Interleukin-2 (IL-2) is the immune-based therapy that has been most extensively studied in HIV. Many people continue to be intrigued by its potential, yet questions about IL-2 remain unanswered, including the most basic one -- is it an effective HIV therapy? IL-2 has also been called an immune booster, an immune modulator and T-cell growth factor. A man-made form of IL-2 was first developed in the early 1980s as a treatment for certain cancers. Although IL-2 has been studied in people with HIV since the 1980s, it hasn't been approved as a treatment for HIV disease.
IL-2 is a cytokine, or chemical messenger, released by activated CD4 cells. When a CD4 cell recognizes a pathogen -- an infectious agent such as a virus or bacteria -- the cell becomes switched on, or activated. Activated CD4 cells send signals to other vital members of the immune system's team. These signals coordinate the body's defense against diseases. At the same time, in order to maintain the immune system's battle, activated CD4 cells begin rapidly copying themselves in a process called proliferation. IL-2 sets off the proliferative response of CD4 cells.
IL-2 also spurs production and full development of many other infection-fighting cells. These include CD8 cytotoxic lymphocytes (CTLs), also known as "killer" T-cells, which seek and destroy infected cells; B cells, which make antibody against pathogens; dendritic cells and macrophages, which process and deliver pathogens to the immune system; and natural killer cells, which can block and kill pathogens. IL-2 research in HIV has focused on its ability to raise CD4 cell counts. The potential benefits or drawbacks of IL-2's effects on these other immune system cells have received less attention.
IL-2's ability to increase CD4 cell counts created a new avenue of research -- looking at IL-2 as an immune-based therapy for HIV disease. Although IL-2 was found to increase the number of CD4 cells in people with HIV, studies conducted before HAART (highly active antiretroviral therapy) became available showed that IL-2 also increased the amount of HIV in people's blood. It appeared that the CD4 cells a person gained after using IL-2 either could not fight HIV or became additional targets for HIV to infect before they had a chance to recognize and respond to HIV. Prior to HAART, there was no way to effectively control HIV, so having more CD4 cells also meant having more HIV.
HAART can lower and control the amount of HIV in a person's bloodstream and provide the immune system with a chance to recover from HIV's attack. HAART alone doesn't completely fix a person's immune system of course, but HAART has made it possible to reexamine the potential benefits of IL-2. It may be an important way to help the immune system maintain enough CD4 cells to fight HIV and opportunistic infections. However, we still need to learn whether these new CD4 cells are effective at recognizing and responding to pathogens.
Synthetic IL-2, also called aldesleukin with the brand name Proleukin, is given as an intravenous infusion (injected into the vein) or by subcutaneous injection (injected under the skin). No one is certain yet of IL-2's best dose or dosing schedule. Although the body naturally secretes IL-2, the amounts given to people as a therapeutic immune booster are much larger and can cause many side effects -- debilitating flu-like symptoms, confusion, depression, and severe toxicities such as damage to the heart, liver and kidneys. Studies have used a very wide dosing range and different scheduling strategies to lessen side effects. Both subcutaneous dosing and lower doses of IL-2 seem to reduce side effects for many people. Information from ongoing and recently completed studies will help identify the lowest possible effective dose.
Meanwhile, if you're considering IL-2 as part of a treatment strategy, prepare yourself by learning as much as possible about what side effects to expect. Many people report that taking ibuprofen and an antihistamine before starting a dosing cycle reduces the side effects. Having a good relationship with your medical provider is particularly important, and talking to people who have used IL-2 can be an excellent source of information.
Although each study was designed differently, all four showed that people who use IL-2 with HAART gain more CD4 cells than those who use HAART alone. In CPCRA 059, for example, the average increase in CD4 cell count in the IL-2 group was 276 compared to 22 in the HAART alone group. Importantly, these studies showed no increase in HIV viral load.
The increase in CD4 counts after IL-2 differed according to what the count was before starting therapy. Overall, the higher a person's CD4 cell count when they started IL-2, the greater the increase after therapy. For example, in ANRS 079, the study of people with 200-500 CD4 cells, the average CD4 cell increase in the IL-2 group was 865. In ANRS 082, the study of people with less than 200 CD4 cells, the average increase in the IL-2 group was 65.
ACTG 328 had an intravenous (IV) IL-2 group and a subcutaneous (SQ) group. The IV IL-2 group had a larger average increase in CD4 cells (309) than the SQ group (240). However, SQ IL-2 dosing was used in the other three studies, and those results suggest that using SQ IL-2 still produces significant gains in CD4 cells. Using lower doses of SQ IL-2 and less frequent dosing cycles may increase CD4 cell counts and lessen the sometimes severe side effects associated with high-dose IV IL-2.
Some of the people in these studies had never taken a protease inhibitor until they entered their study, while others had been on HAART, including a protease inhibitor, for six months before enrolling. What about those people who are very treatment-experienced? Or those who have no treatment options left and are looking for "rescue" therapies? These people need new treatments the most -- we need studies designed to learn if they will benefit from IL-2.
Other important questions about IL-2 remain unanswered:
Adherence to HAART and dealing with the side effects and toxicities it produces can be difficult enough. How many people living with HIV will be able to add IL-2 while enjoying and managing their lives, including holding down a job, taking care of children, partners, other family members and friends? Will the benefit of IL-2 be worthwhile in the long run when compared to the side effects, toxicities and adjustments in quality of life?
Ultimately, we are left with the most important question -- will people with HIV stay healthier longer and live longer as a result of using IL-2?
Tracy Swan has been doing various HIV-related work since 1990 and is excited to be joining ACRIA as a treatment educator.
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