What is new with IL-2?
Raj Gandhi, M.D.
The Hopkins HIV Report - January 2001
Interleukin-2 was one of the first immune-based therapies used to treat HIV infection, and it continues to generate a great deal of interest. Discovered as a factor that causes proliferation of antigen-activated T cells, IL-2 was initially termed T cell growth factor [Morgan, et al. Science, 1976;93:1007; Smith, Science 1988 May 27;240(4856):1169-76]. Since HIV causes a profound T cell deficiency, it was natural to study whether IL-2 could reverse the immunodeficiency of AIDS. Although a number of studies including IL-2 were conducted before the era of highly active antiretroviral therapy (HAART), the immunologic impact of IL-2 in patients on HAART is currently being defined. In addition, IL-2 has been studied in attempts to purge the reservoir of the latently-infected cells that seem to prevent eradication of HIV. Most recently, IL-2 appears to boost the immunogenicity of DNA vaccination in animal models of HIV infection. Despite the many potential uses of this exciting agent, the clinical utility of IL-2 is still not determined.
IL-2: Why in HIV?
HIV is characterized by severe depletion of CD4 cells. Since CD4 cells are important in coordinating the CD8 cytotoxic T lymphocyte (CTL) response and B cell function, loss of CD4 cells results in a severely impaired overall immune response. Suppression of viral replication by HAART clearly improves the immune systems of patients with HIV infection, as evidenced by the striking decreases in AIDS-related complications in the era of HAART. However, the immune system may not completely return to normal, even after prolonged courses of HAART. In addition, not all individuals treated with HAART experience the same degree of immune restoration. For example, some patients have persistently low CD4 counts despite suppression of plasma viremia on HAART.
Because of its central role in T cell immunity, IL-2 was one of the first immune-based therapies to be tested in patients with HIV. IL-2 is produced by activated CD4+ T cells and stimulates the growth and function of T cells and NK cells. IL-2 also promotes the secretion of antibodies by B cells. Since patients with HIV have a progressive decline in IL-2 production, the role of this agent in patients with HIV has generated great interest.
IL-2 Studies Before HAART
IL-2 was first used in patients with advanced cancer, and some clinical responses were seen [Rosenberg, et al. N Engl J Med 1987 Apr 9;316(15):889-97]. These responses led to the approval of IL-2 for treatment of metastatic renal cell carcinoma. However, extremely high doses were given in the initial cancer trials (up to 150 million units per day) resulting in severe toxicity, including capillary leak syndrome, hypotension and pulmonary edema. Many of the first patients treated on this high dose regimen required hospitalization in an intensive care unit.
In studies of IL-2 in patients with HIV, an intermediate dose was given. Kovacs and colleagues [N Engl J Med 1995 Mar 2;332(9):567-75] administered 18 million units per day for five days every eight weeks by continuous intravenous infusion in the hospital. Most patients with baseline CD4 counts >200 cells/mm3 had a significant increase in their CD4 count after receiving IL-2. However, in patients with CD4 counts >200 cells/mm3, the results were much less encouraging. Most of these patients did not have a significant increase in their CD4 counts. In addition, the infusion of IL-2 was commonly associated with side effects such as fever and flu-like symptoms. These side effects were particularly severe in patients with CD4 counts <200 cells/mm3. Importantly, the majority of patients in this trial, performed before the development of HAART, were on AZT or other nucleoside reverse transcriptase inhibitors (NRTIs), and in some of these patients IL-2 was associated with a transient increase in HIV viral load.
Kovacs and colleagues also conducted a randomized trial of IL-2 plus antiretroviral therapy (ART) vs. ART alone in 60 HIV-infected patients with CD4 counts >200 cells/mm3 [N Engl J Med 1996 Oct 31;335(18):1350-6]. Most of the patients in this trial were on NRTIs, alone or in combination. The patients in the IL-2/ART group had a substantial increase in their CD4 counts (from 428 +/- 25 cells/mm3 to 916 +/-128 cells/mm3 by month 12), whereas the mean CD4 count declined in the ART alone group. Following completion of the trial, some patients had persistent elevation of CD4 counts even after stopping IL-2. Others received intermittent IL-2 on a less frequent schedule to maintain their CD4 count. Subsequent trials of intermittent intermediate dose IL-2 have mainly used subcutaneous administration, since this seems to have similar efficacy with less severe side effects, allowing outpatient administration [Levy, et al. Lancet 1999 Jun 5;353(9168):1923-9]. In addition, some have argued for low dose, continuous IL-2 rather than intermittent IL-2 at higher doses [Jacobson, et al. Proc Natl Acad Sci U S A 1996 Sep 17;93(19):10405-10]. Low dose, continuous IL-2 is well-tolerated and a randomized trial seems warranted. However, such a trial has not been published.
What did the trials of IL-2 in the pre-HAART era teach us? First, IL-2 could clearly increase CD4 counts in patients with HIV, but this seemed to be most significant in patients who already had relatively preserved CD4 counts (>200 cells/mm3). Second, IL-2 transiently increased HIV viral loads when given without effective antiretroviral therapy. Third, the toxicity of intravenous IL-2 was substantial, particularly in patients with advanced HIV infection (CD4 count >200 cells/mm3). This toxicity could be reduced by subcutaneous injection of IL-2. These studies set the stage for the current phase of research on the role of IL-2 in patients receiving HAART.
IL-2 in the Era of HAART
Several recent studies of IL-2 in patients with HIV have focused on patients with relatively preserved CD4 counts who are receiving HAART. Davey and colleagues [JAMA 2000 Jul 12;284(2):183-9] performed a randomized study of 82 patients with CD4 counts between 200-500 cells/mm3. These patients were on antiretroviral therapy chosen by their provider for at least two weeks prior to initiating IL-2 and had HIV viral loads >10,000 c/mL. Patients were randomized to continue ART alone or to receive IL-2 in addition. The IL-2 was given for five days by subcutaneous injection every eight weeks. The starting dose was 7.5 million units bid. The group receiving IL-2/ART had a much more substantial increase in CD4 count (mean difference +384 cells/mm3) than the group receiving ART alone (mean difference + 64 cells/mm3). Although a larger percentage of patients in the IL-2/ART group than the ART alone group had final HIV viral load <50 c/mL (67% vs. 36%), this difference became non-significant when only those patients who had received a protease inhibitor in the previous 90 days were analyzed. In addition, the group receiving IL-2 had much more intensive follow-up, including daily visits during administration of the drug, which may have contributed to better adherence in this group. The toxicity of IL-2 was again substantial, with about half of the patients in the IL-2 group developing serious adverse events (grade 3 or greater) compared with 16% in the HAART alone group.
The largest study of IL-2 in patients with relatively preserved CD4 counts was presented by Dr. Donald Abrams at this year's ICAAC [Abstract L-11]. CPCRA 059 randomized 511 patients with CD4 counts >300 cells/mm3 to either continued ART alone or ART plus intermittent subcutaneous IL-2 (at either 4.5 million units or 7.5 million units bid for 5 days every 8 weeks). There was no difference in viral load between the IL-2 and control groups. The IL-2 arms had a significantly greater increase in CD4 count than the control group with a mean CD4 difference of 251 cells/mm3.
Because patients with low CD4 counts (>200 cells/mm3) did poorly when treated with IL-2 in the pre-HAART era, it is particularly important to determine if IL-2 is safe and effective when given to this group along with HAART. Towards this end, ACTG 328 is a study of intermittent IL-2 in 204 PI-naïve patients with CD4 counts between 50-350 cells/mm3 [Mitsuyasu, et al. 5th International Congress on Drug Therapy in HIV Infection]. Patients initially received HAART alone for 12 weeks. If their HIV viral load was <5000 c/mL, they were randomized to continue HAART alone, HAART plus intravenous IL-2, or HAART plus subcutaneous IL-2. Crossover from IV to SQ IL-2 was allowed after three or six cycles and took place in 75% of patients initially in the IV arm. The median daily dose of IL-2 was about nine million units per day in both the IV and SQ arms. The median change in CD4 count was +97 cells/mm3 for patients who received HAART alone, +309 cells/mm3 in patients who received IV IL-2/HAART, and +240 cells/mm3 in patients who received SQ IL-2 plus HAART. Both IL-2 arms had a significantly greater percentage rise in CD4 count when compared to HAART alone. There was no significant difference in the percentage of patients with undetectable viral loads in the three arms. There were five AIDS events in the HAART alone arm vs. one event in each of the IL-2 arms, but these event rates were too small to be statistically significant. Nevertheless, this trial showed that IL-2 could increase CD4 counts in patients with relatively advanced HIV who are receiving HAART.
Finally, a particularly important clinical question is whether IL-2 has any role in patients who do not have a significant rise in their CD4 counts despite treatment with HAART. Arno and colleagues [J Infect Dis 1999 Jul;180(1):56-60] studied 25 patients on a PI-containing regimen who had CD4 counts <250 cells/mm3 and HIV viral load >500 c/mL for at least 24 weeks. Patients were randomized to receive intermittent subcutaneous IL-2 SQ plus HAART or HAART alone. Patients initially received three million units of IL-2 sc bid, but this was decreased to three million units once a day because of substantial initial toxicity. The study showed that the group receiving IL-2/HAART had a greater increase in CD4 count (+105 cells/mm3) than the group receiving HAART alone (+30 cells/mm3) at 24 weeks. However, this was an as-treated analysis, and only 8 of 13 patients in the IL-2/HAART group completed the study compared with 10/12 in the control HAART group.
A key question raised by this study is whether patients who have persistently low CD4 counts (immunologic failure) but virologic suppression on HAART will be able to safely discontinue opportunistic infection prophylaxis if their CD4 count increases with IL-2. Although the answer to this question is not known, IL-2 has been approved for use in France for such patients. Unfortunately, in the absence of randomized trials, we still do not know the true benefit of this approach.
Other uses of IL-2 in HIV Disease
IL-2 and the latent reservoir: Because IL-2 induces T cell proliferation, investigators studied whether it could purge HIV from latently-infected cells when combined with HAART. Despite the report that replication-competent HIV could not be recovered from some patients who had received IL-2 plus HAART [Chun, et al. Nat Med 1999 Jun;5(6):651-5], all those patients had viral rebound when HAART was discontinued. Thus, IL-2 alone does not seem to be able to purge the latent reservoir, possibly because the resting memory T cells that harbor HIV lack the high affinity IL-2 receptor.
IL-2 and vaccines: Another exciting use of IL-2 was recently reported by Barouch and colleagues [Science 2000 Oct 20;290(5491):486-92] who studied the ability of DNA vaccination to prevent SIV infection in macaques, the best animal model of HIV. The researchers found that animals given DNA vaccine along with an IL-2/immunoglobulin (Ig) fusion (either as protein or a plasmid expression vector) developed significant immune responses to SIV, unlike animals that received sham vaccination. Animals that received DNA vaccine alone developed an intermediate immune response. Although the animals that received DNA vaccine plus IL-2/Ig were infected after challenge with SIV, they had much lower SIV viral loads than animals that received sham vaccine. Finally, 8/8 animals that received DNA vaccine along with IL-2/Ig did not develop clinical disease, whereas 7/8 animals who received sham vaccine developed clinical events. Again, the DNA vaccine without IL-2/Ig resulted in an intermediate benefit in terms of viral load reduction and decreased clinical events.
IL-2 and immunotherapy: Although IL-2 is one of the best studied immune-based therapies its role in boosting immune responses that are specific for HIV is still under investigation. An important question is whether IL-2 has any effect on HIV-specific helper cell responses, which have been associated with control of viremia [Rosenberg, et al. Science 1997 Nov 21;278(5342):1447-50]. Because IL-2 causes proliferation of antigen-stimulated cells and because HIV antigens decline in patients on HAART, IL-2 in patients on continuous HAART may not induce expansion of HIV-specific helper cells. However, if IL-2 is given with HIV antigens (analogous to the experience in SIV), it may be possible to elicit HIV-specific immunity. Whether this immune response would be sufficient to control HIV is not known.
Conclusions
IL-2 clearly increases CD4 counts in patients with HIV. Prior to HAART, this effect was limited to patients with relatively preserved CD4 counts; however, recent trials suggest that patients with more advanced disease on HAART also have increased CD4 counts when given IL-2. The major question facing us now is whether this increase in CD4 counts with IL-2 will translate into clinical benefit. Given the toxicity of IL-2, the durability of the CD4 response and the quality-of-life of patients on this medication are also important issues. Two large trials are currently enrolling patients to address these critical questions. The NIH-sponsored ESPRIT trial, sponsored by the NIH (
http://www.clinicaltrials.gov) will enroll patients with CD4 counts >300 cells/mm3 on HAART. The SILCAAT trial, sponsored by Chiron, will enroll patients with CD4 counts between 50 and 299 cells/mm3 on stable HAART. Although we have come a long way in our studies on IL-2, the clinical efficacy of this agent is still under investigation in these two important trials.
From :
http://www.aegis.org/pubs/jhopkins/2001/JH20010101.html