Background:  In combination with ART, subcutaneous, recombinant interleukin-2 (IL-2) raises CD4⁺ cell counts greater than ART alone. Whether the increase in CD4⁺ count with IL-2 results in a lower rate of opportunistic disease (OD) or death from any cause is not known.

Methods:  Patients with CD4⁺ cell count between 50 and 299/mm³ were randomized to IL-2 plus ART (IL-2 group) or to ART alone (control group). The IL-2 regimen consisted of six 5-day cycles (4.5 MIU twice-daily) at 8-week intervals with additional cycles recommended to maintain the CD4 cell count an average 150 cells above baseline. The primary endpoint was OD or death. In addition, life-threatening (grade 4) clinical events were reported as a major secondary endpoint. To detect a 28% difference in OD/death between treatment groups with 80% power, 300 primary endpoints were required. The Data and Safety Monitoring Board for ESPRIT and SILCAAT recommended closure of SILCAAT on the same date as ESPRIT, recognizing that the targeted number of primary events would not likely be achieved.

Results:  The primary analysis included 1695 patients (849 IL-2, 846 control) from 114 clinical sites in 11 countries. At study entry, median CD4⁺ was 202 cells/mm³; nadir CD4⁺ was 60 cells/mm³; 81% had an HIV RNA level ≤500 copies/mL; median duration of ART was 3.9 years; and 32% had a prior AIDS diagnosis. Median follow-up was 7.6 years at study closure in November 2008. Averaged over follow-up, the CD4⁺ cell count was 57/mm³ higher (95%CI 46 to 68; p <0.001) in the IL-2 group compared to the control group; the difference in CD4⁺ cell count at 6 years was 37/mm³ (p <0.001). The percent with HIV RNA ≤500 copies/mL did not differ between treatment groups. Rates per 100 person-years and hazard ratios (HR) for clinical outcomes are shown below.

Conclusions:  Despite a significant difference in CD4⁺ cell counts, IL-2 did not reduce the rate of OD or death. There was no evidence that IL-2 increased the risk of grade 4 clinical events in this population.