Treatment Issues, Vol. 9, No. 2 - February, 1995
Craig Sterritt

There is also a substantial body of evidence suggesting that HIV is controlled in the body during the early period of infection by a strong response by the cell-mediated arm of the immune system (chiefly suppressor and cytotoxic CD8 T- cells activated by IL-2 released by CD4 cells). The cells involved in this response gradually lose their ability to effectively respond to HIV and other pathogens, possibly owing to a decline in IL-2 production by CD4 cells.

Intermittent Continuous IL-2

IL-2 trials in the past found that the molecule's positive influence on CD4 cell numbers disappeared after a few weeks of continuous infusion therapy. Cells seemed to become refractory to IL-2 after chronic exposure to the compound. But an as yet unpublished study of IL-2 conducted by Joseph Kovacs, M.D., and H. Clifford Lane, M.D., at the Laboratory of Immunoregulation (part of the NIH's National Institute of Allergy and Infectious Diseases -- NIAID) for the first time observed substantial and prolonged IL-2-induced CD4 cell increases.

The NIAID trial employed a unique cyclical dosing regimen rather than administering IL-2 on a steady weekly schedule as previous trials have. Every eight weeks, study participants received a five-day continuous IL-2 infusion of six to eighteen million international units (IU) per day. This regimen of intermittent continuous infusion lasted for eleven to 25 months.

In the course of the study, sustained CD4 cell rises of greater than 50 percent were seen in six out of ten patients who started with over 200 CD4 cells per cubic millimeter of blood and were on stable antiretroviral therapy. Three patients experienced three- to four-fold increases in CD4 counts over the course of the trial. In addition, Dr. Lane now reports that three initial responders whom he has followed for nearly three years have been able to maintain CD4 counts in the high normal range of greater that 1,000 by receiving "booster" five-day infusions whenever their CD4s drop below 1,000 (every seven to twelve months). (It should be emphasized that these patients who remained on therapy are the IL-2 "success stories." They do not necessarily represent the average patient's experience with IL-2.)

A new, larger trial is following 60 participants with CD4 counts greater than 200. The trial is comparing intermittent continuous IL-2 (18 million IU/day for five days every eight weeks) combined with antiretroviral drug therapy to antiretroviral therapy alone. The trial is still underway and results are not yet available. Two separate informed sources, however, have told Treatment Issues that CD4 responses similar to those in the first trial are occurring. One source also reported that several participants who received between three and six infusions in the ongoing study have had CD4 counts of over 1,000 for as long as seven to eleven months since their last infusions. As in the follow-up of the first trial, these participants will receive additional five-day courses of IL-2 whenever their CD4 counts drop below 1,000. The source added that CD4 increases in many individual cases are detectable only after several infusions. Rather than diminishing over time, the increase observed after infusion tends to become greater with additional courses of IL-2.

Advanced Disease and Viral Load

Results from experiments using the same IL-2 regimen in patients with lower baseline CD4 counts have been less encouraging. Earlier IL-2 studies had indicated that treatment benefits were less likely to be seen in patients with AIDS or with low numbers of circulating CD4's, and the NIAID data confirmed these findings. Only two of six patients with baseline CD4 counts of 100 to 200 have demonstrated significant CD4 increases (greater than 50 percent) while none of the six patients with CD4 counts lower than 100 had such increases.

The majority of study participants with low CD4 cell counts also had significant, lasting rises in their HIV levels in the blood (as measured by p24 antigen and viral RNA assays). In contrast, the participants in the higher T-cell group had transient increases in HIV RNA just after IL-2 infusion (up to six-fold). Their HIV levels returned to their original point before the next infusion. Those higher CD4 cell participants who added an additional antiretroviral drug during the study had reduced increases in viral load and improved CD4 responses.

There has always been a grave concern that IL-2 stimulates HIV along with T-cells. The virus reproduces in infected, activated CD4 cells, and HIV-free activated CD4 cells are especially vulnerable to becoming infected. The NIAID observations suggest that IL-2 boosts both CD4 counts and viral levels, and that IL-2's treatment effect may be determined by a tradeoff between the ability of IL-2 to stimulate CD4 cells and the ability of increased amounts of HIV to destroy CD4 cells. In addition, NIAID director Anthony Fauci, M.D., has suggested that IL-2 stimulates "CD8 suppressor cells" which block HIV replication within infected cells. These suppressor cells are lost in advanced disease, and this may help explain the different responses to IL-2 in the high and low CD4 cell groups.

Immune Function

Researchers have presumed that a boost in CD4 cells is a good sign. There is, however, no way of knowing at this time if an IL-2-induced CD4 count of 1,000 is as good -- or anywhere near as good -- as a naturally occurring CD4 count of 1,000. We cannot assume that IL-2-induced CD4 increases will translate into any clinical benefit, such as delayed disease progression or prolonged survival.

The NIAID trials unfortunately have not observed the qualitative immune improvements seen in previous IL-2 trials with various regimens. Such markers include increased natural killer (NK) and lymphokine activated killer (LAK) cell function. Indication of heightened cell-mediated immunity -- greater CD8 and cytotoxic lymphocyte (CTL) numbers and activity and a more intense reaction to delayed-type hypersensitivity (DTH) skin tests -- also were lacking. Some of the cell-mediated immunity tests (CTL, DTH) were not carried out during the NIAID trials while others (CD8 numbers) remained unchanged in trial participants.

In a telephone interview, Dr. Lane reported that during lab tests, T-cell replication upon exposure to certain test proteins increased in some patients, and this improvement may correlate with the observed increase in IL-2 receptors on cell membranes. No patients whose CD4 cells were unresponsive in these proliferation tests prior to IL-2 became responsive following IL-2 therapy, though.

Dr. Lane could only speculate as to why indices of NK and LAK cell activity were unchanged by IL-2, which ordinarily stimulates such cell populations. The absence of information about CTL and CD8 activity is particularly worrisome given that this might be the immune system's strongest anti-HIV response.

Clinical Symptoms

Dr. Lane and Dr. Gwen Fyfe (of Chiron Corporation, the manufacturers of Proleukin brand IL-2) expressed concern that once IL-2 therapy is begun, CD4 count and slope (the rate at which CD4 counts are going down) no longer have any value as a prognostic marker or as a tool for making treatment and prophylaxis decisions.

One patient in the NIAID trials (who received IL-2 but was not considered a responder) subsequently developed Pneumocystis carinii pneumonia (PCP) with a relatively high CD4 count of about 400 as well as an extremely high viral burden. In addition, two HIV-positive patients in the Washington, D.C. area developed PCP with CD4 counts over 300 after receiving intermittent continuous IL-2 from their private doctors. (See below for other cautions about community use of IL-2.)

IL-2 may either boost or preserve CD4 numbers without necessarily making those cells competent. Alternatively, IL-2 may simply cause a "retrafficking" of CD4 cells, in which cells enter the blood from the lymph system, where 95 percent of them are concentrated. Dr. Lane is currently examining lymph node and tonsil biopsies before and after IL-2 therapy to ascertain to what extent IL-2 induces CD4 cell increases there as well as in the blood. More exacting methods will probably be necessary to accurately determine the retrafficking phenomenon's extent.

Safety and Toxicity

The original IL-2 dose for these studies was 18 million IU per day, but the majority of patients required dose reductions to either twelve or six million IU, primarily because of the debilitating side-effects that historically have accompanied high-dose IL-2 therapy. These include fever, severe flu-like symptoms, capillary leakage, lung congestion and swelling, liver, kidney and gall bladder disorders, neutropenia (low neutrophils, a type of white blood cell), thrombocytopenia (low platelets), glucose intolerance and irritating dermatologic problems such as psoriasis flare-ups. Some participants have dropped out of the NIAID trials due to the severity of the symptoms. But most found that the side- effects, though very unpleasant, were at least temporary under the intermittent regimen. One participant in the ongoing trial noted that a recovery period of two to three days following the five-day infusion in most cases restored completely normal daily functioning.

Community Use of IL-2

There are various reports that people with HIV and their doctors are obtaining commercial IL-2 (brand name: Proleukin), which is approved for the treatment of renal cell carcinoma, and trying to mimic the NIAID protocol. All of the findings discussed here are preliminary, and there is no indication as yet that IL-2 can yield any clinical benefit to people with HIV. Some community sources also are attempting to administer IL-2 by injecting it under the skin rather than infusing it into a vein. This technique is particularly problematic (see below).

Drs. Lane and Fyfe are wary that patients most likely to seek out an unapproved AIDS therapy, especially a toxic one like IL-2, are those who are failing currently available treatment options and consider themselves to have a poor prognosis. According to the data from the NIAID and earlier trials, such persons are the least likely to reap any immunologic benefit from IL-2 therapy. The NIAID studies further imply that IL-2 can accelerate disease progression in patients with CD4 counts below 200 by substantially increasing HIV levels. Dr. Kovacs has hastened to add on several occasions that the HIV-promoting nature of IL-2 is probably worst among patients in whom HIV has developed resistance to the antiretroviral drugs they are taking. It is possible that drug-resistance in the lower CD4 cell groups, besides higher viral burdens to begin with, contributed to the sustained increases in viral levels.

The current consensus among investigators is that if there is any recipe for success with IL-2, it includes higher baseline CD4 counts, lower baseline HIV levels, and the presence of a strong antiretroviral drug effect during IL-2 therapy. It is hoped that future analyses of ongoing and upcoming trials will be able to determine the specific factors that determine an individual's response to IL-2 therapy -- such as CD4 count, percentage, HIV characteristics and virus level. Persons with HIV who insist on trying IL-2 should have their doctors procure information on contraindications, safety and viral monitoring from investigators involved in ongoing IL-2 trials (See box).

Future Directions

Dr. Lane stated that his lab's first goal, to discover if IL- 2 can be used to sustain significant CD4 increases, has been accomplished in a preliminary fashion. The larger, randomized trial described above is pursuing more detailed data along these lines.

A second goal is to see if the same effects can be accomplished in patients with more advanced HIV disease when IL-2 is administered in conjunction with a potent, new antiretroviral drug -- namely, the Merck protease inhibitor. Preliminary studies of the Merck drug indicate that unlike the nucleoside analogs, it may have a very strong antiviral effect in later-stage HIV infection. As a brand-new drug, HIV resistance to the compound is not an immediate problem either.

Dr. Lane believes that by strongly suppressing viral replication during IL-2 therapy, CD4 responses may be much more pronounced in late-stage patients. A small trial in persons with CD4 counts lower than 100 is currently enrolled, and Dr. Lane is hopeful that this approach can be expanded in a larger follow-up study.

Another goal is to discover ways to achieve the same CD4 effects without the onerous, risky and expensive five-day infusions every eight weeks. As mentioned above, it is possible that following an initial phase of three to six infusion cycles, individuals may be able to maintain normal to above normal CD4 counts with less frequent dosing -- possibly only once or twice a year. Another possibility is to reduce the infusion period to three or four days rather than five -- this will be the subject of a Chiron-sponsored trial.

In a very different approach, investigators are examining the efficacy of IL-2 injected subcutaneously (under the skin). An efficacious subcutaneous regimen is a major goal of Chiron. A company study is evaluating a two-week on/two-week off treatment cycle in which twelve million international units are injected once daily for five days in each "on" week. This study is still underway, but already many participants have had their daily doses reduced to nine or six million IU.

Sources told Treatment Issues that the regimen is not meeting with profound success, possibly due to either the brevity of the treatment intervals or the lack of continuous exposure to IL-2.

NIAID investigators have also found discouraging results with once daily injections of IL-2. They are now seeking to determine if IL-2 blood levels and CD4 rises comparable to those obtained in the intermittent IL-2 infusion trial can be achieved with two to three subcutaneous injections daily for five days every eight weeks.

Another study, conducted by Applied Immune Sciences in California, has yielded data on the effects of twice daily subcutaneous injections for five days every four weeks (with and without concomitant infusion of proliferated CD8 cells taken from the patient). Injected doses of two or four million IU per square meter of body surface per day each caused a 1.4-fold mean CD4 cell increase for the duration of the trial (over nine months). The CD8 infusions gave no extra benefit.

A third goal is to reduce the severity of side-effects associated with higher doses of IL-2. Some suggest that most of the toxic effects of IL-2 therapy are caused by elevated levels of tumor necrosis factor (TNF), an immune system modulator released by cells in response to IL-2, which is also known to increase HIV replication. There are plans to explore intermittent continuous IL-2 in conjunction with such TNF inhibitors as pentoxifylline (PTX), thalidomide and the Centocor anti-TNF monoclonal antibody (MAb). Drs. Lane and Fyfe say PTX and the Centocor MAb will probably be studied in NIAID-sponsored trials, while the thalidomide/IL-2 trial is under consideration by Chiron and investigators in the United Kingdom. Findings from studies of PTX alone, as well as reports from a few patients who have received PTX in conjunction with IL-2, indicate that PTX is not that effective in decreasing TNF levels. Thalidomide and the Centocor MAb (besides newer TNF-inhibitors under development) are now more promising candidates.

Conclusion

Despite the remaining unknowns, there is considerable excitement among IL-2 researchers over the intermittent continuous IL-2 findings. NIAID's Division of AIDS has just commenced working on a comprehensive, long-term development plan for IL-2 in collaboration with Chiron. The plan's purpose is to delineate the fastest and most accurate way to determine if IL-2 should be taken into large-scale efficacy trials and then to envision how to conduct such trials.

A logical next step will be to couple long-term follow-up of patients in current and upcoming IL-2 trials with in-depth analyses of IL-2's biologic effects. There is an immediate need to determine what IL-2's exact effects upon the immune system are and whether those effects are likely to slow the progression of HIV disease. A precise evaluation of the amount of real T-cell proliferation that occurs compared to the amount of T-cell retrafficking is of particular importance. Another objective is a broad determination of the specific types and usefulness of all the immune cells influenced by IL-2 therapy.

IL-2-induced CD4 increases ultimately will need to be correlated with explicit improvements in immune function for the therapy to proceed into large, expensive efficacy phase III trials. Improvements in immune function will then need correlation with clear health and survival benefits in order for IL-2 to be validated and approved as a treatment for HIV infection.

Issues to Consider Before Starting IL-2

IL-2 therapy is not approved for HIV disease. But because it is approved for other conditions, a number of doctors around the country are currently offering IL-2 to HIV-positive patients. Some of these doctors are giving patients injected IL-2, while others are offering infusions of IL-2 similar to those used in the NIH trials. Both doctors and patients should consider the following issues before initiating IL-2 treatment:

1. IL-2 therapy can be very toxic, particularly in high doses (3-18 million IU/day). It can cause severe flu-like symptoms that will interfere with normal daily functioning. During IL- 2 infusions, you should have someone with you in the event that respiratory or other complications arise. Liver and kidney function and blood pressure should be monitored during therapy. Individuals with heart problems or active opportunistic infections should not experiment with IL-2.

2. IL-2 therapy has been shown to increase levels of HIV. These levels often go back to baseline in a matter of days or weeks. Nevertheless, all patients given IL-2 must remain on antiretroviral therapy. Antiviral therapy should include at least one new agent to which your virus is not resistant. New antiviral drugs should not be started at the same time as IL- 2 since it may be impossible to distinguish between side effects from IL-2 and the new drug.

3. HIV levels must be monitored closely in all patients given IL-2. New methods of measuring HIV RNA in the blood, such as PCR or branched DNA tests, should be used both before starting therapy, to establish a baseline level, and several weeks after each infusion. These new HIV tests cost more than $200 a piece. Increasing virus levels are a warning that IL-2 therapy is failing or is counterproductive.

4. It is not clear whether the large increases in CD4 counts often seen with IL-2 therapy have biological significance or translate into any benefit to patients.

5. IL-2 does not appear to increase CD4 cells in patients with low CD4 counts (less than 100). In fact, these patients are far more likely to get an increase in HIV levels from IL- 2. Studies completed so far do suggest that patients with over 200 CD4 cells have a good chance of receiving a CD4 boost from IL-2 therapy.

6. IL-2 infusions are extremely expensive around $2,000 per four or five day cycle. These cycles are repeated every eight weeks. Patient advocates at Chiron, the manufacturer of IL-2, can talk to your insurance company about the cost of the actual drug and will provide it free of charge if your insurer will not pay. This does not include the cost of infusions, which are the most expensive part of IL-2 treatment.

7. If you use IL-2, you may be excluded for clinical trials of new therapies.

8. ACTG 248, a trial of low dose, injected IL-2, will soon begin enrolling individuals with CD4 counts of over 300 at several sites across the country (including New York). Patients will receive IL-2 therapy for at least six months. All necessary blood work and medical monitoring will be included at no cost. For more information, call 800/TRIALS-A. There will be a forum on IL-2 therapy for HIV on March 20, 1995 at 8p.m., at St. Vincent's Hospital, Cronin Building, tenth floor auditorium, Seventh Avenue and Eleventh Street, New York City.

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