PI Perspective #24

April 1998     View PDF

Interleukin 2 (IL-2)

Several studies confirmed the ability of interleukin-2 (IL-2, Proleukin) to induce substantial CD4+ cell increases in HIV-infected people receiving antiviral therapy. Conflicting reports remain regarding the ability of IL-2 to effect changes in the rate of clearance of HIV, particularly HIV lurking in quiet reservoirs.

Dr. Fauci, the Director of the National Institute of Allergy and Infectious Diseases, echoed a theme heard throughout this year’s Retrovirus conference—despite aggressive anti-HIV therapy a group of cells persists which are capable of producing viable and infectious HIV. These cells, it appears, are predominantly inactive or latent CD4+ memory cells in the lymph nodes and they may live for years. This reservoir of HIV remains an obstacle, requiring lifetime treatment to control HIV. There has long been an untested theory that activating these specific infected cells of the immune system, in the context of successful highly active antiretroviral therapy (HAART), could help flush out this reservoir and perhaps complete the elimination of HIV from the body. One way to do this might be by using IL-2, which activates CD4+ cells, in conjunction with HAART. Dr. David Ho’s team is currently planning to test this approach in a group of people who have been successfully treated since the stage of acute infection. In a supportive finding, Dr. Fauci presented data from a laboratory experiment where infected cells were examined with or without IL-2 in the presence of anti-HIV therapy. When IL-2 was added, the reservoir of latent cells was activated and the result was a reduction in the number of infectious virions in the culture. Fauci’s group is now going back to look at stored samples from a study of people receiving IL-2 in combination with HAART and comparing them to samples from people using HAART alone, to see if this same phenomenon happens in people.

Using IL-2 in eradication experiments in combination with anti-HIV therapy in treating people with acute infection certainly needs to be explored. This approach might be the extra push that helps the immune system clear or prevent the establishment of infections. Whatever the results of such an experiment, however, they cannot readily be transferred to people with established infection. The use of IL-2 therapy as part of an eradication regimen in the setting of established infection needs to be researched methodically and wisely. Simply adding IL-2 to an existing anti-HIV regimen is not likely to result in eradication. Whatever hope there is for eradication in people with established infection, it will obviously require the most optimal imaginable conditions, beginning with a perfect response to HAART, sustained long enough for all other reservoirs of infection to clear. Certainly we know that there are people using IL-2 in combination with potent anti-HIV regimen, whose virus is still measurable. This tells us that adding IL-2 therapy can’t overcome imperfect viral suppression. We already know that antiviral therapy is not sufficient to achieve complete viral clearance. It is possible that there are some long-term HAART and IL-2 users whose virus has remained undetectable for many years at the most sensitive levels of detection. Such people should be sought out and offered intensive further laboratory work to see if clues about eradication can be learned from their immunologic and virologic experiences. If any such people are reading this and don’t know where to turn for further investigation, call the PI Hotline for a referral. Several prominent laboratories are anxious to study people with such extremely positive experiences. The implications of Dr. Fauci’s findings is simply that this issue needs to be explored, and strategies to purge the reservoir of infected cells needs to be made a priority if eradication is ever going to become a reality, either in acute infection or chronic infection.

An Italian study of varying doses of IL-2 in people with CD4+ cell counts ranging from 200 to 500 confirm the value of IL-2 in effecting substantial CD4+ cell increases when used in conjunction with anti-HIV therapy. The Italian study included 60 people who had never previously received a protease inhibitor. Volunteers included 35 men and 22 women who received varying doses and routes of administration of IL-2 with a three-drug protease inhibitor containing regimen, or triple-drug therapy alone. Fifteen people were included in each group. A schematic of the study design is shown in the table below.

Table
Group	Therapy
I	three-drug protease inhibitor containing regimen in plus: 1) 12 MIU (million international units) IL-2 for five days, delivered intravenously (in the vein) every eight weeks for two cycles followed by: 2) 7.5 MIU twice daily (total 15 MIU daily) for five days, delivered subcutaneously (injection under the skin) every eight weeks for four cycles
II	three-drug protease inhibitor containing regimen plus: 7.5 MIU twice daily for five days, delivered subcutaneously every eight weeks for six cycles
III	three-drug protease inhibitor containing regimen in addition to 3 MIU twice daily (total 6 MIU daily) for five days, delivered subcutaneously every eight weeks for six cycles
IV	three-drug protease inhibitor containing regimen

After six months of therapy the mean percentage increase in CD4+ cell count over baseline values were 122% in group I, 96% in group II, 129% in group III and only 8% among those receiving only the three-drug anti-HIV regimen. Viral levels decreased in all groups, as a consequence of three-drug therapy, and no viral “rebound” was noted among those receiving IL-2. The unusually poor CD4+ response among those receiving only three-drug therapy may be a product of the protease inhibitor used in this study, which was the old formulation of saquinavir (Invirase). This version of saquinavir maybe taken off the market in the United States due to absorption problems, and replaced with a new and improved version, called Fortovase. The popularity of Invirase in some European countries continues to mystify most U.S. researchers, since its inferiority compared to other protease inhibitors has been confirmed repeatedly. With those receiving IL-2, regardless of dose or route of administration, all had significant CD4+ cell increases to their pre-study levels.

A study in Spain looked at the use of IL-2 among people with CD4+ cell counts less than 250. Among a group of people initiating triple-drug therapy including a potent protease inhibitor, 21 people who had achieved viral suppression below the limit of detection of standard available tests, and sustained this reduction for at least 24 weeks, were given IL-2 or no IL-2. All study participants had previously been on NRTIs (e.g. AZT, ddI, ddC, d4T and 3TC) prior to initiating therapy with the protease inhibitor-containing regimen. Of the 21 people enrolled in the study, eleven received no IL-2 and ten received IL-2 therapy. IL-2 was administered subcutaneously (by injection under the skin) at a dose of 3 MIU, once daily, for five consecutive days every four weeks for at least six cycles. The results from immunologic monitoring are shown in Table 2.

Table 2
	IL-2 (Pre-study)	IL-2 (Week 24)	No IL-2 (Pre-study)	No IL-2 (Week 24)
CD4+	152	299	122	165
CD4%	+ 11	17	10	12
CD8+	843	1086	841	825
CD8%	+ 55	53	58	58
Memory Cells	432	486	582	592
Naive Cells	774	996	530	644

In this study, IL-2 in combination with a three-drug anti-HIV regimen effected a greater increase in CD4+ cell counts then those observed among people receiving triple-drug therapy alone. Moreover, those receiving IL-2 experienced more pronounced rises in CD8+ cell counts. No significant changes were observed in viral levels. Side effects associated with IL-2 use were experienced by 70% of IL-2 users, but at this low dose were relatively mild, primarily fever and fatigue. Side effects were controlled with aspirin.

Commentary
These two studies are among the first to address the use of IL-2 in people with lower CD4+ cell counts. Heretofore, information has been limited to very few studies, most of which were conducted in the pre-protease inhibitor era. Previous studies, not including protease inhibitor anti-HIV regimens, showed that people with low CD4+ cell counts did not appear to realize CD4+ cell increases with IL-2 and that stimulating the immune system with IL-2 may result in increases in HIV replication. The risk of increased HIV replication, coupled with side effects associated with IL-2 use, resulted in a recommendation that people with CD4+ cell counts below 200 do not use IL-2. With the advent of more potent anti-HIV therapies, IL-2 is now being reexamined as an option for people with low CD4+ cell counts. The first study of this nature was conducted at the National Institutes of Health (NIH). Study results, reported a few years back, showed that in the context of protease inhibitor therapy, IL-2 appeared to be useful in bolstering CD4+ cell increases. In the NIH study, however, IL-2 was administered intravenously (continuous five-day infusions, directly into a vein). The studies presented at this conference showed that IL-2, delivered subcutaneously (through injection under the skin), could effect positive CD4+ cell increases, and HIV replication was not impacted significantly. This is important information, as people can self inject IL-2 after being trained by their health care provider, increasing the ease of administering the drug. Moreover, side effects associated with subcutaneous administration are less dramatic than side effects seen when IL-2 is administered intravenously.

A large Phase III study, which will include people with CD4+ cell counts greater than 350, is expected to begin enrolling soon. This study will evaluate use of two different doses of IL-2, administered subcutaneous (by injection under the skin), delivered for five consecutive days, every eight weeks. Volunteers will receive either IL-2 or no IL-2 and be allowed to take any anti-HIV regimen they and their doctor deem appropriate. Volunteers in this study may also elect to participate in a sub-study that will look at the effect of IL-2 on immune tissues, including the effect of IL-2 on the reservoir of quiet cells harboring HIV. To participate in this sub-study, individuals will be required to fly to the National Institutes of Health’s (NIH) campus, in Bethesda, MD. As with most NIH-sponsored studies, airfare and accommodations will be supported by the NIH.

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