PI Perspective #32

March 2001     View PDF     En español

Spotlight on Interleukin-2 (IL-2, Proleukin)

Interleukin-2 (IL-2) is a naturally occurring immune chemical that stimulates CD4+ cells to reproduce. A manmade version is undergoing evaluation as a therapy for HIV infection in two large international studies, called SILCAAT and ESPRIT respectively. Prior to the Conference on Retroviruses and Opportunistic Infections, investigators from both studies met to discuss new data and update one another on the progress of their studies. Additionally, a number of studies involving the use of IL-2 therapy were presented at the Chicago conference.

How Does IL-2 Work?
When someone has increases in their CD4+ cell counts, there could be several explanations as to where these cells are coming from. Dr. Cliff Lane of the National Institutes of Health (NIH) summarized a collection of experiments to shed light on what might be influencing CD4+ cell count increases seen with IL-2. During IL-2 therapy there is a dramatic increase in CD4+ cell reproduction, but overtime IL-2 actually results in a decrease in CD4+ cell reproduction. Interestingly, the way IL-2 therapy may be affecting increases in CD4+ cell counts overtime is by prolonging the survival of cells. This is a new theory and will likely become the focus of further research.

IL-2 Study Results
Unlike anti-HIV drugs that are taken daily, IL-2 therapy is taken twice daily for five days, usually every eight weeks. If people experience large and lasting CD4+ cell count increases, they are then encouraged to decrease the frequency of five-day courses of IL-2 in an attempt to maintain CD4+ cell counts. In this article, when IL-2 therapy is referred to, it infers intermittent five-day courses of IL-2 therapy. Most studies used either a twice daily dose of either 4.5 or 7.5 million international units (MIU) of IL-2. In all studies, unless otherwise noted, IL-2 therapy was delivered through injection under the skin (called subcutaneous injection).

CPCRA 059 is a 511-person study of IL-2 in people with CD4+ cell counts of 300 and above. People received IL-2 or no IL-2 in addition to anti-HIV therapy. Volunteers had CD4+ cell counts of about 540 when they entered the study. Among those receiving IL-2, CD4+ cell counts increased to about 850 over the 12 months of study. Those who received only anti-HIV therapy experienced no change in CD4+ cell count over the study period. Viral load levels were similar between the two groups. It is anticipated that volunteers in the CPCRA 059 study will “rollover” into the larger IL-2 study called ESPRIT, which will follow people for about six years.

An ESPRIT Vanguard study in the United Kingdom enrolled 36 people with CD4+ cell counts above 300, 24 received IL-2 and 12 did not. Neither group received anti-HIV therapy. There were no differences in viral load between the two groups at 64 weeks. Those receiving IL-2 experienced CD4+ cell increases from about 400 to 650. Those receiving no IL-2 therapy experienced a slight CD4+ cell count increase from about 480 to 500. The CD4+ cell count increases observed were less pronounced than those seen in other ESPRIT Vanguard studies that included anti-HIV therapy. The researcher speculates that more profound increases can be realized with the concurrent use of anti-HIV therapy.

An AIDS Clinical Trials Groups study (ACTG 328) evaluated the use of IL-2 in people with CD4+ cell counts between 50 and 350, who achieved viral load suppression to below 5,000 copies/ml after twelve weeks of anti-HIV therapy. After twelve weeks of anti-HIV treatment resulting in viral control, people received IL-2 therapy intravenously (in the vein), by injection or no IL-2 therapy in addition to their anti-HIV treatments. A total of 161 volunteers were included in the 84-week analysis. Results after 84 weeks are summarized below in Table 1.

Table 1
	Increase in CD4 Cell Count	% < 50 copies/ml HIV RNA
Anti-HIV therapy alone	100	84%
Subcutaneous IL-2	240	83%
Intravenous IL-2	310	71%

After 84 weeks those receiving IL-2 had substantial increases in CD4+ cell counts compared to those receiving only anti-HIV therapy. Viral levels were similar between the three groups. Those receiving IL-2 experienced expected side effects associated with five-day courses of therapy, primarily flu-like symptoms.

A study in France, ANRS 82, delivered IL-2 therapy to people who despite long-term anti-HIV therapy had not had their CD4+ cell count go above 200. Participants had CD4+ cell counts between 25 and 200 and viral load below 1,000 copies/ml, despite at least six months of anti-HIV therapy. Most had been on anti-HIV therapy for about 1½ years. At study entry the average CD4+ cell count in the IL-2 group was about 150 and about 140 in the group that did not receive IL-2 therapy (Table 2).

Table 2
	% CD4 >200 @ 24 Week	% CD4 >200 @ 80 Weeks
Anti-HIV Therapy Alone	33%	83%
IL-2	81%	93%

After 24 weeks, the group receiving only anti-HIV therapy was offered IL-2. In essence, after the 24 week (6 month) mark, everyone received IL-2 and thus differences between the two groups can be viewed as the difference between immediate or delayed IL-2 therapy in people with CD4+ cell counts below 200.

This study lead the French government to approve IL-2 therapy for people with CD4+ cell counts below 200. After 80 weeks, except for one case of KS progression seen early in the course of the study, there have been no new AIDS-defining diseases in the group.

The National Institutes of Health (NIH) has conducted the most studies using IL-2. They have followed a number of people who have been receiving IL-2 therapy for six to seven years. The NIH conducted an analysis combining groups receiving injectable IL-2, which included 77 people who elected to participate in the extension phases from three different studies. CD4+ cell counts increased from a mean of 540 to about 1,130 over the course of observation. Each person has used about 10 five-day courses of IL-2 to achieve and maintain these numbers. The mean interval since the last course of therapy is 26 months, slightly over two years, to maintain counts.

Factors Associated with CD4+ Response to IL-2 Therapy
In the CPCRA 059 study it was found that white race and nadir (lowest ever) CD4+ cell count were associated with less robust CD4+ cell count responses. People of color had a better CD4+ cell count increase after three courses of IL-2 therapy compared to the white people. Women of color had the most pronounced increases in CD4+ cell counts, men of color and white women had equivalent responses and white men had the least dramatic increases. CD4+ cell count increases were dramatic among all groups, however. Also, the lower a person’s lowest ever CD4+ cell count (nadir CD4+ cell count), the less likely the person is to experience robust CD4+ cell count increases in response to IL-2 therapy.

Conclusion
This collection of studies show that IL-2 therapy can produce a dramatic and sustainable increase in CD4+ cell counts in people living with HIV. After an initial increase is realized, typically occurring within four to six cycled five-day courses of IL-2 therapy, maintaining CD4+ cell count increases with IL-2 usually requires only yearly therapy in people who start IL-2 when CD4+ cell counts are high (above 300). Among those who initiate IL-2 when CD4+ cell counts are lower, increases greater than what is seen in people taking anti-HIV therapy alone are realized. Those with CD4+ cell counts below 200 who do not experience increases above 200 despite initiating anti-HIV therapy are likely to realize this gain with the use of IL-2.

IL-2 is not without side effects and those contemplating study participation or using IL-2 “off-label” are advised to learn about potential side effects and side effect management before initiating IL-2 therapy. IL-2 users note that side effects can be lessened and managed with proper planning. Nearly everyone taking IL-2 does experience some side effects during the course of therapy, usually worsening over the five days and resolving when therapy is stopped at the end of the five-day course. For more information on these and other studies of IL-2 presented in Chicago and/or a discussion of IL-2 and side effects, read Project Inform's publication, IL-2.

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