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 clinical events is not known.

Methods:  Patients with CD4⁺ cell count ≥300/mm³ were randomized to IL-2 plus ART (IL-2 group) or to ART alone (control group). The IL-2 regimen consisted of three 5-day cycles (7.5 MIU twice daily) at 8 week intervals with additional cycles recommended to maintain the CD4⁺ cell count >twice baseline or ≥1000 cells/mm³. All patients were assessed every 4 months for CD4⁺ cell count, HIV RNA level, and clinical events. The primary endpoint was opportunistic disease (OD) or death from any cause. Serious non-AIDS events and life-threatening (grade 4) clinical events were major secondary endpoints. To detect a 27% difference in OD/death between treatment groups with 80% power, 320 primary endpoints were required.

Results:  The primary analysis included 4111 patients (2071 IL-2, 2040 control) from 252 clinical sites in 25 countries. At study entry, median CD4⁺ was 457 cells/mm³; nadir CD4⁺ was 197 cells/mm³; 80% had an HIV RNA level ≤ 500 copies/mL; median duration of ART was 4.2 years; and 26% had a prior AIDS diagnosis. Median follow-up was 6.9 years at study closure in November 2008. Averaged over follow-up, the CD4⁺ cell count was 153 cells/mm³ higher (95% CI 141 to 165, < 0.001) in the IL-2 group; the difference in CD4⁺ cell count at 6 years was 128/mm³ (p <0.001). The percentage with HIV RNA ≤500 copies/mL did not differ between treatment groups. Rates per 100 person-years and hazard ratios (HR) for clinical outcomes (IL-2 vs control) are below.

Conclusions:  Despite a substantial and sustained CD4⁺ cell increase compared to ART alone, IL-2 plus ART yielded no clinical benefit in this population. The addition of IL-2 was associated with more grade 4 clinical events.