TreatmentUpdate 72, Vol. 8, No. 8; October 1996
Sean Hosein

IL-2 is a chemical produced by the immune system which stimulates the growth of T cells and helps them fight infections. Most studies testing IL-2 in PHAs have used large doses -- millions of units per day. At those doses IL-2 causes side effects including:

* fever

* muscle and bone pain

* tiredness

* headache

Now a group of American researchers have tested low dose of IL-2 and we present their results.

Study details

Doctors at the New York-Cornell Medical Center recruited 16 HIV-infected subjects (the gender of the subjects was not released) with an average of 347 CD4+ cells. The subjects had been infected with the virus for an average of 7 years. All subjects had to use at least one of the following anti-HIV drugs AZT, ddC, ddI, d4T and 3TC for a minimum of 1 month before receiving IL-2. Researchers gave the subjects different doses of IL-2 in an attempt to find a nontoxic dose.

Results -- toxicity and HIV

The researchers found that the highest range of doses subjects could tolerate before side effects developed was 187,500 to 250,000 IU/square metre of skin/day. Moreover, subjects were able to use the drug for six months, without developing side effects. Production of HIV was not significantly affected when subjects used IL-2 at or below this range of doses.

Results: Boosting the immune system

The type of immune response needed to fight many of the infections seen in AIDS is called CMI (cell-mediated immunity). There are no cheap, sophisticated tests to measure CMI so researchers must rely on crude skin tests. Small amounts of protein from microbes (bacteria, fungi and viruses) are injected under the skin. If CMI is intact, within 48-72 hours swelling and redness develop at the injection site. This reaction is called DTH (delayed-type hypersensitivity). In people with weak CMI the reaction is smaller and sometimes there may be no reaction.

* Low-dose IL-2

Three of six subjects receiving 125,000 IU/m2/day or less of interleukin 2 whose skin did not react to testing before they received IL-2 , developed DTH reactions to fungi. This indicates that their immune system detected the fungus and was able to mount a response to attack it.

* High-dose IL-2

Among those subjects who could tolerate doses of IL-2 ranging between 187,500 IU and 250,000 IU/m2/day, four of 10 subjects developed DTH reactions after 6 months of IL-2. Moreover, the size of the skin reactions were on average, double the size of pre-IL-2 reactions. This difference was statistically significant, that is; the increase was likely due to the dose of IL-2 used rather than luck.

* NK cells

Use of IL-2 did not cause increases in the level of CD8+, neutrophils and other cells with the exception of NK (natural killer) and, in some subjects, CD4+ cells. NK cells attack tumours and virus-infected cells. Subjects receiving the high dose IL-2 had their level of NK cells increase to 6 times higher than their pre-study level.

* CD4+ cells

Those subjects receiving 125,000 IU/day had their CD4+ count fall to an average of 276 cells which is about a loss of 28 CD4+ cells/month. Among subjects receiving up to 250,000 IU/m2 the average CD4+ cell count rose to an average of 543 cells or an increase of 28 cells/month. The differences in changes in CD4+ cell counts between the high and low dose groups was statistically significant.

What's next?

Large studies are needed to find out if the daily doses of IL-2 used in this study can:

* delay the appearance of AIDS

* decrease the risk of death

when used in combination with other anti-HIV agents such as indinavir, nelfinavir, ritonavir, saquinavir and VX-478.

REFERENCES:

1. Jacobsen EL, Pilaro F and Smith KA. Rational interleukin-2 therapy for HIV-positive individuals: daily low doses enhance immune function without toxicity. Proceedings of the National Academy of Sciences 1996;10405-10410.

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