Inferiority of IL-2 alone versus IL-2 with HAART in maintaining CD4 T cell counts during HAART interruption: a randomized controlled trial

Abstract

Objective To evaluate if interleukin (IL)-2 in patients with chronic HIV infection can maintain CD4 T cell counts during 6 months of highly active antiretroviral therapy (HAART) interruption. Design Prospective, randomized, controlled, open-label phase II non-inferiority trial comparing IL-2 with HAART interruption or continuous HAART (ICARUS). Methods 41 IL-2-experienced (≥3 prior cycles) HIV-1-infected adults with CD4 ≥500 cells/µl were randomized 2:1 to Interrupted (I=27) or Continuous (C=14) HAART for 6 months (M6) following an initial IL-2 cycle. Subsequent IL-2 cycles were triggered by CD4 T cell counts <90% of baseline. Immune, metabolic, and quality of life indices were compared (Mann-Whitney and Fisher’s Exact tests), defining non-inferiority as a percent difference (C–I) in Treatment Success (CD4 T cells ≥90% of baseline at M6) with a 95% confidence interval (CI) lower limit > −20%. Results Demographic and immune parameters were similar between the groups at baseline. Median CD4 T cell count, HIV viral load, and Treatment Success differed significantly at M6 (I: 866 cells/µl, 39,389 copies/ml, 48.1%; C: 1246 cells/µl, <50 copies/ml, 92.3%; p≤0.001). Group I was inferior to C (% difference = −44.2%; 95% CI: −64.2%, −11.2%; p=0.013). Minor statistically significant differences in HgbA1c and energy level occurred at M6 (I>C). Following HAART interruption, single cases of acute retroviral syndrome, secondary syphilis, Non-Hodgkin’s Lymphoma, and Kaposi’s sarcoma recurrence were observed. Conclusions IL-2 alone was inferior to IL-2 plus HAART in maintaining baseline CD4 T cell counts. HAART interruption had a small impact on metabolic parameters and quality of life.

Interleukin-2 cycling causes transient increases in high-sensitivity C-reactive protein and D-dimer that are not associated with plasma HIV-RNA levels

“…The second study [21, 22] consisted of 40 chronically HIV-infected IL-2-experienced adults who were on HAART therapy prior to receiving a baseline cycle of IL-2 (subcutaneous injections of 7.5 million international units twice daily). Subjects were then randomized 2:1 either to interrupt or continue HAART for 6 months, during which time additional IL-2 cycles were administered with 10 days of peri-cycle HAART, if CD4 T cell counts fell below 90% of baseline.…”

“…The first study [19, 20] evaluated the effect of 3–6 IL-2 cycles added to single or dual nucleoside analogue therapy administered over 1 year compared to antiretroviral therapy alone. The second study [21, 22] evaluated the effect of a baseline IL-2 cycle in patients who either subsequently interrupted or continued HAART for 6 months. Biomarkers and immune parameters were analyzed pre- and post-IL-2 administration, as well as long-term at the end of each trial, in order to characterize the duration of any IL-2 effect, its relationship to HIV viremia and changes in CD4 T cell proliferation.…”

New insights into the regulation of T cells by γc family cytokines

“…IL-2 is already used in the clinic to expand and maintain CD4 + T cell numbers in patients with HIV infection137,138 and as an anti-cancer agent, and this is showing efficacy in treating some patients with melanoma and renal cell carcinoma139. The related cytokine IL-15, the receptor of which consists of IL-2Rβ, γ c and IL-15Rα (FIG.…”

Soluble mediators of inflammation in HIV and their implications for therapeutics and vaccine development

“…The authors concluded that although treatment interruption is not recommended, the use of IL-2 could lengthen the time before ART would need to be restarted. However, contrary to this data, the ICARUS study showed treatment interruption with IL-2 was inferior to IL-2 treatment with continuous HAART in maintaining CD4 + counts[127]. More recently, two additional studies were conducted to evaluate IL-2 treatment with treatment interruption.…”