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Interleukin-2 (IL-2, Proleukin®)

April, 1999

Several studies of IL-2 were reported at the recent conference. Together, they confirm the ability of IL-2, when added to anti-HIV therapy, to produce dramatic CD4+ cell count increases above what is observed when anti-HIV therapy is used alone. Moreover, study results confirm the safety of IL-2 with regard to its impact on HIV replication.

In laboratory experiments, in which IL-2 acts alone independent of other processes of the immune system, IL-2 can dramatically increase HIV replication. It does this by activating T-cells, including those which are infected with HIV, causing them to produce more HIV and to replicate themselves, leading to even more HIV production. In human studies, however, the use of IL-2 has been shown to only temporarily increase HIV replication. Overtime, people receiving IL-2 in addition to standard anti-HIV therapy appear to have control of HIV replication comparable to those receiving only anti-HIV therapy. An important new finding from one study is that people receiving IL-2 with anti-HIV therapy may have even greater suppression of HIV replication compared to what is observed in people receiving anti-HIV therapy alone.


What is the Optimal Starting Dose of IL-2?

An IL-2 study in Argentina included 73 volunteers with CD4+ cell counts greater than 350 who received one of three doses of IL-2 in combination with anti-HIV therapy or anti-HIV therapy alone. Thirty-six volunteers received 1.5, 4.5 or 7.5 million international units (MIU) of IL-2, twice daily, delivered through injection under the skin (subcutaneous injection) for five consecutive days every eight weeks. The remaining 37 volunteers received only anti-HIV therapy.

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At the end of 6 months, the 4.5 and 7.5 MIU, twice daily IL-2 doses produced the most dramatic CD4+ cell increases. Those receiving the 1.5 MIU twice daily dose experienced a mean CD4+ cell count increase of 81 cells, whereas those receiving the 4.5 and 7.5 MIU twice daily doses had increases of 359 and 520 cells over their pre-therapy counts, respectively. Those receiving only anti-HIV therapy experienced an increase of about 100 after 6 months.

These results are similar to those of other dose ranging studies of IL-2. When looked at together, studies seem to suggest that the most immediate and pronounced CD4+ cell increases are seen among people who start IL-2 at the higher (4.5 or 7.5 MIU twice daily) doses. However, even in these studies, most people who start at this highest dose (7.5 MIU, twice daily) experience side effects that necessitate IL-2 dose reductions. A number of different studies appear to show, in general, that after 1 year of IL-2 therapy the 4.5 MIU twice daily dose is the most commonly used dose to maintain CD4+ cell increases.


What is the Effect of IL-2 Therapy on HIV?

Another recent study (known as CS-L2002), examined the impact of IL-2 with anti-HIV ther-apy on CD4+ cell counts and HIV replication. This study concluded that IL-2 might also lead to enhanced control of HIV replication.

CS-L2002 included people with pre-study CD4+ cell counts ranging from 200 to 500. Forty-one volunteers received anti-HIV therapy alone and 37 received IL-2 with anti-HIV therapy. Most studies of IL-2 reported to date were initiated in the pre-protease inhibitor era. This study is among the first initiated after 3-drug regimens had become the standard of care. Therefore, most of the people in the study were on at least a 3-drug combination, typically including a protease inhibitor. Note that a significant percentage of people in all groups started the study with viral load already under control due to their on-going use of anti-HIV therapy. The primary interest of the study was to measure the effect on CD4+ cell counts and to see whether adding IL-2 had any further positive or negative impact on viral load. The following are the results after 1 year:


Results of IL-2 Therapy in Combination
with Anti-HIV Therapy
Viral Load Count At Study Entry Results @ 1 Year
Mean CD4+ cell count (AT alone) 341 405 (18% increase)
Mean CD4+ cell count (AT + IL-2) 355 739 (112% increase)
% with viral load below 500 (AT alone) 44% 46%
% with viral load below 500 (AT + IL-2) 59% 68%
% with viral load below 50 (AT alone) 31% 36%
% with viral load below 50 (AT + IL-2) 39% 65%
AT = Anti-HIV Therapy


Clearly those receiving anti-HIV therapy and IL-2 experienced more dramatic CD4+ cell increases than those receiving only anti-HIV therapy. Perhaps even more interesting is the obvious trends toward better anti-HIV responses among those receiving IL-2. At study entry, the percentage of volunteers with viral load below the limit of detection on the most sensitive test was 31 in the anti-HIV therapy alone group and 39 in the group receiving IL-2. At the end of one year, the number of people with viral load below the limit of detection of the most sensitive test grew only slightly (5%) among those receiving anti-HIV therapy, to 36%. This suggests that simply continuing on potent anti-HIV therapy had little overall effect compared to that seen at the start of the study. In contrast, the group which added IL-2 on top of anti-HIV therapy saw a large increase in the percentage of people with viral level suppression to below the limit of detection after a year, from 39% to 65%. This suggests that IL-2 might be enhancing control of HIV replication.


Commentary

Two large studies of IL-2 are currently enrolling. IL-2 has serious side effects and can be very difficult to use. Fortunately, the side effects usually affect people on the days they use the drug and IL-2 is typically used only for a few days every other month. Knowledge of, preparation for and management of side effects is key to incorporating IL-2 into a treatment regimen. For more information about IL-2 and IL-2 side effects, call the Project Inform hotline.


IL-2: Flushing the Reservoir?

The previous issue PI Perspective reported preliminary results of a study conducted at the National Institutes of Health (NIH). The initial findings suggested that IL-2 therapy, used in conjunction with potent anti-HIV therapy, might enhance control and elimination of HIV from certain reservoirs where the virus is known to be preserved in the body (See "IL-2: A Path Toward Functional Eradication?" PI Perspective 26). At the Chicago meeting, the researchers reported that two of the volunteers have now stopped their use of anti-HIV medications with no rebound in HIV levels after being off therapy for the first three weeks. Researchers will continue to follow these patients to see when and whether HIV replication again becomes detectable. A few other studies presented at the conference did not support the findings observed in the NIH study. Since all of these studies are using somewhat different methods, it is difficult to compare their results. Larger studies are underway which may shed further light on this subject.

One study included people with a mean CD4+ count of 487 at study entry, who received a four-drug anti-HIV therapy regimen (including two protease inhibitors) with or without IL-2 therapy. The goal of the study was to see if adding IL-2 to aggressive anti-HIV therapy will further decrease evidence of HIV infection in deep tissue reservoirs, such as the lymph nodes. Four women and 52 men were included. Lymph node biopsies were performed before initiation of anti-HIV therapy, and again after patients had sustained HIV levels below the limit of detection on the most sensitive test (Roche Ultrasenstive) for greater than six months. Levels of HIV detected in the lymph nodes were similar in both those receiving anti-HIV therapy alone and those receiving anti-HIV therapy and IL-2. After a mean of 150 days after starting anti-HIV therapy, this study showed similar rates of decline of cell-bound HIV in the lymph nodes between the two groups. This suggests that, in this combination, IL-2 did not have an impact on accelerating HIV clearance from reservoirs of HIV infection. However, this study used a somewhat different method of measuring the effect of IL-2 on reservoirs of infection. While based on results from only a small number of people, there was information suggesting that fewer people receiving IL-2 showed evidence of persistent virus production, however.

Another study included only three people, and included a more aggressive eradication approach, combining anti-HIV therapy with IL-2 and a potent but highly toxic immune activator, OKT3. The rationale behind this approach is to see if using IL-2 and OKT3 to activate immune cells, HIV hidden quietly in cells will be forced into view of both anti-HIV drugs as well as anti-HIV responses of the immune system. While there was clearly evidence that IL-2 and OKT3 were activating the immune system, the combined toxic effects of the therapies, particularly the side effects of OKT3, overwhelm any potential benefits of this therapeutic approach. Side effects include severe fevers and rigors. One volunteer experienced temporary kidney (renal) failure.


Back to the Project Inform Perspective April 1999 contents page.




  
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This article was provided by Project Inform. It is a part of the publication Project Inform Perspective. Visit Project Inform's website to find out more about their activities, publications and services.
 

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