IL-2 in HIV Infection: Raises CD4+ Cells, But at What Cost?
IL-2 in HIV Infection: Raises CD4+ Cells, But at What Cost?
Abstract & Commentary
By Dean L. Winslow, MD, FACP, Chief, Division of AIDS Medicine, Santa Clara Valley Medical Center; Clinical Professor of Medicine, Stanford University School of Medicine, Section Editor, HIV, is Associate Editor for Infectious Disease Alert.
Dr. Winslow serves as a consultant to Siemens Diagnostics and is on the Speakers Bureaus of Boehringer-Ingelheim and GSK.
Synopsis: Patients treated with an indinavir-based HAART regimen who had evidence of virologic response at 12 weeks were randomized to continuous infusion IL-2 (IV IL-2), subcutaneous IL-2 (SC IL-2) or HAART alone. Patients receiving IV or SC IL-2 showed greater increases in CD4+ lymphocyte counts than those treated with HAART alone and experienced fewer AIDS-defining events but also experienced more frequent treatment-related adverse events.
Source: Mitsuyasu R, et al. The virologic, immunologic, and clinical effects of interleukin 2 with potent antiretroviral therapy in patients with moderately advanced human immunodeficiency virus infection: a randomized controlled clinical trial--AIDS Clinical Trials Group 328. Arch Intern Med. 2007; 167: 597-605.
ACTG 328 was a multicenter trial that studied HIV-1 infected adults without active AIDS-defining illnesses and with CD4+ lymphocyte counts between 50 and 350/uL. Patients were protease inhibitor (PI) and IL-2 naïve but may have received prior nucleoside analogue therapy. Patients were treated during the first 12 weeks of the study with 2 nucleosides plus indinavir. Patients with ≤ 5,000 copies HIV RNA/uL at week 12 were randomized to continued HAART alone (n = 52), HAART plus continuous infusion IV IL-2 (n = 53), or HAART plus SC IL-2 (n=54). Patients were dosed with IL-2 for 5 days every 8 weeks for up to 9 cycles. Patients receiving IV IL-2 could switch to SC IL-2 after 3 or 6 cycles if they had achieved a > 25% or > 100/uL increase in CD4 count above baseline.
Bottom-line results showed that while there was no difference in deaths between the arms of the study (3 in the HAART-only arm, 2 each in the SC and IV IL-2 arms), there was an intriguing apparent difference in AIDS-defining events (7 vs 1 vs 0 respectively). At all time points, IL-2 recipients had significantly greater numbers of total CD4+ lymphocytes and various subpopulations including CD4 naïve cells than did HAART-only patients. No significant effect on CD8+ lymphocytes was seen in any of the 3 arms. IL-2 did not appear to elevate HIV RNA levels. Treatment related toxicities were significantly more frequent in the IL-2 arms and were most commonly fatigue, fever, chills, skin rash, nausea, vomiting, and diarrhea.
Commentary
Interest in the therapeutic use of IL-2 for HIV infection has been active now for more than 20 years and clinical studies have been conducted in HIV-infected patients since the late 1980s. These early studies conducted in the pre-HAART era generally showed a positive effect of IL-2 in raising CD4 lymphocyte counts, but also raised HIV RNA levels and had either no or a negative effect on clinical outcomes and were associated with significant toxicities. Cliff Lane and his intramural clinical research group at NIAID were involved with many of the early IL-2 trials. Steve Rosenberg at NCI and the DuPont Company (who jointly developed the technology for isolating lymphokine activated NK cells harvested after IL-2 infusion) even conducted a small pilot study of IL-2 plus LAK cells in HIV patients in the late 1980s. These negative trials raised a lot of skepticism on the part of many, but some held out the hope that IL-2 could still be helpful in the treatment of HIV disease if more fully suppressive antiretroviral therapy were available to be used in combination. This ACTG 328 study was initiated in the late 1990s when the first generation of HIV protease inhibitors became available.
The results of this particular trial are intriguing because of the statistically significant apparent clinical benefit of IL-2 over HAART alone in reducing the incidence of AIDS-defining events over the course of the trial. A closer look at the 7 AIDS-defining events seen in the HAART arm showed an unusually large number of malignancies (2 KS, 2 lymphomas, 1 Castleman's Disease), which seems to be a statistical aberration. The paper did not report on other characteristics of these particular patients that may have made them unique such as presence or absence of viral load suppression.
Another interesting finding that casts some doubt on the generalizability of the study results is that while CD4+ lymphocyte counts increased in the IL-2 arms, no beneficial effect of IL-2 was seen on improving skin test reactivity, vaccine response, or in vitro lymphocyte proliferate responses to various antigens. While the results of this pilot study are intriguing, the possible clinical benefit observed needs to be confirmed in larger clinical trials (of which 2 are currently ongoing: The ESPRIT and SILCAAT Phase III trials). Even if these 2 studies eventually confirm some evidence of clinical benefit, I am skeptical that IL-2 will ever be an important agent in treatment of HIV infection due to the need for parenteral route of administration and its significant adverse effect on quality of life due to IL-2 related side effects.
ACTG 328 was a multicenter trial that studied HIV-1 infected adults without active AIDS-defining illnesses and with CD4+ lymphocyte counts between 50 and 350/uL. Patients were protease inhibitor (PI) and IL-2 naïve but may have received prior nucleoside analogue therapy.Subscribe Now for Access
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