Research Initiative Treatment Action (RITA!); Vol 5, No. 2 April 1999
Paul Simmons, RN, ACRN
Since 1996, clinicians have treated HIV-infected patients with combination antiretroviral therapy, which can produce dramatic reductions in viral load and striking improvements in clinical outcome. Investigators have shown that antiviral treatment can also mitigate or even reverse some of the immune deficiency and dysregulation that are the hallmarks of HIV infection.
Combination therapy has limitations, however. The drugs can be toxic, difficult to take and often ineffective for those with a history of extensive treatment. For many patients, combination therapy also fails to provide adequate immune restoration. Moreover, since the life-threatening consequences of HIV disease result from the loss of immunity the virus induces and not from the virus itself, efforts to augment immune function are an important frontier in the management of HIV infection.
The immune-based therapy most investigated to date for HIV disease is interleukin-2 (IL-2), clinical studies of which began in 1983. IL-2 is a cytokine that is licensed in the United States for the treatment of metastatic renal cell carcinoma. Chiron Corporation manufactures recombinant IL-2 under the brand name Proleukin; the generic name is aldesleukin.
Cytokines are soluble molecules that powerfully influence the functioning of the human immune system. T cells produce a large group of cytokines known as interleukins. Interleukins serve a number of functions, but most are involved in directing cells to divide and differentiate. The activities of IL-2 include promotion of activation, proliferation and differentiation of T and B lymphocytes, enhancement of monocyte and natural killer (NK) cell cytotoxicity and increases in the number of NK cells. The chief source of IL-2 is activated CD4 T cells; unfortunately, these are the very cells lost as a consequence of progressive HIV infection. It is therefore unsurprising that HIV disease is marked by a deficiency of IL-2.
CD4 T cells are essential to healthy functioning of the immune system. Infection with HIV results in a progressive loss of these cells, which in turn results in opportunistic infections and malignancies.
Il-2 is a T cell growth factor. In clinical study, investigators have shown that IL-2 produces marked and sustained increases in the CD4 T cell count among subjects infected with HIV. Clinical investigation has also shown that IL-2 may decrease programmed cell death, augment HIV-specific immune responses, diminish the pool of cells susceptible to HIV infection and flush the reservoir of latently-infected cells.
In the last 16 years, investigators have conducted at least 24 clinical trials of IL-2 in HIV-infected subjects, making it the most extensively studied immune-based therapy in the history of the epidemic. Indeed, IL-2 has undergone a longer and more thorough evaluation than most antiretrovirals, which are now generally approved on the basis of short-term surrogate marker data. However, some activists have called for delaying approval of IL-2 for the treatment of HIV infection while the molecule undergoes multi-year clinical endpoint studies.
Collectively, the clinical studies of IL-2 in the setting of HIV infection suggest the following:
Investigators have administered IL-2 in one of three manners, namely continuous intravenous infusion (CIV), intermittent subcutaneous injection or daily low-dose subcutaneous injection. Below are selected clinical trial observations for each method of administration.
Continuous intravenous infusion.
(Kovacs, The New England Journal of Medicine, 335:18, pp. 1350-1356, 1996.)
Description: prospective, randomized study of IL-2 plus antiviral therapy versus antiviral therapy alone.2Population: sixty patients with baseline CD4 counts greater than 200 cells.
Design: subjects randomized 1:1 to antiviral therapy alone or to antiviral therapy plus IL-2,3 administered for 5 days every 2 months for 6 cycles.
Results: after one year of follow-up, 57% of the IL-2 group experienced at least a 50% increase in CD4 count; mean increase from baseline was 412 cells; patients in the control group had a mean decrease of 48 cells; there were no significant changes in viral load 4 for the IL-2 group; 5 of the subjects in the IL-2 arm discontinued because of toxicity.
Intermittent subcutaneous injections.
(Lago Maggiory Conference, 1998.)
Description: prospective, randomized study of intermittent subcutaneous IL-2 plus antiviral therapy versus antiviral therapy alone.Population: 18 patients with a baseline CD4 count of less than 250 cells and viral load less than 500 copies
Design: subjects randomized 1:1 to antiviral therapy alone or antiviral therapy plus IL-2, administered twice a day for 5 days every 4 weeks for six 6 cycles.5
Results: mean increase in CD4 count for the IL-2 group was 134 cells versus 56 cells for the control group; viral load remained undetectable for the duration of the study.
Daily, low-dose subcutaneous injections.6
(Jacobson, Proceedings of the National Academy of Science, 93, pp. 10405-10410, 1996)
Description: uncontrolled, unrandomized study of daily low-dose subcutaneous injections.Population: 16 patients with a mean baseline CD4 count of 367 cells, most of whom were on nucleoside analogue therapy.
Design: subjects were treated daily with doses of IL-2 ranging from 62,500 IU/m2/day to 500,000 IU/m2/day.7
Results: patients experienced a mean increase of 27 cells, per month, with no rise in plasma viremia; natural killer (NK) cells also increased.8
In what is surely the most dramatic investigation of IL-2, scientists at the National Institutes of Health (NIH) examined the cytokine's effect on resting cells latently infected with HIV—cells that pose a barrier to the eradication of the virus.
Twenty-six patients, all with viral loads of less than 50 copies, participated in the NIH study.9 Fourteen of the 26 were on HAART plus IL-2; the other 12 were on HAART alone. In 6 of the 14 subjects on IL-2, no replication-competent virus could be cultured from 10 to 20 million resting peripheral CD4 cells. When a much larger number of cells were cultured—up to 360 million—no replication-competent virus could be recovered from 3 of the 6. By comparison, the NIH team consistently found HIV capable of replicating in each of the 12 patients who received HAART alone.10
HIV sews itself into the genes of resting cells, where it can remain for years—safe from both the immune system and antiviral therapy. IL-2 forces latently infected cells into a state of activation, causing them to express their hidden HIV. By flushing HIV from its hiding places, IL-2 exposes the virus to detection by the immune system and inhibition by antiretroviral drugs.
Adverse events induced by the use of interleukin-2 are dose and schedule-dependent. The doses of IL-2 used for the experimental treatment of HIV infection are lower than those used in the oncology setting; nevertheless, when administered to the HIV-infected patient, interleukin-2 is capable of causing significant toxicity, impairing the receipt's sense of well-being and interfering with activities of daily living.
Side effects of IL-2 therapy include the following:
Four deaths have occurred for which IL-2 may bear at least some culpability. In the oncology setting, patients receiving IL-2 have occasionally required admission to an intensive care unit and mechanical ventilation for fluid accumulation in the lungs. However, lower doses of IL-2 make such a severe capillary leak syndrome unlikely in the management of HIV infection.11
Although the side effects of IL-2 therapy are appreciable, clinicians and patients can take several practical steps to diminish toxicity.
Constitutional side effects.
The onset of constitutional toxicities of IL-2, which include, among others, fever and chills, is generally two to 4 hours post-dose, with resolution occurring 2-3 days after therapy is discontinued. Acetaminophen or non-steroidal anti-inflammatory agents, such as naproxen, may be effective in managing fever and muscle and joint aches. For rigors, the clinician may consider judicious use of the narcotics meperidine and morphine. Mild to moderate chills can be managed with diphenhydramine and warm blankets.
To maintain hydration while avoiding fluid overload, patients should drink electrolyte-containing fluids (e.g., Gatorade). Rising slowly from a supine or sitting position to a standing one can help to prevent orthostatic syncope.
Nausea, vomiting and diarrhea
Anti-emetics can ameliorate nausea and vomiting and anti-motility drugs are useful for controlling diarrhea. Patients should consider eating small, frequent meals and avoiding foods that are greasy or spicy.
Oral ulcers
Oral ulcers, or stomatitis, can be managed with saline rinses, use of a soft-bristled toothbrush and alcohol-free mouthwashes.
Rash
Antihistamines can be used to relieve rash. Patients should avoid prolonged exposure to the sun, skin care products that contain alcohol and soaps that dry the skin. Water or oil-based lotions are helpful, and oatmeal soaps may relieve itching.
Injection site reactions
When IL-2 is administered subcutaneously, injection site reactions are common. Nodules that form as a consequence of IL-2 therapy may take a few weeks or months to resolve.
Discomfort associated with subcutaneous administration can be reduced by bringing syringes to room temperature 15 minutes before injection, rotating injection sites, applying a cold compress to the injection site for several minutes both before and after injection and massaging the injection site following administration.
Houston is a major center for investigation of interleukin-2 for the treatment of HIV infection and will serve as a site for two phase III clinical endpoint studies scheduled to begin this year.
SILCAAT (Subcutaneous IL-2 in HIV-infected Patients With Low CD4 Counts Under Active Antiretroviral Therapy) is a four-year trial in which researchers will randomize 1400 subjects with CD4 counts between 50 cells and 300 cells to interleukin-2 plus antiviral therapy or antiviral therapy alone. The study requires subjects to be on a stable antiviral regimen, have viral loads of less than 10,000 copies and no history of an AIDS-defining illness. Chiron Corporation, maker of Proleukin brand IL-2, is the study sponsor.
In ESPRIT (Evaluation of Subcutaneous Proleukin in a Randomized International Trial), investigators will accrue 4,000 patients, randomize them 1:1 to antiviral therapy plus or minus IL-2 and follow them for at least 4 years. Study participants must have a CD4 cell count of less than or equal to 300 cells, be receiving standard of care antiviral treatment and have no history of an AIDS-defining event; viral load criteria are not specified. The NIH is the study sponsor.
These trials, for which Roberto Arduino, MD, is the Houston investigator, are designed to determine if IL-2 in combination with antiviral therapy can reduce the incidence of AIDS-defining events and death among people infected with HIV.
For more information, call Stephen Garcia, RN, at 713.500.6751.
Chiron has not publicly declared whether it intends to apply to the U.S. Food and Drug Administration (FDA) for accelerated approval of Proleukin while the phase III studies described above are in progress. However, some prominent treatment activists have indicated they would not support such an application (Gonsalves, personal communication). Beyond its potential negative effect on recruiting subjects to clinical endpoint studies, these activists have argued that accelerated approval is not warranted until more is known about the clinical benefit of IL-2 therapy. Specifically, does IL-2 produce longer survival time and fewer opportunistic infections? In the absence of well-defined surrogate markers for immune-based therapies, these treatment advocates oppose FDA approval of an expensive, toxic agent until endpoint studies demonstrate a clinical benefit.
Other activists, while not yet expressing an opinion on accelerated approval, support the availability of IL-2 through patient assistance programs or expanded access, especially where participation in a clinical study is not possible (Lein, personal communication).
HIV disease, although virally-mediated, is a disease of immune deficiency. Maximal suppression of the virus is an important goal of therapy and the one on which most research to date has focused. However, antiviral treatment alone is unlikely to restore fully an immune system battered by HIV.
Therapies that support or augment immune function are the next frontier in the management of the disease and interlekin-2 has emerged as the most promising such treatment. Extensive research has characterized well the potential role, dose, schedule, route and side effects of IL-2 administration. The ultimate clinical utility of IL-2 is not yet known, but the dawn of a new millennium brings the launch of two long-awaited, important clinical endpoint studies.
1 Specifically, meta-analysis of studies involving continuous intravenous infusion of IL-2 shows a trend toward a lower risk of disease progression.
2 Antiviral therapy consisted of either nucleoside monotherapy or dual nucleoside therapy.
3 Starting dose was 18 MIU/d; dose reductions were allowed when needed.
4 Viral load was assayed by bDNA.
5 Dose for the first cycle was 3 MIU twice a day; thereafter, the dose was reduced to 3 MIU once a day.
6 Low-dose administration of IL-2 principally binds high-affinity IL-2 receptors. This decreases the toxicity of IL-2 therapy by diminishing the deluge of pro-inflammatory cytokines.
7 Doses of 500,000 IU/m2/day were tolerated poorly and required dose reduction.
8 These increases were seen only at doses of 187,000 to 250,000 IU/m2/day.
9 This study was not scientifically rigorous; it was not randomized or prospective.
10 36th Meeting of the Infectious Diseases Society of America, 1998.
11 Mild capillary leak syndrome is possible at the doses used to treated HIV infection.
Dysregulation: impaired or improper functioning of a system.
Cytokine: proteins produced by the white cells that act as chemical messengers among cells.
Metastatic: capable of transferring of a disease-producing agent from the original site of a disease to another part of the body with development of a similar lesion in the new location.
Recombinant: an organism whose genome contains integrated genetic material from a different organism.
Surrogate marker: a laboratory measurement that does not directly measure the clinical condition of the patient, but rather predicts the likely effect on their future disease status.
Polyclonal: descended from one or more small groups of cells, especially one of genetically different origins.
Orthostatic syncope: a brief loss of consciousness caused by, or related to a sudden fall of blood pressure resulting from standing upright.
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Copyright © 1999 - Research Initiative Treatment Action (RITA!). Reproduced with permission. RITA! is published by The Center for AIDS. Contact Thomas Gegeny, MS, ELS, Editor, RITA! for permission to reproduce RITA!. tom@centerforaids.org. http://www.centerforaids.org
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