Correspondence

Interleukin-2 Infusions in HIV-Infected Patients

N Engl J Med 1997; 336:1260-1261April 24, 1997

Article

To the Editor:

Kovacs et al. (Oct. 31 issue)1 report that the administration of interleukin-2 (18 million IU per day for five days every two months) in patients with human immunodeficiency virus (HIV) infection resulted in progressive increases in CD4 T cells (an increase of 36.7 cells per cubic millimeter per month) without an increase in plasma HIV RNA levels. However, the authors fail to emphasize how toxic this treatment regimen is.

The dose-limiting side effects include capillary leak, severe influenza-like symptoms, hepatic and renal dysfunction, thrombocytopenia, and neutropenia.1,2 In their earlier study,2 Kovacs et al. found marked viral elevations, with values as much as 50 times as high as the base-line values, when measured at the end of the five-day infusion, the time when constitutional symptoms were most severe. In their follow-up study,1 however, the authors reported only on samples obtained four weeks after the five-day infusion, when the viral titer had returned to the base-line level.

We believe that it is unnecessary to administer such high doses of interleukin-2 and that such severe side effects are unjustified in asymptomatic persons. In a dose-finding study,3 we observed that interleukin-2 given subcutaneously each day for six months at a dose that was 1/50 of that administered by Kovacs et al.1,2 (0.375 million IU per day) resulted in a progressive rise in the number of CD4 T cells (an increase of 29 cells per cubic millimeter per month), with no toxic side effects and without any increases in plasma HIV RNA levels. Moreover, there were also progressive increases in circulating natural killer cells, monocytes, and eosinophils, together with markedly improved results on tests of delayed-type hypersensitivity to common environmental antigens.

Our results indicate that it is possible to augment host defenses with ultra-low doses of interleukin-2 given daily, rather than high doses given intermittently. Interleukin-2 immunotherapy combined with antiviral chemotherapy should be more effective than chemotherapy alone and is fully justified, provided that toxic effects are averted.

Elizabeth Leef Jacobson, M.D.
Fairley Pilaro, B.S.
Kendall A. Smith, M.D.
Cornell Medical Center, New York, NY 10021

3 References

1. 1

   Kovacs JA, Vogel S, Albert JM, et al. Controlled trial of interleukin-2 infusions in patients infected with the human immunodeficiency virus. N Engl J Med 1996;335:1350-1356
   Full Text | Web of Science | Medline

2. 2

   Kovacs JA, Baseler M, Dewar RJ, 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 1995;332:567-575
   Full Text | Web of Science | Medline

3. 3

   Jacobson EL, Pilaro F, Smith KA. Rational interleukin 2 therapy for HIV positive individuals: daily low doses enhance immune function without toxicity. Proc Natl Acad Sci U S A 1996;93:10405-10410
   CrossRef | Web of Science | Medline

Author/Editor Response

The authors reply:

To the Editor: The main difference between our investigations of interleukin-2 and those of Jacobson et al. is not the dose but the fact that we used intermittent doses instead of continuous, daily doses.1-3 The use of intermittent cycles of rest and restimulation selectively induces expression of the high-affinity interleukin-2 receptor on CD4 T lymphocytes and is a more effective way of increasing the number of CD4 T lymphocytes in vivo. This is the only approach that has been demonstrated to result in a statistically significant increase in CD4 counts. In the report by Jacobson et al., the CD4 counts after interleukin-2 therapy were not significantly different from the base-line values for the group with an increase of 28 cells per cubic millimeter per month (95 percent confidence interval, -2 to +58); a significant difference was seen only in a comparison with a nonrandomized cohort that received a lower dose of interleukin-2 and had an unexpectedly rapid decline in the CD4 count (-28 cells per cubic millimeter per month; 95 percent confidence interval, -49 to -7).3

The side effects of interleukin-2 are dose-related and have been well described. In our earliest studies, we reported substantial toxic effects.1 In our subsequent randomized trial, constitutional symptoms were the only moderate or severe side effects during more than 10 percent of the cycles.2 Most recently, we have shown that intermittent administration of subcutaneous interleukin-2 is well tolerated as an outpatient regimen.4

We previously reported that a transient increase in the viral load may occur at the end of an infusion of interleukin-2.1 In our randomized study, despite this transient activation, interleukin-2 did not lead to a sustained increase in the plasma viral load during a year of therapy.2 A slope analysis showed no significant change from the base-line viral burden for the patients treated with interleukin-2 (change in the log of HIV RNA copies per milliliter per month, 0.011; 95 percent confidence interval, -0.0006 to +0.0218). In contrast, the control group had a significant increase in the viral load, as compared with the base-line value (change in the log of HIV RNA copies per milliliter per month, 0.019; 95 percent confidence interval, 0.0054 to 0.0318). According to an unpaired t-test, the two groups were not significantly different.

An intermittent regimen of interleukin-2 is a potentially potent addition to combination antiretroviral therapy. Given the substantial increases in the CD4 count with an acceptable toxicity profile, we believe that phase 3 studies to establish the clinical efficacy of this approach are warranted.

Joseph A. Kovacs, M.D.
Richard T. Davey, Jr., M.D.
H. Clifford Lane, M.D.
National Institutes of Health, Bethesda, MD 20892

4 References

1. 1

   Kovacs JA, Baseler M, Dewar RJ, 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 1995;332:567-575
   Full Text | Web of Science | Medline

2. 2

   Kovacs JA, Vogel S, Albert JM, et al. Controlled trial of interleukin-2 infusions in patients infected with the human immunodeficiency virus. N Engl J Med 1996;335:1350-1356
   Full Text | Web of Science | Medline

3. 3

   Jacobson EL, Pilaro F, Smith KA. Rational interleukin 2 therapy for HIV positive individuals: daily low doses enhance immune function without toxicity. Proc Natl Acad Sci U S A 1996;93:10405-10410
   CrossRef | Web of Science | Medline

4. 4

   Davey RT Jr, Chaitt DG, Piscitelli SC, et al. Subcutaneous administration of interleukin-2 in HIV-1 infected individuals. J Infect Dis (in press).
   

Citing Articles (1)

Citing Articles

1. 1

   Christian Hoffmann, Heinz-August Horst, Michael Weichenthal, Axel Hauschild. (2005) Malignant Melanoma and HIV Infection – Aggressive Course despite Immune Reconstitution. Onkologie 28:1, 35-37
   CrossRef