|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.
by Janet Yee and Fran Pollner
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)