Correspondence

Interleukin-2 as Therapy for HIV Disease

N Engl J Med 1995; 333:192-193July 20, 1995

Article

To the Editor:

The article by Kovacs et al. on interleukin-2 therapy in patients with human immunodeficiency virus (HIV) infection (March 2 issue)1 highlights the dilemma that this disease poses: how to get rid of a virus whose replication is enhanced by activation of the immune system.

The increase in the HIV RNA level after an infusion of interleukin-2 was most consistent in patients with CD4 counts of 200 or fewer cells per cubic millimeter. In this group, interleukin-2 was associated with “few immunologic improvements, and substantial toxic effects,” but increased levels of HIV RNA were also observed in patients with higher CD4 counts. Clark et al.2 reported transient improvement in HIV DNA proviral responses in eight asymptomatic HIV-positive patients treated with interleukin-2 and zidovudine (from a geometric mean of 100 million copies to 20 million to 40 million copies in peripheral-blood mononuclear cells). Nevertheless, after treatment had been terminated, the viral load was four times higher than the base-line value (400 million copies in peripheral-blood mononuclear cells), whereas there was no change during a 13-month period in four controls. The long-term effect of these well-documented increases in viral activation is not known, but caution is obviously warranted.

The opposite strategy, attempting to limit HIV activity by reducing lymphocyte activation through the inhibition of certain cytokines, has been discussed for years. Unfortunately, no definitive data on the efficacy of this approach are available yet. Thalidomide, a selective inhibitor of tumor necrosis factor, has been shown to block HIV replication in vitro. A recent study suggests a role for the drug in the control of aphthous ulcers but without an improvement in the CD4 count.3

My colleagues and I have reported an improvement in CD4 counts in four consecutive HIV-infected patients treated with sulfasalazine for Reiter's syndrome,4 and we are currently organizing a placebo-controlled trial. Sulfasalazine may limit the replication of HIV by decreasing the production of interleukin-2, interleukin-1, and tumor necrosis factor and by reducing the oxidative stress generated by prolonged cytokine stimulation.4

Lymphoid tissue from long-term survivors of HIV infection has diminished formation of germinal centers, in spite of some viral presence, as compared with lymphoid tissue from patients with AIDS.5 This finding could be interpreted as indirect evidence of a more limited activation of lymphocytes with reduced interleukin-2 production and reduced viral activity.

Both strategies should be tested in controlled trials.

Eddys Disla, M.D.
Cabrini Medical Center, New York, NY 10003

5 References

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
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2
Clark AG, Holodniy M, Schwartz DH, Katzenstein DA, Merigan TC. Decrease in HIV provirus in peripheral blood mononuclear cells during zidovudine and human rIL-2 administration. J Acquir Immune Defic Syndr 1992;5:52-59
Web of Science | Medline

3
Paterson DL, Georghiou PR, Allworth AM, Kemp RJ. Thalidomide as treatment of refractory aphthous ulceration related to human immunodeficiency virus infection. Clin Infect Dis 1995;20:250-254
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4
Disla E, Rhim HR, Reddy A, Taranta A. Improvement in CD4 lymphocyte count in HIV-Reiter's syndrome after treatment with sulfasalazine. J Rheumatol 1994;21:662-664
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5
Pantaleo G, Menzo S, Vaccarezza M, et al. Studies in subjects with long-term nonprogressive human immunodeficiency virus infection. N Engl J Med 1995;332:209-216
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To the Editor:

In their study of intermittent courses of interleukin-2 as a treatment for HIV infection, Kovacs et al. concluded that such treatment can improve some immunologic measures in patients with CD4 T-cell counts higher than 200 per cubic millimeter. What is disturbing about the study is the increase in plasma viremia.

Two recent articles in Nature equate a large viral load with progressive disease,1,2 whereas two recent articles in the New England Journal of Medicine equate a small viral load with nonprogressive disease.3,4 To confuse the issue further, Kinter et al. have just reported that HIV replication in vitro is stimulated by exogenous interleukin-2.5

Drs. Kovacs and Lane have pending patent applications related to the research reported in their study. Since interleukin-2 results in increased HIV replication in vitro and in vivo, questions concerning the validity of interleukin-2 as a therapy for HIV infection must be answered impartially.

Billi Goldberg
Dinitrochlorobenzene Study Group, San Francisco, CA 94114

5 References

1
Wei X, Ghosh SK, Taylor ME, et al. Viral dynamics in human immunodeficiency virus type 1 infection. Nature 1995;373:117-122
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2
Ho DD, Neumann AU, Perelson AS, Chen W, Leonard JM, Markowitz M. Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection. Nature 1995;373:123-126
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3
Cao Y, Qin L, Zhang L, Safrit J, Ho DD. Virologic and immunologic characterization of long-term survivors of human immunodeficiency virus type 1 infection. N Engl J Med 1995;332:201-208
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4
Pantaleo G, Menzo S, Vaccarezza M, et al. Studies in subjects with long-term nonprogressive human immunodeficiency virus infection. N Engl J Med 1995;332:209-216
Full Text | Web of Science | Medline

5
Kinter AL, Poli G, Fox L, Hardy E, Fauci AS. HIV replication in IL-2-stimulated peripheral blood mononuclear cells is driven in an autocrine/paracrine manner by endogenous cytokines. J Immunol 1995;154:2448-2459
Web of Science | Medline

To the Editor:

Like Kovacs et al., we used interleukin-2 as a treatment for HIV infection. Our patient was a 42-year-old homosexual man with AIDS and Kaposi's sarcoma who had not had a response to any other medication (interferon, vincristine and bleomycin, or doxorubicin). Interleukin-2 was given intravenously by continuous infusion for three days, with a total of 27 million IU administered in the first cycle, and 54 million IU in the second, administered three weeks later. A temperature over 39°C, nausea, and oliguria were the only side effects, but the Kaposi's sarcoma progressed during the treatment. (Interleukin-2 may act as a growth factor.)

The CD4 count rose from 27 to 76 cells per cubic millimeter during the first cycle and from 58 to 102 cells per cubic millimeter during the second; the CD4 count was 97 cells per cubic millimeter three months later. There was a minor increase in the CD8 count. HIV antigenemia remained absent. The patient, who had already been treated for pneumococcal and mycobacterial infections, did not have any infections during this period. The improvement in his general condition despite the progression of Kaposi's sarcoma allowed us to start further chemotherapy (with vinorelbine), which led to a period of stable disease, followed by a worsening of the Kaposi's sarcoma.

We conclude that therapy with intravenous interleukin-2 was tolerated even though the patient had severe immunodeficiency. There was some improvement in the CD4 count, but interleukin-2 should nevertheless be avoided in patients with HIV infection and associated Kaposi's sarcoma.

Giuseppe Landonio, M.D.
Claudia Baiocchi, M.D.
Massimo Ferrari, M.D.
Niguarda Cà Granda Hospital, 20162 Milan, Italy

Author/Editor Response

The authors reply:

To the Editor: The relations between activation of the immune system and levels of viral replication are complex. A single cytokine, such as interleukin-2, can have a multiplicity of effects in a patient with HIV infection. Activation of CD4 T lymphocytes by interleukin-2 can lead to cell division and an expansion in the numbers of cells, as well as to the replication of HIV. Activation of CD8 T lymphocytes by interleukin-2 can lead to enhanced immunity against viral infections.1,2 Thus, the net effect of interleukin-2 in a given patient is a function of multiple variables. Given the lack of a fully functioning thymic environment in the adult,3 once HIV infection has progressed to the point where there is destruction of the lymph-node architecture and loss of critical elements of the T-cell repertoire, it is unlikely that a fully competent immune system can be regenerated merely by blocking viral replication or by inducing an increase in the CD4 count.

We agree with Dr. Disla that the inflammatory elements of the immune system may be associated with some of the pathophysiologic features of HIV infection, and we encourage a careful evaluation of strategies designed to block proinflammatory cytokines such as tumor necrosis factor α in controlled trials. Some of the side effects of interleukin-2 therapy, as well as a component of the viral burst, may be mediated by tumor necrosis factor α, and studies under way at the National Institutes of Health are attempting to block this mediator transiently through different pathways.

In response to Dr. Landonio and his colleagues, our studies of interleukin-2 in over 30 patients with AIDS-related Kaposi's sarcoma have shown no evidence that such therapy is associated with an acceleration of tumor progression. This result is consistent with the observation that the growth of Kaposi's sarcoma cells, although enhanced by fibroblast growth factor or by interleukin-6, is not influenced by interleukin-2.4

Mr. Goldberg raises the issue of a conflict of interest. Under the Federal Technology Transfer Act of 1986, it is our responsibility as government employees to apply for a patent for any finding generated through the use of taxpayer dollars, if the U.S. government believes that the finding represents an improvement in the state of the art with potential commercial value and that patent protection is necessary to develop the technology.5 In the opinion of an independent committee, our findings were thought to meet these criteria, thus leading to the patent application. As with any new finding in science, confirmation of the early observations is a prerequisite for widespread acceptance. We have encouraged others to pursue independent confirmation and extension of our findings.

Our major point is that it is possible to induce and maintain a polyclonal expansion of CD4 T lymphocytes in some patients with HIV infection through the use of intermittent courses of interleukin-2. The effect this therapy will have on the clinical outcome is unknown. Randomized trials are addressing the long-term effects of this approach on the viral burden, immune function, and clinical progression of disease.

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

5 References

1
Rook AH, Masur H, Lane HC, et al. Interleukin-2 enhances the depressed natural killer and cytomegalovirus-specific cytotoxic activities of lymphocytes from patients with the acquired immune deficiency syndrome. J Clin Invest 1983;72:398-403
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2
Landay AL, Mackewicz CE, Levy JA. An activated CD8+ T cell phenotype correlates with anti-HIV activity and asymptomatic clinical status. Clin Immunol Immunopathol 1993;69:106-116
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3
Mackall CL, Fleisher TA, Brown MR, et al. Age, thymopoiesis, and CD4+ T-lymphocyte regeneration after intensive chemotherapy. N Engl J Med 1995;332:143-149
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