Interleukin-2 redux

HIV and AIDS: Defining clinical progression

Median time for progression to AIDS: 10 years in untreated individuals. Clinical disease progression is described by “AIDS-defining events”, which include opportunistic infections and AIDS-associated cancers. A CD4+ count of <200 cells/mm3 is sometimes considered an AIDS-defining event. Disease progression is gauged by CD4+ counts and the viral load, or number, of HIV RNA copies per milliliter. The CDC classification system groups HIV patients by range: Category 1: >500 cells/mm3; category 2: 200–499 cells/mm3; and category 3: <200 cells/mm3. Normal CD4+ counts are 500–1300 cells/mm3. HIV RNA levels range from undetectable to >1,000,000 copies/mL; <5000 copies/mL indicates a lower risk of progression in 5 years; >50,000 copies/mL indicates a high risk. Source: University of California, San Francisco, HIV InSite Knowledge Base. http://hivinsite.ucsf.edu/.

But HAART cannot eradicate the virus, and long-term treatment can cause metabolic disorders that are dangerous or distressing to the patient. These include abnormal fat deposits in the neck and abdomen, very high cholesterol levels, osteoporosis, anemia, and diabetes. And although 70–90% of patients in clinical studies respond dramatically to HAART, the efficacy rates in urban clinics are as low as 35–40% (2). Departing from the policy of “treat early–treat hard”, the latest NIH treatment guidelines, released in February, recommend considering antiretroviral therapy only when the patient’s CD4+ cell count has fallen below 350 cells/mm³, rather than 500 cells/mm³ as in the previous guidelines (3).

New antiretrovirals and new classes of antiviral agents (such as the fusion inhibitors) now in clinical trials or awaiting approval offer hope for amelioratingthe toxicity and complexity of current antiretroviral regimens. All these agents control the virus by interfering with some stage of its replication. But when HAART is stopped, the virus rapidly rebounds. Long-term control of HIV will likely require immune-based therapies that boost the immune system’s ability to combat both the HIV virus and the opportunistic infections that eventually take the lives of AIDS patients (4).

Enter IL-2
The best-studied immune-based therapy is interleukin-2 (IL-2), a cytokine that increases the CD4+ cell count to counteract HIV-induced loss. Importantly, it serves as a growth factor for CD8+ cells (“killer” or cytolytic T cells), which can then attack and destroy HIV-infected cells.

Approved for the treatment of metastatic renal cell carcinoma and metastatic melanoma, recombinant IL-2 is marketed by Chiron Corp. as Proleukin (aldesleukin). First studied as an HIV therapy in the pre-HAART era,IL-2 was not consistently effective and produced a transient surge in viral load in some patients. Since the advent of antiretrovirals that can suppress viral replication to extremely low levels, IL-2 has found a new role as an adjunctive treatment. In numerous small studies, it substantially increased levels of circulating CD4+ cells, often doubling their baseline levels. Two major Phase III trials of IL-2 are now under way. The NIH-sponsored ESPRIT (Evaluation of Subcutaneous Proleukin in a Randomized International Trial) will enroll 4000 patients at 227 sites in 20 countries, and the SILCAAT (Study of IL-2 in People with Low CD4+ T-cell Counts on Active Anti-HIV Therapy) trial, sponsored by Chiron, will enroll 1400 patients at 100 sites in 8 countries.

Even with thousands of participants, these studies will need five to six years to complete, according to Richard T. Davey, Jr., a senior investigator in the NIH’s National Institute of Allergy and Infectious Diseases and a principal investigator and member of the ESPRIT steering committee. That’s because the goal of both studies is to determine whether the IL-2-induced increase in CD4+ cells will have an effect on clinical progression to AIDS, a question that could not be addressed by the smaller short-term studies reported thus far.

Clinical experience with treated patients suggests that IL-2 therapy improves immune functioning, but the number of patients is too small to be analyzable.“We’re not seeing AIDS-defining events happening at CD4+ counts that are inappropriate. There’s at least a strong suspicion that these CD4+ increases are meaningful, but until you show it in a statistically rigorous manner, it won’t be convincing. That’s the impetus to do these studies,” Davey explained.

IL-2: Adjunct or alternative?
ESPRIT and SILCAAT are examining IL-2 in the context of continued HAART therapy. Although the clinical benefit may prove to be substantial, IL-2 therapy adds expense, complexity, and toxicity to an already expensive, complex, and toxic regimen.

In the most commonly followed protocol, IL-2 is administered as a daily or twice-daily subcutaneous injection (6–15 million IU/day) for five days every eight weeks. During the five days of treatment, patients experience a flulike syndrome of fever, muscle aches, and fatigue, which is believed to result from the release of various proinflammatory cytokines triggered by IL-2. At high doses, IL-2 can cause a potentially fatal capillary leak syndrome, producing severe edema, low blood pressure, and impaired lung function.

In a recently reported trial, more than half of the study participants required dosage adjustments to control the more severe side effects (5). However, the effects of IL-2 treatment are often durable, and Davey notes that many patients maintain their higher CD4+ counts after several IL-2 treatment cycles. “In our latest follow-up of a cohort started on subcutaneous IL-2,” he said, “we’re cycling them on average only once every two or three years.”

The HAART-plus-IL-2 regimen investigated in the SILCAAT and ESPRIT trials is not the only possible approach to IL-2 as an HIV therapy. “Given the way the guidelines for using antiretrovirals are changing, one could envision a strategy of using antiretrovirals plus IL-2 to get the CD4+ count up substantially, then backing off on the antiretrovirals and maintaining the CD4+ count with periodic IL-2 to keep the levels high,” Davey observed. IL-2 would thus be used for “HAART holidays”, which might help limit the toxicity of the antiretrovirals.

Such a strategy is being pursued by a small group of investigators led by Kendall A. Smith, professor of medicine at Cornell University’s Weill Medical College in New York City, who first characterized IL-2 and its receptor in a series of papers in the early 1980s. Smith and colleagues recently reported on nine patients who received long-term treatment on HAART and daily low-dose IL-2, and who then underwent what Smith calls a “diagnostic treatment interruption” to determine their ability to mount an immune response while on IL-2 alone, without HAART (6). Not unexpectedly, the patients relapsed, with some showing a 100-fold increase in viral counts. Then, however, patients’ virus levels began to drop while circulating CD8+ levels increased, suggesting that their immune systems could control the virus.

“We have now followed them 8–12 months off HAART, on IL-2, with low viral load—most of them less than 10,000 copies,” said Smith. “We found that they maintain that viral set point for quite some time. They also maintain their normal levels of circulating CD4+ cells, and they have elevated levels of CD8+ cells and natural killer cells, which are increased by IL-2. None of them have had an increase in viral load, but in some of them, we have found a slow, progressive decrease in CD4+ cells.”

The Cornell researchers are currently recruiting patients for a pilot study of their HAART interruption approach. The study will randomize 92 patients to one of four arms: HAART plus placebo vaccine, HAART plus vaccine, HAART plus IL-2 plus placebo, or HAART plus IL-2 plus the vaccine. HAART will be stopped after 3 months, and the end point is the plateau viral load 8–12 weeks after discontinuation of HAART.

Smith explains the study’s goals: “If we could demonstrate that there was an immune response to HIV itself in these individuals, then we would hope that by therapy directed toward the immune system, as opposed to therapy directed solely toward the virus, we might come up with a combination therapeutic regimen that would allow you to discontinue the antiviral drugs and have the immune system take over and prevent the viral relapse.”

Smith and his colleagues have also been outspoken critics of the dosing regimen used in SILCAAT and ESPRIT as too toxic and have instead advocated a regimen of daily low-dose IL-2 (0.375 million IU/ day) (7). However, this regimen has demonstrated only a modest effect on CD4+ counts.Smith admits, “I haven’t been able to convince them [the HIV cooperative study groups] that low-dose IL-2 is a good way to go.” He argues that the CD8+ arm of the immune system, rather than the CD4+ cells, is more important for reestablishing immune competency and combating HIV. His data do show marked increases in CD8+ cells with the daily low-dose regimen of IL-2.

Despite the absence of data to demonstrate clinically meaningful benefits, IL-2 is already extensively used “off-label”, Davey said. “Physicians are turning to the drug when their patients have relatively advanced disease or because they’ve run out of antiretroviral options. To some degree, that may be self-defeating. The response rate to IL-2 is clearly higher when the baseline CD4+ count is higher, so if patients and physicians using it off-label are waiting until disease is very advanced, they may not see the CD4+ increases that you might see otherwise.”

IL-2 as adjuvant
After many discouraging setbacks, the prospects for an HIV vaccine—which is crucial for controlling the AIDS epidemic in developing countries—are suddenly improved. The breakthrough has been in recognizing the importance of triggering a potent cytotoxic T lymphocyte (CTL) response in conjunction with vaccine administration, and in developing workable protocols for doing so.

Dan H. Barouch, clinical fellow in medicine at Harvard Medical School, was lead author of an important paper published in Science last year, demonstrating that in a monkey model of HIV, a potent immune response could be induced by the combination of a DNA virus and a novel IL-2/immunoglobulin (IL-2/Ig) construct (8).

The study tested the efficacy of IL-2/Ig in boosting the CTL response in two forms, as a fusion protein and a plasmid. According to Barouch, the best immune responses and the best control of virus after challenge was seen in the animals that received IL-2/Ig plasmid in addition to the DNA vaccine. “Other studies that are currently under way or in the planning phases will be clarifying the role of IL-2/Ig plasmid, and perhaps even improving on it,” Barouch said.

In a previous paper, Barouch and colleagues speculated about the feasibility of using IL-2/Ig plasmid in lieu of the IL-2 subcutaneous injections now employed as HIV therapy. The plasmid has several apparent advantages, including a longer circulating half-life in vivo and, in animals, more robust immune stimulatory effects. At this point, Barouch and colleagues are in the early planning stages of clinical trials, and the toxicity in humans has not yet been determined.

References

1. Osmond, D. H. Epidemiology of disease progression in HIV; HIV InSite Knowledge Base, 1998. http://hivinsite.ucsf.edu/InSite.jsp?page=KB.
2. Blankson, J.; Siliciano, R. F. Interleukin 2 treatment for HIV infection. J. Am. Med. Assoc. 2000, 284, 236–238.
3. Panel on Clinical Practices for Treatment of HIV Infection. Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents; Department of Health and Human Services: Washington, DC, 2001.
4. Cohen, P. T. Clinical overview of HIV disease; HIV InSite Knowledge Base, 1998. http://hivinsite.ucsf.edu/InSite.jsp?page=KB.
5. Davey, R. T., et al. Immunologic and virologic effects of subcutaneous interleukin 2 in combination with antiretroviral therapy: A randomized controlled trial. J. Am. Med. Assoc. 2000, 284, 183–189.
6. Smith, K. A., et al. In vivo assessment of antiviral reactivity in chronic HIV infection. HIV Clinical Trials 2000, 1, 16–22.
7. Jacobson, E. L.; Pilaro, F.; Smith, K. A. Interleukin-2 infusions in HIV-infected patients. N. Engl. J. Med. 1997, 336, 1260–1261.
8. Barouch, D. H., et al. Control of viremia and prevention of clinical AIDS in rhesus monkeys by cytokine-augmented DNA vaccination. Science 2000, 290, 486–492.

Carol Hart is a science writer based in Narberth, PA. Send your comments or questions regarding this article to mdd@acs.org or the Editorial Office by fax at 202-776-8166 or by post at 1155 16th Street, NW; Washington, DC 20036.