Study concludes that interleukin-2 has no benefit before HIV treatment interruptions, but increases side-effects

Injections of interleukin-2 (Proleukin) do not allow patients to remain off HIV treatment for longer, according to the final results of a randomised controlled trial. Interleukin-2 also had no effects on patients’ viral loads during treatment interruptions. The study’s results were published in the June edition of The Journal of Acquired Immune Deficiency Diseases.

Interleukin-2 is a naturally occurring immune system messenger or ‘cytokine’ that stimulates the production and maturation of CD4 T-cells. Researchers have studied the use of interleukin-2 in HIV-positive patients since the early 1980s as a way to boost CD4 cell counts in patients who have not yet started anti-HIV treatment.

They have also tested its effects in patients who are planning a break from HIV therapy, to prolong the time they can remain off treatment. The aim of this is to avoid the side-effects and cost of continuous treatment.

Investigators from the AIDS Clinical Trials Group (ACTG) examined the effects of interleukin-2 before treatment interruptions in 47 HIV-positive patients. All of the patients had CD4 cell counts above 500 cells/mm³ and viral loads below 200 copies/ml at the start of the study, after being on antiretroviral treatment for at least six months.

Twenty-three patients were randomised to receive three cycles of interleukin-2 alongside their antiretroviral drugs. Interleukin-2 was given by injection under the skin at a dose of 4.5 million units twice a day for five days every eight weeks. The remaining 24 patients continued to take antiretroviral therapy, but without interleukin-2.

All of the patients with CD4 cell counts above 500 cells/mm³ then stopped antiretroviral therapy, and their CD4 cell counts and viral loads were monitored.

The patients given interleukin-2 had higher CD4 cell counts at the start of the treatment interruption (median 1330 vs. 757 cells/mm³). However, CD4 cell counts fell more rapidly in the patients who took interleukin-2, so that the two groups had similar CD4 cell counts by 72 weeks (614 vs. 534 cells/mm³; p = 0.959).

There were no differences between the two groups in the time taken for CD4 cell counts to fall to below 350 cells/mm³, the threshold at which antiretroviral therapy was re-started (p = 0.749).

In addition, the viral load of the two groups of patients rebounded by similar amounts (4.23 vs. 4.20 log₁₀), and remained at similar ‘steady states’ from eight weeks into the treatment interruption (27,500 vs. 23,400 copies/ml; p = 0.746). There was also no difference in the time to virological rebound between the groups (p = 0.310).

Despite similar responses to treatment interruption in the two groups, the patients taking interleukin-2 had more side-effects that were severe than the patients who did not take it. Fourteen patients taking interleukin-2 had grade 3 or 4 events, compared to five in the control group (p = 0.017). These were mainly typical side-effects of interleukin-2, including chills and fever.

“Our study failed to demonstrate a durable antiretroviral therapy-sparing benefit of interleukin-2 (yet with increased toxicity) and resistance concerns for both arms of the study,” the investigators conclude.

The only factors associated with a longer treatment interruption were a higher lowest-ever or ‘nadir’ CD4 cell count (p < 0.001) and a higher naïve CD4 cell count before the treatment interruption (p = 0.02), as well as the viral load (p = 0.042) and the presence of resistance mutations during the treatment interruption (p < 0.001).

Despite its failure to find a beneficial effect of interleukin-2, this small study did find that CD4 cell count-guided treatment interruptions that aim to keep patients’ CD4 cell counts above 350 cells/mm³ were generally safe, with most patients remaining off treatment for over a year.

The researchers point out that the SMART study, which found elevated rates of disease progression in patients undergoing treatment interruptions, involved re-starting anti-HIV treatment at a CD4 cell count below 250 cells/mm³. This raises the suggestion that re-starting treatment at a higher CD4 cell count may be safer.

"A treatment interruption strategy utilising a CD4 T-cell threshold of less than 350 cells/mm³ for re-starting antiretroviral therapy appears generally safe", they write. “Strategies aimed at avoiding drug resistance and interventions to decrease HIV-1 ribonucleic acid (RNA) rebound during the treatment interruption are potential approaches for future efforts to more safely and effectively prolong time off antiretroviral therapy.”

However, they acknowledge that most treatment interruption studies have produced disappointing results, and are falling out of favour. “Increasingly effective and tolerable potent antiretroviral therapy regimens decrease the incentive to use treatment interruption as an antiretroviral therapy-sparing approach to chronic management,” they write.