The Role of Interleukin-2 in Combination with Antiretroviral Therapy

Interluken-2 Infusions Demonstrate Marked T Cell Gains In Patients With HIV

Remune (Salk Vaccine) Trial Terminated!

HIV Cure

The Role of Interleukin-2 in Combination with Antiretroviral Therapy
Does IL-2 Have A Hidden Antiviral Benefit?
By Matthew Sirinek, MD

The development of combination antiretroviral therapy has led to dramatic and lasting decreases in HIV levels in the blood. While these treatments have led to a profound reduction in the incidence of opportunistic infections and death in the past five years, they appear to fall short of restoring the immune system to normal levels. Currently available therapies primarily work to suppress HIV replication, not necessarily stimulate the functioning of the immune system. With a combination of new immuno-modifying therapies used together with current anti-HIV medications, we may be able to further increase immune system functioning, helping the body to fight HIV more effectively. Interleukin 2 (IL-2) has shown promise in increasing immunologic activity as an adjunct to HAART. IL-2 is known to play a central role in the generation of strong immune responses. It is naturally produced by T cells (and other immune cells) and stimulates the production of more T cells, as well as B cells, natural killer cells and monocytes. Some studies have shown that IL-2 activated T cells also have an improved capacity to suppress HIV replication.

The immune system also has reservoirs of latent (or dormant) T cells where HIV can remain unreached by medications. As IL-2 activates these latent cells, the Г’hiddenГ“ HIV becomes susceptible to the drugs. In essence, IL-2 can help purge HIV from places medications canГ•t reach. Therefore, IL-2 has demonstrated an ability not only to increase T cell counts, but also may aid the medications in suppressing the HIV virus.

IL-2 is commonly administered as a subcutaneous injection either once or twice daily. It is given for five consecutive days every eight weeks for one year. In the eight-week intervals between treatments, the patients simply continue to take their HIV medications as usual. While patients are taking IL-2 for those 5 days, they may experience side effects associated with an activated immune system. These include fatigue, fevers, chills, night sweats, nasal congestion, rash, and other flu-like symptoms. Some patients have developed small red, inflammation and/or painless nodules at the sites of injection that can last for a few weeks. These side effects can be somewhat controlled with ibuprofen and tylenol given as needed. After each 5 day cycle, patients usually quickly recover to normal functioning.

A recent land mark study of IL-2 treatment in combination with potent HIV cocktails was published in JAMA ( July 12, 2000-Vol. 284, No.2). The results uniquely demonstrated that patients on IL-2 treatment had an anti-HIV advantage. The group of individuals on treatment with IL-2 were demonstrated to result in lower viral loads, as well as the immune system benefit. All study patients had T cell counts between 200-500 and HIV viral loads less than 10,000 copies/ml. They were taking at least 3 HIV medications to suppress the virus. The participants in the study were then randomized to either receive subcutaneous IL-2 plus their HIV medications vs. HIV medications alone and without IL-2 (control group).

T cell counts and HIV viral load was measured for 1 year. The mean percentage increase in T cell counts was 112% for the IL-2 treated patients vs. 18% for patients receiving only HIV medications. T cell percentage increased 12% for the IL-2 patients vs. 2.6% for the control patients. 67% of the patients receiving IL-2 were able achieve a viral load below 50 copies/ml compared to only 36% for control patients. All three of the measurements demonstrate that intermittent therapy with IL-2 combined with continuous antiretroviral therapy produced a substantially greater increase in T cells and a larger decrease in HIV viral load than with antiretroviral therapy alone.

At NorthStar Medical Center, we are currently conducting a clinical trial using a new formulation of IL-2 called Г’Monomeric IL-2Г“. This form of IL-2 is structurally different from the traditional IL-2 used in most studies. The one advantage it may have over the traditional IL-2 is that it may not cause the degree of inflammation or undesirable nodules at the injection sites that sometimes occur with traditional IL-2. The study is still open and looking for patients on effective HIV cocktails who have T cells between 300-500 and HIV viral loads less than 10,000. Individuals looking to participate should not have had previous experience with IL-2 and must be off hydroxyurea for at least 4 months to be eligible. Qualified patients are randomized to either 3 doses of the new IL-2, 2 doses of the regular IL-2, or being observed on their antiviral cocktails as a control group however these patients will indeed be eligible for treatment with traditional IL-2 after completing the study of 24 weeks. The IL-2 will be administered twice-a-day for five consecutive days every 8 weeks for three cycles over 6 months. Blood samples will be collected at certain intervals throughout the study, and patients will be required to fill out a diary. All patients are allowed to take over- the-counter medications to control side effects during each 5 day treatment. (If you are interested in screening for this study call Dr. Sirinek at (773) 296-2400).

Interleuken-2 Infusions Demonstrate Marked T Cell Gains In Patients With HIV

Daniel S. Berger MD, FACN  

[AIDS INFOSOURCE, Volume 3, Number 1, Jan./Feb. 1997]

Introduction

Interleukin 2 (IL-2) is part of a group of hormones known as cytokines. These cytokines are, in fact proteins secreted by white blood cells that act on the immune system and white blood cells. IL-2 is secreted by CD4+ lymphocytes and is important for CD4+ T cell proliferation and differentiation; IL-2 increases both T helper cells (CD4) and suppressor (CD8) cells. In addition, IL-2 stimulates proliferation of B cells, that eventually lead to the differentiation of immune globulin's and antibodies. Also, IL-2 and has positive effects on natural killer cells and cytotoxic cells. Therefore, IL-2 plays a key role in maintaining normal immune system functioning.

Interleukin-2 is licensed and currently available as standard treatment for metastatic renal cell carcinoma (cancer of the kidney). However, since IL-2 has unique properties of activation, differentiation and proliferation of T cells, (the chief abnormality occurring in HIV infection), it thus provides a good rationale for further study in this disease. Moreover, a previous uncontrolled study of intravenous IL-2 use in patients with HIV, demonstrated increases in CD4 + T cells with expansion of CD4+ T cell repertoire (N Engl. J Med. 1995; 332; 567-75).

Speaking anecdotally, other clinicians, including this author, have had similar experiences with subcutaneous administration of IL-2 to HIV infected patients. The administration of IL-2 by subcutaneous injection is more practical; also, subcutaneous injection is associated with reduced side effects versus intravenous IL-2 therapy. Overall, there are good reasons to investigate the effect of this immunological therapy in HIV disease.

Controlled IL-2 Trial

A recent article (Oct 31, 1996) of the New England Journal of Medicine (335; 1350-56), reported a randomized controlled trial of IL-2 to determine its long term effects on the immune system as well as on HIV load in patients with CD4,+ T cells of greater than 200. Patients were randomized to receive intravenous IL-2 (starting dose was 18 million IU/day) for five days, every other month, plus antiretroviral therapy vs. antiretro-viral therapy alone. The study was not placebo controlled since the unique side effects of IL2 make "blinding" impossible. 60 patients were enrolled, 30 received IL-2. Two out of three patients were on combination antiviral therapy. During the 14 month study, the 30 patients received 157 cycles of therapy.

Side effects during the study included fatigue or malaise, headache diarrhea, fever, myalgias, sinus congestion and abdominal pain. One patient in the IL-2 group died with rapidly developing mycobacterium avium (MAC). This patient and was given a diagnosis of progressive multifocal leukoencephalopathy (PML) before his death. Two patients in the control group (not receiving IL-2) developed opportunistic disease.

Major increases in CD4 + T cells were observed; a mean increase of 412 cells/ mm^3 in the 29 surviving IL-2 treated patients, versus a decrease of 48 cells in the control arm of the trial.

There were no significant differences between the groups in the mean change of HIV RNA (viral load) or p24 antigen levels. After month 14, an extended phase allowed all patients to receive IL-2. 21 patients of the original IL-2 group continued and 24 in the control group elected to undergo IL-2 administration. (11 patients, subsequently enrolled in a new study with IL-2 and indinavir [Crixivan]).

Four patients died of AIDS complications during long term follow up; of the patients who died, 1 patient was in the IL2 group. The 3 other patients were from the control group. In addition, Hodgkin’s disease developed during week 16 in a patient from the IL-2 group; PCP developed in a control patient after receiving his second cycle of IL-2 and lastly, lymphoma developed at month 20 in a control patient with presumed toxoplasmosis.

Also reported, of the patients in the interleukin treated group, the mean CD4 count remained doubled, from their baseline, during the extended phase of the study. In some instances, patients who did not continue to receive IL-2 treatment, their CD4 increases were sustained for more than a year (without IL-2).

Discussion and Commentary

This study confirms the results of a previous uncontrolled trial, demonstrating substantial increases in CD4 + T cells after intermittent IL-2 administration. The increased T cell counts that were sustained for more than two years, is consistent with an explanation of lymphocyte proliferation associated with IL-2 (and unlikely a phenomenon of trafficking of lymphocytes from other organ sites). However, we do not know whether the effect is the expansion of the full CD4 + T cell repertoire; and thus, more complete restoration of immune function.

In addition, this study, which was done before the advent of protease inhibitors, demonstrated a far greater gain in T cell number than any previous antiviral therapy.

However, it remains to be proven if these surrogate marker changes would increase in magnitude when IL-2 is used in conjunction with triple combination therapy. Also, it may be possible to successfully treat patients who’s baseline T cell counts are lower, while maintaining undetectable viral loads using protease inhibitors. Moreover, Falloon et al presented preliminary data (36^th ICAAC; abstract 1108) from a study of Indinavir and Interleukin-2. The study treated patients in whom mean CD4 counts were below a 200 cell count. However, it is not clear from this data whether the CD4 count increases that were observed were due to IL-2 versus Indinavir.

Another important finding, from this study, is that IL-2 did not lead to long-term increases in plasma viral load. Associated transient bursts in HIV RNA after infusions of IL-2 have previously been reported. This may be due to IL-2 activation of previously latent virus or secondary to the extensive T-cell activation that occurs during IL-2 treatment. However, the clinical importance of this phenomenon is unknown at present.

Anecdotally, at our clinic, we have been administering IL-2 as an immune restorative treatment in a limited number of patients. Administration is by subcutaneous injection daily for 5 consecutive days every 6 to 8 weeks. Upon observation, the CD4 count rises soon after the IL-2 cycle; with each cycle the CD4 count levels increase sequentially. These results are similar to that described in the study above. Plans are being made to study its effect in patients with lower CD4 counts while on protease therapy.

Studies need to be done investigating the effect of IL-2 in conjunction with triple combination therapy. Also, trials need to be pursued in patients who's CD4 counts are in the 100 count range. This author concurs, with the authors of the above study, that the full clinical benefit of IL-2 therapy remains to be established.

Remune (Salk Vaccine) Trial Terminated!

The large multicenter study investigating the immune based vaccine therapy for HIV positive patients has been closed down. 2500 patients were enrolled. The company sited the opinions of the Data Safety Monitoring Board who believed that there was no significant differences in clinical endpoints between patients on treatment vs. the control group. Although the company states that new plans will be made for which to study this treatment vaccine so that it may eventually come to market, this remains to be seen. Currently, the findings that it improves certain immune functions has yet to be established as being clinically important

HIV CURE

By: William M Reiter, MD., FACP., Peter J. Gomatos, MD., PhD.

AIDS INFOSOURCE
[Volume 2, Number 3, September/October 1996]

Cure of HIV infection. The very words suggest a heretofore impossible dream to have in our lifetime, the capacity with medicines to eliminate HIV from an infected person. Yet, this theoretical possibility was in fact the subject of a closed meeting of leading scientists during the recent XI Intemational Conference on AIDS in Vancouver; who openly discussed a possible cure of HIV infection.

The discussions are based on finding that judicious use of two or three anti-HIV drugs lower the amount of HIV circulating in blood below the limit that laboratory tests currently available can detect. When appropriate drug treatment is continued, the amount of virus in blood in most individuals remains at undetectable levels for prolonged periods of time.

During HIV infection, the virus exists in two states: it actively replicates in some cells and remains dormant or latent within other cells. After completion of replication, it is released from cells and is free to infect more and more cells with the passage of time. In this way, new cells become infected and new virus continue to be produced. Current drug treatments interrupt the viral cycle only when the virus is active, namely during replication. As the drugs block the virus from replicating, infection of new cells does not continue. Under certain conditions, combinations of antiviral drugs completely suppress viral replication. The situation is different with latent virus. Cells with latent virus constitute a viral reservoir which is unaffected by drugs effective in blocking viral replication. The latent or dorinant virus can awaken at any time and begin to replicate. Recent data suggest that the latently infected cells have a finite life span of about two or three years. If effective antiviral therapy can be maintained during these two to three years, it could be anticipated that the latently infected cells will all die, to be replaced by healthy cells. During this replacement, on-going drug therapy prevents these healthy new cells from becoming infected. The latently infected cells may be killed by the bodys own immune system, if immune based therapies such as HIV-1 Immunogen Remune now in clinical trials prove to be successful.

Yet, there is a caveat we must address. The development of viral resistance to drug therapy is what may cause this approach to fail. Using this paradigm learned in the treatment of tuberculous, the HIV-infected patient must be treated with at least two drugs to which the virus remains sensitive. For example, if a patient has been on two-drug combination therapy for a length of time and his circulating viral load increases, it is likely that the treatment is failing as his virus has become resistant to the combination. The simple addition of a third drug, such as a protease inhibitor, would not be recommended as the patient would then effectively be on only one drug to which the virus is sensitive. In such circumstances the patient’s therapeutic regimen must be entirely reconsidered. To assist with making the choice of drugs even more objective in the future, laboratory tests are being developed to determine in real time the sensitivity of the patient’s HIV to the known anti-HIV drugs. Once such tests become readily available, therapy can be designed in such away that the patient will always be receiving two drugs to which the virus is sensitive.

Viral eradication in an infected individual, if indeed it can be realized, will not necessarily allow a severely damaged immune system to recover. The immune system damage may be irreversible. To restore the immune system may require immune reconstitution efforts which at the moment remain experimental; such as cell transfer from an uninfected relative, or perhaps from fetal cord blood.

To maintain effective combination drug therapy for a prolonged period of time requires the closest cooperation between physician and patient with absolute dedication of both to the therapeutic regimen. Many of the drugs have side-effects that must be addressed and alleviated and are inconvenient to take in timing and in taste. Skipping drug doses may thwart the entire plan, as it may promote viral resistance. Is all of this trouble and effort worth it? The answer is unequivocally yes. With the possibility of eradication of HIV from the infected individual,HIV, especially early in infection, there is the possibility of reducing are or stopping therapy without return of the virus and living a full life.