Low-Dose Daily Subcutaneous Interleukin-2 in Combination with Highly Active Antiretroviral Therapy in HIV + Patients: A Randomized Controlled Trial

Purpose: Previous studies with intermittent interleukin-2 (IL-2) therapy using intermediate and high levels of IL-2 have demonstrated significant increases in the CD4+ T cell count in HIV-infected patients. Intermittent regimens are amenable to outpatient use, but severe adverse events are frequently experienced with intermediate- and highdose levels of IL-2. Therefore in this study, the effect of daily, subcutaneous low-dose IL2 therapy on safety and immunological endpoints was investigated to determine whether immunological benefit could be achieved without toxicity in HIV-infected patients also receiving highly active antiretroviral therapy (HAART). Method: A total of 115 patients were enrolled in the trial. Fifty-six asymptomatic HIV-infected patients who had CD4+ T cell counts less than 300 cells/µL at screening and a stable HIV viral load received lowdose IL-2 (1.2 million IU [MIU]/m 2 beginning dose) once daily in conjunction with HAART (IL-2 group). Fifty-nine patients received HAART alone (control group). Results: A dramatic effect of IL-2 on the natural killer (NK) cell population was observed with mean increases of 156 cells/µL in the IL-2 group compared to 19.93 cells/µL in the control group (p < .001). Additionally, IL-2‐treated patients experienced a statistically significant increase in the mean percentage of CD4+ T cells (3.52% increase) when compared to control patients (1.33% increase) (p < .001). The expanded CD4+ T cell population was primarily of the naive phenotype, with mean increases of 4.53% for the IL-2 group and 0.31% for the control group (p < .001 for between-group difference). In addition, a higher proportion of IL-2‐treated patients (67%) compared to control patients (33%) achieved increases of greater than 50% in the CD4+ T cell count (p = .08). Adverse events of grade 3 or grade 4 toxicity were infrequent in the current study and were substantially lower by comparison to those in studies of intermittent dose IL-2 therapy. Also, negligible changes in the HIV viral load from baseline to final measurement were observed in both groups. A trend toward a reduced number of modifications of antiretroviral therapy was apparent in the IL-2 group when compared to control patients. Conclusion: Daily, lowdose subcutaneous IL-2 therapy in conjunction with HAART is safe and well tolerated and is effective in expanding lymphocyte cell types including NK cells and naive T cells in individuals who have <300 CD4+ T cells. Key words: interleukin-2, human immunodeficiency virus, naive CD4+ T cells