Interleukin-2 therapy in patients with HIV infection

Abstract

Background: Used in combination with antiretroviral therapy, subcutaneous recombinant interleukin-2 raises CD4+ cell counts more than does antiretroviral therapy alone. The clinical implication of these increases is not known.

Methods: We conducted two trials: the Subcutaneous Recombinant, Human Interleukin-2 in HIV-Infected Patients with Low CD4+ Counts under Active Antiretroviral Therapy (SILCAAT) study and the Evaluation of Subcutaneous Proleukin in a Randomized International Trial (ESPRIT). In each, patients infected with the human immunodeficiency virus (HIV) who had CD4+ cell counts of either 50 to 299 per cubic millimeter (SILCAAT) or 300 or more per cubic millimeter (ESPRIT) were randomly assigned to receive interleukin-2 plus antiretroviral therapy or antiretroviral therapy alone. The interleukin-2 regimen consisted of cycles of 5 consecutive days each, administered at 8-week intervals. The SILCAAT study involved six cycles and a dose of 4.5 million IU of interleukin-2 twice daily; ESPRIT involved three cycles and a dose of 7.5 million IU twice daily. Additional cycles were recommended to maintain the CD4+ cell count above predefined target levels. The primary end point of both studies was opportunistic disease or death from any cause.

Results: In the SILCAAT study, 1695 patients (849 receiving interleukin-2 plus antiretroviral therapy and 846 receiving antiretroviral therapy alone) who had a median CD4+ cell count of 202 cells per cubic millimeter were enrolled; in ESPRIT, 4111 patients (2071 receiving interleukin-2 plus antiretroviral therapy and 2040 receiving antiretroviral therapy alone) who had a median CD4+ cell count of 457 cells per cubic millimeter were enrolled. Over a median follow-up period of 7 to 8 years, the CD4+ cell count was higher in the interleukin-2 group than in the group receiving antiretroviral therapy alone--by 53 and 159 cells per cubic millimeter, on average, in the SILCAAT study and ESPRIT, respectively. Hazard ratios for opportunistic disease or death from any cause with interleukin-2 plus antiretroviral therapy (vs. antiretroviral therapy alone) were 0.91 (95% confidence interval [CI], 0.70 to 1.18; P=0.47) in the SILCAAT study and 0.94 (95% CI, 0.75 to 1.16; P=0.55) in ESPRIT. The hazard ratios for death from any cause and for grade 4 clinical events were 1.06 (P=0.73) and 1.10 (P=0.35), respectively, in the SILCAAT study and 0.90 (P=0.42) and 1.23 (P=0.003), respectively, in ESPRIT.

Conclusions: Despite a substantial and sustained increase in the CD4+ cell count, as compared with antiretroviral therapy alone, interleukin-2 plus antiretroviral therapy yielded no clinical benefit in either study. (ClinicalTrials.gov numbers, NCT00004978 [ESPRIT] and NCT00013611 [SILCAAT study].)

Figure 1. Median CD4+ Cell Counts during the Study Period, According to Study and Treatment Group

The median CD4+ cell counts are shown for the groups receiving interleukin-2 plus antiretroviral therapy (ARV) and the groups receiving ARV alone in the SILCAAT study and ESPRIT. The counts during the first 30 days after a cycle of interleukin-2 are not stable and therefore were excluded. Also shown are the percentages of patients assigned to receive interleukin-2 who were taking the drug during each year of the study.

Figure 2. Cumulative Percentages of Patients with Opportunistic Disease or Death from Any Cause, According to Study and Treatment Group

Panel A shows data for opportunistic disease or death from any cause (primary end point); and Panel B, for death from any cause. ARV denotes antiretroviral therapy.

Figure 3. Between-Group Differences in the CD4+ Cell Count and Hazard Ratios for Opportunistic Disease or Death from Any Cause (Primary End Point), According to Subgroup

Panel A shows data for the SILCAAT study; and Panel B, for ESPRIT. The differences in the CD4+ cell count were calculated by subtracting the count for the group receiving antiretroviral therapy (ARV) alone from the count for the group receiving interleukin-2 plus ARV and are expressed as means ±SE. Race or ethnic group was self-reported; the “other” category in Panel A consists of 1.2% Asians, 9.7% Hispanics, 0.8% other, and 0.1% unknown and in Panel B of 4.4% other and 0.3% unknown. The baseline CD4+ cell count is the approximate median value. In ESPRIT, one patient receiving ARV alone who had an event had missing data for baseline HIV RNA level.