Results from two large randomized studies of interleukin-2 (IL-2) have been published in the New England Journal of Medicine. The data were first presented earlier this year at CROI in Montreal. The trials were SILCAAT, which enrolled 1,695 people with CD4 counts between 50 and 299, and ESPRIT, which enrolled 4,111 people with CD4 counts over 300. In neither case did the addition of IL-2 offer any clinical benefits compared to antiretroviral therapy alone, despite increasing CD4 T cell counts. The results indicate that expanding CD4 T cell numbers with IL-2 does not confer added benefit beyond the increase in CD4 T cells caused by suppression of HIV replication. The researchers note that CD4 T cells induced by signaling through the IL-2 pathway may be functionally compromised and/or have a phenotype (e.g. suppressive) or specificity that is not clinically beneficial. An alternative or overlapping explanation is that the increased rate of adverse events associated with receipt of IL-2 counterbalanced any benefit from CD4 increases.
Although the results have been seen as a blow to immune-based therapy (IBT) development in HIV, they do not necessarily mean that other approaches to increasing CD4 T cell numbers (such as IL-7 or growth hormones) will suffer the same fate. The outcomes of SILCAAT and ESPRIT do however stress the need to evaluate IBTs for clinical benefit. As there are individuals who experience poor CD4 T cell reconstitution despite HIV suppression (sometimes called discordant responders) who remain at increased risk for illness, there is still a potential need for IBTs. Trials evaluating the clinical benefit of newer IBTs in this population should be feasible and would not necessarily require the large numbers involved in SILCAAT and ESPRIT.
New England Journal of Medicine, Volume 361:1548-1559, October 15, 2009, Number 16
The INSIGHT–ESPRIT Study Group and SILCAAT Scientific Committee
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.