Dr. H.C. Lane, NIAID, and collaborators reported in the March 2 issue of the New England Journal of Medicine results from a 25-patient clinical trial demonstrating that recombinant interleukin-2 (IL-2; Proleukin) from Chiron Corp. (Emeryville, CA) produced sustained increases in aspects of immune response in HIV-infected patients tested for up to two years. Dr. Lane stated, ÒThis study provides the strongest evidence so far that it may be possible to rebuild and maintain the damaged immune systems of HIV-infected individuals.Ó Significant improvements and the maintenance of CD4+ T-cell counts was observed in less advanced patients. IL-2 from Chiron is currently approved in the U.S. and other countries for treatment of metastatic renal cancer.
Patients were administered IL-2, initially at 18 million IU (with later reductions to as low as 6 million IU in some patients) by continuous infusion for five days every two months. All patients also received at least one antiretroviral drug during treatment. Upon entry, 10 patients had CD4+ T-cell counts greater than 200, and these patients received from 4-13 courses of IL-2 administration and were followed for 22-40 months. Another 15 patients with CD4+ T-cell counts below 200 were also enrolled and similarly treated.
After 12 months, CD4+ T-cell counts rose and were maintained by over 50% in 6 of the 10 patients who entered the trial with CD4+ T-cell counts over 200, while the counts of the other 4 remained stable or declined only slightly. Dramatic CD4+ T-cell count increases were observed in several of these less advanced patients, including a rise in one individual from 554 to 1,998 (a value above normal for healthy persons) after 12 months of treatment. Dose reductions were required in 8 of the 10 less advanced patients, primarily because of fever and flu-like symptoms.
Seven of the 10 patients entering the trial with CD4+ T-cell counts above 200 showed a decrease of at least 25% in the proportion of CD8+ lymphocytes with surface HLA-DR, a marker of aberrant T-cell activation. Increases in HLA-DR on CD8+ T-cells have been associated with more rapid progression of HIV-infection. Also, the percentage of HLA-DR positive cells was increased (³ 15%) in each of these 10 patients. The percentage of lymphocytes expressing surface high-affinity receptors for IL-2, associated with increased sensitivity to IL-2, increased in 9 of the 10 patients. Increases in IL-2 receptor affinity may play a role in sustaining increases in CD4+ T-cells. The percentage of CD4+ T-cells positive for the alpha chain of the p55 portion of the IL-2 receptor also increased. A decline was observed in lymphocytes positive for CD38, another marker of cell activation.
However, among the 15 patients who entered the study with CD4+ T-cell counts below 200, only two showed a 50% increase. IL-2 appeared to have little effect on disease progression in the more advanced patients. Among the 15 patients with CD4+ T-cell counts below 200 upon entry, few immunologic responses were observed, HIV replication and viral load increased and substantial toxicity was observed. Of the two patients in this group that did show a sustained increase in CD4+ T-cell counts, both had higher counts (about 150) upon entry. No significant increases were observed in the other 13 patients and side effects were Òconsiderably more severeÓ in these more advanced patients.
A major concern with IL-2 treatment of HIV-infected patients was that HIV replication might be increased through IL-2-mediated activation of HIV-infected lymphocytes. No consistent changes in HIV p24 levels were observed in patientsÕ blood, but branched-chain DNA (bDNA) assays revealed a transient increase in HIV RNA levels in the blood of 4 of the 10 patients with baseline CD4+ T-cell counts above 200 shortly after each IL-2 infusion. The investigators suggest that treatment with anti-HIV drugs be combined with IL-2 treatment to minimize any adverse effects from HIV activation that might result from IL-2 treatment. The investigators conclude, ÒAmong the four [less advanced] patients with the most dramatic increases in CD4+ T-cell counts, HIV RNA was undetectable throughout therapy,Ó and no consistent increase was observed in the other patients tested with the bDNA assay.
Side effects, often severe, were common in all patients and included rash, lowering of blood pressure, flu-like symptoms, diarrhea and laboratory anomalies including reduced calcium, albumin and magnesium in the blood. ÒWhile receiving infusions of IL-2, patients were extremely uncomfortable, often with symptoms worse than a very bad bout of the flu. Fortunately, none of the side effects we have observed thus far in these studies appear to be life-threatening.Ó
IL-2, formerly called T-cell growth factor, is a cytokine normally produced by T-cells with potent immune stimulation effects including the proliferation and differentiation of T-cells, B-cells, natural killer cells and other cells of the immune system. IL-2 was one of the first agents to be studied for treatment of HIV-infection and AIDS. In 1982, even before HIV was isolated and identified as linked to AIDS, Dr. Lane and collaborators from the FDA demonstrated that IL-2 could enhance the activity of immune cells isolated from AIDS patients, inducing the proliferation and differentiation of peripheral blood mononuclear cells. Clinical trials at NIH with IL-2 in AIDS patients began in 1983, about the same time that trials for cancer treatment began. Techniques for treatment of HIV-infection have subsequently been significantly refined through in vitro studies and a series of small clinical trials.
Dr. A. Fauci, Director, NIAID, remarked, ÒThe development of this regimen, which involves alternately stimulating the immune system with IL-2 and then letting it rest, is the culmination of 13 years of laboratory studies and clinical research. This work is a model of NIAIDÕs Ôbench-to-bedsideÕ philosophy of research: doing laboratory and preclinical studies, learning from preliminary clinical studies, going back to the laboratory bench for further refinement, and then treating patients with the improved regimen.Ó Implicit in Dr. FauciÕs comments is that NIH is among the few organizations able to fund and follow through on such long-term development efforts. Further NIH research and trials will concentrate on the timing of treatments, finding the lowest effective dose with reduced adverse effects, and will likely include AZT and/or other anti-HIV drugs in combination with IL-2. NIAID has recently started three IL-2 trialsÑone trial is examining the timing of IL-2 infusions and changes in CD4+ T-cell counts; another study is examining the safety and efficacy of subcutaneous IL-2 administration; and another is examining the effects of further increasing IL-2 dosage, expected to block tumor necrosis factor (TNF) production, which may decrease side effects and activation of HIV replication (associated with TNF).
IL-2 has demonstrated significant effects on immunologic markers for efficacy for treatment of less advanced HIV-infected patients, but with significant side effects. IL-2 appears to be capable of reversing major aspects of HIV-related immune deficiency and maintaining major aspects of immune response in HIV-infected persons with CD4+ T-cell counts above 200. Whether these immunological improvements will translate into improved survival and clinical efficacy remains to be determined.