administer the cytokine by subcutaneous injection twice a day for five consecutive days every two months, initially at a standard dose but with adjustments within upper and lower limits, according to individual tolerance of side effects. (Patients not suited to this mode of administration will receive IL-2 by infusion for five consecutive days every two months. Dosages and routes of administration were established in earlier trials.)

The trial is limited to HIV-infected patients with CD4 counts above 350/mm3, the "most practical cutoff," Lane said, because it best reconciled "two competing forces: the lower the CD4 count, the poorer the response to IL-2; the higher the initial CD4 count, the longer it would take to reach an endpoint. Thus, 350 was picked as the lowest count that would still be able to give an acceptable response rating at some degree of disease progression."

Early Trial Results

In initial dose-escalation studies, IL-2 therapy proved capable of elevating CD4 counts in HIV-infected people, but only in those who had baseline CD4 counts above 200/mm3 at the start of the study; those whose initial counts were lower showed little response to IL-2 (J. A. Kovacs et al., "Increases in CD4 T lymphocytes with intermittent courses of interleukin-2 in patients with human immunodeficiency virus infection: a preliminary study,"N Engl J Med 332:567-75, 1995).

"The idea is to come in while the immune system is still intact, so as to expand and protect it. Once the immune system declines too far, it is difficult to reconstitute," Lane said.

In 1993, 60 HIV-infected individuals with baseline CD4 counts above 200 were enrolled in a controlled, randomized (Phase II) study of IL-2. All patients received standard antiviral therapy, but half also received IL-2 by intravenous infusion for five days every two months.

At the end of one year, CD4 counts in the IL-2-treated patients had doubled; the counts in those treated with antiviral drugs alone had declined. The increase was sustained for more than two years by continued IL-2 administration, and in five patients, counts remained above 1,000 for at least 18 months after IL-2 was discontinued.

"To date, no combination of antiretroviral agents has been shown to be capable of inducing increases in CD4 counts of this magnitude or duration," the authors wrote in their second New England Journal of Medicine article on the ongoing research (Kovacs et al., "Controlled trial of interleukin-2 infusions in patients infected with the human immunodeficiency virus," N Engl J Med 335:1350-1357, 1996).

During the course of these trials, patients experienced varying degrees of flu-like symptoms as well as transient increases in their HIV levels. Consequently, the IL-2 dosage was adjusted for each patient, within the range of 3 million to 18 million IU.

Although the bursts of HIV production observed after each IL-2 treatment were worrisome, investigators found no long-term increases in viral levels, as measured by blood levels of HIV RNA and p24 antigen. Similar trials by two other research centers have confirmed these results.

Among the 10 or so IL-2-related protocols conducted at NIH was one led by NIAID's Richard Davey, another coauthor, which evaluated the effectiveness of self-administered subcutaneous IL-2 injection as an alternative to the more complicated and costly infusion route.

The finding that self-administration was an acceptable and effective method enhanced the feasibility of clinical use of IL-2 therapy and served as the basis for the route of administration that is the mainstay of the Phase III protocol design (R. T. Davey et al., "Subcutaneous administration of interleukin-2 in human immunodeficiency virus type 1- infected persons," J Infect Dis 175:781-89, 1997)

Scientific Rationale

HIV-infected individuals become increasingly vulnerable to infections by other pathogens as their immune systems become progressively damaged by the replicating virus. These secondary, or opportunistic, infections are the main cause of health complications and deaths associated with AIDS. The decline in the level of CD4+ T cells, a major immune component in the patient's bloodstream, is indicative of advancing disease. Since IL-2 can stimulate the production of CD4+ T cells, this cytokine may be effective in boosting the immune system of HIV patients. Scientists at the NIH Clinical Center, NIAID, and FCRDC have been collaborating with Chiron Corporation of Emeryville, Calif., to evaluate the long-term effects of treating HIV-infected individuals with recombinant IL-2.

Interpreting the Numbers

CD4+ levels in normal, uninfected adults typically range from 800 to 1,200 cells/mm3 but can be as low as 600 in some healthy people. HIV-infected individuals who have not developed AIDS and are in relatively good health typically have counts above 500. Patients with cell counts between 200 and 500 commonly exhibit some HIV-associated conditions, such as thrush. Major, life-threatening illnesses, such as mycobacterial infections and pneumocystis pneumonia, are typically found in patients with cell counts below 200. Counts approach 800 and above in long-term HIV-infected individuals who remain symptom-free - the "nonprogressors," whose evasion of disease has recently been connected to the absence of a T-cell co-receptor.

The IL-2 Crews: (above) outside the NIAID/CCMD HIV Outpatient Research Clinic (Clinic 8), Bethesda, Maryland; (left) from the Clinical Services Program, AIDS Monitoring Laboratory, Virus Isolation and Serology Laboratory, and the Laboratory of Molecular Biology, SAIC-FCRDC, Frederick, Maryland. These group photos, says Cliff Lane, a PI in the IL-2 studies, epitomizes "what intramural research at NIH is all about - a collaborative effort involving many people, all of whom play very important roles.


Follow-up of Phase II study patients has continued for more than two years, with monitoring of CD4 counts and health status. Patients whose counts drop below 1,000 get another cycle of IL-2 treatment. Individualizing the regimen has enabled the researchers to keep counts up in this "extension" phase of the Phase II trial, while minimizing patient discomfort and inconvenience, according to lead author Joseph Kovacs, of the Clinical Center Critical Care Medicine Department. Increased CD4 levels have also been achieved in patients originally in the control group who started receiving IL-2 during the follow-up period.

At this point, increases have been sustained for more than five years in some patients, Lane said, and there's at least one patient whose high levels have persisted in the absence of additional IL-2 therapy.

Judy Falloon, an NIAID scientist in the Laboratory of Immunoregulation and coauthor in the earlier studies, recently completed another study that showed that CD4 response to IL-2 can be improved in patients with more advanced disease if a protease inhibitor is added to their treatment.

Falloon's findings are the basis of an AIDS Clinical Trial Group multicentered IL-2 trial involving HIV-infected patients with CD4 counts between 50 and 350 - the cohort with poorer or no response to IL-2 in the earlier trials conducted at a time when nucleoside analogs (like AZT) were the only available HIV therapies, Kovacs noted.

Kovacs' "guess," based on early observations from ongoing studies, is that any benefits from IL-2 will be potentiated in the presence of today's "supercompetent" antiviral combinations - both in patients with more advanced disease and in the cohorts of the upcoming Phase III trial.

For more information about the Phase III IL-2 trial and other AIDS trials, call 1-800-AIDS NIH and 1-800-TRIALS A.

Principal Investigators

NIH Clinical Center
(clinical studies)

Joseph Kovacs
Henry Masur

(clinical studies)

Richard Davey
Judith Falloon
Clifford Lane
Michael Polis
Robert Walker

(laboratory studies)

Michael Baseler
Robin Dewar
Laurie Labert
Ven Natarajan
Norman Salzman
Randy Stevens

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